Ceftazidime/avibactam resistance is associated with PER-3-producing ST309 lineage in Chilean clinical isolates of non-carbapenemase producing Pseudomonas aeruginosa.

Ceftazidime/avibactam (CZA) is indicated against multidrug-resistant Pseudomonas aeruginosa, particularly those that are carbapenem resistant. CZA resistance in P. aeruginosa producing PER, a class A extended-spectrum β-lactamase, has been well documented in vitro. However, data regarding clinical isolates are scarce. Our aim was to analyze the contribution of PER to CZA resistance in non-carbapenemase-producing P. aeruginosa clinical isolates that were ceftazidime and/or carbapenem non-susceptible. Antimicrobial susceptibility was determined through agar dilution and broth microdilution, while bla PER 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 bla PER-3 gene was induced in a PER-positive isolate by successive passages at 43°C without antibiotics. Twenty-six of 287 isolates studied (9.1%) were CZA-resistant. Thirteen of 26 CZA-resistant isolates (50%) carried bla PER. One isolate carried bla PER 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 bla PER-3 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 bla PER-3 gene restored susceptibility to CZA, ceftolozane/tazobactam and other β-lactamsin the in vitro evolved isolate. PER-3-producing ST309 P. aeruginosa is a successful multidrug-resistant clone with blaPER-3 gene implicated in resistance to CZA and other β-lactams.

Soto KD ，Alcalde-Rico M ，Ugalde JA ，Olivares-Pacheco J ，Quiroz V ，Brito B ，Rivas LM ，Munita JM ，García PC ，Wozniak A ... -  《Frontiers in Cellular and Infection Microbiology》

Resistance to ceftazidime-avibactam and other new β-lactams in Pseudomonas aeruginosa clinical isolates: a multi-center surveillance study.

Valzano F ，La Bella G ，Lopizzo T ，Curci A ，Lupo L ，Morelli E ，Mosca A ，Marangi M ，Melfitano R ，Rollo T ，De Nittis R ，Arena F ... -  《Microbiology Spectrum》

Molecular characterization of clinically isolated Pseudomonas aeruginosa with varying resistance to ceftazidime-avibactam and ceftolozane-tazobactam collected as a part of the ATLAS global surveillance program from 2020 to 2021.

Li H ，Oliver A ，Shields RK ，Kamat S ，Stone G ，Estabrook M ... -  《-》

Time-Kill Evaluation of Antibiotic Combinations Containing Ceftazidime-Avibactam against Extensively Drug-Resistant Pseudomonas aeruginosa and Their Potential Role against Ceftazidime-Avibactam-Resistant Isolates.

Montero MM ，Domene Ochoa S ，López-Causapé C ，Luque S ，Sorlí L ，Campillo N ，López Montesinos I ，Padilla E ，Prim N ，Angulo-Brunet A ，Grau S ，Oliver A ，Horcajada JP ... -  《Microbiology Spectrum》

Comparison of In Vitro Activity of Ceftazidime-Avibactam and Imipenem-Relebactam against Clinical Isolates of Pseudomonas aeruginosa.

Wang L ，Zhang X ，Zhou X ，Yang F ，Guo Q ，Wang M ... -  《Microbiology Spectrum》