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In Vitro Dynamic Model Evaluation of Meropenem Alone and in Combination with Avibactam Against Carbapenemase-Producing Klebsiella pneumoniae

Year: 2024

Type: article

Abstract: Background: A potential strategy to maintain the efficacy of carbapenems against carbapenemase-producing Klebsiella pneumoniae (CPKP) is their combination with carbapenemase inhibitors. To address these issues, the effectiveness of a novel combination of meropenem with avibactam against CPKP was studied. Additionally, the applicability of a pharmacokinetically-based approach to antibiotic/inhibitor minimum inhibitory concentration (MIC) determinations to better predict efficacy was examined. Methods: CPKP strains were exposed to meropenem alone or in combination with avibactam in an in vitro hollow-fiber infection model. Treatment effects were correlated with simulated antibiotic and antibiotic/inhibitor combination ratios of the area under the concentration–time curve (AUC) to the MIC (AUC/MIC). All MICs were determined at standard and at high inocula; combination MICs were determined using the conventional approach with fixed avibactam concentration or using the pharmacokinetic (PK)-based approach with a fixed meropenem-to-avibactam concentration ratio, equal to the respective drug therapeutic AUC ratios. Results: Meropenem alone was not effective even against a “susceptible” CPKP strain. The addition of avibactam significantly improved both meropenem MICs and its effectiveness. The effects of meropenem alone and in combination with avibactam (merged data) correlated well with AUC/MIC ratios only when MICs were determined at high inocula and using the PK-based approach (r2 0.97); the correlation was worse with the conventional approach (r2 0.73). Conclusions: The effectiveness of meropenem/avibactam against CPKP is promising. A single “effect–AUC/MIC” relationship useful for predicting meropenem efficacy (alone or in combination with avibactam) was obtained using MICs at high inocula and combination MICs determined using a PK-based approach.

Source: Pharmaceuticals

DOI: 10.3390/ph17121683

Authors: Elena N. Strukova, Yury A. Portnoy, Maria V. Golikova, Stephen H. Zinner

Institutions: Gause Institute of New Antibiotics Russian Academy of Medical Sciences, Mount Auburn Hospital, Harvard University

Language: English

Topic: Antibiotics Pharmacokinetics and Efficacy

Subfield: Pharmacology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,296