Ceftazidime/avibactam resistance is associated with PER-3-producing ST309 lineage in Chilean clinical isolates of non-carbapenemase producing Pseudomonas aeruginosa
Journal
Frontiers in Cellular and Infection Microbiology
ISSN
2235-2988
Date Issued
2024
Author(s)
Katherine D. Soto
UGALDE, JUAN ANTONIO
Jorge Olivares Pacheco
Valeria Quiroz
Bárbara Brito
GARCÍA CEBALLOS, PATRICIA
Aniela Wozniak
Type
journal-article
DOI
URL
Abstract
<jats:sec><jats:title>Introduction</jats:title><jats:p>Ceftazidime/avibactam (CZA) is indicated against multidrug-resistant <jats:italic>Pseudomonas aeruginosa</jats:italic>, particularly those that are carbapenem resistant. CZA resistance in <jats:italic>P. aeruginosa</jats:italic> producing PER, a class A extended-spectrum β-lactamase, has been well documented <jats:italic>in vitro</jats:italic>. However, data regarding clinical isolates are scarce. Our aim was to analyze the contribution of PER to CZA resistance in non-carbapenemase-producing <jats:italic>P. aeruginosa</jats:italic> clinical isolates that were ceftazidime and/or carbapenem non-susceptible.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Antimicrobial susceptibility was determined through agar dilution and broth microdilution, while <jats:italic>bla</jats:italic><jats:sub>PER</jats:sub> gene was screened through PCR. All PER-positive isolates and five PER-negative isolates were analyzed through Whole Genome Sequencing. The mutational resistome associated to CZA resistance was determined through sequence analysis of genes coding for PBPs 1b, 3 and 4, MexAB-OprM regulators MexZ, MexR, NalC and NalD, AmpC regulators AmpD and AmpR, and OprD porin. Loss of <jats:italic>bla</jats:italic><jats:sub>PER-3</jats:sub> gene was induced in a PER-positive isolate by successive passages at 43°C without antibiotics. </jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Twenty-six of 287 isolates studied (9.1%) were CZA-resistant. Thirteen of 26 CZA-resistant isolates (50%) carried <jats:italic>bla</jats:italic><jats:sub>PER</jats:sub>. One isolate carried <jats:italic>bla</jats:italic><jats:sub>PER</jats:sub> but was CZA-susceptible. PER-producing isolates had significantly higher MICs for CZA, amikacin, gentamicin, ceftazidime, meropenem and ciprofloxacin than non-PER-producing isolates. All PER-producing isolates were ST309 and their <jats:italic>bla</jats:italic><jats:sub>PER-3</jats:sub> gene was associated to ISCR1, an insertion sequence known to mobilize adjacent DNA. PER-negative isolates were classified as ST41, ST235 (two isolates), ST395 and ST253. PER-negative isolates carried genes for narrow-spectrum β-lactamases and the mutational resistome showed that all isolates had one major alteration in at least one of the genes analyzed. Loss of <jats:italic>bla</jats:italic><jats:sub>PER-3</jats:sub> gene restored susceptibility to CZA, ceftolozane/tazobactam and other β-lactamsin the <jats:italic>in vitro</jats:italic> evolved isolate. </jats:p></jats:sec><jats:sec><jats:title>Discussion</jats:title><jats:p>PER-3-producing ST309 <jats:italic>P. aeruginosa</jats:italic> is a successful multidrug-resistant clone with <jats:italic>bla<jats:sub>PER-3</jats:sub></jats:italic> gene implicated in resistance to CZA and other β-lactams.</jats:p></jats:sec>