# Mechanisms of cefiderocol nonsusceptibility and resistance evolution in carbapenem-resistant pathogens

> **NIH NIH R01** · UNIV OF ARKANSAS FOR MED SCIS · 2024 · $728,695

## Abstract

PROJECT SUMMARY
The continuing emergence and rapid dissemination of antibiotic-resistant pathogens are becoming a major threat
to public health. Infections caused by carbapenem-resistant Enterobacterales and carbapenem-resistant
Acinetobacter, which are difficult to treat, were recognized as one of the urgent threats among patients in medical
facilities. Serious infections caused by antibiotic-resistant pathogens are associated with higher rates of morbidity
and mortality and contribute to significant economic costs. Cefiderocol, which received FDA approval in 2019, is
a novel siderophore-conjugated cephalosporin with expanded activity against carbapenem-resistant Gram-
negative pathogens including strains that produce serine carbapenemases and metallo-β-lactamases.
Cefiderocol-nonsusceptible isolates were reported in surveillance studies but the resistance mechanisms are
largely unknown on many occasions. Antimicrobial heteroresistance describes a phenomenon where
subpopulations of genetically homogeneous bacteria exhibit a range of susceptibilities to a particular antibiotic.
Heteroresistance has considerable clinical relevance because antibiotic treatment may select more resistant
populations. It is considered an important factor contributing to unexplained antibiotic treatment failure.
Heteroresistance has been reported in various bacterial species to many classes of antibiotics. However, there
is a lack of thorough research studying cefiderocol heteroresistance, the underlying mechanisms, and its clinical
relevance. The overall goal of the proposed project is to study preexisting cefiderocol resistance and
heteroresistance without prior cefiderocol exposure and the evolution of cefiderocol resistance after cefiderocol
exposure in vitro and in patients. In Aim 1, we will investigate preexisting cefiderocol resistance and
heteroresistance mechanisms in clinically isolated carbapenem-resistant Gram-negative pathogens. In Aim 2,
we will study in vitro and clinical evolution of cefiderocol resistance following cefiderocol exposure, and
characterize isolates with reduced cefiderocol susceptibility.

## Key facts

- **NIH application ID:** 10803156
- **Project number:** 1R01AI175440-01A1
- **Recipient organization:** UNIV OF ARKANSAS FOR MED SCIS
- **Principal Investigator:** En Huang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $728,695
- **Award type:** 1
- **Project period:** 2024-09-01 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10803156

## Citation

> US National Institutes of Health, RePORTER application 10803156, Mechanisms of cefiderocol nonsusceptibility and resistance evolution in carbapenem-resistant pathogens (1R01AI175440-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10803156. Licensed CC0.

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