Use of a patch containing heat-labile toxin from Escherichia coli against travellers' diarrhoea: a phase II, randomised, double-blind, placebo-controlled field trial.

BACKGROUND: Enterotoxigenic Escherichia coli (ETEC) is a major cause of travellers' diarrhoea. We investigated the rate of diarrhoea attacks, safety, and feasibility of a vaccine containing heat-labile enterotoxin (LT) from ETEC delivered to the skin by patch in travellers to Mexico and Guatemala. METHODS: In this phase II study, healthy adults (aged 18-64 years) who planned to travel to Mexico or Guatemala and had access to a US regional vaccination centre were eligible. A centralised randomisation code was used for allocation, which was masked to participants and site staff. Primary endpoints were to investigate the field rate of ETEC diarrhoea, and to assess the safety of heat-labile toxins from E coli (LT) delivered via patch. Secondary endpoints included vaccine efficacy against travellers' diarrhoea and ETEC. Participants were vaccinated before travel, with two patches given 2-3 weeks apart. Patches contained either 37.5 mug of LT or placebo. Participants tracked stool output on diary cards in country and provided samples for pathogen identification if diarrhoea occurred. Diarrhoea was graded by the number of loose stools in 24 h: mild (three), moderate (four or five), and severe (at least six). Analysis was per protocol. The trial is registered with ClinicalTrials.gov, number NCT00516659. FINDINGS: Recruitment closed after 201 participants were assigned patches. 178 individuals received two vaccinations and travelled and 170 were analysed. 24 (22%) of 111 placebo recipients had diarrhoea, of whom 11 (10%) had ETEC diarrhoea. The vaccine was safe and immunogenic. The 59 LT-patch recipients were protected against moderate-to-severe diarrhoea (protective efficacy [PE] 75%, p=0.0070) and severe diarrhoea (PE 84%, p=0.0332). LT-patch recipients who became ill had shorter episodes of diarrhoea (0.5 days vs 2.1 days, p=0.0006) with fewer loose stools (3.7 vs 10.5, p<0.0001) than placebo. INTERPRETATION: Travellers' diarrhoea is a common ailment, with ETEC diarrhoea illness occurring in 10% of cases. The vaccine patch is safe and feasible, with benefits to the rate and severity of travellers' diarrhoea.

PCR-based assay using occult blood detection cards for detection of diarrheagenic Escherichia coli in specimens from U.S. travelers to Mexico with acute diarrhea.

Large field studies of travelers' diarrhea for multiple destinations are limited by the need to perform stool cultures on site in a timely manner. A method for the collection, transport, and storage of fecal specimens that does not require immediate processing and refrigeration and that is stable for months would be advantageous. This study was designed to determine if enterotoxigenic Escherichia coli (ETEC) and enteroaggregative E. coli (EAEC) DNA could be identified from cards that were processed for the evaluation of fecal occult blood. U.S. students traveling to Mexico during 2005 to 2007 were monitored for the occurrence of diarrheal illness. When ill, students provided a stool specimen for culture and occult blood by the standard methods. Cards then were stored at room temperature prior to DNA extraction. Fecal PCR was performed to identify ETEC and EAEC in DNA extracted from stools and from occult blood cards. Significantly more EAEC cases were identified by PCR that was performed on DNA that was extracted from cards (49%) or from frozen feces (40%) than from culture methods that used HEp-2 adherence assays (13%) (P < 0.001). Similarly, more ETEC cases were detected from card DNA (38%) than from fecal DNA (30%) or by culture that was followed by hybridization (10%) (P < 0.001). The sensitivity and specificity of the card test were 75 and 62%, respectively, compared to those for EAEC by culture and were 50 and 63%, respectively, compared to those for ETEC. DNA extracted from fecal cards that was used for the detection of occult blood is of use in identifying diarrheagenic E. coli.

[Multivariate model to predict Streptococcus pyogenes tonsillitis]. / Modelo multivariado para predecir amigdaltis estreptócócica.

OBJECTIVE: to develop a multivariate model to predict the Streptococcus pyogenes isolation in patients with acute tonsillitis. METHODS: cross-sectional analytic study on patients with acute tonsillitis without a recent history of antimicrobial consumption. We evaluated 14 signs and 18 symptoms. A pharyngeal culture was realized on 5% sheep blood agar. Group A streptococci was identified by standard methods. STATISTICAL ANALYSIS: sensitivity, specificity, predictive values, chi2, Fisher's exact test, crude and adjusted odds ratio (OR) with 95% CI using dichotomical logistic regression with direct method and Hosmer and Lemeshow-goodness-fit test. RESULTS: there were 213 participants, 37% were males; a mean age of 14.9 years. We isolated Streptococcus pyogenes in 15%, and 84 % of them had received antimicrobials. We identified signs and symptoms associated with Streptococcus pyogenes isolation: painful swallowing (OR=4.45, 95% CI = 1.13-17.53); tonsils with exudates (OR=3.20, 95% CI = 1.22-8.43); smelly breath (OR=2.78, 95% CI = 1.09-7.10); painful neck nodes (OR=2.70, 95% CI = 1.05-6.96). The presence of nasal symptoms was a protective factor (OR=0.25, 95% CI = 0.09-0.71). CONCLUSIONS: the prevalence of Streptococcus pyogenes tonsillitis was similar to other reports. We found signs and symptoms associated to Streptococcus pyogenes isolation that allowed us to elaborate a decision algorithm.

A novel single-nucleotide polymorphism in the lactoferrin gene is associated with susceptibility to diarrhea in North American travelers to Mexico.

BACKGROUND: Diarrhea affects 40%-60% of travelers from industrialized nations who visit developing countries and is due to bacterial, viral, and parasitic agents. Lactoferrin is bactericidal to enteric pathogens, modulates the intestinal immune response, and is excreted in stool in response to infection with intestinal organisms. We investigated the impact that selected single-nucleotide polymorphisms (SNPs) in the human lactoferrin gene have on susceptibility to traveler's diarrhea. METHODS: Adults who had recently arrived in Mexico were studied prospectively for the occurrence and causal agent(s) of traveler's diarrhea, and genotyping was performed for 9 distinct lactoferrin SNPs. RESULTS: Of the 9 SNPs studied, only 1 SNP (located in exon 15) was associated with traveler's diarrhea (P=.004). When compared with healthy travelers, and after adjustment for known risk factors for traveler's diarrhea (such as age and duration and season of travel), subjects with the T/T genotype in amino acid position 632 were more likely to develop traveler's diarrhea (67% vs. 33%; relative risk [RR], 1.4; 95% CI, 1.2-1.7; P<.001), to have diarrhea with a pathogen identified (RR, 1.3; 95% CI, 1.1-1.6; P=.03), and to have a marker of intestinal inflammation in stool specimens (blood, mucus, or white blood cells; 52% vs. 38%; P=.036). The association was also significant when norovirus was not identified in stool samples (RR, 1.34; 95% CI, 1.06-1.34; P=.01). CONCLUSIONS: The T/T genotype in position codon 632 of the lactoferrin gene is associated with susceptibility to diarrhea in North Americans traveling to Mexico.

Treatment of travelers' diarrhea: randomized trial comparing rifaximin, rifaximin plus loperamide, and loperamide alone.

BACKGROUND & AIMS: Antimotility agents provide rapid temporary relief of acute diarrhea, whereas antibiotics slowly cure the illness. Thus, the combination of an antimotility agent and an antibiotic may provide greater therapeutic benefit than either drug alone. This study evaluated the efficacy and safety of rifaximin-loperamide in the treatment of travelers' diarrhea. METHODS: Consenting adults with acute diarrhea (> or =3 unformed stools in 24 hours with > or =1 symptom of enteric infection) were randomized to receive rifaximin 200 mg 3 times daily for 3 days; loperamide 4 mg initially followed by 2 mg after each unformed stool; or a combination of both drugs using the same dosing regimen. The primary end point was the median time from beginning therapy until passing the last unformed stool. RESULTS: A total of 310 patients completed treatment with rifaximin (n = 102), loperamide (n = 104), or rifaximin-loperamide combination therapy (n = 104). The groups showed demographic similarity. Rifaximin and rifaximin-loperamide significantly reduced the median time until passage of the last unformed stool (32.5 +/- 4.14 h and 27.3 +/- 4.13 h, respectively) vs loperamide (69 +/- 4.11 h; P = .0019). The mean number of unformed stools passed during illness was lower with rifaximin-loperamide (3.99 +/- 4.28) compared with rifaximin (6.23 +/- 6.90; P = .004) or loperamide alone (6.72 +/- 6.93; P = .002). All treatments were well tolerated with a low incidence of adverse events. CONCLUSIONS: Rifaximin-loperamide therapy provided rapid symptomatic improvement and greater overall wellness compared with either agent alone.

A randomized, double-blind, placebo-controlled trial of rifaximin to prevent travelers' diarrhea.

BACKGROUND: Travelers' diarrhea causes substantial morbidity and postinfectious irritable bowel syndrome. OBJECTIVE: To evaluate nonabsorbable rifaximin for prevention of travelers' diarrhea. DESIGN: Randomized, double-blind, placebo-controlled clinical trial. SETTING: Guadalajara, Mexico. PARTICIPANTS: U.S. students. INTERVENTION: On arrival in Guadalajara, Mexico, 210 U.S. adults received rifaximin (200 mg/d, 200 mg twice daily, or 200 mg 3 times daily) or placebo for 2 weeks. MEASUREMENTS: Participants were followed daily for 3 weeks for enteric disease and symptoms and daily for 5 weeks for drug side effects. Changes in intestinal coliform flora were studied. RESULTS: Travelers' diarrhea developed in 14.74% of participants taking rifaximin and 53.70% of those taking placebo (rate ratio, 0.27 [95% CI, 0.17 to 0.43]). Rifaximin provided 72% and 77% protection against travelers' diarrhea and antibiotic-treated travelers' diarrhea, respectively (P < 0.001 for both), and all rifaximin doses were superior to placebo. In the groups that did not report travelers' diarrhea, rifaximin significantly reduced the occurrence of mild diarrhea (P = 0.02) and moderate and severe intestinal problems (P = 0.009 for pain or cramps; P = 0.02 for excessive gas). Rates of adverse events were comparable in the rifaximin and placebo groups. Minimal changes in coliform flora were found during rifaximin therapy. LIMITATIONS: Rifaximin safely prevented travelers' diarrhea in Mexico, where most cases are caused by diarrhea-producing Escherichia coli. A study is needed in Asia to determine whether rifaximin can prevent diarrhea caused by invasive bacterial pathogens. CONCLUSIONS: Rifaximin prevents travelers' diarrhea with minimal changes in fecal flora, and more liberal chemoprophylaxis against this disease should be considered. Future studies should evaluate whether rifaximin is effective in preventing postinfectious irritable bowel syndrome.

Antibacterial chemoprophylaxis in the prevention of traveler's diarrhea: evaluation of poorly absorbed oral rifaximin.

The use of antibacterial drugs was first shown to effectively reduce the occurrence of traveler's diarrhea nearly 50 years ago. The approach was not encouraged for general use by a Consensus Development Conference in 1985 because of concerns about adverse effects of the drugs and the possible development of resistance against systemically absorbed drugs. When therapy with poorly absorbed rifaximin was shown to be as effective as therapy with systemically absorbed drugs in shortening the duration of traveler's diarrhea, without the development of resistant coliform flora, the use of rifaximin for the prevention of traveler's diarrhea was studied. In the present study, rifaximin provided 72% protection against the development of diarrhea and 77% protection against active or treated diarrhea during 2 weeks of drug administration to United States students in Mexico. Rifaximin offers a potentially useful approach for preventing traveler's diarrhea. Potential areas of future study include use of the drug to prevent diarrhea due to mucosally invasive bacteria, including ciprofloxacin-resistant Campylobacter species, and to reduce the occurrence of postinfectious irritable bowel syndrome.

[Antibody development and frequency of events temporarily associated with measles and rubella vaccines among university health personnel in Jalisco]. / Desarrollo de anticuerpos y frecuencia de eventos temporalmente asociados a las vacunas contra el sarampión y rubéola en personal de salud universitario de Jalisco.

OBJECTIVE: To evaluate the seroprevalence, seroconversion, anamnesic response and events temporally associated with immune status pre and post immunization with measles and rubella vaccine in health personnel from a public University in Guadalajara, Mexico. MATERIAL AND METHODS: We carried out a prospective, longitudinal and comparative study from May to June 2000 among 120 healthy volunteers. Informed consent was obtained from all participants. We administered measles (Schwarz) and rubella (RA 27/3) vaccines. Weekly phone calls during six weeks were recorded from each volunteer to assess local and systemic events temporally associated with immunization non attributable to any other disease. Serum samples were obtained before and after vaccination in 75 volunteers. Antibodies against measles and rubella were measured by an enzyme immunoassay kit (Behring) with cut-off points of 300mUI/mL 8UI/mL respectively. Statistical analysis included mean, standard deviation and paired Student's t-test (P < 0.05). RESULTS: 105/120 participants (87.5%) were followed during 6 weeks. 87.4% were health personnel and 44.6% were males. The age range was 17-71 years (median = 21). We found a prior history of measles in 57.1%. Local events included pain, heat, redness and induration and were reported by 4/105. Systemic events such as fever, exanthema, pain in joints and arthritis was reported by 9/105. The proportion of study subjects with protective antibodies against measles and rubella prior to vaccination was 90.7 and 94.7% respectively. Both groups reached 100% after vaccination. CONCLUSIONS: The proportion of non-immune health personnel was low and similar to other reports. However, the potential spread of measles and rubella virus from a non-immunized infected health care provider could be amplified by the number of patients seen daily during the peak period of 3-5 days. The vaccination of health personnel should be encouraged.

Azithromycin found to be comparable to levofloxacin for the treatment of US travelers with acute diarrhea acquired in Mexico.

Increased drug resistance among enteropathogens is an emergent problem in travelers' diarrhea. This randomized, double-blind trial was conducted in Guadalajara, Mexico, during the summers of 1999-2001 to compare azithromycin with levofloxacin for the treatment of travelers' diarrhea. A total of 217 US adults were randomized to receive a single oral dose of azithromycin (1000 mg; 108 persons) or levofloxacin (500 mg; 109 persons), with a follow-up period of 4 days. Three patients in each group dropped out of the study. The median time between initiation of therapy and passage of the last unformed stool (azithromycin group, 22.3 h; levofloxacin group, 21.5 h) and the number of unformed stools passed during the 4-day follow-up period (azithromycin group, 6.5; levofloxacin group, 5.5) were similar. Treatment failure occurred in 10 patients (9.5%) receiving azithromycin and 8 patients (7.5%) receiving levofloxacin. Possible minor, self-limiting adverse events occurred in 57 patients in each treatment group. Azithromycin was found to be a safe and effective alternative to levofloxacin for the treatment of acute travelers' diarrhea in US adult travelers to Mexico.

Prevention of travelers' diarrhea with rifaximin in US travelers to Mexico.

BACKGROUND: Because bacterial pathogens are the primary cause of travelers' diarrhea (TD), antibiotic prophylaxis is effective in TD prevention. This study assessed the efficacy and safety of the nonsystemic antibiotic rifaximin in preventing TD in US travelers to Mexico. METHODS: Healthy adult students traveling to Mexico received rifaximin 600 mg/d or placebo for 14 days and were followed for 7 days post-treatment. Stool pattern and gastrointestinal symptoms were recorded in daily diary entries. The primary end point was prevention of TD during 14 days of treatment measured by time to first unformed stool. RESULTS: A total of 210 individuals received rifaximin (n = 106) or placebo (n = 104) and were included in the safety population. Median age was 21 years (range, 18-75 y), and the majority of participants were female (65%). Efficacy analyses were conducted in a modified intent-to-treat population of 201 patients who received rifaximin (n = 99) or placebo (n = 102). Rifaximin prophylaxis reduced risk of developing TD versus placebo (p < 0.0001). A smaller percentage of individuals who received rifaximin versus placebo developed all-cause TD (20% vs 48%, respectively; p < 0.0001) or TD requiring antibiotic therapy (14% vs 32%, respectively; p = 0.003). More individuals in the rifaximin group (76%) completed treatment without developing TD versus those in the placebo group (51%; p = 0.0004). Rifaximin provided a 58% protection rate against TD and was associated with fewer adverse events than placebo. CONCLUSIONS: Prophylactic treatment with rifaximin 600 mg/d for 14 days safely and effectively reduced the risk of developing TD in US travelers to Mexico. Rifaximin chemoprevention should be considered for TD in appropriate individuals traveling to high-risk regions.

A single-nucleotide polymorphism in the gene encoding osteoprotegerin, an anti-inflammatory protein produced in response to infection with diarrheagenic Escherichia coli, is associated with an increased risk of nonsecretory bacterial diarrhea in North American travelers to Mexico.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Epidemiology of cryptosporidiosis in North American travelers to Mexico.

We studied 1,179 North American travelers who visited Mexico from 2005 to 2007. Travelers' diarrhea (TD) was reported by 521 (44%) participants. Among subjects with TD, 218 cases were examined for cryptosporidiosis by polymerase chain reaction (PCR) and enzyme-linked immunoassays (ELISA). There were 14 (6%) cases of cryptosporidiosis and 141 cases (64%) of bacterial diarrhea. Compared with bacterial diarrhea, a longer stay in Mexico was a risk factor for cryptosporidiosis. Additionally, Cryptosporidium cases passed greater number of watery stools (P < 0.05), suffered more episodes of diarrhea (P < or = 0.05), and were more likely to experience tenesmus (P < or = 0.05) compared with bacterial causes of TD. ELISA detected seven (3%) cases of Cryptosporidium, whereas PCR identified an additional seven cases (6%). Speciation by 18SrRNA sequencing showed that 13 cases were caused by C. parvum and only 1 case was caused by C. hominis. ELISA showed a sensitivity of 50% and specificity of 100% compared with PCR.

A double blind, randomized, placebo-controlled study of SP-303 (Provir) in the symptomatic treatment of acute diarrhea among travelers to Jamaica and Mexico.

OBJECTIVE: The study was designed to evaluate the effectiveness of SP-303 (Provir), a plant-derived product with novel antisecretory properties, in the treatment of travelers' diarrhea. METHODS: A total of 184 persons from the United States who acquired diarrhea in Jamaica or Mexico were enrolled in a double-blind, placebo-controlled study examining the effectiveness of three doses of SP-303 in reducing illness. Subjects were treated with 125 mg, 250 mg, or 500 mg SP-303 or a matching placebo four times a day for 2 days. Subjects kept daily diaries of symptoms and were seen each day for 3 days. Of the subjects, 169 (92%) were included in the efficacy analysis. RESULTS: The most common etiological agent identified was enterotoxigenic Escherichia coli, found in 19% of subjects. The mean time interval from taking the first dose of medication until passage of the last unformed stool during 48 h therapy (TLUS48) was 38.7 h for the placebo group. TLUS48 was shortened by SP-303: 30.6 h for the 125-mg dose group (p = 0.005); 30.3 h for the 250-mg group; and 32.6 h for the 500-mg group (p = 0.01). Treatment failures were seen in 29.3% in the placebo group compared with 7.3% (p = 0.01), 4.3 (p = 0.002), and 9.8 (p = 0.026) in the three treatment groups. SP-303 was well tolerated at all doses. CONCLUSIONS: SP-303 was effective in shortening the duration of travelers' diarrhea by 21%. This antisecretory approach works directly against the pathophysiology of travelers' diarrhea and is not likely to potentiate invasive forms of diarrhea or to produce posttreatment constipation.

Desarrollo de anticuerpos y frecuencia de eventos temporalmente asociados a las vacunas contra el sarampión y rubéola en personal de salud universitario de Jalisco / Antibody development and frequency of events temporarily with measles and rubella vaccines among university health personnel in Jalisco

Objetivo: Evaluar el estado inmune y la seroconversión o respuesta anamnésica posterior a inmunización con vacuna de sarampión-rubéola (SR) y eventos temporalmente asociados, en personal de salud universitario. Materiales y métodos: Estudio prospectivo, longitudinal y comparativo de mayo a junio de 2000 en 120 adultos sanos de un Hospital de la Universidad Autónoma de Guadalajara. Previo consentimiento informado se aplicó la vacuna SR de sarampión (Schwarz) y rubéola (RA 27/3). Se realizó seguimiento telefónico semanal para identificar eventos locales y sistémicos temporalmente asociados a la vacunación (30 días posteriores a su aplicación, no atribuibles a otro proceso mórbido). Se tomó suero antes y seis semanas después de la vacunación. Los anticuerpos (IgG) contra sarampión y rubéola fueron cuantificados por análisis inmunoenzimático (Enzygnost®, Dade Behring) con puntos de corte de > 300mUI/mL y > 8UI/mL, respectivamente. Análisis: media, desviación estándar (DS), Prueba t de Student pareada (significancia de P < 0.05). Resultados: Se logró seguimiento en 105/120 (87.5%) durante seis semanas. El 87.4% fue personal de salud y 44.6% varones. Rango de edad 17-71 años (mediana = 21). En la historia clínica hubo antecedente de posible sarampión en 57.1%. Se obtuvo suero pareado en 75 casos. La proporción de voluntarios con anticuerpos para sarampión y rubéola antes (90.7 y 94.7%) y después (100 y 100%) de la vacuna se incrementó de manera significativa (P < 0.001). Dolor, calor, rubor e induración en el sitio de inyección se presentó en 4/105 (~4%). Fiebre, exantema, artralgias y artritis en 9/105 (~9%). Conclusiones: La proporción de susceptibles a sarampión fue alta si tomamos en consideración la potencialidad de transmisión del virus de sarampión a la población que atenderían durante el período de contagiosidad (3-5 días). La respuesta de inmunidad postvacunal fue óptima. La vacunación en personal de salud debe ser prioritaria.

Objective: To evaluate the seroprevalence, seroconversion, anamnesic response and events temporally associated with immune status pre and post immunization with measles and rubella vaccine in health personnel from a public University in Guadalajara, Mexico. Material and methods: We carried out a prospective, longitudinal and comparative study from May to June 2000 among 120 healthy volunteers. Informed consent was obtained from all participants. We administered measles (Schwarz) and rubella (RA 27/3) vaccines. Weekly phone calls during six weeks were recorded from each volunteer to assess local and systemic events temporally associated with immunization non attributable to any other disease. Serum samples were obtained before and after vaccination in 75 volunteers. Antibodies against measles and rubella were measured by an enzyme immunoassay kit (Behring) with cut-off points of ³300mUI/mL and ³8UI/mL respectively. Statistical analysis included mean, standard deviation and paired Student's t-test (P < 0.05). Results: 105/120 participants (87.5%) were followed during 6 weeks. 87.4% were health personnel and 44.6% were males. The age range was 17-71 years (median = 21). We found a prior history of measles in 57.1%. Local events included pain, heat, redness and induration and were reported by 4/105. Systemic events such as fever, exanthema, pain in joints and arthritis was reported by 9/105. The proportion of study subjects with protective antibodies against measles and rubella prior to vaccination was 90.7 and 94.7% respectively. Both groups reached 100% after vaccination. Conclusions: The proportion of non-immune health personnel was low and similar to other reports. However, the potential spread of measles and rubella virus from a non-immunized infected health care provider could be amplified by the number of patients seen daily during the peak period of 3-5 days. The vaccination of health personnel should be encouraged.