Use AUC to Optimize Vancomycin Dosing

Vancomycin, a glycopeptide antibiotic derived from Streptomyces orientalis, was first discovered in soil samples from Borneo by Eli Lilly Co in 1952.¹

The FDA approved the antibiotic in 1958. However, both the study and use of the agent were relatively infrequent until the late 1970s and early 1980s when an increasing incidence of methicillin resistance in Staphylococcus aureus began to become problematic.^1,2

Vancomycin follows a pharmacodynamic model of 24-hour area under the curve to minimum inhibitory concentration ratio (AUC24:MIC), with a target of ≥400mg∙h/L.^1,3,4 For years, pharmacists in inpatient and outpatient infusion settings have been involved heavily in the dosing and monitoring of vancomycin, because of the complex interplay between achieving pharmacodynamic targets and minimizing associated toxicity, most notably nephrotoxicity.

Vancomycin induced nephrotoxicity (VIN) is an acute glomerular nephritis that typically has its onset 2 to 5 days into therapy, peaks 5 to 10 days into therapy, and resolves within 19 days in 90% of cases, with an estimated 3% of patients requiring hemodialysis.^4,5 Some patient-related factors are known to increase the risk of VIN. However, with regard to dosing and observed levels, vancomycin doses greater than 4g/d, initial trough levels greater than 15 mcg/mL, and AUC levels of 600 to 800 mg∙h/L appear to be associated with an increased risk of nephrotoxicity.^4,6,7

In the 2009 vancomycin dosing guidelines released by the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists, it was recommended that vancomycin troughs be maintained above 10 mcg/mL for all infections and that goals of 15 to 20 mcg/mL should be targeted for patients with complicated infections, such as bacteremia, endocarditis, meningitis, osteomyelitis, and S aureus pneumonia. The higher trough goal was selected for complicated infections, as it was thought more likely to achieve an AUC24:MIC ≥400 mg∙h/L in most patients when the organism’s MIC was ≤1 mcg/mL.⁴

Although targeting troughs of 15 to 20 mcg/mL may provide a simplistic means of assurance of pharmacodynamic target attainment in complicated infections, concern has arisen that it may also unnecessarily increase nephrotoxicity risk in some patients. The results of 1 study showed that although patients with trough levels >10 mcg/mL were more likely to achieve the pharmacodynamic AUC24:MIC target than those with trough levels <10 mcg/mL, pushing trough levels >15 mcg/mL was not associated with a statistically significant increase in AUC24:MIC target attainment. Additionally, the study results showed that the mean trough in those patients who developed VIN was 19.5 mcg/mL versus 14.5 mcg/mL in those who did not develop VIN. Thus, targeting a higher trough goal increased the risk for the development of VIN but did not increase the proportion of patients achieving the pharmacodynamic target.⁸

Additionally, other pharmacokinetic studies and Monte Carlo simulations have shown that when the organism’s MIC is ≤1 mcg/mL, a relatively high proportion of patients can be expected to achieve the pharmacodynamic target of AUC:MIC ≥400 mg&#8729;h/L, with troughs <15mcg/mL and some even with troughs <10 mcg/mL.^9,10 With new draft vancomycin dosing guidelines in draft pending public comment and given the imbalance between pharmacodynamic target attainment and risk for development of nephrotoxicity within the current dosing recommendations, a shift in dosing to AUC:MIC-targeted strategies should be expected soon.

Pharmacists involved in the therapeutic drug management of patients receiving vancomycin should begin to familiarize themselves with the methods for optimizing this agent using AUC24:MIC-based strategies.

Vancomycin AUC may be determined using a Bayesian approach or equation-based methodology, such as a trapezoidal model or other first-order equations.¹¹ Although both approaches have been shown to accurately predict AUC values, there are several differences.

The Bayesian method is based on Bayes’ Theorem, a theorem of conditional probabilities that describes how evidence from prior experiences and the likelihood of separate events are related. The Bayesian approach starts by using population data to provide estimates of an individual patient’s pharmacokinetic parameters, known as Bayesian prior. Then, after obtaining a single level, a revision of pharmacokinetic parameter estimates is provided. These estimates, referred to as the Bayesian conditional posterior, can be used to estimate a patient-specific AUC. The Bayesian approach to vancomycin dose optimization requires the use of 1 of several commercially available software programs. A recent study compared several programs and 2 first-order equations in a small population of critically ill patients and found varying degrees of accuracy, adaptability, bias, and ease of use.¹²

Advantages of the Bayesian approach include adaptive, fast predictions and potential cost savings realized through a reduction in required vancomycin levels. The primary limitation to the Bayesian methodology is the cost of the software, which varies in price depending on the program and selected subscription model.^11,12

Despite prospective data from a large hospital showing cost savings when using a Bayesian approach, these platform costs may be prohibitive to smaller institutions with lower vancomycin utilization rates.¹³ By contrast to the Bayesian method, equation-based approaches do not require the purchase of special software.

One such approach is the trapezoidal model, which requires obtaining 2 steady-state levels, with 1 level drawn following administration/distribution and another just prior to the next scheduled dose.¹⁴ These levels are used to calculate a patient’s pharmacokinetic parameters, which are then used in the linear trapezoidal and logarithmic trapezoidal formulas to calculate the AUC for a single dose. To determine the AUC24, single-dose AUCs must then be multiplied by the number of daily doses administered.¹⁴ Because the trapezoidal method only provides a static estimation of the AUC, it must be done at a steady state and cannot account for potential changes in AUC as the result of continuing acute physiologic changes.¹² Also, because the trapezoidal formula is not able to account for the entirety of the administration/distribution phase, it is possible that the AUC may be slightly underestimated compared with Bayesian estimates.¹¹

The trapezoidal model’s limitations are its inability to account for acute physiologic changes, its inherent characteristic of possibly underestimating true AUC values, and its requirement of at least 2 vancomycin levels. However, for small institutions or those with concerns regarding the cost of Bayesian software, it may represent a viable option.

Other first-order equation-based methods have been proposed and validated to have similar accuracy and bias compared with Bayesian software-based methods. However, the above limitations of the trapezoidal model still apply to these equations.^11,12

AUC:MIC-based vancomycin dosing is an improvement over trough-based monitoring toward optimization of patient outcomes and minimization of associated toxicity. However, it presents a unique challenge to pharmacists riding the changing wave of vancomycin therapeutic drug monitoring recommendations. With the anticipated transition in vancomycin dosing to AUC24: MIC-based recommendations, hospitals must balance the pro and cons of the described approaches to determine which may best fit the needs of their institutions and patients.

Ryan W. Stevens, PharmD, BCIPD, is an infectious diseases clinical specialist at Providence Alaska Medical Center in Anchorage.Francis Carlo S. Balmes, PharmD, is a PGY-1 pharmacy practice resident at Providence Alaska Medical Center.

References

• Levine DP. Vancomycin: a history. Clin Infect Dis. 2006;42 Suppl 1:S5-12.
• The University of Chicago Medicine. MRSA history timeline: 1959-2017. MRSA Research Center website. mrsa-research-center.bsd.uchicago.edu/timeline.html. Published 2010. Accessed January 10, 2019.
• Dzintars K, Pham PA, Hsu AJ. Vancomycin. Johns Hopkins Medicine website. hopkinsguides.com/hopkins/view/Johns_Hopkins_ABX_Guide/540578/all/Vancomycin. Updated November 4, 2018. Accessed January 10, 2019.
• Rybak 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. Am J Health Syst Pharm. 2009;66(1):82-98. doi: 10.2146/ajhp080434.
• Meaney CJ, Hynicka LM, Tsoukleris MG. Vancomycin-associated nephrotoxicity in adult medicine patients: incidence, outcomes, and risk factors. Pharmacotherapy. 2014;34(7):653-661. doi: 10.1002/phar.1423.
• van Hal SJ, Paterson DL, Lodise TP. Systematic review and meta-analysis of vancomycin-induced nephrotoxicity associated with dosing schedules that maintain troughs between 15 and 20 milligrams per liter. Antimicrob Agents Chemother. 2013;57(2):734-744. doi: 10.1128/AAC.01568-12.
• Zasowski EJ, Murray KP, Trinh TD, et al. Identification of vancomycin exposure-toxicity thresholds in hospitalized patients receiving intravenous vancomycin. Antimicrob Agents Chemother. 2017;62(1). pii: e01684-17. doi: 10.1128/AAC.01684-17.
• Hale CM, Seabury RW, Steele JM, Darko W, Miller CD. Are vancomycin trough concentrations of 15 to 20 mg/L associated with increased attainment of an AUC/MIC ≥ 400 in patients with presumed MRSA infection? J Pharm Pract.2017;30(3):329-335. doi: 10.1177/0897190016642692.
• Neely MN, Youn G, Jones B, et al. Are vancomycin trough concentrations adequate for optimal dosing? Antimicrob Agents Chemother. 2014;58(1):309-316. doi: 10.1128/AAC.01653-13.
• Patel N, Pai MP, Rodvold KA, Lomaestro B, Drusano GL, Lodise TP. Vancomycin: we can’t get there from here. Clin Infect Dis. 2011;52(8):969-974. doi: 10.1093/cid/cir078.
• Pai MP, Neely M, Rodvold KA, Lodise TP. Innovative approaches to optimizing the delivery of vancomycin in individual patients. Adv Drug Deliv Rev. 2014;77:50-57. doi: 10.1016/j.addr.2014.05.016.
• Turner RB, Kojiro K, Shephard EA, et al. Review and validation of Bayesian dose-optimizing software and equations for calculation of vancomycin area under the curve in critically ill patients. Pharmacotherapy. 2018;38(12):1174-1183. doi: 10.1002/phar.2191
• Neely MN, Kato L, Youn G, et al. Prospective trial on the use of trough concentration versus area under the curve to determine therapeutic vancomycin dosing. Antimicrob Agents Chemother. 2018;62(2). pii: e02042-17. doi: 10.1128/AAC.02042-17.
• DeRyke CA, Alexander DP. Optimizing vancomycin dosing through pharmacodynamic assessment targeting area under the concentration-time curve/minimum inhibitory concentration. Hospital Pharmacy. 2009;44(9):751-765. doi: 10.1310/hpj4409-751.

The Society of Infectious Diseases Pharmacists (SIDP) is an association of pharmacists and other allied healthcare professionals who are committed to promoting the appropriate use of antimicrobial agents and supporting practice, teaching, and research in infectious diseases. We aim to advance infectious diseases pharmacy and lead antimicrobial stewardship in order to optimize the care of patients. To learn more about SIDP, visit sidp.org.