Review
Resistance to fosfomycin: Mechanisms, Frequency and Clinical Consequences

https://doi.org/10.1016/j.ijantimicag.2018.09.013Get rights and content

Highlights

  • 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.

ABSTRACT

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.

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

References (86)

  • S. Pakhomova et al.

    Crystal structure of fosfomycin resistance kinase FomA from Streptomyces wedmorensis

    J Biol Chem

    (2008)
  • A.S. Michalopoulos et al.

    The revival of fosfomycin

    Int J Infect Dis

    (2011)
  • M.E. Falagas et al.

    Fosfomycin for the treatment of infections caused by multidrug-resistant non-fermenting Gram-negative bacilli: a systematic review of microbiological, animal and clinical studies

    Int J Antimicrob Agents

    (2009)
  • T. Demir et al.

    Fosfomycin: In vitro efficacy against multidrug-resistant isolates beyond urinary isolates

    J Glob Antimicrob Resist

    (2017)
  • R.A. Wijma et al.

    High interindividual variability in urinary fosfomycin concentrations in healthy female volunteers

    Clin Microbiol Infect

    (2018)
  • N. Roussos et al.

    Clinical significance of the pharmacokinetic and pharmacodynamic characteristics of fosfomycin for the treatment of patients with systemic infections

    Int J Antimicrob Agents

    (2009)
  • B.P. White et al.

    Mechanisms of fosfomycin resistance in carbapenem-resistant Enterobacter sp

    Int J Antimicrob Agents

    (2017)
  • W. Bi et al.

    Antimicrobial susceptibility and mechanisms of fosfomycin resistance in extended-spectrum beta-lactamase-producing Escherichia coli strains from urinary tract infections in Wenzhou, China

    Int J Antimicrob Agents

    (2017)
  • P.L. Lu et al.

    Characterisation of fosfomycin resistance mechanisms and molecular epidemiology in extended-spectrum beta-lactamase-producing Klebsiella pneumoniae isolates

    Int J Antimicrob Agents

    (2016)
  • Y. Jiang et al.

    Dissemination of a clone carrying a fosA3-harbouring plasmid mediates high fosfomycin resistance rate of KPC-producing Klebsiella pneumoniae in China

    Int J Antimicrob Agents

    (2015)
  • R.E. Rigsby et al.

    Fosfomycin resistance proteins: a nexus of glutathione transferases and epoxide hydrolases in a metalloenzyme superfamily

    Methods Enzymol

    (2005)
  • M.E. Falagas et al.

    Fosfomycin

    Clin Microbiol Rev

    (2016)
  • D. Hendlin et al.

    Phosphonomycin, a new antibiotic produced by strains of streptomyces

    Science

    (1969)
  • G.G. Zhanel et al.

    Fosfomycin: A first-line oral therapy for acute uncomplicated cystitis

    Can J Infect Dis Med Microbiol

    (2016)
  • M.E. Falagas et al.

    Fosfomycin: use beyond urinary tract and gastrointestinal infections

    Clin Infect Dis

    (2008)
  • D.C. Bensen et al.

    Structure of MurA (UDP-N-acetylglucosamine enolpyruvyl transferase) from Vibrio fischeri in complex with substrate UDP-N-acetylglucosamine and the drug fosfomycin

    Acta Crystallogr Sect F Struct Biol Cryst Commun

    (2012)
  • N.A. Carlone et al.

    Effect of fosfomycin trometamol on bacterial adhesion in comparison with other chemotherapeutic agents

    Eur Urol

    (1987)
  • S. Yokota et al.

    Fosfomycin suppresses RS-virus-induced Streptococcus pneumoniae and Haemophilus influenzae adhesion to respiratory epithelial cells via the platelet-activating factor receptor

    FEMS Microbiol Lett

    (2010)
  • A.J. McCoy et al.

    In vitro and in vivo functional activity of Chlamydia MurA, a UDP-N-acetylglucosamine enolpyruvyl transferase involved in peptidoglycan synthesis and fosfomycin resistance

    J Bacteriol

    (2003)
  • S. Kumar et al.

    Identification of a novel UDP-N-acetylglucosamine enolpyruvyl transferase (MurA) from Vibrio fischeri that confers high fosfomycin resistance in Escherichia coli

    Arch Microbiol

    (2009)
  • K.A. De Smet et al.

    Alteration of a single amino acid residue reverses fosfomycin resistance of recombinant MurA from Mycobacterium tuberculosis

    Microbiology

    (1999)
  • J. Gisin et al.

    A cell wall recycling shortcut that bypasses peptidoglycan de novo biosynthesis

    Nat Chem Biol

    (2013)
  • M. Borisova et al.

    Blocking peptidoglycan recycling in Pseudomonas aeruginosa attenuates intrinsic resistance to fosfomycin

    Microb Drug Resist

    (2014)
  • M. Scortti et al.

    Coexpression of virulence and fosfomycin susceptibility in Listeria: molecular basis of an antimicrobial in vitro-in vivo paradox

    Nat Med

    (2006)
  • X. Li et al.

    Abrp, a new gene, confers reduced susceptibility to tetracycline, glycylcine, chloramphenicol and fosfomycin classes in Acinetobacter baumannii

    Eur J Clin Microbiol Infect Dis

    (2016)
  • T. Tsuruoka et al.

    Two kinds of mutants defective in multiple carbohydrate utilization isolated from in vitro fosfomycin-resistant strains of Escherichia coli K–12

    J Antibiot (Tokyo)

    (1978)
  • D.E. Karageorgopoulos et al.

    Fosfomycin: evaluation of the published evidence on the emergence of antimicrobial resistance in Gram-negative pathogens

    J Antimicrob Chemother

    (2012)
  • A.I. Nilsson et al.

    Biological costs and mechanisms of fosfomycin resistance in Escherichia coli

    Antimicrob Agents Chemother

    (2003)
  • T. Tsuruoka et al.

    Characterization of spontaneous fosfomycin (phosphonomycin)-resistant cells of Escherichia coli B in vitro

    J Antibiot (Tokyo)

    (1975)
  • P.S. Venkateswaran et al.

    Isolation and characterization of a phosphonomycin-resistant mutant of Escherichia coli K-12

    J Bacteriol

    (1972)
  • A. Couce et al.

    Genomewide overexpression screen for fosfomycin resistance in Escherichia coli: MurA confers clinical resistance at low fitness cost

    Antimicrob Agents Chemother

    (2012)
  • P. Arca et al.

    Formation of an adduct between fosfomycin and glutathione: a new mechanism of antibiotic resistance in bacteria

    Antimicrob Agents Chemother

    (1988)
  • S. Pakhomova et al.

    Structure of fosfomycin resistance protein FosA from transposon Tn2921

    Protein Sci

    (2004)
  • Cited by (0)

    View full text