Emerging issues on Staphylococcus aureus endocarditis and the role in therapy of daptomycin plus fosfomycin.

INTRODUCTION: Methicillin-resistant and -susceptible Staphylococcus aureus (MRSA/MSSA) infections are a major global health-care problem. Bacteremia with S. aureus exhibits high rates of morbidity and mortality and can cause complicated infections such as infective endocarditis (IE). The emerging resistance profile of S. aureus is worrisome, and several international agencies have appealed for new treatment approaches to be developed. AREAS COVERED: Daptomycin presents a rapid bactericidal effect against MRSA and has been considered at least as effective as vancomycin in treating MRSA bacteremia. However, therapy failure is often related to deep-seated infections, e.g. endocarditis, with high bacterial inocula and daptomycin regimens <10 mg/kg/day. Current antibiotic options for treating invasive S. aureus infections have limitations in monotherapy. Daptomycin in combination with other antibiotics, e.g. fosfomycin, may be effective in improving clinical outcomes in patients with MRSA IE. EXPERT OPINION: Exploring therapeutic combinations has shown fosfomycin to have a unique mechanism of action and to be the most effective option in preventing the onset of resistance to and optimizing the efficacy of daptomycin, suggesting the synergistic combination of fosfomycin with daptomycin is a useful alternative treatment option for MSSA or MRSA IE.

Effectiveness of vancomycin plus cloxacillin compared with vancomycin, cloxacillin and daptomycin single therapies in the treatment of methicillin-resistant and methicillin-susceptible Staphylococcus aureus in a rabbit model of experimental endocarditis.

OBJECTIVES: To investigate if the addition of cloxacillin to vancomycin enhances the activity of both monotherapies for treating MSSA and MRSA experimental endocarditis (EE) in rabbits. METHODS: Vancomycin plus cloxacillin was compared with the respective monotherapies and daptomycin. In vitro time-kill studies were performed using standard (105 cfu) and high (108 cfu) inocula of five MRSA, one glycopeptide-intermediate (GISA) and five MSSA strains. One MSSA (MSSA-678) and one MRSA (MRSA-277) strain were selected to be used in the in vivo model. A human-like pharmacokinetics model was applied and the equivalents of cloxacillin 2 g/4 h IV and daptomycin 6 mg/kg/day IV were administered. To optimize vancomycin activity, dosage was adjusted to achieve an AUC/MIC ≥400. RESULTS: Daptomycin sterilized significantly more vegetations than cloxacillin (13/13, 100% versus 9/15, 60%; P = 0.02) and showed a trend of better activity than vancomycin (10/14, 71%; P = 0.09) and vancomycin plus cloxacillin (10/14, 71%; P = 0.09) against MSSA-678. Addition of cloxacillin to vancomycin (13/15, 87%) was significantly more effective than vancomycin (8/16, 50%; P = 0.05) and showed similar activity to daptomycin (13/18, 72%; P = 0.6) against MRSA-277. In all treatment arms, the bacterial isolates recovered from vegetations were re-tested and showed the same daptomycin susceptibility as the original strains. CONCLUSIONS: Vancomycin plus cloxacillin proved synergistic and bactericidal activity against MRSA. Daptomycin was the most efficacious option against MSSA and similar to vancomycin plus cloxacillin against MRSA. In settings with high MRSA prevalence, vancomycin plus cloxacillin might be a good alternative for empirical therapy of S. aureus IE.