Are there clinical variables determining antibiotic prophylaxis-susceptible versus resistant infection in open fractures?

PURPOSE: In Gustilo grade III open fractures, it remains unknown which demographic or clinical features may be associated with an infection resistant to the administered prophylactic agent, compared to one that is susceptible. METHODS: This was a retrospective case-control study on patients hospitalized from 2004 to 2009. RESULTS: We identified 310 patients with Gustilo-III open fractures, 36 (12%) of which became infected after a median of ten days. In 26 (72%) of the episodes the pathogen was susceptible to the prophylactic antibiotic agent prescribed upon admission, while in the other ten it was resistant. All antibiotic prophylaxis was intravenous; the median duration of treatment was three days and the median delay between trauma and surgery was one day. In multivariate analysis adjusting for case-mix, only Gustilo-grade-IIIc fractures (vascular lesions) showed tendency to be infected with resistant pathogens (odds ratio 10; 95% confidence interval 1.0-10; p = 0.058). There were no significant differences between cases caused by antibiotic resistant and susceptible pathogen cases in patient's sex, presence of immune suppression, duration and choice of antibiotic prophylaxis, choice of surgical technique or materials, time delay until surgery, use of bone reaming, fracture localization, or presence of compartment syndrome. CONCLUSION: We were unable to identify any specific clinical parameters associated with infection with antibiotic resistant pathogens in Gustilo-grade III open fractures, other than the severity of the fracture itself. More research is needed to identify patients who might benefit from a broader-spectrum antibiotic prophylaxis.

Evaluation of the activity of cefepime/enmetazobactam against Enterobacterales bacteria collected in Europe from 2019 to 2021, including third-generation cephalosporin-resistant isolates.

OBJECTIVES: This study was performed to investigate the activity of the novel ß-lactam/ß-lactamase inhibitor combination cefepime/enmetazobactam, against recently circulating Enterobacterales isolates from Europe from 2019 to 2021. METHODS: A total of 2627 isolates were collected, and antimicrobial susceptibility was determined according to the European Committee on Antimicrobial Susceptibility Testing guidelines. Isolates with phenotypic resistance to ceftriaxone and ceftazidime (but susceptible to meropenem) and isolates nonsusceptible to meropenem were screened for the presence of ß-lactamases. RESULTS: Overall, susceptibility to third-generation cephalosporins was 77%, and 97.3% were susceptible to meropenem. Cefepime/enmetazobactam susceptibility was 97.9% (72% of these isolates were Klebsiella pneumoniae from Italy), compared with 80.0% susceptibility to piperacillin/tazobactam and 99.4% to ceftazidime/avibactam. A total of 320 isolates (12.2%) were resistant to third-generation cephalosporins but susceptible to meropenem, and virtually all (96.3%) carried an extended-spectrum ß-lactamase with or without an AmpC and these were all susceptible to cefepime/enmetazobactam. Most meropenem-nonsusceptible isolates carried a KPC (68%), which were not inhibited by cefepime/enmetazobactam but were inhibited by ceftazidime/avibactam. Additionally, most meropenem-nonsusceptible isolates carrying OXA-48 (9/12 isolates) were susceptible to cefepime/enmetazobactam. CONCLUSIONS: Cefepime/enmetazobactam was highly active against Enterobacterales isolates, especially those resistant to third-generation cephalosporins. These data suggest that cefepime/enmetazobactam could be used as a carbapenem-sparing agent to replace piperacillin/tazobactam.

Effectiveness and safety of dalbavancin in France: a prospective, multicentre cohort study.

OBJECTIVES: Dalbavancin is a lipoglycopeptide antibiotic approved for the treatment of acute bacterial skin and skin structure infections. However, several studies have suggested that it is used mostly for off-label indications. We aimed to describe the use of dalbavancin in patients who received at least one dose of the antibiotic in France. METHODS: Prospective, observational, multicentre study conducted in France from September 2018 to April 2020. The primary outcome was the clinical response at 30 days after the last dalbavancin dose. RESULTS: A total of 151 patients in 16 centres were included in this study. The main infection sites were bone and joint infections (55.0%), multisite infections (15.9%), and vascular infections (14.6%), and the primary pathogens were coagulase-negative staphylococci (N = 82), Staphylococcus aureus (N = 51), and enterococci (N = 27). Most patients (71.5%) received three previous antibiotic treatments. The number of dalbavancin injections per patient was 1 in 26 patients (17.2%), 2 in 95 patients (62.9%), 3 in 17 patients (11.3%), and more than 3 in 13 patients (8.6%), with a mean cumulative dose of 3089 ± 1461 mg per patient. Among the 129 patients with a complete follow-up, clinical success was achieved in 119 patients (92.2%). At least 1 adverse event was reported in 67 patients (44.4%), including 12 (7.9%) patients with dalbavancin-related adverse events. CONCLUSIONS: The results of the study showed that dalbavancin is used mostly for off-label indications and in heavily pretreated patients in France. The clinical response at 30 days after the last dose was favourable in most patients, with a good safety profile.

Molecular and therapeutic characterization of anti-ectodysplasin A receptor (EDAR) agonist monoclonal antibodies.

The TNF family ligand ectodysplasin A (EDA) and its receptor EDAR are required for proper development of skin appendages such as hair, teeth, and eccrine sweat glands. Loss of function mutations in the Eda gene cause X-linked hypohidrotic ectodermal dysplasia (XLHED), a condition that can be ameliorated in mice and dogs by timely administration of recombinant EDA. In this study, several agonist anti-EDAR monoclonal antibodies were generated that cross-react with the extracellular domains of human, dog, rat, mouse, and chicken EDAR. Their half-life in adult mice was about 11 days. They induced tail hair and sweat gland formation when administered to newborn EDA-deficient Tabby mice, with an EC(50) of 0.1 to 0.7 mg/kg. Divalency was necessary and sufficient for this therapeutic activity. Only some antibodies were also agonists in an in vitro surrogate activity assay based on the activation of the apoptotic Fas pathway. Activity in this assay correlated with small dissociation constants. When administered in utero in mice or at birth in dogs, agonist antibodies reverted several ectodermal dysplasia features, including tooth morphology. These antibodies are therefore predicted to efficiently trigger EDAR signaling in many vertebrate species and will be particularly suited for long term treatments.

Wound dehiscence and stump infection after lower limb amputation: risk factors and association with antibiotic use.

BACKGROUND: Optimal duration of antibiotic prophylaxis following major lower limb amputation in preventing adverse stump outcomes is controversial. OBJECTIVE: We assess the epidemiology and risk factors of wound dehiscence and stump infection after mid-thigh to transmetatarsal amputations with regard to antibiotic administration. METHODS: Our retrospective observational study at the Geneva University Hospital (January 1995-June 2010) includes a total of 289 amputations in 270 adult patients (199 males; median age 70 years). RESULTS: Wound dehiscence and/or stump infection occurred in 47 (16.3%) and 63 (21.8%) patients with a median delay of 24 and 14 days, respectively. No clinical variable was significantly associated with stump infection. Diabetes and older age (>80 years) were associated with dehiscence. Importantly, transcutaneous tissue oxygen tension (TcPO2) and duration of antibiotic administration showed no association with either outcome. CONCLUSION: The duration of antibiotic administration before or after surgery does not change the epidemiology of stump complications.

Duration of post-surgical antibiotic therapy for adult chronic osteomyelitis: a single-centre experience.

PURPOSE: The optimal duration of concomitant antibiotic therapy after surgical intervention for implant-free chronic osteomyelitis is unknown. No randomized data exist. Available recommendations are based on expert's opinion. We evaluated the duration of post-surgical antibiotic treatment related to remission of chronic osteomyelitis. METHODS: This was a retrospective single-centre study at Geneva University Hospitals with a minimal follow-up of two years after treatment. We used multivariate logistic regression analysis with exclusion of pediatric cases and of implant-related chronic osteomyelitis. RESULTS: A total of 49 episodes of implant-free chronic osteomyelitis in 49 adult patients were studied. The median number of surgical interventions was two (range, 1-10). The median duration of post-debridement antibiotic treatment was eight weeks (range, 4-14 weeks). Thirty-nine patients (80%) were in remission after a minimal follow-up of two years. In multivariate logistic regression analysis, one week of intravenous therapy had the same remission as two to three weeks (0.2, 0.1-1.9) or ≥ 3 weeks (0.3, 0.1-2.4). More than six weeks of total antibiotic treatment equalled ≤  six weeks (0.8, 0.1-5.2). CONCLUSIONS: In chronic osteomyelitis in adults, a post-debridement antibiotic therapy beyond six weeks, or an IV treatment longer than one week, did not show enhanced remission incidences. Prospective randomized trials are required to confirm this observation.

Should the methicillin-resistant Staphylococcus aureus carriage status be used as a guide to treatment for skin and soft tissue infections?

OBJECTIVE: Previous skin carriage of methicillin-resistant Staphylococcus aureus (MRSA) leads frequently to empiric antibiotic MRSA coverage for skin & soft tissue infections. METHODS: Retrospective cohort study of orthopaedic patients hospitalized at Geneva University Hospitals (MRSA prevalence; 30%); community-acquired MRSA excluded. RESULTS: A total of 378 skin and soft tissue infections in 346 patients were retrieved. Overall cure was achieved in 330 episodes (87%) after a median antibiotic administration of 15 days. Among all episodes, 102 revealed a positive current MRSA status (during 2 weeks preceding infection; 27%) and 70 (19%) were MRSA carriers in the past. Sensitivity, specificity, positive and negative predictive values of current MRSA skin carriage to predict abscesses due to MRSA were 0.68, 0.77, 0.19, and 0.97, respectively. Fifty-four current MRSA carriers (54/102, 53%) and 30 past carriers (43%) were successfully treated with a non-MRSA antibiotic agent. In multivariate Cox regression analysis, anti-MRSA coverage (hazard ratio 1.2, 95%CI 0.5-2.8) and duration of antibiotic therapy (HR 1.0, 95%CI 0.96-1.02) did not influence treatment failure among patients with positive MRSA carriage. CONCLUSIONS: Current or past HA-MRSA skin carriage poorly predicts the need for anti-MRSA coverage for the antibiotic treatment of skin and soft tissue infections in hospitalized orthopaedic patients.