Contents lists available at ScienceDirect Acta Tropica journal homepage: www.elsevier.com/locate/actatropica Effect of nitazoxanide on diarrhea: A systematic review and network meta- analysis of randomized controlled trials Mohammad Rashidul Hashan a,b,1 , Khaled Mosaad Elhusseiny b,c,1 ,LeHuu-Hoai b,d,e,1 , Thuan Minh Tieu b,f ,SoonKhaiLow b,g ,LeHuuNhatMinh b,d ,ThaiLeBaNghia b,h , LeQuangLoc b,d ,MaiNhuY b,i ,PeterSamuelEid b,j , Mohammed Abed b,k , Salma Said Elkolaly b,l , Gehad Mohamed Tawfik b,m ,NguyenTienHuy n,o, ⁎ a Infectious Disease Division, Respiratory and Enteric Infections Department, International Center for Diarrheal Disease Research, Dhaka, Bangladesh b Online Research Club (http://www.onlineresearchclub.org/), Nagasaki, Japan c Faculty of Medicine, Al-Azhar University, Cairo, Egypt d Saigon General Hospital, Ho Chi Minh City, Vietnam e University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh, Vietnam f Faculty of Health Sciences, McMaster University, Hamilton, ON. Canada g School of Medicine, Faculty of Health and Medical Sciences, Taylor's University, Selangor, Malaysia h Department of Biomedical Engineering, South Dakota School of Mines and Technology, Rapid City, 57701, United States i Department of Chemical and Biological Engineering, South Dakota School of Mines and Technology, Rapid City, 57701, United States j Faculty of Medicine, Ain Shams University, Cairo, Egypt k Institute of Medical Technology, Baghdad, Iraq l Faculty of Medicine, Menoufia University, Yassin Abdel-ghaffar Street, Shebin El-Kom, Menoufia, 32511, Egypt m Faculty of Medicine, Ain Shams University, Cairo, Egypt n Evidence Based Medicine Research Group, Ton Duc Thang University, Ho Chi Minh City, 70000, Vietnam o Faculty of Applied Sciences, Ton Duc Thang University, Ho Chi Minh City, 70000, Vietnam ARTICLEINFO Keywords: Nitazoxanide Diarrhea Antibiotic Systematic review Meta-analysis ABSTRACT We aimed to systematically review evidence pertaining to the safety and efficacy of nitazoxanide in treating infectiousdiarrhea.OnSeptember21,2017,weidentifiedrelevantstudiesusing12databases.Theestimatesof the included studies were pooled as a risk ratio (RR). We conducted a network and pairwise random-effects meta-analysisforbothdirectandindirectcomparisonsofdifferentorganismsthatareknowntocausediarrhea. The primary and secondary analysis outcomes were clinical response until cessation of illness, parasitological response and adverse events. We included 18 studies in our analysis. In cryptosporidiosis, the overall estimate favored nitazoxanide in its clinical response in comparison with placebo RR 1.46 [95% CI 1.22–1.74; P-value <0.0001].Networkmeta-analysisamongpatientswith Giardia intestinalis showedanincreaseintheprobability ofdiarrhealcessationandparasitologicalresponsesincomparisonwithplacebo,RR1.69[95%CI1.08–2.64,P- score 0.27] and RR 2.91 [95% CI 1.72–4.91, P-score 0.55] respectively. In Clostridium difficile infection, the network meta-analysis revealed a non-significantly superior clinical response effect of nitazoxanide to me- tronidazole 31 days after treatment RR 1.21 [95% CI 0.87–1.69, P-score 0.26]. In Entamoeba histolytica, the overall estimate significantly favored nitazoxanide in parasitological response with placebo RR 1.80 [95% CI 1.35–2.40, P-value < 0.001]. We highlighted the effectiveness of nitazoxanide in the cessation of diarrhea caused by Cryptosporidium, Giardia intestinalis and Entamoeba histolytica infection. We also found significant superiorityofNTZtometronidazoleinimprovingtheclinicalresponseto G. intestinalis,thusitmaybeasuitable https://doi.org/10.1016/j.actatropica.2020.105603 Received23November2019;Receivedinrevisedform20June2020;Accepted25June2020 ⁎ Correspondence to: Nguyen Tien Huy, Evidence Based Medicine Research Group & Faculty of Applied Sciences, Ton Duc Thang University, Ho Chi Minh City, Vietnam. E-mail addresses: hasandmck66@gmail.com (M.R. Hashan), khaledelhosiny8@gmail.com (K.M. Elhusseiny), huuhoai.md@gmail.com (L. Huu-Hoai), tieut@mcmaster.ca (T.M. Tieu), soonkhai.low@gmail.com (S.K. Low), lehuunhatminh.md@ump.edu.vn (L.H.N. Minh), banghia0905@gmail.com (T.L.B. Nghia), lequangloc.md@gmail.com (L.Q. Loc), vivianmai1993@gmail.com (M.N. Y), petersamuel86@gmail.com (P.S. Eid), drabedmn@gmail.com (M. Abed), salma.said56.ss@gmail.com (S.S. Elkolaly), dr.gehadmohamed@hotmail.com (G.M. Tawfik), nguyentienhuy@tdtu.edu.vn (N.T. Huy). 1 Authors equally contributed the work. Acta Tropica 210 (2020) 105603 Available online 26 June 2020 0001-706X/ © 2020 Elsevier B.V. All rights reserved. T