Oral Maxillofacial Surg Clin N Am 15 (2003) xi xii

Preface

Current concepts in the management of maxillofacial infections

Daniel M. Laskin, DDS, MS Robert A. Strauss, DDS, MD Guest Editors

There have been many advances in the management of head and neck infections since we last edited a Clinics of North America issue on this subject more than 10 years ago. New classes of antimicrobial agents, noninvasive imaging techniques, improved culturing methods, and a clearer understanding of the normal and pathologic functioning of the immune system are just some of the changes that have occurred. These and other technologic advances have enhanced dramatically our ability to diagnose and treat these infections rapidly and accurately. As a result, the incidence of serious morbidity and mortality from odontogenic infections has fallen significantly over the years. It should be noted, however, that vigilance regarding research and technologic change must be maintained. Just as we have made many advances in the management of these infections, an equal number of new and serious issues have arisen to test our resolve. Newly recognized bacterial and viral strains, the effects of global antibiotic resistance to once universally effective agents, viral mutations, flesh eating bacteria causing necrotizing fasciitis, currently untreatable catastrophic infections, such as those caused by the Ebola virus, and even biologic warfare and bioterrorism have emerged as important issues over the last 10 years, and articles about these issues flood

the public news media and professional journals almost daily. In some cases we even have created new sources of infection ourselves by developing environments conducive to bacterial growth, such as around implants. In this issue of the Oral and Maxillofacial Surgery Clinics of North America, we have attempted to address some of the important and topical areas of knowledge in the diagnosis and management of infectious diseases that practicing oral and maxillofacial surgeons face. Some articles examine new areas of interest, such as peri-implantitis and infections associated with facial skin resurfacing, whereas others provide timely updates of our understanding of continually evolving topics, such as HIV/AIDS, chronic sclerosing osteomyelitis, selection and use of antibiotics, and the changing microbiology of infections of the head and neck. The impressive ability of bacteria and viruses to adapt, change, and mutate in response to our pharmacologic bombardment is a testimony to the complex, surreptitious, and unpredictable nature of these small yet hardy microbes. For every new drug we formulate, resistance develops to an older and oftenused one. For every organism that we eradicate, another one suddenly emerges to take its place. To those of us in the clinical trenches, it seems that we

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are in a war with an ever-expanding number of increasingly virulent and destructive bacteria, fungi, and viruses. At times it seems that despite our advances in technology and knowledge, the outcome of that war is not as clear as we might wish. It is our hope that the information provided by the outstanding contributors to this issue will help to resolve some of the important issues we currently face.

Daniel M. Laskin, DDS, MS* Robert A. Strauss, DDS, MD Department of Oral and Maxillofacial Surgery School of Dentistry Virginia Commonwealth University Richmond, VA 23298-0566, USA E-mail address: dmlaskin@vcu.edu * Corresponding author.

Oral Maxillofacial Surg Clin N Am 15 (2003) 1 15

The changing microbiology of maxillofacial infections

Richard H. Haug, DDS
Division of Oral and Maxillofacial Surgery, University of Kentucky College of Dentistry, D-509 Chandler Medical Center, Lexington, KY 40536-0084, USA

Dramatic headlines in the recent news media have provided such alarming infectious disease stories as Five year-old girl battles flesh eating bacteria, The killers all around: new viruses and drug resistant bacteria are reversing human victories over infectious disease, and Losing the battle of the bugs [1 3]. These reports conjure up images of an almost science fiction type of horror story. Concerns among the lay population regarding the perceived shifting of infectious disease patterns and their subsequent manifestations have become a topic of discussion in the news media, often creating public alarm through misinterpretation and occasional exaggeration of events. For example, Time magazine has suggested that antibiotics are so overused that the human body has become saturated and that the human immune system is so depressed that it provides an environment for the creation of bacterial monsters [2]. The reports of flesh-eating Streptococcus strains and killer bacteria that are resistant to most common antibiotics raise public concerns that the normal bacterial flora is mutating uncontrollably and that infections are much more severe than they used to be [1 3]. Is this actually the case, and if so, do the same principles hold true for oral and maxillofacial infections? The purpose of this article is to review the past and present oral and maxillofacial literature, with a focus on identifying

Portions of this article have been reprinted from Storoe W, Haug RH, Lillich TT. The changing face of odontogenic infections. J Oral Maxillofac Surg 2001;59:739 48; and Haug RH, Assael LA. Infection in the maxillofacial trauma patient. In: Hupp J, Topazian RG, Goldberg MH, editors. Management of infections of the oral and maxillofacial regions. 5th edition. Philadelphia: WB Saunders Co.; 2002; p. 267 92.

any changes that may have occurred over the past decades in infections of the maxillofacial region. It attempts to answer whether there actually have been any changes in the microbiology of maxillofacial infections and, if so, what those changes, patterns, and trends might be. The availability of the wonder drug penicillin in the years immediately after World War II ushered in an era of complacency in infectious disease management. Many traditional management techniques, such as isolation, quarantine, and scrupulous application of aseptic methods in the office and operatory, were minimized or discarded altogether as no longer being necessary because the new drugs were so effective in treating common infections. Antibiotics were prescribed when symptoms initially appeared, without determining either the cause of the disease or antibiotic susceptibility of the microbe. Many infectious disease and public health professionals were ready to declare ultimate victory over infection, being convinced that antibiotics and vaccines would solve any existing and future disease threats. Events of the last five decades suggest that such enthusiasm was premature. Although there have been many dramatic improvements in the rates of morbidity and mortality associated with infectious diseases the past few decades, microorganisms have proved to be adaptable and have displayed the alarming ability to reemerge in continuing cycles of disease in somewhat different forms [4]. In the journal Science, Harold Neu suggested that bacteria are more clever than men [5]. They have adapted to every environmental niche on the planet and are assimilating to surroundings saturated with antibiotics [5]. This ability has been demonstrated over the past decade in an array of infections not previously recognized in humans. The reemergence of diseases in different forms caused by common microorganisms,

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such as Staphylococci, Streptococci, Escherichia coli, and Mycobacterium tuberculosis, further substantiates this observation. The reemergence is caused partly by acquisition of antibiotic resistance mechanisms, either through mutation or by transfer of genetic information from other bacteria; thus, there has been a rise in the antibiotic resistance of important pathogenic genera [4 6]. The most dramatic example in the development of resistance over the past three decades and its effects in terms of costhuman and economichas been the evolution of methicillin-resistant Staphylococcus. It is estimated that methicillin resistance in certain strains of Staphylococcus has risen from 2.4% in 1975 to 29% in 1999 and that the costs of hospitalization for these types of nosocomial infections could approach $3 billion annually in the United States alone [6 16]. One must remember, however, that the ultimate human cost is death and that postsurgical patients who develop nosocomial infections from methicillin-resistant Staphylococcus are twice as likely to die as patients who do not [13,15]. One must ask the question: Do oral and maxillofacial infections follow the same principles of reemergence and resistance as those described in other areas? If so, are the patterns and trends similar? This article attempts to answer those questions using the following format. First, the microorganisms of the maxillofacial region are identified in terms of indigenous flora. If this process is not performed first, abnormalities and outliers could not be identified. Next, oral and maxillofacial infections are identified in terms of odontogenic infections, trauma-related infections, nasal and paranasal sinus infections, and cutaneous infections. Finally, changes or similarities in the microbiology of maxillofacial infections over time are discussed in the context of the previously named categories.

any interaction between the microbes present [17,19,20]. Although there is generally a normal resident flora for any particular anatomic region, a transient flora also may be found to colonize for periods ranging from hours to weeks without being retained permanently. This discussion is limited to the indigenous flora (not transient), which, in the interest of brevity, have been listed in Boxes 1 3. Cutaneous microflora Skin is relatively dry, has a mildly acidic pH, and desquamates. This is an inhospitable environment for microbes [17,21]. In the newborn, the cutaneous flora is initially that of the mothers birth canal. With time, the skin develops its own unique flora (see Box 1) and can include one animal form, five types of yeast, and multiple species of bacteria [17,19,22 24]. This flora is generally present on the hair follicles and stratum corneum. The types and number of microorganisms are relatively constant, with minimal change observed in the healthy individual [17,21]. Oral microflora The mouth, unlike the skin, is warm, has a relatively constant temperature, is wet and dark, possesses environments with and without oxygen,

Box 1. Some of the most common indigenous and colonizing maxillofacial cutaneous flora [17,19,22 24] Aerobic and facultative isolates Acinetobacter species Enterobacteriaceae Corynebacterium species Micrococcus species Staphylococcus epidermidis Staphylococcus species Streptococcus viridans Yeasts Candida albicans Malassezia furfur Pityrosporum ovale Pityrosporum orbiculare Torulopsis glabrata Animal Demodex folliculorum

Normal oral and maxillofacial microflora Factors that affect microbial flora Most areas of the human body harbor an indigenous microbial flora that is specific to the anatomic area and the individual person. [17 21]. The specific ecosystem helps to play a role in protecting the individual from invasion by pathogenic organisms. Numerous factors may alter the type, frequency, and distribution of these microbes, including the anatomic region, the individual hosts immune system, the relative humidity, the presence or lack of oxygen, local surface characteristics, available nutrition, and

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Box 2. Some of the most common indigenous and colonizing oral flora [17 19,22,24] Aerobic and facultative isolates Diphtheroids Lactobacilli Rothia dentocariosa Streptococcus faecalis Streptococcus milleri Streptococcus mitis Streptococcus mutans Streptococcus salivarius Streptococcus sanguis Anaerobic isolates Actinobacillus actinomycetemcomitans Actinomyces israelii Actinomyces naeslundii Actinomyces odontolyticus Actinomyces viscosus Bacteroides asaccharolyticus Bacteroides melaninogenicus Bacteroides oralis Bacteroides ochraceus Bacterionema matruchotii Branhamella catarrhalis Capnocytophaga gingivalis Capnocytophaga ochraceus Capnocytophaga sputigena Eikenella corrodens Fusobacterium plauti Fusobacterium nucleatum Neisseria sicca Peptostreptococcus Veillonella alcalescens Veillonella parvula Spirochetes Spirochaeta species Christispira species Treponema denticola Treponema orale Treponema macrodentium Treponema vincentii Borrelia species Leptospira species Yeasts Aspergillus species Candida albicans Other Candida species Geotrichum species Hemispora species

Penicillium species Scopulariopsis species Viruses Herpes simplex virus Cytomegalovirus Protozoa Entamoeba gingivalis Trichomonas tenax

and provides a constant source of nutrition [17,19 21]. The newborns mouth is not sterile but, like the skin, contains a mixture of organisms representative of the mothers vagina, including Streptococci, Enterococci, and Microaerophilic species [17 21]. The newborn mouth is generally populated with aerobic organisms because there are initially no crevices for the development of an anaerobic environment. That status changes with the eruption of teeth. In adulthood, the flora become more constant in composition (see Box 2) and contain mostly streptococcal bacterial species (30% 60%), other bacteria, yeasts, fungi, protozoa spirochetes, and viruses. Local diseases, such as caries and periodontitis, can alter the microflora [17 20,22,24]. Environmental agents, such as alcohol, tobacco smoke, medications, and radiation therapy, also change the microflora. Nasal and paranasal sinus microflora Unlike the skin and mouth, the nasal passages and paranasal sinuses are sterile at birth. Within days, however, the infant acquires flora that are mostly associated with the mother, nursing staff, and hospital [24 28]. As a human breathes, air and its contents pass through the nose. There the air is filtered, and most of the microorganisms are trapped by mucous secretions and swallowed. These secretions contain enzymes and immunoglobulins that further kill or inhibit the growth of microorganisms. With time and altered host resistance, the sinuses of the adult human acquire an indigenous microflora and occasionally are subjected to colonization (see Box 3) [1,24,25,27,28].

Odontogenic infections Although numerous articles in the surgical literature discuss odontogenic infections, they do not identify changes in the microbiology of these infections over time, nor do they make comparisons using

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case controlled cohorts [23,29 39]. A recent investigation has attempted to identify such changes and make such comparisons [40]. Although not ideal in design (possessing all of the imperfections inherent in a retrospective chart review), it remains the only casecontrolled cohort comparison of odontogenic infections over time. The retrospective record review performed by Storoe et al [40] was conducted at the Cleveland MetroHealth Medical Center, a large county teaching hospital that serves an urban population of 1.9 million and a rural population of 2 million in northeastern Ohio. Hospital charts and radiographs were reviewed from two patient cohorts admitted to that institution; the first during the 81 months between March 1983 and November 1989 (1980s patients) [33] and the other during the 81 months between July 1992 and March 1999 (1990s patients). Admission criteria were face or neck swelling, which suggested abscess or cellulitis and one or more of the following: temperature above 38C, white blood cell count more than 10.8 103/mL, or concern about airway compromise. Patient characteristics reviewed were age, gender, race, admission temperature, admission white blood count count, fascial space(s) involved, tooth of etiology, duration of hospitalization, and bacteria isolated. An exhaustive statistical analysis was undertaken to analyze and compare the two populations and any changes in their microbiology.

Box 3. Some of the most common indigenous and colonizing nasal and paranasal sinus flora [24 28] Aerobic and facultative isolates Corynebacterium diptheria Corynebacterium species Haemophilus influenzae Haemophilus parainfluenza Neisseria species Staphylococcus species Streptococcus pneumoniae Moraxella species Micrococcus species Neisseria meningitidis Staphylococcus aureus Staphylococcus epidermidis Streptococcus viridans Streptococcus pneumonia Anaerobic isolates Propionibacterium acnes

No significant differences were found between the two cohorts for age, gender, race, admission temperature, admission white blood cell count, space involvement, or length of stay. The manner in which the bacterial isolates were reported was limited by the ability to retrieve data in a retrospective review of records. The reporting was performed in the following manner. All isolates obtained from any one patient, whether from a sterile abscess, multiple sites, or multiple cultures, were recorded for that patient. Most patients from the 1980s and 1990s had multiple organisms isolated. The reporting mechanism was the number of isolates per patient per admission. 180 bacterial isolates were identified from 79 patients from the 1980s compared to 115 from 71 patients from the 1990s. For the initial analysis, isolates were grouped into four broad categories: gram-positive cocci, other gram-positive bacteria, gram-negative anaerobes, and other gram-negative bacteria (Table 1). Gram-positive cocci and gramnegative anaerobes were isolated significantly less frequently from the 1990s patients than from the 1980s patients. Table 2 reports the number of isolates per patient per admission. For instance, a-hemolytic streptococci were isolated in 47 patients from among 79 during the 1980s and in 24 patients from among 71 during the 1990s. When individual isolates from the cohorts were compared, significant differences were found for a-hemolytic streptococci, Bacteroides melaninogenicus, coagulase-negative staphylococci, Eikenella corrodens, Staphylococcus epidermidis, Neisseria species, and b-lactamase positive Bacteroides. Culture and antibiotic sensitivity data were available from only ten 1990s patients (14%) (Table 3). The 1980s patient data were unavailable. Of the 32 bacterial isolates, 26 (81%) were resistant to one or more antibiotic. 62% of the resistant bacteria were gram positive and 38% were gram negative; Staphylococcus aureus and coagulase-negative staphylococci were the most common gram-positive antibiotic-resistant bacteria isolated. Klebsiella pneumoniae was the most common gram-negative antibiotic-resistant isolate. Until the mid 1970s, researchers believed that odontogenic infections were caused by a single species of aerobic or facultative bacteria [37]. Subsequently, it has been well established that odontogenic infections are polymicrobial [23,29,30,33 37,39,41 43]. Researchers also have observed that the bacteria identified from odontogenic infections have changed over the decades [37]. Moenning et al [37] reported that the bacterial flora of odontogenic infections is no longer predominately facultative or microaerophilic, with Staphylococcus and Streptococcus as the primary

R.H. Haug / Oral Maxillofacial Surg Clin N Am 15 (2003) 115 Table 1 Bacteria isolated Number isolated from the 1980s patients (percent of total) Gram-positive cocci Other gram-positive bacteria Gram-negative anaerobes Other gram-negative bacteria Total isolates 101 9 41 29 180 (56) (5) (23) (16) (100) Number isolated from the 1990s patients (percent of total) 80 (70) 5 (4) 15 (13) 15 (13) 115 (100) Chi-square statistic 5.357 0.066 4.323 0.520

P value 0.021 0.8 0.038 0.5

From Storoe W, Haug RH, Lillich TT. The changing face of odontogenic infections. J Oral Maxillofac Surg 2001;59:739 48; with permission.

genera, but is more often a mixed flora, with anaerobes outnumbering aerobes 2:1. a-hemolytic streptococci are the most frequently isolated bacteria [23,29,35], although Bacteroides melaninogenicus has been reported as the most common in some studies [30,32]. In one study, 19 bacterial genera or species were isolated in the 1980s patients, with a-hemolytic streptococci predominating almost 2:1 over B. melaninogenicus and b-hemolytic streptococci predominating 3:1 over S. epidermidis and almost 4:1 over S. aureus and E. corrodens (see Table 2). 24 genera or species were isolated in the 1990s patients, with coagulase-negative staphylococci, a-hemolytic streptococci, and b-hemolytic streptococci having nearly a 1:1:1 ratio and predominating equally over all other bacteria by more than a 2:1 ratio (see Table 2). No isolates of B. melaninogenicus were reported in the 1990s patients; however, 13 other Bacteroides isolates were identified. Significant differences between the groups were found for a-hemolytic streptococci, B. melaninogenicus, coagulase-negative staphylococci, E. corrodens, S. epidermidis, Neisseria species, and b-lactamase positive Bacteroides, which suggests that there has been a shift in the microbiologic flora involved in odontogenic infections. a-hemolytic Streptococci were the most common isolates in both groups, which confirms previous reports of the frequency with which these bacteria are isolated from odontogenic infections [23,29,35]. It is clear that these common gram-positive cocci remain a threat to patients with odontogenic infections. The significance of the differences in the other isolates is less clear because of changes in bacterial nomenclature and laboratory protocols in the past 10 years. For example, there was a statistically significant difference between groups for B. melaninogenicus largely because there were no isolates identified from the 1990s patients. This is because B. melaninogenicus was reclassified in 1990; bacteria identified as B. melaninogenicus in the 1980s patients would have

been reported as either Prevotella or Porphyromonas in the 1990s patients [44]. Consequently, the difference between the two groups for this obligate anaerobe is a statistical anomaly. The statistically significant difference between groups for S. epidermidis and coagulase-negative staphylococci can be explained by changes in laboratory protocol. S. epidermidis is a coagulase-negative bacterium. During the 1980s, it was common to speciate isolates, although this provided little clinically useful information. Consequently, protocol changes were made that resulted in all coagulasenegative staphylococci being reported as such without further identification. A more accurate picture of the statistically significant differences between groups emerges by analyzing S. epidermidis and coagulase-negative staphylococci together. When this is done, there is no significant difference between the groups. The significant decreases in Neisseria species and E. corrodens from the 1980s patients to the 1990s patients are most probably caused by laboratory protocol changes and changes in therapy, respectively. The complete absence of Neisseria identified in the 1990s patients suggests a decision by the clinical laboratory not to seek this species in clinical specimens from odontogenic infections. The decrease in E. corrodens isolated from the 1990s patients may be the result of improved treatment of anaerobic infection with antibiotics that have been developed in the past 10 years. Unfortunately, no data about preadmission treatment were available. The only other bacteria with a significant difference between groups were b-lactamase positive Bacteroides, which were not reported at all in the 1980s patients. The reason for this change is unclear, but rather than reflecting some important shift in odontogenic infection etiology, it is probably caused by a change in nomenclature or protocol. For example, it is curious that no Prevotella or Porphyromonas species were reported in the 1990s patients despite

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Table 2 Frequency of bacteria isolated, per patient, per admission Bacteria Gram-positive cocci a-hemolytic streptococci b-hemolytic streptococci Staphylococcus aureus Coagulase-negative staphylococci Staphylococcus epidermidis g-hemolytic streptococci Peptostreptococcus species Enterococcus species Other gram-positive bacteria Diphtheroids Actinomyces species Lactobacillus species Corynebacterium species Gram-negative anacrobes Bacteroides malaninogenicus Bacteroides (b-lactamase +) Bacteroides (b-lactamase ) Bacteroides (not fragilis) Eusobacterium necrophorum Bacteroides fragilis Other gram-negative bacteria Eikenella corrodens Haemophilus influenzae Neisseria species Klebsiella species Enterobacter species Escherichia coli Citrobacter species Haemophilus hemolyticus Proteus mirabilis Actinobacter calcoaceticus (Iwoffi) Sorralia marcescens Pseudomonas aeruginosa Pseudomonas species Stenotrophomonas maltophilia Total isolates 1980s patients 47 22 12 15 2 3 6 2 1 27 1 13 8 9 4 3 3 1 1 180 1990s patients 24 21 8 18 5 3 1 4 1 6 4 2 2 1 3 2 3 1 1 1 1 1 1 1 115 Chi-square statistic 9.900 0.055 0.498 22.759 14.979 0.846a 0.000a 0.003a 0.023a 0.406a 0.000a 0.003a 29.59 4.928a 2.660a 0.622a 0.622a 0.000a 5.870 2.144a 6.704a 0.000a 0.159a 1.155a 0.000a 0.000a 0.003 0.003a 0.003a 0.003a 0.003a 0.003a P value 0.002 0.815 0.480 0.001 0.001 0.358 1.000 0.957 0.878 0.524 1.000 0.957 0.001 0.03 0.103 0.430 0.430 1.000 0.02 0.143 0.01 1.000 0.690 0.283 1.000 1.000 0.957 0.957 0.957 0.957 0.957 0.957

From Storoe W, Haug RH, Lillich TT. The changing face of odontogenic infections. J Oral Maxillofac Surg 2001;59:739 48; with permission. a Continuity adjustment. Chi-square is reported because more than 25% of the cells had expected counts less than 6.

their importance in periodontal and other odontogenic infections. It has been reported that more than 50% of Prevotella species are b-lactamase producers [45]. It is possible that the significant difference seen between groups is another consequence of the nomenclature change in B. melaninogenicus. It can be concluded that contrary to previous suggestions, there has been little change in the kinds of bacteria isolated from odontogenic infections in the two groups of patients 10 years apart; a-hemolytic streptococci remain the most frequently isolated bacteria.

From the limited antibiotic sensitivity data available, it was not possible to determine if there have been changes between groups in the kind, number, and frequency of resistant isolates. There were no data available for the 1980s patients, and only 10% of the 1990s patients had a culture and antibiotic sensitivity test performed at least once during their hospitalization (Table 3). Despite their limitations, the data confirm some disturbing trends. 81% of the isolates were resistant to one or more antibiotics. Despite the relatively low overall occurrence (see

R.H. Haug / Oral Maxillofacial Surg Clin N Am 15 (2003) 115 Table 3 Antibiotic resistance for the 1990s patients isolates Isolate g- streptococci (not Enterococcus) b-streptococci (non A/B) Coagulase-negative staphylococci Enterococcus secies Staphylococcus aureus Total gram positive Acinetobacter calcoacelicus (Iwoffi) Bacteroides species Eikenella species Enterobacter cloacae Klebsiella pneumoniae Pseudomonas aeruginosa Pseudomonas species Stenotrophomonas maltophilia Total gram negative Totals No. Resistant 0 0 6 1 9 16 1 0 1 1 3 1 2 1 10 26 No. Sensitive 1 1 0 0 1 3 0 1 0 0 0 2 0 0 3 6

Total 1 1 6 1 10 19 1 1 1 1 3 3 2 1 13 32

From Storoe W, Haug RH, Lillich TT. The changing face of odontogenic infections. J Oral Maxillofac Surg 2001;59:739 48; with permission.

Table 2), S. aureus was the most frequently identified antibiotic resistant isolate. In addition to its innate virulence, S. aureus is of increasing concern because it, along with other gram-positive cocci, is becoming resistant to most common antibiotics. For example, methicillin-resistant S. aureus that also exhibits intermediate resistance (minimum inhibitory concentration = 8 mg/mL) to vancomycin, the antimicrobial regarded as the antibiotic of last resort for these bacteria, recently has been reported in Japan and the United States [46]. Another trend is the number of antibiotic-resistant, coagulase-negative staphylococci isolated. These bacteria long have been regarded as apathogenic members of the normal flora but are increasingly becoming recognized as important causes of infections, especially those acquired in hospitals [47]. Because most of the infections they cause are nosocomial, it should not be surprising to see increasing multiple antibiotic resistance. Against a background of the empiricism with which many clinicians continue to treat these patients (eg, only 10% of the patients in the 1990s had a culture and antibiotic sensitivity test performed), one may predict that there will be more initial treatment failures and a consequent increase in patient morbidity and total cost of care. Moenning et al [37] suggested that wounds or cavities could become contaminated with normal skin microflora, including Staphylococcal species, through external drainage. It is possible that such contamination occurred during the harvest of culture

material in the cases included in this investigation, but it is unlikely because proper surgical technique and rigorous preoperative antimicrobial skin preparation were used. One would expect surgical technique and skin preparation to improve with time, thereby reducing the incidence of sample contamination from cutaneous sources. This does not seem to be the case in this comparison of odontogenic infections from the 1980s and the 1990s, however, which showed no change in the frequency of Staphylococcus species isolated. Assuming that proper technique was followed and that the sites were prepared properly, it is improbable that there has been a shift in the kinds of bacteria causing odontogenic infections in the last 10 years.

Trauma-related infections Infection is a concern during the management of patients who have sustained maxillofacial trauma [48]. It may be a result of the injury itself or the treatment of that injury. Infection may cause systemic sepsis, fracture nonunion, failure in cutaneous wound healing, and the need for a prolonged hospitalization or additional surgery [49,50]. Infection in the trauma patient also may produce irreversible damage, including disfigurement, dysfunction, and death. From the most empirical standpoint, infection subsequent to trauma involves the introduction or inoculation of microorganisms that routinely exist as normal flora (Boxes 1 3, Table 1) beyond the bodys external

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protective media (the skin or mucosa) and the alteration of the homeostatic relationship between the individual and his or her environment. Nothing more suddenly alters homeostasis than acute trauma, and the major organ systems are mobilized to respond to increased demands. Because of the systemic response to injury, patients who have sustained major trauma are far more susceptible to wound infection than individuals who have suffered mere localized injuries [48,51,52]. The skin and mucosa are essential barriers to the entry of microorganisms into the underlying connective tissue and organs. The integument is normally exposed to bacterial flora only to the depth of the adnexa. Scalp and maxillofacial cutaneous lacerations expose the underlying structures to the microorganisms listed in Box 1. Intraoral lacerations and even simple fractures through the periodontal ligament expose the bone and viscera to the otherwise normal flora (see Box 2). Finally, mid- and upper-facial fractures contaminate the victim with multiple microorganisms from the skin, nose, and paranasal sinuses (Box 3). The introduction of microorganisms beyond the individuals own indigenous flora also may occur with bite wounds (Boxes 4,5) or exposure to a contaminated environment. Streptococcus viridans, Bacteroides species, Peptostreptococcus species, and E. corrodens are among the microorganisms most commonly isolated from humans who develop infections after having been bitten by other humans, and S. aureus, Pasteurella multocida, Streptococci species, and Bacteroides species are pathogens that often have been isolated from mammalian bite wound infections [12,53 64]. The rabies virus is always a concern for raccoon, skunk, fox, or bat bites. Contamination also may include debris or foreign material impacted into the wound, farm-related injuries that inoculate the victim with animal feces (gram-negative enteric organisms, group D streptococci, and anaerobes) [65], earth-borne contaminants, such as Clostridium tetani and Actinomyces species, and contamination with free-standing water (E. coli). Fresh-water contamination, particularly in brackish water, has caused Aeromonas hydrophila infection [59]. This aerobic gram-negative rod can cause severe facial cellulitis and myonecrosis. Enteric organisms such as E. coli also frequently contaminate wounds exposed to coastal seawater. When burns, concussion, maceration, or avulsion injure muscle, myonecrosis may ensue, and if contaminated, it frequently results in infection [66]. Anaerobic bacteria such C. perfringens and C. tetani are the most frequent causes [67]. Through

the use of a rigorous protocol of tetanus globulin and toxoid administration, the incidence of wartime clostridial infection (in US casualties) was reduced from 5% in World War I, to 0.7% in World War II, and finally 0.08% during the Korean War [68]. Civilian data are unavailable.

Box 4. Some of the most common microorganisms transmitted by human bites [53,54,56,58,59,63,64] Aerobic and facultative isolates Acinetobacter species Corynebacterium species Eikenella corrodens Enterococcus species Haemophilus influenzae Haemophilus parainfluenzae Klebsiella pneumonia Neisseria species Nocardia species Proteus species Pseudomonas Staphylococcus aureus Staphylococcus epidermidis Streptococcus n-hemolytic p-hemolytic Group A o-hemolytic Non group A o-hemolytic Anaerobic isolates Bacteroides fragilis group Bacteroides oralis Bacteroides ureolyticus Bifidobacterium species Eubacterium species Fusobacterium nucleatum Fusobacterium necrophorus Peptococcus niger Peptostreptococcus asaccharolyticus Peptostreptococcus magnus Prevotella melaninogenica Prevotella intermedia Veillonella species Other rare pathogens Hepatitis B virus Herpes simplex virus HIV Mycobacterium tuberculosis Treponema pallidum

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Box 5. Some of the most common microorganisms transmitted by animal bites [12,53 64] Aerobic and facultative isolates Acinetobacter species Aeromonas hydrophila Bacillus subtilis Bordetella species Brucella canis Capnocytophagia canimorsus Chromobacterium species Clostridium perfringens Corynebacterium species EF-4 EF-7 Eikenella corrodens Enterococcus species Flavobacterium species Haemophilus aphrophilus Klebsiella Moraxella catarrhalis Moraxella weaveri Neisseria species Proteus species Pasteurella multocida Proteus mirabilis Pseudomonas Serratia marcescens Staphylococcus aureus Staphylococcus epidermidis Staphylococcus saprophyticus Streptococcus species Weeksella zoohelcum Anaerobic isolates Arachnia propionica Bacteroides spp Eubacterium spp Fusobacterium spp Leptotrichia Peptococcus Peptostreptococcus spp Propionibacterium acnes Veillonella spp Other rare pathogens Bartonella henselae Clostridium tetani Francisella tularensis Hepatitis B virus Herpes simplex virus Leptospira species Rabies virus

Rio Bravo virus Simian herpes virus (macaque monkeys only) Spirillum minus Streptobacillus moniliformis Yersinia pestis

Neither the indigenous maxillofacial flora nor the introduction of common contaminants has changed in the management of maxillofacial trauma. Rather, the development of nosocomial infections and the human bodys weakened systemic response to trauma are responsible. Central nervous system injury sharply increases the risk of infection in the trauma patient, with gram-negative pneumonia being among the greatest adverse outcomes [52]. Serratia and Pseudomonas species are becoming more prominent offenders in the head-injured patient because of their frequent presence in intensive care units. The emergence of new and more resistant strains of staphylococci, especially methicillin-resistant S. aureus, has made the management of nosocomial infection tenuous, with the understanding that surgical patients who develop nosocomial methicillin-resistant S. aureus infection are twice as likely to die than those who do not [13,15]. The fear of the emergence of new and resistant strains of bacteria has prompted the trauma surgeon to withhold the administration of antibiotics until after the trauma patient has become infected (if an infection does develop) [7,11]. This trend also has extended to the management of maxillofacial trauma victims. Many patients with clean-contaminated wounds who would previously have been considered candidates for antibiotics are no longer considered such.

Nasal and paranasal sinus infections Acute maxillary sinusitis Sinusitis is a disease that results from an infection of one or more of the paranasal sinuses [69,70]. Acute sinusitis is generally categorized by its etiology: nosocomial or community-acquired and viral, bacterial, or fungal [69,70]. Combinations of causes are possible. Perhaps the most common cause for acute maxillary sinusitis is a rhinovirus infection. The ability to culture viruses accurately is a relatively recent development, and changes or trends in viral pathogenicity have not been established.

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The origin of acute community-acquired bacterial sinusitis (ACABS) has been well substantiated for the past five to six decades (Box 6) [24,69 74]. S. pneumonia and H. influenzae account for more than half of the occurrences of this form of sinusitis. Other Streptococcus speciesS. aureus, M. catarrhalis, a-hemolytic streptococci, and anaerobic bacteriaalso have been isolated. Complicating diagnosis and treatment even more has been the observation that viruses and bacteria may be identified as simultaneously causing ACABS. When cultures fail to yield bacteria for ACABS (approximately 40% of the time), a viral cause should be suspected. Fungi also may be responsible for ACABS but are more associated with nosocomial sinusitis and sinus disease that develops in the compromised host, such as someone with diabetes. S. aureus, P. aeruginosa, Serratia marcescens, K. pneumonia, Enterobacter species, Proteus mirabilis, and Legionella pneumonia are also associated with nosocomial sinusitis and the compromised host [69]. The relative distribution of microorganisms responsible for ACABS has not changed in either appearance or prevalence over the past five decades (Box 6) [69,73,74]. What has changed is their antimicrobial susceptibility. Penicillin-resistant S. aureus has emerged as a difficult offender to manage, along with b-lactam resistant strains of H. influenzae and M. catarrhalis. Worse yet has been the emergence of multiple strains of resistant S. pneumoniae. The changes in the microbiology of acute maxillary sinusitis have not been in the type or frequency of microorganisms but rather the emergence of resistant strains. Chronic maxillary sinusitis The specific cause and pathogenicity of chronic sinusitis disease remain unanswered, and its successful treatment modalities continue to be elusive [49,72,73]. Although some cases of chronic sinusitis disease exist as a separate and distinct entity, it is believed that most cases arise from ACABS treatment failures. S. pneumoniae, H. influenzae, and other streptococcal species have been isolated from patients with chronic sinusitis disease (Box 7) [24,69 74]. Recent reports have identified b-lactamase producing strains of S. pneumonia, H. influenzae, and M. catarrhalis in ACABS aspirates [65,73]. It seems probable that chronic sinusitis disease is merely the continued manifestation of ACABS caused by ineffective treatment. The changes in the microbiology of chronic sinusitis disease have been in the emergence of resistant strains.

Box 6. Some common microorganisms responsible for acute maxillary and ethmoid sinusitis [49,69,70,72,73] Aerobic and facultative isolates Escherichia coli Haemophilus influenzae Moraxella catarrhalis Neisseria species Pseudomonas aeruginosa Staphylococcus aureus Streptococcus pneumoniae Streptococcus pyogenes Streptococcus n-hemolytic o-hemolytic Anaerobic isolates Bacteroides species Fusobacterium species Peptostreptococcus species Viruses Adenovirus Influenza virus Parainfluenza virus Rhinovirus

Infectious rhinitis Infectious rhinitis may be classified as acute, selflimiting, or chronic, and it is the major component of the common cold [75]. Viruses are the most frequent cause of infectious rhinitis, and rhinoviruses are the most frequent etiologic agent among them (Box 8) [26 28,75]. Bacteria are an infrequent cause of isolated nasal infections but are common as a cause of combination nasal/paranasal sinus infections [75]. Granulomatous nasal infections, such as rhinoscleroma, tuberculosis, syphilis, aspergillosis, and mucormycosis, are rare and are caused by numerous microorganisms, including fungi, protozoa, and mycobacterium [26 28,75]. Frontal and sphenoid sinusitis The microbial flora of the infected frontal and sphenoid sinuses are separate and distinct from those of the maxillary and ethmoid sinuses. Acute sphenoid and frontal sinusitis is uncommon and difficult to diagnose and carries with it a significant degree of morbidity but accounts for less than 5% of paranasal sinus infections [76 78]. Headache is the most

R.H. Haug / Oral Maxillofacial Surg Clin N Am 15 (2003) 115

11

consistent finding, and it may be accentuated with activity. The degree of pain associated with it can be debilitating. Several organisms have been associated with this disease (Box 9) [70,76 78]. S. aureus, S. pneumoniae, H. influenzae, and other streptococci are the most frequent pathogens [76 78]. Although changes in the microbiology of frontal and sphenoid sinusitis have not been identified by case-controlled cohort investigations, changes in therapeutic trends point to the need for antibiotics that address b-lactamase producing strains of organisms. Especially problematic are b-lactamase producing staphylococci, streptococci, and H. influenzae. This finding suggests that the changes in the microbiology of acute frontal and sphenoid sinusitis are, as in other nasal and paranasal infections, not in the type or frequency of the microorganisms isolated but in the emergence of resistant strains.

Box 8. Some common microorganisms responsible for rhinitis [26 28,75] Aerobic and facultative isolates Klebsiella rhinoscleromatis Mycobacteria Mycobacterium tuberculosis Spirochetes Treponema pallidum Fungi Absidia species Aspergillus flavus Aspergillus fumigatus Bipolaris species Cladosporium species Curvularia species Exophiala species Exserohilum species Histoplasma capsulatum Mucor species Rhinosporidium seeberi Rhizopus species Wangiel1la species Protozoa Leishmaniasis Viruses Adenovirus Enterovirus Influenza virus Parainfluenza virus Respiratory syncytial virus Rhinovirus

Cutaneous infections A plethora of cutaneous maxillofacial infections occur with relative infrequency in the population [79,80]. Many are rare and exotic, such as noma (cancrum oris), the progressively deforming gangrenous stomatitis most often seen in debilitated and malnourished Third World children. It is believed to result from P. aeruginosa and the fusospirochetal organisms, Borrelia vincentii and Fusobacterium nucleatum [79,80]. Other unusual cutaneous maxillofacial infections include such zoonotic diseases as cat scratch disease, caused by Bartonella henselae; leptospirosis, caused by Leptospira species; and the Bubonic Plague, caused by Y. pestis [81 83]. Zoonotic diseases occur from the inoculation into the humans of microorganisms that exist nonpathogenically in the animal population. Each of

Box 7. Some common microorganisms responsible for chronic maxillary sinusitis [24,69 74] Aerobic and facultative isolates Corynebacterium species Haemophilus influenzae Streptococcus pneumoniae Anaerobic isolates Bacteroides species Peptostreptococcus species Veillonella species

the aforementioned diseases is characterized by raised, red, painful cutaneous lesions that are managed with antibiotic therapy [81 83]. Although exotic and unusual, changes in frequency of appearance or virulence of these types of infections have not been observed. More common cutaneous infections that affect the maxillofacial region are erysipelas, caused by group A streptococci; impetigo, the result of group A streptococci or S. aureus; and furuncles, carbuncles, and folliculitis, which may be caused by S. aureus, C. albicans, or P. aeruginosa [79,80]. Although associated with compromised hosts and institutional and regional outbreaks, there have been neither changes in the frequency of appearance of these infections in the general population nor changes in virulence of the organisms. Buccal cellulitis of infancy, often confused with an odontogenic infec-

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R.H. Haug / Oral Maxillofacial Surg Clin N Am 15 (2003) 115

Box 9. Some common microorganisms responsible for sphenoid and frontal sinusitis [44,70,76,78] Aerobic and facultative isolates o-hemolytic Streptococci Citrobacter Coliform bacilli Enterococci Escherichia coli Haemophilus influenzae Klebsiella pneumonia Pneumococci Proteus Pseudomonas aeruginosa Serratia Staphylococcus aureus Staphylococcus epidermidis Streptococcus pneumoniae Streptococcus viridans Anaerobic isolates Anaerobic Streptococci Fungi Aspergillus

Summary What is considered the indigenous maxillofacial flora begins during birth with the acquisition of the flora of the birth canal and then changes from infancy to adulthood as a result of the specific anatomic region, environmental influences, and host factors. The changes in the microbiology of infections of odontogenic etiology rest in changes in nomenclature and in our ability to isolate organisms. The changes in the microbiology of infections associated with maxillofacial trauma are not caused by the injuries but are related to nosocomial systemic infection and the emergence of resistant microorganisms. The changes in the microbiology of nasal and paranasal sinus infections are associated with the emergence or reemergence of strains of bacteria that are resistant to common antibiotics. Cutaneous infections appear infrequently, but the most common etiologic agent, herpes simplex virus, also has been associated with the isolation of resistant strains at an alarming rate.

References
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tion from the deciduous teeth, is another unusual cutaneous maxillofacial infection [80]. Its cause is H. influenzae, and it is cared for with constitutional support, antibiotics, and antipyretics. This condition also has shown no apparent change in virulence or frequency of distribution. Perhaps the most frequent cutaneous infection of the maxillofacial region is that caused by the herpes simplex virus [9]. Although it may produce mucocutaneous lesions of the entire face, it is mostly limited to the skin and mucosa of the oral cavity and perioral region. Conjunctival and nasal/perinasal manifestations are also common. The virus is introduced into the body through mucosal exposure or abraded skin. Although the initial infection may be subclinical, recurrence is common. More than 90% of adults have antibodies to the herpes simplex virus. Prevalence increases with decreasing socioeconomic status, and it is more prevalent in African Americans and persons living in Western Europe than in the United States. Although relief and complacency developed in the medical and lay populations after the discovery of acyclovir, concern has arisen again because of the increasing frequency of isolation of acyclovir-resistant strains of herpes simplex virus.

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Oral Maxillofacial Surg Clin N Am 15 (2003) 17 38

Antibiotic selection in head and neck infections

Thomas R. Flynn, DMDa,b,*, Leslie R. Halpern, DDS, MD, MPH, PhDa,b
Department of Oral and Maxillofacial Surgery, Harvard School of Dental Medicine, 188 Longwood Avenue, Boston, MA 02115, USA b Department of Oral and Maxillofacial Surgery, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA
a

Oral and maxillofacial surgeons see patients with infections as part of their everyday practice. It is imperative to understand the mechanisms of antimicrobial resistance, its potential problems, and the means of overcoming it. This situation raises several important questions with respect to antimicrobial therapy for odontogenic infections: 1. Is there a problem of antibiotic resistance? 2. How does antibiotic resistance arise? 3. Is antibiotic resistance the fault of the bacteria or the host or the result of treatment (ie, the medical and surgical community)? 4. What can be done to remedy the problem? The purpose of this article is to examine the problem of antimicrobial resistance in the oral cavity and make recommendations for antibiotic selection in the treatment of head and neck infections.

The acquisition of antibiotic resistance genes by bacteria allows such mechanisms to be implemented. There are four specific mechanisms by which bacteria acquire resistance genes: 1. Spontaneous mutation. This is the original source for all antibiotic resistance, because bacteria have maintained genes that encode for resistance of naturally occurring antibiotics of other species. For example, the DNA encoding of b-lactamases and penicillinbinding proteins have several homologous sequences [1]. 2. Gene transfer. Bacteria can undergo conjugation with a transfer of genes as plasmids, which are a composition of cytoplasmic loops of DNA that encode for antibiotic resistance, and transposons, which are able to insert themselves into the genome of the recipient cell. An example of a plasmid-mediated genetic event is acquisition of the ability to produce b-lactamase by some species. 3. Bacteriophages. Viruses infect bacteria and can insert genetic material and take control of the hosts genetic and metabolic machinery, which may encode for antibiotic resistance mechanisms. 4. Mosaic genes. Bacteria can absorb directly the fragments of the virally altered genome of dead members of related species to form a mosaic genome of genetic material from varying sources. This type of gene derivation is responsible for the non b-lactamase penicillin resistance in Streptococcus pneumoniae and meningococci and ampicillin resistance in Haemophilus influenzae and gonococci [1].

Molecular biology of antibiotic resistance Generally speaking, bacteria acquire antibiotic resistance in one of four ways: 1. 2. 3. 4. Alteration of a drugs target site Inability of a drug to reach its target Inactivation of an antimicrobial agent Active elimination of an antibiotic from the cell

* Corresponding author. Department of Oral and Maxillofacial Surgery, Harvard School of Dental Medicine, 188 Longwood Avenue, Boston, MA 02115. E-mail address: thomas_flynn@hsdm.harvard.edu (T.R. Flynn).

1042-3699/03/$ see front matter D 2003, Elsevier Science (USA). All rights reserved. PII: S 1 0 4 2 - 3 6 9 9 ( 0 2 ) 0 0 0 8 2 - 1

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T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 1738

Antibiotic resistance mechanisms Once the genetic machinery is in place, bacteria exert antibiotic resistance by various pathways that are broadly classified in four ways. Drug inactivation or modification. The destruction or inactivation of the antimicrobial agent is accomplished by the induction of specific drug-inactivating enzymes, such as those that inhibit b-lactams or aminoglycosides. Numerous gram-positive and gram-negative bacteria, such as Staphylococcus aureus, Enterococcus faecium, Escherichia coli, Pseudomonas aeruginosa, H. influenzae, Bacteroides, and many strains of Prevotella have this capability. Another method used by bacteria to withstand antimicrobial attack is the ability to synthesize neutralizing enzymes. The best examples are penicillinase and the methylation of erythromycin and clindamycin. Other antibiotics that are neutralized include vancomycin, sulfonamides, aminoglycosides and rifampin. Bacterial organisms with this capability include S. pneumoniae, S. aureus, Clostridium perfringens, Bacteroides fragilis, Campylobacter species, and Neisseria gonorrhoeae. Alteration of microbial membrane permeability. Alterations in membrane permeability can cause decreased uptake or increased efflux of the antibiotic. The types of antibiotics most often affected by this mechanism are the b-lactams, quinolones, tetracyclines, erythromycin, and the aminoglycosides. The gram-negative rods E. coli, P. aeruginosa, and Salmonella typhimurium also have this capability. Porins within the transmembrane protein matrix are specific for various antibiotics, and the loss of a specific porin confers resistance. Lack of the D2 porin, for example, confers imipenem resistance in P. aeruginosa. Increased efflux of the antibiotic before lethal damage occurs is seen in the Enterobacteriae with the mar, norA, and tetA genes, which convey resistance by pumping tetracycline out of the cells. E. coli and Staphylococcus epidermidis also can resist tetracyclines, macrolides and quinolones by this mechanism [1,2]. Alteration of target site. Enzymes responsible for cell wall synthesis, the transpeptidases, can be altered slightly to produce less affinity for penicillins. These altered penicillin-binding proteins are most often seen in S. aureus and S. pneumoniae [3]. Alteration in the concentration of drug target receptors. Many of the gram-negative rods (ie, E. coli and Proteus, Enterobacter, and Klebsiella species) have the ability to alter the number of drug receptors that bind antibiotics. The sulfonamide family is affected by such a mechanism.

Strategies in the prevention of antibiotic resistance Extending surgical prophylaxis beyond 48 hours and inappropriately low dosing that encourages subpopulations of organisms to survive in increasing concentrations of antibiotics can select for resistant bacteria [3]. Although culture and sensitivity studies are crucial and should not preclude empiric therapy when warranted, there is also the risk that the latter can produce bacterial resistance. A case series to examine the bacteriology of dentoalveolar abscesses in patients who received empiric antibiotic therapy suggested that the polymicrobial nature of the abscess and the administration of empiric therapy with ampicillin or cephalosporins often results in resistant strains [4]. The predominant species were anaerobic (ie, Prevotella and Peptostreptococcus species, both resistant to the therapy initially given). Kuriyama et al [5] examined the relationship between past administration of b-lactamase antibiotics and an increase in b-lactamase producing bacteria in patients with odontogenic infections. The algorithm of treatment derived from their study is a course of b-lactamase antibiotics for 1 to 2 days, but if the infection is unresolved by 3 days or more, one should assume the presence of b-lactamase producing organisms, and treatment should involve a penicillinase-stable b-lactam or a non b-lactam antibiotic. No definitive studies with large sample sizes clearly define ways to manage antibiotic resistance in odontogenic infections, however. The question of whether antibiotic resistance in patients with odontogenic infections who need hospitalization is caused by the therapeutic modality given, the characteristics of the patient population, or the ability to isolate and characterize more carefully the vector of disease is paramount because of the possibility that the increased incidence of antibiotic-resistant strains is an unavoidable direct effect of therapy. Retrospective studies that compared populations decades apart have shown that although no clinically significant differences exist between cohorts examined, there are differences in types of microorganisms in terms of their nomenclature [6,7]. Flynn et al [8] performed a prospective study of 34 hospitalized patients with odontogenic infections and found a 26% rate of clinical failure with penicillin therapy and a 60% rate of penicillin resistance. This finding is exemplified by data on treatment of upper respiratory tract infections. In a study of children with pharyngitis, Brook [9] found a 9% incidence of penicillin resistance in throat swab cultures at the initiation of treatment. After 1 week

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of penicillin therapy, 46% of the subjects and 45% of the subjects parents and siblings harbored resistant strains. The number declined to 27% in the subjects over the ensuing 3 months. Several hospitals have substituted the cephalosporins for penicillin/b-lactamase inhibitor combinations, with or without an aminoglycoside, which in some cases has resulted in dramatic recovery of antibiotic susceptibility rates among pathogens such as Enterobacter cloacae, Klebsiella pneumoniae, P. aeruginosa, and Clostridium difficile [1].

Issues in antibiotic selection The selection of an appropriate antibiotic for a given case can be complex, but usually it is a straightforward process. The factors that must be considered can be categorized into host-specific and pharmacologic factors.

antibiotics in early cases. Another factor is the severity of the odontogenic infection. Flynn et al [8] found a clinical failure rate of 26% for penicillin in hospitalized cases. On the other hand, little or no difference was found between the effectiveness of penicillin and various other antibiotics in outpatient odontogenic infections [11 14]. The clinician must keep in mind the occasional pathogen that is resistant to the usual empiric antibiotic of choice. In odontogenic infections and dog and cat bites, Eikenella corrodens is fairly resistant to the penicillins and completely resistant to clindamycin. The fluoroquinolones have become the antibiotic of choice for this pathogen. E. corrodens should be considered a possible pathogen in treatment failure of odontogenic infections and routinely in animal bite wounds [15]. The usual flora of various types of head and neck infections are listed in Table 1. Allergy or intolerance A history of antibiotic allergy is usually readily obtained from the conscious patient or, alternatively, from the family. Penicillin allergy is common, and macrolide (erythromycin family) intolerance and drug interactions are frequent. The choice of clindamycin, metronidazole, or newer antibiotics may be prudent when anamnestic information is unavailable. The penicillins are the antibiotics most frequently prescribed for infections in the oral cavity. It is not surprising that their use is associated with hypersensitivity reactions. Between 1% and 10% of patients who initially take penicillin develop an allergic reaction, and persons who do not develop a reaction have less than a 1% chance of developing an allergy with reexposure [16]. It is judicious to clarify whether the person has a true allergy to penicillin. Cross-sectional studies of penicillin allergy indicate that in many hospital chartings of penicillin allergy, subsequent skin testing proved that more than 60% of patients were not allergic to either penicillin or other b-lactams, which warrants more careful vigilance by doctors who are recording medical histories and allergies of their patients [17,18]. Fortunately, hypersensitivity reaction to clindamycin, often substituted in penicillin-allergic patients, is a rare event. All clinicians should be aware of the potential for cross-allergy between the penicillins and other members of the b-lactam group. Approximately 10% to 15% of penicillin-allergic patients are also sensitive to the cephalosporins. The cross-allergic group tends to include persons who have had an anaphylactoid reaction to the penicillins. The cephalosporins should be avoided in these patients.

Host factors in antibiotic selection Usual pathogens The type of infection that presents can be characterized by cause and location, and each has its own characteristic flora. Odontogenic infections are generally characterized by a combination of facultative streptococci and oral anaerobes. Within the viridans group of facultative streptococci, the Streptococcus milleri group, which consists of S. anginosus, S. intermedius, and S. constellatus, is most frequently associated with orofacial cellulitis and abscess. This is fortunate because only approximately 3% of the strains of these species are resistant to the penicillins. On the other hand, other members of the viridans streptococci, such as Streptococcus mitis, Streptococcus sanguis, and Streptococcus salivarius, are more frequently found in endocarditis, and they can be highly penicillin resistantup to 58% in one study [10]. Among the anaerobes, anaerobic peptostreptococci and members of the genera Prevotella and Porphyromonas predominate. Although the peptostreptococci remain penicillin sensitive, approximately 25% of strains of Prevotella and Porphyromonas are penicillin resistant [8]. The penicillin-sensitive streptococci predominate during the first 3 days of clinical symptoms, and the more resistant gram-negative obligate anaerobes appear in significant numbers thereafter. This fact suggests the selection of the penicillins over other

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Table 1 Major pathogens of head and neck infections Type of infection Odontogenic cellulitis/abscess Microorganisms Streptococcus milleri group Peptostreptococci Prevotella and Porphyromonas Fusobacteria Streptococcus pneumoniae Haemophilus influenzae Head and neck anaerobes (peptostreptococci, Prevotella, Porphyromonas, fusobacteria) Group A b-hemolytic streptococci Staphylococcus aureus Moraxella catarrhalis Viruses Head and neck anaerobes Aspergillus Rhizopus sp. (mucor) Enterobacteriaceae (especially Pseudomonas, Acinetobacter, Escherichia coli) S. aureus Yeasts (Candida species) Odontogenic flora S. aureus and skin flora in trauma Salmonella in sickle cell disease Actinomyces species Group A b-hemolytic streptococci Regional flora (oral and sinus pathogens in head and neck) Candida species Histoplasma species Blastomyces species Aspergillus Rhizopus (mucor)

Rhinosinusitis

Acute

Chronic Fungal Nosocomial (especially if intubated)

Osteomyelitis of the jaws

Acute

Chronic Necrotizing fasciitis

Fungal

Mucosal or disseminated Soft tissue Sinus

The newer b-lactam antibiotics, the monobactams (aztreonam) and the carbapenems (imipenem and meropenem), have much less frequent cross-sensitivity with the penicillin group. A history of adverse reaction or intolerance of an antibiotic, such as phototoxicity with the tetracyclines or antibioticassociated colitis with clindamycin, would preclude its subsequent use unless strongly indicated.

Immune system compromise Because the immunocompromised patient is less able to kill invading pathogens by host resistance mechanisms, a bactericidal rather than bacteriostatic antibiotic should be selected whenever possible. This stratagem should result in a more rapid clinical response. The bactericidal antibiotics generally interfere with either cell wall synthesis, which causes

lysis, or with nucleic acid synthesis, which arrests vital processes. The bacteriostatic antibiotics interfere with protein synthesis, arresting growth and multiplication. Some antibiotics, such as clindamycin, seem to be bacteriostatic at lower doses and bactericidal at higher doses. HIV-infected individuals seem to be able to handle oral bacterial infections almost as well as noninfected persons. This ability is probably caused by the antibody-mediated immunity provided by the B-lymphocytes, which is largely responsible for combating the extracellular bacterial pathogens of most head and neck infections. Resistance to these common infections remains fairly robust until the terminal stages of AIDS, when all types of lymphocytes are severely depleted. On the other hand, fungal and viral infections, which are resisted by cell-mediated immunity (T cells), are prevalent in poorly controlled HIV-infected individuals.

T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 1738 Table 2 Bactericidal and bacteriostatic antibiotics Bactericidal b-lactams penicillins cephalosporins carbapenems monobactams Aminoglycosides Vancomycin Metronidazole Fluoroquinolones Bacteriostatic Macrolides erythromycin clarithromycin azithromycin Clindamycin Tetracyclines Sulfa antibiotics

21

They are discussed in the section on adverse antibiotic reactions.

Pharmacologic factors in antibiotic selection Antimicrobial spectrum The most important pharmacologic consideration in antibiotic selection is whether it is effective against the likely pathogens. Table 3 describes the general spectrum of selected antibiotics. Table 4 lists the bacteria and fungi most likely to be encountered and the antibiotics of choice for those pathogens. The antibiotics effective against the highly resistant organisms are also included in Table 4. Table 5 lists the antibiotics to which selected highly resistant organisms have become resistant. These data, among others, are used in constructing the recommendations for empiric antibiotics of choice for various head and neck infections, and Tables 4 and 5 especially can be used in selecting an appropriate antibiotic for organisms identified by culture, for which sensitivity data may not be available. Tissue distribution of antibiotics Although abscess cavities are not vascular, some penetration of antibiotics into these spaces does occur. The antibiotic that best penetrates an abscess is clindamycin; the abscess concentration of clindamycin reaches 33% of the serum level [22]. This fact may partially explain the usefulness of clindamycin in odontogenic infections. Bone penetration of antibiotics is an important consideration, especially in osteomyelitis. The antibiotics that best penetrate or even accumulate in bone are the tetracyclines, clindamycin, and the fluoroquinolones. Cerebrospinal fluid penetration, or the ability of an antibiotic to cross the blood-brain barrier, is paramount in the treatment of infections that threaten the central nervous system, as in actual or impending cavernous sinus thrombosis. The antibiotics that can attain therapeutic levels in cerebrospinal fluid when the meninges are inflamed are listed in Table 6. The antibiotics that do not penetrate the cerebrospinal fluid well are clindamycin, the macrolides (including clarithromycin and azithromycin), cefazolin, and most other cephalosporins (except those listed in Table 6), aminoglycosides, amphotericin, itraconazole, ethambutol, and saquinavir. Penicillin G in high doses reaches 5% to 10% of the serum concentration in the cerebrospinal fluid

Table 2 lists common antibiotics by their ability to kill bacteria or merely suppress their growth. Previous antibiotic therapy All antibiotic therapy inherently selects for resistant organisms. Studies of patients who are currently taking or recently have taken antibiotics consistently yield a higher incidence and proportion of organisms resistant to that antibiotic [10,19]. On the other hand, these effects persist for a considerable time after antibiotic therapy and may be permanent [19,20]. The previous use of different antibiotics during the course of an acute infection definitely clouds the bacteriologic picture. In this situation, the clinician has the choice of changing the current antibiotic or increasing its dose, perhaps by using the parenteral route. With penicillins V (oral) and G (intravenous), peak serum blood levels are 5.6 mg/mL and 20 mg/mL, respectively. The dramatic increase in efficacy afforded by the parenteral route of administration may be more advantageous than changing to another antibiotic that is less effective than the penicillins. The penicillin resistance rate of the endocarditisassociated viridans streptococci (S. mitis, S. sanguis, and S. salivarius) is highup to 58% [21] in persons with a history of prior endocarditis. Clindamycin resistance of these bacteria in such patients remains low. In patients with a history of endocarditis, it may be advisable to use clindamycin rather than amoxicillin for endocarditis prophylaxis before oral procedures. This approach, however, has not been tested in a clinical study. Special conditions Certain temporary host conditions may affect antibiotic selection, such as childhood and pregnancy.

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Table 3 Spectrum of selected antibiotics Antibiotic category Natural penicillins Antibiotic Penicillin G and V Susceptible organisms Viridans streptococci Oral anaerobes Actinomyces sp. (penicillin G only) Pasteurella multocida As with natural penicillins, plus enterococci Actinomyces As with amoxicillin, plus S. aureus, not MRSA S. epidermidis, not MRSE H. influenzae M. catarrhalis Klebsiella species E. coli Bacteroides fragilis S. aureus, not MRSA S. epidermidis, not MRSE As with natural penicillins, plus S. aureus, not MRSA S. epidermidis, not MRSE H. influenzae M. catarrhalis Klebsiella species E. coli Bacteroides fragilis Enterobacteriaceae (most) Pseudomonas aeruginosa As with antipseudomonal penicillins, plus Actinomyces (imipenem) Enterobacteriaceae, except Salmonella (no data) and Acinetobacter (resistant) Streptococci S. aureus, not MRSA H. influenzae Klebsiella E. coli As with first generation, plus M. catarrhalis (cefuroxime) Oral anaerobes B. fragilis (cefoxitin) As with first generation, plus M. catarrhalis Oral anaerobes Actinomyces (ceftriaxone) Streptococci Actinomyces Peptostreptococci (azithromycin) Streptococci Oral anaerobes Actinomyces S. aureus, not MRSA Obligate anaerobes S. aureus, not MRSA Enterobacteriaceae (most) (continued on next page)

Semisynthetic penicillins b-lactam/b-lactamase inhibitors

Ampicillin Amoxicillin Amoxicillin/clavulanate Ampicillin/sulbactam

Penicillinase-resistant penicillins Antipseudomonal penicillins

Oxacillin Dicloxacillin Ticarcillin/clavulanate Piperacillin/tazobactam

Carbapenems

Monobactam Cephalosporins

Imipenem Meropenem Ertapenem Aztreonam First generation Cephalexin Cefazolin

Second generation Cefaclor Cefuroxime Cefoxitin Third generation Cefotaxime Ceftriaxone Macrolides Erythromycin Clarithromycin Azithromycin Clindamycin

Clindamycin

Metronidazole Fluoroquinolones

Ciprofloxacin

T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 1738 Table 3 (continued ) Antibiotic category Antibiotic Moxifloxacin Susceptible organisms

23

Aminoglycosides

Gentamicin Tobramycin

Glycopeptides

Vancomycin Teicoplanin Linezolid

Oxazolidinones

Pristinamycins

Quinupristin/dalfopristin

Ketolides

Telithromycin

Streptococci Oral anaerobes S. aureus, not MRSA Actinomyces B. fragilis Enterobacteriaceae (most) S. aureus, not MRSA Enterococci (gentamicin synergistic with ampicillin) Enterobacteriaceae (many) Pseudomonas Streptococci S. aureus, including MRSA S. epidermidis, including MRSE (vancomycin) Streptococci Staphylococci, including VISA, VRSE, MRSA, MRSE Peptostreptococci Enterococci, including VRE Streptococci Staphylococci, including VISA, VRSE, MRSA, MRSE Legionella Streptococci S. aureus (not MRSA?) H. influenzae M. catarrhalis Legionella

Abbreviations: MRSA, methicillin-resistant S. aureus; MRSE, methicillin-resistant S. epidermidis; VISA, vancomycin-intermediate S. aureus; VRSE, vancomycin-resistant S. epidermidis.

when the meninges are inflamed. In odontogenic infections that threaten the central nervous system, the addition of metronidazole (30% 100% penetration) to ampicillin (13% 14% penetration) is more efficacious than using penicillin G alone [15]. Pharmacokinetics The effectiveness of some antibiotics, such as the fluoroquinolones and aminoglycosides, is concentration dependent, whereas with other antibiotics, such as the b-lactams and vancomycin, it is time dependent. In concentration-dependent antibiotics, efficacy is determined by the ratio of the serum concentration of the antibiotic to the minimum inhibitory concentration (MIC), which is the concentration of the antibiotic required to kill a given percentage of the strains of a particular species, usually 50% or 90%. In time-dependent antibiotics, it is necessary to maintain the serum concentration above the MIC for at least 40% of the dosage interval. It is necessary with time-dependent antibiotics to know the serum elimination half-life (t/2) of the antibiotic to determine its proper dosage interval.

For example, the t/2 of penicillin G is 0.5 hours. During each half hour, 50% of the remaining penicillin is eliminated from the serum. By five half-lives, or 2.5 hours, only approximately 3% of the peak serum level of penicillin remains. Because the MIC-90 of the viridans streptococci (the concentration that kills 90% of the strains) is 0.2 mg/mL and because the peak serum level achieved with 2 million U of intravenous penicillin G is 20 mg/mL, the serum concentration of penicillin after 4 hours (eight half-lives) is approximately 0.15 mg/mL. The serum level will have fallen below the MIC-90 roughly for only the last 15% of the dosage interval. Intravenous penicillin G, 2 million U every 4 hours, should be highly effective against the viridans group of streptococci. Using the same analysis, the peak blood level achieved with amoxicillin, 500 mg orally, is 7.5 mg/mL, and its t/2 is 1.2 hours. The MIC-90 for the viridans streptococci is 2 mg/mL for amoxicillin. Using an 8-hour dosage interval, the remaining serum concentration of amoxicillin should have fallen below the MIC-90 of the viridans streptococci at approximately 2.5 hours, which is only 31% of the dosage interval. Oral amoxicillin therapy may not kill 90% of all the

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Table 4 Antibiotics of choice for head and neck pathogens Pathogen Actinomyces Type +, R, A First choice antibiotics Penicillin G or ampicillin Alternative antibiotics

Bacteroides fragilis

Clostridium species (except C. difficile) Clostridium difficile Eikenella corrodens

Enterococcus faecalis (group D streptococcus) Enterococcus faecium (group D streptococcus: b-lactamase +, aminoglycoside and vancomycin resistant) Escherichia coli

Fusobacterium species Haemophilus influenzae (b-lactamase positive) Klebsiella pneumoniae

Klebsiella pneumoniae (producing extended spectrum b-lactamases: ESBLs) Pasteurella multocida (eg, dog and cat bites) Peptostreptococcus (and former Peptococcus) Black pigmented oral anaerobes (Prevotella and Porphyromonas) Proteus vulgaris (indole +)

Doxycycline Clindamycin Erythromycin , R, AN Metronidazole Clindamycin Cefoxitin, not cefotetan (DOT) Ampicillin/sulbactam +, R, AN Penicillin G F clindamycin Metronidazole Doxycycline Cephalosporin (1st)a +, R, AN Metronidazole p.o. Vancomycin p.o. Bacitracin p.o. , R, A Penicillin G or V Fluoroquinolones Amoxicillin TMP/SMX (avoid Amoxicillin/clavulanate clindamycin) +, C, F Ampicillin F gentamicin Vancomycin (for endocarditis or meningitis Ampicillin/sulbactam Linezolid +, C, F Linezolid + quinupristin/dalfopristin F Teicoplanin + aminoglycoside choramphenicol F doxycycline (van B) For some strains: no effective regimen (I.D. consultation) Meropenem for central nervous system , R, A Ticarcillin/clavulanate Aztreonam Cephalosporins Imipenem TMP/SMX Tobramycin Fluoroquinolones , R, AN Penicillin G or V Metronidazole Clindamycin , R, F Amoxicillin/clavulanate Cefotaxime (if life threatening) Cefaclor Ciprofloxacin Azithro/clarithromycin TMP/SMX , R, A Cephalosporin (3rd)* Tobramycin Fluoroquinolones Ticarcillin/clavulanate Imipenem/cilastatin , R, A Imipenem/cilastatin Meropenem Fluoroquinolones , R, A Penicillin G Amoxicillin/Clavulanate Doxycline Cephalosporin (2nd)a TMP/SMX Clindamycin Doxycline Vancomycin PCN + metronidazole Amoxicillin Cefotetan Tobramycin Imipenem Ticarcillin/clavulanate Aztreonam + ceftazidime Piperacillin + tobramycin Cefepime + tobramycin Chloramphenicol Amoxicillin TMP/SMX (continued on next page)

+, C, AN Penicillin G or V

, R, AN Clindamycin

, R, A

Cephalosporin (3rd) Fluoroquinolones Ciprofloxacin Tobramycin

Pseudomonas aeruginosa

, R, A

Salmonella typhi

, R, A Fluoroquinolones Ceftriaxone

T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 1738 Table 4 (continued ) Pathogen Serratia marcescens Type First choice antibiotics Alternative antibiotics Gentamicin Aztreonam

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Shigella Staphylococcus aureus (methicillin sensitive) Staphylococcus aureus (methicillin resistant)

, R, A Cephalosporin (3rd) Imipenem Meropenem Fluoroquinolones , R, A Fluoroquinolones Azithromycin +, C, A Penicillinase-resistant penicillin +, C, A Vancomycin

TMP/SMX + ampicillin Cephalosporin (1st)a Vancomycin Clindamycin Teicoplanin Quinupristin-dalfopristin TMP/SMX (some strains) Linezolid Quinupristin/dalfopristin Linezolid Quinupristin/dalfopristin

Staphylococcus aureus (methicillin and vanco mycin resistant) Staphylococcus epidermidis (methicillin resistant)

+, C, A

No effective regimen Try vancomycin F rifampin Vancomycin (+ rifampin + gentamicin for prosthetic valve endocarditis) Quinupristin/dalfopristin Linezolid Penicillin G or V Ceftriaxone Amoxicillin Vancomycin + Rifampin

+, C, A

Staphylococcus epidermidis +, C, A (methicillin and glycopeptide resistant) Streptococcus pneumoniae +, C, A (Pneumococcus) (penicillin sensitive) Streptococcus pneumoniae +, C, A (Pneumococcus) (multiantibiotic resistant, including high-level penicillin, erythromycin, tetracycline, chloramphenicol, and TMP/SMX) Streptococcus pyogenes +, C, A (b-hemolytic streptococcus) Streptococcus viridans +, C, A (a-hemolytic streptococcus) Fungal organisms Blastomyces Fungus Candida Fungus

Vancomycin (high dose) New fluoroquinolones?b (rapid resistance a problem) Cefuroxime, cefipime Imipenem New fluoroquinolonesb Clindamycin New fluoroquinolones (in vitro)

Penicillin G or V (+ gentamicin if serious group B infection) Penicillin G or V

Cephalosporin (1st)a Erythromycin Cephalosporin (1st)a Macrolides Itraconazole (if surface) Fluconazole (if surface) Nystatin (if surface) Clotrimazole (if surface) Ketoconazole (if surface) Itraconazole (if surface) Fluconazole Amphotericin B Itraconazole (immunocompetent) Itraconazole (immunocompromised) Control underlying systemic disease

Amphotericin B (for systemic cases) Fluconazole Amphotericin B (for systemic cases) Itraconazole Amphotericin B (for systemic or immunocompromised cases) Amphotericin B

Coccidioides immitis Histoplasma Mucormyces

Fungus Fungus Fungus

Abbreviations: A, aerobe; AN, anaerobe; C, coccus; DOT, distasonis, ovatus, and thetaiotamicron group of B. fragilis species; F, facultative; PCN, penicillin; R, rod; TMP-SMX, trimethoprim-sulfamethoxazole. Data from Gilbert DN, Moellering RC Jr, Sande MA. The Sanford guide to antimicrobial therapy 2002. 32nd edition. New Hyde Park (VT): Antimicrobial Therapy Inc.; 2002. + = gram positive. = gram negative. a Number in parentheses after cephalosporins refers to generations within the cephalosporin family. b New fluoroquinoles are gati-, gemi-, lero-, moxi-, sparfloxacin.

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Table 5 Highly resistant organisms and the antibiotics to which they are resistant Organism Acinetobacter baumanii Resistant to Penicillins Third generation cephalosporins Antipseudomonal aminoglycosides Fluoroquinolones Imipenem Glycopeptides Streptomycin Gentamicin All b-lactams Glycopeptides Aminoglycosides Glycopeptides Streptomycin Gentamicin all b-lactams Glycopeptides Aminoglycosides Penicillins Third generation cephalosporins Aztreonam Penicillins Cephalosporins Carbapenems Methicillin Methicillin Vancomycin only Vancomycin and teicoplanin (both available glycopeptides) Methicillin Methicillin Glycopeptides Penicillin G

Enterococcus faecalis b-lactamase negative Enterococcus faecalis b-lactamase positive Enterococcus faecium b-lactamase negative Enterococcus faecium b-lactamase positive Klebsiella pneumoniae ESBL positive

strains of the viridans streptococci. Fortunately for oral and maxillofacial surgeons, the Streptococcus milleri group associated with odontogenic infections is highly sensitive to the penicillins, whereas the endocarditisassociated strains are less so. The pharmacokinetics of the clinically available antibiotics have been determined during drug development. It is incumbent on the clinician to prescribe antibiotics within the accepted ranges for dose and interval. Once-daily dosing for the aminoglycosides as a means of reducing their ototoxicity and nephrotoxicity recently has been evaluated in a systematic review [23]. The available well-designed studies indicate that this practice results in a modest increase in therapeutic advantage and possibly a decrease in toxicity. The cost saving of once-daily intravenous dosing makes this approach appealing. Caution is advised in patients with limited volumes of fluid distribution, however. Adverse reactions The adverse reactions and toxicities of the antibiotics commonly used in head and neck infections are generally mild and uncommon. Table 7 lists the major serious adverse reactions of the commonly used antibiotics. The clinician especially should note allergic reactions to the penicillins and cephalosporins, gastrointestinal intolerance of the erythromycins, nephrotoxicity and ototoxicity of the aminoglycosides, and antibiotic-associated colitis with the b-lactam/b-lactamase inhibitor combinations (eg, Augmentin, Unasyn), antipseudomonal penicillins (eg, ticarcillin, piperacillin), cephalosporins, and clindamycin, among others. Special conditions Antibiotics that should be avoided in children include the tetracyclines (under the age of 8), because of permanent intrinsic dental staining, and the fluoroquinolones, because of chondrotoxicity in growing cartilage. Among the carbapenems, imipenem is not recommended because of the risk of seizures. Meropenem is an acceptable alternative. The use of antibiotics in pregnancy almost always involves an evaluation of risk versus benefit. The antibiotics that must be avoided in pregnancy include the antimycobacterial agent, thalidomide, and the antiparasitic agent, quinine, for which the risk clearly outweighs the benefit. Table 8 lists the pregnancy risk categories of selected antibiotics.

Pseudomonas aeruginosa Staphylococcus aureus MRSA S. aureus VISA or GISA

Staphylococcus epidermidis MRSE S. epidermidis VRMRSE Streptococcus pneumoniae penicillin intermediate or resistant S. pneumoniae multi-antibiotic resistant

Penicillins Cephalosporins Aztreonam

Abbreviations: ESBL, extended-spectrum b-lactamase; GISA, glycopeptide-intermediate S. aureus; MRSE, methicillin-resistant S. epidermidis; VRMRSE, vancomycinresistant methicillin-resistant S. epidermidis. Data from Gilbert DN, Moellering RC Jr, Sande MA. The Sanford guide to antimicrobial therapy. 32nd edition. Hyde Park (VT): Antimicrobial Therapy, Inc.; 2002.

T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 1738 Table 6 Selected antibiotics and the blood-brain barrier Cerebrospinal fluid Therapeutic levels achieved Antibiotic Penicillins ampicillin nafcillin penicillin G, high dose ticarcillina piperacillina Cephalosporins ceftazidime cefuroxime ceftriaxone Carbapenem meropenemb Fluoroquinolones levofloxacin ciprofloxacinc Other antibiotics metronidazole trimethoprim/ sulfamethoxazoled vancomycine Antifungal drugs fluconazole flucytosine Antiviral drugs acyclovir foscarnet ganciclovir zidovudine Cephalosporins cefazolin cephalexin Aminoglycosides Macrolides erythromycin clarithromycin azithromycin Clindamycin Antifungal drugs amphotericin itraconazole Antiviral drugs saquinavir zidovudine

27

Antibiotic drug interactions Two important categories of antibiotic drug interaction are interference with the effectiveness of oral contraceptives and interference with the metabolism of drugs, which involves the cytochrome P450 system. These and other selected antibiotic drug interactions are listed in Table 9. Antibiotic interference with the effectiveness of oral contraceptive pills remains a controversial topic. The only antibiotic that has been shown conclusively to interfere with oral contraception is rifampin. The evidence that implicates ampicillin, amoxicillin, dapsone, trimethoprim/sulfamethoxazole, and the antiviral protease inhibitors is less strong. It is important to note that antibiotics do not interfere with injectable or implantable contraceptives. Only oral contraceptives are affected [24]. A possible mechanism for this interaction stems from efforts to decrease the adverse effects, such as thromboembolism and activation of uterine and breast carcinomas associated with older contraceptive formulations that contained higher estrogen doses. Currently, oral contraceptive preparations have minimally effective estrogen doses, and the serum level of the estrogen is supported by enterohepatic recirculation. In this process, the liver conjugates absorbed estrogen with glucuronide, and the estrogen-glucuronide complex is excreted in the bile. In turn, the gut flora breaks the estrogenglucuronide bond, which allows the pure estrogen molecule to be reabsorbed by the gut, thus supporting the serum estrogen level. If an antibiotic kills enough of the gut flora, then the conjugated estrogen is not broken down, and the estrogen-glucuronide complex stays in the intestine until it is excreted. The serum estrogen level falls, which results in breakthrough menstrual bleeding or ovulation and unwanted pregnancy. The cytochrome P450 system is a complex set of drug-metabolizing enzymes that is responsible for the breakdown of many classes of drugs. Enzymes within this system include CYP3A4, CYP2C19, and CYP2D6. Drugs that share this metabolic pathway may interact. The metabolism of one or the other may be either increased or decreased as a result. The adverse affect is usually caused by an increased effect of the drug whose metabolism is inhibited, but in some of the most serious cases, life-threatening or fatal cardiac dysrhythmias, such as ventricular fibrillation and torsade des pointes, have occurred. The most significant interactions involving the cytochrome P450 system are included in Table 9.

Therapeutic levels not achieved

Data from Gilbert DN, Moellering RC Jr, Sande MA. The Sanford guide to antimicrobial therapy. 32nd edition. Hyde Park (VT): Antimicrobial Therapy, Inc.; 2002. a Levels effective for P. aeruginosa and coliforms may not be reached. b Imipenem is avoided in meningitis because of seizure potential. Meropenem is preferred. c Does not reach adequate cerebrospinal fluid levels for streptococci. d Not adequately effective against Neisseria species and coliforms. e High doses are needed for resistant streptococci.

28

Table 7 Major adverse reactions of selected antibiotics Ampicillin, Penicillin G amoxicillin F and V clavulanate + + + + + + + + + + + + + + + Ticarcillin F clavulanate Gentamicin, Cephalexin, Impenem Meropenem tobramycin cefazolin Cefuroxime Cefoxitin Cefotaxime Cefaclor

T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 1738

Adverse reactions Local, phlebitis Hypersensitivity Rash Photosensitivity Anaphylaxis Serum sickness Anemia Nausea, vomiting Diarrhea Antibiotic-associated colitis (AAC) Renal: z BUN, creatinine Headache Seizures Hypotension Ototoxicity Vestibular dysfunction Alcohol interaction Red man flushing Drug interactions Pregnancy risk C or D

+ +

Data from Gilbert DN, Moellering RC Jr, Sande MA. The Sanford guide to antimicrobial therapy. 32nd edition. Hyde Park (VT): Antimicrobial Therapy, Inc.; 2002.

T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 1738

Table 7 (continued ) Erythromycin Local, phlebitis Hypersensitivity Rash Photosensitivity Anaphylaxis Serum sickness Anemia Nausea, vomiting Diarrhea AAC Renal: z BUN, creatinine Headache Seizures Hypotension Ototoxicity Vestibular dysfunction Alcohol interaction Red man flushing Drug interactions Pregnancy risk C or D Clarithromycin, azithromycin Clindamycin Metronidazole Ciprofloxacin Moxifloxacin Vancomycin + + + Tetracycline, doxycycline Linezolid Telithromycin

+ + + + + + + + + + +

+ + + + + + + + + + + + +

29

30

T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 1738

Table 8 Pregnancy risk categories of selected antibiotics Antibiotic Penicillins penicillin G and V ampicillin amoxicillin amoxicillin/clavulanate ticarcillin/clavulanate Cephalosporins cephalexin cefazolin cefaclor cefuroxime cefoxitin cefotaxime Carbapenems imipenem meropenem Macrolides erythromycin clarithromycin azithromycin Antianaerobic clindamycin metronidazole Fluoroquinolones ciprofloxacin moxifloxacin Aminoglycosides gentamicin tobramycin Other vancomycin tetracyclines doxycycline linezolid telithromycin Pregnancy risk category B B B B B B B B B B B C B B C B B B C C D D C D D C B Spontaneous abortions in rabbits Fetal toxicity in rodents and monkeys Ototoxicity in human fetuses Ototoxicity in human fetuses Potential ototoxicity in human fetuses Intrinsic dental staining Intrinsic dental staining Fetal toxicity in rodents Spontaneous abortions in monkeys Pregnancy risk

Fetal defects in mice and monkeys

Data from Gilbert DN, Moellering RC Jr, Sande MA. The Sanford guide to antimicrobial therapy. 32nd edition. Hyde Park (VT): Antimicrobial Therapy, Inc.; 2002. A = Studies in pregnancy; no risk. B = Animal studies no risk, but human studies inadequate or animal toxicity, but human studies no risk. C = Animal studies show toxicity, and human studies inadequate, but benefit of use may outweigh risk. D = Evidence of human risk, but benefits may outweigh risk. X = Risk outweighs benefit.

Cost Although clinical effectiveness and reduction of the morbidity of infection and treatment are of paramount concern in the management of head and neck infections, cost is a factor that should be considered when other factors do not predominate. The costs of oral antibiotic therapy can be compared based on the cost for a standard prescription for the antibiotics of interest, because there is no additional cost of administration, as there is with parenteral antibiotics, espe-

cially by the intravenous route. Table 10 compares the retail cost of a 1-week prescription of the antibiotics listed. The penicillin V cost ratio is calculated by dividing the retail cost of the standard 1-week prescription for the given antibiotic by that of penicillin V. Table 11 compares the cost of intravenous antibiotics. The cost of administration assumes great importance. Each dose requires sterile intravenous administration supplies, professional labor, and hospital sterile processing and drug error prevention systems.In Table 11, these costs are conservatively estimated at

T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 1738 Table 9 Selected antibiotic interactions with other drugsa,b Antibiotic Erythromycin, clarithromycin, ketoconazole, itraconazole Second drug Theophylline Adverse effects Seizures, dysrhythmias Mechanism

31

Erythromycin, clarithromycin, ketoconazole, itraconazole

Cisapride

Erythromycin, clarithromycin, ketoconazole, itraconazole

Alfentanil

Erythromycin, clarithromycin, ketoconazole, itraconazole

Bromocriptine

Erythromycin, clarithromycin, ketoconazole, itraconazole

Carbamazepine

Erythromycin, clarithromycin, ketoconazole, itraconazole

Cyclosporine

Erythromycin, clarithromycin, ketoconazole, itraconazole

Felodipine, possibly other calcium channel blockers

Erythromycin, clarithromycin, ketoconazole, itraconazole

Methylprednisolone, prednisone

Erythromycin, clarithromycin, ketoconazole, itraconazole

Lovastatin, possibly other -statins

Erythromycin, clarithromycin, ketoconazole, itraconazole

Triazolam, oral midazolam

Erythromycin, clarithromycin, ketoconazole, itraconazole

Disopyramide

Erythromycin Erythromycin, tetracyclines

Clindamycin Digoxin

Erythromycin, clarithromycin, metronidazole

Warfarin Anisindione

Antibiotic inhibits cytochrome P450 metabolism of second drug; ketoconazole not implicated Dysrythmias (torsades) Antibiotic inhibits cytochrome P450 metabolism of second drug z Respiratory depression Antibiotic inhibits cytochrome P450 metabolism of second drug; ketoconazole not implicated z CNS effects, hypotension Antibiotic inhibits cytochrome P450 metabolism of second drug Ataxia, vertigo, drowsiness Antibiotic inhibits cytochrome P450 metabolism of second drug z Immunosuppression Antibiotic inhibits and nephrotoxicity cytochrome P450 metabolism of second drug Hypotension, tachycardia, Antibiotic inhibits edema cytochrome P450 metabolism of second drug z Immunosuppression Antibiotic inhibits cytochrome P450 metabolism of second drug Muscle pain, rhabdomyolysis Antibiotic inhibits cytochrome P450 metabolism of second drug z Sedative depth and duration Antibiotic inhibits cytochrome P450 metabolism of second drug Dysrhythmias Antibiotic inhibits cytochrome P450 metabolism of second drug # Antibiotic effect Mutual antagonism Digitalis toxicity, Antibiotic kills dysrhythmias, visual Eubacterium lentum, disturbances, which metabolizes hypersalivation digoxin in the gut z Anticoagulation Antibiotic interferes with metabolism of the second drug (continued on next page)

32 Table 9 (continued ) Antibiotic

T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 1738

Second drug

Adverse effects z Anticoagulation

Mechanism Antibiotic kills gut flora that synthesize vitamin K, which antagonizes the second drug; poor vitamin K intake a factor Antibiotic inhibits acetaldehyde dehydrogenase, causing accumulation of acetaldehyde; ritonavir preparations contain alcohol Antibiotic inhibits lithium excretion by kidney; tetracycline interaction not well established Second drug interferes with absorption of antibiotic; didanosine is formulated with calcium carbonate and magnesium hydroxide buffers Additive effect caused by inherent minor neuromuscular blocking effect of the antibiotic; seen with clindamycin in the presence of low pseudocholinesterase levels and abnormal liver function tests Mutual antagonism Interference with enterohepatic recirculation of estrogen caused by killing of gut flora; rifampin is the only antibiotic in which this has been clinically proven Unknown, possibly caused by hyperuricemia in patients taking allopurinol Additive or potentiating effect Thrombocytopenia Additive effect (continued on next page)

Tetracycline, cefamandole, Warfarin, anisindione cefotetan, cefoperazone, sulfonamides, aminoglycosides

Metronidazole, cephalosporins

Alcohol, ritonavir

Flushing, headache, palpitations, nausea

Metronidazole Metronidazole, tetracyclines

Disulfiram Lithium

Acute toxic psychosis Lithium toxicity: confusion, ataxia, kidney damage

Tetracyclines, fluoroquinolones

Divalent and trivalent cations (dairy, antacids, vitamins) didanosine

# Absorption of antibiotic

Clindamycin, aminoglycosides, tetracyclines, bacitracin

Neuromuscular blocking agents

z Depth and duration of paralysis

Clindamycin Penicillins, cephalosporins, metronidazole, erythromycin, clarithromycin, tetracyclines, rifampin

Erythromycin # Antibiotic effect Estrogen- and progestinContraceptive failure containing oral contraceptives

Ampicillin, amoxicillin

Allopurinol

Rash

Cephalosporins Trimethoprim/sulfamethoxazole Vancomycin

Aminoglycosides Thiazide diuretics Aminoglycosides

z Nephrotoxicity Purpura, bleeding in elderly patients z Renal toxicity

T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 1738 Table 9 (continued ) Antibiotic Fluoroquinolones, sulfonamides, chloramphenicol, fluconazole, itraconazole Ciprofloxacin, sulfonamides, chloramphenicol, fluconazole, ketoconazole, itraconazole Sulfonamides Second drug Oral hypoglycemic agents Adverse effects Hypoglycemia Mechanism Antibiotic displaces second drug from plasma proteins Interference with phenytoin metabolism

33

Phenytoin

z Serum level of phenytoin, confusion, delirium z Methotrexate concentration

Methotrexate

Protease inhibitors (ritonavir, amprenavir, saquinavir, nelfinavir, indinavir, and others)

Hydrocodone, fentanyl, alfentanil, amiodarone, lidocaine, anticonvulsants, loratidine, Benzodiazepines b-blockers Calcium channel blockers Cisapride Corticosteroids -statin type antihyperlipidemics Warfarin Codeine, morphine, contraceptives

z Levels of second drug, with possible toxic effects

Protease inhibitors

# Levels of second drug

Delavirdine (Rescriptor)

Cisapride, clarithromycin, protease inhibitors, warfarin

z Levels of second drug, with possible toxic effects

Didanosine (ddl, Videx) Foscarnet (Foscavir)

Metronidazole Ciprofloxacin

z Risk of peripheral neuropathy z Risk of seizures

Antibiotic displaces methotrexate from plasma proteins Serious interaction: avoid using the drugs in bold print Ritonavir has high affinity for various isoenzymes in the cytochrome P450 system and has the most frequent and severe drug interactions among the protease inhibitors Warfarin reaction is only with ritonavir Antibiotic enhances cytochrome P450 metabolism of second drug Antibiotic inhibits cytochrome P450 metabolism of second drug Additive effect Additive effect

From Flynn TR. Update on the antibiotic therapy of oral and maxillofacial infections. In: Piecuch JF, editor. Oral and maxillofacial surgery knowledge update 2001. Rosemont (IL): American Association of Oral and Maxillofacial Surgeons, 2001; with permission. a Interactions among the various anti-HIV antibiotics are frequent and complex. The reader is referred to appropriate sources on the subject. b This list of antibiotic-drug interactions is only partial and selected according to the interests of oral and maxillofacial surgeons. Drug prescribers remain responsible to ascertain the complete drug interactions of any medications they may prescribe.

$4.00 per dose. Even this small additional cost can make an infrequently administered but more expensive antibiotic more economical than a cheaper, more frequently dosed antibiotic. An example of this effect can be found by comparing the cost ratio of penicillin G (analogous to the penicillin V cost ratio) with cefazolin. Table 11 also illustrates the markedly increased cost of combined antibiotic therapy as compared to monotherapy. For example, 1 weeks intravenous therapy of penicillin G plus metronidazole costs $690, whereas 1 weeks treatment with clindamycin costs only $375, a reduction of 46%. On the other hand, the combination approach may be advantageous

in an infection that threatens the brain, for example, because clindamycin does not cross the blood-brain barrier and penicillin does so only to a limited extent. Metronidazole crosses the blood-brain barrier well.

New antibiotics of interest to oral and maxillofacial surgeons New fluoroquinolones Moxifloxacin (Avelox) and gemifloxacin are two new fluoroquinolones whose spectrum includes

34 Table 10 Oral antibiotic costs Antibiotic

T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 1738

Usual dose (mg) 500 500 500 875 500 500 500 500 500 500 500 333 250 500 500 250 150 300 300 500 160/800 500 100 125

Usual interval (h) 6 8 8 12 6 6 6 6 8 8 6 6 6 24 12 24 6 6 6 6 12 12 12 6

Pharmacy Cost 01 * * $0.14 $0.31 $3.65 $4.76 $0.66 $1.07 $3.11 $0.52 $7.43 $4.00 $0.36 $0.36 $0.31 $12.39 $3.57 $6.75 $0.98 $1.96 $4.22 $0.72 $0.15 $4.15 $0.08 $5.38

Cost for 24 hours $0.56 $0.93 $10.95 $9.52 $2.64 $4.28 $12.44 $2.08 $22.29 $12.00 $1.44 $1.44 $1.24 $12.39 $7.14 $6.75 $3.92 $7.84 $16.88 $2.88 $0.30 $8.30 $0.16 $21.52

Retail cost for 1 weekd $9.99 $13.89 $104.99 $97.59 $26.69 $24.89 $104.99 $70.59 $199.99 $77.59 $13.89 $16.29 $13.49 $63.99 $71.99 $60.59 $31.29 $54.86 $118.27 $10.02 $11.69 $80.59 $9.99 $187.99

Penicillin cost ratioc 1.00 1.39 10.51 9.77 2.67 2.49 10.51 7.07 20.02 7.77 1.39 1.63 1.35 6.41 7.21 6.07 3.13 5.49 11.84 1.00 1.17 8.07 1.00 18.82

Penicillins Penicillin V Amoxicillin Augmentina Augmentin Dicloxacillin Cephalosporins (generation) Cephalexin caps (1st) Keftabs (1st)b Cephradine (1st) Cefuroxime (2nd) Cefaclor (2nd) Erythromycins Erythromycin base Erythromycin stearate Erythromycin estolate Dirythromycin (Dynabec) Clarithromycin (Biaxin) Azithromycin (Zithromax) Anti-anaerobic Clindamycin (generic) Clindamycin (2 T generic) Clindamycin (Cleocin) Metronidazole (250 mg = $0.08) Other Trimethoprim/sulfamethoprim Ciprofloxacin Doxycycline Vancomycin

Usual doses and intervals are for moderate infections, and are not to be considered prescriptive. From Gilbert DN, Moellering RC Jr, Sande MA. The Sanford guide to antimicrobial therapy 2001. 31st edition. Hyde Park (VT): Antimicrobial Therapy, Inc; 2001. a Augmentin = amoxicillin plus clavulanic acid. b Keftab = cephalexin hydrocloride in tablet form (Dista). c Penicillin cost ratio = retail cost of antibiotic for 1 week retail cost of penicillin V for 1 week. d Retail cost/1 week = retail price charged for a 1-week prescription at a large pharmacy chain in the Boston region. Courtesy of Chris Gonzalez, RPh.

the viridans streptococci, oral anaerobes, and actinomyces. They are also effective against sinus pathogens, staphylococci, Enterobacteriaceae, and B. fragilis. Their broad spectrum is a relative disadvantage when the target is a fairly small range of bacteria. These new fluoroquinolones probably should be reserved for situations in which a narrower spectrum alternative antibiotic is not available. Oxazolidinones Linezolid (Zyvox) is the prototype of this new class of antibiotics. It is effective against virtually all

gram-positive pathogens but not against the gramnegative oral anaerobes. Its effectiveness against methicillin- and vancomycin-resistant staphylococci and enterococci indicates that it should be reserved for these highly resistant organisms [25]. Ketolides Telithromycin (Ketek) is the first representative of this new class, which is related to the macrolides. Its spectrum includes the pathogens against which the macrolides have been historically effective, including S. pneumoniae, mycoplasma, H. influenzae, Chlamy-

T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 1738 Table 11 Intravenous antibiotic costs Antibiotic Usual doseb Usual interval (hour)b 6 6 6 6 4 4 8 12 8 8 8 24 8 6 6 24 6 12 8 6 12 6 12 Pharmacy cost 00 $1.33 $1.64 $10.18 $2.68 $12.92 $15.40 $1.74 $11.58 $13.93 $21.16 $28.45 $42.00 $16.97 $30.32 $22.16 $23.70 $7.80 $15.60 $13.88 $19.03 $21.07 $16.42 $30.00 Pharmacy cost 01 $1.32 $1.31 $14.45 $5.14 $13.43 $15.20 $1.90 $11.60 $13.80 $26.38 $28.45 $40.18 $16.97 $30.32 $23.00 $24.44 $8.28 $16.56 $13.88 $15.34 $4.16 $16.42 $30.00 Total cost 24 hours $21.28 $21.24 $73.80 $36.56 $104.58 $115.20 $17.70 $31.20 $53.40 $91.14 $97.35 $44.18 $62.91 $137.28 $108.00 $28.44 $49.12 $41.12 $53.64 $77.36 $16.32 $81.68 $68.00 Total cost for 7 days $148.96 $148.68 $516.60 $255.92 $732.06 $806.40 $123.90 $218.40 $373.80 $637.98 $681.45 $309.26 $440.37 $960.96 $756.00 $199.08 $343.84 $287.84 $375.48 $541.52 $114.24 $571.76 $476.00

35

Penicillin G cost ratioa 1.00 1.00 3.47 1.72 4.91 5.41 0.83 1.47 2.51 4.28 4.57 2.08 2.96 6.45 5.08 1.34 2.31 1.93 2.52 3.64 0.77 3.84 3.20

Penicillins Penicillin G 2 mu Ampicillin 1g Unasyn 2g Oxacillin 1g Ticarcillin 3g Timentin 3.1 g Cephalosporins (generation) Cefazolin (1st) 1g Cefotetan (2nd) 1g Cefuroxime (2nd) 1.5 g Cefotaxime (3rd) 2g Ceftazidime (3rd) 2g Ceftriaxone (3rd) 1g Monobactam Aztreonam 1g Carbapenem Imipenem-cilastatin 0.5 g Penicillin allergy Erythromycinc 1g Azithromycin 0.5 g Vancomycin 0.5 g Vancomycin 1.0 g Anti-anaerobic Clindamycin 0.9 g Metronidazole 0.5 g Other Doxycycline 0.1 g Trimethoprim-sulfa 800 mg Ciprofloxacind 400 mg

Total cost of therapy includes $1.00 for infusion materials and $3.00 labor cost, per dose. From Gilbert DN, Moellering RC Jr, Sande MA. The Sanford guide to antimicrobial therapy 2001. 31st edition. Hyde Park (VT): Antimicrobial Therapy, Inc; 2001. a Penicillin cost ratio = 24-hour cost of antibiotic/24-hour cost of penicillin G. b Usual doses and intervals are for moderate infections and are not to be considered prescriptive. c Only the brand name price is listed in the reference. Price is selected from the lowest available average wholesale price. d Cipro IV is for NPO patients only because of excellent oral absorption.

dia pneumoniae, and Legionella pneumophila. Its most frequent use probably is in respiratory tract infections, especially pneumonia [26,27]. Pristinamycins Quinupristin/dalfopristin (Synercid), a combination of two pristinamycin antibiotics, is especially effective against vancomycin-resistant staphylococci. Its use generally has been reserved for infections caused by these organisms.

Empiric antibiotics of choice for head and neck infections Odontogenic infections Empiric antibiotics are administered before culture and sensitivity test results are available; specific antibiotic therapy is selected based on culture and sensitivity results. Table 12 lists the empiric antibiotics of choice for selected types of head and neck infections, including odontogenic infections.

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T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 1738

In a prospective case series of 34 cases of odontogenic infection, Flynn et al reported therapeutic failure of penicillin in 26% of cases using the following criteria for failure: allergic or toxic reaction (no cases); failure of swelling, temperature, and white blood cell count to decline after at least 48 hours of intravenous penicillin; and a postoperative CT scan that demonstrated adequate surgical drainage. If inadequate drainage was found on the postoperative CT scan, surgery was repeated. All of the patients with therapeutic penicillin failure (8 of 31 cases initially treated with penicillin) subsequently yielded at least one penicillin-resistant strain when culture and sensitivity test results became available. This finding suggests a correlation between infection severity and penicillin resistance and is the basis for the recommendation of clindamycin as the empiric antibiotic of choice in odontogenic infections serious enough to require hospitalization [8]. On the other hand, penicillin resistance has not yet been shown to be a significant problem in outpatient odontogenic infections [11 14]. Penicillin V remains the empiric antibiotic of choice for outpatient odontogenic infections. Because of their ineffectiveness against the oral anaerobes, the macrolides are no longer considered among the empiric antibiotics of choice for odontogenic infections. Because the oral anaerobic gram-negative rods are fairly resistant to most cephalosporins, especially those in the first generation, the cephalosporins remain secondline choices. Sinus infections Acute rhinosinusitis of odontogenic origin is characterized by the same flora as other odontogenic infections, except that not all of the species found in the periapical infection survive in the sinus location [28]. Non-odontogenic acute rhinosinusitis is frequently caused by S. pneumoniae, H. influenzae, Moraxella catarrhalis, and streptococci. S. aureus is found in only approximately 4% of cases of acute rhinosinusitis [15]. Antibiotic treatment should be reserved for patients who already have been treated for 7 days with only decongestants and analgesics and who have maxillary or facial pain or purulent nasal discharge. Patients with severe pain or fever may need antibiotic therapy sooner, and hospitalization may be required in these cases. If antibiotics have been used in the previous month or if the local incidence of penicillin-resistant S. pneumoniae is more than 30%, amoxicillin and clavulanic acid or a secondor third-generation cephalosporin is prescribed for

two weeks [15]. On the other hand, a recent systematic literature review indicates that penicillin or amoxicillin alone is as effective as the other broader spectrum and more expensive antibiotics [29]. In chronic rhinosinusitis, the flora becomes more anaerobic, including B. fragilis and the peptostreptococci, such as Fusobacterium, Prevotella, and Porphyromonas. Antibiotics alone are not usually effective in these cases, and corrective surgery, usually with otorhinolaryngology consultation, is indicated. Fungal infection of the sinuses should be suspected and treated urgently with antibiotics and surgery in patients with acute rhinosinusitis who have diabetes mellitus with acute ketoacidosis, neutropenia, or previous treatment with deferoxamine. Amphotericin B and surgery are indicated, along with discontinuation of deferoxamine, if applicable. Deferoxamine (Desferal) is an iron-chelating agent used in Alzheimers disease. Mucormycosis has been found in patients who are undergoing simultaneous deferoxamine treatment and hemodialysis. Osteomyelitis of the jaw The microbiology of osteomyelitis of the jaws has not been reported specifically in a large case series. It is increasingly apparent from case reports, however, that the usual odontogenic pathogens are the most frequent cause. One also may suspect skin and soil pathogens in traumatic osteomyelitis and salmonella in sickle-cell osteomyelitis. Actinomyces are another prominent pathogen in chronic osteomyelitis, and culture and microscopic examination may be required to identify this organism. Molecular methods ultimately may become the most rapid and reliable method for identifying Actinomyces [30]. Long courses of the antibiotics effective against the Actinomyces are required (see Table 4). Oral penicillins plus probenecid can be used for long-term outpatient therapy. Probenecid inhibits the renal excretion of penicillin and increases the blood level obtained by the oral route. Fungal infections Various fungi cause a wide spectrum of infectious manifestations in the head and neck. An excellent review of the topic can be found in a recent chapter by Bergman [30]. The major fungal infections of concern to oral and maxillofacial surgeons are histoplasmosis and blastomycosis, which may cause granulomatous oral lesions; aspergillosis and mucormycosis, which tend to cause sinusitis; and candidiasis, which causes surface lesions in non-immunocompromised patients

T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 1738 Table 12 Empiric antibiotics of choice for head and neck infections Type of infection Odontogenic infections Outpatient Empiric antibiotic of choice

37

Penicillin allergy Inpatient

Penicillin allergy

Penicillin Clindamycin Cephalexin (or other first-generation cephalosporin) Clindamycin Cephalexin (only if nonanaphylactoid penicillin reaction) Clindamycin Ampicillin + metronidazole Ampicillin + sulbactam Clindamycin Moxifloxacin Cefotaxime (only if nonanaphylactoid penicillin reaction) Amoxicillin Amoxicillin/clavulanate Cefuroxime Moxifloxacin (over 18 years of age) Clarithromycin or azithromycin Telithromycin Moxifloxacin (over 18 years of age) Antibiotics not effective: otolaryngologic consultation Imipenem or meropenem Ticarcillin or piperacillin Ceftazidime + vancomycin Cefepime Amphotericin B Clindamycin Ampicillin + metronidazole Ampicillin + sulbactam Clindamycin Moxifloxacin Itraconazole Fluconazole Amphotericin B (systemic or disseminated)

Rhinosinusitis Acute

Penicillin allergy

Chronic Intubated

Fungal Osteomyelitis of the jaw

Penicillin allergy Histoplasmosis and blastomycosis

Candidiasis Oral, non-AIDS Oral, AIDS

Fluconazole or itraconazole Nystatin or clotrimazole Fluconazole or itraconazole Amphotericin B

Data from Gilbert DN, Moellering RC Jr, Sande MA. The Sanford guide to antimicrobial therapy. 32nd edition. Hyde Park (VT): Antimicrobial Therapy Inc.;2002.

and may cause disseminated and invasive disease in immunocompromised persons. Histoplasmosis, blastomycosis, and mucormycosis are diagnosed by surgical sampling for culture, histologic examination with special stains, and use of molecular methods, such as polymerase chain reaction. In general, fungal

infections are treated with the azole-type antifungal agents for less severe cases and amphotericin B for disseminated and severe disease. In surface candidiasis in a patient with a healthy immune system, clotrimazole is a better-tasting yet economical alternative to nystatin.

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T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 1738 spective double-blind evaluation of penicillin versus clindamycin in the treatment of odontogenic infections. J Oral Maxillofac Surg 1988;46:1065 70. Lewis MA, Carmichael F, MacFarlane TW, Milligan SG. A randomised trial of co-amoxiclav (Augmentin) versus penicillin V in the treatment of acute dentoalveolar abscess. Br Dent J 1993;175:169 74. Paterson SA, Curzon ME. The effect of amoxycillin versus penicillin V in the treatment of acutely abscessed primary teeth. Br Dent J 1993;174:443 9. Gilbert DN, Moellering Jr RC, Sande MA. The Sanford guide to antimicrobial therapy, 32nd edition. Hyde Park (VT): Antimicrobial Therapy Inc.; 2000. Craig TJ, Mende C. Common allergic and allergic-like reactions to mediations: when the cure becomes the curse. Postgrad Med 1999;105:173 81. Bowrey DJ, Morris-Stiff GJ. Drug allergy: fact or fiction? Int J Clin Pract 1998;52:20 1. Warrington RJ, Lee KR, McPhillips S. The value of testing for penicillin allergy in an inpatient population: analysis of the subsequent patient management. Allergy Asthma Proc 2000;21:297 9. DeFonseca MA. Adverse reaction to amoxicillin: a case report. Pediatr Dent 2000;22:401 4. Ebersole JL, Cappelli D. Acute-phase reactants in infections and inflammatory diseases. Periodontology 2000;23:19 49. Bancescu G, Skaug N, Dumitriu S, et al. Antimicrobial susceptibility of some streptococci strains of anginosus group isolated from oral and maxillofacial infections. Roum Arch Microbiol Immunol 1999;58:57 63. Kasten MJ. Clindamycin, metronidazole, and chloramphenicol. Mayo Clin Proc 1999;74:825 33. Fisman DN, Kaye KM. Once-daily dosing of aminoglycoside antibiotics. Infect Dis Clin North Am 2001;14:475 87. Hersh EV. Adverse drug interactions in dental practice: interactions involving antibiotics. Part II. J Am Dent Assoc 1999;130:236 51. Marchese A, Schito GC. The oxazolidinones as a new family of antimicrobial agent. Clin Microbiol Infect 2001;7(Suppl 4):66 74. Felmingham D. Microbiological profile of telithromycin, the first ketolide antimicrobial. Clin Microbiol Infect 2001;7(Suppl 3):2 10. Linden PK. Treatment options for vancomycin-resistant enterococcal infections. Drugs 2002;62:425 41. Brook I, Frazier EH, Gher Jr ME. Microbiology of periapical abscesses and associated maxillary sinusitis. J Periodontol 1996;67:608 10. Williams Jr JW, Aguilar C, Makela M, et al. Antibiotics for acute maxillary sinusitis. Cochrane Library 2000;3:1 51. Bergman SA. Fungal, viral, and protozoal infections of the maxillofacial region. In: Topazian RG, Goldberg MH, Hupp JR, editors. Oral and maxillofacial infections. 4th edition. Philadelphia: W.B. Saunders Co.; 2002. p. 243 78.

Summary Antibiotic selection remains as much of an art as it is a science. It requires the integration of many factors that are host specific, pharmacologic, and even geographic. Much more research is necessary in this field to solve the current problems with the need for more timely culture and sensitivity results, increasing antibiotic resistance, and best practices in antibiotic usage.
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[14]

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References
[1] Flynn TR. Update on the antibiotic therapy of oral and maxillofacial infections. In: Piecuch JF, editor. Oral and maxillofacial surgery knowledge update 2001. Rosemont (IL): American Association of Oral and Maxillofacial Surgeons; 2001. p. 23 50. [2] Molinari JA. Antibiotic resistance and maxillofacial pathogens: emerging treatment issues. J California Dental Assoc 1999;27:386 92. [3] Neu HC. Emerging trends in antimicrobial resistance in surgical infections: a review. Eur J Surg Suppl 1994; 573:7 18. [4] Kulekei G, Inane D, Kocak H, et al. Bacteriology of dentoalveolar abscesses in patients who have received empirical antibiotic therapy. Clin Infect Dis Suppl 1996;1:S51 3. [5] Kuriyama T, Nakagawa K, Karasawa T, et al. Past administration of b-lactam antibiotics and increase in the emergence of b-lactamase-producing bacteria in patients with orofacial odontogenic infections. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2000;89:186 92. [6] Haug RH, Hoffman MJ, Indresano AT. An epidemiologic and anatomic survey of odontogenic infections. J Oral Maxillofac Surg 1991;49:976 80. [7] Storoe W, Haug RH, Lillich TT. The changing face of odontogenic infections. J Oral Maxillofac Surg 2001; 59:739 48. [8] Flynn TR, Wiltz M, Adamo AK, et al. Predicting length of hospital stay and penicillin failure in severe odontogenic infections. Int J Oral Maxillofac Surg 1999;28(Suppl 1):48. [9] Brook I. Microbiology of common infections in the upper respiratory tract. Prim Care 1998;25:637 47. [10] Doern GV, Ferraro MJ, Brueggemann AB, Ruoff KL. Emergence of high rates of antimicrobial resistance among viridans group streptococci in the United States. Antimicrob Agents Chemother 1996; 40:891 4. [11] Fazakerley MW, McGowan P, Hardy P, Martin MV. A comparative study of cephradine, amoxycillin and phenoxymethylpenicillin in the treatment of acute dentoalveolar infection. Br Dent J 1993;174:359 63. [12] Gilmore WC, Jacobus NV, Gorbach SL, et al. A pro-

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Oral Maxillofacial Surg Clin N Am 15 (2003) 39 49

Diagnostic imaging of maxillofacial infections

Thomas E. Underhill, DDS, MDa,*, Fred J. Laine, MDa,b, John George, BSc
Department of Radiology, Division of Neuroradiology, VCU Health Systems/MCV Hospitals and Physicians, 1250 East Marshall Street, PO 980615, Richmond, VA 23298, USA b Department of Otolaryngology, VCU Health Systems/MCV Hospitals and Physicians, 1250 East Marshall Street, PO 980615, Richmond, VA 23298, USA c Medical Student, 8377 NW 57th Drive, Coral Springs, FL 33067, USA
a

Diagnosis and management of head and neck infections are common clinical challenges for the oral and maxillofacial surgeon. Symptoms, signs, and laboratory data are often suggestive of an infectious or inflammatory process. Given the right clinical conditions, however, several noninfectious conditions can mimic these processes. Based on clinical examination and occasionally laboratory data, the examining surgeon must determine the need for advanced imaging studies. Opinions still vary as to whether computed tomography (CT) or magnetic resonance imaging (MRI) is the best imaging modality for acute neck infections [1 4]. When imaging is needed, it is the authors opinion that the least invasive and least expensive examination that adequately evaluates the patient should be used. When an odontogenic origin (necrotic pulp) is suspected as the source of a localized infection, intraoral films or panoramic radiographs are usually adequate. Ultrasound also has been used in the evaluation of superficial neck infections, especially to determine fluid accumulation, but is not recommended for deep neck infections because it cannot penetrate bone or the airway space. Conventional films still can be used for a preliminary survey, especially of the retropharyngeal space and evaluation of the airway. Although most maxillofacial infections remain localized and are managed successfully by antibiotic therapy or surgical intervention, serious and potentially life-threatening complications, such as airway

compromise [5], cavernous sinus thrombosis [4,6], cerebral empyema [4,7], internal jugular vein thrombophlebitis [8], Ludwigs angina [9], or necrotizing fasciitis [10 12], can occur. This article discusses mainly CT and MRI as they relate to localization of infectious processes and the evaluation of abscess cavities.

Techniques Computed tomography Traditional or single slice acquisition CT uses a gantry that houses an x-ray tube and a row of detectors. Images are produced by data collected from the detectors after a 360 rotation. After each tomographic image the patient table is moved and another image obtained. A time delay of 10 to 15 seconds between each slice is necessary. Spiral CT involves the simultaneous movement of the patient table and the x-ray tube, which results in a volume acquisition of data from which individual tomographic images can be reconstructed. Because a volume data set is acquired, excellent multiplanar reformations are possible when using thin image slices (3 mm or less). Picture archival communication systems are becoming more common in hospitals. Some of these systems allow viewing multiplanar reformation in any plane desired, not just the standard sagittal and coronal planes. In the past, CT reformation programs, such as DentaScan, were recommended for true crosssectional images of the jaws, not only for implant planning but also for evaluation of tumors, osteomyelitis, or other pathologic conditions [13,14]. Picture

* Corresponding author. E-mail address: tunderhill@attbi.com (T.E. Underhill).

1042-3699/03/$ see front matter D 2003, Elsevier Science (USA). All rights reserved. PII: S 1 0 4 2 - 3 6 9 9 ( 0 2 ) 0 0 0 7 5 - 4

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archival communication systems with multiplanar reformation capability obviate the need for such programs in the evaluation of pathologic conditions. Other advantages of spiral CT in applications to the head and neck include one breath hold, which minimizes artifacts because of swallowing, and improved vascular opacification and lesion enhancement using a smaller contrast bolus [15]. Multidetector CT is yet another improvement over spiral CT. Whereas spiral CT uses a single row of detectors, multidetector CT uses a matrix of detectors that allows the acquisition of multiple tomographic images per revolution, which greatly increases the speed of imaging. Accuracy of computed tomography Deep neck infections in adult patients Miller et al [16] performed a prospective study that compared the efficacy of contrast-enhanced CT (CECT) to clinical examination in detecting the presence of a drainable fluid collection in suspected deep neck infections. The accuracy (frequency of a test to diagnosis correctly the presence or absence of disease)

of clinical examination alone in identifying a drainable collection was 63%, the sensitivity (ability of a test to identify correctly a disease when it is truly present) was 55%, and the specificity (ability of a test to identify correctly the absence of disease when it is truly absent) was 73%. The accuracy of CECT alone was 77%, the sensitivity was 95%, and the specificity 53%. When CECT and clinical examination were combined, the accuracy in identifying a drainable collection was 89%, the sensitivity was 95%, and the specificity was 80% [16]. Deep neck infections in pediatric patients Nagy et al [3] compared the sensitivity of lateral neck films and CECT in evaluating children with a high index of suspicion for a deep neck infection, based on clinical presentation. More than 25% of lateral neck radiographs were unable to determine the presence of a deep neck infection, whereas CECT had a sensitivity of 100%. They concluded that CECT is the study of choice in the evaluation of children strongly suspected of having a deep neck infection based on clinical presentation [3].

Fig. 1. (A) Chronic dentoalveolar granuloma. Axial T1-weighted MRI without contrast shows the normal bright signal from fatty marrow in the maxillary alveolar ridge. There is a focal area with low signal surrounding the maxillary canine root (arrow), which indicates replacement of normal fatty marrow by either a neoplastic or inflammatory process. (B) Parasagittal T1-weighted MRI with contrast and fat saturation demonstrates enhancement of tissue surrounding the root of the right maxillary canine. The uniform enhancement indicates a granuloma rather than an abscess, which would exhibit only peripheral enhancement.

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Wetmore et al [17] evaluated the use of CT in children with deep neck infections. CECT demonstrated an accuracy of 92% for detection of an abscess confirmed by surgery. In children with superficial neck infections, only 24% of those who were treated surgically showed definite CT evidence of an abscess. The decision to perform surgery was based on clinical findings, such as palpable fluctuance and skin changes [17]. As with adults, the combination of clinical examination and radiographic data yielded the best results. NewTom A new development in maxillofacial imaging is the NewTom (Schick NIM S.r.l., Verona, Italy). This machine performs axial panoramic and multiplanar imaging of the maxillofacial region and produces images similar to those acquired by the DentaScan (General Electric Medical Systems, Milwaukee, WI) as viewed in bone windows. Image acquisition by the NewTom is fundamentally different from conventional CT. The images are derived from a three-dimensional data set acquired from multiple planar images (ie, multiple digital projections), which renders excellent high tissue contrast resolution (bony detail). Because of this ability, the NewTom is excellent for detection of lytic bony lesions; however, it lacks the ability to demonstrate the low tissue contrast resolution needed to detect subtle soft tissue changes as seen with cellulitis, soft tissue abscess, cerebral empyema, or retropharyngeal fluid/edema. The lower neck cannot be imaged. For these reasons, conventional CECT is recommended for the evaluation of head and neck inflammatory processes. Magnetic resonance imaging A disadvantage of MRI is the lack of availability. Most MRI units are tightly booked with long waiting periods for appointments. Even a 1-day wait is not acceptable for a patient with a potentially lifethreatening head and neck infection. Over the years, MRI scanners have become more numerous and are more available for emergent scans. Some imaging centers have time reserved each day for emergency scanning, and some large medical centers have MR scanners in the emergency department. Even with emergency time reserved, however, maxillofacial and neck infections would have a lower priority for the MRI scanner than examinations to evaluate for acute spinal cord compression or acute stroke. An MRI is obtained by placing the patient in a strong and uniform magnetic field. Smaller gradient

coils distort the uniform field, which causes only those hydrogen protons in a certain plane to resonate when excited by a specific radiofrequency. These excited protons emit a signal that, when analyzed by a twodimensional Fourier, is transformed into an image. Accuracy of magnetic resonance imaging Munoz et al [2] prospectively evaluated 47 patients with neck infections. Each patient underwent CT and MRI with contrast of the area of interest using similar slice thickness. MRI was superior to CT in regard to lesion conspicuity, number of anatomic spaces involved, extension, and source. CT was superior to

Fig. 2. Retropharyngeal abscess. Axial image of CT scan with contrast obtained at the level of the maxilla. A 1.5-cm retropharyngeal abscess is present (large arrow). This is seen as a fluid density collection surround by a rim of enhancing tissue. Notice that the density or attenuation of this fluid collection is the same as the cerebrospinal fluid that surrounds the cord. A second area of fluid density, which is not as well defined (smaller arrows), is seen in the lateral neck. This represents a multiloculated abscess. Notice that normal fat on the soft tissue windows is dark. There is an area of edema or infiltration in the fat (stars). This appearance is referred to as dirty fat. Compared to the right sternocleidomastoid muscle (SCM), the left sternocleidomastoid muscle cannot be distinguished from the surrounding inflammatory process. The left jugular vein is compressed and is not visualized. The right jugular vein and the right carotid artery are in their normal location (J,C). The left carotid artery (c) is displaced anteriorly by the inflammatory process.

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MRI in the detection of intralesional gas and calcium and showed fewer motion artifacts. On this basis, MRI was considered superior to CT in the initial evaluation of neck infections. These findings suggest that MRI should be used as the first and perhaps only modality to evaluate patients initially with neck infections [2].

whereas muscle decreases in attenuation on noncontrasted CT [18]. Increased blood flow occurs in inflamed tissue. After administration of iodinated contrast medium, areas of increased blood flow demonstrate enhancement. Intravenous iodinated contrast is indicated for CT evaluation of a patient with suspected cellulitis or abscess. Magnetic resonance imaging The MRI parameters can be manipulated to produce several different appearances. As an oversimplification, T1-weighted images produce images in which fat is bright and fluid such as cerebrospinal fluid is dark. The presence or absence of the bright signal from fat can help detect pathologic processes. Normally fatty marrow is bright. Any pathologic process, such as metastatic disease or infection, that has replaced the normal fatty marrow appears abnormally dark (Fig. 1A). Gadolinium contrast medium is

Interpretation Computed tomography Computed tomography uses the differences in attenuation of the x-ray beam by different tissues to form an image. The lowest attenuation occurs in air, and the highest attenuation occurs in bone, dentin, enamel, or metal. Fat has a lower attenuation than water, which in turn has lower attenuation than muscle. When edema occurs, there is an increase in water content. Edematous fat increases in attenuation,

Fig. 3. (A) Subperiosteal abscess. Axial CT image with contrast at the level of the inferior border of the mandible in a 43-year-old man with painful swelling of the neck. There is a fluid mass density surrounding the angle of the mandible and extending along the inferior border (arrows). This abnormal fluid collection extends on both sides of the mandible. The geniohyoid muscle (asterisks) is displaced medially. (B) Bone window demonstrates a small periapical radiolucency around the distal root of the mandibular right second molar. The next inferior image demonstrates a small break in the cortex. The source of the large subperiosteal abscess was from the necrotic second molar.

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used only with T1-weighted images. When concentrated in tissues, gadolinium contrast medium demonstrates an increase in signal intensity. Unlike imaging the brain, where (usually) no fat is located, in maxillofacial, orbital, or neck imaging, fat saturation is critical when using gadolinium contrast medium. Fat saturation makes the normal fat dark, and normal and abnormal enhancement is much more conspicuous (Fig. 1B). When evaluating a contrasted T1-weighted image of the head and neck, there should be an avid enhancement of the nasal mucosa. If it does not enhance, there is a problem with the contrast bolus and pathologic processes also would fail to enhance. This occurrence could lead to a falsenegative examination result. The ocular muscles normally enhance, but the larger muscles, such as paraspinal muscles or muscles of mastication, do not enhance. With T2-weighted images, the juicier or squishier [19] the tissue, the brighter it is. Stationary fluid,

such as cerebrospinal fluid, appears bright. Edematous or inflamed tissues demonstrate increased signal intensity, especially when fat saturation is used.

Pathology Odontogenic infections In a retrospective study of 210 patients with neck infections, the most common cause was dental infection (43%). Dental infection was the cause of 76% of Ludwigs angina [20]. In patients with deep neck space infections, airway compromise was more frequent and severe in odontogenic than in nonodontogenic deep neck space infections. The parapharyngeal, submandibular, and masticator spaces are more vulnerable in odontogenic deep neck space infections than in nonodontogenic infections. The predilection for certain spaces of the neck to be involved in

Fig. 4. (A) Septic thrombophlebitis. Axial CT examination with contrast performed at the level of the inferior border of the mandible in a 31-year-old woman with a painful swollen left neck. There is an area of low attenuation surrounded by avid enhancement (arrows). Compared to Fig. 1, this has the appearance of an abscess, but the hypodensity extends in a craniocaudal dimension from the skull base to the level of the hyoid bone. This represents a low-density thrombus surrounded by enhancing vasovasorum. Note the normally enhancing jugular vein on the right (JV ). (B) Axial enhanced CT scan at the level of the thyroid gland (T ). Note the normally enhancing jugular vein at this level on the left and the normal carotid arteries (C ).

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odontogenic deep neck space infection originates from the intimate relationship of the mandibular molars to the adjacent deep neck spaces [5] (Fig. 2). Retropharyngeal abscess versus cellulitis On CT, cellulitis appears as soft tissue swelling, increased density of surrounding fat, enhancement of involved muscles, and obliteration of fat planes [3,5]. An abscess is considered to be present if there is a low (fluid) density area with a peripheral rim of enhancement (Fig. 3) [3,5]. Symptoms include fever, neck swelling, sore throat, dysphasia, and cervical rigidity. Sometimes small children present with nonspecific symptoms [21]. Children younger than 5 years who present with poor oral intake, high fever, drooling, and trismus should be suspected of having a peritonsillar abscess. A CT scan of the neck is usually required to confirm a suspected diagnosis [22]. Recurrent deep neck infections Most deep neck infections are the result of suppurative adenitis. The location of the primary focus is usually from the mucosa of the upper aerodigestive tract or from an odontogenic source. Recurrence in these situations is unusual. Less commonly, congenital lesions can present as deep neck infections, and recurrences are common. In patients with recurrence of deep neck infections, the possibility of an underlying congenital lesion, such as branchial cleft cyst, infected lymphangioma, or thyroglossal duct cyst, should be considered [23]. Nontuberculous and tuberculous mycobacteria infection Nontuberculous mycobacteria infection most often presents in children as an asymmetric adenopathy with contiguous low-density ring-enhancing masses, minimal or absent inflammatory stranding of the subcutaneous fat, and cutaneous extension

Fig. 6. Periorbital abscess. Coronal CT scan with contrast in a 14-year-old boy who experienced orbital swelling and pain. Notice the subperiosteal fluid collection adjacent to the orbital roof on the left (arrows). There is opacification of the maxillary sinuses and left ethmoid sinuses. Also notice is the periorbital soft tissue swelling. The left medial rectus (asterisk) is displaced laterally from the lamina propria. The cause for this orbital abscess was spread of infection from ethmoid sinusitis.

[24]. Cervical tuberculous lymphadenitis is also an important cause of a neck mass in many countries. Multilocular low densities with peripheral enhancement and a large confluent low density with a lesser degree of fat plane obliteration than a pyogenic abscess are suggestive features of advanced cervical tuberculous lymphadenitis. Septic thrombophlebitis Septic thrombophlebitis of the jugular vein (Lemierres syndrome) is an uncommon cause of painful neck swelling [8]. On CT, a thrombus within the jugular vein appears as an area of low attenuation with peripheral enhancement (Fig. 4), which easily could be mistaken for abscess. Normal enhancing vascular structures of the neck must be identified

Fig. 5. (A) Sialadenitis with abscess formation. The patient presented with painful swelling in the left floor of the mouth. Clinically, an odontogenic source of infection was suspected. Axial CT scan performed at the level of the submandibular gland showed multiple small locules of gas present as low attenuation or dark areas (arrows). Notice that gas has extended into the submandibular space, buccal space, and parapharyngeal space. Compare to the normal submandibular gland (SMG) on the right. (B) Axial CT image performed superior to the submandibular gland at the level of the floor of the mouth. Note the presence of gas in the fascial plane of the floor of the mouth, with some crossing the midline. The gas is the product of gas-producing organisms. The appearance is concerning for early development of Ludwigs angina. (C) Axial CT scan performed at the level of the maxillary sinuses. Gas in the parapharyngeal space (black arrow) has tracked up toward the skull base. There is also a large amount of gas in the buccal space (white arrow), anterior to the left masticator space.

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for abscess/cellulitis is recommended. Frequently, inflammatory processes in the salivary glands present as a mass and clinically are difficult to distinguish from malignancy. In such cases, contrasted CT or MRI can be used to determine if the mass is intrinsic or extrinsic to the gland [25]. Acute suppurative bacterial sialadenitis is associated with painful, swollen glands. The parotid gland is most commonly involved [1]. Salivary calculi are best seen on CT and appear as a high-density mass along the course of the duct. CT also demonstrates gas in the tissue better than MRI [5].
Fig. 7. Potts puffy tumor. A CT image with contrast at the level of the frontal sinus of a 14-year-old boy with painful frontal swelling. A subperiosteal abscess is present (asterisk). There is erosion of the inner wall of the frontal sinus and abnormal dural enhancement (arrow). A bony sequestrum is present.

Necrotizing fasciitis Craniocervical necrotizing fasciitis is a rapidly progressive, severe bacterial infection of the superficial fascial planes of the head and neck. Group A beta-hemolytic Streptococcus, Staphylococcus aureus, and obligate anaerobic bacteria are commonly involved pathogens. The disease usually results from a dental source or facial trauma. Extensive fascial necrosis and severe systemic toxicity are common manifestations of craniocervical necrotizing fasciitis. Most patients have an underlying medical problem that created an immunocompromised state, usually diabetes mellitus or chronic alcoholism [26]. Constant CT features of necrotizing fasciitis are diffuse cellulitis, diffuse enhancement or thickening of the superficial and deep

and traced in the craniocaudal direction. Tracing of other neck structures also is important. Necrotic lymph nodes also can mimic cervical abscesses on CT scans and result in negative surgical findings [22]. Sialadenitis In general, CT has supplanted sialography for the evaluation of inflammatory processes in the salivary glands (Fig. 5). If salivary calculi are suspected as the cause of an inflammatory process, a noncontrasted CT to detect calculi followed by contrasted CT to evaluate

Fig. 8. (A) Chronic fungal sinusitis. Axial CT image without contrast at the level of the orbits. Notice the high-density material in the ethmoid sinuses (asterisks). This is a chronic process and has caused expansion of the ethmoid sinuses, which resulted in hypertelorism. The fungal sinusitis also caused erosion of the clivus (arrows). The high-density material in the ethmoid sinus is characteristic of fungal sinusitis. The surrounding lower density material represents mucosa. (B) Axial T2-weighted MRI at the same level as (A). Notice the signal void (asterisk), which corresponds to the high-density material seen on the CT examination. This signal void could be mistaken for normal, aerated ethmoid sinus. The lack of signal is highly characteristic of fungal sinusitis.

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cervical fasciae (fasciitis), enhancement and thickening of the neck muscles (myositis), and fluid collections in multiple neck compartments. Sinusitis The paranasal sinuses are a common source of maxillofacial infection. Occasionally, paranasal sinusitis can have devastating sequelae from involvement of the orbits (Fig. 6), cavernous sinuses, or brain parenchyma [4]. Orbital spread is most commonly secondary to bacterial or fungal sinus infections. Optic neuritis that arises from such infections requires prompt recognition and aggressive treatment if vision is to be preserved [27]. Intracranial empyema secondary to sinusitis is generally a disease of young adult men without an antecedent history of sinus disease [7]. The dominant clinical features are fever, intense headache, and facial swelling. The patient

should receive an immediate noncontrasted and contrasted head CT and MRI. If CT is used, additional thin cuts (3 mm or less) in the axial and coronal planes of the paranasal sinuses should be obtained. Because of the late development of the frontal sinuses, frontal sinus infection in children is rare. When present, it can lead to osteomyelitis associated with forehead swelling (Potts puffy tumor) (Fig. 7). Early diagnosis and active treatment prevent progression to life-threatening intracranial spread [28]. In fungal disease of the paranasal sinuses, expansion of the bony walls occurs by increased mucus secretion and fungal growth (Fig. 8). The fungus is confined to the lumen and does not invade the tissues. Within the lumen of the sinus, fungus appears as areas of high attenuation on the CT scan because of the presence of calcium and traces of metallic elements. On MRI, the fungus-filled lumen appears as an area of low signal intensity because of

Fig. 9. (A) Invasive fungal sinusitis. Coronal nonenhanced T1-weighted MRI in a 33-year-old immunocompromised man. There is an oroantral fistula in the region where maxillary teeth were removed because of loss of all bony support. On removal of teeth, there was no normal tissue with which to close the sinus opening. Abnormal tissue along the left infraorbital rim has eroded the bone and replaced the normal bright orbital fat (asterisk). (B) Sagittal postcontrast T1-weighted MRI with fat saturation shows the oroantral fistula (large arrows). Abnormal enhancing tissue extends back to the orbital apex along the expected route of the infraorbital nerve (small arrows). Not imaged on this slice is the abnormal enhancing tissue that extends into the cavernous sinus. This is an example of perineural spread of a fungus infection.

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T.E. Underhill et al / Oral Maxillofacial Surg Clin N Am 15 (2003) 3949 antibiotic and anticoagulation therapy: a case report. Angiology 2000;51:173 7. Nguyen VD, Potter JL, Hersh-Schick MR. Ludwig angina: an uncommon and potentially lethal neck infection. AJNR Am J Neuroradiol 1992;13: 215 9. Haraden BM, Zwemer Jr FL. Descending necrotizing mediastinitis: complication of a simple dental infection. Ann Emerg Med 1997;20:683 6. Raboso E, Llavero MT, Rosell A, Martinez-Vidal A. Craniofacial necrotizing fasciitis secondary to sinusitis. J Laryngol Otol 1998;112:371 2. Tsunoda R, Suda S, Fukaya T, Saito K. Descending necrotizing mediastinitis caused by an odontogenic infection: a case report. J Oral Maxillofac Surg 2000;58: 240 2. Abrahams JJ, Glassberg RM. Dental disease: a frequently unrecognized cause of maxillary sinus abnormalities? AJR Am J Roentgenol 1996;166: 1219 23. King JM, Caldarelli DD, Petasnick JP. DentaScan: a new diagnostic method for evaluating mandibular and maxillary pathology. Laryngoscope 1992;102: 379 87. Heiken J, Brink J, Vannier M. Spiral (helical) CT. Radiology 1993;189:647 56. Miller WD, Furst IM, Sandor GK, Keller MA. A prospective, blinded comparison of clinical examination and computed tomography in deep neck infections. Laryngoscope 1999;109:1873 9. Wetmore RF, Mahboubi S, Soyupak SK. Computed tomography in the evaluation of pediatric neck infections. Otolaryngol Head Neck Surg 1998;119: 624 7. Ariti E, Moriguchi S, Kuroki T, et al. Computed tomography of maxillofacial infections. Dentomaxillofac Radiol 1991;20:147 51. Elster AD, Burdette JH. Introduction to nuclear magnetic resonance. In: Questions and answers in magnetic resonance imaging. St Louis: Mosby; 2001. p. 37. Parhiscar A, Har-El G. Deep neck abscess: a retrospective review of 210 cases. Ann Otol Rhinol Laryngol 2001;110:1051 4. Chan WL, Fernandes VB, Carolan MG. Retropharyngeal abscess on a Ga-67 scan: a case report. Clin Nucl Med 1999;24:942 4. Friedman NR, Mitchell RB, Pereira KD, Younis RT, Lazar RH. Peritonsillar abscess in early childhood: presentation and management. Arch Otolaryngol Head Neck Surg 1997;123:630 2. Nusbaum AO, Som PM, Rothschild MA, Shugar JM. Recurrence of a deep neck infection: a clinical indication of an underlying congenital lesion. Arch Otolaryngol Head Neck Surg 1999;125:1379 82. Robson CD, Hazra R, Barnes PD, Robertson RL, Jones D, Husson RN. Nontuberculous mycobacterial infection of the head and neck in immunocompetent children: CT and MR findings. AJNR Am J Neuroradiol 1999;20:1829 35.

the presence of ferromagnetic elements (Fig. 8) [29]. Invasive fungal sinusitis involves destruction of the bony walls and spread into surrounding structures (Fig. 9) [29].

[9]

Summary Computed tomography and MRI are quick and accurate methods for the evaluation of complex head and neck infections. Because of new spiral CT scanners and picture archival communication systems, multiplanar imaging is common with CT. CT has supplanted sialography for the evaluation of inflammatory processes in the salivary glands. In the search for a drainable abscess collection, MRI is superior to CT in regard to lesion conspicuity and determining the number of anatomic spaces involved and the degree of extension and the source. MRI is also superior to CT for detection of intracranial extension of infection. CT is superior to MRI in the detection of intralesional gas, calcifications, and cortical destruction.

[10]

[11]

[12]

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[15] [16]

References
[1] Ginsberg LE. Inflammatory and infectious lesions of the neck. Semin Ultrasound CT MR 1997;18: 205 219. [2] Munoz A, Castillo M, Melchor MA, Gutierrez RJ. Acute neck infections: prospective comparison between CT and MRI in 47 patients. Comput Assist Tomogr 2001;25:733 41. [3] Nagy M, Backstrom J. Comparison of the sensitivity of lateral neck radiographs and computed tomography scanning in pediatric deep-neck infections. Laryngoscope 1999;109:775 9. [4] Sahjpaul RL, Lee DH. Infratentorial subdural empyema, pituitary abscess, and septic cavernous sinus thrombophlebitis secondary to paranasal sinusitis: case report. Neurosurgery 1999;44:864 6. [5] Kim HJ, Park ED, Kim JH, Hwang EG, Chung SHJ. Odontogenic versus nonodontogenic deep neck space infections: CT manifestations. Comput Assist Tomogr 1997;21:202 8. [6] Feldman DP, Picerno NA, Porubsky ES. Cavernous sinus thrombosis complicating odontogenic parapharyngeal space neck abscess: a case report and discussion. Otolaryngol Head Neck Surg 2000;123: 744 5. [7] Fenton JE, Smyth DA, Viani LG, Walsh MA. Sinogenic brain abscess. Am J Rhinol 1999;13:299 302. [8] Nakamura S, Sadoshima S, Doi Y, Yoshioka M, Yamashita S, Gotoh H, et al. Internal jugular vein thrombosis, Lemierres syndrome, oropharyngeal infection with [17]

[18]

[19]

[20]

[21]

[22]

[23]

[24]

T.E. Underhill et al / Oral Maxillofacial Surg Clin N Am 15 (2003) 3949 [25] Conway W, Laine F, Blinder R. Newer diagnostic imaging techniques. Oral Maxillofacial Surg Clin N Am 1991;3:259 72. [26] Henrich DE, Smith TL, Shockley WW. Fatal craniocervical necrotizing fasciitis in an immunocompetent patient: a case report and literature review. Head Neck 1995;17:351 7. [27] Osguthorpe JD, Hochman M. Inflammatory sinus dis-

49

eases affecting the orbit. Otolaryngol Clin North Am 1993;26:657 71. [28] Hore I, Mitchell RB, Radcliffe G, De Casso, Moxo C. Potts puffy tumour: a rare cause of forehead swelling in a child. Int J Clin Pract 2000;54:267 8. [29] Michaels L, Lloyd G, Phelps P. Origin and spread of allergic fungal disease of the nose and paranasal sinuses. Clin Otolaryngol 2000;25:518 25.

Oral Maxillofacial Surg Clin N Am 15 (2003) 51 58

Diagnosis and treatment of cervicofacial actinomycosis

Morton H. Goldberg, DMD, MDa,b,*
b a Department of Oral and Maxillofacial Surgery, University of Connecticut, USA Department of Dentistry, Hartford Hospital, Seymour Street, Hartford, CT 06107, USA

Actinomycosis is an uncommon and frequently misdiagnosed infection of the cervicofacial region that may be acute or indolent. The term actinomycosis derives from the Greek aktino (ray) and mykos (fungus). Historically, Langenback may have been the first to describe the disease in humans (1848), although it had been considered to be a sarcoma in cattle 20 years earlier by Leblanc. Bollinger (1870) coined the term lumpy jaw in its bovine form, whereas Harz (1877) described the appearance of a ray-like microorganism, which he named Actinomycoses bovis. In 1878, Israel and Ponfick observed and described sulfur granules in human disease, and in 1891, Israel and Wolf isolated the anaerobic filamentous organism from humans. In 1898, the organism found in humans was named Actinomycoses israelii, and by the 1940s further research had confirmed that whereas A. bovis was responsible for lumpy jaw in cattle, A. israelii was the etiologic agent of human disease [1 3]. Originally considered to be a fungus (mykos) because of its slow growth and filamentous appearance, it is currently generally accepted that Actinomyces are bacteria and are taxonomically classified accordingly as members of the order Actinomycetales and the family Actinomycetacae. Other orders classified as Actinomycetales include Mycobacteriaceae and Nocardiaceae. Evidence that Actinomyces are bacteria include their filaments, which are narrower than the hyphae of fungi, their morphology, including bacillary forms,

and their reproduction by typical bacterial fission rather than by budding or by spores. Actinomyces are anaerobic (whereas fungi are aerobic) and lack the nuclear membrane of fungi and yeasts. Actinomyces are destroyed by antibacterial agents such as penicillin and erythromycin but are not affected by antifungal medications, such as amphotericin B (see box 1) [2,3].

Box 1. Taxonomy of the order Actinomycetales [2,38] Class: Schizomycetes Order: Actinomycetales Family: Actinomycetes Genus: Actinomyces * Species: A. israelii A. neerlundi A. viscosus A. odontolyticus A. meyerii A. bovis Family: Mycobacteriaceae Genus: Mycobacterium Family: Nocardiaceae Genus: Nocardia * A. israelii is the etiologic organism of most human actinomycosis, but all species except A. bovis can be commensals in the normal oropharyngeal flora. Human disease is occasionally reported with species other than A. israeii [4].

* Department of Dentistry, Hartford Hospital, 928 Farmington Avenue, West Hartford, CT 06107.

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Microbiology and natural history Actinomyces are endogenous to the human oral cavity and cervicofacial region and are not restricted to soil or soil contaminants as previously hypothesized. The organism is a human commensal, but its presence results only in a low incidence of clinical infection, even when tissue undergoes trauma, such as tooth extraction. This low incidence of infection, despite the high incidence of oral trauma, argues for the organisms minimal potential for invasion and its lack of virulence. Actinomyces require a polymicrobial ecosystem and tissue trauma to proliferate and create clinically evident infection. These microflora work synergistically to destroy vascularized aerobic tissue and create poorly oxygenated granulation tissue, which becomes an environment that supports the growth and multiplication of Actinomyces. The severity and chronicity of tissue trauma are factors that can enhance the development of anaerobic growth by these organisms, which normally exhibit low virulence. Other oral bacterial species involved in this ecosystem include Actinobacillus, Actinomycetencomitans (frequent), Bacteroides, Eikenella, and Fusobacterium (see box 2). Actinomyces have been isolated from teeth, extraction sites, periodontal infections, jaw fractures, postoperative surgical sites, salivary glands, the tongue, tonsils, and other areas of the orofacial and neck region (see box 3).

Box 3. Reported diagnostic sites of head and neck infection by Actinomycoses [2,11,16,26 32,36,37,39 42] Dentigerous cyst Dental caries Dental plaque Dental pulp Ear (external canal and middle ear) Eye (lids, conjunctiva, lacrimal gland) Fascial spaces (submandibular, submental, temporal, masseteric, buccal) Gingiva Larynx Lip Masseter muscle, mandible, maxilla (exodontia, fracture) Osteotomy site Palate Parotid gland Scalp Sinuses Temporal bone Temporomandibular joint Thyroid Tongue Tonsils Tooth (extraction site) Trachea

Histopathology Morphologically, Actinomyces may be filamentous or diptheroidal. If diptheroidal, they may resemble nonpathogenic diptheroids such as Propionibacteria. The thin filaments of Actinomyces may be observed to have V or Y branching and may appear in bacillary or coccoid forms. Sulfur granules are macroscopic yellowish grains of firm consistency that are visible to the eye when on a gauze sponge. They vary in size from 100 to 1000 u in diameter and are visible by light microscopy. When stained with methylene blue, Grams stain, periodic acid-Schiff, or silver methenamine, gram-positive branching mycelia and filaments are visible (Figs. 1,2). The filaments may be mistaken for streptococci. Granules may not always be present or may be few in number, which necessitates multiple microscopic sections of sinus tracts or abscess walls for their identification. One study found only one to three granules in 56% of specimens examined and none at all in seven cases, which were confirmed by culture [5]. Although granule formation is common in A. israelii infection, it is not observed with A. odontolyticus, a noninvader of tissue. The presence of

Box 2. Bacterial ecosystem associated with Actinomycoses infection [1,11,33 35] Actinobacillus actinomycetemcomitas Bacteroides species (pigmented) Capnocytophaga species Eikenella corrodens Fusobacterium species Haemophilus species Peptostreptococcus Porphymonas Streptococcus Staphylococcus gingivalis

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Fig. 1. Low magnification of sulfur granule. Note amorphous center and peripheral rosette of filaments. (Courtesy of Dr. Ellen Eisenberg, University of Connecticut.)

granules in exudate from an infection in the cervicofacial region, although highly suggestive of actinomycosis, is not, of itself, pathognomonic, because granules may be produced by Actinobacillus ligniersi and some pathogenic mycoses, such as Sporotrichum and Phialophore [6], and are found in nocardial infections. Although fluorescent antibody staining may contribute to an accurate diagnosis, confirmation by culture is necessary.

Microscopic examination of an excised or biopsied mass of tissue can reveal acute or chronic inflammation, with loculation of neutrophils, lymphocytes, plasma cells, macrophages, and dense fibrous tissue. The number of plasma cells increases with the chronicity of the lesion. Fibrosis may be mild in early infections, whereas chronicity is associated with intense avascular fibrosis. This tissue is believed to maintain the anaerobic environment that

Fig. 2. Higher magnification of edge of sulfur granule, which demonstrates individual and branching filaments. (Courtesy of Dr. Mark Fletcher, Hartford Hospital.)

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stimulates growth of the actinomyces organisms and inhibits antibiotic penetration [7,8].

Clinical manifestations Actinomycosis is an uncommon disease. It is possible for an oral maxillofacial surgeon to have a lengthy career and never encounter the disease. It may occur at any age, however, most commonly between age 30 and 60. Cases among men outnumber cases that involve women 4:1. In the pediatric population, actinomycosis is rare, and a low level of suspicion may cause diagnostic confusion and delay in treatment [9]. The disease may present as either an acute or chronic form. The less common acute form manifests as a fluctuant swelling that resembles or mimics an acute odontogenic infection. It may be painful and associated with temperature elevation, and it can spread rapidly through tissue [10]. More common, however, is the chronic lesion of actinomycosis, which presents as a slowly enlarging, progressive, inflammatory mass that may or may not be painful and usually is associated with an afebrile course or minimal elevation of temperature. The chronic or chronic-recurring form may develop or progress or recur over weeks, months, or even years, during which time lethargy may be present, but patients do not typically complain of feeling ill. Sedimentation rates tend to remain low or normal, whereas leukocyte counts may be normal or minimally elevated. Reddish-brown discoloration of the facial skin overlying the jaw is common, and recurrent episodes of suppuration result in firm or fluctuant irregular skin masses; hence the historic description of the infection as lumpy jaw. Spread of the infection is independent of lymphatic channels or fascial planes. Ultimately, sinus tracts develop deep in the lesion, burrowing through the dense fibrosis and discharging onto the surface of the skin (or mucosa). These sinus tracts may persist or close, or new tracts may form. A pattern of remission and exacerbation may characterize the disease, especially if the diagnosis remains obscure and short-term episodic antibiotic therapy is performed [2,11,12]. A primary actinomycotic bone infection is uncommon but may occur in up to 12% of cases, because osseous invasion and destruction may result from spread of the infection from adjacent soft tissues, extraction sites, or fractures sites. Such infections occur more commonly in the mandible than the maxilla (4:1) [13 16] (see box 4). Periostitis with evidence of periosteal elevation may be the earliest

radiographic finding. True actinomycotic osteomyelitis may demonstrate imaging evidence of cortical erosion or localized lytic destruction in the midst of increased bone density. Sinus tracts may develop from the bone to the surface. Radiographically, actinomycotic osteomyelitis may be diagnostically interpreted as suppurative osteomyelitis or neoplasm.

Box 4. Differential diagnosis of osteolytic lesions of the jaws associated with lumpy jaw or sinus tracts Infection:  Pyogenic osteomyelitis  Periapical infection  Tuberculosis  Nocardiosis or other fungal infection  Infected hardware Tumor:  Benign bone tumors  Primary or metastatic malignant bone tumors  Gingival carcinoma invading bone

The recovery of Actinomyces and Eikenella from cultures of chronic diffuse sclerosing osteomyelitis by Marx et al suggests that a pathogenic mutalism exists between these organisms and perhaps with Arachnia. This research must be repeated and expanded [17,18]. Although cervicofacial infection may account for 60% of all cases of actinomycosis, other anatomic sites or organ systems may be infected, including the thoracic cavity (15%) and the abdominal cavity (20%), where it may surprise the unsuspecting physician or surgeon. Superficial cutaneous infection and genitourinary tract infection also may occur. Central nervous system infection is uncommon (2%) and can originate by direct extension of cervicofacial infection via the sinuses, orbits, or auditory canals and by perineural pathways [19]. It can gain access to the trigeminal ganglion via the foramen ovale. Meningeal spread may result in diffuse meningitis or brain abscess, and it may be initially misdiagnosed as a tumor. Central nervous system involvement may be the result of hematogenous spread from the oral, pulmonary, abdominal, or pelvic regions. Disseminated hematogenous sepsis is rare but may be fatal. Focal neurologic signs and elevated intracranial pressure should alert the examiner to this possibility. A delay in diagnosis of 2 months or more caries a

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mortality rate of 28%, even when adequate antibiotic therapy is ultimately instituted. The most common diseases occur most frequently; therefore the diagnostician is more likely to be correct when looking for horses rather than uncommon or unlikely zebras. Some diseases masquerade or mimic other diseaseshorses wearing striped pajamas [20]. Actinomycosis that mimics tumors of the maxillary sinus or neural neoplasms is an example of this phenomenon [21,22].

Diagnosis Although history and physical examination are always basic to diagnosis of any disease, the indolent but progressive natural process of actinomycotic infection requires a high index of suspicion of what is often a diagnostic dilemma. With a history of recurrent or late infection after tooth extraction and the presence of one or more sinus tracts not associated with high fever or elevated neutrophil count, actinomycosis should be high on the differential diagnosis list. Radiographs of bone may be helpful in recognizing the extent of the osseous process but are nonspecific for actinomycosis even in the presence of soft tissue swelling and sinus tract. CT and gallium scintigraphy may be useful in differentiating between inflammatory and neoplastic changes. CT may reveal loculations and dense fibrosis, whereas scintigraphy may be useful as a method to determine the efficacy of therapy; however, no single imaging modality is diagnostic. Absolute confirmation of the diagnosis depends on careful culturing of these fastidiously oxygensensitive anaerobes, preferably when the patient has received no antibiotics for 7 to 10 days. If culturing is delayed, improperly performed, or negated by recent or concurrent antibiotic therapy, the diagnosis may remain obscure or uncertain. Culturing may be performed directly from sinus tract drainage, an open biopsy of tissue, or after needle aspiration of the lesion [23]. The clinician must be fastidious in technique to avoid contamination by skin or oral flora and prevent excessive exposure of the specimen to room air. Even with these precautions, recovery of the pathogen is commonly unsuccessful, often in more than 50% of specimens. All cultures should be transported immediately to the microbiology laboratory in a nonaerobic medium with a carbon dioxide atmosphere. If the laboratory has been alerted that Actinomyces is suspected as the pathogen, appropriate culture media in an anaerobic environment can be available, without unnecessary delay, which contributes to a higher

percentage of positive identification. Immediate Gram stain of the specimens may yield a presumptive diagnosis of Actinomyces, especially if sulfur granules have been included [2]. Culture plates must be incubated at least 14 days, under completely anaerobic conditions, in a 5% carbon dioxide atmosphere at 37 C. Blood agar, brain-heart infusion agar, and thioglycolate liquid medium are commonly used. During the incubation period, direct observation of the cultures may reveal sulfur granules, which can be Gram stained, a technique that adds evidence to the final diagnosis [2,11]. The fine-needle aspiration technique permits easier anaerobic transport and rapid inoculation into anaerobic culture media. Gram staining of aspirated material may reveal the filamentous appearance of the Actinomyces. Aspiration is most successful when easily palpable tissue masses can be aspirated accurately rather than when a blind attempt is made to obtain material from deep tissue. Classic microscopic examination of excised tissue (biopsy) can be useful diagnostically but has limitations, especially if intense inflammation is present in the tissue in the early stages of the infection. Histologically, it is difficult to differentiate Actinomyces from Nocardia species. Small colonies or isolated filaments of Actinomyces may be overlooked in routine hematoxylin and eosin stained tissue sections. Other diagnostic tests include fluorescent typing and gel-diffusion techniques, but these are not routinely available in many laboratories. It is important for clinicians, pathologists, and microbiologists to consider that the presence of A. israelii in tissue specimens or even in cultures does not unequivocally confirm its role as the etiologic agent in an infection; it may represent contamination or commensal growth. Its presence should correlate with clinical findings.

Therapy Before the availability of antibiotics, treatment of cervicofacial actinomycosis included surgery, irradiation, vaccination, and the use of iodides and other ineffective nostrums. The successful use of sulfonamides in 1938 simplified the therapy. Penicillin was introduced into the therapeutic regimen for actinomycosis in 1948, and by 1960, prolonged high-level penicillin therapy was being used, as was the radical excision of recalcitrant fibrotic lesions and persistent sinus tracts that resisted antibiotic penetration [24]. Later, Lerner recommended the use of intravenous antibiotics alone for early lesions, whereas resection

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was advised for more mature and densely fibrotic lesions [6,11]. Perhaps the efficacy of penicillin therapy is related not only to its direct effect on A. israelii but also to its antimicrobial suppression of the other microorganisms that participate in the metabolic ecosystem and enable Actinomyces to flourish. In actinomycotic osteomyelitis, sequestrectomy or saucerization of nonvital bone is indicated. Debridement of the dead bone, an excellent anaerobic growth medium that lacks any vascularity and is unpenetrable by antibiotics, contributes to the healing process. Initial therapy for actinomycosis is high-dose intravenous infusion of penicillin. Three to 12 million U daily is recommended and can be administered at home by indwelling heparin-lock intravenous catheter. This treatment should be followed by orally administered penicillin, 2 to 4 g daily, for an additional 3 to 12 months, depending on the infections response [16,25]. This therapeutic regimen may be extended if central nervous system infection is present. If actinomycotic osteomyelitis has developed, intravenous penicillin doses may reach 20 million U daily, given in divided doses. If potassium penicillin is used in high doses for prolonged periods, potassium levels should be monitored and one should observe for hyperkalemia, especially in patients who are simultaneously taking potassium-sparing diuretics or who have impaired renal function. Other antibiotics that are effective include erythromycin, cephaloridine, minocycline, clindamycin, chloramphenicol, and imipenem. Flagyl (metronidazole) and aminoglycosides are ineffective against A. israelii (Table 1). If the clinical response to monoantibiotic therapy is less than optimal, subsequent options include surgical exploration and excision of undrained obscure abscesses or the use of antibiotics in combination. Polyantibiotic therapy may be successful, perhaps

because penicillin-resistant organisms develop in the polymicrobial ecosystem that supports the growth of actinomycoses. After successful therapy, pharmaceutical or surgical, secondary repair or reconstruction may be indicated. Bone loss, absence of teeth, and aesthetically unacceptable scarring from chronic sinus tracts can be treated by bone grafting, soft tissue procedures, or implants, but only when the surgeon is confident that the infection has been completely eliminated.

Medicolegal considerations Because A. israelii is an oral commensal, actinomycotic infection cannot be predicted or prevented. It would seem that malpractice claims secondary to infection are specious and without scientific validity. Nonetheless, the author has reviewed such cases, which are based on the claims that practitioners have failed to diagnose or treat appropriately. The decision whether to prescribe antibiotics at the time of tooth extraction should not be based on the statistically highly unlikely possibility that the patient might eventually develop actinomycosis. Neither routine culturing nor routine antibiotic use after exodontia can be justified medically or economically. The most common causes of early postextraction infection are food trapping (inadequate hygiene) in the operative site or the presence of a small fragment of nonviable bone. Such infections are usually treated with irrigation, debridement, and antibiotics if, in the surgeons judgment, they are indicated. Late or multiple infections should alert the surgeon to the possibility of actinomycotic infection, however. Failure to culture late or recurrent infections and the use of multiple short courses of empirical antibiotic therapy before the eventual establishment of the correct diagnosis are the common filaments in the fabric of actinomycosis malpractice actions. Without a high index of suspicion, clinicians may be lulled into a false sense of security because the infections may be initially subtle, nonpyogenic, and indolent and because actinomycosis may become evident months after the surgery or after years of quiescence.

Table 1 Antibiotic therapy for actinomycosis [2,11] Antibiotic Penicillin G (soft tissue infection) Penicillin G (osseous and central nervous system) Penicillin V Erythromycin Clindamycin Tetracycline Minocycline Mode MIC mg/mL Daily dose IV IV 0.03 0.5 0.03 0.5 3 12 million U 12 20 million U 24 g 2g 1200 mg 2g 2g

Summary [5,7,8] Actinomyces israelii is an anaerobic commensal microorganism of the human oral cavity. It infrequently causes an infection that is polymicrobial and mutalistic in nature. The infection, actinomycosis, has a variable clinical course, which may be acute

PO PO PO PO PO

0.03 0.5 0.12 2.0 8.0

Abbreviations: IV, intravenous; PO, orally.

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or indolently chronic. The differential diagnosis includes pyogenic and fungal infections, tuberculosis, and neoplasm. A high diagnostic index of suspicion for actinomycosis when late or recurrent postextraction infection occurs benefits the patient and the practitioner. A prolonged course of penicillin therapy remains the contemporary treatment of choice. Excisional or secondary restorative surgery may be necessary.

References
[1] Holm P. Studies on the etiology of human actinomycosis. I: The other microbes of actinomycosis and their importance. Acta Pathol Microbiol Scand 1950; 27:736 42. [2] Miller M, Haddad AJ. Cervicofacial actinomycosis. Oral Surg Oral Med Oral Pathol 1998;85:496 508. [3] Richtsmeier WJ, Johns ME. Actinomycosis of the head and neck. CRC Crit Rev Clin Lab Sci 1979;11: 175 202. [4] Pordy RC. Lumpy jaw due to Actinomycoces meyerii: report of the first case and review of the literature. Mt Sinai J Med 1988;55:190 3. [5] Brown JR. Human actinomycosis: a study of 181 subjects. Hum Pathol 1973;4:319 30. [6] Lerner PI. Actinomyces and arachnia. In: Wonsiewicz MJ, editor. Infectious Diseases. Philadelphia: WB Saunders Co.; 1992. p. 1626 32. [7] Bennhoff DF. Actinomycosis: diagnostic and therapeutic considerations and a review of 32 cases. Laryngoscope 1984;94:1198 217. [8] Dusek JJ, Howe AG, Carr RF, et al. Case 37, part II: cervico-facial actinomycosis [clinicopathological conference]. J Oral Maxillofac Surg 1982;40:113 6. [9] Foster SV, Demmier GJ, Hawkins EP, et al. Pediatric cervico-facial actinomycosis. South Med J 1993;86: 1147 50. [10] Nielsen PM, Novak A. Acute cervicofacial actinomycosis. Int J Oral Maxillofac Surg 1987;16:440 4. [11] Lerner PI. The lumpy jaw: cervicofacial actinomycosis. Infect Dis Clin N Am 1988;2:203 19. [12] Schuster GS. Bacterial and protozoal infections with oral manifestations. In: Topazian R, Goldberg M, editors. Oral and maxillofacial infections. 3rd edition. Philadlphia: WB Saunders Co.; 1994. p. 557 77. [13] Gupta DS, Gupta MK, Naidu NG. Mandibular osteomyelitis caused by Actinomyces israelii. J Oral Maxillofac Surg 1986;14:291. [14] Lewis RP, Sutter VL, Finegold SM. Bone infections involving anaerobic bacteria. Medicine (Baltimore) 1978;57:279 305. [15] Schaal KP, Beaman BL. Clinical significance of actinomycetes. In: Goodfellow M, Mordarski M, Williams ST, editors. The biology of the Actinomycetes. New York: Academic Press; 1983. p. 389 424.

[16] Topazian R. Osteomyelitis of the jaws. In: Topazian R, Goldberg M, Hupp J, editors. Oral and maxillofacial infections. 4th edition. Philadelphia: WB Saunders Co.; 2002. p. 231 4. [17] Jacobsson S. Isolation of Actinomyces species and Eichenella corrodens from patients with chronic diffuse sclerosing osteomyelitis [discussion]. J Oral Maxillofac Surg 1994;52:33 4. [18] Marx RE, Carlson ER, Smith BR, et al. Isolation of Actinomyces species and Eichenella corrodens from patients with chronic diffuse sclerosing osteomyelitis. J Oral Maxillofac Surg 1994;52:26 33. [19] Lad SD, Chandy MJ. Craniofacial actinomycosis. Br J Neurosurg 1991;5:361 70. [20] Goldberg MH. Zebra rounds and horses wearing striped pajamas. Pharos 2001;64:53. [21] Har-El G, Prager DA, DeSoto La Paix F, et al. Actinomycotic granuloma masquerading as infraorbital nerve neoplasm. Head Neck 1990;12:261 2. [22] Pradhan S, Datta NR, Prasad KN, et al. Actinomycosis mimicking carcinoma of the maxillary sinus. Indian J Cancer 1993;30:1 4. [23] Das DK. Actinomycosis in fine-needle aspiration cytology. Cytopathology 1994;5:243 50. [24] Peabody JW, Seabury JH. Actinomycosis and nocardiosis. Am J Med 1960;28:99 115. [25] Goldberg MH. Antibiotics: old friends and new acquaintances. Oral Maxillofacial Surg Clin N Am 2001;13:15 30. [26] Barnard NA, Magennis JPM. Intra-masseteric actinomycosis: report of a case. Br J Oral Maxillofac Surg 1992;30:190 1. [27] Bradley P. Actinomycosis of the temporomandibular joint. Br J Oral Surg 1971;9:54 6. [28] Carrau RL, Greenwall K, Canaan RE, et al. Actinomycosis of the infratemporal fossa. Am J Otolaryngol 1993;14:1 4. [29] Chuong R, Goldberg M. Case 60: preauricular mass (clinicopathological conference). J Oral Maxillofac Surg 1986;44:214 7. [30] Deloach-Banta LJ, Barber FA. Nonhealing masses of the right cheek and submandibular areas. Arch Dermatol 1991;127:1831 4. [31] Fenton R, Rotenberg D. Actinomycosis of the parotid. Is it usually a masticator space infection? J Otolaryngol 1977;6:233 8. [32] Ficarra G, DiLollo S, Pierleoni F, et al. Actinomyces of the tongue: a diagnostic challenge. Head Neck 1993; 15:53 5. [33] Jordan HV, Kelly DM. Persistence of associated gramnegative bacteria in experimental actinomycotic lesions in mice. Infect Immunol 1983;40:847 9. [34] Jordan HV, Kelly DM, Heeley JD. Enhancement of experimental actinomycosis in mice by Eikenella corrodens. Infect Immunol 1984;46:367 71. [35] Lerner PI. Susceptibility of pathogenic Actinomycetes to antimicrobial compounds. Antimicrob Agents Chemother 1974;5:302 9. [36] Nakamatsu K, Shinohara M, Takenoshita Y, et al. Two

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M.H. Goldberg / Oral Maxillofacial Surg Clin N Am 15 (2003) 5158 sinuses: a case report and review. Otolaryngol Head Neck Surg 1996;114:818 21. [40] Shaheen S, Ellis F. Actinomycosis of the larynx. J R Soc Med 1983;76:226 8. [41] Weir J, Buck W. Periapical actinomycosis. Oral Surg 1982;54:336 40. [42] Zajac I, Oribovac Z, Bagatin M. Temporal actinomycosis: report of a case. J Oral Maxillofac Surg 1999;57: 1370 2.

cases of actinomycosis of the submandibular region. Jpn J Oral Maxillofac Surg 1986;32:68 74. [37] Ozaki W, Abubaker AQ, Sotereanos GC, et al. Cervicofacial actinomycosis following sagittal split ramus osteotomy: a case report. J Oral Maxillofac Surg 1992;50:649 52. [38] Rippon JW. Medical mycology. In: The pathogenic fungi and the pathogenic actinomycetes. 3rd edition. Philadlphia: WB Saunders Co.; 1988. p. 30 52. [39] Roth M, Montone KT. Actinomycosis of the paranasal

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Diagnosis and treatment of necrotizing fasciitis in the head and neck region
Mark McGurk, MD, FRCS, DLO, FDSRCS
Department of Oral and Maxillofacial Surgery, Guys, Kings, and St. Thomas Dental Institute, Floor 23 Guys Tower, Guys Hospital, London Bridge, London SE1 9RT, UK

A rare event encountered in current medical practice is necrotizing fasciitis. Its presence is occasionally brought to public attention by the press through headlines such as Killer or Flesh-Eating Bug [1], when the impression is conveyed of the advent of a newly discovered disease. Nothing could be further from the truth because the condition was well known to the military surgeons of past centuries. In his book Lectures on Inflammation, J. Thomson, the Regius Professor of Military Surgery at Edinburgh [2], attributed the first description of the disease to L. Gillespie, who was a surgeon in the Royal Navy [3]. The condition was known to Amboise Pare and can be found in the writings of most army surgeons who kept careful records of their experiences. Knowledge of the disease can be traced back to Hippocrates, who gave a classic description of the disease process:
Sometimes a very small wound broke out and if such an accident was neglected great inflammation took place. In most of them the abscess ended in suppurations and there was great falling off of the flesh, tendons and bones; and the defluxion which seated in the parts was not like pus, but a sort of putrefaction and the running was large and of various characters. About the head these things were accompanied by falling off of the hairs of the head and chin, the bones were laid bare and separated and there were excessive runnings; and these symptoms happened in fevers and without fevers. [4]

In modern practice, necrotizing fasciitis occurs sporadically, which makes a true estimate of its prevalence difficult to ascertain. Invasive streptococE-mail address: mark.mcgurk@kcl.ac.uk

cal infections are monitored nationally, and in the 5-year period from1989 to1994, 160 cases of necrotizing fasciitis were reported in England and Wales. Most were attributed to group A streptococci [1]. Because many cases are caused by polymicrobial infection, however, this was almost certainly an underestimate. In the United States, an estimated 10,000 to 15,000 cases of invasive group A streptococcal infections occur annually, of which 5% to 10% are necrotizing fasciitis, with a case fatality of 28% [5]. A prospective population-based study of group A streptococcal necrotizing fasciitis conducted in Ontario between November 1991 and May 1995 showed that the incidence increased from 0.085 per 100,000 population in the first 12 months to 0.4 per 100,000 population in the last year of the study [6]. This pattern mirrors a world trend increase in group A streptococcal infections since 1980 [7]. Typically, necrotizing fasciitis occurs on the abdomen/perineum or lower limbs after trauma or surgery. In a few cases (1% 10%), however, it occurs in the head and neck region, particularly when the patients health is already compromised. Delayed diagnosis is a common event because the condition can arise unexpectedly out of a seemingly trivial infection or injury. The defining characteristic is rapid, progressive tissue destruction that is disproportionate to the initial clinical signs and symptoms. Despite modern advances in medicine, this disease presents similar problems currently just as it did 200 years ago. Necrotizing fasciitis is a clinical syndrome rather than a pathologic entity. Mortality rates have been reported in the region of 40%. Success depends on prompt diagnosis and treatment without delay for microbiologic confirmation.

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An historical perspective The identification of disease entities from historical texts can be difficult because of changing nomenclature and vague clinical descriptions that lack diagnostic detail; however, necrotizing fasciitis was described clearly in the late eighteenth century by Claude Pouteau, chief surgeon to the Hotel Dieu in Lyon in 1783 [8]. At that time the disease complex was given many names, such as malignant ulcer, gangrenous ulcer, putrid ulcer, phagedenis ulcer, phagedena gangraenosa, and hospital gangrene. In the late eighteenth century, a series of outbreaks affected the British Home Fleet. In confined quarters the disease could spread quickly. On HMS San Josef the surgeon observed . . .an ulcer that had devoured the one side of a sailors face, which had followed a blow on the ear, that was attended by a very slight wound [9]. In the early nineteenth century, the disease was reported from military hospitals by the name of hospital gangrene or phagedena gangraenosa. In one case, half the cranium was denuded, the bones having become as black as charcoal; in another the neck was denuded to expose the trachea. The characteristic features of the disease were as follows:
 extreme rapidity with which the disease pro-

Fig. 1. Private Milton Warren, aged 41 years, of the 1st Kentucky Cavalry was captured in August 1863 at the Cumberland River. While in captivity at Richmond he was shot in the right elbow. An amputation was required on June 1, 1864. On June 20, the stump looked inflamed, and by June 24, the whole stump and bone were exposed. He was treated with charcoal and yeast poultices, a generous diet, and ale. By August the sloughing process had stopped and he survived to claim his pension in 1873.

gressed (measured in hours), which distinguishes it from standard gangrene;  a tendency to turn soft parts into a putrid, pulpy substance;  severe pain together with a smell, which was peculiar and extremely offensive;  starting at the site of a wound or following a trivial scratch and attacking young and healthy persons and debilitated soldiers. The disease was recorded in the Gendarmerie Hospital at Brussels after Waterloo [10], and Miss Nightingale noted 80 cases in 1 month at Scutari [11]. The disease was well known to the surgeons in the American Civil War (Fig. 1), and Joseph Jones (Confederate Army surgeon) is credited with the first clear investigation and characterization of hospital gangrene [12]. It is not possible to discriminate between the different types, but 2642 cases were reported, of which 1142 were fatal (Table 1). A serious outbreak occurred in September 1862 in the hospitals at Fredrick and West Philadelphia after the battles of South Mountain and Antietam. In January 1863, because of the poor prisoner of war sanitation in Richmond, three outbreaks occurred as the sick were transferred to Annapolis. The dis-

ease was also present at the Douglas hospital in Fredricksburg [13]. In civilian life it was much less common and occurred sporadically in clusters, being much less contagious. The hospital surgeon of London knew a form of it as a genital disease that was said to be confined to prostitutes and the destitute, and a few cases were admitted to St. Bartholomews Hospital London [14], where the disease was aggressive and if unchecked . . .involves in its ravages the vagina, perineum and anus and sometimes even the bladder and uterus. Fourniers classical description of the condition was of phagedena of the penis and scrotum [15], but case histories demonstrated that it was the same disease process as reported by the military surgeons [16]. Sporadic cases continued to be reported into the early twentieth century. An American surgeon reported a hospital outbreak in Peking, where it was more common than in the West [17]. Melaney isolated a hemolytic Streptococcus from the wounds, and his name subsequently was associated with the disease (Melaneys gangrene). In 1952, Wilson coined the name necrotizing fasciitis, which described the main feature of the disease and emphasized the polymicrobial nature of some of the infections. Currently, it occurs as unexpected isolated attacks so that few oral and maxillofacial surgeons have any experience with it. The effects remain as devastating as ever if not checked, however. This fact is illustrated by the aftermath of the Nevado del Ruiz volcano eruption in Colombia, where 38 patients

M. McGurk / Oral Maxillofacial Surg Clin N Am 15 (2003) 5967 Table 1 Cases of gangrene by site and mortality recorded in the War of Rebellion Site Head and neck Trunk Upper extremity Lower extremity No. of cases of gangrene (n) 60 216 844 1522 Fatal cases of gangrene (n) 23 129 295 695 (38%) (60%) (35%) (46%)

61

From Barnes J. Gangrene. In: Medical and surgical history of the War of Rebellion. 1867; Part III, Vol II Surgical History. Government Printing Office. Washington, DC. p. 823 51.

developed necrotizing fasciitis, and the disease proved fatal in 47.7% of those people. Microbiology Melaney was the first to associate group A streptococcal infections with severe necrotizing conditions, and this organism should be the principal suspect in any rapidly progressive necrotizing infection. Because culture techniques have improved, however, it has become clear that most necrotizing wounds sustain a mixture of bacteria working synergistically. Various bacterial strains may dominate different wounds, but essentially necrotizing fasciitis may be categorized into three types according to the causative organism. (1) In cool and temperate climates it tends to be associated with group A b-hemolytic streptococci (Streptococcus pyogenes) [6] alone or with Staphylococcus aureus. They are the only bacteria that seem to be able to generate solely this clinical picture. Serotypes M1 and M3 are the most common S. pyogenes serotypes associated with invasive disease [7], but multilocus sequence typing has confirmed that a genetically diverse range of strains is associated with these infections [18]. (2) In many cases (up to 60%) the necrotizing fasciitis may be polymicrobial, including one or more obligate anaerobes [19,20]. Brook and Frazier [21] reviewed 87 cases of necrotizing fasciitis over a 17-year period. Of these cases, only 4 were monoinfections with S. pyogenes. In the remaining cases, anaerobic bacteria were predominant, with Peptostreptococcus, Prevotella, Porphyromonas, Bacteroides, and Clostridium the commonest genera isolated. Facultative anaerobic bacteria, such as Enterobacteriacae, are also important. Up to 11 bacterial species have been cultured with various streptococci (groups B and F) in attendance, not just group A [21]. (3) In tropical climates, the condition can be caused by members of the family Vibrionacae, which are of seawater origin [22]. In Colombia, the dominant genus was a

mycosis that was particularly virulent and proved lethal in 70% of cases [23]. Streptococcus pyogenes produce several virulence factors that are likely to be involved in necrotizing fasciitis, including the extracellular pyrogenic exotoxins A, B, and C together with other exotoxins and superantigens [24]. Given this powerful virulence armory, it is perhaps surprising that invasive S. pyogenes infections are relatively rare. One reason for this might be the demonstration that mutations in the two-component CsrS/CsrR 2-component regulatory system led to increased virulence in a mouse model [25]. It could be hypothesized that exotoxin production by S. pyogenes is normally tightly regulated but that when that control is lost through mutation in the regulatory gene, a hypervirulent phenotype results. The pathogenesis of the polymicrobial form of the infection is unclear, although it is well known that consortia of bacteria work together to evade the host defenses and cause tissue damage. Host factors may predispose to the rapid spread of some infections.

Classification, pathogenesis, and clinical features of necrotizing fasciitis The history of necrotizing fasciitis has been dominated by bacteriology. Pruitt [26] and Gorbach et al [27] produced a bacterial classification, each of which comprised five entities, and Simmons [28] produced a third classification, which incorporated seven. Even a simplified clinical classification based on necrotizing cellulitis, necrotizing fasciitis, and myonecrosis [23] is difficult to adopt because these entities are rare and clinical experience is unavailable to distinguish between them. In practice this is not important because the initial treatment for all rapidly progressive necrotizing infections is the same: wide surgical debridement. Attempts to subclassify the disorder are unnecessary [29] and may be a disadvantage if it leads to delay in surgery (even 24 48 hours) to obtain culture results. This principle greatly simplifies the approach to clinical management. Ultimately, success depends on rapid diagnosis of the early lesion and prompt treatment. Pathogenesis The overarching feature of necrotizing fasciitis is a rapid, progressive liquefaction of the subcutaneous fat and connective tissue below a relatively normal looking skin surface. The fascial planes disintegrate, and with the ensuing necrosis come edema and the

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Fig. 2. (A,B) Necrotizing fasciitis arising from an infected tooth. The infection spread relentlessly, first into the neck and then the chest wall. (C) The patient became systemically unwell. (D,E) After wide debridement the patient made a full recovery and is married, with her own family. (Courtesy of Mr. P. McAndrew.)

release of tissue fluid. Early in the development of the disease the veins that traverse the liquefying subdermal fat become inflamed and start to thrombose, which gives the skin first a red and then a mottled color. Later the arterial supply is also jeop-

ardized and the skin becomes pale, which leads to necrosis and wet (coliquative) gangrene. The bacteria initiate an acute local inflammatory response within the dermis that is characterized by an intense polymorphonuclear infiltrate, focal necrosis, and micro-

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Fig. 2 (continued ).

abscess formation. The histologic picture is one of arteriolar and venous thrombosis of the subcutaneous fat, whereas the adjoining muscle shows comparatively little inflammation. Clinical features The rate of necrosis is disproportionate to the signs and symptoms of infection. A small wound can be painful. Early systemic symptoms may be subtle and amount to little more than a feeling of malaise or tachycardia. If there are systemic symptoms in the presence of an apparently innocuous wound, however, necrotizing fasciitis should be considered early. The incidence of this disease increases with age (median age, 57 years) and most adult cases (70%) occur in patients with at least one underlying chronic illness (immunosuppression, diabetes, alcohol/drug abuse, malignancy, or chronic systemic disease). Children by contrast tend not to have chronic illness, but necrotizing fasciitis may complicate chickenpox. Occasionally the disease afflicts apparently healthy individuals. It has been suggested (unconvincingly) that antiinflammatory medication might predispose to these spreading infections by interfering with granulocyte function [30], but Kauls et al [6] could find no such association. In two thirds of cases, the necrosis followed either a skin lesion or trauma. In an otherwise normal Western population, more than 50% of episodes occurred in the limbs,

whereas a few cases involved the trunk and perineum. The head and neck were involved in 1% to 10% of cases. The condition even has been reported after routine dental surgery or dental sepsis (Fig. 2). The variable clinical picture means that delay in diagnosis is common, because the prodromal period in which the synergistic consortia of bacteria are evolving may be only 3 or 4 days before the phase of rapid acceleration. Diagnosis depends on being alert to the possibility of the disease and recognizing the pattern of clinical events, the main feature of which is a rapidly progressive necrotizing infection. The area is acutely painful, and the surrounding tissues are red (the signs depend on the specific mix of bacteria), but on close inspection a central portion of skin is pale and toxic (Fig. 3). The skin subsequently develops a slightly mottled appearance as it becomes congested through venous stasis. As the perfusion is further reduced through arterial failure, the skin starts to blister. Sensory perception is lost as nerves are destroyed and the wound weeps fluid from the underlying liquefaction. Gross edema is a feature of the disease, and gas may be present in up to 40% of cases [21]. The presence of gas is neither a reliable nor discriminatory sign for clostridial infections because it can be absent in gas gangrene and present in various nonclostridial infections [20]. Gas simply denotes the presence of anaerobic bacteria [29]. A marked leukocytosis (median 16,000 leucocytes/mm) is common, but 20% of patients have a normal white cell count, and in some cases the count even may be low. Fever is not always present, especially in the early stages of the disease. With advancing disease the patient becomes progressively unwell, with a general malaise and tachycardia. More than 50% of patients develop significant hypotension. In 10% to 30% of cases the disease is complicated by one or more of the following conditions: acute renal failure, coagulopathy, abnormal liver function, acute respiratory distress syndrome, or hemolytic anemia. The rapid progression of the disease is a distinguishing feature. Diagnosis If the clinical features are suggestive of necrotizing fasciitis, the diagnosis should not wait for the results of bacterial culture. Clinical inspection of the wound demonstrates that the subcutaneous fat has no structural integrity and offers little resistance to the exploring finger. The skin is widely undermined by the progressing infection. Histologic criteria have been described for the early diagnosis of necrotizing fasciitis by frozen section [31], and the typical pattern

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Fig. 3. An emaciated patient presented with a large oral carcinoma (A) and a history of alcoholism with associated liver failure, pancreatitis, and diabetes. Necrosis of the skin flaps occurred abruptly 72 hours after surgery (mixed flora) despite antibiotic prophylaxis (B). Surgical debridement was followed by a regimen of dressing changes every 4 hours (C). Healthy granulating tissue developed eventually (D) and the skin flaps reattached. The patient remains disease free 2 years after surgery (E).

of a dense polymorphonuclear infiltrate in the dermal layers of the skin clinches the diagnosis. Samples of necrotic tissue are uninformative; a biopsy should be taken from normal-looking adjacent tissue. A Grams stain may be helpful in selecting first-line antibiotics, and blood cultures typically produce positive results.

Management Shock and multiorgan failure are relatively common, so resuscitation and general supportive measures are vital in the established case. Two treatments are recommended: (1) surgery and (2) antibiotics, to

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which hyperbaric oxygen might be added. Of these treatments, the single most important modality is surgery. There is no controversy regarding the initial management of spreading necrosis, the extent of debridement being determined clinically [29]. Underlying muscle can be preserved, but all necrotic tissue and overlying skin must be removed. Resected tissue (skin, muscle, connective tissue) should be sent for culture and antibiotic sensitivity (aerobic and anaerobic), and Grams stain results should be obtained. Time is of the essence at this stage, because mortality is associated with delayed intervention. Even if recognized promptly, significant necrosis usually has taken place before resection is undertaken. More than one debridement may be necessary and it is considered prudent to make a second operative inspection of the wound after 24 to 36 hours. Management is similar to that of an extensive burn. The wounds should be washed (hydrogen peroxide is useful for debridement) and packed regularly (every 4 hours) (Fig. 4), a procedure best done personally by the attending surgeon. Slowly the slough clears and shiny granulation tissue emerges

from beneath the yellow slime. The undermined skin at the edge of the wound reattaches to the underlying granulation tissue and the packing can be withdrawn slowly day by day. Regular dressing still should be maintained at 8-hour intervals, which demands a heavy nursing commitment. Ultimately, antibiotic therapy is dictated by the cultures, but intravenous penicillin is the initial drug of choice. If the Grams stain shows a mixed flora, a broad-spectrum antibiotic also should be used (gentamycin), and it can be supplemented as appropriate information is obtained. Finally, hyperbaric oxygen has been suggested as a supportive measure, but there is no definitive evidence of efficacy and there are obvious logistic problems if this technology is contemplated.

Results Despite proper management of necrotizing fasciitis, mortality remains high. A collective review [32] [Janevicious, Han & Batt 1982] of 146 cases reported

Fig. 4. During the preparation of this article a 27-year-old man presented with a recent history of third molar infection (A). He was otherwise healthy. The tooth was removed manually by the patient himself on a Sunday, he was admitted with low-grade cervical infection the following Thursday, and submental necrosis developed overnight (B). Note the ring of ischemia around the ulcer and the congestion in the surrounding tissue. Fluid can be seen leaking from the ulcer. The infection (mixed flora) settled quickly after debridement (C) and standard antibiotic therapy. The wound was allowed to granulate before repair with a split skin graft (D).

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M. McGurk / Oral Maxillofacial Surg Clin N Am 15 (2003) 5967 AE, Simor AE. Population based surveillance for group A streptococcal necrotizing fasciitis: clinical features, prognostic indications and microbiological analysis of seventy seven cases. Am J Med 1977; 103:18 24. Schlievert PM, Aris P, Assimacopoulos Cleary PP. Severe invasive group A streptococcal disease: clinical description and mechanism of pathogenesis. J Lab Clin Med 1996;127:13 22. Blackadder HH. Observations on phagedena gangraenosa. Edinburgh: David Brown; 1818. Trotter T. Medicina nautical. London: Longman, Hurst, Rees and Orme; 1797. p. 1 111. Henne J. Principles of military surgery. Edinburgh: Constable; 1820. Nightingale F. Notes on hospitals, 3rd edition. London: Longman, Green; 1863. Jones J. Investigation upon the nature, causes and treatment of hospital gangrene as it prevailed in the Confederate armies 1861 1865. In: Hamilton FH, editor. United States Sanitary Commission memoirs: surgical II. New York: Riverside Press; 1871. p. 146 70. Barnes J. Gangrene. In: Barnes J, editor. Medical and surgical history of the War of Rebellion. 1867. p. 823 51. Welbank R. On sloughing phagedaena. London: Longmans Brown and Green; 1844. Fournier JA. Gangrene fourdroyant de la verge. Semaine Medicale 1883;3:345 7. Travers T. Two cases of slough ulceration. London Medical and Physical Journal 1824;122 34. Melaney F. Hemolytic Streptococcus gangrene. Arch Surg 1924;9:317 64. Enright MC, Spratt BG, Kalia A, Cross JH, Bessen DE. Multilocus sequence typing of Streptococcus pyogenes and the relationships between emm type and clone. Infect Immunol 2001;69:2416 27. Giuliano A, Lewis F, Hadley K, Blaisdell FW. Bacteriology of necrotizing fasciitis. Am J Surg 1977; 134:52 7. Freischlag JA, Ajalat G, Busuttil RW. Treatment of necrotizing soft tissue infections. Am J Surg 1985; 149:751 5. Brook I, Frazier EH. Clinical and microbiological features of necrotizing fasciitis. J Clin Microbiol 1995; 33:2382 7. Joynt GM, Gommersall CD, Lyon DJ. Severe necrotizing fasciitis of the extremities caused by Vibrionacae: experience of a Hong Kong Territory referral hospital. Hong Kong Med J 1999;5:63 8. Patino J, Castro D, Valencia A, Morales P. Necrotizing soft tissue lesions after a volcanic cataclysm. World J Surg 1991;15:240 7. Cunningham MW. Pathogenesis of group A streptococcal infections. Clin Microbiol Rev 2000;13:470 511. Engleberg NC, Heath A, Miller A, Rivera C, Di Rita VJ. Spontaneous mutations in the CsRS two component regulatory system of Streptococcus pyogenes resulting in enhanced virulence in a murine model of

a 38% mortality rate. In a prospective study, Kaul [6] record ed a case fatality rate of 34%. Pessa and Howard [33] applied severity of illness scoring systems to predict outcome. They found that the scores continued to rise after debridement in patients who were to die, and accurate prediction of survival could be made as early as the third postoperative day. Mortality rates increase with age ( > 50 years of age), concomitant illness (diabetes), delay in diag nosis or treatment [20], inadequate debridement, lesions of the abdomen, and mucormycosis [23,32]. In a multivariate analysis, age, hypotension, and bacteremia were independent variables that predicted mortality. Patients can die from systemic problems some days or weeks after the infection, and in historical texts there are reports of fatal arterial bleeds occurring approximately 10 days after surgery, just as the infective process is settling.

[7]

[8] [9] [10] [11] [12]

Summary Necrotizing fasciitis is a dramatic but rare disease. In the head and neck it often strikes unexpectedly. Early diagnosis and radical treatment are important to maximize the chances of a good outcome. The outcome depends on the clinician having a high threshold of suspicion when rapidly progressive local and systemic symptoms appear in the presence of what was initially an apparently innocuous wound. Diagnosis is achieved principally by inspection and manual examination during explorative surgery but can be supported by frozen section examination. Treatment is mainly surgical, helped by general measures of support to combat the systemic effects of circulating toxins. The key to success is captured in a line by Shakespeare in Macbeth: Be bloody, bold and resolute.

[13]

[14] [15] [16] [17] [18]

[19]

[20]

[21]

References
[22] [1] Deans M. Flesh-eating bugs scare. Lancet 1994; 343:1418. [2] Thomson J. Hospital gangrene or malignant ulcers. In: Lectures on inflammation. Edin: James Ballantyne and Co.; 1813. p. 456 500. [3] Gillespie L. Observations on the putrid ulcer. London Medical Journal 1785;6:373 400. [4] Adams F. The genuine works of Hippocrates. London: Sydenham Society; 1771. p. 400 1. [5] Anonymous. Invasive group A streptococcal infections. JAMA 1994;272:16. [6] Kauls R, McGeer A, Low DE, Green K, Schwartz

[23]

[24] [25]

M. McGurk / Oral Maxillofacial Surg Clin N Am 15 (2003) 5967 skin and soft tissue infection. J Infect Dis 2001;183: 1043 54. Pruitt BA. Burns and soft tissues. In: Polk Jr HC, editor. Infection and the surgical patient: clinical surgery international. London: Churchill-Livingstone; 1982. p. 113 31. Gorbach SL, Bartlett JG, Nichols RL. Manual of surgical infections: skin and soft tissue infections. Boston: Little Brown and Co.; 1984. Simmons RL, Ahrenholz DH. Infections of the skin and soft tissues. In: Howard RJ, Simmons RL, editors. Surgical infections diseases. 2nd edition. Norwalk: Appleton and Lange; 1988. p. 404 8. Dellinger EP. Severe necrotizing soft-tissue infections:

67

[26]

[30]

[27]

[31]

[28]

[32] [33]

multiple disease entities requiring a common approach. JAMA 1981;246:1717 21. Brun-Buisson CJL, Saada M, Trunet P, Rapin M, Roujeau J, Revuz J. Haemolytic streptococcal gangrene and non-steroidal anti-inflammatory drugs. BMJ 1985;290:1786. Stamenkovic I, Lew PD. Early recognition of potentially fatal necrotizing fasciitis: the use of frozen section biopsy. N Engl J Med 1984;310:1689. Janevicius RV, Hann SE, Batt MD. Necrotizing fasciitis. Surg Gynecol Obstet 1982;154:97 102. Pessa ME, Howard RJ. Necrotizing fasciitis. Surg Gynecol Obstet 1985;161:357.

[29]

Oral Maxillofacial Surg Clin N Am 15 (2003) 69 78

Diagnosis and treatment of diffuse sclerosing osteomyelitis of the jaws

Marjut Montonen, MD, DDSa,*, Christian Lindqvist, MD, DDS, PhDa,b
Department of Oral and Maxillofacial Diseases, Helsinki University Central Hospital, Surgical Hospital, P.O. Box 263, Fin-00029 HUS, Finland b Department of Oral and Maxillofacial Surgery, Helsinki University Central Hospital, Institute of Dentistry, P.O. Box 263, Fin - 00029 HUS, Helsinki, Finland
a

Diffuse sclerosing osteomyelitis of the jaws is an inflammatory condition that is a consequence of vascular changes and nonspecific bacterial infection in which bone deposition rather than bone resorption occurs [1 3]. Diagnosis is based on clinical and radiologic findings and histopathologic findings relating to bone specimens. Histopathologic findings in the maxilla and in the mandible are similar, but the symptomswhich are characterized by intermittent pain resistant to almost all treatmentand specific radiological changes relate almost exclusively to the mandible [3 10].

Etiology and pathogenesis In osteomyelitis of the jaws following pulpal or periodontal infections, there is inflammation of both the cortical and cancellous bone. In the acute form, there is pain, swelling, and purulent discharge. The condition is generally curable by antibiotics, drainage, and removal of the offending teeth; however, if the condition is untreated or inadequately treated, the infection becomes chronic and eradication may require extensive sequestrectomy as well as antibiotic therapy. Diffuse sclerosing osteomyelitis differs from the acute and chronic suppurative forms of osteo-

myelitis by its more insidious onset, which is characterized by acute exacerbations of pain and swelling but a general lack of purulent drainage. Most investigators believe that diffuse sclerosing osteomyelitis is caused by bacteria that are not particularly virulent; however, no specific causative micro-organisms have yet been identified. Various bacteria have been reported in some studies, but contamination of the culture specimen by organisms on the skin or oral mucosa could not be excluded [11 13]. It has been suggested that a hyperactive immunologic reaction to the bacterial toxins may be responsible for the chronic inflammatory response. There is generally no identifiable bacterial port of entry, but chronic periodontal disease has been implicated as a possible source. Diffuse sclerosing osteomyelitis is difficult to eradicate and may persist for years, with intermittent symptoms of pain and swelling of the face [5,11,14].

Differential diagnosis Diffuse sclerosing osteomyelitis should be distinguished from secondarily infected florid osseous dysplasia. In the latter, apart from inflammation and reactive changes, histological studies reveal a fibroblastic stroma with bone and cementum-like structures that have been formed as a result of metaplasia [15]. Diffuse sclerosing osteomyelitis may even indicate the mandibular location of SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome [16 19].

* Corresponding author. E-mail address: marjut.montonen@hus.fi (M. Montonen).

1042-3699/03/$ see front matter D 2003, Elsevier Science (USA). All rights reserved. PII: S 1 0 4 2 - 3 6 9 9 ( 0 2 ) 0 0 0 7 3 - 0

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Clinical findings The most important criteria for diagnosis of diffuse sclerosing osteomyelitis of the jaws are history of intermittent pain, swelling, trismus, pressure and paresthesia. These symptoms can appear at any age and often persist for years. Exacerbations are characterized by a marked inflammatory reaction in the bone marrow leading to sensitization and stimulation of primary afferent nociceptive nerves, which results in intense, sometimes unbearable pain, particularly in the lower jaw [8,9,20]. Because pain is the most important symptom of diffuse sclerosing osteomyelitis, standardization of measurement of pain and employment of a questionnaire detailing the history of the pain are useful in clinical examination. Using such means, the nature and intensity of pain can be classified. Classification is necessary from a differential diagnostic point of view, and in deciding treatment and evaluating its effects [20]. Pain can be measured using a visual analogue scale, the McGill Pain Questionnaire,a painrelief scale, or a pain diary [21,22]. The visual analogue scale involves the patient drawing a mark on a 100-mm horizontal line on a piece of paper. The

left edge of the line indicates no pain, and the right edge indicates the worst possible pain [22]. The McGill Pain Questionnaire involves the patient choosing words from various categories that describe the nature of the pain as well as its intensity [21].

Radiologic findings Radiographic and scintigraphic investigations are used to increase diagnostic accuracy and improve prognostic and therapeutic judgements [7,23 26]. Whereas a typical feature of suppurative osteomyelitis of infectious origin is a radiolucent lesion spreading through the cancellous bone, with cortical bone perforation and a lamellated periosteal reaction, in chronic sclerosing osteomyelitis, intermingled sclerotic and osteolytic lesions with a solid periosteal reaction or external bone resorption are common findings [24]. However, with the passage of time, sclerosis becomes increasingly marked, and normalization of bone structure is rare [7]. Panoramic and intraoral radiographs and 99mTcscintigraphy are most often used for diagnosis, determination of disease activity, and follow-up [7,9]. CT

Fig. 1. (A) Vertical and horizontal osteotomies over the osteomyelitic lesion. (B) Removal of the lateral cortical bone to the exposed cancellous bone. (C) Bur holes have been drilled through lingual cortex.

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scans and MRI techniques can also be used to determine extent of disease, especially when planning primary surgical therapy [2,24,27,28]. However, MRI techniques may be less useful during follow-up after surgery because of disturbing artifacts related to the use of metallic instruments. Yoshimura et al [28] showed by CT scan a close interaction between cortical plate disruption and muscle inflammation. Compared with plain film, the extent of the soft tissue involvement could be better appreciated with CT scans, especially in mixed pattern cases [28]. Along with this, detecting and localization of active sequestra will be improved by the use of MRI, CT scans, or single photon emission computerized tomography (SPECT) with 99mTc hydroxymethylene diphosphonate (HDP) when planning surgical debridement [2,29].

Table 1 Unpublished data on patients with diffuse sclerosing osteomyelitis treated in the Department of Oral and Maxillofacial Surgery at Helsinki University Central Hospital Characteristics Sex Female Male Age at onset of symptoms Dental status Edentulous Dentate Location of symptoms Maxilla Mandible Dentate area Other regions Symptoms Pain Swelling Trismus Duration of disease Diagnosis Clinical Radiologic Histologic Conservative treatment Outpatients Inpatients Inpatients in pain clinic Systemic antibiotics Nonsteroidal antiinflammatory drugs Systemic steroids Disodium clodronate Weak or strong opioids Anticonvulsants Antidepressants Physiotherapy Hyperbaric oxygen treatment Surgery Dentoalveolar surgery Revision, removal of sequestrum Decortication Partial resection Resection and reconstruction with microvascular bone craft Combination of conservative therapy and surgery Years Number 59 43 Mean 27.5 Range 5 77 10 92 2 100 102 98 102 100 100 Mean 13.5 Range 0.5 42 102 102 102 102 77 36 102 102 42 36 102 10 8 67 9

Histologic findings Histologic examination and various enzyme immunohistochemical investigations of bone specimens are necessary to establish diagnosis. These can be obtained by using an accurate biopsy technique. Use of a rotating trepan bur is preferred in attempting to obtain representative bone specimens [30]. Sclerotic changes have been described mainly in the subperiosteal parts of biopsy specimens from the lower jaw using this technique. Coarse trabeculae and necrotic foci, partly calcified, thin trabeculae reminiscent of fibrous dysplasia, and granulation tissue with chronic inflammatory cell and foreignbody giant cells have been found in cancellous bone [8,9,30 32]. The histopathology of diffuse sclerosing osteomyelitis in the maxilla and mandible is probably the same; however, diffuse sclerosing osteomyelitis of the maxilla has been mentioned in only a few reports [1,33,34].

Laboratory findings In general, there are no specific laboratory tests for determining the stage of diffuse sclerosing osteomyelitis except for the mean erythrocyte sedimentation rate, which can be slightly elevated during exacerbations. In attempts to discover a suitable tool for evaluation of the results of treatment, the serum levels of alpha-1-antitrypsin, orosomucoid, and haptoglobin have been measured during different stages; however, caution must be exercised when generalizing from results of single measurements. Serum levels of C-reactive proteins seem to reflect the clinical activity of the disease, but a certain mass

28 15 47 2 1

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of inflammation is necessary before elevated values of these proteins can be detected [35]. Leukocyte and platelet counts, as well as serum levels of osteocalcin, parathyroid hormone, creatinine, calcium, phosphate, aspartate aminotransferase, alanine aminotransferase, albumine, and alkaline phosphatase, remained within normal limits [20]. Because the synthesis of immunoglobulins only reflects inflammatory activity indirectly, immunoglobulines are not regarded as appropriate markers of inflammation. However, their concentration in serum can vary with clinical activity [35]. Immunological findings suggest that most patients with diffuse sclerosing osteomyelitis have normal humoral and cellular responses. The inflammatory events and

chronicity of the disease cannot be explained by immunologic findings [11,36].

Bacteriologic findings Various attempts have been made to determine the causes of diffuse sclerosing osteomyelitis. Bacteriologic investigations of specimens from diseased bone have been undertaken, paying particular attention to anaerobic culture techniques. Few studies involving healthy controls have been performed. Some bacteriaincluding Propionibacterium acnes, Peptostreptococcus intermedius, Eikenella corrodens, Actinomyces species, Streptococcus sanguis, Strep-

Fig. 2. (A) Panoramic radiographs of a 17-year-old female with a 9-month history of pain and swelling on the right side of the mandible preceded by prolonged endodontic treatment of the second molar. (B) Wide lytic areas can be seen in connection with the teeth and in the body of the mandible. (C) Uptake of 99mTc-diphosphonate corresponding to the radiographic changes.

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tococcus mitis, and Fusobacterium nucletumhave been found, but in very small numbers [11 13]. However, contamination with skin or oral flora cannot be avoided despite improvements of sampling techniques. The results of bacteriological and serological investigations indicate that Propionibacterium acnes and Peptostreptococcus intermedius may be of significance in relation to the disease but cannot explain its chronicity [11]. One bacteriologic study comparing patients with diffuse sclerosing osteomyelitis of the mandible with healthy controls has been done, and this study found no difference in the quantity or quality of bacteria in the bone samples [13]. No particular group of bacteria was unequivocally associated with disease. Thus, the findings probably reflected contamination.

Therapy Nonsurgical treatment There is no cure for diffuse sclerosing osteomyelitis [37 39]. The main reason is that knowledge of

the disease, its causes, and its natural history is not known. Long-term antibiotic therapy can have a beneficial effect on the course of the disease in its early stages, while corticosteroid therapy and sometimes decortication can be more effective once the condition has become chronic [37]. The type of antibiotics and the exact duration of treatment are difficult to establish [40]. The clinical efficacy of long-term roxithromycin treatment (300 mg/day orally for 68 days to 66 months) in patients with diffuse sclerosing osteomyelitis of the mandible has been studied [41]. In seven of nine cases (77.8%) the symptoms disappeared 1 month to 1 year after the start of therapy. Radiography showed that osteolysis had decreased but that osteosclerosis had persisted or increased by the end of therapy. The optimum duration of treatment should be determined based on the amelioration of symptoms and the disappearance of osteolytic findings on radiographs. The mechanism of action of roxithromycin is not yet fully understood, but long-term roxithromycin treatment may be useful before surgical treatment is considered [41].

Fig. 3. (A) Two years after onset of the disease, an exacerbation occurred with swelling of the mandible and severe pain. (B) Predominantly sclerotic areas are seen in the right body and angle and new lytic areas as present in the ramus of the mandible. (C) An intensive uptake of 99mTc-diphosphonate corresponds to the swollen and painful area of the mandible.

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The inflammatory nature of the disease has been demonstrated by alleviation of ostomyelitic pain through administration of glucocorticosteroids [37]. Hyperbaric oxygen has often been recommended as an adjunct to treatment of diffuse sclerosing osteomyelitis of the jaws with antibiotics and surgery [37,39]. The results of hyperbaric oxygen treatment of chronic osteomyelitis of the jaws have been described by van Merkesteyn et al [39]. Disodium clodronate, a bisphosphonate, is a potent anti-osteolytic agent which has been used to treat diseases of bone and calcium metabolism [42 44]. It has also been found to be useful for treatment of recurrent pain of diffuse sclerosing osteomyelitis unresponsive to conservative or surgical therapy [13,45]. In a randomized, placebo-controlled, double-blind study, patients received disodium clodronate (300 900 mg) or placebo intravenously. Disodium clodronate administration resulted in no better immediate pain relief than administration of placebo. However, 6 months after treatment there was a statistically significant difference in pain intensities between the groups, with the disodium clodronate group experiencing significantly less pain [13].

Surgery Surgical treatment of diffuse sclerosing osteomyelitis involves decortication and removal of any foci of infection and sequestra [37,40,46]. The results of decortication have been described by Hjrting-Hansen [47], Jacobsson and Hollender [37], and Montonen et al [38]. They reported a success rate in relation to to mandibular decortication of about 50%. Symptoms generally recurred within a year of surgery. Advanced age at the time of decortication and the presence of carious or poorly endodontically treated teeth in the decorticated area correlated with recurrence [14]. Decortication can be performed intraorally or extraorally and should be preceded by intravenous antibiotics and hyperbaric oxygen treatment for optimial results. After horizontal and vertical burr cuts have been made in the lateral cortex covering the diseased area, pieces of cortical and cancellous bone can be removed using a chisel. Perforations can then be drilled into the bleeding marrow cavity before closure of the wound to improve bone nutrition (Fig. 1) [38]. In cases in which decortication fails, resection of affected areas has been recommended [48 50]; how-

Fig. 4. (A) The patient was symptom-free 6 months after combined conservative treatment consisting of removal of the third molar, intravenous antibiotics, hyperbaric oxygen, and disodium clodronate. (B) There was remodeling of the mandible bone along with increasing sclerosis of the angle and the body of the mandible.

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ever, resection should be limited to severe, therapyresistant cases because of potential disadvantages such as loss of function of the inferior alveolar nerve and problems related to mandibular reconstruction [14]. It would therefore seem preferable to choose saucerization combined with particulate cancellous bone and marrow grafting as a relatively conservative surgical treatment for diffuse sclerosing osteomyelitis of the mandible [51]. The topical application of a broad spectrum antibiotic to the surgical bed after removal of the affected jaw bone has been reported in only two case reports [46,52]. The outcome of this therapy was not better than decortication alone.

Personal experience Records relating to 102 patients (59 women, 43 men) with diffuse sclerosing osteomyelitis treated between 1962 and 2002 in the Department of Oral Maxillofacial Surgery at Helsinki University Central Hospital were retrospectively analyzed (unpublished data, M. Montonen, 2002). Patients with acute and

subacute suppurative osteomyelitis and osteoradionecrosis were excluded. Thirty-three patients are still being followed and are receiving therapy as necessary. All patients had been clinically and radiographically examined, and the diagnoses have been verified by histological investigation (Table 1). All patients had typical symptoms with intermittent pain, swelling, trismus, and radiological changes. A typical example is a young woman with a 6-year history of the disease whose radiographs are shown in Fig. 2. Her symptoms first occured in the right second molar area at the age of 17. The location of symptoms varied subsequently between the ramus and symphysis of the mandible. Erupting third molars were considered to be the infectious foci and were extracted. Hyperbaric oxygen treatment was undertaken before and after the operation, and antibiotics were administered intravenously (Fig. 3). Bone tissue specimens were taken from the affected mandible by means of minor decortication. They exhibited typical histologic changes, namely subcortical sclerosis and moderate chronic medullar inflammation with mononuclear cell infiltration. Microbial findings

Fig. 5. (A) After a symptom-free period of 13 months, increased pain and swelling occurred in the right ramus, body, and symphysis of the mandible. (B) Panoramic radiograph showing sclerotic changes in the body, angle, and ramus of the mandible and lytic lesions in the coronoid process (arrow) and adjacent to the right first premolar and central incisors, which had a positive response to electrical stimulation. (C) Intense uptake of 99mTc-diphosphonate corresponds in the dentate area of the mandible.

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Fig. 6. (A) Panoramic radiograph of a 22-year-old woman with a 3-year history of diffuse sclerosing osteomyelitis of the mandible taken 2 weeks before surgery. Mixed lytic radiographic lesions are present in the mandibular body, ramus, and condylar process. The teeth with periapical lesions had a positive response to electrical stimulation. (B) Panoramic radiograph taken 6 years after surgery. The mandible appears radiologically normal and the patient is symptom-free.

with spare oral flora were equal from the diseased and the contralateral side of the mandible bone, resembling the results from the previous study with mistaken contamination [13]. Seven months after surgery the patient was symptom-free, but sclerosis in the body and the ramus of the mandible was increasing (Fig. 4). Despite operative treatment; long-term administration of antibiotics, anti-inflammatory drugs, and disodium clodronate; and hyperbaric oxygen treatment, symptoms recurred after 1.5 years in the right premolar and incisor regions. There were lytic radiological changes and increased uptake in the 99m Tc-scintigram (Fig. 5). The teeth in the affected area were vital and were not endodontically treated. If symptoms persist despite continued medical treatment, either the new endodontic therapy of the right second molar should be performed or the tooth should be extracted, because it may act as the focus of infection despite an apparently satisfactory root filling. Only two cases of maxillary diffuse sclerosing osteomyelitis have been reported; the disease mostly affects the mandible. The pain in the maxilla differed from that associated with diffuse sclerosing osteomyelitis of the mandible. These patients had neuropathic pain with a burning sensation or a feeling of dull, deep pressure. In both cases there was a dental problem before symptoms occurred. Radiologically, the disease was characterized by mixed sclerotic and osteolytic changes of the mandibular bone, but there were few radiological findings in the upper jaw. Only 1 of 100 patients with mandibular diffuse sclerosing osteomyelitis experienced complete clinical and radiological recovery from the disease. This patient had suffered typical intermittent symptoms with typical findings for 9 years but has now been free from symptoms for over 10 years (Fig. 6) [38].

Summary Early clinical and radiological diagnosis of diffuse sclerosing osteomyelitis and effective, combined conservative and surgical treatment, including meticulous dental care by a specialist, may improve the chance of avoiding a poor outcome. There should be regular follow-up by a specialist in a facial pain clinic where there are possibilities of oral and maxillofacial consultation. Such an approach should facilitate rapid and efficient evaluation of pain and treatment of exacerbations. To minimize the likelihood of exacerbations, even regular dental checkups and treatments should be performed.

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Oral Maxillofacial Surg Clin N Am 15 (2003) 79 89

Diagnosis and treatment of viral infections

Sol Silverman, Jr, MA, DDSa,*, Craig S. Miller, DMD, MSb
a

Department of Stomatology, University of California School of Dentistry, Box 0422 S-612, 513 Parnassus Avenue, San Francisco, CA 94143, USA b Department of Oral Medicine, Microbiology, Immunology, and Molecular Genetics, University of Kentucky College of Dentistry, College of Medicine, MN-118, Lexington, KY 40536-0297, USA

Viral infections are of concern to dental professionals because of ease of transmission, the oral, latent, recurrent, and systemic diseases they can produce, their association with opportunistic infections and malignant transformation, and their influence on infection control. In this article, information regarding the following viruses is provided: (1) HIV, (2) human herpesviruses, (3) human papillomaviruses, (4) enteroviruses, and (5) hepatitis C virus.

HIV We are currently in the third decade of an RNA virus pandemic. There are approximately 40 million people throughout the world infected with HIV. It is estimated that more than 16,000 new infections occur each day. HIV is spread predominantly by sexual contact, blood or blood products, or perinatal exposure. Infection also results from high-risk activities, such as sharing needles with infected drug users, having unprotected sexual activity with one or more infected partners, receiving infected blood or blood products, or being accidentally exposed to infected materials. In the United States, almost 500,000 persons are reported to be living with HIV and AIDS. More than 2 million persons are believed to be infected, however. Approximately 98% of infections occur in adults and adolescents, and approximately one third of new cases occur in women. New infections are

* Corresponding author. E-mail address: ssjr@itsa.ucsf.edu (S. Silverman).

occurring at a disproportionately higher rate in African Americans. In reversal since the late 1990s, the number of new cases and deaths is increasing once again because of viral resistance to multiple drug therapy, apathy toward barrier techniques, the increasingly large number of individuals living with HIV who serve as a reservoir for transmission, and widespread drug abuse and prostitution. The HIV epidemic is an important concern to the dental profession for many reasons. First, infection control measures are required in the dental office. Second, many oral and systemic manifestations occur in immunocompromised individuals who have falling numbers of physiologically incompetent lymphocytes and rising viral loads. Third, recognition of the signs and symptoms of HIV infection should lead to referral of the patient to a physician for diagnostic testing. Acute HIV infection in most cases produces flulike symptoms that develop 2 to 6 weeks after the initial infection. Soon thereafter, persistent generalized lymphadenopathy occurs, which is followed by a latent phase. Initially the latent phase is asymptomatic. Later as the viral loads rise and the CD4+ cell count drops, lymphadenopathy, weight loss, fever, diarrhea, fatigue, skin anergy, neurologic decline, parotid enlargement, and opportunistic infections develop. Many of the numerous oral lesions that develop are caused by increased individual susceptibility to viral transmission and proliferation. These infections, which involve the herpes family viruses and human papillomaviruses, are more prevalent in HIV-seropositive patients and are usually concurrent and recurrent. An increasing number of HIV patients are coinfected with the hepatitis C virus.

1042-3699/03/$ see front matter D 2003, Elsevier Science (USA). All rights reserved. PII: S 1 0 4 2 - 3 6 9 9 ( 0 2 ) 0 0 0 7 2 - 9

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The final stage of the disease (AIDS) is often marked by fatal respiratory infections, lymphoma, or cancer. Treatment involves the use of highly active antiretroviral agents, such as nucleoside, nucleotide, and nonnucleoside reverse transcriptase inhibitors, and protease inhibitors, which are used in combination to block virus replication and maturation.

Human herpesviruses The human herpesvirus (HHV) family includes herpes simplex viruses (HSV-1 and -2), varicellazoster virus (HVV, HHV-3), Epstein-Barr virus (EBV, HHV-4), cytomegalovirus (CMV, HHV-5), lymphotrophic viruses (HHV-6 and -7), and Kaposis sarcoma virus (HHV-8). These large DNA viruses have the hallmark of establishing latent infection. The latent infection serves as a reservoir for the periodic activation of virus. Although the molecular factors that regulate activation of HHVs are still undefined, aging, immunosuppression, stress, and tissue damage predispose HHVs to reactivation. Reactivation occurs despite cell-mediated and humoral HHV immunity. Clinical manifestations are diverse and are more severe during immunosuppression. Herpes simplex viruses HSV-1, the most common of the HHV oral infections, must contact mucosa or abraded skin to initiate infection. By puberty, most individuals have been

exposed to HSV and have developed circulating antibodies. The virus incubates and replicates for 2 to 12 days within epithelium and then penetrates local nerve endings [1]. After the primary infection, the virus travels to regional ganglia, where it remains latent indefinitely. Asymptomatic shedding and reactivation are common [2]. Although population studies are variable, clinical recurrences are estimated to occur in up to 40% of cases [3]. More than 67% of initial exposures are asymptomatic subclinical infections [4]. The remaining individuals who acquire the primary infection experience marked signs and symptoms that last up to 2 weeks (Fig. 1). Features include gingivostomatitis, lip vesicles and coalescing ulcerations, fever, lymphadenopathy, and oropharyngeal pain. Approximately 10% of adults are not exposed to or do not obtain adequate level of antibodies. These persons are at risk for developing adult-onset acute herpetic gingivostomatitis. Although the signs and symptoms in adults are usually more severe, the attack is usually complete in 2.5 weeks. The initial HSV infection incurs permanent immunity from a similar future attack; however, it does not prevent reactivation and recurrent mucosal and labial flares. Recurrent mucosal (intraoral herpes) and labial (cold sores) infections create a lifetime problem in persons who are susceptible to reactivation of latent HSV (Fig. 2). These lesions recur near the point of entry into the body and are usually caused by HSV-1, although HSV-2 (usually associated with genital herpes) occasionally can be identified. The signs,

Fig. 1. Primary adult-onset herpetic gingivostomatitis in a 28-year-old man. It was manifested by sudden onset, pain, fever, lymphadenopathy, and gingivitis. There had been no similar previous attacks, and the signs and symptoms resolved completely in 2 weeks.

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Fig. 2. Typical recurrent oral herpes manifested by irregular, shallow gingival ulcerations that tend to coalesce and usually resolve within 7 to 10 days. The lesions are often mistaken for trauma.

symptoms, and treatment are similar for both serotypes. Lesions are often preceded by prodromal symptoms of burning, tingling, itching, or pain. Recurrent intraoral HSV is often mistaken for some form of traumatic injury, because lesions appear on periosteal bound mucosa as small, irregular, erosive areas or ulcers that usually disappear within 1 week. An important implication is transmission, because vesicular and ulcerative lesions shed virus during the first 2 to 3 days, during which time HSV can be transmitted. Common sites of spread are the eye (herpetic keratitis) and fingers (herpetic whitlow) (Fig. 3). Cold sores are a problem because of aesthetics, pain, and source of transmission. The nature of HSV recurrences varies and often is preceded by stress, irritation, exposure

to sunlight, cold, fever, trauma, and immunosuppression [5 7]. There are reports that HSV infection can precede, or be subclinically involved in, an attack of erythema multiforme, which indicates a possible antigenic role [8]. Diagnosis of HSV infections is usually based on the history and clinical findings. Cultures, cytologic smears that show multinucleation, and special immunofluorescent processing can be helpful when clinical recognition is uncertain. Serologic diagnosis is of value only to determine past exposure. Definitive treatment includes the use of systemic or topical antiviral drugs [9 12] (Table 1). Precursor antiviral agents, such as valacyclovir and famciclovir, have better oral bioavailability than acyclovir and penciclovir. If not used early in the infection (first 3 to

Fig. 3. Herpetic whitlow of the finger contracted by contact with a cold sore.

82 Table 1 Antiviral drugs Generic (trade name) Systemic:

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Epstein-Barr viruses
Suggested dosage (days)a 400 mg 3 daily (7) 125 mg 1 daily (5) 500 mg 2 daily (5) 5% ointment 1% cream 10% cream (over-the-counter)

acyclovir (Zovirax) famciclovir (Famvir) valacyclovir (Valtrex)

Topical:

acyclovir (Zovirax) penciclovir (Denavir) docosanol (Abreva)

Apply topical medications to oral lesions at least four times daily. a Dosage levels are adjusted according to clinical severity and response. For severe infection: acyclovir 5 10 mg/kg IV q8h for 7 10 days, famciclovir 500 mg t.i.d., or valacyclovir 1000 2000 mg b.i.d. For acyclovir-resistant cases: foscarnet (Foscavir) 40 60 mg/kg IV q8h for 7 10 days, or cidofovir (Vistide) 5 mg/kg.

4 days), antiviral drugs are usually ineffective. Antiseptic, analgesic, and antiinflammatory medications can be beneficial in reducing pain and transmission of the disease. Systemic antiviral agents are used in complicated primary infections, HSV infections in the immunocompromised, prophylaxis for seropositive patients who undergo chemotherapy or transplantation, HSV-associated central nervous system disease, and recurrent erythema multiforme. Systemic antiviral agents are used often as daily prophylaxis. Nephrotoxicity, although rare, is a concern with the use of highdose systemic acyclovir, valacyclovir, and famciclovir, particularly if patients have renal insufficiency.

Epstein-Barr virus is associated with infectious mononucleosis, hairy leukoplakia, nasopharyngeal carcinomas, and lymphomas [13]. The primary infection, referred to as infectious mononucleosis, usually causes a sore throat, fever, cervical lymphadenopathy, malaise and pain, and occasional hepatosplenomegaly. It occurs chiefly in adolescents and young adults. The disease is of low contagiousness, and transmission is through exchange of EBV-contaminated saliva. Affected patients often demonstrate multiple petechiae located on the soft palate or lips. The lymphadenopathy is often bilateral and affects the posterior cervical nodes. Blood studies reveal atypical lymphocytes, heterophile antibodies, and mildly elevated transaminase levels. Treatment in most cases is palliative and supportive. Recovery usually occurs within 1 to 2 months; however, the virus enters latency in lymphocytes. Epstein-Barr virus is associated with hairy leukoplakia, which is a benign manifestation of epithelial hyperplasia and hyperkeratosis that primarily occurs on the lateral border(s) of the tongue. It appears as a corrugated white lesion that does not rub off (Fig. 4). Hairy leukoplakia is predominately seen in individuals infected with HIV; however, it may be seen in nonHIV immunosuppressed patients. Hairy leukoplakia is almost always asymptomatic, with the principal significance being a sign of immunosuppression. The diagnosis of hairy leukoplakia is clinically suggestive and can be confirmed by biopsy. Cytologic scrapings are somewhat characteristic by featuring nucleoprotein condensations in nuclei. Treatment is elective and includes high-dose antiviral drugs, topical podophyllin in 25% tincture of ben-

Fig. 4. Hairy leukoplakia in an HIV-positive patient. The lesion was asymptomatic and chronic.

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tion of EBV latency membrane protein 1 and the NF-kB pathway that alters apoptotic and growth pathways [16]. EBV-associated lymphomas in the head and neck region present as nontender swellings in Waldeyers ring, cervical lymph nodes, salivary glands, oral mucosa, and lytic bone lesions (Fig. 5). Persistent fever of unknown cause, weight loss, malaise, sweating, and abdominal or chest pain often accompany the condition. Radiation and chemotherapy are used for treatment. Of interest is the recent detection of EBV DNA in the serum of patients who have nasopharyngeal carcinoma, certain lymphomas, and gastric carcinoma. Cytomegalovirus Cytomegalovirus rarely causes mouth lesions but can be associated with persistent mucosal ulcerations (Fig. 6) in transplant patients and immunosuppressed persons. Transmission is person-to-person mainly through sexual and blood contacts. The primary infection in most persons goes unrecognized. In utero and perinatal transmission can lead to deafness, learning disabilities, and mental retardation, however. CMV enters latency in peripheral blood mononuclear cells and reactivates during immunosuppression. CMV infection recurs commonly in HIV-infected individuals and presents as pneumonitis, retinitis, or nervous system disease [17]. CMV can infect and replicate in major salivary glands, particularly in immunocompromised patients, which can lead to swelling, pain, and xerostomia, secondary to lymphocytic salivary gland infiltrates. The diagnosis of CMV infection is established by special stains and immunoprocessing (polymerase

Fig. 5. A lytic bone lesion caused by lymphoma.

zoin, or laser vaporization. Recurrence is common. Although the term leukoplakia has been used to describe the condition, there is no known associated precancerous risk. Epstein-Barr virus is well known for its ability to cause lymphocyte immortalization and malignant transformation [13,14]. Such transformation occurs in a small percentage of infected persons. The transformation process is complex and involves the upregulation of several viral and host gene products and immunosuppression [13,15]. Critical is the upregula-

Fig. 6. A painful ulceration of the palate of 1 month duration in an HIV-positive patient. Biopsy showed this to be a CMVinduced lesion that responded to high-dose antiviral medication.

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chain reaction) of biopsy specimens and specific serologic antibody tests. Successful treatment is based on establishing the diagnosis and the use of antiviral agents, such as acyclovir or ganciclovir. Herpes varicella virus or varicella-zoster virus Varicella-zoster virus is well known for causing chickenpox. It is a highly contagious virus that is generally spread during the late winter and spring months to young children who lack antibodies against varicella-zoster virus. After exposure and a 2- to 3-week incubation period, mild prodromal features appear. The first recognizable signs are fever, malaise, and a distinctive red, itchy truncal rash. The rash spreads quickly to the neck, face, and extremities and is followed shortly by the eruption of papules that form vesicles and pustules. Occasionally, oral inflammatory vesicular-ulcerative lesions develop that may be seen on the posterior palate or buccal mucosa. Anorexia, chills, fever, nasopharyngitis, and musculoskeletal aches may accompany the disease. Lesions heal within 7 to 10 days as patient antibody titers rise and control the infection. Complications such as pneumonitis and encephalitis are infrequent. Varicella-zoster virus resides latently in the sensory ganglia of the host after the initial infection. The virus reactivates in approximately 0.2% of adults, more often in elderly and immunosuppressed patients and has an increasing incidence with age. The recurrent attack is known as herpes zoster or shingles. The disease is preceded by hypersensitive skin overlying the area of attack. Within a few days, the classic manifestations are painful vesicles that occur unilaterally along nerve dermatomes. Most commonly,

lesions occur on the trunk between vertebrae T3 and L2 and on the face along the ophthalmic division of the trigeminal nerve and extend up to the midline (Fig. 7). In immunocompetent patients, vesicles break down, scab, and resolve within 2 to 4 weeks. The diagnosis of varicella-zoster virus infection is made by history, clinical findings, and serology. Polymerase chain reaction is used for diagnosis in severe cases that may involve the central nervous system [18]. Treatment involves antiviral drugs in high dosages (acyclovir, 4000 mg/d in divided doses; famciclovir, 1500 mg/d in three divided doses; valacyclovir, 3000 mg/d in two divided doses) given within the first week [19]. Supportive treatment for pain and pruritus is also in order. The most painful and discouraging complication is postherpetic neuropathy, which can be debilitating. Early use of corticosteroids along with antiviral treatment may help minimize, or even prevent, the neuropathy. Longer standing cases benefit from the use of amitriptyline, nortriptyline, topical lidocaine patches, and gabapentin, which should be considered early in the course of treatment [20,21]. A live-attenuated vaccine (Varivax) virus is currently available for the prevention of chickenpox. Human herpesvirus-6 and -7 Human herpesvirus-6 and -7 are T-cell lymphotropic herpesviruses that have significance in dentistry. Like most human herpesviruses, they are ubiquitous and capable of establishing a lifelong, latent infection in humans. HHV-6 is particularly efficient at infecting infants and young children and produces exanthem subitum (roseola) and febrile

Fig. 7. Varicella (herpes) zoster or shingles in a 65-year-old patient. Note the unilateral distribution. The vesicles/ulcers formed scabs and healed after 3 weeks. Treatment was supportive and included high-dose acyclovir.

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seizures. HHV-6 is present in saliva [22] and has been detected in salivary glands and tonsillar tissue [23]. Primary infection in adults can cause a mononucleosis-like illness. The virus is harbored during latency in peripheral blood mononuclear cells, salivary glands, mucosa, and tonsils [23]. Reactivation occurs in the immunocompromised host and is associated with fever, leukopenia, encephalitis, interstitial pneumonitis, skin rash, and bone marrow suppression. A role for HHV-6 in malignant transformation remains to be defined, although HHV-6 can transactivate other viruses, such as human papillomavirus (HPV), associated with malignant disease [24]. Human herpesvirus-7 is associated with exanthem subitum and febrile seizures and is detected in the saliva of healthy adults [25]. HHV-7 infection generally occurs later in childhood after infection with HHV-6. Case reports suggest that HHV-7 may reactivate after immunosuppression or the flu and can cause encephalitis, encephalopathy, and febrile convulsions [26]. Human herpesvirus -8 (Kaposis sarcoma herpesvirus) Human herpesvirus-8 is a sexually transmitted herpesvirus that infects endothelial cells. A secondary source of infection is organ transplantation [27]. Up to 15% of the US adult population is infected [28,29]. Kaposis sarcoma herpesvirus contains several viral oncogenes, and Kaposis sarcoma is the primary disease associated with its infection [30]. Primary effusion lymphoma and multicentric Castlemans disease also have a strong association with this virus [31]. Kaposis sarcoma is a pseudomalignancy that has a particularly high prevalence in immunocompromised patients, homosexual men infected with HIV,

and elderly persons. It attacks many different organs and is usually multifocal. Kaposis sarcoma does not metastasize but can be the cause of death. It occurs most commonly in the skin, with the mouth being the second most common site. Within the mouth, the palate and gingiva are common sites. Kaposis sarcoma is highly vascular and typically appears purplered. The initial appearance of Kaposis sarcoma is a purplish macule that enlarges to become a violaceous papule or nodule. Lesions are single or multifocal, can cause discomfort and bleeding, and can impact appearance (Fig. 8). Since the institution of high activity anti-retroviral therapy, the occurrence of Kaposis sarcoma has been much less frequent. Treatment involves lowdose radiation, chemotherapy (systemic or intralesional), and surgery.

Human papillomavirus Human papillomaviruses are small, doublestranded, non-enveloped DNA viruses That have a propensity for infecting epithelium. Approximately 5.5 million new HPV infections occur every year in the United States, and 10% to 33% of sexually active individuals are infected with the virus. Current estimates indicate that 10% to 18% of adults carry HPV, with the highest rates of infection found in 19- to 26-year-old individuals. There are more than 100 types of HPV, and at least 45 types are known to infect genital and oral epithelium. HPVs can be harbored latently within epithelium for the life of the host, undergo a lytic infection and alter epithelial cell growth and replication, or dysregulate the cell cycle, which results in

Fig. 8. Nodular Kaposi sarcoma of the palate in a patient with AIDS whose CD4 count was less than 200/mm3.

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premalignant changes. Infection outcomes depend on the infecting HPV genotype, anatomic site, and immune response. Benign genotypes (HPV 6, 11, 44, 55) replicate in the lower epidermis and differentiated cells (keratinocytes) and produce increased numbers of epithelial cells and koilocytosis. Highrisk genotypes [16,18,31,33,35] are associated with premalignant and malignant epithelial disease. Low-risk HPV types are associated with benign proliferations, such as the squamous papilloma, verruca vulgaris, condyloma acuminatum (venereal warts), and focal epithelial hyperplasia (Hecks disease). The squamous papilloma is a well-defined, pink-white, exophytic and pedunculated or stalk-like mass. This small, usually asymptomatic growth may occur on any mucosal surface. Condyloma acuminata intraorally appear as small verrucous lesions of varying sizes or they can mimic small fibromas. Condyloma acuminata occur on any mucosal surface and may be single or multiple, clustered or coalesced, and widespread (Fig. 9). Condylomas are more commonly seen in immunocompromised patients and are transmitted by oral sex. A higher prevalence of oral condyloma in HIV-positive patients on antiretroviral drugs compared to HIV-positive patients not on antiretroviral drugs has been reported. Reports have shown a decreased occurrence of most other HIV-associated oral lesions, however, since high-activity antiretroviral therapy was initiated. The common skin wart (verruca vulgaris) is a rare intraoral finding. It is most often seen on the commissures of the lips in children and adolescents and is caused by autoinoculation. Occasionally it occurs on the tongue, labial mucosa, or gingiva. Warts have

a rough, pebbly, clefted surface and a well-demarcated border. Focal epithelial hyperplasia is a multipapular condition associated with HPV-13 and -32 infection that was originally reported in Native American Indians and Eskimos. The infection is transmitted by kissing. The HPV-induced, small, flat papules occur on labial and buccal mucosa and tongue. Lesions coalesce and develop a cobblestone-like surface. Benign HPV lesions can enlarge and spread or resolve spontaneously; however, most do not regress without treatment. Ablative and chemotherapeutic approaches are useful. Surgery, laser treatment, and cryotherapy have good success in removing HPV proliferations when the basal and adjacent epithelium is removed. High-speed evacuation is recommended during laser surgery to prevent aspiration of viral DNA that might be contained within the plume. A useful topical pharmacologic approach involves podofilox 0.5% (Condylox, Oclassen), an agent that causes necrosis by arresting cells in mitosis. It is applied twice daily for 3 days followed by no treatment for the next 4 days; then the cycle is repeated up to four times. Immunomodulatory approaches include intralesional interferon, imiquimod (Aldara) 5% cream at bedtime three times per week for up to 16 weeks (alters cell cytokines and stimulates interferon production), and cimetidine (a histamine receptor antagonist), 30 mg/kg body weight (bw), given daily in divided doses usually over 8 weeks. Recurrence is seen in approximately 10% to 25% of patients generally within 3 months. Sexual partners should be examined and treated to minimize the risk of transmission and recurrences.

Fig. 9. Condyloma accuminatum associated with the human papillomavirus in a sexually active homosexual man. Treatment was by laser surgical removal.

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Infection with high-risk HPV types has an association with precancerous oral leukoplakia and squamous cell carcinoma. In one form of leukoplakia, proliferative verrucous leukoplakia, HPV-16 has been identified frequently. This finding helps explain the high rate of malignant transformation associated with proliferative verrucous leukoplakia. It can be characterized clinically as a progressive leukoplakic lesion that can vary from somewhat corrugated and flat to one that is exophytic and verrucous. Proliferative verrucous leukoplakia may have a red component and a variable microscopic presentation that ranges from hyperkeratosis and epithelial dysplasia to carcinoma. It may be asymptomatic, cause slight discomfort, or be painful. The lesion usually involves more than one mucosal surface. It occurs four times more often in women than men and occurs less commonly in smokers than nonsmokers. In one long-term study [32], more than half of proliferative verrucous leukoplakias were reported to have transformed into carcinoma less than 8 years after diagnosis. Human papillomavirus can be detected in approximately 30% of oral squamous cell carcinoma cases, which suggests that the virus may play a causative role, similar to its role in anogenital carcinoma [33]. The role of HPV in oral cancer seems different from the carcinogenic effects of tobacco and alcohol. For example, HPV-positive oropharyngeal cancers occur less often among moderate to heavy alcohol drinkers and tobacco smokers. Patients in this category also have improved survival from cancer when compared with HPV-negative head and neck squamous cell carcinoma [34]. The role of HPV in carcinogenesis may involve binding to p53 suppressor protein, which in turn enhances epithelial cell proliferation and neoplasia.

Diagnosis of HPV-infected mucosa is based on the history, clinical findings, and cellular characteristics seen in biopsy specimens (koilocytes). Confirmation can be made by immunohistochemistry, in situ hybridization, or polymerase chain reaction processing. Currently, specific identification and typing are complex and expensive. There is no effective vaccine, and antiviral medications do not eliminate latent infection. The most effective treatment is by surgical approaches and behavior modification (eg, barrier techniques). In the future, HPV analyses may prove important for directing treatment, such as by gene therapy.

Enteroviruses Enteroviruses are single-stranded, small RNA positive-sense, nonenveloped viruses that cause a spectrum of human disease. The family includes polioviruses, coxsackieviruses (23 serotypes), echoviruses (32 serotypes), human enteroviruses 68 to 71, hepatitis virus A, and several nonhuman enteric viruses that are well known for causing foot-andmouth disease in livestock. Most nonpolio enteroviruses infect nasopharyngeal cells and inhabit the alimentary (enteric) tract. They are transmitted by ingestion (fecal-oral route) and contaminated saliva of close contacts in poor sanitary environments and warm climates. Many enterovirus infections are endemic in Southeast Asia [35]. The bulk of enterovirus infections are benign and self-limiting, manifested mostly by fever alone [36]. The primary enterovirus infections that involve the oropharyngeal complex are hand-foot-and-mouth disease and herpangina. These infections occur primarily in children. Hand-foot-and-mouth disease is caused

Fig. 10. Oropharyngeal ulcers associated with coxsackievirus infection.

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Fig. 11. Erosive lichen planus of the buccal mucosa developed in a patient who previously had been diagnosed as hepatitis C virus positive. A cause-and-effect relationship has not been proved conclusively.

by various members of the Coxsackie group and enterovirus 71. They produce oral ulcerations and extraoral rashes of the hands and feet (Fig. 10). Herpangina, caused by group A and sometimes group B coxsackieviruses, has the main feature of erythema and multiple vesicles of the oropharynx and posterior tongue. Both conditions are accompanied by pain, fever, headache, lymphadenopathy, and malaise. Infection by nonpolio enteroviruses can produce lymphonodular pharyngitis, which is manifested mainly by nonulcerative oropharyngeal nodules, abdominal pain, vomiting, conjunctivitis, and croup. Serious infections can result in meningitis, encephalitis, paralysis, myocarditis, hepatitis, and death. Although there is no viral latency, patients can become reinfected by one of the many serotypes. The diagnosis of enteroviral infection can be made by viral culture, serology, and nucleic acid amplification [36]. Treatment for self-limiting oropharyngeal enterovirus infections in immunocompetent individuals is supportive and palliative. Immunoglobulin, interferon-a, and the antiviral agent pleconaril are available for treatment of persons with meningitis and an immunocompromised status [37].

Hepatitis C virus Hepatitis C virus (HCV) is a small, single-stranded RNA virus of the Flaviviridae family that was previously known as one of the non-A/non-B hepatitis viruses. Infection by HCV is a widespread global disease. In the United States, it is estimated that 4 million Americans are infected and potential carriers of HCV, with 30,000 new infections and 10,000

deaths each year [38]. Transmission is highest among drug users, who share HCV-contaminated needles, and persons who have large or repeated percutaneous exposures. Of individuals infected, approximately 80% develop hepatitis, and 10% to 20% of those persons develop cirrhosis. Treatment involves combination chemotherapy and liver transplantation. Dental implications relate to the need for bodily fluid borne pathogen control in the dental office, demand for proper sterilization and disinfection protocols, and use of barrier techniques to protect against contaminated blood and saliva. HCV has been detected in saliva [39]; however, it is less infectious than hepatitis B virus. HCV carriers often are not aware of their seropositive status. Many questionable reports [40] indicate a relationship between HCV infection and oral lichen planus. Although this occurrence has not been documented conclusively, there seems to be an unexplainable risk that may not be coincidental. Because oral lichen planus can be a source of oral pain and interfere with oral functions, its diagnosis and treatment are important considerations. The diagnosis of oral lichen planus is based its on clinical characteristics (Wickham striae, erosions, ulcers) and biopsy (Fig. 11). Effective treatment requires the elimination of drugs that can cause similar appearing lichenoid eruptions, followed by the use of topical or systemic corticosteroids.

References
[1] Whitley RJ. Herpes simplex virus infections. Lancet 2001;357:1513 8. [2] Kameyama T, Yamamoto S, Hwang CB, Shillitoe EJ.

S. Silverman, C.S. Miller / Oral Maxillofacial Surg Clin N Am 15 (2003) 7989 Shedding of herpes simplex virus type 1 into saliva. J Oral Pathol 1988;17:478 81. Higgins CR, Tatnall FM, Leigh IM. Natural history, management and complications of herpes labialis. J Med Virol 1993;1:22 6. Langenberg AG, Ashley RL, Leong WP, Straus SE. A prospective study of new infections with herpes simplex virus type 1 and type 2. N Engl J Med 1999;3412: 1432 8. Eisen D. The clinical characteristics of intraoral herpes simplex virus infection in 52 immunocompetent patients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998;86:432 7. Logan HL, Lutgendorf S, Hartwig A, et al. Immune stress, and mood markers related to recurrent oral herpes outbreaks. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998;86:48 54. Miller CS. Diagnosis and management of orofacial herpes simplex virus infections. Dent Clin North Am 1992;36:879 95. Darragh TM, Berger TG, Yen TS. Identification of herpes simplex virus DNA in lesions of erythema multiforme by the polymerase chain reaction. J Am Acad Dermatol 1991;24:23 6. Abramowicz M. Drugs for non-HIV viral infections. Medical Letter 1999;41:113 20. Balfour Jr HH. Antiviral drugs. N Engl J Med 1999; 16:1255 68. Horowitz E, Pisanty S, Czerninski R, et al. A clinical evaluation of a novel liposomal carrier for acyclovir in the topical treatment of recurrent herpes labialis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1999; 87:700 5. Raborn GW, Martel AY, Grace MGA, et al. Oral acyclovir in prevention of herpes labialis: a randomized, double-blind, multi-centered trial. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998;85:55 9. Kieff E. Epstein-Barr virus: new insights. J Infect Dis 1995;171:1323 4. Cruchley AT, Niedobitek G. Epstein-Barr virus: biology and disease. Oral Diseases 1997;S156 63. Knecht H, Al-Homsi AS, McQuain C, Brousset P. Epstein-Barr virus oncogenesis. Crit Rev Oncol Hematol 1997;26:117 35. Hatzivassiliou E. Cellular signaling pathways engaged by the Epstein-Barr virus transforming protein LMP1. Front Biosci 2002;7:319 29. Cunha B. Central nervous system infections in the compromised host: a diagnostic approach. Infect Dis Clin North Am 2001;15:567 90. Markoulatos P, Siafakas N, Plakokefalos E, et al. Laboratory diagnosis of common herpesvirus infections of the central nervous system by a multiplex PCR assay. J Clin Microbiol 2001;39:426 32. Kost RG, Straus SE. Postherpetic neuralgia: pathogenesis, treatment, and prevention. N Engl J Med 1999; 335:32 42. Kanazi GE, Dworkin RH. Treatment of postherpetic neuralgia: an update. Drugs 2000;59:1113 26.

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[21] Watson CPN. A new treatment for postherpetic neuralgia. N Engl J Med 2000;343:1563 5. [22] Levy J. Three new human herpesviruses (HHV6,7, and 8). Lancet 1997;349:558 63. [23] Roush KS, Margraf LR, Krisher K, et al. Prevalence and cellular reservoir of latent human herpesvirus 6 in tonsillar lymphoid tissue. Am J Clin Pathol 2001;116: 648 54. [24] Dockrell DH, Paya CV. Human herpesvirus 6. Mayo Clin Proc 1999;74:163 70. [25] Wyatt LS. Human herpesvirus 7 is a constitutive inhabitant of adult human saliva. J Virol 1992;66:3206 9. [26] Sugaya N, Miura M, Ishizuka T, et al. Influenza encephalopathy associated with infection with human herpesvirus 6 and/or human herpesvirus 7. Clin Infect Dis 2002;34:461 6. [27] Regamey N, Wernli M, Witschi A, et al. Transmission of human herpesvirus 8 infection from renal-transplant donors to recipients. N Engl J Med 1998;339:1358 63. [28] Baillargeon J, Hettler E, Harrison C, et al. Seroprevalence of Kaposis sarcoma-associated herpesvirus infection among blood donors from Texas. Ann Epidemiol 2001;11:512 8. [29] Schulz T. Kaposis sarcoma-associated herpesvirus (human herpesvirus-8). J Gen Virol 1998;79:1573 91. [30] Jaffe HW, Pellett PE. Human herpes virus 8 and Kaposis sarcoma: some answers, more questions. N Engl J Med 1999;340:1912 3. [31] Chadburn A, Nador RG, Liu YF, et al. Kaposis sarcoma-associated herpesvirus sequences in benign lymphoid proliferations not associated with human immunodeficiency virus. Cancer 1997;80:788 97. [32] Silverman S, Gorsky M. Proliferative verrucous leukoplakia: a follow-up of 54 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997;84:154 7. [33] Miller CS. Human papillomavirus as a risk factor for oral squamous cell carcinoma: a meta-analysis, 1982 1997. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2001;91:622 35. [34] Gillison ML, Capone RB, Spafford M, et al. Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst 2000;92:709 20. [35] Lum LC, McMinn PC, Goh AY, et al. Echovirus 7 associated encephalomyelitis. J Clin Virol 2002;23:153 60. [36] Sawyer M. Enterovirus infections: diagnosis and treatment. Curr Opin Pediatr 2001;13:65 9. [37] Nigrovic L. Whats new with enteroviral infections? Curr Opin Pediatr 2001;13:89 94. [38] Lauer GM, Walker BD. Hepatitis C virus infection. N Engl J Med 2001;345:41 52. [39] Hermida MFM, Barral S, Laredo R, et al. Detection of HCV RNA in saliva of patients with hepatitis C virus infection by using a highly sensitive test. J Virol Methods 2002;101:29 35. [40] Bagan JV, Ramon C, Gonzales L, et al. Preliminary investigation of the association of oral lichen planus and hepatitis C. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998;85:532 6.

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Diagnosis and treatment of oropharyngeal candidiasis

Joel B. Epstein, DMD, MSD, FRCD(C)a,b
a

Department of Oral Medicine and Diagnostic Sciences, College of Dentistry, Chicago Cancer Center, 801 South Paulina, Chicago, IL 60612, USA b Interdisciplinary Program on Oral Cancer, College of Medicine, Chicago Cancer Center, 801 South Paulina, Chicago, IL 60612, USA

Candida, a yeast-like fungus, is present in the oral cavity of 40% to 60% of the population [1,2]. Candida albicans is the most commonly isolated species [1,2] and is the one most likely to cause disease in humans [3]. Other Candida species include Candida tropicalis, Candida krusei, (both of which are prevalent in immunosuppressed and cancer patients), Candida guilliermondii, and Candida parapsilosis (of limited pathogenicity but associated with infection of indwelling vascular access devices). The species of colonizing organism is important, because resistance to antifungal agents is more common in some species, including C. tropicalis and C. krusei. Reports of resistance to systemic agents are increasing. Candida is common in the oral and gastrointestinal flora, and presence in the oral cavity is increased in patients with dentures, individuals who smoke, persons with xerostomia, and patients who use broadspectrum antibiotics and steroids. The use of immunosuppressive purine analogus (eg, fludarabine, cladribine) and antithymocyte globulin increases risk of invasion. The risk of invasive candidiasis is increased in persons with neutropenia and mucosal injury. The use of growth factors to promote recovery of white cell count in neutropenic patients may reduce the risk of candidiasis and require further study. Age and prior splenectomy increase the risk of infection. Many sedatives, tranquilizers, and some antihypertensive medications may cause dry mouth, which increases the risk of oropharyngeal infection. The use of dentures and tobacco increases the frequency of colonization of the oropharynx and increases the risk of clinical

E-mail address: jepstein@uic.edu

infection. Cases of superficial and invasive candidiasis are occurring more frequently because of increased use of antibiotics and immunosuppressive agents and advances in medical management, such as chemotherapy, solid organ transplantation and hematopoietic cell transplantation (HCT), parenteral nutrition, and invasive surgical procedures [4]. Candidiasis of the oropharynx and esophagus is associated with HIV infection and is a clinical predictor of disease progression in HIV-infected patients [5,6]. The common portals of entry of Candida are the oropharynx and gut, sites that are commonly colonized by the organisms [7]. Invasive fungal infections are one of the major complications in transplant medicine, potentially resulting in mortality [8]. Heart transplant recipients develop fungal infections in approximately 20% of cases [8]. In renal transplant patients, approximately 5% of infections are caused by Candida species that present as urinary tract infection and fungemia [8]. Diagnosis of systemic infection is difficult, resulting in limited ability to make an early diagnosis, and invasive infection caused by Candida and Aspergillus is potentially fatal in neutropenic patients [7]. Higher rates of infection and mortality are seen in patients with hematologic cancer as compared to patients with solid tumors. Candida accounts for up to 70% of invasive fungal infections in cancer patients, and a doubling of the rate of fungal infections in all hospitalized patients was reported in the 1980s [7]. Candida is the fourth most common pathogen in the blood [7]. Fungal infections, particularly candidiasis and aspergillosis, in HCT are common and result in morbidity and mortality in these high-risk patients [9]. Increasing infections with non-albicans Candida

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have been identified and include species such as C. tropicalis, C. glabrata, C. parapsilosis, and C. krusei, which show increased resistance to a commonly used antifungal agent, fluconazole. C. glabrata and C. parapsilosis are more common in patients with solid tumors, and C. tropicalis and C. krusei are more common in HCT recipients [7]. Intact mucosa serves as a barrier to systemic infection, but cancer therapies may lead to a violation of the barrier, which promotes invasive, systemic infection. Fever caused by fungi typically occurs 7 to 14 days after neutropenia and is the most common cause of fever of unknown origin not responsive to antibiotics [7]. Aspergillus tends to occur later, 20 days after HCT, and most patients have nasal or respiratory symptoms, in contrast to invasive candidiasis, which is typical 7 to 10 days after onset of neutropenia [7]. In transplant medicine, the risk for candidiasis also depends on the occurrence of graftversus-host disease and the use of immunosuppressive therapy for its prevention and management [10]. Gradual restoration of immune function occurs after 3 months of HCT, depending on the discontinuation of immunosuppressive therapy for graft-versus-host disease. The time to engraftment has decreased because of changes in transplantation and use of hematopoietic growth factors, reducing the risk of invasive fungal infection, which occur more commonly during the postengraftment period [10]. Fungal hypersensitivity syndrome, a condition promoted by the public media, has been associated with multiple and nonspecific complaints, including fatigue, impaired concentration and memory, respiratory symptoms and asthma, gastrointestinal complaints, muscle and joint pain, and skin and urogenital problems. Recent support for this possible condition was reported in a study in which nystatin capsules to 116 patients were provided in a 4-week randomized controlled trial. The symptoms were assessed by questionnaire, and the results showed nystatin to be superior to placebo in reducing localized and systemic symptoms [11]. Despite the various topical and systemic agents available to treat patients with oropharyngeal and systemic candidiasis, optimal management can be elusive. Topical therapy is generally effective in uncompromised patients with oropharyngeal candidiasis; however, the optimal treatment for immunocompromised patients and patients with chronic or recurrent infection is not well documented. A general overview of the etiology, pathogenesis, and treatment of candidiasis has been presented [4]. The purpose of this article is to review the local and systemic risk factors for oropharyngeal candidiasis, review the clinical manifestations and diag-

nosis of infection, and discuss current approaches to management.

Risk factors Local and systemic risk factors and characteristics of the organisms increase an individuals susceptibility to candidiasis. Host factors include age (ie, neonates and elderly people), diabetes, oral prostheses (particularly acrylic dentures), use of broad-spectrum antibiotics, steroids and other immunosuppressive drugs, hyposalivation, disruption of oral mucosa, dietary factors (eg, high carbohydrate diet, iron deficiency anemia), tobacco use, cancer and cancer therapy, and HIV infection (see Box 1). Patients may have multiple factors that predispose them to candidiasis.

Box 1. Risk factors for development of oropharyngeal candidiasis Local factors Xerostomia (eg, because of radiotherapy, chemotherapy, Sjogrens syndrome, diabetes, medications) Use of broad-spectrum antibiotics or steroids High carbohydrate diet Leukoplakia, oral cancer Dentures (eg, poor fit, trauma, uncleanliness) Cigarette use Systemic factors Neonate, advanced age Diabetes Nutritional deficiencies (eg, iron, folate or vitamin B12 deficiency) Malignancies (eg, leukemia, agranulocytosis) Immunosuppression (eg, AIDS, steroid use)

Microbial factors Factors related to the organism that have been implicated include cell-wall components that enhance adhesion to epithelial cells, hydrophobicity of the organism, germ tube formation, presence of mycelia, ability to persist in epithelial cells, production of enzymes and toxins, induction of tumor necrosis factor, and phenotypic switching [12]. Candida is a

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dimorphic yeast that demonstrates phenotypic switching from the yeast form to a filamentous form (pseudohyphal), and although the pseudohyphal form has been believed to be more pathogenic, both forms may be associated with clinical infection.

Systemic risk factors Neonates are susceptible to oropharyngeal candidiasis because of their immature immune system and exposure to the organism during or shortly after birth [2]. Exposure to C. albicans from infected bottle nipples or the hands of nurses or the mother also may lead to oropharyngeal candidiasis [2]. The infection usually can be treated effectively with topical agents [13]. Elderly patients may present with a number of risk factors related to reduced saliva production, denture use, and immune function, which result in increased risk, although age alone does not seem to be a risk factor. Patients with diabetes are at increased risk of oropharyngeal candidiasis [2]. They are colonized more commonly and with higher than normal numbers of C. albicans [5,12]. Elevated glucose levels, reduced chemotactic factor in saliva, altered neutrophil function, and reduced saliva volume may play a role in the pathogenesis of clinical infection [2]. Patients with cancer are at high risk for developing oropharyngeal candidiasis [3,6,14 24]. Oropharyngeal candidiasis is reported in up to one third of patients who receive head and neck radiation therapy, and risk is increased in patients who are colonized before radiation therapy [20]. The presence of clinical oropharyngeal candidiasis may complicate oral mucositis; in patients treated with radiotherapy, risk factors include xerostomia, mucosal damage, the presence of oral prostheses, and continuing tobacco and alcohol use during treatment [20]. In addition to causing mucosal damage, chemotherapy may result in transient xerostomia, which may result in acute oropharyngeal infections. Use of antibiotics may result in overgrowth of fungi [22]. Oropharyngeal candidiasis is reported in up to one third of patients with leukemia [1,3,4,18,20,21]. The intensive radiation and chemotherapy used to treat these patients can disrupt the oral mucosa and cause a shift in the oral flora, thus favoring overgrowth of Candida [22]. Frequent treatment with broad-spectrum antibiotics in neutropenic patients also alters the normal oral flora and predisposes to oropharyngeal candidiasis [14]. Candida infections, although generally superficial, can become invasive or systemic in these patients and may result in mortality [16,18]. It has been

reported that systemic candidiasis develops more frequently in patients with leukemia who have oropharyngeal candidiasis than in patients who are colonized before treatment, and it is associated with prolonged neutropenia [16,24]. Candida is present in approximately 90% of patients with acute leukemia who undergo chemotherapy [24]. Candidiasis in patients with leukemia and patients who undergo HCT causes morbidity (eg, altered taste, oral sensitivity, dysphagia caused by esophagitis, fever) and results in considerable risk of mortality during neutropenia [18,19,21,23]. Systemic candidiasis was shown to be increased in patients with leukemia with ulcerative oral mucositis [18]. Oropharyngeal candidiasis also is associated with long-lasting fever and decreased bone marrow function in patients with leukemia [23]. Patients with depletion of CD4+ lymphocytes because of HIV infection are at high risk for oropharyngeal candidiasis. Oropharyngeal candidiasis is the most prevalent opportunistic oral infection in AIDS, and it occurs in as many as 95% of patients [5,6,17,24 27]. The development of candidiasis in HIV-infected patients suggests progression of immunosuppression [5,6], and in patients in whom candidiasis has been controlled with therapy, progression or recurrence of the candidiasis is commonly seen in advancing disease. The clinical manifestations of oropharyngeal candidiasis in AIDS patients include the pseudomembranous and erythematous forms and angular cheilitis [5,26]. Pain and change in taste that often accompany this infection can result in poor appetite, which leads to weight loss [17]. Oropharyngeal candidiasis can extend into the esophagus and cause gastrointestinal bleeding and severe regional and systemic infection [17,25,28,29]. Therapy should consider an altered host response to help combat the infection, frequent relapses, persistent infection that requires prolonged treatment, potential antifungal drug resistance, and adverse drug effects [6]. Broad-spectrum antibiotics create a favorable environment for the proliferation of Candida species by altering the oral flora [30]. Use of corticosteroids also places patients at increased risk [30]. Xerostomiainducing medications may place the patient at risk of infection by affecting saliva.

Local and oral factors Impaired salivary gland function increases the risk of oropharyngeal candidiasis [1,12,30] Because of the decreased saliva secretion and low pH. Saliva protects against candidiasis by diluting and moving organisms

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from mucosal surfaces. Antimicrobial proteins in the saliva, including defensins, lactoferrin, sialoperoxidase, lysozyme, histidine-rich polypeptides, and specific anti-Candida antibodies, interact with the organism [4]. Lactoferrin, a nonspecific defense factor in saliva and mucosal secretions, seems to have fungicidal activity against Candida species. Drugs that cause hyposalivation predispose patients to oropharyngeal candidiasis. Patients with head and neck cancer treated with radiation to the head and neck develop disturbances of the salivary glands that may be permanent [12]. HCT recipients and patients who receive chemotherapy also can experience salivary gland dysfunction [7]. Oropharyngeal candidiasis is reported in up to 65% of older patients who wear full upper dentures [3]. Increased susceptibility to oropharyngeal candidiasis in denture wearers may be caused by enhanced adherence of Candida to acrylic, reduced saliva flow under the denture, poorly fitted dentures, or poor oral hygiene [1,2]. The risk for oropharyngeal candidiasis is increased when there is disruption of the oral mucosa [1,12]. The oral epithelium is a physical barrier that prevents invasion of microorganisms, and epithelial turnover helps clear adherent organisms from the mouth. Patients who receive chemotherapy have an altered rate of mucosal regeneration, which may result in increased vulnerability to infection [12]. Patients with mucositis, especially individuals with an immunocompromised system, are at high risk for invasive candidiasis [9,10,17 19]. Local use of antimicrobial products and antiinflammatory agents (steroids) increases the risk for colonization and infection [31]. Other studies have shown that chronic use of oral topical steroids and steroid inhalers also increases the risk of oropharyngeal candidiasis, possibly by suppressing cellular immunity and inhibiting phagocytosis [2,30,31]. Tobacco use represents a local factor that is associated with increased risk of colonization and clinical infection [20,30].

individuals with chronic immunosuppression, because oropharyngeal manifestations can persist for extended periods regardless of the clinical findings. Box 2. Classification of oropharyngeal candidiasis Pseudomembranous (thrush) Erythematous Denture stomatitis (atrophic) Angular cheilitis Leukoplakia caused by hyperplastic candidiasis Candidal ulceration

Clinical presentation Symptoms that may be associated with Candida infection include oral and pharyngeal burning, sensitivity, altered taste, and change in the sense of smell. If involvement extends to the oropharynx, dysphagia and odynophagia may occur. Oropharyngeal candidiasis can be classified clinically in several ways (see Box 2) [3,30,32]. The use of acute and chronic descriptors of candidiasis should be avoided, particularly in

The classic form of candidiasis is the pseudomembranous form (thrush), which is characterized by soft, yellowish-white plaques on the oral mucosa that can be removed with vigorous rubbing and may leave red or bleeding sites after removal [3,32]. The erythematous form of candidiasis frequently develops in patients who take antibiotics or use steroid inhalers and in patients with HIV [3,30]. This form of candidiasis is characterized by sensitive and painful erythematous mucosa with few, if any, white plaques. The dorsal aspect of the tongue and the palate is generally involved, and the patient presents with red mucosa with loss of papillae on the tongue and patchy red changes in the palate, although any portion of the oral mucosa can be affected [30]. In denture stomatitis, or denture sore mouth (atrophic candidiasis), the palatal mucosa in contact with the denture is affected and is chronically erythematous and edematous. A hyperplastic response may be seen, although patients generally experience no symptoms [3]. Treatment includes correction of denture faults, careful cleaning of dentures, and antifungal therapy [33]. Angular cheilitis, an inflammatory reaction at one or both corners of the mouth, is characterized by painful red fissures. C. albicans is a common pathogen, and infection is frequently accompanied by Staphylococcus aureus infection [3]. Denture wearers and patients with HIV are predisposed to this type of presentation. Although denture stomatitis and angular cheilitis usually do not indicate serious disease, severe infections may occur in immunocompromised individuals [4]. Leukoplakia caused by hyperplastic candidiasis may represent a precancerous condition that presents as unilateral or bilateral, elevated, white mucosal lesions on the buccal mucosa, tongue, lips, and floor of the mouth [3,29]. Candida species are present in

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the tissue, can be identified on biopsy, and may be cultured from the mouth. They may not be the cause of the lesions, however, and may be merely secondary invaders [3]. Clinical signs and symptoms range from painless plaque-like white patches to nodular erythroplakic lesions that cause the patient discomfort. Smoking seems to be a risk factor for development of hyperplastic candidiasis.

Treatment Susceptibility testing: identification of species and resistant strains Susceptibility testing of fungi to antifungal agents is not as standardized as that of bacteria but is evolving, and guidelines are being developed by the National Committee for Clinical Laboratory Standards [37]. The current applicability of in vitro antifungal susceptibility tests is limited by poor standardization and insufficient correlation of in vitro test results with clinical outcome [38 41]. Antifungal susceptibility studies may help clarify which strains are likely to develop resistance during long-term therapy [42]. History of treatment Gentian violet, an aniline dye, was used for topical treatment until the first topical polyene antibiotic, nystatin, became available in 1951 [43]. The first systemic antifungal agent, amphotericin B, was reported in 1956 and is the standard against which newer systemic therapies are compared. The azoles include the imidazoles and the triazoles. The first azole, benzimidazole, was discovered in 1944 [43]. Miconazole and clotrimazole (both identified in 1969) and ketoconazole (1977) are imidazoles. The antifungal activity of the triazoles, including fluconazole and itraconazole, was reported in the mid-1980s. Treatment approach Underlying risk factors for colonization and infection should be managed whenever possible. For example, in patients with hyposalivation, treatment with sialagogues should be considered. Oral prostheses should be disinfected or topical antifungal agents should be applied to impact colonization of the acrylic surface, and instructions in denture use should be provided. If tobacco use is identified as a risk factor, tobacco cessation should be encouraged. In patients with diabetes, improved glucose control may reduce oral candidiasis. In patients with neutropenia, use of hematopoietic growth factors may speed recovery of blood counts, which reduces risk of local and systemic Candida infection. Changes in use of medications that increase the risk of Candida colonization and infection should be considered (eg, it may be possible to replace topical steroid use with the use of other topical immunosuppressive medications). Various systemic and topical agents are available to treat oropharyngeal candidiasis (Table 1) [4,44].

Systemic infection Systemic Candida infection is usually caused by C. albicans and less frequently by C. krusei and C. tropicalis in immunosuppressed patients. Patients with neutropenia caused by leukemia or from treatment of their malignancy, patients with indwelling intravascular lines, and patients who receive antibiotics or parenteral nutrition are at risk for Candida septicemia. Candida endocarditis is related to intravascular trauma (eg, cardiac catheterization, surgery) and is more common on prosthetic valves, where it can become a life-threatening infection. Candidiasis that involves the esophagus, trachea, bronchi, or lungs is an AIDS-defining condition [28]. All forms of systemic disease are serious and cause morbidity and risk of mortality. Intravenous amphotericin B is the treatment of choice, although ketoconazole or fluconazole is preferred for chronic mucocutaneous candidiasis [34].

Diagnosis The diagnosis of candidiasis is based on clinical signs and symptoms, laboratory testing, and the response to antifungal treatment. Laboratory tests include smears from the lesions using Grams stain or a potassium hydroxide preparation or cultures from the skin, mouth, vagina, urine, sputum, or stool [5,35]. A culture is obtained if identification of the species or strain is desired. One must remember, however, that the diagnosis of oropharyngeal candidiasis cannot be based solely on the presence of Candida species because the organism is a common commensal in the oral flora [4]. Studies have shown that high colony counts of Candida species in saliva collections correlate with the presence of clinical infection, and quantitative counts may be used in diagnosis [36]. Occasionally, histologic evidence is necessary, specifically in cases of hyperplastic candidiasis (candidal leukoplakia), mucocutaneous candidiasis, and invasive candida ulceration in immunosuppressed patients.

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Table 1 Routes of action of antifungal agents for the treatment of oropharyngeal candidiasis Route of action Class and agent Polyenes Nystatin Amphotericin B Imidazoles Clotrimazole Miconazole Ketoconazole Triazoles Fluconazole Itraconazole Other Chlorhexidine gluconate 0.2% (antiseptic for denture disinfection) Denture cleansers Topical X X X X X X X X X Systemic

Topical agents have been the mainstay of therapy, particularly in uncomplicated cases. If possible, topical preparations should be used before systemic antifungal drugs [45] because they are not absorbed systemically and lack adverse systemic effects and the possible drug interactions of systemic agents. Salivary action may dilute and rapidly eliminate topical drugs from the oral cavity, however, which reduces their effectiveness [46], and compliance with required repeated topical application impacts efficacy. Topical agents are available in various formulations, including oral rinses, troches, powders, and vaginal tablets and creams. Systemic agents are used when topical therapy has been ineffective or not tolerated, primarily in immunocompromised patients with cancer or HIV infection. Topical and systemic medications are used to attempt prophylaxis in patients who receive HCT. Topical therapy The medication chosen should be appropriate for the conditions in the oral cavity, and cost should be considered. The taste and texture should be considered when selecting a medication and formulation. Unfortunately, many of the oral products include high concentrations of sucrose and have a high cariogenic potential, which is a particularly important consideration in dentate patients with dry mouth. In patients with dry mouth, oral rinses should be used because tablets not only may dissolve poorly but also may become rough with use, which results in physical irritation of the oral tissue. Antifungal creams may be readily applied to the surface of dentures, but their

taste and texture may not be tolerated if they are applied without an occlusive appliance. Creams are easily applied to the corners of the mouth. A singledose trial of an antifungal agent provides guidance on product acceptability by the patient. Gentian violet was commonly used to treat oropharyngeal candidiasis until the advent of polyene antifungal medications [30] and was replaced quickly by the polyenes because of emerging resistance and local side effects, such as staining and irritation of the oral mucosa [43,47]. Three polyenesnystatin, amphotericin B, and natamycin (used only for ocular infection)are available. These agents act by binding to ergosterol in the cell membrane of fungi, altering cell-membrane permeability, and causing pores and leakage of cellular components, which leads to microbial death [43,48]. Nystatin is the most widely used agent for the initial treatment of patients with oropharyngeal candidiasis [1,2]. It is available in oral rinse, topical cream, oral pastille, and vaginal tablet and powder [1,2,5]. Nystatin is not absorbed systemically and lacks serious toxicity. Adverse effects include nausea, vomiting, and diarrhea [43], which can be problematic for cancer patients who are already nauseated from chemotherapy. The oral rinse is heavily sweetened with sucrose, which increases the risk of caries formation. If chosen, nystatin suspension should be used with precautions to reduce caries risk. The oral rinse may be useful for edentulous patients, but the tablets may not dissolve well in the mouth and may be irritating to the mucosa, particularly if it is friable or damaged [1]. Although nystatin is commonly used as prophylaxis for treatment of oropharyngeal candidiasis in AIDS and cancer patients, several reports have cited disappointing results in these patients, with frequent treatment failure and early relapse [6,15,16,19]. Antiseptic agents have been assessed for antifungal effect. An in vitro study of antifungal effects of ListerineR and chlorhexidine (0.12% and 0.2%, respectively) [49] showed potential value in suppression of Candida species. Chlorhexidine rinse has been assessed in patients with leukemia, and suppression of Candida colonization has been demonstrated [31]. In patients with symptomatic oral mucositis, alcohol content, the presence of phenol, and intense flavoring agents may limit use of commercial antiseptic products because of mucosal irritation. Care should be taken when using more than one topical agent simultaneously. Two studies that examined the compatibility of nystatin with chlorhexidine digluconate in the treatment of patients with oropharyngeal candidiasis found that both drugs become ineffective when combined [50,51]. Several studies

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have compared various topical and systemic agents (eg, nystatin and amphotericin B with fluconazole or ketoconazole) to determine what is best tolerated, most effective, and least expensive in different patients [19,52 55]. The azoles are fungistatic and interfere with synthesis of ergosterol in the fungal organism, which causes an increased permeability of the cell membrane [1]. Clotrimazole, an imidazole, was the first broadspectrum antifungal agent of its class [1]. Clotrimazole troches are more palatable than nystatin oral suspension and may be used in patients who cannot tolerate the taste of nystatin [12,56]. Clotrimazaole has been reported to be effective for prophylaxis and treatment of oropharyngeal candidiasis in cancer patients, in whom it may prevent the development of esophagitis [57], but it seems to be less effective than fluconazole in treating HIV-infected patients with oropharyngeal candidiasis [5,58]. Like nystatin oral troches, however, clotrimazole troches may be poorly tolerated by AIDS patients or patients with xerostomia caused by cancer therapy [12]. Miconazole also has been shown to be effective in patients with oropharyngeal and esophageal candidiasis [59]. When topical agents cannot effectively control oropharyngeal candidiasis, combining topical therapy with a systemic agent may eradicate the infection while allowing a lower dose and shorter course of the systemic agent [1]. Systemic therapy Systemic therapy may be necessary in patients with oropharyngeal candidiasis that is refractory to

topical treatment, in patients who cannot tolerate topical agents, and in patients at high risk for systemic infection. It may be chosen for convenience of use and ease of patient compliance (Table 2). Amphotericin B Intravenous amphotericin B has been shown to be effective in patients with severe oropharyngeal candidiasis and in patients with infection refractory to other agents [2,6]. Low-dose, prophylactic use has been shown to be effective in neutropenic HCT recipients [60]. Amphotericin B also has been used prophylactically in solid organ transplant recipients [61]. Amphotericin B is used primarily in patients at risk for progressive and potentially fatal fungal infections because of the potential toxicity of the medication. Potential toxicities include general toxicities (eg, fever, shaking chills, malaise, weight loss), renal toxicity, gastrointestinal effects (eg, nausea, vomiting, diarrhea, cramping, altered liver function), neurologic symptoms (eg, headache, hearing loss, dizziness, visual changes, peripheral neuropathy), muscle/joint pain, dermatologic reactions (eg, rash, itching), hematologic effects (eg, anemia), and cardiovascular and pulmonary toxicity. Despite its toxicity, amphotericin B remains the gold standard of antifungal medications because of its broad spectrum of action, clinical efficacy, and limited evidence of fungal resistance. Azoles The azoles (eg, miconazole, clotrimazole, ketoconazole, fluconazole, and itraconazole) have been

Table 2 Strategy for managing fungal infections in high-risk neutropenic patients Risk factor Oral colonization Oral candidiasis Probable or proven aspergillosis Possible fungal infection (fever of unknown origin) Infection by Candida Infection by Aspergillus Oral Topical antiseptic/polyene Fluconazole 400 mg/d Topical and oral/parenteral Fluconazole 400 mg/d Itraconazole 400 mg/d Itraconazole 400 mg/d Fluconazole 400 mg/d for maintenance Intraconaole 400 mg/d for maintenance Parenteral 200 mg/d if no po 200 mg/d if no po Ambisome 200 mg/d Itraconazole 200 mg/d if no po Ambisome 200 mg/d Itraconazole 200 mg/d if no po Fluconazole 400 mg/d for treatment Ambisome 200 mg/d

Oral route for prophylaxis and maintenance, parenteral for treatment; dose range 200 400 mg/d for fluconazole, with higher doses in North America. Modified from Wingard JR. Approach to invasive fungal infection after blood or marrow transplantation. Transplant Proc 2000;32:1543 4.

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widely used to treat patients with superficial and systemic fungal infections. Ketoconazole was the first imidazole found to have systemic activity, and although it is effective in the treatment of oropharyngeal candidiasis in patients with cancer and HIV, several studies have shown that ketoconazole is less effective than fluconazole [5,14,30,62,63]. Ketoconazole requires gastric acidity for absorption, which may reduce its effectiveness in patients with AIDS or other gastrointestinal disorders and persons with limited food intake [1]. The most frequent adverse effects described for ketoconazole include nausea, vomiting, abdominal pain, and itching [1,62]. The adverse event of greatest concern is hepatotoxicity, which may result in hepatitis and, rarely, hepatic failure [1,40,43,45,62]. Ketoconazole is less costly than the newer azoles. A study by Donnelly et al [54] found ketoconazole to be no more effective than amphotericin B in preventing yeast infection in neutropenic patients, and use was not recommended [64]. The triazoles, fluconazole and itraconazole, are in common use. Both medications have been shown to be effective in the treatment of oropharyngeal candidiasis in patients with cancer and HIV infection, and they are widely used in these patients [15,30,55,57,63,65]. Itraconazole and fluconazole have fewer side effects than the azoles, and are available in oral formulations. Fluconazole offers no protection against Aspergillus species and has been associated with fungal resistance [27], although this may be overcome in many cases by increasing the dose. Fluconazole is useful in patients who require prolonged antifungal therapy, because it is well tolerated and is taken only once a day [25]. Fluconazole prophylaxis against candidiasis in HCT patients and patients with leukemia has been conducted, and it is used in some centers [18,66]. Although studies show reduction in Candida colonization, not all studies have shown an effect on systemic infection [18]. Unfortunately, C. krusei is resistant to fluconazole, and increased infection by C. krusei in patients with leukemia indicates the need for caution in the use of fluconazole in these patients [18]. Further studies are needed to establish optimal doses in patients with HIV infection and different types of oropharyngeal candidiasis [25]; studies are also needed regarding the usefulness of fluconazole in and HCT patients and patients with leukemia [18,66]. Resistance to antifungal agents Resistance of Candida to polyenes is virtually unknown despite years of common clinical use [67]. Reports of resistance to the azoles, however, particularly among AIDS patients, are increasing [26,65,68

76]. Therapeutic failure caused by fluconazole-resistant strains in AIDS patients is increasingly reported [26,68,69,73 76], although one study found fluconazole effective when other agents were not [77]. Risk of resistance seems to develop in patients with advanced HIV disease or after repeated or long-term fluconazole therapy [26,68,69,73]. Resistant species, specifically C. krusei, have been increasingly identified in HCT patients and patients with leukemia because of effective killing of C. albicans and selection for C. krusei [18] and have been described with ketoconazole [68]. A study by Fan-Havard et al [78] did not find largescale resistance in the Candida populations isolated from patients who receive long-term azole therapy. There are reports of fluconazole selecting more resistant strains of Candida species and of cross-resistance between the azoles [30,47,62,72,79]. The optimal management of fungal infections in children with HIV remains to be determined [80]. The azoles, particularly ketoconazole, can interact with many other agents, including antacids, omeprazole, histamine-2 antagonists, rifampin, phenytoin, oral anticoagulants, insulin, cyclosporine, and corticosteroids [5,43,62]. Such interactions may result in either increased or decreased blood levels of these agents, thus altering their potential efficacy or toxicity. New therapies Unlike with the azoles, resistance to polyenes, including amphotericin B, rarely develops during therapy [41]. The drugs principal limitation is its toxicity when used systemically [41,82]. The use of amphotericin B oral suspension as a topical antifungal agent was first studied nearly 40 years ago and has been available commercially in Europe for the treatment of patients with oropharyngeal candidiasis [5,47,48]. In vitro studies have shown that amphotericin B is more active than nystatin against C. albicans [83,84]. Virtually no amphotericin B oral suspension is absorbed systemically, and the toxicity concerns associated with intravenous amphotericin B use are eliminated [47,85 88]. Unfortunately, the formulation is poorly tolerated and the rinse has been withdrawn from the US market [47,62,63,65]. An amphotericin B lozenge/chlorhexidine combination has been used in Scandinavia to treat patients with denture stomatitis [81]. Amphotericin B lozenges are effective in patients susceptible to Candida infection, because long-lasting concentrations of the drug in the saliva can be achieved [81,82]. New formulations of systemic amphotericin B have been developed with the goal of reducing toxicity. Systemic amphotericin B has been studied in

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lipid complex, colloidal dispersion, and liposomal forms. Although there are limited data on the therapeutic advantage of new formulations, toxicity seems to be reduced [8]. New triazoles in late stage development (voriconazole, posaconazole, ravuconazole) have increased the spectrum of antifungal activity, including against Aspergillus and additional Candida species, and safety seems excellent. New classes of antifungal agents, including echinocandin agents that affect the fungal cell membrane (versus cell wall), are in development [7]. These agents, with different mechanisms of action, offer the future potential to manage cases with new drug combinations. Combination therapy antifungal agents Combined therapies have been evaluated to seek synergy of different agents for use in potentially fatal fungal infections, including Cryptococcus, C. albicans, and Aspergillus, in immunocompromised and neutropenic patients [89]. In vitro study of possible synergy of fluconazole and granulocyte-colony stimulating factor (G-CSF), granulocyte-macrophage-colony stimulating factor (GM-CSF), human serum treated neutrophils, showed that the combination caused increased killing by the antifungal agents [89]. Monoclonal antibodies also were shown to facilitate fungal cell death in combination with antifungals, as have combinations with proinflammatory cytokines, interleukin-1, interferon, and tumor necrosis factor-alpha [89]. Use of polyene and azole antifungal agents has interfered with fungal killing in vitro; however, animal studies and clinical trials suggest that dosing schedules of the drugs may be key, and conflicting results may be related to the dosing schedule and the animal model used. Although combining azoles and polyenes may lead to enhanced effect, there are no clear guidelines for their combined use [89].

wearers are also at increased risk for candidiasis. The clinical presentation of this infection may vary and may be asymptomatic or cause severe, persistent symptoms. Common oral findings may include white plaques that can be wiped off, erythema, and, less commonly, leukoplakia. Treatment of uncomplicated oropharyngeal candidiasis in the non-immunocompromised patient is usually straightforward. Selecting the form of a topical medication requires consideration of the oral condition, the length of contact time with the medication, and the taste, texture, and cost of the product. In patients with severe oropharyngeal candidiasis, particularly individuals with a compromised immune system, or in patients with refractory oropharyngeal candidiasis, treatment is often more difficult. Relapses are common, and unless the underlying conditions that predispose to infection are managed effectively, long-term or frequent intermittent therapy is often required. Topical agents are generally effective in uncomplicated cases but may be inadequate in some cases, including complicated infections in patients with AIDS or neutropenic cancer patients. The most effective regimen for fungal prophylaxis in patients with protracted neutropenia has yet to be determined. Systemic agents, such as amphotericin B, ketoconazole, fluconazole, and itraconazole, have been used extensively in these patients. A major concern with these agents, particularly with fluconazole, is the increase in fungal resistance and in selection of non-albicans species, particularly in patients who require long-term or recurrent therapy. Strategies must be developed for preventing and managing the increasing prevalence of more resistant strains of C. albicans and selecting resistant species. Intravenous amphotericin B is the gold standard for patients with systemic mycoses and, occasionally, persons with refractory oropharyngeal candidiasis; however, its routine use for oropharyngeal candidiasis is limited by its toxicity.

Discussion Oropharyngeal candidiasis is increasingly common because of changes in medical care, HIV infection, and advances in medicine that allow patients with cancer and other debilitating diseases to live longer, although in an immunocompromised state. Use of xerostomia-inducing medications, broad-spectrum antibiotics, and topical and systemic steroids has led to increased oropharyngeal colonization and subsequent infection. Patients with xerostomia, persons who smoke tobacco, and denture References
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J.B. Epstein / Oral Maxillofacial Surg Clin N Am 15 (2003) 91102 sion-induction therapy in patients with acute myeloleukemia. Scand J Infect Dis 1991;2:355 66. Bergmann OJ, Andersen PL. Acute oral candidiasis during febrile episodes in immunocompromised patients with haematologic malignancies. Scand J Infect Dis 1990;22:353 8. Rodu B, Carpenter JT, Jones MR. The pathogenesis and clinical significance of cytologically detectable oral Candida in acute leukemia. Cancer 1988;62:2042 6. Dupont B, Graybiull JR, Armstrong D, et al. Fungal infections in AIDS patients. Journal of Medical and Veterinary Mycology 1992;30(Suppl 1):19 28. Koks CHW, Schepens MHJ, Burger DM, et al. Drug development report (9): fluconazole in the treatment and prophylaxis of oral candidosis in HIV-infected patients. J Drug Dev Clin Pract 1993;5:235 49. Heinic GS, Stevens DA, Greenspan D. Fluconazoleresistant Candida in AIDS patients. Oral Surg Oral Med Oral Pathol 1993;76:711 5. Pollock JJ, Santarpia III RP , Heller HM, et al. Determination of salivary anticandidal activities in healthy adults and patients with AIDS: a pilot study. J Acquir Immune Defic Syndr Hum Retrovirol 1992; 5:610 8. Conant MA. The AIDS epidemic. J Am Acad Dermatol 1994;31:847 50. Jewell ME, Sweet DE. Oral and dermatologic manifestations of HIV infection. Postgrad Med 1994;96: 105 16. Edwards JE. Candida species. In: Mandell GL, Bennett JE, Dolin R, editors. Principles and practices of infectious diseases. New York: Churchill-Livingstone; 1995. p. 2289 301. Epstein JB, Komiyama K, Duncan D. Oral topical steroids and secondary oral candidiasis. J Oral Med 1986; 41:223 7. Crislip MA, Edwards JE. Candidiasis. Infect Dis Clin North Am 1989;3:103 33. Lewis MAO, Samaranyake LP, Lamey PJ. Diagnosis and treatment of oral candidiasis. J Oral Maxillofac Surg 1991;49:996 1002. Bissell V, Felix DH, Wray D. Comparative trial of fluconazole and amphotericin in the treatment of denture stomatitis. Oral Surg Oral Med Oral Pathol 1993; 76:35 9. Berkow R. The Merck manual of diagnosis and therapy. 16th edition. Rahway (NJ): Merck & Co.; 1992. Epstein JB, Truelove EL, Izutzu KT. Oral candidiasis: pathogenesis and host defense. Rev Infect Dis 1984; 6:96 106. Epstein JB, Pearshall NN, Truelove EL. Quantitative relationships between Candida albicans in saliva and the clinical status of human subjects. J Clin Microbiol 1980;12:475 6. Rex JH, Cooper CR, Merz WG, et al. Detection of amphotericin B-resistant Candida isolates in a brothbased system. Antimicrob Agents Chemother 1995;39: 906 9. Barchiesi F, Del Poeta M, Morbiducci V, et al. Turbi-

[5] Greenspan D. Treatment of oropharyngeal candidiasis in HIV-positive patients. J Am Acad Dermatol 1994; 31(Suppl):51 5. [6] Meyer RD, Holmberg K. Fungal infection in HIVinfected patients. In: Homberg K, Meyer R, editors. Diagnosis and therapy of systemic fungal infections. New York: Raven Press; 1989. p. 79 100. [7] Wingard JR, Leather HL. Empiric antifungal therapy for the neutropenic patient. Oncology 2001;15:351 69. [8] de Pauw BE. Advances in the management of invasive fungal infections in organ transplant recipients: step by step. Transpl Infect Dis 2000;2:48 50. [9] Donnelly JP. A strategy for managing fungal infections in haematopoietic stem cell transplantation. Transplant Infect Dis 2000;3:88 95. [10] Wingard JR. Approach to invasive fungal infection after blood or marrow transplantation. Transplant Proc 2000;32:1543 4. [11] Santelmann H, Laerum E, Roennevig J, Fagertun HE. Effectiveness of nystatin in polysymptomatic patients: a randomized, double-blind trial with nystatin versus placebo in general practice. Fam Pract 2001;18:258 65. [12] Peterson DE. Oral candidiasis. Clin Geriatr Med 1992; 8:513 27. [13] Dhondt F, Ninane J, De Benle K, et al. Oral candidosis: treatment with absorbable and non-absorbable antifungal agents in children. Mycoses 1992;35:1 8. [14] Francis P, Walsh TJ. Current approaches to the management of fungal infections in cancer patients. Oncology 1992;6:81 92. [15] Prentice AG. Oral and gastrointestinal candidosis: prophylaxis during immunosuppressive therapy. Mycoses 1989;32(Suppl 2):42 6. [16] DeGregorio MW, Lee WMF, Ries CA. Candida infections in patients with acute leukemia: ineffectiveness of nystatin prophylaxis and relationship between oropharyngeal and systemic candidiasis. Cancer 1982;50: 2780 4. [17] Stevens DA, Green SI, Lang OS. Thrush can be prevented in patients with acquired immunodeficiency syndrome and the acquired immunodeficiency syndrome-related complex. Arch Intern Med 1991;151: 2458 64. [18] Epstein JB, Ransier A, Lunn R, Chin E, Jacobson J, Le N, et al. Prophylaxis of candidiasis in patients with leukemia and bone marrow transplants. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1996;81:291 6. [19] Epstein JB, Vickars L, Spinelli J, Reece D. Efficacy of chlorhexidine and nystatin rinses in prevention of oral complications in leukemia and bone marrow transplantation. Oral Surg Oral Med Oral Pathol 1991; 73:682 9. [20] Epstein JB, Freilich MM, Le ND. Risk factors for oropharyngeal candidiasis in patients who receive radiation therapy for malignant conditions of the head and neck. Oral Surg Oral Med Oral Pathol 1993;76: 169 74. [21] Bergmann OJ. Alterations in oral microflora and pathogenesis of acute oral infections during remis-

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Management of head and neck infections in the immunocompromised patient

Newton C. Gordon, DDS, MS*, Stephen Connelly, DDS
Department of Dentistry/Oral and Maxillofacial Surgery, San Francisco General Hospital, 1001 Potrero Avenue, NH-1N1, San Francisco, CA 94110, USA

The term immunocompromised has traditionally been used to describe patients with a serious impairment of one or more aspects of their immune defense mechanisms. As a result, these patients are more susceptible than immunocompetent hosts to the establishment of bacterial and nonbacterial infections [1]. The number of patients classified as immunocompromised has increased in the last 15 years. Among the many factors contributing to the increased numbers of such patients is the fact that people are outliving once fatal diseases because of advances in modern treatment strategies [2]. The most common conditions leading to an immunocompromised state can be divided into four general categories: systemic conditions, congenital defects or primary immunodeficiencies, iatrogenic causes, and social factors (Box 1). The purpose of this article is to review three common causes of immunosuppression in the oral surgery patient: diabetes mellitus, alcoholism/substance abuse, and HIV/ AIDS, with emphasis on their impact on head and neck infections. Each of these conditions leads to a host environment that is more susceptible to severe pathogenic invasion, causing infections such as osteomyelitis, pan-facial abscesses, and necrotizing fascitis. Management of these infections requires accurate diagnosis, aggressive incision and drainage, proper antimicrobial therapy, and improved nutritional status to achieve resolution.

Normal immune system To understand the defects in the immune system produced by these conditions, it is first necessary to discuss the immune system in the noncompromised host. The normal functioning immune system involves a complex network of specialized cells and defensive barriers designed to protect an individual from potential pathogens. Its development begins in the first month of gestation with the hematopoietic stem cells located in the yolk sac [3]. In the third month of gestation, hematopoiesis occurs mainly in the liver and continues up to the point when the skeletal elements are formed and the bone marrow becomes the major site of blood cell formation. A variety of cells differentiate from the hematopoietic stem cell, including granulocytes, monocytes, lymphocytes, megakaryocytes, and erythrocytes. Two months into gestation, lymphocytic cells destined to become T cells emigrate from the bone marrow into the developing thymus for maturation. The maturation of B cells occurs under the influence of stromal reticular cells. As the fetus continues to develop, so do the peripheral components of the immune system, including the blood, thymus, lymphatic system, spleen, skin, and mucosa [4]. The immune system is often divided into the innate and adaptive, or acquired immune systems. Innate immunity consists of antigen-nonspecific defense mechanisms activated immediately on encounter with an antigen [5,6]. These mechanisms include physical barriers like epithelium, fatty acids, mucus, and cilia. Soluble factors such as proteins of the complement cascade, chemokines (proteins that

* Corresponding author. E-mail address: newtong@itsa.ucsf.edu (N.C. Gordon).

1042-3699/03/$ see front matter D 2003, Elsevier Science (USA). All rights reserved. PII: S 1 0 4 2 - 3 6 9 9 ( 0 2 ) 0 0 0 7 9 - 1

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Box 1. Etiology of immunodeficiency Systemic conditions AIDS Diabetes mellitus End-stage renal disease Leukemia/lymphoma Systemic lupus erythematous Advanced age Primary immunodeficiencies X-linked severe combined immunodeficiency Wiskott-Aldrich syndrome Chediak-Higashi syndrome DiGeorge syndrome Iatrogenic causes Immunosuppressive drugs Broad-spectrum antibiotics Chemotherapy Radiation therapy Bone marrow transplantation Social factors Alcoholism Illicit drug use Obesity induce leukocyte migration), cytokines (proteins that modulate leukocyte function), and leukocytes other than T cells and B cells are all part of the innate system that becomes activated in response to the chemical properties of the insulting agent. Adaptive immunity is a system that is antigenspecific. The main effector cells of this antigenspecific system are the T cells and B cells [7,8]. This system requires antigen processing, which involves the recognition of antigenic epitopes by T cells and B cells, clonal expansion, and differentiation of these antigen-specific lymphocytes into effector cells [9]. In addition, random rearrangement of genes that encode T-cell receptors (TCRs) on T cells and immunoglobulins (Ig) on B cells results in a vast repertoire of antigen-specific receptors. This enables the host to react to thousands of foreign substances [10,11]. Ig genes have the ability to increase specificity and affinity of antibodies by undergoing further somatic mutation. TCR genes do not undergo somatic muta-

tion because their specificity, selected during thymic ontogeny, is retained for self nonself discrimination. The adaptive immune system can form memory of antigenic exposure, decreasing the time for the subsequent immune response to re-exposure to an antigen. The antigen-driven clonal expansion of T cells and B cells is central to adaptive immunity and is the basis for immunologic memory. The innate and adaptive immune systems are complementary. For example, the chemokines and cytokines produced by macrophages in an inflammatory reaction serve to attract and modulate T cell and B cell activation and function. In addition, the complement cascade can be activated via the classic pathway by Ig stimulation [12]. The central cellular elements of the immune system are the leukocytes, which consist of granulocytes, specialized antigen-presenting cells, and lymphocytes. Granulocytes include the neutrophils, eosinophils, basophils, and mast cells. The neutrophils, monocytes, and macrophages are responsible for the phagocytic destruction of antigens. Their function is crucial in the acute inflammatory response. Eosinophils play a role in the late phase of allergic inflammation and are responsible for the destruction of parasitic infections. Basophils and mast cells both express IgE and participate in the immediate hypersensitivity immune response. Monocytes, macrophages, Langerhans cells, Kupffer cells, and dendritic cells comprise the antigen processing and presenting cells [13]. There are three major types of lymphocytes: T cells, B cells, and natural killer (NK) cells. T cells are phenotypically defined by the expression of the TCR heterodimeric receptor on their cell surface, which binds antigen displayed by antigen-presenting cells [14]. B cells express transmembrane Ig on their surface, which binds unprocessed antigen independent of antigen-presenting cells. NK cells are morphologically large granular lymphocytes. They are phenotypically defined by the absence of either transmembrane cell surface expression of TCR or Ig and by the presence of the cell surface molecules (protein markers), CD16 and CD56 [15]. T cells and B cells are responsible for clonally specific immune responses, while NK cells provide innate cytotoxic immune responses directed against virus-infected cells and tumor cells. There is also cooperation between the NK cells and the adaptive immune response through Fc-bound IgG and the production of cytokines [4,5]. All nucleated cells of the body display the transmembrane class I human leukocyte antigen (HLA) molecule on their surface, which is encoded by the

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major histocompatability complex. The class I HLA molecule is restricted to presenting linear peptides of 8 to 25 amino acids long to CD8+ T cells [16]. They present endogenous antigens, proteins synthesized within the antigen-presenting cells. These proteins are derived from the processing of genetic information from either viral, intracellular bacterial, or tumor sources. This is consistent with the specificity of CD8+ T cells. Only macrophages, monocytes, dendritic cells, and B lymphocytes present the class II HLA molecule. However, any nucleated cell stimulated with interferon-g may also express the class II HLA molecule [17]. The specific antigen-presenting cells present only the class II HLA molecule to CD4+ cells. The antigens are exogenous peptides, derived from phagocytized bacteria, parasites and virus particles. Class I and II HLA molecules are cell surface heterodimeric structures with a groove for presentation of linear peptides only. However, there is also a mechanism for the presentation of polysaccharides. CD4 and CD8 T-cells are responsive to lipoglycan antigens presented by CD1 molecules, which are expressed on most antigen presenting cells [18]. The TCR is responsible for the specificity and sensitivity of T cell recognition of antigens presented by the HLA molecule [19]. T cells go through a process of positive and negative selection that occurs in the thymus during T cell development. Positive selection occurs in the cortical region of the thymus. T cells whose antigen receptor fails to bind to selfHLA molecules are programmed to die by apoptosis, whereas T cells whose antigen receptor binds to selfHLA molecules survive and migrate to the medulla. Negative selection occurs next when T cells whose antigen receptor binds to self-HLA molecules with too high an affinity display auto-antigens and undergo apoptosis. This process creates T cells that can recognize HLA molecules correctly but yet not bind to those HLA molecules presenting self antigens [20]. T cells can be further defined by their cytokine production and can be either T helper1 (Th1) cells (which generate cell-mediated immune responses) or Th2 cells (which generate humoral allergic immune responses). Both CD4+ and CD8+ T cells can exhibit either cytokine profile. The hallmark of the B cell is the production of Ig. Maturation of B cells depends on bone marrow stromal cells and stromal cell-produced interleukin7 (IL-7) [21]. B cells can express IgM, IgD, IgG1-4, IgE, and IgA1-2 isotypes. IgM and IgD isotypes characterize a nave mature B cell and switching to the other isotypes is T cell dependent. B cell membrane Ig and secreted Ig are alternative products of the differentially spliced Ig heavy chain gene. They

are produced when a specific antigen binds to the membrane Ig receptor, which transduces an intracellular signal stimulating clonal expansion to produce more cells and secretes Ig specific for that antigen. This production is a T cell dependent process, in which these cells direct immunoglobulin isotype switching through a series of cell surface molecular interactions with B cells, resulting in reciprocal intracellular signaling and T cell elaboration of cytokines [22]. Repetitive antigen stimulation is associated with somatic hypermutation within the Ig gene segments, encoding the heavy and light chain variable regions, resulting in Ig with greater antigen specificity. The daughter clones are preferentially expanded and produce antibody with higher affinity, all occurring within the germinal centers of the lymphoid organs. The complement system facilitates antibody-mediated immunity. The complement system consists of plasma proteins activated along an enzymatic cascade, resulting in a spectrum of bioactive molecules that facilitate opsonization, osmotic lysis of targeted cells, and recruitment of phagocytic cells [23]. Through the classic complement pathway, antigen antibody complexes efficiently activate the complement cascade. The alternative pathway involves independent activation of cascade protein C3. Cell adhesion molecules are also very important to the proper functioning of the immune system. Selectins, integrins, and Ig superfamily adhesion molecules are the three families of adhesion molecules that allow leukocytes to attach to extracellular matrices and to adhere to each other. Selectins are found on all leukocytes and function as lectins, which bind to carbohydrate moieties expressed by endothelial cells or other leukocytes. Selectin L, E, and P participate in leukocyte rolling along vascular endothelium. Integrins and Ig superfamily adhesion molecules bind through protein protein interactions, which is important for stopping leukocyte rolling and mediating leukocyte aggregation and transendothelial migration [31]. The adhesion molecules are often dysfunctional in patients with immunocompromising condition, such as diabetes.

Immune defects in specific diseases Diabetes mellitus The negative effects of diabetes mellitus on the immune system have been extensively investigated. These effects impact greatly on the hosts ability to prevent the establishment of, and bring resolution to,

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a variety of head and neck infections [24,25]. The main etiologic factor in diabetes mellitus that leads to dysfunction in the immune system is hyperglycemia [26,27]. All the major cell types involved in the immune defense are affected. Cellular elements of the innate immune system, including neutrophils and monocytes/macrophages, have altered function. In the neutrophils, functions such as adherence, chemotaxis, and phagocytosis may be down- regulated. This results in a less effective defense against a microbial challenge [28 30]. The neutrophils from diabetic patients also produce less free oxygen radicals, which reduce their ability to make toxic metabolites for release against microbes [8]. Monocytes and macrophages may have up-regulated catabolism of pro-inflammatory cytokines as well as increased production of matrix metalloproteases, such as collagenase [31 33]. This creates an imbalance that is detrimental to the containment of head and neck infections. The hyperglycemic state may also lead to a decrease in fibroblast proliferation and synthesis of collagen, impairing tissue turnover and wound repair [34,35]. It has been proposed that the formation of advanced glycation end-products (AGEPs), which form as a result of glucose irreversibly binding to proteins and lipids in the face of prolonged hyperglycemia, is a key event in the generation of the defects seen in diabetes. [29,33]. Glycation endproducts can bind to receptors on various cells, such as leukocytes, and affect their function. The upregulation of tissue destructive cytokines produced by the monocytes and macrophages may be a result of AGEP binding. AGEPs also alter the solubility of collagen and may play a role in the changes seen in small and large blood vessels. This collagen interaction may result in the accumulation of AGEPs on the basement membrane, affecting the exchange of nutrition, neutrophil migration, and the diffusion of antibodies and oxygen. As a group, these effects should have a detrimental effect on the wound healing apparatus. There is a significant body of evidence that indicates that cystolic Ca++ is elevated in many cell types in patients with both type I and type II diabetes mellitus [36,37]. The high levels of cystolic Ca++, ultimately induced by hyperglycemia, could lead to a reduced ATP content and decreased phagocytic ability in neutrophils [38]. Additionally, increased intracellular Ca++ may affect the cellular components of the acquired immune system. B cells may have an impaired proliferative response to mitogen, not unlike that seen in the altered ionic environment of chronic renal failure [39].

Alcoholism It has been demonstrated that ingestion of large amounts of ethanol leads to a relatively broad impairment of host defense mechanisms [40]. Ethanol impairs phagocytic cells, including neutrophils, monocytes, and macrophages [41]. Also, significant decreases in T cell subpopulations, including CD4, CD8, and CD3, are seen in patients with alcoholic hepatitis [42]. These abnormalities were significantly correlated with protein malnutrition or kwashiorkorlike changes, but not with primary caloric malnutrition or marasmus-like changes. In addition, in this same population, it was noted that a large percentage of patients displayed lowered CD4 cell count numbers (250 300 cells/mm3), which were similar to counts seen in HIV-infected individuals vulnerable to the onset of opportunistic infections. Ethanol seems to blunt the activation of normal human circulating CD3 T cells in terms of their ability to produce IL-2 and thus decreases their proliferative potential in response to mitogenic stimulation. The final stages of CD4 T cell maturation may be impaired, affecting the generation of Th1 and Th2 patterns of cytokine response [43]. It is noteworthy that the most profound impairment in T cell proliferation occurred during the period after cessation of ethanol ingestion when withdrawal symptoms are evident. In this period, there are high levels of corticosteroids in the circulation, suggesting that this may be the primary mode for immunosuppression in alcoholics. An additional subset of T cells, the NK cells, have been shown to be dysfunctional in alcoholic patients, decreasing the hosts ability to eliminate virus-infected cells and tumor cells [44]. B cell activation is dependent on the proper functioning of the T cell and its ability to produce a Th2 cytokine response. If this mechanism is dysfunctional, as has been demonstrated in alcoholic patients, then the production of antigen specific immunoglobulins is greatly reduced [45]. HIV-infected patients The characteristic immune defect in HIV infection is the destruction of CD4+ T cells [46]. This loss of CD4+ T cells affects a variety of immune cells and their respective functions. CD4+ T cells exhibit decreased lymphokine secretion (IL-2 and interferon-g) and a decreased response to soluble antigens, increasing susceptibility to opportunistic infections and neoplasms. CD8+ T cells have a decreased cytotoxic response, decreasing a hosts ability to fend off intracellular organisms. NK cells have a decreased

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ability to kill tumor cells. Macrophages exhibit diminished cytotoxic ability, decreased chemotaxis, reduced IL-1 secretion, poor antigen presentation, and decreased class II HLA antigen expression, contributing to a depressed antigen response and defective wound healing. B cells show depressed Ig production in response to new antigens, and they are refractory to normal signals for B cell activation [47]. There is also polyclonal activation of B cells resulting in hypergammaglobulinemia and circulating immune complexes [48]. A significant number of patients with AIDS will develop neutropenia as a result of direct retroviral infection, use of antiretroviral drugs and other drug therapy, systemic infections, and autoimmune mechanisms [49]. In addition, the neutrophils of patients with AIDS have defective bactericidal function and chemotatic defects [50,51]. Consequently, it has been proposed that the impairment in neutrophil function along with defective immunoglobulin synthesis are important causes of the increased risk of bacterial infections in patients with advanced HIV disease [52]. Also, there has been a strong correlation between the degree of neutropenia and risk of developing serious bacterial infections in cancer patients [53].

Management of infections The management of head and neck infections in the immunocompromised patient should follow the same basic steps established for immunocompetent individuals. These steps are outlined in Box 2. The

Box 2. Management of head and neck infections in the immunocompromised patient 1. Airway monitoring and possible surgical airway establishment 2. Comprehensive history and physical examination 3. Obtaining appropriate laboratory and imaging studies 4. Empiric antimicrobial therapy 5. Surgical debridement and irrigation, as needed 6. Culture and antibiotic sensitivity testing of infectious organisms to appropriately adjust antibiotic therapy 7. Close follow-up to monitor for resolution and recurrence

first consideration is assuming that there is no acute airway compromise. If the airway is compromised, the first course of action is either oral or nasal endotracheal intubation. In instances where swelling of the oropharyngeal airway is severe, it may be necessary to perform a tracheostomy to establish a competent airway. Once the airway is secured, the next step should be to obtain a thorough history and physical examination. This provides information about concomitant diseases, social habits, or other processes that may be indications of an immunocompromised status. Such indicators include a positive history of HIV, a previous diagnosis of diabetes, or signs and symptoms of the disease, alcohol or illicit drug use, renal dialysis, and a recent history of recurrent infections. When performing the physical examination, one should keep in mind that immunocompromised individuals may have an attenuated immune response resulting in decreased signs and symptoms of inflammation. Thus, a serious infection may not necessarily have a dramatic clinical presentation. The next step is to obtain the necessary laboratory and imaging studies to establish the diagnosis and determine the extent of the infection. Routine laboratory studies such as a white blood cell count, hemoglobin and hematocrit determination, a platelet count, and measurement of electrolytes, blood urea nitrogen, creatinine, and glucose should be performed. It is also helpful to obtain a differential white cell count. A high percentage of immature neutrophils would indicate that the immune system is struggling to produce cells to fight the infection. Also, a decreased lymphocyte count may be indicative of an HIV infection. Imaging studies may include plain films, CT scans with or without contrast, MRI, and radionucleotide bone scanning (skeletal scintigraphy; see elsewhere in this issue). Empiric antibiotic treatment should be instituted as soon as possible to rapidly obtain minimum inhibitory concentrations in the plasma. A recommended antibiotic regimen is outlined in Box 3. The initial selection is based on the duration of the infection and the level of immunocompetence of the patient. If the polymicrobial infection has been present for less than 3 days, the amount of crosscolonization or synergy that has developed is limited. After 3 days, enough time has passed so that there is increased virulence of some microorganisms due to the changes in the environment. For example, aerobic bacteria may produce a more favorable environment for anaerobic bacteria, allowing them to multiply more readily. If the infection responds well to the empiric use of an antibiotic, the regimen should be

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Box 3. Empiric antibiotic treatment Early infection (first 3 days of symptoms or mildly immunocompromised) Penicillin Clindamycin Cephalexin (or other first-generation cephalosporin) Late infection (after 3 days of symptoms or moderately to severely immunocompromised) Clindamycin (maximum dose) Penicillin and metronidazole Ampicillin and sulbactam Cephalosporin (first or second generation) Mild, moderate, and severe compromise is based on CD4/viral loads, glycemic control, and the degree of alcoholicrelated disease. Modified from Flynn TR. The swollen face. Severe odontogenic infections. Emerg Med Clin N Am 2000;18: 481 519.

continued even if the culture and antibiotic sensitivity test indicates a change may be appropriate. However, in the absence of clinical improvement, the culture and antibiotic sensitivity test results should form the basis for continued antimicrobial therapy. If a patient is mildly immunocompromised, there should be an adequate immune response to assist the antimicrobial drug. However, in the moderate to severely immunocompromised patient there is more dependence on the antimicrobial drug to control the infection. Along with the use of antibiotics, surgical debridement or incision and drainage rank as the most important interventions in the management of head and neck infections. This includes removal of all nidi of infection (teeth, necrotic tissue, and nonvital bone), exploration and irrigation of all involved fascial spaces, and proper wound care. The lack of vascularity can result in failure of immune effectors and antibiotics to reach the infected sites. Proper placement of drains and periodic irrigation through them is essential for the continuous removal of necrotic debris and enhancement of vascularization. Speci-

mens for culture should be taken at the time of surgical debridement or incision and drainage. Both aerobic and anaerobic cultures should be done and antibiotic sensitivity testing should be performed to provide guidance in selecting the correct antimicrobial treatment. Finally, close postoperative monitoring, including repeated imaging studies, additional surgical interventions, and long-term follow-up are mandatory for resolution of the infection. Management of head and neck infections involves the contribution of a triad of factors: the host, the antibiotic, and the surgical intervention. In the normal host, serious polymicrobial infections can be produced by organisms that may not be infectious in pure culture but that become infectious through microbial synergism. Consequently, antimicrobial therapy aimed at one major organism may be enough to break the chain and change the environment sufficiently to allow the immune system to take over and bring about resolution of the infection. In the normal host, surgical intervention, as well as antibiotic therapy, significantly alter the microbial environment, allowing the patients immune system to phagocytize the remaining bacteria. In an immunocompromised patient, the host component of the triad is weakened, leaving the surgeon to rely almost entirely on surgical intervention and antimicrobial therapy to resolve the infection. This is the rationale for recommending aggressive surgical incision and drainage, frequent irrigation of the drains, and use of high-dose, broad-spectrum antimicrobial therapy. Again, it must be emphasized that antimicrobial therapy must be supported by aerobic and anaerobic culturing and antibiotic sensitivity testing.

Summary The immunocompromised host has a potential increased risk for severe head and neck infections that usually require aggressive antimicrobial therapy and prolonged hospitalization. The causes of the immunocompromised status of patients who seek care from the oral and maxillofacial surgeon are multifactorial and include diabetes, malnutrition, obesity, alcohol abuse, tobacco abuse, intravenous drug abuse, cocaine abuse, HIV infection, and AIDS. Patients with other diseases, such as organ transplant recipients and those receiving cancer therapy or therapy for various autoimmune diseases, are not frequently encountered with severe infections of the head and neck. The number of patients with multifaceted causes of immunocompromise will clearly increase in the future as the population ages and medical treatments for

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previously morbid or lethal conditions are improved. Recognizing the conditions associated with decreased immune function is critical for the proper management of these patients. Concurrent with recognition of immunocompromising diseases, it is important to have a basic understanding of the normal immune system and associated defects, because advances in therapy will undoubtedly increase in complexity. For instance, new antimicrobials, as well as pharmaceuticals that alter cytokine function and affect the generation of progenitor cells in the bone marrow stroma, are on the horizon. Future treatment strategies will not only include aggressive use of traditional management methods but also these new approaches. Ultimately, this should provide a shorter course of treatment and improved outcomes for immunocompromised patients with head and neck infections.

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N.C. Gordon, S. Connelly / Oral Maxillofacial Surg Clin N Am 15 (2003) 103110 experimental data. Alcohol Clin Exp Res 1995;19: 551 4. Chiappelli F, Kung M, Lee P, et al. Alcohol modulation of human normal T-cell activation, maturation, and migration. Alcohol Clin Exp Res 1995;19:539 44. Saxena QB, Mezey E, Adler WH. Regulation of natural killer activity in vivo. II: The effect of alcohol consumption on human peripheral blood natural killer activity. Int J Cancer 1980;26:413 7. Smith KA. Interleukin-2: inception, impact, and implications. Science 1988;242:1169 76. Fichtenbaum CJ, Dunagan WC, Powderly WG. Bacteremia in hospitalized patients infected with human immunodeficiency virus: a case-control study of risk factors and outcome. J Acquir Immune Defic Syndr Hum Retrovirol 1995;8:51 7. Janeway CA, Travers P, Hunt S, Walport M. Immunobiology. 3rd edition. New York: Garland Publishing; 1997. p. 153 75. Lane HC, Masur H, Edgar LC, et al. Abnormalities of B-cell activation and immunoregulation in patients with the acquired immunodeficiency syndrome. N Engl J of Med 1983;309:453 8. Murphy MF, Metcalfe P, Waters AH, et al. Incidence and mechanism of neutropenia and thrombocytopenia in patients with HIV. Br J Haematol 1987;66:337 40. Murphy PM, Clifford LH, Fauci AS, et al. Impairment of neutrophil bactericidal capacity in patients with AIDS. J Infect Dis 1988;158:627 30. Nielsen H, Kharazmi A, Faber V. Blood monocyte and neutrophil functions in acquired immune deficiency syndrome. Scand J Immunol 1986;24:291 6. Moore RD, Keruly JC, Chaisson RE. Neutropenia and bacterial infection in acquired immunodeficiency syndrome. Arch Intern Med 1995;155:1965 70. Chanock S. Evolving risk factors for infectious complications of cancer therapy. Hematol Oncol Clin North Am 1993;7:771 93.

[32] Grossi SG, Genco RJ. Periodontal disease and diabetes mellitus: a two-way relationship. Ann Periodontol 1998;3:51 61. [33] Lalla E, Lamster IB, Schmidt AM. Enhanced interaction of advanced glycation end-products with their cellular receptor for RAGE: implications for the pathogenesis of accelerated periodontal disease in diabetes. Ann Periodontol 1998;3:13 9. [34] Golub LM, Nicoll GA, Iacono VJ, et al. In vivo crevicular leukocyte response to a chemotatic challenge: inhibition by experimental diabetes. Infect Imm 1982;37:1013 20. [35] Ryan ME, Ramamurthy NS, Sorsa T, et al. MMP-mediated events in diabetes. Ann N Y Acad Sci 1994;878: 311 34. [36] Draznin B, Lewis D, Houlder N, et al. Mechanism of insulin resistance induced by sustained levels of cytosolic free Ca in rat adipocytes. Endocrinology 1989; 125:2341 9. [37] Rapoport Y, Himelfarb MZ, Zikk D, et al. Cervical necrotizing fasciitis of odontogenic origin. Oral Surg Oral Med Oral Pathol 1991;72:15 8. [38] Alexiewicz J, Kumnar D, Smogorzewski M, et al. Polymorphonuclear leukocytes in non-insulin dependent diabetes mellitus: abnormalities in metabolism and function. Ann Intern Med 1995;123:919 24. [39] Gaciong Z, Alexiwcz JM, Linker-Israeli M, et al. Inhibition of immunoglobulin prodution by parathyroid hormone: implications in chronic renal failure. J Am Soc Nephrol 1990;1:236 44. [40] MacGregor RR. Alcohol and immune defense. JAMA 1986;256:1474 9. [41] Brayton RG, Stokes PE, Schwartz MS, et al. Effect of alcohol and various diseases on leukocyte mobilization, phagocytosis and intracellular bacterial killing. N Engl J Med 1970;282:123 8. [42] Roselle GA, Medenhal CL, Chedid A, et al. Alcohol modulation of immune function: clinical and

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Diagnosis and treatment of recurrent aphthous stomatitis

Ellen Eisenberg, DMD
Division of Oral and Maxillofacial Pathology, University of Connecticut School of Dental Medicine, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA

What is recurrent aphthous stomatitis (RAS)? Is it appropriate to regard it as an infectious disease? Are there effective measures for managing aphthous ulcers? These are just a few of the questions that are continually asked about this benign but highly symptomatic oral problem. Although it is one of the most common recurrent oral ulcerative conditions of adults and children recognized throughout the world, RAS is also one of the least understood oral diseases and is among the most vexing problems faced by affected patients and clinicians alike [1]. The triggering factors that precipitate recurrent episodes in RAS patients seem to be as diverse and unique as the affected individuals themselves [2], which has posed a challenge for scientists in their attempts to identify a specific causation for this disease. Although the origin of RAS remains obscure, there is growing lucidity with regard to its pathogenesis, and that enlightenment has influenced contemporary approaches to its management significantly [3].

Etiology and pathogenesis Historically, conjecture about the origin of RAS focused on a wide spectrum of potential local and systemic factors that encompassed microbial agents, hematologic and hormonal disturbances, physical injury, emotional stress, and other influences [4]. To date, however, despite years of collective effort on the part of many researchers, the precise cause of RAS continues to elude disclosure. Also confounding the search for a singular cause is the observation that

aphthous-like oral ulcers often occur in conjunction with diverse conditions of a systemic nature. Included among those conditions are cyclic neutropenia [5], selected anemias [6], inflammatory bowel diseases [7], Behcets disease (see Box 1) [8,9], gluten-sensitive enteropathy (celiac sprue) [10,11], relapsing polychondritis syndromes (including the so-called MAGIC syndrome, which consists of mouth and genital ulcers with inflamed cartilage) [12], HIV infection [13], the purported symptom complex of recurring fevers, aphthous stomatitis, pharyngitis, and lymphadenopathy (FAPA syndrome) [14], and others [2,4 6,15]. Given the various presentations of RAS as either an exclusively local oral phenomenon or as a systemically related oral condition, it is not surprising that the search for its origin has proved frustrating. In recent years a body of evidence has emerged to suggest a genetic and an immunologic basis for RAS. These revelations largely have eclipsed speculation that RAS is caused by an infectious microorganism or one of the other previously suspected etiologic factors. They also have led to more rational and effective contemporary approaches to the management of RAS [16].

Genetic factors There is an apparent familial predisposition for aphthous stomatitis. As compared to the general population, the prevalence of RAS is higher when there is a positive family history, especially when both parents are affected [17]. There is also increased disease correlation observed in identical twins as compared to fraternal twins [18]. In familial cases of RAS, the onset of disease is earlier and attacks tend to occur more frequently than in nonfamilial cases [19].

E-mail address: eeisenberg@nso2.uchc.edu

1042-3699/03/$ see front matter D 2003, Elsevier Science (USA). All rights reserved. PII: S 1 0 4 2 - 3 6 9 9 ( 0 2 ) 0 0 0 7 0 - 5

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Box 1. Behcets disease A recurrent, multisystemic, immunologically mediated vasculitic syndrome Essential diagnostic component: Oral aphthous ulcers (three or more recurrences in one 12-month period) accompanied by any two of the following: Skin  Pustular or nodular cutaneous lesions  Positive cutaneous pathergy (ie, pustule formation at injection site 24 to 48 hours after injection of sterile solution of inert substance)  Superficial thrombophlebitis, erythema, ulcerations, acneiform lesions Ocular  Uveitis  Retinal vasculitis Genital  Recurring ulcers of penis, scrotum, or vulva Less common manifestations: Inflammatory bowel disease-related symptoms Arthritis Neurologic disturbances  Psychiatric disorders  Meningoencephalitis  Brain stem abnormalities Data from International Study Group for Behcets Disease. Criteria for diagnosis of Behcets disease. Lancet 335:1078, 1990.

which there is immune-induced gluten sensitivity and resultant intestinal malabsorption), and patients with inflammatory bowel diseases (specifically Crohns disease and ulcerative colitis) and oral aphthae [7,10].

Immunologic factors Although findings have not been entirely consistent and conflicting theories persist, mounting scientific testimony supports immune dysregulation as a key mechanism underlying the pathogenesis of RAS. It is believed that the altered immune reactivity arises perhaps in response to, or in concert with, a state of presumably heightened antigenic stimulation [16] exacted on a diminished mucosal barrier [2]. A constellation of cell-mediated immunologic phenomena seems to be a consistent factor in the disease. Serologic studies that compared RAS patients and unaffected controls revealed diminished ratios of circulating CD4+ helper cells to CD8+ suppressor cells in the former group [20,21]. It has been proposed that in RAS some unspecified antigenic influence [2,22] is at the epicenter of an antibody-dependent, T cell-mediated immune response that involves a shift in local lymphocytic subpopulations that eventuates in tissue damage [23 25]. From the observations of several investigators it has been hypothesized that the entire process of aphthous ulceration, from initiation through progression, is instigated by the expression on oral epithelial cells of not only normally found HLA class I antigens but also HLA class II antigens [26]. Presumably, this renders the cells antigenically foreign and consequently they become the targets of a cell-mediated immune reaction perpetrated by lymphocytes and Langerhans cells [26]. It has been shown that in patients with aphthous stomatitis there is a heightened lymphocytotoxic effect directed against oral epithelial cells when compared to unaffected controls [25 27]. Evidence for this pathogenetic mechanism is also inferred from observations that tissue biopsies of newly erupted aphthous ulcerations demonstrate agglomeration of activated T lymphocytes at the periphery of the lesions, whereas in well-established aphthae the initially predominant CD4+ helper/suppressor cell population is subsumed and succeeded by cytotoxic CD8+ lymphocytes [24,25]. Additional indirect support for primary immune dysregulation is reflected in the long-recognized correlation between stress and outbreaks of aphthous ulcers that is reported by many RAS patients, in contrast to the notable decrease in frequency of episodes during periods of reduced stress [28]. This observed

The likelihood that RAS is a genetically grounded disease is further supported by the recognized, although not entirely consistent, identification of certain histocompatibility antigen (HLA) types (eg, HLA B12, B51, Cw7), among some groups of aphthous patients [2]. The latter type includes the largest group of individuals whose aphthous ulcers (canker sores) are isolated to the oral cavity exclusively, without an attendant underlying systemic disease, individuals with the mucocutaneous form of Behcets disease [8], persons with celiac disease (in

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association is not entirely surprising, because stress is known to affect immunologic function [2]. It also has been observed that HIV-infected patients experience oral aphthous-like ulcerations with relatively high frequency. With advancing immune depletion, their aphthous outbreaks are often dominated by larger ulcers that run a more protracted course [13,29,30]. Attempts to explore the possibility that RAS is fundamentally an antibody-driven disorder have disclosed findings that are at best inconsistent and largely unsupportive. It seems that any previously held conjecture that aphthous ulcers stem from a centrally generated humoral immune mechanism rather than from local cellular immune responses to an antigenically modified oral mucous membrane was predicated on assumptions that have since been discredited [3,18,31 33].

consideration also could be applied to the other human herpes viruses, varicella-zoster virus and cytomegalovirus, which are known to affect such subclinical phenomena as asymptomatic viral shedding and elevated viral titers, similar to HSV [35,36].) It must be emphasized, however, that regarding most aphthous patients, any suggestion of a causative nexus between RAS and HSV seems to represent unsubstantiated conjecture rather than proven fact [16].

Nutritional factors Other issues explored in the quest to determine a cause for RAS include the possible relationship of attacks to excess or deficiency of various nutritional factors, such as serum iron, folate, and vitamin B12, and speculation that aphthous ulcers represent the manifestation of an allergic reaction to certain foods or other ingested or contacted substances. Apart from variably favorable responses to the avoidance of gluten products in aphthous patients with documented intestinal malabsorption disease (compared to controls [37]) and in some aphthous stomatitis patients with normal intestinal function [38], evidence that RAS primarily represents an allergic response or is etiologically linked to diminished serum iron, vitamin B12, or folate levels is lacking or, at best, equivocal [6,16,24,28,39]. For any RAS patient who exhibits physical signs and symptoms that suggest the possibility of an underlying malabsorption or nutritional deficiency state or a blood dyscrasia, it is prudent to obtain a complete blood count and assays for serum folate, vitamin B12, and ferritin. Should any of these tests yield findings that suggest an underlying systemic abnormality, referral to an internist or a hematologist is indicated [6].

Microbial factors To date, investigations have yielded little, if any, consistent evidence to support the hypothesis that RAS represents an infectious disease. In particular, from studies to determine whether there might be a connection between previously suspect L-forms of streptococci and RAS, or the adenoviruses, herpes simplex virus (HSV), varicella-zoster virus, or cytomegalovirus and RAS, the available evidence suggests that none of these microorganisms seems to be directly culpable for RAS despite continued speculation about their possible role [2,6]. One should note that an antiviral agent, acyclovir, offers no beneficial effect in preventing or attenuating episodic flares of the condition [34], which serves to weaken arguments in favor of a possible viral causation for RAS [16]. From occasional anecdotal cases in which patients report an apparent consistent temporal relationship between their aphthous outbreaks and an immediately antecedent reactivated (recurrent) HSV infection, it is tempting to postulate that in a narrow subset of individuals who get RAS, the herpes virus may serve as an antigenic trigger that initiates the cascade of immunologic events that result in ulceration [2]. In a limited subset of RAS patients, it is possible that this is actually the case. Presumably, such patients would benefit from appropriate therapeutic and prophylactic antiviral therapy, coupled with treatments specifically aimed at lessening the severity and frequency of the RAS episodes by modulating their supposedly heightened immune responses to the viral trigger [6]. Such therapeutic strategies probably would be best carried out in consultation with an infectious disease specialist [6]. (Analogous speculation and therapeutic

Clinical features The classic clinical features of RAS are generally well known and usually suffice for diagnostic purposes [6]. The lesions affect the oral cavity exclusively and, with the occasional exception of the dorsal aspect of the tongue, overwhelmingly favor nonkeratinizing, freely moveable mucosal surfaces. From the latter characteristic, one might infer that the abridged mucosal barrier of these attenuated epithelial surfaces allows for intensified antigenic stimulation, which in turn launches the autoimmune reaction that results in mucosal disruption. Involvement of keratinized epithelial surfaces is distinctly

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uncommon and almost always represents extension of ulceration from its origin on an adjacent nonkeratinized epithelial surface [2]. When a cluster of ulcers is confined to a single keratinized mucosal location (eg, hard palate, attached gingiva), the possibility that they represent ruptured vesicles of a recurrent HSV infection (Table 1) or are traumatic ulcers must be considered in the differential diagnosis as more likely than aphthous ulcers [6,40,41]. Aphthous ulcers preference for buccal and labial mucosa and the lateral-ventral tongue surfaces also lends oblique support to the conditions immunerelated nature, because these sites are especially susceptible to friction and prone to trauma. It is not uncommon for some patients to report that their aphthous ulcers typically arise on such locations shortly after a preceding minor traumatic event, such as an accidental self-inflicted bite, frictional irritation or injury from tooth clenching or bruxing, or after an inadvertent nonpenetrating stab from a utensil during a meal [42]. These events are examples of the so-called Koebner phenomenon, in which lesions that are characteristic of a specific immunologically mediated mucocutaneous disorder (eg, psoriatic plaques in psoriasis) develop on sites of recently traumatized but previously lesion-free skin or mucosa [43]. Koebnerization also occurs in individuals with diseases such as lichen planus [44], various types of lupus erythematosus, and others [45]. It seems that a subset of individuals with RAS

tends to experience a similar phenomenon with relation to the location of at least some of their aphthous lesions in the context of some, if not all, of their outbreaks. Unlike the ulcerations seen in primary or recurrent oral HSV infections, aphthous ulcers are not preceded by vesicles [6]. Although individual aphthae are often categorized into one of three possible subtypes (minor, major, and herpetiform) based primarily on their respective size differences, this classification is purely descriptive rather than substantive. Regardless of an individual lesions dimensions, all of the subtypes seem to represent mere superficial variations of a single disease entity [2]. Any individual recurrence may feature as few as one or two isolated ulcers or upwards of virtually dozens of aphthous lesions. Any one of the subtypes or various combinations of each of the three subtypes can occur in the course of a single RAS outbreak [16]. Notwithstanding size, all aphthous ulcers are painful, and in many cases, patients also relate histories of prodromal discomfort or other symptoms that routinely augur impending recurrences [40]. The frequency and severity of recurrences vary widely among affected individuals. Some patients experience recurrences at fairly regular intervals, whereas for others the episodes occur with less predictability. In many cases the attacks are precipitated by a particular identifiable factor (eg, intense stress [15] or, as reported by some women, in temporal relation to their menstrual cycles [46]), whereas

Table 1 Distinctions: Recurrent aphthous ulcers and recurrent (reactivated) intraoral HSV lesions Factor Etiology Antecedents Prodromal awareness Location of lesions Distribution Lesions Symptoms Diagnostic Confirmation Recurrent aphthous ulcers Focal immune dysregulation Commonly stress, trauma; other factors diverse and unique as the affected individuals Sporadic Non-keratinizing moveable mucosa and tongue dorsum Unifocal or multifocal throughout oral cavity Ulcers of varying size and number possible per episode Pain (regardless of lesion size) History, clinical features; negative cytology for virally-modified epithelial cells; biopsy usually not necessary 7 to 14 days, no scarring (minor and herpetiform types); greater than 14 days, scarring possible (major types) Palliative agents, corticosteroids, other immune modulating agents Recurrent HSV HSV-I (HSV-II rarely) Local trauma, stress, systemic immune alteration Typical Keratinizing (bound down) mucosa only Unifocal only (in immunocompetent individuals) Unifocal cluster of vesicles that ulcerate Pain History, clinical features; positive viral cytopathic changes on smear; biopsy usually not necessary 7 to 14 days (in immunocompetent individuals) Antiviral agents

Clinical course Management

Modified from Regezi JA, Sciubba JJ. Vesiculo-bullous diseases: Herpes simplex infections. In: Regezi JA, Sciubba JJ, editors. Oral pathology: Clinical-pathologic correlations. 2nd edition. Philadelphia: W.B. Saunders; 1993; p. 9; with permission.

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Fig. 1. Minor aphthous ulcers, lower labial mucosa.

some patients outbreaks arise without any identifiable triggering factor [16]. Episodes may occur rarely or with some frequency, accompanied by a range of symptomatic intensity. Most troubling for a small subset of individuals is the experience of overlapping recurrences for periods of time that can involve weeks or months or, rarely, a year or more of almost perpetual mucosal disruption from aphthous ulcerations. During such periods of seemingly relentless outbreaks, a patients ability to function comfortably and even their emotional stability may be compromised drastically because of protracted oral mucosal pain [2]. Under such circumstances, patients are occasionally suspected of having Behc ets disease [8] or some other major systemic disorder. Accordingly, they are often referred to appropriate medical or dental specialists for a diagnostic consultation and evaluation. One should note that in most cases even the most exacting and thorough systemic evaluation fails to reveal evidence that supports a diagnosis either of Behcets or any other identifiable systemic disease. Instead, such evaluations only serve to confirm that the condition is confined to the oral cavity and is simply an extreme expression of RAS alone [2,6]. Commonly, RAS patients report sensations of burning, tingling, or other mucosal discomfort just before an outbreak of aphthous ulcers, similar to the prodromal symptoms that frequently precede recurrent HSV infections [40]. During the prodromal phase of RAS it may be possible to observe a transient erythematous macule or papule at the site of mucosal discomfort. Such lesions typically emerge onto moveable oral mucosal surfaces or the dorsal aspect of the tongue and can antecede the actual aphthous ulcerations by at least several hours or longer. These preulcerative lesions are succeeded by characteristically painful ulcers with round, symmetrical, yellow-white or gray fibrinonecrotic centers surrounded

by slightly raised, erythematous, halo-like borders. Several ulcers in close apposition to one another may become confluent and result in a larger area of mucosal disruption [2]. So-called minor (typical) aphthous ulcers are smaller than 1 cm in diameter and tend to heal within 10 to 14 days (Fig. 1). Their larger counterparts, socalled major aphthous ulcers (Mickuliczs aphthae, periadenitis mucosa necrotica recurrens, Suttons aphthae), are not as common. They are 1 cm in diameter or larger, with edematous borders, and classically involve a greater depth of submucosal tissue destruction. For this reason, these types of aphthous ulcers tend to run a more extended clinical course; they can take significantly longer than 2 weeks to resolve and sometimes heal with scar formation (Figs. 2,3). Herpetiform aphthous ulcers, the least common type, tend to be distributed in tight clusters of small ulcers, 1 to 3 mm in diameter, that bear superficial resemblance to the ruptured vesicles of oral HSV infections [2,4,6,36]. Frequently, close crops of these ulcers coalesce to involve a broad surface area (Figs. 4,5). Although their small size allows for resolution of herpetiform aphthae within a 7- to 10-day period, some patients experience recurrences that flare at relatively close intervals. Although herpetiform aphthae also exhibit a strong predilection for nonkeratinized epithelium, unlike their minor and major counterparts they coalesce readily and can occur on any oral mucosal surfaces, including those that are keratinized [2].

Histopathology Once an aphthous ulcer has emerged onto the oral mucosa, biopsy is usually not required for diagnostic

Fig. 2. Major aphthous ulcer of longer than 8 weeks duration. Located on anterior buccal-labial mucosa, the lesion had been secondarily traumatized.

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Fig. 3. Hyperplastic scar tissue from healed major aphthous ulcer, lower right vestibular mucosa adjacent to mandibular canine and first premolar tooth. Scar resembles epulis fissuratum.

Fig. 5. Herpetiform aphthous ulcers on the soft palate and uvula. These clusters of small ulcerations have coalesced to form extensive lesions that resemble major aphthae.

confirmation because there are no defined pathognomonic microscopic features of this disorder. At the tissue level, the clearly nonvesicular nature of the ulcerative lesion and the absence of virally modified epithelial cells may serve to distinguish an early aphthous ulcer from an herpetic lesion in cases in which there is clinical diagnostic ambiguity [4,40]. Relatively early in their course, aphthous lesions demonstrate an ulcer base covered by a fibrinopurulent pseudomembrane. The marginal epithelium may appear spongiotic with attendant lymphocytosis, especially in the basal-most strata. At the marginal epithelial-stromal interface, tagging of lymphocytes is prominent, and throughout the superficial stroma polymorphonuclear leukocytes and chronic inflammatory infiltrates dominated by lymphocytes and histiocytes prevail. Within the deeper submucosa, perivascular infiltrates of lymphocytes and histiocytes

may be seen [2]. As an aphthous ulcer ages, the histopathologic findings become increasingly nonspecific [16]. Biopsy of any long-standing, nonhealing oral ulcer may be indicated, however, to determine whether the lesion is benign or malignant or representative of some unsuspected unusual diagnostic entity, such as a granulomatous infection or inflammatory disease.

Management of recurrent aphthous stomatitis General considerations Conventional wisdom and clinical experience strongly suggest that most cases of RAS are isolated to the oral cavity and are neither attributable to nor associated with an underlying systemic disease or some other generalized pathologic condition. If the medical history is positive for or suggestive of any of the systemic conditions known to be linked to oral aphthae, however, and the patient experiences severe bouts or unusually frequent recurrences of aphthous stomatitis, it may be prudent to rule out the possibility that the oral flare up reflects an exacerbation of the systemic disease. Should that suspicion be confirmed through an appropriately focused evaluation in consultation with the patients primary care provider or an appropriate medical specialist, the apparent inciting condition must be addressed and treated accordingly. The expectation is that once the underlying systemic problem is brought under control, at least temporary remission or regression of the RAS can be achieved [2,6,16]. Whether it is of value to include complete hematologic screening of RAS patients as part of the

Fig. 4. Minor, major, and herpetiform aphthae occurring synchronously on right soft palatal mucosa.

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standard diagnostic and treatment planning evaluation is debatable. Although low serum iron and ferritin levels have been documented in some patients by some investigators [47,48], others have found that RAS patients generally have normal erythrocyte counts and hemoglobin levels, similar to those of controls [49,50]. Some researchers recommend that children with RAS be screened hematologically because in approximately 20% of children who get aphthous ulcers, dormant serum iron deficiencies unaccompanied by anemia have been disclosed [51]. Regardless of the patients age, if hematologic testing reveals a deficiency state or other abnormality, management of the blood dyscrasia also may constitute a key strategy for managing the oral lesions.

Box 2. Recurrent aphthous stomatitis: treatment options No treatment Palliative approach  Topical agents: home remedies, overthe-counter medications, prescribed analgesics, cauterizing agents Antiinflammatory and antimicrobial agents Immunomodulation*  Topical: corticosteroid creams, ointments, gels, rinses; intralesional (perilesional) corticosteroid injections  Systemic: corticosteroids, nonsteroidal immunosuppressive agents, antiinflammatory agents Combined therapy: topical and systemic agents, systemic agents in combination * Most efficacious approaches.

Objectives, principles, and caveats Treatment is targeted at reducing the duration and expediting the resolution of ulcers, alleviating pain, lessening the frequency of attacks, and forestalling recurrences. Management decisions should be dictated by each patients perceptions of the severity of the oral lesions, the frequency of recurrences, and the degree of debilitation that attends the outbreaks. All treatment efforts must be applied in balance with the safest, most judicious use of therapeutic agents available. In patients with strictly oral manifestations of RAS and no concomitant systemic abnormality, a broad scope of possible treatment options is available. At the extremes, choices range from doing essentially nothing other than to confirm the diagnosis to prescribing major therapeutic agents aimed at prevention and control of the immunologic mechanisms that produce aphthous ulcers. In between these extremes several relatively conservative strategies are available for alleviating symptoms exclusively, curtailing the duration and pain of a single episode, attenuating an active outbreak that may be part of a series of overlapping or frequent outbreaks of RAS, and preventing future episodes (see Box 2). It is vitally important for the patient and the clinician to bear in mind that any and all interventions for RAS, regardless of severity, are neither curative nor intended for persistent use [16]. Rather, they are prescribed to effect temporary respite from a disease with a proclivity for recurrences [1 4,6,16,28,40]. Because aphthous stomatitis is an immunologically mediated disease, therapies centered in immunomodulation are most appropriate. They can be applied successfully for managing individual epis-

odic flares and can be used on an intermittent basis as a preemptive strategy for attenuating an incipient attack or they can be used to abort an imminent aphthous outbreak in its prodromal stage. The unremitting use of immunomodulating agents for this essentially benign disease, whether topical, systemic, or combined, is contraindicated, given these agents recognized potential for pernicious side effects [2,3,6].

First-line therapeutic choices When a recurrent episode consists of a relatively limited number of aphthous lesions that are either small or large, closely apposed to one another, and distributed on readily accessible oral surfaces such as the labial or vestibular mucosa or the anterior portion of the tongue, first-line therapeutic management should involve regimens based on conservative topical therapy [2 4,6,16]. Among the options available are any of the over-the-counter nonsteroidal occlusive preparations, such as Orabase, with or without topical analgesic (usually benzocaine) that may be applied primarily for symptomatic relief or nonsteroidal antiinflammatory preparations, such as amlexanox 5% paste (Aphthasol oral paste). Applied directly to active lesions, amlexanox promotes pain reduction by inhibiting release of his-

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tamine and leukotrienes. It has been shown that aphthous ulcers treated with amlexanox resolve in less time (by 1 day) than their untreated counterparts [2 4,6]. Topical corticosteroid gels, creams, or ointments that are selectively prescribed and judiciously applied to active lesions constitute an effective conservative modality for managing RAS. The cream or ointment preparations are preferred, because some patients report stinging or burning with the use of corticosteroid gels [3,40]. Some patients who wish to use topical corticosteroid gels, creams, or ointments are reluctant to do so or fail to comply because of the fear that attends reading the warning on prescription packaging inserts or receiving pharmacists admonishments that topical corticosteroid preparations are for external use only. Clinicians should reassure their patients that the use of these topical agents strictly as prescribed for limited periods of time is not likely to produce untoward effects and is safe [3,40,52]. Over the course of several days, starting as early as possible from the onset of the outbreak, direct application of a thin film of the corticosteroid agent three to five times daily and at bedtime after gentle drying of the affected area alleviates discomfort and reduces the duration of ulcers so that they heal within several days, rather than linger for a week or more, as is typical of untreated lesions [6]. Among the recognized vagaries inherent in using creams or ointments on oral mucous membranes is the likelihood that they rapidly wash away from the site of application and thereby diminish the therapeutic efficacy of the medication. This problem can be addressed either by prescribing a topical corticosteroid compounded with tissue adhesive (eg, 0.1% or 0.5% triamcinolone acetonide [Aristocort A, Kenalog] in Orabase) or, as an alternative, by prescribing more potent topical corticosteroids, such as 0.05% betamethasone dipropionate cream or ointment (Diprolene; Lotrisone), 0.05% fluocinonide cream or ointment (Lidex), or 0.05% clobetasol propionate ointment or cream (Temovate) alone, without tissue adhesive [2 4,6]. The latter three topical agents seem to provide greater therapeutic efficacy than those compounded in an occlusive or adherent base, despite their limited time in contact with active lesions [3]. There seems to be no appreciable therapeutic advantage to applying corticosteroid in a base preparation (ie, compounded in Orabase or some other inert mucous membrane dressing) as compared to applying a base preparation alone (ie, without corticosteroid) [53]. Regardless of whether a base preparation or corticosteroid alone or a compound of both is applied, avoidance of food and

drink for 30 minutes after application is advised to promote adherence of the preparation to the ulcerations. To prevent or address corticosteroid-induced candidiasis, an antifungal medication can be compounded into the corticosteroid cream or ointment, with or without a tissue adhesive base when indicated [40]. For aphthous ulcers that are difficult to reach with a fingerpredominantly ulcers that involve the most posterior oral regionsor are so numerous and widely distributed as to render the direct application of creams or ointments impractical, corticosteroid rinses are an excellent topical therapeutic alternative [2 4, 6,16,28,40]. Rinsing over a period of several days with betamethasone (Celestone) syrup 0.6 mg/5 mL, dexamethasone (Decadron) elixir 0.5 mg/5 mL, or a specially compounded aqueous suspension of 0.1% or 0.2% triamcinolone acetonide accelerates resolution of the ulcers and alleviates discomfort. Three to four times daily and before retiring for the night, 1 teaspoonful of the liquid is held and swished in the mouth for 2 to 3 minutes and then expectorated. The rinse regimen is followed by avoidance of food and drink for 30 to 60 minutes afterward. This is not only an effective method for addressing active RAS outbreaks but also may be useful for aborting an imminent attack in its prodromal phase [16]. The author also has found that customized prophylactic corticosteroid rinse regimens can be adapted to an individual patients needs, particularly in cases in which it is necessary to intercept and prevent episodes known to occur with some regularity or frequency. Triamcinolone acetonide suspension can be compounded with nystatin (Nystatin oral suspension USP) for individuals predisposed to oral candidiasis or with 2% lidocaine (Xylocaine 2% viscous solution) if there is a need for expedient pain relief (Karen A. Baker, MS Pharm, personal communication, 2001). Another method for applying topical corticosteroid medication to active lesions (particularly major aphthous ulcers or other types of aphthae located primarily in intertriginous-like regions of the oral mucosa, such as the upper or lower buccal or labial vestibules or the sublingual vestibule) involves using a gauze sponge either soaked in corticosteroid rinse preparation or on which a small amount of corticosteroid cream or ointment has been applied for delivery. By laying the gauze sponge directly onto the lesion or lesions and holding it in place for 15 to 20 minutes two or three times daily during waking hours, the concentrated contact method for delivery of the medication requires fewer applications and promotes more expeditious healing of ulcers [3,4].

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Perilesional injection Perilesional injection of corticosteroid medication is another therapeutic alternative. Such injections can be highly efficacious for treating major aphthous ulcers that have been resistant to other more conservative topical approaches or are unresponsive to systemic treatment [2]. The author has found that this route of corticosteroid administration can reduce significantly the diameter of either a newly erupted or a long-standing major aphthous lesion within the 24- to 48-hour postinjection period and dramatically shorten healing time. The procedure the author uses is based on a modification of the adjuvant intralesional corticosteroid injection regimen described for use in treating recalcitrant pemphigus lesions [54]. After administration of local anesthesia (with vasoconstrictor), 10 to 40 mg of sterile triamcinolone acetonide injectable suspension, USP (Kenalog-40) 40 mg/mL diluted to 10 mg/mL strength, is injected into the perilesional tissue immediately adjacent to the ulcer border. The lesion is clinically evaluated 48 hours after injection to determine whether the treatment was adequate. If there seems to be neither improvement in symptoms nor evidence of progression toward healing, it may be necessary to repeat the procedure. Usually a single administration of corticosteroid is sufficiently therapeutic, however, so that even large, painful, or stubbornly recalcitrant major aphthous lesions that were present for many weeks before the injection resolve within 5 to 7 days.

Indications for second-line therapy Prednisolone (Prelone) or betamethasone (Celestone) syrup preparations can be used exclusively as rinses or as several times daily rinse-and-swallow regimens for cases that are recalcitrant to the topical approach alone. The latter combined route of administration can be helpful for treating major aphthae and is especially effective in cases in which the aphthous ulcers are concentrated in the posterior oral cavity, soft palate, and tonsillar fauces and are attended by considerable pain. Used in this manner, the corticosteroid agent provides topical and systemic immunomodulatory benefits and is considered to be a second-line type of therapy [2]. For the occasional patient plagued by frequent or overlapping RAS attacks over a protracted period of time and whose quality of life has been eroded as a result, the goal of treatment is two-

fold. The first goal is to remedy the current attack. The second goal is to attempt to break the apparent cycle of recurrence to achieve at least a temporary period of remission or an interim in which recurrences are less frequent, ulcerations are fewer, and symptoms are less intense. Achieving this goal may require an approach that briefly couples systemic corticosteroid burst therapy with topical corticosteroid therapy initially, followed by a prophylactic maintenance regimen with continuance of the topical corticosteroid alone. The author has found that individual case-centered modifications of the therapeutic approach reported by Vincent and Lilly [16] can be effective in most cases for accomplishing these goals. They recommend using a burst therapeutic regimen of prednisone (40 mg taken 1 hour after rising in the morning for 5 days, followed by 20 mg every other day for an additional week) along with oral rinses with compounded 0.1% triamcinolone acetonide aqueous suspension (5 mL of liquid swished four times daily for 2 to 3 minutes and expectorated ; NPO for 1 hour afterward). If the triamcinolone suspension is not available, dexamethasone elixir used similarly three to four times daily at outset also can be effective. In the authors experience, burst therapy also can be used safely over a 3-week period if necessary (eg, 40 mg prednisone every morning for 7 days followed by 20 mg every morning for 7 additional days followed by 20 mg every other morning for another 7 days) and does not require any further tapered doses [16]. Coupled with the initial fourtimes-daily corticosteroid rinse regimen, burst therapy is more effective than 5 to 7 days of abbreviated systemic corticosteroid (dosepak) therapy alone for obtaining control of an active outbreak and intercepting and preventing subsequent recurrences [16]. Once the systemic corticosteroid regimen is completed, a prophylactic rinse regimen (eg, either one to three times daily or one to three times on alternate days as needed; NPO for 30 minutes to 1 hour after rinsing) can provide long-term preventive maintenance. Although systemic complications from using attenuated corticosteroid rinse regimens over extended periods of time do not seem to be a significant problem [16], oral candidiasis can be a potential problem for some individuals on this therapy, particularly individuals whose cell-mediated immune responses are compromised by an underlying medical condition, such as diabetes. In such cases, intervention with ketoconazole (Fluconazole, Nizoral) tablets or clotrimazole (Mycelex) troches may be indicated [2,3].

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Other medications Various other medications and methods too numerous to mention in this article and of highly variable efficacy have been used for managing aphthous stomatitis. These medications include inert and more active prescribed preparations (antimicrobial agents, cauterizing solutions, monoamine oxidase inhibitors, tissue films, and others) and myriad home remedies [2,4]. When cases are resistant to corticosteroid-based immunomodulatory regimens exclusively, other nonsteroidal immunosuppressive agents, such as cyclosporine (Sandimmune, Neoral), dapsone, or azathioprine (Imuran) given systemically in combination with adrenal-sparing doses of prednisone and other agents with antiinflammatory, immunomodulatory properties alone (eg, pentoxyphylline [Trental] or colchicine) may or may not prove useful as alternative second- or third-line therapies [2 4,6,16,28,40]. Their potential for producing serious side effects does limit case selection for their use. Recently, thalidomide (Thalomid), a potent immunosuppressive medication, was found to be effective for treating HIV-infected patients with severe RAS when prescribed at daily doses of 100 to 200 mg [55] and for managing oral aphthae in immunocompetent individuals with Crohns disease [56] and Behcets disease [8,57]. Because of thalidomides recognized potential for profound side effects, however, its use must be reserved only for patients whose aphthous ulcers have been so unrelenting and sufficiently symptomatic as to significantly compromise quality of life and who, after exhaustive efforts, also have failed to respond to other, more conservative therapeutic measures. Use of this systemic agent requires strict adherence to guidelines for patient selection. Patients who take thalidomide must be monitored frequently to intercept and prevent its potential toxic effects [2,6].

origin and pathogenesis, combined with ongoing research directed toward the development of safer, more effective immunomodulating agents, render the prospect of a cure for RAS increasingly plausible.

Acknowledgment The author wishes to express sincere gratitude to Marilyn R. Holt, MS, for her technical expertise and invaluable assistance in preparing the manuscript.

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The surgical treatment of periodontal infections

Norman Trieger, DMD, MD*
Department of Dentistry, Oral and Maxillofacial Surgery, Albert Einstein College of Medicine, Montefiore Medical Center, 111 E. 210th Street, Bronx, NY 10467, USA

Identification of the specific pathogenic microorganisms responsible for periodontal destruction has led to newer treatment methods. The basis for this approach has been the application of well-established surgical principles of infection management: the identification of the responsible pathogens; mechan ical debridement of the infected sites to decrease the bacterial load as well as products of the inflammatory immune response; and the introduction of systemic antibiotics known to be effective against the offending bacteria. Experience has shown that eradication of the infection is possible and regeneration of attachment and bone regrowth in vertical defects is accomplished when several important guidelines are followed. The oral cavity is regarded as one ecosystem, with microorganisms readily transported to multiple sites by saliva, food, and the toothbrush. Treatment by debriding only one quadrant at a time allows reinfection of the site within the ecosystem from other untreated quadrants. The usual pattern of multiple oral hygiene visits before definitive full mouth debridement meant to prepare the mouth for surgery does not eliminate the infection that is harbored in biofilms in deep pockets. Eliminating the deep infection should take precedence over the repeated superficial scalings. Brushing, flossing and various mouth rinses do not reach pockets deeper than 4 to 5 mm despite the diligence of enhanced home care. The periodontal attachment continues to secrete extracrevicular fluid that inactivates and rapidly washes away any substances squirted into the pocket. It should be noted that topical antimicrobials (eg, chlorhexidine) as

* 55 Lakeside Drive, Larchmont, NY 10538. E-mail address: n.triege@verizon.net

well as topical antibiotics are cytotoxic [1]. They provoke the death of healthy cells and elicit their own inflammatory reactions. The field of periodontal disease has undergone rapid expansion of basic information with respect to microbiology and the origin and characterization of endotoxins produced by gram-negative anaerobes, which are responsible for various kinds of periodontitis. The endotoxins (lipopolysaccharides) from the outer cell wall of the specific anaerobes are now known to be water soluble, and their localization on the cementum of the root is superficial and not deeply imbedded [2 5]. Smart et al [6] and others have reported that endotoxin can be washed away or brushed away without resorting to root planing, which destroys the cementum. Recently, the treatment concept has changed from aggressive root planing to debridement. It also has been shown that connective tissue regrowth in the periodontal crevice is positively influenced by the presence of adjacent cementum. In the absence of cementum, reattachment to dentin does not readily occur. Following periodontal connective tissue reattachment, bone fills the vertical defects, and the mobility of teeth decreases when the infection is resolved. It is difficult to identify the origin of the practice of root planing. There is no scientific evidence to show that root planing is any more efficacious than debridement, without destroying cementum. The shibboleth of scaling and root planing with which we were taught to begin every treatment plan deserves to be seriously questioned. In addition to being destructive, the removal of cementum also leads to thermal hypersensitivity and more postoperative pain. It is likely that the original intent to remove scale, formed from salivary calculus, was extended down onto the exposed root surface and

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continued even in the absence of calculus deposits. Calculus deposits come from saliva and are most pronounced opposite the openings of Whartons and Stensens ducts. Calculus does not cause periodontitis but may constitute a mechanical irritant and be aesthetically objectionable. Calculus, when identified, is best removed using an ultrasonic cleaner or by discrete curetting, which clears away just the deposit and does not strip the cementum.

Diagnosis of periodontitis A major contribution was made by Loesche [7], who introduced the specific plaque hypothesis. Other investigators have identified several periopathogens associated with patterns of bone loss, primarily by using the techniques of deep-pocket sampling and rapid anaerobic subculturing. Periodontitis was thus identified not as a single entity but as a series of infections based on microbiologic sources, host immunocompetency, and the interaction between these factors. Various syndromes of periodontal infections have been identified. Rapidly progressive periodontitis This is seen in children, young adults, and adults who are immunocompromised, especially by virtue of impaired cell-mediated immunity (eg, neutropenia, cancer chemotherapy, acquired immunodeficiency syndrome, etc.). Juvenile periodontitis Formerly known as periodontosis, this is a disease of late childhood and early adolescence caused by Actinobacillus actinomycetemcomitans, a gram-negative facultative organism that produces a potent leukotoxin. Early in childhood the organism is found in the tonsillar crypts and may cause repeated bouts of tonsillitis. Later on, in addition to dental pathology it may be found on damaged heart valves, causing infective endocarditis. This organism is susceptible to the tetracyclines and not consistently to the penicillin derivatives or clindamycin. Another important aspect of this syndrome is that there is usually a qualitative inherited defect in the behavior of the patients neutrophilic leukocytes. Acute necrotizing ulcerative gingivitis This uncommon infection, once called trench mouth, is most often noted in young smokers.

Borrelia vincenti and Prevotella intermedia are two major pathogens readily identified in this condition which is often associated with susceptible individuals who have been subjected to major psychologic stress, such as a divorce, familial death, or dismissal from college. Under these circumstances, direct invasion by the periopathogens has been demonstrated, leading to necrosis, loss of interdental papillae, lymphadenitis, gingival bleeding, and fetid odor. Treatment should be directed first to using a systemic antibiotic, such as penicillin or amoxicillin, to control the acute phase before launching into painful manipulations, such as curettage. Chronic adult periodontitis Several specific organisms have been associated with the localized areas of periodontal bone destruction (Table 1). These organisms include Porphyromonas gingivalis, Bacteroides forsythus, Prevotella intermedia, Capnocytophaga species, Campylobacter rectus, Eikenella corrodens, and Fusobacterium nucleatum. Other periopathogens will undoubtedly be identified as the field expands. Many of these organisms produce an endotoxin (ie, lipopolysaccharide) that provokes the release of host-tissue factors, contributing to further breakdown. Cytokines such as interleukin-1b and tumor necrosis factor-a from host lymphocytes and other mononuclear phagocytes are released. These and other substances can destroy collagen and bone, causing advancing destruction of the periodontium. Bacteriologic culturing

Table 1 Species identified in refractory or recurrent periodontitis (n = 196) Organism Bacteroides forsythus Spirochetes Motile rods Fusobacterium species Porphyromonas gingivalis Campylobacter rectus Capnocytophaga species Prevotella intermedia Peptostreptococcus micros Actinobacillus actinomycetemcomitans Candida species Enteric rods Percentage of sites 84 83 76 68 63 47 38 23 18 16 14 9

Resistance to penicillin, tetracycline, and metronidazole was high. Adapted from Listgarten MA, Lai C-H, Young V: Microbiota and antibiotic resistance (abstract). J Dent Res 1993:72:819. [8]

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and the use of specific DNA probes (eg, University of Pennsylvania Microbiological Testing Laboratory, Philadelphia, PA) have served to identify putative organisms. Other tests have been proposed based on the enzymatic characteristics of the particular pathogens. Loesche et al [9] have reported on the use of the benzoyl-DL-arginine naphthylamide (BANA) test at chairside. BANA identifies three known pathogens: P. gingivalis, B. forsythus, and Treponema denticola. The ultimate aim is to develop a chairside test that will identify the predominant organisms and guide treatment and follow-up monitoring. Periodontitis is readily transmissable between spouses and other cohabitants [10,11]. In the authors experience, 80% of patients requiring treatment have mates with similar organisms. To prevent pingponging the disease, both partners should be placed on antibiotics while the primary patient undergoes surgical debridement and proceeds into a maintenance phase. Radiographs reflect the bone level (ie, bone loss) but do not indicate the current status of the infection. Bone loss does not necessarily translate into mobility or condemn a tooth to extraction. Satisfactory resolution of the infection leads to reduction in bleeding, pocket depth, and mobility, and new bone often forms and fills vertical defects [12 14].

Box 1. A summary of guiding surgical treatment of periodontal infections

1. Periodontitis is an infectious disease attributable to a relatively small number of gram-negative oral pathogenic bacteria that produce endotoxins. 2. Piecemeal mechanical treatment (by quadrant or sextant) via scaling and root planing above is incomplete and invites relapse. 3. The mouth is one ecosystem that must be treated as a comprehensive unit to eradicate the infection, preferably under intravenous sedation and local anesthesia. 4. Periodontitis may be considered a sexually transmitted disease. 5. Soft tissue debridement of periodontal pockets without destruction of root cementum (planing) is the goal, in conjunction with systemic antibiotics effective against the specific bacterial pathogens. 6. Topical irrigants, including antibiotic and antimicrobial agents, are cytotoxic and jeopardize healing and regeneration. 7. Regrowth of bone follows reattachment when the infection is resolved and the cementum is intact. It is a curable disease. 8. Reinfection is possible, and continued vigilance and follow-up care are important. 9. Individual immune status affects the incidence and long-term response to therapy. Examples of immunocompromised status include diabetes, HIV, and qualitative and quantitative white blood cell abnormalities. 10. Calculus has a minimal role in the initiation and progression of periodontitis. The periodontal literature supports each of these principles and should lead to a modification of practice.

Surgical techniques Current management of periodontitis has moved away from some of the prior practices (see Box 1). The gingivectomy is passe, as is the practice of bony recontouring. The author prefers early, one-stage, full-mouth debridement guided by the severity of attachment and bone loss. Pockets deeper than 4 or 5 mm merit use of a conservative access flap reflected just to the bone margin (Fig. 1). This provides visibility for surgical curettage of the granulation tissue and avoids the postoperative edema and pain caused by excessive exposure of labial bone. Pockets that measure less than 4 or 5 mm are debrided and curetted at the same appointment without flap reflection. With the patient under intravenous sedation and local anesthesia, the crevicular incisions are made in areas where pocket depths exceed 4 to 5 mm, preserving the interdental papillae and marginal gingivae. Bony crypts are debrided with a large Prichard curette followed by use of Gracey curettes to reach into and under bony defects. Copious saline irrigation is used during debridement instead of cytotoxic agents such as chlorhexidine and topical antibiotic

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Fig. 1. (A) Crevicular incision reflected just to bony margin for debridement. (B) New bone regrowth in absence of infection.

solutions, which damage healthy cells [15,16]. It is important to remove the granulation tissue that adheres to the underside of the mucoperiosteal flap either by curettage or with a soft-tissue rongeur (Nipro Medical, Miami, FL) or nipper. With the flap reflected, deposits on the cemental surface can be discretely removed with a scaler or Cavitron. Another important component of the recommended technique is to avoid root planing. The periodontal literature is finally recognizing that root planing is destructive and compromises reattachment. Cementum is necessary to induce and enhance fibroblastic proliferation and reattachment [4,5]. The apparent indication to remove diseased cementum is predicated on the presence of endotoxin [2,3]. Endotoxin, a product of gram-negative anaerobic organisms, is water soluble and not deeply imbedded in the cementum. It is limited to 40 50 mm of the surface cementum and can be washed or even brushed away. Cementum has specific growth-enhancing factors that stimulate the fibroblasts necessary for repair and reattachment of the periodontal membrane. Therefore, planing the cementum is a waste of time and effort. Furthermore, root planing jeopardizes softtissue regeneration and bone support and often leads to thermal hypersensitivity. The surgical objectives should be to clear the infection by mechanical debridement and to use antibiotics effectively. Minimal periodontitis can be read-

ily controlled by frequent periodic debridement probably because it disrupts the colonies that re-form in the pocket. When bone loss has advanced beyond 4 to 5 mm, however, it does not make good sense to rely only on conservative treatment and wait until the infection recurs and is finally classified as refractory. Treatment should be comprehensive and aim to debride with the least possible damage to cementum, bone, and mucoperiosteum. This should be accompanied by the administration of systemic antibiotics known to be effective against gram-negative anaerobes. Clindamycin, metronidazole, or amoxicillin/clavulanic acid have been used for 7 to 10 days with rewarding results. The tetracyclines usually are prescribed for 2 to 3 weeks to treat juvenile periodontitis [12 14,17,18]. Flaps are closed with interrupted sutures, avoiding apical repositioning (Fig. 1). Healing and bony regrowth are favored by adequate mucoperiosteal covering. The surgeon should not try to eliminate the pocket. The cervical defect fills initially with a blood clot, which then differentiates into connective tissue and subsequently into new bone. Periodontal packs are never used; they retard healing and are cumbersome, difficult to clean, and inappropriate when treating an anaerobic infection (Fig. 2). Even in the advanced periodontitis cases, the operating time for this procedure is usually 1 to 2.5 hours. Very few patients undergo repeated sessions with the hygienist before the main surgical debridement. It is

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Fig. 2. (Left) Preoperative first molar bone loss. (Right) One year postoperative bone regeneration.

the primary intent to reduce the bacterial load in deep pockets that are beyond the reach of the patients home care or the hygienists scaling. Postoperatively, the patient is given a prescription for a nonsteroidal antiinflammatory agent and instructed to continue the prescribed antibiotic for 7 to 10 days. Brushing is avoided in the sutured areas, and either saline irrigation or a chlorhexidine rinse is recommended for home hygiene. A new brush is provided on the 1-week return visit and a simple Bass brushing technique is demonstrated. Patients are maintained on a soft diet and rarely report pain or swelling after the first day. The pockets are reprobed at 1 month to evaluate healing and pocket reduction. At this time, the patient can be referred back to his or her dentist for definitive restorative care. Individual persistent deep pockets may now be addressed if pocket elimination is requested by the restorative dentist. Successive 3-month follow-up visits are scheduled during the first year to evaluate the long-term results. Reprobing characteristically finds pockets significantly reduced, with no bleeding on probing or brushing. If this is not the case, additional antimicrobial therapy is pursued after culturing or taking a sample for DNA probe analysis [14]. Periodic (every 3 months) disruption of reforming colonies by deep scaling has been shown to provide adequate control if the case has been refractory to previous treatment. Topical application of fluoride gel

or use of a toothpaste with 1.1% sodium fluoride on a daily basis at home is effective in preventing reinfection from a supragingival source. The use of a chlorhexidine mouth rinse is also helpful in controlling supragingival organisms. Concern has been expressed about the development of enterocolitis caused by Clostridium difficile, a gram-positive organism that produces exotoxin and damages the cells lining the intestinal tract. This complication is seen with a number of antibiotics, such as clindamycin, the cephalosporins, and amoxicillin. Patients are routinely alerted to this possibility when postoperative instructions are given. They are advised that approximately 10% of patients may develop diarrhea after taking the antibiotic for at least 4 to 5 days. If this occurs, they are instructed to discontinue the drug and call the office. The diarrhea usually abates within 24 to 48 hours. If it persists, oral metronidazole is recommended as the drug of first choice (250 mg four times per day). The success rate of combined mechanical and antibiotic therapy has been cited by others [11 14, 17,18] to be superior to that of periodontal therapy alone. When treating a destructive infectious disease in the year 2002 it does not make sense to avoid using effective antibiotics. This technique also has distinct advantages in the salvage of failing implants. The principles of debridement and irrigation and the effective use of systemic antibiotics can enhance the

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N. Trieger / Oral Maxillofacial Surg Clin N Am 15 (2003) 123128 [6] Smart JJ, Wilson M, Davies EH, et al. The assessment of ultrasonic root debridement by determination of residual endotoxin levels. J Clin Periodontol 1990; 17:174. [7] Loesche WJ. The bacterial etiology of periodontal disease: the specific plaque hypothesis. In: Clark JW, editor. Clinical dentistry. Philadelphia: Harper & Row; 1987. p. 11 20. [8] Listgarten MA, Lai C-H, Young V. Microbiota and antibiotic resistance [abstract]. J Dent Res 1993; 72:819. [9] Loesche WJ, Giordano J, Hujael PP. The utility of the BANA test for monitoring anaerobic infections due to spirochetes (Treponema denticola) in periodontal disease. J Dent Res 1990;69:1696. [10] Asikainen S, Chen C, Aloluusua S, et al. Can one acquire periodontal bacteria and periodontitis from a family member? J Am Dent Assoc 1997;128:1263. [11] Offenbacher S, Olsvik B, Tonder A. The similarity of periodontal microorganisms between husband and wife cohabitants. J Periodontol 1985;56:317 23. [12] Trieger N, Mark L, McKittrick J, et al. Clindamycin v. tetracycline in the surgical treatment of advanced periodontitis: a double blind study with applicability for implant salvage. Int J Oral Maxillofac Implants 1991;7:31. [13] Trieger N. Surgical treatment of periodontal infections. Atlas of Oral and Maxillofacial Surgery Clinics of North America 2000;8:127 34. [14] Loesche WJ, Giordano JR, Soehren S, Kaciroti N. The nonsurgical treatment of patients with periodontal disease-results after five years. J Am Dent Assoc 2002;133:311 20. [15] Pucher JJ, Daniel JC. The effects of chlorhexidine digluconate on human fibroblasts in vitro. J Periodontol 1992;63:526. [16] Dahlen G, Wennstrome JL, Grondahl K, Heijl L. Microbiological observations at periodic subgingival antimicrobial irrigation of periodontal pockets. J Dent Res 1989;68:1714 5. [17] Loesche WJ, Schmidt E, Smith BA, Morrison EC, Caffesse R, Hujael PP. Effects of metromidazole on periodontal treatment needs. J Periodontol 1991; 62:247 57. [18] Trieger N, Chomenko A. New concepts in the treatment of periodontitis. J Oral Maxillofac Surg 1982; 40:701 8. [19] Golub LM, Wolff M, Roberts S, et al. Treating periodontal diseases by blocking tissue destructive enzymes. J Am Dent Assoc 1994;125:163. [20] Beck J, Garcia R, Heiss G, et al. Periodontal disease and cardiovascular disease. Periodontol 1996;27:1123.

repair of endosseous implants that are losing bone support. No one knowingly root planes an implant. A soft-tissue debridement is indicated instead [12]. The recognition that specific cytokines, prostaglandins, growth factors, and interleukins, are active participants responding to the elaboration of bacterial lipopolysaccharide sheds new light on methods that may influence the clinical outcome. Golub and coworkers [19] have shown that the tetracyclines, in low doses, also inhibit matrix metalloproteinases such as collagenase and prevents damage to the attachment apparatus. Perhaps most intriguing is the realization that immune-mediated injury is not only an integral part of the host response to periodontitis, but it has also been shown to be a significant contributor to myocarditis [20]. Cytokines released from activated T-lymphocytes have been identified as releasing tumor necrosis factor- a and other injurious molecules that also cause myocardial and vascular injury. Subsequent myocardial fibrosis correlates with the presence of T-lymphocytes and macrophages, which release fibrogenic cytokines such as fibroblast growth factor and tissue growth factor-b Our knowledge base is growing rapidly, and the future will bring fascinating new therapies for the management of periodontal infections.

References
[1] Shahan M. The effect of chlorhexidine irrigation on tensile wound strength [abstract]. J Periodontol 1992; 63:1012. [2] Hughes FJ, Auger DW, Smales FC. Investigation of the distribution of cementum-associated lipopolysaccharides in periodontal disease by scanning electron microscope immunohistochemistry. J Periodontol Res 1988;23:100. [3] Nakib NM, Bissada NF, Simmelink JW, Goldstine SN. Endotoxin penetration into root cementum of periodontally healthy and diseased human teeth. J Periodontol 1982;368 78. [4] Fukazawa E, Nishimura K. Superficial cemental curettage: its efficacy in promoting improved attachment on human root surfaces previously damaged by periodontitis. J Periodontol 1994;65:2, 168. [5] Cobb CM. Non-surgical pocket therapy. Mechanical Annals of Periodontology 1996;1:472.

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Management of peri-implantitis
R. Gilbert Triplett, DDS, PhDa,*, J. Adam Andrews, DDS, MDa, William W. Hallmon, DDSb
a Department of Oral and Maxillofacial Surgery and Pharmacology, Baylor College of Dentistry, TAMUSHSC and Baylor University Medical Center, 3302 Gaston Avenue, Dallas, TX 75246, USA b Department of Periodontics, Baylor College of Dentistry, TAMUSHSC, 3302 Gaston Avenue, Dallas, TX 75246, USA

Failure of osseointegrated dental implants is a frustrating problem for the patient and dentist. Periimplantitis and occlusal overload are the most common causes of implant failure after osseointegration, and they often require removal of the involved implant. A single failed implant can result in complete prosthetic failure when load-sharing mechanics of the prosthesis depend on the health and integrity of each individual implant. Peri-implantitis, which is an inflammatory process around an osseointegrated dental implant in function with resulting bone loss, affects approximately 5% to 10% of osseointegrated implants [1]. Peri-implant mucositis refers to reversible inflammation of the peri-implant soft tissues without bone loss [1,2]. Accurate diagnosis and appropriate intervention are essential if implant salvage techniques are to be successful in preventing implant failure. This article focuses on the methods available for diagnosis and treatment of peri-implantitis that involve various implant systems.

The role of bacteria in the development of peri-implantitis The experimental gingivitis model of Loe and Silness elegantly displays the interaction between bacterial plaque and gingivitis in a human model [3]. This landmark study provided the foundation for

* Corresponding author. E-mail address: gtriplett@tambcd.edu (R.G. Triplett).

the indisputable evidence that linked bacteria to periodontal disease and was later repeated in several experimental mucositis/implantitis models [1]. The evidence compiled from these well-designed studies identified bacteria as the primary culprit in the development of peri-implantitis. Large numbers of gram-negative anaerobic bacteria (A. actinomycetemcomitans, P. gingivalis, P. intermedia) tend to be found around implants with objective signs of periimplantitis, whereas healthy implants are most often colonized with flora dominated by gram-positive cocci [1]. Endotoxins produced by gram-negative bacteria have the capability to adhere to the implant surface and produce inflammation and resulting bone loss around implants in a similar fashion to periodontitis [1]. Several studies have demonstrated the ability of periodontal pathogens to infect peri-implant tissues in partially edentulous patients (Fig. 1). This observation may account for the higher implant success rates reported in several studies when implants were placed in edentulous mouths versus partially edentulous mouths. The convincing evidence that suggests a bacterial cause of peri-implantitis provokes several interesting clinical scenarios regarding the optimal restorative treatment of the partially edentulous patient. Extrapolation of research data, which suggest that implant failures may be significantly higher in partially edentulous patients with a history of periodontitis, may lead to the possible recommendation of extraction of questionable teeth before implant placement. A possible alternative is treatment of the periodontally diseased tissues before implant placement in persons with a history of severe periodontal prob-

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Fig. 1. (A) Peri-implantitis in the partially edentulous patient. (B,C) Peri-implant mucositis demonstrated by soft tissue inflammation and increased probing depths without bone loss.

lems. Edentulous mouths tend to host a more benign flora because of the lack of deep pockets and crevices that commonly harbor gram-negative anaerobes and spirochetes in patients with periodontal disease. Restoration of a more benign oral microbiota seems to be a logical goal before implant placement if long-term implant and prosthetic success is to be achieved. Several protocols for local and systemic decontamination of periodontal tissues have been published; however, the overall long-term benefit depends on many variables and is often unpredictable [4].

Titanium implant surface characteristics and the relationship with implant success and failure The implant market has been inundated with various systems that use different materials, surface coatings, and manufacturing processes. Implants can be categorized by differences in macrostructure (eg, cylindrical, threaded, screw design) and microstruc-

ture (rough versus smooth, commercially pure titanium versus titanium alloy). It seems evident, based on sound clinical and experimental data, that the same surface implant characteristics that enhance osseointegration may possibly increase the risk of peri-implantitis when placed under certain unfavorable conditions. Patient selection is as important as the type of implant used if favorable long-term success rates are to be expected. Implant selection should be based on a combination of patient-dependent clinical and biologic considerations. Several recent studies have concluded that rough surface implants demonstrate a significantly higher percentage of bone-to-implant contact and faster and stronger osseointegration when compared to machined surface titanium implants [5 7]. A study by Trisi et al [5] evaluated differences in the rate of osseointegration between smooth and rough surface implants in low-density human jaw bone. At 12 months, the implant-to-bone contact rates for smooth and rough surface titanium implants were noted to be 6.7% and 76.75%, respectively. The study

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concluded that although a rough surface may enhance the rate of osseointegration, it is not able to improve bone density [5]. The surface oxide layer on commercially pure titanium and titanium alloy (Ti-6Al-4V) determines the biocompatibility of a particular implant because it is the only portion of the implant in contact with host tissues [6]. The same surface oxide layer has been shown to exist on rough titanium surfaces, which may contribute to enhanced osseointegration when compared to machined surfaces of the identical material [6]. Several other studies have reported significantly better bone anchorage with titaniumoxide-blasted (TiO2-blasted) screw implants than with machined implants of similar composition and higher torque removal for implants with increased surface roughness [6]. Schwartz et al demonstrated that as the surface roughness of titanium implants increases, the cytokine and growth factor production by host osteoblast-like cells also increases and could account for improved bone formation around the roughened implant surface [6,8]. Osteoblasts also have been found to display a more mature phenotype when grown on rougher surfaces [6]. Studies that compared different types of roughened titanium surfaces concluded that rougher titanium plasmasprayed surfaces, corundum-blasted surfaces, and sandblasted surfaces alone are inferior to surfaces that are treated with a combination of sandblasting and acid-etching [5,6,9]. Despite the convincing evidence that rough titanium surfaces may enhance osseointegration and implant stability, several studies have suggested that a rough surface may contribute to plaque formation and higher implant failure rates from peri-implantitis. Tillmanns et al [9] experimentally induced periimplantitis in a canine model with three different types of implant surfaces (smooth, blasted, and hydroxyapatite coated). The results after 3 and 6 months revealed plaque accumulation and the same amount of peri-implant bone loss among all implant surfaces studied. The study concluded that the three implant surfaces are equally susceptible to ligatureinduced peri-implantitis [9]. The conclusion is in direct contrast to most experimental results that compared implant surfaces. The finding seems to be well supported that bacterial plaque formation depends on the surface properties of the implant material. A surface roughness (Ra) more than 0.2 mm facilitates early plaque formation in an experimental model but may be favorable to soft tissue sealing around transmucosal abutments. Anything below this Ra value (smoothening) seems to be ineffective in reducing the amount of plaque formation, but it

prevents soft tissue attachment to the implant surface [10]. Recently published results that evaluated different surface coatings on rough surface implants concluded that titanium nitride or zirconium nitride can reduce the accumulation of plaque by coating the underlying more reactive titanium surface (independent of surface roughness), which may reduce periimplant mucositis and peri-implantitis [10].

Considerations with hydroxyapatite-coated titanium implants Hydroxyapatite is a bioactive material with osteoconductive properties [11]. Hydroxyapatite-coated titanium alloy implants were first introduced in 1984 for use in restoring partially or totally edentulous maxillas and mandibles [12]. Plasma-sprayed hydroxyapatite-coated implants demonstrate greater tolerance to unfavorable healing conditions and promote bone growth into gaps that measure less than 1 mm [11]. Early reports of faster osseointegration (biointegration), a stronger bone-to-implant interface (compared to titanium surfaces), and vertically directed bone growth along the implant surface were met with optimism among the implant community [12,13]. Short- and long-term studies have demonstrated higher implant-to-bone contact in hydroxyapatite implants at 6 weeks when compared to titanium implants. At 12 weeks, however, the titanium implants displayed superior implant-to-bone contact compared to hydroxyapatite-coated implants and had an increase in total implant-to-bone contact surface area after 1 year. The hydroxyapatite-coated implants showed a reduction in the implant-bone contact area over the same period with a significant decrease in shear strength [12,14,15]. A combination of clinical observation and prospective research suggests that hydroxyapatite-coated implants may be more prone to enhanced plaque growth and peri-implantitis because of the questionable long-term quality of the hydroxyapatite-to-bone bond and the affinity of microorganisms for the hydroxyapatite surface [12]. Johnson reported sudden and rapid bone loss around hydroxyapatite-coated implants after an initial period of apparent success (Fig. 2A) [12]. Several clinical reports claim that failure of hydroxyapatite-coated implants involves significant morbidity and permanent destruction of bone tissue, whereas titanium implants tend to fail with minimal loss of bone volume and typically regenerate to the original dimension of the alveolus (Fig. 2B) [12]. Despite the claims of higher long-term failure rates with hydroxyapatite-coated implants,

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Fig. 2. (A) Hydroxyapatite-coated implants with significant bone and attachment loss. (B) Threaded, machined surface titanium implants with significant attachment and bone loss.

many clinicians have found them valuable in situations that involve unfavorable bone quantity or quality [16]. Recommendations and special considerations regarding the salvage of infected hydroxyapatitecoated implants are discussed in this article.

Diagnosis of the failing implant and peri-implantitis Much debate exists regarding the definition of implant failure. The endeavor to define implant failure should be preceded with a definition of success. The First European Workshop on Periodontology defined success as absence of implant mobility, an average radiographic marginal bone loss of less than 1.5 mm during the first year of function and less than 0.2 mm annually thereafter, and absence of pain and paresthesia [2]. Because this definition was based on the mean marginal bone loss around Branemark implants, it seems presumptuous to conclude that different implants would behave in a similar manner. Much attention has been given to the terms ailing and failing when referring to implant health. It has been proposed that an ailing implant demonstrates radiographic evidence of bone loss and probing depths more than 5 mm that are stable when reevaluated at 3 to 4 months. A failing implant demonstrates increasing probing depths, suppuration or bleeding when probed, and progressive bone loss [18]. A failed implant no longer is osseointegrated or never achieved osseointegration. These implants display peri-implant radiolucency caused by fibrous tissue encapsulation, are clinically mobile, and demonstrate dullness to percussion. Failed implants must be removed to prevent chronic bone loss and the possibility of osteomyelitis (Fig. 3) [18]. Esposito et al [19] concluded that radiographic examination and mobility testing were the most reliable parameters in determining the prognosis of osseointegrated implants. Marginal bone loss around the neck of the implant can be evaluated radiographically and by peri-implant probing. Reproducing the

Retrograde peri-implantitis Radiolucencies around the apical aspect of dental implants have been attributed to several causes, including contamination of the implant surface, overheating of bone, occlusal overload, preexisting bone pathology, presence of residual root fragments or foreign bodies in implant sites, lack of biocompatibility, placement of the implant in poor quality bone, and drilling through the inferior border of the mandible or lingual cortex [17]. The term retrograde peri-implantitis was first used to describe radiographic periapical bone loss around a dental implant without evidence of peri-implant soft tissue inflammation [16]. It was proposed that a radiolucent lesion found on plain film radiography was caused by traumatic or premature implant loading that resulted in microfractures of the peri-implant bone and subsequent resorption. Because the microflora around implants that suffered from retrograde peri-implantitis have been shown to be similar to the microflora around healthy implants, one can assume that infective failure is not experienced with this type of implant lesion [3,16]. Because bacteria do not seem to be a causative factor in this type of implant failure, normal probing depths without bleeding are often observed, and resolution of the periapical radiolucency may be observed if traumatic loading of the implant is relieved.

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Fig. 3. Failed implant with fibrous tissue encapsulation and clinical mobility.

exact radiographic exposure geometry is difficult and can lead to clinically significant variability. Despite the latter finding, it seems that serial radiographs are more reliable in monitoring peri-implant conditions than probing, particularly in the setting of inflamed peri-implant tissues and bony defects [19]. Digital subtraction radiography eventually may prove to be superior to traditional radiographic techniques in evaluating subtle changes in peri-implant bone density, and it is highly recommended, if available [19,20]. If no clinical evidence of inflammation is present, radiographs should be obtained 1 year after implant placement and not more than every 2 years thereafter [1]. Radiographs should be taken more frequently if clinical evidence of peri-implant inflammation (increased probing depths) raises suspicion of peri-implantitis [1]. Differences among implant systems make the task of quantitatively defining the normal amount of marginal bone loss difficult. Several studies have demonstrated that marginal bone loss and biologic width are determined largely by the implant system and the host response. Gargiulo [21] demonstrated that natural teeth have a normal biologic width of 2.73 mm. Hermann et al [22] evaluated the anatomic location of the biologic width around various types of dental implants and determined that the one-piece (single-stage) nonsubmerged implant with a rough/ smooth border placed at or 1 mm apical to the alveolar crest resulted in a biologic width that most closely resembled that of natural teeth (2.84 mm). They also concluded that the presence of a microgap (component interface) in two-piece implant systems significantly affects the level of crestal bone and soft tissue dimensions. The presence of a microgap in two-stage implant systems may play an important role in the development of peri-implantitis because

bacterial contamination of this interface has been demonstrated [22]. Peri-implant probing may provide valuable information regarding implant health or progression of disease. Healthy implants generally have probing depths less than 4 mm, with interproximal probing depths normally 0.5 to 1 mm more than the buccal and lingual probing depths [20]. Peri-implant pockets of 5 mm or more should be considered an indicator of peri-implantitis because deep pockets have been shown to harbor a microflora consistent with inflammation and bone loss [1]. There has been much debate over the location of the probe tip and the effect on the peri-implant tissues during peri-implant probing in disease and health. Several studies suggest that there is a resilient soft tissue collar in peri-implant health and mucositis. The tip of the probe may travel without impedance to the alveolar crest in peri-implantitis, however [20]. It has been demonstrated experimentally that the probe tip penetrates apically to the laterally displaced junc tional epithelium with Branemark implants, resulting in the probe tip approaching the alveolar crest [18]. This is in contrast to the findings around ITI dental implants, which demonstrate the probe tip location at the apical termination of the junctional epithelium (0.05 mm in healthy sites and 0.02 mm in diseased sites) [19]. Issues regarding the practicality and reproducibility of probing depths have brought the entire practice of peri-implant probing into question. Several studies have concluded that peri-implant probing damages the peri-implant soft tissues, but the magnitude and long-term effects have yet to be determined [19]. It can be said that there is a positive correlation between peri-implant probing depths and the degree of peri-implant mucosal inflammation, but not necessarily bone loss [19]. More important than a single measurement at a single point in time is documentation of progressive peri-implant bone loss as evidenced by increasing probing depths. It is recommended that baseline probing depths be acquired at the time of prosthetic reconstruction to account for the predictable marginal bone loss during the first several months after implant placement. Assuming that probing has been accepted by the surgeon as a method of providing beneficial clinical information that exceeds the potential for harming the peri-implant tissues, the frequency and interval must be tailored to each individual patient based on compliance, oral hygiene, and other risk factors. Probing attachment levels relate probing depths to a fixed reference point on the implant or abutment and provide valuable information regarding attachment loss over time. Probing attachment level

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increases of 2 mm or more should be interpreted as marginal bone loss [19]. In addition to providing information regarding attachment level and bone loss, peri-implant probing can demonstrate peri-implant inflammation clinically. Bleeding on probing is another controversial issue regarding the diagnosis of peri-implantitis. No correlation has been shown between bleeding and the histologic or radiographic changes associated with peri-implant mucositis or peri-implantitis around smooth surface threaded implants [19]. Another study demonstrated that the absence of bleeding on probing around ITI implants was associated with implant health, whereas bleeding on probing correlated highly with peri-implant mucositis and peri-implantitis [19]. Because the reason for these differences may be caused by inconsistent probing forces or other factors, bleeding on probing is not scientifically supported as a method of diagnosing peri-implantitis [19]. Several authors still maintain that probing depth measurements related to a fixed landmark on the implant and examination of the bleeding tendency of the peri-implant tissues seem to be well-suited for the longitudinal monitoring of peri-implant stability [1]. It has been recommended that nonmetallic probes (eg, plastic) with a calibrated constant probing force be used for more reliable, less traumatic measurements. A probing force of 0.25 N has been recommended by several authors to fulfill the previously mentioned criteria [1,20]. Mombelli and Lang [1] recommend the use of standardized probes, such as the Audio Probe, titanium plasma-sprayed probe, or the HAWE Click Probe, for consistent measurements. Implant mobility in a previously healthy implant should be considered a sign of failure. Even implants that show significant bone loss usually are immobile if any direct implant-to-bone contact remains. Several devices and methods have been proposed for evaluating implant mobility. Periotest (Siemens AG, Bensheim, Germany) is a device used for measuring the damping effect of the supporting tissues to a standardized force as an indicator of slight changes in implant mobility. Although several studies have reported its success in detecting subtle changes in the bone-to-implant interface, its usefulness and accuracy are still being evaluated [1,18]. A torque wrench that delivers a set amount of force is another method for determining implant osseointegration. An implant is considered to be osseointegrated if a torque of 10 to 20 Ncm is applied to the implant without resulting mobility [18]. Although not scientifically supported, the percussion test is reported to be a simple and sensitive method of determining osseointegration. The implant abutment interface is percussed with the blunt

end of an instrument and the sound is interpreted. A ringing sound in considered favorable for osseointegration, whereas a dull sound suggests fibrous tissue encapsulation [18]. Finally, OSSTELL (Integration Diagnostics, Inc., Savedalen, Sweden) is a new Food and Drug Administration approved device that uses resonance frequency analysis to assess implant stability. The reliability and usefulness of the device in implant dentistry still are being evaluated. A systematic approach should be used when evaluating implants for possible disease. It is often more prudent to evaluate the implant by assuming disease and proving health because this mode of reasoning tends to eliminate the possibility of falsenegative screening results. If probing is to be performed at the recall visit, the new probing depths should be compared to baseline measurements and the overall trend observed. Attachment levels also should be recorded because peri-implant pockets potentially can remain normal as marginal bone loss progresses and the attachment and marginal tissue level follows. If no attachment loss is evident and probing depths are normal, one can assume that the implant is associated with a nonpathogenic microflora and that the peri-implant tissues are not clinically inflamed [1].

Implant salvage The type of intervention for implant salvage depends largely on clinical findings and implant characteristics. Peri-implant mucositis is a reversible process that often responds well to conservative, noninvasive treatment because increased probing depths are usually caused by soft tissue inflammation and not crestal bone loss. Implants that show evidence of mucosal inflammation, plaque, and accumulation of calculus but lack suppuration and probing depths more than 3 mm are often treated effectively with mechanical debridement. Special nonmetallic instruments should be used for debridement to minimize surface defects and the theoretical possibility of galvanic corrosion. Special rubber cups and implant polishing paste can be used to remove plaque [20]. Subgingival chlorhexidine irrigation may be added to the regimen for cases in which probing depths have increased to 4 to 5 mm and inflammation and plaque/calculus deposits are noted. Generally, treatment for 3 to 4 weeks with chlorhexidine as a daily rinse or gel is required to achieve the desired result [20]. Lang et al [20] recommend antibiotic treatment in addition to mechanical debridement and antiseptic

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treatment for peri-implant probing depths more than 6 mm. Tetracycline has been used for many years in treating periodontally involved teeth because of its antibiotic properties and facilitating effect on fibroblastic growth and attachment on root surfaces [16]. The decision to use tetracycline in implant therapy may depend on the type of implant surface because of the possibility of tetracycline altering the composition of the hydroxyapatite coating [16]. Treating titanium implant surfaces with topical tetracycline (50 mg/mL) for 3 minutes before regenerative techniques has been reported as successful [23]. Actisite (Alza, Palo Alto, CA) is a local delivery system that consists of nonresorbable tetracycline fibers for local use around periodontally involved teeth. It has been supplanted largely by resorbable delivery systems. Several case reports have documented the effectiveness of the tetracycline fibers around infected dental implants [20]. Some authors advocate systemic antibiotics before and during implant salvage techniques. Three recommended regimens are (1) clindamycin, 150 mg orally three times a day, (2) doxycycline hyclate, 100 mg orally twice daily, and (3) amoxicillin with or without clavulonic acid, 500 mg four times a day. Some authors recommend the addition of metronidazole if amoxicillin is selected for systemic treatment. All regimens should be started 2 days before implant salvage treatment and continued for 10 days after [18]. Peri-implantitis has been shown to be an endotoxin-mediated host response that progresses to implant failure if not treated. Differences among implant surface characteristics are important when selecting appropriate interventional techniques for implant salvage. Zablotsky et al [24] published a landmark study in 1992 that compared the abilities of various chemotherapeutic modalities to detoxify endotoxin-contaminated implant surfaces (grit-blasted titanium alloy and grit-blasted titanium alloy with a hydroxyapatite plasma spray coating). The study concluded that detoxification of hydroxyapatitecoated implants is best accomplished with anhydrous citric acid reconstituted to a 40% pH 1 (supersaturated) solution that is applied to the implant surface for 30 seconds to 1 minute [24]. This effect is caused by a demineralization of the superficial hydroxyapatite layer. The titanium grit-blasted surface was effectively decontaminated by burnishing with saline or citric acid for 1 minute. Air powder abrasives, such as sodium bicarbonate mixed with sterile water, also have been shown to be effective in decontaminating implant surfaces [25]. Stannous fluoride treatment seems to result in significantly greater levels of

endotoxin on both types of implant surfaces when compared with controls, whereas treatment with chlorhexidine gluconate, tetracycline HCl, hydrogen peroxide, and chloramine T is less effective at decreasing levels of endotoxin than saline burnishing alone. Charge interactions have been proposed as the reason for endotoxin having a greater affinity for hydroxyapatite-coated surfaces than grit-blasted titanium alloy surfaces [24]. Studies also have shown that chlorhexidine and stannous fluoride can result in the binding of endotoxin to the hydroxyapatite implant surface because of the inherent charge characteristics of these two compounds [16]. Surgical treatment should be considered for any implant that displays radiographic evidence of progressive crestal bone loss that still has adequate residual bony anchorage. If surgical treatment is to be initiated, the patient first should be placed on antibiotics, then a mucoperiosteal flap is elevated to expose the defect, and the implant surface is decontaminated by one of the methods described previously. Any granulation tissue should be removed with instruments that do not scratch or contaminate the titanium surface so that it is more favorable for regenerated tissue or osseointegration. Hydroxyapatite implants should be inspected for evidence of surface pitting, cracking, or color changes. If the hydroxyapatite shows wear or contamination, the entire layer should be removed mechanically and the underlying titanium surface decontaminated in the manner described previously. Guided bone regeneration (GBR) also can be used to treat osseous defects around failing implants (Fig. 4) [16]. Decontamination of the diseased implant surface is paramount if this technique is to be used. The process for GBR involves placing a resorbable or nonresorbable membrane over an osseous defect to permit new bone growth into the defect while inhibiting soft tissue infiltration [26]. GBR has been performed around peri-implant osseous defects with and without grafting; however, bone fill and attachment gain seem to be better achieved when a grafting material is used in conjunction with a barrier membrane [16]. Several different materials, including demineralized freeze-dried bone, autologous bone, and resorbable bovine-derived hydroxyapatite, have been used in various forms as grafting material in GBR. It has been proposed that an alloplast, such as nonresorbable hydroxyapatite or bioactive glass, be used if the implant surface is difficult to decontaminate because of the presence of vents, holes, or tortuous osseous defects [18]. Alloplasts do not achieve biologic healing in these cases but are effective in filling bony defects and minimizing peri-implant

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Fig. 4. Guided bone regeneration around a failing implant. (A) Large bony defect of a rough surface implant with increased probing depths and radiographic evidence of bone loss. (B) Bony defect covered with graft material after surface debridement and decontamination with tetracycline HCl paste. (C) Resorbable collagen membrane prepared to cover the graft material and necks of implants. (D) Collagen membrane in place. (E) Water-tight closure around implants and surgical site (some authors advocate burying single-stage implant systems after this procedure). (Courtesy of Dr. Tinou Roncone.)

pockets [18]. Although studies have demonstrated that GBR is effective around implants, questions have been raised regarding the ability of the regenerated bone to re-osseointegrate with the implant surface. Persson et al [27] published a study investigating whether re-osseointegration could be accomplished after the treatment of peri-implantitis. The study con-

cluded that re-osseointegration could not be achieved with a smooth (turned) surface but was consistently successful with a decontaminated sandblasted, large grit, acid-etched surface [27]. If bone loss has progressed to the apical one third of the implant, removal is indicated because there is little chance of successful salvage [25].

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The membrane selected for GBR should be biocompatible and easy to place, maintain its original shape, and be capable of functioning as a barrier for at least 6 weeks [16]. A commonly used nonresorbable material, expanded-polytetrafluorethylene, has provided good results for many years. Several resorbable membranes recently have gained popularity, however, because of a reduced number of complications from infection or exposure and because they do not require retrieval surgery. Although it is acceptable to leave a membrane exposed during immediate implant placement in fresh extraction sites, primary closure over the membrane is necessary in implant salvage to prevent contamination and infection of the involved area. If GBR is to be used as a salvage procedure for implants, it is imperative that a nonresorbable membrane remain covered for as long as possible because premature removal decreases the chances of success and results in less-than-optimal bone fill [16]. Many authors recommend a minimum of 6 weeks before removal of a nonresorbable membrane [23]. If a resorbable membrane is to be used, it should provide barrier function for at least 6 weeks. It has been suggested that all patients remain on an antiseptic mouth rinse, such as chlorhexidine gluconate 0.12%, for 6 weeks or until the membrane is retrieved to minimize the chance of membrane infection [28]. If the membrane becomes prematurely exposed, however, immediate removal is indicated to prevent contamination of the regenerating tissues [16]. Single-stage implant systems ideally should be submerged during GBR salvage procedures to minimize contamination of the membrane and regenerating tissues.

lead to increased failure rates when these implants are affected by peri-implantitis. In the presence of adequate apical osseointegration, compromised implants that present with peri-implantitis must undergo thorough debridement and be decontaminated before any attempt at GBR. GBR may be accomplished successfully with many different types of membranes and grafting materials if the implant surface is thoroughly decontaminated before regenerative therapy. Implant salvage is an important, yet often ignored, component of clinical practice that can prevent implant and prosthetic failure if the principles of decontamination, biomodification, and guided tissue regeneration are understood and followed.

References
[1] Mombelli A, Lang N. The diagnosis and treatment of peri-implantitis. Periodontology 2000;17:63 76. [2] Albrektsson T, Isidor F, et al. Consensus report of session IV. In: Lang NP, Karring T, editors. Proceedings of the First European Workshop on Periodontology. London: Quintessence; 1994. p. 365 9. [3] Loe H, Morrison E. Epidemiology of periodontal dis ease. In: Genco RJ, Goldman HM, Cohen DW, editors. Contemporary periodontics. St. Louis: CV Mosby Co.; 1990. p. 106 16. [4] Hammond BF, Genco RJ. Sensitivity of periodontal organisms to antibiotics and other antimicrobial agents. In: Genco RJ, Goldman HM, Cohen DW, editors. Contemporary periodontics. St. Louis: C.V. Mosby Co.; 1990. p. 161 9. [5] Trisi P, Rao W, Rebaudi A. A histometric comparison of smooth and rough titanium implants in human lowdensity jawbone. Int J Oral Maxillofac Implants 1999; 14:689 98. [6] De Leonardis D, Garg A, Pecora G. Osseointegration of rough acid-etched titanium implants: 5-year followup of 100 Minimatic implants. Int J Oral Maxillofac Implants 1999;14:384 91. [7] De Leonardis D, Garg A, Pecora G, et al. Osseointegration of rough acid-etched implants: one-year follow-up of placement of 100 Minimatic implants. Int J Oral Maxillofac Implants 1997;12:65 73. [8] Schwartz Z, Kieswetter K, Dean DD, Boyan BD. Underlying mechanisms at the bone-surface interface during regeneration. J Periodont Res 1997;32:166 71. [9] Tillmans HW, Hermann JS, Tiffee JC, et al. Evaluation of three different dental implants in ligature-induced peri-implantitis in the beagle dog. Part II. Histology and microbiology. Int J Oral Maxillofac Implants 1998;13:59 68. [10] Grobner-Schreiber B, Griepentrog M, Haustein I, et al. Plaque formation on surface modified dental implants: an in vitro study. Clin Oral Implants Res 2001;12: 543 51.

Summary Peri-implantitis is a treatable disease that affects functioning osseointegrated implants. Although unfavorable mechanical loading may play a contributing role, peri-implantitis seems to be mediated primarily by the endotoxins from gram-negative bacteria and the host response around the implant site. Many patients who were previously considered unfavorable candidates for implant therapy are being treated successfully when certain treatment considerations and implant maintenance programs are implemented. It is essential that implant surgeons have a firm understanding of the favorable aspects of implant design and the potential liabilities when these systems are placed in unfavorable clinical conditions. Studies have demonstrated that the same potential benefits of implant materials and surface characteristics also may

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R.G. Triplett et al / Oral Maxillofacial Surg Clin N Am 15 (2003) 129138 cations with dental implants: their prevention, diagnosis and treatment. Clin Oral Implant Res 2000;11: 146 55. Garqinto AW, Wentz FM, Orban B. Dimensions and relations of the dontogingival junction in humans. Journal of Periodontology 1961;32:261 7. Hermann J, Buser D, Schenk RK, et al. Biologic width around one- and two-piece titanium implants: a histometric evaluation of unloaded nonsubmerged and submerged implants in the canine mandible. Clin Oral Implants Res 2001;12:559 71. Mellonig JT, Griffiths G, Mathys E, et al. Treatment of the failing implant: case reports. International Journal of Periodontics and Restorative Dentistry 1995;15: 385 95. Zablotsky MH, Diedrich DL, Meffert RM. Detoxification of endotoxin contaminated titanium and hydroxyapatite-coated surfaces utilizing various chemotherapeutic and mechanical modalities. Implant Dentistry 1992;1:154 8. Jovanovic SA. The management of peri-implant breakdown around functioning osseointegrated dental implants. J Periodontol 1993;64:1176 83. Rominger JW, Triplett RG. The use of guided tissue regeneration to improve implant osseointegration. J Oral Maxillofac Surg 1994;52:106 12. Persson LG, Berglundh T, Sennerby L, et al. Re-osseointegration after treatment of peri-implantitis at different implant surfaces: an experimental study in the dog. Clin Oral Implant Res 2001;12:595 603. Lehmann B, Bragger U, Hammerle CHF, et al. Treatment of an early implant failure according to the principles of guided tissue regeneration (GTR). Clin Oral Implant Res 1992;3:42 8.

[11] Strnad Z, Strnad J, Povysil C, et al. Effect of plasmasprayed hydroxyapatite coating on the osteoconductivity of commercially pure titanium implants. Int J Oral Maxillofac Implants 2000;15:483 90. [12] Johnson BW. HA-coated dental implants: long-term consequences. CDA Journal of the California Dental Association 1992;20:33 41. [13] Meffert RM, Block MS, Kent JN. What is osseointegration? International Journal of Periodontics and Restorative Dentistry 1987;7:9 21. [14] Cook SD, Kay JF, et al. Interface mechanics and histology of titanium and hydroxyapatite-coated titanium for implant applications. Int J Oral Maxillofac Implants 1987;2:15 22. [15] Gottlander M, Albrektsson T. Histomorphometric studies of hydroxyapatite-coated and uncoated CP titanium threaded implants in bone. Int J Oral Maxillofac Implants 1991;6:399 404. [16] Meffert RM. Periodontitis vs. peri-implantitis: the same disease? The same treatment? Crit Rev Oral Biol Med 1996;7:278 91. [17] Scarano A, Di Domizio P, Petrone G, et al. Implant periapical lesion: a clinical and histologic case report. J Oral Implantol 2000;26:109 13. [18] Martin RM, Carter JB, Barber HD. Surgical implant failures. In: Fonseca R, Powers MP, Barber HD, editors. Oral and maxillofacial surgery: reconstructive and implant surgery. Philadelphia: W.B. Saunders Co.; 2000. p. 275 308. [19] Esposito M, Hirsch J-M, Lekholm U, et al. Biological factors contributing to failures of osseointegrated oral implants (I). Success criteria and epidemiology. Eur J Oral Sci 1998;106:527 51. [20] Lang NP, Wilson TG, Corbet EF. Biological compli-

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Management of posttraumatic soft tissue infections

A. Omar Abubaker, DMD, PhD
Department of Oral and Maxillofacial Surgery, School of Dentistry, Virginia Commonwealth University, 521 North 11th Street, PO Box 980566, Richmond, VA 23298, USA

Between 10 and 12 million traumatic wounds are treated annually in emergency departments in the United States [1,2]. More than 50% of these lacerations are caused by blunt trauma. The others are caused by sharp objects, such as metal, glass, and wood. Only a small percentage of these wounds is caused by mammalian and nonmammalian bites [3,4]. Most of these lacerations occur on the face, scalp, and arms, mostly in young men [2]. Because of these locations, an important goal of management of these wounds is to avoid infection, which can lead to cosmetically and functionally unacceptable scars [5]. The current management of traumatic soft tissue injuries incorporates many of the surgical principles developed over the past century. These principles include a thorough understanding of the pathophysiology of wounding, the risk factors for infection, the basic mechanisms by which posttraumatic sepsis develops, and the appropriate methods for treatment of these injuries and the prevention of complications. This article reviews the defense mechanisms involved in soft tissue wound healing, describes the risk factors for posttraumatic wound infections, and discusses the prevention and treatment of such infections.

Physiologic effects of wounding The human body has evolved several defense mechanisms body to protect itself from the microbiologic invasion that causes wound infection. These mechanisms include efficient mechanical barriers to bacteria and competent biologic protection mechanisms. The mechanical barriers to bacterial invasion
E-mail address: Abubaker@vcu.edu

include the epithelium of the skin and mucous membranes. The skin also grants chemical protection in the form of surface lipids, and the mucous membranes provide protection by surface Ig A and an acidic pH. The skin and oral mucosal surfaces are also inhabited by normal flora that can compete with potential microbial pathogens. Biologic protection is provided in the form of various internal mechanisms that are induced by local tissue damage. These mechanisms are triggered when the mechanical line of defense is violated. Once this damage ensues, an intense chemical activity is triggered, which involves activation of the kallikreinkinin system, the release of amines, and an increase in vascular permeability that allows for influx of humoral and cellular immunologic elements. These elements are ultimately responsible for recognition of the organisms involved and their subsequent phagocytosis [6]. Traumatic wounds carry with them a higher degree of contamination because the mechanical protective features of the skin and mucous membrane are disrupted, which allows direct invasion of microorganisms into the deeper tissues. The internal systemic biologic mechanisms of host defense are also compromised by the effects of the trauma. For example, with major trauma there is a decrease in cellular immune functions, intracellular killing, and endothelial system function [7,8]. There is also a decrease in humoral factors, such as the immunoglobulins and the complement system [8]. If traumatic shock develops, there is also a decrease in systemic perfusion, which, in the presence of local tissue damage, may reduce blood flow to the wounded area and further compromise containment of invading bacteria [9,10].

1042-3699/03/$ see front matter D 2003, Elsevier Science (USA). All rights reserved. PII: S 1 0 4 2 - 3 6 9 9 ( 0 2 ) 0 0 0 6 8 - 7

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Risk factors for posttraumatic wound infections Studies on management of traumatic wounds have shown that the rate of infection ranges between 2.5% and 11.5% [11 13]. This rate is influenced by several variables, which are often referred to as risk factors. Some of these factors are related to the host, the environment, and the type of wound, whereas others are related to the techniques used to manage the wounds [12,14 16]. Factors related to the wound and patient include (1) size, configuration, and depth of the wound, (2) location of the injury, (3) mechanism of injury, (4) type and amount of contamination, including presence of a foreign body, (5) time between injury and wound closure, (6) care of the wound between injury and definitive care, and (7) age and systemic condition of the patient. The technical risk factors for development of wound infection include (1) inadequate debridement of foreign bodies, further bacterial contamination, and presence of devitalized tissues, (2) inadvertent introduction of foreign materials into the wound during cleansing, (3) inadequate hemostasis and failure to eliminate dead space, which provides an environment for bacterial colonization, (4) using an excessive number of sutures to close the wound, and (5) placing excessive tension on the sutures used to approximate the tissue edges and compromising local tissue perfusion.

1:100,000 or 1: 200,000 epinephrine). Inserting the needle through the open part of the laceration can decrease the pain of the injection [18,19]. Use of a field block is beneficial in reducing distortion of the operative site when accurate approximation of the wound edges is necessary. If there are skin or tissue flaps of doubtful viability, the use of lidocaine without epinephrine is desirable to avoid further impairing circulation [20]. Local anesthesia can be supplemented with analgesics or sedatives, if necessary. General anesthesia is preferable for uncooperative or combative patients and for children. General anesthesia is also often indicated in patients who require prolonged procedures, as in extensive lacerations, lacerations that require flap rotation or grafts for closure, and concomitant repair of facial bones fractures [21]. Patients with confirmed or suspected involvement of important structures, such as joints, nerves, or tendons, also may be better treated in an operating room setting [5,19,22]. Wound preparation Once the patient is comfortable and the wound is adequately anesthetized, a complete and methodical cleansing of the wound should be achieved. The process involves irrigation and debridement of the wound before draping of the operative site in preparation for wound closure. Irrigation is essential in preventing infection because it removes debris, dirt, microorganisms, and devitalized tissue from the wound, which results in a reduction in infection rate [3]. Irrigation with normal saline solution using a 50-mL syringe and a 16-gauge needle is adequate for most lacerations [23,24]. In general, 250 to 500 cc of solution provides adequate irrigation for small wounds [24]. High-pressure irrigation is occasionally indicated for large wounds and when a high degree of contamination is present [17]. High-pressure irrigation has been shown to decrease the bacterial count of wounded tissues and decrease the rate of infection [25]. Vigorous irrigation in general, however, and high-pressure irrigation in particular may force debris into the wound and can cause further tissue damage [26,27]. For these reasons, high-pressure irrigation should be used with discretion and reserved for heavily contaminated wounds in which its benefits may outweigh its risks [17]. Similarly, use of concentrated povidone-iodine, hydrogen peroxide, and detergents may cause significant tissue damage and should be avoided [28]. Some authors even questioned the value of any form of wound irrigation in noncontaminated facial and scalp wounds [29].

Prevention of posttraumatic wound infection by proper wound care The greatest deterrent to posttraumatic wound infection is a healthy wound. This status can be accomplished by (1) thorough cleansing, (2) identifica tion, assessment, and atraumatic debridement of all devitalized tissues, (3) removal of all foreign materials, and (4) careful handling of the tissues. Evacuation of any hematoma and obliteration of all potential dead spaces by proper wound repair and approximation of all tissue layers are also essential elements in the prevention of soft tissue infections. Appropriate use of prophylactic antibiotics and tetanus prophylaxis are also important preventive measures [17]. Anesthesia Before one begins definitive wound management, adequate patient comfort should be ensured not only to permit maximum wound repair but also to allow thorough examination, cleansing, and debridement of the wound. In most patients, comfort can be accomplished with local anesthesia (lidocaine with

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Decontamination of the skin around the wound is another step in preventing wound infection. Decontamination can be accomplished effectively with mild soap and water or with a providone iodine or hexachlorphene solution. Use of chemical solutions should be limited to the adjacent skin surface, and caution should be used to avoid getting them into the wound because these agents are noxious to tissues. Because shaving may damage hair follicles and allow for bacterial access and increase the risk of wound infection, it should be kept to a minimum. In areas such as the eyebrows, it should be avoided totally [23]. Debridement is considered by many to be the most important step in avoiding infection. One goal of wound debridement is to remove all foreign materials that may be attached to, or embedded in, the edges of the laceration or abrasion. Removing foreign material can be accomplished by thorough irrigation of the wound, vigorous scrubbing, or even surgical excision using a surgical blade or small curette. The second goal of debridement is the removal of devitalized tissue. The general rule regarding debridement of devitalized tissue is that all crushed or frayed edges that may become necrotic, all obviously nonviable tissue, and all grossly contaminated tissue should be removed. Exceptions to this rule involve certain anatomic areas, such as the eyebrow and vermilion border of the lip, where such debridement may compromise accurate realignment of the tissues and in instances in which tissue debridement would result in excessive tension on the suture line. In these instances, it is preferable to avoid extensive trimming of the tissue and to approximate the irregular edges without tension [30]. In the management of facial wounds, only minimal debridement is generally required because of the excellent blood supply. When tissue loss is present, it is recommended to save all tissue that has a chance to survive to provide the basis for secondary reconstruction at a later time [22]. Wound closure Once the devitalized tissue has been removed, a decision must be made regarding the timing and type of wound closure. There are at least three major choices [16]: (1) primary closure and healing by primary intention, (2) leaving the wound open, treating it with frequent dressing changes, and allowing it to heal by secondary intention and wound contracture, and (3) using delayed primary closure, in which the wound is splinted in a position of rest with an occlusive dressing and is closed in 3 to 5 days when it is free of infection and necrotic tissue. The choice of

method is generally based on the assessment for risks of infection. It is often difficult to determine which treatment to use for a given wound, and the length of the golden period within which it can be closed primarily varies [31]. In general, there is a direct correlation between the time from injury to closure of the wound and the risk of infection. It is generally accepted that wounds with a high risk of infection should be closed as soon as possible (within the first 6 8 hours), whereas wounds with low risk of infection, such as those in the head and neck area, can be closed primarily within the first 18 to 24 hours after injury [17,24]. After 24 hours, for most wounds, consideration should be given to packing them open and performing a secondary repair 4 to 8 days later [17,30].

Postoperative wound care For most wounds, patients should be instructed to keep them covered with a nonadherent dressing for at least 24 to 48 hours to protect the wound from gross contamination. After this period, the patient should wash, but not scrub or soak, the wound. Once the wound is left open, it should be cleaned two to three times a day with a cotton applicator stick and hydrogen peroxide or soap and water. The patient also should be instructed to place a topical antibiotic ointment on the wound. Prospective and retrospective studies have shown the value of topical antibiotic agents in decreasing infection in certain wounds [32,33]. Their benefit beyond day 5 of wound closure remains controversial, however [19]. A topical antibiotic ointment also keeps the wound moist, which speeds the rate of wound epithelialization [34]. The routine use of systemic prophylactic antibiotics to prevent infection of soft tissue wounds is not recommended [35]. Because traumatic wounds are, by definition, contaminated wounds, however, some of them are prone to infection despite all attempts to follow the principles of appropriate wound care. In such instances, and when the consequences of wound infection may be devastating, prophylactic antibiotics may be indicated [16]. The use of prophylactic antibiotics should be tailored individually based on factors such as the degree of bacterial contamination and the presence of the predisposing risk factors discussed previously. Several studies suggest that the administration of an antibiotic to prevent infection of the soft tissues after trauma may be of more value when given prophylactically within the first 3 to 4 hours of the injury and continued until the wound is sutured than when given

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for a therapeutic course postoperatively [16]. Some authors recommend that prophylactic antibiotics be continued for 24 hours [36], however, with additional doses if the operative procedure is prolonged. Tetanus continues to occur worldwide despite the availability of an effective vaccine. Consideration always should be given to administration of tetanus prophylaxis at the time of initial wound examination. A summary guide to tetanus prophylaxis is available through the Centers for Disease Control (Table 1) [37].

Treatment of posttraumatic soft tissue wound infections Because traumatic wounds are caused by different types of trauma, the resulting soft tissue damage often ranges from blunt damage to penetrating and complex tissue injuries. The spectrum of microbiologic soft tissue contamination also varies and ranges from simple wound colonization without invasion to frank tissue infection and necrosis. Contamination of posttraumatic wounds can occur from introduction of endogenous normally nonpathogenic bacteria into the wound, from missiles or other objects, or from contact with various surfaces at the time of injury. The variation in degree of tissue injury and microbial invasion can result in a wide spectrum of wound infections, including general inflammation, a cellulitis or simple abscess, a diffuse inflammation and spreading cellulitis with or without signs of systemic toxicity, or a progressive necrotizing soft tissue infection [16]. Once wound infection occurs, it results in the immediate release of inflammatory cytokines from the monocytes and macrophages, which causes a delay in wound healing. These cytokines also may result in the release of growth factors that stimulate fibrosis and result in localized scar hypertrophy [20].

Regardless of the mechanism of injury and the degree of suspected wound contamination, once the signs and symptoms of wound infection become clinically evident, the goals of treatment should be to optimize tissue perfusion and nutrition, remove devitalized tissue, prevent further spread of the infection or further tissue destruction, and achieve wound closure [38]. To attain these goals, Fields et al described a five-phase unified approach to treatment of posttraumatic soft tissue infections [6]. The phases of this systematic approach that are applicable to wounds in the head and neck are phase 1: early recognition of infection; phase 2: rapid initiation of empiric antibiotics; phase 3: immediate surgical incision and drainage or debridement, when necessary; and phase 4: early wound closure. Early recognition Early recognition and diagnosis are essential to treating wound infections successfully and minimizing morbidity [16]. The diagnosis of infection should be based on the clinical signs and symptoms, the laboratory findings, and identification of predisposing factors. A definitive diagnosis can be made later based on culture of the microorganisms and examination of histologic specimens if debridement was performed. Because a minor inflammatory reaction, pain, and swelling are normal components of the early stages of wound healing, recognition of infection based on these cardinal signs can be difficult and wound infections can be missed [16]. Changes in these signs on frequent examination of the wound and observation of increased swelling, tenderness, induration, discoloration, and fluctuation should increase the index of suspicion [6,16,39]. Systemic signs of infection, such as malaise, fever, tachycardia, and leukocytosis, may be present in patients with infected

Table 1 Recommendations for prophylaxis against tetanus After clean, minor wounds History of tetanus immunization Number of previous doses < 3 or not known Number of previous doses ! 3 Timing of last dose Within 5 y Within 5 10 y > 10 y ago
a

After all other woundsa Tetanus-diphtheria toxoid Yes Tetanus immunoglobulin Yes

Tetanus-diphtheria toxoid Yes

Tetanus immunoglobulin No

No No Yes

No No No

No Yes Yes

No No No

Examples of these wounds include contaminated wounds, puncture wounds, avulsions, burns, and crush injuries.

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wounds. Severe infections also may be associated with altered glucose metabolism, respiratory distress, altered mental status, and hypotension [40]. These signs and symptoms are nonspecific, however, especially in critically ill patients. When such signs and symptoms and local signs of wound infection are present, they are indicative of a serious problem and may be associated with progression of the infection into deeper tissue. Bacterial growth on culture provides essential information for treatment, although this is not essential for the diagnosis of posttraumatic wound infection. Because bacteria can colonize traumatic wounds even in the absence of infection, interpretation of culture results must be conducted with care. Finally, when there is an associated open fracture, differentiation between infection that originates in soft tissues and infection that is related to the fracture should be made by surgical exploration, microscopic examination of tissue samples, culture of organisms from the bone, or radiographic examination [41]. Also important in the recognition and diagnosis of posttraumatic infection is differentiation between superficial, or local soft tissue infection, and deep infections that involve fascia and muscle. Risk factors for the presence of deep soft tissue infection include systemic diseases, such as diabetes, immunocompromised status, underlying malignancy, and local factors, such as gross contamination and delay of wound closure. Empiric antibiotics The choice of empiric antibiotics should be based on the location and depth of the wound and the systemic status of the patient. For most posttraumatic head and neck soft tissue infections, first-generation, second-generation, and third-generation cephalosporins remain the drugs of choice for Staphylococcus aureus [42,43]. In most of the severe posttraumatic soft tissue infections, a combination of antibiotics is often used until data from culture and antibiotic sensitivity testing become available on day 2 or 3 [6]. Fungal infections are uncommon in posttraumatic wounds. Candida albicans and, less commonly, Phycomycetes are opportunistic organisms that may cause secondary infection after systemic antibiotic therapy, however. Fluconazole and amphotericin B are the most commonly used agents for treatment of these fungal infections [33,43]. Viral infections are also rare in posttraumatic wound infections but can be present in immunocompromised patients, patients with major multisystemic trauma, and burn patients [44]. The presence of these infections increases the

likelihood of sepsis from bacterial infection. Viral infections should be treated with such agents as systemic acyclovir. Debridement The sine qua non of treatment of wound infection is to provide wide drainage of any purulent material and debride all necrotic tissue [16]. Devitalized tissue acts as a culture medium for bacteria, creates an anaerobic environment, and impairs the cellular and humoral immune defenses [6,45]. It is imper ative that debridement be performed if nonviable tissue is present on the margins of the wound. In instances in which tissue necrosis continues beyond the time of injury, such as in blast gun shot wounds, repeated debridement may be necessary. Frequent cleansing of the wound and repeated dressing changes should be instituted to assist in removal of bacteria, exudate, and devitalized tissue. It is important that a representative tissue specimen or a sample of purulent discharge be submitted for microbiologic identification of the offending organisms and for diagnosis of the extent of tissue necrosis. These specimens are best obtained from beneath the intact skin, away from the wound, because bacteria recovered from these sites are more likely to represent the true pathogens and not part of the wound colonization [6]. Wound closure Wound closure should be performed when all the infection is resolved and healthy granulation tissue is present [6,46]. This goal usually can be accomplished by secondary intention or primary closure if the wound is small. Large wounds may require splitthickness skin grafting or flaps, however.

Management of bite wounds Each year 1% of all visits to emergency rooms (approximately 300,000 visits) are related to bite injuries [47,48]. Ninety percent of these injuries are dog and cat bites, and the rest are human or other animal bites. Although most of these bites involve the hand, a significant percentage (16%) of dog bites are in the face and scalp, whereas only a small percentage (2%) of cat bites are in these regions [4,48]. Approximately 3% to 18% of dog bites and 28% to 80% of cat bites become infected [48,49]. The risk of infection is greatest for crush injuries, puncture wounds, and wounds to the hand [47]. Human bites,

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although less common than dog and cat bites, were believed to be more prone to infection than those inflicted by animals. Such reports are biased by emphasis on human bites of the hand that present late with infection already present, however [50]. The generally reported poor prognosis in such cases is probably caused by the delay in treatment and location of the wound rather than the cause of injury. Human bites to the face, lips, and ears have a lower risk of infection (less than 3%), than human bites elsewhere (10% 12%) if treated properly [50,51]. With proper wound care, the rate of dog bite infections in the head and neck is also as low as 1.4%, even when prophylactic antibiotics were not used [52]. Wound infection from cat bites to the face is 3%, whereas it is 19% in the hand and 18% in the lower extremities [53]. The management of bite wounds remains somewhat controversial because there is considerable variation in the patients studied and in wound severity, and there is a relatively small number of cases in the studies reported [47]. There is general agreement, however, that the most effective method for preventing infection of these wounds is through proper initial management, which should include thorough irrigation with a copious volume of normal saline, debridement when necessary, and closure of the wound when appropriate. The wound also should be cultured. Radiographic examination of the adjacent facial bones may be indicated in cases in which a fracture is suspected. Proper selection and administration of antimicrobial therapy, which is based on the suspected flora and the risk of the wound for infection, are also important elements of treatment. The most commonly isolated organism from infected dog and cat bites is Pasteurella species, 50% and 75%, respectively [48,49]. Pasteurella canis is the most common isolate from dog bites, whereas P. multocida subspecies multocida and septica are the most common isolates from cat bites. Other common aerobic organisms isolated from dog and cat bites include streptococci, staphylococci, Moraxella, and Neisseria [48]. Common anaerobic organisms that are isolated from mixed infections include Fusobacterium, Bacteroides, Porophyromonas, and Prevotella. Isolates from human bites include S. aureus, Eikenella corrodens, Haemophilus influenzae, and beta-lactamase producing oral anaerobic bacteria [48,49]. Based on this spectrum of organisms, the empirical therapy for animal bites should be directed against Pasteurella, streptococci, staphylococci, and anaerobes Commonly used empiric antibiotic

therapy for outpatients includes penicillin or dicloxacillin, ampicillin, or a first-generation cephalosporin [49,54,55]. A recent multicenter study of infected animal bites concluded that optimal therapeutic agents for this purpose include a combination of a b-lactam antibiotic and b-lactamase inhibitor, a second-generation cephalosporin with anaerobic activity, or combination therapy with either penicillin and a first-generation cephalosporin or clindamycin and fluoroquinolone [48]. Based on their in vitro activity, azithromycin, trovafloxacin, and ketolide antibiotics are also effective against all of the common aerobic and anaerobic isolates from these bites [56 58]. For treatment of high-risk human bites, empiric therapy includes penicillin and antistaphylococcal agents, such as dicloxacillin and nafcillin [59]. An alternative to this combination is oral amoxicillin-clavulanic acid, which provides excellent in vitro coverage of the suspected pathogens [57,60]. Ertapenem also has an excellent potency against the full range of animal and human bite pathogens [58]. Use of prophylactic antibiotics for prevention of bite wound infection remains an area of considerable controversy. Some authors argue that such use is cost effective in selected cases. These cases include wounds seen more than 8 hours after injury, wounds that affect the hand, wounds that involve bone and joints, cat bite puncture wounds, especially near a joint or joint prosthesis, and wounds in patients with a compromised immune system. In such cases, the use of prophylactic antibiotic may decrease the rate of infection from 15% to 20% to approximately 5% [47,49,54,61]. Excluding these instances, most authors believe that prophylactic antibiotics are not indicated, especially for patients with bite wounds in the head and neck and patients who present within the first few hours after injury and show no evidence of infection [51,53,54,62,63]. This conclusion is based on the fact that most studies that showed a benefit of prophylactic antibiotics used diverse treatment protocols for wounds that were not of similar severity. Most of these studies also were biased by inclusion of hand wounds, which have a higher incidence of infection. Several studies have shown that with early surgical intervention using irrigation, debridement, and primary closure, the wound infection rate in the face, with and without the use of prophylactic antibiotics, is similar and routine antibiotic prophylaxis is not justified [52,53,55,64,65]. The timing of closure of bite wounds also continues to be controversial. In general, the time of wound closure is influenced by the period between injury and presentation for care. Researchers gen-

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erally agree that bite wounds in the face, where cosmesis is a major concern, can be closed primarily or covered with skin graft when necessaryeven 4 days after injurywith an acceptably low risk for infection because of the rich blood supply [51,63,66].

Summary With improvements in surgical techniques and the availability of effective systemic antibiotics, the incidence of posttraumatic soft tissue wound infections is relatively low. When such infections occur, however, they can result in significant morbidity. These complications can be reduced by prompt initial management of the wound and proper treatment if infection occurs.

References
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[12] Hollander JE, Singer AJ, Valentine SM, et al. Risk factors in patients with traumatic lacerations. Acad Emerg Med 2001;8:716 20. [13] Stamou SC, Maltezou HC, Psaltopoulou T, et al. Wound infection after minor limb laceration: risk factors and the role of antimicrobial agents. J Trauma 1999;46:1078 81. [14] Cruse PJE, Foord R. A five-year prospective study of 23,649 surgical wounds. Arch Surg 1973;107:206 10. [15] Fernandoz AM, Herruzo CR, Gomez-Sanch F, et al. Four year study of the risk factors of surgical wound infection in 5260 traumatological patients. Minerva Med 1996;87:189 94. [16] Molnar JA, Burke JF. Prevention and management of infection in trauma. World Surg 1983;7:158 63. [17] Curtin JW. Basic plastic surgical techniques in repair of facial lacerations. Surg Clin North Am 1973; 53:33 46. [18] Kelly A-M, Cohen M, Richards D. Minimizing the pain of local infiltration anesthesia for wounds by injection into the wound edges. J Emerg Med 1994;12: 593 5. [19] Leach J. Proper handling of soft tissue in the acute phase. Facial Plast Surg 2001;17:227 38. [20] Key SJ, Thomas DW, Shepherd JP. The management of soft tissue facial wounds. Br J Oral Maxillofac Surg 1995;33:76 85. [21] Sacchetti A, Schafermeyer R, Geradi M, et al. Pediatric analgesia and sedation. Ann Emerg Med 1995;23: 237 50. [22] Dickinson JT, Jaquiss GW, Thompson JN. Soft tissue trauma. Otolaryngol Clin North Am 1976;13:130 4. [23] Singer AJ, Hollander JE, et al. Pressure dynamics of various irrigation techniques commonly used in the emergency department. Ann Emerg Med 1994;24: 36 40. [24] Stuzin JM, Engrav LH, Buchler PK. Emergency treatment of facial lacerations. Postgrad Med 1982;71: 88 94. [25] Madden J, Edlich RF, Schauerhamer R, et al. Application of principles of fluid dynamics to surgical wound irrigation. Curr Top Surg Res 1971;3:85. [26] Feng LJ, Eaton C. Soft tissue infection in lower extremity trauma. Clin Plast Surg 1986;13:735 45. [27] Wheeler CB, Rodeheaver GT, Thacker JG, et al. Side effects of high pressure irrigation. Surg Gynecol Obstet 1976;143:775 8. [28] Oberg MS, Lindsey D. Do not put hydrogen peroxide or povidone iodine into wounds! Am J Dis Child 1987;141:27 8. [29] Hollander JE, Richman PB, Werblud M, Miller T, Huggler J, Singer AJ. Irrigation in facial and scalp lacerations: does it alter outcome? Ann Emerg Med 1998;31:73 7. [30] Zook EG. The care of facial lacerations. J Fam Pract 1978;6:1089 95. [31] Berk WA, Osbourne DD, Taylor DD. Evaluation of the golden period for wound repair: 204 cases from a Third World emergency department. Ann Emerg Med 1988;17:496 500.

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A.O. Abubaker / Oral Maxillofacial Surg Clin N Am 15 (2003) 139146 [50] Callahan M. Prophylactic antibiotics in common dog bite wounds: a controlled study. Ann Emerg Med 1980;9:410 4. [51] Chen E, Hornig S, Shepherd SM, Hollander JE. Primary closure of mammalian bites. Acad Emerg Med 2000;7:156 61. [52] Guy JR, Zook EG. Successful treatment of acute head and neck dog bite wounds without antibiotics. Ann Plast Surg 1986;17:45 58. [53] Dire DJ. Cat bite wounds: risk factors for infection. Ann Emerg Med 1991;20:973 9. [54] Callahan M. Controversies in antibiotic choices for bite wounds. Ann Emerg Med 1988;17:1321 30. [55] Wolff KD. Management of animal bite injuries of the face: experience with 94 patients. J Oral Maxillofac Surg 1998;56:838 43. [56] Goldstein EJC, Citron DM, Gerardo SH, Hudspeth M, Merriam CV. Activities of HMR 3004 (RU 64004) and HMR 3647 (RU 66647) compared to those of erythromycin, azithromycin, clarithromycin, roxithromycin, and eight other antimicrobial agents against unusual aerobic and anaerobic human and animal bite pathogens isolated from skin and soft tissue infections in humans. Antimicrob Agents Chemother 1998;42: 1127 32. [57] Goldstein EJC, Citron DM, Hudspeth M, Gerardo SH, Merriam CV. In vitro activity of BAY 12 8039, a new 8-methoxyquinolone, compared to the activities of 11 other oral antimicrobial agents against 390 aerobic and anaerobic bacteria isolated from human and animal bite sound skin and soft tissue infections in humans. Antimicrob Agents Chemother 1997;41: 1552 7. [58] Goldstein EJC, Citron DM, Merriam CV, et al. Comparative in vitro activity of ertapenem and 11 other antimicrobial agents against aerobic and anaerobic pathogens isolated from skin and soft tissue animal and human bite wound infections. J Antimicrob Chemother 2001;48:641 6. [59] Fallouji MA. Traumatic love bites. Br J Surg 1990;77: 100 1. [60] Lindsey D, Christopher M, Hollenbach J, et al. Natural course of human bite wound. J Trauma 1987;27: 45 8. [61] Bunzli WF, Wright DH, Hoang AT, et al. Current management of human bites. Pharmacotherapy 1998;18: 227 34. [62] Chidzonga M. Human bites of the face. S Afr Med J 1998;88:150 2. [63] Donkor P, Bankas DO. A study of primary closure of human bite injuries to the face. J Oral Maxillofac Surg 1997;55:479 81. [64] Medeiros I, Saconato H. Antibiotic prophylaxis for mammalian bites. Cochrane Database Syst Rev 2001; 2:CDO1738. [65] Venter TH. Human bites of the face: early surgical management. S Afr Med J 1988;74:277 9. [66] Agrawal K, Mishra S, Panda KN. Primary reconstruction of major human bite injuries to the face. Plast Reconstr Surg 1992;90:394 8.

[32] Halasz NA. Wound infection and topical antibiotics. Arch Surg 1977;112:1240 4. [33] Teepe RG, Koebrugge EJ, Lowick C, et al. Cytotoxin effects of topical antimicrobial and antiseptic agents on human keratinocytes in vitro. J Trauma 1993;35: 8 19. [34] Dire DJ, Coppola M, Dwyer DA, Lorrette JJ, Karr JL. A prospective evaluation of topical antibiotics for preventing infections in uncomplicated soft-tissue wounds repaired in the ED. Acad Emerg Med 1995; 2:4 10. [35] Cummings P, Del Beccaro MA. Antibiotics to prevent infection of simple wounds: a meta-analysis of randomized studies. Am J Emerg Med 1995;13: 396 400. [36] Robson MC, Heggers JP. Delayed wound closure based on bacterial count. J Surg Res 1970;2:379 83. [37] Centers for Disease Control. Diphtheria, tetanus and pertussis: Recommendations for vaccine use and other preventive measures. Recommendation of the Immunization Practices Advisory Committee (ACIP). Morbidity and Mortality Weekly Report 1991;40:1 22. [38] Klein DG, Fritsch DE, Amin SG. Wound infection following trauma and burn injuries. Critical Care Nursing Clinics of North America 1995;7:627 42. [39] Esrig BC, Frazee L, Stephenson SFS, et al. The predisposition to infection following hemorrhagic shock. Surg Gynecol Obstet 1977;144:915. [40] Pruitt BA, Yurt RW. Treating burn and soft tissue infections. Infections in Surgery 1983;2:625 8. [41] Garner JS, Harvis WR, Emori TG, et al. CDC definitions for nosocomial infections. Am J Infect Control 1988;16:128 40. [42] Seligman M, Martyn JAJ. Burn wound infections. In: Martyn JAJ, editor. Acute management of the burned patient. Philadelphia: WB Saunders; 1990. p. 288 305. [43] Vitale P. Antimycotic and antifungal agents. In: Williams BR, Baer CL, editors. Essentials of clinical pharmacology in nursing. Springhouse (PA): Springhouse Corp.; 1994. p. 451 62. [44] Kagan RJ, Naragi S, et al. Herpes simplex virus and cytomegalovirus infections in burned patients. J Trauma 1985;25:40 5. [45] Haury B, Rodeheaver G, Vensko J, Edgerton MT, Ed lich RF. Debridement: an essential component of traumatic wound care. Am J Surg 1978;135: 238 42. [46] Fratianne R, Papay F, Housini I, et al. Keratinocyte allografts accelerate healing of split-thickness donor sites: applications for improved treatment of burns. J Burn Care Rehabil 1993;14:148 54. [47] Goldstein EJC. Bite wounds and infection. Clin Infect Dis 1992;14:433 8. [48] Talan DA, Citron DM, Fredrick AM, et al. Bacteriologic analysis of infected dog and cat bites. N Engl J Med 1999;340:8592 7. [49] Goldstein EJC, Citron DM, Finegold SM. Dog bite wounds and infection: a prospective clinical study. Ann Emerg Med 1980;9:508 12.

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Management of infections associated with laser-assisted cosmetic skin resurfacing

Robert A. Strauss, DDS, MD
Department of Oral and Maxillofacial Surgery, Virginia Commonwealth University, Medical College of Virginia, PO Box 980566, Richmond, VA 23298, USA

The last decade has seen a large increase in the number of cosmetic surgical procedures performed in the United States. New operations, techniques, and technologies seem to appear each year. Although the exact reason for this increase is not totally clear, cultural and social factors have played a role. Once limited only to older women, cosmetic surgery is currently sought by younger people, men, and even children. Much controversy has been generated concerning the wisdom of our society seeking the performance of totally elective surgery. Proponents make arguments based on psychological well-being and the relative safety of these procedures, whereas critics point out that even with all the technologic advances, cosmetic surgery is still associated with a low, but inevitable, degree of morbidity and even occasional mortality. Among the more recent advances in aesthetic facial surgery has been the development of laser-assisted cosmetic skin resurfacing (CSR), which has become one of the most popular procedures performed by maxillofacial cosmetic surgeons [1]. Similar in effect to chemical peeling and dermabrasion (which also are associated with the same incidence and types of infections), CSR has gained in popularity because of new advances in laser technology that allow precise, targeted, tissue ablation and the fact that these devices are relatively affordable and portable enough for office-based use. Combining this technology with a better understanding of the physiology of skin wound healing and the availability of new scientifically based pharmaceuticals for preoperative and postoperative

E-mail address: rastrauss@vcu.edu

skin care has made the procedure easily and safely performed by various practitioners. Thousands of these procedures have been performed with generally excellent aesthetic results. Although currently well accepted as a useful surgical procedure in the cosmetic surgeons armamentarium, CSR has had its share of controversy. As with many technology-based procedures, the rapid availability of the ever-changing types of hardware, coupled with the need and desire of the practitioner to generate a positive cash flow from these expensive devices, has brought with it an immediate influx of practitioners of varying backgrounds, surgical expertise, and laser experience. Unfortunately, the rapid advances in laser technology and widespread use of CSR preceded the ability of researchers to provide a clear understanding of the pathophysiology involved, the mechanism of laser action, the indications and contraindications for their use, and some of the potential and inevitable complications that were to be expected. As a consequence, CSR has been associated with several serious and occasionally disastrous complications. With time and much scientific research, many of the unknowns that led to some of the initial problems have been answered. Reasonable technique and patient selection protocols, based on defensible science, have decreased the incidence of complications dramatically. They do occur, however, and the wise surgeon always should be wary and diligent in looking for early evidence of untoward intraoperative and postoperative sequelae. Some of the complications seen to date include scarring, hypopigmentation and hyperpigmentation, blotchiness, pruritis, ectropion, and infection. Of these complications, infection associated with CSR

1042-3699/03/$ see front matter D 2003, Elsevier Science (USA). All rights reserved. PII: S 1 0 4 2 - 3 6 9 9 ( 0 2 ) 0 0 0 8 1 - X

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has proved to be one of the more controversial areas in terms of prophylaxis and treatment.

Normal healing of the skin When a wound is created in skin, a series of important biochemical and histopathologic changes occurs. Shortly after injury, the adjacent basal cell layer ceases its normal role of vertical migration and maturation and begins the process of horizontal migration to cover the exposed tissues. Any adnexal epithelial structures that remain in the wound also begin to form surface epithelium and proliferate in all directions. Simultaneously, collagen formation is accelerated in the wound to fill the defect. The more rapid the reepithelialization of the wound from external and internal sources, the less collagen formation that occurs and the less likelihood there is of any significant scarring. The main goal in all of the skin resurfacing methods is to remove the epidermis and papillary dermis and preserve the reticular dermis with its intact epithelial adnexal structures to allow for speedy internal and external reepithelialization. The skin is a fundamental physical barrier to the entrance of microorganisms into the body and a vitally important functioning member of the overall immune system [2]. CSR, by its very design, removes the entire epidermis and a significant portion of the dermis, thereby altering the immune mechanism and enhancing the ability of various microorganisms to colonize the exposed surface. For this reason a calculable incidence of infection after CSR is to be expected.

not surprisingly, aerobic or facultative anaerobes (eg, Staphylococcus epidermidis and other Staphylococcus species, Streptococcus viridans, and Corynebacterium species). As would also be expected, the most common fungal organism seen is Candida albicans, although species of Pityrosporum, Malassezia, and Torulopsis are also present. Not only does CSR result in loss of the protective epidermal barrier but it also changes the postoperative environment. This result, plus the medicaments used after surgery, produces a dramatic change in the local immune system and allows for overgrowth of the normal inhabitants and infection by organisms from adjacent areas, such as the oral cavity and nares.

Bacterial infections Numerous studies have examined the incidence and microbiology of postoperative infections after CSR [5 10]. The incidence seems to be variable, ranging from near zero in some studies to alarming rates in others, even with the use of prophylactic antibiotics. Weinstein et al, in a study of more than 1900 patients, showed an overall rate of bacterial infection of only 0.5% [10]. Similarly, in a study of 500 consecutive patients, Nanni and Alster reported an overall rate of infection of less than 1% [7]. Conversely, Walia and Alster reported an infection rate of 24% in a subset of their population who received intraoperative and postoperative antibiotics [9]. Gaspar et al also reported that 4 of 14 patients (28%) not given prophylactic antibiotics also developed postoperative bacterial infections [5]. Several other studies have shown rates generally in the range of 4% to 8% [6,8]. There seem to be multiple reasons for such diverse findings, and understanding this is important to critically analyzing the literature in this area. One of the main obstacles to studying the incidence of postoperative infections is the difficulty in defining the term infection. It is variably defined in different studies as a positive culture associated with signs and symptoms, a positive culture regardless of signs and symptoms, or the presence of clinical signs and symptoms with or without any culture results. Even more nonspecific, some studies defined the patient as being infected whenever the clinician, in his or her judgment, decided to institute systemic antibiotics regardless of the culture results [11]. Such variations render interstudy comparisons difficult or impossible. Other reasons for the diversity of findings likely include the wide variations in the use of prophy-

Normal microbiology of the skin Unlike the oral cavity, the skin of the face is generally not a particularly good place for the habitation of microorganisms. The skin, being dry and having a slightly acidic pH, makes a hostile environment, and the constant desquamation makes it difficult for organisms to attain sufficient numbers to cause clinical infection [3]. Various bacteria and yeasts consistently inhabit the skin in predictable and stable numbers, typically residing in the stratum corneum or along the hair shafts and follicles [4]. Patients with acute or chronic acne present a much more diverse and complicated microbiologic picture. Because the epidermis is constantly exposed to the environment, most of the bacteria found on skin are,

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lactic antibiotics, the differences in postoperative dressing management, and even when the study was performed, because differences in these everevolving techniques and technologies must play a role in the incidence of infection. Other factors that have been shown to make significant and dramatic differences in infection rate are the size and location of the operative site. Full-face resurfacing seems to have a much higher incidence of infection than resurfacing restricted to only one or two cosmetic units. Anunt et al, in their study of 396 patients, showed an eightfold decrease in infection when only partial resurfacing was performed, and no infections occurred in patients who received resurfacing of only a single cometic unit [8]. The clinical signs and symptoms of a postoperative infection after CSR are well recognized [7,9,10]. Persistent or increasing pain (especially if the quality of the pain differs from the initial sunburn pain normally felt for the first 48 hours), burning, erythema (localized, worse than the surrounding operated skin, and often showing crusting), pruritis that lasts more than 72 hours, and a yellow exudate are common findings. Papules, pustules, and erosions also may be seen. There may be an associated fever, but this not a consistent finding. Depending on the microbes involved, a foul odor may be noted by the patient. Although postoperative bacterial infections may be obvious and overt, one should remember that some individuals present with only subtle findings, such as prolonged patchy erythema. Given the consequences that can result and the success rate of early treatment, the astute clinician always should suspect an infection when any finding is out of the ordinary or there is an atypical complaint from the patient after a CSR procedure and appropriately rule out this possibility. The microbiology of postoperative bacterial infections varies and can be altered by many factors, such as the use of prophylactic antibiotics and the type of postoperative management (eg, closed versus open dressings). Because the overall infection rate is relatively low, no large-scale studies have shown a statistically significant classification of the organisms most likely involved in CSR. A review of the literature shows that the most prevalent organisms are Staphyloccocus aureus, S. epidermidis, and Pseudomonas aeruginosa, but occasionally Enterobacter, Escherichia coli, Proteus, and Serratia species are found. These organisms are similar to the organisms typically responsible for burn wound infections, because the wound created by CSR is essentially a partial-thickness burn [12].

Factors that affect the rate of bacterial infection One interesting factor regarding postoperative infection is the time of presentation. Although most infections occur in the first 3 to 10 days after surgery, when the wound has not yet epithelialized [8,13], some studies have shown that infections can occur several weeks after surgery [14]. This occurrence can be explained by the concept that there may be at least two different mechanisms of infection. One is related to the immediate loss of the protective immunity supplied by the epidermal covering and the type of initial postoperative management, and the other is related to the long-term medicaments applied to the surgical site. Another factor that may affect the incidence and treatment of bacterial infection is the change in local immunity caused by previous operations on the face. Repeated procedures, such as CSR or chemical peeling, especially when there is diffuse scarring, can lead to infections that may be refractory to the normal first-line antibiotics of choice. Although most postoperative bacterial infections are community acquired, patients who undergo surgery in the hospital environment or who have had recent hospitalizations must be considered at risk for nosocomial infections, such as those caused by methicillin-resistant S. aureus or Pseudomonas. Finally, the role of the immunosuppressive effects of short-term systemic or topical steroids in the development of postoperative infections has yet to be evaluated. One of the most controversial areas in CSR is the choice of open versus closed dressings for postoperative management. The advantage of open dressings (the use of topical creams or ointments to maintain a moist environment through the course of reepithelialization) is that the patient and doctor have direct visual access to the wound, can perform hygiene procedures often, and can recognize infections early. The advantages of closed dressings (the use of occlusive and semiocclusive materials to cover the wound) are that they eliminate the need for the patient to be responsible for cleaning the wounds in the immediate postoperative period and they are associated with less discomfort. Researchers have questioned whether the warm, moist, enclosed environment created under such dressings engenders the growth of infective organisms. Although some authors contend that there is an increased incidence of infection when occlusive dressings are used [15], others claim that there is no difference [16]. It is clear that if the dressings are used, use should be limited to 48 hours, followed by either removal or

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thorough wound cleansing and replacement [17]. Even in cases in which a higher incidence of infection followed the use of closed dressings, changing or eliminating the dressing early either dramatically decreased or eliminated the problem [16,17]. Whether real or not, the general feeling that these dressings may increase the infection rates, along with the tendency toward smaller unit CSR (rather than full faces), has swung the pendulum for many surgeons in favor of open dressings.

Treatment of viral infections Among the infections seen after CSR, viral infections are probably the most common. This finding is not unexpected given the prevalence of herpes simplex virus-1 (HSV-1) in the population and the proximity of the operative sites to the most common place of hibernation for that organism. The virus lies dormant and quiescent in the trigeminal ganglion but may be activated at any time throughout life by a chemical, mechanical, or traumatic stimulus or when the immune system is compromised significantly. Widespread herpetic infections, with subsequent scarring of the face, have been well documented in the past in burn patients and persons who undergo dermabrasion and chemical peeling [19,20]. It is not surprising that patients who undergo perioral CSR are at high risk for an HSV reactivation. One also should remember that although HSV-1 is the most common cause of such infections, HSV-2 (typically associated with genital lesions and transmitted by sexual contact) also can be the causative agent in some patients. Herpes simplex virus infection is not an insignificant complication. The incidence of HSV reactivation after dermabrasion and chemical peeling, without the use of antiviral agents, has been reported to be as high as 50% [21]. Before the introduction of effective and specific antiviral agents, trigger areas such as the perioral area were purposely avoided during chemical peeling or dermabrasion to decrease the risk of an HSV outbreak. Alternatively, patients with chronic or recurrent HSV were considered unacceptable candidates for these types of procedures [22]. Reactivation of the perioral HSV is manifested by severe burning pain in the operated site that is different from the usual stinging felt for the first 48 hours after surgery. Commonly the pain occurs just after the cessation of antiviral therapy, but in patients who do not receive prophylactic antibiotics, it occurs within the first 7 to 10 days before reepithelialization. Within 24 hours of the initial infection, the patient develops a dermatomal erythema followed by the typical vesicular lesions associated with HSV. As the vesicles rupture, the area develops ulcerated, weepy patches. The infection may be difficult to diagnose because the entire surgical site is already denuded by the CSR. An HSV infection should be considered in any patient who develops fever or malaise within the first week after surgery. Because of the large amount of deepithelialized skin (loss of the normal protective epidermal barrier), the infection can spread rapidly to any or all of the treated areas, with potentially disastrous consequences.

Treatment of bacterial infections Once a patients infection by clinical examination has been determined, it is imperative that the treatment be immediate, aggressive, and appropriate. This response is vital to limiting the chance of long-term scarring or other sequelae. Empirical treatment should be started, but culture and antibiotic sensitivity testing, a Tzanck stain, and a KOH preparation should be performed as soon as possible to guide therapy should the infection not respond to the initial course of drugs. Because many CSR-related infections are mixed in nature (ie, they include either multiple bacterial organisms or combined bacterial and fungal or viral organisms), some authors recommend beginning treatment with an antibiotic, an antifungal, and an antiviral agent [8]. These choices can be refined when the results of the cultures and stains are obtained. The choice of an empirical antibiotic always should be based on the likely organisms involved in the infection. Given the proclivity for staphylococcal infection, a drug that is effective against treating gram-positive cocci, such as a cephalosporin, is logical, but because there is also a high incidence of Pseudomonas and other gram-negative infections, most authors recommend a broader spectrum agent, such as ciprofloxacin, 500 to 750 mg twice daily for 7 days [8,9]. Topical antibiotics are less effective and may alter the local flora, which results in the production of resistant organisms. They should not be used in place of systemic antibiotics when any significant infection exists. Topical agents, such as mupiricin ointment, may be added to systemic treatment for local management of cutaneous erosions, however. When considering therapy, one should remember that patients admitted to the hospital for intravenous antibiotics or hydration are at greater risk for developing methicillin-resistant S. aureus infections or infections caused by drug-resistant strains of Pseudomonas, and repeated culturing is appropriate [18].

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Initially, a history of recurrent perioral HSV infection was considered a true contraindication for CSR. With the use of prophylactic antiviral therapy this is no longer the case. Much controversy has been generated in the literature about which drugs to administer and what protocol to follow. Questions regarding when to begin therapy, how much to give, and when to cease therapy are still not clear and are being investigated. Because it was the first modern antiviral agent to be commercially available, acyclovir has been used extensively on patients who undergo CSR procedures. Perkins and Sklarew showed that with typical low-dose prophylaxis of 600 mg per day, breakthroughs were still common (8.3%, although not nearly as common as the 50% reactivation rate they found in untreated patients) [21]. Weinstein et al showed that at 1000 mg per day the rate dropped to 0.3% [10]. When Perkins and Sklarew began their prophylactic regimen 2 days before surgery at an increased dose of 2400 mg per day and continued it for 2 weeks after surgery, their reactivation rate dropped to zero [20]. Although acyclovir has been shown to be effective, its low absorption and bioavailability necessitate high dosages for long periods. Newer agents, such as famcyclovir and valacyclovir, have much better bioavailability and are probably better choices [23,24]. Valacyclovir, 500 mg twice daily, started the day of or the day before surgery and continued for 14 days postoperatively has been shown to be 100% effective in eliminating HSV reactivation in CSR patients [25]. Although patients with a history of recurrent HSV outbreaks or at least a previous single outbreak have a documented higher risk of infection if they do not receive prophylactic antivirals, patients who deny such a history should not be considered at low risk. Several studies have demonstrated a high incidence of apparent or proven HSV reactivation in patients who denied any prior history of such lesions [25,26]. When reactivation does occur, recognition is of paramount importance. Tzanck stains or viral cultures may be useful in making the diagnosis, but given the potential for disastrous sequelae and the low incidence of adverse reactions to the drugs, the initiation of high-dose therapy should not be delayed pending the results of these tests. Acyclovir should be increased to 4000 mg per day in five divided doses, and valacyclovir should be increased to 1000 mg three times per day. This high-dose therapy should be continued for at least 2 weeks after the lesions disappear.

Treatment of candidal infections Fungal infections also have been reported after CSR [1,9,27]. The postoperative environmental conditions of the face (ie, warm, moist, denuded epithelium) provide an ideal growth medium for fungal growth. To date, Candida organisms are isolated almost exclusively. One should note, however, that several authors have found that candidal infection is often associated with bacterial and viral infections [8,9]. Candidal infection after CSR should be suspected when the skin develops a fine, white film with an undersurface that bleeds when wiped gently with gauze. Pain, burning, and delayed healing are also typical signs. In some cases, yeast pustules also may form. When Candida is suspected, a KOH preparation and fungal cultures confirm the diagnosis. The treatment for fungal infection is straightforward. The patient should be placed on systemic antifungal therapy using 200 mg per day of either fluconazole or itraconazole. A course of 2 to 4 days seems to be adequate to resolve most fungal infections. Topical antifungal agents, such as ketoconazole cream (Nizoral), may be used to complement the systemic therapy. Some authors have suggested using prophylactic fluconazole therapy for 1 day before surgery in women who have a history of chronic vaginal yeast infections [27]. At least one study has suggested that prophylactic fluconazole therapy, 300 mg per day given between 3 and 8 days postoperatively, may speed reepithelialization, although this report remains controversial [28]. Manuskiatti et al reported a 1.8% to 2.2% incidence of yeast infection in 356 consecutively operated patients, but this rate dropped to zero with the use of prophylactic antifungal therapy [6]. Each clinician must determine whether this low incidence of infection warrants the use of prophylactic therapy.

Prevention of infections Because of the grave sequelae that can accompany infections after CSR, much emphasis has been placed on prevention protocols and treatment protocols [29]. This has proved to be one of the most controversial issues in the still-evolving field of facial rejuvenation. The wisdom of prophylactic antibiotic, antiviral, and antifungal agents, the use of closed versus open dressings, and various postoperative wound hygiene techniques have come under scrutiny. The use and type of prophylactic antibiotics, in particular, have become sources of discussion.

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Prophylactic antibiotics are considered appropriate to prevent infection either when the risk is exceptionally high or when the ramifications of the infection are grave. The benefits of the therapy must outweigh the risks of adverse effects. CSR is considered a cleancontaminated procedure because of the intimate proximity of the surgical site to contaminated areas, such as the oral and nasal cavities. In general, it is anticipated that clean-contaminated surgery has an expected infection rate of approximately 10%. The actual infection rate of CSR procedures reported in the literature ranges from 1% to 9%. With improved posttreatment protocols currently being used, the current rate is likely at the low end of this range. Despite the low incidence, many surgeons still provide prophylactic coverage to their patients [30,31]. Although at least one study has shown that using antibiotics can lead to a decreased incidence of infection (decreased from 8.2% to 4.3% using ciprofloxacin and open dressings) [6], several other studies that showed similar results either were based on small samples [13] or involved retrospective studies with multiple variables (such as the type of postoperative dressing applied) that could have affected the infection rate [8]. If one decides to use prophylactic antibiotics, it is wise to use narrow-spectrum agents. The reasons for not giving prophylactic antibiotics are also compelling, including the cost of the drugs, possible allergic or other untoward reactions, alteration of the normal skin flora, and selection of resistant organisms or development of superinfection. Several studies also have shown no decrease in infection rate with the use of prophylactic therapy [9,32,33]. The use of topical antibiotics also has been evaluated as a means of postoperative management and for prophylaxis. Postoperative use of antibiotic ointments has been associated with the development of milia, selection of resistant organisms, and a significant risk of contact dermatitis, especially in deepithelialized, laser-abraded skin [13,34]. The use of antibiotics is probably best avoided. Mupirocin, an intranasal, topical, antistaphylococcal spray, also has been tested for prophylaxis without success [6]. Although the evidence seems to indicate that use of prophylactic antibiotics after CSR probably is not necessary, the use of closed dressings may alter this paradigm. In the opinion of many authors (even authors opposed to antibiotic use with open dressings), the surface environment associated with closed dressings increases the risk of infection sufficiently to warrant the use of prophylactic agents [14]. Although the use of prophylactic agents to prevent bacterial or fungal infection has generated some controversy, there is no confusion as to the necessity for preoper-

ative and postoperative antiviral therapy. This necessity is well documented and well accepted. One area of interest that is often overlooked but must be considered in any discussion of postoperative infection is wound hygiene. Changing or eliminating closed dressings early, meticulous wound cleansing, and strict hand washing are imperative. The patient also should be instructed carefully on the avoidance of double dippingusing the fingers or the hands to apply postoperative topical agents and then placing them back into the container for more material. This practice quickly contaminates the container and leads to re-inoculation. Contamination can be avoided by using fresh cotton swabs and removing the entire amount of agent needed at one time.

Summary Infections after CSR are to be expected in a small number of patients, and they can be bacterial, viral, or fungal. Despite the low incidence, these infections can have devastating sequelae. When they occur, they should be investigated promptly and thoroughly to determine their cause and the best course of treatment. The use of prophylactic antibiotics and antifungal agents is still controversial, and their use seems in many cases to be dictated primarily by legal and patient demands rather than good science. It is hoped that future studies will better elucidate when and if these agents are necessary and what drugs should be used. Conversely, antiviral therapy is considered vital in the prevention of herpetic outbreaks, and it has been well documented that failure to use such agents leads to an unacceptably high incidence of infection and subsequent scarring, even in patients with no previous history of HSV. Finally, there is still much to be learned regarding the most ideal posttreatment protocols to minimize the incidence of infection. Proponents of closed and open dressings must demonstrate convincing evidence to show that one regimen is better than the other.

References
[1] Fitzpatrick RE. Laser resurfacing of rhytides. Dermatol Clin 1997;15:431 47. [2] Gilchrest BA. Skin aging and photoaging. Dermatol Nurs 1990;2:79 84. [3] Gallis HA. Normal flora and opportunistic infections. In: Joklik WK, Willet HP, Amos DB, et al, editors. Zinsser microbiology. 19th edition. Norwalk (CT): Appleton and Lange; 1988. p. 337 42.

R.A. Strauss / Oral Maxillofacial Surg Clin N Am 15 (2003) 147153 [4] Schuster GS. Microbiology of the orofacial region. In: Topazian RG, Goldberg MH, Hupp JR, editors. Oral and maxillofacial infections. 4th edition. Philadelphia: W.B. Saunders Co.; 2002. p. 30 42. [5] Gaspar Z, Vincuillo C, Elliot T. Antibiotic prophylaxis for full face laser resurfacing: is it necessary? Arch Dermatol 2001;137:1251 2. [6] Manuskiatti W, Fitzpatrick RE, Goldman MP, et al. Prophylactic antibiotics in patients undergoing laser resurfacing of the skin. J Am Acad Dermatol 1999; 40:77 84. [7] Nanni CA, Alster TS. Complications of carbon dioxide laser resurfacing: an evaluation of 500 patients. Dermatol Surg 1998;24:315 20. [8] Sriprachya-Anunt S, Fitzpatrick RE, Goldman MP, et al. Infections complicating pulsed carbon dioxide laser resurfacing for photoaged facial skin. Dermatol Surg 1997;23:527 35. [9] Walia S, Alster TS. Cutaneous CO2 laser resurfacing infection rate with and without prophylactic antibiotics. Dermatol Surg 1999;25:857 61. [10] Weinstein C, Pozner JN, Ramirez OM. Complications of carbon dioxide laser resurfacing and their prevention. Aesthetic Surgery Journal 1997;17:216 22. [11] Futoryan T, Grande D. Postoperative wound infection rates in dermatologic surgery. Dermatol Surg 1995;21: 509 14. [12] Husain MT, Karim QN, Tajuri S. Analysis of infection in a burn wound. Burns 1989;15:299 302. [13] Ross EV, Amesbury EC, Barile A, et al. Incidence of postoperative infection or positive culture after facial laser resurfacing: a pilot study, a case report, and a proposal for rational approach to antibiotic prophylaxis. J Am Acad Dermatol 1998;39:975 81. [14] Christian MM, Behroozan DS, Moy RL. Delayed infections following full-face CO2 laser resurfacing and occlusive dressing use. Dermatol Surg 2000;26:32 6. [15] Lawrence N, Coleman WP. Postoperative care after laser resurfacing. In: Coleman WP, Lawrence N, editors. Skin resurfacing. Baltimore: Williams and Wilkins; 1998. p. 189 95. [16] Newman JP, Fitzgerald P, Kock RJ. Review of closed dressing after laser resurfacing. Dermatol Surg 2000;26: 562 71. [17] Goldman MP. Pre- and postoperative care of the laser resurfacing patient. International Journal of Aesthetic and Restorative Surgery 1997;5: 46 9. [18] Bellman B, Brandt FS, Holtmann M, et al. Infection with methicillin-resistant Staphylococcus aureus after carbon dioxide resurfacing of the face: successful treatment with minocycline, rifampin, and mucipirin ointment. Dermatol Surg 1998;24:279 82. [19] Kagan RJ, Naraqi S, Matsuda T, et al. Herpes simplex

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virus and cytomegalovirus infections in burned patients. J Trauma 1985;25:40 5. Rappaport MJ, Kramer F. Exacerbation of facial herpes simplex after phenol facial peels. J Dermatol Surg Oncol 1984;10:57 8. Perkins SW, Sklarew EC. Prevention of facial herpetic infections after chemical peel and dermabrasion: new treatment strategies in the prophylaxis of patients undergoing procedures of the perioral area. Plast Reconstr Surg 1996;98:427 33. Farber GA. Chemical peeling in the treatment of certain cosmetic defects and diseases of the skin. In: Burks JW, editor. Dermabrasion and chemical peeling. Springfield (IL): Charles Thomas Publishing; 1979. p. 209 26. Alster TS, Nanni CA. Famciclovir prophylaxis of herpes simplex virus reactivation after laser skin resurfacing. Dermatol Surg 1999;25:242 6. Wall SH, Ramey SJ, Wall F. Famciclovir as antiviral prophylaxis in laser resurfacing procedures. Plast Reconstr Surg 1999;104:1103 8. Gilbert S, McBurney E. Use of valacyclovir for herpes simplex virus-1 (HSV-1) prophylaxis after facial resurfacing: a randomized clinical trial of dosing regimens. Dermatol Surg 2000;1:50 4. Rendon-Pellerano MI, Lentini J, Eaglestein WE, et al. Laser resurfacing: usual and unusual complications. Dermatol Surg 1999;5:360 6. Kilmer SL. Laser resurfacing complications: how to treat them and avoid them. International Journal of Aesthetic and Restorative Surgery 1997;5:41 5. Conn H, Nanda VS. Prophylactic fluconazole promotes reepithelialization in full-face carbon dioxide laser skin resurfacing. Lasers Surg Med 2000;26: 201 7. Strauss RA, McMunn W, Gregory BA. Cosmetic skin resurfacing. Selected Readings in Oral and Maxillofacial Surgery 2001;9:1 32. Friedman PM, Geronemus RG. Antibiotic prophylaxes in laser resurfacing patients. Dermatol Surg 2000;26: 695 6. Kauvar ANB. Laser skin resurfacing: perspectives at the millennium. Dermatol Surg 2000;26:174 7. Alster TS. Against antibiotic prophylaxis for cutaneous laser resurfacing. Dermatol Surg 2000;26:697 8. Gaspar Z, Apfelberg DB. Summary of the 1997 ASAPRS/ASPRS laser task force survey on laser resurfacing and laser blepharoplasty. Plast Reconstr Surg 1998;101:511 8. Waldorf HA, Kauvar ANB, Grossman MC, et al. Skin resurfacing of fine to deep rhytids using a char free carbon dioxide laser in 47 patients. Dermatol Surg 1995;21:940 6.

Oral Maxillofacial Surg Clin N Am 15 (2003) 155 160

The use of prophylactic antibiotics for the prevention of postoperative infections

Daniel M. Laskin, DDS, MS
Department of Oral and Maxillofacial Surgery School of Dentistry, Virginia Commonwealth University, Richmond, VA 23298-0566, USA

Despite use of the best surgical techniques, some operations still carry a high risk of wound infection. Basic and clinical studies have shown that this risk can be reduced by the administration of prophylactic antibiotics. There are certain inherent risks associated with the use of these agents, however, such as toxic and allergic reactions, emergence of resistant bacteria, drug interactions, and superinfections. Moreover, prophylactic antibiotics do not prevent all postoperative infections. For these reasons, their use should be based on an understanding of certain basic principles. This article reviews these principles and discusses their application in specific clinical situations.

recommendations that are made by the authors. It also may account for some of the contradictory findings that have been reported in the literature. As the result of the basic studies of Miles and Burke et al [1,2] and several well-controlled clinical studies, the principles of proper antibiotic prophylaxis have been established for general surgery, and they are applicable to the field of oral and maxillofacial surgery. These principles are (1) that the intended procedure must carry a significant risk of postoperative infection, (2) that the correct antibiotic must be selected, and (3) that the antibiotic is administered properly. To these principles one may add a fourth principle: not to rely solely on prophylactic antibiotics to prevent postoperative infections.

Principles of prophylactic antibiotics Risk of infection Antibiotic prophylaxis has been defined as the preoperative use of antibiotics to prevent infection. Prophylactic use of antibiotics is in contradistinction to the therapeutic use of antibiotics, which are given to treat an already existing infection. Not only are the purposes different but also the manner in which the drugs should be administered for an optimum effect are different. A review of the literature clearly indicates that, in many instances, antibiotics are given postoperatively rather than preoperatively, although it is still referred to as a prophylactic procedure. This difference must be taken into consideration when evaluating the conclusions that are reached and the Although such factors as age of the patient, nutritional status, nature of any underlying disease, presence of necrotic tissue, and a decreased blood supply can increase the potential for postoperative infection, perhaps the most important factor is wound contamination. Altemeier et al [3] developed a classification of general surgical wounds relating contamination to the risk of infection. In this classification, operative wounds are categorized as clean, clean-contaminated, contaminated, or dirty, with contamination resulting from planned or unplanned entry into the respiratory, gastrointestinal, or genitourinary tracts. Because of the difference in host response to such contamination and oral contamination, this classification cannot be used for intraoral wounds. It can be modified, however, to

E-mail address: dmlaskin@vcu.edu

1042-3699/03/$ see front matter D 2003, Elsevier Science (USA). All rights reserved. PII: S 1 0 4 2 - 3 6 9 9 ( 0 2 ) 0 0 0 6 7 - 5

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establish the indications for prophylactic antibiotics in other forms of oral and maxillofacial surgery. According to this modified classification, extraoral wounds are still categorized in terms of increasing risk of infection as clean, clean-contaminated, contaminated, and dirty. However, the definitions must be altered to fit the regional differences. Clean surgical wounds, which have a low infection rate, usually involve no significant tissue trauma or inflammation, the incision is closed primarily, the wound is not drained, and there is no communication with the oral cavity. Clean-contaminated surgical wounds are similar to clean wounds except that there is a greater risk of infection because communication with the oral cavity occurs. Contaminated wounds are fresh traumatic injuries that involve the oral cavity, whereas dirty wounds are traumatic injuries with delayed treatment that communicate with the oral cavity and contain devitalized tissue or foreign bodies. Clean surgical wounds do not require antibiotic prophylaxis; however, it should be used in cleancontaminated wounds. Contaminated wounds usually can be managed with preoperative prophylactic antibiotics if there are no other significant risk factors. Otherwise, patients with such wounds also should receive postoperative prophylactic antibiotics. Patients with dirty wounds, which are already infected, require preoperative and postoperative therapeutic antibiotics. The decision not to use antibiotics or to use only preoperative prophylactic antibiotics is always based on the assumption that the patient does not have any significant medical risk factors that could affect the bodys humoral and cellular defense mechanisms. These risk factors include poorly controlled diabetes, end-state renal disease and uremia, severe alcoholism, an immunocompromising disease (eg, leukemia, lymphoma, or an advanced malignant neoplasm), and the use of chemotherapeutic agents or other immunosuppressive drugs. In such patients, one is concerned not only with preventing the initial contamination of the wound but also with the possibility of recontamination during the postoperative period. Therefore, postoperative prophylaxis is also indicated.

pathogen that may be encountered. Expanded antibiotic coverage serves only to increase the rate of bacterial resistance and the development of superinfections. The most commonly encountered organisms from oral contamination are the streptococci, anaerobic gram-positive cocci, and anaerobic gramnegative rods, whereas contamination from the sinus and nose may include Haemophilus influenzae, diptheroids, and peptostreptococci [4]. When the skin is involved, the presence of Staphylococcus aureus and epidermidis also must be considered. Although the first consideration is that the antibiotic selected is effective against the major contaminating organisms, it also must be nontoxic and relatively nonallergenic, bactericidal, capable of achieving therapeutic tissue concentrations, and have a long half-life so that redosing is generally not required during the procedure. The antibiotic that currently still fulfills these requirements best is penicillin. When skin contaminants are a concern, however, a first-generation cephalosporin, such as cefazolin, can be used because of its effectiveness against most staphylococci.

Antibiotic administration Although one selects the appropriate antibiotic for prophylaxis, its ultimate effectiveness in preventing infection still depends on proper administration. This decision varies according to whether one is dealing with normal patients, in whom there is only concern about the initial bacterial contamination that can occur during the operation, or patients with other significant risk factors that decrease the bodys defenses and retard healing, which makes them more susceptible to recontamination during the healing period. In the first instance, the antibiotic must be administered intravenously or intramuscularly within 30 minutes of the incision time at twice the therapeutic dose [5]. For penicillin, the dose is 2 million U, and for cefazolin it is 1 g. This dose generally provides adequate coverage for up to 4 hours. If the procedure is prolonged, however, it is advisable to administer additional doses every 4 hours until the operation is completed. In patients who are medically compromised or immunosuppressed, it may be advisable to continue prophylactic oral antibiotics until biologic sealing of the wound has occurred. No data exist on how long this period should be or even if it prevents postoperative infections. In fact, one must be concerned about promoting the emergence of resistant strains and causing superinfections. In a wound that is healing by primary intention, the period should

Antibiotic selection Once it has been determined that prophylactic antibiotics are indicated in a particular patient, the second principle involves making the appropriate selection. The choice of antibiotic is determined largely by its effectiveness against the pathogens commonly encountered at the specific surgical site. It need not be able to eradicate every potential

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probably be no longer than 48 hours postoperatively and in a wound healing by secondary intention it should be no longer than 3 to 5 days, at which time a biologic seal should have occurred.

Impacted third molar surgery Although many practitioners routinely prescribe antibiotics for patients who have impacted third molars removed [7,8], they are generally prescribed postoperatively. This practice does not accomplish the true purpose of using prophylactic antibiotics: having a high tissue concentration present at the time of surgery when the wound is exposed to bacterial contamination. It is not surprising that no convincing data show a significant reduction in postoperative infections after third molar removal when antibiotics are used in this manner [7,9]. The fact that such infections are relatively uncommon also may be a contributing factor to such findings [10,11]. Most studies that report high postoperative infection rates [12] include alveolar osteitis (dry socket) and fascial space infections. In such studies, however, there is still not a significant reduction in either type of problem, whether the antibiotics are given postoperatively or preoperatively [13 15]. Although isolated cases of severe fascial space infections after third molar removal have been reported [16], the incidence is too low to justify the routine use of prophylactic antibiotics. Such treatment should be reserved only for patients with significant medical risk factors for infection [1,17]. In these cases it should be given immediately before surgery and for 3 to 5 days after surgery to provide an adequate period of coverage.

Adjunctive procedures Although the correct use of prophylactic antibiotics significantly reduces the incidence of postoperative infections, their occurrence can be reduced further by careful attention to proper surgical technique. Proper technique involves adequate cleansing of the surgical site, strict adherence to sterile technique, avoiding tissue trauma, and minimizing operating time. In general, the risk of infection has been shown to increase with each hour of surgery. Shaving the skin in the surgical site with a razor the evening before the operation also has been shown to increase the infection rate, probably because of bacterial proliferation in the areas of minor trauma produced by shaving [6]. When shaving is necessary, it should be done just before preparation of the surgical site. The use of drains also may contribute to postoperative infections. When drains are necessary in noninfected wounds, the closed-suction type is preferable to open drains. They should not be placed through the operative incision and should be removed as soon as possible. Paying proper attention to these details during management of the surgical patient greatly improves the effectiveness of antibiotic prophylaxis.

Dental implants Specific applications in oral and maxillofacial surgery (Table 1) Exodontia and dentoalveolar surgery Although intraoral surgical wounds are contaminated by the oral flora, the ability of patients normally to tolerate this bacterial population and the excellent blood supply to the oral tissues allow such wounds to be managed similarly to clean wounds. It is unnecessary to use prophylactic antibiotics to prevent infection when performing most types of exodontia and dentoalveolar surgery unless there are other contributing risk factors (Table 1). If the procedure involves the maxillary sinus or nasal cavity, however, this can result in cross-contamination with new organisms, and prophylactic antibiotics should be used except when there is already infection in these areas. In the latter instance, therapeutic antibiotics are indicated. Few studies have been conducted on the effect of antibiotics on the infection rate after implant placement. Two studies in which no control group was used [18,19] concluded that preoperative prophylactic antibiotics were effective in preventing postoperative infections. In a subsequent, better controlled study [20], however, no difference in postoperative infections or implant failure was found between the two groups. In a more recent, large, multicenter study, Dent et al [21] analyzed implant failures (which probably included some cases with infection) and found significantly fewer failures up to stage 2 surgery, when high-dose preoperative antibiotics (penicillin in 69% of cases) were administered. These findings were confirmed in a follow-up study at 36 months in the same patient population (4.6% versus 10% failure) [22]. Thus, there seems to be a benefit in using prophylactic antibiotics in dental implant patients.

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Table 1 Indications for prophylactic antibiotics Procedure Exodontic and dentoalveolar surgery Impacted third molar surgery Dental implants Orthognathic surgery (extraoral approach) Orthognathic surgery (intraoral approach) Mandibular fractures (no oral communication) Mandibular fractures (oral communication) Facial bone fractures Soft tissue trauma (oral injuries) Soft tissue trauma (clean extraoral lacerations) Soft tissue trauma (blunt trauma, gunshot wounds, bites, orocutaneous communication) Major head and neck surgery Antibiotic regimen None None Preoperative None Preoperative and 1-day postoperative None Preoperative and 12 hours postoperative Preoperative None None Preoperative Preoperative Exceptionsa High risk for infection; communication with sinus or oral cavity High risk for infection Also postoperative prophylaxis when high risk of infection Preoperative when anticipate possible oral contamination None None Use prophylactic antibiotics 3 5 days postoperatively when treatment delayed None Preoperative when high risk for infection Preoperative when high risk for infection Postoperative prophylaxis for 3 5 days when high risk for infection Postoperative prophylaxis 3 5 days when packs or drains used; lack of watertight closure; high risk for infection

High risk for infection refers to such factors as poor nutritional status, complicating medical problems, presence of necrotic tissue or foreign bodies, and decreased blood supply to the region.

Orthognathic surgery Orthognathic surgery performed via an extraoral approach is considered a clean procedure and prophylactic antibiotics should not be necessary unless communication with the mouth is anticipated [23]. Intraoral procedures and procedures that involve the maxillary sinus and nasal passages are clean-contaminated operations, and short-term prophylactic antibiotics have been shown to reduce the postoperative infection rate [24,25]. There seems to be no advantage in prolonged postoperative antibiotic administration [25,26]. In one study in which a 5-day regimen was shown to be better than a 1-day regimen [27], as pointed out by Abubaker [24], the difference was caused by the difference in the criteria used to establish wound infection. Mandibular fractures Patients with condylar process fractures treated by either open or closed reduction require no prophylactic antibiotics. The same is true for fractures in other non tooth-bearing areas that are not in communication with the mouth, because these are all clean wounds. In patients with compound mandibular fractures, however, which are contaminated wounds, studies have shown that the use of anti-

biotics is effective in reducing postoperative infections [28,29]. In most of these studies, however, the antibiotics were given not only preoperatively but also for a long period postoperatively. More recent investigations [28,30] have shown that prophylactic antibiotics given preoperatively and for no longer than 12 hours postoperatively are just as effective as long-term use in preventing postoperative infections. These findings apply only to fractures that are treated shortly after the injury has occurred. Fractures for which there is delayed treatment should be considered dirty wounds, and such patients should receive therapeutic antibiotics postoperatively. Facial bone fractures Although it has been suggested that any midfacial fracture compounded into the mouth, nose, or paranasal sinuses requires antibiotic coverage [31,32], other studies [28,33] have shown that it may not be necessary. Because one of these studies [33] was not well controlled and the other [28] had a relatively small number of cases, the issue remains unresolved. Based on the fact that such compound fractures communicate with a contaminated cavity, they should be considered as clean-contaminated wounds and preoperative prophylactic antibiotics should be used.

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Soft tissue trauma Patients with traumatic injuries that involve the oral mucosa, gingiva, or tongue do not require prophylactic antibiotics because such wounds, although contaminated, generally heal without infection. Simple extraoral lacerations from relatively clean objects that are closed within 4 hours also have a low infection rate and do not require prophylactic antibiotics [34]. Extraoral soft tissue injuries, such as those caused by blunt trauma, gunshot wounds, and bites and injuries that involve orocutaneous communication, fall into either the category of clean-contaminated or contaminated wounds, and the patient should receive pretreatment antibiotic prophylaxis. If the wounds are extremely dirty, the patient also should receive postoperative therapeutic antibiotics. Major head and neck surgery Researchers generally agree that patients who undergo major surgical procedures in the head and neck region, such as oncologic and reconstructive surgery, should receive preoperative prophylactic antibiotics [31,35 39]. There is a question regarding how long they should be used postoperatively. Several studies [31,35,36,38,39] that have shown that there is no advantage in extending the prophylactic antibiotics beyond 1 day after surgery in such cases unless there are packs or drains in the wound or it is not possible to obtain a watertight closure and there is prolonged leakage of saliva into the wound [40].

administer appears to transcend therapeutic rationale and provokes the use of antibiotics for purposes often obscure and irrelevant. It is only natural that great inventions and discoveries should gain wide acclaim and enthusiastic endorsement and enjoy universal acceptance far in excess of which they merit.

References
[1] Miles AA, Miles EM, Burke J. The value and duration of defense reaction of the skin to primary lodgment of bacteria. British Journal of Experimental Pathology 1957;38:79 86. [2] Burke JF. The effective period of preventive antibiotic action in experimental incisions and dermal lesions. Surgery 1961;50:161 8. [3] Altemeier WA, Burke JF, Pruitt Jr BA, et al. Manual on control of infection in surgical patients. 2nd edition. Philadelphia: JB Lippincott; 1984. p. 26 9. [4] Gagliano NC, Leisure GS. Perioperative pharmacology. In: Stone OJ, Bogdonoff DL, Leisure GS, et al, editors. Perioperative care: anesthesia, medicine, and surgery. St. Louis: Mosby; 1998. p. 486. [5] Peterson LJ. Principles of antibiotic therapy. In: Topazian RG, Goldberg MH, editors. Oral and maxillofacial infections. 3rd edition. Philadelphia: WB Saunders; 1994. p. 160 97. [6] Cameron JL. Current surgical therapy. 7th edition. St. Louis: Mosby; 2001. p. 1281. [7] Capuzzi P, Montebugnoli L, Vaccaro MA. Extraction of impacted third molars: a longitudinal, prospective study. Oral Surg Oral Med Oral Pathol 1994;77: 341 3. [8] Piecuch JF, Arzadon J, Lieblich SE. Prophylactic antibiotics for third molar surgery: a supportive opinion. J Oral Maxillofac Surg 1995;53:53 60. [9] Chiapasco M, Cicco LD, Marrone G. Side effects and complications associated with third molar surgery. Oral Surg Oral Med Oral Pathol 1993;76:312 20. [10] Goldberg MA, Nemarich AN, Marco WP. Complications after mandibular third molar surgery: a statistical analysis of 500 consecutive procedures in private practice. J Am Dent Assoc 1985;111:277 9. [11] Osborn TP, Frederickson G, Small IA, et al. A prospective study of complications related to mandibular third molar surgery. J Oral Maxillofac Surg 1985;43:767 9. [12] Mitchell DA. A controlled clinical trial of prophylactic tinidazole for chemoprophylaxis in third molar surgery. Br Dent J 1986;160:284 6. [13] Curran JB, Kennett S, Young AR. An assessment of the use of prophylactic antibiotics in third molar surgery. Int J Oral Surg 1974;3:1 6. [14] Happonen R-P, Backstrom A-C, Ylipaavalniemi P. Prophylactic use of phenoxy-methylpenicillin and tinidazole in mandibular third molar surgery: a comparative placebo controlled clinical trial. Br J Oral Maxillofac Surg 1990;28:12 5.

Summary Although prophylactic antibiotics do not prevent all postoperative infections, they can reduce the incidence significantly when administered correctly. However, they should be used only in patients in whom the surgical procedure or the medical condition puts them at a high risk of developing such infections. As a general rule, the anticipated risk should exceed 10% [41]. Use of antibiotics in low-risk cases in an attempt to prevent postoperative infections, especially when used for prolonged periods, can result in adverse drug effects, superinfections, and the emergence of resistant strains without providing any significant benefits. As Furstenburg [42] stated so succinctly more than 50 years ago: With the discovery of penicillin, its allied agents, and their mass production, clinicians have employed them in different forms and by various methods for almost every illness in the category of medicine. The urge to

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D.M. Laskin / Oral Maxillofacial Surg Clin N Am 15 (2003) 155160 [29] Zallen RD, Curry JT. A study of antibiotic usage in compound mandibular fractures. J Oral Surg 1975;33: 431 4. [30] Abubaker AO, Rollert MA. Postoperative antibiotic prophylaxis in mandibular fractures: a preliminary randomized, double-blind, and placebo-controlled clinical study. J Oral Maxillofac Surg 2001;59:1415 9. [31] Eschelman LT, Schleuning AJ, Brummett RE. Prophylactic antibiotics in otolaryngologic surgery: a doubleblind study. Transactions of American Academy Opthalmology and Otolaryngology 1971;75:387 94. [32] Zallen RD, Black SL. Antibiotic therapy in oral and maxillofacial surgery. J Oral Surg 1976;34:349 51. [33] Paterson JA, Cordo Jr VA, Stratigas GT. An examination of antibiotic prophylaxis in oral and maxillofacial surgery. J Oral Maxillofac Surg 1970;28:753 9. [34] Dellinger ED. Antibiotic use. In: Trunkey DD, Lewis Jr FR, editors. Current therapy of trauma. 3rd edition. St. Louis: Mosby; 1991. p. 47. [35] Conover M, Kaban LB, Mulliken JB. Antibiotic prophylaxis for major maxillocraniofacial surgery. J Oral Maxillofac Surg 1985;43:865 70. [36] Fee Jr WE, Glenn M, Handen C, et al. One day versus 2 days of prophylactic antibiotics in patients undergoing major head and neck surgery. Laryngoscope 1984;94:612 4. [37] Johnson JT, Myers EN, Thearle PB, et al. Antibiotic prophylaxis for contaminated head and neck surgery. Laryngoscope 1984;94:46 51. [38] Johnson JT, Schuller DE, Silver E, et al. Antibiotic prophylaxis in high-risk head and neck surgery: oneday vs five-day therapy. Otolaryngol Head Neck Surg 1986;95:554 7. [39] Mombelli G, Coppens I, Dor P, et al. Antibiotic prophylaxis in surgery for head and neck cancer: comparative study of short and prolonged administration of carbenicillin. J Antimicrob Chemother 1987;7: 667 71. [40] Shapiro M. Prophylaxis in otolaryngologic surgery and neurosurgery: a critical review. Rev Infect Dis 1991;13(Suppl 10):S858 68. [41] Burkett HG, Quick RG, Gott DT. Essential surgery: problems, diagnosis and management. 2nd edition. Edinburgh: Churchill-Livingstone; 1998. p. 70. [42] Furstenburg AC. Antibiotics in the treatment of disease of the ear, nose, and throat. Ann Otol 1949;58:5 17.

[15] Thomas DW, Hill CM. An audit of antibiotic prescribing in third molar surgery. Br J Oral Maxillofac Surg 1997;35:126 8. [16] Indresano AT, Haug RH, Hoffman MJ. The third molar as a cause of deep space infections. J Oral Maxillofac Surg 1992;50:33 5. [17] MacGregor AJ. Reduction in morbidity in the surgery of the third molar removal. Dent Update 1990;17: 411 4. [18] Larsen P, McGlumphy E. Antibiotic prophylaxis for placement of dental implants. J Oral Maxillofac Surg 1993;51:194. [19] Peterson L, McGlumphy E, Halikas L. Long-term antibiotic prophylaxis is not necessary for placement of dental implants. J Oral Maxillofac Surg 1996;54:76. [20] Gynther G, Kondell P, Moberg L, et al. Dental implant installation without antibiotic prophylaxis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998;85: 509 22. [21] Dent CD, Olson JW, Farish SE, et al. Influence of preoperative antibiotics on success of endosseous implants up to and including Stage 2 surgery: a study of 2,641 implants. J Oral Maxillofac Surg 1997;55: 19 24. [22] Laskin DM, Dent CD, Morris HF, et al. The influence of preoperative antibiotics on success of endosseous implants at 36 months. Ann Periodontol 2000;5: 166 74. [23] Zallen RD, Strader RJ. The use of prophylactic antibiotics in extraoral procedures for mandibular prognathism. J Oral Surg 1971;29:178 9. [24] Abubaker AO. Antibiotic prophylaxis in orthognathic surgery: a 1-day versus 5-day regimen [discussion]. J Oral Maxillofac Surg 1999;57:230 2. [25] Ruggles JE, Hann JR. Antibiotic prophylaxis in intraoral orthognathic surgery. J Oral Maxillofac Surg 1984;42:797 801. [26] Fridrich KL, Partnoy BE, Zeitler DL. Prospective analysis of antibiotic prophylaxis for orthognathic surgery. Int J Adult Orthod Orthognath Surg 1994;9:129 31. [27] Bentley KC, Head TW, Aiello GA. Antibiotic prophylaxis in orthognathic surgery: a 1-day versus 5-day regimen. J Oral Maxillofac Surg 1999;57:226 30. [28] Chole RA, Yee J. Antibiotic prophylaxis for facial fractures: a prospective, randomized clinical trial. Arch Otolaryngol Head Neck Surg 1987;113:1055 6.

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Index
Note: Page numbers of article titles are in boldface type.

A
Abscesses, retropharyngeal, versus cellulitis, imaging of, 47 Actinomycosis, cervicofacial. See Cervicofacial actinomycosis. Acyclovir, for viral infections, due to laser-assisted skin resurfacing, 155 AIDS. See also HIV infection; Immunocompromised patients. and oropharyngeal candidiasis, 93 94 immune defects in, 107 Airway management, in head and neck infections, 107 Alcoholism, immune defects in, 106 Aminoglycosides, for head and neck infections, 26 Amoxicillin, for head and neck infections, 23 Amphotericin B, for oropharyngeal candidiasis, 97 99 Antibiotics, for bite wounds, 146 147 for head and neck infections. See Head and neck infections. for infections due to laser-assisted skin resurfacing, 154, 156 for peri-implantitis, 135 for post-traumatic soft tissue infections, 143 144, 145 to prevent maxillofacial infections. See Maxillofacial infections. Antiseptic agents, for oropharyngeal candidiasis, 97 Avelox, for head and neck infections, 33034 Azoles, for oropharyngeal candidiasis, 97, 98 Bisphosphonates, for diffuse sclerosing osteomyelitis, of jaws, 76 Bite wounds, management of, 145 147 Bone penetration, by antibiotics, 21

C
Candidal infections, laser-assisted skin resurfacing and, 155 oropharyngeal. See Oropharyngeal candidiasis. Cellulitis, versus retropharyngeal abscesses, imaging of, 47 Cerebrospinal fluid penetration, by antibiotics, 21, 23 Cervicofacial actinomycosis, 51 58 clinical features of, 55 56 diagnosis of, 56 57 histopathology of, 54 55 historical aspects of, 53 management of, 57 58 medicolegal considerations in, 58 microbiology of, 54 natural history of, 54 Chemotherapy, and oropharyngeal candidiasis, 93 Clotrimazole, for oropharyngeal candidiasis, 97, 98 Computed tomography, of maxillofacial infections. See Maxillofacial infections. Condyloma acuminatum, dental issues in, 86 87 Corticosteroids, for recurrent aphthous stomatitis. See Recurrent aphthous stomatitis. Cutaneous maxillofacial infections, microbiology of, 11 12 Cytochrome P450 system, and antibiotic metabolism, 27 Cytomegalovirus, dental issues in, 84 85

B
Bacterial infections, laser-assisted skin resurfacing and, 152 154

1042-3699/03/$ see front matter D 2003, Elsevier Science (USA). All rights reserved. PII: S1042-3699(02)00097-3

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D
Deep neck infections, recurrent, imaging of, 47 Dental implant surgery, prophylactic antibiotics in, 161 162 Dentoalveolar surgery, prophylactic antibiotics in, 161 Denture wearers, oropharyngeal candidiasis in, 94, 95 Diabetes mellitus, and oropharyngeal candidiasis, 93 immune defects in, 105 106 Diffuse sclerosing osteomyelitis, of jaws, 69 78 case report of, 77 78 clinical features of, 72 differential diagnosis of, 71 etiology of, 71 histology of, 73 imaging of, 72 73 laboratory tests for, 73 74 management of, 75 77 microbiology of, 74 75 pathogenesis of, 71 Disodium clodrenate, for diffuse sclerosing osteomyelitis, of jaws, 76

G
Gemifloxacin, for head and neck infections, 33034 Guided bone regeneration, for peri-implantitis, 135 137

H
Head and neck, necrotizing fasciitis of. See Necrotizing fasciitis. Head and neck cancer, and oropharyngeal candidiasis, 93 Head and neck infections. See also Maxillofacial infections. antibiotics for, 17 38 fluoroquinolones, 33 34 for fungal infections, 36 37 for odontogenic infections, 35 36 for osteomyelitis of jaw, 36 for sinus infections, 36 ketolides, 34 35 oxazolidinones, 34 pristinamycins, 35 resistance to, mechanisms of, 18 molecular biology of, 17 prevention of, 18 19 selection of, adverse reactions in, 26 allergy or intolerance in, 19 20 antimicrobial spectrum in, 21 cost in, 27, 30, 33 drug interactions in, 26 27 for usual pathogens, 19 in children, 26 in immunocompromised patients, 20 21 in pregnancy, 26 pharmacokinetics in, 23, 26 previous antibiotic therapy and, 21 tissue distribution in, 21, 23 prevention of, antibiotics in, 163 Hepatitis C virus infections, dental issues in, 88 Herpes simplex virus infections, dental issues in, 82 83 laser-assisted skin resurfacing and, 154 155 maxillofacial, microbiology of, 12 Herpesvirus infections, dental issues in, 82 83, 85 86 HIV infection. See also AIDS; Immunocompromised patients. and oropharyngeal candidiasis, 93 dental issues in, 81 82 head and neck infections with, antibiotics for, 20 immune defects in, 106 107

E
Enterocolitis, periodontal surgery and, 127 Enteroviruses, dental issues in, 87 88 Epstein-Barr viruses, dental issues in, 83 84 Exodontia, prophylactic antibiotics in, 161

F
Facial bone fractures, antibiotics for, 162 163 Fluconazole, for candidal infections, due to laserassisted skin resurfacing, 155 for oropharyngeal candidiasis, 97 Fluoroquinolones, for head and neck infections, 33034 Fractures, facial bone, antibiotics for, 162 163 mandibular, antibiotics for, 162 Frontal sinusitis, microbiology of, 10 11 Fungal infections, laser-assisted skin resurfacing and, 155 of head and neck, antibiotics for, 36 37

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Human papillomavirus, dental issues in, 86 87 Hyposalivation, and oropharyngeal candidiasis, 94

I
Immunocompromised patients. See also AIDS; HIV infection. head and neck infections in, 103 110 AIDS patients, 107 airway management in, 107 alcoholic patients, 106 antibiotics for, 20 21, 107 108 diabetic patients, 105 106 HIV-positive patients, 106 107 versus normal immune system, 103 105 Impacted third molar surgery, prophylactic antibiotics in, 161 Infections, head and neck. See Head and neck infections. laser-assisted skin resurfacing and. See Laser-assisted skin resurfacing. maxillofacial. See Maxillofacial infections. periodontal. See Periodontal infections. post-traumatic soft tissue. See Post-traumatic soft tissue infections. Infectious rhinitis, microbiology of, 10 Itraconazole, for oropharyngeal candidiasis, 97

Laser-assisted skin resurfacing, and infections, 147 153 bacterial, 148 152 candidal, 152 fungal, 152 prevention of, 151 152 versus normal skin healing, 150 versus normal skin microbiology, 150 viral, 152 153 Leukoplakia, dental issues in, 83 84 oropharyngeal candidiasis and, 95 Lichen planus, oral, dental issues in, 88 Linezolid, for head and neck infections, 34

M
Magnetic resonance imaging, of maxillofacial infections. See Maxillofacial infections. Mandibular fractures, antibiotics for, 162 Maxillary sinusitis, microbiology of, 9 10 Maxillofacial infections. See also Head and neck infections. imaging of, 39 49 computed tomography in, interpretation of, 44 necrotizing fasciitis, 48 49 retropharyngeal abscess versus cellulitis, 47 septic thrombophlebitis, 47 48 sialadenitis, 48 sinusitis, 49 technique for, 41 43 magnetic resonance imaging in, interpretation of, 44 45 sinusitis, 49 technique for, 43 44 microbiology of, 1 15 acute maxillary sinusitis, 9 10 chronic maxillary sinusitis, 10 cutaneous infections, 11 12 frontal and sphenoid sinusitis, 10 110 herpes simplex infections, 12 infectious rhinitis, 10 odontogenic infections, 4 7 antibiotic-resistant, 7 culture and antibiotic sensitivity in, 4 isolates per patient in, 4 patient characteristics in, 4 polymicrobial, 4 6 trauma-related, 7 9 prevention of, antibiotics in, 155 160 adjunctive procedures with, 158

J
Jaws, diffuse sclerosing osteomyelitis of. See Diffuse sclerosing osteomyelitis. osteomyelitis of, antibiotics for, 36

K
Kaposis sarcoma, dental issues in, 96 Ketek, for head and neck infections, 34 35 Ketoconazole, for oropharyngeal candidiasis, 97 Ketolides, for head and neck infections, 34 35 Koebner phenomenon, in recurrent aphthous stomatitis, 114

L
b-Lactam antibiotics, for head and neck infections, 19 20

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administration of, 157 158 choice of, 157 for dental implants, 158 159 for exodontia and dentoalveolar surgery, 158 for facial bone fractures, 159 160 for impacted third molar surgery, 158 for major head and neck surgery, 160 for mandibular fractures, 159 for orthognathic surgery, 159 for post-traumatic soft tissue infections, 160 principles of, 156 risk of, 156 157 versus normal microflora, 2 3 cutaneous, 2 3 nasal and paranasal, 3 oral, 3 viral, 79 89 cytomegalovirus, 84 85 enteroviruses, 87 88 Epstein-Barr viruses, 83 84 hepatitis C virus, 88 herpes simplex, 82 83 herpesvirus 8, 86 herpesviruses 6 and 7, 85 HIV infection, 81 82 human papillomavirus, 86 87 Kaposis sarcoma virus, 86 varicella-zoster virus, 85 Miconazole, for oropharyngeal candidiasis, 97 Mononucleosis, dental issues in, 83 84 Moxifloxacin, for head and neck infections, 33034 Mycobacterial infections, maxillofacial, imaging of, 47

Nontuberculous mycobacterial infections, maxillofacial, imaging of, 47 Nystatin, for oropharyngeal candidiasis, 96 97

O
Odontogenic infections, antibiotics for, 35 36 imaging of, 45, 47 microbiology of. See Maxillofacial infections. Oral contraceptives, failure of, antibiotics and, 27 Oral mucosa, disruption of, and oropharyngeal candidiasis, 94 Oropharyngeal candidiasis, 91 102 clinical features of, 94 95 diagnosis of, 95 management of, 95 99 amphotericin B in, 97 99 antiseptic agents in, 97 choice of, 95 96 combination therapy in, 99 nystatin in, 96 97 polyene antifungal agents in, 96 99 resistance to, 98 susceptibility testing in, 95 risk factors for, 92 94 local and oral, 94 microbial, 93 systemic, 93 94 systemic, 95 Orthognathic surgery, prophylactic antibiotics in, 162 Osteomyelitis, diffuse sclerosing. See Diffuse sclerosing osteomyelitis. of jaw, antibiotics for, 36 Oxazolidinones, for head and neck infections, 34

N
Nasal sinus infections, microbiology of. See Maxillofacial infections. Necrotizing fasciitis, of head and neck, 59 67 classification of, 63 clinical features of, 65 diagnosis of, 65 66 historical aspects of, 61 63 imaging of, 48 49 management of, 66 67 results of, 67 68 microbiology of, 63 pathogenesis of, 63 65 NewTom imaging, of maxillofacial infections, 43

P
Paranasal sinus infections, microbiology of. See Maxillofacial infections. Penicillins, for cervicofacial actinomycosis, 57 for head and neck infections, 19, 36 cerebrospinal fluid penetration by, 21, 23 pharmacokinetics of, 23 Peri-implantitis, 129 138 diagnosis of, 132 134 implant salvage in, 134 137 antibiotics in, 135 guided bone regeneration in, 135 137 microbiology of, 129 130

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retrograde, 132 titanium implants and, 130 131 hydroxyapatite-coated, 131 132 Periodontal infections, 123 128 diagnosis of, 124 125 in adults, 124 125 in children, 124 management of, 125 128 complications of, 127 Plain films, of peri-implantitis, 133 Polyene antifungal agents, for oropharyngeal candidiasis, 96 99 Post-traumatic soft tissue infections, 139 146 antibiotics for, 143 144, 145, 163 bite wounds and, 145 147 antibiotics for, 146 147 debridement of, 143, 145 postoperative care for, 143 144 prevention of, 142 143 risk factors for, 142 wound closure in, 143, 145 wounding mechanism in, 141 142 Pregnancy, head and neck infections in, antibiotics for, 26 Pristinamycins, for head and neck infections, 35

Retropharyngeal abscesses, versus cellulitis, imaging of, 47 Rhinitis, infectious, microbiology of, 10

S
Salivary gland function, impaired, and oropharyngeal candidiasis, 94 Septic thrombophlebitis, maxillofacial, imaging of, 47 48 Sialadenitis, imaging of, 48 Sinusitis, antibiotics for, 36 imaging of, 49 microbiology of. See Maxillofacial infections. Skin resurfacing, laser-assisted. See Laser-assisted skin resurfacing. Soft tissue infections, post-traumatic. See Post-traumatic soft tissue infections. Sphenoid sinusitis, microbiology of, 10 11 Squamous cell carcinoma, oral, dental issues in, 87 Synercid, for head and neck infections, 35

T
Telithromycin, for head and neck infections, 34 35 Tetracycline, for peri-implantitis, 135 Thalidomide, for recurrent aphthous stomatitis, 120 Third molar surgery, prophylactic antibiotics in, 161 Thrombophlebitis, septic, maxillofacial, imaging of, 47 48 Titanium implants, hydroxyapatite-coated, success and failure of, 131 132 success and failure of, 130 131 Trauma, maxillofacial, and infections, 7 9 Tuberculous infections, maxillofacial, imaging of, 47

Q
Quinupristin/dalfopristin, for head and neck infections, 35

R
Recurrent aphthous stomatitis, 111 122 clinical features of, 114 116 etiology of, 111 genetic factors in, 112 histopathology of, 116 immunologic factors in, 112 113 management of, 116 120 burst therapy in, 119 120 corticosteroid injections in, 119 corticosteroid rinses in, 118 119 corticosteroid syrup in, 119 120 objectives, principles, and caveats of, 117 thalidomide in, 120 topical corticosteroids in, 118 119 microbiology of, 113 nutritional factors in, 113 114 pathogenesis of, 111 112

V
Varicella-zoster virus, dental issues in, 85 Verruca vulgaris, dental issues in, 87 Verrucous leukoplakia, dental issues in, 87 Viral infections, laser-assisted skin resurfacing and, 154 155

Z
Zyvox, for head and neck infections, 34