Emergence of Resistance to Imipenem in Enterobacter Isolates Masquerading as Klebsiella pneumoniae During Therapy with Imipenem/Cilastatin

Ehrhardt, Anton F.; Sanders, Christine C.; Thomson, Kenneth S.; Watanakunakorn, Chatrchai; Trujillano-Martín, I.

doi:10.1093/clinids/17.1.120

Cited by 22 publications

(15 citation statements)

References 6 publications

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“…The phenomenon of E. aerogenes misidentified as K. pneumoniae or K. terrigena due to delayed or negative ornithine decarboxylase and motility was reported previously, and was also discovered because of unexpected imipenem resistance of the so-called K. pneumoniae isolates [8]. Also in this case, subculture and prolonged incubation restored the positivity for these characteristics.…”

Section: Discussionsupporting

confidence: 56%

“…This can be deduced from the following considerations: i) this phenomenon of misidentification of E. aerogenes was already reported in 1993 [8], ii) the phenomenon occurred in genotypically different organisms, iii) the isolates were found over an extended period of time – also recently, and finally iv) we received similar strains from other Belgian hospitals (unpublished data). It should be noted that misidentification also occurred when using the newer and automated systems like Vitek2 and Phoenix.…”

Section: Discussionmentioning

confidence: 68%

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Extended-Spectrum β-lactamase (ESBL) producing Enterobacter aerogenes phenotypically misidentified as Klebsiella pneumoniae or K. terrigena

et al. 2004

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Background: Enterobacter aerogenes and Klebsiella pneumoniae are common isolates in clinical microbiology and important as producers of extended spectrum β-lactamases (ESBL). The discrimination between both species, which is routinely based on biochemical characteristics, is generally accepted to be straightforward. Here we report that genotypically unrelated strains of E. aerogenes can be misidentified as K. pneumoniae by routine laboratories using standard biochemical identification and using identification automates.

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Section: Discussionsupporting

confidence: 56%

Section: Discussionmentioning

confidence: 68%

Extended-Spectrum β-lactamase (ESBL) producing Enterobacter aerogenes phenotypically misidentified as Klebsiella pneumoniae or K. terrigena

et al. 2004

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“…Carbapenems, such as imipenem and meropenem, often are used to treat multidrug-resistant isolates of Enterobacter, especially those producing extendedspectrum ␤-lactamases (11,25). However, a significant increase in the frequency of carbapenem resistance for E. aerogenes has been observed (13,31), complicating therapy of these infections.…”

Section: Discussionmentioning

confidence: 99%

“…Resistance to ␤-lactams is usually a result of ␤-lactamase production or alteration of porins (5,6,8), but it may be due to modification of the target site (the penicillin binding proteins) or drug efflux (19). Carbapenems often have been used to treat infections caused by multidrug-resistant E. aerogenes strains; however, resistance to carbapenems is starting to emerge (11,13). The mechanism of carbapenem resistance is often a combination of specific carbapenemase production and alteration of porins (3,31).…”

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confidence: 99%

Carbapenem Resistance in a Clinical Isolate of Enterobacter aerogenes Is Associated with Decreased Expression of OmpF and OmpC Porin Analogs

Yigit

Anderson

Biddle

et al. 2002

Antimicrob Agents Chemother

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We investigated the mechanism of imipenem resistance in Enterobacter aerogenes strain 810, a clinical isolate from the United States for which the imipenem MIC was 16 g/ml and the meropenem MIC was 8 g/ml. An imipenem-susceptible revertant, strain 810-REV, was obtained after multiple passages of the strain on nonselective media. For the revertant, the imipenem MIC was <1 g/ml and the meropenem MIC was <0.25 g/ ml. Cefepime MICs also decreased from 8 to 1 g/ml; however, the MICs of ceftazidime (>128 g/ml), cefoxitin (>32 g/ml), and cefotaxime (>64 g/ml) remained the same. The ␤-lactamase and porin profiles of the parent, the revertant, and carbapenem-susceptible type strain E. aerogenes ATCC 13048 were determined. Strains 810 and 810-REV each produced two ␤-lactamases with pIs of 8.2 and 5.4. The ␤-lactamase activities of the parent and revertant were similar, even after induction with subinhibitory concentrations of imipenem. While 810-REV produced two major outer membrane proteins of 42 and 39 kDa that corresponded to Escherichia coli porins OmpC and OmpF, respectively, the parent strain appeared to produce similar quantities of the 39-kDa protein (OmpF) but decreased amounts of the 42-kDa protein (OmpC). When the parent strain was grown in the presence of imipenem, the 42-kDa protein was not detectable by gel electrophoresis. However, Western blot analysis of the outer membrane proteins of the parent and revertant with polyclonal antisera raised to the OmpC and OmpF analogs of Klebsiella pneumoniae (anti-OmpK36 and anti-OmpK35, respectively) showed that strain 810 expressed only the 42-kDa OmpC analog in the absence of imipenem (the 39-kDa protein was not recognized by the anti-OmpF antisera) and neither the OmpC nor the OmpF analog in the presence of imipenem. The OmpC analog is apparently down-regulated in the presence of imipenem; however, 810-REV expressed both OmpC and OmpF analogs. These data suggest that imipenem resistance in E. aerogenes 810 is primarily associated with the lack of expression of the analogs of the OmpC (42-kDa) and OmpF (39-kDa) outer membrane proteins, which also results in decreased susceptibility to meropenem and cefepime.

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“…First, high-level production of chromosomal AmpC cephalosporinases combined with substantially decreased outer membrane permeability may result in carbapenem resistance in Enterobacter cloacae, Enterobacter aerogenes, and Proteus rettgeri (8,11,13,16,24,41). Second, resistance may result from the synthesis of ,-lactamases able to hydrolyze carbapenems (27).…”

mentioning

confidence: 99%

Cloning and sequence analysis of the gene for a carbapenem-hydrolyzing class A beta-lactamase, Sme-1, from Serratia marcescens S6

Naas

Vandel

Sougakoff

et al. 1994

Antimicrob Agents Chemother

163

122

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Serratia marcescens S6 produces a pl 9.7 carbapenem-hydrolyzing ,-lactamase that is probably encoded by the chromosome (Y. Yang, P. Wu, and D. M. Livermore, Antimicrob. Agents Chemother. 34:755-758, 1990). A total of 11.3 kb of genomic DNA from this strain was cloned into plasmid pACYC184 in Escherichia coli. After further subclonings, the carbapenem-hydrolyzing ,I-lactamase gene (blaSme1) was sequenced (EMBL accession number Z28968). The gene corresponded to an 882-bp open reading frame which encoded a 294-amino-acid polypeptide. This open reading frame was preceded by a -10 and a -35 region consistent with a putative promoter sequence of members of the family Enterobacteriaceae. This promoter was active in E. coli and S. marcescens, as demonstrated by primer extension analysis. N-terminal sequencing showed that the Sme-1 enzyme had a 27-amino-acid leader peptide and enabled calculation of the molecular mass of the mature protein (29.3 kDa). Sequence alignment revealed that Sme-i is a class A serine ,I-lactamase and not a class B metalloenzyme. The earlier view that the enzyme was zinc dependent was discounted. Among class A j8-lactamases, Sme-i had the greatest amino acid identity (70%) with the pl 6.9 carbapenem-hydrolyzing I-lactamase, NMC-A, from Enterobacter cloacae NOR-1. Comparison of these two protein sequences suggested a role for specific residues in carbapenem hydrolysis. The relatedness of Sme-i to other class A ,-lactamases such as the TEM and SHV types was remote. This work details the sequence of the second carbapenemhydrolyzing class A P-lactamase from an enterobacterial species and the first in the genus Serratia.Despite widespread therapeutic usage, resistance to imipenem remains very rare in clinical isolates of the family Enterobacteriaceae, but resistance can arise via two mechanisms. First, high-level production of chromosomal AmpC cephalosporinases combined with substantially decreased outer membrane permeability may result in carbapenem resistance in Enterobacter cloacae, Enterobacter aerogenes, and Proteus rettgeri (8,11,13,16,24,41). Second, resistance may result from the synthesis of ,-lactamases able to hydrolyze carbapenems (27). So far, only three enterobacterial strains have been well described as producing carbapenem-hydrolyzing ,-lactamases. Specifically, Serratia marcescens S6 and S8 produce similar pI 9.7 carbapenem-hydrolyzing P-lactamases and E. cloacae NOR-1 produces a pl 6.9 enzyme, NMC-A (34, 50). These strains also have AmpC cephalosporinases. The carbapenem-hydrolyzing 1-lactamases of S. marcescens S6 and E. cloacae NOR-1 have similar hydrolytic properties and are partially inhibited by similar concentrations of clavulanic acid. The NMC-A enzyme has been sequenced and has been shown to be a class A serine 1-lactamase (35), but the S. marcescens S6 enzyme remains unsequenced and was initially inferred to be a metalloenzyme on the basis of data suggesting inhibition by EDTA (50).In the present report, we describe the cloning and DNA and

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Emergence of Resistance to Imipenem in Enterobacter Isolates Masquerading as Klebsiella pneumoniae During Therapy with Imipenem/Cilastatin

Cited by 22 publications

References 6 publications

Extended-Spectrum β-lactamase (ESBL) producing Enterobacter aerogenes phenotypically misidentified as Klebsiella pneumoniae or K. terrigena

Extended-Spectrum β-lactamase (ESBL) producing Enterobacter aerogenes phenotypically misidentified as Klebsiella pneumoniae or K. terrigena

Carbapenem Resistance in a Clinical Isolate of Enterobacter aerogenes Is Associated with Decreased Expression of OmpF and OmpC Porin Analogs

Cloning and sequence analysis of the gene for a carbapenem-hydrolyzing class A beta-lactamase, Sme-1, from Serratia marcescens S6

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