Ceftolozane/tazobactam Heteroresistance in Cystic Fibrosis-related Infections

Overview

Journal JAC Antimicrob Resist

Publisher Oxford University Press

Specialty Infectious Diseases

Date 2023 Jul 13

PMID 37441352

Authors

Marguerite L Monogue

James M Sanders

Christine A Pybus

Jiwoong Kim

Xiaowei Zhan

Andrew E Clark

David E Greenberg

Affiliations

Soon will be listed here.

Abstract

Objectives: Cystic fibrosis (CF) patients are often colonized with . During treatment, can develop subpopulations exhibiting variable antimicrobial (ABX) susceptibility patterns. Heteroresistance (HR) may underlie reported discrepancies between susceptibility results and clinical responses to various ABXs. Here, we sought to examine the presence and nature of polyclonal HR (PHR) and monoclonal HR (MHR) to ceftolozane/tazobactam in isolates originating from CF pulmonary exacerbations.

Methods: This was a single-centre, non-controlled study. Two hundred and forty-six isolates from 26 adult CF patients were included. PHR was defined as the presence of different ceftolozane/tazobactam minimum inhibitory concentration (MIC) values among isolates originating from a single patient specimen. Population analysis profiles (PAPs) were performed to assess the presence of MHR, defined as ≥4-fold change in the ceftolozane/tazobactam MIC from a single colony.

Results: Sixteen of 26 patient specimens (62%) contained PHR populations. Of these 16 patients, 6 (23%) had specimens in which PHR isolates exhibited ceftolozane/tazobactam MICs with categorical differences (i.e. susceptible versus resistant) compared to results reported as part of routine care. One isolate, PSA 1311, demonstrated MHR. Canonical ceftolozane/tazobactam resistance genes were not found in the MHR isolates (MHR PSA 1311 or PHR PSA 6130).

Conclusions: Ceftolozane/tazobactam PHR exists among isolates in this work, and approximately a quarter of these populations contained isolates with ceftolozane/tazobactam susceptibiilty interpretations different from what was reported clinically, supporting concerns surrounding the utility of traditional susceptibility testing methodology in the setting of CF specimens. Genome sequencing of isolates with acquired MHR to ceftolozane/tazobactam revealed variants of unknown significance. Future work will be centred on determining the significance of these mutations to better understand these data in clinical context.

References

Oikonomou O, Panopoulou M, Ikonomidis A . Investigation of carbapenem heteroresistance among different sequence types of Pseudomonas aeruginosa clinical isolates reveals further diversity. J Med Microbiol. 2011; 60(Pt 10):1556-1558. DOI: 10.1099/jmm.0.032276-0. View

Dewachter L, Fauvart M, Michiels J . Bacterial Heterogeneity and Antibiotic Survival: Understanding and Combatting Persistence and Heteroresistance. Mol Cell. 2019; 76(2):255-267. DOI: 10.1016/j.molcel.2019.09.028. View

Tian Y, Zhang Q, Wen L, Chen J . Combined effect of Polymyxin B and Tigecycline to overcome Heteroresistance in Carbapenem-Resistant Klebsiella pneumoniae. Microbiol Spectr. 2021; 9(2):e0015221. PMC: 8549724. DOI: 10.1128/Spectrum.00152-21. View

Nicoloff H, Hjort K, Levin B, Andersson D . The high prevalence of antibiotic heteroresistance in pathogenic bacteria is mainly caused by gene amplification. Nat Microbiol. 2019; 4(3):504-514. DOI: 10.1038/s41564-018-0342-0. View

He J, Jia X, Yang S, Xu X, Sun K, Li C . Heteroresistance to carbapenems in invasive Pseudomonas aeruginosa infections. Int J Antimicrob Agents. 2017; 51(3):413-421. DOI: 10.1016/j.ijantimicag.2017.10.014. View

Bankevich A, Nurk S, Antipov D, Gurevich A, Dvorkin M, Kulikov A . SPAdes: a new genome assembly algorithm and its applications to single-cell sequencing. J Comput Biol. 2012; 19(5):455-77. PMC: 3342519. DOI: 10.1089/cmb.2012.0021. View

Sader H, Castanheira M, Duncan L, Mendes R . Antimicrobial activities of ceftazidime/avibactam, ceftolozane/tazobactam, imipenem/relebactam, meropenem/vaborbactam, and comparators against Pseudomonas aeruginosa from patients with skin and soft tissue infections. Int J Infect Dis. 2021; 113:279-281. DOI: 10.1016/j.ijid.2021.10.022. View

Shelburne S, Kim J, Munita J, Sahasrabhojane P, Shields R, Press E . Whole-Genome Sequencing Accurately Identifies Resistance to Extended-Spectrum β-Lactams for Major Gram-Negative Bacterial Pathogens. Clin Infect Dis. 2017; 65(5):738-745. PMC: 5850535. DOI: 10.1093/cid/cix417. View

Li H, Durbin R . Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009; 25(14):1754-60. PMC: 2705234. DOI: 10.1093/bioinformatics/btp324. View

10.

Maxwell D, Kim J, Pybus C, White L, Medford R, Filkins L . Clinically undetected polyclonal heteroresistance among Pseudomonas aeruginosa isolated from cystic fibrosis respiratory specimens. J Antimicrob Chemother. 2022; 77(12):3321-3330. DOI: 10.1093/jac/dkac320. View

11.

Band V, Hufnagel D, Jaggavarapu S, Sherman E, Wozniak J, Satola S . Antibiotic combinations that exploit heteroresistance to multiple drugs effectively control infection. Nat Microbiol. 2019; 4(10):1627-1635. PMC: 7205309. DOI: 10.1038/s41564-019-0480-z. View

12.

Rees V, Lucas D, Lopez-Causape C, Huang Y, Kotsimbos T, Bulitta J . Characterization of Hypermutator Pseudomonas aeruginosa Isolates from Patients with Cystic Fibrosis in Australia. Antimicrob Agents Chemother. 2019; 63(4). PMC: 6437500. DOI: 10.1128/AAC.02538-18. View

13.

Kurtz S, Phillippy A, Delcher A, Smoot M, Shumway M, Antonescu C . Versatile and open software for comparing large genomes. Genome Biol. 2004; 5(2):R12. PMC: 395750. DOI: 10.1186/gb-2004-5-2-r12. View

14.

Howard-Anderson J, Davis M, Page A, Bower C, Smith G, Jacob J . Prevalence of colistin heteroresistance in carbapenem-resistant Pseudomonas aeruginosa and association with clinical outcomes in patients: an observational study. J Antimicrob Chemother. 2021; 77(3):793-798. PMC: 9097253. DOI: 10.1093/jac/dkab461. View

15.

Choby J, Ozturk T, Satola S, Jacob J, Weiss D . Widespread cefiderocol heteroresistance in carbapenem-resistant Gram-negative pathogens. Lancet Infect Dis. 2021; 21(5):597-598. PMC: 8175093. DOI: 10.1016/S1473-3099(21)00194-8. View

16.

Paradis E, Schliep K . ape 5.0: an environment for modern phylogenetics and evolutionary analyses in R. Bioinformatics. 2018; 35(3):526-528. DOI: 10.1093/bioinformatics/bty633. View

17.

Andersson D, Nicoloff H, Hjort K . Mechanisms and clinical relevance of bacterial heteroresistance. Nat Rev Microbiol. 2019; 17(8):479-496. DOI: 10.1038/s41579-019-0218-1. View

18.

El-Halfawy O, Valvano M . Antimicrobial heteroresistance: an emerging field in need of clarity. Clin Microbiol Rev. 2015; 28(1):191-207. PMC: 4284305. DOI: 10.1128/CMR.00058-14. View

19.

Yu G . Using ggtree to Visualize Data on Tree-Like Structures. Curr Protoc Bioinformatics. 2020; 69(1):e96. DOI: 10.1002/cpbi.96. View

20.

Juhasz E, Ivan M, Pinter E, Pongracz J, Kristof K . Colistin resistance among blood culture isolates at a tertiary care centre in Hungary. J Glob Antimicrob Resist. 2017; 11:167-170. DOI: 10.1016/j.jgar.2017.08.002. View