JAC Advance Access originally published online on February 6, 2007
Journal of Antimicrobial Chemotherapy 2007 59(4):627-632; doi:10.1093/jac/dkl544
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IMP-4 and OXA ß-lactamases in Acinetobacter baumannii from Singapore
1 Department of Pathology, Singapore General Hospital, Outram Road, Singapore 169608, Singapore 2 Department of Internal Medicine, Singapore General Hospital, Outram Road, Singapore 169608, Singapore 3 Department of Clinical Research, Singapore General Hospital, Outram Road, Singapore 169608, Singapore
* Corresponding author. Tel: +65-6321-4505; Fax: +65-6222-6826; E-mail: koh.tse.hsien{at}sgh.com.sg
Received 4 October 2006; returned 13 November 2006; revised 23 November 2006; accepted 12 December 2006
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Abstract |
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Objective: To compare the incidence of carbapenemase genes in Acinetobacter baumannii between two time periods.
Methods: We studied 114 isolates of imipenem-resistant A. baumannii collected over two 5 month periods (in 1996 and 2001). Isolates showing carbapenemase activity by plate bioassay were screened for carbapenemase genes using PCR. Chromosomal DNA from strains carrying carbapenemase genes was subjected to PFGE after digestion with ApaI.
Results: The incidence of imipenem-resistant A. baumannii in our hospital rose from 1.1 per 1000 admissions in 1996 to 2.3 per 1000 admissions in 2001. However, the number of carbapenemase-producing A. baumannii rose only slightly in 2001 (0.8 per 1000 admissions) compared to 1996 (0.5 per 1000 admissions). Of 44 isolates with carbapenemase activity, 4 isolates carried blaIMP-4, 5 carried blaOXA-58, and 40 carried blaOXA-23. In addition, most isolates carried a blaOXA-51-type ß-lactamase gene. All strains with blaIMP-4, also carried blaOXA-58 and blaPSE-1, but not blaOXA-51-type ß-lactamase genes. PCR analysis repeated on seven recent isolates of susceptible A. baumannii showed only the presence of blaOXA-51-type ß-lactamase genes. A total of five novel blaOXA-51-type ß-lactamase genes (blaOXA-88,-91,-93,-94, and -95) and one new blaOXA-58-type ß-lactamase gene (blaOXA-96) were found.
Conclusions: The incidence of carbapenemase genes did not vary significantly between the two study periods. There is a wide diversity of OXA genes in A. baumannii in Singapore. The most common carbapenemase gene found in our study was blaOXA-23.
Keywords: carbapenemase , metallo-ß-lactamase , resistance
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Introduction |
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Carbapenem-resistant Acinetobacter baumannii are an increasingly important cause of nosocomial infection worldwide. Several mechanisms are responsible for carbapenem resistance in A. baumannii and include modification to the penicillin-binding proteins, impermeability and carbapenemases.1 Carbapenemases found in A. baumannii so far belong to either the OXA class D family of serine ß-lactamases or IMP/VIM class B family of metallo-ß-lactamases.2,3
The Class D oxacillinases associated with carbapenem-resistant A. baumannii may be classified into at least four subgroups. Within the first group, OXA-23, and -27 differ by only two amino acid residues; and share only 60% identity with the second group, comprising OXA-24, -25, -26 and -40.4 A third and rapidly expanding subgroup of OXA ß-lactamases, comprising OXA-51, -64, -65, -66, -68, -69, -70 and -71, has recently been described.5 OXA-58 falls outside of this scheme with < 50% identity with the other enzymes.6
The aim of this study was to compare the incidence of carbapenem resistance and characterize the carbapenemase genes in clinical isolates of A. baumannii collected in our hospital over two 5 month periods.
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Materials and methods |
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The Singapore General Hospital is a tertiary 1600 bed hospital. From 1 May to 30 September 1996, and 1 August to 31 December 2001, all consecutive, non-duplicate clinical isolates of A. baumannii from in-patients that were identified as imipenem-resistant by the NCCLS disc diffusion method were collected.7 The isolates were identified using standard biochemical tests and the API 20NE system (BioMerieux, Marcy l'Etoile, France). Detection of carbapenemase activity was carried out using plate bioassays on crude extracts.8
Isolates showing carbapenemase activity were screened for carbapenemase genes. The primers used for the detection and sequencing of blaIMP, blaVIM, and blaOXA genes are shown in Table 1.6,9–14 Because carbapenemase genes have been described on integrons, we used the primers described by Levesque to detect the presence of integrons (Table 1).15
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PFGE was performed on chromosomal DNA extracts after digestion using ApaI.16 The resulting gel images were collated using Molecular Analyst v1.6 (Bio-Rad, Hercules, CA) and analysed using the Dice coefficient and the unweighted-pair group method using average linkages. Identical strains were assigned pulsotypes with the same alphanumeric code. Strains with more than 85% similarity were considered to be related and were assigned the same alphabetical code but with different numerical codes to indicate the subtypes if necessary.
Antimicrobial susceptibility to piperacillin-tazobactam, levofloxacin, minocycline, tigecycline and imipenem, was tested by microbroth dilution using Dade Microscan Custom Panels (Dade Behring Inc, West Sacramento, CA).
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Results |
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In 1996, of 518 isolates of A. baumannii from various clinical sources, 40 isolates (7.7%) were resistant to imipenem. Nineteen isolates (47.5% of the imipenem-resistant isolates) demonstrated carbapenemase activity. Two isolates had blaIMP-4 and 17 isolates had blaOXA-23.
In 2001, of 348 isolates of A. baumannii, 74 (21.2%) were resistant to imipenem. Twenty-five isolates (33.8% of imipenem-resistant isolates) demonstrated carbapenemase activity. Two isolates had blaIMP-4 and 23 isolates had blaOXA-23.
All blaIMP-4 and blaOXA-23 nucleotide sequences were identical to the original sequences in the GenBank database (blaOXA-23, accession number AJ132105 [GenBank] ; blaIMP-4, accession numbers AF288045 [GenBank] and AF244145 [GenBank] ). No strains tested positive for blaOXA-24, blaVIM-1 or blaVIM-2-like genes.
We detected blaOXA-51-type genes in 77.3% of the strains. Because there is a suggestion that blaOXA-51-type genes may be ubiquitous in this species, we also tested seven strains of A. baumannii isolated in 2005 which were susceptible to ampicillin-sulbactam, cefepime, piperacillin-tazobactam and imipenem by the NCCLS disc diffusion method.7 Five of these strains carried a variety of blaOXA-51-type genes (Table 2) but none carried blaOXA-58, -23, -24, -IMP, or blaVIM-type ß-lactamase genes. A total of five novel blaOXA-51-type ß-lactamase genes (blaOXA-88, -91, -93, -94, and -95) were found whose translated sequences differed from that of OXA-51 by five to eight amino acids.
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We used the primers described by Levesque in an attempt to define the flanking regions of blaIMP-4 in strains DB60079/01, DM22501/01 and DR32226/06. However, we amplified a 1.7 kb fragment containing blaPSE-1 instead. We then further tested a sample of 19 A. baumannii isolates for blaPSE-1 using the primers PSE-F and PSE-R (Table 1). Only DR25612/96 (also blaIMP-4 positive) carried blaPSE-1.
To specifically amplify the flanking regions of blaIMP-4, we used a combination of IMP1B and Levesque 5'-CS, and IMP1F and Levesque 3'-CS primers (Table 1).15,17 The resulting sequences were assembled to form a 2.8 kb fragment which was identical for all three strains. This class I integron contained in order, blaIMP-4, a quaternary ammonium compound resistance gene (qacG), an aminoglycoside 6'-N-acetyltransferase gene (aacA4) and a chloramphenicol acetyltransferase gene variant (catB3). We suspect that in the original PCR reaction, the small integron, containing blaPSE-1, was being preferentially amplified at the expense of the larger one (containing blaIMP-4). This may be because extension to form the smaller PCR product is likely to be more complete in each cycle. Therefore there will be more DNA template for each subsequent round of amplification.
All four strains which were positive for blaIMP-4 (and blaPSE-1) also had blaOXA-58. In addition one more strain with blaOXA-23 also had blaOXA-58 (DM18619/96). All strains with blaOXA-58 were negative for blaOXA-51-type ß-lactamases. One strain (DU16891/96) had a novel blaOXA-58-type sequence and has been designated blaOXA-96. This particular strain was remarkable for containing the genes for no less than three different OXA ß-lactamases (OXA-23, -64, -96). blaOXA-96 differs from blaOXA-58 with a guanine for adenine substitution at position 483. OXA-96 differs from OXA-58 by one amino acid with methionine substituting for isoleucine at position 161.
The PFGE showed that were 16 pulsotypes. The largest clone (pulsotype A) accounted for 36.3% of carbapenemase producing isolates (Table 2). Pulsotypes A and B were found in both 1996 and 2001, and contained blaOXA-23 and blaOXA-64 or blaOXA-66. Pulsotype C was only found in 2001 and contained blaOXA-23 and blaOXA-69. Pulsotypes A to C were distributed throughout the hospital, affecting patients in intensive care, orthopaedic, respiratory, surgical, medical and oncology wards (data not shown). Pulsotype D was only found in 1996 among burns/plastic surgery patients and carried blaOXA-23 and blaOXA-88. The two pulsotype E strains were isolated from haematology patients from Indonesia and carried blaPSE-1, blaOXA-58 and blaIMP-4.
The antimicrobial susceptibilities by microbroth dilution are shown in Table 2. Carbapenemase-producing strains remained susceptible to levofloxacin, minocycline and tigecycline.
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Discussion |
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The OXA-23 enzyme (previously called ARI-1) was first described in an A. baumannii strain isolated in Scotland in 1985.18 That appeared to be an isolated incident as it would be almost a decade before OXA-23 was to reappear in the literature. It is therefore ironic that many of the multidrug-resistant A. baumannii which started spreading in south-east England in 2003–2004 turned out to be OXA-23 producers.19
We found that the majority (91%) of carbapenemase-producing A. baumannii in our hospital carried the blaOXA-23 gene. Since the numbers remained fairly stable between the two time periods, it is possible that OXA-23-producing strains have existed in Singapore prior to 1996. We did not find any examples of the related enzyme OXA-27, which has so far only been described from a single isolate of A. baumannii from another hospital in Singapore.12
OXA-51 was first described from two imipenem-resistant A. baumannii clones from Argentina and has 56% and 61–62% amino acid homology with subgroup 1 and subgroup 2 respectively.20 Seven ß-lactamases related to OXA-51 were described recently by Brown et al., including OXA-66 and OXA-69 from A. baumannii from a third hospital in Singapore.5
In our study, which involves a larger collection of isolates over two time periods, it is clear that the picture is much more complex. Most of the 1996 OXA-51-types were OXA-64, whereas most of the 2001 OXA-51-types were OXA-66. OXA-69 only appeared in 2001. In addition, we have found five new OXA-51-type enzymes in this study: OXA-88, -91, -93, -94 and -95. These differ from OXA-51 by 5–8 amino acids. Three of these were from a sample of carbapenem-susceptible strains collected in 2005. In fact, it is now thought that OXA-51-type enzymes may be naturally occurring in A. baumannii.14 The correlation between OXA-51 type and pulsotypes in our study does suggest that the different A. baumannii clones possess their own natural oxacillinase.
OXA-58 was first described in unrelated A. baumannii in France.6 In an outbreak in an intensive care unit in Greece, many A. baumannii isolates contained both blaOXA-58 and blaOXA-51-type ß-lactamase genes.21 Coelho et al. also found blaOXA-58 and blaOXA-51-type ß-lactamase genes co-existing in Acinetobacter spp. collected from Argentina, Kuwait and Southern England over a 10 year period.22 This is in contrast to our own results where the four blaOXA-58 strains were all negative for blaOXA-51-type ß-lactamase genes.
The contribution of carbapenem-hydrolysing oxacillinases to carbapenem resistance has only been defined for a few enzymes, notably OXA-23, -40 and -58.4 It should be noted that the biochemical activities of many of the OXA enzymes in A. baumannii remain to be characterized. In addition, carbapenem-hydrolysing activity is often weak, therefore mere possession of blaOXA carbapenemase genes may not explain carbapenem resistance. For example the OXA-51-like enzymes were initially thought not to contribute much to the intrinsic resistance of A. baumannii to ß-lactams.14 However, Turton et al. have recently found that in isolates with blaOXA-51-like enzymes as the sole carbapenemase, carbapenem resistance was associated with an insertion sequence, ISAbaI situated upstream. They suggest this could possibly provide a promoter for hyper-production of ß-lactamase genes.23
Unlike OXA-type ß-lactamases, the IMP-type ß-lactamases have much stronger carbapenem-hydrolysing activity.24 The IMP-4 metallo-ß-lactamase was first described independently in 2001 by Chu et al. from A. baumannii in Hong Kong and by Hawkey et al. from Citrobacter youngae in Guangdong.10,25 Some of these strains had existed in Hong Kong at least as far back as 1994. There followed a 3 year hiatus until Peleg et al. described IMP-4 in Pseudomonas aeruginosa in Australia.26 This was closely followed by a report of IMP-4 in Klebsiella pneumoniae and Escherichia coli.27 It is a sobering lesson that blaIMP-4 in the space of 1 year succeeded in disseminating among Gram-negative pathogens in Australia including Citrobacter amalonaticus, Serratia marcescens and Enterobacter cloacae.28,29 IMP-4 has also been found in Acinetobacter calcoaceticus in Malaysia though this is only known from an entry in GenBank (accession number DQ307573 [GenBank] ).
In our study all strains that carried blaIMP-4 also contained blaOXA-58. In a recent paper, Peleg et al. also described the same combination of ß-lactamases in a strain of Acinetobacter junii in Australia.30
In our study, the integrons containing blaIMP-4 had identical nucleotide sequences despite the fact that the four strains had three different PFGE patterns. What is remarkable is that the order of genes in the integron was identical to that of A. baumannii from Hong Kong (Genbank AF445082 [GenBank] .1) and K. pneumoniae (Genbank AJ609296 [GenBank] .1) from Australia. The Hong Kong and Australian integron sequences are essentially identical and differ from the Singapore sequences by a few base pairs. This suggests the possibility of international spread of the resistance determinant as all three countries are geographically quite close. In fact, three of the four blaIMP-4 strains were isolated from haematology patients from Indonesia, a country situated between Singapore and Australia, which has not reported a problem with metallo-ß-lactamases.
In summary, the incidence of imipenem-resistant A. baumannii in our hospital doubled from 1.1 per 1000 admissions in 1996 to 2.3 per 1000 admissions in 2001. However, the number of carbapenemase-producing A. baumannii rose only slightly in 2001 (0.8 per 1000 admissions) compared to 1996 (0.5 per 1000 admissions). Therefore, other mechanisms for reduced carbapenem susceptibility must be increasing. OXA-23 enzymes are the predominant carbapenemase. IMP-4-producing strains do not appear to be endemic and may be imported.
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Nucleotide sequence accession numbers |
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The following sequences were submitted to GenBank. blaOXA-23 (accession number AY795964 [GenBank] ), blaOXA-88 (accession number DQ392963 [GenBank] ), blaOXA-91 (accession number DQ519086 [GenBank] ), blaOXA-93 (accession number DQ519087 [GenBank] ), blaOXA-94 (accession number DQ519088 [GenBank] ), blaOXA-95 (accession number DQ519089 [GenBank] ) and blaOXA-96 (accession number DQ519090 [GenBank] ), blaIMP-4 (accession numbers AY795963 [GenBank] , AY590475 [GenBank] and AY795964 [GenBank] ). blaIMP-4 and blaPSE-1 integrons (accession numbers DQ532122 [GenBank] and DQ519091 [GenBank] ).
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Transparency declarations |
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None to declare.
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Footnotes |
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Present address. Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 5 Lower Kent Ridge Road, Singapore 119074, Singapore 
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Acknowledgements |
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We thank Ms Lan Huay Ong for her technical help. The Dade Microscan panels were kindly provided by International Health Management Associates Inc. This study was funded by a Singhealth Cluster Research Grant EX012/2001.
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References |
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Heritier C, Poirel L, Lambert T, et al. (2005) Contribution of acquired carbapenem-hydrolyzing oxacillinases to carbapenem resistance in Acinetobacter baumannii. Antimicrob Agents Chemother 49:3198–202.
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Chu YW, Afzal-Shah M, Houang ET, et al. (2001) IMP-4, a novel metallo-beta-lactamase from nosocomial Acinetobacter spp. collected in Hong Kong between 1994 and 1998. Antimicrob Agents Chemother 45:710–14.
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Yan JJ, Hsueh PR, Ko WC, et al. (2001) Metallo-beta-lactamases in clinical Pseudomonas isolates in Taiwan and identification of VIM-3, a novel variant of the VIM-2 enzyme. Antimicrob Agents Chemother 45:2224–8.
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Afzal-Shah M, Woodford N, Livermore DM. (2001) Characterization of OXA-25, OXA-26, and OXA-27, molecular class D beta-lactamases associated with carbapenem resistance in clinical isolates of Acinetobacter baumannii. Antimicrob Agents Chemother 45:583–8.
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19
Turton JF, Kaufmann ME, Glover J, et al. (2005) Detection and typing of integrons in epidemic strains of Acinetobacter baumannii found in the United Kingdom. J Clin Microbiol 43:3074–82.
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21
Pournaras S, Markogiannakis A, Ikonomidis A, et al. (2006) Outbreak of multiple clones of imipenem-resistant Acinetobacter baumannii isolates expressing OXA-58 carbapenemase in an intensive care unit. J Antimicrob Chemother 57:557–61.
22
Coelho J, Woodford N, Afzal-Shah M, et al. (2006) Occurrence of OXA-58-like carbapenemases in Acinetobacter spp. collected over 10 years in three continents. Antimicrob Agents Chemother 50:756–8.
23 Turton JF, Ward ME, Woodford N, et al. (2006) The role of ISAba1 in expression of OXA carbapenemase genes in Acinetobacter baumannii. FEMS Microbiol Lett 258:72–7.[CrossRef][Web of Science][Medline]
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Peleg AY, Franklin C, Bell J, et al. (2004) Emergence of IMP-4 metallo-beta-lactamase in a clinical isolate from Australia. J Antimicrob Chemother 54:699–700.
27 Poirel L, Pham JN, Cabanne L, et al. (2004) Carbapenem-hydrolysing metallo-beta-lactamases from Klebsiella pneumoniae and Escherichia coli isolated in Australia. Pathology 36:366–7.[CrossRef][Web of Science][Medline]
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29 Peleg AY, Franklin C, Bell JM, et al. (2005) Dissemination of the metallo-beta-lactamase gene blaIMP-4 among gram-negative pathogens in a clinical setting in Australia. Clin Infect Dis 41:1549–56.[CrossRef][Web of Science][Medline]
30
Peleg AY, Franklin C, Walters LJ, et al. (2006) OXA-58 and IMP-4 carbapenem-hydrolyzing beta-lactamases in an Acinetobacter junii blood culture isolate from Australia. Antimicrob Agents Chemother 50:399–400.
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