Background The management of urinary tract infections is complicatedby the increasing prevalence of antibiotic-resistant strainsof Escherichia coli. We studied the clonal composition of E.coli isolates that were resistant to trimethoprim–sulfamethoxazolefrom women with community-acquired urinary tract infections.
Methods Prospectively collected E. coli isolates from womenwith urinary tract infections in a university community in Californiawere evaluated for antibiotic susceptibility, O:H serotype,DNA fingerprinting, pulsed-field gel electrophoretic pattern,and virulence factors. The prevalence and characteristics ofan antibiotic-resistant clone were evaluated in this group ofisolates and in those from comparison cohorts in Michigan andMinnesota.
Results Fifty-five of the 255 E. coli isolates (22 percent)from the California cohort were resistant to trimethoprim–sulfamethoxazoleas well as other antibiotics. There was a common pattern ofDNA fingerprinting, suggesting that the isolates belonged tothe same clonal group (clonal group A), in 28 of 55 isolateswith trimethoprim–sulfamethoxazole resistance (51 percent)and in 2 of 50 randomly selected isolates that were susceptibleto trimethoprim–sulfamethoxazole (4 percent, P<0.001).In addition, 11 of 29 resistant isolates (38 percent) from theMichigan cohort and 7 of 18 (39 percent) from the Minnesotacohort belonged to clonal group A. Most of the clonal groupA isolates were serotype O11:H(nt) or O77:H(nt), with similarpatterns of virulence factors, antibiotic susceptibility, andelectrophoretic features.
Conclusions In three geographically diverse communities, a singleclonal group accounted for nearly half of community-acquiredurinary tract infections in women that were caused by E. colistrains with resistance to trimethoprim–sulfamethoxazole.The widespread distribution and high prevalence of E. coli clonalgroup A have major public health implications.
An estimated 11 percent of women in the United States reportat least one physician-diagnosed urinary tract infection peryear, and the lifetime probability that a woman will have aurinary tract infection is 60 percent.1 The clinical managementof urinary tract infection is complicated by the increasingincidence of infections caused by strains of Escherichia colithat are resistant to commonly used antimicrobial agents. Inrecent studies in the United States, the rates of resistanceto trimethoprim–sulfamethoxazole among E. coli isolatesfrom women with urinary tract infections ranged from 15 to 18percent.2,3,4
Although urinary tract infection is not usually thought of asa disease associated with community-wide outbreaks, certainmultidrug-resistant, uropathogenic lineages of E. coli haveexhibited epidemic behavior.5E. coli O15:K52:H1 caused an outbreakof community-acquired cystitis, pyelonephritis, and septicemiain South London in 1987 and 19885 and is an endemic cause ofurinary tract infection in Barcelona, Spain.6 This clonal group'sdistinctive profile of antibiotic resistance contributed toits identification in Europe.5
We studied the clonal composition of E. coli isolates from women(age range, 17 to 68 years) with uncomplicated, community-acquiredurinary tract infections that were resistant to trimethoprim–sulfamethoxazolein order to ascertain whether any clonal group of E. coli wasdisproportionately represented.
Methods
Study Cohorts
The study subjects included three cohorts of women (definedas those who were at least 17 years old) with urinary tractinfections and a comparison group of healthy women whose stoolspecimens were analyzed to identify the E. coli isolates. Thestudy was approved by the Committee for Protection of HumanSubjects of the University of California at Berkeley; informedconsent was not obtained, because the study involved neitherdirect interviews nor chart reviews. The California cohort consistedof women with symptoms of urinary tract infection who were seenat a university health service and were consecutively enrolledin the study between October 11, 1999, and January 31, 2000.A case of E. coli urinary tract infection was defined as symptomssuggestive of infection4 and a culture of a clean-catch urinespecimen with more than 102 colony-forming units of E. coliper milliliter.7
The two comparison cohorts were women with uncomplicated cystitiswho were seen at university health services in Minnesota andMichigan. For the Minnesota cohort, we analyzed all E. coliurinary isolates that were resistant to trimethoprim–sulfamethoxazoleand 20 isolates that were susceptible to the combined drugs.The isolates were obtained from students with uncomplicatedcystitis who were enrolled in a study between June 1998 andAugust 1999. For the Michigan cohort, we analyzed a similarlyselected sample of urinary isolates from women with acute cystitiswho were enrolled in a university-based study between September1996 and May 1999.
Another comparison cohort consisted of 41 healthy residentsat least two years of age (18 male subjects and 23 female subjects)of the university community in California who were free of urinarytract infection. Between August 1998 and November 2000, samplesof freshly passed stool obtained from each subject monthly forsix months were cultured for E. coli.
Isolation of E. coli
In California and Minnesota, urine samples were cultured onMacConkey agar. Colonies that were positive for lactose andindole were presumptively identified as E. coli. Culture methodsfor the Michigan cohort have been described previously.8 Oneputative E. coli colony from each urine culture was arbitrarilyselected for further analyses. Five E. coli colonies per monthlyfecal sample were selected for DNA fingerprinting with a polymerase-chain-reaction(PCR) assay.
Antibiotic Susceptibility Testing
E. coli isolates were screened for susceptibility to trimethoprim–sulfamethoxazolewith the use of E-test strips (AB Biodisk, Solna, Sweden) inCalifornia, the MicroScan system (Dade Behring, Sacramento,Calif.) in Michigan, and a standard disk-diffusion assay9 inMinnesota. E. coli strain 25922 (from the American Type CultureCollection) was used as the reference strain. Susceptibilityto 18 additional antimicrobial agents was assessed for selectedisolates by the disk-diffusion method,10 with the use of standardinterpretive criteria.9 Intermediate susceptibility was interpretedas full susceptibility.
DNA Fingerprinting
For each of the three cohorts of women with urinary tract infections,all isolates that were resistant to trimethoprim–sulfamethoxazoleand subgroups of susceptible isolates, selected either randomly(in California and Michigan) or arbitrarily (in Minnesota),were screened with the enterobacterial repetitive intergenicconsensus (ERIC2) PCR fingerprinting assay,11,12,13,14,15 aspreviously described.16 Isolates with fingerprints that wereindistinguishable on visual inspection were considered to belongto a single clonal group. Pattern A was defined by four predominantbands that were approximately 1145, 1029, 908, and 720 bp; isolatesexhibiting this pattern were considered to be members of clonalgroup A. A pyelonephritogenic isolate CFT073 (O6:K2:H1),17 providedby Dr. Harry Mobley at the University of Maryland, was usedas a reference strain for each ERIC2 PCR run.
Pulsed-Field Gel Electrophoresis
The standardized protocol for molecular subtyping of E. coli(O157:H7) by pulsed-field gel electrophoresis (PFGE), as establishedby the Centers for Disease Control and Prevention,18 was usedto identify a subgroup of the E. coli isolates that were indistinguishableby ERIC2 fingerprinting. XbaI-digested DNA was electrophoresedin the CHEF DR-II apparatus (Bio-Rad, Hercules, Calif.). Isolatesthat had indistinguishable PFGE patterns with the use of XbaIwere reanalyzed with a second enzyme, AvrII. The criteria forstrain relatedness established by Tenover et al. were used tocompare PFGE patterns.19 The most frequently identified patternamong the California isolates was designated XbaI PFGE patternA.
Virulence Genotyping
Genotypes for 31 putative virulence factors and the 12 knownpapA alleles were determined by multiplex PCR assays, supplementedby dot-blot hybridization, as previously described.20,21,22
Serotyping
Serotyping was performed on E. coli isolates at the E. colireference center in University Park, Pennsylvania. Strains thatwere motile but that did not react with O or H antiserum wereclassified as nontypable (nt) — O(nt) and H(nt), respectively.
Conjugation Experiments
Selected wild-type isolates that were resistant to trimethoprim–sulfamethoxazolewere conjugated with nalidixic acid–resistant, lactose-negativelaboratory strain JM109,23 according to a standard procedure,24,25and plated on Luria–Bertani agar26 containing trimethoprim–sulfamethoxazole(16 and 350 µg per milliliter, respectively) and nalidixicacid (20 µg per milliliter). The putative transconjugantswere tested for susceptibility to 18 antimicrobial agents bya disk-diffusion method to identify markers of resistance toadditional antimicrobial agents.
Statistical Analysis
Chi-square analysis with the use of generalized estimating equationsbased on the PROC GENMOD procedure in SAS (version 8.01, SASInstitute, Cary, N.C.) was used to account for clustered samplingin the California cohort, which included women with multipleurinary tract infections. An exchangeable correlation structurewas used in the analysis. The chi-square test or Fisher's exacttest was also used in analyses in which the data were restrictedto the first (primary) episode of urinary tract infection duringthe study period.
Results
Prevalence of Trimethoprim–Sulfamethoxazole Resistance
A total of 228 women (median age, 22 years) seen at the universityhealth service in California had symptoms suggestive of acuteurinary tract infection. A total of 505 consecutive urine samplesfrom these women were cultured, 255 of which yielded more than102 colony-forming units of E. coli per milliliter. Twenty-fourwomen had repeated urinary tract infections during the studyperiod: 21 (9 percent) had two infections, and 3 (1 percent)had three infections.
Fifty-five of the 255 E. coli isolates (22 percent) were resistantto trimethoprim–sulfamethoxazole (Table 1). All 55 resistantisolates, which were from 47 women, and 50 susceptible isolates,from 49 other women, were selected for further analysis. Inthe Minnesota cohort, 18 of 82 E. coli isolates (22 percent)were resistant to trimethoprim–sulfamethoxazole. All 18resistant isolates (from 18 women), plus 20 susceptible isolates(from 20 women), were selected for further analysis. In theMichigan cohort, 29 resistant isolates (from 28 women) and 20susceptible isolates (from 20 other women) were selected forfurther analysis (Table 1).
Table 1. Results of Fingerprinting Analysis of Escherichia coli Isolates Obtained from Women with Urinary Tract Infections in California, Michigan, and Minnesota.
ERIC2 PCR Fingerprinting
In the California cohort, 28 of the 55 E. coli isolates thatwere resistant to trimethoprim–sulfamethoxazole (51 percent)exhibited the same four-band ERIC2 pattern and were thereforeidentified as belonging to clonal group A (Figure 1 and Table 1),as compared with only 2 of 50 randomly selected susceptibleisolates (4 percent; P<0.001, with adjustment for clusteredsampling). In the Minnesota cohort, 7 of 18 isolates that wereresistant to trimethoprim–sulfamethoxazole exhibited clonalpattern A (39 percent), as compared with only 1 of 20 susceptibleisolates (5 percent, P=0.02). Likewise, in the Michigan cohort,11 of 29 isolates that were resistant to trimethoprim–sulfamethoxazoleexhibited clonal pattern A (38 percent), as compared with noneof the 20 susceptible isolates (P=0.001 by Fisher's exact test)(Figure 1 and Table 1).
Figure 1. Fingerprint Patterns of Escherichia coli Isolates with Resistance to Trimethoprim–Sulfamethoxazole.
Fingerprinting was performed with the use of the enterobacterial repetitive intergenic consensus polymerase-chain-reaction assay. The E. coli isolates from California (lanes 3, 4, and 5), Michigan (lanes 6, 7, and 8), and Minnesota (lanes 9, 10, and 11) show the same four-band (two dark and two light) pattern (designated pattern A), indicating that they are all members of clonal group A. Lane 1 shows a 1-kb ladder, lane 2 CFT073 (the reference strain), and lane 12 a negative control.
ERIC2 PCR was also used to evaluate 925 colonies of E. coliisolated from the stool samples obtained from the group of 41healthy persons. Clonal group A isolates were identified inone or more fecal samples from 5 of the 18 male subjects (28percent) and 10 of the 23 female subjects (43 percent). Thirteenof the 26 clonal group A isolates (50 percent) were resistantto trimethoprim–sulfamethoxazole (data not shown).
Results of PFGE Analysis
XbaI PFGE analysis was performed on 38 clonal group A isolates(23 from the California cohort and a total of 15 from the othertwo cohorts). Eleven of the California isolates (48 percent)had indistinguishable PFGE findings (designated XbaI PFGE patternA); 7 isolates (30 percent) differed from this pattern by onlyone to three bands, 4 (17 percent) by four to six bands, and1 (4 percent) by more than six bands (Figure 2 and Table 2).AvrII PFGE performed on six of the isolates with XbaI PFGE patternA showed that four were indistinguishable, and the other twodiffered by only two bands. Although none of the isolates fromMichigan and Minnesota had patterns that were identical to XbaIPFGE pattern A of the isolates from California, two of the eightMichigan isolates and all seven Minnesota isolates had patternsthat were moderately or very similar (Table 2).
Figure 2. Molecular Subtyping of Clonal Group A Isolates with Resistance to Trimethoprim–Sulfamethoxazole.
Pulsed-field gel electrophoresis with XbaI was used for subtyping. Lane 1 shows CFT073 (the reference strain). Clonal group A isolates from California are shown in lanes 2, 3, and 4; those from Michigan in lanes 5, 6, and 7; and those from Minnesota in lanes 8, 9, and 10.
Table 2. Serotype and Pulsed-Field Gel Electrophoretic (PFGE) Pattern of Selected Clonal Group A Isolates from California, Michigan, and Minnesota.
Antibiotic Susceptibility
Clonal group A isolates from all three cohorts had a significantlyhigher prevalence of resistance to multiple antibiotics thandid the comparison strains (Table 3). A pattern of resistanceto six drugs was found in 8 of 19 clonal group A strains (42percent) but in none of the other strains (P<0.001).
Table 3. Prevalence of Antibiotic-Resistance Patterns and Virulence-Factor Profiles of Escherichia coli Isolates.
Serotyping
Of 41 representative clonal group A isolates from the threecohorts with urinary tract infections, 32 (78 percent) exhibitedone of two distinctive serotypes: O11:H(nt) or O77:H(nt). SerotypeO11:H(nt) predominated among the California isolates but wasrare or nonexistent among the Michigan and Minnesota isolates,whereas serotype O77:H(nt) accounted for large proportions ofthe Michigan and Minnesota isolates (Table 2). Three of theremaining clonal group A isolates (7 percent of the total) exhibiteda unique O antigen, and 6 (15 percent of the total) could notbe typed. Of the 13 clonal group A fecal isolates that wereserotyped, 9 (69 percent) were O11:H(nt), 2 were other serotypes,and 2 could not be typed.
Virulence Genotyping
Clonal group A was characterized by a distinctive profile ofvirulence factors that included a complete copy of pap, theF16 papA allele, papG allele II, iutA, kpsMTII, and traT, andthe absence of sfa/foc, afa/dra, hly, cnf, iroN, iss, and malX(Table 3). This profile, which corresponds with that previouslydocumented for the O15:K52:H1 clonal group,6,27 was consistentamong isolates from all three cohorts, whether or not the strainswere resistant to trimethoprim–sulfamethoxazole.
Conjugation
JM109 transconjugants were derived from five clonal group Aisolates in California that were resistant to trimethoprim–sulfamethoxazole.The transconjugants acquired resistance not only to trimethoprim–sulfamethoxazolebut also to ampicillin, tetracycline, chloramphenicol, and streptomycin(data not shown).
Discussion
We found that 11 percent of uncomplicated, community-acquiredurinary tract infections in women seen during a four-month periodat a university health service in California were caused bya single, previously unrecognized clonal group of multidrug-resistantE. coli, clonal group A. This clonal group accounted for 51percent of urinary tract infections caused by E. coli strainsthat were resistant to trimethoprim–sulfamethoxazole atthis health center and for high proportions of such isolatesfrom women seen at university health centers in Michigan andMinnesota (38 and 39 percent, respectively). Although a limitednumber of isolates and locations were surveyed, these data suggestthat a single E. coli clonal group may have contributed to therecently documented increase in antibiotic resistance amongE. coli isolates from patients with urinary tract infectionsin some parts of the United States.3,4 In the California cohort,if it had not been for this drug-resistant clonal group, theproportion of all primary episodes of urinary tract infectionscaused by E. coli strains that were resistant to trimethoprim–sulfamethoxazolewould have been 11 percent instead of 21 percent.
That the E. coli isolates with resistance to trimethoprim–sulfamethoxazolerepresent a phylogenetically distinct clonal group was suggestedby their similarities to one another and their differences fromother strains with respect to five characteristics: the ERIC2fingerprinting pattern; O:H serotype, with the unusual serotypesO77:H(nt) or O11:H(nt) predominating among members of clonalgroup A; PFGE profiles; virulence-factor profiles; and patternsof antibiotic susceptibility. Clonal group A isolates accountedfor 11 percent of all urinary tract infections in Californiaand for 9 percent in Minnesota, which represents a substantialprevalence for a single E. coli clonal group.20,27 This findingindicates that clonal group A contributes substantially notonly to drug-resistant urinary tract infections but also tourinary tract infections in general.
Clonal group A appears to represent a new lineage of multidrug-resistant,uropathogenic E. coli rather than an established virulent clonethat has acquired antibiotic resistance. In previous studiesof E. coli isolates from urinary tract infections, O11 and O77somatic antigens have not been noted, and serogroups O1, O2,O4, O6, O7, O16, O18, O25, and O75 have consistently predominated,accounting for up to 81 percent of isolates.27,28,29,30
Although urinary tract infection is usually regarded as a sporadicdisease caused by organisms from the host's own fecal flora,transmission of E. coli between sex partners and household membershas been reported.31,32 Nosocomial outbreaks of E. coli pyelonephritishave also been documented.33 A community-wide outbreak of urinarytract infection due to a single strain occurred in South Londonin 1986 and 1987.5 In this outbreak, isolates of E. coli O15:K52:H1that exhibited a distinctive multidrug-resistance phenotypesimilar to that of the clonal group A isolates in our studywere recovered from community-acquired cases of pyelonephritisand bacteremia. This serotype was subsequently identified asa cause of endemic urinary tract infection and bacteremia inother European countries34,35,36 and, more recently, in theUnited States.6 The clonal group A strains exhibit a virulencegenotype that is very similar to that of the O15:K52:H1 clonalgroup, including the F16 papA allele, papG allele II, iutA,fyuA, kpsMTII, and traT.6
We identified clonal group A strains in fecal samples obtainedduring the study period from healthy members of the universitycommunity in California. The proportion of healthy subjectsidentified as having fecal colonization with clonal group Aon one or more occasions is probably an overestimate of thetrue prevalence of this infection in the community because ofthe sampling strategy used. Nevertheless, this analysis doesshow that clonal group A was circulating in members of the communitywhen the cases of urinary tract infection occurred.
The apparent emergence of clonal group A in three states suggestseither the simultaneous expansion in multiple locations of apreviously introduced endemic clonal group, possibly as a consequenceof increasing antimicrobial selection pressure, or the recentintroduction of the clonal group into new environments. Thehigh degree of genetic homogeneity among the California isolatesfavors the latter hypothesis. One possible explanation for theobserved temporal and geographic clustering of a single E. coliPFGE type (pattern A) in California is that the strains werespread by one or more contaminated products ingested by communityresidents, which is similar to the way an enteric pathogen,such as E. coli O157:H7, causes community-wide outbreaks afterbeing disseminated by the consumption of contaminated foods.18,37If a large proportion of urinary tract infections caused bydrug-resistant strains of E. coli in a community were due tothe ingestion of widely consumed, contaminated foods, this wouldconstitute a serious and novel public health problem.
Clonal group A isolates were resistant to antibiotics that arecommonly used in the outpatient setting to treat urinary tractinfection and a wide variety of other infections. Resistanceto these agents may persist with the use of any of the antibioticsrepresented in the resistance phenotype. Additional studiesare needed to establish the geographic and temporal distributionof this emerging E. coli clonal group and to determine whetherit is spread by the ingestion of contaminated foods.
Supported by grants from the Alameda County District AttorneyGeneral's Fund (to Dr. Riley); the Office of Research and Development,Medical Research Service, Department of Veterans Affairs (toDr. Johnson); the National Institutes of Health (DK-47504, toDr. Johnson, and DK35368, to Dr. Foxman); and the National ResearchInitiative Competitive Grants Program and the Department ofAgriculture (00-35212-9408, to Dr. Johnson).
We are indebted to Peter Dietrich, M.D., M.P.H., and the staffof the clinical laboratory at the University of California,Berkeley, Health Services, for their assistance in enrollingpatients and collecting samples; to David Wang, M.D., and thenursing and laboratory staff at the Minnesota clinic; to SharonAbbott, Jan O'Connell, and Jim Ware at the California Departmentof Health for technical assistance with PFGE; and to Brent Sugimoto,M.P.H., for assistance in collecting and analyzing the fecalsamples.
Source Information
From the Division of Epidemiology and Public Health Biology, School of Public Health, University of California at Berkeley, Berkeley (A.R.M., K.E.F., L.W.R.); the Medical Service, Minneapolis Veterans Affairs Medical Center, and the Department of Medicine, University of Minnesota, Minneapolis (J.R.J., T.T.O.); and the Department of Epidemiology, University of Michigan, School of Public Health, Ann Arbor (B.F.).
Address reprint requests to Dr. Riley at the Division of Epidemiology and Public Health Biology, School of Public Health, University of California, 140 Warren Hall, Berkeley, CA 94720, or at lwriley{at}uclink4.berkeley.edu.
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