Journal of Antimicrobial Chemotherapy

JAC Advance Access originally published online on October 27, 2008
Journal of Antimicrobial Chemotherapy 2009 63(1):55-59; doi:10.1093/jac/dkn434

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Original research

Emergence and widespread dissemination of OXA-23, -24/40 and -58 carbapenemases among Acinetobacter spp. in Asia-Pacific nations: report from the SENTRY Surveillance Program

Rodrigo E. Mendes^1,*, Jan M. Bell², John D. Turnidge^2,3, Mariana Castanheira¹ and Ronald N. Jones^1,4

¹ JMI Laboratories, North Liberty, IA 52317, USA ² Women's and Children's Hospital, Adelaide, Australia ³ University of Adelaide, Adelaide, Australia ⁴ Tufts University School of Medicine, Boston, MA 02111, USA

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^* Corresponding author. Tel: +1-319-665-3370; Fax: +1-319-655-3371; E-mail: rodrigo-mendes{at}jmilabs.com

Received 1 May 2008; returned 7 July 2008; revised 23 September 2008; accepted 23 September 2008

	Abstract

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Objectives: The aim of this study was to evaluate the occurrence and dissemination of acquired carbapenem-hydrolysing class D β-lactamase (class D carbapenemase)- and metallo-β-lactamase (MBL)-encoding genes among Acinetobacter spp. isolates recovered from medical centres in the Asia-Pacific (APAC) region.

Methods: During 2006–07, 41 medical centres located in 10 countries in the APAC region forwarded to a central monitoring site 544 Acinetobacter spp. isolates, which were tested for susceptibility by the reference broth microdilution method. Isolates non-susceptible to imipenem or meropenem (MIC 8 mg/L) were screened for OXA-23-, OXA-24/40-, OXA-58- and MBL-encoding genes and confirmed by sequencing. Clonality was assessed by ribotyping and PFGE.

Results: Polymyxins (99.1% susceptible) and tigecycline (98.9% susceptible) were the most active antimicrobial agents tested. Among the isolates, 230 (42.3%) were non-susceptible to imipenem or meropenem, and class D carbapenemase- or MBL-encoding genes were detected in 162 (70.4%). bla_OXA-23 was found in isolates recovered from six countries, while bla_OXA-24/40 and bla_OXA-58 were less common. Several isolates harboured more than one class D carbapenemase, and MBL-encoding genes were detected in one Acinetobacter johnsonii from the Philippines (bla_IMP-4) and one Acinetobacter baumannii from Korea (bla_VIM-2). Overall, clonal dissemination was noted within medical centres; however, genetic relatedness was also noted among class D carbapenemase-producing A. baumannii isolates recovered from different countries.

Conclusions: This study shows a high distribution of class D carbapenemase-encoding genes, mainly bla_OXA-23, in Acinetobacter spp. isolates. In addition, clonal dissemination among medical centres located in different countries in the APAC region, previously documented in many regions of Europe, emphasizes the epidemic potential of these bacteria.

Keywords: class D carbapenemase , clonal dissemination , acquired , resistance

	Introduction

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Acinetobacter spp. are opportunistic pathogens, frequently associated with immunosuppressed patients as well as those with serious underlying diseases or subjected to invasive procedures and treated with broad-spectrum antimicrobial agents.¹ During the past decade, several reports have described the association of these pathogens with numerous outbreaks,² mainly in intensive care units. This corresponds with the emergence of resistance to nearly all clinically used classes of antimicrobial agents on a worldwide scale.³ As such, carbapenems are important therapeutic options for treating infections caused by Acinetobacter spp.; however, these antimicrobial agents may be hydrolysed by Ambler class B metallo-β-lactamases (MBLs) as well as by carbapenem-hydrolysing class D β-lactamases (class D carbapenemase).⁴

Six groups of acquired MBL-encoding genes have been identified;⁵ however, only bla_IMP- and bla_VIM-like, and more recently bla_SIM-1, have been reported in Acinetobacter spp.⁴ IMP variants have been described in several Far Eastern countries, including Japan, China (Hong Kong), South Korea and Australia, while VIM variants have rarely been detected in those nations.⁴ Conversely, acquired class D carbapenemase-encoding genes have been more frequently detected in Acinetobacter spp.¹ and are clustered in three major subfamilies, bla_OXA-23-, bla_OXA-24- and bla_OXA-58-types.⁶

Given the presence of these resistance determinants within mobile elements and the genetic potential of Acinetobacter spp. for acquiring foreign DNA from the environment,¹ intensive surveillance to assist infection control interventions has become very important to minimize the dissemination of resistant isolates and/or resistance genes. The objective of this surveillance study was to evaluate the occurrence and dissemination of acquired class D carbapenemase- and MBL-encoding genes among Acinetobacter spp. isolates recovered from medical centres in the Asia-Pacific (APAC) region.

	Materials and methods

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Bacterial isolates

During 2006–07, 41 medical centres located in 10 countries in the APAC region were recruited to participate in the SENTRY Antimicrobial Surveillance Program. A total of 544 isolates were consecutively collected from bloodstream, respiratory tract, skin and skin structure and urinary tract infections, according to defined protocols, from Republic of China (182 isolates), India (132), Indonesia (67), Thailand (48), Korea (47), Taiwan (24), Singapore (21), Australia (9), Hong Kong (8) and the Philippines (6). Only isolates responsible for documented infections were included in the study; one per patient episode. Species identification was performed by standard biochemical tests and by use of the Vitek system (bioMérieux, Hazelwood, MO, USA), when necessary. Additionally, species identification was confirmed by sequencing of the 16S ribosomal RNA gene on those isolates showing negative PCR results for bla_OXA-51/69-like.⁶

Antimicrobial susceptibility testing

All isolates were tested for susceptibility and the results were interpreted as described previously.³ Tigecycline MIC results were interpreted according to the breakpoints for Enterobacteriaceae approved by the United States Food and Drug Administration (USA-FDA; breakpoint for susceptibility, 2 mg/L; breakpoint for resistance, 8 mg/L).³ Escherichia coli ATCC 25922 and Pseudomonas aeruginosa ATCC 27853 were concurrently tested for quality control purposes; all results were within published ranges.

Class D carbapenemase- and MBL-encoding genes detection

Isolates non-susceptible to imipenem or meropenem (MIC, 8 mg/L) were screened using primers able to detect and distinguish alleles encoding three subfamilies of acquired class D carbapenemase (bla_OXA-23-like, bla_OXA-24/40-like and bla_OXA-58-like) and the intrinsic subgroup of bla_OXA-51/69-like (Acinetobacter baumannii) genes in a multiplex PCR assay format.⁶ MBL screening was performed using generic primers able to detect VIM- and IMP-like, SPM-1-, GIM-1- and SIM-1-encoding genes in a multiplex real-time platform.⁷ Positive controls for all screened genes were run simultaneously. Amplicons were sequenced on both strands. The nucleotide sequences and deduced amino acid sequences were analysed using the Lasergene software package (DNASTAR, Madison, WI, USA) and compared with the sequences available through the internet using BLAST (http://www.ncbi.nlm.nih.gov/blast/).

Molecular typing

Clinical isolates recovered within each medical centre that harboured carbapenemase-encoding genes were typed using the Riboprinter^TM Microbial Characterization system (DuPont Qualicon, Wilmington, DE, USA). Isolates showing identical ribotypes were further characterized by PFGE, as described previously.⁸ Gel pattern analysis was carried out using the GelCompar II software (Applied Math, Kortrijk, Belgium). Percentage similarities were identified on a dendrogram derived from the unweighted pair group method using arithmetic averages and based on Dice coefficients. Band position tolerance and optimization were set at 1.3% and 0.5%, respectively.⁸ Isolates showing a similarity coefficient of >80% were considered as genetically related for this study. The PFGE pattern was determined based on the number of the medical centre followed by a capital letter (A, B, C). Isolates were assigned with the same PFGE pattern when the similarity coefficient was 100%. When this coefficient was in between 80% and 100%, the isolates were assigned as a subtype or variant of the major type, which was designated with the same capital letter followed by an Arabic number (e.g. C1, C2, C3).

	Results

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Bacterial isolates and antimicrobial susceptibility profile

A total of 544 Acinetobacter spp. isolates were recovered during 2006–07 from medical centres located in the APAC region. The vast majority were identified as A. baumannii (94.1%), followed by a lower prevalence of Acinetobacter junii (2.8%), Acinetobacter lwoffii (1.8%), Acinetobacter haemolyticus (0.4%), Acinetobacter johnsonii (0.2%), Acinetobacter calcoaceticus (0.2%) and Acinetobacter radioresistens (0.2%). Two isolates could not be identified to the species level (0.4%). Polymyxins (99.1% susceptible) and glycylcyclines (tigecycline; 98.9% of isolates showed MIC 2 mg/L) were the most active antimicrobial agents tested, followed by the carbapenems, imipenem and meropenem (52.0% and 51.3% susceptible, respectively). The remaining antimicrobials evaluated showed activity at 41.2%. Among the isolates, 230 (42.3%) were non-susceptible (MIC 8 mg/L) to imipenem or meropenem, and this resistance phenotype was most common in isolates recovered from Singapore (95.2%), Korea (87.0%), Taiwan (62.5%), Thailand (59.2%) and Hong Kong (50.0%).

Class D carbapenemase- and MBL-encoding genes

Among the carbapenem non-susceptible isolates, class D carbapenemase- and MBL-encoding genes were detected in 70.0% (160 isolates) and 0.8% of the isolates (two isolates), respectively. bla_OXA-23 was the most common gene, which accounted for 95.0% of the class D carbapenemase-encoding genes detected, followed by a lower occurrence of bla_OXA-58 (11.9%) and bla_OXA-24/40 (5.6%). bla_OXA-23 was found in isolates distributed among six nations (Table 1), which included all nations participating in the SENTRY Program (APAC), except Australia and Indonesia; while bla_OXA-24/40 was detected only in isolates recovered from Taiwan, Thailand and Indonesia, and bla_OXA-58 was detected in isolates recovered from China, India and Thailand. Several isolates harbouring more than one class D carbapenemase-encoding gene were found in China (bla_OXA-23 plus bla_OXA-58) and Thailand (bla_OXA-24/40 plus bla_OXA-58, and bla_OXA-23 plus bla_OXA-24/40 plus bla_OXA-58; Table 1), including an A. radioresistens clinical isolate recovered from India harbouring bla_OXA-58 in addition to the intrinsic bla_OXA-23-like.⁹ Sequencing results of this intrinsic gene revealed the presence of a novel variant, named bla_OXA-133 (accession no. EU571228 [GenBank] ). MBL-encoding genes were detected in one A. johnsonii recovered from the Philippines (bla_IMP-4) and one A. baumannii recovered from Korea (bla_VIM-2).

View this table: [in this window] [in a new window]   Table 1. Molecular epidemiology data from class D carbapenemase-producing Acinetobacter spp. isolates at each medical centre

 
Molecular typing

Clonal dissemination of bla_OXA-23-carrying A. baumannii was noted in medical centres 204, 217, 218, 224, 231, 243 and 246; while bla_OXA-23-carrying A. baumannii from the remaining centres showed greater genetic diversity (Table 1). Among bla_OXA-24/40-carrying A. baumannii recovered from Taiwan and Thailand, dissemination of related and unrelated clinical isolates was noted, respectively. Additionally, clonal spread was observed among isolates showing multiple bla_OXA genes [bla_OXA-23- and bla_OXA-58- carrying A. baumannii recovered from China (site 231) and bla_OXA-23-, bla_OXA-24/40- and bla_OXA-58-carrying A. baumannii recovered from Thailand (site 226)].

Figure 1 shows a dendrogram containing representative isolates belonging to each dominant clone within each medical site and according to carbapenemase production. bla_OXA-23-carrying A. baumannii representative isolates belonging to clones ACB-252-B and ACB-248-G recovered from different medical sites in India were considered genetically related (similarity coefficient of 82.8%). Similar findings were noted with bla_OXA-23-carrying A. baumannii belonging to clones ACB-218-A and ACB-238-A recovered from two medical sites located in Beijing, China (similarity coefficient of 86.7%). bla_OXA-24/40-carrying A. baumannii belonging to clone ACB-223-A isolated from Taiwan clustered with bla_OXA-23-carrying A. baumannii belonging to clones ACB-225-B and ACB-217-A recovered from Korea and Singapore (similarity coefficient 85.7%; Figure 1), respectively, and these isolates also showed the same ribogroup. In addition, the representative isolate harbouring bla_OXA-24/40 from Thailand (226-24-A) clustered with the representative isolate harbouring bla_OXA-23 from Hong Kong (similarity coefficient of 82.4%; Figure 1). The isolate harbouring bla_OXA-24/40 and bla_OXA-58 from Thailand was clustered with OXA-23-, OXA-24/40- and OXA-58-producing A. baumannii recovered from the same medical site (ACB-226-A; Figure 1). Genetic relatedness was not found among other minor clones.

View larger version (16K): [in this window] [in a new window] [Download PowerPoint slide]   Figure 1. PFGE profile of ApaI-digested genomic DNA from representative isolates belonging to the dominant clones within each medical institution and according to carbapenemase production. Band position tolerance and optimization were set at 1.3% and 0.5%, respectively. Isolates showing a similarity coefficient of >80% were considered as genetically related for this study. Isolate number, clone designation and carbapenemase detected are shown, as well as the PFGE profile of A. baumannii COL 20820 strain for comparison purposes. NA, not applicable.

 

	Discussion

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Overall, this study showed low susceptibility rates to most of the clinically available antimicrobial agents for the treatment of infections caused by Acinetobacter spp., except for polymyxin B and the novel glycylcycline, tigecycline, which may represent valuable antimicrobial options for the treatment of infections caused by these isolates.³ Among those isolates showing a resistant phenotype towards imipenem, 75.4% harboured at least one acquired class D carbapenemase-encoding gene, while among those isolates showing intermediate resistance towards this drug, only 11.1% harboured an acquired gene (data not shown). Therefore, the high prevalence of class D carbapenemase-encoding genes among the clinical isolates from the APAC region appears responsible for low susceptibility rates for imipenem [P < 0.001; OR = 0.04 (0.01–0.20)].

Recently, Zhou et al.² reported that 94.2% of imipenem-resistant A. baumannii isolates from China harboured bla_OXA-23, while Wang et al.¹⁰ described that 97.7% and 4.1% of the imipenem-resistant Acinetobacter spp. isolates harboured bla_OXA-23 and bla_OXA-58, respectively. In this study, bla_OXA-carrying Acinetobacter spp. represented 68.2% (30 of 44) of imipenem-resistant isolates from China. Among these isolates, 90.0% (27 of 30) and 46.6% (14 of 30) harboured bla_OXA-23 and bla_OXA-58, respectively. However, among the isolates harbouring bla_OXA-23, 40.7% (11 of 27) also possessed bla_OXA-58, suggesting that the epidemiology of class D carbapenemase-encoding genes has significantly changed in Acinetobacter spp. clinical isolates recovered from China.

Two clusters (ACB-252-B and ACB-248-G) considered genetically related (similarity coefficient of 82.8%) were noted in two different cities in India. However, clonal dissemination within each medical centre was predominantly observed, suggesting that the isolates from this study mostly belonged to local clones causing sporadic or endemic outbreaks within each medical institution. Previously published reports have shown clonal dissemination of OXA-23-producing A. baumannii among several medical centres located in different cities in China,^2,10 which contrasts with our findings. In this study, only the clones ACB-218-A and ACB-238-A, considered genetically related, were noted in different institutions from China (similarity coefficient of 86.7%); however, these medical centres were located in the same city (Beijing). These contrasting results may have been due to the fact that the carbapenem-resistant isolates from this study were recovered from a smaller number of medical centres and cities other than those included in those previous studies.^2,10 Interestingly, genetically related isolates were observed among medical centres located in different countries [Taiwan, Singapore and Korea (similarity coefficient 85.7%), and Hong Kong and Thailand (similarity coefficient of 82.4%)], suggesting these isolates derived from a common ancestor. Furthermore, these clones may have been spreading in this region as previously documented for many regions in Europe, where the European clones I and II have become epidemic since 1980.¹¹

bla_IMP-4 has been previously detected in Acinetobacter spp. and Citrobacter youngae from China, and subsequently, bla_IMP-4-carrying P. aeruginosa emerged and this resistance gene rapidly disseminated among several Gram-negative pathogens in an Australian hospital setting.⁵ Although the prevalence of MBL genes was very low in our study, the detection of a bla_IMP-4- carrying A. johnsonii recovered from a patient in the Philippines underscores the continued spread of this gene in the geographic region. This highlights the importance of active hospital surveillance to avoid possible infection outbreaks by such organisms.⁵ Furthermore, there have been only a few detections of VIM variants in Acinetobacter spp. in the APAC region, predominantly represented by the occurrence of bla_VIM-2 in South Korea,⁴ and our study highlights the continued detection of this determinant in that country, albeit at low frequency.

The presence of multiple class D carbapenemase-encoding genes in single isolates was noted in China, India and Thailand (Table 1). Additionally, the detection of an A. radioresistens clinical isolate carrying the intrinsic bla_OXA-23-like and bla_OXA-58 emphasizes (i) the natural occurrence of class D carbapenemase-encoding genes among Acinetobacter species,^4,9 (ii) the ability for acquiring and/or exchanging foreign DNA,¹ and (iii) the diversity of resistance genes in the hospital environment. These findings also provide strong evidence that the hospital environment has become the main reservoir of these resistance determinants,⁹ which may facilitate DNA exchange among endemic nosocomial pathogens.

	Funding

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No specific funding was received for this study.

	Transparency declarations

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R. N. J. has received research/education grants in the last 2 years from AB BIODISK, Abbott, API, Arpida, Astellas, AstraZeneca, Bayer, Cadence, Cempra, Cerexa, Cornerstone, Cubist, Daiichi, Elan, Elanco, Enanta, GlaxoSmithKline, Johnson & Johnson (Ortho McNeil), Merck, Novartis, Optimer, Ordway, Pacific Beach, Pfizer, Protez, Replidyne, Schering-Plough, Sequoia, Shionogi, Theravance, TREK Diagnostics, ViroPharma and Wyeth. All other authors: none to declare.

	Acknowledgements

 
We would like to thank Professor Harald Seifert for kindly providing the PFGE reference standard strain A. baumannii COL20820 and Professor Thomas Fritsche for carefully reading the manuscript.

	References

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1 Perez F, Hujer AM, Hujer KM, et al. Global challenge of multidrug-resistant Acinetobacter baumannii. Antimicrob Agents Chemother (2007) 51:3471–84.[Free Full Text]

2 Zhou H, Yang Q, Yu YS, et al. Clonal spread of imipenem-resistant Acinetobacter baumannii among different cities of China. J Clin Microbiol (2007) 45:4054–7.[Abstract/Free Full Text]

3 Mendes RE, Fritsche TR, Sader HS, et al. Increased antimicrobial susceptibility profile among polymyxin-resistant Acinetobacter baumannii clinical isolates. Clin Infect Dis (2008) 46:1324–6.[CrossRef][Web of Science][Medline]

4 Poirel L, Pitout JD, Nordmann P. Carbapenemases: molecular diversity and clinical consequences. Future Microbiol (2007) 2:501–12.[CrossRef][Medline]

5 Rossolini GM. Acquired metallo-β-lactamases: an increasing clinical threat. Clin Infect Dis (2005) 41:1557–8.[CrossRef][Web of Science][Medline]

6 Woodford N, Ellington MJ, Coelho JM, et al. Multiplex PCR for genes encoding prevalent OXA carbapenemases in Acinetobacter spp. Int J Antimicrob Agents (2006) 27:351–3.[CrossRef][Web of Science][Medline]

7 Mendes RE, Kiyota KA, Monteiro J, et al. Rapid detection and identification of metallo-β-lactamase-encoding genes by multiplex real-time PCR assay and melt curve analysis. J Clin Microbiol (2007) 45:544–7.[Abstract/Free Full Text]

8 Seifert H, Dolzani L, Bressan R, et al. Standardization and interlaboratory reproducibility assessment of pulsed-field gel electrophoresis-generated fingerprints of Acinetobacter baumannii. J Clin Microbiol (2005) 43:4328–35.[Abstract/Free Full Text]

9 Poirel L, Figueiredo S, Cattoir V, et al. Acinetobacter radioresistens as a silent source of carbapenem resistance for Acinetobacter spp. Antimicrob Agents Chemother (2008) 52:1252–6.[Abstract/Free Full Text]

10 Wang H, Guo P, Sun H, et al. Molecular epidemiology of clinical isolates of carbapenem-resistant Acinetobacter spp. from Chinese hospitals. Antimicrob Agents Chemother (2007) 51:4022–8.[Abstract/Free Full Text]

11 van Dessel H, Dijkshoorn L, van der Reijden T, et al. Identification of a new geographically widespread multiresistant Acinetobacter baumannii clone from European hospitals. Res Microbiol (2004) 155:105–12.[Medline]

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