NYMC Faculty Publications

Nafcillin Enhances Innate Immune-Mediated Killing of Methicillin-Resistant Staphylococcus Aureus

Author Type(s)

Faculty

DOI

10.1007/s00109-013-1100-7

Journal Title

Journal of Molecular Medicine

First Page

139

Last Page

149

Document Type

Article

Publication Date

2-1-2014

Department

Medicine

Keywords

Animals, Anti-Bacterial Agents, Antimicrobial Cationic Peptides, Bacteremia, Cell Line, Cells, Cultured, Daptomycin, Dose-Response Relationship, Drug, Drug Synergism, Drug Therapy, Combination, Female, Humans, Immunity, Innate, Keratinocytes, Male, Methicillin-Resistant Staphylococcus aureus, Mice, Microbial Viability, Middle Aged, Nafcillin, Neutrophils, Phagocytosis, Staphylococcal Infections, Cathelicidins

Disciplines

Medicine and Health Sciences

Abstract

UNLABELLED: 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.

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