Original Article

Journal of Molecular Medicine

, Volume 92, Issue 2, pp 139-149

Nafcillin enhances innate immune-mediated killing of methicillin-resistant Staphylococcus aureus

  • George SakoulasAffiliated withDepartment of Pediatrics, University of California, San DiegoDivision of Pediatric Pharmacology & Drug Discovery, University of California San Diego School of Medicine Email author 
  • , Cheryl Y. OkumuraAffiliated withDepartment of Pediatrics, University of California, San DiegoDepartment of Biology, Occidental College
  • , Wdee ThienphrapaAffiliated withDepartment of Pediatrics, University of California, San Diego
  • , Joshua OlsonAffiliated withDepartment of Pediatrics, University of California, San Diego
  • , Poochit NonejuieAffiliated withDepartment of Biological Sciences, University of California, San Diego
  • , Quang DamAffiliated withDepartment of Pediatrics, University of California, San Diego
  • , Abhay DhandAffiliated withDepartment of Medicine, New York Medical College
  • , Joseph PoglianoAffiliated withDepartment of Biological Sciences, University of California, San Diego
  • , Michael R. YeamanAffiliated withDavid Geffen School of Medicine at UCLA and the Los Angeles Biomedical Research Institute at Harbor–UCLA Medical Center
    • , Mary E. HenslerAffiliated withDepartment of Pediatrics, University of California, San Diego
    • , Arnold S. BayerAffiliated withDavid Geffen School of Medicine at UCLA and the Los Angeles Biomedical Research Institute at Harbor–UCLA Medical Center
    • , Victor NizetAffiliated withDepartment of Pediatrics, University of California, San DiegoSkaggs School of Pharmacy & Pharmaceutical Sciences, University of California, San DiegoDivision of Pediatric Pharmacology & Drug Discovery, University of California San Diego School of Medicine Email author 

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Abstract

Based on in vitro synergy studies, the addition of nafcillin to daptomycin was used to treat refractory methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. Daptomycin is a de facto cationic antimicrobial peptide in vivo, with antistaphylococcal mechanisms reminiscent of innate host defense peptides (HDPs). In this study, the effects of nafcillin on HDP activity against MRSA were examined in vitro and in vivo. Exposures to β-lactam antimicrobials in general, and nafcillin in particular, significantly increased killing of S. aureus by selected HDPs from keratinocytes, neutrophils, and platelets. This finding correlated with enhanced killing of MRSA by whole blood, neutrophils, and keratinocytes after growth in nafcillin. Finally, nafcillin pretreatment ex vivo reduced MRSA virulence in a murine subcutaneous infection model. Despite the lack of direct activity against MRSA, these studies show potent, consistent, and generalized nafcillin-mediated “sensitization” to increased killing of MRSA by various components of the innate host response. The use of nafcillin as adjunctive therapy in MRSA bacteremia merits further study and should be considered in cases refractory to standard therapy.

Key messages

  • Nafcillin has been used as adjunctive therapy to clear persistent MRSA bacteremia.

  • Nafcillin enhances killing of MRSA by a cadre of innate host defense peptides.

  • Nafcillin increases binding of human cathelicidin LL-37 to the MRSA membrane.

  • Nafcillin enhances killing of MRSA by neutrophils.

  • Nafcillin reduces virulence of MRSA in a murine subcutaneous infection model.

Keywords

MRSA Innate immunity Beta-lactams Nafcillin Host defense peptides