Cloxacillin plus fosfomycin versus cloxacillin alone for methicillin-susceptible Staphylococcus aureus bacteremia: a randomized trial
Authors: Grillo Sara , Pujol Miquel , Miró Josep M. , López-Contreras Joaquín , Euba Gorane , Gasch Oriol , Boix-Palop Lucia , Garcia-País Maria José , Pérez-Rodríguez Maria Teresa , Gomez-Zorrilla Silvia , Oriol Isabel , López-Cortés Luis Eduardo , Pedro-Botet Maria Luisa , San-Juan Rafael , Aguado José María , Gioia Francesca , Iftimie Simona , Morata Laura , Jover-Sáenz Alfredo , García-Pardo Graciano , Loeches Belén , Izquierdo-Cárdenas Álvaro , Goikoetxea Ane Josune , Gomila-Grange Aina , Dietl Beatriz , Berbel Damaris , Videla Sebastian , Hereu Pilar , Padullés Ariadna , Pallarès Natalia , Tebé Cristian , Cuervo Guillermo , Carratalà Jordi ,   SAFO study group, Rivera Maria Alba , Aguirregabiria Malen , Rodríguez-Álvarez Regino , Blanco-Vidal María José , Alguacil-Guillen Marina , Xercavins Mariona , Pomar Virginia , Siverio-Parés Ana , de Cueto Marina , Moreno-Mellado Elisa , Sousa Adrián , Vasallo-Vidal Francisco José , Borjabad Beatriz , Coloma-Conde Ana , Clivillé-Abad Raquel , González-di Lauro Sabina Ximena , Tiago-Silva Jose , Orellana Maria Angeles , Ruíz-Bastián Mario , Vizcarra Pilar , Garcia Carles , Ballester Frédéric , Ramírez-Hidalgo María Fernanda , Bellés-Bellés Alba , Meije Yolanda , Ribera Alba , LLaberia Jaume , Domínguez María Ángeles , Rigo-Bonnin Raul Francisco , Horna Gertrudis , Mediavilla Dominica , Sanllorente Mireia , Picó-Plana Ester , Soriano Alex , Pitart Cristina , Sanchez-Diaz Ana Maria 
Published: October 2023

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.