WikiGuidelines

With the humility of uncertainty

Based on observational studies, we do not recommend the routine use of plain X-rays (inadequate sensitivity, specificity) or CT scans (inadequate sensitivity) for all patients with a possible diagnosis of osteomyelitis (Table 1) as they may result in unnecessary radiation and use of resources. However, these studies may be helpful if a fracture or other non-infectious cause of bone pain (e.g., tumor, foreign object, etc.) is prioritized on the differential diagnosis, and/or the pre-test probability of osteomyelitis is lower (e.g., ≤15%). Magnetic resonance imaging (MRI) and certain tagged white cell scans are the most accurate imaging modalities for diagnosing osteomyelitis. Inflammatory biomarkers are insufficiently accurate, and we do not recommend their routine use for osteomyelitis diagnosis. Blood cultures have variable sensitivity but if the patient has systemic symptoms or risk factors for bacteremia (e.g., intravenous drug use), isolating likely pathogens (e.g., Staphylococcus aureus) can be helpful to target therapy, and potentially obviate the need for bone biopsy. If available, bone biopsy for histopathology is highly accurate if positive, but cannot rule out osteomyelitis if negative. Culture of biopsy specimens of the affected bone may help identify etiology and target antimicrobial therapy.

Diabetic Foot Osteomyelitis (DFO)

Based on observational studies, plain X-rays have low sensitivity and specificity for diagnosing DFO (Table 1). The probe-to-bone (PTB) test is simple, non-invasive, and has reasonable sensitivity and specificity as a diagnostic method for DFO, which may preclude the need for imaging in some settings. MRI and certain tagged white cell scans are the most accurate imaging modalities for diagnosing DFO, although their specificities are lower than their sensitivities. Inflammatory biomarkers are insufficiently accurate, and we do not recommend their routine use for diagnosis. If available, percutaneous bone biopsy for deep microbiological cultures may help target antimicrobial therapy; surface cultures are not accurate and not recommended.

Osteomyelitis with Prosthetic Joint Infection (PJI)

There is no established, accurate referent standard diagnostic test for PJI. Certain tagged white cell scans are the most accurate imaging studies for PJI (Table 1), however given the limitations of individual tests, published algorithms are sometimes recommended to establish the diagnosis. Data are limited and inadequate to compare the relative accuracies of competing algorithms. Practically, the diagnosis is typically made from a combination of history, physical exam, imaging studies to assess alternate causes of pain and instability, inflammatory markers, synovial fluid analysis, and/or operative specimens. Molecular diagnostic testing is a promising approach, but data are mixed and inadequate to recommend for or against its use as of 2022.

TABLE 1

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OVERALL SUMMARY

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OVERALL SUMMARY

Q3: When should empiric therapy be administered in the treatment of osteomyelitis?

Some observational studies suggest that administration of antibiotics prior to bone biopsy or surgical management may modestly decrease yield of bone cultures for patients with osteomyelitis, including DFO and PJI. Thus, presuming other microbiological methods (e.g., blood cultures) have not already established a microbial etiology, it is reasonable to consider deferring antimicrobial therapy initiation until bone/joint microbiological samples are obtained for clinically stable patients. However, other studies are not concordant, and histopathology results are unlikely to be affected by prior short-term antibiotics. Decisions regarding the delay of empiric therapy therefore balance potential harm due to the risk of progression of life-threatening infection (e.g., sepsis) or impending spinal cord compression against the potential benefit of microbiological data.

Q4: Are there preferred antibiotics with which to treat osteomyelitis?

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Which empiric antimicrobial agents are preferred for osteomyelitis?

Question 3

Based on observational and randomized controlled studies, aerobic gram-positive cocci, primarily S. aureus, have been the organisms most frequently isolated from culture in patients with osteomyelitis, including DFO. Enterobacterales have been the predominant group of gram-negative pathogens, with E. coli the most common. Thus, when treating osteomyelitis, it is reasonable to empirically cover gram-positive cocci, primarily Staphylococcus spp., and gram-negative bacilli if therapy cannot be delayed until culture availability (Table 2). For DFO, many physicians add anaerobic activity; however, data are not available to determine the benefit or harm of this approach. Pseudomonal activity is generally not necessary in treating osteomyelitis unless patients have been exposed to multiple prior courses of antibiotics, the wound is gangrenous, the organism has been previously cultured, the patient underwent a recent (e.g., < 3 months) surgical procedure in a healthcare setting, or the patient has a specific site of infection particularly prone to P. aeruginosa (e.g., malignant otitis externa).

For early, late, and hematogenous PJI, S. aureus and coagulase-negative Staphylococcus have been the most commonly isolated organisms. Gram-negative bacilli, most commonly Enterobacterales, have also been regularly isolated. Thus, reasonable empiric therapy for PJI of all stages generally includes coverage for gram-positive cocci and Enterobacterales. Antibiotic regimens to treat early (< 3 months since procedure), but not later, PJI may include coverage for P. aeruginosa, although some authors feel this is not routinely necessary depending on local microbiology. Anaerobes, such as Peptostreptococcus and C. acnes, are isolated infrequently. C. acnes is more often isolated in shoulder PJI compared to other joints, and thus would warrant empiric coverage for shoulder PJI; however, this is usually accomplished with anti-staphylococcal coverage. In all cases, local susceptibility profiles inform empiric therapy.

MRSA Coverage

Pseudomonal Coverage

Bone Penetration of Abx

Adjunctive Rifampin

Long-acting glycopeptides

Tables and Figures

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OVERALL SUMMARY

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Preferred Empiric Agents

Bone Penetration of Abx

Adjunctive Rifampin

Long-acting glycopeptides

Tables and Figures

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OVERALL SUMMARY

When should antimicrobial coverage against MRSA be included?

Based on observational and RCT data, rates of MRSA bone and joint infections vary by country. In areas with low MRSA prevalence, and for patients who are not known to be colonized by MRSA, it may be reasonable to hold MRSA coverage, and focus on MSSA coverage. In patients known to be colonized by MRSA (the largest individual risk factor for MRSA infection), or at centers with higher rates of MRSA among their S. aureus isolates, it is reasonable to initiate an anti-MRSA agent empirically while waiting for culture results, particularly for clinically unstable patients.

When should antimicrobial coverage against P. aeruginosa be included?

Observational studies demonstrate that P. aeruginosa is an uncommon cause of osteomyelitis outside of patients with specific risk factors. Thus, empiric therapy including antipseudomonal agents can be limited to patients with such risk factors. For example, Pseudomonas spp. are more prevalent in patients residing in subtropical and tropical climates than in temperate climates. Other risk factors include the presence of chronic wound infections with multiple prior antibiotic courses, gangrene, a history of positive culture with Pseudomonas spp. in the past, a recent (e.g., < 3 months) surgical procedure in a healthcare setting (e.g., early PJI), or specific sites of infection (e.g., malignant otitis externa).

Question 1

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Preferred Empiric Agents

MRSA Coverage

Pseudomonal Coverage

Long-acting glycopeptides

Tables and Figures

Question 5

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OVERALL SUMMARY

Bone penetration of antibiotic agents for the treatment of osteomyelitis is a frequently discussed yet poorly studied drug property (Table 3). There are numerous limitations that need to be considered when evaluating bone penetration studies. While it is intuitive that antibiotics cannot successfully treat an infection if they do not reach the site at a concentration sufficient to inhibit microbial growth, there are limited outcomes data for osteomyelitis to support this concept.

Numerous observational studies and three small RCTs found that patients with osteomyelitis, with or without a retained implant, had improved clinical success rates, due to reduced relapse, when treated with adjunctive rifampin (rifampin monotherapy is never advisable due to concerns about emergence of resistance on therapy). However, other observational studies and one small RCT did not find a benefit of adjunctive rifampin. Meta-analysis of the four RCTs suggests a benefit of rifampin therapy (Figures 1-2). However, given the small size of these studies and the heterogeneity in results, patient populations, rifampin dosing, and background antibiotic therapy, these data remain hypothesis-generating, and a Clear Recommendation cannot be made for or against such therapy. A large RCT is necessary to clarify or disprove efficacy. In the meantime, it may be reasonable to consider adjunctive rifampin therapy for osteomyelitis caused by gram-positive cocci or non-fermenting gram-negative bacilli, with or without a retained implant, in individual patients based on risk:benefit assessment. Such assessment should include the uncertainty of the efficacy data balanced against potential drug interactions and adverse events of rifampin. If used, the dosing of rifampin has varied widely in studies. However, 450-600 mg per dose likely increases PD target attainment and adherence, and hence may be preferred, compared to 300 mg multiple daily dosing. Whether dose escalation to 900 mg once daily or 600 twice daily improves efficacy and/or worsens safety for treating osteomyelitis is unknown. To minimize emergence of resistance and treatment failure, it may be prudent to initiate rifampin only after bacteremia is cleared and surgical source control is achieved if it is necessary.

Question 1

Question 2

Question 3

Preferred Empiric Agents

MRSA Coverage

Pseudomonal Coverage

Bone Penetration of Abx

Adjunctive Rifampin

Tables and Figures

Question 5

Question 6

Question 7

OVERALL SUMMARY

What is the role of long-acting glycopeptide antibiotics?

The two long-acting glycopeptides available on the market, dalbavancin and oritavancin, are not licensed for the treatment of osteomyelitis, but are licensed for the treatment of acute bacterial skin and soft tissue infection (ABSSI). One RCT of dalbavancin (n = 70 patients) vs. standard of care, which was largely vancomycin (n = 10), showed similar cure rates for non-vertebral osteomyelitis without prosthetic material, and a shorter length of hospital stay in the dalbavancin arm. No other randomized trial data are available for long-acting glycopeptides and osteomyelitis. Multiple, small, single-center, observational studies (all n < 50) have reported similar outcomes with both dalbavancin and oritavancin and comparator regimens. Few safety concerns were raised in these studies, and the glycopeptides were rarely stopped due to adverse events. There are currently no data to suggest that long-acting glycopeptides would have superiority over other regimens, including oral therapy options. Thus, based on available evidence, the most likely role for long-acting glycopeptides in osteomyelitis is for patients with non-vertebral osteomyelitis:

1. who are unlikely/unable to take an oral regimen, or
   
2. where an oral regimen is contraindicated (e.g., due to resistance patterns).
   

There is minimal evidence of long-acting glycopeptide therapy for osteomyelitis in the presence of prosthetic material and for vertebral osteomyelitis, so caution is warranted in these settings.