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Efficacy of cloxacillin versus cefazolin for methicillin-susceptible Staphylococcus aureus bacteraemia (CloCeBa): study protocol for a randomised, controlled, non-inferiority trial.

ABSTRACT: INTRODUCTION:Methicillin-susceptible Staphylococcus aureus (MSSA) bacteraemia is a common and severe disease responsible for approximately 65?000 deaths every year in Europe. Intravenous antistaphylococcal penicillins (ASP) such as cloxacillin are the current recommended antibiotics. However, increasing reports of toxicity and recurrent stock-outs of ASP prompted healthcare providers to seek for alternative antibiotic treatment. Based on retrospective studies, cefazolin, a first-generation cephalosporin, is recommended in patients at risk of severe ASP-associated toxicity.We hypothesised that cefazolin has a non-inferior efficacy in comparison to cloxacillin, with a better safety profile for the treatment of MSSA bacteraemia. METHODS AND ANALYSIS:The CloCeBa trial is an open-label, randomised, controlled, non-inferiority trial conducted in academic centres throughout France. Eligible patients are adults with MSSA bacteraemia without intravascular device or suspicion of central nervous system infection. Patients will be randomised (1:1) to receive either cloxacillin or cefazolin by the intravenous route, for the first 14 days of therapy. The evaluation criteria is a composite criteria of negative blood cultures at day 5, survival, absence of relapse and clinical success at day 90 after randomisation. Secondary evaluation criteria include both efficacy and safety assessments. Three ancillary studies are planned to describe the epidemiology of ?-lactamase encoding genes, the ecological impact and pharmacokinetic/pharmacodynamic parameters of cefazolin and cloxacillin. Including 300 patients will provide 80% power to demonstrate the non-inferiority of cefazolin over cloxacillin, assuming 85% success rate with cloxacillin and taking into account loss-to-follow-up, with a 0.12 non-inferiority margin and a one-sided type I error of 0.025. ETHICS AND DISSEMINATION:This protocol received authorisation from the ethics committee Sud-Est I on 13 November 2017 (2017-87-PP)and French National Agency for Medicines and Health Products (170661A-43). Results will be disseminated to the scientific community through congresses and publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER:NCT03248063 and 2017-003967-36.

SUBMITTER: Burdet C

PROVIDER: S-EPMC6120654 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Efficacy of cloxacillin versus cefazolin for methicillin-susceptible <i>Staphylococcus aureus</i> bacteraemia (CloCeBa): study protocol for a randomised, controlled, non-inferiority trial.

Burdet Charles C Loubet Paul P Le Moing Vincent V Vindrios William W Esposito-Farèse Marina M Linard Morgane M Ferry Tristan T Massias Laurent L Tattevin Pierre P Wolff Michel M Vandenesch François F Grall Nathalie N Quintin Caroline C Mentré France F Duval Xavier X Lescure François-Xavier FX

BMJ open 20180901 8

<h4>Introduction</h4>Methicillin-susceptible <i>Staphylococcus aureus</i> (MSSA) bacteraemia is a common and severe disease responsible for approximately 65 000 deaths every year in Europe. Intravenous antistaphylococcal penicillins (ASP) such as cloxacillin are the current recommended antibiotics. However, increasing reports of toxicity and recurrent stock-outs of ASP prompted healthcare providers to seek for alternative antibiotic treatment. Based on retrospective studies, cefazolin, a first-g ...[more]

PMID: 30173161

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Project description:Treatment failure occurs in about 25% of patients with methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia. We assessed whether cloxacillin plus fosfomycin achieves better treatment success than cloxacillin alone in hospitalized adults with MSSA bacteremia. We conducted a multicenter, open-label, phase III-IV superiority randomized clinical trial. We randomly assigned patients (1:1) to receive 2 g of intravenous cloxacillin alone every 4 h or with 3 g of intravenous fosfomycin every 6 h for the initial 7 days. The primary endpoint was treatment success at day 7, a composite endpoint with the following criteria: patient alive, stable or with improved quick Sequential Organ Failure Assessment score, afebrile and with negative blood cultures for MSSA, adjudicated by an independent committee blinded to treatment allocation. We randomized 215 patients, of whom 105 received cloxacillin plus fosfomycin and 110 received cloxacillin alone. We analyzed the primary endpoint with the intention-to-treat approach in 214 patients who received at least 1 day of treatment. Treatment success at day 7 after randomization was achieved in 83 (79.8%) of 104 patients receiving combination treatment versus 82 (74.5%) of 110 patients receiving monotherapy (risk difference 5.3%; 95% confidence interval (CI), -5.95-16.48). Secondary endpoints, including mortality and adverse events, were similar in the two groups except for persistent bacteremia at day 3, which was less common in the combination arm. In a prespecified interim analysis, the independent committee recommended stopping recruitment for futility prior to meeting the planned randomization of 366 patients. Cloxacillin plus fosfomycin did not achieve better treatment success at day 7 of therapy than cloxacillin alone in MSSA bacteremia. Further trials should consider the intrinsic heterogeneity of the infection by using a more personalized approach. ClinicalTrials.gov registration: NCT03959345 .

Project description:IntroductionMethicillin-susceptible Staphylococcus aureus (MSSA) bacteraemia is a frequent condition, with high mortality rates. There is a growing interest in identifying new therapeutic regimens able to reduce therapeutic failure and mortality observed with the standard of care of beta-lactam monotherapy. In vitro and small-scale studies have found synergy between cloxacillin and fosfomycin against S. aureus. Our aim is to test the hypothesis that cloxacillin plus fosfomycin achieves higher treatment success than cloxacillin alone in patients with MSSA bacteraemia.MethodsWe will perform a superiority, randomised, open-label, phase IV-III, two-armed parallel group (1:1) clinical trial at 20 Spanish tertiary hospitals. Adults (≥18 years) with isolation of MSSA from at least one blood culture ≤72 hours before inclusion with evidence of infection, will be randomly allocated to receive either cloxacillin 2 g/4-hour intravenous plus fosfomycin 3 g/6-hour intravenous or cloxacillin 2 g/4-hour intravenous alone for 7 days. After the first week, sequential treatment and total duration of antibiotic therapy will be determined according to clinical criteria by the attending physician.Primary endpoints: (1) Treatment success at day 7, a composite endpoint comprising all the following criteria: patient alive, stable or with improved quick-Sequential Organ Failure Assessment score, afebrile and with negative blood cultures for MSSA at day 7. (2) Treatment success at test of cure (TOC) visit: patient alive and no isolation of MSSA in blood culture or at another sterile site from day 8 until TOC (12 weeks after randomisation).We assume a rate of treatment success of 74% in the cloxacillin group. Accepting alpha risk of 0.05 and beta risk of 0.2 in a two-sided test, 183 subjects will be required in each of the control and experimental groups to obtain statistically significant difference of 12% (considered clinically significant).Ethics and disseminationEthical approval has been obtained from the Ethics Committee of Bellvitge University Hospital (AC069/18) and from the Spanish Medicines and Healthcare Product Regulatory Agency (AEMPS, AC069/18), and is valid for all participating centres under existing Spanish legislation. The results will be presented at international meetings and will be made available to patients and funders.Trial registration numberThe protocol has been approved by AEMPS with the Trial Registration Number EudraCT 2018-001207-37. ClinicalTrials.gov Identifier: NCT03959345; Pre-results.

Project description:IntroductionMethicillin-susceptible Staphylococcus aureus (MSSA) is a common cause of infection in humans. Beta-lactam antibiotics are the preferred agents, with anti-staphylococcal penicillins (ASPs) or the first-generation cephalosporin, cefazolin, favored by clinicians. Recent studies comparing the two strategies suggest similar outcomes between the agents. The purpose of this meta-analysis was to explore differences between cefazolin and ASPs for the treatment of MSSA infections.MethodsWe performed a meta-analysis with trial sequential analysis (TSA) of observational or cohort studies using a random-effects model. Two blinded reviewers independently assessed studies for inclusion, risk of bias, and data extraction. The primary outcome was all-cause mortality. Secondary outcomes included clinical failure, infection recurrence, and antibiotic discontinuation due to adverse events. Subgroup analyses were conducted for the primary outcome by type of ASP, studies with a high percentage of deep-seated infections, and studies of low to moderate risk of bias.ResultsAfter performing a comprehensive search of the literature, and screening for study inclusion, 19 studies (13,390 patients) were included in the final meta-analysis. Fifteen of the 19 studies (79%) were judged as having a low or moderate risk of bias. Use of cefazolin was associated with lower all-cause mortality [odds ratio (OR) 0.71, 95% confidence interval (CI) 0.56-0.91, p = 0.006, I2 = 28%], clinical failure (OR 0.55, 95% CI 0.41-0.74, p < 0.001, I2 = 0%), and antibiotic discontinuation due to adverse events (OR 0.25, 95% CI 0.16-0.39, p < 0.001, I2 = 23%). Infection recurrence was higher in the cefazolin patients (OR 1.41, 95% CI 1.04-1.93, p = 0.03, I2 = 0%).ConclusionThis meta-analysis demonstrated that the use of cefazolin was associated with significant reductions in all-cause mortality, clinical failure, and discontinuation due to adverse events, but was associated with an increased risk of infection recurrence.FundingUniversity of Florida Open Access Publishing Fund funded the Rapid Service Fees.Trial registrationPROSPERO International Prospective Register of Systematic Reviews (study ID: CRD42018106442).

Dataset Information

Efficacy of cloxacillin versus cefazolin for methicillin-susceptible Staphylococcus aureus bacteraemia (CloCeBa): study protocol for a randomised, controlled, non-inferiority trial.

Publications

Efficacy of cloxacillin versus cefazolin for methicillin-susceptible <i>Staphylococcus aureus</i> bacteraemia (CloCeBa): study protocol for a randomised, controlled, non-inferiority trial.

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