{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T02:28:26Z","timestamp":1784687306559,"version":"3.55.0"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,6,5]],"date-time":"2024-06-05T00:00:00Z","timestamp":1717545600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"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 \u03b2-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\u00b0C 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 \u03b2-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 \u03b2-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 \u03b2-lactams.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcimb.2024.1410834","type":"journal-article","created":{"date-parts":[[2024,6,5]],"date-time":"2024-06-05T09:59:01Z","timestamp":1717581541000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Ceftazidime\/avibactam resistance is associated with PER-3-producing ST309 lineage in Chilean clinical isolates of non-carbapenemase producing Pseudomonas aeruginosa"],"prefix":"10.3389","volume":"14","author":[{"given":"Katherine D.","family":"Soto","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Alcalde-Rico","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan A.","family":"Ugalde","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge","family":"Olivares-Pacheco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Quiroz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B\u00e1rbara","family":"Brito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lina M.","family":"Rivas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 M.","family":"Munita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia C.","family":"Garc\u00eda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aniela","family":"Wozniak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,6,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"4308","DOI":"10.1128\/JB.184.15.4308-4312.2002","article-title":"The mexR repressor of the mexAB-oprM multidrug efflux operon in Pseudomonas aeruginosa: characterization of mutations compromising activity","volume":"184","author":"Adewoye","year":"2002","journal-title":"J. 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