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Antimicrobial Agents and Chemotherapy, December 2003, p. 3881-3889, Vol. 47, No. 12
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.12.3881-3889.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Carbapenem-Resistant Strain of Klebsiella oxytoca Harboring Carbapenem-Hydrolyzing ß-Lactamase KPC-2

Hesna Yigit,1 Anne Marie Queenan,2 J. Kamile Rasheed,3 James W. Biddle,3 Antonio Domenech-Sanchez,4 Sebastian Alberti,5 Karen Bush,2 and Fred C. Tenover3*

Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut 06492,1 The R. W. Johnson Pharmaceutical Research Institute, Raritan, New Jersey 08869,2 Division of Healthcare Quality Promotion, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia 30333,3 Unidad de Investigacion, Hospital Son Dureta, Andrea Doria, Palma de Mallorca 07014,4 Area de Microbiologia, Universidad de las Islas Baleares, Crtra.Valldemosa, Palma de Mallorca 07071, Spain5

Received 6 May 2003/ Returned for modification 14 July 2003/ Accepted 31 August 2003

We investigated a Klebsiella oxytoca isolate demonstrating resistance to imipenem, meropenem, extended-spectrum cephalosporins, and aztreonam. The MICs of both imipenem and meropenem were 32 µg/ml. The ß-lactamase activity against imipenem and meropenem was inhibited in the presence of clavulanic acid. Isoelectric focusing studies demonstrated five ß-lactamases with pIs of 8.2 (SHV-46), 6.7 (KPC-2), 6.5 (unknown), 6.4 (probable OXY-2), and 5.4 (TEM-1). The presence of the blaSHV and blaTEM genes was confirmed by specific PCR assays and DNA sequence analysis. Transformation and conjugation studies with Escherichia coli showed that the ß-lactamase with a pI of 6.7, Klebsiella pneumoniae carbapenemase-2 (KPC-2), was encoded on an approximately 70-kb conjugative plasmid that also carried SHV-46, TEM-1, and the ß-lactamase with a pI of 6.5. The blaKPC-2 determinant was cloned in E. coli and conferred resistance to imipenem, meropenem, extended-spectrum cephalosporins, and aztreonam. The amino acid sequence of KPC-2 showed a single amino acid difference, S174G, when compared with KPC-1, another carbapenem-hydrolyzing ß-lactamase from K. pneumoniae 1534. Hydrolysis studies showed that purified KPC-2 hydrolyzed not only carbapenems but also penicillins, cephalosporins, and aztreonam. KPC-2 had the highest affinity for meropenem. The kinetic studies revealed that KPC-2 was inhibited by clavulanic acid and tazobactam. An examination of the outer membrane proteins of the parent K. oxytoca strain demonstrated that it expressed detectable levels of OmpK36 (the homolog of OmpC) and a higher-molecular-weight OmpK35 (the homolog of OmpF). Thus, carbapenem resistance in K. oxytoca 3127 is due to production of the Bush group 2f, class A, carbapenem-hydrolyzing ß-lactamase KPC-2. This ß-lactamase is likely located on a transposon that is part of a conjugative plasmid and thus has a very high potential for dissemination.

* Corresponding author. Mailing address: Division of Healthcare Quality Promotion (G08), Centers for Disease Control and Prevention, 1600 Clifton Rd., Atlanta, GA 30333. Phone: (404) 639-3375. Fax: (404) 639-1381. E-mail: fnt1{at}cdc.gov.

Antimicrobial Agents and Chemotherapy, December 2003, p. 3881-3889, Vol. 47, No. 12
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.12.3881-3889.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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