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

Tropical Diseases, Travel Medicine and Vaccines - Tập 8 Số 1 - 2022
Keya Lahiri1, Raghvendra Singh2, Mohini Apte3, Mahantesh Patil4, Amar Taksande5, Rafael Varona6, Godhuli Chatterjee7, Manish Verma8, Sandrine Brette9, Marcos III Perez10
1D Y Patil Medical College and Hospital, Nerul, Navi Mumbai, India
2Maulana Azad Medical College and Lok Nayak Hospital, 2 Bahadur Shah Zafar Road, New Delhi, India
3Government Medical College and Hospital, Medical College Square, Nagpur, India
4JN Medical College & KLES Dr. Prabhakar Kore Hospital & MRC, Nehru Nagar, Belgaum, India
5Acharya Vinoba Bhave Rural Hospital, Jawaharlal Nehru Medical College, Datta Meghe Institute of Medical Sciences, Sawangi (Meghe), Wardha, India
6Global Medical, Consumer Healthcare, Sanofi-Aventis, Gentilly, France
7Senior Medical Advisor and Clinical Study Unit Safety Lead, Clinical Study Unit (India-South East Asia Cluster), Sanofi Healthcare India Private Limited, Mumbai, Maharashtra, India
8Sanofi Healthcare India Private Limited, Mumbai, Maharashtra, India
9Aixial, Boulogne-Billancourt, France
10Global Medical, Consumer Healthcare, Sanofi-Aventis Deutschland GmbH, Frankfurt, Germany

Tóm tắt

Abstract 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).

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Tài liệu tham khảo

GBD 2017 Diarrhoeal Disease Collaborators. Quantifying risks and interventions that have affected the burden of diarrhoea among children younger than 5 years: an analysis of the Global Burden of Disease Study 2017. Lancet Infect Dis. 2020;20(1):37–59. https://doi.org/10.1016/S1473-3099(19)30401-3.

Richardson V, Hernandez-Pichardo J, Quintanar-Solares M, Esparza-Aguilar M, Johnson B, Gomez-Altamirano CM, et al. Effect of rotavirus vaccination on death from childhood diarrhea in Mexico. N Engl J Med. 2010;362(4):299–305. https://doi.org/10.1056/NEJMoa0905211.

do Carmo GMI, Yen C, Cortes J, Siqueira AA, de Oliveira WK, Cortez-Escalante JJ, et al. Decline in diarrhea mortality and admissions after routine childhood rotavirus immunization in Brazil: a time-series analysis. PLoS Med. 2011;8(4):e1001024. https://doi.org/10.1371/journal.pmed.1001024.

GBD 2016 Diarrhoeal Disease Collaborators. Estimates of the global, regional, and national morbidity, mortality, and aetiologies of diarrhea in 195 countries: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Infect Dis. 2018;18(11):1211–28. https://doi.org/10.1016/S1473-3099(18)30362-1.

Lakshminarayanan S, Jayalakshmy R. Diarrheal diseases among children in India: current scenario and future perspectives. J Nat Sci Biol Med. 2015;6(1):24–8. https://doi.org/10.4103/0976-9668.149073.

Kotloff KL, Nataro JP, Blackwelder WC, Nasrin D, Farag TH, Panchalingam S, et al. Burden and aetiology of diarrheal disease in infants and young children in developing countries (the Global Enteric Multicenter Study, GEMS): a prospective, case-control study. Lancet. 2013;382(9888):209–22. https://doi.org/10.1016/S0140-6736(13)60844-2.

Walker CLF, Rudan I, Liu L, Nair H, Theodoratou E, Bhutta ZK, et al. Global burden of childhood pneumonia and diarrhoea. Lancet. 2013;381(9875):1405–16. https://doi.org/10.1016/S0140-6736(13)60222-6.

World Health Organization. Diarrheal Disease. Fact sheet. 2017. https://www.who.int/en/news-room/fact-sheets/detail/diarrhoeal-disease. Accessed 8 Dec 2021.

Collaborators MDS, Bassani DG, Kumar R, Awasthi S, Morris SK, Paul VK, et al. Causes of neonatal and child mortality in India: a nationally representative mortality survey. Lancet. 2010;376(9755):1853–60. https://doi.org/10.1016/S0140-6736(10)61461-4.

Farthing M, Salam MA, Lindberg G, Dite P, Khalif I, Salazar-Lindo E, et al. Acute diarrhea in adults and children: a global perspective. J Clin Gastroenterol. 2013;47(1):12–20. https://doi.org/10.1097/MCG.0b013e31826df662.

Park K. Park's textbook of preventive and social medicine. 18th ed. Jabalpur: M/S? Banarsidas Bhanot; 2005.

Baral R, Nonvignon J, Debellut F, Agyemang SA, Clark A, Pecenka C. Cost of illness for childhood diarrhea in low- and middle-income countries: a systematic review of evidence and modelled estimates. BMC Public Health. 2020;20(1):619. https://doi.org/10.1186/s12889-020-08595-8.

World Health Organization. The treatment of diarrhoea: a manual for physicians and other senior health workers. 2005. https://apps.who.int/iris/bitstream/handle/10665/43209/9241593180.pdf. Accessed 8 Dec 2021.

Duggan C, Fontaine O, Pierce NF, Roger IG, Dilip M, Nur HA, et al. Scientific rationale for a change in the composition of oral rehydration solution. JAMA. 2004;291(21):2628–31. https://doi.org/10.1001/jama.291.21.2628.

Fooks LJ, Gibson GR. Probiotics as modulators of the gut flora. Br J Nutr. 2002;88(Suppl 1):S39–49. https://doi.org/10.1079/BJN2002628.

Bermudez-Brito M, Plaza-Díaz J, Muñoz-Quezada S, Gómez-Llorente C, Gil A. Probiotic mechanisms of action. Ann Nutr Metab. 2012;61(2):160–74. https://doi.org/10.1159/000342079.

Allen SJ, Martinez EG, Gregorio GV, Dans LF. Probiotics for treating acute infectious diarrhoea. Cochrane Database Syst Rev. 2010;2010(11):CD003048. https://doi.org/10.1002/14651858.CD003048.pub3.

Szajewska H, Skórka A, Ruszczyński M, Gieruszczak-Białek D. Meta-analysis: Lactobacillus GG for treating acute gastroenteritis in children — updated analysis of randomised controlled trials. Aliment Pharmacol Ther. 2013;38(5):467–76. https://doi.org/10.1111/apt.12403.

Feizizadeh S, Salehi-Abargouei A, Akbari V. Efficacy and safety of Saccharomyces boulardii for acute diarrhea. Pediatrics. 2014;134(1):e176–91. https://doi.org/10.1542/peds.2013-3950.

Guarino AAS, Gendrel D, Lo Vecchio A, Shamir R, Szajewska H. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition; European Society for Pediatric Infectious Diseases. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition/European Society for Pediatric Infectious Diseases evidence-based guidelines for the management of acute gastroenteritis in children in Europe: update 2014. J Pediatr Gastroenterol Nutr. 2014;59(1):132–52. https://doi.org/10.1097/MPG.0000000000000375.

Lo Vecchio A, Amil Dias J, Berkley JA, Boey C, Cohen MB, Cruchet S, et al. Comparison of recommendations in clinical practice guidelines for acute gastroenteritis in children. J Pediatr Gastroenterol Nutr. 2016;63(2):226–35. https://doi.org/10.1097/MPG.0000000000001133.

Duc LH, Hong HA, Barbosa TM, Henriques AO, Cutting SM. Characterization of Bacillus probiotics available for human use. Appl Environ Microbiol. 2004;70(4):2161–71. https://doi.org/10.1128/AEM.70.4.2161-2171.2004.

Buts JP, Bernasconi P. Saccharomyces boulardii: basic science and clinical applications in gastroenterology. Gastroenterol Clin North Am. 2005;34(3):515–32. https://doi.org/10.1016/j.gtc.2005.05.009.

Ghelardi E, Celandroni F, Salvetti S, Gueye SA, Lupetti A, Senesi S. Survival and persistence of Bacillus clausii in the human gastrointestinal tract following oral administration as spore-based probiotic formulation. J Appl Microbiol. 2015;119(2):552–9. https://doi.org/10.1111/jam.12848.

Guandalini S, Pensabene L, Zikri MA, Dias JA, Casali LG, Hoekstra H, et al. Lactobacillus GG administered in oral rehydration solution to children with acute diarrhea: a multicenter European trial. J Pediatr Gastroenterol Nutr. 2000;30(1):54–60. https://doi.org/10.1097/00005176-200001000-00018.

Ianiro G, Rizzatti G, Plomer M, Lopetuso L, Scaldaferri F, Franceschi F, et al. Bacillus clausii for the treatment of acute diarrhea in children: a systematic review and meta-analysis of randomized controlled trials. Nutrients. 2018;10(8):1074. https://doi.org/10.3390/nu10081074.

Nista EC, Candelli M, Cremonini F, Cazzato IA, Zocco MA, Franceschi F, et al. Bacillus clausii therapy to reduce side-effects of anti-Helicobacter pylori treatment: randomized, double-blind, placebo-controlled trial. Aliment Pharmacol Ther. 2004;20(10):1181–8. https://doi.org/10.1111/j.1365-2036.2004.02274.x.

Sudha MR, Bhonagiri S, Kumar MA. Efficacy of Bacillus clausii strain UBBC-07 in the treatment of patients suffering from acute diarrhea. Benef Microbes. 2013;4(2):211–6. https://doi.org/10.3920/BM2012.0034.

Smiyan OI, Smiian-Horbunova KO, Bynda TP, Loboda AM, Popov SV, Vysotsky IY, et al. Optimization of the treatment of rotavirus infection in children by using bacillus clausii. Wiad Lek. 2019;72(7):1320–3. https://doi.org/10.36740/WLek201907117.

Burns PB, Rohrich RJ, Chung KC. The levels of evidence and their role in evidence-based medicine. Plast Reconstr Surg. 2011;128(1):305–10. https://doi.org/10.1097/PRS.0b013e318219c171.

de Castro J-A, Kesavelu D, Lahiri KR, Chaijitraruch N, Chongsrisawat V, Jog PP, et al. 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. Trop Dis Travel Med Vaccines. 2020;6(1):21. https://doi.org/10.1186/s40794-020-00120-4.

Brandt KG, Castro Antunes MM, Silva GA. Acute diarrhea: evidence-based management. J Pediatr. 2015;91(6 Suppl 1):S36–43. https://doi.org/10.1016/j.jped.2015.06.002.

Gupta P, Shah D. Nutrition and macronutrient disorders. In: Ghai OP, Gupta P, Paul VK, editors. Essential Pediatrics. 6th ed. New Delhi: CBS Publishers and Distributors; 2007. p. 93–118.

Fischbach W, Andresen V, Eberlin M, Mueck T, Layer P. A comprehensive comparison of the efficacy and tolerability of racecadotril with other treatments of acute diarrhea in adults. Front Med (Lausanne). 2016;3:44. https://doi.org/10.3389/fmed.2016.00044.

O'Donnell L, Virjee J, Heaton KW. Detection of pseudodiarrhoea by simple clinical assessment of intestinal transit rate. BMJ. 1990;300(6722):439–40. https://doi.org/10.1136/bmj.300.6722.439.

Sanofi-Aventis. ENIGMA Study (EudraCT # 2014–004636-19). 2008. https://www.sanofi.com/en/science-and-innovation/clinical-trials-and-results/our-disclosure-commitments/pharma/-/media/Project/One-Sanofi-Web/Websites/Global/Sanofi-COM/Home/common/docs/clinical-study-results/ENTER_L_01486_summary.pdf. Accessed 8 Dec 2021.

Akdag AI, Gupta S, Khan N, Upadhayay A, Ray P. Epidemiology and clinical features of rotavirus, adenovirus, and astrovirus infections and coinfections in children with acute gastroenteritis prior to rotavirus vaccine introduction in Meerut. North India J Med Virol. 2020;92(8):1102–9. https://doi.org/10.1002/jmv.25645.

de Castro J-A, Villa-Real Guno MJ, Perez MO. Bacillus clausii as adjunctive treatment for acute community-acquired diarrhea among Filipino children: a large-scale, multicenter, open-label study (CODDLE). Trop Dis Travel Med Vaccines. 2019;5(1):14. https://doi.org/10.1186/s40794-019-0089-5.

Hall AJ, Lopman BA, Payne DC, Patel MM, Gastañaduy PA, Vinjé J, et al. Norovirus disease in the United States. Emerg Infect Dis. 2013;19(8):1198–205. https://doi.org/10.3201/eid1908.130465.

Payne DC, Vinjé J, Szilagyi PG, Edwards KM, Staat MA, Weinberg GA, et al. Norovirus and medically attended gastroenteritis in U.S. children. N Engl J Med. 2013;368(12):1121–30. https://doi.org/10.1056/NEJMsa1206589.

Freedman SB, Williamson-Urquhart S, Farion KJ, Gouin S, Willan AR, Poonaiet N, et al. PERC PROGUT trial group. Multicenter trial of a combination probiotic for children with gastroenteritis. N Engl J Med. 2018;379(21):2015–26. https://doi.org/10.1056/NEJMoa1802597.

Schnadower D, Tarr PI, Casper TC, Gorelick MH, Dean JM, O'Connell KJ, et al. Lactobacillus rhamnosus GG versus placebo for acute gastroenteritis in children. N Engl J Med. 2018;379(21):2002–14. https://doi.org/10.1056/NEJMoa1802598.

Freedman SB, Xie J, Nettel-Aguirre A, Pang X-L, Chui L, Williamson-Urquhart S, et al. Pediatric Emergency Research Canada Probiotic (PERC) Regimen for Outpatient Gastroenteritis Utility of Treatment (PROGUT) Trial Group. A randomized trial evaluating virus-specific effects of a combination probiotic in children with acute gastroenteritis. Nat Commun. 2020;11(1):2533. https://doi.org/10.1038/s41467-020-16308-3.

Szajewska H, Guarino A, Hojsak I, Indrio F, Kolacek S, Orel R, et al. Use of probiotics for the Management of Acute Gastroenteritis in children: an update. J Pediatr Gastroenterol Nutr. 2020;71(2):261–9. https://doi.org/10.1097/MPG.0000000000002751.

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Tropical Diseases, Travel Medicine and Vaccines

Tập 8 Số 1

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