ReviewResistance to fosfomycin: Mechanisms, Frequency and Clinical Consequences
Introduction
Fosfomycin was discovered in 1969 and is a low molecular mass (138 Da) derivative of a phosphoric acid isolated from cultures of Streptomyces spp. (Streptomyces fradiae, Streptomyces viridochromogenes, and Streptomyces wedomorensis) [1], [2], [3]. It is also produced in a biosynthetic process involving a unique combination of carbon and phosphorous [1], [3]. The structure of fosfomycin has two key features: an epoxide group, which is essential for its biological activity, and a phosphonic acid moiety.
Fosfomycin remains one of the first-line agents for the treatment of acute uncomplicated urinary tract infections (UTIs) mainly caused by Escherichia coli (+/- extended spectrum β-lactamase [ESBL]), Klebsiella spp., Proteus mirabilis, Staphylococcus saprophyticus, Enterococcus spp., and Streptococcus agalactiae [3], [4]. Intravenous fosfomycin is also approved in several European countries for the treatment of infections outside the urinary tract [4]. There is a global interest to further investigate fosfomycin as monotherapy and in combination with other antimicrobial agents for the treatment of serious systemic infections due to multidrug-resistant (MDR) Gram-negative bacteria [5], [6], [7], [8]. Hence, mechanisms of resistance, potential for development of resistance, frequency of resistant isolates, and possible clinical consequences are of major importance. These issues will be summarized in this review.
Section snippets
Mechanism of action
Fosfomycin invades the bacterium through two different membrane transportation systems: L-alpha glycerol-3-phosphate and the glucose-6-phosphate transporter (G6P) (GlpT and UhpT, respectively) [1]. The chemical structure of fosfomycin imitates both glycerol-3-phosphate and G6P, which are normally transferred trough GlpT and UhpT and induce their expression [8]. Cyclic adenosine monophosphate (cAMP) is also essential for the expression of the genes of both transportation systems [1].
The
Mechanisms of resistance
Fosfomycin remains active against a significant proportion of Gram-negative and Gram-positive bacteria. MDR pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococci (VRE), and ESBL- and carbapenemase-producing Enterobacteriaceae are also susceptible to fosfomycin [1], [11] (Table 1). However, several resistance mechanisms have been described. Specifically, mechanisms that constitute bacteria inherently resistant to fosfomycin have been
Frequency of fosfomycin resistance
Early in vitro reports indicated that fosfomycin exhibited considerable antimicrobial activity against Gram-negative and Gram-positive urinary isolates, including Enterobacteriaceae, staphylococci (including both methicillin-susceptible S. aureus [MSSA] and MRSA) and E. faecalis, but not against P. aeruginosa and Acinetobacter baumannii [47]. Reviews reported that fosfomycin exhibited cumulative susceptibility rates of 87.9% against MRSA and 87.2% against penicillin-non-susceptible pneumococcal
Factors influencing resistance mutation frequency
The frequency of mutations resulting in fosfomycin resistance in Gram-negative bacteria has been evaluated in several studies [21]. Mutants that are resistant to fosfomycin generally develop rapidly in vitro [24]. This occurs at higher frequency for strains of P. aeruginosa or K. pneumoniae compared with E. coli [57], [58]. In addition, fosfomycin-resistant mutants of E. coli strains appeared more frequently than rifampin-resistant mutants; similarly, fosfomycin-resistant mutants of P.
Clinical significance of fosfomycin resistance
Historically, mutations in nutrient transporters were the mechanisms of resistance most frequently observed in vitro; Table 2 shows this remains the most common mechanism of resistance in contemporary studies [19], [51], [68], [69], [70], [71], [72], [73], [74], [75]. Mutations in MurA gene and in ptsI and cyaA genes are relatively uncommon in clinical isolates. The importance of MurA in PG synthesis and of ptsI and cyaA in regulation of cAMP levels indicates that such mutations may be
Conclusion
Fosfomycin is an old antibiotic that is being reconsidered for the treatment of lower urinary tract and other systemic infections caused by Gram-positive and Gram-negative bacteria. Its re-emergence as an antibiotic of interest is due to the global increasing resistance of several bacteria to numerous antimicrobials. There are several mechanisms of resistance to fosfomycin; the contribution of fosfomycin susceptibility rates varies in an evolving environment. Each mechanism may provide
Funding
The review was conducted as part of our daily schedule.
Declarations
MEF participated in advisory boards of AstraZeneca, Infectopharm, Tetraphase, Shionogi, and Xellia; received lecture honoraria from Cipla, Merck, and Pfizer; and received research support from Shionogi, Tetraphase, Helperby and Xellia. The other authors have no conflicts of interest.
Conflict of interest
None
Ethical approval
None
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