Enhanced Killing of Methicillin-Resistant Staphylococcus aureus With Ceftaroline or Vancomycin in Combination With Carbapenems

  • J Infect Dis. 2025 Jul 30;232(1):181-190. doi: 10.1093/infdis/jiaf010.
Allen Jankeel  1 ,  Gabriel Pérez-Parra  1 ,  Anuj K Khetarpal  1 ,  Ivan A Alvarado  1 ,  Victor Nizet  2  3 ,  George Sakoulas  3  4 ,  Erlinda R Ulloa  1  5
Affiliations
  • 1. Department of Pediatrics, University of California, Irvine School of Medicine.
  • 2. Department of Pediatrics, Division of Host-Microbe Systems and Therapeutics.
  • 3. Collaborative to Halt Antibiotic-Resistant Microbes (CHARM), Department of Pediatrics, University of California, San Diego School of Medicine, La Jolla.
  • 4. Division of Infectious Diseases, Sharp Rees-Stealy Medical Group, San Diego, California.
  • 5. Division of Infectious Disease, Children's Hospital of Orange County, Orange, California.
PMID: 39777519 DOI: 10.1093/infdis/jiaf010
Abstract

Background: 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 bacteremia, we examined the utility of adjunctive carbapenems (ertapenem or meropenem) to enhance the efficacy of ceftaroline or vancomycin for treatment of MRSA.

Methods: 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 isolates were used to treat platelets, and cytotoxicity was assessed via Lactate Dehydrogenase release assays.

Results: Although not 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 isolates 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.

Conclusions: The therapeutic success of adjunctive carbapenems appears 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.

Keywords
MRSA; bacteremia; carbapenems; ceftaroline; combination therapy; endocarditis; ertapenem; meropenem; vancomycin.
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