Cefiderocol Heteroresistance Associated With Mutations in TonB-Dependent Receptor Genes in Pseudomonas aeruginosa of Clinical Origin

Authors

Stephanie L Egge
Samie A Rizvi
Shelby R Simar
Manuel Alcalde
Jose R W Martinez
Blake M Hanson
An Q Dinh
Rodrigo P Baptista
Truc T Tran
Samuel A Shelburne
Jose M Munita
Cesar A Arias
Morgan Hakki
William R Miller

Publication Date

8-7-2024

Journal

Antimicrobial Agents and Chemotherapy

Abstract

The siderophore-cephalosporin cefiderocol (FDC) presents a promising treatment option for carbapenem-resistant (CR) P. aeruginosa (PA). FDC circumvents traditional porin and efflux-mediated resistance by utilizing TonB-dependent receptors (TBDRs) to access the periplasmic space. Emerging FDC resistance has been associated with loss of function mutations within TBDR genes or the regulatory genes controlling TBDR expression. Further, difficulties with antimicrobial susceptibility testing (AST) and unexpected negative clinical treatment outcomes have prompted concerns for heteroresistance, where a single lineage isolate contains resistant subpopulations not detectable by standard AST. This study aimed to evaluate the prevalence of TBDR mutations among clinical isolates of P. aeruginosa and the phenotypic effect on FDC susceptibility and heteroresistance. We evaluated the sequence of pirR, pirS, pirA, piuA, or piuD from 498 unique isolates collected before the introduction of FDC from four clinical sites in Portland, OR (1), Houston, TX (2), and Santiago, Chile (1). At some clinical sites, TBDR mutations were seen in up to 25% of isolates, and insertion, deletion, or frameshift mutations were predicted to impair protein function were seen in 3% of all isolates (n = 15). Using population analysis profile testing, we found that P. aeruginosa with major TBDR mutations were enriched for a heteroresistant phenotype and undergo a shift in the susceptibility distribution of the population as compared to susceptible strains with wild-type TBDR genes. Our results indicate that mutations in TBDR genes predate the clinical introduction of FDC, and these mutations may predispose to the emergence of FDC resistance.

Keywords

Gram-negative resistance, Pseudomonas aeurginosa, TonB-dependent receptor, beta-lactamases, cefiderocol, heteroresistance, multi-drug resistance

Comments

PMID: 38995033