Susceptibility

Distribution of Extended-Spectrum β-Lactamases, AmpC β-Lactamases, and Carbapenemases among Enterobacteriaceae Isolates Causing Intra-Abdominal Infections in the Asia-Pacific Region: Results of the Study for Monitoring Antimicrobial Resistance Trends (SMART)

Wang-Huei Sheng, Robert E. Badal, Po-Ren Hsueh
and on behalf of the SMART Program
DOI: 10.1128/AAC.00971-12

ABSTRACT

The increasing trend of β-lactam resistance among Enterobacteriaceae is a worldwide threat. Enterobacteriaceae isolates causing intra-abdominal infections (IAI) from the Study for Monitoring Antimicrobial Resistance Trends (SMART) collected in 2008 and 2009 from the Asia-Pacific region were investigated. Detection of extended-spectrum β-lactamases (ESBLs), AmpC β-lactamases, and carbapenemases was performed by multiplex PCR. A total of 699 Enterobacteriaceae isolates with positive genotypic results, included Escherichia coli (n = 443), Klebsiella pneumoniae (n = 187), Enterobacter cloacae (n = 45), Klebsiella oxytoca (n = 9), Citrobacter freundii (n = 5), Proteus mirabilis (n = 3), Enterobacter aerogenes (n = 2), Morganella morganii (n = 2), and one each of Enterobacter asburiae, Proteus vulgaris, and Providencia rettgeri were analyzed. Nearly 20% of these β-lactamase-producing Enterobacteriaceae isolates were from community-associated IAI. CTX-M (588 isolates, including 428 [72.8%] with CTX-M-15) was the most common ESBL, followed by SHV (n = 59) and TEM (n = 4). CMY (n = 110, including 102 [92.7%] with CMY-2) was the most common AmpC β-lactamase, followed by DHA (n = 46) and ACT/MIR (n = 40). NDM (n = 65, including 62 [95.4%] with NDM-1) was the most common carbapenemase, followed by IMP (n = 7) and OXA (n = 7). Isolates from hospital-associated IAI had more complicated β-lactamase combinations than isolates from the community. Carbapenemases were all exclusively detected in Enterobacteriaceae isolates from India, except that IMP β-lactamases were also detected in Philippines and Australia. CTX-M β-lactamases were the predominant ESBLs produced by Enterobacteriaceae causing IAI in the Asia-Pacific region. Emergence of CTX-M-15-, CMY-2-, and NDM-1-producing Enterobacteriaceae isolates is of major concern and highlights the need for further surveillance in this area.

INTRODUCTION

Enterobacteriaceae producing β-lactamases are a worldwide problem (1, 2). Certain enzymes of the Ambler classes, such as metallo-β-lactamases (IMP and VIM), OXA-β-lactamases, and Klebsiella pneumoniae carbapenemase (KPC), could lead to resistance to penicillins, expanded-spectrum cephalosporins, and carbapenems (2–4). Furthermore, β-lactamase-producing Enterobacteriaceae are commonly cross-resistant to other classes of antibiotics, such as fluoroquinolones, trimethoprim-sulfamethoxazole, and aminoglycosides, resulting in limited therapeutic options to treat infections caused by these pathogens (2–4). In the most recent decade, β-lactamase-producing Enterobacteriaceae have occurred in community-associated infections, affecting ambulatory and previously healthy adults (3, 5) and leading to higher mortality rates and medical costs than non-β-lactamase-producing Enterobacteriaceae (6). Therefore, surveillance for the existence of β-lactamase-producing Enterobacteriaceae is important for clinical care.

The prevalences of extended-spectrum β-lactamase (ESBL)-expressing bacteria vary across different geographic regions. For example, data from a review published in 2005 showed that less than 10% of Enterobacteriaceae isolates expressed ESBLs in Australia, Sweden, Japan, Korea, and Singapore, compared to rates higher than 30% in Portugal, Italy, Turkey, and most Latin American countries (7). In another report, ESBL-positive Escherichia coli rates were described as being higher than 50% in China, India, and Thailand (8). Interspecies plasmid transfer is observed in these bacteria, which further exacerbates public health concerns (1). Up-to-date epidemiology of antimicrobial resistance surveillance and understanding of the resistance mechanisms are crucial to selection of appropriate treatment for infection.

The Study for Monitoring Antimicrobial Resistance Trends (SMART) monitors the in vitro activities of several antimicrobial agents against Gram-negative aerobic pathogens from intra-abdominal infections (IAI). This program has been ongoing since 2002 in most regions of the world, with nearly 200 hospitals participating in 2012. In this report, we present a comprehensive geographic distribution and genetic analysis of ESBL-, AmpC-, and carbapenemase-producing Enterobacteriaceae isolates collected from the SMART program in the Asia-Pacific region in 2008 and 2009.

(This work was presented in part at the Interscience Conference on Antimicrobial Agents and Chemotherapy [ICAAC] in Chicago, IL, 2011.)

MATERIALS AND METHODS

Study countries and isolates.A total of 34 medical centers from 11 countries in the Asia-Pacific region participated in the SMART 2008-2009 project, including Australia (n = 1), China (n = 7), India (n = 7), Malaysia (n = 2), New Zealand (n = 3), Philippines (n = 1), Singapore (n = 2), South Korea (n = 1), Taiwan (n = 8), Thailand (n = 1), and Vietnam (n = 1). During 2008 and 2009, this study prospectively collected consecutive, nonduplicate isolates of aerobic and facultative Gram-negative bacilli from patients with IAI at each center. Bacteria were initially identified by standard methods used in the participating clinical microbiology laboratories as previously described (9). Isolates collected within 48 h of the patient's admission to hospital were presumptively categorized as community-associated IAIs (CA-IAI) and those collected more than 48 h after admission as hospital-associated IAIs (HA-IAI).

Screening tests for ESBL and carbapenemases.The identifications and antimicrobial susceptibility tests of all isolates except those from China were performed by a central laboratory (International Health Management Associates, Inc., Schaumburg, IL); isolates collected in China were sent to a central laboratory in Beijing (Peking Union Medical College, Beijing, China), following the same protocols as in the U.S. central laboratory. The molecular analyses were all performed in the U.S. central laboratory. Antimicrobial susceptibility tests were performed by following the recommendations of the Clinical and Laboratory Standards Institute (CLSI) (10). Ertapenem nonsusceptibility was defined as a MIC of ertapenem of >0.5 μg/ml (11). Enterobacteriaceae were confirmed as ESBL-producing isolates if there was at least an 8-fold reduction of the MIC for ceftazidime or cefotaxime tested in combination with clavulanic acid versus their MICs when either drug was tested alone (10, 11). Quality control (QC) testing was done by the central laboratory on each day of testing using the CLSI-recommended QC strains E. coli ATCC 25922, K. pneumoniae ATCC 700603 (positive ESBL control), and Pseudomonas aeruginosa ATCC 27853 (12). ESBL-confirmed Enterobacteriaceae isolates and isolates with MICs of ertapenem of ≥0.5 μg/ml were checked for ESBLs, AmpCs, and carbapenemases via multiplex PCR.

Molecular detection of ESBLs, AmpCs, and carbapenemases.Whole genomic DNA was extracted using the QIAamp DNA minikit and a QIAcube instrument (Qiagen, Valencia, CA) from overnight colonies grown on agar (Remel, Lenexa, KS). We used a multiplex PCR for the rapid detection of ESBL (blaTEM, blaSHV, and blaCTX-M) and AmpC (blaCMY, blaDHA, blaFOX, blaMOX, blaACC, blaMIR, and blaACT) genes and for confirmation of the presence of the blaKPC, blaVIM, blaIMP, blaNDM, and blaOXA genes (13, 14).

RESULTS

Bacterial isolates and distribution of phenotypic resistance.Overall, 6,510 clinical isolates (of which 5,585 were Enterobacteriaceae) from 34 medical centers in 11 countries located in the Asia-Pacific region were collected and tested during the study period. A total of 758 Enterobacteriaceae isolates that either were phenotypically positive for ESBL production or had elevated ertapenem MICs (MIC ≥ 0.5 μg/ml) were tested for existence of ESBLs, AmpCs, and carbapenemases. The CLSI phenotypic test for ESBL production of E. coli, K. pneumoniae, Klebsiella oxytoca, and Proteus mirabilis was used for all Enterobacteriaceae isolates. All the Enterobacteriaceae species with elevated ertapenem MICs (MIC ≥ 0.5 μg/ml) were also tested for ESBLs, AmpCs, and carbapenemases by multiplex PCR assay. Ultimately, 699 isolates with β-lactamase genes detected in multiplex PCR assay were analyzed, including E. coli (n = 443), K. pneumoniae (n = 187), Enterobacter cloacae (n = 45), K. oxytoca (n = 9), Citrobacter freundii (n = 5), P. mirabilis (n = 3), Enterobacter aerogenes (n = 2), Morganella morganii (n = 2), Enterobacter asburiae (n = 1), Proteus vulgaris (n = 1), and Providencia rettgeri (n = 1). A total of 281 isolates were found with elevated ertapenem MICs (≥0.5 μg/ml), including E. coli (n = 137; 45 with ESBL, 23 with AmpC, and 69 with both ESBL and AmpC), K. pneumoniae (n = 90; 54 with ESBL, 18 with AmpC, and 18 with both ESBL and AmpC), E. cloacae (n = 39; 3 with ESBL, 27 with AmpC, and 9 with both ESBL and AmpC), C. freundii (n = 5; 3 with ESBL and 2 with AmpC), K. oxytoca (n = 4; 2 with ESBL and 2 with both ESBL and AmpC), M. morganii (n = 2 with both ESBL and AmpC), E. aerogenes (n = 1 with ESBL), E. asburiae (n = 1 with both ESBL and AmpC), P. vulgaris (n = 1 with AmpC), and P. rettgeri (n = 1 with AmpC). Of 627 ESBL-producing Enterobacteriaceae isolates, 128 (20.4%) and 66 (10.5%) coproduced AmpC β-lactamases and carbapenemases, respectively. Of 72 non-ESBL-producing Enterobacteriaceae isolates with elevated ertapenem MICs, 66 (91.7%) produced AmpC β-lactamases and 11 (15.3%) produced carbapenemases (Fig. 1). All isolates that produced carbapenemases had ertapenem MICs of ≥1 μg/ml.

Fig 1
Fig 1

Enterobacteriaceae isolates enrolled in this study.

Ertapenem susceptibility among ESBL-producing Enterobacteriaceae isolates: HA-IAI isolates versus CA-IAI isolates.For ESBL-producing Enterobacteriaceae isolates, nearly 20% were CA-IAI isolates and 80% were HA-IAI isolates. For example, of 77 ESBL-producing E. coli isolates nonsusceptible to ertapenem (ertapenem MIC > 0.5 μg/ml), 14 (18.2%) were CA-IAI isolates and 63 (81.8%) were HA-IAI isolates. Of 343 ertapenem-susceptible (ertapenem MIC ≤ 0.5 μg/ml) ESBL-producing E. coli isolates, 103 (30%) were CA-IAI isolates, while 240 (70%) were HA-IAI isolates. Similar to E. coli, 12 of 58 (20.7%) ESBL-producing K. pneumoniae isolates with ertapenem nonsusceptibility were CA-IAI isolates, while 46 of 58 (79.3%) were HA-IAI isolates. Of 111 ertapenem-susceptible K. pneumoniae isolates, 21 (18.9%) were CA-IAI isolates, while 90 (81.1%) were HA-IAI isolates (Table 1).

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Table 1

Distribution of various β-lactamases (ESBLs, AmpCs, and carbapenemases) among Enterobacteriaceae causing intra-abdominal infections obtained within or after 48 h of hospitalization

Genotypic distribution of various β-lactamases among Enterobacteriaceae causing IAI.In this study, we identified three ESBL types (CTX-M, SHV, and TEM), three AmpC types (CMY, DHA, and ACT/MIR), and three carbapenemase types (NDM, IMP, and OXA) in Enterobacteriaceae isolates causing IAI from the Asia-Pacific area. Table 2 illustrates the distributions of β-lactamases in these isolates. HA-IAI isolates had more complicated β-lactamase combinations than CA-IAI isolates. The most common ESBLs were CTX-M types (n = 588), followed by SHV (n = 59) and TEM (n = 4). CTX-M-15 and CTX-M-14 were the dominant CTX-M-type ESBLs in Enterobacteriaceae isolates in this study. SHV-12 was the dominant SHV variant for both E. coli and K. pneumoniae isolates. The most common AmpC β-lactamase types were CMY (n = 110), followed by DHA (n = 46) and ACT/MIR (n = 40), in Enterobacteriaceae isolates in this study. CMY-2, DHA-1, and ACT/MIR were the most dominant AmpC-type β-lactamases in E. coli, K. pneumoniae, and E. cloacae isolates, respectively. The most common carbapenemases were NDM types (n = 65), followed by IMP (n = 7) and OXA (n = 7). NDM-1 was the most dominant carbapenemase. More than 90% of NDM-1 isolates were HA-IAI isolates (23 of 25 [92%]). The IMP- and OXA-type carbapenemases were less common, and there were no Klebsiella pneumoniae carbapenemases (KPCs) detected in this study (Table 2).

View this table:
Table 2

Genotypic distribution of various β-lactamase combinations among 699 Enterobacteriaceae causing intra-abdominal infections

Geographic distribution of ESBLs, AmpCs, and carbapenemases.The geographic distribution of ESBLs, AmpCs, and carbapenemases was variable (Table 3). CTX-M-type ESBLs were common in most countries, including India (331 of 347 [95.4%]), China (64 of 66 [97.0%]), Philippines (38 of 52 [73.1%]), South Korea (35 of 41 [85.4%]), Taiwan (35 of 51 [68.6%]), Malaysia (27 of 29 [93.1%]), and Singapore (27 of 31 [87.1%]). CTX-M-14 was dominant in China (33 of 66 [50%]), South Korea (15 of 41 [36.6%]), and Taiwan (18 of 51 [35.3%]), while CTX-M-15 was dominant in India (323 of 347 [93.1%]), Malaysia (17 of 29 [58.6%]), Philippines (26 of 52 [50%]), and Singapore (18 of 31 [58.1%]). SHV-type ESBLs were prevalent in Taiwan (15 of 51 [29.4%]) and Philippines (13 of 52 [25%]). Two-thirds of the SHV-type ESBLs were SHV-12 (40 of 59 [67.8%]). AmpC CMY-type β-lactamases were prevalent in India (85 of 109 [78.0%]), Taiwan (17 of 37 [45.9%]), South Korea (4 of 9 [44.4%]), and Vietnam (2 of 4 [50%]). More than 90% of the CMY-type AmpC β-lactamases were CMY-2 (102 of 110 [92.7%]). AmpC DHA-type β-lactamases were dominant in Philippines (13 of 16 [81.3%]) and Singapore (4 of 8 [50%]), while ACT/MIR β-lactamases were dominant in New Zealand (6 of 7 [85.7%]) and South Korea (4 of 9 [44.4%]). DHA-1 (11 of 37 [29.7%]) was more dominant in Taiwan than ACT/MIR (9 of 37 [24.3%]). Except for IMP β-lactamases detected in Philippines and Australia, carbapenemases were exclusively detected in Enterobacteriaceae isolates from India (Table 3).

View this table:
Table 3

Geographic distribution of various β-lactamases among Enterobacteriaceae causing intra-abdominal infections in different countries

DISCUSSION

ESBLs are the major cause of resistance to oxyimino-cephalosporins in Enterobacteriaceae (2, 7). At present, more than 300 different ESBL variants have been described (7). Most ESBLs can be divided into three groups: TEM, SHV, and CTX-M types. During the past decade, CTX-M-type ESBLs have been increasingly reported, and these enzymes have now replaced TEM and SHV as the most common type of ESBLs in many countries (15–17). In line with these reports (15–17), our results confirm that CTX-M-type ESBLs, particularly CTX-M-14 (dominant in China, Taiwan, and South Korea) and CTX-M-15 (dominant in Australia, India, Malaysia, New Zealand, Philippines, Singapore, Thailand, and Vietnam), have become the most prevalent ESBLs in the Asia-Pacific region.

Bonnet reported that the presence of the mobile genetic platform ISEcp1 was predominantly found upstream of blaCTX-M-15, blaCTX-M-9, and blaCTX-M-14 in CTX-M-producing E. coli isolates that might be involved in both the spread and expression of these genes in Enterobacteriaceae resistance (15). The spread of blaCTX-M-15 was essentially caused by the clonal expansion of E. coli isolates belonging to the international pandemic ST131 clone (18, 19), and these strains have been reported to occur in healthy people as a part of the commensal flora (20). Our results show the emergence of CTX-M genes (blaCTX-M-14 and blaCTX-M-15) across different species, including primarily E. coli and Klebsiella and Enterobacter spp. The dissemination of blaCTX-M genes in Enterobacteriaceae species suggests that the diffusion of epidemic plasmids carrying blaCTX-M already has taken place and plays an important role in the spread of this gene in the Asia-Pacific region. More epidemiological studies are necessary to elucidate this point.

SHV-12 was the dominant SHV type for both ESBL-producing E. coli and K. pneumoniae isolates in various countries, such as in India, Taiwan, and Philippines. TEM-52- and SHV-12-producing strains have been found in hospitals in Europe (18), as well as in in animals and in river waters, indicating that all ESBLs, not just CTX-M enzymes, could disseminate out of hospitals (21, 22). In addition, SHV-12 has been reported to be associated with high-level resistance to ceftazidime in this area (8). Compatible with a previous report in Thailand (23), our findings indicate that ESBL genes in the Asia-Pacific region are part of a gene pool capable of broad horizontal gene transfer, in that these genes might transfer between different species of Enterobacteriaceae.

AmpC β-lactamases are clinically important cephalosporinases encoded on the chromosomes of many of the Enterobacteriaceae, where they mediate resistance to cephalothin, cefazolin, cefoxitin, most penicillins, and β-lactamase inhibitors (4). In many Enterobacteriaceae, AmpC expression is low but inducible in response to β-lactam exposure (4, 7). However, transmissible plasmids for AmpC enzymes, including CMY-2, the most common plasmid-mediated AmpC β-lactamase worldwide, could appear in bacteria lacking or poorly expressing chromosomal blaAmpC genes, such as E. coli, K. pneumoniae, and P. mirabilis (24). In this study, we observed that various types of AmpC β-lactamases were found in different Enterobacteriaceae species: CMY-2 in E. coli, DHA-1 in K. pneumoniae, and ACT/MIR in E. cloacae. Recently, plasmids carrying both blaDHA-1 and qnrB, a gene mediating resistance to fluoroquinolones, were observed among isolates of Enterobacteriaceae (25). Similar to a previous survey in the United States (26), we have shown that AmpC β-lactamase production in Enterobacteriaceae isolates frequently coexists with ESBL (n = 128, 66%) or carbapenemase production (n = 43, 22%) in the Asia-Pacific region.

The detection of carbapenemase-producing Enterobacteriaceae strains has been a challenging issue for clinical laboratories. Our results, based on PCR methodology, confirm that the recently lowered CLSI susceptibility breakpoints for carbapenems (11) enhance the classification of carbapenemase producers as nonsusceptible. In this study, based on applying newer ertapenem susceptibility criteria published by the CLSI (11) and PCR analysis, we did not find any KPC-producing Enterobacteriaceae isolates in the SMART 2008-2009 program in the Asia-Pacific region. Although ESBL-producing Enterobacteriaceae isolates coproducing carbapenemase (10.5% in this study) have not been shown to be major pathogens for IAI, the trends of carbapenem resistance should be carefully monitored.

Our study had the following limitations. First, the numbers of Enterobacteriaceae isolates screened from each country were not equal. The detailed epidemiological information on individual resistance rates and the population coverage of each participant hospital were not disclosed; therefore, selection bias might have existed. Second, we found 59 isolates that were ESBL screen positive but did not have a bla gene identified on the multiplex PCR used. Because the PCR primers of common β-lactamases (ESBLs, AmpC β-lactamases, and carbapenemases) were prospectively designed, some minor ESBL variants, such as blaVEB, did not have PCR primers in this study. In addition, high ertapenem MICs might also be due to development of active efflux pumps or changes in membrane porins. Third, the CLSI phenotypic confirmation methods (i.e., using ceftazidime or cefotaxime with and without clavulanic acid) are validated only for E. coli, K. pneumoniae, K. oxytoca, and P. mirabilis and may not be adequate for Enterobacter species due to the presence of constitutive chromosomal inducible AmpC β-lactamase.

One study suggested that testing with cefepime may be more reliable in detecting the ESBL phenotype in Enterobacter species (27). Finally, molecular epidemiology, such as pulsed-field gel electrophoresis (PFGE), and highly transmissible mobile genetic elements (ISEcp1) were not studied in this survey. Therefore, the epidemiological relatedness of the multiple-drug-resistant isolates and whether dissemination of resistant lineages (e.g., ST131 E. coli) or interspecies plasmid transfer in these bacteria exacerbates public health concerns in this area need further investigation.

In conclusion, our results reveal the high prevalence of CTX-M-type ESBLs, including CTX-M-14 and CTX-M-15, within many Enterobacteriaceae species in the Asia-Pacific region. Coexistence of plasmid-mediated AmpC β-lactamases, such as DHA and CMY, with ESBLs or carbapenemases is common in this region. HA-IAI isolates had more complicated β-lactamase combinations than CA-IAI isolates. Although ESBL-producing isolates with relatively low rates of resistance to carbapenems were found in a previous SMART study (8), we have shown the rapid emergence of NDM-producing isolates in the current SMART study, at least in India. The rapid emergence of multiresistant ESBL-producing Enterobacteriaceae isolates is of major concern and highlights the need for further surveillance in this area. Empirical use of carbapenems for the treatment of IAI should be carefully monitored in countries with higher prevalences of carbapenemase-producing Enterobacteriaceae.

ACKNOWLEDGMENTS

We thank all the investigators in the Asia-Pacific region for their participation in the SMART program. The Asia-Pacific SMART team included the following: Tony Korman, Monash Medical Center, Australia; David Paterson, Royal Brisbane Hospital, Australia; Geoffrey Coombs, Royal Perth Hospital, Australia; Lee Thomas, Westmead Hospital, Australia; Bi Jie Hu, Fu Dan University Affiliated Zhong Shan Hospital, Shanghai, China; Ziyong Sun, Tongji Medical School of Mid-China, Wuhan, China; Wenxiang Huang, Chongqing Medical University Affiliate No. 1 Hospital, Chongqing, China; Yingchun Xu, Peking Union Medical College Hospital, Beijing, China; Yu Xing Ni, Shanghai Rui Jin Hospital, Shanghai, China; Yun Song Yu, Zhe Jiang University College of Medicine Affiliate, Hangzhou, China; Kang Liao, 1st Affiliated Hospital of Sun Yat-Sen University, China; Xianju Feng, 1st Affiliated Hospital of Zhengzhou University, China; Chu Yun Zhuo, First Hospital of China Medical University, China; Dingxia Shen, General Hospital of PLA, China; Zhidong Hu, General Hospital of Tianjin Medical University, China; Yong Wang, Provincial Hospital Shandong University, China; Huang Xun, Xiangya Hospital of Central South University, China; Thomas Kin Wah Ling, Prince of Wales Hospital, Hong Kong SAR, Hong Kong; Raymond Leung, Queen Mary Hospital, Hong Kong; Bhaskar N. Chaudhuri, AMRI Hospitals, Kolkata, India; Camilla Rodrigues, P. D. Hinduja National Hospital and Medical Research C, Mumbai, India; Ranganathan Iyer, Global Hospitals, Hyderabad, India; Sangeeta Joshi, Manipal Hospital, Bangalore, India; T. N. Dhole, SCPGI, Lucknow, India; Uma Sekar, Sri Ramachandra Medical College, Chennai, Porur, India; V. Balaji, Christian Medical College, Vellore, India; Datin Ganeswrie, Hospital Sultanah Aminah, Johor Bahru, Malaysia; Muhammand Nazri, Hospital Kuala Lumpur, Kuala Lumpur, Malaysia; Myrna Mendoza, Philippines General Hospital, Manila, Philippines; Evelina Lagamayo, St. Luke's Medical Center, Philippines; Prabha Unny Krishnan, Tan Tock Seng Hospital, Singapore, Singapore; Thean Yen Tan, Changi General Hospital, Singapore, Singapore; Wee-Gyo Lee, Ajou University Hospital, Suwon, South Korea; Chun-Eng Liu, Changhua Christian Hospital, Changhua, Taiwan; Jen-Hsien Wang, China Medical College-Hospital, Taichung, Taiwan; Kenneth Yin-Ching Chuang, Chi-Mei Medical Center, Tainan, Taiwan; Kwok-Woon Yu, Taipei Veterans General Hospital, Taipei, Taiwan; Po-Liang Lu, Chung-Ho Memorial Hospital, Kaohsiung, Taiwan; Po-Ren Hsueh, National Taiwan University Hospital, Taipei, Taiwan; Yao-Shen Chen, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; Wen-Chien Ko, National Cheng Kung University Hospital, Tainan, Taiwan; Sineenart Kalnauwakul, Songklanakarin Hospital, Songkla, Thailand; Pattarchai Kirathisin, Siriraj Hospital, Thailand; Tran Thi Lan Phuong, Benh Vien Viet Duc, Hanoi, Vietnam; Nguyen Tran My Phoung, Bihn Dan Hospital, Vietnam; Tran Thi Than Nga, Cho Ray Hospital, Vietnam; Tim Blackmore, Wellington Hospital, Wellington, New Zealand; Sally Roberts, Auckland City Hospital, Auckland, New Zealand; Susan Taylor, Middlemore Hospital at Counties Manukau District, Otahuhu, New Zealand; and Dragana Drinkovic, North Shore Hospital, New Zealand.

The SMART surveillance study was sponsored by Merck & Co., Inc.

FOOTNOTES

    • Received 9 May 2012.
    • Returned for modification 12 August 2012.
    • Accepted 7 April 2013.
    • Accepted manuscript posted online 15 April 2013.

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