Cloxacillin plus fosfomycin versus cloxacillin alone for methicillin-susceptible Staphylococcus aureus bacteremia: a randomized trial.

"Competing interests M.P. received a research grant from Laboratorios ERN. J.M.M. has received consulting honoraria and/or research grants from Angelini Pharma, ContraFect, Genentech, Gilead Sciences, Janssen, Lysovant, Medtronic, Merck Sharp & Dohme (MSD), Novartis, Pfizer and ViiV Healthcare, outside the submitted work. J.L.C. has received speaker honoraria from Pfizer, MSD, AstraZeneca, Guerbet and Hartmann. L.E.L.C. has served as scientific advisor for Angelini Pharma, speaker for Angelini Pharma, ViiV Healthcare, Gilead Sciences and Correvio, and trainer for ViiV Healthcare. J.M.A. has received honoraria for speaking at symposia organised on behalf of Pfizer, Astellas, MSD, Angelini Pharma, Shionogi, Takeda and Gilead Sciences, and has sat on advisory boards on behalf of Pfizer, Astellas, MSD, Angelini Pharma, Gilead Sciences and Takeda. Á.I.C. has received speaker honoraria from Pfizer, Bristol Myers Squibb, Esteve and Bayer. C.T. has received speaker honoraria from Gedeon Richter. G.C. has received support for attending national and international scientific congresses from Angelini Pharma Spain, Pfizer Spain and MSD, and speaker honoraria from Pfizer Spain and Gilead Sciences Europe. J.C. has received speaker honoraria from MSD and Gilead Sciences, and has participated as an investigator in trials on COVID-19 by Roche and Gilead Sciences. The rest of the authors do not declare any conflicts of interest."

"This study was funded by the Spanish Ministry of Health (grant no. PI17/01116), Instituto de Salud Carlos III, Madrid, Spain, and Laboratorios ERN, Barcelona, Spain (grant no. 19PNJ145). We thank the Spanish Clinical Research Network (SCReN), Instituto de Salud Carlos II, for its support through projects PT17/0017/0010 and PT20/000008, integrated into the ‘Plan Estatal de I + D + I’ 2013–2016 and co-financed by the European Regional Development Fund (FEDER). J.M.M. received a personal 80:20 research grant from Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain, for the 2017–2024 period. O.G. received a research grant from the ‘Pla estratègic de recerca i innovació en salut (PERIS) 2019–2021’ (Departament de Salut, Generalitat de Catalunya). We also thank the CERCA Program and the Generalitat de Catalunya for institutional support. The funders did not contribute to the design or conduct of the study; collection, management, analysis or interpretation of the data; preparation, review or approval of the manuscript; or the decision to submit the manuscript for publication."

"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."