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Cefiderocol resistance genomics in sequential chronic Pseudomonas aeruginosa isolates from cystic fibrosis patients

Carla López-Causapé¹, Ainhize Maruri-Aransolo², María A Gomis-Font¹

¹Servicio de Microbiología, Hospital Universitario Son Espases-IdISBa, Palma de Mallorca, Spain; CIBER Enfermedades Infecciosas (CIBERINFEC), Madrid, Spain.

Clinical Microbiology and Infection : the Official Publication of the European Society of Clinical Microbiology and Infectious Diseases

|November 26, 2022

Abstract

Objective:

To evaluate the activity of cefiderocol against sequential P. aeruginosa isolates from chronically-infected cystic fibrosis patients as well as to investigate the potential mechanisms involved in resistance through whole genome sequencing.

Methods:

Three sequential P. aeruginosa isolates from each of 50 chronically-colonized cystic fibrosis patients were studied. MICs for novel and classical antipseudomonal agents were determined by broth microdilution and whole genome sequences (n = 150) were obtained to investigate the presence of mutations within a set of chromosomal genes involved in P. aeruginosa antibiotic resistance (n = 40) and iron uptake (n = 120).

Results:

Cefiderocol showed the lowest MIC_50/90 values and its susceptibility rate was comparable to other novel antipseudomonal agents. Clinical resistance was documented in 9 isolates from 6 patients. Resistance genes associated with a statistically significant increase in cefiderocol MICs included ampC, pmrAB, galU, fusA1 and those coding the penicillin-binding proteins PBP2 and PBP3. Likewise, mutations within several genes participating in different iron-uptake systems were found to be significantly associated with resistance, including genes participating in the pyochelin and pyoverdin biosynthesis and several tonB-dependent receptors. Mutator and small colony variants isolates were also associated with increased cefiderocol MICs.

Discussion:

Cefiderocol resistance is modulated by a complex mutational resistome, potentially conferring cross-resistance to novel beta-lactam beta-lactamase combinations, as well as an extended list of mutated iron-uptake genes. Monitoring the acquisition of mutations in all these genes will be helpful to guide treatments and mitigate the emergence and spread of resistance to this novel antibiotic.

Insights

Cefiderocol remains effective against Pseudomonas aeruginosa in cystic fibrosis patients, but resistance can emerge due to mutations in specific genes. Monitoring these genetic changes is key to preserving antibiotic efficacy.

Area of Science:

Medical Microbiology
Genomics
Infectious Diseases

Background:

Chronic Pseudomonas aeruginosa infections are a major challenge in cystic fibrosis (CF) patients.
Antibiotic resistance in P. aeruginosa necessitates the evaluation of novel therapeutic agents.

Purpose of the Study:

To assess cefiderocol activity against sequential P. aeruginosa isolates from CF patients.
To identify genetic mechanisms contributing to cefiderocol resistance through whole genome sequencing.

Main Methods:

Studied 150 sequential P. aeruginosa isolates from 50 chronically infected CF patients.
Determined Minimum Inhibitory Concentrations (MICs) using broth microdilution.
Performed whole genome sequencing to identify mutations in antibiotic resistance and iron uptake genes.

Main Results:

Cefiderocol demonstrated low MIC50/90 values, with susceptibility comparable to other novel agents.
Resistance was observed in 9 isolates (6 patients), associated with mutations in ampC, pmrAB, galU, fusA1, PBP2, and PBP3.
Mutations in iron uptake genes (pyochelin, pyoverdin biosynthesis, tonB-dependent receptors) and small colony variants were linked to increased cefiderocol MICs.

Conclusions:

Cefiderocol resistance is complex, involving a resistome that may confer cross-resistance to other antibiotics.
Mutations in iron uptake systems significantly contribute to cefiderocol resistance.
Monitoring these genetic mutations is crucial for guiding treatment and preventing resistance spread.

Read full analysis

Keywords:

Cefiderocol resistance Iron-uptake Mutational resistome P. aeruginosa Siderophore

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