In vitro susceptibilities of aerobic and facultative Gram-negative bacilli isolated from patients with intra-abdominal infections worldwide: the 2003 Study for Monitoring Antimicrobial Resistance Trends (SMART)

David L. Paterson1, Flávia Rossi2, Fernando Baquero3, Po-Ren Hsueh4, Gail L. Woods5, Vilas Satishchandran6, Theresa A. Snyder6, Charlotte M. Harvey6, Hedy Teppler6, Mark J. DiNubile6 and Joseph W. Chow6,*

1 University of Pittsburgh Medical Center, Pittsburgh, PA, USA; 2 Hospital das Clinicas da Faculdade de Medicina, São Paulo, Brazil; 3 Hospital Ramon y Cajal, Madrid, Spain; 4 National Taiwan University Hospital, Taipei, Taiwan; 5 ARUP Laboratories and University of Utah, Salt Lake City, UT, USA; 6 Merck Research Laboratories, West Point, PA, USA


* Corresponding author. Email: joseph_chow{at}merck.com

Received 20 January 2005; returned 14 February 2005; revised 10 March 2005; accepted 11 March 2005


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Objectives: The SMART (Study for Monitoring Antimicrobial Resistance Trends) surveillance programme was begun in 2002 to monitor antimicrobial resistance trends among aerobic and facultative Gram-negative bacilli (GNB) isolated from intra-abdominal infections worldwide.

Methods: In 2003, 74 medical centres from 23 countries collected isolates for testing. Antimicrobial susceptibility testing was performed using broth microdilution according to the NCCLS guidelines for MIC testing.

Results: A total of 5658 aerobic and facultative GNB were isolated from intra-abdominal infections. Enterobacteriaceae composed 84% of the total isolates. Among the agents tested, the carbapenems were the most consistently active against the Enterobacteriaceae. E. coli was the most common isolate (46%), and the susceptibility rate to the quinolone (70–90% susceptible), cephalosporin (80–97% susceptible), aminoglycoside (77–100% susceptible) and carbapenem (99–100% susceptible) agents tested varied among geographic regions, with isolates from the Asia/Pacific region generally being the most resistant. Extended-spectrum beta-lactamases (ESBLs) were detected phenotypically in 9% of E. coli, 14% of Klebsiella spp., and 14% of Enterobacter spp. worldwide. ESBL producers generally had a more antibiotic-resistant profile than non-ESBL producers.

Conclusions: Antimicrobial resistance among GNB isolated from intra-abdominal infections is a problem worldwide, especially in the Asia/Pacific region. The carbapenems ertapenem, meropenem and imipenem are highly active in vitro against Enterobacteriaceae isolated from intra-abdominal sites, including organisms that produce ESBLs.

Keywords: extended spectrum ß-lactamases , ESBLs , carbapenems , ertapenem , Enterobacteriaceae


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
With emergence of antimicrobial resistance in bacteria as a global problem, national and international surveillance programmes have been developed to monitor resistance.15 These studies serve not only to report point prevalence of resistance, but to detect potential resistance trends over time and may provide guidance in choosing empirical antimicrobial therapy for selected infections. The Study for Monitoring Antimicrobial Resistance Trends (SMART) was begun in 2002, and is the only global surveillance programme designed to monitor longitudinally the in vitro antimicrobial susceptibility of aerobic and facultative Gram-negative bacilli (GNB) isolated exclusively from intra-abdominal sites. This report provides an overview of the results from January to December 2003, the first full year of the study.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Seventy-four medical centres from 23 countries in five geographic regions participated in the study in 2003, which included Asia/Pacific [total 18 centres: China (4), Taiwan (4), Korea (2), Australia (3), Thailand (1), Malaysia (1), New Zealand (2), Philippines (1)], North America [total 13 centres: USA (13)], Europe [total 25 centres: Spain (13), Portugal (5), Germany (3), Belgium (2), Italy (2)], Latin America [total 11 centres in Central and South America: Mexico (2), Brazil (3), Puerto Rico (1), Guatemala (1), Argentina (2), Ecuador (1), Peru (1)] and the Middle East [total seven centres: Israel (4), Turkey (3)]. Each centre prospectively collected up to 100 consecutive unique aerobic and facultative Gram-negative bacilli isolated from intra-abdominal infections in 2003. Acceptable specimens included tissue, fluid or deep wound cultures obtained intraoperatively, and fluid from paracentesis or percutaneous aspiration of abscesses. By protocol, duplicate isolates (the same genus and species from the same patient) were excluded, regardless of the elapsed time between procurement of the specimens and differences in antimicrobial susceptibilities. Isolates obtained from abdominal drains or drainage bottles, stool, superficial wounds, or perirectal abscesses were excluded. Bacteria were identified by standard methods used in the participating clinical microbiology laboratories. Organisms were divided into those isolated within <48 h of hospitalization and those isolated ≥48 h after hospitalization. Custom-made microtitre trays (Dade Microscan, Inc., Sacramento, CA, USA) were shipped to each participating study centre for susceptibility testing. Antimicrobial susceptibility testing was performed using broth microdilution according to guidelines for MIC testing from the National Committee for Clinical Laboratory Standards.6 Susceptibility was based on NCCLS breakpoints.7 Twelve antimicrobial agents used to treat intra-abdominal infections were tested: ertapenem, imipenem, meropenem, ceftriaxone, ceftazidime, cefoxitin, cefepime, piperacillin/tazobactam, amikacin, tobramycin, ciprofloxacin and levofloxacin. Reference strains Escherichia coli ATCC 25922 and Pseudomonas aeruginosa ATCC 27853 were used as quality control strains for each batch of MIC tests, and were shipped to each laboratory if the strains were not available at the study site. MIC testing was repeated if results for ATCC strains were outside the expected range recommended by the NCCLS. Phenotypic identification of extended-spectrum ß-lactamase (ESBL) production was expanded to include E. coli, Klebsiella spp. and Enterobacter spp., and was performed using a modification of the NCCLS method.7 If the ceftazidime, ceftriaxone, or cefepime MIC was ≥2 mg/L, then the MIC of cefepime was compared with the MIC of cefepime + clavulanic acid (10 µg). ESBL production was defined as ≥8-fold decrease in the MIC for cefepime when tested in combination with clavulanic acid versus the cefepime MIC when tested in the absence of clavulanic acid. E. coli, Klebsiella spp. and Enterobacter spp. confirmed phenotypically to produce ESBLs were designated as resistant to ceftazidime, ceftriaxone and cefepime regardless of whether their MICs were within the NCCLS breakpoint for susceptibility.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
A total of 5658 aerobic and facultative Gram-negative bacilli were isolated from intra-abdominal infections in 4838 patients from the 74 participating study centres worldwide in 2003. Susceptibility results for the most frequently isolated organisms (≥1.0% of total isolates) are presented in Table 1.


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Table 1. In vitro susceptibility rates (% susceptible) of the most commonly isolated organisms from 74 SMART study centres worldwide in 2003

 
Enterobacteriaceae

Enterobacteriaceae composed 84% (4766/5658) of the total isolates, with Escherichia coli (46%; 2620/5658), Klebsiella spp. (17%; 971/5658) and Enterobacter spp. (8%; 471/5658) the most commonly isolated. Organisms in these three categories accounted for 72% (4062/5658) of all isolates and 85% (4062/4766) of Enterobacteriaceae isolated. Among the antimicrobial agents tested, the three carbapenems ertapenem, imipenem and meropenem were overall the most consistently active in vitro against the Enterobacteriaceae (Table 1).

E. coli
Table 2 shows the susceptibility of E. coli to 12 antimicrobial agents in the five broad geographic regions of Asia/Pacific, Europe, Latin America, USA and the Middle East. Ertapenem, imipenem and meropenem were the most active (99.3–100% susceptible) in each region. The MIC90s of ertapenem, imipenem and meropenem were 0.03, 0.25 and 0.03 mg/L, respectively (Table 3). Ciprofloxacin and levofloxacin were the least active agents in all regions, with the lowest activity seen in Asia/Pacific (70.3% and 72.6% susceptible, respectively) (Table 2). The MIC90s of ciprofloxacin and levofloxacin were > 4 and 8 mg/L, respectively.


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Table 2. In vitro susceptibility rates (% susceptible) of E. coli by geographic region

 

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Table 3. Susceptibility (MIC90) for Escherichia coli, Klebsiella pneumoniae and Klebsiella oxytoca worldwide in 2003

 
Overall, E. coli isolated <48 h after hospitalization were more often susceptible to the agents tested than E. coli isolated ≥48 h after hospitalization (Table 4). There was essentially no difference in percentage susceptibility between these two groups of E. coli for the carbapenems, but there were appreciable differences for the other agents tested, especially ciprofloxacin (83.6% susceptible versus 71.8% susceptible) and levofloxacin (84.5% susceptible versus 74.5% susceptible).


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Table 4. In vitro susceptibility rates (% susceptible) of E. coli, Klebsiella spp. and P. aeruginosa isolated < 48 h versus ≥48 h after admission to hospital

 
Klebsiella spp
Table 5 shows the susceptibility of Klebsiella spp. to 12 antimicrobial agents in the five broad geographic regions of Asia/Pacific, Europe, Latin America, USA and the Middle East. Klebsiella pneumoniae was the most common species isolated (72%), followed by Klebsiella oxytoca (20%), Klebsiella ozaenae (1%) and Klebsiella ornithinolytica (0.3%). Approximately 7% (65/971) of Klebsiella spp. were not identified to the species level. Ertapenem, imipenem and meropenem were again the most consistently active agents in all regions (Table 5). The MIC90 results for K. pneumoniae and K. oxytoca are shown in Table 3. Overall, Klebsiella spp. isolated <48 h after hospitalization were more likely to be susceptible to the agents tested than Klebsiella spp. isolated ≥48 h after hospitalization (Table 4). There was essentially no difference in percentage susceptibility between these two groups of Klebsiella spp. for the carbapenems, but there were perceptible differences for all the other agents tested (Table 4).


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Table 5. In vitro susceptibility rates (% susceptible) of Klebsiella spp. by geographic region

 
Enterobacter spp
The susceptibility of Enterobacter spp. worldwide to 12 antimicrobial agents is shown in Table 1. Enterobacter cloacae was the most common species isolated (72%), followed by Enterobacter aerogenes (16%), Enterobacter asburiae (0.4%), Enterobacter gergoviae (0.4%), Enterobacter sakazakii (0.4%), Enterobacter amnigenus (0.2%), Enterobacter intermedius (0.2%) and Enterobacter cancerogenus (0.2%). Approximately 9% (44/471) of Enterobacter spp. were not identified to the species level. Enterobacter spp. isolated <48 h after hospitalization were generally more likely to be susceptible to the agents tested than Enterobacter spp. isolated ≥48 h after hospitalization (Table 4).

ESBL production
Extended-spectrum ß-lactamase production was screen test positive versus confirmed positive in 13% versus 9% (235/2620) of E. coli, 18% versus 14% (133/971) of Klebsiella spp. (with similar frequency in K. pneumoniae and K. oxytoca), and 50% versus 14% (68/471) of Enterobacter spp. (16% E. cloacae and 12% E. aerogenes confirmed positive). The prevalence of confirmed ESBL-positive isolates in the USA, Europe, Latin America, the Middle East and Asia/Pacific among E. coli was 3%, 5%, 10%, 13% and 17%, among Klebsiella spp. was 7%, 11%, 14%, 20% and 18%, and among Enterobacter spp. was 16%, 7%, 20%, 12% and 21%, respectively. Overall, ESBLs were detected less frequently in organisms isolated <48 h after hospitalization than in organisms isolated ≥48 h after hospitalization among E. coli (5% versus 13%), Klebsiella spp. (8% versus 19%), and Enterobacter spp. (9% versus 17%). When the percentage susceptibilities of ESBL and non-ESBL producers were compared, the differences in susceptibility to ertapenem, imipenem and meropenem were generally small between the two groups, whereas the differences in susceptibility to the other agents tested were typically much greater (Table 6).


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Table 6. In vitro susceptibility rates (% susceptible) of ESBL and non-ESBL-producing E. coli, Klebsiella spp. and Enterobacter spp.

 
Non-fermentative and fermentative non-Enterobacteriaceae

Non-Enterobacteriaceae comprised 16% (892/5658) of all isolates in the study. Pseudomonas aeruginosa was the most common non-fermentative GNB isolated, comprising 11% (605/5658) of the total isolates. Thirty-two percent of P. aeruginosa were isolated <48 h after hospitalization and 68% were isolated ≥48 h after hospitalization. Among the anti-pseudomonal agents tested, piperacillin/tazobactam (90.9% susceptible) and amikacin (90.1% susceptible) were the most frequently active agents, whereas ciprofloxacin and levofloxacin exhibited the lowest activity (77.0% and 77.2% susceptible, respectively) (Tables 1 and 7). For all the agents tested, P. aeruginosa isolated earlier were more susceptible than those isolated later in the hospitalization (Table 4).


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Table 7. In vitro susceptibility rates (% susceptible) of Pseudomonas aeruginosa by region

 
Acinetobacter baumannii was the second most commonly isolated non-fermentative GNB, but comprised just 1.5% (84/5658) of all isolates. Eighty-five percent (71/84) of A. baumannii were isolated ≥48 h after hospitalization. Imipenem was the most active agent against A. baumannii (64.3% susceptible), followed by meropenem (53.6% susceptible). All other agents tested exhibited much less consistent activity against A. baumannii (range 22.6% to 41.7% susceptible; Table 1).


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Emerging bacterial resistance remains a concern worldwide.8 Ongoing antimicrobial surveillance studies may reveal resistance trends over time, and may potentially help to guide the selection of empirical therapy in select clinical settings.

E. coli was by far the most common isolate in our study (46% of all isolates). The lower susceptibility rate of E. coli to ciprofloxacin and levofloxacin compared with the other agents tested was consistent in all geographic regions worldwide, but particularly outside the USA (Table 2). Consequently, whether quinolones should remain among the first line choices for empirical therapy of complicated intra-abdominal infections9,10 in some geographic regions may be open for further discussion. Although E. coli isolated <48 h after admission to hospital (and presumed to be community-acquired) were more susceptible to ciprofloxacin and levofloxacin than those isolated ≥48 h after hospitalization, all the other agents tested still had more reliable activity against this subgroup of isolates (Table 4). While clinical outcomes may not always reflect in vitro susceptibility results in intra-abdominal infections where surgical drainage has a major impact, results of surveillance data may still provide useful guidance in selecting empirical antimicrobial therapy for some patients, especially given that intra-operative cultures are not routinely obtained at initial intervention in these patients.

Enterobacteriaceae as expected were the most commonly isolated aerobic GNB in intra-abdominal infections, and were the most consistently susceptible to the carbapenems. While the susceptibility of E. coli and Klebsiella spp. to the carbapenems did not vary among the five geographic regions, susceptibility to the other agents tested often varied by region, with susceptibility rates generally lowest in Asia/Pacific, Latin America and the Middle East (Tables 2 and 5). Not surprisingly, organisms isolated ≥48 h after hospitalization were in general more often resistant than those isolated <48 h after hospitalization (Table 5), except that E. coli, Klebsiella spp. and Enterobacter spp. remained consistently susceptible to the carbapenems regardless of when the cultures were obtained.

The division of cultures into those performed <48 h versus ≥48 h after hospitalization was intended to separate organisms acquired in the community from those acquired in a hospital setting. This division, based solely on time of culture, has its limitations. For example, an isolate obtained <48 h after hospitalization in a patient recently discharged from hospital may not have been truly ‘community-acquired’, and an isolate from an outpatient admitted with an intra-abdominal infection that was cultured ≥48 h after hospitalization may not have been truly ‘hospital-acquired’. Nonetheless, these results are consistent with the concept that isolates acquired in the hospital are generally more resistant than those acquired in the community.

The emergence of ESBLs among Enterobacteriaceae has made in vitro susceptibility testing more complicated since the MIC of some cephalosporins for certain ESBL producers can fall below the traditional NCCLS susceptibility breakpoint.11 ESBLs have been reported most commonly among E. coli and Klebsiella spp., but are now detected increasingly in other Enterobacteriaceae as well.11 The current NCCLS guidelines for screening and confirming ESBL in E. coli, K. pneumoniae and K. oxytoca may not be appropriate for testing Enterobacteriaceae that possess the inducible ampC ß-lactamase gene.11,12 One proposed solution is to include cefepime as a screening agent, as well as in the confirmatory test in combination with clavulanic acid.1216 However, the use of cefepime as the only cephalosporin with clavulanic acid as the confirmatory ESBL test may have potentially resulted in under-reporting of the presence of ESBLs in this study. Our results confirm previous reports that ESBL-producing isolates are not merely confined to the hospital setting, but are increasingly isolated from the community.17 There was a surprisingly high frequency of Enterobacter in our study that were identified as ESBL-producers (7–21%). In particular areas of the world, this has been reported to be mainly due to the inter-country spread of Enterobacter clones producing TEM-24 or SHV-7.18,19 In any case, the high frequency of ESBL isolation in Enterobacteriaceae that was observed in some regions in our study is noteworthy, and suggests that third- and fourth-generation cephalosporins may not be an ideal choice in the empirical therapy of intra-abdominal infections in some geographic areas.

There remains some controversy as to whether phenotypic screening and confirmation tests for ESBL should be performed in Enterobacteriaceae other than the three species currently recommended by the NCCLS, E. coli, K. pneumoniae and K. oxytoca, since the prevalence of ESBL in other genera and species has been reported to be low in some studies.11,15,20 In one study, 51% (355/690) of other Enterobacteriaceae (other than E. coli and Klebsiella spp.) were screen test positive for ESBL, but only 2% (15/690) were confirmed as ESBL producers using the NCCLS recommended method.20 In the same study, 83% (126/152) of Enterobacter spp. were screen test positive, but only 2% (3/152) were confirmed to be ESBL producers using both cefotaxime and ceftazidime with clavulanate.20 Enterobacter spp. were the third most common Enterobacteriaceae isolated in our study. While only 50% (234/471) of Enterobacter spp. were screen test positive for ESBL, 14% (68/471) were confirmed as ESBL producers using cefepime + clavulanate. This result supports what has been suggested by others that cefepime + clavulanate may be useful in detecting ESBL production in Enterobacter spp.1116

All surveillance studies have their limitations.21,22 Although the 2003 SMART study was global, it included only 74 study sites, and the distribution of sites in each geographic region was not always uniform, which largely reflected the ease of recruiting study sites in some countries as well as the difficulty with recruiting sites in other countries. Therefore, the results from any one country or region should be interpreted carefully. As with most surveillance studies, resistant isolates may be over-represented as complicated patients who may have received multiple antibiotics might be sampled more frequently. Even so, this surveillance programme does provide a helpful overview of general antimicrobial resistance patterns among Gram-negative bacilli isolated from intra-abdominal infections worldwide, and will be continuing on an annual basis.


    Acknowledgements
 
We thank Ian Friedland for his contributions in design and initiation of the study. We also thank Anthony Posca and Elena Glozman for database support and Kathleen McCarroll and Carolyn Maass for statistical support. Funding for the SMART study is provided by Merck & Co., Inc.

We thank the following investigators who participated in the study: Sara Celia Kaufman, Hospital Juan A. Fernandez, Buenos Aires, Argentina; Jorgelina Smayevsky, Centro de Educacion Medica e Investigaciones, Buenos Aires, Argentina; Clarence Fernandes, Royal North Shore Hospital, St. Leonards, Australia; Irene Lim, Institute of Medical & Veterinary Science, Adelaide, SA, Australia; Graeme Nimmo, QHPS Princess Alexandra Hospital, Queensland, Australia; Hans De Beenhouwer, Onze Lieve Vrouw Ziekenhuis, Aalst, Belgium; Herman Goossens, Universitair Ziekenhuis Antwerp, Antwerp, Belgium; Luis Fernando Camargo Aranha, Hospital Israelita Albert Einstein, São Paulo, Brazil; Julival Ribeiro, Hospital de Base, Brasília, Brazil; Flávia Rossi, Hospital das Clinicas da Faculdade de Medicina, São Paulo, Brazil; Thomas Kin Wah Ling, Chinese University of Hong Kong, Prince of Wales Hospital, Hong-Kong, China; Ni Yu Xing, Rui Jin Hospital, Shanghai Second Medical University, Shanghai, China; Yingchun Xu, Peking Union Medical College Hospital, Beijing, China; Buyun Zhong, The First Hospital of Zhejiang University, Hang Zhou, China; Julio Ayabaca, Hospital General de las Fuerzas Armadas, Quito, Ecuador; Herbert Hof, Universitätsklinikum Mannheim, Mannheim, Germany; Uwe Mai, Institute of Medical Microbiology, Klinikum Hannover, Hannover, Germany; Stefan Zimmermann, Institut für Medizinkishe Mikrobiologie, Marburg, Germany; Carlos Mejia, Hospital Roosevelt, Guatemala City, Guatemala; Colin Block, Hadassah Medical Center, Jerusalem, Israel; Hanna Shprecher, Rambam Medical Center, Haifa, Israel; Nati Keller, Sheba Medical Center, Tel-Hashomer, Israel; Pavlo Yagupsky, Soroka Medical Center, Beer-Sheba, Israel; Massimo Clementi, San Raffaele Hospital, Milan, Italy; Antonio Goglio, Spallanzani Hospital, Bergamo, Italy; Mi-Na Kim, Asan Medical Center, Seoul, Korea; Kyung Won Lee, Yonsei University College of Medicine, Seoul, Korea; Navaratnam Parasakthi, University Hospital, Jalan University, Kuala Lumpur, Malaysia; Jose Sifuentes Osornio, Instituto Nacional de Nutricion Salvador Zubiran, Tlalpan, Mexico; Nora Quintero Perez, Hospital Civil Nuevo de Guadalajara, Guadalajara, Mexico; Timothy Blackmore, Wellington Hospital, Wellington South, New Zealand; Sally Roberts, LabPlus, Auckland Healthcare, Auckland, New Zealand; Sara Palomino, Hospital Nacional Edgardo Rebagliati, Lima, Peru; Myrna Mendoza, Philippines General Hospital, Manila, Philippines; Maria fe Fatima Cardozo, Hospitais da Universidade de Coimbra, Coimbra, Portugal; Jose Diogo, Do Hospital Garcia de Orta, Pragal, Portugal; Dolores Pinheiro, Hospital de S. Joao, Porto, Portugal; Maria Jose Reis, Hospital Espirito Santo, Evora, Portugal; Ana Paula Fontes Rocha, Hospital Geral de Sto. Antonio, Porto, Portugal; Zelma Fuxench, San Pablo Hospital, Bayamon, Puerto Rico; Fernando Baquero, Hospital Ramon y Cajal, Madrid, Spain; Emilio Bouza, Hospital Gregorio Maranon, Madrid, Spain; Carmen Rubio Calvo, Hospital Clinico Lozano Blesa, Zaragoza, Spain; Ramon Cisterna, Hospital de Basurto, Bilbao, Spain; Miguel Gobernado, Hospital La Fe, Valencia, Spain; Pedro Manchado, Hospital Carlos Haya, Malaga, Spain; Rogelio Martin, Hospital de Belvitge, Barcelona, Spain; Alvaro Pascual, Hospital Virgen de la Macarena, Seville, Spain; Jose Luis Perez, Hospital Son Dureta, Palma de Mallorca, Spain; Juan Picazo, Hospital Clinico San Carlos, Madrid, Spain; Guillermo Prats, Hospital Valle de Hebron, Barcelona, Spain; Jose Angel Garcia Rodriguez, Hospital Universitario de Salamanca, Salamanca, Spain; Manuel de la Rosa, Hospital Virgen de las Nieves, Granada, Spain; Po-Ren Hsueh, National Taiwan University Hospital, Taipei, Taiwan; Chun-Ming Lee, Mackay Memorial Hospital, Taipei City, Taiwan; Hsieh-Shong Leu, Chang Gung Memorial Hospital, Taoyuan Hsien, Taiwan; Jen-Hsien Wang, China Medical College-Hospital, Taichung, Taiwan; Malai Vorachit, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; Semra Calangu, Istanbul University School of Medicine, Istanbul, Turkey; Serhat Unal, Hacettepe University School of Medicine, Ankara, Turkey; Alaaddin Pahsa, Gulhane Military School of Medicine, Ankara, Turkey; Ellen Jo Baron, Stanford University Medical Center, Stanford, CA, USA; Tim Cleary, Jackson Memorial Hospital, Miami, FL, USA; Robyn Goodrich, Schumpert Medical Center, Shreveport, LA, USA; Jeraldine Hall, The Cleveland Clinic Foundation, Cleveland, OH, USA; Dwight Hardy, University of Rochester Medical Center, Rochester, NY, USA; Judith Johnson, University of Maryland/VA Maryland Health Care System, Baltimore, MD, USA; Jan Monahan, University of Colorado Hospital, Denver, CO, USA; David J. Pombo, LDS Hospital Intermountain Health Care, Salt Lake City, UT, USA; Ananth Ramani, Columbia Memorial Hospital, Catskill, NY, USA; Seema Singh, Queens Medical Center, Honolulu, HI, USA; Yun F. Wang, Grady Memorial Hospital, Atlanta, GA, USA; Audrey Wanger, University of Texas Medical School, Houston, TX, USA; Marcus J. Zervos, William Beaumont Hospital Research Institute, Royal Oak, MI, USA.

Transparency declarations

D. L. P. has received a consulting fee at a Merck infectious diseases advisory board meeting, honoraria for speaking at symposia that received educational support from Merck, and research funding from Merck's investigator initiated studies programme. F. R. and F. B. received a consulting fee for an infectious diseases expert input forum sponsored by Merck. G. L. W. was formerly employed at Merck and has received research funding from Merck's investigator initiated studies programme. F. R., P. R. H. and G. L. W. were reimbursed for travel to attend a SMART scientific steering committee meeting.


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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