Systemic Antibiotic Therapy for Chronic Osteomyelitis in Adults

The standard recommendation for treating chronic osteomyelitis is 6 weeks of parenteral antibiotic therapy. However, oral antibiotics are available that achieve adequate levels in bone, and there are now more published studies of oral than parenteral antibiotic therapy for patients with chronic osteomyelitis. Oral and parenteral therapies achieve similar cure rates; however, oral therapy avoids risks associated with intravenous catheters and is generally less expensive, making it a reasonable choice for osteomyelitis caused by susceptible organisms. Addition of adjunctive rifampin to other antibiotics may improve cure rates. The optimal duration of therapy for chronic osteomyelitis remains uncertain. There is no evidence that antibiotic therapy for > 4–6 weeks improves outcomes compared with shorter regimens. In view of concerns about encouraging antibiotic resistance to unnecessarily prolonged treatment, deﬁning the optimal route and duration of antibiotic therapy and the role of surgical debridement in treating chronic osteomyelitis are important, unmet needs.

Chronic osteomyelitis is an infection of bone that does not result from acute hematogenous seeding or penetrating injury and usually occurs by contiguous spread and has been present for several weeks. Perhaps the earliest known case of chronic osteomyelitis dates to the Permian era, in an unfortunate dimetrodon that developed infection in a fractured spinal shaft [1]. This 250 million-year-old case highlights 3 of the problems that remain common when managing chronic osteomyelitis: (1) the diagnosis was established only after bone (or rather fossil) biopsy; (2) no cultures were performed to define the etiologic organism; and (3) treatment (if any) was probably delayed and certainly ineffective.
In the antibiotic era, chronic osteomyelitis remains difficult to treat and has a high rate of relapse after apparently successful treatment [2][3][4]. Indeed, case reports have described relapses of osteomyelitis up to 80 years after the initial presentation [5][6][7][8]. These relapses are probably due to bacterial evasion of host defenses by hiding intracellularly and as nonreplicating persisters within biofilm [9]. Because of these concerns, clinicians often treat chronic osteomyelitis with antibiotic therapy that is parenteral, high dose, and prolonged. This standard recommendation derives largely from the belief that it takes 3-4 weeks for infected bone to revascularize as well as from experience treating children with acute osteomyelitis. It was codified by a seminal case series by Waldvogel et al [10][11][12] in 1970. The authors stated that ''osteomyelitis is rarely controlled without the combination of careful, complete surgical debridement and prolonged (4-6 weeks) parenteral antibiotic therapy at high dosage.'' However, this case series was retrospective and uncontrolled, and it included a heterogeneous patient population, and parenteral penicillin was the predominant antibiotic administered.
What have we learned about treating chronic osteomyelitis in the past few decades? Previous reviews of this topic have concluded that available literature is inadequate to determine the best agent, route, or duration of antibiotic therapy [13][14][15]. Undeterred, we set out to review studies published since 1970 in an attempt to address 4 fundamental questions regarding treatment of chronic osteomyelitis in adults: (1) Are certain antibiotic agents preferred choices? (2) Are oral regimens acceptable for selected cases? (3) For how long should antibiotic therapy be given? and (4) Is surgical debridement always necessary for cure? We searched PubMed and ScienceDirect for the term ''osteomyelitis'' from 1970 to 2011, and EBSCO, Web of Science, and Google Scholar for any types of studies on treatment of chronic osteomyelitis in adults. We reviewed all articles if they, or at least their abstracts, were in English.

PHARMACOLOGY OF OSTEOMYELITIS THERAPY
Parenteral Antibiotic Agents b-Lactam antibiotics (penicillins, cephalosporins, and carbapenems) penetrate bone at levels ranging from 5% to 20% of those in serum (Table 1). Nevertheless, because serum levels of Abbreviation: NA, not applicable. a Full article not available in English; the abstract reported a 10% ratio.
b Assuming peak ampicillin serum levels of 120 and 60 lg/mL at doses of 2 and 1 g, respectively [39,40], peak sulbactam levels of 60 and 30 lg/mL at doses of 1 and 0.5 g [39,40], and a peak cefazolin level of 80 lg/mL at a dose of 1 g [41]. c Assuming peak serum levels of 75 lg/mL for ceftazidime [42] and 12.5 lg/mL and 25 lg/mL for imipenem at doses of 500 and 1000 mg, respectively [43,44,45].
d As specified in the study abstract.
parenterally delivered b-lactam antibiotics are so high, absolute bone levels likely exceed target minimum inhibitory concentrations (MICs) of etiologic bacteria in most cases. In contrast, because serum levels of oral b-lactam agents are ,10% of those of parenteral agents, oral dosing is unlikely to achieve adequate bone levels. b-lactam penetration is higher in infected than in uninfected bone [31,33,34], but it is markedly decreased in patients with peripheral vascular disease [29,46] and is probably low in sequestra. Similar to b-lactam antibiotics, vancomycin penetrates bone poorly [24] (Table 1). However, when serum levels of vancomycin were .35 lg/mL, its penetration of sternal bone (30% of serum concentrations) was better than in axial skeletal bone [47,48]. Daptomycin also penetrates bone relatively poorly (Table 1), but levels are probably high enough to exceed the target MICs for bacteria in bone [25,49].

Oral Antibiotic Agents
Recent studies demonstrate that oral antibiotics can achieve levels in bone that exceed MICs of targeted organisms (Table 2). In particular, fluoroquinolones, linezolid, and trimethoprim have been found to achieve bone concentrations at 50% of serum [52,53,55] (Table 2). Although the sulfamethoxazole component of trimethoprim-sulfamethoxazole (TMP-SMX) has poorer penetration (10%-20%), its serum concentrations are 20-fold higher than those of trimethoprim, so its bone concentrations generally exceed the MICs of susceptible organisms. Because TMP-SMX exhibits concentration-dependent killing [88][89][90], higher doses (ie, 7-10 mg/kg trimethoprim, or 2 doublestrength tablets twice per day) may result in greater efficacy when treating chronic osteomyelitis. The lack of a fixed 1:5 ratio of concentrations of trimethoprim and sulfamethoxazole at the site of infection does not hinder their synergy [91].
In summary, oral options for the treatment of chronic osteomyelitis based on pharmacokinetic considerations include fluoroquinolones, TMP-SMX, or fosfomycin for susceptible gram-negative bacilli, and TMP-SMX, clindamycin, and linezolid for susceptible gram-positive infections. Rifampin and fusidic acid are reasonable adjunctive agents for combination therapy.

ANIMAL MODELS OF CHRONIC OSTEOMYELITIS
Standard models of chronic staphylococcal osteomyelitis include those in which infection is induced in long bones of rabbits and rats [2]. In such models, in vitro kill curves do not reliably predict in vivo efficacy. For example, in both models, rifampin was more active in vivo than clindamycin, azithromycin, vancomycin, trimethoprim, and ciprofloxacin, and it was synergistic in vivo with each of these agents as well as with cephalothin, despite being either indifferent or antagonistic to all of them in vitro [82,101,105]. In addition, ciprofloxacin monotherapy had minimal in vivo effect when treating infection caused by S. aureus strains susceptible to ciprofloxacin in vitro [82]. Thus, rifampin exhibits synergistic activity in vivo with myriad antibiotics, and clinicians should be cautious about using ciprofloxacin monotherapy to treat osteomyelitis caused by S. aureus, regardless of the MIC of the isolate.

Parenteral Therapy
In nonrandomized studies of adults with chronic osteomyelitis, 4-6 weeks of parenteral b-lactam antibiotic therapy has cured 60%-90% of cases (Table 3). The varying cure rates may be related to variable diagnostic criteria, use of concomitant surgical debridement (specifically reported in only 2 studies [107,108]), or duration of follow-up. In multiple studies, the cure rates of infections caused by Pseudomonas were lower than those for other pathogens [108,109,112].
Vancomycin achieves low cure rates for chronic osteomyelitis [117,121,122]. In patients receiving outpatient parenteral antibiotic therapy of osteomyelitis, treatment of S. aureus infection with vancomycin (compared with b-lactam agents) had an odds ratio (OR) for recurrence of 2.5 by multivariate analysis [121,122]. Other independent risk factors for recurrence included the presence of diabetes mellitus (OR, 1.9), peripheral vascular disease (OR, 7.9), and infection with Pseudomonas (OR, 2.2).
In a salvage study of patients with MRSA osteomyelitis that had failed to respond to previous therapy, all 9   Abbreviations: NA, not applicable; TMP-SMX, trimethoprim-sulfamethoxazole. a Levels in infected (osteomyelitic) bone after debridement.

Oral Therapy: Fluoroquinolones
There are more studies of fluoroquinolones for treating chronic osteomyelitis than of all other antibiotic classes (Table 4). Crossstudy comparisons are difficult because of the varied criteria for enrollment, utilization of debridement, antibiotic dosing regimens, duration of follow-up, and definitions of cure. Nevertheless, we draw several general inferences from these studies.
2. Cure rates were similar to debridement rates (when reported), but because none of the studies specifically reported cure rates of patients who did and did not undergo debridement, the benefit of debridement can only be inferred.
3. The majority of failures occurred in patients infected with Pseudomonas, and to a lesser extent, patients infected with S. aureus.
4. Therapy was typically given for 12-16 weeks, and at doses higher than those used for most other infections (eg, ciprofloxacin at $1500 mg/d), but it is not possible from the available data to conclude that this high-dose and prolonged treatment is necessary.

Oral Therapy: Other Agents
Although it should never be used alone for treating osteomyelitis, several reports have shown that rifampin improves treatment outcomes when used in combination with other antibiotics (Table 4). Norden et al [101] added rifampin to therapy with a b-lactam, doxycycline, or an aminoglycoside in 14 patients, most of whom had had osteomyelitis for .15 years and in whom multiple prior treatment attempts had failed. Overall, 50% were cured, and patients in whom treatment failed were all infected with gram-negative bacilli resistant to the nonrifampin agent. In another study of patients with S. aureus osteomyelitis, there were no relapses among 15 patients in whom rifampin was added to treatment with various other antibiotic agents compared with 5 relapses among 20 patients who did not receive adjunctive rifampin [118]. Finally, adjunctive rifampin improved cure rates of prosthetic joint infections in 2 recent studies [143,144].
TMP-SMX is second only to ciprofloxacin in the number of published studies of its effectiveness for treatment of chronic osteomyelitis. Saengnipanthkul et al [148] reported a 45% cure rate using standard dose TMP-SMX (1 double-strength tablet twice daily) to treat 66 patients with chronic osteomyelitis, only 55% of whom underwent surgical debridement. Cure rates based on surgical debridement were not separately reported. In contrast, Sanchez et al [149] treated 27 patients with staphylococcal osteomyelitis (25 S. aureus) with a higher -than-usual dose of TMP-SMX (7 mg/kg/d of trimethoprim divided into 2 or 3 daily doses) along with rifampin for a mean of 5 weeks, in addition to surgical debridement. After follow-up of 6 months to 5 years, all of the patients were cured.
Javaloyas de Morlius et al [78] reported their results with treating 37 patients with 44 episodes of osteomyelitis, 34 of which were associated with an orthopedic implant. After a week of parenteral antibiotic therapy, the patients received a median of 10 weeks of oral treatment with TMP-SMX plus rifampin (23 patients), TMP-SMX alone (5 patients), or rifampin plus ciprofloxacin (7 patients). At 2 years of follow-up, all 10 patients who had their hardware removed were cured, compared with 18 of 24 patients (75%) in whom hardware was left in place.
Stein et al [150] prescribed TMP-SMX for 6-9 months to treat 39 patients with prosthetic devices infected with MRSA. The overall success rate was 67% in the intention-to-treat population and 87% in the per-protocol population (after exclusion of 9 patients who were unable to tolerate completing the treatment). Significantly more patients who had their infected prosthetics removed were cured compared with those who did not. Likewise, de Barros et al [84] treated 60 patients with chronic osteomyelitis with TMP-SMX for 6 months, along with appropriate surgical debridement; 59 (98%) were cured after 12-60 months of follow-up. Finally, Nguyen et al [151] reported that either TMP-SMX (8 mg/kg/d) or linezolid combined with rifampin cured 79%-89% of patients with infected orthopedic implants or chronic osteomyelitis. Taken together, these data support the efficacy of high-dose TMP-SMX, the importance of concurrent surgical debridement, and the possible benefit of adjunctive rifampin therapy and prolonged therapy when treating chronic osteomyelitis, especially in patients with an associated infected implant.
Consistent with their excellent bone penetration, both fosfomycin [72,152] and fusidic acid [156,157], the latter preferably in combination with another anti-staphylococcal agent, have also demonstrated efficacy in treating chronic osteomyelitis. Others have summarized results of the numerous published case series describing fusidic acid combination therapy for osteomyelitis [156].

Randomized Clinical Trials
There have been few randomized trials of systemic therapy for osteomyelitis in adults. A systematic review published in 2009 found only 8 small trials, with a total of 228 evaluable subjects [158]. A composite analysis of the 5 trials that compared oral with parenteral treatment found no significant difference in remission rate at $12 months of follow-up, but the rate of moderate or severe adverse events was significantly higher with parenteral than with oral agents (15.5% vs 4.8%, respectively). Adjunctive rifampin therapy has been studied in 2 randomized clinical trials of patients with chronic osteomyelitis caused by S. aureus [159,160] (Table 5). Summarizing their results, more patients who received rifampin in addition to other antibiotics were cured compared with those who did not (17 of 20 [85%] vs 12 of 21 [57%]; P 5 .05 by Fisher's exact test), and no patient terminated therapy due to rifampin-related adverse effects. In another trial, Zimmerli et al [163] randomized patients with prosthetic devices infected with Staphylococcus spp. to receive either rifampin or placebo, plus ciprofloxacin, for 3-6 months. In the per-protocol population, cure rates were 100% for rifampin-treated versus 58% for placebo-treated patients (P , .02). Of note, the causative pathogen in 4 of the 5 patients whose infection failed to respond to ciprofloxacin monotherapy developed resistance to ciprofloxacin.
Six studies randomized patients with chronic osteomyelitis to receive either an oral fluoroquinolone (ciprofloxacin in 3 [164][165][166], ofloxacin in 3 [167][168][169]) or standard intravenous therapy (Table 5). In all, cure rates were similar for those treated with oral and intravenous therapy. Finally, Euba et al [170] randomized 50 patients with chronic osteomyelitis caused by methicillin-sensitive S. aureus to treatment with intravenous cloxacillin or oral TMP-SMX plus rifampin for 8 weeks. All patients underwent surgical debridement, and 20 (40%) patients had prosthetic implants. At the end of therapy, cure rates were nearly identical for the 2 regimens (91% and 89%, respectively), as were the rates of antibiotic-related adverse events (3 in each arm). Furthermore, at median follow-up of 10 years (interquartile range, 4-13 years), the relapse rate was similarly low (10% and 11%, respectively). Among the 3 patients who relapsed on oral therapy, 2 had retained prosthetic material.

CONCLUSIONS
Assessing treatments of chronic osteomyelitis is confounded by several factors, including the difficulty in diagnosing the condition or establishing a microbiological etiology, the presence of necrotic bone in most (and prosthetic implants in many) patients, and the lack of a consensus definition of cure. Nevertheless, we draw several conclusions from available published studies.  First, oral antibiotic therapy with highly bioavailable agents is an acceptable alternative to parenteral therapy. The widely held preference for parenteral therapy for chronic osteomyelitis is based more on custom than evidence. There are actually fewer published studies of parenteral than oral therapy for osteomyelitis, and success rates are consistently similar for both routes. Furthermore, oral therapy is generally simpler for the patient, avoids risks associated with intravenous catheters, and is less expensive. Preferred oral agents, based on both pharmacokinetic and clinical data, include fluoroquinolones or TMP-SMX, which achieve high cure rates when administered for 8-16 weeks, particularly in the context of concomitant surgical debridement. We would like to see studies of shorter durations of treatment (eg, 4-6 weeks) to determine whether they produce similar results. It may be advisable to use higherthan-usual doses (eg, ciprofloxacin at 750 mg twice daily and TMP-SMX at 7-10 mg/kg/d of trimethoprim) when treating chronic osteomyelitis. Because gram-positive cocci have a high propensity to develop resistance during fluoroquinolone therapy [171], the reported relapses of staphylococcal osteomyelitis after ciprofloxacin or ofloxacin treatment are not surprising. Therefore, TMP-SMX and probably clindamycin are preferable for treating osteomyelitis caused by gram-positive cocci. Other options for selected cases could include linezolid or doxycycline, although toxicity with prolonged treatment limits use of the former agent, and no clinical data are available for the latter. For anaerobic osteomyelitis, oral metronidazole is the agent of choice, given its outstanding bone penetration and efficacy in case reports. Although the theory is still being debated, there is no evidence that bactericidal agents are superior to bacteriostatic in the treatment of osteomyelitis [172].
Second, adding rifampin to a variety of antibiotic regimens has been shown to improve the cure rates in: (1) animal models, (2) retrospective studies in humans, and (3) randomized clinical trials of chronic osteomyelitis and orthopedic implant infections. Hence, clinicians should consider adjunctive rifampin therapy (ie, combined with another active agent) for patients who are able to tolerate it and who do not require concomitant treatment with drugs with which it is likely to interact.
Third, clinicians must individualize the duration of antibiotic therapy based on the patient's clinical and radiographic response, with continued monitoring after cessation of therapy. No strong evidence supports the standard recommendation of 4-6 weeks of therapy after surgical debridement [4], nor is there evidence that more prolonged therapy further improves cure rates. Unfortunately, there are no well established markers of successful treatment and relapse rates remain substantial, even after prolonged antibiotic therapy. Defining the optimal duration of therapy for chronic osteomyelitis is an area of urgent need.
Fourth, surgical resection of necrotic and infected bone, in conjunction with antibiotic therapy, appears to increase the cure rate of chronic osteomyelitis. However, not all cases of chronic osteomyelitis require surgical debridement for cure, and we need studies to clarify which may and which may not. We need comparative effectiveness studies to answer these and a number of other questions regarding therapy of chronic osteomyelitis.