Enteroaggregative Escherichia coli: A Review of Trends .... Coli-Infect in Med... · 100 INFECTIONS in MEDICINE March 2007 DIARRHEAL ILLNESS T he 6 recognized pathotypes of diarrheagenic

100 INFECTIONS in MEDICINE March 2007

DIARRHEAL ILLNESS

The 6 recognized pathotypes ofdiarrheagenic Escherichia coliare enterotoxigenic, enteroag-

gregative, enteropathogenic, entero-hemorrhagic, enteroinvasive, anddiffusely adherent E coli. Enteroag-gregative E coli (EAEC) has recentlyreceived increasing attention as anemerging enteric pathogen. The pur-pose of this article is to providehealth care workers with an update

on the epidemiology, clinical mani-festations, diagnostic modalities, andtreatment of EAEC infection.

EPIDEMIOLOGYEAEC was first detected in 1987 inthe stool of a Peruvian child with di-arrheal illness. On examination ofher stool, a characteristic “stacked-brick” adherence to HEp-2 cells wasnoted.1 Since this observation, EAEC

has been implicated in both acuteand chronic diarrheal illness amongadults and children in industrializedand developing countries.2

Travelers to developing regionssuch as India, Jamaica, and Mexicoare at increased risk for EAEC infec-tion. International travelers are atparticular risk because they oftenhave limited exposure to thispathogen at home and, thus, have di-minished immunity to EAEC infec-tion.3 North American and Europeantravelers to developing regions suchGuadalajara, Mexico; Ocho Rios, Ja-maica; and Goa, India, frequently ex-perience diarrheal illness caused byEAEC infection.4 Collectively, inthese 3 regions, EAEC was isolatedin 26% of cases of diarrheal illness;this was second only to enterotoxi-genic E coli, which was isolated in30% of cases.5 The rates of EAEC in-fection varied; the rate was 33% intravelers to Mexico, 26% in travelersto Jamaica, and 19% in travelers toIndia.

Case series and cohort field stud-ies indicate that EAEC is endemic insome regions. In a study of childrenyounger than 5 years in Vietnam,Nguyen and colleagues6 identifiedEAEC in 11.6% of stool samples fromthose presenting with diarrhea, com-pared with 4.4% of age-matched con-trols without diarrhea.

Enteroaggregative Escherichia coli:A Review of Trends, Diagnosis, and TreatmentDavid J. Cennimo, MD, Hoonmo Koo, MD, Jamal A. Mohamed, PhD, David B. Huang, MD, PhD,and Tom Chiang, MD

Enteroaggregative Escherichia coli (EAEC) is an increasingly recognized cause of acute diarrhea among both children andadults. Travelers to developing regions such as India, Jamaica,and Mexico are at increased risk. Contamination of food andwater plays a central role in transmission. The clinical presenta-tion of EAEC infection is characterized by watery diarrhea, usually unaccompanied by blood or mucus. The gold standardfor diagnosis is the HEp-2 cell adherence assay; the unique“stacked-brick” aggregative pattern of adherence is characteris-tic of this pathogen. However, because laboratory diagnosisis not routinely available, symptomatic infections are usuallytreated empirically. In most regions, EAEC strains are suscepti-ble to the fluoroquinolones and rifaximin. [Infect Med. 2007;24:100-110]

Key words: Enteroaggregative Escherichia coli ■ Diarrhea

Dr Cennimo is a fellow in infectious diseases at the University of Medicine and Dentistry of NewJersey (UMDNJ)–New Jersey Medical School in Newark. Dr Koo is a fellow in infectious diseasesat Baylor College of Medicine in Houston. Dr Mohamed is a research scientist at the University ofTexas Health Science Center in Houston. Dr Huang is an attending physician the Veterans AffairsNew Jersey Health Care System (VANJHCS) in East Orange. Dr Chiang is assistant professor ofmedicine at UMDNJ and an infectious diseases attending physician at VA NJHCS.

0703IIM202087chilay 5/15/07 4:29 PM Page 100

Linda

Stamp

Linda

Text Box

Subscription Information for:

http://gw.vtrenz.net/?FCT2P980XC

March 2007 INFECTIONS in MEDICINE 101

DIARRHEAL ILLNESS

Pabst and colleagues,7 who inves-tigated the prevalence of EAEC inSwiss children, found EAEC in 19(10.2%) of 187 specimens from chil-dren with diarrhea, compared with 3(2.2%) of 137 specimens from thosewithout diarrhea. When the analysiswas limited to children younger than5 years, specimens were positive forEAEC in 11.9% of those with diar-rhea compared with 2.2% of controls.This association was strongest in theyounger children and was correlatedwith recent international travel.7

EAEC has been isolated from 2%to 68% of patients with diarrhea andfrom 0% to 15% of controls fromIndia, South America, Europe, andthe Middle East.1,8,9 It has also beenimplicated in outbreaks of diarrhealillness in both adults and children. In1993, a massive outbreak affected2697 children in Japan, representingan attack rate of 40%.10 The children

consumed contaminated schoollunches and began having symp-toms an average of 40 to 50 hourslater. At least 30 children sufferedprolonged diarrhea.10

Ameta-analysis of 41 case-controlstudies demonstrated an associationbetween EAEC and acute diarrheaamong children and adults living indeveloping and industrialized re-gions, adult travelers to developingregions, and HIV-infected patients indeveloping nations.2 The presence ofEAEC identified with the HEp-2 celladherence assay was found to be sig-nificantly associated with acute diar-rheal illness among children residingin developing regions (odds ratio[OR], 1.58; 95% confidence interval[CI], 1.36 - 1.83) and industrializedregions (OR, 1.23; 95% CI, 1.03 - 1.48),adults with HIV infection residing indeveloping regions (OR, 6.43; 95%CI, 2.91 - 14.16), adults residing in

developing regions (OR, 7.15; 95%CI, 1.96 - 26.04), and internationaltravelers to developing regions (OR,6.72; 95% CI, 2.62 - 17.20) (Figure 1).2

Although most EAEC studieshave been conducted in developingregions, 2 epidemiologic studieshave examined the prevalence ofEAEC in the United States. The firstprospective study was conductedamong children in Cincinnati.11 Tenpercent of children younger than 1year who presented to the emer-gency department (ED) and approx-imately 5% of inpatients with diar-rhea had evidence of EAEC infec-tion.11 The second prospective cohortstudy investigated the cause of diar-rhea in patients who presented toEDs and clinics in New Haven,Conn, and Baltimore and found thatEAEC was the single most commonbacterial cause of diarrhea; it wasisolated in 37 (4.5%) of 823 of case pa-tients, versus 1.7% of controls.12

PATHOGENESISEAEC is transmitted by the fecal-oralroute. Contamination of food andwater play a central role in transmis-sion. A volunteer study has shownthat oral challenge with 1010 colony-forming units of EAEC causes diar-rheal illness.5 Once EAEC is ingest-ed, it can bind to the mucosa of thesmall and large intestines. EAEC thatis bound to the intestinal mucosastimulates epithelial cells to producea thick mucous layer above the intactenterocyte brush border,13 and EAECelicits inflammatory mediators thatproduce cytotoxic effects involvingthe intestinal mucosa.14

Not all EAEC infections cause di-arrheal illness. EAEC is a very het-erogeneous bacterium. Many viru-lence genes have been identified.aggR, the master regulator of EAECvirulence, controls the expression ofadherence factors, a dispersin pro-tein, and a cluster of genes encod-ed on the EAEC chromosome.15 As

Po

ole

d o

dd

s ra

tio

(95%

CI)

Children(DR,

n = 22)

Children(IR,

n = 9)

HIV-infectedadults(DR,

n = 3)

HIV-infectedadults

(IR,n = 2)

Adults (DR,n = 2)

International travelers

(DR,n = 1)

Adults (IR,

n = 2)

0

1

2

3

4

5

6

7

8

Figure 1 – Enteroaggregative Escherichia coli has been associated with acute diarrhea amongchildren and adults living in developing and industrialized regions, adult travelers to develop-ing regions, and HIV-infected patients in developing nations. The odds ratios range from 1.58in some pediatric populations to as high as 7.15 in some adult populations. (CI, confidence in-terval; n, number of published studies; DR, developing regions; IR, industrialized regions.)



DIARRHEAL ILLNESS continued

a result of the importance of the aggR region, EAEC that carries aggRhas been designated typical EAEC.Many of the EAEC genes encodedon its chromosome are homologuesin other Gram-negative bacteria, andthese genes have been proposed toconstitute a type IV secretion sys-tem.16 Other genes have been identi-fied, and their significance in viru-lence is being studied.

Adherence factors enable EAECto adhere to the intestinal mucosa.17

Three AAF structural subunits havebeen identified: aggA encodesAAF/I,18 aafA encodes AAF/II,19

and agg-3 encodes AAF/III.20 AAF/Iand AAF/II are regulated by tran-scriptional activator aggR.

Outer membrane proteins play animportant role in EAEC adherenceand hemagglutination of animalcells.21 A type IV pilus that con-tributes to plasmid conjugation, ep-ithelial cell adherence, and adher-ence to abiotic surfaces has recentlybeen described.16 There are probablymore AAF structural subunits andadherence factors that are yet to beidentified.

EAEC has a type III secretion sys-tem (T3SS), designated ETT2.22 Itsspecific role has not yet been charac-terized, but the type secretion sys-tems typically export protein mole-cules across Gram-negative bacterialmembranes directly into the hostcells. This is accomplished via a vari-ety of mechanisms, from simple one-component systems to complexmulti-component pathways. Thereare 6 types of nonhomologous pro-tein secretion systems. For EAEC,the T3SS is located on the glyU locusof prototype EAEC strain 042. TheT3SS of EAEC and the presumed effectors are located on differentchromosomal islands and are coor-dinately activated by EilA. EilA, likeaggR, appears to serve as a virulence-related regulon for EAEC genes involved with adherence, aggrega-

tion, and the T3SS.22

Dispersin protein, encoded byaap, is an important secreted low mo-lecular weight protein responsiblefor mediating dispersal of EAECacross the intestinal mucosa to allowfor efficient adherence and aggrega-tion. This protein is exported by anATP-binding cassette transportercomplex that is encoded by a genet-ic locus on the EAEC virulence plas-mid pAA223; aap is regulated by thetranscriptional activator AggR.

Once EAEC binds to the mucosaof the small and large intestines, itstimulates the epithelial cells to pro-duce a thick mucous layer above theenterocytes, which forms biofilm.This mucous layer surrounds theEAEC and may explain why personsinfected with EAEC have mucoidstools. Most EAEC isolates producebiofilm, and biofilm formation is as-sociated with the multiple EAECgenes: aggR, set1A, aatA, and irp2.24

EAEC isolates that possess the aap,astA, irp2, pet, and set1A genes in theaggR background produce morebiofilm than aggR-lacking back-ground, suggesting that aggR regu-lates other genes needed for biofilmformation in EAEC.24 Biofilm pro-duction by EAEC isolates from pa-tients with traveler’s diarrhea hasbeen associated with the carriage ofvirulence genes, particularly aggR,set1A, and aatA.24

Wakimoto and associates25 report-ed that the aggR-positive EAEC iso-lates showed significantly strongerbiofilm formation than the aggR-neg-ative EAEC isolates. Another studyidentified EAEC adhesions to be al-lelic in nature, and biofilm formationwas shared by all members of theAAF family.26 Other genes have beenassociated with biofilm productionamong EAEC. Fis and yafK are medi-ated by AAF and have been iden-tified as important genes in thebiofilm production of EAEC strain042, a prototype EAEC strain.27 It is

clear that we still have to decipherthe genetic basis of biofilm formationby EAEC, including quorum sensingin the GI tract.

EAEC isolates release toxins thatbind to the intestinal mucosa andelicit inflammatory mediators thatproduce cytotoxic effects and in-testinal secretion. The best-studied toxins are plasmid-encoded toxin (pet),28 EAEC heat-stable enterotoxin(EAST1),29 and Shigella enterotoxin 1(set1A). These toxins are destructiveto the tips and sides of intestinal villiand enterocytes. Host inflammatorymediators of EAEC infection includethe production of intestinal cyto-kines and inflammatory markers,such as interleukin (IL)-1ra, IL-1�,IL-8, interferon-�, lactoferrin, fecalleukocytes, and occult blood.30-32

In vitro studies suggest that manyof these inflammatory responses aremediated by flagellin (fliC), a majorbacterial surface protein of EAEC.33

Flagellin binds to toll-like receptor 5and induces transcription of proin-flammatory cytokines such as IL-8.IL-8 is a neutrophil chemoattractantthat facilitates intestinal secretion.34

Other in vitro studies indicate thatother proinflammatory genes are up-regulated, including IL-6, tumornecrosis factor �, growth-relatedgene product (GRO)-�, GRO-�, in-tracellular adhesion molecule-1,granulocyte-macrophage colony-stimulating factor, and IL-1ra.35

HOST SUSCEPTIBILITYGenetics plays an important role indetermining the host’s susceptibilityto diarrheal illness. Two genes thatare important in determining sus-ceptibility to EAEC infection are thegenes for IL-8 and lactoferrin. IL-8 isa proinflammatory chemokine thatfunctions as a neutrophil chemoat-tractant, and lactoferrin is an impor-tant element of the intestinal im-mune system.

A single nucleotide polymor-



DIARRHEAL ILLNESS

phism of the AA genotype in the�251 position of the IL-8 gene pro-moter has been identified as an im-portant gene associated with diar-rheal illness and greater levels offecal IL-8 caused by EAEC infec-tion.36 Recently, a single nucleotidepolymorphism with T/C substitu-tion in exon15 (LTFEx15 codon 632[T/C]) of the lactoferrin gene was as-sociated with susceptibility to in-flammatory diarrhea caused byEAEC in North Americans whowere traveling in Mexico.37 Muchwork is still needed to identify otherhost genetic factors that are impor-tant in determining susceptibility toEAEC infection.

CLINICAL PRESENTATIONOne of the most common clinicalmanifestations of EAEC infection iswatery diarrhea, usually unaccom-panied by blood or mucus. Typically,patients are afebrile.15 Less common-ly reported associated symptomsand signs include low-grade fever;vomiting; abdominal pain; and thepresence of fecal blood, mucus, orleukocytes.8,12,32,38 The incubation pe-riod for illness ranges from 8 to 18hours.1,5,14

These signs and symptoms areusually self-limited even without an-tibiotic therapy. However, persistentdiarrhea (lasting more than 14 days)may occur in select populations, in-cluding HIV/AIDS patients andmalnourished children in develop-ing countries.39,40 Patients infectedwith EAEC can be asymptomatic.41

This mixed spectrum of clinical man-ifestations reflects the heterogeneousnature of EAEC strains bearing dif-ferent virulence properties as well asdiffering host immunity.

DIAGNOSISThe differential diagnosis of EAEC-associated diarrhea does not differfrom that of viral, other bacterial, or parasitic enteric pathogens that

cause community-acquired andtraveler’s diarrhea. Physical findingsare nonspecific and do not help nar-row the differential diagnosis forEAEC diarrhea. Typically, EAEC isidentified among patients who havetraveled to developing areas whereEAEC is endemic.

The HEp-2 cell adherence assayremains the gold standard for diag-nosing EAEC infection.1 The unique“stacked-brick” aggregative patternof adherence is characteristic of thispathogen. Essential components ofthis adherence pattern include bind-ing of the bacteria to the glass sur-face, to the human epithelial cell bor-ders, and to one another (Figure 2).Further characterization of this ag-gregative pattern has been recentlydescribed as typical honeycomb for-mation, lack of honeycombing, andaggregative adherence with lined-upcells.25,42

The use of formalin-fixed HEp-2cells has been demonstrated to be aviable option for the storage of HEp-2 cells for future use, with a sensitiv-

ity (94% to 98%) and a specificity(100%) that are similar to those of thetraditional assay.43 Limitations of theHEp-2 cell assay include time re-quirements and limited availabilityin reference laboratories. These limi-tations have led to the search forother diagnostic methods, includingpolymerase chain reaction (PCR) as-says, DNA probes, and quantitativebiofilm assays (Table).

Currently, there is a lack of con-sensus in the literature regardingwhich EAEC genes should bescreened with PCR detection. Multi-ple genes have been investigated, in-cluding aggR, aatA (CVD432), aggA,aafA, and astA.12,25,44 Unfortunately,the sensitivity of primers based onthese genes appears to markedlyvary given the heterogeneous pres-ence of virulence genes in differentEAEC strains.

PCR detection of aggR may notprove to be an appropriate initialscreening test for EAEC, but it is in-formative because it can identifytypical EAEC, which is postulated to

Figure 2 – This HEp-2 cell adherence assay shows the “stacked-brick” aggregative adherence toother bacteria, the coverslip, and the HEp-2 cells. This pattern of adherence is characteristic ofenteroaggregative Escherichia coli.




have a more pathogenic role thanEAEC lacking aggR.35 Multiplex PCRassays for multiple EAEC genes mayhelp overcome the diverse geneticcomposition of EAEC strains withimproved sensitivity, but problemswith specificity continue to necessi-tate confirmation with the HEp-2 cellassay.45,46 Real-time PCR has beendemonstrated to be at least as sensi-tive as conventional PCR for the de-tection of EAEC.47

Another diagnostic tool is a DNAprobe to the pCVD432 (aatA) genesequence. Although this test is spe-cific (99%), its sensitivity is variable(15% to 89%).35,41 This test may helpidentify more virulent typical EAECstrains because a positive result canbe considered a surrogate marker forthe presence of aggR.15

The biofilm assay using a mi-crotiter plate has potential as a pre-liminary screening tool in develop-ing countries because it is relativelyquick. However, the test’s sensitivity(77%) and specificity (100%) requirethe HEp-2 cell assay for more accu-rate detection of EAEC.25

TREATMENTMany EAEC infections are self-limit-ed.31 Symptomatic infections areusually treated empirically becauselaboratory diagnosis is not routinelyavailable. EAEC susceptibility variesby region. In most regions, EAECstrains are susceptible to the fluoro-quinolones, azithromycin, rifaximin,amoxicillin/clavulanic acid, and na-lidixic acid.48,49 In a study conductedby Sobieszczanska and colleagues,50

EAEC strains identified in the stoolsof Polish children with diarrheawere resistant to ampicillin, tetracy-cline, trimethoprim, sulfamethoxa-zole, and chloramphenicol. In Thai-land, EAEC strains were resistant toseveral antibiotics routinely used forgastroenteritis, including co-trimox-azole and amoxicillin. Most of thestrains, however, were sensitive tothe fluoroquinolones.51

Three clinical trials have beenconducted on the treatment of EAECdiarrheal illness; 2 were conductedamong travelers to developing coun-tries and 1 was conducted amongHIV-infected patients in a develop-

ing country. Glandt and colleagues48

compared the clinical responses tociprofloxacin treatment with re-sponses to placebo among 29 UStravelers to Jamaica and Mexico whohad EAEC diarrhea. Sixteen travel-ers were treated with ciprofloxacin,500 mg bid for 3 days, and 13 re-ceived placebo. The patients whowere treated with ciprofloxacin hada significantly reduced duration ofdiarrhea compared with the controls(35 vs 56 hours).

A multicenter trial that includedUS travelers to Guatemala; Kenya;and Guadalajara, Mexico,49 com-pared the clinical responses to rifax-imin with responses to placeboamong 43 patients with EAEC diar-rhea. Thirty patients were treatedwith rifaximin (200 or 400 mg bid for3 days), and 13 received placebo. Thepatients treated with rifaximin had asignificantly shorter duration of ill-ness than those who received place-bo (22 vs 72 hours). In a double-blind, placebo-controlled, crossovertreatment trial involving 24 HIV-infected patients with EAEC diar-

Table – Diagnostic modalities for identifying enteroaggregative Escherichia coli

Diagnostic test Study location Sensitivity Specificity

Formalin-preserved Guadalajara, Mexico43 92% - 98% 100%HEp-2 cell assay

PCR assay (astA, aafA, Zacatenco, Mexico53 86% - 94% 78% - 100%aggA, aggR) Barcelona, Spain54

Mendoza, Argentina55

Taichung, Taiwan44

Multiplex PCR assay (CVD432) Sao Paulo, Brazil56 100% 100%Hanoi, Vietnam6

Stockholm6

Real-time PCR assay Zurich47 100% 100%

DNA probe (CVD432) Tehran, Iran46 15% - 89% 99%Sao Paulo, Brazil57

Quantitative biofilm Kagoshima, Japan25 100% 99%assay (OD570 > 0.2)

PCR, polymerase chain reaction.



DIARRHEAL ILLNESS

rhea, those treated with ciprofloxa-cin (500 mg bid for 7 days) reported50% fewer bowel movements and a42% decrease in other enteric symp-toms compared with those who re-ceived placebo.52

These 3 clinical studies indicatethat the fluoroquinolones, especiallyciprofloxacin, 500 mg bid for 3 to 7days, and rifaximin, 200 or 400 mgbid for 3 days, may be the antimicro-bial treatments of choice for symp-tomatic EAEC infections.

CONCLUSIONEAEC is recognized as an emergingcause of diarrhea. It has been impli-cated in acute and chronic diarrheaamong travelers, children, adults,and HIV-infected persons in both in-dustrialized and developing coun-tries. Volunteer studies, outbreak reports, case-control studies, andclinical trials in industrialized anddeveloping countries have shown anassociation of EAEC with acute diar-rhea. The pathogenesis is complex,and EAEC has a host of heteroge-neous virulence factors.

Currently, identification of EAECis not routinely performed. In thenear future, efficient ways of identi-fying EAEC will allow for standard-ized laboratory testing. Since EAECinfection is usually a self-limited dis-ease, management should be indi-vidualized. Most EAEC infectionscan be treated conservatively withoral hydration. Clinical trials haveshown that EAEC diarrhea is re-sponsive to treatment with fluoro-quinolones and rifaximin. ❖

REFERENCES1. Nataro JP, Steiner T, Guerrant RL. Enteroag-

gregative Escherichia coli. Emerg Infect Dis. 1998;4:251-261.

2. Huang DB, Nataro JP, DuPont HL, et al. En-teroaggregative Escherichia coli is a cause ofacute diarrheal illness: a meta-analysis. Clin In-fect Dis. 2006;43:556-563.

3. Mathewson JJ, Johnson PC, DuPont HL, et al. Anewly recognized cause of traveler’s diarrhea:enteroaddherent Escherichia coli. J Infect Dis.1985;151:471-475.

4. Adachi JA, Jaing ZD, Mathewson JJ, et al. En-teroaggregative Escherichia coli as a major etio-logic agent in traveler’s diarrhea in 3 regions ofthe world. Clin Infect Dis. 2001;32:1706-1709.

5. Nataro JP, Deng Y, Cookson S, et al. Hetero-geneity of enteroaggregative Escherichia coli vir-ulence demonstrated in volunteers. J Infect Dis.1995;171:465-468.

6. Nguyen TV, Le Van P, Le Huy C, et al. Detectionand characterization of diarrheagenic Esch-erichia coli from young children in Hanoi, Viet-nam. J Clin Microbiol. 2005;43:755-760.

7. Pabst WL, Altwegg M, Kind C, et al. Prevalenceof enteroaggregative Escherichia coli amongchildren with and without diarrhea in Switzer-land. J Clin Microbiol. 2003;41:2289-2293.

8. Kahali S, Sarkar B, Rajendran K, et al. Virulencecharacteristics and molecular epidemiology ofenteroaggregative Escherichia coli isolates fromhospitalized diarrheal patients in Kolkata, In-dia. J Clin Microbiol. 2004;42:4111-4120.

9. Presterl E, Zwick RH, Reichmann S, et al. Fre-quency and virulence properties of diarrhe-agenic Escherichia coli in children with diarrheain Gabon. Am J Trop Med Hyg. 2003;69:406-410.

10. Itoh Y, Nagano I, Kunishima M, Ezaki T. Labo-ratory investigation of enteroaggregative Esch-erichia coli O untypable:H10 associated with amassive outbreak of gastrointestinal illness. J Clin Microbiol. 1997;35:2546-2550.

11. Cohen MB, Nataro JP, Bernstein DI, et al. Preva-lence of diarrheagenic Escherichia coli in acutechildhood enteritis: a prospective controlledstudy. J Pediatr. 2005;146:54-61.

12. Nataro JP, Mai V, Johnson J, et al. DiarrheagenicEscherichia coli infection in Baltimore, Mary-land, and New Haven, Connecticut. Clin InfectDis. 2006;43:402-407.

13. Hicks S, Candy DC, Phillips AD. Adhesion ofenteroaggregative Escherichia coli to pediatricintestinal mucosa in vitro. Infect Immun. 1996;64:4751-4760.

14. Harrington SM, Dudley EG, Nataro JP. Patho-genesis of enteroaggregative Escherichia coli in-

fection. FEMS Microbiol Lett. 2006;254:12-18.15. Nataro JP. Enteroaggregative Escherichia coli

pathogenesis. Curr Opin Gastroenterol. 2005;21:4-8.

16. Dudley EG, Abe C, Ghigo JM, et al. An IncI1plasmid contributes to the adherence of theatypical enteroaggregative Escherichia coli strainC1096 to cultured cells and abiotic surfaces. In-fect Immun. 2006;74:2102-2114.

17. Moreira CG, Carneiro SM, Nataro JP, et al. Roleof type I fimbriae in the aggregative adhesionpattern of enteroaggregative Escherichia coli.FEMS Microbiol Lett. 2003;226:79-85.

18. Nataro JP, Yikang D, Giron JA, et al. Aggrega-tive adherence fimbria I expression in en-teroaggregative Escherichia coli requires two un-linked plasmid regions. Infect Immun. 1993;61:1126-1131.

19. Czeczulin JR, Balepur S, Hicks S, et al. Ag-gregative adherence fimbria II, a second fimbri-al antigen mediating aggregative adherence inenteroaggregative Escherichia coli. Infect Immun.1997;65:4135-4145.

20. Bernier C, Gounon P, Le Bouguenec C. Identi-fication of an aggregative adhesion fimbria(AAF) type III-encoding operon in enteroag-gregative Escherichia coli as a sensitive probe fordetecting the AAF-encoding operon family. In-fect Immun. 2002;70:4302-4311.

21. Spencer J, Chart H, Smith HR, Rowe B. Ex-pression of membrane-associated proteins bystrains of enteroaggregative Escherichia coli.FEMS Microbiol Lett. 1998;161:325-330.

22. Sheikh J, Dudley EG, Sui B, et al. EilA, a HilA-like regulator in enteroaggregative Escherichiacoli. Mol Microbiol. 2006;61:338-350.

23. Nishi J, Sheikh J, Mizuguchi K, et al. The exportof coat protein from enteroaggregative Esch-erichia coli by a specific ATP-binding cassettetransporter system. J Biol Chem. 2003;278:45680-45689.

24. Mohamed JA, Jiang ZD, DuPont HL, et al. Asingle nucleotide polymorphism (SNP) in theexon15 region of the lactoferrin gene (LTFEx15)is associated with travelers’ diarrhea (TD). Pre-sented at: 44th Annual Meeting of InfectiousDiseases Society of America; October 12-15,2006; Toronto. Abstract 63.

25. Wakimoto N, Nishi J, Sheikh J, et al. Quantita-tive biofilm assay using a microtiter plate toscreen for enteroaggregative Escherichia coli. AmJ Trop Med Hyg. 2004;71:687-690.

26. Bhardwaj R, Majumdar S, Ganguly NK, et al.Characterization of adhesin variants in Indianisolates of enteroaggregative Escherichia coli.FEMS Microbiol Lett. 2006;258:274-283.

27. Sheikh J, Hicks S, Dall’Agnol M, et al. Roles forFis and YafK in biofilm formation by enteroag-gregative Escherichia coli. Mol Microbiol. 2001;41:983-997.

28. Navarro-Garcia F, Canizalez-Roman A, Luna J,et al. Plasmid-encoded toxin of enteroaggrega-tive Escherichia coli is internalized by epithelialcells. Infect Immun. 2001;69:1053-1060.

29. Beausoleil HE, Lepine F, Dubreuil JD. LC-MSanalysis of pig intestine sulfatides: interactionwith Escherichia coli STb enterotoxin and char-acterization of molecular species present.FEMS Microbiol Lett. 2002;209:183-188.

30. Jiang ZD, Greenberg D, Nataro JP, et al. Rate ofoccurrence and pathogenic effect of enteroag-gregative Escherichia coli virulence factors in in-ternational travelers. J Clin Microbiol. 2002;40:4185-4190.

31. Huang DB, Okhuysen PC, Jiang ZD, DuPontHL. Enteroaggregative Escherichia coli: anemerging enteric pathogen. Am J Gastroenterol.

Therapeutic agents mentioned in this article

Amoxicillin

Amoxicillin/clavulanic acid

Ampicillin

Azithromycin

Chloramphenicol

Ciprofloxacin

Co-trimoxazole

Nalidixic acid

Rifaximin

Sulfamethoxazole

Tetracycline

Trimethoprim

continued


Send UsYour Slides!

Your contributions are invited:

Clinical photographs,tissue samples,photomicrographs,imaging studies.

Send slides or high-quality prints.Please include a 1- or 2-paragraph descrip-

tion of what is shown, data about the patient(age, sex, clinical status), and anything unusual or unique about the image. Forphotomicrographs, please indicate magnification of original image.

Photographs willbe accepted forpublication on thebasis of subjectmatter, technical quality, and aesthetic quality.Contributors will re-ceive an honorari-um. Unused sub-missions will be returned.

Please send your images to:Images

Infections in Medicine330 Boston Post Road

PO Box 4027Darien, CT 06820-4027

ImagesinInfectiousDisease



2004;99:383-389.32. Bouckenooghe AR, DuPont HL, Jiang ZD, et al. Markers of enteric inflamma-

tion in enteroaggregative Escherichia coli diarrhea in travelers. Am J Trop MedHyg. 2000;62:711-713.

33. Steiner TS, Nataro JP, Poteet-Smith CE, et al. Enteroaggregative Escherichia coliexpresses a novel flagellin that causes IL-8 release from intestinal epithelialcells. J Clin Invest. 2000;105:1769-1777.

34. Sansonetti PJ, Arondel J, Huerre M, et al. Interleukin-8 controls bacterialtransepithelial translocation at the cost of epithelial destruction in experimen-tal shigellosis. Infect Immun. 1999;67:1471-1480.

35. Harrington SM, Strauman MC, Abe CM, Nataro JP. Aggregative adherencefimbriae contribute to the inflammatory response of epithelial cells infectedwith enteroaggregative Escherichia coli. Cell Microbiol. 2005;7:1565-1578.

36. Jiang Z, Okhuysen P, Guo D, et al. Genetic susceptibility to enteroaggregativeEscherichia coli diarrhea: polymorphism in the interleukin-8 promotor region.J Infect Dis. 2003;188:506-511.

37. Mohamed J, Jiang Z, DuPont H, et al. The lactoferrin gene is associated withsusceptibility to inflammatory diarrhea caused by EAEC in North Americanstraveling to Mexico. Presented at: Infectious Diseases Society of America An-nual Meeting; October 12-15, 2006; Toronto. Abstract.

38. Regua-Mangia A, Gomes T, Vieira M, et al. Frequency and characteristics of di-arrhoeagenic Escherichia coli strains isolated from children with and withoutdiarrhoea in Rio de Janeiro, Brazil. J Infect. 2004;48:161-167.

39. Mayer H, Wanke C. Enteroaggregative Escherichia coli as a possible cause of di-arrhea in an HIV-infected patient. N Engl J Med. 1995;332:273-274.

40. Cobeljic M, Milikovic-Selimovic B, Paunovic-Todosijevid D, et al. Enteroag-gregative Escherichia coli associated with an outbreak of diarrhea in neonatalnursery ward. Epidemiol Infect. 1996;117:11-16.

41. Adachi J, Ericsson C, Jiang Z, et al. Natural history of enteroaggregative Esch-erichia coli and emterotoxigenic Escherichia coli infection among US travelers toGuadalajara, Mexico. J Infect Dis. 2002;185:1681-1683.

42. Sarantuya J, Nishi J, Wakimoto N, et al. Typical enteroaggregative Escherichiacoli is the most prevalent pathotype among E. coli strains causing diarrhea inMongolian children. J Clin Microbiol. 2004;42:133-139.

43. Miqdady M, Jiang Z, Nataro J, DuPont H. Detection of enteroaggregative Esch-erichia coli with formalin-preserved HEp-2 cells. J Clin Microbiol. 2002;40:3066-3067.

44. Tsai C, Cehn S, Tsen H. Screening the enteroaggregative Escherichia coli activi-ty and detection of the aggA, aafA, and astA genes with novel PcR primers forthe Escherichia coli isolates from diarrhea cases in Taiwan. Diagn Microbiol In-fect Dis. 2003;46:159-165.

45. Jenkins C, Chart H, Willshaw GA, et al. Genotyping of enteroaggregative Esch-erichia coli and identification of target genes for the detection of both typicaland atypical strains. Diagn Microbiol Infect Dis. 2006;55:13-19.

46. Bouzari S, Jafari A, Zarepour M. Distribution of virulence related genes amongenteroaggregative Escherichia coli isolates: using multiplex PCR and hybrid-ization. Infect Genet Evol. 2005;5:79-83.

47. Bischoff C, Luthy J, Altwegg M, Baggi F. Rapid detection of diarrheagenic E.coli by real-time PCR. J Microbiol Methods. 2005;61:335-341.

48. Glandt M, Adachi JA, Mathewson JJ, et al. Enteroaggregative Escherichia coli asa cause of traveler’s diarrhea: clinical response to ciprofloxacin. Clin Infect Dis.1999;29:335-338.

49. Infante RM, Ericsson CD, Jiang ZD, et al. Enteroaggregative Escherichia coli di-arrhea in travelers: response to rifaximin therapy. Clin Gastroenterol Hepatol.2004;2:135-138.

50. Sobieszczanska B, Kowalska-Krochmal B, Mowszet K, Pytrus T. Susceptibili-ty to antimicrobial agents of enteroaggregative Escherichia coli strains isolatedfrom children with diarrhea [in Polish]. Przegl Epidemiol. 2003;57:499-503.

51. Yamamoto T, Echeverria P, Yokota T. Drug resistance and adherence to humanintestines of enteroaggregative Escherichia coli. J Infect Dis. 1992;165:744-749.

52. Wanke CA, Gerrior J, Blais V, et al. Successful treatment of diarrheal diseaseassociated with enteroaggregative Escherichia coli in adults infected withhuman immunodeficiency virus. J Infect Dis. 1998;178:1369-1372.

53. Cerna JF, Nataro JP, Estrada-Garcia T. Multiplex PCR for detection of threeplasmid-borne genes of enteroaggregative Escherichia coli strains. J Clin Micro-biol. 2003;41:2138-2140.

54. Ruiz-Blazquez J, Vargas M, Nataro JP, et al. Validation of a PCR technique forthe detection of enteroagreggative Escherichia coli causing traveler’s diarrhea.Enferm Infecc Microbiol Clin. 2005;23:479-481.

55. Ruttler ME, Renna NF, Balbi L, et al. Characterization of enteroaggregativeEscherichia coli strains isolated from children with acute diarrhea, in Mendoza,Argentina. Rev Argent Microbiol. 2002;34:167-170.

56. Aranda KR, Fagundes-Neto U, Scaletsky IC. Evaluation of multiplex PCRs fordiagnosis of infection with diarrheagenic Escherichia coli and Shigella spp. J ClinMicrobiol. 2004;42:5849-5853.

57. Scaletsky IC, Fabbricotti SH, Aranda KR, et al. Comparison of DNA hy-bridization and PCR assays for detection of putative pathogenic enteroadher-ent Escherichia coli. J Clin Microbiol. 2002;40:1254-1258.


Documents

Enteroaggregative Escherichia coli: A Review of Trends .... Coli-Infect in Med... · 100 INFECTIONS in MEDICINE March 2007 DIARRHEAL ILLNESS T he 6 recognized pathotypes of diarrheagenic