1887

Abstract

Serious infections in intensive care unit patients caused by multidrug-resistant (MDR) represent a major threat worldwide owing to increased mortality and limited treatment options. With the application of tigecycline for MDR pathogens, tigecycline-non-susceptible isolates have recently emerged in China. To identify the susceptibility profile of MDR to tigecycline and evaluate the molecular characterization of tigecycline resistance, 214 MDR isolates were collected from blood samples of patients in intensive care units. MICs and clonal relatedness were determined by standard broth microdilution and multilocus sequence typing, respectively. Expression levels of efflux pumps and their global regulators were examined using real-time PCR. Mutations of local repressor were identified by PCR and sequencing. Our results show that the tigecycline resistance rate of 214 MDR isolates was 6.07 %. ST11 was the predominant clone type of tigecycline-non-susceptible isolates. Expression of efflux pump AcrB and global regulator RamA correlated with tigecycline MICs (AcrB: =8.91, =0.03; RamA: =13.91, <0.01), and mean expression levels of AcrB for the MICs ≥4 mg l were significantly higher than MICs ≤2 mg l (=2.48, =0.029). In addition, one tigecycline-resistant isolate harboured a deletion mutation in the gene. These data indicated a linear correlative trend for overexpression of the AcrB and the tigecycline MICs resulting from the upregulation of RamA. The emergence of molecular type ST11 of MDR isolates should be monitored to identify factors that contribute to tigecycline resistance in intensive care units.

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2016-08-01
2024-12-08
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References

  1. Bratu S., Landman D., George A., Salvani J., Quale J. 2009; Correlation of the expression of acrB and the regulatory genes marA, soxS and ramA with antimicrobial resistance in clinical isolates of Klebsiella pneumoniae endemic to New York City. J Antimicrob Chemother 64:278–283 [View Article][PubMed]
    [Google Scholar]
  2. Denys G. A., Callister S. M., Dowzicky M. J. 2013; Antimicrobial susceptibility among gram-negative isolates collected in the USA between 2005 and 2011 as part of the Tigecycline Evaluation and Surveillance Trial (T.E.S.T.). Ann Clin Microbiol Antimicrob 12:24 [View Article][PubMed]
    [Google Scholar]
  3. Giakkoupi P., Papagiannitsis C. C., Miriagou V., Pappa O., Polemis M., Tryfinopoulou K., Tzouvelekis L. S., Vatopoulos A. C. 2011; An update of the evolving epidemic of blaKPC–2-carrying Klebsiella pneumoniae in Greece (2009–10). J Antimicrob Chemother 66:1510–1513 [View Article][PubMed]
    [Google Scholar]
  4. Hansen L. H., Johannesen E., Burmølle M., Sørensen A. H., Sørensen S. J. 2004; Plasmid-encoded multidrug efflux pump conferring resistance to olaquindox in Escherichia coli. Antimicrob Agents Chemother 48:3332–3337 [View Article][PubMed]
    [Google Scholar]
  5. Hansen L. H., Jensen L. B., Sørensen H. I., Sørensen S. J. 2007; Substrate specificity of the OqxAB multidrug resistance pump in Escherichia coli and selected enteric bacteria. J Antimicrob Chemother 60:145–147 [View Article][PubMed]
    [Google Scholar]
  6. He F., Fu Y., Chen Q., Ruan Z., Hua X., Zhou H., Yu Y. 2015; Tigecycline susceptibility and the role of efflux pumps in tigecycline resistance in KPC-producing Klebsiella pneumoniae. PLoS One 10:e0119064 [View Article][PubMed]
    [Google Scholar]
  7. Henderson K. L., Müller-Pebody B., Johnson A. P., Wade A., Sharland M., Gilbert R. 2013; Community-acquired, healthcare-associated and hospital-acquired bloodstream infection definitions in children: a systematic review demonstrating inconsistent criteria. J Hosp Infect 85:94–105 [View Article][PubMed]
    [Google Scholar]
  8. Hentschke M., Wolters M., Sobottka I., Rohde H., Aepfelbacher M. 2010; ramR mutations in clinical isolates of Klebsiella pneumoniae with reduced susceptibility to tigecycline. Antimicrob Agents Chemother 54:2720–2723 [View Article][PubMed]
    [Google Scholar]
  9. Howden B. P., Beaume M., Harrison P. F., Hernandez D., Schrenzel J., Seemann T., Francois P., Stinear T. P. 2013; Analysis of the small RNA transcriptional response in multidrug-resistant Staphylococcus aureus after antimicrobial exposure. Antimicrob Agents Chemother 57:3864–3874 [View Article][PubMed]
    [Google Scholar]
  10. Jenner L., Starosta A. L., Terry D. S., Mikolajka A., Filonava L., Yusupov M., Blanchard S. C., Wilson D. N., Yusupova G. 2013; Structural basis for potent inhibitory activity of the antibiotic tigecycline during protein synthesis. Proc Natl Acad Sci U S A 110:3812–3816 [View Article][PubMed]
    [Google Scholar]
  11. Karaiskos I., Giamarellou H. 2014; Multidrug-resistant and extensively drug-resistant Gram-negative pathogens: current and emerging therapeutic approaches. Expert Opin Pharmacother 15:1351–1370 [View Article][PubMed]
    [Google Scholar]
  12. Li H., Zhang J., Liu Y., Zheng R., Chen H., Wang X., Wang Z., Cao B., Wang H. 2014; Molecular characteristics of carbapenemase-producing Enterobacteriaceae in China from 2008 to 2011: predominance of KPC-2 enzyme. Diagn Microbiol Infect Dis 78:63–65 [View Article][PubMed]
    [Google Scholar]
  13. Ma D., Alberti M., Lynch C., Nikaido H., Hearst J. E. 1996; The local repressor AcrR plays a modulating role in the regulation of acrAB genes of Escherichia coli by global stress signals. Mol Microbiol 19:101–112 [View Article][PubMed]
    [Google Scholar]
  14. Magiorakos A. P., Srinivasan A., Carey R. B., Carmeli Y., Falagas M. E., Giske C. G., Harbarth S., Hindler J. F., Kahlmeter G. et al. 2012; Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect 18:268–281 [View Article][PubMed]
    [Google Scholar]
  15. Mavroidi A., Likousi S., Palla E., Katsiari M., Roussou Z., Maguina A., Platsouka E. D. 2015; Molecular identification of tigecycline- and colistin-resistant carbapenemase-producing Acinetobacter baumannii from a Greek hospital from 2011 to 2013. J Med Microbiol 64:993–997 [View Article][PubMed]
    [Google Scholar]
  16. Munoz-Price L. S., Poirel L., Bonomo R. A., Schwaber M. J., Daikos G. L., Cormican M., Cornaglia G., Garau J., Gniadkowski M. et al. 2013; Clinical epidemiology of the global expansion of Klebsiella pneumoniae carbapenemases. Lancet Infect Dis 13:785–796 [View Article][PubMed]
    [Google Scholar]
  17. Nielsen L. E., Snesrud E. C., Onmus-Leone F., Kwak Y., Avilés R., Steele E. D., Sutter D. E., Waterman P. E., Lesho E. P. 2014; IS5 element integration, a novel mechanism for rapid in vivo emergence of tigecycline nonsusceptibility in Klebsiella pneumoniae. Antimicrob Agents Chemother 58:6151–6156 [View Article][PubMed]
    [Google Scholar]
  18. Pankey G. A. 2005; Tigecycline. J Antimicrob Chemother 56:470–480 [View Article][PubMed]
    [Google Scholar]
  19. Pereira P. S., de Araujo C. F., Seki L. M., Zahner V., Carvalho-Assef A. P., Asensi M. D. 2013; Update of the molecular epidemiology of KPC-2-producing Klebsiella pneumoniae in Brazil: spread of clonal complex 11 (ST11, ST437 and ST340). J Antimicrob Chemother 68:312–316 [View Article][PubMed]
    [Google Scholar]
  20. Rodríguez-Martínez J. M., Díaz de Alba P., Briales A., Machuca J., Lossa M., Fernández-Cuenca F., Rodríguez Baño J., Martínez-Martínez L., Pascual Á. 2013; Contribution of OqxAB efflux pumps to quinolone resistance in extended-spectrum-β-lactamase-producing Klebsiella pneumoniae. J Antimicrob Chemother 68:68–73 [View Article][PubMed]
    [Google Scholar]
  21. Ruzin A., Visalli M. A., Keeney D., Bradford P. A. 2005; Influence of transcriptional activator RamA on expression of multidrug efflux pump AcrAB and tigecycline susceptibility in Klebsiella pneumoniae. Antimicrob Agents Chemother 49:1017–1022 [View Article][PubMed]
    [Google Scholar]
  22. Ruzin A., Immermann F. W., Bradford P. A. 2008; Real-time PCR and statistical analyses of acrAB and ramA expression in clinical isolates of Klebsiella pneumoniae. Antimicrob Agents Chemother 52:3430–3432 [View Article][PubMed]
    [Google Scholar]
  23. Tzouvelekis L. S., Markogiannakis A., Psichogiou M., Tassios P. T., Daikos G. L. 2012; Carbapenemases in Klebsiella pneumoniae and other Enterobacteriaceae: an evolving crisis of global dimensions. Clin Microbiol Rev 25:682–707 [View Article][PubMed]
    [Google Scholar]
  24. Veleba M., Schneiders T. 2012; Tigecycline resistance can occur independently of the ramA gene in Klebsiella pneumoniae. Antimicrob Agents Chemother 56:4466–4467 [View Article][PubMed]
    [Google Scholar]
  25. Veleba M., Higgins P. G., Gonzalez G., Seifert H., Schneiders T. 2012; Characterization of RarA, a novel AraC family multidrug resistance regulator in Klebsiella pneumoniae. Antimicrob Agents Chemother 56:4450–4458 [View Article][PubMed]
    [Google Scholar]
  26. Veleba M., De Majumdar S., Hornsey M., Woodford N., Schneiders T. 2013; Genetic characterization of tigecycline resistance in clinical isolates of Enterobacter cloacae and Enterobacter aerogenes. J Antimicrob Chemother 68:1011–1018 [View Article][PubMed]
    [Google Scholar]
  27. Villa L., Feudi C., Fortini D., García-Fernández A., Carattoli A. 2014; Genomics of KPC-producing Klebsiella pneumoniae sequence type 512 clone highlights the role of RamR and ribosomal S10 protein mutations in conferring tigecycline resistance. Antimicrob Agents Chemother 58:1707–1712 [View Article][PubMed]
    [Google Scholar]
  28. Zhang Y., Yang J., Ye L., Luo Y., Wang W., Zhou W., Cui Z., Han L. 2012; Characterization of clinical multidrug-resistant Escherichia coli and Klebsiella pneumoniae isolates, 2007–2009, China. Microb Drug Resist 18:465–470 [View Article][PubMed]
    [Google Scholar]
  29. Zhong X., Xu H., Chen D., Zhou H., Hu X., Cheng G. 2014; First emergence of acrAB and oqxAB mediated tigecycline resistance in clinical isolates of Klebsiella pneumoniae pre-dating the use of tigecycline in a Chinese hospital. PLoS One 9:e115185 [View Article][PubMed]
    [Google Scholar]
  30. Zhou T., Zhang Y., Li M., Yu X., Sun Y., Xu J. 2015; An outbreak of infections caused by extensively drug-resistant Klebsiella pneumoniae strains during a short period of time in a Chinese teaching hospital: epidemiology study and molecular characteristics. Diagn Microbiol Infect Dis 82:240–244 [View Article][PubMed]
    [Google Scholar]
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