WOUND HEALING

Treating Osteomyelitis: Antibiotics and Surgery

Nalini Rao, M.D. Bruce H. Ziran, M.D. Benjamin A. Lipsky, M.D.
Pittsburgh, Pa.; Atlanta, Ga.; and Seattle, Wash.

Background: Osteomyelitis is an inflammatory disorder of bone caused by infection leading to necrosis and destruction. It can affect all ages and involve any bone. Osteomyelitis may become chronic and cause persistent morbidity. Despite new imaging techniques, diagnosis can be difficult and often delayed. Because infection can recur years after apparent cure, remission is a more appropriate term. Methods: The study is a nonsystematic review of literature. Results: Osteomyelitis usually requires some antibiotic treatment, usually administered systemically but sometimes supplemented by antibiotic-containing beads or cement. Acute hematogenous osteomyelitis can be treated with antibiotics alone. Chronic osteomyelitis, often accompanied by necrotic bone, usually requires surgical therapy. Unfortunately, evidence for optimal treatment regimens or therapy durations largely based upon expert opinion, case series, and animal models. Antimicrobial therapy is now complicated by the increasing prevalence of antibioticresistant organisms, especially methicillin-resistant Staphylococcus aureus. Without surgical resection of infected bone, antibiotic treatment must be prolonged ( 4 to 6 weeks). Advances in surgical technique have increased the potential for bone (and often limb) salvage and infection remission. Conclusions: Osteomyelitis is best managed by a multidisciplinary team. It requires accurate diagnosis and optimization of host defenses, appropriate anti-infective therapy, and often bone debridement and reconstructive surgery. The antibiotic regimen must target the likely (or optimally proven) causative pathogen, with few adverse effects and reasonable costs. The authors offer practical guidance to the medical and surgical aspects of treating osteomyelitis. (Plast. Reconstr. Surg. 127 (Suppl.): 177S, 2011.)

uccessful management of osteomyelitis requires knowing how to diagnose bone infection, the pathogenesis of the disease, the usual and unusual etiological agents, the principles of anti-infective therapy, and when and how to undertake surgical debridement and recon structive procedures. Sometimes adjunctive treatments, such as revascularization or hyperbaric oxygen therapy, are useful. A multidisciplinary team, which may include an infectious disease specialist and various surgeons (e.g., orthopedic, plastic, vascular), usually ensures optimal treatment. Nonsurgical treatment starts with improving host deficiencies (e.g., correcting anemia, hypoxemia, hyperglycemia, or other metabolic derangements). Clinicians must then select an appropriate initial antibiotic regimen, which should then be reFrom the University of Pittsburgh School of Medicine, Atlanta Medical Center, and Veterans Affairs Puget Sound Health Care System, University of Washington. Received for publication May 28, 2010; accepted September 7, 2010. Copyright 2010 by the American Society of Plastic Surgeons DOI: 10.1097/PRS.0b013e3182001f0f

viewed and modified (if needed) based on the clinical response and culture and susceptibility data. Appropriate antibiotic therapy is crucial for a favorable outcome. Treatment should usually be systemic, often parenteral, at least initially, and usually prolonged. It may be delivered by outpatient parenteral therapy, or with highly bioavailable oral agents (that attain therapeutic serum and tissue concentrations). Some patients can be treated with locally delivered antibiotics mixed in polymethylmethacrylate or calcium sulfate beads or biodegradable cement,1,2 sometimes alone but usually combined with systemic therapy.

CAUSATIVE ORGANISMS
Identifying the causative organism(s) aids in making a definitive diagnosis and selecting an

Disclosure: Dr. Lipsky has been a consultant to and received research funding from Pfizer, Ortho-McNeil/ Johnson & Johnson, Cubist, and Merck. The other authors have no financial interest to disclose.

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appropriate antibiotic regimen (Table 1).3 Specimens for culture should optimally be obtained from bone (the criterion standard for diagnosing infection) or from blood (in acute hematogenous osteomyelitis). Sinus tract cultures are generally unreliable and specimens from overlying softtissue infection, or even deep soft-tissue aspiration, do not correlate well with bone cultures.4 The most commonly isolated pathogen is Staphylococcus aureus. This likely relates to its various virulence factors, including glycocalyx secretion and biofilm production (see below). Hematogenous osteomyelitis is usually caused by a single pathogen, while polymicrobial infection is common in contiguous focus osteomyelitis. Gram-negative rods may cause vertebral osteomyelitis in injection drug users and in patients with urinary tract infection. Other unusual pathogens occur in specific clinical settings (Table 1).3 The clinical pattern may be acute (days to weeks), or chronic (i.e., evolving over months or years) and be characterized by low-grade inflammation. Osteomyelitis is characterized grossly by purulent secretions, necrotic bone, compromised soft tissue, or fistulas. Histological examination reveals necrosis and inflammatory cells, including polymorphonuclear leukocytes (in acute infections) and plasma cells and monocytes (in chronic infections); it may be helpful in patients with negative bone culture caused by previous antibiotic therapy.4,5

ROLE OF BIOFILM
Biofilm is a highly structured heterogeneous community of sessile bacteria surrounded by an extracellular polymer matrix. Such bacteria adopt a distinct phenotype, communicate through cell to cell signals, and adhere to inert or living surfaces (Fig. 1).6,7 Species that form biofilm include S. aureus, Staphylococcus epidermidis, group A streptococci, and Pseudomonas aeruginosa. Biofilm bacterial characteristics make them difficult to eradicate. This derives from a combination of phenotypic, mechanical, and metabolic mechanisms. Antibiotics face mechanical and osmotic challenges in penetrating biofilm and are less able to damage metabolically inactive bacteria. Although some antibiotics have more activity against biofilm bacteria than others, the most effective treatment is surgical debridement.8 Animal models have shown that the quorum-sensing inhibitor RNA IIIinhibiting peptide can help prevent staphylococcal biofilm formation and infection.9 11

Table 1. Organisms That May Be Isolated in Osteomyelitis

Organism Staphylococcus aureus Coagulase-negative staphylococci Propionibacterium species Enterobacteriaceae species Pseudomonas aeruginosa Streptococcus species Obligate anaerobic bacteria Salmonella species Streptococcus pneumoniae Bartonella henselae Pasteurella multocida Eikenella corrodens Aspergillus species, Mycobacterium aviumintracellulare, or Candida albicans Mycobacterium tuberculosis Brucella species, Coxiella burnetii (cause of chronic Q fever), or fungi found in specific geographic areas Comments Most common isolate in virtually all musculoskeletal infections Often contaminants but can be pathogens, especially in foreign-bodyassociated infections Seen in nosocomial infections or those following antibiotic therapy Associated with bites, fist injuries caused by contact with another persons mouth, diabetic foot lesions, decubitus ulcers In bacteremic infections or sickle cell disease In patients with human immunodeficiency virus infection Infections following human or animal bites In immunocompromised patients Populations in which tuberculosis is prevalent Populations in which these pathogens are endemic

PRINCIPLES OF ANTIMICROBIAL THERAPY

Antibiotic therapy is the mainstay of treating acute osteomyelitis. In contrast with chronic osteomyelitis, the infective nidus harbors sessile matrixprotected pathogens that are impermeable to antibiotics, requiring radical debridement; anti biotics play an adjunctive role. Other issues to consider when selecting an antibiotic regimen include distribution of the drug(s), especially penetration into the osseous tissue; effectiveness against the likely pathogens; frequency of dosing; drug toxicity; and treatment cost. The need for long-term treatment makes proper selection and monitoring of antibiotic therapy crucial. To treat osteomyelitis, an antibiotic must reliably penetrate bone. The available evidence indicates that for most antibiotics serum concentration predicts bone concentration, and they usually achieve a concentration that exceeds the minimum inhibitory concentration of the targeted organisms. Table 2 shows reported serum-to-bone

Adapted from Lew DP, Waldvogel FA. Osteomyelitis. Lancet 2004; 364:369 379.

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Fig. 1. (Above) Schematic diagram showing the five stages of development of biofilm. (1) Initial attachment of cells to a surface. (2) Production of extracellular polysaccharide resulting in firmly adherent and irreversible attachment. (3) Early development of biofilm architecture. (4) Maturation of biofilm architecture. (5) Dispersion of single (planktonic) cells from the biofilm. (Below) The same processes as represented by photomicrographs of Pseudomonas aeruginosa grown under continuous flow conditions on a glass substratum. Adapted with permission from Stoodley P, Sauer K, Davies DG, Costerton JW. Biofilms as complex differentiated communities. Annu Rev Microbiol. 2002;56:187209.

concentration associated with antibiotics commonly used for osteomyelitis.12,13 Base dosing regimens on pharmacodynamic principles to optimize drug delivery to the target site.14 The killing activity of an antibiotic is generally classified as either time-dependent (i.e., most effective when the concentration remains above the organisms minimum inhibitory concentration for most of the dosing interval) or concentration-dependent (i.e., effectiveness is directly proportionate to concentration above the organisms minimum inhibitory concentration, within safety limits).14 Beta-lactam agents (e.g., penicillins and cephalosporins) are among the most commonly used antibiotics for osteomyelitis. They demonstrate time-dependent killing, maximal when the serum concentration is four times the minimum inhibitory concentration.15 These agents do not exhibit a postantibiotic effect; that is, continued antibacterial activity after antibiotic concentrations are subtherapeutic. In contrast, fluoroquinolones and aminoglycosides demonstrate concentration-dependent activity and a postantibiotic effect.16 Dosing of concentration-dependent drugs is usually limited by their toxicity (e.g., nephrotoxicity or

ototoxicity related to aminoglycosides). Therefore, systemic aminoglycosides are usually recommended for prolonged therapy only when equally efficacious and less toxic alternative agents are unavailable. Aminoglycosides can safely achieve high levels at the site of infection when implanted locally (e.g., in antibiotic-impregnated polymethylmethacrylate cement).17 Glycopeptides, such as vancomycin, are sometimes described as time-dependent antibiotics. For osteomyelitis due to methicillin-resistant S. aureus, vancomycin is the mainstay of the treatment. Minimum inhibitory concentrations to vancomycin among S. aureus strains have risen over the past decade, but aiming for slightly higher trough levels usually overcomes this problem. Resistance of staphylococci to vancomycin remains very rare, with fewer than 15 cases reported globally. In light of suboptimal responses to vancomycin therapy in staphylococcal infections, newer agents, such as linezolid and daptomycin, have been investigated and found effective in treating staphyloccal osteomyelitis.18 One randomized study found that high-dose continuous-infusion vancomycin, compared with the usual intermittent dosing, pro-

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Table 2. Penetration of Antibiotics into Bone*
Range of Time after Last Dose (hr) 2 0.56 0.254 0.254 1 1 1 1.623.8 0.28 0.9 12 2 0.252 0.56.5 days 12 214 3.54.5 424 0.72 0.513 24.5 0.76 17 0.51.5 0.9 2 Range of Mean Bone: Serum Concentration Ratios 0.170.31 0.010.09 0.110.71 0.110.71 0.180.23 0.220.26 0.11 0.130.19 0.070.17 0.17 0.460.76 0.54 0.180.28 2.56.3 0.210.45 0.080.56 0.57 0.351.95 0.361.0 0.271.2 0.42 0.050.67 0.27 0.40.51 0.23 1.08

Antibiotic Agent Amoxicillin Clavulanic acid Ampicillin Sulbactam Piperacillin Tazobactam Oxacillin Ertapenem Ceftriaxone Cefazolin Cefepime Ceftazidime Erythromycin Azithromycin Clindamycin Rifampicin Rifampicin (osteomyelitis) Tigecycline Levofloxacin Ciprofloxacin Ciprofloxacin (osteomyelitis) Vancomycin Vancomycin (osteomyelitis) Linezolid Linezolid (osteomyelitis) Daptomycin

nopathy) and perhaps a higher association with developing Clostridium difficile infection. Rifampin has a unique role in the treatment of S. aureus osteomyelitisit appears to kill inactive sessile bacteria within biofilm, making it useful for bone and joint infections with retained hardware. It is highly bioavailable and associated with few adverse effects. To avoid emergence of rifampin resistance, it should be only used in combination with another antibiotic agent that is active against S. aureus, such as vancomycin, trimethoprim-sulfamethoxazole, or fluroquinolones. Good outcomes have been reported in staphylococcal osteomyelitis (including with methicillin-resistant S. aureus species) with rifampin-containing regimens.22

INITIAL ANTIBIOTIC REGIMENS IN PATIENTS WITH OSTEOMYELITIS

Table 33 outlines suggested initial antibiotic agents and doses based on the causative organism. Antimicrobial therapy for osteomyelitis must often be relatively prolonged and can usually be managed in the outpatient setting. Some patients require parenteral therapy, either because of the agent used (e.g., vancomycin) or gastrointestinal absorption problems, but little evidence supports that this is superior to oral treatment. Outpatient parenteral antibiotic therapy is a convenient and cost-effective way to provide treatment for patients who meet selection criteria as outlined by the Infectious Disease Society of America practice guidelines (Table 4).23,24 Many patients can be treated with any of several bio-available oral antibiotics to which the causative pathogens are susceptible (Table 5).23 When prolonged treatment is required, it is especially important to consider potential antibiotic toxicities and drug interactions when selecting a regimen (Table 6).25 It is very difficult to compare the outcomes of treatment of osteomyelitis with various antibiotic regimens. There are few comparative trials, they involve different types of infections, and they may or may not include concomitant surgical therapy.26

*Adapted and modified from Landersdorfer CB, Bulitta JB, Kinzig M, Holzgrabe U, Sorgel F. Penetration of antibacterials into bone: Phar macokinetic, pharmacodynamic and bioanalytical considerations. Clin Pharmacokinet. 2009;48:89 124; and Traunmuller F, Schintler MV, Metzler J, et al. Soft tissue and bone penetration abilities of daptomycin in diabetic patients with bacterial foot infections. J Antimicrob Chemother. 2010;65:12521257. Concentration ratios have been calculated as concentration in bone (mg/kg)/concentration in serum (mg/L). A bone density of 1 kg was assumed.

duced similar outcomes with less variation of serum concentrations and fewer adverse affects.19 Clindamycin, tetracycline, and linezolid are bacteriostatic antibiotics; that is, they do not kill bacteria but prevent them from undergoing additional cell growth. They achieve both adequate concentrations in osseous tissue and typically have a prolonged postantibiotic effect.20 Fluoroquinolone antibiotics have high oral bioavailability and cover most bone pathogens, other than methicillin-resistant S. aureus. Although beta-lactams have long been considered the standard for treatment of osteomyelitis, recent studies (including one meta-analysis) suggest that fluoroquinolones are also highly effective, generally safe, and offer a good alternative.21 Some authorities avoid fluoroquinolone therapy because of the risk of adverse effects (e.g., tendi-

ANTIBIOTIC IMPREGNATED CEMENT AND BEADS FOR ORTHOPEDIC INFECTIONS

Local antibiotic therapy via antibiotics impregnated in bone cement was first used to treat infected arthroplasties,27 then antibiotic-impregnated cement was used for osteomyelitis. As an alternative to introducing large deposits of antibiotic-impregnated cement at sites of chronic osteomyelitis, gentamicin-impregnated cement

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Table 3. Suggested Regimens for Antibiotic Therapy of Osteomyelitis*
Microorganism Penicillin-sensitive Staphyloccus aureus Penicillin-resistant S. aureus First-Line Treatment Penicillin G (1220 million units IV every 24 hr) Nafcillin or oxacillin (12 g IV every 46 hr) Alternatives Cefazolin (1 g IV every 68 hr); clindamycin (600 mg IV every 6 hr); vancomycin (15 mg/kg IV every 12 hr) Cefazolin (12 g every 8 hr); vancomycin (15 mg/kg IV every 12 hr) Linezolid (600 mg IV or PO every 12 hr); daptomycin (46 mg/kg IV every 24 hr); clindamycin (600 mg IV or PO every 6 hr) Linezolid (600 mg IV or PO every 12 hr) Oral Therapy Amoxicillin (500875 mg every 8 hr); clindamycin 300450 mg every 6 hr) Cephalexin 500 mg PO every 6 hr; clindamycin (300450 mg every 6 hr) Levofloxacin (500750 PO QD) rifampin (600900 mg PO every 24 hr); cotrimoxazole (2 DS every 12 hr) Levofloxacin (500750 PO QD) or doxycycline (100 mg every 24 hr) rifampin (600900 mg PO every 24 hr); cotrimoxazole (2 DS every 12 hr) Amoxicillin (500 mg every 8 hr); clindamycin (300450 mg every 6 hr) Amoxicillin (500 mg every 8 hr) Amoxicillin/clavulanate (875/125 mg every 8 hr); ciprofloxacin (500750 mg every 12 hr); cotrimoxazole (2 DS every 12 hr) Ciprofloxacin (750 every 12 hr)

Oxacillin Vancomycin (15 mg/kg IV (methicillin)every 12 hr) resistant S. aureus Coagulase-negative staphylococci (most are methicillin resistant) Streptococci Enterococcus spp. Enterobacteriaceae Vancomycin (15 mg/kg IV every 12 hr)

Penicillin G (1020 million units IV every 24 hr) Ampicillin 2 g IV every 4 hr gentamicin (1 mg/kg every 8 hr) Ampicillin/sulbactam (1.53 g IV every 6 hr) Cefepime (2 g IV every 12 hr) or ceftazidime (2 g IV every 812 hr) Clindamycin (600 mg IV or PO every 6 hr)

Ceftriaxone (12 g IV every 24 hr); clindamycin (600 mg IV every 6 hr) Vancomyin (15 mg/kg IV q12h); linezolid (600 mg IV/PO q12h) Ceftriaxone (12 g IV every 24 hr); ciprofloxacin (400 mg IV every 812 hr)

Pseudomonas aeruginosa or Enterobacter spp. Obligate anaerobes

Empiric regimen: urgent nonurgent or follow on therapy

Ciprofloxacin (400 mg IV every 8 hr); meropenem (1 g IV every 8 hr) Metronidazole (500 mg IV or Amoxicillin/clavulanate (875/125 PO every 68 hr); mg everey 8 hr); clindamycin ampicilln/sulbactam (300450 mg every 6 hr) (1.53 g IV every 6 hr) Vancomycin (1 g IV every 12 Linezolid (600 mg IV or PO Linezolid (600 mg every 12 hr) or hr) ceftazidime (2 g IV every 12 hr) ciprofloxacin clindamycin 450 mg every 6 hr) every 8 hr); vancomycin (750 mg IV or PO every 12 ciprofloxacin (750 mg every 12 (1 g IV every 12 hr) alone hr); ceftriaxone (12 g hr); amoxicillin/clavulanate (875/ every 24 hr); ampicillin/ 125 mg every 8 hr) sulbactam (1.53 g IV every 6 hr)

IV, intravenous; PO, per os (orally); QD, every day; DS, double strength. *In polymicrobial infections, attempt to select the narrowest spectrum agent(s) that will cover all presumed pathogens, and consider consulting an infectious diseases expert. Agents separated by a semicolon are alternative (not additional) recommendations. Suggested regimens are largely based on U.S. formularies, represent the high end of recommended antibiotic doses, and are for patients having normal renal function. Adapted from Lew DP, Waldvogel FA. Osteomyelitis. Lancet 2004;364:369 379. Oral therapy may be follow-on to initial parenteral or primary therapy; column does not repeat oral regimens noted in the alternatives column. Consider adding rifampin (600 mg orally four times a day) to an anti-staphylococcal agent for complicated infections caused by penicillinresistant staphylococci. If available, can substitute teicoplanin 800 mg on day 1, then 400 mg every 24 hr thereafter.

beads can temporarily fill the dead space created by the debridement of infected bone. One series reported a cure rate of 91.4 percent among 128 patients so treated for chronic osteomyelitis.28 Antibiotic powder is mixed with powdered cement polymer before adding the methylmethacrylate, then the liquid. The mixture can be molded into 3- to 10-mm beads that can be used singly or be strung by surgical suture wire.29 The antibiotic selected must be active against the targeted bacterial pathogens, be available as a powder that will harden properly, and be stable to the heat gen-

erated during polymerization. Commercially available antibiotic-impregnated polymethylmethacrylate cements include Palacos (used primarily in Europe) and Simplex P (used in the United Kingdom and United States). Gentamicin-containing Palacos (Zimmer, Warsaw, Ind.) polymethylmethacrylate beads (Septopal) are produced commercially in Germany. In the United States, antibiotic cement or beads are usually prepared (mostly with tobramycin) in the operating room just before use. Antibiotic release from cement is biphasic, with most occurring

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Table 4. Guidelines for Selecting Patients for Outpatient Intravenous Parenteral Antimicrobial Therapy*
Alternate routes of or sites for antimicrobial delivery are not feasible or indicated. Qualified healthcare provider determines OPAT is most appropriate. Infection does not require that patient be in a hospital. Patient understands the benefits, risks, and financial implications of OPAT. Patient is willing and able to be compliant with OPAT. Site for antibiotic administration can safely support the use of OPAT. Therapy can be monitored by appropriate and accessible healthcare personnel.
OPAT, outpatient intravenous parenteral antimicrobial therapy. *Adapted from Tice AD, Rehm SJ, Dalovisio JR, et al. Practice guidelines for outpatient parenteral antimicrobial therapy: IDSA guidelines. Clin Infect Dis. 2004;38:16511672.

Another material for local delivery of antibiotics is antibiotic-impregnated calcium sulfate beads. These provide a more rapid release of high concentrations of antibiotics and may be useful for situations such as infection prophylaxis following open fractures.32 Other advantages of calcium sulfate beads are that they, unlike the polymethylmethacrylate type, dissolve and do not need to be surgically removed. Furthermore, they do not generate heat when formed, allowing more types of antibiotics to be used. Gentamicin-impregnated hydroxyapatite ceramic beads simulate a bone graft by serving as an osteoconductive matrix and when used to fill dead space do not have to be removed.33,34 Gentamicin-impregnated polylactide-polyglycolide copolymer implants are biodegradable, precluding the need for removal.35

Table 5. Selected Oral Antimicrobial Agents with Excellent Oral Bioavailability Commonly Used to Treat Patients with Osteomyelitis*
Antimicrobial Agent Fluroquinolones Miscellaneous Dose Ciprofloxacin 750 mg every 12 hr Levofloxacin 750 mg every 24 hr Moxifloxacin 400 mg every 24 hr Metronidazole 500 mg every 8 hr Linezolid 600 mg every 12 hr Rifampin 300 mg every 12 hr Trimethoprim-sulfa 1 DS every 12 hr Minocycline 100 mg every 12 hr Clindamycin 450 mg every 8 hr Fluconazole 400 mg every 24 hr Itraconazole 200 mg every 12 hr Voriconazole 200 mg every 12 hr

SURGICAL STAGING AND MANAGEMENT OF OSTEOMYELITIS

Before any operative treatment, the surgeon should establish the likelihood, and extent, of bone infection. The most common system used in clinical practice to assess osteomyelitis is the Cierny-Mader classification (Fig. 2). In addition to the bone, this system classifies the general condition of the patient (host) and the implications for treatment (Table 7).36 38 Because host immune status is a crucial factor in successful treatment, the patients nutrition should be optimized, any anemia or metabolic derangements corrected, and any medical comorbidity controlled. The blood supply to the site must be assessed and any ischemia addressed. Treating osteomyelitis should be a team effort, with internists optimizing host status, infectious disease consultants managing antibacterial treatment, and surgeons addressing any operative treatments. A major surgical advance is the ability to provide early and definitive vascularized coverage of infected bone, usually via microvascular procedures. Where microvascular support is unavailable or not appropriate, other techniques may be useful. Surgeons must also establish a healthy soft-tissue envelope. Osteocutaneous bone transport (the Ilizarov technique) relocates a bone-muscle-skin segment into a defect created after resection of infection.39 43 Surgical procedures should aim to be curative, when possible; a wide resection with clear margins is the ideal, but frequently unachievable, goal. Any avascular material should be resected. A marginal resection may leave behind bacteria containing soft tissue or bone that is vital to the survival and function of the limb. Any colonized surface

Azoles

*Adapted and modified from Osmon DR, Berbari EF. Outpatient intravenous antimicrobial therapy for the practicing orthopaedic surgeon. Clin Orthop Relat Res. 2002;403:80 86.

during the first hours to days after implantation and the remaining eluting for weeks, and sometimes years.30 Clindamycin is not available as a pharmaceutical grade powder,31 and use of fluoroquinolones in cement powder has not been reported. Early studies of erythromycin-impregnated cement demonstrated efficacy, but a subsequent study found inadequate elution. No data are available for other macrolides or azalides. Tetracycline and colistin fail to elute from the cement in clinically meaningful quantities. The limited studies of antibiotic-impregnated polymethylmethacrylate beads suggest that they are effective either as an alternative or a supplement to systemic antimicrobial therapy. They allow for delivery of high local concentration of several classes of antibiotics while avoiding the potential toxicity of high systemic concentrations.

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Table 6. Potential Toxicities and Interactions of Antimicrobial Agents Used in Treating Osteomyelitis*
Drug Beta-lactams Adverse Effects Antibiotic associated diarrhea Pseudomembranous colitis Genital moniliasis Hepatic dysfunction Rash Hepatotoxicity Prolongation of QT interval Phototoxicity Tendon rupture Arrhythmia Disturbance in blood glucose level Lower seizure threshold Peripheral neuropathy Ataxia Disulfiram-like reaction Myelosuppression Peripheral and optic neuropathy Nausea, vomiting, photosensitivity Skin discoloration Permanent tooth discoloration in children Drug-induced lupus Dizziness, light-headedness, vertigo Pseudotumor cerebri Orange discoloration of body secretions Hepatotoxicity Myelosuppression Elevated creatinine level Elevated potassium level Nephrotoxicity Crystaluria Disulfiram-like reaction Creatine phosphokinase elevation with or without myopathy Liver function test and lactate dehydrogenase elevation C lostridium difficile colitis Red man syndrome Phlebitis Neutropenia Drug fever Cautions Avoid if documented history of penicillin allergy

Fluconazole Fluroquinolones

Propensity for drugdrug interaction Should not be taken with antacids

Metronidazole Linezolid Tetracycline

Concurrence use with oral anticoagulants can increase the risk of bleeding Tyramine-containing food should be avoided May interact with adrenergic or serotonergic agents Should not be taken with antacids or iron Concurrent use of oral anticoagulants can increase bleeding Decreases effectiveness of contraceptive drugs

Rifampin Trimethoprimsulfamethoxazole

Propensity for drugdrug interaction Requires increased dosage of anticoagulant drugs May decrease effectiveness of contraceptive drugs May enhance hypoglycemic effect of sulfonylureas Requires decreased dosage of anticoagulant drugs

Daptomycin

May cause renal impairment in combination with aminoglycosides

Vancomycin

May cause renal impairment in high doses and in combination with aminoglycosides Monitor trough levels to avoid nephrotoxicity

*Adapted and modified from Sia IG, Berbari EF, Karchmer AW. Prosthetic joint infections. Infect Dis Clin North Am. 2005;19:885914.

will be a nidus for recurrence. If an infected section of bone is critical for axial stability, the surgeon has two choices: resection of the bone with subsequent destabilization of the limb (conversion of type III to type IV), which will require much more effort and time, or leaving the tissue and attempting to eradicate (or at least contain) the infection. The patients ability to endure either surgery or prolonged antibiotic treatment must be considered. Amputation or chronic suppressive treatment may be preferable for some B, and many C, hosts. When infection presents after a recent open reduction and internal fixation procedure, the key

issues are: is the site is really infected; if so, what to do with an unhealed fracture. Grossly infected wounds require acute surgical debridement and irrigation. If the site shows satisfactory fixation and stability, aggressive surgical debridement, wash ing, and debulking of the contamination load, perhaps with the addition of antibiotic delivering depots, may achieve success. Using antibiotic-impregnated cement depots, although not Food and Drug Administrationapproved and probably not curative, may help reduce subsequent colonization of inert surfaces. All hardware should be considered colonized and a potential nidus for recurrence. If it is re-

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Fig. 2. Cierny-Mader classification of bone. Adapted from Cierny G III, Mader JT, Penninck JJ. A clinical staging system for adult osteomyelitis. Clin Orthop Relat Res. 2003;414:724.

Table 7. Cierny-Mader Classification of the Host*

Host Class A B, systemic Description Healthy physiology and limb Diabetes, stable multiple organ disease, nicotine use, substance abuse, immunologic deficiency, malnutrition, malignancy, old age, vascular disease Trauma context: multiple injuries Previous trauma, burns, previous surgery, vascular disease, cellulitis, scarring, previous radiation treatment, lymphedema Trauma context: zone of injury Combinations of systemic and local conditions Multiple uncorrectable comorbidities. Unable to tolerate extent of surgical resection required. Treatment of the disease is worse than the disease itself

B, local

B, systemic/local C

*Adapted from Cierny G III, Mader JT, Penninck JJ. A clinical staging system for adult osteomyelitis. Clin Orthop Relat Res. 2003;414:724.

tained, consider suppressing infection with systemic antibiotic therapy until there is adequate healing. If this approach is not successful, consider complete removal and debridement of inert sub

stances, insertion of an antibiotic depot system, temporary stabilization with an external fixator or cast, and staged reconstruction.44 Bones can heal in the presence of active infection; with a fracture (unlike an arthroplasty), the implant can be removed after healing. Patients at high risk for failure (e.g., with open fractures, an intramedullary nail, poor host status) should be counseled on alternatives, such as staged reconstruction (see Algorithm for Acute Infection, below). Complex infections defy simple algorithms but general guidelines are useful. Any axial instability or segmental loss will usually require skeletal reconstitution. There are several methods for the required bone grafting or osteogenic modalities. In smaller defects ( 3 cm), simple, autogenous, or allogenic bone grafts may suffice if adequate resection and a healthy wound bed are achievable. For moderate-sized defects (3 to 6 cm), there are several advanced technologies, but distraction osteogenesis remains one of the most reliable and time-saving methods. We have used this method to reconstitute bone defects of up

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to 22 cm, in conjunction with bifocal or trifocal transport segments followed by conversion to internal fixation.45,46
Table 8. Infectious Disease Society of America Classification on Diabetic Foot Infections*
PEDIS Grade 1 2 IDSA Infection Severity Uninfected Mild

ALGORITHM FOR ACUTE INFECTION AFTER OPEN REDUCTION AND INTERNAL FIXATION
The algorithm for acute infection after open reduction and internal fixation is as follows: Hardware stable bone not healed: Retain hardware; antibiotics until healed, then remove hardware. (If history of open fracture, intramedullary nail, or poor host functioning, consider debridement and exchange nail.) Hardware unstable bone not healed: Remove hardware, antibiotics, temporary stabilization, spacer, and reconstruction when clean. Hardware stable bone healed: Remove hardware, debride (trying to avoid destabilization), control dead space, antibiotics.

Clinical Manifestation of Infection No symptoms or signs of infection Infection involving the skin and the subcutaneous tissue only (without involvement of deeper tissues and without systemic signs or symptoms as described below). Either purulent discharge (thick, opaque to white, or sanguineous secretion) or at least two of the following items are present: Local swelling or induration Erythema 0.52 cm around the ulcer Local tenderness or pain Local warmth Other causes of an inflammatory response of the skin should be excluded (e.g., trauma, gout, acute Charcot neuroosteoarthropathy, fracture, thrombosis, venous stasis) Infection with erythema 2 cm plus one of the items described above (swelling, tenderness, warmth, or discharge) Or Infection involving structures deeper than skin and subcutaneous tissues, such as abscess, osteomyelitis, septic arthritis, or fasciitis No systemic inflammatory response signs, as described below Any foot infection accompanied by evidence of severe metabolic perturbations or with two or more of the following signs of a systemic inflammatory response syndrome: Temperature 38C or 36C Heart rate 90 beats/min Respiratory rate 20 breaths/ min or PaCO2 32 mmHg White blood cell count 12,000 or 4000 cu/mm or 10% immature (band) forms

DIABETIC FOOT OSTEOMYELITIS

Foot infections are a common complication of diabetes. These can be defined and classified by a simple, validated system (Table 8).14 Involvement of underlying bone, usually by contiguous spreading from overlying soft-tissue infection, complicates about 20 percent of diabetic foot infections and markedly increases the risk of lower extremity amputation. Factors predisposing to diabetic foot osteomyelitis include deep wounds, peripheral neuropathy, Charcots arthropathy, arterial insufficiency, poor glycemic control, and immune dysfunction. The most frequently isolated organisms in diabetic foot osteomyelitis are skin flora, especially S. aureus. Methicillin-resistant S. aureus and, to a lesser degree, resistant Gram-negative organisms are occasionally pathogens in diabetic foot osteomyelitis.4750 The antimicrobial therapy for diabetic foot osteomyelitis follows the same principal as other types of osteomyelitis. Selection of antibiotics should be based on in vitro susceptibility of the agent against the pathogenpreferably one isolated from bone, or at least deep tissue, at the time if debridement or by percutaneous biopsy. Treatment of diabetic foot osteomyelitis is often complicated by ischemia of the involved limb secondary to peripheral vascular disease; thus, revascularization may be needed in some patients. This vasculopathy, as well as metabolic derangements, emphasizes the need for a multidisciplinary approach. Many advocate surgical resection of infected and especially necrotic bone, but surgeons who are able to or willing to under-

Moderate

Severe

PEDIS, perfusion, extent/size, depth/tissue loss, infection, and sensation; IDSA, Infectious Diseases Society of America; IWGDF, International Working Group on the Diabetic Foot. *Adapted from Byren I, Peters EJG, Hoey C, Berendt A, Lipsky BA. Pharmacotherapy of diabetic foot osteomyelitis. Expert Opin Pharmacother. 2009;10:30333047.

take one resection may be unavailable or patients may refuse a surgical procedure. Numerous reports demonstrate apparent remission of diabetic foot osteomyelitis in patients treated with antibiotic therapy alone.51 Urgent surgery is usually needed only for soft-tissue infections; osteomyeli-

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tis is most often a chronic process, allowing for elective surgery. Unfortunately, a substantial proportion of patients have a poor outcome despite protracted courses of antibiotics. Thus, minor (involving toes or forefoot) and sometimes major (above the ankle) amputations are needed. Guidelines developed by both the Infectious Disease Society of America and International Working Group on the Diabetic Foot provide useful guidance on managing diabetic foot osteomyelitis.52,53 Adjunctive Measures Hyperbaric oxygen therapy has now been more convincingly shown to help heal diabetic foot wounds, but there are no good data supporting its usefulness in treating osteomyelitis. Similarly, some have advocated treatments, such as granulocyte colony-stimulating factors, topical negative pressure therapy (with or without antibiotic instillation), growth factors, gene therapy, and platelet-rich plasma therapy. None of these has been shown to be effective in properly conducted clinical trials.54,55 Osteomyelitis Associated with Pressure Sores Osteomyelitis affects up to a third of stage IV pressure ulcers. They occur predominantly in elderly patients with limited mobility.56 Diagnosis is facilitated by bone cultures, which allow for targeted systemic antibiotic therapy for 2 to 4 weeks. Jamshidi core needle bone biopsy compares favorably with radiographic and other laboratory modalities (erythrocyte sedimentation rate and Creactive protein level).57 Surgical debridement with removal of all nonviable tissue and infected bone, along with viable flap tissue reconstruction, remains the mainstay of treatment. Bone cultures with targeted antibiotics may allow for a shorter course of therapy when the offending tissue has been adequately debrided and closed with viable tissue flap coverage.58
Nalini Rao, M.D. 5750 Centre Avenue, Suite 510 Pittsburgh, Pa. 15206 raon@upmc.edu

REFERENCES
1. Mader JT, Ortiz M, Calhoun JH. Update on the diagnosis and management of osteomyelitis. Clin Podiatr Med Surg. 1996; 13:701724. 2. Mader JT, Shirtliff ME, Bergquist SC, Calhoun J. Antimicrobial treatment of chronic osteomyelitis. Clin Orthop Relat Res. 1999;360:4765. 3. Lew DP, Waldvogel FA. Osteomyelitis. Lancet 2004;364:369 379. 4. Mackowiak PA, Jones SR, Smith JW. Diagnostic value of sinus-tract cultures in chronic osteomyelitis. JAMA. 1978; 239:27722775. 5. Howard CB, Einhorn M, Dagan R, Yagupski P, Porat S. Fineneedle bone biopsy to diagnose osteomyelitis. J Bone Joint Surg Br. 1994;76:311314. 6. Costerton JW, Lewandowski Z, Caldwell DE, Korber DR, Lappin-Scott HM. Microbial biofilms. Annu Rev Microbiol. 1995;49:711745. 7. Davies DG, Parsek MR, Pearson JP, Iglewski BH, Costerton JW, Greenberg EP. The involvement of cell-to-cell signals in the development of a bacterial biofilm. Science 1998;280:295 298. 8. Lynch AS, Abbanat D. New antibiotic agents and approaches to treat biofilm-associated infections. Expert Opin Ther Pat. 2010;20:13731387. 9. DellAcqua G, Giacometti A, Cirioni O, et al. Suppression of drug-resistant staphylococcal infections by the quorum-sensing inhibitor RNAIII-inhibiting peptide. J Infect Dis. 2004; 190:318320. 10. Cirioni O, Giacometti A, Ghiselli R, et al. Prophylactic efficacy of topical temporin A and RNAIII-inhibiting peptide in a subcutaneous rate pouch model of graft infection attributable to staphylococci with intermediate resistance to glycopeptides. Circulation 2003;108:767771. 11. Balaban N, Collins IV, Cullor JS, et al. Prevention of diseases caused by Staphylococcus aureus using the peptide RIP. Peptides 2000;21:13011311. 12. Landersdorfer CB, Bulitta JB, Kinzig M, Holzgrabe U, Sorgel F. Penetration of antibacterials into bone: Pharmacokinetic, pharmacodynamic and bioanalytical considerations. Clin Pharmacokinet. 2009;48:89124. 13. Traunmuller F, Schintler MV, Metzler J, et al. Soft tissue and bone penetration abilities of daptomycin in diabetic patients with bacterial foot infections. J Antimicrob Chemother. 2010; 65:12521257. 14. Byren I, Peters EJG, Hoey C, Berendt A, Lipsky BA. Pharmacotherapy of diabetic foot osteomyelitis. Expert Opin Pharmacother. 2009;10:30333047. 15. McKinnon PS, Davis SL. Pharmacokinetic and pharmacodynamic issues in the treatment of bacterial infectious diseases. Eur J Clin Microbiol Infect Dis. 2004;23:271288. 16. Jacobs MR. Optimization of antimicrobial therapy using pharmacokinetic and pharmacodynamic parameters. Clin Microbiol Infect. 2001;7:589596. 17. Andes D, Craig WA. Pharmacokinetics and pharmacodynamics of outpatient intravenous antimicrobial therapy. Infect Dis Clin North Am. 1998;12:849860, vi. 18. Fraimow HS. Systemic antimicrobial therapy in osteomyelitis. Semin Plast Surg. 2009;23:9099.

CONCLUSIONS
Successful treatment of osteomyelitis requires accurate diagnosis, optimal surgical technique, and properly targeted antimicrobial regimens. Surgical technique is complex and involves assessment of both the limb and the host. Intraoperative cultures, optimally obtained from bone with the patient off antibiotics, are very useful for selecting appropriate antimicrobial therapy. Close collaboration among orthopedists, vascular surgeons, and infectious disease specialists is required to achieve an optimal outcome.

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19. Perencevich EN, Kaye KS, Strausbaugh LJ, Fisman DN, Harris AD. Acceptable rates of treatment failure in osteomyelitis involving the diabetic foot: A survey of infectious diseases consultants. Clin Infect Dis. 2004;38:476482. 20. Levison ME. Pharmacodynamics of antimicrobial drugs. Infect Dis Clin North Am. 2004;18:451465, vii. 21. Karamanis EM, Matthaiou DK, Moraitis LI, Falagas ME. Fluoroquinolones versus beta-lactam based regimens for the treatment of osteomyelitis: A meta-analysis of randomized controlled trials. Spine (Phila Pa 1976) 2008;33:E297E304. 22. Perlroth J, Kuo M, Tan J, Bayer AS, Miller LG. Adjunctive use of rifampin for the treatment of Staphylococcus aureus infections: A systematic review of the literature. Arch Intern Med. 2008;168:805819. 23. Osmon DR, Berbari EF. Outpatient intravenous antimicrobial therapy for the practicing orthopaedic surgeon. Clin Orthop Relat Res. 2002;403:8086. 24. Tice AD, Rehm SJ, Dalovisio JR, et al. 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