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Differences in Fosfomycin Resistance Mechanisms between Pseudomonas aeruginosa and Enterobacterales
Dina Zheng1, Phillip J Bergen2, Cornelia B Landersdorfer2
1University of Minnesota College of Pharmacy, Minneapolis, Minnesota, USA.
Abstract:
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.
Insights
Multidrug-resistant Pseudomonas aeruginosa poses a significant public health threat. Understanding fosfomycin resistance mechanisms in P. aeruginosa is crucial for effective treatment, as current breakpoints extrapolated from E. coli are unreliable.
Area of Science:
- Microbiology
- Infectious Diseases
- Pharmacology
Background:
- Multidrug-resistant (MDR) Pseudomonas aeruginosa is a major cause of difficult-to-treat nosocomial infections, such as urinary tract infections (UTIs).
- Fosfomycin, an older antibiotic with a unique mechanism of action, is being reconsidered for treating MDR pathogens.
- Clinical use of fosfomycin for P. aeruginosa is hindered by a lack of specific susceptibility breakpoints and understanding of resistance mechanisms.
Purpose of the Study:
- To review and update the identified mechanisms of fosfomycin resistance in P. aeruginosa.
- To contrast these mechanisms with those found in Enterobacterales.
- To emphasize the unsuitability of extrapolating susceptibility breakpoints from E. coli to P. aeruginosa.
Main Methods:
- Narrative review of current literature on fosfomycin resistance mechanisms.
- Focus on resistance mechanisms specific to P. aeruginosa, including peptidoglycan recycling enzymes, chromosomal Fos enzymes, and transporter mutations.
- Summary and comparison of resistance mechanisms in Enterobacterales, such as plasmid-mediated enzymes and murA modification.
Main Results:
- P. aeruginosa exhibits distinct fosfomycin resistance mechanisms, including alterations in peptidoglycan recycling and chromosomal Fos enzymes.
- Resistance mechanisms in Enterobacterales involve transporters, plasmid-mediated enzymes, and murA modifications.
- Fosfomycin resistance mechanisms can lead to different minimum inhibitory concentration (MIC) values in P. aeruginosa compared to Enterobacterales.
Conclusions:
- Fosfomycin resistance mechanisms in P. aeruginosa differ from those in Enterobacterales.
- Extrapolating susceptibility breakpoints from E. coli to P. aeruginosa is not supported by current evidence and should be avoided.
- Further research is needed to establish reliable clinical breakpoints for fosfomycin in P. aeruginosa infections.
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