Patient-to-Patient Transmission of Klebsiella pneumoniae Carbapenemase Variants with Reduced Ceftazidime-Avibactam Susceptibility

ABSTRACT We report patient-to-patient transmission of Enterobacter hormaechei isolates with reduced susceptibility to ceftazidime-avibactam due to production of KPC-40, a variant of KPC-3 with a two-amino-acid insertion in the Ω-loop region (L167_E168dup). The index patient had received a prolonged course of ceftazidime-avibactam therapy, whereas the second patient had not received the agent and still became colonized with the KPC-40-producing strain. The complex dynamics of KPC (Klebsiella pneumoniae carbapenemase) described here highlight several key diagnostic and therapeutic considerations.

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KPC-50 Confers Resistance to Ceftazidime-Avibactam Associated with Reduced Carbapenemase Activity

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00321-20 ◽

2020 ◽

Vol 64 (8) ◽

Cited By ~ 3

Author(s):

Laurent Poirel ◽

Xavier Vuillemin ◽

Mario Juhas ◽

Amandine Masseron ◽

Ursina Bechtel-Grosch ◽

...

Keyword(s):

Amino Acids ◽

Amino Acid ◽

Klebsiella Pneumoniae ◽

Clinical Isolate ◽

Sharp Reduction ◽

Content Type ◽

Amino Acid Insertion

ABSTRACT KPC-50 is a KPC-3 variant identified from a Klebsiella pneumoniae clinical isolate recovered in Switzerland in 2019. Compared to KPC-3, KPC-50 shows (i) a three-amino-acid insertion (Glu-Ala-Val) between amino acids 276 and 277, (ii) an increased affinity to ceftazidime, (iii) a decreased sensitivity to avibactam, explaining the ceftazidime-avibactam resistance, and (iv) an association with a sharp reduction of its carbapenemase activity.

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Phenotypic, Biochemical, and Genetic Analysis of KPC-41, a KPC-3 Variant Conferring Resistance to Ceftazidime-Avibactam and Exhibiting Reduced Carbapenemase Activity

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01111-19 ◽

2019 ◽

Vol 63 (12) ◽

Cited By ~ 11

Author(s):

Linda Mueller ◽

Amandine Masseron ◽

Guy Prod’Hom ◽

Tatiana Galperine ◽

Gilbert Greub ◽

...

Keyword(s):

Escherichia Coli ◽

Amino Acids ◽

Amino Acid ◽

Klebsiella Pneumoniae ◽

Genetic Analysis ◽

Amino Acid Sequence ◽

Cloning And Expression ◽

Content Type ◽

Amino Acid Insertion

ABSTRACT A novel KPC variant, KPC-41, was identified in a Klebsiella pneumoniae clinical isolate from Switzerland. This β-lactamase possessed a 3-amino-acid insertion (Pro-Asn-Lys) located between amino acids 269 and 270 compared to the KPC-3 amino acid sequence. Cloning and expression of the blaKPC-41 gene in Escherichia coli, followed by determination of MIC values and kinetic parameters, showed that KPC-41, compared to those of KPC-3, has an increased affinity to ceftazidime and a decreased sensitivity to avibactam, leading to resistance to ceftazidime-avibactam once produced in K. pneumoniae. Furthermore, KPC-41 exhibited a drastic decrease of its carbapenemase activity. This report highlights that a diversity of KPC variants conferring resistance to ceftazidime-avibactam already circulate in Europe.

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Use of a cohorting-unit and systematic surveillance cultures to control a Klebsiella pneumoniae carbapenemase (KPC)–producing Enterobacteriaceae outbreak

Infection Control and Hospital Epidemiology ◽

10.1017/ice.2019.99 ◽

2019 ◽

Vol 40 (7) ◽

pp. 767-773 ◽

Cited By ~ 3

Author(s):

Allison E. Reeme ◽

Sarah L. Bowler ◽

Blake W. Buchan ◽

Mary Beth Graham ◽

Elizabeth Behrens ◽

...

Keyword(s):

Klebsiella Pneumoniae ◽

Infection Control ◽

Organ Transplant ◽

Index Patient ◽

Molecular Characteristics ◽

Solid Organ ◽

The Novel ◽

Transplant Recipients ◽

Klebsiella Pneumoniae Carbapenemase ◽

Surveillance Cultures

AbstractObjective:Describe the epidemiological and molecular characteristics of an outbreak of Klebsiella pneumoniae carbapenemase (KPC)–producing organisms and the novel use of a cohorting unit for its control.Design:Observational study.Setting:A 566-room academic teaching facility in Milwaukee, Wisconsin.Patients:Solid-organ transplant recipients.Methods:Infection control bundles were used throughout the time of observation. All KPC cases were intermittently housed in a cohorting unit with dedicated nurses and nursing aids. The rooms used in the cohorting unit had anterooms where clean supplies and linens were placed. Spread of KPC-producing organisms was determined using rectal surveillance cultures on admission and weekly thereafter among all consecutive patients admitted to the involved units. KPC-positive strains underwent pulsed-field gel electrophoresis and whole-genome sequencing.Results:A total of 8 KPC cases (5 identified by surveillance) were identified from April 2016 to April 2017. After the index patient, 3 patients acquired KPC-producing organisms despite implementation of an infection control bundle. This prompted the use of a cohorting unit, which immediately halted transmission, and the single remaining KPC case was transferred out of the cohorting unit. However, additional KPC cases were identified within 2 months. Once the cohorting unit was reopened, no additional KPC cases occurred. The KPC-positive species identified during this outbreak included Klebsiella pneumoniae, Enterobacter cloacae complex, and Escherichia coli. blaKPC was identified on at least 2 plasmid backbones.Conclusions:A complex KPC outbreak involving both clonal and plasmid-mediated dissemination was controlled using weekly surveillances and a cohorting unit.

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Effect of an Amino Acid Insertion into the Omega Loop Region of a Class C β-Lactamase on Its Substrate Specificity†

Biochemistry ◽

10.1021/bi980184i ◽

1998 ◽

Vol 37 (29) ◽

pp. 10461-10468 ◽

Cited By ~ 26

Author(s):

Michiyoshi Nukaga ◽

Kazuo Taniguchi ◽

Yukio Washio ◽

Tetsuo Sawai

Keyword(s):

Amino Acid ◽

Substrate Specificity ◽

Loop Region ◽

Amino Acid Insertion ◽

Omega Loop ◽

Class C

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Amino Acid Substitutions of CrrB Responsible for Resistance to Colistin through CrrC in Klebsiella pneumoniae

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00009-16 ◽

2016 ◽

Vol 60 (6) ◽

pp. 3709-3716 ◽

Cited By ~ 49

Author(s):

Yi-Hsiang Cheng ◽

Tzu-Lung Lin ◽

Yi-Tsung Lin ◽

Jin-Town Wang

Keyword(s):

Amino Acid ◽

Klebsiella Pneumoniae ◽

Site Directed Mutagenesis ◽

Amino Acid Substitutions ◽

Missense Mutations ◽

Colistin Resistance ◽

Two Component System ◽

Content Type ◽

Carbapenem Resistant ◽

Elevated Expression

Colistin is a last-resort antibiotic for treatment of carbapenem-resistantKlebsiella pneumoniae. A recent study indicated that missense mutations in the CrrB protein contribute to colistin resistance. In our previous study, mechanisms of colistin resistance were defined in 17 of 26 colistin-resistantK. pneumoniaeclinical isolates. Of the remaining nine strains, eight were highly resistant to colistin. In the present study,crrABsequences were determined for these eight strains. Six separate amino acid substitutions in CrrB (Q10L, Y31H, W140R, N141I, P151S, and S195N) were detected. Site-directed mutagenesis was used to generatecrrBloci harboring individual missense mutations; introduction of the mutated genes into a susceptible strain, A4528, resulted in 64- to 1,024-fold increases in colistin MICs. ThesecrrBmutants showed increased accumulation ofH239_3062,H239_3059,pmrA,pmrC, andpmrHtranscripts by quantitative reverse transcription (qRT)-PCR. Deletion ofH239_3062(but not that ofH239_3059) in the A4528crrB(N141I) strain attenuated resistance to colistin, andH239_3062was accordingly namedcrrC. Similarly, accumulation ofpmrA,pmrC, andpmrHtranscripts induced bycrrB(N141I) was significantly attenuated upon deletion ofcrrC. Complementation ofcrrCrestored resistance to colistin and accumulation ofpmrA,pmrC, andpmrHtranscripts in acrrB(N141I) ΔcrrCstrain. In conclusion, novel individual CrrB amino acid substitutions (Y31H, W140R, N141I, P151S, and S195N) were shown to be responsible for colistin resistance. We hypothesize that CrrB mutations induce CrrC expression, thereby inducing elevated expression of thepmrHFIJKLMoperon andpmrC(an effect mediated via the PmrAB two-component system) and yielding increased colistin resistance.

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Nosocomial Outbreak of Klebsiella pneumoniae Carbapenemase-Producing Klebsiella oxytoca in Austria

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.05440-11 ◽

2012 ◽

Vol 56 (4) ◽

pp. 2158-2161 ◽

Cited By ~ 23

Author(s):

Martin Hoenigl ◽

Thomas Valentin ◽

Gernot Zarfel ◽

Benjamin Wuerstl ◽

Eva Leitner ◽

...

Keyword(s):

Intensive Care Unit ◽

Intensive Care ◽

Klebsiella Pneumoniae ◽

Medical Intensive Care Unit ◽

Klebsiella Oxytoca ◽

Nosocomial Outbreak ◽

Content Type ◽

Klebsiella Pneumoniae Carbapenemase ◽

Medical Intensive Care

ABSTRACTTo date, no outbreak of carbapenemase-producing bacteria has been reported for Austria. While outbreaks ofKlebsiella pneumoniaecarbapenemase (KPC)-producingK. pneumoniaehave been increasingly reported, no outbreak caused by KPC-producingKlebsiella oxytocahas been described yet, to the best of our knowledge. We report an outbreak of KPC-producingK. oxytoca. In 5 months, 31 KPC-producingKlebsiella oxytocastrains were isolated from five patients. All patients were admitted to the same medical intensive care unit in Austria.

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Doripenem, Gentamicin, and Colistin, Alone and in Combinations, against Gentamicin-Susceptible, KPC-Producing Klebsiella pneumoniae Strains with VariousompK36Genotypes

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01949-13 ◽

2014 ◽

Vol 58 (6) ◽

pp. 3521-3525 ◽

Cited By ~ 26

Author(s):

Cornelius J. Clancy ◽

Binghua Hao ◽

Ryan K. Shields ◽

Liang Chen ◽

David S. Perlin ◽

...

Keyword(s):

Antimicrobial Activity ◽

Amino Acid ◽

Klebsiella Pneumoniae ◽

Aspartic Acid ◽

Wild Type ◽

Content Type ◽

Drug Regimens

ABSTRACTGentamicin doses of 2 and 10 μg/ml were bactericidal against 64% and 100%, respectively, of gentamicin-susceptible KPC-2-producingKlebsiella pneumoniaestrains. Treatment with the combination of doripenem (8 μg/ml) plus colistin (2 μg/ml) was inferior to treatment with gentamicin (2 μg/ml), doripenem-gentamicin, gentamicin-colistin, and doripenem-gentamicin-colistin against strains with glycine and aspartic acid insertions in OpmK36 porin at amino acid (aa) positions 134 and 135 (n= 9). Doripenem-colistin was comparable to other 2- or 3-drug regimens and superior to single drugs against wild-type/minorompK36mutants (n= 5). An algorithm incorporatingompK36genotypes and susceptibility to gentamicin and doripenem may predict antimicrobial activity against KPC-producingK. pneumoniae.

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Global Molecular Epidemiology of IMP-Producing Enterobacteriaceae

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02729-16 ◽

2017 ◽

Vol 61 (4) ◽

Cited By ~ 23

Author(s):

Yasufumi Matsumura ◽

Gisele Peirano ◽

Mary R. Motyl ◽

Mark D. Adams ◽

Liang Chen ◽

...

Keyword(s):

Klebsiella Pneumoniae ◽

Molecular Epidemiology ◽

Common Species ◽

Molecular Techniques ◽

Content Type ◽

Class 1 ◽

Surveillance Programs ◽

International Data ◽

Enterobacter Hormaechei ◽

Insight Into

ABSTRACT International data on the molecular epidemiology of Enterobacteriaceae with IMP carbapenemases are lacking. We performed short-read (Illumina) whole-genome sequencing on a global collection of 38 IMP-producing clinical Enterobacteriaceae (2008 to 2014). IMP-producing Enterobacteriaceae (7 varieties within 11 class 1 integrons) were mainly present in the South Pacific and Asia. Specific bla IMP-containing integrons (In809 with bla IMP-4, In722 with bla IMP-6, and In687 with bla IMP-14) were circulating among different bacteria in countries such as Australia, Japan, and Thailand. In1312 with bla IMP-1 was present in Klebsiella pneumoniae from Japan and Citrobacter freundii from Brazil. Klebsiella pneumoniae (n = 22) was the most common species; clonal complex 14 (CC14) from Philippines and Japan was the most common clone and contained In1310 with bla IMP-26 and In1321 with bla IMP-6. The Enterobacter cloacae complex (n = 9) consisted of Enterobacter hormaechei and E. cloacae cluster III. CC78 (from Taiwan) containing In73 with bla IMP-8 was the most common clone among the E. cloacae complex. This study highlights the importance of surveillance programs using the latest molecular techniques for providing insight into the characteristics and global distribution of Enterobacteriaceae with bla IMP genes.

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Mutations of theompK36Porin Gene and Promoter Impact Responses of Sequence Type 258, KPC-2-Producing Klebsiella pneumoniae Strains to Doripenem and Doripenem-Colistin

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01069-13 ◽

2013 ◽

Vol 57 (11) ◽

pp. 5258-5265 ◽

Cited By ~ 57

Author(s):

Cornelius J. Clancy ◽

Liang Chen ◽

Jae H. Hong ◽

Shaoji Cheng ◽

Binghua Hao ◽

...

Keyword(s):

Multivariate Analysis ◽

Amino Acid ◽

Klebsiella Pneumoniae ◽

Independent Predictor ◽

Gene Mutations ◽

Sequence Type ◽

Wild Type ◽

Content Type ◽

Time Kill

ABSTRACTDoripenem-colistin exerts synergy against some, but not all,Klebsiella pneumoniaecarbapenemase (KPC)-producingK. pneumoniaestrainsin vitro. We determined if doripenem MICs and/orompK36porin 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 mutantompK36, respectively. The most common mutations were IS5promoter 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-typeompK36(allPvalues ≤ 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 IS5mutants (P= 0.007 and 0.0007). By multivariate analysis, the absence of ins aa134-135 GD or IS5mutations was the only independent predictor of doripenem-colistin responses at 24 h (P= 0.002). In conclusion,ompK36genotypes identified ST258 KPC-K. pneumoniaestrains that were most likely to respond to doripenem-colistin.

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Coproduction of 16S rRNA Methyltransferase RmtD or RmtG with KPC-2 and CTX-M Group Extended-Spectrum β-Lactamases in Klebsiella pneumoniae

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02108-12 ◽

2013 ◽

Vol 57 (5) ◽

pp. 2397-2400 ◽

Cited By ~ 63

Author(s):

Maria Fernanda C. Bueno ◽

Gabriela R. Francisco ◽

Jessica A. O'Hara ◽

Doroti de Oliveira Garcia ◽

Yohei Doi

Keyword(s):

Amino Acid ◽

16S Rrna ◽

Klebsiella Pneumoniae ◽

Amino Acid Identity ◽

Aminoglycoside Resistance ◽

Content Type ◽

Acid Identity ◽

Paulo State ◽

Extended Spectrum ◽

High Level

ABSTRACTEightKlebsiella pneumoniaeclinical strains with high-level aminoglycoside resistance were collected from eight hospitals in São Paulo State, Brazil, in 2010 and 2011. Three of them produced an RmtD group 16S rRNA methyltransferase, RmtD1 or RmtD2. Five strains were found to produce a novel 16S rRNA methyltransferase, designated RmtG, which shared 57 to 58% amino acid identity with RmtD1 and RmtD2. Seven strains coproduced KPC-2 with or without various CTX-M group extended-spectrum β-lactamases, while the remaining strain coproduced CTX-M-2.

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