In Vitro Activity of the Ultrabroad-Spectrum Beta-Lactamase Inhibitor QPX7728 in Combination with Multiple Beta-Lactam Antibiotics against Pseudomonas aeruginosa.
Antimicrob Agents Chemother
; 65(6)2021 05 18.
Article
em En
| MEDLINE
| ID: mdl-33782010
ABSTRACT
QPX7728 is an ultrabroad-spectrum beta-lactamase inhibitor with potent inhibition of key serine and metallo beta-lactamases. QPX7728 enhances the potency of multiple beta-lactams in beta-lactamase-producing Enterobacterales and Acinetobacter spp. In this study, we evaluated the in vitro activity of QPX7728 (QPX; 8 µg/ml) combined with multiple beta-lactams against clinical isolates of Pseudomonas aeruginosa with various beta-lactam resistance mechanisms. Seven hundred ninety clinical isolates were included in this study; 500 isolates, termed a "representative panel," were selected to be representative of the MIC distribution of meropenem (MEM), ceftazidime-avibactam (CAZ-AVI), and ceftolozane-tazobactam (TOL-TAZ) resistance for clinical isolates according to 2017 SENTRY surveillance data. An additional 290 selected isolates ("challenge panel") that were either nonsusceptible to MEM or were resistant to TOL-TAZ or CAZ-AVI were also tested; 61 strains carried metallo-beta-lactamases (MBLs), 211 strains were defective in the carbapenem porin OprD, and 185 strains had the MexAB-OprM efflux pump overproduced based on a phenotypic test. Against the representative panel, susceptibility for all QPX7728/beta-lactam combinations was >90%. For the challenge panel, QPX-ceftolozane (TOL) was the most active combination (78.6% susceptible) followed by equipotent QPX-piperacillin (PIP) and QPX-cefepime (FEP), restoring susceptibility in 70.3% of strains (CLSI breakpoints for the beta-lactam compound alone). For MBL-negative strains, QPX-TOL and QPX-FEP restored the MIC values to susceptibility rates in â¼90% and â¼80% of strains, respectively, versus 68% to 70% for QPX-MEM and QPX-PIP and 63% to 65% for TOL-TAZ and CAZ-AVI, respectively. For MBL-positive strains, QPX-PIP restored the MIC to susceptibility values for â¼70% of strains versus 2% to 40% for other combinations. Increased efflux and impaired OprD had various effect on QPX7728 combination depending on the partner beta-lactam tested. QPX7728 enhanced the potency of multiple beta-lactams against P. aeruginosa, with varied results according to beta-lactamase production and other intrinsic resistance mechanisms.
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Texto completo:
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pseudomonas aeruginosa
/
Infecções por Pseudomonas
Limite:
Humans
Idioma:
En
Revista:
Antimicrob Agents Chemother
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Estados Unidos