Daptomycin Plus Fosfomycin Versus Daptomycin Alone for Methicillin-resistant Staphylococcus aureus Bacteremia and Endocarditis: A Randomized Clinical Trial

Miquel Pujol, José-María Miró, Evelyn Shaw, Jose-María Aguado, Rafael San-Juan, Mireia Puig-Asensio, Carles Pigrau, Esther Calbo, Miguel Montejo, Regino Rodriguez-Álvarez, María-Jose Garcia-Pais, Vicente Pintado, Rosa Escudero-Sánchez, Joaquín Lopez-Contreras, Laura Morata, Milagros Montero, Marta Andrés, Juan Pasquau, María-Del-Mar Arenas, Belén Padilla, Javier Murillas, Alfredo Jover-Sáenz, Luis-Eduardo López-Cortes, Graciano García-Pardo, Oriol Gasch, Sebastian Videla, Pilar Hereu, Cristian Tebé, Natalia Pallarès, Mireia Sanllorente, María-Ángeles Domínguez, Jordi Càmara, Anna Ferrer, Ariadna Padullés, Guillermo Cuervo, Jordi Carratalà, MRSA Bacteremia (BACSARM) Trial Investigators, Alex Soriano, Manel Almela, Frederic Gómez, Fernando Chávez, Beatriz Mirelis, Emma Padilla, Maria Dolores Pérez-Ramírez, Mateu Espasa, Ana Maria Sánchez-Díaz, Emilia Cercenado, Enrique Ruiz de Gopegui, Ana Siverio, Marina de Cueto, Fernando García-Garrote, Mercè Garcia, Mariona Xercavins, Maria Nieves Larrosa, Miquel Pujol, José-María Miró, Evelyn Shaw, Jose-María Aguado, Rafael San-Juan, Mireia Puig-Asensio, Carles Pigrau, Esther Calbo, Miguel Montejo, Regino Rodriguez-Álvarez, María-Jose Garcia-Pais, Vicente Pintado, Rosa Escudero-Sánchez, Joaquín Lopez-Contreras, Laura Morata, Milagros Montero, Marta Andrés, Juan Pasquau, María-Del-Mar Arenas, Belén Padilla, Javier Murillas, Alfredo Jover-Sáenz, Luis-Eduardo López-Cortes, Graciano García-Pardo, Oriol Gasch, Sebastian Videla, Pilar Hereu, Cristian Tebé, Natalia Pallarès, Mireia Sanllorente, María-Ángeles Domínguez, Jordi Càmara, Anna Ferrer, Ariadna Padullés, Guillermo Cuervo, Jordi Carratalà, MRSA Bacteremia (BACSARM) Trial Investigators, Alex Soriano, Manel Almela, Frederic Gómez, Fernando Chávez, Beatriz Mirelis, Emma Padilla, Maria Dolores Pérez-Ramírez, Mateu Espasa, Ana Maria Sánchez-Díaz, Emilia Cercenado, Enrique Ruiz de Gopegui, Ana Siverio, Marina de Cueto, Fernando García-Garrote, Mercè Garcia, Mariona Xercavins, Maria Nieves Larrosa

Abstract

Background: We aimed to determine whether daptomycin plus fosfomycin provides higher treatment success than daptomycin alone for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia and endocarditis.

Methods: A randomized (1:1) phase 3 superiority, open-label, and parallel group clinical trial of adult inpatients with MRSA bacteremia was conducted at 18 Spanish hospitals. Patients were randomly assigned to receive either 10 mg/kg of daptomycin intravenously daily plus 2 g of fosfomycin intravenously every 6 hours, or 10 mg/kg of daptomycin intravenously daily. Primary endpoint was treatment success 6 weeks after the end of therapy.

Results: Of 167 patients randomized, 155 completed the trial and were assessed for the primary endpoint. Treatment success at 6 weeks after the end of therapy was achieved in 40 of 74 patients who received daptomycin plus fosfomycin and in 34 of 81 patients who were given daptomycin alone (54.1% vs 42.0%; relative risk, 1.29 [95% confidence interval, .93-1.8]; P = .135). At 6 weeks, daptomycin plus fosfomycin was associated with lower microbiologic failure (0 vs 9 patients; P = .003) and lower complicated bacteremia (16.2% vs 32.1%; P = .022). Adverse events leading to treatment discontinuation occurred in 13 of 74 patients (17.6%) receiving daptomycin plus fosfomycin, and in 4 of 81 patients (4.9%) receiving daptomycin alone (P = .018).

Conclusions: Daptomycin plus fosfomycin provided 12% higher rate of treatment success than daptomycin alone, but this difference did not reach statistical significance. This antibiotic combination prevented microbiological failure and complicated bacteremia, but it was more often associated with adverse events.

Clinical trials registration: NCT01898338.

Keywords: MRSA; bacteremia; clinical trial; daptomycin; fosfomycin.

© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.

Figures

Figure 1.
Figure 1.
Trial profile. *Reasons for exclusion after randomization were as follows: patient randomized twice (n = 2); positive blood culture >72 hours before randomization (n = 3); patient received

Figure 2.

Primary endpoint.

Figure 2.

Primary endpoint.

Figure 2.
Primary endpoint.
Figure 2.
Figure 2.
Primary endpoint.

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