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. 2023 Apr 25:13:1098944.
doi: 10.3389/fcimb.2023.1098944. eCollection 2023.

Multifactorial resistance mechanisms associated with resistance to ceftazidime-avibactam in clinical Pseudomonas aeruginosa isolates from Switzerland

Baharak Babouee Flury  1   2 , Anja Bösch  1   2 , Valentin Gisler  3   4 , Adrian Egli  5 , Salome N Seiffert  6 , Oliver Nolte  6 , Jacqueline Findlay  7
Affiliations

Multifactorial resistance mechanisms associated with resistance to ceftazidime-avibactam in clinical Pseudomonas aeruginosa isolates from Switzerland

Baharak Babouee Flury et al. Front Cell Infect Microbiol. .

Erratum in

Abstract

Background: Increasing reports of multidrug resistance (MDR) in clinical Pseudomonas aeruginosa have led to a necessity for new antimicrobials. Ceftazidime-avibactam (CZA) is indicated for use against MDR P. aeruginosa across a broad range of infection types and particularly those that are carbapenem resistant. This study sought to determine the molecular mechanisms of CZA and imipenem (IPM)-resistance in clinical P. aeruginosa isolates obtained from Swiss hospitals.

Methods: Clinical P. aeruginosa isolates were obtained from inpatients in three hospitals in Switzerland. Susceptibility was determined by either antibiotic disc testing or broth microdilution according to EUCAST methodology. AmpC activity was determined using cloxacillin and efflux activity was determined using phenylalanine-arginine β-naphthylamide, in agar plates. Whole Genome Sequencing was performed on 18 clinical isolates. Sequence types (STs) and resistance genes were ascertained using the Centre for Genomic Epidemiology platform. Genes of interest were extracted from sequenced isolates and compared to reference strain P. aeruginosa PAO1.

Results: Sixteen different STs were identified amongst the 18 isolates in this study indicating a high degree of genomic diversity. No carbapenemases were detected but one isolate did harbor the ESBL bla PER-1. Eight isolates were CZA-resistant with MICs ranging from 16-64 mg/L, and the remaining ten isolates had either low/wildtype MICs (n=6; 1-2 mg/L) or elevated, but still susceptible, MICs (n=4; 4-8 mg/L). Ten isolates were IPM-resistant, seven of which had mutations resulting in truncations of OprD, and the remaining nine IPM-susceptible isolates had intact oprD genes. Within CZA-R isolates, and those with reduced susceptibility, mutations resulting in ampC derepression, OprD loss, mexAB overexpression and ESBL (bla PER-1) carriage were observed in various combinations and one harbored a truncation of the PBP4 dacB gene. Within the six isolates with wildtype-resistance levels, five had no mutations that would affect any antimicrobial resistance (AMR) genes of interest when compared to PAO1.

Conclusion: This preliminary study highlights that CZA-resistance in P. aeruginosa is multifactorial and could be caused by the interplay between different resistance mechanisms including ESBL carriage, increased efflux, loss of permeability and derepression of its intrinsic ampC.

Keywords: Pseudomonas aeruginosa; ceftazidime-avibactam (CZA); imipenem; molecular resistance mechanisms; whole genome sequencing (WGS).

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References

    1. Aguilar-Rodea P., Zúñiga G., Cerritos R., Rodríguez-Espino B. A., Gomez-Ramirez U., Nolasco-Romero C. G., et al. (2022). Nucleotide substitutions in the mexR, nalC and nalD regulator genes of the MexAB-OprM efflux pump are maintained in pseudomonas aeruginosa genetic lineages. PloS One 17, e0266742. doi: 10.1371/journal.pone.0266742 - DOI - PMC - PubMed
    1. Bolger A. M., Lohse M., Usadel B. (2014). Trimmomatic: a flexible trimmer for illumina sequence data. Bioinformatics 30, 2114–2120. doi: 10.1093/bioinformatics/btu170 - DOI - PMC - PubMed
    1. Braz V. S., Furlan J. P. R., Fernandes A. F. T., Stehling E. G. (2016). Mutations in NalC induce MexAB-OprM overexpression resulting in high level of aztreonam resistance in environmental isolates of Pseudomonas aeruginosa . FEMS Microbiol. Lett. 363, fnw166. doi: 10.1093/femsle/fnw166 - DOI - PubMed
    1. Buehrle D. J., Shields R. K., Clarke L. G., Potoski B. A., Clancy C. J., Nguyen M. H. (2017). Carbapenem-resistant pseudomonas aeruginosa bacteremia: risk factors for mortality and microbiologic treatment failure. Antimicrob. Agents Chemother. 61, e01243–e01216. doi: 10.1128/AAC.01243-16 - DOI - PMC - PubMed
    1. Cabot G., Zamorano L., Moyà B., Juan C., Navas A., Blázquez J., et al. (2016). Evolution of pseudomonas aeruginosa antimicrobial resistance and fitness under low and high mutation rates. Antimicrob. Agents Chemother. 60, 1767–1778. doi: 10.1128/AAC.02676-15 - DOI - PMC - PubMed