Synergy between Vancomycin and Nafcillin against Staphylococcus aureus in an In Vitro Pharmacokinetic/Pharmacodynamic Model

PLOS ONE, Dec 2019

Introduction Continued pressure from glycopeptide use has led to non-susceptible strains of Staphylococcus aureus including heterogeneously vancomycin-intermediate S. aureus (hVISA). Infections with hVISA are associated with poor patient outcomes, thus incentivizing novel treatments. Evidence suggests that vancomycin and anti-staphylococcal penicillin susceptibility are inversely related which indicates that the use of this combination may be particularly useful against methicillin-resistant S. aureus with reduced susceptibility to vancomycin, such as hVISA. The aim of this study was to evaluate the potential for synergy between vancomycin and nafcillin against hVISA. Methods Twenty-five hVISA strains were evaluated for vancomycin and nafcillin minimum inhibitory concentration (MIC) by broth microdilution in duplicate. Potential for synergy was assessed by time-kill at 1/2x MIC in triplicate. Five strains were chosen, representing the range nafcillin MIC’s available in the cohort –4, 16, 64, 128, and 256 µg/mL, and were run in an in vitro pharmacokinetic/pharmacodynamic (PK/PD) model in duplicate over 72 hours to evaluate the potential of the combination with simulated human pharmacokinetics. In addition, 4 fully glycopeptide susceptible strains of S. aureus including 2 methicillin-susceptible (MSSA) and 2 methicillin-resistant (MRSA) were run in the PK/PD model for comparison. Results In the time-kill, 92% of strains (23 of 25) displayed synergy with the combination of vancomycin and nafcillin. In the PK/PD model, all five strains of hVISA showed an improvement in overall activity (P≤0.004) and organism burden at 72 hours (P≤0.001) with the combination compared to either drug alone. The combination was also successful against both MRSA and MSSA in overall activity (P≤0.009) and organism burden at 72 hours (P≤0.016), though the magnitude of the effect was diminished against MSSA. Conclusions The combination of vancomycin and nafcillin significantly improved antibacterial activity against hVISA, MRSA, and MSSA compared to either drug alone.

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Synergy between Vancomycin and Nafcillin against Staphylococcus aureus in an In Vitro Pharmacokinetic/Pharmacodynamic Model

Citation: Leonard SN (2012) Synergy between Vancomycin and Nafcillin against Staphylococcus aureus in an In Vitro Pharmacokinetic/Pharmacodynamic Model. PLoS ONE 7(7): e42103. doi:10.1371/journal.pone.0042103 Synergy between Vancomycin and Nafcillin against Staphylococcus aureus in an In Vitro Pharmacokinetic/ Pharmacodynamic Model Steven N. Leonard 0 Martin Rottman, Harvard Medical School, United States of America 0 1 School of Pharmacy, Bouve College of Health Sciences, Northeastern University , Boston , Massachusetts, United States of America, 2 Department of Pharmacy, Brigham and Women's Hospital , Boston, Massachusetts , United States of America Introduction: Continued pressure from glycopeptide use has led to non-susceptible strains of Staphylococcus aureus including heterogeneously vancomycin-intermediate S. aureus (hVISA). Infections with hVISA are associated with poor patient outcomes, thus incentivizing novel treatments. Evidence suggests that vancomycin and anti-staphylococcal penicillin susceptibility are inversely related which indicates that the use of this combination may be particularly useful against methicillin-resistant S. aureus with reduced susceptibility to vancomycin, such as hVISA. The aim of this study was to evaluate the potential for synergy between vancomycin and nafcillin against hVISA. Methods: Twenty-five hVISA strains were evaluated for vancomycin and nafcillin minimum inhibitory concentration (MIC) by broth microdilution in duplicate. Potential for synergy was assessed by time-kill at 1/2x MIC in triplicate. Five strains were chosen, representing the range nafcillin MIC's available in the cohort -4, 16, 64, 128, and 256 mg/mL, and were run in an in vitro pharmacokinetic/pharmacodynamic (PK/PD) model in duplicate over 72 hours to evaluate the potential of the combination with simulated human pharmacokinetics. In addition, 4 fully glycopeptide susceptible strains of S. aureus including 2 methicillin-susceptible (MSSA) and 2 methicillin-resistant (MRSA) were run in the PK/PD model for comparison. Results: In the time-kill, 92% of strains (23 of 25) displayed synergy with the combination of vancomycin and nafcillin. In the PK/PD model, all five strains of hVISA showed an improvement in overall activity (P#0.004) and organism burden at 72 hours (P#0.001) with the combination compared to either drug alone. The combination was also successful against both MRSA and MSSA in overall activity (P#0.009) and organism burden at 72 hours (P#0.016), though the magnitude of the effect was diminished against MSSA. Conclusions: The combination of vancomycin and nafcillin significantly improved antibacterial activity against hVISA, MRSA, and MSSA compared to either drug alone. - Funding: This work was supported in part by a Northeastern University, Bouve College of Health Sciences Proposal Development Grant. No other specific funding was received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The author has declared that no competing interests exist. The worldwide dissemination and poor treatment outcomes of methicillin-resistant Staphylococcus aureus (MRSA) presents therapeutic difficulties for clinicians. Historically vancomycin has been the mainstay of therapy for MRSA infections, however decades of selective pressure has led to evolutionary changes in S. aureus diminishing the utility of this agent. [1,2,3,4,5,6,7] Of note is the emergence of heterogeneously vancomycin intermediate S. aureus (hVISA); a particularly concerning organism as it is not detected by traditional susceptibility testing or automated systems commonly utilized in clinical microbiology laboratories. [4,8,9] Due to these detection difficulties the true prevalence is difficult to estimate but generally ranges from 515% (although this varies widely based on geographic location, testing method used, time period of isolates tested, etc.). [4,9,10,11] It has also been shown that the prevalence of hVISA may be rising. [9] This is concerning as preliminary studies have found an association between infection with hVISA and poor treatment outcomes including prolonged fever and bacteremia, increased length of hospital stay, vancomycin treatment failure, and longer total duration of antibiotic therapy. [1,2,3,4,5,6,11]. The use of combination antimicrobial therapy is a common occurrence and represents a potential treatment option for infections caused by hVISA. [10] Multiple guidelines from the Infectious Diseases Society of America (IDSA) advocate for the use of a myriad of combination antimicrobial therapies for different purposes. [12,13,14,15] The clinical use of combination therapy for MRSA, outside of the clinical practice guidelines above, has become ubiquitous and thus there is an ongoing need to characterize antimicrobial interactions to find the most potentially useful combinations. Several previous (...truncated)


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Steven N. Leonard. Synergy between Vancomycin and Nafcillin against Staphylococcus aureus in an In Vitro Pharmacokinetic/Pharmacodynamic Model, PLOS ONE, 2012, Volume 7, Issue 7, DOI: 10.1371/journal.pone.0042103