Expression of SHV-2 β-Lactamase and of Reduced Amounts of OmpK36 Porin in
            <i>Klebsiella pneumoniae</i>
            Results in Increased Resistance to Cephalosporins and Carbapenems

Crowley, Brendan; Benedí, Vicente J.; Doménech-Sánchez, Antonio

doi:10.1128/aac.46.11.3679-3682.2002

Cited by 77 publications

(67 citation statements)

References 13 publications

(7 reference statements)

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“…In this study, the CTX MIC of 0.5 mg/liter in combination with our genetic testing identified all ␤-lactam resistance mechanisms studied (carbapenemases, CTX-M, and AmpC), with the exception of TEM, most examples of which (e.g., TEM-1) produce no CTX-R phenotype. ETP MICs appear to be bimodally distributed in K. pneumoniae, and this seems to correlate with defects and variations in OmpK36, as previously reported in association with KPC-producing isolates, and with ESBL and AmpC-type ␤-lactamases (8,40,55,56). We found a large diversity of OmpK36 defects in our set of ETP-resistant K. pneumoniae isolates, all of which were reported previously: frameshift mutations (43), IS (57), a premature stop codon (58,59), and a GD duplication in loop 3 (44,45,60).…”

Section: Discussionsupporting

confidence: 49%

“…Carbapenems have been the antibiotics of choice for treating ESBLs and other multidrug-resistant strains, but carbapenem resistance is increasingly common (5). This is mostly attributed to the production of specific carbapenemases (6), but the expression of AmpC or ESBL enzymes in isolates with altered outer membrane porins is also associated with decreased susceptibility to carbapenems (7)(8)(9). Mutations in major outer membrane porins may be required for clinically relevant carbapenem resistance in K. pneumoniae isolates expressing carbapenemases, such as KPC and OXA-48-like enzymes, which rarely elicit clinically important antibiotic resistance in E. coli (6).…”

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confidence: 99%

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Predictability of Phenotype in Relation to Common β-Lactam Resistance Mechanisms in Escherichia coli and Klebsiella pneumoniae

et al. 2016

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cThe minimal concentration of antibiotic required to inhibit the growth of different isolates of a given species with no acquired resistance mechanisms has a normal distribution. We have previously shown that the presence or absence of transmissible antibiotic resistance genes has excellent predictive power for phenotype. In this study, we analyzed the distribution of six ␤-lactam antibiotic susceptibility phenotypes associated with commonly acquired resistance genes in Enterobacteriaceae in Sydney, Australia. Escherichia coli (n ‫؍‬ 200) and Klebsiella pneumoniae (n ‫؍‬ 178) clinical isolates, with relevant transmissible resistance genes (bla TEM , n ‫؍‬ 33; plasmid AmpC, n ‫؍‬ 69; extended-spectrum ␤-lactamase [ESBL], n ‫؍‬ 116; and carbapenemase, n ‫؍‬ 100), were characterized. A group of 60 isolates with no phenotypic resistance to any antibiotics tested and carrying none of the important ␤-lactamase genes served as comparators. The MICs for all drug-bacterium combinations had a normal distribution, varying only in the presence of additional genes relevant to the phenotype or, for ertapenem resistance in K. pneumoniae, with a loss or change in the outer membrane porin protein OmpK36. We demonstrated mutations in ompK36 or absence of OmpK36 in all isolates in which reduced susceptibility to ertapenem (MIC, >1 mg/liter) was evident. Ertapenem nonsusceptibility in K. pneumoniae was most common in the context of an OmpK36 variant with an ESBL or AmpC gene. Surveillance strategies to define appropriate antimicrobial therapies should include genotype-phenotype relationships for all major transmissible resistance genes and the characterization of mutations in relevant porins in organisms, like K. pneumoniae. E scherichia coli and Klebsiella pneumoniae are among the most important pathogens in community and hospital settings, and their increasing resistance to extended-spectrum (third-and fourth-generation) cephalosporin and carbapenem antibiotics is a major health threat. In Gram-negative bacteria, such as these, a variety of mechanisms may confer ␤-lactam resistance (1), but the spread of transmissible genes encoding extended-spectrum ␤-lactamases (ESBLs) (2), plasmid-mediated AmpC ␤-lactamases (pAmpCs) (3), and carbapenemases (4) is particularly significant. Carbapenems have been the antibiotics of choice for treating ESBLs and other multidrug-resistant strains, but carbapenem resistance is increasingly common (5). This is mostly attributed to the production of specific carbapenemases (6), but the expression of AmpC or ESBL enzymes in isolates with altered outer membrane porins is also associated with decreased susceptibility to carbapenems (7-9). Mutations in major outer membrane porins may be required for clinically relevant carbapenem resistance in K. pneumoniae isolates expressing carbapenemases, such as KPC and OXA-48-like enzymes, which rarely elicit clinically important antibiotic resistance in E. coli (6).The clinical definitions of antibiotic susceptibility are developed by the collection and analysis of...

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Section: Discussionsupporting

confidence: 49%

mentioning

confidence: 99%

Predictability of Phenotype in Relation to Common β-Lactam Resistance Mechanisms in Escherichia coli and Klebsiella pneumoniae

et al. 2016

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“…Such isolates are sporadically reported and are usually accompanied by the presence of an ESBL or AmpC type ␤-lactamase (6,9,16,20). We report for the first time the large dissemination of an ertapenemresistant K. pneumoniae outbreak strain possessing the bla CTX-M-15 gene.…”

Section: Discussionmentioning

confidence: 90%

“…In the past there have been mainly sporadic case reports of carbapenem-resistant K. pneumoniae isolates with porin defects and simultaneous production of an ESBL or AmpC type enzyme (9,(15)(16)(17)(18)(19)(20). However, reports presenting outbreaks or large dissemination of such strains are limited (14,15).…”

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confidence: 99%

Outbreak Caused by an Ertapenem-Resistant, CTX-M-15-Producing Klebsiella pneumoniae Sequence Type 101 Clone Carrying an OmpK36 Porin Variant

et al. 2013

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Although numerous studies have documented outbreaks of carbapenem-resistant Klebsiella pneumoniae (CRKP) possessing various carbapenemases, reports on outbreaks due to CRKP possessing extended-spectrum ␤-lactamases (ESBLs) and/or AmpCs with porin lesions have been limited. Here, we describe an outbreak caused by an ertapenem-resistant, CTX-M-15-producing clonal K. pneumoniae strain expressing an OmpK36 porin variant. From May 2012 to November 2012, 37 ertapenem-resistant K. pneumoniae isolates phenotypically negative for carbapenemase production were recovered from 19 patients hospitalized in the intensive care unit of a Greek hospital. The isolates were either susceptible or intermediate to other carbapenems and resistant to all remaining ␤-lactams but cefotetan. Phenotypic and molecular analysis revealed the presence in all isolates of the bla CTX-M-15 gene on a conjugative 100-kb plasmid, disruption in the expression of the ompK35 gene, and the production of an Ompk36 porin variant. The index case was a patient admitted from another hospital. Active surveillance upon admission and on a weekly basis was immediately initiated; environmental samples were also periodically tested. Molecular typing showed that all clinical isolates as well as two ertapenem-resistant environmental K. pneumoniae isolates belonged to the same clonal type and were assigned to multilocus sequence typing (MLST) sequence type 101 (ST101). As all colonized/infected patients were hospitalized during overlapping periods, cross-infection was considered the main route for the dissemination of the outbreak strain. Despite reinforcement of infection control measures and active surveillance, the outbreak lasted approximately 7 months. Identification of hidden carriers upon admission and by screening on a weekly basis was found valuable for early recognition and subsequent successful management of the outbreak.

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“…In the past, it was distinctly unusual among Klebsiella pneumoniae isolates and was attributed mostly to porin loss in combination with an AmpC-type enzyme or extended-spectrum ␤-lactamase (ESBL) (5,8). In recent years, however, carbapenem resistance has emerged among K. pneumoniae isolates in many geographical locations due to the acquisition of carbapenemases, which usually belong to Ambler class B metallo-␤-lactamases (MBLs) or to Ambler class A KPC-type enzymes (25).…”

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confidence: 99%

Evaluation of Boronic Acid Disk Tests for Differentiating KPC-Possessing Klebsiella pneumoniae Isolates in the Clinical Laboratory

et al. 2009

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The worldwide increase in the occurrence and dissemination of KPC ␤-lactamases among gram-negative pathogens makes critical the early detection of these enzymes. Boronic acid disk tests using different antibiotic substrates were evaluated for detection of KPC-possessing Klebsiella pneumoniae isolates. A total of 57 genotypically confirmed KPC-possessing K. pneumoniae isolates with varying carbapenem MICs were examined. To measure the specificity of the tests, 106 non-KPC-possessing isolates (89 K. pneumoniae and 17 Escherichia coli isolates) were randomly selected among those exhibiting reduced susceptibility to cefoxitin, expanded-spectrum cephalosporins, or carbapenems. As many as 56, 53, and 40 of the non-KPC-possessing isolates harbored extended-spectrum ␤-lactamases, metallo-␤-lactamases, and plasmidmediated AmpC ␤-lactamases, respectively. By use of CLSI methodology and disks containing imipenem, meropenem, or cefepime, either alone or in combination with 400 g of boronic acid, all 57 KPC producers gave positive results (sensitivity, 100%) whereas all 106 non-KPC producers were negative (specificity, 100%). The meropenem duplicate disk with or without boronic acid demonstrated the largest differences in inhibition zone diameters between KPC producers and non-KPC producers. By use of disks containing ertapenem, all isolates were correctly differentiated except for five AmpC producers that gave falsepositive results (sensitivity, 100%; specificity, 95.3%). These practical and simple boronic acid disk tests promise to be very helpful for the accurate differentiation of KPC-possessing K. pneumoniae isolates, even in regions where different broad-spectrum ␤-lactamases are widespread.

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Expression of SHV-2 β-Lactamase and of Reduced Amounts of OmpK36 Porin in Klebsiella pneumoniae Results in Increased Resistance to Cephalosporins and Carbapenems

Cited by 77 publications

References 13 publications

Predictability of Phenotype in Relation to Common β-Lactam Resistance Mechanisms in Escherichia coli and Klebsiella pneumoniae

Predictability of Phenotype in Relation to Common β-Lactam Resistance Mechanisms in Escherichia coli and Klebsiella pneumoniae

Outbreak Caused by an Ertapenem-Resistant, CTX-M-15-Producing Klebsiella pneumoniae Sequence Type 101 Clone Carrying an OmpK36 Porin Variant

Evaluation of Boronic Acid Disk Tests for Differentiating KPC-Possessing Klebsiella pneumoniae Isolates in the Clinical Laboratory

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