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Effects of vancomycin versus nafcillin in enhancing killing of methicillin-susceptible Staphylococcus aureus causing bacteremia by human cathelicidin LL-37

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Abstract

Recent studies have demonstrated that anti-staphylococcal beta-lactam antibiotics, like nafcillin, render methicillin-resistant Staphylococcus aureus (MRSA) more susceptible to killing by innate host defense peptides (HDPs), such as cathelicidin LL-37. We compared the effects of growth in 1/4 minimum inhibitory concentration (MIC) of nafcillin or vancomycin on the LL-37 killing of 92 methicillin-susceptible S. aureus (MSSA) isolates. For three randomly selected strains among these, we examined the effects of nafcillin, vancomycin, daptomycin, or linezolid on LL-37 killing and autolysis. Growth in the presence of subinhibitory nafcillin significantly enhanced LL-37 killing of MSSA compared to vancomycin and antibiotic-free controls. Nafcillin also reduced MSSA production of the golden staphylococcal pigment staphyloxanthin in 39 % of pigmented strains vs. 14 % for vancomycin. Among the antibiotics tested, only nafcillin resulted in significantly increased MSSA autolysis. These studies point to additional mechanisms of anti-staphylococcal activity of nafcillin beyond direct bactericidal activity, properties that vancomycin and other antibiotic classes do not exhibit. The ability of nafcillin to enhance sensitivity to innate HDPs may contribute to its superior effectiveness against MSSA, as suggested by studies comparing clinical outcomes to vancomycin treatment.

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Authors and Affiliations

  1. Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive, MC 0714, La Jolla, CA, 92093-0714, USA

    J. Le & V. Nizet

  2. University of California San Diego School of Medicine, La Jolla, CA, USA

    Q. Dam, W. Thienphrapa, V. Nizet & G. Sakoulas

  3. Iowa City VA Health Care System, Iowa City, IA, USA

    M. Schweizer

  4. University of Iowa Carver College of Medicine, Iowa City, IA, USA

    M. Schweizer

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  1. J. Le
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  2. Q. Dam
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  3. M. Schweizer
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  4. W. Thienphrapa
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  5. V. Nizet
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  6. G. Sakoulas
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Correspondence to J. Le.

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Funding

Funding for this research was provided by U54 HD071600-01 09/26/2011-06/30/2016 from the National Institute of Child Health and Human Development on Developmental and Translational Pharmacology of Pediatric Antimicrobial Therapy (J.L., G.S., and V.N.), K23AI089978 from the National Institute of Allergy And Infectious Diseases (J.L.), and the Great Lakes Regional Center for Excellence in Biodefense and Emerging Infectious Disease Research (AI057153, V.N.). No funding bodies had any role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Conflict of interest

G.S. has received speaking honoraria from Cubist, Forest, and Novartis Pharmaceuticals, consulting fees from Cubist and Forest Pharmaceuticals, and research grant support from Forest Pharmaceuticals.

Ethical approval

The bacterial strains studied were obtained from a previously published retrospective clinical study, which was approved by the institutional review board of the University of Maryland, Baltimore.

Informed consent

Informed consent was not necessary for the conduct of this in vitro study.

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Le, J., Dam, Q., Schweizer, M. et al. Effects of vancomycin versus nafcillin in enhancing killing of methicillin-susceptible Staphylococcus aureus causing bacteremia by human cathelicidin LL-37. Eur J Clin Microbiol Infect Dis 35, 1441–1447 (2016). https://doi.org/10.1007/s10096-016-2682-0

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  • DOI: https://doi.org/10.1007/s10096-016-2682-0

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