A systematic review of the effectiveness of interventions in the management of infection in the diabetic foot.

The International Working Group on the Diabetic Foot expert panel on infection conducted a systematic review of the published evidence relating to treatment of foot infection in diabetes. Our search of the literature published prior to August 2010 identified 7517 articles, 29 of which fulfilled predefined criteria for detailed data extraction. Four additional eligible papers were identified from other sources. Of the total of 33 studies, 29 were randomized controlled trials, and four were cohort studies. Among 12 studies comparing different antibiotic regimens in the management of skin and soft-tissue infection, none reported a better response with any particular regimen. Of seven studies that compared antibiotic regimens in patients with infection involving both soft tissue and bone, one reported a better clinical outcome in those treated with cefoxitin compared with ampicillin/sulbactam, but the others reported no differences between treatment regimens. In two health economic analyses, there was a small saving using one regimen versus another. No published data support the superiority of any particular route of delivery of systemic antibiotics or clarify the optimal duration of antibiotic therapy in either soft-tissue infection or osteomyelitis. In one non-randomized cohort study, the outcome of treatment of osteomyelitis was better when the antibiotic choice was based on culture of bone specimens as opposed to wound swabs, but this study was not randomized, and the results may have been affected by confounding factors. Results from two studies suggested that early surgical intervention was associated with a significant reduction in major amputation, but the methodological quality of both was low. In two studies, the use of superoxidized water was associated with a better outcome than soap or povidone iodine, but both had a high risk of bias. Studies using granulocyte-colony stimulating factor reported mixed results. There was no improvement in infection outcomes associated with hyperbaric oxygen therapy. No benefit has been reported with any other intervention, and, overall, there are currently no trial data to justify the adoption of any particular therapeutic approach in diabetic patients with infection of either soft tissue or bone of the foot.

Expert opinion on the management of infections in the diabetic foot.

This update of the International Working Group on the Diabetic Foot incorporates some information from a related review of diabetic foot osteomyelitis (DFO) and a systematic review of the management of infection of the diabetic foot. The pathophysiology of these infections is now well understood, and there is a validated system for classifying the severity of infections based on their clinical findings. Diagnosing osteomyelitis remains difficult, but several recent publications have clarified the role of clinical, laboratory and imaging tests. Magnetic resonance imaging has emerged as the most accurate means of diagnosing bone infection, but bone biopsy for culture and histopathology remains the criterion standard. Determining the organisms responsible for a diabetic foot infection via culture of appropriately collected tissue specimens enables clinicians to make optimal antibiotic choices based on culture and sensitivity results. In addition to culture-directed antibiotic therapy, most infections require some surgical intervention, ranging from minor debridement to major resection, amputation or revascularization. Clinicians must also provide proper wound care to ensure healing of the wound. Various adjunctive therapies may benefit some patients, but the data supporting them are weak. If properly treated, most diabetic foot infections can be cured. Providers practising in developing countries, and their patients, face especially challenging situations.

The microbiology of chronic osteomyelitis: prevalence of resistance to common empirical anti-microbial regimens.

OBJECTIVES: This study describes the microbiological spectrum of chronic osteomyelitis and so guides the choice of empirical antibiotics for this condition. METHODS: We performed a prospective review of a 166 prospective patient series of chronic osteomyelitis from Oxford, UK in which a standardised surgical sampling protocol was used. RESULTS: Staphylococcus aureus was most commonly isolated (32%) amongst a wide range of organisms including gram negative bacilli, anaerobes and coagulase negative staphylococci. Low grade pathogens were not confined to patients with a history of metalwork, a high proportion of cases were polymicrobial (29%) and culture negative cases were common (28%). No clear predictors of causative organism could be established. Many isolates were found to be resistant to commonly used empirical anti-microbial regimens. CONCLUSIONS: The wide range of causative organisms and degree of resistance to commonly used anti-microbials supports the importance of extensive intra-operative sampling and provides important information to guide clinicians' choice of empirical antibiotics.

Two-stage revision for prosthetic joint infection: predictors of outcome and the role of reimplantation microbiology.

OBJECTIVES: We describe rates of success for two-stage revision of prosthetic joint infection (PJI), including data on reimplantation microbiology. METHODS: We retrospectively collected data from all the cases of PJI that were managed with two-stage revision over a 4 year period. Patients were managed with an antibiotic-free period before reimplantation, in order to confirm, clinically and microbiologically, that infection was successfully treated. RESULTS: One hundred and fifty-two cases were identified. The overall success rate (i.e. retention of the prosthesis over 5.75 years of follow-up) was 83%, but was 89% for first revisions and 73% for re-revisions [hazard ratio = 2.9, 95% confidence interval (CI) 1.2-7.4, P = 0.023]. Reimplantation microbiology was frequently positive (14%), but did not predict outcome (hazard ratio = 1.3, 95% CI 0.4-3.7, P = 0.6). Furthermore, most unplanned debridements following the first stage were carried out before antibiotics were stopped (25 versus 2 debridements). CONCLUSIONS: We did not identify evidence supporting the use of an antibiotic-free period before reimplantation and routine reimplantation microbiology. Re-revision was associated with a significantly worse outcome.

Pharmacotherapy of diabetic foot osteomyelitis.

Diabetic foot osteomyelitis (DFO) complicates about 20% of diabetic foot infections (DFIs) and increases the risk of lower extremity amputation. This contentious infection is important to discuss, given the frequency with which diabetes mellitus and its complications occur and the devastating consequences of amputation. The diagnosis and management of DFO is complicated by the diverse presentations, delayed recognition, poorly defined diagnostic criteria, and lack of validated treatment regimens. Major issues of concern include when to undertake bone resection surgery and which antimicrobial agents to use, by what route, and for how long. Patients in whom DFO is suspected are best cared for by a multidisciplinary team, including infectious disease physicians or clinical microbiologists, orthopaedic, plastic and vascular surgeons, diabetologists, primary care physicians, podiatrists and specialist (especially tissue viability) nurses. Such multidisciplinary teams have repeatedly been shown to improve disease outcomes. We herein analyse the limited, and recently published, literature on the pharmacotherapy of DFO and put it into the broader context of management of DFI and osteomyelitis.

One hundred and twelve infected arthroplasties treated with 'DAIR' (debridement, antibiotics and implant retention): antibiotic duration and outcome.

OBJECTIVES: We describe treatment failure rates by antibiotic duration for prosthetic joint infection (PJI) managed with debridement, antibiotics and implant retention (DAIR). METHODS: We retrospectively collected data from all the cases of PJI that were managed with DAIR over a 5 year period. Surgical debridement, microbiological sampling, early intravenous antibiotics and prolonged oral follow-on antibiotics were used. RESULTS: One hundred and twelve cases of PJI were identified. Twenty infections (18%) recurred during a mean follow-up of 2.3 years. The mean duration of antibiotic use was 1.5 years. Failure was more common after arthroscopic debridement, for previously revised joints and for Staphylococcus aureus infection. There were 12 failures after stopping antibiotics and 8 while on antibiotics [hazard ratio (HR) = 4.3, 95% confidence interval (CI) 1.4-12.8, P = 0.01]. However, during the first 3 months of follow-up, there were eight failures after stopping antibiotics and two while on antibiotics (HR = 7.0, 95% CI 1.5-33, P = 0.015). The duration of antibiotic therapy prior to stopping did not predict outcome. CONCLUSIONS: PJI may be managed by DAIR. The risk of failure with this strategy rises after stopping oral antibiotics, but lengthening antibiotic therapy may simply postpone, rather than prevent, failure.

Unresolved issues in the management of ulcers of the foot in diabetes.

Management of diabetic foot ulcers presents a major clinical challenge. The response to treatment is often poor and the outcome disappointing, while the costs are high for both healthcare providers and the patient. In such circumstances, it is essential that management should be based on firm evidence and follow consensus. In the case of the diabetic foot, however, clinical practice can vary widely. It is for these reasons that the International Working Group on the Diabetic Foot has published guidelines for adoption worldwide. The Group has now also completed a series of non-systematic and systematic reviews on the subjects of soft tissue infection, osteomyelitis, offloading and other interventions designed to promote ulcer healing. The current article collates the results of this work in order to demonstrate the extent and quality of the evidence which is available in these areas. In general, the available scientific evidence is thin, leaving many issues unresolved. Although the complex nature of diabetic foot disease presents particular difficulties in the design of robust clinical trials, and the absence of published evidence to support the use of an intervention does not always mean that the intervention is ineffective, there is a clear need for more research in the area. Evidence from sound clinical studies is urgently needed to guide consensus and to underpin clinical practice. It is only in this way that patients suffering with these frequently neglected complications of diabetes can be offered the best hope for a favourable outcome, at the least cost.

Pristinamycin as adjunctive therapy in the management of Gram-positive multi-drug resistant organism (MDRO) osteoarticular infection.

OBJECTIVE: Osteoarticular infection often requires prolonged antibiotic therapy as an adjunct to surgery. We report our experience using pristinamycin, an oral streptogramin, when conventional antibiotics were poorly tolerated or inappropriate because of multi-drug resistant organisms (MDROs). METHODS: We retrospectively identified, from pharmacy records, all patients prescribed pristinamycin between 1/1/2004 and 31/12/2006. We collected clinical and microbiological data. RESULTS: Twenty-one patients were identified (13 male and eight female patients, age range 18-83 years). Sixteen patients (76%) had infection due to MDROs and five (24%) were intolerant of conventional antibiotics. Ten patients received other concurrent oral antibiotics. Eleven of 21 (52%) patients remained free of recurrent infection off antibiotics at a mean follow up duration of 13 months, (range 4-25 months). Suppression of infection while still on therapy was achieved in a further four patients (19%) with a mean follow up of 11.5 months (range 5-15 months). Six patients (29%) failed therapy, all requiring a further surgical procedure. CONCLUSION: Oral pristinamycin was a well tolerated and useful adjunctive treatment in this group with complex orthopaedic infection. Pristinamycin can be considered in patients with osteoarticular infection due to Gram-positive organisms when antibiotic multi-resistance or intolerance makes conventional therapies impossible. SUMMARY: We report our experiences of using pristinamycin in the management of 21 patients with Gram-positive MDRO osteoarticular infection or who were unable to tolerate more conventional regimens. Our results show that pristinamycin is well tolerated with outcomes comparable to those of other agents described in the literature on osteoarticular infection.

Diabetic foot osteomyelitis: a progress report on diagnosis and a systematic review of treatment.

The International Working Group on the Diabetic Foot appointed an expert panel to provide evidence-based guidance on the management of osteomyelitis in the diabetic foot. Initially, the panel formulated a consensus scheme for the diagnosis of diabetic foot osteomyelitis (DFO) for research purposes, and undertook a systematic review of the evidence relating to treatment. The consensus diagnostic scheme was based on expert opinion; the systematic review was based on a search for reports of the effectiveness of treatment for DFO published prior to December 2006. The panel reached consensus on a proposed scheme that assesses the probability of DFO, based on clinical findings and the results of imaging and laboratory investigations. The literature review identified 1168 papers, 19 of which fulfilled criteria for detailed data extraction. No significant differences in outcome were associated with any particular treatment strategy. There was no evidence that surgical debridement of the infected bone is routinely necessary. Culture and sensitivity of isolates from bone biopsy may assist in selecting properly targeted antibiotic regimens, but empirical regimens should include agents active against staphylococci, administered either intravenously or orally (with a highly bioavailable agent). There are no data to support the superiority of any particular route of delivery of systemic antibiotics or to inform the optimal duration of antibiotic therapy. No available evidence supports the use of any adjunctive therapies, such as hyperbaric oxygen, granulocyte-colony stimulating factor or larvae. We have proposed a scheme for diagnosing DFO for research purposes. Data to inform treatment choices in DFO are limited, and further research is urgently needed.

Guiding empirical antibiotic therapy in orthopaedics: The microbiology of prosthetic joint infection managed by debridement, irrigation and prosthesis retention.

OBJECTIVES: This study describes the microbiological spectrum of prosthetic joint infection (PJI) managed by debridement, washout and retention and so guides the choice of empirical antibiotics within this patient group. METHODS: We performed a retrospective review of all patients admitted to our specialist tertiary unit for PJI who were managed with debridement and irrigation or arthroscopic washout of infected prosthetic joints between 1st January 1998 and 30th April 2003. Clinical and microbiological data sets were analysed using the Access database. RESULTS: One hundred and twelve patients met the criteria for inclusion. 69% received their surgical intervention in the first three months after implantation ('early') and 21% after 12 months. Overall the most frequently isolated organisms were coagulase negative staphylococci (47% patients) and methicillin-sensitive Staphylococcus aureus (MSSA, 44% patients). 8% grew methicillin-resistant Staphylococcus aureus (MRSA) and 7% grew anaerobes. Most Gram-negative isolates were resistant to cefuroxime; all were sensitive to meropenem. Eighty-six percent of polymicrobial cultures occurred in early infections when 47% of patients grew more than one organism. MSSA was the most frequently isolated organism at all time points. CONCLUSIONS: Most infections involved staphylococci. MRSA was infrequently isolated. Most polymicrobial infections occurred in early infection. A high rate of resistance to cephalosporins among Gram-negative organisms justifies the use of a broader agent such as a carbapenem in the early empirical antibiotic regime for PJI.

Counterpoint: hyperbaric oxygen for diabetic foot wounds is not effective.

BACKGROUND: Diabetic foot ulceration is common, affecting 1.0%-4.1% of diabetic persons per year and up to 25% in a lifetime. Diabetic foot ulcers are multifactorial in origin, and many are slow to heal and/or are complicated by infection, frequently leading to amputation. Hyperbaric oxygen therapy has been suggested for numerous indications, and it is recognized by funding agencies for a smaller number including diabetic foot wounds. METHODS: I reviewed the literature about the history and practice of hyperbaric oxygen therapy and key issues relevant to efficacy, effectiveness, and cost-effectiveness. RESULTS: Although recognized for reimbursement by Medicare and major insurers, the evidence base for hyperbaric oxygen therapy for diabetic foot care remains weak. A systematic review for the Cochrane Collaboration concluded that hyperbaric oxygen therapy may have value in treating diabetic wounds, but the studies reviewed all had methodological weaknesses, and the positive effect of treatment was not seen in the single reviewed randomized trial to include a sham treatment arm. Hyperbaric oxygen therapy consumes very substantial resources--and has the potential to consume far more--that could be better spent on other aspects of management or prevention of diabetic foot ulceration. CONCLUSIONS: Hyperbaric oxygen therapy should not be offered for diabetic foot wounds until large-scale, adequately blinded, controlled, and powered randomized studies have clearly demonstrated efficacy and cost effectiveness in the healing of ulcers and the prevention of major amputation.

MRI of mycetoma of the foot: two cases demonstrating the dot-in-circle sign.

Radiological and histological findings of two patients with fungal mycetoma of the foot are presented. MRI revealed multiple 2-5 mm lesions of high signal intensity interspersed within a low-intensity matrix. Within many of the lesions a minute low-intensity focus was identified. Ultrasound showed distinct hyperechoic foci within a hypoechoic mass. We speculate that the low-signal matrix represents fibrous tissue, the high-intensity lesions correspond to granulomata and the central low-signal focus to the characteristic organised fungal elements (grains) present in this condition. This "dot-in-circle sign" on MRI reflects the unique pathological features of mycetoma and is likely to be a highly specific sign for this lesion.

Fibronectin-binding protein A of Staphylococcus aureus has multiple, substituting, binding regions that mediate adherence to fibronectin and invasion of endothelial cells.

Invasive Staphylococcus aureus infection frequently involves bacterial seeding from the bloodstream to other body tissues, a process necessarily involving interactions between circulating bacteria and vascular endothelial cells. Staphylococcus aureus fibronectin-binding protein is central to the invasion of endothelium, fibronectin forming a bridge between bacterial fibronectin-binding proteins and host cell receptors. To dissect further the mechanisms of invasion of endothelial cells by S. aureus, a series of truncated FnBPA proteins that lacked one or more of the A, B, C or D regions were expressed on the surface of S. aureus and tested in fibronectin adhesion, endothelial cell adhesion and invasion assays. We found that this protein has multiple, substituting, fibronectin-binding regions, each capable of conferring both adherence to fibronectin and endothelial cells, and endothelial cell invasion. By expressing S. aureus FnBPA on the surface of the non-invasive Gram-positive organism Lactococcus lactis, we have found that no other bacterial factor is required for invasion. Furthermore, we have demonstrated that, as with other cell types, invasion of endothelial cells is mediated by integrin alpha5beta1. These findings may be of relevance to the development of preventive measures against systemic infection, and bacterial spread in the bacteraemic patient.

A link between virulence and ecological abundance in natural populations of Staphylococcus aureus.

Staphylococcus aureus is a major cause of severe infection in humans and yet is carried without symptoms by a large proportion of the population. We used multilocus sequence typing to characterize isolates of S. aureus recovered from asymptomatic nasal carriage and from episodes of severe disease within a defined population. We identified a number of frequently carried genotypes that were disproportionately common as causes of disease, even taking into account their relative abundance among carriage isolates. The existence of these ecologically abundant hypervirulent clones suggests that factors promoting the ecological fitness of this important pathogen also increase its virulence.

Histological and microbiological findings in non-infected and infected revision arthroplasty tissues. The OSIRIS Collaborative Study Group. Oxford Skeletal Infection Research and Intervention Service.

An assessment of clinical and laboratory findings is generally required to distinguish between septic and aseptic loosening of a hip implant. In order to evaluate the diagnostic utility of histological and microbiological investigative techniques to differentiate between these two conditions, we analysed their results in 617 patients with hip implant loosening. Histology and microbiology study confirmed the clinical diagnosis of septic loosening in approximately 98% and 89%. respectively. The clinical diagnosis of aseptic loosening was confirmed by histology in 99% of cases. In all but 2 of 81 cases of septic loosening, in which an organism was isolated on microbiological culture, the histological diagnosis of septic loosening was made on the basis of the degree of the acute inflammatory infiltrate (i.e. the presence of 1 or more neutrophil polymorphs per high power field (x 400) on average after examination of at least 10 high power fields) in periprosthetic tissues. In 10 patients for whom there was a strong clinical suspicion of septic loosening but no organisms were isolated on microbiological culture, the histological findings, using the above criteria, were in keeping with the clinical diagnosis of septic loosening. As almost 11% of cases of septic loosening would not have been diagnosed by microbiological investigation alone, our findings indicate that histological examination of periprosthetic tissues should form part of the investigative protocol to distinguish between aseptic and septic loosening.

Principles and practice of antibiotic therapy of diabetic foot infections.

Foot infections are a common and serious problem in diabetic patients. They usually occur as a consequence of a skin ulceration, which initially is colonized with normal flora, and later infected with pathogens. Infection is defined clinically by evidence of inflammation, and appropriate cultures can determine the microbial etiology. Aerobic gram-positive cocci are the most important pathogens; in chronic, complex or previously treated wounds, gram-negative bacilli and anaerobes may join in a polymicrobial infection. In all diabetic foot infections a primary consideration is whether or not surgical intervention is required, e.g. for undrained pus, wound debridement or revascularization. Antibiotic regimens are usually selected empirically initially, then modified if needed based on results of culture and sensitivity tests and the patient's clinical response. Initial therapy, especially in serious infections, may need to be broad-spectrum, but definitive therapy can often be more targeted. Severe infections usually require intravenous therapy initially, but milder cases can be treated with oral agents. Treatment duration ranges from 1-2 weeks (for mild soft tissue infection) to more than 6 weeks (for osteomyelitis). The choice of a specific agent should be based on the usual microbiology of these infections, data from published clinical trials, the severity of the patient's infection, and the culture results. Extension of infection into underlying bone can be difficult to diagnose and may require imaging tests, e.g. magnetic resonance scans. Cure of osteomyelitis usually requires resection of infected bone, but can be accomplished with prolonged antibiotic therapy. Various non-antimicrobial adjunct therapies may sometimes be helpful. Published in 2000 by John Wiley & Sons, Ltd.

Clinical isolates of Staphylococcus aureus exhibit diversity in fnb genes and adhesion to human fibronectin.

OBJECTIVES: The fibronectin-binding proteins (FnBPs) of Staphylococcus aureus are involved in the pathogenesis of infection, but their characteristics in clinical isolates are incompletely defined. The aim of this study was to evaluate phenotypic and genotypic characteristics of the FnBPs of a large collection of recent isolates. METHODS: The adherence of 163 S. aureus isolates to immobilized fibronectin was compared with that of S. aureus 8325-4 using a microtitre assay. The presence of the genes encoding the fibronectin-binding proteins FnBPA and FnBPB was evaluated by Southern dot blot using probes specific for region A of fnbA or fnbB. RESULTS: The adherence of clinical isolates to fibronectin (expressed as a percentage of the mean adherence of S. aureus 8325-4) was 56%-125% for 155 isolates (95%), and less than 20% for eight isolates (5%). Adherence of the bacterial group associated with orthopaedic implant-associated infection was significantly greater than that for isolates associated with nasal carriage, endocarditis, or septic arthritis/osteomyelitis. Southern dot blot demonstrated that 126/163 isolates had two genes (77%) and 37/163 had one detectable gene (23%). There was no difference in adherence between isolates with one or two fnb, but isolates associated with invasive disease (endocarditis or primary septic arthritis and/or osteomyelitis) were more likely to have two genes. CONCLUSIONS: These data demonstrate diversity in the FnBPs of clinical isolates of S. aureus. The findings suggest that the interplay between pathogenesis and a single virulence determinant is unlikely to be a uniform process across a spectrum of infections. This confirms the need to extend the study of staphylococcal pathogenesis from the laboratory to non-uniform populations of clinically relevant isolates.