Jean-Louis Richard

Effect of Topical Basic Fibroblast Growth Factor on the Healing of Chronic Diabetic Neuropathic Ulcer of the foot: A pilot, randomized, double-blind, placebo-controlled study

OBJECTIVE To assess the efficacy and safety of topical human recombinant basic fibroblast growth factor (bFGF) on the healing of diabetic neurotrophic foot ulcers. RESEARCH DESIGN AND METHODS Seventeen diabetic patients suffering from chronic neuropathic ulcer of the plantar surface of the foot entered a pilot, randomized, double-blind study comparing local application of bFGF with placebo. Main inclusion criteria were a typical neuropathic ulcer of Wagner grade I-III, more than 0.5 cm in the largest diameter, with an abnormally high vibration perception threshold in the absence of significant peripheral vascular disease or wound infection. bFGF or placebo was applied daily during the 6 weeks as inpatients then twice a week for 12 weeks. Evolution of ulcer size was assessed through weekly clinical examination and computerized photographs. RESULTS In the bFGF group, three of nine ulcers healed compared with five of eight in the placebo group (NS). The weekly reduction in ulcer perimeter and area was identical in both groups, as was the rate of linear advance from entry to the 6th week of treatment (bFGF: 0.053 ± 0.048 mm vs. placebo: 0.116 ± 1.129 mm): the same result was obtained at the 11th week. Moreover, percent healed area at the end of the study did not differ significantly. No side effects were observed during bFGF application. CONCLUSIONS Topical application of bFGF has no advantage over placebo for healing chronic neuropathic diabetic ulcer of the foot. Because diabetes causes significant wound-healing defects, we hypothesized that using a single growth factor might be insufficient to accelerate wound closure of diabetic ulcers.

Serum procalcitonin and C-reactive protein concentrations to distinguish mildly infected from non-infected diabetic foot ulcers: a pilot study

Aims/hypothesisInfection of diabetic foot ulcers is common; at early stages it is difficult to differentiate between non-infected ulcers (or those colonised with normal flora) and ulcers infected with virulent bacteria that lead to deterioration. This pilot study aimed to assess the diagnostic accuracy of inflammatory markers as an aid to making this distinction.MethodsWe included 93 diabetic patients who had an episode of foot ulcer and had not received antibiotics during the 6 months preceding the study. Ulcers were classified as infected or uninfected, according to the Infectious Diseases Society of America–International Working Group on the Diabetic Foot classification. Diabetic patients without ulcers (n = 102) served as controls. C-reactive protein (CRP), orosomucoid, haptoglobin and procalcitonin were measured together with white blood cell and neutrophil counts. The diagnostic performance of each marker, in combination (using logistic regression) or alone, was assessed.ResultsAs a single marker, CRP was the most informative for differentiating grade 1 from grade 2 ulcers (sensitivity 0.727, specificity 1.000, positive predictive value 1.000, negative predictive value 0.793) with an optimal cut-off value of 17 mg/l. In contrast, white blood cell and neutrophil counts were not predictive. The most relevant combination derived from the logistic regression was the association of CRP and procalcitonin (AUC 0.947), which resulted in a significantly more effective determination of ulcer grades, as shown by comparing receiver operating characteristic curves.Conclusions/interpretationMeasurement of only two inflammatory markers, CRP and procalcitonin, might be of value for distinguishing between infected and non-infected foot ulcers in subgroups of diabetic patients, to help ensure the appropriate allocation of antibiotic treatment. Nevertheless, external validation of the diagnostic value of procalcitonin and CRP in diabetic foot ulcers is needed before routine use can be recommended.

Virulence Potential of Staphylococcus aureus Strains Isolated From Diabetic Foot Ulcers: A new paradigm

OBJECTIVE—The purpose of this study was to assess the virulence potential of Staphylococcus aureus strains isolated from diabetic foot ulcers and to discriminate noninfected from infected ulcers. RESEARCH DESIGN AND METHODS—Diabetic patients hospitalized in a diabetic foot department with a foot ulcer were prospectively enrolled if they had been free of antibiotic treatment over the previous 6 months. At admission, ulcers were classified as infected or noninfected on the basis of clinical examination, according to the International Working Group on the Diabetic Foot system. Only patients carrying S. aureus as the sole pathogen were included. In individuals with a grade 1 ulcer, a second bacterial specimen was obtained 1 month later. Using virulence genotyping markers, clonality tools, and an in vivo Caenorhabditis elegans model, we correlated the virulence of 132 S. aureus strains with grade, time of collection, and ulcer outcome. RESULTS—Among virulence genes, the most relevant combination derived from the logistic regression was the association of cap8, sea, sei, lukE, and hlgv (area under the curve 0.958). These markers were useful to distinguish noninfected (grade 1) from infected (grades 2–4) ulcers and to predict wound status at the follow-up. With use of the nematode model, S. aureus strains isolated from grade 1 ulcers were found to be significantly less virulent than strains from ulcers at or above grade 2 (P < 0.001). CONCLUSIONS—This study highlights the coexistence of two S. aureus populations on diabetic foot ulcers. A combination of five genes that may help distinguish colonized grade 1 from infected grade ≥2 wounds, predict ulcer outcome, and contribute to more appropriate use of antibiotics was discovered.

New insights in diabetic foot infection

Foot ulcers are common in diabetic patients, have a cumulative lifetime incidence rate as high as 25% and frequently become infected. The spread of infection to soft tissue and bone is a major causal factor for lower-limb amputation. For this reason, early diagnosis and appropriate treatment are essential, including treatment which is both local (of the foot) and systemic (metabolic), and this requires coordination by a multidisciplinary team. Optimal treatment also often involves extensive surgical debridement and management of the wound base, effective antibiotic therapy, consideration for revascularization and correction of metabolic abnormalities such as hyperglycemia. This article focuses on diagnosis and management of diabetic foot infections in the light of recently published data in order to help clinicians in identification, assessment and antibiotic therapy of diabetic foot infections.

Management of patients hospitalized for diabetic foot infection: results of the French OPIDIA study.

AIM This study was an analysis of how diabetic patients with infected foot wounds are managed in hospital by departments specializing in diabetic foot pathology, including an evaluation of the outcome 1 year after discharge. METHODS This was a prospective study of a cohort of patients hospitalized for diabetic foot infection at 38 hospital centres in France and followed-up for 1 year after discharge. RESULTS Altogether, 291 patients were included (73% male; 85% type 2 diabetes; mean age: 64.3±11.7 years). Most of the wounds were located on the toes and forefoot, and infection was most often graded as moderate; nevertheless, in about 50% of patients, osteomyelitis was suspected. Also, 87% of patients had peripheral neuropathy and 50-62% had peripheral artery disease. Gram-positive cocci, and Staphylococcus aureus in particular, were by far the most frequently isolated microorganisms. During hospitalization, lower-limb amputation was performed in 35% of patients; in 52%, the wound healed or had a favourable outcome. A year after discharge, 150 non-amputated patients were examined: at this time, 19% had to undergo amputation, whereas 79% had healed their wounds with no relapse. Risk factors for amputation were location (toes), severity of the wound and presence of osteomyelitis. Peripheral artery disease was associated with a poor prognosis, yet was very often neglected. CONCLUSION In spite of being managed at specialized centres that were, in general, following the agreed-upon published guidelines, the prognosis for diabetic foot infection remains poor, with a high rate (48%) of lower-limb amputation.

Risk factors and healing impact of multidrug-resistant bacteria in diabetic foot ulcers

AIM To determine the risk factors for acquiring multidrug-resistant organisms (MDRO) and their impact on outcome in infected diabetic foot ulcers. METHODS Patients hospitalized in our diabetic foot unit for an episode of infected foot ulcer were prospectively included. Diagnosis of infection was based on clinical findings using the International Working Group on the Diabetic Foot-Infectious Diseases Society of America (IWGDF-ISDA) system, and wound specimens were obtained for bacterial cultures. Each patient was followed-up for 1 year. Univariate analysis was performed to compare infected ulcers according to the presence or absence of MDRO; logistic regression was used to identify explanatory variables for MDRO presence. Factors related to healing time were evaluated by univariate and multivariate survival analyses. RESULTS MDRO were isolated in 45 (23.9%) of the 188 patients studied. Deep and recurrent ulcer, previous hospitalization, HbA(1c) level, nephropathy and retinopathy were significantly associated with MDRO-infected ulceration. By multivariate analysis, previous hospitalization (OR=99.6, 95% CI=[19.9-499.0]) and proliferative retinopathy (OR=7.4, 95% CI=[1.6-33.7]) significantly increased the risk of MDRO infection. Superficial ulcers were associated with a significant decrease in healing time, whereas neuroischaemic ulcer, proliferative retinopathy and high HbA(1c) level were associated with an increased healing time. In the multivariate analysis, presence of MDRO had no significant influence on healing time. CONCLUSION MDRO are pathogens frequently isolated from diabetic foot infection in our foot clinic. Nevertheless, their presence appears to have no significant impact on healing time if early aggressive treatment, as in the present study, is given, including empirical broad-spectrum antibiotic treatment, later adjusted according to microbiological findings.

Miniaturized Oligonucleotide Arrays A new tool for discriminating colonization from infection due to Staphylococcus aureus in diabetic foot ulcers

OBJECTIVE—We sought to evaluate the use of oligonucleotide arrays to discriminate colonization from infection due to Staphylococcus aureus in diabetic foot ulcers. RESEARCH DESIGN AND METHODS—We included diabetic patients hospitalized in a diabetic foot department for an episode of foot ulcer. Only patients who had no antibiotic treatment during the previous 6 months were included. At admission, ulcers were classified on clinical examination, according to the Infectious Diseases Society of America system. Seventy-two patients with a culture positive only for S. aureus as the sole pathogen were included. In individuals with a grade 1 ulcer, a second wound bacterial specimen was obtained 1 month later. Using oligonucleotide arrays, S. aureus resistance and virulence genes were compared between grade 1 and grades 2–4 ulcers. RESULTS—S. aureus was initially isolated from 22 grade 1 and 50 grade 2–4 ulcers: 35 were methicillin resistant and 37 methicillin sensitive. In 20 grade 1 ulcers (92%), no virulence genes were identified, whereas these genes were present in all but 1 grade 2–4 ulcers. During follow-up, the two grade 1 ulcers that were infected with strains carrying virulence genes rapidly deteriored; the array technology showed unchanged genotype profiles. On the contrary, two grade 1 ulcers healed: the genotype profiles were different from those at inclusion but without appearance of virulence genes. CONCLUSIONS—The DNA array appears as a promising technique and is easy to perform. Our observational study suggests that it might help distinguish colonized grade 1 from infected grade 2 wounds, predict ulcer outcome, and contribute to a more adequate use of antibiotics.

Diabetes and foot infection: more than double trouble

Infection of foot ulcers is a common, often severe and costly complication in diabetes. Many factors linked to the host, mainly immune defects, neuropathy and arteriopathy, as well as bacteria‐related factors, interact in a complex way and account for the susceptibility of diabetic individuals to foot infections, the severity of such infections and difficulty to treat them.

Beneficial effects of implementing guidelines on microbiology and costs of infected diabetic foot ulcers

Aims/hypothesisIn 2003, guidelines for management of diabetic foot infection (DFI) were written by the authors’ team according to the guidelines of the International Working Group on the Diabetic Foot. The effects of implementing these guidelines on the microbiology and costs of infected diabetic foot ulcers were assessed.MethodsFrom 2003 to 2007, potential beneficial effects of implementing these guidelines were assessed by comparison over time of bacteriological data (number of bacterial samples, number of microorganisms isolated in cultures, prevalence of multidrug-resistant organisms [MDRO] and colonising flora), and costs related to use of antimicrobial agents and microbiology laboratory workload.ResultsThe study included 405 consecutive diabetic patients referred to the Diabetic Foot Unit for a suspected DFI. From 2003 to 2007, a significant decrease was observed in the median number of bacteria species per sample (from 4.1 to 1.6), prevalence of MDRO (35.2% vs 16.3%) and methicillin-resistant Staphylococcus aureus (52.2% vs 18.9%) (p < 0.001). Moreover, prevalence of pathogens considered as colonisers dramatically fell from 23.1% to 5.8% of all isolates (p < 0.001). In parallel, implementation of guidelines was associated with a saving of €14,914 (US

Distinguishing Colonization From Infection With Staphylococcus aureus in Diabetic Foot Ulcers With Miniaturized Oligonucleotide Arrays: A French multicenter study

20,046) related to a reduced microbiology laboratory workload and €109,305 (US