García de la Mària, CristinaGasch, OriolCastañeda, XimenaGarcía González, JavierSoy, DolorsCañas, Maria AlexandraAmbrosioni, JuanAlmela, ManelPericàs, Juan M.Téllez, AdriánFalces Salvador, CarlesHernández-Meneses, MartaSandoval, ElenaQuintana, EduardVidal, BarbaraTolosana, José M. (José María)Fuster, DavidLlopis, JaumeMoreno, AsuncionMarco, FrancescMiró Meda, José M. (José María), 1956-Hospital Clínic Endocarditis Study Group2022-03-232022-03-232020-120305-7453https://hdl.handle.net/2445/184344Background: 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 < 0.001 for both combinations] and showed better activity than cloxacillin alone [0/10 (0%), P < 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.7 p.application/pdfeng(c) García de la Mària, Cristina et al., 2020EndocarditisMedicaments antibacteriansStaphylococcus aureusEndocarditisAntibacterial agentsStaphylococcus aureusinfo:eu-repo/semantics/article7093732022-03-23info:eu-repo/semantics/openAccess805234232853336