Guidelines and Literature
Guidelines
Rybak 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. American Journal of Health-System Pharmacy, 19 March 2020, zxaa036
Liu et al. Clinical Practice Guidelines by the Infectious Diseases Society of America for the Treatment of Methicillin-Resistant Staphylococcus aureus Infections in Adults and Children. Clinical Infectious Diseases, Volume 52, Issue 3, 1 February 2011, Pages e18–e55
Cuello et al. Vancomycin therapeutic monitoring for serious methicillin-resistant Staphylococcus aureus infections. Ottawa: CADTH; September 2020
Efficacy
Among 154 patients with complicated MRSA skin and soft tissue infections (SSTI) classification and regression tree (CART) analysis identified an AUC > 435 mg*hr/L for timely clinical success. Attainment of this AUC was associated with improved clinical outcomes in a retrospective, single center, cohort study.
Among 252 adult patients receiving vancomycin comparing trough versus AUC estimates for target therapeutic ranges, only 19% of trough concentrations versus 70% of AUCs were therapeutic. Use of Bayesian AUC-guided dosing was associated with fewer blood samples, shorter therapy durations, and reduced nephrotoxicity.
Among 100 patients with confirmed MRSA infections, failure of target attainment of a trough > 10 mg/L were 73% less likely to achieve an AUC/MIC > 400 mg*hr/L , however no difference was found related to AUC/MIC target attainment in patients with troughs of 10-14.9 mg/L, 15-20 mg/L, or > 20 mg/L. Higher rates of nephrotoxicity were found in patients with trough levels > 10 mg/L.
A retrospective, single center cohort study of 46 patients receiving vancomycin for MRSA bacteremia demonstrated overall clinical success and nephrotoxicity rates of 81.8% and 13.0%, respectively. CART-derived vancomycin AUC thresholds for clinical success and nephrotoxicity were >297 mg*hr/L and >710 mg*hr/L , respectively, indicating that vancomycin AUC targets should aim for values of 400-600 mg*hr/L when using two-point kinetics.
Safety
A systematic review and meta-analysis of eight observational studies of 2491 patients demonstrated that AUC less than 650 mg*hr/L was associated with decreased AKI in the first 48 hours and AUC monitoring strategies were associated with reduced AKI rates compared to trough-guided monitoring.
Nephrotoxicity associated with vancomycin necessitates more accurate and precise vancomycin dosing models, particularly in high-risk subpopulations including obese patients, critically-ill, and those with reduced glomerular filtration rates.
Among 127 consecutive patients with MRSA bacteremia who received vancomycin monotherapy for at least 14 days, AKI was observed in 15.7% of patients. Higher trough concentrations (17.2 mg/L v 13.1 mg/L) were associated with AKI, with classification and regression tree analysis identifying a vancomycin AUC threshold for AKI of >563 mg*hr/L .
A prospective multicenter observational study of 265 hospitalized patients with MRSA bacteremia who received vancomycin were found to have treatment failure (death within 30 days or persistent bacteremia >7 days) at a rate of 18% and AKI at a rate of 26%, and patients with day 2 AUC < 515 mg*hr/L experienced the best global outcomes (no treatment failure nor AKI).
Among 1280 patients at Detroit Medical Center, AUC-guided dosing was independently associated with lower nephrotoxicity (OR 0.52) compared to traditional trough-based dosing, with reduced nephrotoxicity associated with reduced vancomycin exposure.
NEW! Lodise TP, Drusano G. Vancomycin Area Under the Curve–Guided Dosing and Monitoring for Adult and Pediatric Patients With Suspected or Documented Serious Methicillin-Resistant Staphylococcus aureus Infections: Putting the Safety of Our Patients First
Despite a lack of double-blind, randomized, controlled trials, best-available evidence indicates that vancomycin is nephrotoxic with risk of AKI driven by increasing daily AUC. Trough measurements are more imprecise and unable to ensure safety nor efficacy. Transitioning to AUC-guided dosing for vancomycin may be a challenge, but it is necessary to maintain safety for patients, otherwise use of alternative agents for severe MRSA infections should be considered.
NEW! 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
A systematic review and meta-analysis demonstrated that increased (>20 μg/ml) vancomycin trough concentrations were associated with higher incidence of acute kidney injury compared to ranges of 15-20 μg/ml (OR 2.39, 95% CI 1.78-3.20). AUC/MIC of 400-600 resulted in lower treatment failure rates (OR 0.28, 95% CI 0.18-0.45), while AUC/MIC greater than 600 significantly increased the risk of AKI (2.10, 95% CI 1.13-3.89). Incidence of AKI was lower in patients receiving vancomycin via AUC-guided monitoring compared to trough-guided monitoring.
NEW! Post-Blahnik A, Moenster R. Association between vancomycin area under the curve (AUC) and nephrotoxicity
A retrospective cohort of 200 patients demonstrated that patients with vancomycin AUC > 550 were associated with higher peak serum creatinine (1.48 mg/dl v 1.22 mg/dl, p=0.015) and higher rates of AKI (42% v 2%, P<0.05) compared to those with AUC < 550. Age > 70 years, CrCl < 50ml/min, and AUC > 550 were found to be associated with AKI risk.
NEW! Avedissian AN et al. The pharmacodynamics-toxicodynamic relationship and Cmax in vancomycin-induced kidney injury in an animal model
Animal studies and PK analyses demonstrated kidney injury marker-1 (KIM-1) values were increased in more infrequent vancomycin dosing strategies (i.e. 300-400mg/kg/day divided in once or twice daily dosing compared to three or four times daily dosing). Exposure-response relationships were seen for KIM-1 and Cmax0-24, with Cmax0-24 being the most predictive PK-TD contributor of vancomycin-induced AKI.
Special Populations
Among 346 obese and super obese patients with BMI ranging from 30.1-85.7 kg/m2, Monte Carlo simulation demonstrated that maintenance vancomycin doses > 4500 mg/day were not required to achieve pharmacodynamics AUC targets. A population modeling using linear combinations of age, SCr, sex, and total body weight (scaled allometrically to an exponent of 0.75) was more predictive of clearance.
Retrospective study of 66 critically ill patients to determine the AUC and pharmacokinetic parameters on the first day of vancomycin administration using Bayesian models within PrecisePK software. The clearance (Cl) of vancomycin correlated with creatinine clearance, and volume of distribution (Vd) significantly correlated with age and body weight. Among critically ill patients, Vd and Cl values were higher and larger vancomycin loading doses (25-30 mg/kg) may be necessary to achieve target AUC within the first 24 hours of therapy.
Development and evaluation of a population pharmacokinetic model for vancomycin in adult patients on extracorporeal membrane oxygenation (ECMO). This study demonstrated that it is difficult to achieve efficacy and safety AUC/MIC (400-600) targets in patients on ECMO when using population dosing and Monte Carlo simulations.
NEW! Yoo R et al. Impact of initial vancomycin pharmacokinetic/pharmacodynamic parameters on the clinical and microbiological outcomes of methicillin-resistant Staphylococcus aureus bacteremia in children
A retrospective observational study of 73 pediatric patients (aged 2 months to 18 years) with MRSA bacteremia demonstrated a weak linear relationship between Ctrough and the corresponding AUC/MIC (r=0.234). Initial AUC/MIC < 300 may be a predictor for persistent MRSA bacteremia beyond 48 hours, however this should be validated in prospective trials.
Implementation
Improved safety, including reduced rates of AKI, can be achieved by implementing AUC-based vancomycin dosing led by pharmacists in conjunction with support and education from hospital partners.
A survey of 127 pharmacists who completed vancomycin dosing training before and after transitioning to AUC-guided pharmacist dosing program at UMMC found that AUC-based dosing was supported to a greater degree than trough-based dosing. AUC-based dosing took slightly longer to perform (15 min v 8 min), was associated with a sense of practicing at the highest degree of one’s licensure, and computer decision support is key to a successful rollout.
Three stages including preparation, implementation, and evaluation were used to establish an AUC-based vancomycin dosing strategy. This strategy required education to key stakeholders, training of pharmacy staff, development of monitoring guideline documents, institution-wide education, technology development and support, and quality improvement research.
Among 296 patients who received vancomycin before and after an AUC-based dosing strategy (using two-point kinetics) was implemented at Stanford Health, AUC-based dosing was associated with improved therapeutic target attainment (400-800 mg*hr/L) compared to trough-based strategies with lower rates of nephrotoxicity, albeit non-significant.
NEW! Bradley et al. Assessment of the implementation of AUC dosing and monitoring practices with vancomycin at hospitals across the United States
A survey study of 200 pharmacists demonstrated that most respondents have yet to implement AUC dosing (70.3%) but plan to do so in the next year (57%). Intended methods of AUC dosing varied between purchased Bayesian software (38%) and homemade software (35%), with user friendliness identified as a highly-valued factor.
NEW! Bland et al. Transitioning from guidelines approval to practical implementation of AUC-based monitoring of vancomycin
A survey study of 309 ACCP members demonstrated an array of vancomycin dosing strategies including: non-pharmacists clinicians dosed vancomycin in majority of patients (19%), institutions planned to continue using trough-based monitoring strategies (18%), and hospitals employing an infectious diseases pharmacist were more likely to report recent/pending transition to AUC-based dosing.
NEW! Rybak et al. Validity of 2020 vancomycin consensus recommendations and further guidance for practical application
Based on available evidence, vancomycin is nephrotoxic and drives AKI, with trough monitoring being an imprecise measurement of AUC. AUC is a preferred method to reduce risk of AKI while optimizing efficacy, and should be done to prioritize the safety of patients despite the implementation barriers.
NEW! Gregory et al. Vancomycin area under the curve dosing and monitoring at an academic medical center: Transition strategies and lessons learned
Successful implementation of vancomycin AUC monitoring requires an organized process and inclusion of key stakeholders to ensure all users are educated once technology has been developed. Throughout the implementation process, continued support for end-users should be available. Additionally, evaluation and dissemination of AUC-based dosing results should occur.
NEW! Lee et al. Cost-benefit analysis comparing tough, two-level AUC and Bayesian AUC dosing for vancomycin
A cost-benefit analysis demonstrated two-sample AUC versus trough dosing saved an average of $846 per patient encounter and a single-sample Bayesian AUC versus trough dosing saved $2065 per patient encounter. Based on these findings, only 41 patients would have to be dosed and monitored using a Bayesian software program (costing up to $100,000) in order to be cost-effective.
Microbiology
The SENTRY Antimicrobial Surveillance Program evaluated in vitro activity of 191,460 S. aureus isolates, of which 40.3% were MRSA. Forty-seven percent of those isolates originated from North America, indicating occurrence rates of 33.1% (1997-2000), 44.2% (2005-2008), 42.3% (2009-2012), and 39.0% (2013-2016), with no demonstrated increase of MIC > 1 mg/L in any of the isolates.
Bayesian and Pharmacokinetic Models
Five Bayesian dose-optimizing software programs including Adult and Pediatric Kinetics, BestDose, DoseMe, InsightRx, and Precise PK, along with two first-order pharmacokinetic equations were evaluated among a dataset of 19 critically ill patients for validation of the AUC estimate. The study found that InsightRx was the most adaptable, easiest to use, and featured the most company support. Precise PK and BestDose had the most accurate estimates despite increased difficulty in use and the accuracy values of BestDose exhibited the most variability. By using two levels, pharmacokinetic equations produced similar or better accuracy and bias as compared with Bayesian software.
The Albany Medical Center performed Bayesian PK (ADAPT V) sampling of 12 obese patients receiving vancomycin for suspected or confirmed Gram-positive infections with 5 PK concentrations for each patient using four different PK models as Bayesian priors. The authors found that AUC using two-level peak and trough provided the best approximation for the vancomycin AUC.
Retrospective data from 82 adult ICU patients who received vancomycin were used to predict serum concentrations a priori or with Bayesian forecasting among 12 vancomycin models, with the Goti model being the only clinically acceptable model for both a priori and Bayesian forecasting. The Llopis and Roberts model were also clinically appropriate using Bayesian forecasting.
A systematic evaluation of 31 population models for vancomycin in NONMEM®7.4 using data from 292 hospitalized patients to predict forecasting bias, precision, and visual predictive checks found that a priori predication varied substantially and was best for models that included body weight and creatinine clearance as covariates, with the Goti model providing the best predictive performance, most accurate visual predictive checks, and AUC predictions.
Demonstrates the value of continuous learning for model-informed precision dosing to prevent error or bias in dose selection due to use of models that were developed in alternative patient populations. This study describes that current pediatric pharmacokinetic models in literature could be improved to reduce prediction error by up to 13% by tailoring models to an institution’s patient population.
External validation of modified Goti model in patients over 65 years old with serum creatinine (SCr) less than 1 mg/dl using InsightRX Nova platform. Authors used actual SCr values instead of rounding up to 1mg/dl in these patients to assess the predictive performance compared to the traditional Goti model. Mean percentage error of predicted and observed levels was significantly reduced (-16.1% vs -31.6%) by using actual SCr rather than age-adjusted SCr values. This study serves an example of how continuous learning is very important for precision dosing and use of actual SCr in elderly patients may reduce bias and error in other models.
Disclaimer
The information provided by the MAD-ID Vancomycin Task Force (“we,” “us” or “our”) on this website (the “Site”) is for general informational purposes only. All information on the Site is provided in good faith, however we make no formal endorsement(s) of any kind regarding use of any proprietary materials found within this content. Under no circumstance shall we have any liability to you for any loss or damage of any kind incurred as a result of the use of the site or reliance on any information provided on the site. Your use of the site and your reliance on any information on the site is solely at your own risk.