JAC Advance Access originally published online on January 28, 2003
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Journal of Antimicrobial Chemotherapy (2003) 51, 711-714
© 2003 The British Society for Antimicrobial Chemotherapy
Plasmid-mediated, carbapenem-hydrolysing ß-lactamase, KPC-2, in Klebsiella pneumoniae isolates
1 Department of Medical Microbiology and Immunology, Creighton University School of Medicine, 2500 California Plaza, Omaha, NE 68178; 2 Baltimore Veterans Administration Medical Center, Baltimore, MD, USA
Received 28 June 2002; returned 23 October 2002; revised 13 December 2002; accepted 14 December 2002
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Abstract |
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 Top Abstract IntroductionMaterials and methodsResultsDiscussionReferences |
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Four isolates of Klebsiella pneumoniae obtained from patients at a Maryland medical centre exhibited reduced susceptibility to carbapenems and were found to produce the novel, class A, plasmid-mediated, carbapenem-hydrolysing enzyme, KPC-2. This enzyme has 99% identity with the plasmid-mediated, carbapenem-hydrolysing enzyme KPC-1, reported previously in a North Carolina K. pneumoniae isolate. The KPC-2-producing isolates were either susceptible or intermediate to imipenem and meropenem, unlike the KPC-1-producing isolate, which was resistant to these agents. Detection of KPC-2 may be a problem for clinical laboratories because in this study it was associated with positive extended-spectrum ß-lactamase (ESBL) confirmation tests (clavulanate-potentiated activities of ceftriaxone, ceftazidime, cefepime and aztreonam). Therefore, a failure to recognize the significance of reduced carbapenem susceptibility in the isolates that remained susceptible to imipenem or meropenem could have resulted in the isolates being incorrectly identified as ESBL producers.
Keywords: imipenem, meropenem, ertapenem, ß-lactamase, carbapenemase
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Introduction |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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Molecular class A carbapenem-hydrolysing enzymes (Bush group 2f) are infrequently encountered ß-lactamases that hydrolyse a wide range of ß-lactam antibiotics. They have greater rates of hydrolysis of ampicillin and early cephalosporins than carbapenems, a characteristic that may explain their emergence and maintenance in bacteria not exposed to the selective pressure of carbapenems.1–3 They differ from the metallo-ß-lactamases (molecular class B, Bush group 3) in being inhibited by clavulanate and tazobactam, hydrolysing aztreonam and not requiring zinc at the active site for activity. To date, class A carbapenem-hydrolysing enzymes have been reported in rare isolates of Serratia marcescens (enzymes Sme-1 and Sme-2),2,4 Enterobacter cloacae (NMC-A and IMI-1)3,5 and in a single isolate of Klebsiella pneumoniae (KPC-1).6 Little is known of their clinical significance and therapeutic implications.1–3
In this report, we describe four clinical isolates of K. pneumoniae that produce the novel class A carbapenem-hydrolysing enzyme KPC-2. The isolates were obtained from patients at the Baltimore Veterans Administration Medical Center, MD, USA, between July 1998 and November 1999.
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Materials and methods |
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Bacterial strains
The four strains (UMM3, UMM12, UMM21 and UMM30) were isolated from samples of blood, sputum and urine (two patients) from four patients in July 1998 and January, June and November 1999. They were identified as K. pneumoniae by API 20E (bioMérieux, Marcy-l’Étoile, France), and one strain (UMM3) was confirmed by 16S rRNA analysis (MIDI LABS, Newark, DE, USA).
Antimicrobial susceptibility testing
Antibiotic susceptibilities were determined by overnight microdilution MIC testing using dehydrated custom-prepared panels provided by Dade MicroScan, Inc. (Sacramento, CA, USA) and by TREK Diagnostic Systems, Inc. (Westlake, OH, USA). Results were interpreted according to current NCCLS breakpoints and recommendations.7
Disc diffusion susceptibilities were determined by NCCLS methodology7 on Mueller–Hinton agar plates (Oxoid LTD, Basingstoke, UK) using BD Biosciences discs (Sparks, MD, USA).
Microbiological assay
A modification of the bioassay of Masuda et al.8 was performed using solutions containing 50 mg/L imipenem and 50 mg/L ertapenem on Mueller–Hinton agar plates that had been inoculated with a lawn of Escherichia coli ATCC 25922.
Conjugal transfer experiments
Direct transfer of carbapenem resistance into E. coli strains C600N (nalidixic acid resistant) and J53 Azir (sodium azide resistant) was attempted by a filter mating procedure. Transconjugant selection was performed on Mueller–Hinton agar containing nalidixic acid (25 mg/L), ertapenem (8 mg/L) and ceftazidime (2 mg/L) for the transfers to strain C600N, and sodium azide (200 mg/L), ertapenem (8 mg/L) and ceftazidime (2 mg/L) for transfer to strain J53 Azir.
Isoelectric focusing and ß-lactamase assays
The crude ß-lactamase extracts were subjected to analytical isoelectric focusing (IEF) on an ampholine polyacrylamide gel (pH range 3.5–9.5) to assess isoelectric points (pIs) and general inhibitor characteristics as described previously.9 Inducibility of the UMM3 isolate by imipenem (1 mg/L) and cefoxitin (2 mg/L) was investigated by the broth induction method10 and also by the disc approximation method using BBL discs containing cefoxitin and imipenem as inducing agents, and ceftriaxone, aztreonam, cefepime and ceftazidime as substrates.11 ß-Lactamase activity and inhibition characteristics were determined by spectrophotometric hydrolysis assay12 using 100 µM imipenem as substrate and the following inhibitors: 1.0 M NaCl, 1 M tazobactam and 0.25 M EDTA. The total protein content was measured with the Bio-Rad Protein assay kit (Bio-Rad, Hercules, CA, USA).
Molecular investigations
Gene identification was investigated by PCR using primers designed from the NMC-A, IMI-1 and KPC-1 sequences. PCR products were generated using primers designed from the blaKPC-1 nucleotide sequence.6 Primers used for amplification were forward primer KPC1F (5'-GCTACACCTAGCTCCACCTTC-3') and reverse primer KPC1R (5'-GCATGGATTACCAACCACTGT-5'). Products were generated and sequenced at least twice, as described previously.13
PFGE
The relatedness of the K. pneumoniae isolates was analysed by PFGE using XbaI as described previously.14
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Results |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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The four K. pneumoniae isolates exhibited reduced susceptibility to carbapenems with imipenem MICs of 2, 4, 4 and 8 mg/L, ertapenem MICs
8 mg/L and meropenem MICs of 1, 4, 8 and 8 mg/L (Table 1). By NCCLS interpretive criteria three of the isolates were susceptible to imipenem, whereas the fourth, UMM3, was intermediate. Two isolates were susceptible to meropenem and two were intermediate. All isolates were resistant to ertapenem. MICs of all other ß-lactam agents tested were also elevated (Table 1). PFGE patterns indicated that the strains were unrelated (data not shown), a finding consistent with the lengthy intervals (5–6 months) between their dates of isolation.
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Some phenotypic tests were suggestive of extended-spectrum ß-lactamase (ESBL) production. In the presence of 2 mg/L clavulanate, ceftriaxone MICs for all strains were decreased at least 32-fold. In addition, double disc tests indicated that clavulanate potentiated the activities of ceftazidime, cefepime, aztreonam and imipenem. These results indicated the production of a clavulanate-susceptible enzyme (or enzymes) that could hydrolyse these ß-lactam agents. One strain, UMM30, produced an SHV-5-like ESBL, but the other three strains produced only TEM-1- and SHV-1-like enzymes in addition to KPC-2 (data not shown). Optimal double disc test results were obtained on 5% NaCl-supplemented medium, which provided larger inhibition zones, making the test more sensitive with these highly ß-lactam-resistant isolates. Double disc tests with imipenem and unsupplemented medium were also positive, but the smaller inhibition zones obtained with this medium made these tests technically more difficult to set up and interpret (data not shown).
Although the above-mentioned tests involving ceftriaxone, cefepime and aztreonam tested alone and in combination with clavulanate were suggestive of ESBL production, it was interesting that the NCCLS ESBL confirmatory disc tests were positive for only the strain that produced the SHV-5-like ESBL (Table 2).
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IEF showed that the isolates produced either two or three ß-lactamases, including a common enzyme with a pI of
6.9 (data not shown). Isolates UMM3 and UMM21 also produced a TEM-1-like ß-lactamase with a pI of 5.4. Isolate UMM12 also produced a TEM-1-like ß-lactamase with a pI of 5.4 and an SHV-1-like ß-lactamase with a pI of 7.6. Isolate UMM30 also produced SHV-1- and SHV-5-like ß-lactamases with pIs of 7.6 and 8.2, respectively. All ß-lactamases of the four isolates were inhibited by clavulanate, but not cloxacillin in the IEF overlay tests. Using cell-free enzyme preparations, hydrolysis of imipenem and ertapenem was demonstrated in bioassays, and imipenem hydrolysis was detected in spectrophotometric assays. In spectrophotometric hydrolysis assays, carbapenem-hydrolysing activity was inhibited by tazobactam, but not EDTA or NaCl. No induction of ß-lactamase activity was detected in tests using cefoxitin or imipenem as inducing agents (data not shown). Conjugation studies resulted in the transfer of reduced carbapenem susceptibility from three of the four isolates. IEF and plasmid profile results for the E. coli transconjugants indicated that the KPC-2 enzyme was transferred by conjugal transfer of large molecular weight plasmids. Using a set of primers specific for the blaKPC-1 gene, PCR-amplified products were generated and the resulting sequence was compared with the KPC-1 gene, with the sequence analysis indicating a point mutation (A to G) at nucleotide position 650. This point mutation resulted in the amino acid substitution of serine to glycine that distinguishes KPC-2 from KPC-1 (GenBank nucleotide sequence accession number AY034847).
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Discussion |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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This study identified a new Bush group 2f, molecular class A, plasmid-mediated, carbapenem-hydrolysing ß-lactamase, KPC-2. It was produced by four unrelated isolates of K. pneumoniae that were investigated because of reduced carbapenem susceptibility. None of the isolates was resistant to imipenem or meropenem by microbroth dilution testing. KPC-2 has 99% amino acid identity to a related plasmid-mediated, carbapenem-hydrolysing ß-lactamase, KPC-1, which was recently reported by Yigit et al.6 to be produced by a North Carolina isolate of K. pneumoniae. In contrast to KPC-2, the previously described KPC-1 enzyme was associated with imipenem and meropenem resistance (microdilution MIC 16 mg/L for both agents). Yigit et al.6 suggested that although KPC-1 production occurred in combination with reduced expression of porins OmpK35 and OmpK37, the carbapenem resistance detected was mainly due to the production of KPC-1. Another difference between KPC-1 and KPC-2 is that KPC-2 could be transferred from three of its clinical host strains by conjugation, whereas KPC-1 could not be transferred from its clinical host strain by conjugation.
At present, there are no clinical outcome data to assess the implications of KPC-1 or KPC-2 for carbapenem therapy. Determining the clinical significance of these enzymes is likely to prove difficult because they appear to be rare and microbiologists are unlikely to recognize their occurrence unless they carefully evaluate reductions in carbapenem susceptibility. The capability to detect enzymes such as KPC-2 requires the qualities of a good microbiologist: careful observation, experience and judgement. In the case of the KPC-2-producing isolates, failure to observe the reduced susceptibility to carbapenems (MICs > 1 mg/L), combined with certain test results suggestive of ESBL production, could prove very misleading to an inexperienced microbiologist.
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Acknowledgements |
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We thank Dr George Jacoby (Lahey Clinic, Department of Infectious Disease, Burlington, MA, USA) for providing the sodium azide-resistant E. coli strain J53. This study was supported in part by Merck & Co., Inc.
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Footnotes |
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* Corresponding author. Tel: +1-402-280-4096; Fax: +1-402-280-1875; E-mail: kstaac{at}creighton.edu
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G. A. Jacoby, K. E. Walsh, and V. J. Walker Identification of Extended-Spectrum, AmpC, and Carbapenem- Hydrolyzing {beta}-Lactamases in Escherichia coli and Klebsiella pneumoniae by Disk Tests. J. Clin. Microbiol., June 1, 2006; 44(6): 1971 - 1976. [Abstract] [Full Text] [PDF]
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J. Alba, Y. Ishii, K. Thomson, E. S. Moland, and K. Yamaguchi Kinetics Study of KPC-3, a Plasmid-Encoded Class A Carbapenem-Hydrolyzing {beta}-Lactamase Antimicrob. Agents Chemother., November 1, 2005; 49(11): 4760 - 4762. [Abstract] [Full Text] [PDF]
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D. L. Paterson and R. A. Bonomo Extended-Spectrum {beta}-Lactamases: a Clinical Update Clin. Microbiol. Rev., October 1, 2005; 18(4): 657 - 686. [Abstract] [Full Text] [PDF]
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T. Naas, P. Nordmann, G. Vedel, and C. Poyart Plasmid-Mediated Carbapenem-Hydrolyzing {beta}-Lactamase KPC in a Klebsiella pneumoniae Isolate from France Antimicrob. Agents Chemother., October 1, 2005; 49(10): 4423 - 4424. [Full Text] [PDF]
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Z.-Q. Wei, Y.-G. Chen, Y.-S. Yu, W.-X. Lu, and L.-J. Li Nosocomial spread of multi-resistant Klebsiella pneumoniae containing a plasmid encoding multiple {beta}-lactamases J. Med. Microbiol., September 1, 2005; 54(9): 885 - 888. [Abstract] [Full Text] [PDF]
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P. E. Coudron Inhibitor-Based Methods for Detection of Plasmid-Mediated AmpC {beta}-Lactamases in Klebsiella spp., Escherichia coli, and Proteus mirabilis J. Clin. Microbiol., August 1, 2005; 43(8): 4163 - 4167. [Abstract] [Full Text] [PDF]
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S. Bratu, M. Mooty, S. Nichani, D. Landman, C. Gullans, B. Pettinato, U. Karumudi, P. Tolaney, and J. Quale Emergence of KPC-Possessing Klebsiella pneumoniae in Brooklyn, New York: Epidemiology and Recommendations for Detection Antimicrob. Agents Chemother., July 1, 2005; 49(7): 3018 - 3020. [Abstract] [Full Text] [PDF]
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S. Bratu, P. Tolaney, U. Karumudi, J. Quale, M. Mooty, S. Nichani, and D. Landman Carbapenemase-producing Klebsiella pneumoniae in Brooklyn, NY: molecular epidemiology and in vitro activity of polymyxin B and other agents J. Antimicrob. Chemother., July 1, 2005; 56(1): 128 - 132. [Abstract] [Full Text] [PDF]
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S. Bratu, D. Landman, M. Alam, E. Tolentino, and J. Quale Detection of KPC Carbapenem-Hydrolyzing Enzymes in Enterobacter spp. from Brooklyn, New York Antimicrob. Agents Chemother., February 1, 2005; 49(2): 776 - 778. [Abstract] [Full Text] [PDF]
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N. Woodford, P. M. Tierno Jr., K. Young, L. Tysall, M.-F. I. Palepou, E. Ward, R. E. Painter, D. F. Suber, D. Shungu, L. L. Silver, et al. Outbreak of Klebsiella pneumoniae Producing a New Carbapenem- Hydrolyzing Class A {beta}-Lactamase, KPC-3, in a New York Medical Center Antimicrob. Agents Chemother., December 1, 2004; 48(12): 4793 - 4799. [Abstract] [Full Text] [PDF]
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A. Hossain, M. J. Ferraro, R. M. Pino, R. B. Dew III, E. S. Moland, T. J. Lockhart, K. S. Thomson, R. V. Goering, and N. D. Hanson Plasmid-Mediated Carbapenem-Hydrolyzing Enzyme KPC-2 in an Enterobacter sp. Antimicrob. Agents Chemother., November 1, 2004; 48(11): 4438 - 4440. [Abstract] [Full Text] [PDF]
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I. Henriques, A. Moura, A. Alves, M. J. Saavedra, and A. Correia Molecular Characterization of a Carbapenem-Hydrolyzing Class A {beta}-Lactamase, SFC-1, from Serratia fonticola UTAD54 Antimicrob. Agents Chemother., June 1, 2004; 48(6): 2321 - 2324. [Abstract] [Full Text] [PDF]
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H. Yigit, A. M. Queenan, J. K. Rasheed, J. W. Biddle, A. Domenech-Sanchez, S. Alberti, K. Bush, and F. C. Tenover Carbapenem-Resistant Strain of Klebsiella oxytoca Harboring Carbapenem-Hydrolyzing {beta}-Lactamase KPC-2 Antimicrob. Agents Chemother., December 1, 2003; 47(12): 3881 - 3889. [Abstract] [Full Text] [PDF]
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