Methicillin-resistant Staphylococcus 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 (DAP(r)) 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 DAP(r) MRSA 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 (DAP(s))/Dap(r) MRSA strains originally obtained from patients that failed DAP monotherapy. Both in vitro (MIC, synergy-kill curve) and in 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 DAP(r) MRSA 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 of in vitro mutant selection was observed when DAP(s) MRSA strains were exposed to DAP. Importantly, the combination of DAP and a β-
lactam prevented the selection of DAP(r) variants. In summary, our data show that the DAP-β-
lactam combination may significantly enhance both the in vitro and in vivo efficacy of anti-MRSA therapeutic options against DAP(r) MRSA
infections and represent an option in preventing DAP(r) selection in persistent or refractory MRSA
infections.