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
Identifieur interne : 006E96 ( Main/Merge ); précédent : 006E95; suivant : 006E97Mutations of the ompK36 Porin Gene and Promoter Impact Responses of Sequence Type 258, KPC-2-Producing Klebsiella pneumoniae Strains to Doripenem and Doripenem-Colistin
Auteurs : Cornelius J. Clancy [États-Unis] ; LIANG CHEN [États-Unis] ; Jae H. Hong [États-Unis] ; SHAOJI CHENG [États-Unis] ; BINGHUA HAO [États-Unis] ; Ryan K. Shields [États-Unis] ; Annie N. Farrell [États-Unis] ; YOHEI DOI [États-Unis] ; YANAN ZHAO [États-Unis] ; David S. Perlin [États-Unis] ; Barry N. Kreiswirth [États-Unis] ; M. Hong Nguyen [États-Unis]Source :
- Antimicrobial agents and chemotherapy [ 0066-4804 ] ; 2013.
Descripteurs français
- Pascal (Inist)
- Wicri :
- topic : Génétique, Antibiotique.
English descriptors
- KwdEn :
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.
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a">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</title>
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<settlement type="city">Pittsburgh</settlement>
</placeName>
<orgName type="university">Université de Pittsburgh</orgName>
</affiliation>
</author>
<author><name sortKey="Yohei Doi" sort="Yohei Doi" uniqKey="Yohei Doi" last="Yohei Doi">YOHEI DOI</name>
<affiliation wicri:level="4"><inist:fA14 i1="01"><s1>University of Pittsburgh</s1>
<s2>Pittsburgh, Pennsylvania</s2>
<s3>USA</s3>
<sZ>1 aut.</sZ>
<sZ>3 aut.</sZ>
<sZ>4 aut.</sZ>
<sZ>5 aut.</sZ>
<sZ>6 aut.</sZ>
<sZ>7 aut.</sZ>
<sZ>8 aut.</sZ>
<sZ>12 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<placeName><region type="state">Pennsylvanie</region>
<settlement type="city">Pittsburgh</settlement>
</placeName>
<orgName type="university">Université de Pittsburgh</orgName>
</affiliation>
</author>
<author><name sortKey="Yanan Zhao" sort="Yanan Zhao" uniqKey="Yanan Zhao" last="Yanan Zhao">YANAN ZHAO</name>
<affiliation wicri:level="2"><inist:fA14 i1="04"><s1>Public Health Research Institute, New Jersey Medical School-University of Medicine and Dentistry of New Jersey</s1>
<s2>Newark, New Jersey</s2>
<s3>USA</s3>
<sZ>2 aut.</sZ>
<sZ>9 aut.</sZ>
<sZ>10 aut.</sZ>
<sZ>11 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<placeName><region type="state">New Jersey</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Perlin, David S" sort="Perlin, David S" uniqKey="Perlin D" first="David S." last="Perlin">David S. Perlin</name>
<affiliation wicri:level="2"><inist:fA14 i1="04"><s1>Public Health Research Institute, New Jersey Medical School-University of Medicine and Dentistry of New Jersey</s1>
<s2>Newark, New Jersey</s2>
<s3>USA</s3>
<sZ>2 aut.</sZ>
<sZ>9 aut.</sZ>
<sZ>10 aut.</sZ>
<sZ>11 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<placeName><region type="state">New Jersey</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Kreiswirth, Barry N" sort="Kreiswirth, Barry N" uniqKey="Kreiswirth B" first="Barry N." last="Kreiswirth">Barry N. Kreiswirth</name>
<affiliation wicri:level="2"><inist:fA14 i1="04"><s1>Public Health Research Institute, New Jersey Medical School-University of Medicine and Dentistry of New Jersey</s1>
<s2>Newark, New Jersey</s2>
<s3>USA</s3>
<sZ>2 aut.</sZ>
<sZ>9 aut.</sZ>
<sZ>10 aut.</sZ>
<sZ>11 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<placeName><region type="state">New Jersey</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Hong Nguyen, M" sort="Hong Nguyen, M" uniqKey="Hong Nguyen M" first="M." last="Hong Nguyen">M. Hong Nguyen</name>
<affiliation wicri:level="4"><inist:fA14 i1="01"><s1>University of Pittsburgh</s1>
<s2>Pittsburgh, Pennsylvania</s2>
<s3>USA</s3>
<sZ>1 aut.</sZ>
<sZ>3 aut.</sZ>
<sZ>4 aut.</sZ>
<sZ>5 aut.</sZ>
<sZ>6 aut.</sZ>
<sZ>7 aut.</sZ>
<sZ>8 aut.</sZ>
<sZ>12 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<placeName><region type="state">Pennsylvanie</region>
<settlement type="city">Pittsburgh</settlement>
</placeName>
<orgName type="university">Université de Pittsburgh</orgName>
</affiliation>
<affiliation wicri:level="2"><inist:fA14 i1="02"><s1>XDR Pathogen Laboratory, University of Pittsburgh Medical Center</s1>
<s2>Pittsburgh, Pennsylvania</s2>
<s3>USA</s3>
<sZ>1 aut.</sZ>
<sZ>5 aut.</sZ>
<sZ>6 aut.</sZ>
<sZ>12 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<placeName><region type="state">Pennsylvanie</region>
</placeName>
</affiliation>
</author>
</analytic>
<series><title level="j" type="main">Antimicrobial agents and chemotherapy</title>
<title level="j" type="abbreviated">Antimicrob. agents chemother.</title>
<idno type="ISSN">0066-4804</idno>
<imprint><date when="2013">2013</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
<seriesStmt><title level="j" type="main">Antimicrobial agents and chemotherapy</title>
<title level="j" type="abbreviated">Antimicrob. agents chemother.</title>
<idno type="ISSN">0066-4804</idno>
</seriesStmt>
</fileDesc>
<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Antibacterial agent</term>
<term>Antibiotic</term>
<term>Colistin</term>
<term>Doripenem</term>
<term>Gene</term>
<term>Genetics</term>
<term>Klebsiella pneumoniae</term>
<term>Mutation</term>
<term>Porin</term>
<term>Promoter</term>
<term>Strain</term>
</keywords>
<keywords scheme="Pascal" xml:lang="fr"><term>Mutation</term>
<term>Génétique</term>
<term>Porine</term>
<term>Gène</term>
<term>Promoteur</term>
<term>Klebsiella pneumoniae</term>
<term>Souche</term>
<term>Doripénem</term>
<term>Colistine</term>
<term>Antibactérien</term>
<term>Antibiotique</term>
</keywords>
<keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Génétique</term>
<term>Antibiotique</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en">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.</div>
</front>
</TEI>
<affiliations><list><country><li>États-Unis</li>
</country>
<region><li>New Jersey</li>
<li>Pennsylvanie</li>
</region>
<settlement><li>Pittsburgh</li>
</settlement>
<orgName><li>Université de Pittsburgh</li>
</orgName>
</list>
<tree><country name="États-Unis"><region name="Pennsylvanie"><name sortKey="Clancy, Cornelius J" sort="Clancy, Cornelius J" uniqKey="Clancy C" first="Cornelius J." last="Clancy">Cornelius J. Clancy</name>
</region>
<name sortKey="Binghua Hao" sort="Binghua Hao" uniqKey="Binghua Hao" last="Binghua Hao">BINGHUA HAO</name>
<name sortKey="Binghua Hao" sort="Binghua Hao" uniqKey="Binghua Hao" last="Binghua Hao">BINGHUA HAO</name>
<name sortKey="Clancy, Cornelius J" sort="Clancy, Cornelius J" uniqKey="Clancy C" first="Cornelius J." last="Clancy">Cornelius J. Clancy</name>
<name sortKey="Clancy, Cornelius J" sort="Clancy, Cornelius J" uniqKey="Clancy C" first="Cornelius J." last="Clancy">Cornelius J. Clancy</name>
<name sortKey="Farrell, Annie N" sort="Farrell, Annie N" uniqKey="Farrell A" first="Annie N." last="Farrell">Annie N. Farrell</name>
<name sortKey="Hong Nguyen, M" sort="Hong Nguyen, M" uniqKey="Hong Nguyen M" first="M." last="Hong Nguyen">M. Hong Nguyen</name>
<name sortKey="Hong Nguyen, M" sort="Hong Nguyen, M" uniqKey="Hong Nguyen M" first="M." last="Hong Nguyen">M. Hong Nguyen</name>
<name sortKey="Hong, Jae H" sort="Hong, Jae H" uniqKey="Hong J" first="Jae H." last="Hong">Jae H. Hong</name>
<name sortKey="Kreiswirth, Barry N" sort="Kreiswirth, Barry N" uniqKey="Kreiswirth B" first="Barry N." last="Kreiswirth">Barry N. Kreiswirth</name>
<name sortKey="Liang Chen" sort="Liang Chen" uniqKey="Liang Chen" last="Liang Chen">LIANG CHEN</name>
<name sortKey="Perlin, David S" sort="Perlin, David S" uniqKey="Perlin D" first="David S." last="Perlin">David S. Perlin</name>
<name sortKey="Shaoji Cheng" sort="Shaoji Cheng" uniqKey="Shaoji Cheng" last="Shaoji Cheng">SHAOJI CHENG</name>
<name sortKey="Shields, Ryan K" sort="Shields, Ryan K" uniqKey="Shields R" first="Ryan K." last="Shields">Ryan K. Shields</name>
<name sortKey="Shields, Ryan K" sort="Shields, Ryan K" uniqKey="Shields R" first="Ryan K." last="Shields">Ryan K. Shields</name>
<name sortKey="Yanan Zhao" sort="Yanan Zhao" uniqKey="Yanan Zhao" last="Yanan Zhao">YANAN ZHAO</name>
<name sortKey="Yohei Doi" sort="Yohei Doi" uniqKey="Yohei Doi" last="Yohei Doi">YOHEI DOI</name>
</country>
</tree>
</affiliations>
</record>
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