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Maryam Nadeem et al, International Journal of Pharmaceutical Sciences, Vol.

2 (2), 2010, 67-75

A Review Article

Drug Therapy in Osteomyelitis


Maryam Nadeema, Sundas Nadeem a, Khawaja Tahir Mahmoodb
a

Department of Pharmacy, Lahore College For Women University; b Drug Testing Lab, Lahore

Abstract

Osteomyelitis (OM) is a progressive infection of the bone marrow and cortex resulting in inflammatory destruction of the bone .Osteomyelitis is a disease with ongoing changes in predisposing factors & causative micro-organisms. The incidence of bone infections is related to joint replacements, complex surgical interventions and wound infections. The advancing age, increase in the incidence of diabetes and peripheral vascular disease are predisposing and complicating factors of OM. Disease prevalence is higher in men than women, and it is more often seen in children and people over 50. Antibiotic therapy has virtually eliminated mortality but OM is still a serious infection with potentially severe consequences.Dramatic changes in therapy include new antibiotics, new surgical techniques and parenteral antimicrobial therapy. Treatment varies according to the severity of the infection and the health status of the patient. Inadequate treatment can lead to the development of chronic low-grade infection. Overall both patient education and medication have a clinically important influence on patients quality of life. The Prevalence, clinical and diagnosis and management are being discussed in this review.
Key Words: Osteomyelitis(OM), Staphylococcus aureus, Antibiotics, Patient Compliance. INTRODUCTION Since antiquity osteomyelitis is a difficult to treat infection characterized by progressive inflammatory destruction and new apposition of bone. This review focuses on the current knowledge of the disease including its pathogenesis, diagnosis and treatment options available. The words Osteomyelitis is derived from two words osteon (bone) and myelo (marrow) which are combined with itis (inflammation) to define the clinical state in which bone is infected with micro organisms. Osteomyelitis is an infection of the medullary or cortical bone[1]. The condition can affect any bone in the body, and is not limited by gender or age. Children who suffer from osteomyelitis are often affected in the femur, or upper leg bone, or the lower leg bone (the tibia) as well as the bones found in the arm. Adults who suffer from osteomyelitis most often suffer the bone infection in the pelvis or the spine. Pathogenesis :Normally bone is highly resistant to the infection which can occur due to trauma or presence of large number of foreign bodies. The degree of contamination, presence of foreign bodies(i.e; internal fixation) and host factors such as immunological conditions and health status determine the development of ostemyelitis [2,3]. The most frequently observed etiological agents are: Staphylococcus aureus, Gram negative and group B Streptococcus spp. In the majority of cases the metaphyses of the long bone are the most commonly implicated sites, although infection may spread to the contiguous epiphysis and joint in neonates [4]. Certain major causes of infection, such as Staphylococcus aureus, adhere to bone by expressing receptors (adhesins) for components of bone matrix (fibronectin, laminin, collagen, and bone sialoglycoprotein) [5] ; the expression of the collagen-binding adhesion permits the attachment of the pathogen to cartilage [6]. The

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Maryam Nadeem et al, International Journal of Pharmaceutical Sciences, Vol.2 (2), 2010, 67-75

role of the fibronectin-binding adhesions of S. aureus in the attachment of bacteria to devices surgically implanted in bone has been very important. S. aureus that has been internalized by cultured osteoblasts can survive intracellularly [7].The intracellular survival of bacteria (sometimes in a metabolically altered state, in which they appear as so-called smallcolony variants) may explain the persistence of bone infections [8]. Once the microorganisms adhere to bone, they express phenotypic resistance to antimicrobial treatment, which may also explain the high failure rate of short courses of therapy [9]. Normal bone remodeling requires the coordinated interplay of osteoblasts and osteoclasts [10]. Cytokines (such as interleukin-1, interleukin-6, interleukin-11, and tumor necrosis factor) generated locally by inflammatory and bone cells are potent osteolytic factors. The role of bone growth factors in normal bone remodeling and their therapeutic usefulness are still unclear. During infection, phagocytes attempt to contain invading microorganisms and, in the process, generate toxic oxygen radicals and release proteolytic enzymes that lyse surrounding tissues.Several bacterial components act directly or indirectly as bone-modulating factors [11]. The presence of arachidonic acid metabolites, such as prostaglandin, which is a strong osteoclast agonist generated in response to fracture, decreases the amount of the bacterial inoculum needed to produce infection. Pus spreads into vascular channels, raising the intraosseous pressure and impairing blood flow. The ischemic necrosis of bone results in the separation of devascularized fragments, which are called sequestra. Microorganisms, infiltrations of neutrophils, and congested or thrombosed blood vessels are therefore the principal histologic findings in acute osteomyelitis. One of the distinguishing features of chronic osteomyelitis is necrotic bone, which can be recognized by the absence of living osteocytes. Classification :Bone infections are currently classified by the Waldvogel or the Cierny-Mader classification.Waldvogel classification is an

etiologic system and the Cierny-Mader classification is descriptive, both classifications can be simultaneously used [3,12]. The Waldvogel classification system for Osteomyelitis is shown in Table-1[13].
Table 1

The more recent Cierny-Mader staging system is based on the status of the disease process, not etiology, chronicity or other factors. The terms acute and chronic are not used in the Cierny-Mader system. The stages in this system are dynamic and may be altered by changes in the medical condition of the patient (host), successful antibiotic therapy and other treatments . Table-2 shows the Cierny Mader Staging System [14]. This system is most commonly used in clinical practice for diagnosis and management of osteomyelitis.
Table- 2 (Cierny Mader Staging System)

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Risk Factors:In the majority of cases the metaphyses of the long bone are the most commonly implicated sites, although infection may spread to the contiguous epiphysis and joint in neonates patients with sickle cell disease and those with nail puncture wounds [15,16,17]. The lower extremities are most commonly affected [16]. Haematogenous spread is considered to be the most important route. The incidence is increasing in older patients. The source of infection in the elderly has been related to the use of intravenous access devices and the asymptomatic urinary infections. In young patients the increase has been correlated with the growing number of intravenous drug abusers and with immigrants from areas where tuberculosis is still endemic [18]. Open fractures of the tibia and ankle are common in motor vehicle accidents and are particularly prone to the development of osteomyelitis. Wound contamination and damage to the soft tissue envelope because of the relatively superficial position of these bones places them at particular risk. The dangers of internal fixation in the face of a traumatized soft tissue envelope is becoming known to surgeons especially about the distal tibia and calcaneus [19,20,21,22]. In patients with diabetes or vascular insufficiency, osteomyelitis is found almost exclusively in the feet [23]. DIAGNOSIS OF OSTEOMYELITIS Clinical Features Of Osteomyelitis :The term acute osteomyelitis is used clinically to signify a newly recognized bone infection; the relapse of a previously treated or untreated infection is considered a sign of chronic disease. Clinical signs persisting for more than 10 days correlate roughly with the development of necrotic bone and chronic osteomyelitis [24]. Children and adults with hematogenous osteomyelitis may present with acute signs of infection including pain of limb involved, fever, irritability, lethargy, and local signs of inflammation [11,12]. Patients with contiguous focus osteomyelitis often present with localized bone and joint pain, erythema, swelling, and drainage around the area of trauma, surgery, or

wound infection. Signs of bacteremia such as fever, chills, and night sweats may be present in the acute phase of osteomyelitis but are not seen in the chronic phase. Both hematogenous and contiguous focus osteomyelitis can progress to a chronic condition. Local bone loss, sequestrum formation, and bone sclerosis are common. Persistent drainage and/or sinus tracts are often found adjacent to the area of infection. Microbiology :The specific microorganism(s) isolated from patients with bacterial osteomyelitis is often associated with the age of the patient or the clinical scenario (Table-3) [25]. Staphylococcus aureus is implicated in most cases of acute hematogenous osteomyelitis and is responsible for up to 90 percent of cases in otherwise healthy children [26] . Staphylococcus epidermidis, S. aureus, Pseudomonas aeruginosa, Serratia marcescens and Escherichia coli are commonly isolated in patients with chronic osteomyelitis.
Table-3

The identification of the causative microorganisms is essential for diagnosis and

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treatment. Surgical sampling or a needle biopsy of infected tissue provides this indispensable information. Evidence from swabs of ulcers or fistulae, however, is often misleading [27]. Laboratory Findings :The leukocyte count may be elevated in cases of acute osteomyelitis, but it is often normal in chronic cases. The erythrocyte sedimentation rate is usually elevated in both acute and chronic osteomyelitis, and it decreases after successful treatment. The erythrocyte sedimentation rate usually rises immediately after operative dbridement. An erythrocyte sedimentation rate that returns to normal during the course of therapy is a favorable prognostic sign [28,29,30,31,32] The C-reactive protein level is another inflammatory index that rises in acute and chronic osteomyelitis and decreases faster than the erythrocyte sedimentation rate in successfully treated patients. In a study of children with acute osteomyelitis, the Creactive protein level was found to decrease markedly after three days of antibiotic treatment in the patients with favorable outcomes, whereas higher values were observed in those with complications [30]. Radiological Diagnosis :In osteomyelitis of the extremities, plainfilm radiography and bone scintigraphy remain the primary investigative tools [33,34] Radiographic evidence of bone destruction by osteomyelitis may not appear until approximately two weeks after the onset of infection. The radiographs may reveal osteolysis, periosteal reaction and sequestra (segments of necrotic bone separated from living bone by granulation tissue) [35]. A bone abscess found during the subacute or chronic stage of hematogenous osteomyelitis is known as a Brodies abscess. For nuclear imaging, technetium Tc-99m methylene diphosphonate is the radiopharmaceutical agent of choice [36]. . MANAGEMENT The successful outcome depends on early diagnosis and prompt, adequate therapy. The principles of treatment are symptomatic

measures, bedrest and operative intervention, if necessary, with drainage of pus and debridement of any necrotic material, together with antibiotic treatment in sufficient concentration and for sufficient duration. The goal of treatment is to prevent complications such as concomitant septic arthritis with its high risk of persistent joint damage, growth disturbance or chronic osteomyelitis [37].The clinical management of osteomyelitis requires accurate microbiological diagnosis that will identify appropriate antibacterials to which the pathogenic organisms are sensitive. Therapy will largely depend on the type of bacteria, the route by which the bacteria reach the bone, the presence of any orthopedic devices and the patient's ability to mount an immune response. Consequently, therapy often requires a combination of medical and surgical management [38]. If the patient is a compromised host, an effort is made to correct or reduce the host defect or defects. In particular, attention should be paid to good nutrition, to a smoking cessation program, and to control of specific diseases such as diabetes. Antibiotic therapy In most patients with osteomyelitis, early antibiotic therapy produces the best results [39]. Decisions about antibiotics should be made after assessments of pertinent clinical information, laboratory and microbiology information, ease of administration, patient compliance, potential adverse effects, cost, local resistance patterns and available evidence supporting various treatment options [40]. The traditional duration of treatment in most stages of osteomyelitis (Cierny-Mader Stages 1, 3, and 4) is four to six weeks. The rationale for this duration is based on the results of animal studies [41] and the observation that revascularization of bone after debridement takes about four weeks. Longer courses of intravenous or oral antibiotics (six months or more) have been attempted by some authors [42,43,44], but the outcomes of those trials do not suggest any improvement in comparison with those following six weeks of therapy. Failures occur in all clinical trials, whatever the duration of treatment, mostly as a

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result of emergence of resistant strains or inadequate surgical dbridement. Antibiotic classes used in the treatment of osteomyelitis include penicillins, betalactamase inhibitors, cephalosporins, other beta-lactams (aztreonam and imipenem), vancomycin, clindamycin, rifampin, aminoglycosides, fluoroquinolones, trimethoprim-sulfamethoxazole, metronidazole, and new investigational agents including teicoplanin, quinupristin/dalfopristin, and oxazolidinones [45]. The decision to use oral rather than parenteral antibiotics should be based on results regarding microorganism sensitivity, patient compliance, infectious disease consultation, and the surgeons experience. A combination of parenteral and oral antibiotics has been used in some situations [46]. Acute hematogenous osteomyelitis is best managed with careful evaluation of microbial etiology and susceptibilities and a four- to six week course of appropriate antibiotic therapy. Surgical debridement is not necessary when the diagnosis of hematogenous osteomyelitis is made early. Current treatment recommendations rarely require surgical debridement. However, if antibiotic therapy fails, debridement (or repeated debridement) and another four- to six-week course of parenteral antibiotic therapy is essential [47-49] After cultures have been obtained, an empiric parenteral antibiotic regimen (nafcillin plus either cefotaxime or ceftriaxone) is initiated to cover clinically suspected organisms. When the culture results are known, the antibiotic regimen is revised. Children with acute osteomyelitis should receive two weeks of initial parenteral antibiotic therapy before they are given an oral agent [49, 50]. Chronic osteomyelitis in adults is generally treated with antibiotics and surgical debridement. Depending on the type of chronic osteomyelitis, patients may be treated with parenteral antibiotics for two to six weeks. However, without adequate debridement, chronic osteomyelitis does not respond to most antibiotic regimens, no matter what the duration of therapy is [49,50]. Several

antibiotic regimens have been proposed for chronic osteomyelitis treatment. The first antibiotics, which showed a really good therapeutic efficacy, were beta-lactams, (mainly the newer cephalosporins), used alone or in combination with other drugs [51,52]. Third generation cephalosporins are effective, but they are mainly indicated for an ambulatory treatment of Staphylococcus aureus osteomyelitis [51, 24, 52]. More recently great interest has been shown in the use of fluoroquinolones, because they can be taken by the oral route, are well tolerated for longregimen treatments, have a good bone distribution and a rapid efficacy on many gram positive and negative bacteria [53, 54, 56]. The efficacy of these treatments ranged from 65% [57] to 95% [58]. Oral quinolones are commonly used in the treatment of osteomyelitis [55, 56-65]. Moreover it was [63] claimed that they are safe and effective if they are given for a prolonged course of treatment for infections caused by susceptible grampositive as well as gram-negative organisms and in combination with adequate surgical debridement. Some also [55] reported a 90% clinical success with ciprofloxacin and ofloxacin in osteomyelitis caused by enterobacteria. Quinolones have several advantages over other traditional compounds in the therapy for osteomyelitis because: a) after an initial course of intravenous therapy they can be administered orally with excellent bioavailability; b) they are relatively non-toxic; c) they penetrate bone at sufficient concentrations to inhibit most members of the Enterobacteriaceae family , as well as a large percentage of Pseudomonas spp. and Staphylococcus strains [53].A group of fourteen patients, who had chronic osteomyelitis and were treated with oral ciprofloxacin, was compared with a group of twelve patients of similar age who had chronic osteomyelitis and received standard parenteral antibiotic therapy consisting of nafcillin, clindamycin, and gentamicin, singly or in combination. The osteomyelitis was arrested at the end of therapy and on follow-up examination of eleven patients in the first group

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and ten in the second group. The average duration of antibiotic therapy (thirty-eight days) and follow-up (approximately thirty months) were about the same for both groups. Oral administration of ciprofloxacin was as effective and safe as parenteral therapy for the treatment of osteomyelitis in these adults [65]. Thus Fluoroquinolones are as effective as betalactams for the treatment of osteomyelitis and can be considered as a useful alternative in the physician's armamentarium [67].Osteomyelitis is becoming more difficult to cure with the increasing prevalence of methicillin- resistant organisms. A patient with recurrent methicillinresistant Staphylococcus aureus (MRSA) osteomyelitis and bacteremia successfully treated with combination antibiotic therapy. Vancomycin, gentamicin, and rifampin were administered for 8 weeks. Combination antibiotic therapy with vancomycin, rifampin, and low-dose gentamicin (1 mg/kg q12h) may be useful for deep-seated tissue infection caused by MRSA [68]. Antibiotic Treatment by Stage: Stage-1 osteomyelitis in children can usually be treated with antibiotics alone[69,70] because the bones of children are very vascular and have an effective response to infection. Stage-1 osteomyelitis in adults is more refractory to therapy and is usually treated with antibiotics and operative intervention. The patient is treated with appropriate parenteral antimicrobial therapy for four weeks, if the initial medical management fails and the patient is clinically compromised by a recurrent infection, bone and/ or soft-tissue dbridement is necessary in conjunction with another fourweek course of antibiotics. In Stage-2 osteomyelitis, shorter courses of antibiotics are usually needed. In a study in which a two week course of antibiotics was given following dbridement of the cortex and soft-tissue coverage, the osteomyelitis was arrested in close to 100% of A hosts and 79% of B hosts [71]. We treat patients with Stage-3 or 4 osteomyelitis with antimicrobial therapy for four to six weeks. Without adequate dbridement, the failure rate is high regardless of the duration of therapy. Even when all

necrotic tissue has been adequately dbrided, the remaining bed of tissue must be considered contaminated with the responsible pathogen or pathogens. Therefore, it is important to treat the patient with antibiotics for at least four weeks [13]. The arrest rate is about 98% in A hosts and 80% (for Stage 4) to 92% (for Stage 3) in B hosts[71]. Operative Treatment Operative management of osteomyelitis can be very challenging. The principles of treating any infection are equally applicable to the treatment of infection in bone. These principles include adequate drainage, extensive dbridement of all necrotic tissue, obliteration of dead spaces, adequate soft-tissue coverage, and restoration of an effective blood supply [71, 72].Operative treatment of a compromised host is even more challenging. The functional impairment caused by the disease, reconstructive operations, and metabolic consequences of aggressive therapy influence the selection of patients for treatment. Follow-up Assessment during Therapy Clinical assessment at 4 weeks is useful for assessing the response to treatment. Lack of improvement in symptoms or a persistently elevated C-reactive protein level (above 30 mg per liter) is a predictor of treatment failure [73]. Early antibiotic therapy, before extensive destruction of bone, produces the best results in patients with osteomyelitis. During treatment, patients should be followed closely for signs and symptoms of worsening infection. After the completion of treatment, follow-up should be based on the response to therapy and the overall health of the patient. CONCLUSION Osteomyelitis (OM) remains challenging and expensive to treat, despite advances in antibiotics and new operative techniques. Drugs are the only part of the overall treatment for patients with OM and all patients require a holistic approach to OM assessment and management. To conclude, an appropriate treatment of osteomyelitis involves adequate antimicrobial therapy and operative dbridement of all necrotic bone and soft

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tissues. Antimicrobial treatment often involves a combination of antibiotics and the decision to use oral or parenteral antibiotics should be based on results regarding microorganism sensitivity, patient compliance, infectious disease consultation, and the surgeons experience. The safety of prolonged use of the various antimicrobial agents , the cost and feasibility of the therapeutic regimen should be the parameters for a rational choice of the antibiotics. During treatment, patients should be followed closely for signs and symptoms of worsening infection. After the completion of treatment, follow-up should be based on the response to therapy and the overall health of the patient. Collaboration between patient, physician and pharmacist is essential in the treatment of this disease. Pharmacists are in ideal situation to improve compliance by educating patient and clinician and by establishing a supportive relationship with patient. RECOMMENDATIONS Following are recommendations to Osteomyelitis patients; Take drugs regularly because inadequate treatment can lead to the development of chronic low-grade infection. Eat healthy diet. Avoid Cigarette smoking. Avoid actions that strain fractures. Maintain hygienic conditions to avoid further spread of infection. Avoid self medication of intravenous drugs. Regular counseling with pharmacist. Maintain record of all medicines and allergy history. Take food supplements to improve your immune system. ACKNOWLEDGEMENT : My gratitude to respected Vice Chancellor, Prof. Dr. Bushra Mateen (L.C.W.U) for her support and giving this opportunity as well as to my Head of Pharmacy Department, Dr. Hafeez Ikram. Special thanks to my honorable teachers Dr. Khawaja Tahir Mahmood and Dr. Fatima Amin for their guidance.

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