WikiGuidelines

With the humility of uncertainty

Use of Novel Strategies to Develop Guidelines for Management of Pyogenic Osteomyelitis in Adults

A WikiGuidelines Group Consensus Statement

Question

Can a novel methodology using collaborative research coordinated online be successfully applied to the development of a guideline for the diagnosis and treatment of a common infectious disease, pyogenic osteomyelitis?

Findings

This consensus statement and systematic review using a novel WikiGuidelines methodology addresses 7 questions regarding the management of osteomyelitis, resulting in the establishment of 2 clear recommendations (concerning oral antibiotic therapy for pyogenic osteomyelitis and duration of therapy) and 5 clinical reviews that outline a present lack of adequate, hypothesis-confirming data.

Meaning

These results suggest that this novel, egalitarian methodology enables a clear separation of established care standards based on hypothesis-confirming evidence from practice preferences that are based on lower quality or no evidence.

Importance: Traditional approaches to practice guidelines frequently result in dissociation between strength of recommendation and quality of evidence.

Objective: To construct a clinical guideline for pyogenic osteomyelitis management, with a new standard of evidence to resolve the gap between strength of recommendation and quality of evidence, through the use of a novel open access approach utilizing social media tools.

Evidence Review: This consensus statement and systematic review study used a novel approach from the WikiGuidelines Group, an open access collaborative research project, to construct clinical guidelines for pyogenic osteomyelitis. In June 2021 and February 2022, authors recruited via social media conducted multiple PubMed literature searches, including all years and languages, regarding osteomyelitis management; criteria for article quality and inclusion were specified in the group’s charter. The GRADE system for evaluating evidence was not used based on previously published concerns regarding the potential dissociation between strength of recommendation and quality of evidence. Instead, the charter required that clear recommendations be made only when reproducible, prospective, controlled studies provided hypothesis-confirming evidence. In the absence of such data, clinical reviews were drafted to discuss pros and cons of care choices. Both clear recommendations and clinical reviews were planned with the intention to be regularly updated as new data become available.

Findings: Sixty-three participants with diverse expertise from 8 countries developed the group’s charter and its first guideline on pyogenic osteomyelitis. These participants included both nonacademic and academic physicians and pharmacists specializing in general internal medicine or hospital medicine, infectious diseases, orthopedic surgery, pharmacology, and medical microbiology. Of the 7 questions addressed in the guideline, 2 clear recommendations were offered for the use of oral antibiotic therapy and the duration of therapy. In addition, 5 clinical reviews were authored addressing diagnosis, approaches to osteomyelitis underlying a pressure ulcer, timing for the administration of empirical therapy, specific antimicrobial options (including empirical regimens, use of antimicrobials targeting resistant pathogens, the role of bone penetration, and the use of rifampin as adjunctive therapy), and the role of biomarkers and imaging to assess responses to therapy.

Conclusions and Relevance: The WikiGuidelines approach offers a novel methodology for clinical guideline development that precludes recommendations based on low-quality data or opinion. The primary limitation is the need for more rigorous clinical investigations, enabling additional clear recommendations for clinical questions currently unresolved by high-quality data.

An important limitation of traditional clinical guidelines is the frequent dissociation between quality of evidence and strength of recommendations.[1-6] As a result, some past guideline recommendations have endorsed harmful care, which was only subsequently recognized when high-quality, prospective controlled trials were conducted.[7] To overcome this limitation, we developed a novel approach, called WikiGuidelines, to establish clear recommendations only when high-quality, hypothesis-confirming evidence is available (see group charter).

Our initial social media poll revealed a desire for renewed guidance on a common infectious disease, pyogenic osteomyelitis. Pyogenic osteomyelitis occurs at a rate of approximately 20 cases per 100 000 person-years, with rates rising among patients with diabetes and older patients, as well as those with prosthetic joints.[8-10] In low- and lower-middle-income countries (LMIC), osteomyelitis may be more common in younger patients as a result of traumatic injury.[11] Nevertheless, the global economic burden of osteomyelitis is considerable for high-income countries and LMIC. [9,10,12-14]

Osteomyelitis is an ancient disease, with the earliest documented case in an unfortunate, 250-million-year-old dimetredon with a fractured spinal shaft.[15] In the modern era, radiography, surgical methods, and antibiotics have revolutionized its management. However, these successful interventions have resulted in long-standing diagnostic and therapeutic paradigms that have guided treatment despite lacking strong evidence, including the need for diagnostic x-rays and intravenous-only antibiotic therapy for all patients.[16] Recent studies have begun to challenge these dogmas.[16-18] This guideline focuses on data regarding management of pyogenic osteomyelitis in adults (see Executive Summary & Overall Summary for the complete guidelines).

The WikiGuidelines Group formed on Twitter by participants who were dissatisfied with traditional guideline methodologies. The group constructed a charter that specifically chose not to use the GRADE system for evaluating strength of evidence based on previously published concerns regarding bias, poor interrater reliability, and, most importantly, the dissociation between strength of recommendation and quality of evidence.[1-7]

Instead, the group sought to incorporate the “humility of uncertainty” [7] by only providing clear recommendations when reproducible, high-quality, hypothesis-confirming evidence is available, requiring at a minimum:

(1) One properly conducted, adequately powered randomized controlled trial (RCT)

(2) at least one other concordant, prospective, controlled clinical study—either a second RCT, a quasi-experimental pre-post study, a pragmatic nonrandomized trial, or a carefully conducted historically controlled study. In the absence of such data, the charter requires provision of clinical reviews that discuss care choices. However, recognizing the core ethical and clinical principle of “first do no harm,” authors could recommend against the routine provision of unsubstantiated care as part of clinical reviews. We also sought to incorporate principles of high value care (ie, right care, right place, right cost) and health care quality (ie, safe, effective, patient-centered, timely, efficient, equitable). [19]

Drafting members participated in reviews for 7 questions regarding the diagnosis and management of pyogenic osteomyelitis. For each question, members conducted their own literature review using PubMed, including all years and languages, with key words that varied by the question being asked. Articles were assessed for quality and inclusion by criteria specified in the charter. References from identified articles were also searched for potential inclusion. When divergent opinions on article interpretation or clinical practice existed among the authors, we did not attempt to force consensus; rather, in accord with the charter, we sought to transparently highlight those diverging opinions by discussing care alternatives. For answers based on more than 1 relevant RCT, meta-analysis was conducted using Review Manager 5.4.1 (Cochrane Collaboration).

The consortium that established the WikiGuidelines Charter consisted of 63 participants from 8 countries: Australia, Canada, Colombia, Saudi Arabia, Spain, Switzerland, the United Kingdom, and the US. These participants included physicians, pharmacists, and microbiologists with expertise in general internal and hospital medicine, pediatrics, infectious diseases, orthopedic surgery, pharmacology, and medical microbiology.

The participants addressed 7 questions regarding the diagnosis and management of pyogenic osteomyelitis but found data sufficient to establish clear recommendations for only 2:

• oral antibiotic therapy for pyogenic osteomyelitis.
  
• duration of therapy.
  

In contrast, 5 questions were addressed with clinical reviews in the absence of high-quality data:

• Diagnosis of pyogenic osteomyelitis.
  
• Management of osteomyelitis underlying pressure ulcers.
  
• Appropriate timing of empirical therapy.
  
• Rational selection of antimicrobial options.
  
• Use of serial biomarkers or imaging studies to evaluate therapeutic response.
  

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, noninvasive, 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 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 examination, 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

Does Adjunctive Rifampin Alter Osteomyelitis Treatment Outcomes; for Which Organisms Is Rifampin Therapy Potentially Useful, and If It Is Used, Is There a Preferred Dosing?

Some observational studies and small RCTs suggest that addition of rifampin to standard therapy may improve long-term outcomes by reducing relapse of osteomyelitis, with or without retained implants or hardware. However, other observational studies and 1 small RCT are contrary. Overall, the data are mixed and remain uncertain (eFigure 1 and 2 in Supplement 2). The use of rifampin in this setting is based on culture results (principally targeting gram-positive cocci or nonfermenting gram-negative bacilli) and individual patient risk-benefit considerations, acknowledging the uncertainty of the efficacy data, side effects, and potential drug interactions (especially those disrupting stable, chronic medications, such as oral anticoagulants or opiates). Studies have not elucidated optimal total daily dosing, except that 450 to 600 mg per dose likely increases pharmacodynamic target attainment and adherence compared with 300 mg multiple daily dosing.[22-26]

What Is the Role of Long-Acting Glycopeptide Antibiotics in Treating Osteomyelitis?

One RCT and several small, largely single-center, observational studies have examined the role of 2 long-acting glycopeptides, dalbavancin and oritavancin, for the treatment of osteomyelitis.[27,28] In these studies, the long-acting agents performed similarly to comparator regimens. There are no data supporting their superiority, so the use of these agents is based on risk-benefit considerations, as well as cost and complexity vs other regimens for individual patients and health system contexts.

FIGURE.

Oral Antibiotics

IV Antibiotics

Osteomyelitis (Including DFO) Without a Retained Implant

Based on small RCTs, 3 or 4 weeks may be a reasonable duration of antibiotics for debrided osteomyelitis, whether hematogenous or contiguous (including DFO); however, confirmatory data are desired. Based on observational studies and 1 small RCT, it is reasonable to refrain from antibiotic use after total resection of infected bone if the treating physicians are confident that all infected bone has been resected. If administered, we do not recommend exceeding 2 to 5 days of therapy if there is no complicating soft tissue infection.