Associated resistance of Escherichia coli isolated from humans and animals to polymyxin and beta-lactam antibiotics

Escherichia coli isolates from various sources from 2018 to 2019 were included in the study. Mcr-1 genes were found in two of 105 animal strains (2%) and seven of 928 human strains (0.8%). All mcr-1-positive strains showed a low level of resistance to colistin (MIC ranged from 4 to 8 µg/ml). Both strains isolated from animals remained sensitive to betalactam antibiotics and did not contain beta-lactamase genes. Beta-lactamases were absent only in one of the strains isolated from humans. Four strains were resistant to cephalosporins with sensitivity to carbapenems and carried class A (blaCTX-M-15 or blaCTX-M-1) or class C (blaCMY-2) extended-spectrum beta-lactamases genes. One strain showed resistance to cephalosporins and meropenem and contained four beta-lactamase genes: blaNDM-1, blaCTX-M-15, blaTEM-1B, and blaCMY-6. Only one strain isolated from animals remained sensitive to ciprofloxacin, the rest showed high level of resistance, had amino acid substitutions in the DNA gyrase genes or mutations leading to overexpression of the mdfA gene. In terms of resistance to aminoglycosides, the strains varied widely and carried up to four aminoglycoside-modifying enzyme genes. One strain isolated from humans showed resistance to tigecycline, but no genes conferring resistance to this antibiotic were found. The data obtained substantiate the need for extended studies on the molecular epidemiology of associated resistance to polymyxins and beta-lactams.

1. Gregoire N., Aranzana-Climent V., Magréault S. et al. Clinical pharmacokinetics and pharmacodynamics of colistin. Clin Pharmacokinet. 2017; 56 (12): 1441–1460. doi: 10.1007/s40262-017-0561-1.

2. Nation R.L., Velkov T., Li J. Colistin and polymyxin B: peas in a pod, or chalk and cheese? Clin Infect Dis. 2014. 59 (1): 88–94. doi: 10.1093/cid/ciu213. Epub 2014 Apr 3.

3. Lee J.Y., Park Y.K., Chung E.S. et al. Evolved resistance to colistin and its loss due to genetic reversion in Pseudomonas aeruginosa. Sci Rep. 2016; 6: 25543. doi: 10.1038/srep25543.

4. Lee J.Y., Park Y.K., Chung E.S. et al. Corrigendum: Evolved resistance to colistin and its loss due to genetic reversion in Pseudomonas aeruginosa. Sci Rep. 2016; 6: 30365. doi: 10.1038/srep30365.

5. Bialvaei A.Z., Kafil H.S. Colistin, mechanisms and prevalence of resistance. Curr Med Res Opin. 2015; 31 (4): 707–721. doi: 10.1185/03007995.2015.1018989. Epub 2015 Mar 19.

6. Falagas M.E., Kasiakou S.K. Colistin: the revival of polymyxins for the management of multidrug-resistant gram-negative bacterial infections. Clin Infect Dis. 2005; 40 (9): 1333–1341. doi: 10.1086/429323. Epub 2005 Mar 22.

7. Storm D.R., Rosenthal K.S., Swanson P.E. Polymyxin and related peptide antibiotics. Annu Rev Biochem. 1977; 46: 723–763. doi: 10.1146/ annurev.bi.46.070177.003451.

8. Poirel L., Jayol A., Nordmann P. Polymyxins: Antibacterial activity, susceptibility testing, and resistance mechanisms encoded by plasmids or chromosomes. Clin Microbiol Rev. 2017; 30 (2): 557–596. doi: 10.1128/CMR.00064-16.

9. Liu Y.Y., Wang Y., Walsh T.R. et al. Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study. Lancet Infect Dis. 2016. 16 (2): 161–168. doi: 10.1016/S1473-3099(15)00424-7. Epub 2015 Nov 19.

10. Poirel L., Kieffer N., Fernandez-Garayzabal J.F. et al. MCR-2-mediated plasmid-borne polymyxin resistance most likely originates from Moraxella pluranimalium. J Antimicrob Chemother. 2017; 72 (10): 2947–2949. doi: 10.1093/jac/dkx225.

11. Elbediwi M., Li Y., Paudyal N. et al. Global burden of colistin-resistant bacteria: mobilized colistin resistance genes study (1980–2018). Microorganisms. 2019; 7 (10): 461. doi: 10.3390/microorganisms7100461.

12. Xavier B.B., Lammens C., Ruhal R. et al. Identification of a novel plasmid-mediated colistin-resistance gene, mcr-2, in Escherichia coli, Belgium, June 2016. Euro Surveill. 2016; 21 (27). doi: 10.2807/1560-7917.ES.2016.21.27.30280.

13. Yin W. et al. Novel plasmid-mediated colistin resistance gene mcr-3 in Escherichia coli. mBio. 2017; 8 (3): e00543-17. doi: 10.1128/mBio.00543-17

14. Yin W., Li H., Shen Y. et al. Erratum for Yin et al. Novel plasmid-mediated colistin resistance gene mcr-3 in Escherichia coli. mBio. 2017; 8 (4): e01166-17. doi: 10.1128/mBio.01166-17.

15. Carattoli A., Villa L., Feudi C. et al. Novel plasmid-mediated colistin resistance mcr-4 gene in Salmonella and Escherichia coli, Italy 2013, Spain and Belgium, 2015 to 2016. Euro Surveill. 2017; 22 (31): 30589. doi: 10.2807/1560-7917.ES.2017.22.31.30589.

16. Borowiak M., Fisher J., Hammerl J.A. et al. Identification of a novel transposon-associated phosphoethanolamine transferase gene, mcr-5, conferring colistin resistance in d-tartrate fermenting Salmonella enterica subsp. enterica serovar Paratyphi B. J Antimicrob Chemother. 2017; 72 (12): 3317–3324. doi: 10.1093/jac/dkx327.

17. AbuOun M., Stubberfield E.J., Duggett N.A. et al. mcr-1 and mcr-2 (mcr-6.1) variant genes identified in Moraxella species isolated from pigs in Great Britain from 2014 to 2015. J Antimicrob Chemother. 2018; 73 (10): 2904. doi: 10.1093/jac/dky272.

18. Yang Y.Q., Li Y-X., Lei C-W. et al. Novel plasmid-mediated colistin resistance gene mcr-7.1 in Klebsiella pneumoniae. J Antimicrob Chemother. 2018; 73 (7): 1791-1795. doi: 10.1093/jac/dky111.

19. Wang X., Wang Y., Zhou Y. et al. Emergence of a novel mobile colistin resistance gene, mcr-8, in NDM-producing Klebsiella pneumoniae. Emerg Microbes Infect. 2018; 7 (1): 122. doi: 10.1038/s41426-018-0124-z.

20. Carroll L.M., Gaballa A., Guldimann C. et al. Identification of novel mobilized colistin resistance gene mcr-9 in a multidrug-resistant, colistinsusceptible Salmonella enterica serotype typhimurium isolate. mBio. 2019; 10 (3): e00853-19. doi: 10.1128/mBio.00853-19.

21. Shen Z., Wang Y., Shen Y. et al. Early emergence of mcr-1 in Escherichia coli from food-producing animals. The Lancet Infectious Diseases. 2016; 16 (3): 293. doi: 10.1016/S1473-3099(16)00061-X.

22. The European Committee on Antimicrobial Susceptibility Testing. Breakpoint tables for interpretation of MICs and zone diameters. Version 11.0, 2021. http://www.eucast.org

23. Liu X., Chan E.W.-C., Chen S. Transmission and stable inheritance of carbapenemase gene (blaKPC-2 or blaNDM-1)-encoding and mcr-1-encoding plasmids in c doi: 10.1016/j.jgar.2021.05.022. Epub 2021 Jul 7.linical Enterobacteriaceae strains. Journal of Global Antimicrobial Resistance, 2021; 26: 255–261.

24. Sun J., Zhang H., Liu Y-H. et al. Towards understanding MCR-like colistin resistance. Trends Microbiol. 2018; 26 (9): 794–808. doi: 10.1016j.tim.2018.02.006.

25. Meinersmann R.J., Ladely S.R., Plumblee J.R. et al. Prevalence of mcr-1 in the cecal contents of food animals in the United States. . Antimicrob. Agents Chemother. 2017; 61: e02244-16. doi: 10.1128/AAC.02244-16.

26. Irrgang A., Roschanski N., Tenhagen B-A. et al. Prevalence of mcr-1 in E.coli from livestock and food in Germany, 2010–2015. PLoS One. 2016; 11: e0159863. doi: 10.1371/journal.pone.0159863. eCollection 2016.

27. Shen C. et al. Dynamics of mcr-1 prevalence and mcr-1-positive Escherichia coli after the cessation of colistin use as a feed additive for animals in China: a prospective cross-sectional and whole genome sequencingbased molecular epidemiological study. Lancet Microbe. 2020; 1 (1): e34-e43.

28. Wang Y., Xu C., Zhang R. et al. Changes in colistin resistance and mcr-1 abundance in Escherichia coli of animal and human origins following the ban of colistin-positive additives in China: an epidemiological comparative study. Lancet Infect Dis. 2020; 20 (10): 1161–1171. doi:10.1016/S1473-3099(20)30149-3.

29. Usui M., Nozawa Y., Fukuda A. et al. Decreased colistin resistance and mcr-1 prevalence in pig-derived Escherichia coli in Japan after banning colistin as a feed additive. J Glob Antimicrob Resist. 2021; 24: 383-386. doi: 10.1016/j.jgar.2021.01.016. Epub 2021 Feb 3.

30. Ling, Z., yin W., Shen Z. et al. Epidemiology of mobile colistin resistance genes mcr-1 to mcr-9. J Antimicrob Chemother. 2020; 75 (11): 3087–3095. doi: 10.1093/jac/dkaa205.

31. Jiang B., Du P., Jia P. et al. Antimicrobial susceptibility and virulence of mcr-1-positive Enterobacteriaceae in China, a Multicenter Longitudinal Epidemiological Study. Front Microbiol. 2020; 11: 1611. doi: 10.3389/fmicb.2020.01611. eCollection 2020.

32. Wang Y., Tian G-B., Zhang R. et al. Prevalence, riskfactors, outcomes, and molecular epidemiologyof mcr-1-positive Enterobacteriaceae in patients and healthy adults from China: an epidemiological and clinical study. Lancet Infect.Dis. 2017; 17: 390–399. doi: 10.1016/S1473-3099(16)30527-8. Epub 2017 Jan 28.

33. Quan J., Li X., Chen Y. et al. Prevalenceof mcr-1 in Escherichia coli and Klebsiella pneumoniae recovered from bloodstream infections in China: a multicentre longitudinal study. Lancet Infect Dis. 2017; 17 (4): 400–410. doi: 10.1016/S1473-3099(16)30528-X. Epub 2017 Jan 28.

34. Zheng B., Xu H., Yu X. et al. Low prevalence of MCR-1-producing Klebsiella pneumoniae in bloodstream infections in China. Clin Microbiol Infect. 2018; 24: 205–206. doi: 10.1016/j.cmi.2017.08.004. Epub 2017 Aug 12.

35. Fan R., Li C., Duan R. et al. Retrospective screening and analysis of mcr-1 and blaNDM in gram-negative bacteria in China, 2010–2019. Front Microbiol. 2020; 11: 121. doi: 10.3389/fmicb.2020.00121. eCollection 2020.

36. Huang H., Dong N., Shu L. et al. Colistin-resistance gene mcr in clinical carbapenem-resistant Enterobacteriaceae strains in China, 2014–2019. Emerg Microbes Infect. 2020; 9 (1): 237–245. doi: 10.1080/22221751.2020.1717380.

37. Kim J.S., Yu J.K., Jeon S.J. et al. Distribution of mcr genes among carbapenem-resistant Enterobacterales clinical isolates: High prevalence of mcr-positive Enterobacter cloacae complex in Seoul, Republic of Korea. Int J Antimicrob Agents. 2021; 58 (5): 106418. doi: 10.1016/j.ijantimicag.2021.106418.

38. Malchione M.D., Torres L., Hartley D.M. et al. Carbapenem and colistin resistance in Enterobacteriaceae in Southeast Asia: Review and mapping of emerging and overlapping challenges. Int J Antimicrob Agents. 2019; 54 (4): 381–399. doi: 10.1016/j.ijantimicag.2019.07.019. Epub 2019 Jul 29.

39. Falgenhauer L., Waezsada S-E., Yao Y. et al. Colistin resistance gene mcr-1 in extended-spectrum β-lactamase-producing and carbapenemase-producing Gram-negative bacteria in Germany. The Lancet Infecti Dis. 2016; 16 (3): 282-283. doi: 10.1016/S1473-3099(16)00009-8.

40. Corbella M., Mariani B., Ferrari C. et al. Three cases of mcr-1-positive colistin-resistant Escherichia coli bloodstream infections in Italy, August 2016 to January 2017. Euro Surveill. 2017; 22: e30517. doi: 10.2807/1560-7917.ES.2017.22.16.30517.

41. Hasman H., Hammerum A.M., Hansen F. et al. Detection of mcr-1 encoding plasmid-mediated colistin-resistant Escherichia coli isolates from human bloodstream infection and imported chicken meat, Denmark 2015. Euro Surveill. 2015; 20 (49). doi: 10.2807/1560-7917.ES.2015.20.49.30085

42. Ageevets V., Lazareva I., Mrugova T. et al. IncX4 plasmids harbouring mcr-1 genes: Further dissemination. J Glob Antimicrob Resist. 2019; 18: 166–167. doi: 10.1016/j.jgar.2019.07.002.

43. Sulian O., Ageevets V., Lazareva I. et al. Co-production of MCR-1 and NDM-1 by Escherichia coli sequence type 31 isolated from a newborn in Moscow, Russia. Int J Infect Dis. 2020; 101: 4–5. doi: 10.1016/j.ijid.2020.09.1422. Epub 2020 Sep 24.

44. Tarabai H., Valcek A., Jamborova I. et al. Plasmid-mediated mcr-1 colistin resistance in Escherichia coli from a Black Kite in Russia. Antimicrob Agents Chemother. 2019; 63 (9): e01266-19. doi: 10.1128/AAC.01266-19.

45. Liakopoulos A., Mevius D.J., Olsen B. et al. The colistin resistance mcr-1 gene is going wild. J Antimicrob Chemother. 2016; 71 (8): 2335–6. doi:10.1093/jac/dkw262. Epub 2016 Jun 20.