Therapeutic monitoring of vancomycin for serious methicillin-resistant Staphylococcus aureus infections: A revised consensus guideline and review by ASHP/PIDS/SIDP/IDSA

Abstract

Recent clinical data on vancomycin pharmacokinetics and pharmacodynamics suggest a reevaluation of current dosing and monitoring recommendations. The previous 2009 vancomycin consensus guidelines recommend trough monitoring as a surrogate marker for the target area under the curve over 24 hours to minimum inhibitory concentration (AUC/MIC). However, recent data suggest that trough monitoring is associated with higher nephrotoxicity. This document is an executive summary of the new vancomycin consensus guidelines for vancomycin dosing and monitoring. It was developed by the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists vancomycin consensus guidelines committee. These consensus guidelines recommend an AUC/MIC ratio of 400–600 mg*hour/L (assuming a broth microdilution MIC of 1 mg/L) to achieve clinical efficacy and ensure safety for patients being trea ted for serious methicillin-resistant Staphylococcus aureus infections.

Keywords: vancomycin consensus guidelines, vancomycin, pharmacokinetics and pharmacodynamics, target attainment, nephrotoxicity

Executive Summary

The revised vancomycin consensus guidelines for dosing and monitoring vancomycin is an updated version of the 2009 guidelines developed by the American Society of Health-Systems Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists vancomycin guidelines committee. The following is an executive summary of key recommendations and grading system used for this document (Tables 1, 2) [1, 2].

Despite more than 61 years of clinical use of vancomycin, knowledge gaps regarding the most appropriate approach for optimizing therapy and minimizing toxicity still exist. The area under the curve over 24 hours to minimum inhibitory concentration ratio (AUC/MIC) has been documented as the primary pharmacokinetic/pharmacodynamic (PK/PD) target for glycopeptides, including vancomycin. The previous consensus guidelines in 2009 recommended the use of trough monitoring (target 15–20 mg/L) as a surrogate marker of the AUC/MIC (target 400 mg*hour/L) for ease of managing therapy and simplifying dose adjustments and monitoring. At that time, the primary reason for increasing the exposure of vancomycin via specific trough monitoring targets was to improve the likelihood of achieving the AUC/MIC target of 400 mg*hour/L and thereby increasing efficacy. However, since the implementation of these recommendations, there have been numerous reports of increased nephrotoxicity in adults and pediatrics when trough level monitoring using these targets has been applied. Recent PK/PD and toxicodynamic studies have demonstrated a significantly reduction in vancomycin exposure and nephrotoxicity rates without compromising outcomes when AUC/MIC monitoring has been employed vs traditional trough monitoring approaches.

When using AUC/MIC-guided empiric dosing, the MIC should be assumed to be 1 mg/L based on broth microdilution methods, extensive antibiotic susceptibility data, and the inaccuracies or variability of automated susceptibility testing (±1 log₂ dilutions). Specific information regarding MIC evaluation and automated susceptibility testing can be found under the MIC susceptibility section of the full guideline [1]. A target AUC between 400 and 600 mg*hour/L is suggested for methicillin-resistant Staphylococcus aureus (MRSA) invasive infections in adults and pediatrics based on clinical efficacy and safety data. These AUC targets should be achieved early in the course of therapy (24–48 hours) given the importance of early and appropriate therapy. Loading doses based on actual body weight are suggested for patients who are critically ill, requiring renal replacement therapy, or receiving continuous infusion therapy. Specific recommendations for patients with obesity on renal replacement therapy and, for the first time, pediatric patients are now included in the revised guidelines [1].

It should be noted that almost all data available on vancomycin PK/PD and toxicodynamics have been derived from patients who have been treated for serious infections of MRSA. Furthermore, the majority of the data have been derived from patients with complicated bloodstream infections. Therefore, caution should be applied when extrapolating this information to mild noninvasive infections or other bacterial species susceptible to vancomycin. These guidelines conclude that AUC-guided dosing and monitoring is the most accurate and safest way to dose vancomycin. The recommendations in this document should not circumvent sound clinical judgment in managing patients who require vancomycin therapy. Specific details for each section of the document, including references, can be found in the primary publication [1].

Notes

Potential conflicts of interest.  T. P. L. is a board member of Motif; is a consultant for Paratek, Melinta, Merck, and Motif; has received grants from Merck and Motif; and is on the speaker’s bureaus of Melinta and Sunovion. B. A. M. has received grants from NxStage and Merck, and personal fees from Wolters-Kluwer. M. P. P. reports personal fees from Paratek and grants from Merck. K. A. R. is a consultant, on the speaker’s bureau, and/or served on advisory boards for the following companies: Achaogen, Allergan, Bayer, BLC USA, Entasis Therapeutics, GSK, Janssen Pharmaceuticals, Meiji, Melinta Therapeutics, Medicine Company, Merck, Motif Bio PLC, Nabriva Therapeutics, Qpex Biopharma, Rempex, Shionogi, Spero Therapeutics, Theravance Biopharma, Tetraphase, Wockhardt, and Zavante Therapeutics; and has received research grants and contracts (paid to the University of Illinois at Chicago) from Theravance Biopharma and Allergan. M. J. R. has received grants and personal fees from Allergan, Melinta, Merck, Motif, Paratek, Shionogi, and Tetraphase; personal fees from InsightRx; and grants from Contrafect. A. W.-B. has received grants from Merck and Allergan, and from Nabriva Therapeutics and Paratek Pharmaceuticals. All other authors report no potential conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

References

1. Rybak MJ, Le J, Lodise TP, et al. Therapeutic monitoring of vancomycin for serious methicillin-resistant Staphylococcus aureus infections: a revised consensus guideline and review of the American Society of Health-System Pharmacists, the Infectious Diseases Society by America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists. Am J Health-Syst Pharm 2020; 77: 835–64. doi:10.1093/ajhp/zxaa036
2. The periodic health examination. Canadian Task Force on the Periodic Health Examination. Can Med Assoc J 1979; 121:1193–254.