Mutations of the ompK36 porin gene and promoter impact responses of sequence Type 258, KPC-2-producing Klebsiella pneumoniae strains to doripenem and doripenem-colistin

Cornelius J. Clancy, Liang Chen, Jae H. Hong, Shaoji Cheng, Binghua Hao, Ryan K. Shields, Annie N. Farrell, Yohei Doi, Yanan Zhao, David S. Perlin, Barry N. Kreiswirth, M. Hong Nguyen

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56 Citations (Scopus)

Abstract

Doripenem-colistin exerts synergy against some, but not all, Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae strains in vitro. We determined if doripenem MICs and/or ompK36 porin gene mutations impacted the responses of 23 sequence type 258 (ST258), KPC-2-producing strains to the combination of doripenem (8 μg/ml) and colistin (2 μg/ml) during time-kill assays. The median doripenem and colistin MICs were 32 and 4 μg/ml. Doripenem MICs did not correlate with KPC-2 expression levels. Five and 18 strains had wild-type and mutant ompK36, respectively. The most common mutations were IS5 promoter insertions (n = 7) and insertions encoding glycine and aspartic acid at amino acid (aa) positions 134 and 135 (ins aa134-135 GD; n = 8), which were associated with higher doripenem MICs than other mutations or wild-type ompK36 (all P values ≤ 0.04). Bactericidal activity (24 h) was achieved by doripenem-colistin against 12%, 43%, and 75% of ins aa134-135 GD, IS5, and wild-type/other mutants, respectively (P = 0.04). Doripenem-colistin was more active in time-kill studies than colistin at 12 and 24 h if the doripenem MIC was ≤8 μg/ml (P = 0.0007 and 0.09, respectively), but not if the MIC was >8 μg/ml (P = 0.10 and 0.16). Likewise, doripenem-colistin was more active at 12 and 24 h against the wild type/other mutants than ins aa134-135 GD or IS5 mutants (P = 0.007 and 0.0007). By multivariate analysis, the absence of ins aa134-135 GD or IS5 mutations was the only independent predictor of doripenem-colistin responses at 24 h (P = 0.002). In conclusion, ompK36 genotypes identified ST258 KPC-K. pneumoniae strains that were most likely to respond to doripenem-colistin.

Original languageEnglish
Pages (from-to)5258-5265
Number of pages8
JournalAntimicrobial agents and chemotherapy
Volume57
Issue number11
DOIs
Publication statusPublished - 01-11-2013
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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    Clancy, C. J., Chen, L., Hong, J. H., Cheng, S., Hao, B., Shields, R. K., Farrell, A. N., Doi, Y., Zhao, Y., Perlin, D. S., Kreiswirth, B. N., & Nguyen, M. H. (2013). Mutations of the ompK36 porin gene and promoter impact responses of sequence Type 258, KPC-2-producing Klebsiella pneumoniae strains to doripenem and doripenem-colistin. Antimicrobial agents and chemotherapy, 57(11), 5258-5265. https://doi.org/10.1128/AAC.01069-13