Journal of Pediatric Infectious Diseases 4 (2009) 53–65 DOI 10.

3233/JPI-2009-0151 IOS Press

53

Review Article

Choosing antimicrobials for anaerobic infections
Ellie J. C. Goldsteina,∗ and Gary E. Steinb
a b

UCLA School of Medicine and R.M. Alden Research Laboratory, Santa Monica, CA, USA Department of Medicine, Michigan State University, East Lansing, MI, USA

Received 11 May 2008 Revised 21 May 2008 Accepted 25 May 2008

Abstract. Anaerobes are opportunistic pathogens that are the predominant indigenous normal flora of the skin and mucous membranes in humans. Anaerobic infections are common, often found in proximity to their anatomical locations, and may be difficult to treat. Anaerobes are usually found in mixed culture along with aerobes. This article reviews the activity of various classes of antimicrobials used against anaerobes, along with their pharmacodynamics, and the susceptibility patterns and resistance mechanisms of important anaerobic pathogens such as Bacteroides fragilis. It is hoped that the reader will be able to use this information and synthesize it into an approach on how to select antimicrobials for anaerobic therapy. Keywords: Anaerobic bacteria, B. fragilis, carbapenems, antimicrobial resistance, pharmacokinetics

1. Introduction Anaerobes are ‘secret’ and recondite pathogens, despite being the predominant normal flora of humans. In association with aerobic bacteria, anaerobes are involved in many serious infections, including sinusitis, aspiration pneumonia, appendicitis, and abscesses [1,2]. Despite advances in medical microbiology, the clinical diagnosis of anaerobic infections is underappreciated, their isolation by clinical laboratories requires substantial improvement, and their susceptibility patterns are under-reported and often unappreciated. Each patient is an experiment, and therapeutic success or failure depends on the happenstance of human immune defenses, surgical skill and an antimicrobial that is empirically selected [2,3].
Ellie J.C. Goldstein, MD, R.M. Alden Research Laboratory, 2021 Santa Monica Boulevard, Suite 740 E, Santa Monica, CA 90404, USA. Tel.: +1 310 315 1511; Fax: +1 310 315 3663; E-mail: ejcgmd@aol.com.
∗ Correspondence:

The clinical consequences of anaerobic infection, especially those that are missed, include prolonged hospital stay, increased costs and increased morbidity and mortality. The specific site of infection will determine the type of complication encountered. When milder infections are unrecognized and left untreated, the infections will linger causing increased malaise and discomfort. The more serious infections may provoke fevers, repeated hospitalizations, and additional surgical procedures for abscess formation and tissue debridement. Failure to recognize the mixed aerobic/anaerobic nature of necrotizing fasciitis can lead to disfiguring surgery and even death. Failure to treat the anaerobic component of an intra-abdominal infection often requires broader spectrum antibiotics and leads to re-operation and prolonged hospital stay. There is also an associated increased risk of development of resistant isolates, both aerobic and anaerobic [2,3]. The dilemma of selecting an appropriate antimicrobial agent to treat anaerobic infections is predicated upon the slow growth of anaerobes as compared to aer-

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gingivitis and periodontitis. These factors differ between the species. Intra-abdominal infections are commonly recognized as the quintessential prototype for mixed aerobic anaerobic infections. As the predominant bioflora of the vagina [10]. Anaerobes require an environment with a low oxidation-reduction potential (eH gradient). This review acts as a basis for understanding how to select an antimicrobial for anaerobic infections in children and adults.E. they range from those that are extremely oxygen sensitive (which are usually isolated only in normal flora studies) to those that can survive on the surface of a fresh agar plate in the presence of atmospheric oxygen. in their lifetimes. lectins). An animal model of intra-abdominal abscess [13– 15] demonstrated that intra-abdominal infections have 2.8]. acne. In the colon. Recent taxonomic advances have led to the reclassification and renaming of many anaerobic species. lipopolysaccharise). most always in combination with aerobic bacteria. they are also consummate opportunistic pathogens that cause serious and lethal infection. inhibit phagocytosis (capsule.C. Anaerobic bacteria were first described by Pasteur and were shown to be human pathogens by Prevot in 1898 [5]. pharmacokinetics and pharmacodynamics properties. hemagglutinins. Stein / Antimicrobials in anaerobic infections obes and the resultant lack of specific culture data for directed therapy. Anaerobic bacteria possess a variety of virulence factors [12] that facilitate adhesion (fimbriae. tissue destruction. or act as toxins (endotoxins and enterotoxins). they help maintain vaginal health and pH. such as Bacteroides fragilis.000 to 1 with the average human colon contains between 10 and 100 trillion organisms [7. Consequently. When the oral flora is aspirated into the lung. neuraminidases. Colon anaerobes are involved in appendicitis (the most frequent cause for abdominal surgery). Published antimicrobial susceptibility surveys may not reflect the clonality of local isolates and their unique susceptibility patterns and may therefore lead one astray as to selecting appropriate specific therapy [4]. Although the term anaerobe suggests that they grow in the absence of oxygen. heparinases. Many hospital clinical microbiology laboratories are unfamiliar with anaerobes or may not have the expertise or facilities to isolate them. causing confusion by many clinicians and laboratorians [6]. clinicians are forced to rely upon original governmental regulatory drug indications which often list efficacy (either in vitro or in vivo) of a very few genera and species for a limited number of indications. This extrapolation may not be appropriate to the clinical situation facing the medical care team. to reproduce or express pathogenicity factors. Anaerobes can also cause skin and soft tissue infections in proximity to the fecal flora-such as gas gangrene and Fournier’s gangrene of the scrotum – and in the feet of diabetic patients (fetid foot) [9]. the result is bacterial vaginosis. but when that balance is upset. Propionibacterium acnes. via transmitter substances. exotoxins. lung abscesses and empyema. The burden of infection from anaerobic bacteria As the predominant indigenous normal flora of the human cutaneous and mucous membrane surfaces (Fig. infectious diseases consultants. reviews the categories of potentially useful individual antimicrobial agents including their in vitro activity. cause the common bane of teenagers. the problem of obtaining accurate susceptibility results due to various discrepancies of testing methods and culminates to synthesize how one may attempt to select an appropriate antimicrobial agent. assist invasion and tissue destruction (proteases. anaerobes outnumber aerobes by up to 1. al- . 1. hemolysins). pili. In the oral cavity. Goldstein and G. It highlights the example of mixed aerobic/anaerobic intra-abdominal infections and their infectious burden. Treatment of these infections often requires a multidisciplinary approach with co-operation between. Diseases associated with mixed aerobic/anaerobic infections are seen in Fig. 1). However. surgeons and radiologists [3]. primary care doctors of pediatrics or internal medicine. in interaction with the sebaceous secretions.54 E. fecal peritonitis and cholecystitis) that are grouped together by anatomical coincidence. On the skin. They are categorized by Gram stain reaction as well as biochemical reactions. anaerobes outnumber aerobes by 10 to 1 and are involved in the most common of human infections.J. anaerobes perform many beneficial functions. 3. which occurs in ∼50% of all women. byproducts from aerobic bacterial metabolism and low oxygen content. diverticulitis. and communities of bacteria communicate with each other (quorum sensing) [11] and help direct the individual organisms. The flora of these infections is complex. abdominal abscess and peritonitis. The intra-abdominal infection model Intra-abdominal infections encompass a spectrum of specific infections (such as appendicitis. which is associated with low pH. anaerobes are involved in causing aspiration pneumonia.

the intensity of . There was no mortality in animals that received single isolates of enterococci. Upjohn. In a subsequent experiment. varium. Copyright Dr.C. coli and B. and resultant infections are generally mild and made up of fewer organisms. 1976.17]. B. Kalamazoo. From the terminal ileum. coli. B. duodenum and upper small intestines contain a sparse amount of bacteria. Copyright Dr.E. Finegold). Prevotella. Sutter VL. Acute mortality was associated only with E. stomach. individual pathogens and all possible dual combinations of E. Upjohn. An inoculum of 5 × 10 7 was associated with 100% mortality within two days. fragilis and Fusobacterium varium were implanted into the peritoneal cavities of Wistar rats. Porphyromonas 1976. fragilis Clostridia Peptostreptococci Lungs Aspiration pneumonia Empyema Lung abscess Female genital tract Lactobacillus Peptostreptococcus Pigmented Bacteroides Diabetic foot Gas gangrene Necrotizing fasciitis Endometritis Salpingitis Bacterial vaginosis Post-abortal sepsis Fournier s gangrene Vulvar abscess Colon Bacteroides fragilis group Prevotella Peptostreptococcus Clostridium sp Eubacterium Bifidobacterium Diarrhea C difficile Toxogenic B fragilis Fig. the highest rate of abscess formation was caused by combination of E. MI. Kalamazoo. a biphasic nature. Sutter VL: Diagnosis and Management of Anaerobic Infections.E. The initial stage of peritonitis was associated with Escherichia coli bacteremia and 43% mortality [15]. Abscesses occurred in 89– 100% of animals that received a combination of one facultative and one anaerobic bacterium.) Fusobacterium nucleatum Chronic sinusitis Peptostreptococcus Chronic otitis media Actinomyces Necrobacillosis Eubacterium Peritonsilar abscess Gingivitis Periodontitis Dental abscess Post extraction infection Peritonitis Hepatic abscess Appendicitis Chronic cholecystitis Post-operative infection/abscess 55 Bacteremia B. Stein / Antimicrobials in anaerobic infections Figure 1 Skin Oral cavity and upper respiratory Propionibacterium acnes Predominant anaerobes of the normal flora and associated diseases. Goldstein and G. Adapted from Finegold passages Peptostreptococcus SM. The upper gastrointestinal tract. whereas a 50% reduction of the size of the inoculum resulted in 65% mortality. Intra-abdominal infections exemplify the biphasic nature of infections that result from fecal contamination of the peritoneal cavity and highlight the importance of the synergistic interactions of aerobic and anaerobic bacteria. coli and was associated with the size of the inoculum.J. fragilis [15]. MI. “All animals surviving the acute peritonitis stage developed localized intra-abdominal abscesses by the 7th postoperative day” [15]. Finegold. There was no abscess formation found on autopsy in any of the 80 animals that received single isolate challenges. Diagnosis and Management of Anaerobic Infections. 1. Predominant anaerobes of the normal flora and associated diseases (Adapted from Finegold SM. enterococci. fragilis or F. through the entire colon and until the rectum. The specific bacteriology of an intra-abdominal infection depends on which organ is involved and its specific flora [16.

each individual agent has a unique profile. aeruginosa 11% vs. Porphyromonas and Fusobacterium can express resistance. coli despite an identical number.21) studied perforated appendicitis and in a small number of patients found differences in the bacteriology. While there are often class characteristics. Ureidopenicillins. 4. the parent beta-lactam agent can run the gauntlet and bind to the PBPs. coli in 70% of patients with gangrenous appendicitis and 77% in perforated appendicitis. Penicillinase-producing Fusobacterium species and Clostridium species express penicillinases that are typically inhibited by clavulanic acid. sulbactam.23–25]. Beta-lactamase inhibitors may not inactivate carbapenem resistance [26]. such as oxacillin. [19] studied gangrenous appendicitis and he and colleagues (20.17] aerobes account for 48% and anaerobes for 52% of isolates. betalactam-betalactamase inhibitor combinations.1.7 anaerobes and 7.56 E. tazobactam) can also prove effective. Goldstein and G. Figure 2 lists the relative frequency of various aerobic and anaerobic bacteria found in intra-abdominal infections. In a variety of studies [16. Resistance to these agents is infrequent.C. Production of beta-lactamase enzymes by anaerobic bacteria other than B.4 anaerobes per specimen. Beta-lactam/beta lactamase inhibitor combinations Combinations of a parent beta-lactam compound (such as ampicillin. cephalosporins. 19% vs. are useful against many strains of penicillinase producing Staphylococcus aureus. exhibit timedependent killing. 4. and inhibit cell wall synthesis by binding to penicillin binding proteins (PBPs). which include penicillinases (most commonly found in B. These differences included E. block cell wall synthesis by adhering to PBPs. viridans streptococci. but are less active than penicillin against anaerobes. e. with between 10–100 trillion colony forming units in the large intestine or about 10 12 cfu/g of feces [7. 4. All share a beta-lactam ring as a component of the structure. although some exceptions in Clostridium spp. the bacterial beta-lactamase-inactivating enzymes have a greater affinity to these beta-lactamase inhibitors than to the parent beta-lactam agents. Stein / Antimicrobials in anaerobic infections microorganisms increases dramatically. 43%.2. occur [27.g. etc.1. and permeability barriers (porin channel alterations). Each organism has its own PBPs that are numbered. 4.J. allowing these agents to have good activity against B. PBP1. then specific therapy should be instituted. fragilis and many other beta-lactamase-producing anaerobes. and carbapenems. but at some centers [18] as high as a 15% rate of isolation.. PBP2. The isolation of Pseudomonas aeruginosa occurs in varying rates. macrolides and sulfamethoxazole-trimethoprim. Microbiological studies [19–22] have isolated more than 21 genera and 40 species from patients with perforated appendicitis and recovered 2. Pediatric studies have yielded generally similar results except that Pseudomonas can occur in up to 35% of cases [3. fragilis as in E. Below we discuss the main compounds with anti-anaerobe activity. The in vitro activity of various antimicrobial agents is summarized in Table 1.1. Benion et al. Some antimicrobials. have no appreciable anti-anaerobe activity. Beta-lactams This class includes penicillins.E. there has been an updated recommendation regarding therapy for both children and adults [3]. While antibiotic therapy is often instituted empirically. Penicillins Penicillins. Each PBP drug-binding complex may have a different effect on the cell structure and resultant mechanism of cell injury [26]. target-site alteration (which can create low-affinity PBPs). Penicillinaseresistant penicillins. aminoglycosides. amoxicillin and piperacillin) with a beta-lactamase inhibitor (such as clavulanic acid. advantages. PBP numbering is specific to a genus/species and may be the same or unique in individual species. and P. respectively. are not appreciably more active against anaerobes. They are active against many anaerobes from the normal flora [26]. often ∼5%. . fragilis has been less well studied. but when one encounters the term PBP1 this may not be the same PBP1 found in B. and disadvantages. such as monobactams. Thus.28]. such as piperacillin. which have a thiozolidine ring and side chains in addition to a beta-lactam ring. Antibiotics against anaerobes Antimicrobials are divided into classes based on their chemical structures and derivation. fragilis group species and Prevotella species).1. All are bactericidal. Resistance to β-lactam antibiotics occurs by betalactamase-inactivating enzymes. but strains of Clostridium. Recently. once culture data is available. Betalactamase inhibitors restore activity of the associated compound by acting as ‘suicide’ inhibitors. They adhere to different PBPs in different bacteria. 18%.8].

a cephamycin due to its methoxy group on the C-6 position. has activity against anaerobes. and P. relegating this drug to second line therapy.3. Klebsiella spp Enterobacter spp Pseudomonas aeruginosa Staphylococcus aureus Other streptococci Other aerobes Aerobes 48% 8% 24% 15% Anaerobes 52% 9% 4% Bacteroides fragilis 6% Other Bacteroides species Clostridia 38% 5% 5% Peptostreptococci Fusobacteria Peptococci 10% Propionibacteria 11% 12% Veillonella Other Fig. anaerobic isolates are resistant to carbapenems owing to efflux mechanisms or zinc metallo-beta-lactamases. fragilis group species. imipenem and doripenem.1. as well as a hydroxyl-methyl on the C-6 position. resistance to cefoxitin has become fairly widespread.C.1. Rarely. Beta-lactamase inhibitors do not inactivate carbapenemases. Carbapenems Carbapenems. fragilis. The zinc carbapenemases are encoded by either ccrA or cfiA genes of B. have activity against MRSA. meropenem. aeruginosa. such as ertapenem. Cephalosporins have differences of activity that are due to various substitutions on the C-3 and C-7 position. including those of most anaerobes.E. fragilis group [30] and inactivate all β-lactam antibiotics. Class 3 agents. Cephalosporins Cephalosporins are bicyclic agents with a betalactam ring that is associated with a six-membered dihydrothiazine ring.E. aeruginosa. fragilis group species [29]. Each cephalosporin may have either a class or a specific individual agent enzyme that will inactive it. not yet clinically available. including B. Stein / Antimicrobials in anaerobic infections Escherichia coli 14% 24% 2% 3% 5% 5% 57 Enterococcus faecalis Proteus spp. Class 2 agents include doripenem. First generation cephalosporins (such as cefazolin) and third generation cephalosporins (such as cefotaxime. 2. 4. These enzymes are expressed in < . Acinetobacter spp.4. imipenem and meropenem and also have activity against enterococci. Distribution of aerobic and anaerobic bacteria isolated from intra-abdominal infections (Adapted from refs 15–19). 4. Class 1 agents include ertapenem and are active against most aerobic Gram-positives (except for enterococci) and fermentative Gram-negative aerobes but not Acinetobacter spp.J. and P. Bacterial cephalinosporinases of the 2e class inactivate most cephalosporins against anaerobes. The second generation cephalosporin cefoxitin. However. ceftizoxime and cefepime) do not have reliable anaerobic activity especially against B. are semi-synthetic bicyclic structures with a four-membered beta-lactam ring associated with a five-membered carbapenem ring. Goldstein and G. such as the cefoxitin-inactivating enzymes that occur in many B. They are stable against many beta-lactamases. Carbapenems are grouped by classes on the basis of their aerobic activity.

causing depolarization and disruption of the membrane. ertapenem. 4. Tigecycline. Vancomycin is active against most Grampositive anaerobes. Its activity against anaerobes is variable and varies geographically.4. 4.. Oxazolidinones These are synthetic. It is not affected by beta-lactamases and is primarily excreted in the feces as unchanged drug. Vancomycin Vancomycin is the prototype glycopeptide antibiotics and inhibits the synthesis of peptidogylcans for the cell wall. − = Resistant.2.g. fragilis from the US. Clindamycin Clindamycin is a bacteriostatic agent that inhibits protein synthesis by binding to the 50S ribosome. The only available oxazolidinone. Side effects of clindamycin include Clostridium difficile associated diarrhea [34]. 4. Propionibacterium species. Approximately 30% of B. ampicillin/sulbactam. It has calcium-dependent binding to the cell membrane. This class of agent is not used in children whose teeth are still growing [36]. but acts locally and is not absorbed systemically [34]. Goldstein and G. including B.58 E.C. and are bridged with a carbonyl group. ∗∗∗ Carbapenems: Imipenem. 4. Doxycycline and minocycline are more active than tetracycline against aerobic bacteria. inhibitor-β-lactam combination (e. such as Clostridium species. ∗∗ β-Lactamase 1% of B. Intra-abdominal pediatric B. but may be present in up to 3% of Bacteroides strains. exhibits a broad spectrum of activity against anaerobic bacteria. although most oral anaerobes remain susceptible. Stein / Antimicrobials in anaerobic infections Table 1 Antimicrobial susceptibility patterns for anaerobic bacteria∗ Drugs ∗∗∗ Moxifloxacin Clindamycin Metronidazole Penicillin Beta-lactamase Cefoxitin Tigecycline Carbapenems inhibitors∗∗ Bacteroides fragilis − ++ + + ++ + V ++ Bacteroides thetaiotaomicron − ++ V + + V V ++ Other Bacteroides fragilis group − ++ V + + + V ++ Prevotella species V ++ + ++ + + ++ Fusobacterium nucleatum V ++ + ++ V + ++ Fusobacterium necrophorum + ++ + ++ V + ++ Porphyromonas species + ++ + ++ + + ++ Peptostreptococci + ++ + ++ V + − Propionibacterium acnes + + + ++ + + V Veillonella + + + ++ + + ++ Actinomyces + + + ++ + + − Clostridia + + V + + V V + ∗ Based Bacteria on sundry in vitro susceptibility studies from various laboratories and using various source clinical isolates. difficile diarrhea.6.3. fragilis [35]. is active against Gram-positive anaerobes and has shown some Gram-negative anti-anaerobic activity [38]. Hungary and Kuwait suggested that more than one mechanism of activation exists [31]. . + = Susceptible. However.J. doripenem. piperacillin/tazobactam). meropenem. and is rapidly bactericidal [37]. which can carry ccrA or cfiA. V = Variable activity. amoxicillin clavulanate. linezolid. Eubacterium species and peptostreptococci. thetaiotaomicron isolates have shown 80% clindamycin resistance in one small study [33].5. 4. and is inactive against Gram-negative bacteria (as lipopeptides cannot cross the membranes of Gramnegative bacteria). fragilis and Bacteroides thetaiotaomicron species are resistant [22. An oral formulation is useful for the treatment of C. fragilis isolates in the United States. heterocyclic agents with a five membered ring that includes a nitrogen and an oxygen molecule. A study of 15 strains of imipenemresistant.32] to clindamycin. but have limited anti-anaerobic activity. daptomycin has limited activity against lactobacilli. cifA-positive B. Tetracyclines Tetracyclines are bacteriostatic agents that bind to the 30S ribosome and have a broad spectrum of activity.E. a parenteral glyclcycline that is derived from minocycline. Daptomycin Daptomycin is a novel lipopeptide agent that is active against some Gram-positive aerobic and anaerobic bacteria.

8. It is active against most Gram-positive and Gramnegative anaerobes. Pharmacodynamic parameters integrate both pharmacokinetic and MIC data (Fig. only five clinical cases of B. the infection inoculum and pH may not be the same as those that are used in the laboratory when determining the MIC for an antibiotic. Stein / Antimicrobials in anaerobic infections 59 4.7. 4.9. Substitutions on the 8 position improved anaerobic activity and pharmacokinetic properties as well [40. Goldstein and G.41]. 4. 3). Moreover. and the ratio between the area under the serum concentration-time curve (AUC) and the MIC (AUC/MIC) [48]. To date. They are active against almost all anaerobes.41]. β-lactam antibiotics β−lactams primarily exhibit concentration-independent activity. Moxifloxacin has improved activity against anaerobic Gram-positive and Gram-negative organisms. and the focus has been on T > MIC as a predictive parameter. tinidazole. except those that are microaerophilic (such as Actinomyces and P. but is not active against Enterobacter and Pseudomonas species.35. skin and skin-structure infections in adults but not children [45]. which enhances their activity against Gram-positive organisms.50]. There are very few differences between these considerations in adults and children [49. Recommendations suggest that serum levels should . However.E. heteroaromatic rings that bind to topoisomerase II (also known as DNA gyrase) and thereby inhibits DNA replication. Fluoroquinolones These are synthetic agents with bicyclic. fragilis group species. Most pharmacodynamic studies have found that a continuous infusion of β-lactams is at least as effective as more conventional intermittent dosing. ribosomal mutation or enzymatic inactivation by an acetyltransferase. It is also active against Rickettsia. A bacteriostatic agent inhibits protein synthesis by directly inhibiting the 50S ribosomal subunit and preventing peptide bond formation. fragilis group species and peptostreptococci is of concern [4. Plasmid-mediated chloramphenicol resistance may also encode for multidrug resistance [26].E. While not frequently used in the developed world due to potential marrow suppression and aplastic anemia. Nitroimidazoles Metronidazole. Moxifloxacin was recently approved for therapy against mixed aerobic and anaerobic intraabdominal. Resistance may occur by reduced membrane permeability. These agents are generally not used in children unless a resistant Gram-negative rod such as Serratia or Pseudomonas is present and there are no other therapeutic options [3. including B. it is widely used in the developing world because it is cheap. 5.3]. 26. Nitroimidazoles have no aerobic activity and are used in combination with agents that are active against common aerobic pathogens [2. but the development of resistance. 5. To optimize antibiotic activity. Fluoroquinolone resistance among Bacteroides spp. Concentration-dependent (or time-independent) antibiotics kill at a greater rate and to a greater extent with increasing antibiotic concentrations. and ornidazole are the members of the Nitroimidazole class of agents.C. fragilis resistance to metronidazole have been reported [26]. on the other hand. also inactivate topoisomerase IV. such as gemifloxacin and moxifloxacin.39]. Chloramphenicol Chloramphenicol is an inexpensive synthetic agent with broad-spectrum aerobic and anaerobic activity.1. although several limitations of this laboratory method exist [46]. or from an efflux pump mechanism [42–44]. whereas concentration-independent (time-dependent) agents kill bacteria at the same rate and to the same extent once an appropriate antibiotic concentration has been achieved. Pharmacodynamics. the ratio between the peak (C max ) concentration and MIC (Cmax /MIC). Mycoplasma and Chlamydia. The MIC is based on static drug concentrations in serum and does not represent free drug levels at the site of infection.J. it is important to know whether the drug kills in a concentration-dependent or independent fashion. acnes). Such parameters include the time (t) for which antibiotic concentration remains above the MIC (t > MIC). has been attributed to either a mutation in the quinolone resistance-determining region of the gyrase A gene (gyrA). especially by B. Antibiotic pharmacodynamics The MIC has long been used clinically for choosing an antimicrobial. describes the relationship between antibiotic concentrations in serum or at the infection site and biological effect [47]. its minimal inhibitory concentrations (MICs) often cluster near the MIC breakpoint. Several of the newer fluoroquinolone agents. and that very high doses do not increase efficacy.

The MIC is the minimal inhibitory concentration that a drug needs to achieve to inhibit bacterial growth (this does not mean that it “kills” the organism but inhibits its growth in an in vitro system). fragilis. Recent pharmacodynamic studies have shown that a prolonged infusion (3 hr) can improve bactericidal exposure compared to 30-min infusions and is comparable to continuous infusion strategies [52]. coli. 5. Some feel that it is the size of the “area under the curve” compared to the MIC that is important in killing efficacy.C. In an ex vivo study in healthy adult subjects. The rates of killing were also similar for a given isolate-dosing regimen combination. These parameters are studied for new drugs in order to help predict efficacy and efficient dosing regimens and schedules. . tigecycline has demonstrated time-dependent killing. Stein / Antimicrobials in anaerobic infections Fig. In ex vivo studies.5. Therefore. 5. Pharmacokinetics of antimicrobial dosing relative to the minimal inhibitory concentration (MIC) of an organism. fragilis and E. which enables manipulation of metronidazole dosing regimens. metronidazole reduced colony counts of anaerobic bacteria at least 3 log cfu/mL regardless of whether dosed thrice daily or once daily [57]. In experimental intraabdominal abscesses caused by B. Tigecycline Similar to tetracyclines.J.E. 5. One scenario is “concentration dependent killing” in which the higher the C max compared to the MIC means increased and enhanced killing of a microorganism. For anaerobic bacteria it is thought that if the time the drug concentration is greater than the MIC (minimum >50% of the time) is associated with effective killing. In contrast to studies with aerobic bacteria.4. B. Time dependent killing suggest that killing occurs during the time the drug concentration is higher than the MIC of the bacteria. the goal of clindamycin dosing should be to achieve a drug concentration at the site of infection that is close to the MIC for an extended period [56]. Fusobacterium nucleatum. cephalosporins and carbapenems. There are two different ways in which antimicrobials are thought to be effective in inhibiting bacterial grow. the ratio of AUC/MIC is the index that best correlates to bacterial eradication [59]. Goldstein and G. fragilis and produce survival rates comparable to those resulting from treatment with clindamycin plus gentamicin [54]. and Prevotella melaninogenica [53].60 E. In time-kill experiments. different serum levels of metronidazole were found to have similar bactericidal activity against various anaerobes [58]. time-kill experiments found that low (AUC/MIC > 11) serum levels of fluoroquinolones can produce a significant killing against anaerobes [53]. Clindamycin Clindamycin exhibits concentration-independent bactericidal characteristics against anaerobic bacteria [55]. fluoroquinolones (such as trovafloxacin) were able to significantly reduce colonies of B. 5. Metronidazole This antibiotic provides concentration-dependent killing and has a long half-life. This agent is not indicated for children. For β-lactams that are highly protein bound (> 90%). In animal models. The other scenario is “time dependent killing” as occurs with beta-lactam agents such as penicllins. perfringens. the time free drug is kept above the MIC should be maximized. Time-kill data suggests that the antimicrobial activity of clindamycin is maximized near the MIC of the organism. Fluoroquinolones The pharmacodynamic measure that best correlates with bactericidal activity of fluoroquinolones is the AUC/MIC ratio.2. exceed the MIC by 2–4 multiples for between 30% and 100% of the dosage interval [51]. This diagram shows the concentration of an antimicrobial given in intermittent bolus dosing (y axis) which reaches a C max or peak level after attaining the volume of distribution in the body and then declines over time (x axis).3. Peptostreptococcus magnus. Fluoroquinolones and aminoglycosides kill by this method. 3. both high-dose levofloxacin (750 mg) and moxifloxacin (400 mg) have exhibited prolonged serum bactericidal activity against anaerobes such as C.

doxycycline. as many laboratories do not perform anaerobic susceptibility testing. or joint. or patient’s health plan. and Clostridium spp. moxifloxacin or ertapenem susceptibility. fragilis group member species. However. since there may be restricted access to specific antibiotics on the hospital’s formulary. The most frequently tested antimicrobial against anaerobes is metronidazole (16%). Empirical selection of an antibiotic should take into account local patterns of susceptibility and resistance. and the empirical antibiotics that have been selected should be adjusted to cover the specific pathogens isolated once this information is clinically available. and even by hospital [22. b. .J. such as blood. This is commercially available. swabs are subject to sampling error) from an acceptable specimen source (specimens contaminated by normal flora. are not acceptable) and stored in a non-nutritive transport media. or oral flora contaminated wounds such as human or animal bites. foul odor to a discharge or wound. which include infection in proximity of a mucous membrane surface where anaerobes are predominant normal flora.61]. it is unwise to continue it and another agent or class of agents should be used. imipenem (8%). sterile site and wound cultures [64]. Prevotella spp. and prior to instituting antibiotic therapy. A recent survey showed that 76% of hospital labs now perform some anaerobic bacteriology. cefoxitin (9%).3]. Selecting an appropriate empirical therapy To select an empirical therapy. Once it is clear that anaerobes are involved. this is equally true for anaerobic infections [2. infections associated with necrotic tissue. 3) isolates were recovered from the blood. Just as in aerobic bacteriology obtaining specific samples for culture is the basis to guide therapy. Knowledge of the usual flora at the location of infection is an indispensable guide in selecting and instituting empirical antimicrobial therapy [8]. and chloramphenicol (5%) [55]. Microbroth dilution method (reserved only for the B. When susceptibility testing was done. Etest (A–B Biodisk. Consequently. The limitations of susceptibility testing Limitations of susceptibility testing occur because clinical laboratories vary in their capabilities and interest in the isolation and identification of anaerobes and in their performance of anaerobic susceptibility testing [62–67]. They also suggest that hospitals should periodically perform surveys for inclusion in the hospital antibiogram for the B. 4) when therapy has failed and 5) when organisms with unpredictable susceptibility patterns are suspected. fragilis group). Solna. cultures should be collected (pus and aspirates of pus are best. which are available to the clinician. Patterns of resistance will vary by country and by city. the Food and Drug Administration indications. piperacillin/tazobactam (7%).E. No hospital lab tested for tigecycline. agents with less frequent testing included penicillin/ ampicillin (15%). brain.3]. including tumors and Gram stain with many organisms. Stein / Antimicrobials in anaerobic infections 61 6.. one must assume that clinicians must be using information from the manufacturer. the selection of the antimicrobials tested was dependent on the agents from commercial panels that were available to laboratories. wrong guesses may lead to adverse outcomes A variety of susceptibility testing methods is available: a. These samples should be analyzed. There are various clinical clues to the involvement of anaerobes in a clinical infection [60]. 7. 2) for long-term therapy. such as sputum.C. Sweden) [67]. It is of paramount importance that doctors know what antibiotics a patient has recently taken. only 21% of hospital labs perform anaerobic susceptibility testing in house [64].. clindamycin (15%). clinicians must often rely on published studies. If an agent has failed to treat a specific infection prior to the visit. These rates have declined from 70% in 1990 [62] and 33% in 1993 [63]. For anaerobic bacteria. published study/survey data or just guessing at appropriate empirical as well as directed therapy. Goldstein and G. crepitus or gas in tissues. Since specific data is limited. knowing the susceptibility of the isolate to available agents will help clinicians in their selection of empirical therapy [2. Fusobacterium spp. which do not grow on routine aerobic cultures. Recommendations by Clinical and Laboratory Standards Institute [65] and the American Society for Microbiology [66] suggest that hospitals should test individual patient isolates when: 1) it is critical for disease management. a plastic strip with an interpretative MIC scale on one side and predetermined antimicrobial concentration gradient on the other side and which is suitable for performing tests on individual isolates.E. doctors must select the agent/s that is/are active against the most likely pathogens to be encountered at a site of infection. bone. The antimicrobial agents that are tested against clinical isolates should be those.

4% to piperacillin tazobactam.9%) and tigecycline (96. By contrast.C. The survey reported that B. Bacteroides uniformis.62 E. but can be useful if penicillin therapy is being considered. fragilis isolates. 1.3%). 5% to both cefoxitin. metronidazole and chloramphenicol (MIC < 16 ug/mL) were active against all isolates. the year of isolation.4%). Goldstein et al.5% susceptible at 2 ug/mL. cefoxitin (70.6%. but local patterns of E. distasonis isolates were generally less susceptible to ampicillin-sulbactam (83.6%). Agents with good. It is important to note the susceptibility results may be different and vary greatly depending on the clinical source of the isolates (that is. Again.7%. fragilis accounted for 52% of isolates.3% to 35.66]. Agar dilution method.7%. Chloramphenicol is also generally very active. 66.4% and each of the other species (B. piperacillin-tazobactam. Clindamycin resistance was found in ∼20% of B. and tigecycline.33. Broth disk elution and disk diffusion tests should not be performed for anaerobic bacteria. but variable. but so far. B. the severity of the infection and anatomical location will dictate appropriate choices. Bacteroides ovatus for 10. ?” as resistance has occurred to all available agents [69]. Bacteroides distasonis. activity include ampicillin-sulbactam. precluding its empirical use against most species. and approximately 1% were resistant to carbapenems. Only a few reference labs scattered throughout the world do these surveys. Ampicillin-sulbactam and amoxicillin clavulanate are also very active against anaerobes.225 B. Beta-lactamase testing provides very limited data. therapy is maintained and evaluated by clinical response. Publication of its pivotal studies and further surveillance data will indicate whether tigecycline can be used. clindamycin.7% to ampicillinsulbactam. as their susceptibility results do not correlate with the agar dilution reference method [65. 83. Susceptibility to other agents varied as follows: cefoxitin. thetaiotaomicron for 18. [32] examined 5. intra-abdominal. Stein / Antimicrobials in anaerobic infections c.2%. B. These disparities between survey by Snydman [32] and by Goldstein [4] demonstrate that caution must be observed in interpreting any one survey’s results. especially empirically. fragilis ATCC 25285 and B.41. and differences in geographic patterns [22. technical and methodological factors. There is no single agent that can be assigned as an answer to the question of “what is the best therapy for . thetaiotaomicron ATCC 29741 and Eubacterium lentum ATCC 43055 limited to use with the agar dilution or ETest methods [65. Quality control strains that should be used for anaerobic bacteria are B. 0. [4] reported a different susceptibility to moxifloxacin: 85. skin and soft tissues. fragilis group isolates (clinical sources not reported) from 10 geographically representative medical centers from 1997 to 2004. Susceptibility surveys Since most clinicians do not have access to specific isolate susceptibility data for their patients. As many labs do not perform anaerobic susceptibility testing (and when performed these results are often delayed). How to select an anti-anaerobic agent The selection of an anti-anaerobic agent for both empirical and specific therapy is complicated by the frequent lack of local data to predicate empirical selection. .68]. B. Clindamycin resistance (MIC > 8 ug/mL) was frequent (19. it appears to be an active agent [59].E.8%).66]. B. Snydman et al. In part. Goldstein and G. published surveys may act as an imperfect guide for empirical antimicrobial selection. and moxifloxacin was found in 27% of isolates.J. thetaiotaomicron isolates were very susceptible to carbapenems and piperacillin-tazobactam (99. Only one metronidazole-resistant isolate from 2002 was found. local and specific data can be very useful. Overall. coli resistance often limit their use. e. . d. A paucity of recent data exists about pediatric intra-abdominal isolates and their susceptibilities. which is reference method but is cumbersome and expensive and therefore done only by research centers.1%) and clindamycin (70. [32] reported that carbapenems. blood and so on). [4] of 923 intra-abdominal isolates found 13% resistance to moxifloxacin (with MICs of 2 ug/mL). a study by Goldstein et al. 9. A recent US survey by Snydman et al. Bacteroides vulgatus and other species) for 3–6% [32]. piperacillin-tazobactam and metronidazole (in combination). isolate distribution. ampicillin-sulbactam (97.2%). fragilis was generally the most susceptible to antimicrobials. and moxifloxacin 73. 8. but potential side effects limit its use. Reliable broad-spectrum activity for almost all isolates can be achieved individually with the carbapenems. Clindamycin is active against most respiratory isolates (aspiration pneumonia) and is used . cefoxitin and moxifloxacin [53] and their use is situation dependent.

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