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. 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 . 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= .05 by Fisher’s exact test), and no patient terminated therapy due to rifampin-related adverse effects. In another trial, Zimmerli et al 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, ofloxacin in 3]) or standard intravenous therapy. In all, cure rates were similar for those treated with oral and intravenous therapy. Finally, Euba et al 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 higher-than-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, 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.

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, 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.