Abstract
Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is associated with high rates of treatment failure, even when antibiotics showing in vitro susceptibility are used. Early optimization of therapy is crucial to reduce morbidity and mortality. Building on our previous research on carbapenem therapy for 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 treatment of MRSA. The effectiveness of combination therapy versus monotherapy against MRSA was assessed using checkerboard, time-kill, and human whole blood killing assays, as well as a murine bacteremia model. Additionally, we performed transcriptomic analysis and conducted human platelet and antimicrobial peptide killing assays on MRSA pretreated with subtherapeutic concentrations of ceftaroline and carbapenems. The supernatants from these MRSA were used to treat platelets, and cytotoxicity was assessed via LDH release assays. Although not typically used for MRSA, we identified striking in vitro and in vivo synergy between carbapenems and ceftaroline or vancomycin. MRSA pretreated with subtherapeutic ceftaroline-carbapenem therapy revealed transcriptional shifts indicative of reduced antibiotic resistance, virulence, and host immune evasion. Supernatants from these MRSA also caused less platelet injury compared to monotherapy. Furthermore, MRSA pretreated with ceftaroline and carbapenems demonstrated increased susceptibility 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.
Published Version
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