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BMJ Open. 2018 Sep 1;8(8):e023151. doi: 10.1136/bmjopen-2018-023151.

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

Author information

1
IAME, UMR 1137, INSERM, Université Paris Diderot, Sorbonne Paris Cité, INSERM, Paris, France.
2
Hôpital Bichat Claude Bernard-Département d'Epidémiologie, Biostatistiques et recherche Clinique, Assistance Publique-Hopitaux de Paris, Paris, France.
3
Hôpital Bichat Claude Bernard-Service de maladies infectieuses, Assistance Publique-Hopitaux de Paris, Paris, France.
4
CHU de Montpellier, Montpellier, France.
5
Hôpital Bichat Claude Bernard-Unité de recherche Clinique, Assistance Publique-Hopitaux de Paris, Paris, France.
6
Inserm CIC 1425, Centre d'Investigation Clinique, AP-HP, Hôpital Bichat-Claude Bernard, Paris, France.
7
Service de Maladies Infectieuses, Hopital de la Croix-Rousse, Lyon, France.
8
Hôpital Bichat Claude Bernard-Laboratoire de toxicologie, Assistance Publique-Hopitaux de Paris, Paris, Île-de-France, France.
9
Service de Maladies Infectieuses et Réanimation Médicale, Hôpital Pontchaillou, Rennes, France.
10
Hôpital Bichat Claude Bernard-Service de réanimation médicale et infectieuse, Assistance Publique-Hopitaux de Paris, Paris, France.
11
Centre National de Références des Staphylocoques, Bron, France.
12
Hôpital Bichat lLaude Bernard-Laboratoire de bactériologie, Assistance Publique-Hopitaux de Paris, Paris, France.

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 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 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.

KEYWORDS:

bacteremia; cefazolin; cloxacillin; efficacy; safety; staphylococcus aureus

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