Printer Friendly

Global distribution and epidemiologic associations of Escherichia coli clonal group A, 1998-2007.

Extraintestinal infections caused by Escherichia coli are a substantial source of illness, death, and increased health care costs and have become increasingly challenging to manage because of the rising prevalence of resistance to first-line antimicrobial drugs (1). The resistance problem is now recognized as having a prominent clonal component attributable in large part to the emergence and dissemination of specific antimicrobial drug-resistant clonal groups of extraintestinal pathogenic E. coli (2-6).

One such emergent antimicrobial drug-resistant extraintestinal pathogenic E. coli clonal group is clonal group A (CGA) (2). Most traditionally recognized extraintestinal pathogenic E. coli clonal groups derive from E. coli phylogenetic group B2; however, CGA derives from phylogenetic group D (7), and, according to multilocus sequence typing (MLST), CGA corresponds with clonal complex 69 (8,9).

CGA first came to attention during the late 1990s as a prominent cause of trimethoprim/sulfamethoxazole (TMP/ SMZ)-resistant urinary tract infections among otherwise healthy women across the United States (2,10). Isolates of CGA typically exhibit a fairly conserved virulence genotype that includes P fimbriae (with the F16 structural subunit variant), group 2 capsule (with the K52 capsular antigen), and the aerobactin and yersiniabactin siderophore systems. They also commonly exhibit resistance to multiple antimicrobial agents other than TMP/SMZ, including tetracycline, chloramphenicol, streptomycin, and spectinomycin, with the corresponding resistance genes carried either on a large conjugative plasmid (2) or within a genomic resistance module (11).

CGA has been recognized primarily as a cause of community-acquired cystitis and pyelonephritis in adult women mainly in the United States (2,10,12,13). It is largely unknown to what extent CGA might have broader pathogenic capabilities with respect to anatomic site of infection (urine vs. nonurine), site of acquisition (hospital vs. community), and host age (adult vs. child). Likewise, although a global survey of E. coli clinical isolates from 2001 found CGA was significantly associated with the United States (14), assessment of its distribution beyond the United States has been limited (5). Furthermore, no recent data are available regarding whether the overall prevalence of CGA is rising, stable, or waning, as can occur on a local level for CGA and other extraintestinal pathogenic E. coli clonal groups (3,13). Therefore, because of the major public health implications of CGA, we assessed the prevalence of this E. coli clonal group during 1998-2007 in multiple locales in the United States and internationally, paying specific attention to specimen type, inpatient versus outpatient status of host, and host age.



Sets of unpublished human clinical extraintestinal E. coli isolates were obtained from 32 clinical microbiology laboratories and affiliated repositories worldwide (online Technical Appendix, Submitters were asked to provide [approximately equal to]25 consecutive TMP/SMZ-resistant extraintestinal E. coli isolates and 25 concurrent TMP/SMZ-susceptible extraintestinal E. coli controls (1 per patient), or more, as available. When possible, isolates were to be distributed evenly by inpatient versus outpatient source and, within each of these categories, by specimen type (urine vs. other). Information was requested about the adult (age [greater than or equal to]18 years) versus child (age <18 years) status of the hosts and the local overall prevalence of TMP/SMZ-resistant E. coli.

Isolates were submitted to the research laboratory (J.R.J.) in agar stabs and frozen at -80[degrees]C in 15% glycerol pending further analysis. Selected isolates underwent additional screening, by breakpoint agar dilution and disk diffusion, for confirmation of TMP/SMZ phenotype.

Molecular Analysis

Major E. coli phylogenetic group (A, B1, B2, D) was defined by triplex PCR (15). Group D isolates were assessed for CGA (i.e., clonal complex 69) status in a staged fashion. First, all were screened by PCR for CGA-associated single-nucleotide polymorphisms (SNPs) in fumC (16). AllfumC SNP-positive isolates (which included all CGA isolates, plus any non-CGA isolates containing the same fumC SNPs) then underwent pulsed-field gel electrophoresis (PFGE) analysis of JSaI-restricted total DNA (17). Those with [greater than or equal to]94% PFGE profile similarity to a known CGA isolate (determined on the basis of previous fumC and gyrB SNP analysis or 7-locus MLST) (5) were defined as CGA because this degree of PFGE similarity reliably predicts identity by MLST (J.R. Johnson, unpub. data). The fumC SNP-positive isolates without a PFGE profile match of [greater than or equal to]94% to a known CGA isolate were individually screened by PCR for CGA-associated SNPs in gyrB. If the isolates were positive for gyrB SNPs and for the CGA-associated fumC SNPs, which together provide highly accurate identification of CGA isolates, they were defined as CGA isolates (5,6,16).

Statistical Analysis

Unpaired and paired comparisons of proportions were tested by using the Fisher exact and McNemar tests, respectively. Selected variables were assessed as predictors of CGA status by using generalized linear models based on the generalized estimating equation (GEE; logistic GEE regression) to account for clustering by locale, supplemented by univariable and multivariable logistic regression analysis, as needed. Statistical analyses were conducted by using SPSS version 19.0 (IBM, Somers, NY, USA).


Study Population

A total of 2,210 E. coli clinical isolates from 32 globally dispersed centers were studied (Table 1); the isolates differed from those used in a prior global survey (14). Each center provided a median of 54 isolates (range 24-320). All centers but 1 provided TMP/SMZ-susceptible and TMP/SMZ-resistant isolates in approximately equal numbers. The median year of isolation was 2002 (range 1998-2007). Seventeen centers provided isolates for the first half of the study period only (1998-2002); 12 centers provided isolates for the last half of the study period only (2003-2007); and 3 centers provided isolates for both halves of the study period.

The 32 centers were in 19 countries, each represented by a single center, except the United States, which was represented by 14 centers. The 6 inhabited continents were each represented by multiple centers, as follows: Africa, 2; Asia, 4; Australia/New Zealand, 2; Europe, 5; North America, 15; and South/Central America, 4. Of the 15 centers in North America, 1 was in Canada and 14 in the United States (5 in Minnesota and 9 in other states).

Of the 32 centers, 31 reported the age (i.e., adult vs. child) of the patients from whom the clinical specimens were obtained. All 31 centers provided isolates derived from specimens from adults (n = 1,909), and 19 centers also provided isolates derived from specimens from children (n = 250). Of the 32 centers, 31 provided urine-source isolates (n = 1,511); 28 centers also provided isolates from other (nonurine) sources (n = 653). Outpatient versus inpatient source for clinical samples was reported by 29 centers, all of which provided isolates from outpatient specimens (n = 1,135); 26 centers also provided isolates from inpatient specimens (n = 926). As reported by 31 centers, the prevalence of E. coli TMP/SMZ susceptibility, by center, ranged from 36% to 90% (median 78%).

Phylogenetic Group and CGA Status versus TMP/SMZ Phenotype

Within the total group of isolates, phylogenetic group distribution was significantly associated with TMP/SMZ phenotype (Table 2). Although the susceptible (n = 1,083) and resistant (n = 1,127) populations exhibited the same rank order for phylogenetic group prevalence (i.e., B2 >D >A >B1), absolute prevalences differed greatly by TMP/ SMZ phenotype. That is, among susceptible isolates, group B2 predominated overwhelmingly, being nearly 3x as prevalent as group D. In contrast, among resistant isolates, phylogenetic groups B2 and D were closely matched (approximately one third of isolates each). Accordingly, group D was strongly associated with TMP/SMZ resistance.

Molecular typing identified 144 CGA isolates (Table 1), which accounted for 6.5% of all isolates and 25.2% of the group D isolates (Table 2). CGA was strongly associated with TMP/SMZ resistance, accounting for 10.1% of resistant isolates overall but for only 2.8% of susceptible isolates (p<0.001) (Table 2). Even within phylogenetic group D, CGA was nearly 2x as prevalent among resistant as among susceptible isolates (29.8% [114/383] vs. 16.0% [30/188], p<0.001) (Table 2).

CGA Status in Relation to Geography

Of the 32 centers, 26 provided at least 1 CGA isolate (Table 1). The prevalence of CGA by center varied greatly, ranging from 0% to 34% (median 5%) for TMP/SMZ-resistant isolates and from 0% to 9.4% (median 1.4%) for TMP/SMZ-susceptible isolates. In all but 2 centers, CGA was at least as prevalent among TMP/SMZ-resistant as among TMP-SMZ-susceptible isolates; in 5 of the centers, the difference in prevalence was statistically significant. The 5 centers with the highest prevalence of CGA isolates (2 in the United States, 3 in other countries) had [greater than or equal to]20% CGA prevalence among resistant isolates, and another 5 (1 United States, 4 in other countries) had 10%-19% prevalence. At the other extreme, 6 centers (3 in the United States, 3 in other countries) had no CGA isolates.

The prevalence of CGA also varied substantially by continent, in a resistance-dependent manner (Table 3). Among TMP/SMZ-susceptible isolates the prevalence of CGA was uniformly low, regardless of continent (median prevalence 3.0%, range 0%-3.8%), whereas among TMP/ SMZ-resistant isolates it was substantially higher in the Western world (Australia/New Zealand, Europe, North America, and South/Central America; median prevalence 13.1%, range 9.7%-13.2%), compared with Africa and Asia (4.2% and 4.0%, respectively) (Table 3).

Accordingly, data for Africa and Asia were combined for comparison with data from other regions. Among TMP/ SMZ-susceptible isolates, CGA was similarly prevalent among the isolates from Africa and Asia combined and the isolates from other areas (3.3% vs. 2.8%, p>0.10). In contrast, among TMP/SMZ-resistant isolates, CGA was significantly more prevalent among isolates from areas other than Africa and Asia than it was among isolates from Africa and Asia (12.5% vs. 4.0%, p<0.001) (Table 3). Likewise, CGA was significantly associated with TMP/ SMZ resistance among the isolates from areas other than Africa and Asia (p<0.001) but not among the isolates from Africa and Asia (p>0.10) (Table 3).

CGA Status versus Other Variables

We also examined the prevalence of CGA in relation to other variables, after stratification for TMP/SMZ phenotype (Table 4). For each variable (i.e., specimen type, host age group, host inpatient/outpatient status, and year isolate was obtained from patient specimen), CGA was significantly more prevalent among TMP/SMZ-resistant than TMP/ SMZ-susceptible isolates. In contrast, for a given TMP/ SMZ phenotype, the prevalence of CGA varied minimally in relation to the other variables. Specifically, CGA was similarly (and, in some instances, slightly more) prevalent among isolates from nonurine versus urine specimens, children versus adults, inpatients versus outpatients, the first half versus the second half of the study period (Table 4), and centers with isolates with a below-median versus above-median prevalence of TMP/SMZ resistance (not shown). This finding suggested that continent and TMP/ SMZ status were closely associated with CGA status, whereas other study variables were not.

Logistic GEE Models and Multivariable Analysis

To account for possible confounding of these associations because of clustering by center, we used logistic GEE regression models to assess associations of CGA with TMP/SMZ phenotype, continent (as Africa/ Asia vs. other), and the other nongeographic variables. Univariable analyses identified the same significant associations (or lack thereof) with CGA as noted initially; only TMP/SMZ phenotype and continent were confirmed as significant correlates of CGA status (Table 5).

Accordingly, we constructed a multivariable logistic GEE regression model based on TMP/SMZ phenotype and continent to assess the independent association of these 2 variables with CGA status. However, the model did not run to completion, possibly because of small numbers in certain cells (not shown). Univariable logistic regression analysis yielded results for these 2 variables separately that were similar to those obtained with the (univariable) generalized linear models (Table 5), which provided evidence that clustering by center had little effect on the associations. Therefore, a multivariable logistic regression model was constructed with TMP/SMZ phenotype and continent as the candidate predictor variables. This model yielded results similar to those of the univariable models, which provided evidence that the associations of CGA with TMP/ SMZ phenotype and continent are largely independent of each other (Table 5).


In this global survey for the recently recognized E. coli lineage CGA among extraintestinal clinical isolates from humans during 1998-2007, we identified strong associations of CGA with TMP/SMZ resistance and with regions other than Africa and Asia; this evidence indicates that CGA is primarily a TMP/SMZ-resistant pathogen concentrated within the Western world. In contrast, we found no association of CGA with other epidemiologic variables, which suggests that CGA is a similarly prominent pathogen among children and adults, among inpatients and outpatients, and within and outside the urinary tract. Finally, the fairly stable prevalence of CGA throughout the study period suggests that CGA had fully emerged by the late 1990s and now is an endemic public health threat in many centers worldwide.

The observed overall association of CGA with TMP/ SMZ resistance is consistent with the findings of multiple studies (2,10,12-14,18-20). However, we did not find this association in Africa and Asia. Overall prevalence of CGA was also lowest in these regions. Taken together, these findings suggest that the TMP/SMZ-resistant variants of CGA had a selective advantage in the Western world but not in Asia and Africa, which led to the lineage's expansion in Europe, the Americas, and Australia but not in Asia and Africa. Why such an expansion seemingly has not occurred in Africa and Asia is unclear. One possibility is that TMP/ SMZ-resistant CGA isolates emerged first in the Western world and have had insufficient time to diffuse to and expand within Africa and Asia. Alternatively, Africa and Asia may already have had an abundance of successful endemic TMP/SMZ-resistant clones competing with CGA for the same niche, effectively excluding it, or conditions in Africa and Asia may be somehow less permissive to the dispersal and expansion of this clonal group. Further comparisons of the TMP/SMZ-resistant populations from Africa and Asia versus other locales could be informative in this regard.

Clear-cut variation in the prevalence of CGA was evident at the continent level. However, marked differences also were apparent even among closely located centers, as noted in our smaller global survey (14). For example, whereas 1 Minneapolis center had no CGA isolates, another center had a high prevalence of CGA. To what extent these differences are real, rather than a reflection of the inherent imprecision of small samples, is unclear. However, because different hospitals in the same locale often serve different patient populations and may draw from different catchment areas, the possibility of true variation by hospital is plausible. The determinants of this local variation, if real, would be potentially useful to discover as a step toward developing preventive measures. The center with the highest prevalence was in Denver, Colorado, USA, which also was the site of a previous survey with a high CGA prevalence; that survey involved different isolates than those included here (12). This consistency across studies suggests that Denver may be a focus of high-level endemicity for CGA.

CGA has been reported primarily as a urine pathogen among ambulatory women (2,10,13,19,20), which might be interpreted as indicating that urine is the favored niche or context of the clonal group. However, CGA has been reported in other clinical contexts, including, for example, as a cause of community-acquired pneumonia in a male renal transplant recipient (21). We found no association of CGA with urine versus nonurine (extraintestinal) source, inpatient versus outpatient host status, and host age (child vs. adult). This absence of discernible niche specialization suggests that CGA is a generalist, able to cause different types of infection in diverse host populations, in the hospital and community alike. In terms of niche specialization, CGA is analogous to E. coli O18:K1:H7, which, although best known as an agent of neonatal meningitis, is also a prominent cause of acute cystitis in women (22,23). The pathogenic versatility of CGA has no doubt contributed to its epidemiologic success.

We found no evidence of a time trend for the prevalence of CGA, even with locale taken into account, which suggests that CGA had already emerged and established widespread endemicity by 1998, the start of the study period. Overall, CGA was not as prevalent in this study as it was in the initial reports from the mid- to late 1990s (2,10). This discrepancy could reflect selection bias rather than a true prevalence decrease by the time of the present study (i.e., our study included all patient specimens sent to clinical microbiology laboratories; the early studies included specimens from women with acute cystitis and uncomplicated pyelonephritis).

Even in regions in which prevalence was highest, CGA accounted for only a minority of TMP/SMZ-resistant isolates. This finding suggests that other resistant clonal groups are likely present, some of which could be similarly or more prominent compared with CGA (3,5,6,13,20,24,25). Identification of such clonal groups and investigation of their epidemiology could help clarify the basis for the non-CGA component of TMP/SMZ resistance in E. coli, which represents a major ongoing public health threat.

Study limitations must be acknowledged. First, lack of information regarding the infected host (e.g., clinical symptoms, underlying health status, and sex) limits our understanding of the study population and precludes assessment of these variables in relation to CGA status. Second, variability by center in the completeness of epidemiologic data reporting reduced power for analyses involving those variables and may have introduced unrecognized bias. Third, limited sampling of certain geographic regions (especially Africa and Australia/ New Zealand) and host groups (children) constrained the inferences that could be drawn about those variables. Fourth, uncertainty regarding how closely each site followed the requested selection criteria allowed for possibly biased sample distribution by site.

Study strengths also must be acknowledged. First, the large sample size enhanced statistical power and permitted subgroup analyses that were not possible in previous studies. Second, the broad geographic distribution and multicenter design improved generalizability and allowed analyses by region. Third, the availability of basic epidemiologic data for most isolates enabled statistical analysis of these variables. Fourth, the predominantly prospective, consecutive sampling would be expected to provide a more broadly representative sample than a sample limited to a specific syndrome or host group. Fifth, the combined use of univariable and multivariable modeling, including adjustment for clustering, enabled optimal assessment of associations between individual variables and CGA.

In summary, our global survey for CGA during 1998-2007 identified strong associations of CGA with TMP/ SMZ resistance and non-African/Asian origin but not with other epidemiologic variables-evidence that suggests CGA is a similarly prominent extraintestinal pathogen among children and adults, for inpatients and outpatients, and within and outside the urinary tract. The fairly stable prevalence of CGA through the 10-year study period suggests that CGA had fully emerged by the late 1990s and now is endemic worldwide as an antimicrobial drug-resistant public health threat.

Trans-Global Initiative for Antimicrobial Resistance Analysis investigators who contributed data for this article: Oladipo Aboderin (Obafemi Awolowo University, Ile-Ife, Osun-State, Nigeria), Jo-Ellen Abraham (Abbott Northwestern Hospital, Minneapolis, Minnesota, USA), Leslie Baken (Methodist Hospital, St. Louis Park, Minnesota, USA), Johan Bakken (St. Luke's Infectious Disease Associates, Duluth, Minnesota, USA), Claudio Bravo (Universidad Catolica de la Santisima Concepcion, Concepcion, Chile), Sheldon Campbell (Yale University and VA Connecticut Healthcare System, West Haven, Connecticut, USA), Karen Carroll (ARUP Laboratories, Salt Lake City, Utah, USA), Therese Carson (Northern Michigan Regional Hospital, Petoskey, Michigan, USA), Elizabeth Castano (Hospital del Nino, Panama City, Panama), Jagdish Chander (Government Medical College, Chandigarh, India), Osvaldo Cisternas (Hospital del Nino, Panama City), Adriana Correa (International Center for Medical Research and Training, CIDEIM [Centro Internacional de Entrenamiento e Investigaciones Medicas], Cali, Columbia), George L Daikos (University of Athens Medical School, Athens, Greece), Julie Fleming (Northfield Hospital, Northfield, Minnesota, USA), Coralith Garcia (Instituto de Medicina Tropical Alexander von Humboldt, Lima, Peru), Varsha Gupta (Government Medical College, Chandigarh), Stuart Johnson (Loyola University and Hines Veterans Affairs Medical Center, Chicago, Illinois, USA), Luis Martinez-Martinez (Hospital Universitario Marques de Valdecilla, Santander, Spain), Tetsuro Muratani (University of Occupational and Environmental Health, Kitakyushu, Japan), James Mwansa (University Teaching Hospital, Lusaka, Zambia), Lynn Nimmo (University of Colorado Medical Center, Denver, Colorado, USA), Patricia Person (Merit Care Medical Center, Fargo, North Dakota, USA), Jean-Claude Piffaretti (Istituto Cantonale di Microbiologia, Bellinzona, Switzerland), Johann Pitout (Calgary Laboratory Services, Calgary, Alberta, Canada), Julie A. Ribes (University of Kentucky Hospital, Lexington, Kentucky, USA), Lynn Rogers and Richard Squires (Massey University, Palmerston North, New Zealand), Charles Stager (Ben Taub General Hospital and Baylor College of Medicine, Houston, Texas, USA), Paul Tambyah (National University of Singapore, Singapore), Antonio Toniolo (University of Insubria and Ospedale Varese, Varese, Italy), Dana Towle (VA Connecticut Healthcare System, West Haven), Maria Virginia Villegas (International Center for Medical Research and Training, CIDEIM, Cali), and Mark Yuen (National University of Singapore, Singapore)



We thank Susan Collins, I-Wen Huang, and Timothy T. O'Bryan for providing invaluable laboratory assistance.

This material is based on work supported by Office of Research and Development, Medical Research Service, US Department of Veterans Affairs (J.R.J.). J.R.J. has received research support (grant and contract) from Merck, Inc., and Rochester Medical Group.

Dr Johnson is professor of medicine and associate director of the infectious disease fellowship program at the University of Minnesota and head of the molecular epidemiology laboratory at the Minneapolis VA Medical Center. His research focuses on the molecular epidemiology, ecology, evolution, and virulence of extraintestinal pathogenic and antimicrobial resistant E. coli.


(1.) Russo TA, Johnson JR. Medical and economic impact of extraintestinal infections due to Escherichia coli: an overlooked epidemic. Microbes Infect. 2003;5:449-56. doi:10.1016/S1286-4579(03)00049-2

(2.) Manges AR, Johnson JR, Foxman B, O'Bryan TT, Fullerton KE, Riley LW. Widespread distribution of urinary tract infections caused by a multidrug-resistant Escherichia coli clonal group. N Engl J Med. 2001;345:1007-13. doi:10.1056/NEJMoa011265

(3.) Manges AR, Naterajan P, Solberg OD, Dietrich PS, Riley LW. The changing prevalence of drug-resistant Escherichia coli clonal groups in a community: evidence for community outbreaks of urinary tract infections. Epidemiol Infect. 2006;134:425-31. doi:10.1017/ S0950268805005005

(4.) Nicolas-Chanoine M-H, Blanco J, Leflon-Guibout V, Demarty R, Alonso MP, Cani9a MM, et al. Intercontinental emergence of Escherichia coli clone O25:H4-ST131 producing CTX-M-15. J Antimicrob Chemother. 2008;61:273-81. doi:10.1093/jac/dkm464

(5.) Johnson JR, Menard M, Johnston B, Kuskowski MA, Nichol K, Zhanel GG. Epidemic clonal groups of Escherichia coli as a cause of antimicrobial-resistant urinary tract infections in Canada, 2002-2004. Antimicrob Agents Chemother. 2009;53:2733-9. doi:10.1128/ AAC.00297-09

(6.) Johnson JR, Johnston B, Clabots C, Kuskowski MA, Castanheira M. Escherichia coli sequence type ST131 as the major cause of serious multidrug-resistant E. coli infections in the United States (2007). Clin Infect Dis. 2010;51:286-94. doi:10.1086/653932

(7.) Russo TA, Johnson JR. A proposal for an inclusive designation for extraintestinal pathogenic Escherichia coli: ExPEC. J Infect Dis. 2000;181:1753-4. doi:10.1086/315418

(8.) Tartof SY, Solberg OD, Manges AR, Riley LW. Analysis of a uropathogenic Escherichia coli clonal group by multilocus sequence typing. J Clin Microbiol. 2005;43:5860-4. doi:10.1128/ JCM.43.12.5860-5864.2005

(9.) Johnson JR, Owens KL, Clabots CR, Weissman SJ, Cannon SB. Phylogenetic relationships among clonal groups of extraintestinal pathogenic Escherichia coli as assessed by multi-locus sequence analysis. Microbes Infect. 2006;8:1702-13. doi:10.1016/j. micinf.2006.02.007

(10.) Johnson JR, Manges AR, O'Bryan TT, Riley LR. A disseminated multidrug-resistant clonal group of uropathogenic Escherichia coli in pyelonephritis. Lancet. 2002;359:2249-51. doi:10.1016/S0140-6736(02)09264-4

(11.) Lescat M, Calteau A, Hoede C, Barbe V, Touchon M, Rocha E, et al. A module located at a chromosomal integration hot spot is responsible for the multidrug resistance of a reference strain from Escherichia coli clonal group A. Antimicrob Agents Chemother. 2009;53:2283-8. doi:10.1128/AAC.00123-09

(12.) Burman WJ, Breese PE, Murray BE, Singh KV, Batal HA, MacKenzie TD, et al. Conventional and molecular epidemiology of trimethoprim/sulfamethoxazole resistance among urinary Esch erichia coli isolates. Am J Med. 2003;115:358-64. doi:10.1016/ S0002-9343(03)00372-3

(13.) Smith SP, Manges AR, Riley LW. Temporal changes in the prevalence of community-acquired antimicrobial-resistant urinary tract infection affected by Escherichia coli clonal group composition. Clin Infect Dis. 2008;46:689-95. doi:10.1086/527386

(14.) Johnson JR, Murray AC, Kuskowski MA, Schubert S, Prere MF, Picard B, et al. Distribution and characteristics of Escherichia coli clonal group A. Emerg Infect Dis. 2005;11:141-5.

(15.) Clermont O, Bonacorsi S, Bingen E. Rapid and simple determination of the Escherichia coli phylogenetic group. Appl Environ Microbiol. 2000;66:4555-8. doi:10.1128/AEM.66.10.4555-4558.2000

(16.) Johnson JR. Owens, Manges A, Riley L. Rapid and specific detection of Escherichia coli clonal group A by gene-specific PCR. J Clin Microbiol. 2004;42:2618-22. doi:10.1128/JCM.42.6.2618-2622.2004

(17.) Ribot EM, Fair MA, Gautom R, Cameron DN, Hunter SB, Swaminathan B, et al. Standardization of pulsed-field gel electrophoresis protocols for the subtyping of Escherichia coli O157:H7, Salmonella, and Shigella for PulseNet. Foodborne Pathog Dis. 2006;3:59-67. doi:10.1089/fpd.2006.3.59

(18.) Boczek LA, Rice EW, Johnston B, Johnson JR. Occurrence of antibiotic-resistant uropathogenic Escherichia coli clonal group A in wastewater effluents. Appl Environ Microbiol. 2007;73:4180-4. doi:10.1128/AEM.02225-06

(19.) Colgan R, Johnson JR, Kuskowski M, Gupta K. Risk factors for trimethoprim/sulfamethoxazole resistance in patients with acute uncomplicated cystitis. Antimicrob Agents Chemother. 2008;52:846-51. doi:10.1128/AAC.01200-07

(20.) Manges AR, Dietrich PS, Riley LW. Multidrug-resistant Escherichia coli clonal groups causing community-acquired pyelonephritis. Clin Infect Dis. 2004;38:329-34. doi:10.1086/380640

(21.) Johnson JR, Russo TA. Uropathogenic Escherichia coli as agents of diverse non-urinary tract extraintestinal infections. J Infect Dis. 2002;186:859-64. doi:10.1086/342490

(22.) Johnson JR, Delavari P, O'Bryan T. Escherichia coli O18:K1:H7 isolates from acute cystitis and neonatal meningitis exhibit common phylogenetic origins and virulence factor profiles. J Infect Dis. 2001;183:425-34. doi:10.1086/318086

(23.) Kunin CM, Hua TH, Krishman C, Van Arsdale White L, Hacker J. Isolation of a nicotinamide-requiring clone of Escherichia coli O18:K1:H7 from women with acute cystitis: resemblance to strains found in neonatal meningitis. Clin Infect Dis. 1993;16:412-6. doi:10.1093/clind/16.3.412

(24.) Cagnacci S, Gualco L, Debbia E, Schito GC, Marchese A. European emergence of ciprofloxacin-resistant Escherichia coli clonal groups O25:H4-ST 131 and O15:K52:H1 causing community-acquired uncomplicated cystitis. J Clin Microbiol. 2008;46:2605-12. doi:10.1128/JCM.00640-08

(25.) Johnson JR, Stell AL, O'Bryan TT, Kuskowski M, Nowicki B, Johnson C, et al. Global molecular epidemiology of the O15:K52:H1 extraintestinal pathogenic Escherichia coli clonal group: evidence of distribution beyond Europe. J Clin Microbiol. 2002;40:1913-23. doi:10.1128/JCM.40.6.1913-1923.2002

James R. Johnson, Megan E. Menard, Tsai-Ling Lauderdale, Chris Kosmidis, David Gordon, Peter Collignon, Joel N. Maslow, Arjana Tambic Andrasevic, Michael A. Kuskowski, and the Trans-Global Initiative for Antimicrobial Resistance Analysis Investigators [1]

[1] Investigators who contributed data are listed at the end of this article.

Address for correspondence: James R. Johnson, Infectious Diseases (111F), VA Medical Center, 1 Veterans Dr, Minneapolis, MN 55417, USA; email:

Author affiliations: Veterans Affairs Medical Center, Minneapolis, Minnesota, USA (J.R. Johnson, M.E. Menard, M.A. Kuskowski); University of Minnesota, Minneapolis (J.R. Johnson, M.A. Kuskowski); National Health Research Institutes, Zhunan, Taiwan (T.-L. Lauderdale); University of Athens Medical School, Athens, Greece (C. Kosmidis); Australian National University, Canberra, Australian Capital Territory, Australia (D. Gordon, P. Collignon); Canberra Hospital, Canberra (P. Collignon); Veterans Affairs Medical Center, Philadelphia, Pennsylvania, USA (J.N. Maslow); University of Pennsylvania, Philadelphia (J.N. Maslow); and University Hospital for Infectious Diseases, Zagreb, Croatia (A. Tambic Andrasevic)

The opinions expressed by authors contributing to this journal do not necessarily reflect the opinions of the Centers for Disease Control and Prevention or the institutions with which the authors are affiliated.


Medscape, LLC is pleased to provide online continuing medical education (CME) for this journal article, allowing clinicians the opportunity to earn CME credit.

This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of Medscape, LLC and Emerging Infectious Diseases. Medscape, LLC is accredited by the ACCME to provide continuing medical education for physicians.

Medscape, LLC designates this Journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit(s)TM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 70% minimum passing score and complete the evaluation at; (4) view/print certificate.

Release date: October 20, 2011; Expiration date: October 20, 2012

Learning Objectives

Upon completion of this activity, participants will be able to:

* Analyze the prevalence of trimethoprim/sulfamethoxazole resistance among Escherichia coli clonal group A (CGA) isolates

* Distinguish geographic locations with the highest prevalence of CGA

* Assess variables that significantly affect the prevalence of CGA

* Evaluate temporal trends in the prevalence of CGA


Claudia Chesley, Technical Writer/Editor, Emerging Infectious Diseases. Disclosure: Claudia Chesley has disclosed no relevant financial relationships.

CME Author

Charles P. Vega, MD, Associate Professor; Residency Director, Department of Family Medicine, University of California, Irvine. Disclosure: Charles P. Vega, MD, has disclosed no relevant financial relationships.


Disclosures: Megan E. Menard, MS; Tsai-Ling Lauderdale, PhD; Chris Kosmidis, MD; David Gordon, PhD; Joel N. Maslow, MD; and Michael A. Kuskowski, PhD, have disclosed no relevant financial relationships. James R. Johnson, MD, has disclosed the following relevant financial relationships: received grants for clinical research from Merck & Co., Inc., and Rochester Medical Group. Peter Collignon, MD, has disclosed the following relevant financial relationships: served as a speaker at the Zimmer Orthopaedic Meeting in Melbourne, Victoria, Australia. Arjana Andrasevic, MD, has disclosed the following relevant financial relationships: served as a speaker or a member of a speakers bureau for Pfizer, Novartis, and MSD. James R. Johnson, MD, on behalf of the Trans-Global Initiative for Antimicrobial Resistance Analysis Investigators, has disclosed no relevant financial relationships.

CME Questions

1. Which of the following statements regarding clonal group A (CGA) and resistance to trimethoprim/sulfamethoxazole (TMP/SMZ) in the current study is most accurate?

A. Most Escherichia coli isolates resistant to TMP/SMZ were from CGA worldwide

B. Most E. coli isolates resistant to TMP/SMZ were from CGA only among children

C. The prevalence of CGA was higher among E. coli isolates resistant to TMP/SMZ

D. The overall prevalence of CGA was approximately 25% among all E. coli isolates

2. Which of the following countries had the highest prevalence of CGA in the current study?

A. United States

B. Taiwan

C. Nigeria

D. Zambia

3. Which of the following variables had the most significant impact on the prevalence of CGA in the current study?

A. Geographic location

B. Age (adult vs. child)

C. Inpatient vs. outpatient status

D. Isolates from urine vs. nonurine specimens

4. Which of the following statements regarding the prevalence of CGA between 1998 and 2007 in the current study is most accurate?

A. The overall prevalence remained roughly similar between the periods from 1998 to 2002 and 2003 to 2007

B. The overall prevalence doubled between the periods from

1998 to 2002 and 2003 to 2007

C. The overall prevalence increased fivefold between the periods from 1998 to 2002 and 2003 to 2007

D. The overall prevalence declined by more than half between the periods from 1998 to 2002 and 2003 to 2007
Table 1. Origin and epidemiologic background
of 2,210 extraintestinal Escherichia coli isolates
from 32 globally distributed centers and
susceptibility to trimethoprim/sulfamethoxazole,
1998-2007 *

 Year(s) of no. Source, no.
Continent, location ([dagger]) isolation isolates S, % isolates



 Ile-Ife, Nigeria 2004 41 NK 41
 Lusaka, Zambia 2001 51 59 4

 Chandigarh, India 2006 50 60 37
 Kitakyushu, Japan 2001-2005 56 80 37
 Singapore 2002 50 60 43
 Taiwan 1998-2004 320 46 256

Australia/New Zealand
 Canberra, Australia 1998-2001 121 80 50
 Palmerston North, New 2006 51 78 36

 Zagreb, Croatia 2001-2002 91 81 44
 Athens, Greece 2003-2005 149 66 96
 Varese, Italy 2006 51 75 35
 Santander, Spain 2003 53 70 35
 Bellinzona, Switzerland 2006 54 75 36

North America
 Calgary, Alberta, Canada 2001 54 78 36
 United States
 Denver, CO 2001 100 78 50
 West Haven, CT 2006 34 76 24
 Chicago, Il 2001 60 74 40
 Lexington, KY 2001 60 80 40
 Petoskey, MI 2001 45 89 NK.
 Duluth, MN 2001 50 90 39
 Minneapolis, MN ([dagger]) 2001 66 87 56
 Minneapolis, MN ([dagger]) 2001 46 90 38
 Northfield, MN 2001 24 95 24
 St. Louis Park, MN 2001 64 83 64
 Fargo, ND 2001 54 90 49
 Philadelphia, PA 2006 94 78 87
 Houston, TX 2001 60 65 40
 Salt Lake City, UT 2001 47 85 31

South/Central America
 Concepcion, Chile 2006 51 57 36
 Cali, Columbia 2005-2006 51 52 36
 Panama City, Panama 2007 54 36 36
 Lima, Peru 2002-2006 58 82 39

Continent, location ([dagger]) Source, no. isolates

 Specimen ([double
 type Setting dagger])

 Nonurine In Out

 Ile-Ife, Nigeria 0 22 19 4
 Lusaka, Zambia 37 NK NK 0

 Chandigarh, India 13 34 16 9
 Kitakyushu, Japan 19 36 20 7
 Singapore 7 NK NK 0
 Taiwan 64 66 254 73

Australia/New Zealand
 Canberra, Australia 71 0 121 5
 Palmerston North, New 15 18 33 3

 Zagreb, Croatia 47 58 33 0
 Athens, Greece 53 92 57 3
 Varese, Italy 16 31 20 3
 Santander, Spain 18 19 34 9
 Bellinzona, Switzerland 18 34 20 2

North America
 Calgary, Alberta, Canada 18 34 20 10
 United States
 Denver, CO 50 50 50 0
 West Haven, CT 10 17 17 0
 Chicago, Il 20 37 23 0
 Lexington, KY 20 7 53 5
 Petoskey, MI NK NK NK 0
 Duluth, MN 11 8 42 0
 Minneapolis, MN ([dagger]) 10 15 51 0
 Minneapolis, MN ([dagger]) 8 21 25 0
 Northfield, MN 0 0 24 0
 St. Louis Park, MN 0 0 64 7
 Fargo, ND 5 5 49 11
 Philadelphia, PA 7 13 81 0
 Houston, TX 20 35 25 9
 Salt Lake City, UT 16 24 23 4

South/Central America
 Concepcion, Chile 15 33 18 NK
 Cali, Columbia 15 27 24 16
 Panama City, Panama 18 19 35 52
 Lima, Peru 19 30 28 18

 No. CGA
Continent, location ([dagger]) isolates/total no. (%)

 R S

 Ile-Ife, Nigeria 3/36 (8) 0/5 (0)
 Lusaka, Zambia 0/31 (0) 0/20 (0)

 Chandigarh, India 0/36 (0) 0/14 (0)
 Kitakyushu, Japan 1/29 (3) 0/27 (0)
 Singapore 1/25 (4) 0/25 (0)
 Taiwan 8/161 (5) 8/159 (5)

Australia/New Zealand
 Canberra, Australia 10/60 (17) 3/61 (5)
 Palmerston North, New 1/24 (4) 0/27 (0)

 Zagreb, Croatia 8/46 (17) 1/45 (2)
 Athens, Greece 15/75 (20) 1/74 (1)
 Varese, Italy 0/26 (0) 0/25 (0)
 Santander, Spain 0/26 (0) 2/27 (7)
 Bellinzona, Switzerland 3/27 (11) 0/27 (0)

North America
 Calgary, Alberta, Canada 6/27 (22) 1/27 (4)
 United States
 Denver, CO 17/50 (34) 3/50 (6)
 West Haven, CT 0/16 (0) 0/18 (0)
 Chicago, Il 0/30 (0) 0/30 (0)
 Lexington, KY 3/30 (10) 1/30 (3)
 Petoskey, MI 5/21 (24) 0/24 (0)
 Duluth, MN 4/26 (15) 0/24 (0)
 Minneapolis, MN ([dagger]) 1/26 (4) 1/40 (3)
 Minneapolis, MN ([dagger]) 0/18 (0) 0/28 (0)
 Northfield, MN 1/12 (8) 0/12 (0)
 St. Louis Park, MN 9/32 (28) 3/32 (9)
 Fargo, ND 1/27 (4) 1/27 (4)
 Philadelphia, PA 2/22 (9) 0/72 (0)
 Houston, TX 1/30 (3) 1/30 (3)
 Salt Lake City, UT 1/21 (5) 1/26 (4)

South/Central America
 Concepcion, Chile 5/24 (21) 1/27 (4)
 Cali, Columbia 3/24 (13) 1/27 (4)
 Panama City, Panama 1/27 (4) 1/27 (4)
 Lima, Peru 4/58 (7) Not done

* S, susceptible to trimethoprim/sulfamethoxazole; in,
inpatient; out, outpatient; CGA, clonal group A; R,
resistant to trimethoprim/sulfamethoxazole; NK,
not known.

([dagger]) A list of the 32 centers is provided in
the online Technical Appendix (
/11-0488-Techapp.pdf). Note that 2 centers were located
in Minneapolis.

([double dagger]) <18 y of age.

Table 2. Phylogenetic group distribution and clonal
group A status of extraintestinal Escherichia coli
isolates from 32 globally distributed centers, 1998-2007 *

Phylogenetic group No. clonal group A
and clonal group A isolates/total no.
status isolates (%)

 TMP/SMZ susceptible,
 Total, n = 2,210 n = 1,083

E. coli
 A 345 (15.6) 141 (13.0)
 B1 223 (10.1) 121 (11.2)
 B2 1,071 (48.5) 633 (58.4)
 D 571 (25.8) 188 (17.4)

Clonal group A 144 (6.5) 30 (2.8)

Phylogenetic group No. clonal group A
and clonal group A isolates/total no.
status isolates (%)

 TMP/SMZ resistant, p value
 n = 1,127 ([dagger])

E. coli
 A 204 (18.1) 0.001
 B1 102 (9.1)
 B2 438 (38.9) <0.001
 D 383 (34.0) <0.001

Clonal group A 114 (10.1) <0.001

* TMP/SMZ, trimethoprim/sulfamethoxazole.

([dagger]) p values, by Fisher exact test, for
TMP/SMZ-susceptible vs. -resistant isolates are
shown where p<0.05; otherwise, p>0.10.

Table 3. Prevalence of clonal group A, by region
and TMP/SMZ phenotype, among 2,210 extraintestinal
Escherichia coli isolates from
32 globally distributed centers, 1998-2007 *

Region No. clonal group A
 isolates/total no. (%)


Overall 144/2,210 (6.5)
Africa 3/92 (3.3)
Asia 18/476 (3.8)
Australia/New Zealand 14/172 (8.1)
Europe 30/398 (7.5)
North America 63/858 (7.3)
South/Central America 16/214 (7.5)
Africa/Asia combined 21/568 (3.7)
Not Africa/Asia 123/1,642 (7.5)

Region No. clonal group A
 isolates/total no. (%)

 TMP/SMZ susceptible

Overall 30/1,083 (2.8)
Africa 0/21 (0)
Asia 8/225 (3.6)
Australia/New Zealand 3/88 (3.4)
Europe 4/198 (2.0)
North America 12/471 (2.5)
South/Central America 3/80 (3.8)
Africa/Asia combined 8/246 (3.3) ([double dagger])
Not Africa/Asia 22/837 (2.6) ([double dagger])

Region No. clonal group A
 isolates/total no. (%)

 TMP/SMZ resistant

Overall 114/1,127 (10.1)
Africa 3/71 (4.2)
Asia 10/251 (4.0)
Australia/New Zealand 11/84 (13.1)
Europe 26/200 (13.0)
North America 51/387 (13.2)
South/Central America 13/134 (9.7)
Africa/Asia combined 13/322 (4.0) ([section])
Not Africa/Asia 101/805 (12.5) ([section])

Region p value ([dagger])

Overall <0.001
Australia/New Zealand 0.025
Europe <0.001
North America <0.001
South/Central America
Africa/Asia combined
Not Africa/Asia <0.001

* TMP/SMZ, trimethoprim/sulfamethoxazole.

([dagger]) p values, by Fisher exact test, for
TMP/SMZ-susceptible vs. -resistant isolates are
shown where p<0.05; otherwise, p>0.10.

([double dagger]) For Africa/Asia vs. other, p>0.10.

([section]) For Africa/Asia vs. other, p<0.001.

Table 4. Prevalence of clonal group A, by clinical/host
variables, among 2,210 extraintestinal Escherichia
coli isolates from 32 globally
distributed centers, 1998-2007 *

Clinical/host variable No. clonal group A
and year isolate isolates/total no.
obtained from patient isolates (%) ([dagger])
clinical specimen

 Total TMP/SMZ susceptible

Specimen type
 Nonurine 48/653 (7.4) 9/318 (2.8)
 Urine 88/1,470 (6.0) 21/739 (2.8)

Host age group, y
 <18 16/250 (6.4) 4/118 (3.4)
 [greater than or 122/1,909 (6.4) 25/938 (2.7)
 equal to] 18

Host hospital status
 Outpatient 84/1,135 (7.4) 17/573 (3.0)
 Inpatient 54/926 (5.8) 13/434 (3.0)

Year isolated
 1998-2002 95/1,330 (7.1) 21/661 (3.2)
 2003-2007 49/880 (5.6) 9/422 (2.1)

Clinical/host variable No. clonal group A p value
and year isolate isolates/total no. ([double
obtained from patient isolates (%) ([dagger]) dagger])
clinical specimen

 TMP/SMZ resistant

Specimen type
 Nonurine 39/335 (11.6) <0.001
 Urine 67/731 (9.2) <0.001

Host age group, y
 <18 12/132 (9.1) 0.08
 [greater than or 97/971 (10.0) <0.001
 equal to] 18

Host hospital status
 Outpatient 67/562 (11.9) <0.001
 Inpatient 41/488 (8.4) <0.001

Year isolated
 1998-2002 74/669 (11.1) <0.001
 2003-2007 40/458 (8.7) <0.001

* TMP/SMZ, trimethoprim/sulfamethoxazole.

([dagger]) Data for each clinical variable include only
isolates for which status with respect to the particular
variable was known.

([double dagger]) p values, by Fisher exact test, for
comparisons of TMP/SMZ-susceptible vs. -resistant isolates
within each subgroup. For all comparisons between
subgroups within a given category (whether overall or
by TMP/SMZ phenotype), p>0.10.

Table 5. Generalized linear modeling and logistic regression
analysis of TMP/SMZ phenotype and region as predictors of
clonal group A status among extraintestinal Escherichia coli
isolates from 32 globally distributed centers, 1998-2007 *

Method, type of model,
variable ([dagger]) OR (95% CI) p value

GEE ([double dagger])
 TMP/SMZ resistance 3.90 (2.04-7.46) <0.001
 Africa/Asia 0.39 (0.18-0.89) 0.02

Logistic regression
 TMP/SMZ resistance 4.14 (2.74-6.26) <0.001
 Africa/Asia 0.43 (0.26-0.69) <0.001
 TMP/SMZ resistance 3.95 (2.62-5.96) <0.001
 Africa/Asia 0.47 (0.30-0.76) 0.002

* TMP/SMZ, trimethoprim/sulfamethoxazole;
OR, odds ratio; CI, confidence
interval; GEE, generalized estimating

([dagger]) Univariable models, but not
multivariable models, included the following
as candidate predictor variables, each
of which yielded a p value >0.10:
specimen type (urine vs. nonurine),
host age group (<18 vs. >18), host
hospital status (inpatient vs.
outpatient), local prevalence of TMP/SMZ
resistance, and year isolate obtained.

([double dagger]) Because the multivariable
GEE model that used TMP/SMZ phenotype
and Africa/Asia as candidate predictor
variables could not run to
completion, logistic regression
analysis was used instead.
COPYRIGHT 2011 U.S. National Center for Infectious Diseases
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2011 Gale, Cengage Learning. All rights reserved.

Article Details
Printer friendly Cite/link Email Feedback
Author:Johnson, James R.; Menard, Megan E.; Lauderdale, Tsai-Ling; Kosmidis, Chris; Gordon, David; Colligno
Publication:Emerging Infectious Diseases
Geographic Code:60AFR
Date:Nov 1, 2011
Previous Article:Deaths associated with pandemic (H1N1) 2009 among children, Japan, 2009-2010.
Next Article:Group A Streptococcus emm gene types in pharyngeal isolates, Ontario, Canada, 2002-2010.

Terms of use | Privacy policy | Copyright © 2021 Farlex, Inc. | Feedback | For webmasters |