Ceftazidime/avibactam Resistance is Associated with PER-3-producing ST309 Lineage in Chilean Clinical Isolates of Non-carbapenemase Producing

Overview

Journal Front Cell Infect Microbiol

Specialties Cell Biology
Infectious Diseases
Microbiology

Date 2024 Jun 21

PMID 38903939

Authors

Katherine D Soto

Manuel Alcalde-Rico

Juan A Ugalde

Jorge Olivares-Pacheco

Valeria Quiroz

Barbara Brito

Lina M Rivas

Jose M Munita

Patricia C Garcia

Aniela Wozniak

Affiliations

Soon will be listed here.

Abstract

Introduction: Ceftazidime/avibactam (CZA) is indicated against multidrug-resistant , particularly those that are carbapenem resistant. CZA resistance in producing PER, a class A extended-spectrum β-lactamase, has been well documented . However, data regarding clinical isolates are scarce. Our aim was to analyze the contribution of PER to CZA resistance in non-carbapenemase-producing clinical isolates that were ceftazidime and/or carbapenem non-susceptible.

Methods: Antimicrobial susceptibility was determined through agar dilution and broth microdilution, while 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 gene was induced in a PER-positive isolate by successive passages at 43°C without antibiotics.

Results: Twenty-six of 287 isolates studied (9.1%) were CZA-resistant. Thirteen of 26 CZA-resistant isolates (50%) carried . One isolate carried 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 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 gene restored susceptibility to CZA, ceftolozane/tazobactam and other β-lactamsin the evolved isolate.

Discussion: PER-3-producing ST309 is a successful multidrug-resistant clone with gene implicated in resistance to CZA and other β-lactams.

References

Haghighi S, Goli H . High prevalence of , and genes in beta-lactam resistant clinical isolates of . AIMS Microbiol. 2022; 8(2):153-166. PMC: 9329875. DOI: 10.3934/microbiol.2022013. View

Arduino S, Roy P, Jacoby G, Orman B, Pineiro S, Centron D . blaCTX-M-2 is located in an unusual class 1 integron (In35) which includes Orf513. Antimicrob Agents Chemother. 2002; 46(7):2303-6. PMC: 127297. DOI: 10.1128/AAC.46.7.2303-2306.2002. View

Wang Y, Wang J, Wang R, Cai Y . Resistance to ceftazidime-avibactam and underlying mechanisms. J Glob Antimicrob Resist. 2019; 22:18-27. DOI: 10.1016/j.jgar.2019.12.009. View

Chavez-Jacobo V, Hernandez-Ramirez K, Romo-Rodriguez P, Perez-Gallardo R, Campos-Garcia J, Gutierrez-Corona J . CrpP Is a Novel Ciprofloxacin-Modifying Enzyme Encoded by the Pseudomonas aeruginosa pUM505 Plasmid. Antimicrob Agents Chemother. 2018; 62(6). PMC: 5971611. DOI: 10.1128/AAC.02629-17. View

Zamudio R, Hijazi K, Joshi C, Aitken E, Oggioni M, Gould I . Phylogenetic analysis of resistance to ceftazidime/avibactam, ceftolozane/tazobactam and carbapenems in piperacillin/tazobactam-resistant Pseudomonas aeruginosa from cystic fibrosis patients. Int J Antimicrob Agents. 2019; 53(6):774-780. DOI: 10.1016/j.ijantimicag.2019.02.022. View

de la Rosa J, Nordmann P, Poirel L . ESBLs and resistance to ceftazidime/avibactam and ceftolozane/tazobactam combinations in Escherichia coli and Pseudomonas aeruginosa. J Antimicrob Chemother. 2019; 74(7):1934-1939. DOI: 10.1093/jac/dkz149. View

Mojica M, De la Cadena E, Garcia-Betancur J, Porras J, Novoa-Caicedo I, Paez-Zamora L . Molecular Mechanisms of Resistance to Ceftazidime/Avibactam in Clinical Isolates of and Pseudomonas aeruginosa in Latin American Hospitals. mSphere. 2023; 8(2):e0065122. PMC: 10117078. DOI: 10.1128/msphere.00651-22. View

Fernandez L, Jenssen H, Bains M, Wiegand I, Gooderham W, Hancock R . The two-component system CprRS senses cationic peptides and triggers adaptive resistance in Pseudomonas aeruginosa independently of ParRS. Antimicrob Agents Chemother. 2012; 56(12):6212-22. PMC: 3497197. DOI: 10.1128/AAC.01530-12. View

Philippon A, Slama P, Deny P, Labia R . A Structure-Based Classification of Class A β-Lactamases, a Broadly Diverse Family of Enzymes. Clin Microbiol Rev. 2015; 29(1):29-57. PMC: 4771212. DOI: 10.1128/CMR.00019-15. View

10.

Guerin E, Cambray G, Sanchez-Alberola N, Campoy S, Erill I, Da Re S . The SOS response controls integron recombination. Science. 2009; 324(5930):1034. DOI: 10.1126/science.1172914. View

11.

Mendes R, Castanheira M, Woosley L, Stone G, Bradford P, Flamm R . Characterization of β-Lactamase Content of Ceftazidime-Resistant Pathogens Recovered during the Pathogen-Directed Phase 3 REPRISE Trial for Ceftazidime-Avibactam: Correlation of Efficacy against β-Lactamase Producers. Antimicrob Agents Chemother. 2019; 63(6). PMC: 6535560. DOI: 10.1128/AAC.02655-18. View

12.

Fonseca E, Morgado S, Caldart R, Freitas F, Vicente A . Emergence of a VIM-2-producing extensively drug-resistant (XDR) Pseudomonas aeruginosa ST309 in South America: a comparative genomic analysis. Int J Antimicrob Agents. 2021; 59(2):106507. DOI: 10.1016/j.ijantimicag.2021.106507. View

13.

Zamorano L, Moya B, Juan C, Oliver A . Differential beta-lactam resistance response driven by ampD or dacB (PBP4) inactivation in genetically diverse Pseudomonas aeruginosa strains. J Antimicrob Chemother. 2010; 65(7):1540-2. DOI: 10.1093/jac/dkq142. View

14.

Wick R, Judd L, Cerdeira L, Hawkey J, Meric G, Vezina B . Trycycler: consensus long-read assemblies for bacterial genomes. Genome Biol. 2021; 22(1):266. PMC: 8442456. DOI: 10.1186/s13059-021-02483-z. View

15.

Vaser R, Adusumalli S, Leng S, Sikic M, Ng P . SIFT missense predictions for genomes. Nat Protoc. 2015; 11(1):1-9. DOI: 10.1038/nprot.2015.123. View

16.

Karlowsky J, Kazmierczak K, Bouchillon S, de Jonge B, Stone G, Sahm D . Activity of Ceftazidime-Avibactam against Clinical Isolates of Enterobacteriaceae and Pseudomonas aeruginosa Collected in Asia-Pacific Countries: Results from the INFORM Global Surveillance Program, 2012 to 2015. Antimicrob Agents Chemother. 2018; 62(7). PMC: 6021687. DOI: 10.1128/AAC.02569-17. View

17.

Wozniak A, Rodriguez N, Alcalde-Rico M, Castillo C, Garcia P . [First isolate of SPM-1- producing Pseudomonas aeruginosa (Sao Paulo metallo-β-lactamase) in a Chilean patient]. Rev Chilena Infectol. 2022; 38(5):724-726. DOI: 10.4067/s0716-10182021000500724. View

18.

Wu J, Xie L, Zhang F, Ni Y, Sun J . Molecular characterization of ISCR1-mediated blaPER-1 in a non-O1, non-O139 Vibrio cholerae strain from China. Antimicrob Agents Chemother. 2015; 59(7):4293-5. PMC: 4468672. DOI: 10.1128/AAC.00166-15. View

19.

Xie L, Wu J, Zhang F, Han L, Guo X, Ni Y . Molecular Epidemiology and Genetic Characteristics of Various blaPER Genes in Shanghai, China. Antimicrob Agents Chemother. 2016; 60(6):3849-53. PMC: 4879356. DOI: 10.1128/AAC.00258-16. View

20.

Babouee Flury B, Bosch A, Gisler V, Egli A, Seiffert S, Nolte O . Multifactorial resistance mechanisms associated with resistance to ceftazidime-avibactam in clinical isolates from Switzerland. Front Cell Infect Microbiol. 2023; 13:1098944. PMC: 10166991. DOI: 10.3389/fcimb.2023.1098944. View