Efficacy and safety of Bacillus clausii (O/C, N/R, SIN, T) probiotic combined with oral rehydration therapy (ORT) and zinc in acute diarrhea in children: a randomized, double-blind, placebo-controlled study in India.

BACKGROUND: Childhood diarrhea remains a major disease burden, particularly in developing countries, and is a leading cause of death in children aged < 5 years, worldwide. Treatment of acute diarrhea now includes probiotics to potentially reduce the duration and severity of the illness. This phase 3, randomized, placebo-controlled, double-blind study assessed the efficacy and safety of four strains (O/C, N/R, SIN, T) of Bacillus clausii probiotic (Enterogermina®) plus oral rehydration therapy (ORT) and zinc, versus placebo plus ORT and zinc, in infants and children in India with acute moderate diarrhea. METHODS: Patients aged 6 months to 5 years with acute moderate diarrhea (WHO 2005 definition) of < 48 h' duration were randomly assigned to receive one mini bottle of either polyantibiotic-resistant B. clausii (oral suspension of 2 billion spores per 5 mL bottle) or matching placebo twice daily (morning and evening) for 5 days. Exclusion criteria included known hypersensitivity to B. clausii or excipients in the study treatment, or to other probiotics. Patients were admitted to hospital from Day 1 and discharged ≥6 h after diarrhea resolution, or a maximum of 5 days. The primary endpoint was duration of acute diarrhea from randomization to recovery. Secondary endpoints included frequency of stools, diapers with stools, or dehydration status. RESULTS: In total, 457 patients were randomized; 454 were treated. Similar proportions of patients showed recovery from diarrhea over the 120 h after randomization (97.0% in the B. clausii group [n = 227]; 98.0% on placebo [n = 227]). Median time to recovery was also similar: 42.83 (95% CI: 40.90-44.90) hours for B. clausii and 42.13 (95% CI: 39.80-43.87) hours for placebo. However, no statistically significant difference was observed between groups (hazard ratio = 0.93 [95% CI: 0.77-1.13]; p = 0.6968); nor were there statistically significant differences between groups for the secondary endpoints. Treatment with B. clausii was well tolerated with incidence of adverse events (9.7%) similar to that for placebo (12.3%). CONCLUSIONS: No significant difference in efficacy between B. clausii and placebo was demonstrated. Sample size may have been inadequate to allow detection of a between-group difference in efficacy, given the mild/moderate severity (only ~ 20% of patients had nausea/vomiting or abdominal pains) and short duration of disease among subjects, the relatively late start of treatment (most were already on Day 2 of their disease episode when study treatment started) and the effectiveness of the standard of care with ORT and zinc in both treatment groups. TRIAL REGISTRATION: CTRI number CTRI/2018/10/016053 . Registered on 17 October 2018. EudraCT number 2016-005165-31 . Registered 14 May 2020 (retrospectively registered).

Recommendations for the adjuvant use of the poly-antibiotic-resistant probiotic Bacillus clausii (O/C, SIN, N/R, T) in acute, chronic, and antibiotic-associated diarrhea in children: consensus from Asian experts.

This paper proposes recommendations for probiotics in pediatric gastrointestinal diseases in the Asia-Pacific region. Evidence-based recommendations and randomized controlled trials in the region are included. Cultural aspects, health management issues and economic factors were also considered. Final recommendations were approved by utilizing a modified Delphi process and applying the Likert scale in an electronic voting process. Bacillus clausii was recommended as an adjunct treatment with oral rehydration solution for acute viral diarrhea. B. clausii may also be considered for prevention of antibiotic-associated diarrhea, Clostridium difficile-induced diarrhea, and as adjunct treatment of Helicobacter pylori. There is insufficient evidence for recommendations in other conditions. Despite a diversity of epidemiological, socioeconomical and health system conditions, similar recommendations currently apply to most Asia-Pacific countries. Ideally, these need to be validated with local randomized-controlled trials.

Device-handling study of a novel breath-actuated inhaler, Synchrobreathe®, versus a pMDI.

INTRODUCTION: Synchrobreathe®, a new-generation, novel breath-actuated inhaler (BAI) can address the key issues arising during the use of both pressurised metered dose inhalers ([pMDIs]; hand-breath coordination) and dry powder inhalers ([DPIs]; high inspiratory flow required) with respect to optimal drug deposition. MATERIALS AND METHODS: This was an open-label, prospective, 2-week, multicentre study that assessed device handling, ease of use, errors and participant perception regarding the use of Synchrobreathe® versus a pMDI in patients with chronic obstructive pulmonary disease (COPD) (n = 162) or asthma (n = 239) and inhaler-naïve healthy volunteers (n = 59). Ability to use the device without errors at the first attempt, total number of errors before and after training, time taken to use the device correctly and total number of training sessions, and number of attempts to perform the correct technique on Day 1 and Day 14 were evaluated. Device handling and preference questionnaires were also administered on Day 14. RESULTS: Of 460 participants, 421 completed the study. The number of participants using Synchrobreathe without any error after reading the patient information leaflet (PIL) was significantly low (p < 0.05) on Day 1. On Day 14, significantly more number of participants used Synchrobreathe without any error (p < 0.001). The total number of errors before and after training with Synchrobreathe was significantly less (p < 0.001). The average time required to perform the inhalation technique correctly (p < 0.01) and the total number of attempts (P < 0.001) with Synchrobreathe were significantly lower. The average number of attempts to inhale correctly was significantly (p < 0.001) less with Synchrobreathe on Day1 and Day 14. Most participants rated Synchrobreathe as their choice of inhaler. CONCLUSION: Synchrobreathe is an easy-to-use and easy-to-handle device with significantly less number of errors, which may have positive implications for disease control in asthma and COPD.

Approach to chronic cough.

Chronic cough does affect quality of life in children. Most of the times it is treated with over-the-counter cough syrups and antibiotics. The etiology of chronic cough is so diverse, that treatment needs to be directed to the specific etiology, rather than treating symptomatically. Grossly, chronic cough is classified as specific and non-specific cough. Allergic conditions, followed by tuberculosis are more commonly encountered etiologies in India. Baseline investigations to be performed are chest radiograph and peak flow metry. If specific cause of cough is not obvious, then therapeutic trial with ß2 agonist, followed by peak flowmetry to evaluate reversibility of airway hypersensitivity, is useful to label the child asthmatic or non-asthmatic. Rampant uses of antibiotics need to be avoided for conditions like asthma. If tuberculosis is diagnosed or suspected, it is better to treat the child, rather than giving therapeutic trial. Over-the-counter cough syrups are as good as placebo, and should be avoided. Trial of anti asthma, anti allergic rhinitis and anti reflux therapies are avoided, unless the diagnosis is one of these conditions. If the child is distressed or the case seems to be complicated, it is best to refer the child to a tertiary care centre and keep a close follow up.