SLR - March 2016 - Ashley Varner

Title: Six-Week Versus Twelve-Week Antibiotic Therapy for Nonsurgically Treated Diabetic Foot Osteomyelitis: A Multicenter Open-label Controlled Randomized Study

Reference: Tone A, Nguyen S, Devemy F, Topolinski H, Valette M, Cazaubiel M, Fayard A, Beltrand E, Lemaire C, Senneville E. Six-Week Versus Twelve-Week Antibiotic Therapy for Nonsurgically Treated Diabetic Foot Osteomyelitis: A Multicenter Open-label Controlled Randomized Study. Diabetes Care. 2015 Feb; 38(2): 302-7.  

Scientific Literature Review

Reviewed By: Ashley Varner, DPM
Residency Program: Beaumont Hospital, Farmington Hills

Podiatric Relevance: Effective treatment of diabetic foot osteomyelitis (DFO) has been a subject of debate for many years. The question often explored is whether or not diabetic foot osteomyelitis can be treated without removing the involved bone. Older studies, where antimicrobial therapy was used alone, showed disappointing results. However, more recent clinical studies have shown promising results in using antibiotic therapy without bone resection. However, even with these new promising results, appropriate duration of the antibiotic treatment is unknown. The goal of this study is to compare the effectiveness and tolerance of patients with DFO who were treated non-surgically with six weeks vs.12 weeks of antibiotic therapy using rifampin or fluoroquinolone combinations as a first-line therapy.

Methods: A prospective randomized study was conducted at five northern France investigational centers comparing six vs.12 week durations of antibiotic treatment in diabetic patients treated nonsurgically. Inclusion criteria for this study involved patients that were at least 18 years old with type 2 diabetes and osteomyelitis of the foot. The patients were also required to have a wound present for the duration greater than or equal to two weeks. The wound had to have a surface area of greater than or equal to 2 cm^2 or be greater than or equal to 3 mm in depth. These wounds had to probe to bone and/or have some abnormalities consistent with osteomyelitis on x-ray, bone scans or MRI. To confirm the diagnosis of osteomyelitis, a transcutaneous bone biopsy was performed on all participants after an antibiotic-free period of at least two weeks. Exclusion criteria for the study included patients with absent anterior and posterior pedal pulses upon doppler arterial exam, showed significant stenosis or occlusions. Patients who had gangrene, those who required bone resection because of bone and/ or joint destruction or those patients requiring amputation due to severe peri-osteoarticular damage were excluded from the study. 211 patients were evaluated for DFO. Ultimately 40 patients met the study criteria and were included in the study.

Empirical antibiotics were prescribed while waiting on bone biopsy culture results if the physician considered it necessary. Antibiotics directed by bone biopsy cultures were started as soon as definitive results were available. Antibiotic therapy was begun with a median delay of 14 days after bone biopsy. For gram-positive cocci infections, rifampin was used in combination with levofloxicin, trimethoprim sulfamethoxazole, doxycycline, linezolid and other active agents against the bone pathogens. For gram negative bacilli infections, levofloxcin or ciprofloxacin were used in combination with cefotaxime, ceftriaxone or cefepime for the first two weeks and then used as monotherapy. All antibiotic combinations were chosen according to the susceptibility profile of the bone pathogens. All antibiotics were administered orally the entire treatment or intravenously for a short period (5 to 7 days) followed by a long course of oral therapy. A computerized random number generator was used to generate random allocation of 6 vs.12 week durations of treatment.

Adverse events related to the antibiotic treatment were documented. Reduction in daily dosage and/or discontinuation due to intolerance was also documented. All participating physicians adopted a standardized approach for the patient’s wound debridement and care. Physicians also utilized offloading devices to remove pressure from the wound.

Results: The primary outcome measure investigated the proportion of patients in each group with remission of DFO and the secondary outcome measure examined the number of episodes of adverse events attributable to the antibiotic treatments noted in each group.

At the end of the 12 months, 26 (66 percent) of patients were considered to be in remission. Remission was defined as stabilized or improved radiographic abnormalities, absence of any local or systemic signs of infection, and complete sustained healing of the wound responsible for the underlying DFO. Of the 26 patients in remission, 12 were from the six weeks group and 14 from the 12 week group. Among the failure patients, there was no significant difference between the 6 and 12 week groups in terms of those patients that went on to have relapsing osteomyelitis, spread of osteomyelitis to contiguous sites, worsening radiological bone abnormalities and those that ended up needing a bone resection or major amputation.

Antibiotic related adverse events were found in 16 (40 percent) of patients, 6 (30 percent) of 6 week group and 10 (50 percent) of the 12 week group. The most common adverse event was gastrointestinal in nature and all were attributable to rifampin. Other adverse events included skin allergy, drug-drug interactions, dizziness, acute renal insufficiency and thrush.

Conclusions: The use of antibiotic treatment as a first line therapy for DFO can be a considerable option in those patients that are not good surgical candidates. Infectious Disease Society of America guidelines suggest that antibiotic therapy should be continued for six to 12 weeks if infected soft tissue or bone remains after surgery. In addition, the guidelines also state that antibiotics should continue for 12 weeks or more in those patients where resection of infected or necrotic bone could not be done. The results of this study suggest that a six-week duration of antibiotic treatment has an outcome similar to that of 12 week duration in DFO patients treated non-surgically. This is an interesting finding considering the increased concerns with extensive antibiotic use with the emergence of bacterial resistance and clostridium difficile- associated diarrhea. If shortening the duration of treatment can still result in a favorable or similar outcome, then one can ponder whether or not we can also reduce the unfavorable consequences associated with long term antibiotic therapy. The results of this study expose the need for additional larger scale investigations exploring other benefits of reducing the duration of antibiotic therapy when treating diabetic foot osteomyelitis. 

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