Few topics in infectious diseases pharmacotherapy provoke such strong emotions and opinions in so broad an audience as vancomycin dosing and monitoring. After more than 6 decades of experience with the archetypal glycopeptide, clinicians are still learning how best to optimize its dosing.
In 1987, pharmacokinetic/pharmacodynamic data from mouse thigh models were presented that showed that the 24-hour area under the concentration time curve to minimum inhibitory concentration ratio, or AUC:MIC, was the best predictor of vancomycin efficacy against Staphylococcus aureus
Now, more than 30 years later, we are in the middle of a paradigm shift from trough-guided vancomycin dosing to true AUC-guided dosing.
LAY OFF THE TROUGH AND EMBRACE THE CURVE
Consensus guidelines on vancomycin therapeutic drug monitoring, published in 2009, suggest a serum trough concentration range of 15 to 20 mg/L as a surrogate goal for an AUC:MIC ≥400 in patients with moderate to severe S aureus
More recent evidence, however, suggests troughs are not an ideal surrogate for AUC, with many patients able to achieve a goal AUC:MIC with troughs less than 15 mg/L.3-5
Furthermore, vancomycin troughs of 15 to 20 mg/L have been associated with increased risk of nephrotoxicity,6
with no corresponding benefit in terms of efficacy.7
A growing body of retrospective observational evidence, in addition to a few prospective single-center studies, has supported the efficacy of AUC-guided vancomycin dosing for a number of moderate to severe infection types.8-16
Prospective, multicenter, observational data have been preliminarily presented, and the full results are eagerly anticipated.17
LEVEL UP AND CRUNCH THE NUMBERS
There are a handful of methods of AUC estimation that span a continuum in terms of reliability. The Moise-Broder equation,18
which is the total daily dose of vancomycin divided by a creatinine clearance (CrCl)-based estimate of vancomycin clearance, is a straightforward method requiring no serum concentrations. There is evidence, however, suggesting CrCl-based equations underestimate actual AUC.19
Another equation-based process, and the one chosen by our institution, is the Sawchuk-Zaske method,20
which uses 2-level pharmacokinetics and assumes a 1-compartment model. Two steady state, postdistribution vancomycin levels drawn during the same interval can be used to calculate the area of the linear and logarithmic trapezoids of the vancomycin concentration time curve, resulting in a patient-specific AUC estimate. Dosing calculators, whether home-grown, electronic medical record (EMR)-based, or commercially available, can make the Sawchuk-Zaske method achievable for many institutions.
The third major method is map Bayesian modeling, which uses population pharmacokinetic data, as well as 1 or more patient-specific serum vancomycin levels, to create probability distributions. Although this method results in the most accurate AUC predictions, Bayesian modeling software have not historically been widely available for clinical use in a user-friendly format. This has been changing in recent years, and Bayesian modeling may one day be the standard for most hospitals.
THEORY TO BEDSIDE: AVOIDING IMPLEMENTATION EXASPERATION
The first step is determining the best method for calculating AUC at your institution. Multiple Bayesian modeling programs are available or in development.21
Some can even be incorporated into EMRs, although at a significant cost. AUC calculation based on 2-level pharmacokinetics is likely the least expensive and quickest to implement compared with purchasing and integrating a Bayesian program. Any home-grown calculators, however, will need to be carefully created and validated. If your institution is able to purchase an online software program or create an electronic calculator in the EMR, these would likely be more user-friendly and provide more transparency for physicians and pharmacists. If a significant investment is required (ie, time and money), a simpler approach using a spreadsheet-based or web-based calculator may be preferred.
Once an AUC calculation method is chosen, a new institutional guideline will need to be created for all pharmacists involved in vancomycin dosing. It should provide a clear step-by-step process and outline indications for which AUC-guided dosing is indicated (Table
) to minimize errors and confusion. In addition, EMR documentation will need to be updated to incorporate additional vancomycin levels and pharmacokinetic data points involved in AUC calculations.
Once a plan is in place, the next step is obtaining medical and pharmacy staff support. Prior to the 2009 guideline, pharmacists and physicians routinely measured peak and trough concentrations. Then they were told peaks were unnecessary and only troughs mattered. Now with AUC-guided dosing, peaks and troughs are needed again, but for different reasons. Many current pharmacists and physicians haven’t practiced in a world of vancomycin peaks and are unfamiliar with the math involved in AUC-guided dosing. This may result in hesitation and confusion. Gaining support from infectious diseases physicians and the Pharmacy and Therapeutics Committee is vital. They need to understand the impact of the new dosing scheme on patient outcomes and the overall clinical workflow.
Once approved, the next step is education of all impacted members of the health care team. This includes physicians, pharmacists, nurses, and laboratory staff. Physicians need to be aware that multiple vancomycin levels will be obtained for select patients and they shouldn’t panic when they see a vancomycin concentration greater than 20 mg/L. Given the logistics of checking multiple levels and the complexity of AUC calculations, physicians may consult pharmacy for all vancomycin patients, if this is not already common practice. They will also need education on the new documentation process, as well as a best practice for follow-up monitoring for patients discharged on vancomycin. Physician education can occur via email, posters/flyers in the doctor’s lounge, and one-to-one direct detailing.
For pharmacists, we developed a comprehensive training and validation process to ensure all were competent in initial dosing and AUC monitoring. This included a prerecorded voiceover slideshow presentation, several practice cases utilizing the new guideline and spreadsheet calculator, small group discussions to address questions or concerns, and random audit and feedback of individual cases after the new dosing method was rolled out.
Nursing and laboratory personnel, particularly phlebotomists, need education on the importance of timely collection and documentation of serum vancomycin levels and documentation of doses. Errors may lead to inaccurate estimation of AUC, inappropriate dose adjustments, or the need for repeat blood draws. Education can occur via in-services on high-volume units, email, and posters/flyers in staff lounges. Feedback to nursing and laboratory leaders will likely be needed to ensure accountability of staff.
The final step is validation at a local level. This can be accomplished with a simple medication-use evaluation to determine the reliability of the new dosing guideline and calculator in reaching the target AUC:MIC or a larger study evaluating clinical outcomes, including safety and efficacy.
THE FORESEEABLE FUTURE
An updated consensus vancomycin dosing and monitoring guideline is currently under development and is anticipated to support the shift to AUC-guided dosing. Many opportunities remain for prospective studies to add to our current knowledge, and increasing availability of Bayesian modeling software may further revolutionize and simplify AUC-guided vancomycin dosing in the not-too-distant future.
Dr. Kisgen is the antimicrobial stewardship pharmacy lead and PGY1 pharmacy practice residency program director at Sarasota Memorial Hospital in Florida. He implemented AUC-guided vancomycin dosing at his large community teaching hospital in spring 2017. Dr. Seddon is an antimicrobial stewardship pharmacist at Sarasota Memorial Hospital in Florida. She implemented AUC-guided vancomycin dosing at her large community teaching hospital in spring 2017.
- Ebert S. In vivo cidal activity and pharmacokinetic parameters for vancomycin against methicillin-susceptible and -resistant S. aureus. In: Program and Abstracts of the 27th Interscience Conference on Antimicrobial Agents and Chemotherapy; October 4-7, 1987; New York, NY Abstract 439.
- Rybak MJ, Lomaestro BM, Rotscahfer JC, et al. Vancomycin therapeutic guidelines: a summary of consensus recommendations from the infectious diseases Society of America, the American Society of Health-System Pharmacists, and the Society of Infectious Diseases Pharmacists. Clin Infect Dis. 2009;49(3):325-327. doi: 10.1086/600877.
- Ghosh N, Chavada R, Maley M, van Hal SJ. Impact of source of infection and vancomycin AUC0-24/MICBMD targets on treatment failure in patients with methicillin-resistant Staphylococcus aureus bacteraemia. Clin Microbiol Infect. 2014;20(12):O1098-O1105. doi: 10.1111/1469-0691.12695.
- 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.
- 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.
- 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.
- Prybylski JP. Vancomycin trough concentration as a predictor of clinical outcomes in patients with Staphylococcus aureus bacteremia: a meta-analysis of observational studies. Pharmacotherapy. 2015;35(10):889-898. doi: 10.1002/phar.1638.
- Brown J, Brown K, Forrest A. Vancomycin AUC24/MIC ratio in patients with complicated bacteremia and infective endocarditis due to methicillin-resistant Staphylococcus aureus and its association with attributable mortality during hospitalization. Antimicrob Agents Chemother. 2012;56(2):634-638. doi: 10.1128/AAC.05609-11.
- Casapao AM, Lodise TP, Davis SL, et al. Association between vancomycin day 1 exposure profile and outcomes among patients with methicillin-resistant Staphylococcus aureus infective endocarditis. Antimicrob Agents Chemother. 2015;59(6):2978-2985. doi: 10.1128/AAC.03970-14.
- Holmes NE, Turnidge JD, Munckhof WJ, et al. Vancomycin AUC/MIC ratio and 30-day mortality in patients with Staphylococcus aureus bacteremia. Antimicrob Agents Chemother. 2013;57(4):1654-1663. doi: 10.1128/AAC.01485-12.
- Jung Y, Song KH, Cho J, et al. Area under the concentration-time curve to minimum inhibitory concentration ratio as a predictor of vancomycin treatment outcome in methicillin-resistant Staphylococcus aureus bacteraemia. Int J Antimicrob Agents. 2014;43(2):179-183. doi: 10.1016/j.ijantimicag.2013.10.017.
- Kullar R, Davis SL, Levine DP, Rybak MJ. Impact of vancomycin exposure on outcomes in patients with methicillin-resistant Staphylococcus aureus bacteremia: support for consensus guidelines suggested targets. Clin Infect Dis. 2011;52(8):975-981. doi: 10.1093/cid/cir124.
- Lodise TP, Drusano GL, Zasowski E, et al. Vancomycin exposure in patients with methicillin-resistant Staphylococcus aureus bloodstream infections: how much is enough? Clin Infect Dis. 2014;59(5):666-675. doi: 10.1093/cid/ciu398.
- Men P, Li HB, Zhai SD, Zhao RS. Association between the AUC0-24/MIC Ratio of vancomycin and its clinical effectiveness: a systematic review and meta-analysis. PLoS One. 2016;11(1):e0146224. doi: 10.1371/journal.pone.0146224.
- Song KH, Kim HB, Kim HS, et al. Impact of area under the concentration-time curve to minimum inhibitory concentration ratio on vancomycin treatment outcomes in methicillin-resistant Staphylococcus aureus bacteraemia. Int J Antimicrob Agents. 2015;46(6):689-695. doi: 10.1016/j.ijantimicag.2015.09.010.
- Zelenitsky S, Rubinstein E, Ariano R, et al; Cooperative Antimicrobial Therapy of Septic Shock-CATSS Database Research Group. Vancomycin pharmacodynamics and survival in patients with methicillin-resistant Staphylococcus aureus-associated septic shock. Int J Antimicrob Agents. 2013;41(3):255-260. doi: 10.1016/j.ijantimicag.2012.10.015.
- Lodise T. The Emperor’s New Clothes: Prospective Observational Evaluation of the Association between Day 2 Vancomycin Exposure and Failure Rates among Adult Hospitalized Patients with MRSA Bloodstream Infections (PROVIDE). Presented at: 2017 ID Week; October 4-7, 2017; San Diego, CA. Abstract 985. idsa.confex.com/idsa/2017/webprogram/Paper65435.html. Accessed January 14, 2019.
- Moise-Broder PA, Forrest A, Birmingham MC, Schentag JJ. Pharmacodynamics of vancomycin and other antimicrobials in patients with Staphylococcus aureus lower respiratory tract infections. Clin Pharmacokinet. 2004;43(13):925-942. doi: 10.2165/00003088-200443130-00005.
- Jin SJ, Yoon JH, Ahn BS, Chung JA, Song YG. Underestimation of the calculated area under the concentration-time curve based on serum creatinine for vancomycin dosing. Infect Chemother. 2014;46(1):21-29. doi: 10.3947/ic.2014.46.1.21.
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- Heil EL, Claeys KC, Mynatt RP, et al. Making the change to area under the curve-based vancomycin dosing. Am J Health Syst Pharm. 2018;75(24):1986-1995. doi: 10.2146/ajhp180034.