Consecutive mutations leading to the emergence in vivo of imipenem resistance in a clinical strain of Enterobacter aerogenes

Tzouvelekis, L. S.; Tzelepi, E.; Kaufmann, M. E.; Mentis, Αndreas

doi:10.1099/00222615-40-6-403

Cited by 24 publications

(17 citation statements)

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“…Reduced imipenem susceptibility (MIC 8 to 32 g/ml) has also been reported in porin-deficient clinical isolates of K. pneumoniae making AmpC enzymes ACC-1 (34), CMY-2 (171), CMY-4 (49), DHA-1 (171), or an uncharacterized AmpC-type enzyme (246). The same scenario has been described for clinical isolates of E. aerogenes (59,71,317,325,349), E. cloacae (168), and C. freundii (192) as well as laboratory mutants (131,270,327). In E. coli, reduced carbapenem susceptibility or frank resistance (imipenem MIC of 8 to 128 g/ml) in porin-deficient clinical isolates producing CMY-2 (183) or CMY-4 (303) has been described, while a Salmonella enterica strain lacking a porin and making CMY-4 reached an imipenem MIC of 32 g/ml (8).…”

Section: Treatment Of Ampc-producing Organismsmentioning

confidence: 76%

AmpC β-Lactamases

2009

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SUMMARY AmpC β-lactamases are clinically important cephalosporinases encoded on the chromosomes of many of the Enterobacteriaceae and a few other organisms, where they mediate resistance to cephalothin, cefazolin, cefoxitin, most penicillins, and β-lactamase inhibitor-β-lactam combinations. In many bacteria, AmpC enzymes are inducible and can be expressed at high levels by mutation. Overexpression confers resistance to broad-spectrum cephalosporins including cefotaxime, ceftazidime, and ceftriaxone and is a problem especially in infections due to Enterobacter aerogenes and Enterobacter cloacae, where an isolate initially susceptible to these agents may become resistant upon therapy. Transmissible plasmids have acquired genes for AmpC enzymes, which consequently can now appear in bacteria lacking or poorly expressing a chromosomal blaAmpC gene, such as Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis. Resistance due to plasmid-mediated AmpC enzymes is less common than extended-spectrum β-lactamase production in most parts of the world but may be both harder to detect and broader in spectrum. AmpC enzymes encoded by both chromosomal and plasmid genes are also evolving to hydrolyze broad-spectrum cephalosporins more efficiently. Techniques to identify AmpC β-lactamase-producing isolates are available but are still evolving and are not yet optimized for the clinical laboratory, which probably now underestimates this resistance mechanism. Carbapenems can usually be used to treat infections due to AmpC-producing bacteria, but carbapenem resistance can arise in some organisms by mutations that reduce influx (outer membrane porin loss) or enhance efflux (efflux pump activation).

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Section: Treatment Of Ampc-producing Organismsmentioning

confidence: 76%

AmpC β-Lactamases

2009

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“…There are limited reports regarding the role of AmpD in adaptive carbapenem resistance in K. aerogenes strains (23, 24), although the role of AmpD in AmpC expression in E. cloacae has been well established (25). In silico modeling of K. aerogenes AmpD using the C. freundii AmpD crystal structure (15) predicted that Arg161 His and Trp95Leu substitutions due to SNPs in the outbreak strains would likely impact enzymatic activity (Fig.…”

Section: Discussionmentioning

confidence: 99%

Next-generation sequencing based hospital outbreak investigation yields insight into Klebsiella aerogenes population structure and determinants of carbapenem resistance and virulence

Malek

McGlynn

Taffner

et al. 2018

Preprint

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49Klebsiella aerogenes is a nosocomial pathogen associated with drug resistance 50 and outbreaks in intensive care units. In a 5-month period in 2017, we experienced an 51 increased incidence of cultures for carbapenem-resistant K. aerogenes (CR-KA) from 52 an adult cardiothoracic intensive care unit (CICU) involving 15 patients. Phylogenomic 53 analysis following whole-genome sequencing (WGS) identified the outbreak CR-KA 54 isolates to group together as a tight clonal cluster (<7 SNPs apart), suggestive of a 55 protracted intra-ward transmission event. No clonal relationships were identified 56 between the CICU CR-KA strains and additional hospital CR-KA patient isolates from 57 different wards and/or previous years. Genes encoding carbapenemases or drug-58 resistant plasmids were absent in the outbreak strains, and carbapenem resistance was 59 attributed to mutations impacting AmpD activity and membrane permeability. The CICU 60 outbreak strains harbored an integrative conjugative element (ICEKp10), which has 61 been associated with pathogenicity in hypervirulent Klebsiella pneumoniae lineages. 62Comparative genomics with global K. aerogenes genomes showed our outbreak strains 63 to group closely with global ST4 strains, which along with ST93 likely represent 64 dominant K. aerogenes lineages associated with human infections. WGS is a powerful 65 tool that goes beyond high-resolution tracking of transmission events into identifying the 66 genetic basis of drug-resistance and virulence, which are not part of conventional 67 diagnostic workflows. With an increasing availability of sequenced genomes from 68 across the globe, population structure analysis offers opportunities to identify emerging 69 trends and dominant clones associated with specific syndromes and geographical 70 locations for poorly characterized pathogens. 71

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“…In E. aerogenes, resistance can result from the loss or reduction of a major porin or from the expression of a porin altered in the constriction area, which decreases the diameter and modifies the electrostatic field or the expression of an efflux mechanism (10,12,13,18,29,45). The implications of this complex phenotype, which includes a deficit in porin synthesis and multidrug resistance, has been studied in two clinical multidrugresistant E. aerogenes strains isolated in our laboratory (12).…”

Section: Discussionmentioning

confidence: 99%

Modification of Outer Membrane Protein Profile and Evidence Suggesting an Active Drug Pump in Enterobacter aerogenes Clinical Strains

Gayet¹,

Chollet²,

Molle

et al. 2003

Antimicrob Agents Chemother

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Two clinical strains of Enterobacter aerogenes that exhibited phenotypes of multiresistance to ␤-lactam antibiotics, fluoroquinolones, chloramphenicol, tetracycline, and kanamycin were investigated. Both strains showed a porin pattern different from that of a susceptible strain, with a drastic reduction in the amount of the major porin but with an apparently conserved normal structure (size and immunogenicity), together with overproduction of two known outer membrane proteins, OmpX and LamB. In addition, the full-length Opolysaccharide phenotype was replaced by a semirough Ra phenotype. Moreover, in one isolate the intracellular accumulation of chloramphenicol was increased in the presence of the energy uncoupler carbonyl cyanide m-chlorophenylhydrazone, suggesting an energy-dependent efflux of chloramphenicol in this strain. The resistance strategies used by these isolates appear to be similar to that induced by stress in Escherichia coli cells.Bacteria have developed various regulatory systems which coordinate their adaptive responses with the different environmental stresses to which they are exposed. Recently, the wholegenome transcriptional profiles, or "transcriptomes," were determined in vitro for an Escherichia coli strain exposed to an inducer of the soxRS or marRAB system and an E. coli strain constitutively expressing MarA (7,39). Under these conditions, the expression of several genes appeared to be significantly activated or down-regulated. These modulations of gene expression alter the sensitivities of the bacteria to a broad range of antibiotics (1, 2).Enterobacter aerogenes is one of the more frequently described gram-negative bacteria responsible for nosocomial respiratory tract infections (5, 17). In the last 5 years, it has been shown that clinical isolates of this species, which are naturally resistant to aminopenicillins through their production of a chromosomal cephalosporinase, often express an extendedspectrum ␤-lactamase, TEM-24, which gives rise to resistance to ␤-lactam antibiotics (5,17,19,31). Moreover, E. aerogenes exhibits acquired resistance to other families of antimicrobial agents. Previous studies have reported that clinical strains exhibiting an efflux process are resistant to ␤-lactam antibiotics, quinolones, tetracycline, and chloramphenicol (12, 29). Drug efflux can be coincident with a drastic reduction in drug uptake due to the loss of porin content (16,22,23,29).Two E. aerogenes clinical isolates, isolates 117 and 119, were selected from up to 100 strains isolated in our laboratory (12). These two strains exhibited a phenotype of multiresistance to ␤-lactam antibiotics, fluoroquinolones, chloramphenicol, tetracycline, and kanamycin comparable to that of E. aerogenes strains lacking nonspecific porins or expressing mutated porins (12, 29).The aim of this work was to examine some factors that may contribute to the resistance to antimicrobial agents in these two E. aerogenes clinical strains. MATERIALS AND METHODSBacterial strains, growth conditions, and antibiotic suscepti...

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Consecutive mutations leading to the emergence in vivo of imipenem resistance in a clinical strain of Enterobacter aerogenes

Cited by 24 publications

References 1 publication

AmpC β-Lactamases

AmpC β-Lactamases

Next-generation sequencing based hospital outbreak investigation yields insight into Klebsiella aerogenes population structure and determinants of carbapenem resistance and virulence

Modification of Outer Membrane Protein Profile and Evidence Suggesting an Active Drug Pump in Enterobacter aerogenes Clinical Strains

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