Intrapulmonary concentrations of meropenem administered by continuous infusion in critically ill patients with nosocomial pneumonia: a randomized pharmacokinetic trial

Abstract

Background: Optimal antimicrobial drug exposure in the lung is required for successful treatment outcomes for nosocomial pneumonia. Little is known about the intrapulmonary pharmacokinetics (PK) of meropenem when administered by continuous infusion (CI). The aim of this study was to evaluate the PK of two dosages of meropenem (3 g vs 6 g/day by CI) in the plasma and epithelial lining fluid (ELF) in critically ill patients with nosocomial pneumonia.Methods: Thirty-one patients (81% male, median (IQR) age 72 (22) years) were enrolled in a prospective, randomized, clinical trial. Sixteen patients received 1 g/8 h and 15 2 g/8 h by CI (8 h infusion). Plasma and ELF meropenem concentrations were modeled using a population methodology, and Monte Carlo simulations were performed to estimate the probability of attaining (PTA) a free ELF concentration of 50% of time above MIC (50% fT>MIC), which results in logarithmic killing and the suppression of resistance in experimental models of pneumonia. Results: The median (IQR) of meropenem AUC 0-24 h in the plasma and ELF was 287.6 (190.2) and 84.1 (78.8) mg h/ L in the 1 g/8 h group vs 448.1 (231.8) and 163.0 (201.8) mg h/L in the 2 g/8 h group, respectively. The penetration ratio was approximately 30% and was comparable between the dosage groups. In the Monte Carlo simulations, only the highest approved dose of meropenem of 2 g/8 h by CI allowed to achieve an optimal PTA for all isolates with a MIC < 4 mg/L.

Meropenem: continuous or extended infusion?

“…Thirdly, studies performed in critically ill patients with nosocomial pneumonia showed a high interindividual variability in the β-lactams concentrations in ELF whatever the mode of infusion [1][2][3][4]. We agree with Benitez-Cano et al that even the highest dosage of meropenem (2 g/8 h) administered by either CI or EI could not result in an optimal ELF target attainment for a substantial fraction of the population, particularly in patients with augmented renal clearance.…”

“…In our opinion, a PK/PD target of 100% fT > MIC was more suitable, since the study was performed under CI. Indeed, despite the fact that the authors stated that "a precise estimate of the concentration-time profile in ELF was not possible because all ELF samples were obtained at the same time," CI of β-lactams allows reasonably a 24/24 stable concentration both in plasma and ELF, as illustrated in the figures 2 and 6 for the plasma and ELF, respectively [1], and as shown in other studies [2,3].…”

“…We read with interest the article by Benitez-Cano and colleagues about intrapulmonary concentrations of meropenem administered by continuous infusion (CI) in critically ill patients with nosocomial pneumonia and would like to make some comments [1].…”

Beta-Lactams Dosing in Critically Ill Patients with Gram-Negative Bacterial Infections: A PK/PD Approach

“…Increased total daily doses of meropenem may be necessary to achieve 50% fT > MIC in ELF [59]. Benitez-Cano, et al evaluated intrapulmonary concentrations of CI meropenem.…”

Pharmacokinetics and Pharmacodynamics of Meropenem by Extended or Continuous Infusion in Low Body Weight Critically Ill Patients

“…Meropenem concentrations were measured using a validated high-performance liquid chromatography method [23] at the Pharmacy Department of Hospital del Mar. The assay was linear from 0.5 to 80 mg/L.…”