Jose Flores-Figueroa

MD FACP
JM Research · Clinical Research

Publications

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    ABSTRACT: Background Rifamycin SV is under development for treatment of travelers' diarrhea (TD) in a new oral formulation, Rifamycin SV MMX® (RIF-MMX; Santarus Inc., San Diego, CA, USA), which targets its delivery to the colon, making it a unique rifamycin drug.Methods This was a randomized, double-blind, phase 3 study of adult travelers to Mexico or Guatemala experiencing acute diarrhea. A total of 264 patients received RIF-MMX (2 × 200 mg twice daily for 3 days, n = 199) or placebo (n = 65) in a 3 : 1 ratio. The primary endpoint was the length of time between the administration of first dose of study drug and passage of the last unformed stool (TLUS; after which clinical cure was declared). Other endpoints included eradication of pathogens from the stools, pathogen minimum inhibitory concentration (MIC), and adverse events (AEs).ResultsTLUS was significantly shorter in the RIF-MMX group (median: 46.0 hours) compared with placebo (median: 68.0 hours; p = 0.0008) and a larger percentage of RIF-MMX treated patients (81.4%) achieved clinical cure compared with placebo patients (56.9%). TLUS was significantly shorter in the subgroups of patients with enteroaggregative, enterotoxigenic, or diffusely adherent Escherichia coli infections (p = 0.0035) with nonsignificant activity against invasive bacteria (p = 0.3804). Overall pathogen eradication rates were numerically higher in the RIF-MMX group (67.0%) compared with placebo (54.8%) but the difference did not reach significance (p = 0.0836). In vitro resistance to rifamycin SV was observed in some bacteria remaining after treatment of patients with RIF-MMX but was not associated with lower efficacy in them. AEs appeared to be more frequent with placebo (38.5%) than with RIF-MMX (29.6%).ConclusionsRIF-MMX shortened the duration of TD in patients with a broad range of pathogens and was well tolerated. The unique pharmacokinetic properties of the drug offer evidence that TD pathogens work at the level of the colon.
    Journal of Travel Medicine 11/2014; 21(6). · 1.68 Impact Factor
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    ABSTRACT: Postinfectious irritable bowel syndrome (PI-IBS) has been reported as a complication of bacterial diarrhea including travelers' diarrhea (TD). This study assessed the role of TD among US students in Mexico in triggering the onset of persistent abdominal symptoms (PAS) and IBS. We conducted a 6-month follow-up of a cohort of 817 US students in Mexico as short-term study to assess the frequency of PAS and IBS. Using Rome II criteria for IBS, groups of students with PAS were then categorized as PI-IBS if they met the symptom criteria for IBS or as suffering from functional abdominal disorder (FAD) if they did not meet the criteria. FAD and IBS were commonly found in US students 6 months after leaving Mexico. Important variables in their development were younger adult age, longer stays in Mexico and occurrence of acute diarrhea while in Mexico. Diarrhea while in Mexico occurred more commonly for those later diagnosed with FAD, 101/196 (52%), relative risk (RR) = 1.5 [confidence interval (CI) 1.2-1.8; p = 0.001]; IBS, 20/32 (63%), RR = 2.5 (CI 1.2-5.0; p = 0.007); and PAS (FAD + IBS), 121/228 (53%), RR = 1.5 (CI 1.2-1.8; p < 0.001) compared with subjects who had experienced diarrhea while in Mexico but were not diagnosed with PAS at 6 months, 227/589 (39%). Diarrhea caused by heat-labile enterotoxin-producing enterotoxigenic Escherichia coli or Providencia ssp. demonstrated a greater risk of developing PAS. PAS occurred commonly in a subset of younger adult travelers who stayed longer in Mexico and experienced acute diarrhea while there. Further studies with this cohort will focus on host genetic associations with the development of PAS.
    Journal of Travel Medicine 03/2014; · 1.68 Impact Factor
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    ABSTRACT: Background: Travelers’ diarrhea (TD) is the most common gastrointestinal illness contracted by persons visiting developing countries. In a study conducted in Guatemala and Mexico, rifamycin SV MMX®(RIF-MMX), a novel broad-spectrum, negligibly-absorbed antibiotic coupled with technology to target drug delivery to the colon, was assessed as oral treatment for TD. Methods: A total of 264 adult tourists, presenting within 72 h of TD onset, were randomized (3:1) to receive 3-day treatment with RIF-MMX 400 mg twice daily (N=199) or placebo (PBO; N=65). Patients documented symptoms through Day 5. Stool samples for microbiologic evaluation were collected at baseline and post-treatment. Results: In the intent-to-treat population (mean [SD] age 28 [12] years; 50% male; 88% Caucasian), median (95% CI) time from starting drug to last unformed stool before recovery (TLUS; primary endpoint) in the RIF-MMX group was 46.0 (42.8, 50.5) h vs. 68.0 (48.7, not calculable) h in the PBO group (p=0.0008). Fewer patients in the RIF‑MMX group (37; 19%) failed to achieve clinical cure or required rescue medication vs. the PBO group (28; 43%; p<0.001). During the 48-72 h post-treatment time interval, 78 (40%) patients treated with RIF-MMX reported complete resolution of signs and symptoms of TD compared with 12 (19%) patients treated with PBO. The pathogen mix at 4 sites that enrolled 90% (237/264) of patients was similar (positive-detection rate 72%), with diarrheagenic E. coli (141 [60%] patients) being the most common non-invasive pathogen at baseline. For these sites, E.coli eradication was observed post-treatment in 53 (50%) patients in the RIF-MMX group vs. 16 (44%) patients in the PBO group. No statistically significant difference was observed in eradication rates between groups (p=0.532). Treatment-emergent adverse events were more frequent with PBO (38.5%) than with RIF‑MMX (29.6%), consistent with reduced risk of systemic side effects with colonic delivery of a negligibly-absorbed antibiotic. Conclusion: The results of this study indicated that RIF-MMX provided effective treatment for TD caused by non‑invasive pathogens, with a positive safety profile.
    IDWeek 2013 Meeting of the Infectious Diseases Society of America; 10/2013
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    ABSTRACT: Mexico and Central America are important travel destinations for North American and European travelers. There is limited information on regional differences in travel related morbidity. We describe the morbidity among 4779 ill travelers returned from Mexico and Central America who were evaluated at GeoSentinel network clinics during December 1996 to February 2010. The most frequent presenting syndromes included acute and chronic diarrhea, dermatologic diseases, febrile systemic illness, and respiratory disease. A higher proportion of ill travelers from the United States had acute diarrhea, compared with their Canadian and European counterparts (odds ratio, 1.9; P < .0001). During the 2009 H1N1 influenza outbreak from March 2009 through February 2010, the proportionate morbidity (PM) associated with respiratory illnesses in ill travelers increased among those returned from Mexico, compared with prior years (196.0 cases per 1000 ill returned travelers vs 53.7 cases per 1000 ill returned travelers; P < .0001); the PM remained constant in the rest of Central America (57.3 cases per 1000 ill returned travelers). We identified 50 travelers returned from Mexico and Central America who developed influenza, including infection due to 2009 H1N1 strains and influenza-like illness. The overall risk of malaria was low; only 4 cases of malaria were acquired in Mexico (PM, 2.2 cases per 1000 ill returned travelers) in 13 years, compared with 18 from Honduras (PM, 79.6 cases per 1000 ill returned travelers) and 14 from Guatemala (PM, 34.4 cases per 1000 ill returned travelers) during the same period. Plasmodium vivax malaria was the most frequent malaria diagnosis. Travel medicine practitioners advising and treating travelers visiting these regions should dedicate special attention to vaccine-preventable illnesses and should consider the uncommon occurrence of acute hepatitis A, leptospirosis, neurocysticercosis, acute Chagas disease, onchocerciasis, mucocutaneous leishmaniasis, neurocysticercosis, HIV, malaria, and brucellosis.
    Clinical Infectious Diseases 09/2011; 53(6):523-31. · 9.37 Impact Factor
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    ABSTRACT: Rifaximin has been shown to be effective in treating and preventing travelers' diarrhea (TD) during the summer season. The goal of this double-blinded multicenter trial was to assess the efficacy and safety of rifaximin 550 mg administered once daily for 14 days compared with placebo in the prevention of TD during the dry season in Mexico. There were 101 participants randomized. Overall, 25 participants developed TD during the 3 weeks of the study: 22% from the rifaximin group and 29% from the placebo group (p = 0.4). Mild diarrhea (defined as only one or two unformed stools during a 24-h period plus at least one abdominal symptoms) developed in only 3 (6%) participants taking rifaximin compared with 10 (21%) taking placebo during the first week of study (p = 0.03). No clinically significant or serious adverse events were reported. Antibiotic prophylaxis of TD in Mexico during the dry season needs to be further studied and its benefits weighed against the benefits of self-treatment.
    Journal of Travel Medicine 09/2011; 18(5):333-6. · 1.68 Impact Factor
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    ABSTRACT: Diarrhea is the most common complaint reported by travelers from industrialized countries visiting developing nations. High-risk areas for travelers' diarrhea (TD) include South Asia, Sub-Saharan Africa, and Latin America, while moderate-risk areas include Southeast Asia, Middle East, Oceania and the Caribbean. Bacterial pathogens are the major cause of TD. Recent advances in the therapy for diarrhea include a better understanding of the potential benefit of symptomatic and antimicrobial therapy. The mainstay of treatment includes antibacterial therapy with one of three drugs, a fluoroquinolone, rifaximin, or azithromycin. Probiotics have been used in preliminary studies for both treatment and prevention of TD, but more studies are needed with these biologic agents. The aim of this review is to identify the recent advances in the therapy of TD and to provide recommendations for treatment during international travel.
    Current Gastroenterology Reports 07/2011; 13(5):402-7.
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    ABSTRACT: Under normal conditions, the expression of CD14, which is the principal receptor for bacterial lipopolysaccharide, is down-regulated in the intestinal mucosa but increases in response to inflammatory stimuli. The aim of the present study was to investigate whether fecal CD14 levels increased in response to infection with diarrheagenic Escherichia coli and whether single nucleotide polymorphisms (SNPs) in the CD14 gene were associated with an increased susceptibility to traveler's diarrhea (TD) in US visitors to Mexico. Six SNPs located at the promoter, exon, and untranslated regions of CD14 were typed in a prospective cohort study of 1360 visitors to Mexico at risk for TD. Stools from visitors with TD were studied for enteric pathogens by culture, colony hybridization, and polymerase chain reaction. Fecal soluble CD14 (sCD14) was measured in a subgroup of 203 adults with diarrhea and 66 healthy controls by enzyme-linked immunosorbent assay. The minor allele frequencies for CD14 SNPs were significantly different among the various racial and ethnic groups studied. Two SNPs in the promoter region of CD14 (-159 C > T; rs2569190 and -4191 C > T; rs5744441) were found to be associated with TD in White visitors. The -159 TT genotype was associated with a higher risk for TD (Relative risk [RR], 1.21; 95% confidence interval [CI], 1.05-1.38; P = .008), whereas individuals with the -4191 TT genotype were protected from infection (RR, 0.82; 95% CI, 0.71-0.92; P = .006). Subjects with TD excreted higher levels of fecal CD14 than did healthy controls (33,480 pg/mL vs 6178 pg/mL; P < .02). Fecal sCD14 levels were higher in stool samples from visitors with TD and the -159 TT genotype than they were in visitors with the CC/CT genotypes (P = .02), and stool samples from subjects with the -4191 CC genotype had higher fecal sCD14 levels than did stool samples from visitors with the CT/TT (P = .005) genotype. In a multivariate analysis with haplotypes constructed with the 6 SNPs studied, subjects with the haplotype containing the -159 C and the -4191 T allele were less likely to acquire TD (P = .015). Our study suggests that CD14 levels increase in response to bacterial diarrhea and that polymorphisms in the CD14 gene influence susceptibility to TD. Intestinal CD14 plays an important role in the innate immune response to enteric pathogens.
    Clinical Infectious Diseases 06/2011; 52(11):1332-41. · 9.37 Impact Factor
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    ABSTRACT: Up to 60% of the US visitors to Mexico develop travelers' diarrhea (TD). In Mexico, rates of diarrhea have been associated with the rainy season and increase in ambient temperature. However, the seasonality of the various diarrheagenic Escherichia coli pathotypes in travelers has not been well described. A study was undertaken to determine if ambient temperature and rainfall have an impact on the acquisition of TD due to different diarrheagenic E coli pathotypes in Mexico. We conducted a cohort study of the US adult students traveling to Cuernavaca, Mexico, who were followed during their stay and provided a stool sample with the onset of TD. The presence of E coli was analyzed by a direct fecal multiplex polymerase chain reaction for common E coli pathotypes including enterotoxigenic, enteropathogenic, enteroinvasive, shiga toxin-producing, and enteroaggregative E coli (ETEC, EPEC, EIEC, STEC, and EAEC respectively). The presence of pathotypes was correlated with daily rainfall, average, maximum, and minimum temperatures. A total of 515 adults were enrolled from January 2006 to February 2007. The weekly attack rate of TD for newly arrived travelers was lower in the winter months (range 6.8%-16.3%) than in summer months (range 11.5%-25%; p = 0.05). The rate of ETEC infection increased by 7% for each degree centigrade increase in weekly ambient temperature (p = 0.003). In contrast, EPEC and EAEC were identified in similar proportions during the winter and summer seasons. Temperature variations in central Mexico influenced the rate of ETEC but not EAEC-associated diarrhea in the US visitors. This epidemiological finding could influence seasonal recommendations for the use of ETEC vaccines in Mexico.
    Journal of Travel Medicine 03/2011; 18(2):121-5. · 1.68 Impact Factor
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    ABSTRACT: Campylobacter jejuni is an unusual cause of travelers' diarrhea acquired in Mexico, but previous studies have relied only on stool culture for diagnosis. We conducted a cohort study to determine if antibody seroconversion to C jejuni would better reflect the occurrence of infection acquired in Mexico. Serum IgG, IgA, and IgM antibodies to Campylobacter seroconverted in only 2 of 353 participants (0.6%). These data further support that C jejuni infection is an unusual cause of travelers' diarrhea in US visitors to Mexico.
    Journal of Travel Medicine 01/2011; 18(1):56-8. · 1.68 Impact Factor
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    ABSTRACT: Traveler's diarrhea is the most common medical complaint of international visitors to developing regions. Previous findings suggested that noroviruses (NoVs) are an underappreciated cause of traveler's diarrhea. METHODS. In the present study, we sought to define the presence of NoVs in 320 acute diarrheic stool samples collected from 299 US students who traveled to Guadalajara, Cuernavaca, or Puerto Vallarta, Mexico, during the period from 2007 through 2008. Conventional and quantitative real-time polymerase chain reaction assays were used to detect and determine NoV loads in stool samples. NoV strains were characterized by purification of viral RNA followed by sequencing of the viral capsid protein 1 gene. Sequences were compared using multiple sequence alignment, and phylogenetic trees were generated to evaluate the evolutionary relatedness of the viral strains associated with cases of traveler's diarrhea. NoV RNA was detected in 30 (9.4%) of 320 samples. Twelve strains belonged to genogroup I, and 18 strains belonged to genogroup II. NoV prevalence was higher in the winter season than in the summer season (23% vs 7%, respectively; P = .001). The cDNA viral loads of genogroup I viruses were found to be 500-fold higher than those of genogroup II strains. Phylogenetic analysis revealed a diverse population of NoV strains over different locations and years. NoV strains are important causes of traveler's diarrhea in Mexico, especially during the wintertime, and US students in Mexico may represent a suitable group for future NoV vaccine efficacy trials.
    Clinical Infectious Diseases 07/2010; 51(2):123-30. · 9.37 Impact Factor
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    ABSTRACT: Molecular characterization of Escherichia coli with use of the random amplified polymorphic DNA (RAPD) assay allows the determination of clonal origin and geographic clustering. Presumed enterotoxigenic Escherichia coli (ETEC) from 213 adults with travelers' diarrhea acquired in Mexico during the summer months of 2004-2007 were studied. Biochemical testing strips determined a 7-digit fingerprint on the basis of 21 biochemical reactions. E. coli producing enterotoxin were evaluated for clonality by RAPD assay. Dendrograms were developed using Pearson correlations with 80% similarity to determine clonal groups. Of the presumed ETEC, 85% were confirmed to be E. coli on the basis of biochemical analysis. Other enterotoxigenic bacteria included Citrobacter species (9%) and other coliforms (all 2%). RAPD analysis with primers 1247 and 1254 determined 24 ETEC clonal groups containing 2-9 subjects each, of which 15 spanned the 4 years and 8 spanned both cities. Complete biochemical evaluation of E. coli-like, enterotoxigenic organisms is crucial in ETEC identification. In addition, other enterotoxigenic organisms identified should be studied further for their role in enteric disease. Travelers to Mexico are exposed to a large pool of different ETEC strains from multiple sources, with a small number of dominant types showing a widespread and persistent reservoir of infection.
    The Journal of Infectious Diseases 06/2010; 201(12):1831-8. · 5.85 Impact Factor
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    ABSTRACT: Enterotoxigenic Escherichia coli (ETEC), which produces heat-labile toxin (LT), is a common cause of travelers' diarrhea (TD). The B subunit of ETEC LT is immunologically related to the B subunit of Vibrio cholerae toxin (CT). In this pilot study we evaluated the whole-blood gamma interferon response to CT B in 17 U.S. adults traveling to Mexico. Only one of nine subjects who demonstrated a cellular immune response as determined by whole-blood gamma interferon production to CT B on arrival to Mexico developed diarrhea, whereas five of eight without a cellular response developed diarrhea. Markers of the cellular immune response to ETEC LT could help in identifying individuals immune to ETEC LT, and these markers deserve additional study.
    Clinical and vaccine Immunology: CVI 03/2010; 17(5):879-81. · 2.60 Impact Factor
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    ABSTRACT: Background: Enteroaggregative Escherichia coli (EAEC) are a common bacterial pathogen isolated in patients suffering from infectious diarrhea in developed and developing countries. Dispersin, a 10.2 kDa protein encoded by aap, is a well defined putative virulence factor and has previously only been described in EAEC. We have observed that up to 25% of diarrheagenic non-EAEC strains harbor the app gene and that some individuals suffering from diarrhea due to non-EAEC strains may develop anti-dispersin antibodies during convalescence. Objective: To demonstrate the presence and expression of dispersin in non-EAEC strains. Methods: Previously characterized non-EAEC strains collected from adult travelers suffering from diarrhea in a larger epidemiological cohort study in Mexico were studied. Twelve non-EAEC strains harboring the aap, but not aggR or aatA, genes were tested for bioflm formation, IL-8 induction, and expression of dispersin by reverse transcriptase polymerase chain reaction (RT-PCR). Results: One non-EAEC (7248-C) strain harboring the aap and Stx1 genes expressed dispersin by RT-PCR when cultured in arabinose enriched media. None of the other eleven strains expressed dispersin by RT-PCR. Nine of the twelve tested strains, including 7248-C, elicited an increased IL-8 response of co-cultured intestinal HCT-8 cells. None of the twelve tested strains produced biofilm by the microtiter plate assay with the crystal violet staining method. Conclusions: We provide evidence that a putative EAEC virulence factor can be produced by E. coli isolated from patients with diarrhea that otherwise would not be classified as diarrheagenic E. coli. It is unknown if the expression of dispersin confers disease causing virulence to non-EAEC strains or if the transcription of aap occurs when other neighboring plasmid genes are expressed.
    Infectious Diseases Society of America 2009 Annual Meeting; 10/2009
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    ABSTRACT: Background: Travelers’ diarrhea (TD) is the most common illness in adults from developed countries visiting developing nations. The majority of infections are due to enterotoxigenic E. coli (ETEC) and enteroaggregative E. coli (EAEC). Objective: To investigate the incidence of the different diarrheagenic pathotypes of E. coli among travelers in Mexico developing diarrhea. Methods: We conducted a prospective cohort study in US students traveling to Cuernavaca, Mexico during 2004 to 2007. The participants were followed for the development of acute diarrhea and a stool specimen was collected for microbiological analysis. Five individual E. coli-like colonies from each clinical specimen were characterized for adherence by the HEp2 assay and for the presence of Enteroinvasive E. coli (EIEC) ipaH,ETEC(lt, st), EPEC (eaeA, bfpA), STEC (stx1, stx2), and EAEC (aap, aatA, and aggR) by colony and direct stool multiplexed PCR. Results: We studied 953 subjects (74.3% female, mean age = 34 yr.) traveling for mean of three weeks 72.7% (693) visited Mexico during the summer months. Three hundred and eighty seven (40.7%) travelers developed diarrhea while in Mexico and 284 (73.4%) provided a stool specimen for microbiological examination. Fecal or colony PCR identified EAEC in 93 (35.2%) subjects, ETEC in 77 (29.2%), EPEC in 65 (24.6%) 4/65 strains were defined as typical EPEC (eae+,bfp+) and 61/65 were atypical (eae+,bfp-, EIEC was found in 15 (5.7%) and 33 (12.5%) subjects had STEC. Conclusions: Clinically, diarrhea due to EPEC, EIEC and STEC was indistinguishable from diarrhea due to ETEC and EAEC. EPEC and STEC warrant additional study as causal agents of TD in US adult travelers to Mexico.
    Infectious Diseases Society of America 2009 Annual Meeting; 10/2009
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    Jose Flores, Pablo C Okhuysen
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    ABSTRACT: This review examines recent developments in human genetic susceptibility to enteropathogens that cause infectious diarrhea. The affinity of specific norovirus genogroups to different histoblood group antigens (HBGAs) on secretor cells has been studied in different epidemiologic studies. HBGAs are also used as receptors by Vibrio cholerae with different degrees of affinity between biotypes. Polymorphisms in the CD14, lactoferrin and osteoprotegerin promoter genes were associated to diarrhea in travelers. Single nucleotide polymorphisms in the IL-8 genes are also associated to increased risk for enteroaggregative Escherichia coli and Clostridium difficile infection. IL-10 haplotypes were associated to enterotoxigenic E. coli associated diarrhea in exposed individuals. A family-based study showed a significant association of the LPLUNC1 gene and cholera. The major histocompatibility complex class II antigens are associated to different degrees of susceptibility and resistance to Salmonella, Cryptosporidium and Entamoeba infection. Variants in genes that encode molecules that mediate attachment, pathogen recognition, inflammatory cytokine response, innate and acquired immunity are being identified as determinants of host genetic susceptibility to infectious diarrhea.
    Current Opinion in Infectious Diseases 08/2009; 22(5):471-6. · 5.03 Impact Factor
  • Jose Flores, Pablo C Okhuysen
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    ABSTRACT: To review studies that improve the current knowledge on the epidemiology, virulence factors, detection, and chronic complications of enteroaggregative Escherichia coli (EAEC) infection. EAEC infection is an important cause of diarrhea in outbreak and non-outbreak settings in developing and developed countries. In the USA, EAEC is one of the most common bacterial pathogens identified in cases of diarrhea not associated with immunodeficiency or foreign travel. Important advances have been made in the understanding of the pathogenesis of this enteropathogen. The extracellular matrix proteins fibronectin, laminin, and collagen IV have been shown to function as receptors for adherence frimbriae. A distinct aggregative adherence pilin hdaA has been identrified. The diagnosis of EAEC depends on the observation of the characteristic 'stacked-brick' like adhesion pattern when co-cultured with HEp-2 cells. At the molecular level, strains demonstrating the aggregative phenotype are heterogeneous; however, several virulence factors can be detected by polymerase chain reaction. Several EAEC proteins have shown antigenicity and could become vaccine candidates. Recently, infection with EAEC has been implicated in the development of irritable bowel syndrome, but this remains to be confirmed. There has been significant progress in understanding the pathogenesis and clinical profile of EAEC infection.
    Current opinion in gastroenterology 02/2009; 25(1):8-11. · 4.33 Impact Factor
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    ABSTRACT: Osteoprotegerin (OPG), an immunoregulatory member of the TNF receptor superfamily, is expressed in inflamed intestinal mucosa. We investigated whether OPG is produced by intestinal epithelial cells and tested the hypothesis that single-nucleotide polymorphisms (SNPs) in the gene encoding OPG (TNFRSF11B) are associated with traveler's diarrhea (TD) among North American travelers to Mexico. OPG concentration was measured in the supernatants of T84 cells infected with various diarrheagenic Escherichia coli pathotypes. Genotyping was performed for 4 SNPs in the OPG gene for 968 North American travelers with or without TD. Stool samples from travelers with TD were evaluated for the presence of enteric pathogens. T84 cells produced higher OPG levels in response to infection with various diarrheagenic E. coli pathotypes than with E. coli controls (P<.05). A SNP in the exon 1 region of the OPG gene (OPG+1181G>C) was associated with TD in white travelers who stayed in Mexico for >1 week during the summer (P=.009) and for TD due to nonsecretory pathogens (P=.001). Our study suggests that OPG is secreted by intestinal epithelial cells in response to enteropathogens and that a polymorphism in the OPG gene is associated with an increased susceptibility to TD.
    The Journal of Infectious Diseases 01/2009; 199(4):477-85. · 5.85 Impact Factor
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    ABSTRACT: Background: The human intestinal mucosa has the ability to tolerate commensal organisms and respond to enteric pathogens when needed. We hypothesized that the balance between colonization and symptomatic infection with enteropathogens partially depends on host genetic factors and that single nucleotide polymorphisms (SNPs) in genes coding for these molecules would correlate with susceptibility to travelers’ diarrhea (TD). Methods: We studied the impact of 28 SNPs in 17 genes, potentially involved in susceptibility, injury and control of enteropathogens, in 1,915 US travelers to Mexico at risk for TD. Analysis was limited to SNPs in Harding-Weinberg equilibrium, with minor allele frequencies of >5%, and with ≥300 participants with genotypes available for analysis. Results: SNPs in 6 genes showed an association with susceptibility to TD due to all causes. SNPs in four genes were involved in LPS response and signaling (CD14, TLR4, Lactoferrin, CARD 15), one in inflammatory response (IL-6) and one in anti-inflammatory response (osteoprotegerin). In contrast, genes not associated with TD due to all causes included SNPs in collectins (MBL, Surfactant D), pathogen receptors (CD55, CFTR, FUT-2, Guanylate Cyclase, and TLR5), pro-inflammatory cytokines (TNFα, IL-1, IL-6 and IL-8) and anti-inflammatory cytokines (IL-10). Conclusions: These data suggest that SNPs in host molecules involved in LPS response and signaling are important determinants of susceptibility to TD. The innate immune response to LPS may be a stereotypical reaction to infection with various Gram negative enteropathogens. The study of SNP associations with specific agents of diarrhea is ongoing.
    Infectious Diseases Society of America 2008 Annual Meeting; 10/2008
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    ABSTRACT: Background: Travelers’ diarrhea (TD) affects 40-60% of US adult visitors to Mexico and is due to enterotoxigenic E. coli (ETEC), enteroaggregative E. coli (EAEC) and other bacterial, viral and protozoan enteropathogens. Shiga toxin-producing E. coli (STEC) has been previously identified in a small percentage of cases. We sought to determine the incidence and clinical features of STEC-associated TD in US travelers to Mexico. Methods: US students (n=327) in Mexico with TD from 2004-2008 were examined for enteropathogens, fecal leukocytes and occult blood. E. coli colonies were tested by PCR for STEC (stx1 and stx2), EAEC, ETEC, enteroinvasive E. coli, and enteropathogenic E. coli genes. Stools (n=88) were studied for the presence of Shiga toxin by ELISA. Fecal excretion patterns of 21 cytokines in cases with STEC were compared to pathogen-negative cases. Results: Of 327 fecal samples, 51 (16%) were positive by PCR for stx1 or stx2 genes. Shigella spp. was found in only one specimen. Eight (11%) of 75 specimens tested by ELISA showed the presence of Shiga toxin. Of the 75 ELISA-tested specimens, Shiga toxin was found in 6 of 42 specimens that were PCR-positive for stx1 or stx2. Only 1 of the STEC PCR-positive and none of the STEC ELISA-positive fecal specimens contained WBCs, blood, or mucus. In subjects with STEC identified in stools, fecal cytokine levels did not differ from those measured in stools in which a pathogen was not identified. Conclusions: STEC is more commonly associated with travelers’ diarrhea than historically believed with the majority of cases showing non-inflammatory diarrhea. The clinical features and epidemiology of STEC infection acquired during travel differs from the STEC cases reported domestically.
    Infectious Diseases Society of America 2008 Annual Meeting; 10/2008
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    ABSTRACT: Background: Up to 60% of US visitors to Mexico develop travelers’ diarrhea (TD) which is mostly due to enterotoxigenic Escherichia coli (ETEC). Since ETEC LT and cholera toxin B (CT-B) are structurally very similar, antibody production and whole blood gamma interferon response (WBGIR) to ETEC-LT can be measured using CTB. WBGIR has been widely used to determine T-cell immune response to different infectious agents. Objectives: We conducted a pilot prospective study in 16 US adults traveling to México during the summer months of 2007 to determine if ETEC-LT WBGIR was present on arrival and and correlated with resistance to TD. Methods: US travelers to Mexico provided blood at arrival and prior to leaving Mexico, and were followed for the presence of diarrhea during their stay with daily clinic visits and 24h medical care. Results: 16 Caucasian adults with a mean age of 30 years were followed during three weeks of stay in Mexico, 12 were female, and 5 (31.25%) developed TD. There was no difference in age, length of stay, or race for the development of diarrhea. Nine individuals (56%) had a WBGIR to ETEC-LT on arrival to Mexico. Only one of 9 subjects (11%) with WBGIR developed TD while in Mexico. In contrast, 4 of the 7 (57%) subjects without a WBGIR at baseline developed diarrhea. One individual without a WBGIR converted at departure. Conclusions: A WBIGR can be measured in response to CT-B in US visitors to Mexico suggesting a role for LT in T cell immune response to ETEC. Additional studies are needed to determine if WBIGR correlates with protection from ETEC-LT infection or vaccination.
    Infectious Diseases Society of America 2008 Annual Meeting; 10/2008

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