The revised consensus guidelines on therapeutic monitoring of vancomycin for serious methicillin-resistant Staphylococcus aureus (MRSA) infections from the American Society of Health-System Pharmacists (ASHP), the Infectious Diseases Society of America (IDSA), the Pediatric Infectious Diseases Society (PIDS), and the Society of Infectious Diseases Pharmacists (SIDP) were published to provide updated recommendations in regards to specific dosing and monitoring of vancomycin, which was not reflected in the original consensus guidelines published in 2009. Trough-only monitoring, with a target of 15 to 20 mg/L, is no longer recommended based on efficacy and nephrotoxicity data in patients with serious infections due to MRSA. Given the narrow vancomycin area under the curve (AUC) range for therapeutic effect and minimal acute kidney injury (AKI) risk, it is now recommended that the most accurate and optimal way to manage vancomycin dosing is through AUC-guided dosing and monitoring. [1], [2]
To accomplish this, the guidelines recommend two approaches, one of which relies on the collection of 2 concentrations (obtained near steady-state, post-distributional peak concentration [Cmax] at 1 to 2 hours after infusion and trough concentration [Cmin] at the end of the dosing interval), preferably but not required during the same dosing interval (if possible) and utilizing first order pharmacokinetic (PK) equations to estimate the AUC. The preferred approach to monitor AUC, however, involves the use of Bayesian software programs, embedded with a PK model based on richly sampled vancomycin data as the Bayesian prior, to optimize the delivery of vancomycin based on the collection of 1 or 2 vancomycin concentrations, with at least 1 PK sample representing a trough. With this approach, it is preferred to obtain 2 PK samples (i.e., at 1 to 2 hours post-infusion and at the end of the dosing interval) to estimate the AUC. A trough concentration alone may be sufficient to estimate the AUC with the Bayesian approach in some patients, but more data are needed across different patient populations to confirm the viability of using trough-only data. [1]
For patients with suspected or definitive serious MRSA infections, an individualized target of AUC over 24 hours to minimum inhibitory concentration (MIC) determined by broth microdilution (AUC/MICBMD) ratio of 400 to 600 mg*h/L (assuming a vancomycin MICBMD of 1 mg/L) should be advocated to achieve clinical efficacy while improving patient safety. Doses of 15 to 20 mg/kg (based on actual body weight) administered every 8 to 12 hours as an intermittent infusion are recommended for most patients with normal renal function when assuming a MICBMD of 1 mg/L. In patients with normal renal function, such doses may not achieve the therapeutic AUC/MIC target when the MIC is ≥2 mg/L. It should be noted that there is insufficient evidence to provide recommendations on whether trough-only or AUC-guided vancomycin monitoring should be used among patients with noninvasive MRSA or other infections. [1]
A 2021 review discusses the most substantial changes in the revised 2020 vancomycin consensus guidelines including the recommendation to transition from trough-only to AUC-guided dosing and monitoring for patients receiving vancomycin for “suspected or definitive serious invasive MRSA infections” and to maintain daily AUCs between 400 to 600 mg*h/L. In general, the basis for the shift from troughs of 15-20 mg/L to AUC-guided dosing and monitoring was to minimize vancomycin-associated acute kidney injury (VA-AKI) while maintaining similar effectiveness. Available data indicate that VA-AKI increases as a function of the intensity and duration of vancomycin exposure. Despite being widely utilized in practice, data demonstrating the clinical benefits of maintaining higher troughs are lacking. The 2009 consensus guidelines recommended maintaining troughs between 15 and 20 mg/L to simplify dosing and monitoring, but there were a lack of high-quality efficacy and safety data to support this recommendation at the time, and it was solely based on the fact that a trough within this range will consistently ensure a daily AUC greater than 400 mg*h/L. Despite this, the 2009 consensus guidelines did not account for the fact that a wide range of upper AUC values can occur with any given trough value. When examining the relationship between day 2 trough and AUC among simulated subjects with troughs between 15 and 20 mg/L, 48% of patients will have daily AUCs greater than 600 mg*h/L, which could result in a higher risk for VA-AKI. [1], [2], [3]
The AUC can be estimated with limited PK sampling in real time with either Bayesian software programs or simple analytic PK equations, but the former is suggested to be the preferred approach for precision dosing for desired AUCs. As Bayesian programs are flexible and adaptable, vancomycin concentrations can be obtained at any time, even over different dosing intervals; vancomycin concentrations do not need to be collected at “steady state” conditions. Additionally, the Bayesian approach provides the ability to include covariates, such as creatinine clearance, in the structural PK models to provide optimal dosing in patients with fluctuating renal function. [3]
There are now data indicating that AUC-guided dosing relative to trough-based monitoring is associated with less VA-AKI and comparable outcomes. In a retrospective, quasi-experimental study of 1,280 hospitalized patients (Table 1), AUC-guided dosing was found to be independently associated with a significant decrease in AKI (odds ratio [OR] 0.52, 95% confidence interval [CI] 0.34 to 0.80). In a prospective National Institutes of Health-funded study (Table 2), patients were monitored via troughs (range of 10 to 20 mg/L) in year 1 versus estimated Bayesian AUCs of ≥400 mg*h/L in years 2 and 3. Nephrotoxicity occurred in 8% of subjects in year 1 compared with 0% and 2% of subjects in years 2 and 3 (p= 0.01). Additionally, there was no difference in efficacy between the approaches. Overall, the authors suggest that having a landmark double-blind, well-powered randomized controlled trial (RCT) would be ideal to drive recent recommendations. However, an RCT of this nature is unlikely given that vancomycin has been in existence for over 50 years and there has yet to be one RCT published to define optimal monitoring practices. [3], [4], [5]
A 2023 systematic review and meta-analysis evaluated vancomycin-associated nephrotoxicity associated with AUC-guided versus trough-guided dosing. The analysis was conducted based on data from 57 studies, encompassing mostly adult and elderly patients. Of these, 4 studies directly compared AUC-guided versus trough-guided monitoring, with pooled results finding a significantly lower incidence of nephrotoxicity in the AUC-guided group (OR 0.53; 95% CI 0.32 to 0.89; p= 0.02; I2= 45%). The risk of nephrotoxicity was unaffected by the AUC derivation method. AUC thresholds correlated with nephrotoxicity only within the first 96 hours of therapy. Some individual studies reported the AUC-guided group to have statistically lower vancomycin cumulative and maintenance doses along with decreased overall drug exposure in comparison to the trough-guided group. A multivariate analysis (n= 38 studies) found concurrent nephrotoxins (68.4%), higher vancomycin trough concentrations (68.4%), and vancomycin duration of use (31.6%) to be predictors of nephrotoxicity. These results support conclusions made by other available studies, suggesting AUC-guided monitoring is associated with lower risk of vancomycin-related nephrotoxicity compared to trough-guided monitoring. In addition to heterogeneity, possibly related to varying definitions and durations of monitoring, the overall patient sample included mostly adult and older adult patients, hindering generalizability to other patient groups. [6]
A 2022 systematic review synthesized findings from 19 clinical investigations, comprising a total of 482 patients, to evaluate the efficacy, safety, and pharmacokinetics of both intravenous (IV) and intraventricular (IVT) vancomycin in the treatment of central nervous system (CNS) infections, including meningitis, ventriculitis, and CNS device-associated infections. The review highlighted that the optimal dosing regimens still remain unclear, and therapeutic drug monitoring (TDM) is often conducted to ensure adequate cerebrospinal fluid (CSF) concentrations. Across the included studies, IV vancomycin doses ranged from 1,000 to 3,000 mg/day, with dosing frequencies commonly at 15 mg/kg every 6 hours. IVT vancomycin doses spanned from 2 to 20 mg/day, typically administered once daily. TDM was conducted in 14 of the reviewed studies, although no consistent relationship was found between CSF vancomycin concentrations and therapeutic efficacy or toxicity. Pharmacokinetic data revealed wide variability in CSF concentrations for both IV (0.06 to 22.3 mg/L) and IVT (2.5 to 292.9 mg/L) administration routes. Notably, CSF-to-serum ratios varied significantly, ranging from 0.00 to 0.81 mg/L, with some studies suggesting enhanced penetration in the presence of meningeal inflammation. No clear relationships were found between vancomycin CSF levels and efficacy or toxicity. No serious adverse effects, including nephrotoxicity, were attributed to either IV or IVT vancomycin administration. Clinical outcomes indicated favorable responses in most cases, with CSF sterilization achieved in 88.4% of patients treated with IVT vancomycin alone. Despite observed efficacy and an acceptable safety profile, the review highlighted the need for high-quality clinical trials to further delineate optimal dosing strategies and characterize CNS pharmacokinetics to inform therapeutic decision-making in CNS infections. [7]
A 2021 systematic review and meta-analysis evaluating the relationship between vancomycin monitoring strategies and vancomycin effectiveness and safety included subjects who had MRSA bacteremia only for analysis of the effectiveness. As considerable variation in the AUC/MIC ratio was noted across included studies likely due to differences in methodological and technical measurements, researchers rounded the AUC within 15%. As such, the cut-off value of AUC/MIC ratios of 340-460 mg*h/L was defined as 400 mg*h/L, and AUC values of 510-690 mg*h/L were defined as 600mg*h/L. Pooled meta-analysis of effectiveness and safety each contained five studies, primarily retrospective in design. Results found individuals with vancomycin trough concentrations ≥15 mcg/mL had significantly lower treatment failure rates (OR 0.63, 95% CI 0.47 to 0.85). Compared to those with a trough of 15 to 20 mcg/mL, adult patients with a trough concentration ≥20 mcg/mL had a significantly higher risk of developing acute kidney injury (AKI) (OR 2.39; 95% CI 1.78 to 3.20). The analysis of target AUC/MIC found high AUC/MIC level (cut-off 400 mg*h/L ± 15%) to be associated with significantly lower treatment failure rates (OR 0.28; 95% CI 0.18 to 0.45), whereas a level of 600 mg*h/L ± 15% significantly increased the risk of AKI (OR 2.10; 95% CI 1.13 to 3.89). Overall, the pooled analysis did not report significant differences in the incidence of AKI and mortality between AUC-guided monitoring and trough-guided monitoring, though AUC-guided monitoring yielded numerically lower risks (OR 0.54; 95% CI 0.28 to 1.01). Nevertheless, the findings may be limited by the lack of high-quality randomized trials, variations in AUC calculations, and different definitions of AKI. [8]