Rifaximin Fails to Prevent Campylobacteriosis in the Human Challenge Model: A Randomized, Double-Blind, Placebo-Controlled Trial.

Background: Campylobacter species are a leading cause of diarrheal disease globally with significant morbidity. Primary prevention efforts have yielded limited results. Rifaximin chemoprophylaxis decreases rates of travelers' diarrhea and may be suitable for high-risk persons. We assessed the efficacy of rifaximin in the controlled human infection model for Campylobacter jejuni. Methods: Twenty-eight subjects were admitted to an inpatient facility and randomized to a twice-daily dose of 550 mg rifaximin or placebo. The following day, subjects ingested 1.7 × 105 colony-forming units of C. jejuni strain CG8421. Subjects continued prophylaxis for 3 additional days, were followed for campylobacteriosis for 144 hours, and were subsequently treated with azithromycin and ciprofloxacin. Samples were collected to assess immunologic responses to CG8421. Results: There was no difference (P = 1.0) in the frequency of campylobacteriosis in those receiving rifaximin (86.7%) or placebo (84.6%). Additionally, there were no differences in the clinical signs and symptoms of C. jejuni infection to include abdominal pain/cramps (P = 1.0), nausea (P = 1.0), vomiting (P = .2), or fever (P = 1.0) across study groups. Immune responses to the CG8421 strain were comparable across treatment groups. Conclusions: Rifaximin did not prevent campylobacteriosis in this controlled human infection model. Given the morbidity associated with Campylobacter infection, primary prevention efforts remain a significant need. Clinical Trials Registration: NCT02280044.

Individual-specific changes in the human gut microbiota after challenge with enterotoxigenic Escherichia coli and subsequent ciprofloxacin treatment.

BACKGROUND: Enterotoxigenic Escherichia coli (ETEC) is a major cause of diarrhea in inhabitants from low-income countries and in visitors to these countries. The impact of the human intestinal microbiota on the initiation and progression of ETEC diarrhea is not yet well understood. RESULTS: We used 16S rRNA (ribosomal RNA) gene sequencing to study changes in the fecal microbiota of 12 volunteers during a human challenge study with ETEC (H10407) and subsequent treatment with ciprofloxacin. Five subjects developed severe diarrhea and seven experienced few or no symptoms. Diarrheal symptoms were associated with high concentrations of fecal E. coli as measured by quantitative culture, quantitative PCR, and normalized number of 16S rRNA gene sequences. Large changes in other members of the microbiota varied greatly from individual to individual, whether or not diarrhea occurred. Nonetheless the variation within an individual was small compared to variation between individuals. Ciprofloxacin treatment reorganized microbiota populations; however, the original structure was largely restored at one and three month follow-up visits. CONCLUSION: Symptomatic ETEC infections, but not asymptomatic infections, were associated with high fecal concentrations of E. coli. Both infection and ciprofloxacin treatment caused variable changes in other bacteria that generally reverted to baseline levels after three months.

Double-blind cluster randomised controlled trial of wheat flour chapatti fortified with micronutrients on the status of vitamin A and iron in school-aged children in rural Bangladesh.

Food fortification is a cost-effective and sustainable strategy to prevent or correct micronutrient deficiencies. A double-blind cluster (bari) randomised controlled trial was conducted in a rural community in Bangladesh to evaluate the impact of consumption of chapatti made of micronutrient-fortified wheat flour for 6 months by school-aged children on their vitamin A, haemoglobin and iron status. A total of 43 baris (group of households) were randomly selected. The baris were randomly assigned to either intervention or control group. The intervention group received wheat flour fortified with added micronutrients (including 66 mg hydrogen-reduced elemental iron and 3030 µg retinol equivalent as retinyl palmitate per kilogram of flour), while the control group received wheat flour without added micronutrients. A total of 352 children were enrolled in the trial, 203 in the intervention group and 149 in the control group. Analyses were carried out on children who completed the study (191 in the intervention group and 143 in the control group). Micronutrient-fortified wheat flour chapatti significantly increased serum retinol concentration at 6 months by 0.12 µmol L(-1) [95% confidence interval (CI): 0.06, 0.19; P < 0.01]. The odds of vitamin A deficiency was significantly lower for children in the intervention group at 3 months [odds ratio (OR) = 0.26; 95% confidence interval (CI): 0.07, 0.89; P < 0.05] and 6 months (OR = 0.21; 95% CI: 0.06, 0.68; P < 0.01). No demonstrable effect of fortified chapatti consumption on iron status, haemoglobin levels or anaemia was observed. Consumption of fortified chapattis demonstrated a significant improvement in the vitamin A status, but not in iron, haemoglobin or anaemia status.

Changing trend of persistent diarrhoea in young children over two decades: observations from a large diarrhoeal disease hospital in Bangladesh.

AIM: We studied the changing trend and factors associated with persistent diarrhoea (PD) in under-five children presenting to a large diarrhoeal disease hospital in urban Dhaka, Bangladesh, over the last two decades. METHODS: We used an unmatched case-control design, with a case (persistent diarrhoea; n=944) to control (acute diarrhoea; n=2832) ratio of 1:3 attending the Dhaka Hospital of icddr,b between 1991 and 2010. RESULTS: The proportion of children with PD decreased significantly from 8% in 1991 to 1% in 2010. The proportion of breastfeeding practices, measles vaccination coverage and vitamin A supplementation among 12-59 months old improved from 79% to 85%, 69% to 85% and 26% to 74%, respectively, which were significant. Although the isolation of rotavirus from stool in children with PD and acute diarrhoea increased, the isolation of Shigella spp., and Vibrio cholerae O1 decreased significantly. In a logistic regression analysis, wasting (OR=1.62), use of antibiotic before attending hospital (OR=5.94), absent clinical dehydration (OR=1.53) and bloody/mucoid stool (OR=3.33) were significantly associated with persistent diarrhoea. CONCLUSION: There, thus, is a need to integrate an appropriate and sustainable deterrent strategy to take the benefit of the significant reduction in prevalence as well as risks of PD in such population.

Scaling up zinc treatment of childhood diarrhoea in Bangladesh: theoretical and practical considerations guiding the SUZY Project.

In 2003, the International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B), in partnership with the Bangladesh Ministry of Health and Family Welfare (MOHFW) and the private sector embarked on a national exercise to scale up zinc treatment of childhood diarrhoea as an adjunct to oral rehydration solution (ORS). Private sector participation included national associations representing licensed and unlicensed health care providers, a local pharmaceutical laboratory, a marketing agency and a technology transfer from the European patent holder of the dispersible zinc tablet formulation promoted in the scale-up campaign. This project was a response to several years of research in the preceding decade demonstrating that zinc supplementation during a diarrhoeal illness episode significantly reduces illness severity and duration as well as prevents subsequent morbidity and mortality. It has been estimated that zinc treatment has the potential to annually save nearly 400 000 under-5 lives, thus significantly impacting on Millennium Development Goal #4. This paper summarizes the primary coverage outcomes of the Scaling Up of Zinc in Early Childhood (SUZY) Project into its third year (December 2006 to October 2009). These results are assessed in relation to the Project's theoretical foundations and the performance framework that was jointly planned and implemented through a public-private partnership. The scale-up campaign encountered numerous constraints, but also benefited from several facilitating factors which are summarized under an assessment framework developed to identify barriers and better promote the scaling up of key health interventions in low- and middle-income countries. The lessons learned are described with the intent that this will contribute to the more effective scale-up of life-saving interventions that will reach those in greatest need.

Zinc treatment for 5 or 10 days is equally efficacious in preventing diarrhea in the subsequent 3 months among Bangladeshi children.

We conducted a randomized, double-blind placebo controlled, community trial in rural Bangladesh in children 4-59 mo of age to compare the efficacy of a 5- and 10-d course of zinc therapy on the incidence and duration of diarrhea over the subsequent 90-d follow-up after initial treatment for an acute childhood diarrheal (ACD) episode. Children (n = 1622) with ACD were randomly allocated to either 5 or 10 d of zinc treatment. Female field workers visited each child daily, supervised the administration of zinc, recorded the duration of current episode, and the occurrence and duration of diarrhea over the subsequent 3 mo. The incidence of diarrhea over the 90 d of follow-up did not differ between the 5-d (1.08 ± 1.38 episodes) and 10-d (1.02 ± 1.35 episodes) groups (P = 0.35). Children in both groups experienced a comparable duration of diarrheal episodes (3.1 ± 5.6 d vs. 2.9 ± 5.6 d, 5-d vs. 10-d, respectively; P = 0.64) with a mean difference between groups within the defined range of equivalence. Time to onset of the first episode and the proportion children experiencing diarrhea during the 90-d follow-up also did not differ between groups. These findings suggest that among Bangladeshi children, a 5-d zinc treatment for ACD is as efficacious as 10 d in preventing diarrhea in the subsequent 3 mo.

Decrease in shigellosis-related deaths without Shigella spp.-specific interventions, Asia.

In 1999, a review of the literature for 1966-1997 suggested that ≈1.1 million persons die annually of shigellosis, including ≈880,000 in Asia. Our recent review of the literature for 1990-2009 indicates that ≈125 million shigellosis cases occur annually in Asia, of which ≈14,000 are fatal. This estimate for illnesses is similar to the earlier estimate, but the number of deaths is 98% lower; that is, the lower estimate of deaths is associated with markedly reduced case-fatality rates rather than fewer cases. Shigella spp.-related deaths decreased substantially during a period without Shigella spp.-specific interventions. We speculate that nonspecific interventions, e.g., measles vaccination, vitamin A supplementation, and improved nutrition, may have led to the reduced number of shigellosis-related deaths.

A double-blind, placebo-controlled, exploratory trial of chromium picolinate in atypical depression: effect on carbohydrate craving.

BACKGROUND: : In a small pilot trial, patients with atypical depression demonstrated significant positive therapeutic response to chromium picolinate. This finding is of interest because of the demonstrated link between depression, decreased insulin sensitivity, and subsequent diabetes and chromium picolinate's insulin enhancing effect. METHODS: : In this double-blind, multicenter, 8-week replication study, 113 adult outpatients with atypical depression were randomized 2:1 to receive 600 mug/day of elemental chromium, as provided by chromium picolinate (CrPic), or placebo. Primary efficacy measures were the 29-item Hamilton Depression Rating Scale (HAM-D-29) and the Clinical Global Impressions Improvement Scale (CGI-I). RESULTS: : Of the 113 randomized patients, 110 (70 CrPic, 40 placebo) constituted the intent-to-treat (ITT) population (i.e., received at least one dose of study medication and completed at least one efficacy evaluation) and 75 (50 CrPic, 25 placebo) were evaluable (i.e., took at least 80% of study drug with no significant protocol deviations). In the evaluable population, mean age was 46 years, 69% were female, 81% were Caucasian, and mean body mass index (BMI) was 29.7. There was no significant difference between the CrPic and placebo groups in both the ITT and evaluable populations on the primary efficacy measures, with both groups showing significant improvement from baseline on total HAM-D-29 scores during the course of treatment (p < 0.0001). However, in the evaluable population, the CrPic group showed significant improvements from baseline compared with the placebo group on 4 HAM-D-29 items: appetite increase, increased eating, carbohydrate craving, and diurnal variation of feelings. A supplemental analysis of data from the subset of 41 patients in the ITT population with high carbohydrate craving (26 CrPic, 15 placebo; mean BMI = 31.1) showed that the CrPic patients had significantly greater response on total HAM-D-29 scores than the placebo group (65% vs. 33%; p < 0.05) as well as significantly greater improvements on the following HAM-D-29 items: appetite increase, increased eating, carbohydrate craving, and genital symptoms (e.g., level of libido). Chromium treatment was well-tolerated. LIMITATIONS: : The study did not include a placebo run-in period, did not require minimum duration or severity of depression, and enrolled patients with major depression, dysthymia, or depression NOS. CONCLUSIONS: : In a population of adults with atypical depression, most of whom were overweight or obese, CrPic produced improvement on the following HAM-D-29 items: appetite increase, increased eating, carbohydrate craving, and diurnal variation of feelings. In a subpopulation of patients with high carbohydrate craving, overall HAM-D-29 scores improved significantly in patients treated with CrPic compared with placebo. The results of this study suggest that the main effect of chromium was on carbohydrate craving and appetite regulation in depressed patients and that 600 mug of elemental chromium may be beneficial for patients with atypical depression who also have severe carbohydrate craving. Further studies are needed to evaluate chromium in depressed patients specifically selected for symptoms of increased appetite and carbohydrate craving as well as to determine whether a higher dose of chromium would have an effect on mood.

Antidiarrheal effects of L-histidine-supplemented rice-based oral rehydration solution in the treatment of male adults with severe cholera in Bangladesh: a double-blind, randomized trial.

BACKGROUND: Because of the antisecretory potential of L-histidine in the intestinal tract, its antidiarrheal effects were determined in cholera. METHODS: In a double-blind trial of 126 adult male patients with cholera, L-histidine (2.5 g/L) was mixed with a rice-based oral rehydration solution (ORS) and administered to 62 patients; 64 patients received the same ORS without L-histidine. All patients received ciprofloxacin at a dosage of 500 mg every 12 h for 72 h. Fluid output (of stool, urine, and vomit) and intake (of ORS, water, and intravenous fluid) were determined every 8 h for 72 h. RESULTS: Administration of ORS with L-histidine significantly (P<.05) reduced the frequency of stool output during 32-64 h after initiation of ORS treatment, compared with that in patients given ORS without L-histidine ([all data are means+/-SD] 32-48 h, 11.5+/-6.9 mL/kg vs. 18.8+/-16.0 mL/kg; 40-48 h, 6.7+/-4.4 mL/kg vs. 11.5+/-9.7 mL/kg; and 56-64 h, 6.3+/-5.8 mL/kg vs. 7.8+/-4.1 mL/kg). An overall reduction of 22% in the volume of stool was observed in patients given ORS without L-histidine. The amount of required unscheduled intravenous fluid was lower in patients given ORS with L-histidine, compared with that in patients given ORS without L-histidine (0-24 h, 82.5+/-44.4 mL/kg vs. 158.6+/-72.2 mL/kg [P<.01]; and 24-48 h, 41.6+/-40.4 mL/kg vs. 52.5+/-22.1 mL/kg [P>.05]). Administration of ORS with L-histidine also significantly reduced (P<.05) the intake of ORS and the duration of illness. No adverse effects were observed in these patients. CONCLUSIONS: L-histidine reduces the weight of stool and the frequency of stool output in cholera and could be a useful and safe adjunct treatment that will increase the success rate of ORS and antibiotic therapy in cholera.