Genomic analysis of Fosfomycin resistance in multi-drug resistant uropathogens and comparison of in-vitro susceptibility methods uropathogens
Abstract
Background and Objectives: Urinary tract infection is one of the most common bacterial infections causing high morbidity and mortality. The alarming rise of multidrug-resistant uropathogens worldwide forced the clinician to rethink the old drugs like Fosfomycin for its therapeutic management. Our objective was to compare agar dilution, disc diffusion and E-test method for antimicrobial susceptibility testing of Fosfomycin against different drug-resistant uropathogens.
Materials and Methods: Consecutive 181 uropathogens were tested for Fosfomycin susceptibility using agar dilution, disc diffusion and E-test. Results were interpreted using Clinical and Laboratory Standards Institute (CLSI) and European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints. Whole genome sequencing analysis was done on the 4 XDR/PDR Fosfomycin resistant Klebsiella pneumoniae isolates.
Results: Escherichia coli was found as the most common (62.4%) uropathogen followed by Klebsiella pneumoniae (21%). Considering agar dilution as the gold standard, 6.1% of isolates were resistant to Fosfomycin. Following CLSI breakpoints, the susceptibility of Escherichia coli, Klebsiella pneumoniae, other Enterobacterales and Pseudomonas aeruginosa were 92.9%, 92.1%, 100%, 100%; whereas using EUCAST breakpoints the susceptibility rates were 85.7%, 86.9%, 92.9%, and 100%, respectively. The essential agreement, categorical agreement, major error, and very major error for E-test/ disc diffusion for all the organisms were 91.2%/Not Applicable, 95%/93.9%, 1.8%/4.7%, 9.1%/9.1%, respectively. Whole-genome sequencing showed mutation UhpT gene as well as the presence of plasmid-mediated fosA5 or fosA6 genes conferring Fosfomycin resistance.
Conclusion: This result supports very low resistance of Enterobacterales against Fosfomycin; hence should be considered a valuable option to treat multidrug-resistant uropathogens. Disc diffusion was observed to be a convenient method for Fosfomycin susceptibility testing compared to agar dilution.
2. Foxman B. Epidemiology of urinary tract infections: incidence, morbidity, and economic costs. Am J Med 2002; 113 Suppl 1A: 5S-13S.
3. Griebling TL. Urologic diseases in America project: trends in resource use for urinary tract infections in men. J Urol 2005; 173: 1288-1294.
4. Foxman B. Urinary tract infection syndromes: occurrence, recurrence, bacteriology, risk factors, and disease burden. Infect Dis Clin North Am 2014; 28: 1-13.
5. Gupta K, Hooton TM, Naber KG, Wullt B, Colgan R, Miller LG, et al. International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis 2011; 52(5): e103-20.
6. Raz R. Fosfomycin: an old--new antibiotic. Clin Microbiol Infect 2012; 18: 4-7.
7. Perdigao-Neto LV, Oliveira MS, Rizek CF, Carrilho CM, Costa SF, Levin AS. Susceptibility of multiresistant gram-negative bacteria to fosfomycin and performance of different susceptibility testing methods. Antimicrob Agents Chemother 2014; 58: 1763-1767.
8. Mezzatesta ML, La Rosa G, Maugeri G, Zingali T, Caio C, Novelli A, et al. In vitro activity of fosfomycin trometamol and other oral antibiotics against multidrug-resistant uropathogens. Int J Antimicrob Agents 2017; 49: 763-766.
9. Falagas ME, Vouloumanou EK, Samonis G, Vardakas KZ. Fosfomycin. Clin Microbiol Rev 2016; 29: 321-347.
10. Demir T, Buyukguclu T. Fosfomycin: In vitro efficacy against multidrug-resistant isolates beyond urinary isolates. J Glob Antimicrob Resist 2017; 8: 164-168.
11. CLSI (2019). Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing: approved standard Wayne PA, USA.
12. EUCAST. The European Committee on Antimicrobial Susceptibility Testing.Breakpoint tables for interpretation of MICs and zone diameters. Version 9.0, 2019. https://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/Breakpoint_tables/v_9.0_Breakpoint_Tables.pdf
13. Magiorakos A-P, Srinivasan A, Carey RB, Carmeli Y, Falagas ME, Giske CG, et al. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect 2012; 18: 268-281.
14. CLSI (2008). Clinical and Laboratory Standards Institute. Development of in-vitro susceptibility testing criteria and quality control parameters; approved guideline third edition. Wayne PA, USA.
15. Behera B, Mohanty S, Sahu S, Praharaj AK. In vitro activity of fosfomycin against multidrug-resistant urinary and nonurinary Gram-negative isolates. Indian J Crit Care Med 2018; 22: 533-536.
16. Karageorgopoulos DE, Wang R, Yu X-H, Falagas ME. Fosfomycin: evaluation of the published evidence on the emergence of antimicrobial resistance in Gram-negative pathogens. J Antimicrob Chemother 2012; 67: 255-268.
17. Pasteran F, Lucero C, Rapoport M, Guerriero L, Barreiro I, Albornoz E, et al. Tigecycline and intravenous fosfomycin zone breakpoints equivalent to the EUCAST MIC criteria for Enterobacteriaceae. J Infect Dev Ctries 2012; 6: 452-456.
18. Ruiz Ramos J, Salavert Lleti M. Fosfomycin in infections caused by multidrug-resistant Gram-negative pathogens. Rev Esp Quimioter 2019; 32 Suppl 1 (Suppl 1): 45-54.
19. Jiang Y, Shen P, Wei Z, Liu L, He F, Shi K, 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; 45: 66-70.
20. Vardakas KZ, Legakis NJ, Triarides N, Falagas ME. Susceptibility of contemporary isolates to fosfomycin: a systematic review of the literature. Int J Antimicrob Agents 2016; 47: 269-285.
21. Smith EC, Brigman HV, Anderson JC, Emery CL, Bias TE, Bergen PJ, et al. Performance of four fosfomycin susceptibility testing methods against an international collection of clinical Pseudomonas aeruginosa isolates. J Clin Microbiol 2020; 58(10): e1121-1120.
22. Ramirez-Castillo FY, Moreno-Flores AC, Avelar-Gonzalez FJ, Marquez-Diaz F, Harel J, Guerrero-Barrera AL. An evaluation of multidrug-resistant Escherichia coli isolates in urinary tract infections from Aguascalientes, Mexico: cross-sectional study. Ann Clin Microbiol Antimicrob 2018; 17: 34.
23. Hirsch EB, Raux BR, Zucchi PC, Kim Y, McCoy C, Kirby JE, et al. Activity of fosfomycin and comparison of several susceptibility testing methods against contemporary urine isolates. Int J Antimicrob Agents 2015; 46: 642-647.
24. Butcu M, Akcay SS, Inan AS, Aksaray S, Engin DO, Calisici G. In vitro susceptibility of enterococci strains isolated from urine samples to fosfomycin and other antibiotics. J Infect Chemother 2011; 17: 575-578.
25. Lepuschitz S, Schill S, Stoeger A, Pekard-Amenitsch S, Huhulescu S, Inreiter N, et al. Whole genome sequencing reveals resemblance between ESBL-producing and carbapenem resistant Klebsiella pneumoniae isolates from Austrian rivers and clinical isolates from hospitals. Sci Total Environ 2019; 662: 227-235.
26. Surleac M, Czobor Barbu I, Paraschiv S, Popa LI, Gheorghe I, Marutescu L, et al. Whole genome sequencing snapshot of multi-drug resistant Klebsiella pneumoniae strains from hospitals and receiving wastewater treatment plants in Southern Romania. PLoS One 2020; 15(1): e0228079.
27. Huang L, Hu YY, Zhang R. Prevalence of fosfomycin resistance and plasmid-mediated fosfomycin-modifying enzymes among carbapenem-resistant Enterobacteriaceae in Zhejiang, China. J Med Microbiol 2017; 66: 1332-1334.
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Issue | Vol 14 No 5 (2022) | |
Section | Original Article(s) | |
DOI | https://doi.org/10.18502/ijm.v14i5.10956 | |
Keywords | ||
Fosfomycin; Agar dilution; Disc diffusion; E-test; Enterobacterales |
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