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Current Concepts In Treating Osteomyelitis

With diabetic foot osteomyelitis historically considered a condition warranting surgery, these authors share evidence from the literature that challenges that traditional thinking and note that emerging research may support less aggressive surgical or medical intervention in some cases. 

The treatment of diabetic foot osteomyelitis and its complications continues to be an increasing burden on the health-care system.1 Commonly occurring in infected diabetic foot ulcers (DFUs), osteomyelitis is present in 10 to 15 percent of moderate infections and 50 percent of severe infections.2 Diabetic foot osteomyelitis is a serious complication of peripheral neuropathy, peripheral arterial disease and decreased healing potential in those with diabetes.3,4 Osteomyelitis most frequently affects the forefoot (90 percent) followed by the midfoot (five percent) and the hindfoot (five percent).5,6 

In 1970, Waldvogel and colleagues formulated a classification system that broadly divided osteomyelitis into hematogenous infections versus contiguous infections.7 One can subdivide contiguous infections into those with and without vascular insufficiency, and further categorize these infections as either acute or chronic. Most patients with diabetic foot osteomyelitis have contiguous infection from a diabetic foot ulcer.4,8 As opposed to acute osteomyelitis, chronic osteomyelitis can be much more insidious and difficult to eradicate, especially in patients with a non-healing ulcer. Although systemic symptoms generally subside, one or more foci in the bone may still contain infected tissue or a sequestrum. One may find the infected foci surrounded by sclerotic, avascular bone or a thickened periosteum or involucrum.9 As a result, intermittent exacerbations may occur for years and often present clinically as “acute on chronic” infections. 

The management of diabetic foot osteomyelitis is one of the most debated aspects regarding treatment of the diabetic foot.3,10,11 Surgical resection of infected bone followed by a course of systemic antibiotic therapy is long considered the standard treatment for for these chronic cases.3,12 Yet complications including recurrence of osteomyelitis, subsequent bone infection at adjacent sites and the formation of new ulcerations continue to pose challenges for many clinicians.5,6,13,14 

Evidence in the past decade, however, challenges this standard of care by showing successful outcomes with alternative treatment approaches.8,15,16 Recently, the International Working Group on the Diabetic Foot (IWGDF) updated its guidelines based on a systematic review produced by a group of individual experts in various fields of study.17 Based on recent data, the updated guidelines support conservative antibiotic and surgical approaches in the treatment of uncomplicated forefoot diabetic foot osteomyelitis. 

With these concepts and challenges in mind, let us take a closer look at the evidence when it comes to conservative versus surgical management, the route of antibiotic therapy and the duration of antibiotic therapy for osteomyelitis. Additionally, we will review the history of the management of diabetic foot osteomyelitis and how it has led to the current national and global guidelines. 

What The Literature Reveals About Conservative Versus Surgical Treatment 

Whether surgical or medical management is the optimal approach to treat diabetic foot osteomyelitis is a decades-long topic of debate. In the pre-antibiotic era, surgical resection was the only viable treatment option.7,13 While the advent of antibiotics significantly altered the treatment approach, many physicians still consider diabetic foot osteomyelitis to primarily be a surgical disease.14 

In 1970, Waldvogel and colleagues reported a low cure rate with initial conservative surgical treatment in 31 patients with osteomyelitis (including 26 patients with diabetes).7 The conservative surgeries included incision and drainage, and toe amputations. The study authors noted high cure rates for patients who went on to transmetatarsal amputations or below-knee amputations. As a result of these findings, these authors concluded that providers should primarily treat uncomplicated forefoot diabetic foot osteomyelitis with amputation. 

Lew and Waldvogel further explained that the avascular envelope, or involucrum, that forms in chronic osteomyelitis makes systemic antibiotics virtually ineffective.5 Therefore, surgical intervention is necessary to eliminate dead bone, which acts as foreign material.5 In 1994, Karchmer and Gibbons reported that inadequate bone debridement was the main reason for the high rate of recurrence of osteomyelitis.6 Therefore, these authors maintained that the most optimal approach was aggressive debridement down to viable bone followed by a short course of antibiotics to heal the remaining soft tissue infection. 

In a single center retrospective study of 224 patients between 1993 to 2000, Henke and team tested the hypothesis that early surgical therapy would result in an improved chance of wound healing and limb salvage in comparison with antibiotics alone.14 In the study, 95 patients had surgery for diabetic foot osteomyelitis and 129 patients received antibiotic therapy alone. Surgeries included local debridement (77 percent), toe amputation (20 percent) and partial foot amputation (three percent). All patients at index admission received empiric broad-spectrum antibiotics. Fifty-two percent of patients had previous outpatient antibiotic therapy with a mean duration of five months. Henke and colleagues found a significant correlation between initial surgical therapy and wound healing whereas pre-admission antibiotic use was associated with decreased wound healing.14 

Among those who had surgery, three percent required further local debridement, 8.5 percent required a later toe amputation and 18 percent required a major amputation.14 When stratifying for specific surgical procedures, researchers found that those who had minor amputation had a lower mortality risk, lower risk of major amputation and lower rate of unfavorable discharge. At 31 months, the study authors reported a 82 percent limb salvage rate in the surgical group. Similarly, those treated by medical management alone had an 81 percent limb salvage rate, showing no statistically significant difference from the surgery group. Therefore, while initial surgical therapy had a significant association with wound healing, there was not a significant association with a greater rate of limb salvage.14 

While a number of studies in the past demonstrated successful eradication of bone infection with surgery, it is important to consider that this is not the endpoint for many patients. Evidence shows that surgical treatment of osteomyelitis leads to biomechanical changes, resulting in new ulcerations and episodes of osteomyelitis. Studies evaluating outcomes after hallux or partial first ray amputations for hallux ulcers reported that two-thirds of patients developed new ulcerations and amputations.9,18 The psychosocial impact of going through multiple amputations can prove devastating for patients.19 Alternatively, utilizing limited resection of bone without performing amputations and/or antibiotic therapy alone may be effective, and also preserve anatomic integrity.8,15 

In 2014, Lazaro-Martinez and coworkers performed the very first prospective randomized comparative study comparing conservative surgery versus antibiotic treatment in 52 patients with forefoot diabetic foot osteomyelitis.8 Researchers excluded patients with severe infections, according to the Infectious Diseases Society of America (IDSA) classification, necrotizing soft tissue infections, peripheral arterial disease or Charcot foot. Of the 46 patients who completed the study, 24 patients received a 90-day course of antibiotics and 22 patients had surgical debridement of only infected bone without amputation, and received postoperative antibiotics for 10 days. 

In the 12-week follow-up period, 18 (75 percent) patients in the antibiotic group achieved primary healing with a median time to healing of seven weeks and four patients (16.6 percent) worsened and underwent surgery.8 In the surgery group, 19 patients (86.3 percent) achieved primary healing with a median time to healing of six weeks. Three patients (13.6 percent) required reoperations. There were no differences between the two groups regarding minor amputations from complications. 

Lazaro-Martinez and colleagues concluded that antibiotic therapy and surgical treatment had similar outcomes for forefoot diabetic foot osteomyelitis in terms of healing rates, time to healing and short-term complications.8 The limitations of the study included a small study sample, no midterm or long-term follow-up, and a lack of diagnosis of osteomyelitis by bone biopsy. Despite these limitations, the results suggest that patients with forefoot diabetic foot osteomyelitis in the mild to moderate IDSA classification, without ischemia or necrotizing soft tissue infection, may have successful outcomes with antibiotic therapy alone.8 

Furthermore, in a retrospective study, Lesens and colleagues compared treatment outcomes in 74 patients with Staphylococcus aureus diabetic foot osteomyelitis who either had surgery with subsequent antibiotic therapy or antibiotic therapy with bedside debridement only.20 In a mean follow-up of 21 months, the authors found favorable outcomes (no relapse, impaired wound healing or amputation) in greater than 80 percent of patients in both groups with no statistically significant difference. Patients in the antibiotic-only group had less frequent hospitalization and shorter lengths of hospital stay. Patients in the surgery group received a significantly shorter course of antibiotics with fewer side effects (nine percent versus 33 percent in the medical management group). The authors concluded that except for significant differences in duration of hospitalization and antibiotic therapy, both groups had similar outcomes.20 

The updated International Working Group on the Diabetic Foot guidelines state that in patients with uncomplicated forefoot diabetic foot osteomyelitis, for whom there is no other indication for surgical treatment, antibiotic therapy without surgical resection of bone is a consideration.17 However, the guidelines do not discuss details regarding specific surgical procedures due to the lack of evidence. 

Does The Route Of Antibiotics Matter? 

Traditionally, one would treat severe and some moderate diabetic foot infections with parenteral antibiotic therapy, and switch to oral therapy when the patient shows signs of improvement.21 In the past, experts believed parenteral delivery achieved higher levels of antibiotic bone concentration than oral delivery.22 In recent years, researchers have challenged this thinking with mounting evidence supporting oral agents with high bioavailability and good tissue penetration as the initial route of treatment.13,22-25 This fundamental shift began over 20 years ago with a study investigating complications of central venous catheters in pediatric hematogenous osteomyelitis.24 The study authors noted complication rates as high as 40 percent with catheter malfunction, catheter site infections and catheter-related bloodstream infections being the main complications.24 

In 2013, a Cochrane systematic review pooled data from eight randomized trials, which included 248 people with chronic osteomyelitis.25 The most common etiology of osteomyelitis was post-traumatic and mostly located in the tibia and femur. In four trials comparing oral versus parenteral routes, there was no significant difference between the two groups in remission rate 12 or more months after treatment (77 versus 81 percent). Additionally, there was no significant difference between the two groups for mild adverse events (17 versus 15 percent) or severe adverse events (six versus 10 percent). The authors concluded that based on the limited evidence, the route of antibiotic administration did not affect the rate of disease remission.25 

These results are further supported by a recent multicenter, randomized, controlled trial called the Oral Versus Intravenous Antibiotics for Bone and Joint Infections (OVIVA) trial.23 In 2019, the study authors reported outcomes of 1,054 patients with a clinical diagnosis of bone, joint or orthopedic hardware-associated infection. Approximately 20 percent of patients had diabetic foot osteomyelitis. In the study, 527 patients received either oral or intravenous antibiotics for the first six weeks of therapy. Thirty-nine participants did not complete the follow-up and researchers did not record endpoint data, resulting in the modified intention-to-treat analysis of 1015 participants. 

Primary endpoint results revealed that 74 out of 506 patients (14.62 percent) in the intravenous group and 67 out of 509 patients (13.16 percent) in the oral group had definitive treatment failure at one year with no statistically significant difference between the two groups.23 The authors defined treatment failure as the presence of at least one clinical, microbiological or histological infection criterion. The median hospital stay was significantly longer in the intravenous group than the oral group (14 versus 11 days) and similar to previous trials.23 

There was no statistically significant difference in serious adverse events between the two groups with the exception of IV catheter complications (9.4 percent in the intravenous group versus 1.0 percent in the oral group).23 The results suggest that oral antibiotic therapy was non-inferior to intravenous antibiotic therapy when researchers used it during the first six weeks of treatment for bone and joint infections, and oral therapy resulted in shorter hospital stays and less complications. 

It is important to note that while the authors did not stratify outcomes for patients specifically with diabetic foot osteomyelitis, the robust data from both of these studies poses a challenge to the traditional approach to treating diabetic foot osteomyelitis, and warrants further comparative studies in this population.23,25 

What Is The Optimal Duration Of Antibiotic Therapy? 

The emergence of bacterial resistance and its impact on recurrence rate in diabetic foot osteomyelitis is an important consideration when discussing the duration of antibiotic therapy.26,27 In 2012, the IDSA published guidelines recommending at least three months of antibiotic therapy for diabetic foot osteomyelitis treated by medical management alone.28 The organization made this recommendation based on historical data showing success rates of 65 to 80 percent in diabetic foot osteomyelitis cases managed by a prolonged course of antibiotics without surgery.29,30 However, there is no evidence suggesting that antibiotic therapy for more than six weeks improves cure rate.31 Additionally, growing reports of adverse events, such as the development of pseudomembranous colitis, and the rising cost of antibiotic treatment has led to newer evidence in the literature showing positive outcomes with shorter durations of treatment. 

In a randomized trial, Tone and colleagues assessed 40 patients with diabetic foot osteomyelitis and without peripheral artery disease who received either six weeks or 12 weeks of antibiotics therapy.31 Sixty percent of patients had remission at six weeks in comparison to 70 percent at 12 weeks. Gastrointestinal adverse events were less frequent in the group treated for six weeks in comparison to those treated for 12 weeks (15 percent versus 45 percent). These results suggest that six weeks duration of antibiotic therapy may be sufficient in patients with diabetic foot osteomyelitis treated without surgical debridement or amputation, and correlates with better gastrointestinal tolerance. 

One notable strength of this study was that the researchers evaluated patient outcomes at least one year after the end of treatment.31 Although the sample size of this study was small, this well-designed trial warrants larger-scale studies to assess the efficacy and benefits of a shorter duration of therapy. 

In a retrospective study, Gariani and coworkers investigated whether the route or duration of antibiotic therapy was associated with diabetic foot infection recurrence.32 Among 1,018 episodes of diabetic foot infection in 482 patients, including 392 cases of osteomyelitis, the median total duration of antibiotic use was 20 days, which included parenteral therapy for the first five days. After a median follow-up of three years, the results showed that neither the duration nor the route of antibiotic therapy affected the risk of recurrence. When the researchers stratified for osteomyelitis cases, the results were the same. However, the study authors could not determine a threshold for an optimal antibiotic duration, which is consistent with other current studies in the literature.32 

In Conclusion 

Diabetic foot osteomyelitis is a source of high burden on the health-care system. With the increasing incidence of diabetes worldwide, these infections will likely become more prevalent. It is therefore crucial to employ evidence-based guidelines to manage this difficult condition. Research over the past decade has significantly increased our understanding of the diagnosis and management of diabetic foot ostemyelitis. 

Recent evidence in the literature supports the value of using more conservative antibiotic and surgical approaches in the treatment of uncomplicated forefoot cases. Current guidelines from the International Working Group on the Diabetic Foot state that primarily surgical or primarily non-surgical approaches in selected patients without peripheral artery disease and without exposed bone or abscess have similar outcomes.17 The guidelines also recommend that the duration of antibiotic treatment for diabetic foot infections should not exceed six weeks in patients with osteomyelitis who do not undergo surgical resection of infected bone. Aragón-Sánchez and Lipsky stated in their expert review that “antibiotic therapy, preferably with oral agents guided by results of bone culture, for a duration of no more than six weeks appears to be as safe and effective as surgery in cases of uncomplicated forefoot (diabetic foot osteomyelitis).”10 

Given the growing effort to formulate evidence-based clinical pathways in the management of diabetic foot osteomyelitis, we must continue to emphasize preventative measures such as patient education, proper footwear, offloading and glycemic control as essential aspects in evidence-based guidelines. Further studies that strictly adhere to the definitions of diagnosis and treatment of diabetic foot osteomyelitis are necessary to evaluate outcomes and improve management in the future.  

Dr. Kim is a first-year podiatry resident at Mercy Hospital and Medical Center in Chicago. 

Dr. Wu is the Dean and a Professor of Surgery at the Dr. William M. Scholl College of Podiatric Medicine, and a Professor of Stem Cell and Regenerative Medicine at the School of Graduate Medical Sciences at the Rosalind Franklin University of Medicine and Science in Chicago. She is also the Director of the Center for Lower Extremity Ambulatory Research (CLEAR) in Chicago. 

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By John J. Kim, DPM and Stephanie C. Wu, DPM, MSc, FACFAS
References

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