The 2020 American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists (ASHP/PIDS/SIDP/IDSA) vancomycin guidelines for serious methicillin-resistant Staphylococcus aureus (MRSA) infections underscore that most current exposure-response data for area under the concentration-time curve to minimum inhibitory concentration (AUC/MIC) ratio targets derive from studies of MRSA bacteremia, with additional smaller bodies of evidence in pneumonia and infective endocarditis. The panel states that, based on available evidence, an AUC/MIC ratio of ≤600 is associated with a higher risk of treatment failure in patients with MRSA infective endocarditis, even after accounting for factors such as ICU admission and underlying comorbidities. Some retrospective analyses suggest that lower AUC/MIC thresholds may still be effective; however, when adjusted for differences in MIC determination methods, these findings are consistent with the currently recommended AUC/MIC ratio. [1]
A 2015 retrospective cohort analysis evaluated the association between day 1 vancomycin exposure and clinical outcomes in 139 adult patients diagnosed with MRSA infective endocarditis (IE) at the Detroit Medical Center between 2002 and 2013. Using a population pharmacokinetic model and the Maximum a Posteriori (MAP) Bayesian estimation method in ADAPT 5, investigators estimated individual vancomycin exposure profiles based on serum concentrations collected within the first 72 hours of therapy. The primary pharmacokinetic/pharmacodynamic (PK/PD) indices assessed included the area under the concentration-time curve over 24 hours (AUC0–24), trough concentration at 24 hours (Cmin 24), and AUC0–24 to minimum inhibitory concentration (MIC) ratio determined by both broth microdilution (BMD) and E-test methods. Vancomycin treatment failure, defined as persistent bacteremia beyond 7 days and/or 30-day attributable mortality, occurred in 64% (89/139) of patients. Through classification and regression tree (CART) analysis and logistic regression modeling, a significant association was identified between lower vancomycin AUC0–24/MICBMD ratios and treatment failure. Specifically, an AUC0–24/MICBMD ratio of <600 was independently associated with a 2.3-fold increased odds of failure (adjusted OR, 2.33; 95% CI, 1.01–5.37; p = 0.047). Among patients with subtherapeutic exposure, 69.8% experienced failure compared to 54.7% in those with exposure ≥600. In contrast, no statistically significant association was observed between day 1 Cmin 24 or AUC0–24/MICEtest and outcomes, although a breakpoint AUC0–24/MICEtest value of 290 was noted. The findings underscore the clinical relevance of early individualized vancomycin exposure optimization, with AUC0–24/MICBMD thresholds above 600 potentially associated with reduced likelihood of persistent bacteremia in MRSA IE. [2]
In a 2017 rabbit model study of MRSA infective endocarditis, researchers compared standard and higher vancomycin dosing to evaluate AUC/MIC ratio effectiveness. Investigators utilized three clinical MRSA strains (MICs of 0.5 mg/L, 1.5 mg/L, and 2 mg/L by Etest) and randomly assigned infected animals to either a standard vancomycin dosing regimen (1 g every 12 hours) or to higher, adjusted dosing intended to achieve an AUC/MIC ≥400. Despite achieving higher drug exposure and concentrations, the higher-dose regimens did not significantly improve vegetation sterilization across different MRSA strains. The study concluded that AUC/MIC ratios are poor predictors of vancomycin efficacy in endocarditis, likely due to challenges with drug penetration into biofilm-rich valve vegetations and bacterial metabolic states. These findings suggest that pharmacokinetic/pharmacodynamic targets from other infection types may not be directly applicable to endovascular infections. [3]