Carbapenemase-Producing Gram-Negative Bacteria: Current Epidemics, Antimicrobial Susceptibility and Treatment Options

Jean, Shio Shin; Lee, Wen Sen; Lam, Carlos; Hsu, Chin Wang; Chen, Ray Jade; Hsueh, Po-Ren

doi:10.2217/fmb.14.135

Cited by 105 publications

(109 citation statements)

References 195 publications

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“…Of the several carbapenemases previously described worldwide, the bla KPC has been reported as the predominant carbapenemase gene associated with CRE intrahospital infections [36]. Nevertheless, in the recent years, bla NDM-1 gene has frequently been associated with outbreaks, particularly with strains of K .…”

Section: Discussionmentioning

confidence: 99%

Molecular and microbiological report of a hospital outbreak of NDM-1-carrying Enterobacteriaceae in Mexico

et al. 2017

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ObjectivesTo characterize the microbiological, molecular and epidemiological data of an outbreak of carbapenem-resistant Enterobacteriaceae (CRE) in a tertiary-care hospital in Mexico.MethodsFrom September 2014 to July 2015, all CRE clinical isolates recovered during an outbreak in the Hospital Civil "Fray Antonio Alcalde" in Jalisco, Mexico were screened for antimicrobial susceptibility, carbapenemase production, carbapenemase-encoding genes, and plasmid profiles. Horizontal transfer of imipenem resistance; and clonal diversity by pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST); as well as biofilm production and the presence of 14 virulence genes were analyzed in selected isolates.ResultsFifty-two carbapenem-resistant isolates corresponding to 5 species were detected, i.e., Klebsiella pneumoniae (n = 46), Enterobacter cloacae (n = 3), Escherichia coli (n = 1), Providencia rettgeri (n = 1) and Citrobacter freundii (n = 1) with carbapenemase encoding genes blaNDM-1 (n = 48), blaVIM (n = 3), blaIMP (n = 1) and blaKPC (n = 1) detected in these isolates.The blaNDM-1 gene was detected in plasmids from 130- to 170-kb in K. pneumoniae (n = 46); E. cloacae (n = 3), E. coli (n = 1) and P. rettgeri (n = 1). The transfer of plasmids harboring the blaNDM-1 gene was obtained in eight transconjugants. One plasmid restriction pattern was detected, with the blaNDM-1 identified in different restriction fragments.Predominant clone A of K. pneumoniae isolates archived 28/46 (60%) isolates and belongs to ST392. Besides, ST307, ST309, ST846, ST2399, and ST2400 were detected for K. pneumoniae; as well as E. cloacae ST182 and E. coli ST10.The fimA and uge genes were more likely to be identified in K. pneumoniae carbapenem-susceptible isolates (p = <0.001) and biofilm production was more liable to be observed in carbapenem-resistant isolates (p = <0.05).ConclusionsFour Enterobacteriaceae species harboring the blaNDM-1 gene were detected in a nosocomial outbreak in Mexico; horizontal transfer and strain transmission were demonstrated for the blaNDM-1 gene. Given the variation in the size of the plasmid harboring blaNDM-1, complex rearrangements must also be occurring.

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Section: Discussionmentioning

confidence: 99%

Molecular and microbiological report of a hospital outbreak of NDM-1-carrying Enterobacteriaceae in Mexico

et al. 2017

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“…Over 1300 such enzymes have now been identified in isolates of diverse clinical origin . While the spectrum of activity against different β‐lactam classes varies between enzymes, carbapenem‐hydrolysing β‐lactamases are attracting increasing attention due to the efficiency with which they hydrolyse most β‐lactam classes and the growing frequency with which they are isolated from patients .…”

Section: Introductionmentioning

confidence: 99%

Crystal structures of VIM‐1 complexes explain active site heterogeneity in VIM‐class metallo‐β‐lactamases

et al. 2018

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Metallo‐β‐Lactamases (MBLs) protect bacteria from almost all β‐lactam antibiotics. Verona integron‐encoded MBL (VIM) enzymes are among the most clinically important MBLs, with VIM‐1 increasing in carbapenem‐resistant Enterobacteriaceae ( Escherichia coli , Klebsiella pneumoniae ) that are among the hardest bacterial pathogens to treat. VIM enzymes display sequence variation at residues (224 and 228) that in related MBLs are conserved and participate in substrate binding. How they accommodate this variability, while retaining catalytic efficiency against a broad substrate range, has remained unclear. Here, we present crystal structures of VIM‐1 and its complexes with a substrate‐mimicking thioenolate inhibitor, ML302F, that restores meropenem activity against a range of VIM‐1 producing clinical strains, and the hydrolysed product of the carbapenem meropenem. Comparison of these two structures identifies a water‐mediated hydrogen bond, between the carboxylate group of substrate/inhibitor and the backbone carbonyl of the active site zinc ligand Cys221, that is common to both complexes. Structural comparisons show that the responsible Cys221‐bound water is observed in all known VIM structures, participates in carboxylate binding with other inhibitor classes, and thus effectively replicates the role of the conserved Lys224 in analogous complexes with other MBLs. These results provide a mechanism for substrate binding that permits the variation at positions 224 and 228 that is a hallmark of VIM MBLs. Enzymes EC 3.5.2.6 Databases Co‐ordinates and structure factors for protein structures described in this manuscript have been deposited in the Protein Data Bank ( www.rcsb.org/pdb ) with accession codes 5N5G (VIM‐1), 5N5H (VIM‐1:ML302F complex) and 5N5I (VIM‐1‐hydrolysed meropenem complex).

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“…Interestingly, ceftazidime is now proposed in combination with ß-lactamase inhibitors 12, 14–16 for the treatment of ß-lactamase-producing Enterobacteriaceae , an emerging risk documented by a recent ECDC report (http://ecdc.europa.eu/en/publications/Publications/antimicrobial-resistance-europe-2014.pdf). The uptake of CAZ may be studied using our conditions in order to evaluate the influx and the stability of CAZ in the periplasmic space of ESBL-producing Enterobacteriaceae .…”

Section: Discussionmentioning

confidence: 99%

“…Today a key challenge for hospital microbiologists is to bypass the resistance in a Gram-negative strain that can produce carbapenemase and/or ß-lactamase 12, 13 . Recent studies proposed an alternative way by using a combination of ceftazidime (CAZ) + ß-lactamase inhibitor 14–16 .…”

Section: Introductionmentioning

confidence: 99%

Microspectrofluorimetry to dissect the permeation of ceftazidime in Gram-negative bacteria

Allam

Maigre

Vergalli

et al. 2017

Sci Rep

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A main challenge in chemotherapy is to determine the in cellulo parameters modulating the drug concentration required for therapeutic action. It is absolutely urgent to understand membrane permeation and intracellular concentration of antibiotics in clinical isolates: passing the membrane barrier to reach the threshold concentration inside the bacterial periplasm or cytoplasm is the pivotal step of antibacterial activity. Ceftazidime (CAZ) is a key molecule of the combination therapy for treating resistant bacteria. We designed and synthesized different fluorescent CAZ derivatives (CAZ*, CAZ**) to dissect the early step of translocation-accumulation across bacterial membrane. Their activities were determined on E. coli strains and on selected clinical isolates overexpressing ß-lactamases. The accumulation of CAZ* and CAZ** were determined by microspectrofluorimetry and epifluorimetry. The derivatives were properly translocated to the periplasmic space when we permeabilize the outer membrane barrier. The periplasmic location of CAZ** was related to a significant antibacterial activity and with the outer membrane permeability. This study demonstrated the correlation between periplasmic accumulation and antibiotic activity. We also validated the method for approaching ß-lactam permeation relative to membrane permeability and paved the way for an original matrix for determining “Structure Intracellular Accumulation Activity Relationship” for the development of new therapeutic candidates.

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Carbapenemase-Producing Gram-Negative Bacteria: Current Epidemics, Antimicrobial Susceptibility and Treatment Options

Cited by 105 publications

References 195 publications

Molecular and microbiological report of a hospital outbreak of NDM-1-carrying Enterobacteriaceae in Mexico

Molecular and microbiological report of a hospital outbreak of NDM-1-carrying Enterobacteriaceae in Mexico

Crystal structures of VIM‐1 complexes explain active site heterogeneity in VIM‐class metallo‐β‐lactamases

Microspectrofluorimetry to dissect the permeation of ceftazidime in Gram-negative bacteria

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