Cloxacillin versus cefazolin for meticillin-susceptible Staphylococcus aureus bacteraemia (CloCeBa): a prospective, open-label, multicentre, non-inferiority, randomised clinical trial
Charles Burdet, Nadia Saïdani, Céline Dupieux, Adrien Lemaignen, Étienne Canouï, Laure Surgers, Marc-Olivier Vareil, A. Lefort, R. Lepeule, Nathan Peiffer‐Smadja, Alexandre Charmillon, Vincent Le Moing, David Boutoille, Violaine Tolsma, Sophie Abgrall, Michel Wolff, Pierre Tattevin, Marina Esposito‐Farèse, François Vandenesch, Xavier Duval, Sarah Tubiana, François-Xavier Lescure, Sophie Abgrall, Corentine Alauzet, Laure Alleman, Céline Alloux, Antoine Bachelard, Sévrine Barbault-Foucher, Romane Belot, Louis Bernard, Antoine Bernier, Hélène Berthomé, Laura Bertin, Nicolas Billard, Alexandre Bleibtreu, Laura Bouetard, Hassina Bouguerra, Charlotte Boulle, Hélène Bourgoin, Charlotte Bourgoin, David Boutoille, Florence Braun, Sophie Bréaud-Briand, Charles Burdet, Philippe Cailloux, Ruxandra Calin, Etienne Canoui, Florence Capelle, Muriel Carvalho, Claudia Carvalho Schneider, Nicolas Cassou, Lynda Chalal, Anne Chambon, Malikhone Chansombat, Fanny Charbonnier Beaupel, Alexandre Charmillon, Thibault Chiarabini, David Chirio, Johan Courjon, François Coustilleres, Corinne Da Costa Ribeiro Coutinho, Andrea De La Selle, Victoire De Lastours, Elisa Demonchy, Agnès Didier, Nikita Dobremel, Alexandra Doloy, Jean-Luc Donnay, Vincent Dubée, Gilles Dumondin, Céline Dupieux, Hélène Durand, Xavier Duval, Marina Esposito-Farese, Marie-Sarah Fangous, Tristan Ferry, Laurent Flet, Adrien Galy, Naura Gamany, Pauline Garnier, Vincent Gendrin, Carine Ghionda, Virginie Godard, Sylvain Godreuil, Nathalie Grall, Brice Guerpillon, Abdeslam Guettar, Signara Gueye, Christelle Guillet Caruba, Meriem Harrabi, Brigitte Hoedt, Elena Holeindre, Virginie Huart, Emila Ilic Habensus, Simon Jamard, Clarisse Joubert, Cecile Kedzia, Marie Kempf, Lydie Khatchatourian, Chaimae Khoutam
Abstract
BACKGROUND: Although widely used, cefazolin efficacy for the treatment of meticillin-susceptible Staphylococcus aureus (MSSA) bacteraemia has not thus far been investigated in a clinical trial. In this study, we aimed to compare the efficacy and safety of cefazolin with that of cloxacillin in patients with MSSA bacteraemia. METHODS: We conducted an open-label, non-inferiority, randomised clinical trial in 21 university and non-university hospitals in France in adults (aged ≥18 years) with MSSA bacteraemia, without intravascular implant or suspicion of CNS infection. Participants were randomly assigned (1:1) to receive intravenously cefazolin (25-50 mg/kg every 8 h) or cloxacillin (25-50 mg/kg every 4-6 h) for the first 7 days of therapy using computer-generated blocks of various sizes and stratification on vascular-access associated bacteraemia and centre. Subsequent treatment was left to the choice of the investigator (total duration ≥14 days). The primary endpoint was a composite of sterile blood cultures at day 3 (day 5 for endocarditis) without relapse of bacteraemia, survival, and clinical success at day 90, and was assessed in the intention-to-treat population. A non-inferiority margin of 12% was chosen. This trial is registered on ClinicalTrials.gov (NCT03248063) and is complete. FINDINGS: Between Sept 5, 2018, and Nov 16, 2023, 315 participants were enrolled and assigned to cefazolin (n=158) or cloxacillin (n=157); 12 participants were excluded from analysis in the cefazolin group, and 11 in the cloxacillin group (final population of 146 in each group). Mean age was 62·7 years (SD 16·4), 215 (74%) participants were male, and race or ethnicity data were not collected. Median Pitt score was 0 (IQR 0-0). The primary endpoint was met in 109 (75%) of 146 participants in the cefazolin group versus 108 (74%) of 146 participants in the cloxacillin group (treatment difference -1%; 95% CI -11 to 9; p=0·012). At the end of study treatment, 22 (15%) of 146 participants assigned to cefazolin and 40 (27%) of 146 participants assigned to cloxacillin had had a serious adverse event (p=0·010). Acute kidney injury occurred more frequently in participants assigned to cloxacillin (15 [12%] of 128) than in those assigned to cefazolin (one [1%] of 134; p=0·0002). INTERPRETATION: Cefazolin constitutes an alternative to cloxacillin for the treatment of MSSA bacteraemia, offering non-inferior clinical efficacy and potentially enhanced tolerability. FUNDING: French Ministry of Health.