Optimizing Meropenem in Highly Resistant Klebsiella pneumoniae Environments: Population Pharmacokinetics and Dosing Simulations in Critically Ill Patients

Abstract

Critically ill patients are characterized by substantial pathophysiological changes that alter the pharmacokinetics (PK) of hydrophilic antibiotics, including carbapenems. Meropenem is a key antibiotic for multidrug-resistant Gram-negative bacilli, and such pathophysiological alterations can worsen treatment outcomes. This study aimed to determine the population PK of meropenem and to propose optimized dosing regimens for the treatment of multidrug-resistant Klebsiella pneumoniae in critically ill patients. Two plasma samples were collected from eligible patients over a dosing interval. Nonparametric population PK modeling was performed using Pmetrics. Monte Carlo simulations were applied to different dosing regimens to determine the probability of target attainment and the cumulative fraction of response, taking into account the local MIC distribution for K. pneumoniae. The targets of 40% and 100% for the fraction of time that free drug concentrations remained above the MIC (ƒT>MIC) were tested, as suggested for critically ill patients. A one-compartment PK model using data from 27 patients showed high interindividual variability. Significant PK covariates were the 8-h creatinine clearance for meropenem and the presence of an indwelling catheter for pleural, abdominal, or cerebrospinal fluid drainage for the meropenem volume of distribution. The target 100% ƒT>MIC for K. pneumoniae, with a MIC of ≤2 mg/liter, could be attained by the use of a continuous infusion of 2.0 g/day. Meropenem therapy in critically ill patients could be optimized for K. pneumoniae isolates with an MIC of ≤2 mg/liter by using a continuous infusion in settings with more than 50% isolates have a MIC of ≥32mg/L.

Keywords: Klebsiella pneumoniae; critically ill; dose optimization; meropenem.

FIG 1

Goodness-of-fit plots (A) and visual predictive check (B) of the final covariate model of meropenem. (A, left) Observed versus population-predicted concentrations: R² = 0.483, bias = 1.4, and imprecision = 53.8. (A, right) Individual predicted concentrations: R² = 0.991, bias = 0.113, and imprecision = 0.355. (B) The observed meropenem concentrations are represented by circles and black lines that are the 5th, 50th, and 95th simulated percentiles. The gray area shows the 95% confidence interval of the simulated meropenem concentrations.

FIG 2

MIC distribution of meropenem against 110 K. pneumoniae isolates collected in the intensive care unit department during the study period.

FIG 3

Simulated meropenem total daily dose for achieving at least 90% probability of target attainment for different MIC values at targets of 40% ƒT>MIC (A) and 100% ƒT>MIC (B). Green lines, continuous infusion; orange lines, extended infusion with 6-h interval (EI6); black lines, extended infusion with 8-h interval (EI8); solid lines, augmented renal clearance; dashed lines, nonaugmented renal clearance; dashed gray lines, exposure beyond toxicity thresholds.

FIG 4

Cumulative fraction of response (CFR) and percentage of patients exceeding toxicity thresholds, based on increasing the daily dose of meropenem administered as a continuous infusion, 6-hour extended infusion, and 8-hour extended infusion dosing regimens for targets of 40% ƒT>MIC and 100% ƒT>MIC against 3 subpopulations of K. pneumoniae in patients with and without augmented renal clearance. Black lines, CFR for K. pneumoniae with MIC of ≤1 mg/liter; yellow lines, CFR for K. pneumoniae with MIC of 2 mg/liter; blue lines, CFR for K. pneumoniae with MIC of ≥4 mg/liter; red lines, percentage of patients having meropenem plasma exposure exceeding the upper limit concentration. The upper horizontal dashed line represents 95% of simulated profiles achieving the target, and the lower horizontal dotted line represents the 10% cutoff for patients reaching the toxicity threshold.