Aggressive joint pharmacokinetic/pharmacodynamic target attainment of TDM-guided continuous infusion meropenem-vaborbactam monotherapy: a valuable strategy for maximizing the microbiological outcome of documented KPC-producing Enterobacterales infections?

Objective: To assess whether attaining an aggressive joint pharmacokinetic/pharmacodynamic (PK/PD) target of therapeutic drug monitoring (TDM)-guided continuous infusion (CI) meropenem-vaborbactam monotherapy may be a valuable strategy for maximizing the microbiological outcome of documented KPC-producing Enterobacterales infections. Methods: This retrospective cohort study was performed in patients receiving CI meropenem-vaborbactam monotherapy for KPC-producing Enterobacterales infections and undergoing real-time TDM. Free fractions of plasma steady-state concentrations (fCss) of meropenem and vaborbactam were calculated according to a protein binding of 2% and 33%, respectively. Aggressive joint PK/PD target attainment was defined as a meropenem fCss/MIC ratio >4 coupled with a vaborbactam free area under time-to-concentration curve (fAUC)/target concentration (CT) ratio >24. Multivariate analysis was performed for assessing potential independent predictors of microbiological failure. Results: Overall, 55 patients were included. Aggressive joint PK/PD target of meropenem-vaborbactam was attained in 96.3% (53/55) of cases. Among 44/55 patients having follow-up cultures (80.0%), 9 experienced microbiological failure (20.5%), and 2 developed 90-day resistance (4.5%). Continuous renal replacement therapy (OR 15.00; 95%CI 1.75-128.40; p=0.013) and intrabdominal infection (OR 10.00; 95%CI 1.36-73.33; p=0.024) emerged as independent predictors of microbiological failure. Aggressive joint PK/PD target was non-attained more frequently among patients having microbiological failure than in those having microbiological eradication (22.2% vs. 0.0%; p=0.038), although not statistically significant at multivariate analysis. Conclusions: Our findings suggest that a TDM-guided monotherapy of documented KPC-producing Enterobacterales infections focused on aggressive joint PK/PD target attainment with CI meropenem-vaborbactam could represent a valuable strategy either for granting microbiological cure and for counteracting resistance development.