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Abstract

Purpose. With an increase in the numbers of bacterial isolates resistant to first-line antibiotics, there has been a revival in the use of older drugs including fosfomycin with novel mechanisms of action. We aimed to investigate the prevalence and genotypic nature of fosfomycin resistance in Escherichia coli from urinary tract infections (UTIs) using the various methods available in the clinical microbiology laboratory.

Methodology. In total, 1000 culture-positive urine samples were assessed for the presence of E. coli and fosfomycin susceptibility was determined using the MAST Uri system, microbroth dilution, agar dilution and E-test strips.

Results/Key findings. Initial investigation using breakpoint susceptibility testing on the MAST Uri system identified 62 of 657 (9.5 %) E. coli isolates as fosfomycin-resistant (MIC≥32 µg ml). However, on further testing, a lower rate of eight of the 62 (1.3 %) were robustly confirmed to be resistant using microbroth dilution, agar dilution and E-test strips. These true resistant isolates belonged to diverse E. coli multi-locus sequence types and each had a unique set of chromosomal alterations in genes associated with fosfomycin resistance. Fosfomycin-resistant isolates were not multiply drug resistant and did not carry plasmidic fosfomycin resistance genes. Therefore, the use of fosfomycin may be unlikely to drive selection of a particular clone or movement of transferrable resistance genes.

Conclusion. Fosfomycin remains a viable option for the treatment of E. coli in uncomplicated UTIs; different susceptibility testing platforms can give very different results regarding the prevalence of fosfomycin resistance, with false positives being a potential problem that may unnecessarily limit the use of this agent.

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2018-12-13
2024-04-19
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References

  1. Livermore DM. Has the era of untreatable infections arrived?. J Antimicrob Chemother 2009; 64:i29–i36 [View Article][PubMed]
    [Google Scholar]
  2. Falagas ME, Grammatikos AP, Michalopoulos A. Potential of old-generation antibiotics to address current need for new antibiotics. Expert Review of Anti-infective Therapy 2008; 6:593–600 [View Article]
    [Google Scholar]
  3. Michalopoulos AS, Livaditis IG, Gougoutas V. The revival of fosfomycin. International J of Dis 2011; 15:e732e739 [View Article]
    [Google Scholar]
  4. Kahan FM, Kahan JS, Cassidy PJ, Kropp H. The mechanism of action of fosfomycin (phosphonomycin). Ann N Y Acad Sci 1974; 235:364–386[PubMed]
    [Google Scholar]
  5. Alper MD, Ames BN. Transport of antibiotics and metabolite analogs by systems under cyclic AMP control: positive selection of Salmonella typhimurium cya and crp mutants. J Bacteriol 1978; 133:149–157[PubMed]
    [Google Scholar]
  6. Larson TJ, Ye SZ, Weissenborn DL, Hoffmann HJ, Schweizer H. Purification and characterization of the repressor for the sn-glycerol 3-phosphate regulon of Escherichia coli K12. J Biol Chem 1987; 262:15869–15874[PubMed]
    [Google Scholar]
  7. Sonna LA, Ambudkar SV, Maloney PC. The mechanism of glucose 6-phosphate transport by Escherichia coli . J Biol Chem 1988; 263:6625–6630
    [Google Scholar]
  8. Brown ED, Vivas EI, Walsh CT, Kolter R. MurA (MurZ), the enzyme that catalyzes the first committed step in peptidoglycan biosynthesis, is essential in Escherichia coli . J Bacteriol 1995; 177:4194–4197 [View Article][PubMed]
    [Google Scholar]
  9. Falagas ME, Kastoris AC, Kapaskelis AM, Karageorgopoulos DE. Fosfomycin for the treatment of multidrug-resistant, including extended-spectrum beta-lactamase producing, Enterobacteriaceae infections: a systematic review. Lancet Infect Dis 2010; 10:43–50 [View Article][PubMed]
    [Google Scholar]
  10. Castañeda-García A, Blázquez J, Rodríguez-Rojas A. Molecular mechanisms and clinical impact of acquired and intrinsic fosfomycin resistance. Antibiotics 2013; 2:217–236 [View Article][PubMed]
    [Google Scholar]
  11. Cordaro JC, Melton T, Stratis JP, Atagün M, Gladding C et al. Fosfomycin resistance: selection method for internal and extended deletions of the phosphoenolpyruvate:sugar phosphotransferase genes of Salmonella typhimurium. J Bacteriol 1976; 128:785–793
    [Google Scholar]
  12. Kim DH, Lees WJ, Kempsell KE, Lane WS, Duncan K et al. Characterization of a Cys115 to Asp substitution in the Escherichia coli cell wall biosynthetic enzyme UDP-GlcNAc enolpyruvyl transferase (MurA) that confers resistance to inactivation by the antibiotic fosfomycin. Biochemistry 1996; 35:4923–4928 [View Article][PubMed]
    [Google Scholar]
  13. Venkateswaran PS, Wu HC. Isolation and characterization of a phosphonomycin-resistant mutant of Escherichia coli K-12. J Bacteriol 1972; 110:935–944[PubMed]
    [Google Scholar]
  14. Takahata S, Ida T, Hiraishi T, Sakakibara S, Maebashi K et al. Molecular mechanisms of fosfomycin resistance in clinical isolates of Escherichia coli . Int J Antimicrob Agents 2010; 35:333–337 [View Article][PubMed]
    [Google Scholar]
  15. Horii T, Kimura T, Sato K, Shibayama K, Ohta M. Emergence of fosfomycin-resistant isolates of Shiga-like toxin-producing Escherichia coli O26. Antimicrob Agents Chemother 1999; 43:789–793 [View Article][PubMed]
    [Google Scholar]
  16. Couce A, Briales A, Rodríguez-Rojas A, Costas C, Pascual A et al. Genomewide overexpression screen for fosfomycin resistance in Escherichia coli: MurA confers clinical resistance at low fitness cost. Antimicrob Agents Chemother 2012; 56:2767–2769 [View Article][PubMed]
    [Google Scholar]
  17. Fillgrove KL, Pakhomova S, Newcomer ME, Armstrong RN. Mechanistic diversity of fosfomycin resistance in pathogenic microorganisms. J Am Chem Soc 2003; 125:15730–15731 [View Article][PubMed]
    [Google Scholar]
  18. Mendes AC, Rodrigues C, Pires J, Amorim J, Ramos MH et al. Importation of Fosfomycin Resistance fosA3 Gene to Europe. Emerg Infect Dis 2016; 22:346–348 [View Article][PubMed]
    [Google Scholar]
  19. Rigsby RE, Fillgrove KL, Beihoffer LA, Armstrong RN. Fosfomycin resistance proteins: A nexus of glutathione transferases and epoxide hydrolases in a metalloenzyme superfamily. In Sies H, Packer L. (editors) Gluthione Transferases and Gamma-Glutamyl Transpeptidases vol.401 San Diego: Elsevier Academic Press Inc; 2005 pp. 367–379
    [Google Scholar]
  20. Nilsson AI, Berg OG, Aspevall O, Kahlmeter G, Andersson DI. Biological costs and mechanisms of fosfomycin resistance in Escherichia coli . Antimicrob Agents Chemother 2003; 47:2850–2858 [View Article][PubMed]
    [Google Scholar]
  21. Tsuruoka T, Yamada Y. Charactertization of spontaneous fosfomycin (phosphonomycin)-resistant cells of Escherichia coli B in vitro . J Antibiot 1975; 28:906–911 [View Article][PubMed]
    [Google Scholar]
  22. Schito GC. Why fosfomycin trometamol as first line therapy for uncomplicated UTI?. Int J Antimicrob Agents 2003; 22:Suppl 279–83 [View Article][PubMed]
    [Google Scholar]
  23. Popovic M, Steinort D, Pillai S, Joukhadar C. Fosfomycin: an old, new friend? . Eur J Clin Microbiol Infect Dis 2010; 29:127–142 [View Article][PubMed]
    [Google Scholar]
  24. Patel SS, Balfour JA, Bryson HM. Fosfomycin tromethamine. A review of its antibacterial activity, pharmacokinetic properties and therapeutic efficacy as a single-dose oral treatment for acute uncomplicated lower urinary tract infections. Drugs 1997; 53:637–656 [View Article][PubMed]
    [Google Scholar]
  25. Hhasci C. Prescription cost analyis England 2012/2013, health and social care information centre; 2013/2014; V1.0
  26. Andrews JM. Determination of minimum inhibitory concentrations. J Antimicrob Chemother 2001; 48:5–16 [View Article]
    [Google Scholar]
  27. Zerbino DR. Using the Velvet de novo assembler for short-read sequencing technologies. Curr Protoc Bioinformatics 2010; Chapter 11:Unit 11.5 Andreas D Baxevanis [et al] [View Article][PubMed]
    [Google Scholar]
  28. Seemann T. Prokka: rapid prokaryotic genome annotation. Bioinformatics 2014; 30:2068–2069 [View Article][PubMed]
    [Google Scholar]
  29. Mcarthur AG, Waglechner N, Nizam F, Yan A, Azad MA et al. The comprehensive antibiotic resistance database. Antimicrob Agents Chemother 2013; 57:3348–3357 [View Article][PubMed]
    [Google Scholar]
  30. EUCAST Breakpoint tables for the interpretation ofMICs and zone diameters, Version 6.0; 2016 http://www.eucast.org/
  31. Pasteran F, Lucero C, Rapoport M, Guerriero L, Barreiro I et al. Tigecycline and intravenous fosfomycin zone breakpoints equivalent to the EUCAST MIC criteria for Enterobacteriaceae. J Infect Dev Ctries 2012; 6:452–456 [View Article][PubMed]
    [Google Scholar]
  32. Doumith M, Day M, Ciesielczuk H, Hope R, Underwood A et al. Rapid identification of major Escherichia coli sequence types causing urinary tract and bloodstream infections. J Clin Microbiol 2015; 53:160–166 [View Article][PubMed]
    [Google Scholar]
  33. Kahlmeter G. ECO.SENS An international survey of the antimicrobial susceptibility of pathogens from uncomplicated urinary tract infections: the ECO.SENS Project . J Antimicrob Chemother 2003; 51:69–76 [View Article][PubMed]
    [Google Scholar]
  34. Falagas ME, Maraki S, Karageorgopoulos DE, Kastoris AC, Mavromanolakis E et al. Antimicrobial susceptibility of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Enterobacteriaceae isolates to fosfomycin. Int J Antimicrob Agents 2010; 35:240–243 [View Article][PubMed]
    [Google Scholar]
  35. Maraki S, Samonis G, Rafailidis PI, Vouloumanou EK, Mavromanolakis E et al. Susceptibility of urinary tract bacteria to fosfomycin. Antimicrob Agents Chemother 2009; 53:4508–4510 [View Article][PubMed]
    [Google Scholar]
  36. Clinical and Laboratory Standards Institute M100-S23 Performance Standards for Antimicrobial susceptibility testing; twenty-third information supplement; 2013 http://reflab.yums.ac.ir/uploads/clsi_m100-s23-2013.pdf
  37. Chin TL, Macgowan AP, Bowker KE, Elder F, Beck CR et al. Prevalence of antibiotic resistance in Escherichia coli isolated from urine samples routinely referred by general practitioners in a large urban centre in south-west England. J Antimicrob Chemother 2015; 70:2167–2169 [View Article][PubMed]
    [Google Scholar]
  38. Chislett RJ, White G, Hills T, Turner DP. Fosfomycin susceptibility among extended-spectrum-beta-lactamase-producing Escherichia coli in Nottingham, UK. J Antimicrob Chemother 2010; 65:1076–1077 [View Article][PubMed]
    [Google Scholar]
  39. Lu CL, Liu CY, Huang YT, Liao CH, Teng LJ et al. Antimicrobial susceptibilities of commonly encountered bacterial isolates to fosfomycin determined by agar dilution and disk diffusion methods. Antimicrob Agents Chemother 2011; 55:4295–4301 [View Article][PubMed]
    [Google Scholar]
  40. Li Y, Zheng B, Li Y, Zhu S, Xue F et al. Antimicrobial susceptibility and molecular mechanisms of fosfomycin resistance in clinical Escherichia coli isolates in Mainland China. PLoS One 2015; 10: 7:e0135269 [View Article][PubMed]
    [Google Scholar]
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