The purpose of this study is to evaluate whether antibiotic treatment of non-dysentery Shigella associated watery diarrhea (NDSD) cases improves clinical outcomes and growth in children.

Children with NDSD seeking care for diarrhea at the study hospitals in Bangladesh and Zambia will be enrolled and randomized to receive Azithromycin or placebo (a look-alike substance that contains no drug). Enrolled children will be followed for three months with household visits.

The investigators will determine whether antibiotic treatment of NDSD reduces the duration of diarrhea and time to microbiological cure (shedding of Shigella in stool), and whether it improves growth in children compared with the placebo group.

The current World Health Organization (WHO) guidelines for the treatment of diarrhea recommend antibiotics when visible blood is present in the stool and in cases suspected of cholera. Currently, >50% of Shigella-associated diarrhea cases are non-dysentery or watery diarrhea in nature; thus, would not be treated with antibiotics according to guidelines. Absence of dysentery does not exclude Shigella as a cause of diarrhea and may not indicate a lower risk of death. For particularly vulnerable younger or malnourished children, identification and treatment of Shigella infection might be lifesaving. Consequently, a critical question remains to be answered. Should cases of non-dysentery Shigella associated watery diarrhea (NDSD) be treated with antibiotics? The goal of this study is to determine whether antibiotic treatment of NDSD cases improves clinical outcomes and growth in children.

This is a phase 2B, randomized, double-blind, placebo-controlled study. Children aged >6-59 months with NDSD who are seeking care for diarrhea at the study hospitals in Bangladesh and Zambia will be enrolled and randomized to receive either Azithromycin or a placebo (a look-alike substance that contains no drug). All children will be rehydrated with either oral rehydration solution or intravenous fluids, depending on the degree of dehydration, and will receive zinc in accordance with standard of care. Enrolled children will be followed for three months through household visits to collect morbidity and anthropometry data.

Primary Outcomes

• Time to Cessation of Diarrhea (TCD) between intervention and placebo
• Change of Weight-for-age z-score (∆WAZ) in the 90 days following enrolment between intervention and placebo arms.

Secondary Outcomes

• Change in linear growth measured as change in length-for-age z score (∆LAZ) in the 90 days following enrolment between the placebo and treatment arms
• Time to microbiological cure between the intervention and placebo groups.

Inclusion Criteria:

• Patients >6 and ≤59 months of age seeking care in the study hospitals
• Patients residing within the study catchment area
• Present with watery diarrhea and positive for Shigella by RLDT
• Willing to be available for sample and data collection during the follow up visits

Exclusion Criteria:

• Inability or unwillingness of a participant's parent/guardian to give written informed consent or comply with study protocol
• Diarrhea started more than 96 hours before enrollment
• Antibiotics related to shigellosis treatment (including the investigational drug azithromycin) taken in the past 5 days
• More than 2 doses of antidiarrheal drugs taken in the past 24 hours
• History of allergy to Azithromycin
• Presence of visible blood in stool
• Children with severe acute malnutrition (below -3z scores of the median WHO growth standards).
• History of congenital heart diseases, known gastrointestinal abnormalities, including short bowel syndrome, chronic (inflammatory or irritable) bowel disease, inherited or acquired immune system deficiency rendering the patient immunocompromised, including chronic/long-term steroid treatment or other immunosuppressive treatment
• Fever over 39°C (102°F) with other complications that require antibiotic treatment
• Past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements or that may impact the quality or interpretation of the data obtained from the study

All participating parties with the exception of the study statistician will be masked.