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Antibiotic resistance is a major public health concern that arises when bacteria evolve mechanisms to withstand the effects of antibiotic treatments. This resistance can be intrinsic, acquired through genetic mutations, or transferred between bacteria via horizontal gene transfer. The development of antibiotic resistance poses significant challenges in treating bacterial infections and necessitates ongoing research to develop new therapeutic strategies.Intrinsic resistance occurs when bacterial...
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Author Spotlight: Advancing Antibiotic Resistance Research Using an Efflux-Deficient Bacterial Strain and a Single-Copy Gene Expression System
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Acinetobacter baumannii and Cefiderocol, between Cidality and Adaptability.

Stefano Stracquadanio1, Carmelo Bonomo1, Andrea Marino2

  • 1Biomedical and Biotechnological Sciences Department, University of Cataniagrid.8158.4, Catania, Italy.

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|September 29, 2022
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Summary
This summary is machine-generated.

Acinetobacter baumannii exhibits heteroresistance to cefiderocol (FDC), a novel cephalosporin, with unstable subpopulations emerging after FDC exposure. Combination therapy may restore FDC activity against this challenging pathogen.

Keywords:
ASTAcinetobacter baumanniiBLIantimicrobial susceptibility testingcefiderocolheteroresistanceβ-lactamases inhibitors

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Area of Science:

  • Microbiology
  • Infectious Diseases
  • Pharmacology

Background:

  • Acinetobacter baumannii is a critical ESKAPE pathogen known for antibiotic resistance.
  • Cefiderocol (FDC) is a novel cephalosporin with activity against Gram-negative bacteria, including A. baumannii.
  • Therapeutic failures with FDC have been reported despite in vitro susceptibility.

Purpose of the Study:

  • To investigate the interactions between cefiderocol (FDC) and 10 Acinetobacter baumannii strains.
  • To understand the mechanisms of FDC resistance and adaptation in A. baumannii.
  • To evaluate the potential of combination therapy for treating FDC-resistant infections.

Main Methods:

  • Antimicrobial susceptibility testing (MIC, MBC) against FDC.
  • Phenotypic analysis of bacterial regrowth, colony morphology, and cell shape.
  • Genomic analysis to identify mutations in PBP3 and TonB3.
  • Evaluation of β-lactamase inhibitors in combination with FDC.

Main Results:

  • Diverse FDC susceptibility profiles were observed, with some strains showing resistance near EUCAST breakpoints.
  • Bacterial regrowth and morphological changes occurred after FDC exposure, indicating adaptation.
  • One strain developed a nonsusceptible phenotype, and heteroresistant subpopulations were found in 8/10 strains.
  • Mutations in PBP3 and TonB3 were common across all strains, irrespective of FDC susceptibility.
  • β-lactamase inhibitors restored FDC activity, suggesting a role for β-lactamase activity in FDC resistance.

Conclusions:

  • Acinetobacter baumannii can develop heteroresistance and instability to cefiderocol (FDC) through adaptive mechanisms.
  • Genomic alterations in PBP3 and TonB3 are associated with FDC resistance.
  • Combination therapy, including β-lactamase inhibitors, holds promise for overcoming FDC resistance in A. baumannii infections.