By: Darien Lee, Pharm D Candidate c/o 2021
Vancomycin, a glycopeptide antibiotic, is one of the most commonly used medications in hospitals. Its widespread use is attributed to its efficacy for the treatment and prevention of bacterial infections caused by gram-positive bacteria. One of its most notable features is its coverage of methicillin-resistant Staphylococcus aureus (MRSA), an organism that can cause serious bacterial infections with few treatment options. Although the prevalence of MRSA in the United States has been steadily declining each year, healthcare providers cannot rule out the possibility of MRSA in a patient, often including vancomycin in the patient’s empiric medication regimen.1 The therapeutic monitoring of vancomycin for serious MRSA infections has primarily been based on guidelines published 11 years ago, in January 2009. Since then, numerous publications have had an impact on the 2009 guidelines as more data became available. In March 2020, a revised consensus guideline was published 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. This article serves to highlight updates to the guideline, focusing on optimizations in vancomycin dosing and monitoring in the adult population.
One of the most significant changes to the guidelines is the recommendation for an optimal monitoring parameter for vancomycin concentrations. The authors of the 2009 guidelines recognized that the ratio of area under the curve over 24 hours to minimum inhibitory concentration (AUC/MIC) was a pharmacodynamically linked parameter for measuring vancomycin’s effectiveness in treating MRSA.2 However, due to the difficulty in estimating AUC in clinical practice, the guidelines recommended maintaining trough serum vancomycin concentrations between 15-20 mg/L as a surrogate marker to achieve the AUC/MIC target of ≥400 in most patients with MIC ≤1 mg/L.2 The authors noted that there were limitations to this recommendation as few prospective or randomized trials of vancomycin monitoring were available to support its efficacy and safety.2
The investigators of the 2020 guidelines corroborate these limitations as their updated recommendation abandon the use of trough-only monitoring based on recent efficacy and nephrotoxicity data.3 Investigators have determined that trough-only monitoring has yielded less accurate AUC estimations compared to other methods.3 Although targeting trough concentrations of 15-20 mg/L will achieve minimum AUC/MIC values of 400, studies have shown that a wide range of concentration-time profiles can result from an identical trough value.3 In other words, the trough level will not be able to accurately estimate AUC values before the time of its measurement. This type of monitoring puts the patient at risk as higher unmonitored AUC values can result in serious acute kidney injury (AKI). As such, the 2020 guidelines recommend monitoring vancomycin efficacy and safety by directly targeting an AUC/MIC ratio of 400 to 600 through the use of Bayesian software programs.3 The Bayesian method associates a vancomycin population pharmacokinetic (PK) model with the individual patient’s drug concentrations to establish the patient’s PK parameters and optimize current and future dosing regimens.3 Although this method can similarly be accomplished with first-order PK equations, Bayesian software programs offer many advantages. The use of equations requires near steady-state conditions and only provides the estimation of AUC during the specific time period when levels are collected. 3 On the other hand, Bayesian software has the ability to collect vancomycin concentrations within the first 24-48 hours (rather than at steady-state conditions), adapt to physiologic changes in the patient’s PK profile during or after the sampling period, and account for patients with multiple dosing regimens within a 24-hour period.3 In all, the 2020 guidelines currently value Bayesian software programs as the preferred approach to monitor AUC and recommends estimation using 2 vancomycin concentrations (peak and trough). The dosing recommendation of 15-20 mg/kg (based on actual body weight) administered every 8 to 12 hours as an intermittent infusion (II) for patients with normal renal function remains the same between both guidelines.
In addition to therapeutic monitoring parameters, the authors of the 2020 guidelines also took a more comprehensive look at the clinical applications of vancomycin continuous infusion (CI) administration. The previous 2009 guidelines did not have any recommendations for CI due to little to no data supporting improved patient outcomes.2 But, recent studies have led the 2020 guideline panel to recommend CI as a viable alternative to conventional II dosing when the AUC target cannot be achieved.3 Target serum concentrations can be achieved more quickly with CI as it is easier for clinicians to measure steady-state concentrations and modify the rate of infusion.3 Although it appears that CI has similar or lower risk of nephrotoxicity, more studies are needed to make a definitive recommendation.3 Furthermore, one of the greatest disadvantages to CI administration is its incompatibility with other drugs, challenging healthcare providers to use alternative agents, independent lines, or multiple catheters.3
Loading dose recommendations are mostly the same between both guidelines; however, the 2020 guidelines provided extended guidance on dosing recommendations for obese adult patients. The current guidelines broadened the loading dose from 25-30 mg/kg to 20-35 mg/kg, with a maximum dose of 3,000 mg.3 Typically, a higher dose within this range is used for critically ill patients, while a lower dose is used for patients who are obese and/or receiving CI administration.3,4
Overall, the current guidelines addressed many gaps in the 2009 guidelines. However, the 2020 guidelines still present a few concerns and unanswered questions. Although most situations of empiric vancomycin dosing can assume a MIC of 1 mg/L, there are some occasions in which patients demonstrate a MIC >1 mg/L. The investigators recognize that the probability of achieving an AUC/MIC target of ≥400 is low with conventional dosing in this population group; however, higher doses to compensate for higher MIC values may put the patient at an increased risk for nephrotoxicity.3 As more studies are required to determine an optimal AUC/MIC target for patients with MIC > 1 mg/L, healthcare providers must consider the use of alternative antibiotics.3 Another concern related to AUC/MIC monitoring is the actual implementation of Bayesian software programs. Although these programs provide accurate and individualized dosing, its implementation will require additional costs to the institution, specialized training, and informatic resources to integrate software.5
- Kourtis AP, Hatfield K, Baggs J, et al. Vital Signs: Epidemiology and Recent Trends in Methicillin-Resistant and in Methicillin-Susceptible Staphylococcus aureus Bloodstream Infections — United States. Centers for Disease Control and Prevention. https://www.cdc.gov/mmwr/volumes/68/wr/mm6809e1.htm. Published March 8, 2019. Accessed September 13, 2020.
- Ryback M, Lomaestro B, Rotschafer JC, et al. Therapeutic monitoring of vancomycin in adult patients: A consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. American Journal of Health-System Pharmacy. https://academic-oup-com.jerome.stjohns.edu/ajhp/article/66/1/82/5130248. Published January 1, 2009. Accessed September 13, 2020.
- 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 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. American Journal of Health-System Pharmacy. https://academic-oup-com.jerome.stjohns.edu/ajhp/article/77/11/835/5810200. Published March 19, 2020. Accessed September 13, 2020.
- Approach to vancomycin dosing for adults with normal kidney function. Uptodate. https://www.uptodate.com/contents/image?imageKey=ID%2F128911&topicKey=ID%2F7027&source=see_link. Updated July 28, 2020. Accessed September 13, 2020.
- Turner RB, Kojiro K, Shephard EA, et al. Review and Validation of Bayesian Dose‐Optimizing Software and Equations for Calculation of the Vancomycin Area Under the Curve in Critically Ill Patients. American College of Clinical Pharmacy. https://accpjournals-onlinelibrary-wiley-com.jerome.stjohns.edu/doi/full/10.1002/phar.2191. Published October 26, 2018. Accessed September 13, 2020.