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
Received 20 January 2005; returned 14 February 2005; revised 10 March 2005; accepted 11 March 2005
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Abstract |
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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 (7090% susceptible), cephalosporin (8097% susceptible), aminoglycoside (77100% susceptible) and carbapenem (99100% 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
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Introduction |
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Materials and methods |
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Results |
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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 (99.3100% 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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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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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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Discussion |
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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 (721%). 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.
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Acknowledgements |
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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.
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