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Antimicrobial Agents and Chemotherapy, December 2002, p. 3817-3822, Vol. 46, No. 12
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.12.3817-3822.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

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

Hesna Yigit,^1, Gregory J. Anderson,¹ James W. Biddle,¹ Christine D. Steward,¹ J. Kamile Rasheed,¹ Lourdes L. Valera,² John E. McGowan Jr.,³ and Fred C. Tenover^1*

Division of Healthcare Quality Promotion, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia 30333,¹ Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut 06492,² Rollins School of Public Health, Emory University, Atlanta, Georgia 30322³

Received 4 March 2002/ Returned for modification 9 April 2002/ Accepted 13 August 2002

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 µg/ml and the meropenem MIC was 8 µg/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 µg/ml and the meropenem MIC was 0.25 µg/ml. Cefepime MICs also decreased from 8 to 1 µg/ml; however, the MICs of ceftazidime (128 µg/ml), cefoxitin (32 µg/ml), and cefotaxime (64 µg/ml) remained the same. The ß-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 ß-lactamases with pIs of 8.2 and 5.4. The ß-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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* Corresponding author. Mailing address: Division of Healthcare Quality Promotion (G08), Centers for Disease Control and Prevention, 1600 Clifton Rd. NE, Atlanta, GA 30333. Phone: (404) 639-3375. Fax: (404) 639-1381. E-mail: fnt1{at}cdc.gov.

Present address: Bristol-Myers Squibb Pharmaceutical Research Institute, PRI ID Virology 106, Wallingford, CT 06492.

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Antimicrobial Agents and Chemotherapy, December 2002, p. 3817-3822, Vol. 46, No. 12
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.12.3817-3822.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

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