Nafcillin enhances innate immune-mediated killing of methicillin-resistant Staphylococcus aureus
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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.
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.
- Nafcillin enhances innate immune-mediated killing of methicillin-resistant Staphylococcus aureus
Journal of Molecular Medicine
Volume 92, Issue 2 , pp 139-149
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- Springer Berlin Heidelberg
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- Innate immunity
- Host defense peptides
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- Author Affiliations
- 1. Department of Pediatrics, University of California, San Diego, La Jolla, CA, 92093, USA
- 7. Division of Pediatric Pharmacology & Drug Discovery, University of California San Diego School of Medicine, 9500 Gilman Drive, Mail Code 0687, La Jolla, CA, 92093-0687, USA
- 4. Department of Biology, Occidental College, Los Angeles, CA, 90041, USA
- 3. Department of Biological Sciences, University of California, San Diego, La Jolla, CA, 92093, USA
- 5. Department of Medicine, New York Medical College, Valhalla, NY, 10595, USA
- 6. David Geffen School of Medicine at UCLA and the Los Angeles Biomedical Research Institute at Harbor–UCLA Medical Center, Torrance, CA, 90509, USA
- 2. Skaggs School of Pharmacy & Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, 92093, USA