Cloxacillin or fosfomycin plus daptomycin combinations are more active than cloxacillin monotherapy or combined with gentamicin against MSSA in a rabbit model of experimental endocarditis
Authors: García-de-la-Mària Cristina , Gasch Oriol , Castañeda Ximena , García-González Javier , Soy Dolors , Cañas Maria-Alexandra , Ambrosioni Juan , Almela Manel , Pericàs Juan M , Téllez Adrián , Falces Carlos , Hernández-Meneses Marta , Sandoval Elena , Quintana Eduard , Vidal Barbara , Tolosana Jose M , Fuster David , Llopis Jaume , Moreno Asuncion , Marco Francesc , Miró Jose M ,   the Hospital Clínic Endocarditis Study Group, Miró Jose M Juan , Ambrosioni Adrian , Téllez Juan M , Pericàs Anders , Dahl Asuncion , Moreno Cristina García , de la Mària Yolanda , Armero Javier , García-González Maria-Alejandra , Cañas-Pacheco Manel , Almela Climent , Casals Francisco-Javier , Morales Francesc , Marco Jordi , Vila Eduard , Quintana Elena , Sandoval Juan C , Paré Carlos , Falces Daniel , Pereda Ramon , Cartañá Salvador , Ninot Manel , Azqueta Marta , Sitges Barbara , Vidal José L , Pomar Manuel , Castella José M , Tolosana José , Ortiz Guillermina , Fita Irene , Rovira David , Fuster Jose , Ramírez Mercè , Brunet Dolors , Soy Pedro , Castro Jaume , Llopis Jaume 
Published: August 2020

Abstract

Background
In vitro and in vivo activity of daptomycin alone or plus either cloxacillin or fosfomycin compared with cloxacillin alone and cloxacillin plus gentamicin were evaluated in a rabbit model of MSSA experimental endocarditis (EE).

Methods
Five MSSA strains were used in the in vitro time–kill studies at standard (105–106 cfu/mL) and high (108 cfu/mL) inocula. In the in vivo EE model, the following antibiotic combinations were evaluated: cloxacillin (2 g/4 h) alone or combined with gentamicin (1 mg/kg/8 h) or daptomycin (6 mg/kg once daily); and daptomycin (6 mg/kg/day) alone or combined with fosfomycin (2 g/6 h).

Results
At standard and high inocula, daptomycin plus fosfomycin or cloxacillin were bactericidal against 4/5 and 5/5 strains, respectively, while cloxacillin plus gentamicin was bactericidal against 3/5 strains at standard inocula but against none at high inocula. Fosfomycin, cloxacillin, gentamicin and daptomycin MIC/MBCs of the MSSA-678 strain used in the EE model were: 8/64, 0.25/0.5, 0.25/0.5 and 1/8 mg/L, respectively. Adding gentamicin to cloxacillin significantly reduced bacterial density in vegetations compared with cloxacillin monotherapy (P = 0.026). Adding fosfomycin or cloxacillin to daptomycin [10/11 (93%) and 8/11 (73%), respectively] significantly improved the efficacy of daptomycin in sterilizing vegetations [0/11 (0%), P &lt; 0.001 for both combinations] and showed better activity than cloxacillin alone [0/10 (0%), P &lt; 0.001 for both combinations] and cloxacillin plus gentamicin [3/10 (30%), P = 0.086 for cloxacillin plus daptomycin and P = 0.008 for fosfomycin plus daptomycin]. No recovered isolates showed increased daptomycin MIC.

Conclusions
The addition of cloxacillin or fosfomycin to daptomycin is synergistic and rapidly bactericidal, showing better activity than cloxacillin plus gentamicin for treating MSSA EE, supporting their clinical use.