Kimberly C Claeys, PharmD, Karrine D Brade, PharmD, BCID, Emily L Heil, PharmD, BCID
The pharmacokinetic-pharmacodynamic parameter best correlated with efficacy of vancomycin in the treatment of infections with methicillin-resistant Staphylococcus aureus (MRSA) is the 24-h ratio of area under the curve (AUC) to minimum inhibitory concentration (MIC).1,2 Given the need for multiple measurements of vancomycin level and complex calculations, the trough level has historically been used as a surrogate marker. In the 2009 guidelines for therapeutic monitoring of vancomycin,3 troughs of 15–20 μg/mL were recommended, on the basis that these levels should correlate with an AUC/MIC of at least 400 mg*h/L, the true efficacy target. Since the implementation of these recommendations, reports of increased toxic effects have raised concerns about overly aggressive dosing, and clinicians have attempted to identify strategies to better balance targeted clinical efficacy with the risk of toxic effects.
There is known interpatient variability in the correlation between measured trough, which is a single point estimate, and target AUC/MIC.4–6 Pai and others5 detailed the mathematical relation between trough and AUC and demonstrated, through Monte Carlo simulations, that only 50% of interindividual variability in exposure is explained by trough values. Pragmatically, Hale and others6 evaluated vancomycin levels in 100 patients in an attempt to correlate trough concentrations with AUC/MIC of at least 400. They found that troughs less than 10 μg/mL were unlikely to achieve an AUC of at least 400 (p = 0.045); however, there was no difference between troughs of 10–14.9 μg/mL and 15–20 μg/mL (p = 0.817). Therefore, without the corresponding AUC, a trough value alone is minimally useful.
Data regarding the vancomycin trough level as a surrogate marker for AUC/MIC in the context of MRSA bacteremia also highlight that troughs of 15–20 μg/mL are likely to attain the pharmacokinetic-pharmacodynamic target, but may also lead to unnecessary exposure and risk of toxicity.4,7,8 In their meta-analysis, van Hal and others7 reviewed 15 studies and found that vancomycin trough levels of 15 μg/mL or above were associated with increased odds of nephrotoxicity relative to trough levels below 15 μg/mL (odds ratio [OR] 2.67, 95% confidence interval [CI] 1.95–3.65), a difference that persisted after adjustment for clinically relevant covariates. Bosso and others9 came to a similar conclusion when evaluating vancomycin levels in 291 patients across 7 sites. Fifty-five patients met the definition for nephrotoxicity, of whom 76.4% had troughs above 15 μg/mL. In a multivariable analysis, relative to lower trough values, troughs above 15 μg/mL were independently associated with increased risk of nephrotoxicity. These findings are supported by the quasi-experimental study of Finch and others,10 who examined the impact of changing from trough-based to AUC/MIC-based monitoring. In a study of more than 1000 patients, AUC/MIC-based monitoring was independently associated with lower odds of nephrotoxicity relative to trough-based monitoring (OR 0.53, 95% CI 0.34–0.8).
Data correlating attainment of the target vancomycin trough with improved clinical outcomes are lacking.11 Jung and others12 evaluated vancomycin treatment failure in patients with MRSA bacteremia and found no difference in the proportion of treatment failures between those who did and those who did not achieve troughs of 15–20 μg/mL. They did determine that AUC/MIC below 430 was associated with more treatment failure than AUC/MIC above 430 (50% versus 25%, p = 0.039). Kullar and others11 found a similar result. Among 320 patients, they reported a 52.5% failure rate and found that patients with AUC/MIC below 421 had an increased risk of failure relative to those with AUC/MIC above 421 (61.2% versus 48.6%, p = 0.038). Brown and others13 found a significant 4-fold increased risk of death with AUC/MIC below 211 (with MIC determined by Etest) relative to AUC/MIC above 211 in patients with MRSA bacteremia and infective endocarditis (63% versus 19%, p = 0.02). Admittedly, most of the literature supporting the use of AUC as a marker of clinical outcomes is based on AUC approximations; nonetheless, these studies still provide more evidence than is available for trough-based monitoring. As outlined above, data supporting either measure to improve clinical outcomes are lacking; however, AUC/MIC-based monitoring to limit toxic effects is more robust than trough-based monitoring. This conclusion is supported by a recent, prospective evaluation of vancomycin AUC/MIC exposures in 265 patients with MRSA bacteremia. Lodise and others14 were not able to identify an AUC/MIC threshold associated with treatment success but did find that patients with AUC/MIC less than or equal to 515 experienced the best global outcomes, including a limited risk of nephrotoxicity.
As mentioned, vancomycin troughs of 15–20 μg/mL have been recommended as a surrogate marker because of challenges in estimating AUC in clinical practice.3 The consensus guidelines for therapeutic monitoring of vancomycin have recently been updated to recommend target attainment based on AUC/MIC, stating that use of 2-level AUC calculators or Bayesian software programs now makes quick and reliable calculations feasible.15 There remains considerable hesitation among clinical pharmacists, however, regarding the practical application of AUC/MIC-based monitoring.16–18 As reported by those surveyed, common concerns have included unclear benefit of and lack of familiarity with AUC/MIC-based monitoring, training requirements, and resource allocation in terms of pharmacist time and laboratory costs. The paradigm of trough-based monitoring has been so long engrained in clinical practice that the need for extensive education to address the lack of familiarity with AUC/MIC-based monitoring is a valid concern.
To assist others, several clinicians have published their experiences with implementing AUC/MIC-based monitoring.19–21 These publications highlight the need for extensive education of not only clinical pharmacists, but also front-line nurses, phlebotomists, and ordering providers. This culture change does not happen overnight, but successful implementation of this strategy has proven feasible across numerous and varied practice sites. Although resource allocation related to the number of levels measured per patient is a justifiable concern, recent publications have not supported this.18,19,22 In a prospective trial investigating a transition from trough-based to AUC/MIC-based monitoring using Bayesian software, Neely and others23 reported fewer blood samples per patient, shorter duration of therapy, and decreased nephrotoxicity. Numerous programs are now available that utilize richly sampled patient populations and Bayesian-based mathematical modelling to assist in optimizing AUC/MIC without the need to measure vancomycin level numerous times for each patient.24 Additionally, if the cost of these programs is a concern, 2-level AUC-based calculators, either developed separately or integrated with the electronic medical record, have been commonly used to implement AUC/MIC-based monitoring.19–21 It is also important to note that among those who have changed to AUC/MIC-based monitoring, the perception of clinical relevance shifts from “unknown” to “of clinical importance”, evidence that a paradigm shift is in fact possible.18,21
1 Craig WA. Basic pharmacodynamics of antibacterials with clinical applications to the use of beta-lactams, glycopeptides, and linezolid. Infect Dis Clin North Am. 2003;17(3):479–501.
2 Rybak MJ. The pharmacokinetic and pharmacodynamic properties of vancomycin. Clin Infect Dis. 2006;42 Suppl 1:S35–9.
3 Rybak MJ, Lomaestro BM, Rotschafer JC, Moellering RC Jr, Craig WA, Billeter M, et al. Therapeutic monitoring of vancomycin in adults: summary of consensus recommendations from the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Pharmacotherapy. 2009;29(11):1275–9. 
4 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):969–74.
5 Pai MP, Neely M, Rodvold KA, Lodise TP. Innovative approaches to optimizing the delivery of vancomycin in individual patients. Adv Drug Deliv Rev. 2014;77:50–7.
6 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):329–35.
7 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):734–44. 
8 Lodise TP, Patel N, Lomaestro BM, Rodvold KA, Drusano GL. Relationship between initial vancomycin concentration-time profile and nephrotoxicity among hospitalized patients. Clin Infect Dis. 2009;49(4):507–14.
9 Bosso JA, Nappi J, Rudisill C, Wellein M, Bookstaver PB, Swindler J, et al. Relationship between vancomycin trough concentrations and nephrotoxicity: a prospective multicenter trial. Antimicrob Agents Chemother. 2011;55(12): 5475–9.
10 Finch NA, Zasowski EJ, Murray KP, Mynatt RP, Zhao JJ, Yost R, et al. A quasi-experiment to study the impact of vancomycin area under the concentration-time curve-guided dosing on vancomycin-associated nephrotoxicity. Antimicrob Agents Chemother. 2017;61(12):e01293–17.
11 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):975–81.
12 Jung Y, Song KH, Cho Je, Kim Hs, Kim NH, Kim TS, 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):179–83.
13 Brown J, Brown K, Forrest A. Vancomycin AUC24/MIC ratio in patients with complicated bacteremia and infective endocarditis due to methicillinresistant Staphylococcus aureus and its association with attributable mortality during hospitalization. Antimicrob Agents Chemother. 2012;56(2):634–8.
14 Lodise TP, Rosenkranz SL, Finnemeyer M, Evans S, Sims M, Zervos MJ, et al.; Antibacterial Resistance Leadership Group. The emperor’s new clothes: prospective observational evaluation of the association between initial vancomycin exposure and failure rates among adult hospitalized patients with methicillin-resistant Staphylococcus aureus bloodstream infections (PROVIDE). Clin Infect Dis. 2019;70(8):1536–45.
15 Rybak MJ, Le J, Lodise TP, Levine DP, Bradley JS, Liu C, 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. Am J Health System Pharm. 2020;77(11): 835–64.
16 Kufel WD, Seabury RW, Mogle BT, Beccari MV, Probst LA, Steele JM. Readiness to implement vancomycin monitoring based on area under the concentration-time curve: a cross-sectional survey of a national health consortium. Am J Health Syst Pharm. 2019;76(12):889–94.
17 Gregory ER, Burgess DR, Cotner SE, VanHoose JD, Flannery AH, Gardner B, et al. Pharmacist survey: pharmacist perception of vancomycin area under the curve therapeutic drug monitoring. J Pharm Pract. 2019 Aug 18:897190019867494. doi: 10.1177/0897190019867494. [Epub ahead of print].
18 Claeys KC, Hopkins TL, Brown J, Heil EL. Pharmacists’ perceptions of implementing a pharmacist-managed area under the concentration time curve-guided vancomycin dosing program at a large academic medical center. J Am Coll Clin Pharm. 2019;2(5):482–7.
19 Meng L, Wong T, Huang S, Mui E, Nguyen V, Espinosa G, et al. Conversion from vancomycin trough concentration-guided dosing to area under the curve-guided dosing using two sample measurements in adults: implementation at an academic medical center. Pharmacotherapy. 2019;39(4):433–42.
20 Heil EL, Claeys KC, Mynatt RP, Hopkins TL, Brade K, Watt I, et al. Making the change to area under the curve-based vancomycin dosing. Am J Health Syst Pharm. 2018;75(24):1986–95.
21 Gregory ER, Burgess DR, Cotner SE, VanHoose JD, Flannery AH, Gardner B, et al. Vancomycin area under the curve dosing and monitoring at an academic medical center: transition strategies and lessons learned. J Pharm Pract. 2019 Mar 10;897190019834369. doi: 10.1177/0897190019834369. [Epub ahead of print].
22 Stoessel AM, Hale CM, Seabury RW, Miller CD, Steele JM. The impact of AUC-based monitoring on pharmacist-directed vancomycin dose adjustments in complicated methicillin-resistant Staphylococcus aureus infection. J Pharm Pract. 2019;32(4):442–6.
23 Neely MN, Kato L, Youn G, Kraler L, Bayard D, van Guilder M, 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):e02042–17.
24 Turner RB, Kojiro K, Shephard EA, Won R, Chang E, Chan D, 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. Pharmacotherapy. 2018;38(12):1174–83.
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3 Tong SYC, Lye DC, Yahav D, Sud A, Robinson JO, Nelson J, et al. Effect of vancomycin or daptomycin with vs without an antistaphylococcal beta-lactam on mortality, bacteremia, relapse, or treatment failure in patients with MRSA bacteremia: a randomized clinical trial. JAMA. 2020;323(6):527–37.
4 Thwaites GE, Scarborough M, Szubert A, Nsutebu E, Tilley R, Greig J, et al. Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 2018;391(10121):668–78.
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6 Rybak M, Lomaestro B, Rotschafer JC, Moellering R Jr, Craig W, Billeter M, 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.
7 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):734–44.
8 Sakoulas G, Moise-Broder PA, Schentag J, Forrest A, Moellering RC Jr, Eliopoulos GM. Relationship of MIC and bactericidal activity to efficacy of vancomycin for treatment of methicillin-resistant Staphylococcus aureus bacteremia. J Clin Microbiol. 2004;42(6):2398–402.
9 Lodise TP, Graves J, Evans A, Graffunder E, Helmecke M, Lomaestro BM, et al. Relationship between vancomycin MIC and failure among patients with methicillin-resistant Staphylococcus aureus bacteremia treated with vancomycin. Antimicrob Agents Chemother. 2008;52(9):3315–20.
10 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):969–74.
11 Neely MN, Youn G, Jones B, Jelliffe RW, Drusano GL, Rodvold KA, et al. Are vancomycin trough concentrations adequate for optimal dosing? Antimicrob Agents Chemother. 2014;58(1):309–16.
12 Hsu DI, Hidayat LK, Quist R, Hindler J, Karlsson A, Yusof A, et al. Comparison of method-specific vancomycin minimum inhibitory concentration values and their predictability for treatment outcome of methicillin-resistant Staphylococcus aureus (MRSA) infections. Int J Antimicrob Agents. 2008;32(5):378–85.
13 Diekema DJ, Pfaller MA, Shortridge D, Zervos M, Jones RN. Twenty-year trends in antimicrobial susceptibilities among Staphylococcus aureus from the SENTRY Antimicrobial Surveillance Program. Open Forum Infect Dis. 2019;6(Suppl 1):S47–S53.
14 Diaz R, Afreixo V, Ramalheira E, Rodrigues C, Gago B. Evaluation of vancomycin MIC creep in methicillin-resistant Staphylococcus aureus infections—a systematic review and meta-analysis. Clin Microbiol Infect. 2018;24(2):97–104.
15 van Hal SJ, Fowler VG Jr. Is it time to replace vancomycin in the treatment of methicillin-resistant Staphylococcus aureus infections? Clin Infect Dis. 2013;56(12):1779–88.
16 Wong-Beringer A, Joo J, Tse E, Beringer P. Vancomycin-associated nephrotoxicity: a critical appraisal of risk with high-dose therapy. Int J Antimicrob Agents. 2011;37(2):95–101.
17 Rybak MJ, Le J, Lodise TP, Levine DP, Bradley JS, Liu C, 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. Am J Health Syst Pharm. 2020;77(11): 835–64.
18 Moise PA, Forrest A, Bhavnani SM, Birmingham MC, Schentag JJ. Area under the inhibitory curve and a pneumonia scoring system for predicting outcomes of vancomycin therapy for respiratory infections by Staphylococcus aureus. Am J Health Syst Pharm. 2000;57 Suppl 2:S4–9.
19 Moise-Broder PA, Forrest A, Birmingham MC, Schentag JJ. Pharmaco-dynamics of vancomycin and other antimicrobials in patients with Staphylococcus aureus lower respiratory tract infections. Clin Pharmacokinet. 2004;43(13):925–42.
20 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):975–81.
21 Jung Y, Song KH, Cho Je, Kim Hs, Kim NH, Kim TS, 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): 179–83.
22 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):634–8.
23 Gawronski KM, Goff DA, Brown J, Khadem TM, Bauer KA. A stewardship program’s retrospective evaluation of vancomycin AUC24/MIC and time to microbiological clearance in patients with methicillin-resistant Staphylococcus aureus bacteremia and osteomyelitis. Clin Ther. 2013;35(6):772–9.
24 Casapao AM, Lodise TP, Davis SL, Claeys KC, Kullar R, Levine DP, 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):2978–85.
25 Zelenitsky S, Rubinstein E, Ariano R, Iacovides H, Dodek P, Mirzanejad Y, et al. Vancomycin pharmacodynamics and survival in patients with methicillin-resistant Staphylococcus aureus-associated septic shock. Int J Antimicrob Agents. 2013;41(3):255–60.
26 Dalton BR, Rajakumar I, Langevin A, Ondro C, Sabuda D, Griener TP, et al. Vancomycin area under the curve to minimum inhibitory concentration ratio predicting clinical outcome: a systematic review and meta-analysis with pooled sensitivity and specificity. Clin Microbiol Infect. 2020;26(4):436–46.
27 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):O1098–105.
28 Ampe E, Delaere B, Hecq JD, Tulkens PM, Glupczynski Y. Implementation of a protocol for administration of vancomycin by continuous infusion: pharmacokinetic, pharmacodynamic and toxicological aspects. Int J Antimicrob Agents. 2013;41(5):439–46.
29 Lodise TP, Drusano GL, Zasowski E, Dihmess A, Lazariu V, Cosler L, et al. Vancomycin exposure in patients with methicillin-resistant Staphylococcus aureus bloodstream infections: how much is enough? Clin Infect Dis. 2014;59(5):666–75.
30 Mizokami F, Shibasaki M, Yoshizue Y, Noro T, Mizuno T, Furuta K. Pharmacodynamics of vancomycin in elderly patients aged 75 years or older with methicillin-resistant Staphylococcus aureus hospital-acquired pneumonia. Clin Interv Aging. 2013;8:1015–21.
31 Lodise TP, Rosenkranz SL, Finnemeyer M, Evans S, Sims M, Zervos MJ, et al. The emperor’s new clothes: prospective observational evaluation of the association between initial vancomycin exposure and failure rates among adult hospitalized patients with methicillin-resistant Staphylococcus aureus bloodstream infections (PROVIDE). Clin Infect Dis. 2019;70(8):1536–45.
32 Ruiz J, García-Robles A, Marqués MR, Company MJ, Solana A, Poveda JL. Influence of pharmacokinetic/pharmacodynamic ratio on vancomycin treatment response in paediatric patients with Staphylococcus aureus bacteremia. Minerva Pediatr. 2018 Apr 12. doi: 10.23736/S0026-4946.18.04978-2. [Epub ahead of print].
33 Mogle BT, Steele JM, Seabury RW, Dang UJ, Kufel WD. Implementation of a two-point pharmacokinetic AUC-based vancomycin therapeutic drug monitoring approach in patients with methicillin-resistant Staphylococcus aureus bacteraemia. Int J Antimicrob Agents. 2018;52(6):805–10.
34 Song KH, Kim HB, Kim HS, Lee MJ, Jung Y, Kim G, et al. Impact of area under the concentration-time curve to minimum inhibitory concentration ratio on vancomycin treatment outcomes in methicillinresistant Staphylococcus aureus bacteraemia. Int J Antimicrob Agents. 2015;46(6):689–95.
35 Shime N, Kosaka T, Fujita N. The importance of a judicious and early empiric choice of antimicrobial for methicillin-resistant Staphylococcus aureus bacteraemia. Eur J Clin Microbiol Infect Dis. 2010;29(12):1475–9.
36 Hahn A, Frenck RW Jr, Allen-Staat M, Zou Y, Vinks AA. Evaluation of target attainment of vancomycin area under the curve in children with methicillin-resistant Staphylococcus aureus bacteremia. Ther Drug Monit. 2015;37(5):619–25.
37 Wysocki M, Delatour F, Faurisson F, Rauss A, Pean Y, Misset B, et al. Continuous versus intermittent infusion of vancomycin in severe staphylococcal infections: prospective multicenter randomized study. Antimicrob Agents Chemother. 2001;45(9):2460–7.
38 Britt NS, Patel N, Horvat RT, Steed ME. Vancomycin 24-hour area under the curve/minimum bactericidal concentration ratio as a novel predictor of mortality in methicillin-resistant Staphylococcus aureus bacteremia. Antimicrob Agents Chemother. 2016;60(5):3070–5.
39 Arun A, Swamy S, Jacob K, Sharma R, Kohlhoff SA, Hammerschlag MR. Evaluation of clinical outcome in children and adolescents receiving vancomycin for invasive infections due to methicillin-resistant Staphylococcus aureus: impact of increasing vancomycin MICs. Minerva Pediatr. 2018;70(3):207–11.
40 Fukumori S, Tsuji Y, Mizoguchi A, Kasai H, Ishibashi T, Iwamura N, et al. Association of the clinical efficacy of vancomycin with the novel pharmacokinetic parameter area under the trough level (AUTL) in elderly patients with hospital-acquired pneumonia. J Clin Pharm Ther. 2016; 41(4):399–402.
41 Liu P, Capitano B, Stein A, El-Solh AA. Clinical outcomes of linezolid and vancomycin in patients with nosocomial pneumonia caused by methicillin-resistant Staphylococcus aureus stratified by baseline renal function: a retrospective, cohort analysis. BMC Nephrol. 2017;18(1): Article 168.
42 Neuner EA, Casabar E, Reichley R, McKinnon PS. Clinical, microbiologic, and genetic determinants of persistent methicillin-resistant Staphylococcus aureus bacteremia. Diagn Microbiol Infect Dis. 2010; 67(3):228–33.
43 Shen K, Yang M, Fan Y, Liang X, Chen Y, Wu J, et al. Model-based evaluation of the clinical and microbiological efficacy of vancomycin: a prospective study of Chinese adult in-house patients. Clin Infect Dis. 2018;67(Suppl 2):S256–S262.
44 Holmes NE, Turnidge JD, Munckhof WJ, Robinson JO, Korman TM, O’Sullivan MV, et al. Vancomycin AUC/MIC ratio and 30-day mortality in patients with Staphylococcus aureus bacteremia. Antimicrob Agents Chemother. 2013;57(4):1654–63.
45 van Hal SJ, Lodise TP, Paterson DL. The clinical significance of vancomycin minimum inhibitory concentration in Staphylococcus aureus infections: a systematic review and meta-analysis. Clin Infect Dis. 2012;54(6):755–71.
46 Jeffres MN, Isakow W, Doherty JA, Micek ST, Kollef MH. A retrospective analysis of possible renal toxicity associated with vancomycin in patients with health care-associated methicillin-resistant Staphylococcus aureus pneumonia. Clin Ther. 2007;29(6):1107–15.
47 Chavada R, Ghosh N, Sandaradura I, Maley M, Van Hal SJ. Establishment of an AUC0–24 threshold for nephrotoxicity is a step towards individualized vancomycin dosing for methicillin-resistant Staphylococcus aureus bacteremia. Antimicrob Agents Chemother. 2017;61(5):e02535–16.
48 Finch NA, Zasowski EJ, Murray KP, Mynatt RP, Zhao JJ, Yost R, et al. A quasi-experiment to study the impact of vancomycin area under the concentration-time curve-guided dosing on vancomycin-associated nephrotoxicity. Antimicrob Agents Chemother. 2017;61(12):e01293–17.
49 Issaranggoon Na Ayuthaya S, Katip W, Oberdorfer P, Lucksiri A. Correlation of the vancomycin 24-h area under the concentration-time curve (AUC24) and trough serum concentration in children with severe infection: a clinical pharmacokinetic study. Int J Infect Dis. 2020;92:151–9.
50 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):21–9.
51 Neely MN, Kato L, Youn G, Kraler L, Bayard D, van Guilder M, 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):e02042–17.
52 Pai MP, Neely M, Rodvold KA, Lodise TP. Innovative approaches to optimizing the delivery of vancomycin in individual patients. Adv Drug Deliv Rev. 2014;77:50–7.
53 Suchartlikitwong P, Anugulruengkitt S, Wacharachaisurapol N, Jantarabenjakul W, Sophonphan J, Theerawit T, et al. Optimizing vancomycin use through 2-point AUC-based therapeutic drug monitoring in pediatric patients. J Clin Pharmacol. 2019;59(12):1597–605.
54 Zasowski EJ, Murray KP, Trinh TD, Finch NA, Pogue JM, Mynatt RP, et al. Identification of vancomycin exposure-toxicity thresholds in hospitalized patients receiving intravenous vancomycin. Antimicrob Agents Chemother. 2018;62(1):e01684–17.
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56 Suzuki Y, Kawasaki K, Sato Y, Tokimatsu I, Itoh H, Hiramatsu K, et al. Is peak concentration needed in therapeutic drug monitoring of vancomycin? A pharmacokinetic-pharmacodynamic analysis in patients with methicillin-resistant Staphylococcus aureus pneumonia. Chemotherapy. 2012;58(4):308–12.
57 Lodise TP, Patel N, Lomaestro BM, Rodvold KA, Drusano GL. Relationship between initial vancomycin concentration-time profile and nephrotoxicity among hospitalized patients. Clin Infect Dis. 2009;49(4): 507–14.
58 Alsultan A, Abouelkheir M, Albassam A, Alharbi E, Assiri A, Alqahtani S. AUC- vs. trough-guided monitoring of vancomycin in infants. Indian J Pediatr. 2020;87(5):359–64.
59 Smit C, Wasmann RE, Goulooze SC, Wiezer MJ, van Dongen EPA, Mouton JW, et al. Population pharmacokinetics of vancomycin in obesity: finding the optimal dose for (morbidly) obese individuals. Br J Clin Pharmacol. 2020;86(2):303–17.
Competing interests: For activities outside the scope of this article, Kimberly Claeys has received a speaker’s honorarium from GenMark Diagnostics, and has also received nonfinancial support (in the form of study supplies) from GenMark Diagnostics and BioFire Diagnostics. No other competing interests were declared. ( Return to Text )
Sarah C J Jorgensen, BSc, BScPhm, PharmD, MPH, BCPS, BCIDP, AAHIVP, Linda D Dresser, BScPhm, PharmD, FCSHP, Bruce R Dalton, BScPharm, PharmD
New practices in infectious disease pharmacotherapy are often promoted because they should work, according to our understanding of pathophysiology, microbiology, and pharmacokinetics and pharmacodynamics. However, theoretical advantages frequently fail to produce tangible benefit and occasionally result in harm.1 Recent examples of failures in the translation from theory to practice include inhaled antibiotics for ventilatorassociated pneumonia,2 combination therapy for methicillinresistant Staphylococcus aureus (MRSA) bacteremia3,4 and carbapenem-resistant Acinetobacter baumannii infections,5 and—of particular relevance to the topic of this Point Counterpoint debate—the use of vancomycin troughs of 15 to 20 mg/L to guide treatment for invasive MRSA infections.6,7 When the first iteration of the vancomycin monitoring guideline was published in 2009,6 concerns over the emergence of S. aureus strains with reduced vancomycin susceptibility led some researchers and clinicians to advocate for an aggressive dosing approach in the absence of high-quality data.8,9 Since then, evidence has suggested that trough levels of at least 15 mg/L may not be necessary to achieve the guideline target for area under the curve (AUC) of at least 400.10 Furthermore, the described “creep” in vancomycin minimum inhibitory concentration (MIC) may be an artifact of the testing method, and changes in pathogen virulence and/or lack of source control may often be responsible for antibiotic failure.11–15 In addition, the clinical benefit of maintaining trough levels between 15 and 20 mg/L has not been well documented, and available data indicate that levels within this range are associated with an increase in nephrotoxicity.7,16
The updated vancomycin guideline, published earlier this year, now recommends AUC/MIC monitoring for serious MRSA infections, with abandonment of trough-based monitoring.17 This recommendation creates a significant shift in how clinicians mange vancomycin therapy and may have substantial monetary and opportunity costs. These costs are justified only if AUC-based monitoring improves clinical or safety outcomes. Below we outline our view that the recommendation for AUC-based monitoring is drawn from weak evidence, which is not sufficient to justify widespread adoption.
The threshold AUC/MIC value of 400 originates from a single-centre, retrospective study of S. aureus pneumonia from the early 2000s.18,19 In that study, an AUC/MIC value greater than or equal to 350, as determined by classification and regression tree analysis (CART) in 50 clinically evaluable patients, was associated with a greater likelihood of clinical success, whereas an AUC/MIC value greater than or equal to 400 (n = 34 patients) was associated with bacterial eradication.18,19 Several points pertaining to this study deserve emphasis: first, the estimated AUC was calculated on the basis of all anti-staphylococcal antibiotics administered during the course of therapy, including combination therapy with β-lactams and aminoglycosides, for which AUC/MIC is not the relevant pharmacokinetic-pharmacodynamic index; second, the majority (63%) of S. aureus isolates were methicillin-susceptible; and finally, the outcome of bacterial eradication from respiratory samples has uncertain clinical value.
Many studies have since examined the relationship between vancomycin AUC/MIC and clinical outcomes in patients with MRSA infections, coming to divergent conclusions and identifying a wide range of thresholds.20–44 Most have been small (fewer than 100 participants),23,25,28,30,32,33,35,36,38–40 retrospective,23–25,27–30,32,33,35,36,38,40–42 single-centre23,24,27–30,32,33,35,36,38,40,42 studies in which vancomycin dosing was managed by assessment of trough levels.23,24,27,29,32,34–36,39–43 Study registration, planned analyses, and power calculations were rarely discussed in the published reports. Vancomycin MIC was determined by a variety of testing methods, and many of the studies used formulas to estimate AUC that were based on daily vancomycin dose, population pharmacokinetics, and estimated renal function.25,27,32,39,42 The guideline authors acknowledged technical issues with determination of vancomycin MIC and suggested the assumption that MIC = 1 mg/L.17 However, using this assumption for dosing decisions in individual patients is problematic because most studies have not assumed MIC = 1 mg/L. High MIC on its own may be predictive of response, and when used as the denominator, a higher value of MIC drives down the AUC/MIC value, creating a spurious correlation.45 In addition, in many studies CART was used as an exploratory method to identify cut points for dichotomizing AUC/MIC data without validation in an independent external data set.23–25,27,28,33,34,38,40 Threshold values identified by CART have ranged from as low as 21122 to as high as 667,28 with some studies identifying multiple thresholds. 21,24,27,29,30 In the only study to date that attempted to validate alternative CART-derived AUC/MIC thresholds (day-2 AUC/MIC ≥ 650 and ≥ 320, with MIC determined by broth microdilution and Etest, respectively) in a multicentre, prospective study of an external population, there was no significant difference in mortality or persistent bacteremia using these vancomycin exposure thresholds.31 Additionally, that study did not identify alternative thresholds or confirm AUC/MIC of at least 400 as predictive of clinical failure.31
Among studies assessing the relationship between clinical outcomes and a prespecified AUC/MIC threshold of 400,11,32,35,36,39 only one, which involved 51 pediatric patients with S. aureus bacteremia, found a statistically significant relationship between AUC/MIC of at least 400 and clinical response32; however, no significant association was found between AUC/MIC of at least 400 and mortality or microbiological response. Interestingly, one study found no significant reduction in 30-day mortality among patients with S. aureus bacteremia who achieved AUC/MIC of at least 400, but found that an alternative CART-derived threshold of 373 was statistically significant.44 In another study, patients who experienced clinical failure paradoxically had a significantly higher mean vancomycin AUC than those who experienced clinical success.37 Many other studies also found no statistically significant relationship between AUC (or AUC/MIC) and outcomes, and therefore the authors did not go on to perform CART (or other) analyses.35,36,38–43,46 None of these studies reported a formal power calculation, so type II errors cannot be excluded.11,32,35,36,39 Surprisingly, many studies with negative or nonsignificant results35,38–43,46 were not mentioned in the guideline update, even though the guideline methods suggested that all relevant literature published in English had been reviewed.17
AUC-based vancomycin monitoring may still be valuable if it is a safer alternative than trough-based monitoring. A large body of observational literature collectively suggests that the incidence of nephrotoxicity increases as a function of vancomycin exposure, whether measured by trough level or AUC.11,31,37,46–57 A wide range of threshold AUC values have been identified (563–1300 mg*h/L),33,47,54,56,57 and the observational data are conflicting with regard to which pharmacokinetic parameter—trough level or AUC—is most closely correlated with nephrotoxicity.47,56,57 In some studies, which used Monte Carlo simulation or population pharmacokinetic data to estimate AUC, trough levels have been only moderately correlated with AUC.10,52 However, recent clinical studies using human data (rather than simulation) have found remarkably high correlation between trough level and AUC (R2 = 0.88–0.95).47,49,50,53,58,59 Such high correlation makes distinguishing a “better” measure of exposure a fool’s errand, since one predictor can easily and reasonably accurately be approximated by the other.
Two recent observational studies reported lower rates of nephrotoxicity with the implementation of AUC-based monitoring relative to previously used trough-based monitoring.48,51 Importantly however, all48 or many51 patients in the trough-based monitoring arms of these studies received vancomycin regimens targeting trough levels of 15 to 20 mg/L, an approach to vancomycin therapy that is known to be harmful.7,16 Average doses and trough levels were significantly lower in the AUC-based groups, which reaffirms that lower vancomycin exposure confers a decreased risk of nephrotoxicity, regardless of the monitoring method. An important knowledge gap is the issue of whether AUC-based monitoring is safer than trough-based monitoring that targets pre–guideline era troughs between 5 and 15 mg/L. We hypothesize that there would be little observable difference.
In summary, the collective evidence on vancomycin AUC-based therapeutic drug monitoring for MRSA infections is primarily hypothesis-generating and inconsistent. Although AUC-based monitoring may have appeal because of its perceived sophistication, it has not met the stated criteria of improving clinical outcomes or safety. In fact, the multiple blood samples required for AUC-based monitoring will affect patient comfort and convenience and may cause harm. Pharmacists and other clinicians should advocate for interventions that are valuable to patients and the health care system, rather than assuming that newer, more complex, more expensive, and more time-consuming strategies will lead to better outcomes.
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Competing interests: Linda Dresser has received personal fees from Sunovion for an educational event outside the scope of this article. No other competing interests were declared. ( Return to Text )
Canadian Journal of Hospital Pharmacy, VOLUME 73, NUMBER 3, May-June 2020