PKPD modeling of the inoculum effect of combined ceftazidime/avibactam and colistin against KPC-3 Klebsiella pneumoniae isolate
Romain Aubry, Julien M. Buyck, Alexia Chauzy, Laure Prouvensier, Jean-Winoc Decousser, Patrice Nordmann, Sebastian G. Wicha, Sandrine Marchand, Nicolas Grégoire
TL;DR
This study models how bacterial load affects antibiotic effectiveness in a drug combination against a resistant Klebsiella strain.
Contribution
A pharmacokinetic/pharmacodynamic model quantifies inoculum effects in ceftazidime/avibactam and colistin combination therapy.
Findings
Combination therapy prevented resistance emergence at high inocula.
Inoculum effect reduced ceftazidime/avibactam's maximum effect and increased colistin's EC50.
No significant interaction between the drugs' inoculum effects was observed.
Abstract
The inoculum effect (IE) characterizes a decrease in the antimicrobial effect of antibiotics with increasing inoculum. To face antimicrobial resistance, antibiotic combinations are progressively used. In this context, the effect of combination may be affected by IE, especially drugs for which an IE has been described. The objective was to characterize the IE of a carbapenemase (KPC-3) Klebsiella pneumoniae isolate on the combination of ceftazidime/avibactam (CZA) and colistin (CST). In vitro time-kill curves with single and combined drugs were performed at four different inocula. The IE of each drug was described using pharmacokinetic/pharmacodynamic modeling, and interactions on IE were investigated with the general pharmacodynamic interaction model when drugs were combined. The IE was assessed by evaluating the significance of the parameters associated with the IE model compared to…
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Taxonomy
TopicsAntibiotic Resistance in Bacteria · Antibiotics Pharmacokinetics and Efficacy · Antibiotic Use and Resistance