Efficacy of cloxacillin versus cefazolin for methicillin-susceptibleStaphylococcus aureusbacteraemia (CloCeBa): study protocol for a randomised, controlled, non-inferiority trial

Abstract

IntroductionMethicillin-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 analysisThe 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 β-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 disseminationThis 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 numberNCT03248063 and 2017-003967-36.

Cefazolin in the treatment of central nervous system infections: A narrative review and recommendation

“…The collective results of these studies reassure clinicians that cefazolin is not only a practical alternative to nafcillin, but also a drug of choice for MSSA BSI 7,52,53 . A randomized, controlled, non‐inferiority clinical trial (CloCeBa) comparing cloxacillin versus cefazolin efficacy and safety in patients with MSSA BSI is currently enrolling 54 . Many patients in these aforementioned cohort studies had complicated MSSA BSI including left‐sided infective endocarditis.…”

Therapeutic Options for Adult Patients With Persistent Methicillin-Susceptible Staphylococcus aureus Bacteremia: A Narrative Review

“…Regardless of CzIE, adequate source control is a pivotal component in effectively managing bacteremia; however, in the event source control cannot be accomplished, bacteremia persists, or clinical improvement is limited, acknowledging the possibility of CzIE and re-evaluating therapeutic options may be considered until further high-quality studies are performed. 69 Clinicians may consider evaluating clindamycin and erythromycin susceptibilities as a possible surrogate marker for CzIE given their high specificity and negative predictive value (92.9% and 82.3%, respectively), optimizing cefazolin doses, or switching to an antistaphylococcal penicillin, daptomycin, or ceftaroline given preliminary in vitro and in vivo data. 35,49 Combination Therapy With Non-β-Lactam Agents Adjunctive rifampin.…”

Emerging Treatment Options for Acute Bacterial Skin and Skin Structure Infections and Bloodstream Infections Caused by Staphylococcus aureus: A Comprehensive Review of the Evidence

“…As for MSSA ABSSSI, cefazolin has been proposed as a possible first-line alternative to the antistaphylococcal penicillins in the treatment of MSSA BSI. This possibility is supported by a lower risk of nephrotoxicity and the favorable results of many recent observational studies and meta-analyses, 67–82 although, while waiting for the results of ongoing RCTs that could ultimately resolve the issue (more than one RCT may be necessary for eventually reaching a solid consensus), 83 some caution may still remain necessary due to the nonrandomized nature of the currently available comparative evidence and because of a described potential risk of cefazolin treatment failure in the case of high-inoculum infections. 7 , 84 For penicillin-susceptible S. aureus BSI, some studies also suggest a possible role of penicillin as an alternative to antistaphylococcal penicillins, although based on retrospective evidence.…”