How to Optimize Vancomycin Dosing Using Therapeutic Drug monitoring?
For many clinicians, vancomycin dosing may seem routine. As a commonly used antibiotic (1), it is part of daily clinical practice. Because of its narrow therapeutic window, therapeutic drug monitoring, the measurement of vancomycin concentration in patient’s blood, is widely used, primarily to reduce the risk of vancomycin-associated nephrotoxicity (1). However, despite being used for more than 65 years (2), vancomycin dosing remains heavily debated in the literature (1), with guidelines recommending markedly different practices (3) and meta-analyses reaching conflicting conclusions (4). In this blog post, I critically appraise the literature to address the following question:
What are the different strategies for monitoring vancomycin, and what are their respective strengths and weaknesses?
What are the different strategies for monitoring vancomycin, and what are their respective strengths and weaknesses?
To optimize vancomycin dosing from a pharmacodynamic perspective , the ratio of the 24-hour area under the curve (AUC24) to the minimum inhibitory concentration (MIC) should be optimized. In clinical practice, three main methods are used to achieve this:
a. Intermittent dosing based on trough concentration-guided monitoring
b. Intermittent dosing based on AUC-guided monitoring
c. Continuous infusion of vancomycin
A. Intermittent dosing based on trough concentration-guided monitoring
In this method, the minimum vancomycin concentration (trough level) is measured just before the third to fifth dose (5,6). This concentration is then used as a surrogate for the 24-hour AUC. Measuring trough concentrations is common and is still recommended by some guidelines (3).
Efficacy: Most guidelines recommend steady-state trough levels of 10-15 mg/L for most infections and 15-20 mg/L for severe infections. This approach assumes that trough levels correlate well with AUC, an association supported by multiple studies (9). However, some studies, including Monte Carlo simulations, have failed to confirm this correlation (7,8), leading some authors to question this assumption (8). Moreover, the higher target for severe infections is based on a single study that observed better outcomes in Staphylococcus aureus lower respiratory tract infection with higher trough levels (7). So far, this finding has not been confirmed by other studies (7).
Some remarks on target trough levels:
- To achieve a target AUC24 of more than 400 mg.h/L, the average required concentration is just 16.7 mg/L (9), implying that a trough level of 15 mg/L may be excessive for many patients. In one study, for instance, 68% of patients with an AUC24 > 400 mg.h/L had a trough level less than 15 mg/L (9).
- Trough levels have shown poor correlation with key clinical outcomes, such as treatment failure and mortality (11). In one meta-analysis, trough concentrations less than 15 mg/L were associated with a significantly lower all-cause mortality (11). However, in 3 of the 9 included studies, patients in the high-trough group were more severely ill. Furthermore, in two high-quality randomized controlled trials comparing vancomycin with other antimicrobials, higher vancomycin levels were only associated with more acute kidney injury, without any mortality benefit (7).
Safety: All consulted studies agree that higher vancomycin trough levels lead to more nephrotoxicity (3,4). One quantitative meta-analysis identified a threshold of 14.55 mg/L as best predictor of nephrotoxicity (3). Another meta-analysis reported nephrotoxicity rates of 0-33% at low trough levels versus 7-67% at high levels (11). It is important to note that nephrotoxicity in these studies is typically defined by an increase in serum creatinine rather than by vancomycin-attributable acute kidney injury or the need for renal replacement therapy (1).
Other benefits and drawbacks:
- Because only one sample is required, this is the simplest method for implementing vancomycin therapeutic drug monitoring.
- Therapeutic drug monitoring can only be done once a a steady state is reached, mostly after at least three doses. Because empiric vancomycin is often discontinued after 48-72 hours (1), this delay can render therapeutic drug monitoring futile in some cases (1).
- The timing of trough sample collection is highly variable, complicating interpretation (12).
B. Intermittent dosing based on AUC-guided monitoring
The latest version of the ‘American’ guidelines on therapeutic monitoring of vancomycin recommends targeting an AUC24/MIC of 400 to 600 mg.h/L, rather than relying on surrogate measurements such as trough levels (9). This can be achieved in two ways.
I. Bayesian dose-optimization software. These programs use Bayesian methods combined with specific population pharmacokinetic models (9). Acquiring this commercial software can be costly (12) and the embedded population model should be appropriate for the intended patient population (9). A key advantage of this method is that often only a single vancomycin level is required to estimate AUC (9). In addition, blood samples can be drawn even when the patient is not at steady state(12).
II. First-order pharmacokinetic (trapezoidal) models. In this approach, two vancomycin levels are drawn within the same dosing interval, separated by a few hours (6). Exact timing is flexible, provided that sample times are accurately documented and occur after the distribution phase (more than 1 to 2 hours after infusion end) (12). Using first-order pharmacokinetic equations, most commonly the modified Sawchuk-Zaske method (12), the AUC is calculated and a new dosing regimen is proposed (6). Although these calculations can be performed in a simple spreadsheet (6), one study suggested it was equivalent or even superior to Bayesian software (13).
Efficacy and safety: The primary rationale for shifting to AUC-guided monitoring in the latest ‘American’ guidelines was an improved safety profile (less nephrotoxicity), rather than clearly demonstrated gains in clinical efficacy (1). For example, a meta-analysis published in the same year as the guidelines could not withhold a clear association between AUC/MIC targets and clinical success, concluding that the evidence base for AUC-guided monitoring remained limited (15). In terms of safety, another meta-analysis reported a trend towards lower acute kidney injury with AUC-guided dosing compared with trough-guided monitoring (4). Moreover, some centers have reported reductions in nephrotoxicity after implementation of first-order pharmacokinetic models (12). However, another quantitative meta-analysis demonstrated that trough-guided monitoring can be an adequate alternative for AUC-guided monitoring as long as it is targeting a trough level between 10-15 mg/L (16).
Other benefits and drawbacks:
- A key advantage of AUC-guided monitoring is a faster and more precise target attainment (6, 15)
- In critically ill patients, pharmacokinetics change rapidly in the first days, making AUC estimates less accurate. Some authors therefore advocate using simple trough-based monitoring initially, then transitioning to AUC-guided dosing once the patient stabilizes (17).
- AUC-guided monitoring increases monitoring costs, either through acquisition of specific software or by requiring additional vancomycin level measurements (17).
C. Continuous infusion of vancomycin
After a loading dose, vancomycin is administered by continuous infusion. The latest ‘American’ guidelines, considers this a reasonable alternative to intermittent dosing in selected patients (1).
Efficacy and safety: Evidence comparing continuous with intermittent vancomycin infusion - predominantly trough-based intermittent dosing - remains limited. No consistent difference in clinical efficacy has been demonstrated (18), although two recent meta-analyses reported lower nephrotoxicity with continuous infusion (18,19). However, some authors have questioned whether confounding factors - such as substantial differences in dosing targets between the two strategies - rather than a true better safety profile of continuous infusion explain this finding (20). In the largest prospective comparative study, nephrotoxicity rates were similar between continuous and intermittent infusion (21). Overall, the potential nephroprotective advantage of continuous infusion remains uncertain.
Other benefits and drawbacks:
- Continuous infusion of vancomycin relies on substantially fewer assumptions (12) than intermittent administration, facilitating target attainment (18,19).
- Therapeutic drug monitoring may require only one vancomycin level, obtained after steady state has been reached. This is typically at least 24 hours after initiation or dose adjustment of the continuous infusion (18). Nevertheless, in practice, additional sampling remains common (5). Furthermore, unlike with intermittent dosing, timely collection of the blood sample is less critical (18).
- Experimental data indicate that a continuous vancomycin infusion may cause greater endothelial toxicity than intermittent infusion (18). To reduce the risk of phlebitis, most institutions administer it only through a central venous catheter (5). Moreover, because vancomycin is incompatible with many medications, it should generally be infused through a dedicated lumen or intravenous line (5).
References:
1. Dilworth TJ, Schulz LT, Rose WE. Vancomycin Advanced Therapeutic Drug Monitoring: Exercise in Futility or Virtuous Endeavor to Improve Drug Efficacy and Safety? Clin Infect Dis. 2021 May 18;72(10):e675-e681.
2. Rose W, Volk C, Dilworth TJ, et al. Approaching 65 Years: Is It Time to Consider Retirement of Vancomycin for Treating Methicillin-Resistant Staphylococcus aureus Endovascular Infections? Open Forum Infect Dis. 2022 Apr 9;9(5):ofac137.
3. Yang W, Zhang K, Chen Y, Fan Y, Zhang J. Is It Still Beneficial to Monitor the Trough Concentration of Vancomycin? A Quantitative Meta-Analysis of Nephrotoxicity and Efficacy. Antibiotics (Basel). 2024 May 28;13(6):497.
4. Tsutsuura M, Moriyama H, Kojima N, et al. The monitoring of vancomycin: a systematic review and meta-analyses of area under the concentration-time curve-guided dosing and trough-guided dosing. BMC Infect Dis. 2021 Feb 6;21(1):153.
5. Van Der Heggen T, Buyle FM, et al. Vancomycin dosing and therapeutic drug monitoring practices: guidelines versus real-life. Int J Clin Pharm. 2021 Oct;43(5):1394-1403.
6. Farkas J. PulmCrit - vancomycin pharmacokinetics: make vancomycin great again. https://emcrit.org/pulmcrit/vanco/ (accessed on November 18th, 2025).
7. Wright WF, Jorgensen SCJ, Spellberg B. Heaping the Pelion of Vancomycin on the Ossa of Methicillin-resistant Staphylococcus aureus: Back to Basics in Clinical Care and Guidelines. Clin Infect Dis. 2021 May 18;72(10):e682-e684.
8. Rybak MJ, Le J, Lodise TP, et al. Questions on Vancomycin Dosing. Clin Infect Dis. 2021 Oct 5;73(7):e1777-e1778.
9. Stewart JJ, Jorgensen SC, Dresser L, et al. A Canadian perspective on the revised 2020 ASHP-IDSA-PIDS-SIDP guidelines for vancomycin AUC-based therapeutic drug monitoring for serious MRSA infections. J Assoc Med Microbiol Infect Dis Can. 2021 May 3;6(1):3-9.
10. Hou Y, Ren J, Li J, et al. Relationship Between Mean Vancomycin Trough Concentration and Mortality in Critically Ill Patients: A Multicenter Retrospective Study. Front Pharmacol. 2021 Jul 19;12:690157
11. Chander S, Kumari R, Wang HY, et al. Effect of low vs. high vancomycin trough level on the clinical outcomes of adult patients with sepsis or gram-positive bacterial infections: a systematic review and meta-analysis. BMC Infect Dis. 2024 Oct 7;24(1):1114.
12. Drennan PG, Begg EJ, Gardiner SJ, et al. The dosing and monitoring of vancomycin: what is the best way forward? Int J Antimicrob Agents. 2019 Apr;53(4):401-407.
13. 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. Pharmacotherapy. 2018 Dec;38(12):1174-1183.
14. 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. Am J Health Syst Pharm. 2020 May 19;77(11):835-864.
15. Dalton BR, Rajakumar I, Langevin A, 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 Apr;26(4):436-446.
16. Yang W, Zhang K, Chen Y, et al. Is It Still Beneficial to Monitor the Trough Concentration of Vancomycin? A Quantitative Meta-Analysis of Nephrotoxicity and Efficacy. Antibiotics (Basel). 2024 May 28;13(6):497.
17. Huang J, Chan JD, Nguyen T, et al. Doing More With Less: Pragmatic Implementation of Vancomycin Area-Under-the-Curve (AUC) Monitoring. J Pharm Pract. 2023 Feb;36(1):10-14.
18. Flannery AH, Bissell BD, Bastin MT, et al. Continuous Versus Intermittent Infusion of Vancomycin and the Risk of Acute Kidney Injury in Critically Ill Adults: A Systematic Review and Meta-Analysis. Crit Care Med. 2020 Jun;48(6):912-918.
19. Chu Y, Luo Y, Quan X, et al. Intermittent vs. continuous vancomycin infusion for gram-positive infections: A systematic review and meta-analysis. J Infect Public Health. 2020 Apr;13(4):591-597.
20. Honore PM, Redant S, De Bels D. Continuous Versus Intermittent Infusion of Vancomycin: Toward the End of the Controversy or Even Closer to the Swan Song? Crit Care Med. 2020 Jun;48(6):932-933.
21. Wysocki M, Delatour F, Faurisson F, et al. Continuous versus intermittent infusion of vancomycin in severe Staphylococcal infections: prospective multicenter randomized study. Antimicrob Agents Chemother. 2001 Sep;45(9):2460-7.
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