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.2023 Dec 7;12(12):1707.
doi: 10.3390/antibiotics12121707.

In Vitro Evaluation of Increasing Avibactam Concentrations on Ceftazidime Activity against Ceftazidime/Avibactam-Susceptible and Resistant KPC-ProducingKlebsiella pneumoniae Clinical Isolates

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In Vitro Evaluation of Increasing Avibactam Concentrations on Ceftazidime Activity against Ceftazidime/Avibactam-Susceptible and Resistant KPC-ProducingKlebsiella pneumoniae Clinical Isolates

Marta Palombo et al. Antibiotics (Basel)..

Abstract

The novel β-lactam/β-lactamase inhibitor combinations (βL-βLICs) are one of the last-line resources available against multidrug-resistant (MDR) Gram-negative bacteria. Among βL-βLICs, ceftazidime/avibactam (CAZ-AVI) demonstrated strong activity against carbapenem-resistantEnterobacterales (CRE). Avibactam was proven to restore bactericidal activity of ceftazidime, inhibiting both KPC and OXA-48-like β-lactamases. Despite this, emergence of CAZ-AVI-resistant strains inEnterobacterales has been reported. Herein, we evaluated the in vitro ceftazidime activity in the presence of increasing concentrations of avibactam by the broth microdilution method against CAZ-AVI-susceptible and resistant genome-characterized KPC-producingK. pneumoniae (KPC-Kp) clinical isolates. Strains expressing KPC and co-expressing KPC/OXA-181 carbapenemase were selected on the basis of the different phenotypic traits for novel βL-βLICs and cefiderocol. Notably, avibactam at 8 mg/L maintained the MIC of ceftazidime above the clinical breakpoint in 14 out of 15 (93%) KPC-Kp resistant to CAZ-AVI. A high concentration of avibactam (i.e., 64 mg/L) is required to observe a bactericidal activity of ceftazidime against 9 out of 15 (60%) CAZ-AVI-resistant isolates. In vitro evaluation showed that with the increase in the concentration of avibactam, ceftazidime showed high activity against CAZ-AVI-susceptible strains. High concentrations of avibactam in vivo are required for ceftazidime to be active against CAZ-AVI-resistant KPC-Kp.

Keywords: KPC-producers; multidrug resistant; whole-genome sequencing; βL-βLICs.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
MICs of ceftazidime obtained with the broth microdilution method in presence of different concentrations of avibactam (1, 2, 4, 8, 16, 32, or 64 mg/L) against 24 KPC-producingK. pneumoniae. The values obtained for CAZ-AVI-sensitive and -resistant strains are reported in black and white, respectively. Dotted lines indicate CAZ-AVI breakpoint.
Figure 2
Figure 2
MICs of ceftazidime obtained with broth microdilution method in presence of different concentration of avibactam (1, 2, 4, 8, 16, 32, or 64 mg/L) against 14 KPC-producing (A) and 10 Kp-co-producing KPC/OXA-181 (B)K. pneumoniae. The values obtained for CAZ-AVI-sensitive and -resistant strains are reported in black and white rings, respectively. Dotted lines indicate CAZ-AVI breakpoint.
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