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JAC Advance Access originally published online on November 30, 2005
Journal of Antimicrobial Chemotherapy 2006 57(1):24-30; doi:10.1093/jac/dki429
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© The Author 2005. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

CTX-M-15 extended-spectrum ß-lactamase from Nigerian Klebsiella pneumoniae

Olusegun O. Soge1,2, Anne Marie Queenan3, Kayode K. Ojo2, Bolanle A. Adeniyi1 and Marilyn C. Roberts2,*

1 Department of Pharmaceutical Microbiology, University of Ibadan, Ibadan, Nigeria; 2 Department of Pathobiology, School of Public Health and Community Medicine, University of Washington, Seattle, WA 98195, USA; 3 Johnson & Johnson Pharmaceutical Research and Development, L.L.C., Raritan, NJ, USA

* Corresponding author. Tel: +1-206-543-8001; Fax: +1-206-543-3873; E-mail: marilynr{at}u.washington.edu

Received 8 August 2005; returned 26 September 2005; revised 28 October 2005; accepted 1 November 2005


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Objectives: In this study, extended-spectrum ß-lactamases (ESBLs) were characterized from 30 selected multidrug-resistant Klebsiella pneumoniae strains isolated from patients with community-acquired urinary tract infections from Southwest Nigeria.

Methods: The ß-lactamases were phenotypically characterized using isoelectric focusing, genotypically characterized using PCR assays and hybridization of the PCR products. Two of the blaCTX-M genes were completely sequenced. The location of the CTX-M-type genes was determined using transformation, DNA–DNA hybridization, PCR assays and hybridization of the PCR products from the Escherichia coli transformants.

Results: All 30 isolates produced at least one ß-lactamase. Seventeen of the isolates were resistant to cefotaxime, and had ≥100-fold reduction in susceptibility with cefotaxime plus clavulanic acid (4 mg/L), indicating the presence of an ESBL. The 17 isolates were shown to have blaCTX-M genes that were associated with large plasmids (≥58 kb), which also carried a tetracycline resistance gene, tet(A), and various aminoglycoside resistance genes. Two CTX-M-type genes were sequenced and had amino acid sequences indistinguishable from previously sequenced CTX-M-15 ß-lactamases. The ISEcp1 element was located upstream of blaCTX-M-15 in the same position as previously described. In addition, 23 of the isolates produced TEM ß-lactamases, 27 produced SHV ß-lactamases and four produced AmpC ß-lactamases.

Conclusions: Thirty K. pneumoniae produced multiple ß-lactamases, with 57% producing CTX-M enzymes. This is the first characterization of CTX-M-15-positive K. pneumoniae in Western Africa.

Keywords: K. pneumoniae , ESBLs , CTX-M enzymes


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The extended-spectrum ß-lactamases (ESBLs) were first identified shortly after the introduction of the broad-spectrum oxyimino-cephalosporins.1 While the majority of the ESBLs belong to the TEM and SHV families, in the past 10 years, 50 different CTX-M-type ß-lactamase enzymes have been identified from around the world.2 These enzymes have higher levels of hydrolytic activity against cefotaxime compared with ceftazidime, but lose activity in the presence of ß-lactamase inhibitors like clavulanic acid and tazobactam.1 The first CTX-M-type ß-lactamases were identified as plasmid-encoded enzymes in clinical isolates from the Enterobacteriaceae.3

CTX-M-positive isolates have been associated with nosocomial infections but have also been reported in clinical isolates from community-acquired infections.4 Since the mid-1990s, CTX-M-positive strains have been identified in most parts of the world including Asia, Europe, North America and South America.3 However, a much more limited picture of CTX-M-positive strains is available in Africa. In one report, a CTX-M-12-positive Klebsiella pneumoniae was identified from Kenya,5 and in other reports, CTX-M-15-positive Klebsiella spp. and Escherichia coli have been identified in Cameroon and Tanzania.6,7

In this study, we characterized the ß-lactamases from 30 multidrug-resistant K. pneumoniae strains isolated from patients with community-acquired urinary tract infections (UTI) in Southwest Nigeria. All 30 isolates produced at least one ß-lactamase and 17 (57%) produced a CTX-M ß-lactamase. The CTX-M genes from two isolates were identified as the CTX-M-15 enzyme. This is the first characterization of Klebsiella CTX-M enzymes from West Africa.


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Bacterial isolates

Thirty multidrug-resistant K. pneumoniae were selected from a random collection of 96 strains from men and women with UTI seen in the University Teaching Hospitals, Federal Medical Centers and Specialist Hospitals from six Southwestern States of Nigeria. The 30 isolates were from unrelated patients and epidemiologically unlinked. The isolates were chosen to represent the variation in the antibiotic susceptibility pattern to both ß-lactams and other antibiotics found in each of the six states. The isolates were collected from 2002 to 2003 and verified as K. pneumoniae using standard biochemical methods.8 All isolates were collected under approved ethical standards.

Antibiotic susceptibility

The MICs were determined using the agar dilution method according to the CLSI (formerly known as NCCLS) guidelines.9 Two sets of cefotaxime plates were made and one set was also supplemented with 4 mg/L of clavulanic acid at each agar dilution. The MIC of piperacillin/tazobactam was determined by Etest following the manufacturer's instructions (AB Biodisk, NA, Inc., USA). The non-ß-lactam resistant susceptibilities were determined by disc diffusion on Mueller–Hinton agar (Remel, Inc., Lenexa, KS, USA) according to the CLSI guidelines.10 E. coli ATCC 25922 was used as a control.

ESBL characterization by isoelectric focusing

Isoelectric focusing (IEF) was performed on all isolates using Ampholine PAGplate 3.5–9.5 IEF gels (GE-Amersham Biosciences). Gels were loaded with clarified freeze/thaw lysates11 and run at 1000 V for 90 min. ß-Lactamase bands were visualized by overlaying the gel with 25 g/L of nitrocefin. Bands that hydrolysed cefotaxime were identified using a bioassay performed by overlaying the IEF gel with Luria–Bertani agar (Difco Laboratories, Division of Becton Dickinson & Co., Sparks, MD, USA) with 1 mg/L of cefotaxime and swabbing with a sensitive indicator organism, E. coli ATCC 25922. Areas of growth over a band indicated cefotaxime hydrolysis. Cefotaxime hydrolysis in the lysates was confirmed spectrophotometrically.12 The pI standards were ß-lactamases; TEM-1, pI 5.4, K1, pI 6.5, SHV-1 pI 7.6, P99, pI 7.8 and ACT-1 pI 9.0 (Figure 1). The AmpC enzymes were identified as ß-lactamases that were inhibited when filter paper soaked in 100 µM aztreonam was overlaid on the IEF gel for 10 min before development with nitrocefin.



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  		Figure 1.. IEF profiles of Nigerian K. pneumoniae. Kpn1 to Kpn30 and CTX-M control (CTX-M-10 enzyme). +, Positive ESBL test using cefotaxime agar dilution; –, negative ESBL test using cefotaxime agar dilution.

 
Identification of the blaCTX-M genes

All the isolates were used as templates with four PCR assays that differentiated between CTX-M-1, -2, -8 and -9 groups of enzymes using primers and methods previously described.13,14 The primers are listed in Table 1. An E. coli producing a blaCTX-M-10 enzyme belonging to CTX-M-1 group was used as a positive control. The PCR products were hybridized with 32P-radiolabelled internal probes for verification.


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  		Table 1.. List of oligonucleotide primers used in this study

 
Cloning and sequencing of CTX-M enzymes

The specific PCR products from the CTX-M-1 group PCR assay were selected from Kpn1 and Kpn19 isolates, cloned into the pCR®T7/NT-TOPO® vector (Invitrogen, Carlsbad, CA, USA) and transformed into E. coli TOP10 according to manufacturer's instructions. For the complete gene, the primers used were 2CTX-MIF and 2CTX-MIR (Table 1) and both cloned and uncloned PCR products were used for sequencing. Primers for the forward and reverse T7 were used for sequencing the complete blaCTX-M genes at the University of Washington, Department of Biochemistry Sequencing Facility. The nucleotide sequences and resulting amino acid sequences were compared with sequences from GenBank via the National Center for Biotechnology Information Internet server.

To verify the sequences, the CTX-M plasmids from Kpn1 and Kpn19 were digested with PstI enzyme (New England BioLabs, Ipswich, MA, USA) and the fragment carrying the blaCTX-M gene identified and cloned into the PstI site within the blaTEM-1 gene of pACYC177 (New England BioLabs). The transformants were selected on Luria–Bertani agar (Difco Laboratories) supplemented with 64 mg/L of cefotaxime. The resulting plasmids, pMRC151 and pMRC152, were shown to carry a blaCTX-M gene by PCR. These plasmids were used as templates for sequencing using the primers 2CTX-MII (Table 1). The nucleotide sequences were indistinguishable from sequences obtained from the PCR templates. Linkage of blaCTX-M with the mobile insertion sequence ISEcp1 was investigated with primers PROM+ and PRECTX-M-3B as previously described.15 The blaCTX-M-15 sequence has been assigned GenBank accession no. AY995205 [GenBank] , and the second blaCTX-M-15 assigned GenBank accession no. AY995206 [GenBank] .

Detection of the blaTEM and blaSHV genes

The presence of blaTEM-like and blaSHV-like genes was identified using DNA–DNA hybridization of whole plasmid and chromosomal DNA dot blots with the appropriate 32P-labelled probes as previously described.16 The probes were internal primers designed from the coding sequences of blaTEM and blaSHV genes (Table 1).

E. coli transformation

Plasmid DNA was isolated from the K. pneumoniae isolates using the alkaline lysis method.17 Transformation of K. pneumoniae plasmids was done using the heat shock method into CaCl2-treated competent E. coli DH5{alpha} cells. Transformants were selected on Luria–Bertani agar (Difco Laboratories) supplemented with 20 mg/L of tetracycline and 100 mg/L of ampicillin. Multiple transformants were selected and their plasmids isolated and visualized on 0.8% agarose gels stained with ethidium bromide. Transformants that carried a single large plasmid and hybridized with 32P-labelled blaCTX-M probe were selected for further study as previously described.16,17 The probes used in the study are listed in Table 1.

Genotyping of tetracycline and aminoglycoside resistance genes in transformants

The other antibiotic resistance genes carried by the E. coli transformants were determined using DNA–DNA hybridization with 32P-labelled probes and PCR assays as previously described.16,18 The following genes were screened: tetracycline resistance genes tet(A) tet(B), tet(C) and tet(D); and aminoglycoside resistance genes aac(3)-II and aac(6')-Ib. Probes and primers are listed in Table 1.


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Susceptibilities to ß-lactam antibiotics

The MICs of the ß-lactam antibiotics are listed in Table 2. Based on the cefotaxime MICs, the isolates could be divided into two groups. The first group included 17 isolates that had cefotaxime MICs from 256 to >512 mg/L and the second group of 13 isolates had cefotaxime MICs of ≤4 mg/L (Table 2). Within the first group, cefotaxime MICs were reduced ≥100-fold in the presence of 4 mg/L of clavulanic acid, whereas in the second group, cefotaxime MICs were reduced ≤10-fold in the presence of 4 mg/L of clavulanic acid. In the first group, organisms were uniformly resistant to seven of the other ß-lactam antibiotics tested and variable for cefotetan and imipenem, whereas in the second group, isolates were susceptible and/or variable for the other ß-lactam antibiotics tested (Table 2).


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  		Table 2.. Antimicrobial susceptibilities and ß-lactamase determinants of K. pneumoniae isolates

 
Identification of ß-lactamases

IEF identified multiple ß-lactamases with pI values ranging between 5.4 and 9 and all isolates producing between one and five enzymes with different pI values within this range (Table 2 and Figure 1). All 17 cefotaxime-resistant isolates expressed a pI 9 ß-lactamase that hydrolysed cefotaxime in the bioassay. In addition, four isolates with identical IEF profiles expressed an AmpC ß-lactamase (Figure 1), which was identified because these enzymes were inhibited in the presence of 100 µM of aztreonam (data not shown). To verify the presence of the CTX-M-type enzyme, a PCR assay using universal CTX-M primers was used and the 17 cefotaxime-resistant isolates gave PCR products of the correct size that hybridized with an internal probe. In contrast, the cefotaxime-susceptible isolates were negative in this PCR assay.

The presence of the other SHV-like or TEM-like ß-lactamases was determined by DNA–DNA hybridization of group-specific probes. Twenty-seven (90%) of the isolates were positive for the blaSHV-like and 23 (77%) were positive for the blaTEM-like ß-lactamases (Table 2). All cefotaxime-resistant isolates produced at least two ß-lactamases and included four with blaCTX-M-like, blaTEM-like, blaSHV-like and blaAmpC; 10 with blaCTX-M-like, blaTEM-like and blaSHV-like; two with blaCTX-M-like and blaTEM-like (these two strains, Kpn8 and Kpn10, also produced a pI 6.5 ß-lactamase with cefotaxime hydrolysis in the bioassay); and one with blaCTX-M-like and blaSHV-like genes. Among the 13 cefotaxime-susceptible isolates, six were positive for blaTEM-like and blaSHV-like, six were positive for blaSHV-like and one was positive for blaTEM-like genes (Table 2).

Characterization of the CTX-M enzymes

Four PCR assays specific for blaCTX-M-1, blaCTX-M-2, blaCTX-M-8 or blaCTX-M-9 groups, respectively, were used. For the blaCTX-M-1 group PCR assay, PCR products of the correct size were hybridized with the internal probe. In contrast, no PCR products were found with the other three PCR assays. This suggested that these isolates carried blaCTX-M-1-group, which includes blaCTX-M-1, blaCTX-M-3, blaCTX-M-10, blaCTX-M-12, blaCTX-M-15, blaCTX-M-22, blaCTX-M-23 and blaCTX-M-28 enzymes.3

To identify which CTX-M gene was present, we completely sequenced the blaCTX-M-1-group genes from Kpn1 and Kpn19. Both enzymes were indistinguishable at the nucleotide and amino acid sequence level from blaCTX-M-15 and are found in GenBank accession nos AY995205 [GenBank] and AY995206 [GenBank] . The –35 and –10 promoter regions necessary for expression of the blaCTX-M-15 was located at the end of the ISEcp1-like element upstream of its inverted repeat, which was 48 bp from the start codon as previously described for blaCTX-M-15 from India.19 The 193 bp upstream and 212 bp downstream in both plasmids pMRC151 and pMRC152 as blaCTX-M-15 genes were indistinguishable from that previously sequenced from an Indian E. coli (AY458016 [GenBank] ) (Figure 2).



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  		Figure 2.. Nucleotide sequence of the 3' end of the ISEcp1 and the start region of pMRC151 and pMRC152 blaCTX-M-15 gene. The promoter sequences are underlined. IRR is the right inverted repeat. ATG is the start codon for the blaCTX-M-15 gene.

 
Location of the CTX-M enzymes

The blaCTX-M genes are usually located on plasmids and the 30 K. pneumoniae strains carried a variety of plasmids that differed in size. Among the 17 cefotaxime-resistant isolates, we detected between one and five plasmids on an agarose gel (data not shown), with all carrying a large plasmid (≥58 kb). This large plasmid appeared to carry the blaCTX-M genes and a tet(A) gene, coding for tetracycline resistance. To verify this, we transformed the K. pneumoniae plasmid DNA into E. coli and selected for ampicillin and tetracycline resistance. All transformants carried the ≥58 kb plasmid; a single isolate per transformation, carrying only one plasmid, was selected for further studies (Table 3). All were resistant to cefotaxime, hybridized with the blaCTX-M-1 group, blaTEM-like and tet(A) probes, and had reduced MICs in the presence of 4 mg/L of clavulanic acid, suggesting that the transformants carried at least two ß-lactamases. This was confirmed by IEF (Table 3). Fourteen of the E. coli transformants were also resistant to kanamycin, gentamicin and tobramycin and carried aac(3)-II and aac(6')-Ib aminoglycoside resistance genes, whereas the three tobramycin-susceptible transformants did not carry either of these aminoglycoside genes (Table 3).


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  		Table 3.. Transformants compared with their parental K. pneumoniae

 

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The CTX-M family of ESBLs has been increasingly detected worldwide.3 In this study, we characterized 30 K. pneumoniae isolates from community-acquired UTI patients in Nigeria. The isolates produced 1–5 ß-lactamases, with 17 isolates positive for the blaCTX-M-1-group gene and 80% producing at least two ß-lactamases. Two blaCTX-M-1-group genes were sequenced and were identified as blaCTX-M-15. A blaCTX-M-15-positive K. pneumoniae was first identified in India in 1999,19 and more recently in Portugal,20 Korea21 and one isolate each from Cameroon and Tanzania.6,7 The ISEcp1 element was found to be located upstream of the 3' end of blaCTX-M-15 in the same position as reported previously in CTX-M-15-producing isolates from India and Turkey.19,22

Clinical isolates expressing CTX-M ß-lactamases often display much higher resistance to cefotaxime versus ceftazidime. In this collection of isolates, all of the cefotaxime-resistant K. pneumoniae and their E. coli transformants were also resistant to ceftazidime. CTX-M-15 belongs to a small group of the CTX-M ß-lactamases with measurable ceftazidime hydrolysis that results in higher ceftazidime MIC values.15 The blaCTX-M genes were associated with large plasmids that also carried the tet(A) gene. In addition, fourteen plasmids carried previously characterized aminoglycoside resistance genes, aac(3)-II and aac(6')-Ib, whereas three plasmids carried other aminoglycoside resistance genes. However, some of the antibiotic resistance genes usually associated with mobile elements were not associated with these K. pneumoniae plasmids. These results are similar to reports from other studies.18,23 The multiple antibiotic resistance genes on these plasmids may allow the maintenance and spread of CTX-M ß-lactamases in pathogen bacterial populations, even if patients are not treated with extended-spectrum cephalosporins, especially in Nigeria and other developing countries where antibiotics are unregulated.24

From the study of these 30 K. pneumoniae clinical isolates it is clear that the CTX-M ß-lactamases are expanding throughout Africa. To define the extent of this spread, the characterization of antibiotic-resistant bacteria needs to be done in each geographical area, especially in areas where resources are limited and antibiotics can be obtained without prescriptions.


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None to declare.


   Acknowledgements
 
Prof. H. A. Odelola was part of this work until his death. We thank Rafael Cantón for the E. coli/CTX-M-10 strain, Ellyn Wira for preliminary VITEK MICs and Karen Bush for helpful suggestions. Some of the data in this study were presented at the 105th Annual General Meeting of the American Society for Microbiology, Atlanta, GA, 2005.


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1. Bradford PA. Extended-spectrum ß-lactamases in the 21st century: characterization, epidemiology, and detection of this important resistance threat. Clin Microbiol Rev 2001; 14: 933–51.[Abstract/Free Full Text]

2. Jacoby GA, Bush K. Amino acid sequences for TEM, SHV and OXA extended-spectrum and inhibitor resistant ß-lactamases. http://www.lahey.org.studies/webt.htm (27 September 2005, date last accessed).

3. Bonnet R. Growing group of extended-spectrum ß-lactamases: the CTX-M enzymes. Antimicrob Agents Chemother 2004; 48: 1–14.[Free Full Text]

4. Woodford N, Ward ME, Kaufmann ME et al. Community and hospital spread of Escherichia coli producing CTX-M extended-spectrum ß-lactamases in the UK. J Antimicrob Chemother 2004; 54: 735–43.[Abstract/Free Full Text]

5. Kariuki S, Corkill JE, Revathi G et al. Molecular characterization of a novel plasmid-encoded cefotaximase (CTX-M-12) found in clinical Klebsiella pneumoniae isolates from Kenya. Antimicrob Agents Chemother 2001; 45: 2141–3.[Abstract/Free Full Text]

6. Gangoue-Pieboji J, Miriagou V, Vourli S et al. Emergence of CTX-M-15-producing enterobacteria in Cameroon and characterization of a blaCTX-M-15-carrying element. Antimicrob Agents Chemother 2005; 49: 441–3.[Abstract/Free Full Text]

7. Blomberg B, Jureen R, Manji KP et al. High rate of fatal cases of pediatric septicemia caused by gram-negative bacteria with extended-spectrum ß-lactamases in Dar es Salaam, Tanzania. J Clin Microbiol 2005; 43: 745–9.[Abstract/Free Full Text]

8. Murray PR, Baron EJ, Jorgensen JH et al. Manual of Clinical Microbiology. Washington, DC: ASM Press, 2003.

9. National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically—Sixth Edition: Approved Standard M7-A6. NCCLS, Wayne, PA, USA, 2003.

10. National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Disk Susceptibility Tests—Eighth Edition: Approved Standard M2-A8. NCCLS, Wayne, PA, USA, 2003.

11. Bush K, Singer SB. Effective cooling allows sonication to be used for liberation of ß-lactamases from gram negative bacteria. J Antimicrob Chemother 1989; 24: 82–4.[Free Full Text]

12. Sykes RB, Bonner DP, Bush K et al. Azthreonam (SQ 26,776), a synthetic monobactam specifically active against aerobic gram-negative bacteria. Antimicrob Agents Chemother 1982; 21: 85–92.[Abstract/Free Full Text]

13. Pagani L, Dell'Amico E, Migliavacca R et al. Multiple CTX-M-type extended-spectrum ß-lactamases in nosocomial isolates of Enterobacteriaceae from a hospital in northern Italy. J Clin Microbiol 2003; 41: 4264–9.[Abstract/Free Full Text]

14. Villegas MV, Correa A, Perez F et al. CTX-M-12 ß-lactamase in a Klebsiella pneumoniae clinical isolate in Colombia. Antimicrob Agents Chemother 2004; 48: 629–31.[Abstract/Free Full Text]

15. Poirel L, Gniadkowski M, Nordmann P. Biochemical analysis of the ceftazidime-hydrolysing extended-spectrum ß-lactamase CTX-M-15 and of its structurally related ß-lactamase CTX-M-3. J Antimicrob Chemother 2002; 50:1031–4.[Abstract/Free Full Text]

16. Miranda CD, Kehrenberg C, Ulep C et al. Diversity of tetracycline resistance genes in bacteria from Chilean salmon farms. Antimicrob Agents Chemother 2003; 47: 883–8.[Abstract/Free Full Text]

17. Sambrook J, Russel DW. Extraction and purification of plasmid; screening of bacterial colonies by hybridization. In: Molecular Cloning: A Laboratory Manual. New York: Cold Spring Harbor Laboratory Press, 2001; 1.31–8, 1.126–32.

18. Leflon-Guibout V, Jurand C, Bonacorsi S et al. Emergence and spread of three clonally related virulent isolates of CTX-M-15-producing Escherichia coli with variable resistance to aminoglycosides and tetracycline in a French geriatric hospital. Antimicrob Agents Chemother 2004; 48: 3736–42.[Abstract/Free Full Text]

19. Karim A, Poirel L, Nagarajan S et al. Plasmid-mediated extended-spectrum ß-lactamase (CTX-M-3 like) from India and gene association with insertion sequence ISEcp1. FEMS Microbiol Lett 2001; 201: 237–41.[Web of Science][Medline]

20. Conceicao T, Brizio A, Duarte A et al. First description of CTX-M-15-producing Klebsiella pneumoniae in Portugal. Antimicrob Agents Chemother 2005; 49: 477–8.[Free Full Text]

21. Kim J, Lim YM, Jeong YS et al. Occurrence of CTX-M-3, CTX-M-15, CTX-M-14, and CTX-M-9 extended-spectrum ß-lactamases in Enterobacteriaceae clinical isolates in Korea. Antimicrob Agents Chemother 2005; 49: 1572–5.[Abstract/Free Full Text]

22. Lartigue MF, Poirel L, Heritier C et al. First description of CTX-M-15-producing Klebsiella pneumoniae in Turkey. J Antimicrob Chemother 2003; 52: 315–6.[Free Full Text]

23. Eckert C, Gautier V, Saladin-Allard M et al. Dissemination of CTX-M-type ß-lactamases among clinical isolates of Enterobacteriaceae in Paris, France. Antimicrob Agents Chemother 2004; 48:1249–55.[Abstract/Free Full Text]

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