Suboptimal Concentrations of Ceftazidime/Avibactam (CAZ-AVI) May Select for CAZ-AVI Resistance in Extensively Drug-Resistant Pseudomonas aeruginosa: In Vivo and In Vitro Evidence

This study correlates in vivo findings in a patient with an extensively drug-resistant (XDR) P. aeruginosa infection who developed resistance to ceftazidime-avibactam (CAZ-AVI) with in vitro results of a 7-day hollow-fiber infection model (HFIM) testing the same bacterial strain. The patient was critically ill with ventilator-associated pneumonia caused by XDR P. aeruginosa ST175 with CAZ-AVI MIC of 6 mg/L and was treated with CAZ-AVI in continuous infusion at doses adjusted for renal function. Plasma concentrations of CAZ-AVI were analyzed on days 3, 7, and 10. In the HIFM, the efficacy of different steady-state concentrations (Css) of CAZ-AVI (12, 18, 30 and 48 mg/L) was evaluated. In both models, a correlation was observed between the decreasing plasma levels of CAZ-AVI and the emergence of resistance. In the HIFM, a Css of 30 and 48 mg/L (corresponding to 5x and 8x MIC) had a bactericidal effect without selecting resistant mutants, whereas a Css of 12 and 18 mg/L (corresponding to 2x and 3x MIC) failed to prevent the emergence of resistance. CAZ/AVI resistance development was caused by the selection of a single ampC mutation in both patient and HFIM. Until further data are available, strategies to achieve plasma CAZ-AVI levels at least 4x MIC could be of interest, particularly in severe and high-inoculum infections caused by XDR P. aeruginosa with high CAZ-AVI MICs.

Automated summary

This study correlates the in vivo and in vitro findings of a patient with extensively drug-resistant P. aeruginosa infection, indicating a correlation between decreasing plasma levels of CAZ-AVI and the emergence of resistance. The study suggests that maintaining plasma CAZ-AVI levels at least 4 times the minimum inhibitory concentration (MIC) can prevent the development of resistance.