Quantitative performance of humanized plasma and epithelial lining fluid exposures of meropenem, cefiderocol and tobramycin against a challenge set of Klebsiella pneumoniae and Pseudomonas aeruginosa in a standardized neutropenic murine pneumonia model

Abstract

Background: The COMBINE murine neutropenic pneumonia model looks to standardize an important element of preclinical development and provide interlaboratory uniformity. Herein we provide quantitative bacterial density in lung benchmark efficacy data of humanized exposures of meropenem, cefiderocol and tobramycin in plasma and epithelial lining fluid (ELF) against a collection of Klebsiella pneumoniae and Pseudomonas aeruginosa.

Methods: In accordance with the COMBINE protocol, human-simulated regimens (HSRs) based on both plasma and ELF exposures of meropenem, cefiderocol (both as 2 g q8h as 3 h infusions) and tobramycin 7 mg/kg as 30 min infusions were tested against K. pneumoniae and P. aeruginosa isolates. The 24 h change in cfu/lung for each HSR was calculated. Each isolate was tested in duplicate against both the plasma and ELF HSRs on separate experiment days.

Results: Meropenem HSRs demonstrated >1 log10 kill against all P. aeruginosa isolates with MICs of ≤16 mg/L, but only against K. pneumoniae isolates with MICs of ≤2 mg/L as isolates with MICs of >2 mg/L generally harboured carbapenemases. Cefiderocol HSRs uniformly achieved >1 log10 kill against both species at MICs of ≤8 mg/L, with net growth and extensive variability in P. aeruginosa isolates with MICs of 16 mg/L. All tobramycin-susceptible isolates demonstrated >1 log10 kill, while non-susceptible isolates did not. Differences in cfu/lung magnitude between the plasma and ELF HSRs were most pronounced around the clinical breakpoints.

Conclusions: In the COMBINE pneumonia model, administration of plasma and ELF HSRs of meropenem, cefiderocol and tobramycin demonstrated 24 h cfu/lung within reason of expectation given known PK/PD properties and existing clinical breakpoints.

Figure 1.

Quantitative cfu/lung data following administration of humanized meropenem (2 g every 8 h as 3 h infusion) plasma and ELF exposures in the COMBINE murine neutropenic pneumonia model against (a) Klebsiella pneumoniae and (b) Pseudomonas aeruginosa isolates. Boxes represent IQR, with horizontal line denoting the median. Whiskers determined by Tukey’s test and outliers displayed as individual dots. Solid line denotes stasis. Dashed line denotes 1 log₁₀ kill. Red dotted line denotes 2 log₁₀ kill. S/I/R, susceptible/intermediate/resistant according to CLSI M100 Thirty-Fifth Edition.

Figure 2.

Quantitative cfu/lung data following administration of humanized cefiderocol (2 g every 8 h as 3 h infusion) plasma and ELF exposures in the COMBINE murine neutropenic pneumonia model against (a) Klebsiella pneumoniae and (b) Pseudomonas aeruginosa isolates. Boxes represent IQR, with horizontal line denoting the median. Whiskers determined by Tukey’s test and outliers displayed as individual dots. Solid line denotes stasis. Dashed line denotes 1 log₁₀ kill. Red dotted line denotes 2 log₁₀ kill. S/I/R, susceptible/intermediate/resistant according to CLSI M100 Thirty-Fifth Edition.

Figure 3.

Quantitative cfu/lung data following administration of humanized tobramycin (7 mg/kg as 30 min infusion) plasma and ELF exposures in the COMBINE murine neutropenic pneumonia model against (a) Klebsiella pneumoniae and (b) Pseudomonas aeruginosa isolates. Boxes represent IQR, with horizontal line denoting the median. Whiskers determined by Tukey’s test and outliers displayed as individual dots. Solid line denotes stasis. Dashed line denotes 1 log₁₀ kill. Red dotted line denotes 2 log₁₀ kill. S/I/R, susceptible/intermediate/resistant according to CLSI M100 Thirty-Fifth Edition.