β-Lactams Increase the Antibacterial Activity of Daptomycin against Clinical Methicillin-Resistant Staphylococcus aureus Strains and Prevent Selection of Daptomycin-Resistant Derivatives

Abstract

ABSTRACTMethicillin-resistantStaphylococcus aureus(MRSA) has emerged to be one of the most important pathogens both in health care and in community-onset infections. Daptomycin (DAP) is a cyclic anionic lipopeptide recommended for treatment of skin infections, bacteremia, and right-sided endocarditis caused by MRSA. Resistance to DAP (DAPr) has been reported in MRSA and is mostly accompanied by a parallel decrease in oxacillin resistance, a process known as the “seesaw effect.” Our study provides evidence that the seesaw effect applies to other β-lactams and carbapenems of clinical use, including nafcillin (NAF), cefotaxime (CTX), amoxicillin-clavulanic (AMC), and imipenem (IMP), in heterogeneous DAPrMRSA strains but not in MRSA strains expressing homogeneous β-lactam resistance. The antibacterial efficacy of DAP in combination with β-lactams was evaluated in isogenic DAP-susceptible (DAPs)/DaprMRSA strains originally obtained from patients that failed DAP monotherapy. Bothin vitro(MIC, synergy-kill curve) andin vivo(wax worm model) approaches were used. In these models, DAP and a β-lactam proved to be highly synergistic against both heterogeneous and homogeneous clinical DAPrMRSA strains. Mechanistically, β-lactams induced a reduction in the cell net positive surface charge, reverting the increased repulsion provoked by DAP alone, an effect that may favor the binding of DAP to the cell surface. The ease ofin vitromutant selection was observed when DAPsMRSA strains were exposed to DAP. Importantly, the combination of DAP and a β-lactam prevented the selection of DAPrvariants. In summary, our data show that the DAP–β-lactam combination may significantly enhance both thein vitroandin vivoefficacy of anti-MRSA therapeutic options against DAPrMRSA infections and represent an option in preventing DAPrselection in persistent or refractory MRSA infections.