The mainstay of medical management of osteomyelitis is prompt and appropriate antibiotic therapy. Studies have shown that antibiotics alone may eliminate bone infection in many cases [9]. Antibiotic therapy should ideally target the pathogen(s) with a narrow spectrum when feasible, utilizing bone culture results when possible [17].

The initial antibiotic regimen should treat the likely causative pathogen, with few adverse effects. Treatment may be modified once the organism is identified. Parenteral and oral antibiotics may be used alone or in combination depending on microorganism sensitivity and patient compliance. There are many factors that affect treatment choices, such as antibiotic bone penetration, method of administration, and duration of therapy. Systematic reviews have demonstrated the lack of evidence supporting specific antibiotics for diabetic foot osteomyelitis [18], and no antibiotic has shown superiority in the eradication of osteomyelitis. The clinical outcome was better for acute than chronic osteomyelitis in 8 of the 12 studies which allowed comparison and few statistically significant differences were observed between the tested treatments [19].

There are many factors that may affect treatment choices, such as spectrum of antimicrobial activity, antibiotic bone penetration, method of administration, and duration of therapy. The choice of antimicrobial therapy is now complicated by the increasing prevalence of antibiotic-resistant organisms, including methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant gram-negative pathogens. Systematic reviews have demonstrated the poor evidence base for making any specific recommendation on antibiotic therapy for diabetic foot osteomyelitis [20–22].

Overall, antibiotic treatment of acute and chronic osteomyelitis should be considered as two distinct entities with regard to the choice of the most appropriate antibiotics and the need for surgery. Antibiotic treatment can be further divided into empirical and targeted treatment. Empirical therapy is necessary when initially treating an infection and when it is not possible to isolate causative organisms from the infection site. Targeted therapy is making an antibiotic choice which is tailored to the organisms isolated from cultures preferably obtained from infected bone. Empirical and targeted therapy will be considered for both acute and chronic osteomyelitis.

Empirical antibiotic therapy should treat the pathogens that are expected according to the severity of infection and the patient’s medical history. In acute infection, it is essential to start antibiotic treatment immediately, and as early as possible in the infectious process, and in this setting empirical antibiotic therapy should be prescribed while waiting for the culture results [23]. In acute osteomyelitis, S. aureus and β-hemolytic streptococci are the leading organisms, but enterobacteriaceae can also be involved. In acute osteomyelitis, infections should be assumed to be polymicrobial, and include mixtures of aerobic and anaerobic organisms [24, 25]. Antibiotics with activity predominantly against gram-positive organisms (staphylococci and streptococci) [24] and broad-spectrum antibiotics with increased activity against gram-negative organisms and obligate anaerobes [26] appear equally effective. Initial empiric regimens may need to include multiple antibiotics with activity against different classes of pathogens [24]. It is still not clear if antibiotic therapy should be selected based on the sensitivities of all isolated organisms or only those judged most likely to be pathogenic.

There is controversy regarding the choice of specific antibiotics. A recent systematic review demonstrated the poor evidence base for making any recommendation on antibiotic therapy for diabetic foot osteomyelitis [18]. There is no specific evidence for superiority of any specific antibiotic agent or treatment strategy, route, or duration of therapy. Some authorities advise broad-spectrum antibiotic therapy to treat as many as possible of the likely organisms that can cause osteomyelitis including gram-positive, gram-negative, and anaerobic organisms. Use of broad-spectrum agents such as ampicillin-sulbactam, piperacillin-tazobactam, or a carbapenem will provide empiric activity against most potential aerobic and anaerobic pathogens. β-lactams are the best-suited agents for the treatment of acute bacterial osteomyelitis given their intense bactericidal activity and bone concentration β-Lactam antibiotics (penicillins, cephalosporins, and carbapenems) penetrate bone at levels ranging from ∼5 to 20 % of those in serum [19]. However, because serum levels of parenterally delivered β-lactam antibiotics are so high, absolute bone levels are likely to exceed target minimum inhibitory concentrations of causative bacteria in most cases. β-lactam penetration is higher in infected than in uninfected bone [25]. The main limitation of antibiotic therapy in these situations is the size of the infecting inoculum that may reduce its efficacy and may favor the selection of resistance. A rapid decrease in the size of the inoculum is essential to prevent development toward a chronic stage of osteomyelitis. Surgical debridement is the most effective way to rapidly and efficiently reduce the inoculum especially in cases of abscesses and wet gangrene which contain very large infecting inoculums [23].

The choice of antimicrobial therapy is complicated by the increasing prevalence of antibiotic-resistant organisms, especially MRSA, and vancomycin may be included as initial empiric therapy. Among the most recently available antibiotics, ertapenem and daptomycin are promising agents for the outpatient treatment of osteomyelitis due to antibiotic-resistant organisms. Addition of adjunctive rifampicin to other antibiotics may improve cure rates. Examples of scenarios influencing antibiotic choice are given in Table 6.2.

Dosages are suggested but may need adjustment according to clinical state

After empirical parenteral therapy, targeted therapy, dependent on culture results, should be initiated intravenously, with eventual transfer to oral therapy. The recent IDSA guidelines recommend a short duration (2–5 days) when a radical resection leaves no remaining infected tissue, and a prolonged treatment (>4 weeks) when there is persistent infected and/or necrotic bone [12]. If there is a need to continue intravenous antibiotics, ceftriaxone and ertapenem are useful for prolonged courses of outpatient antibiotic therapy based on convenient once daily dosing.

In nonrandomized studies of adults with chronic osteomyelitis, 4–6 weeks of parenteral β-lactam antibiotic therapy cures 60–90 % of cases. The varying cure rates may be related to variable diagnostic criteria, use of concomitant surgical debridement notably reported in only two studies [26, 27], or duration of follow-up. In multiple studies, the cure rates of infections caused by Pseudomonas were lower than those for other pathogens [28, 29]. Vancomycin achieves low cure rates for chronic osteomyelitis [30]. In patients receiving outpatient parenteral antibiotic therapy of osteomyelitis, treatment of S. aureus infection with vancomycin (compared with β-lactam agents) had an odds ratio (OR) for recurrence of 2.5 by multivariate analysis [31, 32]. Other independent risk factors for recurrence were diabetes mellitus (OR, 1.9), peripheral arterial disease (OR, 7.9), and infection with Pseudomonas (OR, 2.2). Antibiotics with high propensity to select resistance within the infecting population (e.g., rifampicin, fluoroquinolones, fusidic acid, fosfomycin) should not be used empirically in monotherapy, especially at the start of treatment as the inoculum size is the largest [23].

In most cases, the antibiotic therapy of chronic osteomyelitis is less urgent compared with acute osteomyelitis. The aim of the antibiotic therapy of chronic osteomyelitis is to complete the microbial eradication that depends, for the most part, on the efficacy of surgical debridement. Antibiotics with activity on stationary phase growth, intracellular and biofilm diffusion may play a major role in the eradication of the latent bacteria responsible for chronic osteomyelitis. Thus, despite the limitations of clinical and experimental studies, rifampicin may have a role in the treatment of staphylococcal chronic osteomyelitis as has ciprofloxacin in the treatment of gram-negative chronic osteomyelitis and levofloxacin for staphylococcal osteomyelitis.

A retrospective cohort study over 6 years treated diabetic forefoot ulcers with underlying osteomyelitis with empirical antibiotic therapy targeting S. aureus and β-haemolytic streptococci, the most common organisms involved [33]. Co-amoxiclav was chosen as the first-line treatment because of its good oral bioavailability and bone penetration. Treatment was monitored with MRI and if there was no change in the associated bone signal on MRI, the antibiotics were continued for a further 3-month cycle with repeat MRI. This treatment achieved high rates of healing and low rates of amputation.

After starting initial empiric therapy, good microbiologic data are critical in developing a further antibiotic treatment plan in chronic osteomyelitis. Antibiotic therapy directed by culture of bone (as compared with empiric therapy) was associated with a significantly higher rate of resolution of the bone infection without surgery after a mean of 12 months’ follow-up [34]. It is still not clear if antibiotic therapy should be based on the sensitivities of all isolated organisms or against those judged, most likely to be pathogenic. Antibiotics may be less effective in treating areas of necrotic bone. Also antibiotic delivery is limited where biofilm formation reduces penetration of antibiotics to the infective focus. Thus the standard surgical practice has been to remove infected and necrotic bone in chronic osteomyelitis. However, in some cases, successful treatment of diabetic foot osteomyelitis can be achieved with antibiotic therapy alone [35].

Penetration of antibiotics into bone has been extensively assessed using different methods for sample preparation, drug analysis, and data handling. The published data show substantial variability in the reported mean bone penetration between drugs and between different studies of the same drug. Landersdorfer et al. conducted a systematic literature research of published articles on bone penetration of antibiotics [36]. Mean bone to serum concentration ratios range from 0.3 to 1.2 for quinolones, macrolides, and linezolid, from 0.15 to 0.3 for cephalosporins and glycopeptides, and from 0.1 to 0.3 for penicillins. For the majority of antibiotics studied, the ratios were higher for cancellous bone than for cortical bone and for lipophilic versus hydrophilic antibiotics [36]. Satisfactory bone concentrations of a given antibiotic, and low minimal inhibitory concentrations (MICs) against the offending pathogens routinely assessed at the microbiology laboratory, do not guarantee a satisfactory result in chronic osteomyelitis [23]. A subpopulation of bacteria in a slow-growth phase (the so-called small colony variants) is capable of penetrating cells and surviving intracellularly [37]. These bacteria are insensitive to those antibiotics which are only active on replicating microorganisms (e.g., β-lactams and glycopeptides) and those without intracellular diffusion. After antibiotic treatment, bacteria in latency can return to a logarithmic growth phase, which may partially explain why chronic osteomyelitis may relapse. Bacteria identified in these relapsing infections retain the same antibiotic susceptibility profile as the original strains [38]. Other orally available agents to which many community-associated strains of methicillin-resistant Staphylococcus aureus (MRSA) are usually susceptible are doxycycline and clindamycin. Doxycycline penetrates, and discolors, teeth and bone, but concentrations range from as low as 2 % in axial skeletal bone [39] to as high as 86 % in mandibular bone [40]. Clindamycin penetrates bone at levels of approximately 40–70 % of serum, and its bone levels should exceed the MICs of susceptible MRSA isolates. Fluoroquinolones, linezolid, and trimethoprim have been found to achieve bone concentrations at ∼50 % of serum [41]. Although the sulfamethoxazole component of trimethoprim-sulfamethoxazole (TMP-SMX) has inferior penetration (10–20 %), its serum concentrations are 20-fold higher than those of trimethoprim. Thus its bone concentrations generally exceed the MICs of susceptible organisms. Because TMP-SMX exhibits concentration-dependent killing, higher doses (i.e., 7–10 mg/kg trimethoprim, or two double-strength tablets twice per day) (one double strength tablet is trimethoprim–sulfamethoxazole 160 mg–800 mg) 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 impair their synergy [42].

An oral antibiotic option for treatment of anaerobic osteomyelitis is metronidazole, which penetrates bone at concentrations approximating those in serum. Rifampicin also achieves concentrations in bone near, or exceeding, those in serum. Because serum concentrations of rifampicin increase markedly at doses >450 mg/day [43], prescribing 600 mg once daily should be sufficient. Adjunctive rifampicin therapy has been studied in two randomized clinical trials of patients with chronic osteomyelitis caused by S. aureus [44, 45]. More patients who received rifampicin 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 rifampicin-related adverse effects. Finally, both fusidic acid and fosfomycin penetrate bone extremely well, at concentrations in excess of target MICs.

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. Rifampicin and fusidic acid are reasonable adjunctive agents for combination therapy.

There have been few randomized trials of systemic therapy for osteomyelitis in adults. A systematic review published in 2009 found only eight small trials, with a total of 228 evaluable subjects [46]. A composite analysis of the five trials that compared oral with parenteral treatment did not find a 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). Conterno and da Silva Filho [46] showed there was no statistically significant difference between patients treated with oral versus parenteral antibiotics, in the remission rate 12 or more months after treatment. Single trials with very few participants have found no statistically significant differences in remission rates or adverse events for the following three comparisons: parenteral plus oral versus parenteral only administration; two oral antibiotic regimens; and two parenteral antibiotic regimens. Limited evidence suggests that the method of antibiotic administration (oral versus parenteral) does not affect the rate of disease remission if the bacteria are sensitive to the antibiotic used. Despite advances in both antibiotics and surgical treatment of chronic osteomyelitis long-term recurrence may be 20–30 % [46].

Antibiotic choice should be tailored to the organism isolated from infected bone, when and if possible. Below are sample organisms and recommended definitive antibiotic treatment with a summary in Table 6.3.