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

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 < 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.

The Effectiveness of Combination Therapy for Treating Methicillin-Susceptible Staphylococcus aureus Bacteremia: A Systematic Literature Review and a Meta-Analysis

“…These results contrast with reports describing successful outcomes when using ceftaroline plus daptomycin as salvage therapy, especially in patients with persistent MRSA bacteremia [ 34 , 35 , 36 ]. Although an experimental model of infective endocarditis suggested that cloxacillin plus daptomycin have a synergistic effect [ 37 ], further clinical studies are needed.…”

Treatment of Enterococcus faecalis Infective Endocarditis: A Continuing Challenge

“…Therefore, this alternative could be considered in resistant isolates or when adverse events appear, but not to simplify antibiotic treatment. Taking also account the synergistic activity between daptomycin and beta-lactams [ 83 , 84 , 130 ] fosfomycin [ 85 , 86 , 87 , 88 , 89 , 90 , 91 ] or tigecycline, a combination regimen with high doses seems to be preferable, whereas single therapy with this drug should be used with caution.…”

Treatment of <em>Enterococcus faecalis</em> Infective Endocarditis: A Continuing Challenge

“…Current oral fosfomycin use is limited to uncomplicated urinary tract infections due to limited absorption and intravenous formulation are yet unavailable in the USA. However, fosfomycin has demonstrated utility against MSSA and MRSA endocarditis in combination with daptomycin or imipenem [113][114][115][116] and a study of in vitro and in vivo with the guinea pig model using intraperitoneal fosfomycin demonstrated promising activity against both planktonic and biofilm-forming E. faecalis when the drug was used in combination with gentamicin and daptomycin 117 . Thus, new therapeutic options with this drug could be considered in the future for E. faecalis IE.…”