Individual meropenem epithelial lining fluid and plasma PK/PD target attainment

Abstract

It is unclear whether plasma is a reliable surrogate for target attainment in the epithelial lining fluid (ELF). The objective of this study was to characterize meropenem target attainment in plasma and ELF using prospective samples. The first 24-hour T_>MIC was evaluated vs 1xMIC and 4xMIC targets at the patient (i.e., fixed MIC of 2 mg/L) and population [i.e., cumulative fraction of response (CFR) according to EUCAST MIC distributions] levels for both plasma and ELF. Among 65 patients receiving ≥24 hours of treatment, 40% of patients failed to achieve >50% T_>4xMIC in plasma and ELF, and 30% of patients who achieved >50% T_>4xMIC in plasma had <50% T_>4xMIC in ELF. At 1xMIC and 4xMIC targets, 3% and 25% of patients with >95% T_>MIC in plasma had <50% T_>MIC in ELF, respectively. Those with a CRCL >115 mL/min were less likely to achieve >50%T_>4xMIC in ELF (P < 0.025). In the population, CFR for Escherichia coli at 1xMIC and 4xMIC was >97%. For Pseudomonas aeruginosa, CFR was ≥90% in plasma and ranged 80%-85% in ELF at 1xMIC when a loading dose was applied. CFR was reduced in plasma (range: 75%-81%) and ELF (range: 44%-60%) in the absence of a loading dose at 1xMIC. At 4xMIC, CFR for P. aeruginosa was 60%-86% with a loading dose and 18%-62% without a loading dose. We found that plasma overestimated ELF target attainment inup to 30% of meropenem-treated patients, CRCL >115 mL/min decreased target attainment in ELF, and loading doses increased CFR in the population.

Keywords: hospital-acquired pneumonia; maximum-accuracy predictive model; pharmacokinetics, pharmacodynamics.

Fig 1

Individual observed vs predicted meropenem in plasma and ELF Individual observed meropenem (ordinate) and model predicted meropenem (abscissa) concentrations in plasma (A) and ELF (B) in patients with pneumonia.

Fig 2

First 24-hour meropenem target attainment in plasma and ELF in 65 patients (Panel A). Of 65 patients who received continuous dosing during the first 24 hours of treatment, 63 had acceptable (green) attainment in both plasma and ELF, and two had suboptimal attainment in ELF while demonstrating optimal plasma attainment (red) at the 1xMIC target. Dashed lines at 95%T_>1xMIC target in plasma or ELF.(Panel B). Of 65 patients who received continuous dosing during the first 24 hours of treatment, 39 had acceptable (green) attainment in both plasma and ELF, 3 patients had suboptimal attainment in plasma while demonstrating acceptable ELF attainment (blue), 17 had suboptimal attainment in ELF while demonstrating acceptable or optimal plasma attainment (red), and six had suboptimal attainment in both plasma and ELF (purple) at the 4xMIC target. Dashed lines at 95%T_>4xMIC target in plasma or ELF.