Importance: Many of the 4.5 billion annual episodes of diarrhea are treated unnecessarily with antibiotics; prevalence of antibiotic resistance among diarrheal pathogens is increasing. Knowledge-based antibiotic stewardship interventions typically yield little change in antibiotic use. Objective: To compare antibiotic use among adult outpatients with diarrhea given bismuth subsalicylate (BSS) or placebo. Design, Setting, and Participants: This randomized clinical trial took place from April to October 2014. Participants were patients aged 15 to 65 years with acute, nonbloody diarrhea from 22 outpatient clinics in Karachi, Pakistan. Participants were interviewed about symptoms and health care utilization during the 5 days after enrollment. Group assignment was concealed from participants, field staff, and the statistician. Primary analysis occurred from August to September 2015. Interventions: Participants were randomly assigned (1:1) to receive BSS or placebo for 48 hours or less. Main Outcomes and Measures: Use of systemic antibiotics within 5 days of enrollment. Secondary outcomes included measures of duration and severity of illness. Results: Among eligible patients, 39 declined to participate, 440 enrolled, and 1 enrolled participant was lost to follow-up, for a total of 439 patients included in the analysis. Median (interquartile range) participant age was 32 (23-45) years and 187 (43%) were male. Two hundred twenty patients were randomized to BSS and 220 were randomized to placebo. Overall, 54 participants (12%) used systemic antibiotics (16% in the placebo group and 9% in the BSS group); all antibiotic use followed consultation with a physician. Use of any antibiotic was significantly lower in the BSS group (20 of 220 vs 34 of 219 patients; odds ratio [OR], 0.54; 95% CI, 0.30-0.98), as was use of fluoroquinolones (8 of 220 vs 20 of 219 patients; OR, 0.38; 95% CI, 0.16-0.88). Rates of care seeking and hospitalization were similar between groups and no difference was detected in timing of diarrhea resolution. However, those in the BSS group less commonly received intravenous rehydration (14 of 220 vs 27 of 219 patients; OR, 0.48; 95% CI, 0.25-0.95) and missed less work (median [interquartile range], 0 [0-1] vs 1 [0-1] day; P = .04) during follow-up. Conclusions and Relevance: This study found less antibiotic use among participants given BSS for acute diarrhea in a setting where antibiotics are commonly used to treat diarrhea. Encouraging health care professionals in such settings to recommend BSS as frontline treatment for adults with diarrhea, and promoting BSS for diarrhea self-management, may reduce antibiotic use and rates of antibiotic resistance globally. Trial Registration: ClinicalTrials.gov identifier: NCT02047162.

In south Asia, where diarrhea is common and antibiotics are accessible without prescription, antimicrobial resistance is an emerging and serious problem. However, beliefs and behaviors related to antimicrobial resistance are poorly understood. We explored laypersons' and health-care providers' (HCP) awareness and perceptions of antimicrobial resistance in the context of treatment of adult diarrheal disease in Karachi, Pakistan. In-depth, open-ended interviews were conducted with 40 laypersons and 45 HCPs in a lower-middle-class urban neighborhood. Interviews conducted in Urdu were audiotaped, transcribed, translated, and coded using applied thematic analysis. Slightly over half of laypersons and two-thirds of HCPs were aware that antimicrobial medication could lose effectiveness, but misperceptions were common. Laypersons and HCPs often believed that "the body becomes immune" or "bacteria attack more strongly" if medications are taken "improperly." Another prevalent theme was that causes and effects of antimicrobial resistance are limited to the individual taking the antimicrobial medication and to the specific diarrheal episode. Participants often attributed antimicrobial resistance to patient behaviors; HCP behavior was rarely discussed. Less than half of the HCPs were aware of treatment guidelines. To combat antimicrobial resistance in urban Pakistan, a health systems strategy and community-supported outreach campaigns on appropriate antimicrobial use are needed.

Previous studies have shown bismuth subsalicylate (BSS) has antimicrobial properties, but few studies have addressed the mechanism of action. Furthermore, following BSS ingestion other bismuth salts form throughout the gastrointestinal tract including bismuth oxychloride (BiOCl) that also act upon enteric pathogens. To further understand the antimicrobial activity of bismuth in infectious diarrhea, the antimicrobial effect of BSS and BiOCl on Clostridium difficile, Salmonella, Shigella, Shiga toxin-producing Escherichia coli strains and norovirus (NoV) were measured. Bacterial enteric pathogens in pure culture or in human fecal material were exposed to 35mg/ml BSS or BiOCl with or without a vehicle suspension. BSS and BiOCl treated samples were quantified and visualized by transmission electron microscopy. To measure the effect on NoV, reduction of infectious murine NoV (MNV), a surrogate for human NoV, and Norwalk virus RNA levels were measured by viral plaque assay and RT-qPCR, respectively. BSS and BiOCl reduced bacterial growth by 3-9 logs in all strains with majority resulting in populations of <10 cfu/ml within 24 h. Similar results were found when fecal material was included. Microscopy images detected bismuth on bacterial membranes and within the bacterial organisms at 30 min post-treatment. At 8.8mg/ml BSS and BiOCl reduced infectivity of MNV significantly by 2.7 and 2.0 log after 24 h of exposure. In addition, both BSS and BiOCl slightly reduced the level of Norwalk replicon-bearing cells suggesting that bismuth may inhibit NoV in vivo. Collectively, our results confirm and build on existing data that BSS has antimicrobial properties against a wide-range of diarrhea-causing pathogens.