High Potency Killing of Methicillin-Resistant Staphylococcus aureus with Adjunctive Carbapenem Combination Therapy

Despite the aggressive use of first-line antibiotics demonstrating in vitro susceptibility, methicillin-resistant Staphylococcus aureus (MRSA) bacteremia continues to be associated with high rates of treatment failures. Early optimization of treatment is crucial, as each additional day of bacteremia significantly increases the risk of death and morbidity among survivors. Building on our success with adjunctive carbapenem therapy for persistent methicillin-susceptible S. aureus (MSSA) bacteremia, we examined the utility of adjunctive carbapenems (ertapenem or meropenem) to enhance the efficacy of ceftaroline or vancomycin for MRSA treatment in both in vitro and in vivo models. Although carbapenems are not typically used clinically for MRSA, our study demonstrated striking bactericidal synergy between carbapenems and ceftaroline, as assessed through checkerboard, time-kill, and human whole blood killing assays. In a murine bacteremia model, the combination of ceftaroline or vancomycin with ertapenem or meropenem showed superior activity compared to monotherapy. Transcriptomic analysis of MRSA pretreated with subtherapeutic concentrations of ceftaroline and carbapenems revealed transcriptional shifts indicative of reduced antibiotic resistance, virulence, and host immune evasion. Additionally, supernatants from MRSA pretreated with the subtherapeutic combination therapy produced less platelet injury, as measured by LDH release. These pretreated MRSA were also markedly more susceptible to killing by human platelets and the antimicrobial peptide LL-37. The therapeutic success of adjunctive carbapenems appears to be driven by multiple mechanisms, including direct drug-drug synergy with first-line anti-MRSA agents, attenuation of resistance and virulence factors, and enhancement of immune-mediated killing, each warranting further investigation.