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 : 001675 ( PascalFrancis/Checkpoint ); précédent : 001674; suivant : 001676Mutations 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
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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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Clancy</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><affiliation wicri:level="2"><inist:fA14 i1="03"><s1>Pittsburgh VA Healthcare System</s1><s2>Pittsburgh, Pennsylvania</s2><s3>USA</s3><sZ>1 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Liang Chen" sort="Liang Chen" uniqKey="Liang Chen" last="Liang Chen">LIANG CHEN</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, Jae H" sort="Hong, Jae H" uniqKey="Hong J" first="Jae H." last="Hong">Jae H. 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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></titleStmt><publicationStmt><idno type="wicri:source">INIST</idno><idno type="inist">14-0002524</idno><date when="2013">2013</date><idno type="stanalyst">PASCAL 14-0002524 INIST</idno><idno type="RBID">Pascal:14-0002524</idno><idno type="wicri:Area/PascalFrancis/Corpus">001263</idno><idno type="wicri:Area/PascalFrancis/Curation">003337</idno><idno type="wicri:Area/PascalFrancis/Checkpoint">001675</idno><idno type="wicri:explorRef" wicri:stream="PascalFrancis" wicri:step="Checkpoint">001675</idno></publicationStmt><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><author><name sortKey="Clancy, Cornelius J" sort="Clancy, Cornelius J" uniqKey="Clancy C" first="Cornelius J." last="Clancy">Cornelius J. Clancy</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><affiliation wicri:level="2"><inist:fA14 i1="03"><s1>Pittsburgh VA Healthcare System</s1><s2>Pittsburgh, Pennsylvania</s2><s3>USA</s3><sZ>1 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Liang Chen" sort="Liang Chen" uniqKey="Liang Chen" last="Liang Chen">LIANG CHEN</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, Jae H" sort="Hong, Jae H" uniqKey="Hong J" first="Jae H." last="Hong">Jae H. Hong</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="Shaoji Cheng" sort="Shaoji Cheng" uniqKey="Shaoji Cheng" last="Shaoji Cheng">SHAOJI CHENG</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="Binghua Hao" sort="Binghua Hao" uniqKey="Binghua Hao" last="Binghua Hao">BINGHUA HAO</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><author><name sortKey="Shields, Ryan K" sort="Shields, Ryan K" uniqKey="Shields R" first="Ryan K." last="Shields">Ryan K. Shields</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><author><name sortKey="Farrell, Annie N" sort="Farrell, Annie N" uniqKey="Farrell A" first="Annie N." last="Farrell">Annie N. Farrell</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="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><inist><standard h6="B"><pA><fA01 i1="01" i2="1"><s0>0066-4804</s0></fA01><fA02 i1="01"><s0>AACHAX</s0></fA02><fA03 i2="1"><s0>Antimicrob. agents chemother.</s0></fA03><fA05><s2>57</s2></fA05><fA06><s2>11</s2></fA06><fA08 i1="01" i2="1" l="ENG"><s1>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</s1></fA08><fA11 i1="01" i2="1"><s1>CLANCY (Cornelius J.)</s1></fA11><fA11 i1="02" i2="1"><s1>LIANG CHEN</s1></fA11><fA11 i1="03" i2="1"><s1>HONG (Jae H.)</s1></fA11><fA11 i1="04" i2="1"><s1>SHAOJI CHENG</s1></fA11><fA11 i1="05" i2="1"><s1>BINGHUA HAO</s1></fA11><fA11 i1="06" i2="1"><s1>SHIELDS (Ryan K.)</s1></fA11><fA11 i1="07" i2="1"><s1>FARRELL (Annie N.)</s1></fA11><fA11 i1="08" i2="1"><s1>YOHEI DOI</s1></fA11><fA11 i1="09" i2="1"><s1>YANAN ZHAO</s1></fA11><fA11 i1="10" i2="1"><s1>PERLIN (David S.)</s1></fA11><fA11 i1="11" i2="1"><s1>KREISWIRTH (Barry N.)</s1></fA11><fA11 i1="12" i2="1"><s1>HONG NGUYEN (M.)</s1></fA11><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></fA14><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></fA14><fA14 i1="03"><s1>Pittsburgh VA Healthcare System</s1><s2>Pittsburgh, Pennsylvania</s2><s3>USA</s3><sZ>1 aut.</sZ></fA14><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></fA14><fA20><s1>5258-5265</s1></fA20><fA21><s1>2013</s1></fA21><fA23 i1="01"><s0>ENG</s0></fA23><fA43 i1="01"><s1>INIST</s1><s2>13334</s2><s5>354000507428660090</s5></fA43><fA44><s0>0000</s0><s1>© 2014 INIST-CNRS. All rights reserved.</s1></fA44><fA45><s0>43 ref.</s0></fA45><fA47 i1="01" i2="1"><s0>14-0002524</s0></fA47><fA60><s1>P</s1></fA60><fA61><s0>A</s0></fA61><fA64 i1="01" i2="1"><s0>Antimicrobial agents and chemotherapy</s0></fA64><fA66 i1="01"><s0>USA</s0></fA66><fC01 i1="01" l="ENG"><s0>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.</s0></fC01><fC02 i1="01" i2="X"><s0>002B02S</s0></fC02><fC03 i1="01" i2="X" l="FRE"><s0>Mutation</s0><s5>01</s5></fC03><fC03 i1="01" i2="X" l="ENG"><s0>Mutation</s0><s5>01</s5></fC03><fC03 i1="01" i2="X" l="SPA"><s0>Mutación</s0><s5>01</s5></fC03><fC03 i1="02" i2="X" l="FRE"><s0>Génétique</s0><s5>02</s5></fC03><fC03 i1="02" i2="X" l="ENG"><s0>Genetics</s0><s5>02</s5></fC03><fC03 i1="02" i2="X" l="SPA"><s0>Genética</s0><s5>02</s5></fC03><fC03 i1="03" i2="X" l="FRE"><s0>Porine</s0><s5>03</s5></fC03><fC03 i1="03" i2="X" l="ENG"><s0>Porin</s0><s5>03</s5></fC03><fC03 i1="03" i2="X" l="SPA"><s0>Porina</s0><s5>03</s5></fC03><fC03 i1="04" i2="X" l="FRE"><s0>Gène</s0><s5>04</s5></fC03><fC03 i1="04" i2="X" l="ENG"><s0>Gene</s0><s5>04</s5></fC03><fC03 i1="04" i2="X" l="SPA"><s0>Gen</s0><s5>04</s5></fC03><fC03 i1="05" i2="X" l="FRE"><s0>Promoteur</s0><s5>05</s5></fC03><fC03 i1="05" i2="X" l="ENG"><s0>Promoter</s0><s5>05</s5></fC03><fC03 i1="05" i2="X" l="SPA"><s0>Promotor</s0><s5>05</s5></fC03><fC03 i1="06" i2="X" l="FRE"><s0>Klebsiella pneumoniae</s0><s2>NS</s2><s5>06</s5></fC03><fC03 i1="06" i2="X" l="ENG"><s0>Klebsiella pneumoniae</s0><s2>NS</s2><s5>06</s5></fC03><fC03 i1="06" i2="X" l="SPA"><s0>Klebsiella pneumoniae</s0><s2>NS</s2><s5>06</s5></fC03><fC03 i1="07" i2="X" l="FRE"><s0>Souche</s0><s5>07</s5></fC03><fC03 i1="07" i2="X" l="ENG"><s0>Strain</s0><s5>07</s5></fC03><fC03 i1="07" i2="X" l="SPA"><s0>Cepa</s0><s5>07</s5></fC03><fC03 i1="08" i2="X" l="FRE"><s0>Doripénem</s0><s2>NK</s2><s2>FR</s2><s5>08</s5></fC03><fC03 i1="08" i2="X" l="ENG"><s0>Doripenem</s0><s2>NK</s2><s2>FR</s2><s5>08</s5></fC03><fC03 i1="08" i2="X" l="SPA"><s0>Doripenem</s0><s2>NK</s2><s2>FR</s2><s5>08</s5></fC03><fC03 i1="09" i2="X" l="FRE"><s0>Colistine</s0><s2>NK</s2><s2>FR</s2><s5>09</s5></fC03><fC03 i1="09" i2="X" l="ENG"><s0>Colistin</s0><s2>NK</s2><s2>FR</s2><s5>09</s5></fC03><fC03 i1="09" i2="X" l="SPA"><s0>Colistina</s0><s2>NK</s2><s2>FR</s2><s5>09</s5></fC03><fC03 i1="10" i2="X" l="FRE"><s0>Antibactérien</s0><s5>23</s5></fC03><fC03 i1="10" i2="X" l="ENG"><s0>Antibacterial agent</s0><s5>23</s5></fC03><fC03 i1="10" i2="X" l="SPA"><s0>Antibacteriano</s0><s5>23</s5></fC03><fC03 i1="11" i2="X" l="FRE"><s0>Antibiotique</s0><s5>24</s5></fC03><fC03 i1="11" i2="X" l="ENG"><s0>Antibiotic</s0><s5>24</s5></fC03><fC03 i1="11" i2="X" l="SPA"><s0>Antibiótico</s0><s5>24</s5></fC03><fC07 i1="01" i2="X" l="FRE"><s0>Enterobacteriaceae</s0><s2>NS</s2></fC07><fC07 i1="01" i2="X" l="ENG"><s0>Enterobacteriaceae</s0><s2>NS</s2></fC07><fC07 i1="01" i2="X" l="SPA"><s0>Enterobacteriaceae</s0><s2>NS</s2></fC07><fC07 i1="02" i2="X" l="FRE"><s0>Bactérie</s0></fC07><fC07 i1="02" i2="X" l="ENG"><s0>Bacteria</s0></fC07><fC07 i1="02" i2="X" l="SPA"><s0>Bacteria</s0></fC07><fC07 i1="03" i2="X" l="FRE"><s0>Dérivé du carbapénème</s0><s5>37</s5></fC07><fC07 i1="03" i2="X" l="ENG"><s0>Carbapenem derivatives</s0><s5>37</s5></fC07><fC07 i1="03" i2="X" l="SPA"><s0>Carbapenem derivado</s0><s5>37</s5></fC07><fC07 i1="04" i2="X" l="FRE"><s0>Peptide cyclique</s0><s5>38</s5></fC07><fC07 i1="04" i2="X" l="ENG"><s0>Cyclic peptides</s0><s5>38</s5></fC07><fC07 i1="04" i2="X" l="SPA"><s0>Péptido cíclico</s0><s5>38</s5></fC07><fC07 i1="05" i2="X" l="FRE"><s0>Polypeptide</s0><s5>39</s5></fC07><fC07 i1="05" i2="X" l="ENG"><s0>Polypeptide</s0><s5>39</s5></fC07><fC07 i1="05" i2="X" l="SPA"><s0>Polipéptido</s0><s5>39</s5></fC07><fC07 i1="06" i2="X" l="FRE"><s0>β-Lactamines</s0><s5>40</s5></fC07><fC07 i1="06" i2="X" l="ENG"><s0>β-Lactams</s0><s5>40</s5></fC07><fC07 i1="06" i2="X" l="SPA"><s0>β-Lactams</s0><s5>40</s5></fC07><fN21><s1>006</s1></fN21><fN44 i1="01"><s1>OTO</s1></fN44><fN82><s1>OTO</s1></fN82></pA></standard></inist><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>Pour manipuler ce document sous Unix (Dilib)
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