Resistance to fosfomycin: Mechanisms, Frequency and Clinical Consequences

•Fosfomycin has re-emerged as a useful antibiotic in the context of increasing antibiotic resistance.•Fosfomycin resistance currently seems low-to-moderate.•Fosfomycin is a potential therapeutic option, particularly in combination with other antibiotics.•Fosfomycin may be particularly useful for pat...

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Bibliographic Details
Published in:International journal of antimicrobial agents 2019-01, Vol.53 (1), p.22-28
Main Authors: Falagas, Matthew E., Athanasaki, Florentia, Voulgaris, Georgios L., Triarides, Nikolaos A., Vardakas, Konstantinos Z.
Format: Article
Language:English
Subjects:
Acinetobacter
Enterococcus
Escherichia coli
Fosfomycin resistance
Klebsiella
Staphylococcus
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Summary:•Fosfomycin has re-emerged as a useful antibiotic in the context of increasing antibiotic resistance.•Fosfomycin resistance currently seems low-to-moderate.•Fosfomycin is a potential therapeutic option, particularly in combination with other antibiotics.•Fosfomycin may be particularly useful for patients with multidrug-resistant bacterial infections. Fosfomycin has been used for the treatment of infections due to susceptible and multidrug-resistant (MDR) bacteria. It inhibits bacterial cell wall synthesis through a unique mechanism of action at a step prior to that inhibited by β-lactams. Fosfomycin enters the bacterium through membrane channels/transporters and inhibits MurA, which initiates peptidoglycan (PG) biosynthesis of the bacterial cell wall. Several bacteria display inherent resistance to fosfomycin mainly through MurA mutations. Acquired resistance involves, in order of decreasing frequency, modifications of membrane transporters that prevent fosfomycin from entering the bacterial cell, acquisition of plasmid-encoded genes that inactivate fosfomycin, and MurA mutations. Fosfomycin resistance develops readily in vitro but less so in vivo. Mutation frequency is higher among Pseudomonas aeruginosa and Klebsiella spp. compared with Escherichia coli and is associated with fosfomycin concentration. Mutations in cAMP regulators, fosfomycin transporters and MurA seem to be associated with higher biological cost in Enterobacteriaceae but not in Pseudomonas spp. The contribution of fosfomycin inactivating enzymes in emergence and spread of fosfomycin resistance currently seems low-to-moderate, but their presence in transferable plasmids may potentially provide the best means for the spread of fosfomycin resistance in the future. Their co-existence with genes conferring resistance to other antibiotic classes may increase the emergence of MDR strains. Although susceptibility rates vary, rates seem to increase in settings with higher fosfomycin use and among multidrug-resistant pathogens.
ISSN:0924-8579
1872-7913
DOI:10.1016/j.ijantimicag.2018.09.013