Abstract

Objectives: SMART (Study for Monitoring Antimicrobial Resistance Trends) is an ongoing study to monitor worldwide antimicrobial resistance trends among aerobic and facultatively anaerobic Gram-negative bacilli (GNB) isolated from intra-abdominal infections. This 2004 report summarizes the most recently completed annual data from SMART.

Methods: During 2004, 81 medical centres from 28 countries in five global regions collected intra-abdominal GNB for antimicrobial susceptibility testing using broth microdilution according to the Clinical and Laboratory Standards Institute guidelines.

Results: A total of 6156 unique aerobic and facultatively anaerobic GNB were isolated from intra-abdominal infections. Enterobacteriaceae composed 86% of the total isolates. Among the 12 antimicrobial agents tested, the carbapenems and amikacin were the most consistently active against the Enterobacteriaceae. Escherichia coli was the most commonly isolated species (48%), and the susceptibility rate to the quinolones was lowest in Asia/Pacific and Latin America. Extended-spectrum β-lactamases (ESBLs) were detected phenotypically in 10% of E. coli, 17% of Klebsiella spp. and 22% of Enterobacter spp. worldwide, representing a slight increase over the two previous years. ESBL producers typically had a more antibiotic-resistant profile than non-ESBL producers but were usually susceptible to the carbapenems.

Conclusions: Antimicrobial resistance among GNB isolated from intra-abdominal infections continued to be a problem worldwide in 2004, with the highest rates of resistance overall in the Asia/Pacific region. The carbapenems and amikacin were the most consistently active agents in vitro against Enterobacteriaceae isolated from intra-abdominal infections worldwide.

Introduction

International surveillance programmes have been developed to monitor the emerging global threat of antibiotic-resistant bacteria. The Study for Monitoring Antimicrobial Resistance Trends (SMART), begun in 2002, is the only worldwide surveillance programme specifically designed to monitor longitudinally the in vitro antimicrobial susceptibility of aerobic and facultatively anaerobic Gram-negative bacilli (GNB) isolated exclusively from intra-abdominal sites. Results from SMART in 2003, the first full year of the study, showed that Enterobacteriaceae composed the vast majority of aerobic or facultatively anaerobic GNB isolated from intra-abdominal infections, with Escherichia coli being the most commonly isolated species.1 Antimicrobial resistance was confirmed to be a worldwide problem, especially in the Asia/Pacific region.1 This report summarizes results for 2004, the second full year of the study.

Materials and methods

Eighty-one medical centres from 28 countries in five geographic regions participated in SMART during 2004, including sites in Asia/Pacific [14 centres: China (4), Taiwan (3), Korea (2), Australia (2), New Zealand (2), Philippines (1)], North America [12 centres: USA (12)], Europe [31 centres: Spain (12), Portugal (5), France (4), Germany (3), Belgium (2), Italy (2), Estonia (1), Finland (1), Greece (1)], Latin America [17 centres in Central and South America: Argentina (3), Brazil (3), Chile (2), Mexico (2), Puerto Rico (2), Colombia (1), Ecuador (1), Guatemala (1), Panama (1), Venezuela (1)] and the Middle East/Africa [7 centres: Israel (4), South Africa (3)].

Collection and antimicrobial susceptibility testing of aerobic and facultatively anaerobic GNB from intra-abdominal infections was performed as previously reported.1 Reference strains E. coli ATCC 25922, Klebsiella pneumoniae ATCC 700603 and Pseudomonas aeruginosa ATCC 27853 were used as quality control strains for each batch of MIC tests. Phenotypic identification of extended-spectrum β-lactamase (ESBL) production was applied to test E. coli, Klebsiella spp. and Enterobacter spp., and performed using a modification of the CLSI method.2 If the ceftazidime, ceftriaxone or cefepime MIC was ≥2 mg/L, then the MIC of cefepime was compared with the MIC of cefepime plus clavulanic acid (10 μg). ESBL production was operationally defined as a ≥8-fold decrease in the cefepime MIC when tested in combination with clavulanic acid compared with 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 below the CLSI breakpoint for susceptibility.

For comparisons of susceptibility rates, 95% confidence intervals were calculated for the difference using the method of Miettenen and Nurminen.3 No formal hypothesis-testing was performed. No statistical adjustment was made for computing multiple confidence intervals.

Results and discussion

A total of 6156 aerobic and facultatively anaerobic GNB were isolated from intra-abdominal infections in 5731 patients from the 81 participating study centres in 28 countries worldwide in 2004. Susceptibility results for the most frequently isolated GNB (n ≥ 10 isolates) are presented in Table 1. Enterobacteriaceae composed 86% (5317/6156) of the total isolates, with E. coli (48%; 2979/6156), Klebsiella spp. (16%; 977/6156) and Enterobacter spp. (9%; 542/6156) contributing the majority of isolates. These three genera accounted for 73% (4498/6156) of all isolates and 85% (4498/5317) of the Enterobacteriaceae isolates. Among the antimicrobial agents tested, the three carbapenems (ertapenem, imipenem and meropenem) and amikacin were the most consistently active in vitro against the Enterobacteriaceae.

Table 1

In vitro susceptibility rates (% susceptible) of the most commonly isolated organisms from 81 SMART study centres in 2004 (no. of isolates ≥10)

Bacteria No. of isolates (% of total, 6156) EPM IPM MEM CRO CAZ FOX FEP TZP AMK TOB CIP LVX 
Escherichia coli 2979 (48.4%) 98.8 99.6 99.5 89.0 89.2 90.9 90.3 94.9 98.8 87.6 76.5 78.2 
Klebsiella pneumoniae 724 (11.8%) 97.9 99.9 99.6 81.9 81.5 87.2 82.5 86.0 93.6 83.7 83.6 86.7 
Pseudomonas aeruginosa 586 (9.5%) NAa 81.2 86.2 15.7 81.2 NAa 79.5 91.3 88.9 84.8 77.6 75.9 
Enterobacter cloacae 386 (6.3%) 97.7 99.7 99.7 60.6 61.7 5.7 78.0 74.4 94.0 82.1 84.7 87.8 
Proteus mirabilis 229 (3.7%) 100.0 98.3 100.0 94.3 97.4 96.5 95.2 98.7 99.1 90.0 84.7 93.0 
Klebsiella oxytoca 198 (3.2%) 99.5 100.0 100.0 83.3 84.3 95.5 85.4 86.9 98.0 92.4 93.9 97.5 
Citrobacter freundii 171 (2.8%) 99.4 99.4 100.0 69.0 67.3 12.3 94.7 82.5 95.3 88.3 86.0 87.7 
Morganella morganii 113 (1.8%) 99.1 99.1 99.1 85.0 71.7 82.3 95.6 92.9 99.1 89.4 79.6 89.4 
Enterobacter aerogenes 102 (1.7%) 93.1 95.1 98.0 60.8 56.9 8.8 75.5 72.5 94.1 91.2 81.4 89.2 
Serratia marcescens 101 (1.6%) 98.0 100.0 100.0 84.2 89.1 33.7 92.1 87.1 89.1 75.2 76.2 83.2 
Acinetobacter baumannii 81 (1.3%) NAa 67.9 59.3 21.0 30.9 NAa 29.6 38.3 42.0 37.0 29.6 38.3 
Stenotrophomonas maltophilia 65 (1.1%) NAa 7.7 7.7 6.2 46.2 NAa 16.9 9.2 20.0 20.0 35.4 89.2 
Other Klebsiellab 56 (0.9%) 98.2 98.2 100.0 85.7 87.5 89.3 87.5 92.9 100.0 94.6 92.9 94.6 
Other Enterobacterc 54 (0.9%) 94.4 96.3 96.3 68.5 64.8 16.7 81.5 81.5 98.1 87.0 88.9 88.9 
Citrobacter koseri 43 (0.7%) 100.0 100.0 100.0 97.7 97.7 86.0 100.0 97.7 100.0 100.0 95.3 97.7 
Other Citrobacterd 40 (0.6%) 100.0 100.0 100.0 60.0 75.0 30.0 97.5 85.0 97.5 92.5 80.0 82.5 
Proteus vulgaris 37 (0.6%) 100.0 97.3 100.0 56.8 97.3 97.3 97.3 100.0 100.0 97.3 97.3 97.3 
Aeromonas hydrophila 30 (0.5%) NAa 76.7 80.0 86.7 90.0 NAa 96.7 83.3 96.7 86.7 96.7 96.7 
Hafnia alvei 22 (0.4%) 95.5 100.0 100.0 77.3 63.6 72.7 90.9 81.8 100.0 100.0 100.0 100.0 
Acinetobacter calcoaceticus 12 (0.2%) NAa 50.0 50.0 16.7 16.7 NAa 16.7 25.0 33.3 50.0 33.3 33.3 
Bacteria No. of isolates (% of total, 6156) EPM IPM MEM CRO CAZ FOX FEP TZP AMK TOB CIP LVX 
Escherichia coli 2979 (48.4%) 98.8 99.6 99.5 89.0 89.2 90.9 90.3 94.9 98.8 87.6 76.5 78.2 
Klebsiella pneumoniae 724 (11.8%) 97.9 99.9 99.6 81.9 81.5 87.2 82.5 86.0 93.6 83.7 83.6 86.7 
Pseudomonas aeruginosa 586 (9.5%) NAa 81.2 86.2 15.7 81.2 NAa 79.5 91.3 88.9 84.8 77.6 75.9 
Enterobacter cloacae 386 (6.3%) 97.7 99.7 99.7 60.6 61.7 5.7 78.0 74.4 94.0 82.1 84.7 87.8 
Proteus mirabilis 229 (3.7%) 100.0 98.3 100.0 94.3 97.4 96.5 95.2 98.7 99.1 90.0 84.7 93.0 
Klebsiella oxytoca 198 (3.2%) 99.5 100.0 100.0 83.3 84.3 95.5 85.4 86.9 98.0 92.4 93.9 97.5 
Citrobacter freundii 171 (2.8%) 99.4 99.4 100.0 69.0 67.3 12.3 94.7 82.5 95.3 88.3 86.0 87.7 
Morganella morganii 113 (1.8%) 99.1 99.1 99.1 85.0 71.7 82.3 95.6 92.9 99.1 89.4 79.6 89.4 
Enterobacter aerogenes 102 (1.7%) 93.1 95.1 98.0 60.8 56.9 8.8 75.5 72.5 94.1 91.2 81.4 89.2 
Serratia marcescens 101 (1.6%) 98.0 100.0 100.0 84.2 89.1 33.7 92.1 87.1 89.1 75.2 76.2 83.2 
Acinetobacter baumannii 81 (1.3%) NAa 67.9 59.3 21.0 30.9 NAa 29.6 38.3 42.0 37.0 29.6 38.3 
Stenotrophomonas maltophilia 65 (1.1%) NAa 7.7 7.7 6.2 46.2 NAa 16.9 9.2 20.0 20.0 35.4 89.2 
Other Klebsiellab 56 (0.9%) 98.2 98.2 100.0 85.7 87.5 89.3 87.5 92.9 100.0 94.6 92.9 94.6 
Other Enterobacterc 54 (0.9%) 94.4 96.3 96.3 68.5 64.8 16.7 81.5 81.5 98.1 87.0 88.9 88.9 
Citrobacter koseri 43 (0.7%) 100.0 100.0 100.0 97.7 97.7 86.0 100.0 97.7 100.0 100.0 95.3 97.7 
Other Citrobacterd 40 (0.6%) 100.0 100.0 100.0 60.0 75.0 30.0 97.5 85.0 97.5 92.5 80.0 82.5 
Proteus vulgaris 37 (0.6%) 100.0 97.3 100.0 56.8 97.3 97.3 97.3 100.0 100.0 97.3 97.3 97.3 
Aeromonas hydrophila 30 (0.5%) NAa 76.7 80.0 86.7 90.0 NAa 96.7 83.3 96.7 86.7 96.7 96.7 
Hafnia alvei 22 (0.4%) 95.5 100.0 100.0 77.3 63.6 72.7 90.9 81.8 100.0 100.0 100.0 100.0 
Acinetobacter calcoaceticus 12 (0.2%) NAa 50.0 50.0 16.7 16.7 NAa 16.7 25.0 33.3 50.0 33.3 33.3 

EPM, ertapenem; IPM, imipenem; MEM, meropenem; CRO, ceftriaxone; CAZ, ceftazidime; FOX, cefoxitin; FEP, cefepime; TZP, piperacillin/tazobactam; AMK, amikacin; TOB, tobramycin; CIP, ciprofloxacin; LVX, levofloxacin; NA, not applicable.

aMIC breakpoints for ertapenem and cefoxitin in non-Enterobacteriaceae have not been defined by CLSI.

bIncludes 33 Klebsiella isolates that were not identified to the species level and 23 speciated non-pneumoniae/non-oxytoca Klebsiella.

cIncludes 37 Enterobacter isolates that were not identified to the species level and 17 speciated non-cloacae/non-aerogenes Enterobacter.

dIncludes 20 Citrobacter isolates that were not identified to the species level and 20 speciated non-freundii/non-koseri Citrobacter.

Ciprofloxacin and levofloxacin were the least reliably active agents against E. coli overall with the lowest activity seen in Asia/Pacific (64.5% and 66.0% susceptible, respectively) and Latin America (72.1% and 74.3% susceptible, respectively). The low susceptibility rates observed for E. coli to ciprofloxacin and levofloxacin compared with the other agents tested were consistent in all geographic regions worldwide. The least active agents against Klebsiella spp. were ceftriaxone, ceftazidime and cefepime, especially in Latin America (range 70.6–72.4%) and Middle East/Africa (72.6%). The least active agents against Enterobacter spp. were ceftriaxone and ceftazidime, most notably in Asia/Pacific (45.8% and 44.8% susceptible, respectively) and the USA (51.6% and 52.7% susceptible, respectively). Cefepime was more active than ceftriaxone and ceftazidime against Enterobacter spp. overall, but its activity varied by region, ranging from 63.5% susceptible in Asia/Pacific to 88.2% susceptible in Europe.

For logistical reasons, only 60 of the 74 SMART centres from 2003 were able to continue participation in 2004. The susceptibility rates of Enterobacteriaceae isolated at these 60 centres in 2003 and 2004 are juxtaposed in Table 2. A slight decrease in susceptibility to the extended-spectrum cephalosporins and the quinolones was observed from 2003 to 2004. Whether this observation portends a long-term trend remains to be determined as the SMART study continues to accumulate annual data in subsequent years. Other investigators have noted a decrease in fluoroquinolone susceptibilities among Enterobacteriaceae in recent years.4 A retrospective cohort study identified fluoroquinolone resistance to be an independent risk factor for mortality in patients with healthcare-acquired E. coli and K. pneumoniae infections,5 perhaps attributable in part to a delay in the initiation of appropriate antimicrobial therapy in patients with fluoroquinolone-resistant infections.

Table 2

In vitro susceptibility rates (% susceptible) of Enterobacteriaceae isolated from 81 SMART centres in 2004 and from the 60 centres that participated in both 2003 and 2004

Bacteria No. of isolate (% of total) EPM IPM MEM CRO CAZ FOX FEP TZP AMK TOB CIP LVX 
Enterobacteriaceae 2004 (all 81 centres) 5317 (86.4%) 98.5 99.4 99.5 83.9 84.3 77.8 88.5 90.8 97.3 87.2 80.3 83.1 
Enterobacteriaceae 2004 (60 common centres) 3973 (85.6%) 99.0 99.4 99.6 83.7 83.9 77.7 88.3 90.6 97.4 86.8 79.9 82.7 
Enterobacteriaceae 2003 (60 common centres) 4016 (84.8%) 99.1 99.6 99.7 86.6 85.8 77.9 90.9 91.3 97.4 88.7 82.5 84.7 
Difference (95% CI)a  0.1 (−0.4, 0.5) 0.1 (−0.2, 0.4) 0.0 (−0.2, 0.3) 2.9 (1.3, 4.4) 1.9 (0.3, 3.4) 0.1 (−1.7, 2.0) 2.6 (1.2, 3.9) 0.6 (−0.6, 1.9) 0.0 (−0.7, 0.7) 1.9 (0.5, 3.3) 2.6 (0.9, 4.3) 2.1 (0.5, 3.7) 
Bacteria No. of isolate (% of total) EPM IPM MEM CRO CAZ FOX FEP TZP AMK TOB CIP LVX 
Enterobacteriaceae 2004 (all 81 centres) 5317 (86.4%) 98.5 99.4 99.5 83.9 84.3 77.8 88.5 90.8 97.3 87.2 80.3 83.1 
Enterobacteriaceae 2004 (60 common centres) 3973 (85.6%) 99.0 99.4 99.6 83.7 83.9 77.7 88.3 90.6 97.4 86.8 79.9 82.7 
Enterobacteriaceae 2003 (60 common centres) 4016 (84.8%) 99.1 99.6 99.7 86.6 85.8 77.9 90.9 91.3 97.4 88.7 82.5 84.7 
Difference (95% CI)a  0.1 (−0.4, 0.5) 0.1 (−0.2, 0.4) 0.0 (−0.2, 0.3) 2.9 (1.3, 4.4) 1.9 (0.3, 3.4) 0.1 (−1.7, 2.0) 2.6 (1.2, 3.9) 0.6 (−0.6, 1.9) 0.0 (−0.7, 0.7) 1.9 (0.5, 3.3) 2.6 (0.9, 4.3) 2.1 (0.5, 3.7) 

EPM, ertapenem; IPM, imipenem; MEM, meropenem; CRO, ceftriaxone; CAZ, ceftazidime; FOX, cefoxitin; FEP, cefepime; TZP, piperacillin/tazobactam; AMK, amikacin; TOB, tobramycin; CIP, ciprofloxacin; LVX, levofloxacin.

aThe 95% confidence intervals (CI) for the difference calculated as the % susceptible rate for Enterobacteriaceae in 2003 minus the % susceptible rate for Enterobacteriaceae in 2004 were determined using the Miettinen–Nurminen method.

ESBL production was detected phenotypically in 10% of E. coli, 17% of Klebsiella spp. (18% K. pneumoniae and 15% Klebsiella oxytoca) and 22% of Enterobacter spp. (22% Enterobacter cloacae and 24% Enterobacter aerogenes) worldwide. The prevalence of confirmed ESBL-positive isolates in the USA, Europe, Latin America, Middle East/Africa and Asia/Pacific among E. coli was 2.8%, 6.4%, 12.0%, 10.0% and 19.6%; among Klebsiella spp. was 5.3%, 8.8%, 27.6%, 27.4% and 22.9%; and among Enterobacter spp. was 25.3%, 11.8%, 31.1%, 17.8% and 36.4%, respectively. When susceptibilities of ESBL and non-ESBL producers were compared, the differences in susceptibility rates for the carbapenems were smaller than the differences in susceptibility rates for the other agents tested (Table 3). Overall, ESBLs were detected less frequently in organisms isolated <48 h after hospitalization than in organisms isolated ≥48 h after hospitalization among E. coli (6.7% versus 13.2%), Klebsiella spp. (9.0% versus 21.9%) and Enterobacter spp. (15.7% versus 24.8%).

Table 3

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

Bacteria No. of isolates EPM IPM MEM FOX TZP AMK TOB CIP LVX 
E. coli 
    non-ESBL 2690 99.4 99.8 99.9 93.4 97.1 99.6 92.5 81.5 82.9 
    ESBL 289 93.8 97.6 96.2 67.5 74.7 91.0 42.9 30.1 34.3 
    difference (95% CI)a  5.6 (3.3, 9.0) 2.2 (0.9, 4.7) 3.7 (2.0, 6.5) 25.9 (20.7, 31.6) 22.3 (17.6, 27.7) 8.6 (5.8, 12.5) 49.5 (43.7, 55.2) 51.4 (45.7, 56.6) 48.7 (42.9, 54.1) 
K. pneumoniae 
    non-ESBL 597 99.2 100.0 100.0 91.1 96.1 99.0 96.0 92.8 94.6 
    ESBL 127 92.1 99.2 97.6 68.5 38.6 68.5 26.0 40.2 49.6 
    difference (95% CI)a  7.0 (3.4, 13.1) 0.8 (0.1, 4.3) 2.4 (0.8, 6.7) 22.6 (14.8, 31.4) 57.6 (48.7, 65.7) 30.5 (23.0, 39.1) 70.0 (61.6, 77.0) 52.6 (43.7, 61.0) 45.0 (36.2, 53.8) 
K. oxytoca 
    non-ESBL 169 100.0 100.0 100.0 96.4 94.7 99.4 98.2 97.6 99.4 
    ESBL 29 96.6 100.0 100.0 89.7 41.4 89.7 58.6 72.4 86.2 
    difference (95% CI)a  3.4 (0.6, 17.2) 0.0 (−2.2, 11.8) 0.0 (−2.2, 11.8) 6.8 (−1.0, 23.1) 53.3 (35.0, 69.6) 9.8 (2.8, 25.9) 39.6 (23.5, 57.6) 25.2 (12.0, 43.5) 13.2 (4.7, 30.1) 
E. cloacae 
    non-ESBL 301 99.3 99.7 99.7 6.6 85.0 100.0 94.4 92.7 95.0 
    ESBL 85 91.8 100.0 100.0 2.4 36.5 72.9 38.8 56.5 62.4 
    difference (95% CI)a  7.6 (3.2, 15.4) −0.3 (−1.9, 4.0) −0.3 (−1.9, 4.0) 4.3 (−1.9, 4.0) 48.6 (37.2, 58.9) 27.1 (18.8, 37.4) 55.5 (44.5, 65.5) 36.2 (25.7, 47.2) 32.7 (22.7, 43.6) 
E. aerogenes 
    non-ESBL 77 92.2 96.1 97.4 11.7 84.4 100.0 100.0 88.3 93.5 
    ESBL 25 96.0 92.0 100.0 0.0 36.0 76.0 64.0 60.0 76.0 
    difference (95% CI)a  −3.8 (−13.1, 12.4) 4.1 (−5.0, 21.5) −2.6 (−9.0, 10.9) 11.7 (−2.1, 20.8) 48.4 (26.9, 66.2) 24.0 (11.5, 43.5) 36.0 (20.2, 55.6) 28.3 (9.5, 48.8) 17.5 (3.0, 37.6) 
Bacteria No. of isolates EPM IPM MEM FOX TZP AMK TOB CIP LVX 
E. coli 
    non-ESBL 2690 99.4 99.8 99.9 93.4 97.1 99.6 92.5 81.5 82.9 
    ESBL 289 93.8 97.6 96.2 67.5 74.7 91.0 42.9 30.1 34.3 
    difference (95% CI)a  5.6 (3.3, 9.0) 2.2 (0.9, 4.7) 3.7 (2.0, 6.5) 25.9 (20.7, 31.6) 22.3 (17.6, 27.7) 8.6 (5.8, 12.5) 49.5 (43.7, 55.2) 51.4 (45.7, 56.6) 48.7 (42.9, 54.1) 
K. pneumoniae 
    non-ESBL 597 99.2 100.0 100.0 91.1 96.1 99.0 96.0 92.8 94.6 
    ESBL 127 92.1 99.2 97.6 68.5 38.6 68.5 26.0 40.2 49.6 
    difference (95% CI)a  7.0 (3.4, 13.1) 0.8 (0.1, 4.3) 2.4 (0.8, 6.7) 22.6 (14.8, 31.4) 57.6 (48.7, 65.7) 30.5 (23.0, 39.1) 70.0 (61.6, 77.0) 52.6 (43.7, 61.0) 45.0 (36.2, 53.8) 
K. oxytoca 
    non-ESBL 169 100.0 100.0 100.0 96.4 94.7 99.4 98.2 97.6 99.4 
    ESBL 29 96.6 100.0 100.0 89.7 41.4 89.7 58.6 72.4 86.2 
    difference (95% CI)a  3.4 (0.6, 17.2) 0.0 (−2.2, 11.8) 0.0 (−2.2, 11.8) 6.8 (−1.0, 23.1) 53.3 (35.0, 69.6) 9.8 (2.8, 25.9) 39.6 (23.5, 57.6) 25.2 (12.0, 43.5) 13.2 (4.7, 30.1) 
E. cloacae 
    non-ESBL 301 99.3 99.7 99.7 6.6 85.0 100.0 94.4 92.7 95.0 
    ESBL 85 91.8 100.0 100.0 2.4 36.5 72.9 38.8 56.5 62.4 
    difference (95% CI)a  7.6 (3.2, 15.4) −0.3 (−1.9, 4.0) −0.3 (−1.9, 4.0) 4.3 (−1.9, 4.0) 48.6 (37.2, 58.9) 27.1 (18.8, 37.4) 55.5 (44.5, 65.5) 36.2 (25.7, 47.2) 32.7 (22.7, 43.6) 
E. aerogenes 
    non-ESBL 77 92.2 96.1 97.4 11.7 84.4 100.0 100.0 88.3 93.5 
    ESBL 25 96.0 92.0 100.0 0.0 36.0 76.0 64.0 60.0 76.0 
    difference (95% CI)a  −3.8 (−13.1, 12.4) 4.1 (−5.0, 21.5) −2.6 (−9.0, 10.9) 11.7 (−2.1, 20.8) 48.4 (26.9, 66.2) 24.0 (11.5, 43.5) 36.0 (20.2, 55.6) 28.3 (9.5, 48.8) 17.5 (3.0, 37.6) 

EPM, ertapenem; IPM, imipenem; MEM, meropenem; FOX, cefoxitin; TZP, piperacillin/tazobactam; AMK, amikacin; TOB, tobramycin; CIP, ciprofloxacin; LVX, levofloxacin.

aThe 95% confidence intervals (CI) for the difference calculated as the % susceptible rate for non-ESBL producers minus the % susceptible rate for ESBL producers were determined using the Miettinen–Nurminen method.

The emergence of ESBL-producing Enterobacteriaceae has made in vitro susceptibility testing more complicated. Although the MIC of some cephalosporins for certain ESBL producers can fall below the traditional CLSI susceptibility breakpoint, these GNB should be considered resistant to cephalosporins (except cephamycins) if an ESBL is confirmed.6 The current CLSI guidelines for screening and confirming ESBL in E. coli, K. pneumoniae and K. oxytoca (and Proteus mirabilis when clinically relevant) may not be appropriate for testing other Enterobacteriaceae such as Enterobacter spp. that possess the inducible chromosomal ampC β-lactamase gene or Klebsiella spp. that possess a plasmid-mediated ampC gene.6,7 Since both cefotaxime and ceftazidime are susceptible to hydrolysis by the AmpC enzyme, the presence of an ESBL may not be detected in an organism that also produces a significant amount of AmpC when these two agents are used in combination with clavulanic acid in the ESBL confirmatory test. One proposed modification is to add cefepime as a screening agent, as well as in the confirmatory test in combination with clavulanic acid, since cefepime is relatively resistant to hydrolysis by AmpC.7–9 However, our exclusive use of cefepime as the only cephalosporin with clavulanic acid in the confirmatory ESBL test may have potentially resulted in under-reporting of the prevalence of ESBLs, since the activity of individual cephalosporins against certain ESBL-producing organisms may vary.

ESBLs were detected in slightly higher numbers in the 2004 than the 2003 SMART study among E. coli (10% versus 9%), Klebsiella spp. (17% versus 14%) and Enterobacter spp. (22% versus 14%).1 The high frequency of ESBL isolation observed in some regions in our study is noteworthy (for example, 19.6% of E. coli in Asia/Pacific; 27.6% of Klebsiella spp. in Latin America and 36.4% of Enterobacter spp. in Asia/Pacific) and raises the question of whether extended-spectrum cephalosporins should still be considered among the optimal empirical regimens for intra-abdominal infections in some geographic areas. There were relatively small differences in susceptibility rates for the carbapenems between the ESBL producers and the non-ESBL producers, as compared with the generally much larger differences in susceptibility rates for piperacillin/tazobactam, ciprofloxacin, levofloxacin, tobramycin and amikacin. These data are consistent with previous reports linking resistance to non-β-lactam agents with the presence of ESBLs.10

All surveillance studies have their limitations. Although the 2004 SMART study was global, and included 81 study sites (compared with 74 sites in 2003), sites in each geographic region were not uniformly distributed. Consequently, the results from any country or region should be extrapolated cautiously. Only sixty of the 74 study sites from 2003 participated in 2004, confounding direct comparisons between these two years. Since there is an ongoing effort to recruit more study sites in countries that are under-represented or not represented at all, it is anticipated that the study in future years will not only have more centres, but also a more balanced geographic distribution. As data accrue on an annual basis, SMART will be able to provide analyses of longitudinal trends in regional antimicrobial resistance patterns among GNB isolated from intra-abdominal infections.

Transparency declarations

D. L. P. has received consulting fees at Merck infectious diseases advisory board meetings, 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. have received a consulting fee for an infectious diseases expert input forum sponsored by Merck. P. R. H. has received an honorarium for speaking at a SMART investigators forum sponsored by Merck. F. R., F. B. and P. R. H. have received reimbursement for travel to attend a SMART scientific steering committee meeting.

We thank Hedy Teppler and Charlotte Harvey for assistance with conducting the study, Edward Kelly & Elena Glozman for database support, Carolyn Maass for statistical programming support, Richard Gesser for reviewing the manuscript and Joann DiLullo for editorial assistance. Funding for the SMART study is provided by Merck & Co., Inc.

We thank the following investigators who participated in the 2004 study: Miguel Angel Distefano, Hospital Central de Mendoza, Mendoza, Argentina; 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; 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; F. R., Hospital das Clinicas da Faculdade de Medicina, São Paulo, Brazil; Dona Benadof, Clinica Davila, Santiago, Chile; Patricia Garcia, Centro Medico San Joaquin, Santiago, Chile; Thomas Kin Wah Ling, Chinese Univ. of Hong Kong, Prince of Wales Hospital, Hong Kong, China; Yu Xing Ni, 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; Carlos Perez, Military Hospital, Bogota, Colombia; Julio Ayabaca, Hospital General de las Fuerzas Armadas, Quito, Ecuador; Paul Naaber, Referente Labor of Tartu University Clinicum, Tartu, Estonia; Martti Vaara, Helsinki University Hospital, Helsinki, Finland; Ronald Bismuth, CHU Pittie-Salpetriere, Paris, France; Henri Drugeon, CHU Hotel Dieu, Nantes, France; Yves Rio, CHR Gpt de Metz, Metz, France; Claude-James Soussy, Hopital Henry Mondor, Creteil, France; Herbert Hof, Universitätsklinikum Mannheim, Mannheim, Germany; Uwe Mai, Institute of Med. Microbiology, Klinikum Hannover, Hannover, Germany; Stefan Zimmermann, Institut für Medizinkishe Mikrobiologie, Marburg, Germany; Evangelos Anastassiou, University Hospital of Patras, Rio of Achaia, Greece; Rudy Lopez, Hospital General de Enfermedad Común, 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, Milani, 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; 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; Silvio Vega, Universidad de Panama, Panama City, Panama; 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; Diana Otero, Hospital HIMA, Caguas, Puerto Rico; Frik Botha, AMPATH, Pretoria, S. Africa; Adrian Brink, AMPATH MilPark Hospital, Parktown, S. Africa; Normal Miller, Dr's Bouwer and Partners, Durban, S. Africa; F. B., 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; Luis Martinez, Hospital Marques de Valdecilla of Santander, Santander, Spain; Alvaro Pascual, Hospital Virgen de la Macarena, Sevilla, Spain; Jose Luis Perez, Hospital Son Dureta, Palma de Mallorca, Spain; Juan Picazo, Hospital Clinico San Carlos, Madrid, Spain; Jose Angel Garcia Rodriguez, Hospital Universitario de Salamanca, Salamanca, Spain; P. R. H., National Taiwan University Hospital, Taipei, Taiwan; Hsieh-Shong Leu, Chang Gung Memorial Hospital, Taoyuan Hsien, Taiwan; Jen-Hsien Wang, China Medical College-Hospital, Taichung, Taiwan; Ellen Jo Baron, Stanford University Medical Center, Stanford, CA, USA; Tim Cleary, Jackson Memorial Hospital, Miami, FL, USA; Paul P. Cook, The Brody School of Medicine, Greenville, NC, USA; Jeraldine Hall, The Cleveland Clinic Foundation, Cleveland, OH, USA; Dwight Hardy, University of Rochester Medical Center, Rochester, NY, 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; Kenneth H. Rand, University of Florida College of Medicine, Gainesville, FL, USA; Seema Singh, Queens Medical Center, Honolulu, HI, USA; Audrey Wanger, University of Texas Medical School, Houston, TX, USA; Marcus J. Zervos, William Beaumont Hospital Research Institute, Royal Oak, MI, USA; Manuel Guzman Blanco, Hospital Universitario de Caracas, Caracas, Venezuela.

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