Differences in Fosfomycin Resistance Mechanisms between Pseudomonas aeruginosa and Enterobacterales

Dina Zheng, Phillip J. Bergen, Cornelia B. Landersdorfer, Elizabeth B. Hirsch

Research output: Contribution to journalReview articlepeer-review

9 Scopus citations


Multidrug-resistant (MDR) Pseudomonas aeruginosa presents a serious threat to public health due to its widespread resistance to numerous antibiotics. P. aeruginosa commonly causes nosocomial infections including urinary tract infections (UTI) which have become increasingly difficult to treat. The lack of effective therapeutic agents has renewed interest in fosfomycin, an old drug discovered in the 1960s and approved prior to the rigorous standards now required for drug approval. Fosfomycin has a unique structure and mechanism of action, making it a favorable therapeutic alternative for MDR pathogens that are resistant to other classes of antibiotics. The absence of susceptibility breakpoints for fosfomycin against P. aeruginosa limits its clinical use and interpretation due to extrapolation of breakpoints established for Escherichia coli or Enterobacterales without supporting evidence. Furthermore, fosfomycin use and efficacy for treatment of P. aeruginosa are also limited by both inherent and acquired resistance mechanisms. This narrative review provides an update on currently identified mechanisms of resistance to fosfomycin, with a focus on those mediated by P. aeruginosa such as peptidoglycan recycling enzymes, chromosomal Fos enzymes, and transporter mutation. Additional fosfomycin resistance mechanisms exhibited by Enterobacterales, including mutations in transporters and associated regulators, plasmid- mediated Fos enzymes, kinases, and murA modification, are also summarized and contrasted. These data highlight that different fosfomycin resistance mechanisms may be associated with elevated MIC values in P. aeruginosa compared to Enterobacterales, emphasizing that extrapolation of E. coli breakpoints to P. aeruginosa should be avoided.

Original languageEnglish (US)
Article numbere01446-21
JournalAntimicrobial agents and chemotherapy
Issue number2
StatePublished - Feb 2022

Bibliographical note

Funding Information:
Address correspondence to Elizabeth B. Hirsch, ebhirsch@umn.edu. The authors declare a conflict of interest. EBH has received grant funding from Merck and advisory board honoraria from Merck, MeMed, and Melinta. All others declare no potential conflicts of interest. Accepted manuscript posted online 22 November 2021 Published

Publisher Copyright:
© 2022 American Society for Microbiology.


  • Enterobacterales
  • Escherichia coli
  • Fosfomycin resistance
  • Pseudomonas aeruginosa

PubMed: MeSH publication types

  • Journal Article
  • Review


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