TARGET

The challenge

Young children in low-resource settings are prone to frequent episodes of acute watery diarrhoea, which can be severe enough to lead to hospitalisation and death. Although an estimated 25–50% of diarrhoeal cases are likely caused by bacterial infections, WHO does not currently recommend antibiotic treatment because evidence of benefit is limited and because antibiotic use could drive antimicrobial resistance. Many children receive antibiotics despite WHO’s recommendations against them; however, the antibiotics they receive are often not effective against the bacteria that cause diarrhoeal disease.

The case for antibiotic use would be stronger if children most likely to benefit could be identified, so antibiotics could be used sparingly and only where specifically needed. Unfortunately, no simple tests distinguish between viral, bacterial, and parasitic gut infections, and testing for specific pathogens is not feasible in most settings in sub-Saharan Africa.

Diarrhoeal disease is one of the biggest risk factors for death among children with malnutrition. Such children are also more likely to have diarrhoeal disease caused by bacterial infections. A recent trial therefore assessed whether antibiotic treatment would reduce hospitalisation or death in young children with acute watery diarrhoea plus either dehydration, severe stunting or moderate wasting. The group as a whole showed a small benefit, but the effect was much larger when the analysis focused only on children with malnutrition, in whom the risk of hospitalisation and death was cut by more than a third. 

The project team calculated that in settings with high morbidity and mortality from malnutrition, fewer than 20 children would need to be treated for watery diarrhoea to prevent one case of hospitalisation or death, lower than the comparable figure for other conditions (such as pneumonia) for which WHO recommends antibiotic use.  Therefore, if the study results show a benefit of antibiotic treatment for children with malnutrition and watery diarrhoea, they could impact WHO diarrhoea treatment recommendations. 

Additionally, climate change could increase both cases of watery diarrhoea due to bacteria and the rates of malnutrition, suggesting that antibiotics could be more beneficial in the future. Understanding whether antibiotics work, and which children could benefit most from them now and in the future, is therefore urgently needed. 

The project

Based on these challenges, the TARGET project is carrying out a trial to assess whether antibiotic treatment for young children with acute watery diarrhoea and malnutrition can reduce their risk of hospitalisation and death. At sites in Kenya and Tanzania where malnutrition is common, 2,800 children under 5 years of age will be recruited and randomised to one of two antibiotics with known efficacy against intestinal pathogens – azithromycin and ciprofloxacin – or standard care alone. 

The project will characterise the causes of infection, assess whether a child's clinical characteristics at presentation can predict treatment response, and evaluate a point-of-care stool haemoglobin assay, which shows promise as a simple way to detect bacterial infections in care settings.

To assess whether antibiotics increase the risk of antimicrobial resistance, bacteria will be sequenced to identify potential antimicrobial resistance genes when children do not respond to therapy. The project will also assess antibiotics’ risk of increasing antimicrobial resistance in the wider gut microbiome over time. 

The epidemiology of diarrhoeal disease is likely to be significantly affected by geography and climate change. The project will use publicly available data and trial data to predict whether antibiotics are beneficial for watery diarrhoea in new settings.  The project is collaborating with another EU-funded project (SPRINGS), which is developing methods to predict how the distribution of organisms causing diarrhoeal disease will be affected by a changing climate. The TARGET project will install weather stations, work with meteorological agencies, and assess local environmental conditions to determine how current and future climate will alter bacterial diarrhoeal disease.  This information will help predict which other sites might see a similar distribution of gut pathogens because they share similar environmental conditions.

Impact

The TARGET project could have a major impact on treating diarrhoeal disease in young children in sub-Saharan Africa. It will:

• Demonstrate whether a highly vulnerable group – young children with acute watery diarrhoea and malnutrition – benefits from the use of widely available antibiotics.
• Evaluate whether a simple point-of-care test could be used more generally to detect bacterial gut infections requiring antibiotic treatment. 
• Understand whether benefits of antibiotic treatment are generalisable over other geographies and under projected future climate scenarios.
• Generate additional information on the risk of antimicrobial resistance following antibiotic usage by tracking changes in antimicrobial resistance genes in bacterial gut pathogens and in the gut microbiome following antibiotic therapies.

Targeted treatment of acute watery diarrhoea in young children with malnutrition could save lives and reduce the risk of hospitalisation, which can have a catastrophic impact on household finances and add to the financial pressures on health systems. By ensuring that antibiotics are targeted where most needed, the project could also reduce the development of antimicrobial resistance in bacteria causing diarrhoeal disease.