Optimization of meropenem continuous infusion based on Monte Carlo simulation integrating with degradation study

Objective: Meropenem degradation poses a challenge to continuous infusion (CI) implementation. However, data about the impact of degradation on the probability of target attainment (PTA) of meropenem has been limited. This study evaluated the stability of meropenem brands and the consequence of in-bottle degradation on PTA in different environmental scenarios.

Method: Seven meropenem generic brands prepared at concentrations of 1 g/48mL and 2 g/48mL in saline were examined at 25, 30, and 37°C over 8 h. A linear mixed-effects model was used to estimate degradation rate constant and potential covariates. In-bottle stability data was subsequently integrated as input for a deterministic and stochastic simulation using a published population pharmacokinetic model of critical illness. The impact of the degradation on target attainment at 98%fT>MIC was assessed.

Results: Time, temperature, and infusion concentration were factors affecting the stability of the meropenem solution for all products. The differences in the degradation of seven generics were subtle, so their simulated plasma concentrations were equal. Meropenem CI with 8 h renewal infusion achieved a higher PTA than the extended 3 h infusion, even at the highest degradation condition. The impact of meropenem degradation on PTA was minimal vis-à-vis the meropenem dose, patient's renal function, and microbial susceptibility. Meropenem degradation reduced PTA by an observable magnitude in patients with augmented renal clearance and difficult-to-treat pathogens. Dose escalation up to 1.5-2g every 8 h could restore this reduction to the target 90% PTA.

Conclusion: Meropenem CI with 8 h of renewal infusion, considering stability even in tropical areas, was feasible to maximize the efficacy to difficult-to-treat pathogens.