Impact of continuous-infusion meropenem degradation and infusion bag changes on bacterial killing of Pseudomonas aeruginosa based on model-informed translation

Background: Continuous infusion of meropenem has been proposed to increase target attainment in critically ill patients, although stability might limit its practical use. This study investigated the impact of meropenem degradation and infusion bag changes on the concentration-time profiles and bacterial growth and killing of P. aeruginosa given different continuous-infusion solutions.

Methods: A semi-mechanistic pharmacokinetic-pharmacodynamic (PK-PD) model quantifying meropenem concentrations (C_MEM) and bacterial counts of a resistant P. aeruginosa strain (ARU552, MIC = 16 mg/L) over 24 h was used to translate in vitro antibiotic effects to patients with severe infections. Concentration-dependent drug degradation of saline infusion solutions was considered using an additional compartment in the population PK model. C_MEM, fT_>MIC (time that concentrations exceed the MIC) and total bacterial load (B_TOT) after 24 h were simulated for different scenarios (n = 144), considering low- and high-dose regimens (3000/6000 mg/day±loading dose), clinically relevant infusion solutions (20/40/50 mg/mL), different intervals of infusion bag changes (every 8/24 h, q8/24 h), and varied renal function (creatinine clearance 40/80/120 mL/min) and MIC values (8/16 mg/L).

Results: Highest deviations between changing infusion bags q8h and q24h were observed for 50 mg/mL solutions and scenarios with C_{MEM_24h} close to the MIC, with differences (Δ) in C_{MEM_24h} up to 4.9 mg/L, ΔfT_>MIC≤65.7%, and ΔB_{TOT_24h}≤1.1 log10 CFU/mL, thus affecting conclusions on whether bacteriostasis was reached.

Conclusions: In summary, this study indicated that for continuous infusion of meropenem, eight-hourly infusion bag changes improved PK/PD target attainment and might be beneficial particularly for high meropenem concentrations of saline infusion solutions and for plasma concentrations in close proximity to the MIC.