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. 2021 Feb 17;65(3):e02461-20.
doi: 10.1128/AAC.02461-20. Print 2021 Feb 17.

Molecular Characterization of Baseline Enterobacterales and Pseudomonas aeruginosa Isolates from a Phase 3 Nosocomial Pneumonia (ASPECT-NP) Clinical Trial

Mariana Castanheira  1 , Matthew G Johnson  2 , Brian Yu  2 , Jennifer A Huntington  2 , Patricia Carmelitano  2 , Christopher Bruno  2 , Elizabeth G Rhee  2 , Mary Motyl  2
Affiliations

Molecular Characterization of Baseline Enterobacterales and Pseudomonas aeruginosa Isolates from a Phase 3 Nosocomial Pneumonia (ASPECT-NP) Clinical Trial

Mariana Castanheira et al. Antimicrob Agents Chemother. .

Abstract

We reviewed β-lactam-resistant baseline Enterobacterales species and Pseudomonas aeruginosa lower respiratory tract isolates collected during the ASPECT-NP phase 3 clinical trial that evaluated the safety and efficacy of ceftolozane-tazobactam compared with meropenem for the treatment of nosocomial pneumonia in ventilated adults. Isolates were subjected to whole-genome sequencing, real-time PCR for the quantification of the expression levels of β-lactamase and efflux pump genes, and Western blot analysis for the detection of OprD (P. aeruginosa only). Extended-spectrum β-lactamase (ESBL) genes were detected in 168 of 262 Enterobacterales isolates, and among these, blaCTX-M-15 was the most common, detected in 125 isolates. Sixty-one Enterobacterales isolates carried genes encoding carbapenemases, while 33 isolates did not carry ESBLs or carbapenemases. Carbapenemase-producing isolates carried mainly NDM and OXA-48 variants, with ceftolozane-tazobactam MIC values ranging from 4 to 128 µg/ml. Most ceftolozane-tazobactam-nonsusceptible Enterobacterales isolates that did not carry carbapenemases were Klebsiella pneumoniae isolates that exhibited disrupted OmpK35, specific mutations in OmpK36, and, in some isolates, elevated expression of blaCTX-M-15 Among 89 P. aeruginosa isolates, carbapenemases and ESBL-encoding genes were observed in 12 and 22 isolates, respectively. P. aeruginosa isolates without acquired β-lactamases displaying elevated expression of AmpC (14 isolates), elevated expression of efflux pumps (11 isolates), and/or a decrease or loss of OprD (22 isolates) were susceptible to ceftolozane-tazobactam. Ceftolozane-tazobactam was active against >75% of the Enterobacterales isolates from the ASPECT-NP trial that did not carry carbapenemases. K. pneumoniae strains resistant to ceftolozane-tazobactam might represent a challenge for treatment due to their multiple resistance mechanisms. Ceftolozane-tazobactam was among the agents that displayed the greatest activity against P. aeruginosa isolates. (This study has been registered at ClinicalTrials.gov under registration no. NCT02070757.).

Keywords: ceftolozane-tazobactam; clinical trial; β-lactam resistance.

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Figures

FIG 1
FIG 1
Activities of ceftolozane-tazobactam and comparator agents against Enterobacterales isolates. a, for CLSI criteria, see reference ; b, data for cefepime represent susceptible-dose-dependent isolates.
FIG 2
FIG 2
Activities of ceftolozane-tazobactam and comparator agents against Pseudomonas aeruginosa isolates. a, for CLSI criteria, see reference ; b, data for cefepime represent susceptible-dose-dependent isolates.
FIG 3
FIG 3
Antimicrobial activities of ceftolozane-tazobactam against ESBL-positive Enterobacterales isolates without carbapenemases.
FIG 4
FIG 4
β-Lactam resistance mechanisms and MIC values for 89 P. aeruginosa isolates.
See this image and copyright information in PMC

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