Lay Title

A study to compare antibiotics used to treat children with severe acute malnutrition.

What is the problem?

Children with severe malnutrition who are admitted sick to hospitals have a high mortality, usually because of infection. All children with severe malnutrition admitted to hospitals are treated with antibiotics. However, we are not sure that the current antibiotics are the most effective. It is possible that the antibiotics that are currently used as second-line should be used first. No studies have been carried out to determine if the current antibiotics used for treating malnourished children are the most appropriate. We will therefore carry out this large trial comparing different antibiotics to find out this.

What questions are we trying to answer?

We want to find out if a revised antibiotic regime for children with complicated severe acute malnutrition is safe, reduces the risk of death and improves nutritional recovery. We also want to find out how often children carry bacteria that are resistant to antibiotics in their intestines and the effects of different antibiotics on the ability for bacteria to resist antibiotic treatment and the costs to hospitals and to families of treating malnourished (SAM) and without SAM children with the different antibiotics.

Where is the study taking place, how many people does it involve and how are they selected?

We will carry out the study in Kilifi County Hospital, Coast General Hospital in Mombasa, and Mbagathi hospital in Nairobi, Kenya and Mbale Regional Referral Hospital, Uganda. We will enrol 2,000 children with severe malnutrition admitted to hospital. We will ask parents and guardians of all children between the ages of 2 months to 13 years who are admitted to hospital with severe malnutrition and would normally be treated with antibiotics according to current guideline to participate and enrol an equal number of children at each site who are admitted without SAM to examine faecal samples for bacteria that may be resistant to antibiotics.

What does the study involve for those who are in it?

After informed consent, a study clinician will examine the child and prescribe antibiotics that have been randomly allocated. A small volume of blood and a faecal sample will be taken for this research in addition to the routine tests for care at admission before antibiotic administration, and again at discharge. The children will be reviewed daily by the study team, working together with the hospital staff to provide the best care available in the hospital. Children will be followed up for 90 days from enrolment with 3 scheduled follow up visits involving a health questionnaire, anthropometry and the collection of a faecal sample at two of the visits. The levels of the antibiotics being used will be checked in the blood of 120 participants at Kenyan sites whilst in hospital. Parents and carers of approximately 650 children in both SAM and without SAM across all sites may also be interviewed about any costs they have met as a result of the child needing healthcare. If a child requires readmission to hospital, a small volume of blood will be drawn to try and determine the cause. Results of blood tests will be fed back to the clinical team to assist in care. For non-severely malnourished children, a rectal swab will be taken at admission and discharge, and information collected during admission, but we will do no additional samples or further follow up.

What are the benefits and risks/costs of the study for those involved? 

How will the study benefit society? 

Knowing how better to use antibiotics in malnourished children when they are admitted to hospital will help decision-making to improve their health and survival. The findings from this research will directly inform policy and program management decisions related to the care of the sick child.

When does the study start and finish?

Children with complicated severe acute malnutrition (SAM) admitted to hospital in sub-Saharan Africa have a case fatality between 12% and more than 20%. Because children with SAM may not exhibit the usual signs of infection, WHO guidelines recommend routine antibiotics. However, this is based on “low quality evidence”. There is evidence from CGMR-C, Kilifi and from other centres in Africa that bacterial resistance to the currently recommended first-line antibiotics (gentamicin plus ampicillin or penicillin) may be less effective than potential alternatives. Some hospitals in Africa are already increasing use of ceftriaxone as a first-line treatment. However, this is not based on any data that ceftriaxone actually improves outcomes. Of concern is that ceftriaxone use may also lead to increased antimicrobial resistance, including inducing extended spectrum beta-lactamase (ESBL) and other classes of resistance. We are currently undertaking a study to assess the prevalence of carriage of bacteria expressing ESBL (KEMRI/SERU/CGMR-C/023/3161; OxTREC 47-15). A further area where evidence for policy is lacking is the use of metronidazole in severely malnourished children. The WHO guidelines recommend “Metronidazole 7.5 mg/kg every 8 h for 7 days may be given in addition to broad-spectrum antibiotics; however, the efficacy of this treatment has not been established in clinical trials.” Metronidazole is effective against anaerobic bacteria, small bowel bacterial overgrowth, Clostridium difficile colitis and also Giardia, which is common amongst children with SAM. Small cohort studies of metronidazole usage suggest there may be benefits for nutritional recovery in malnourished children. However, metronidazole can cause nausea and anorexia, potentially impairing recovery from malnutrition and may also rarely cause liver and neurological toxicity. This multicentre clinical trial will assess the efficacy of two interventions, ceftriaxone and metronidazole, on mortality and nutritional recovery in sick, severely malnourished children in a 2x2 factorial design. There will also be an analysis of antimicrobial resistance and an economic analysis. To extend our understanding of metronidazole and ceftriaxone pharmacokinetics from protocol KEMRI/SERU/CGMR-C/023/3161; OxTREC 47-15’, additional pharmacokinetic data for the dosing schedule used in the trial will be collected from 120 participants. The trial will be conducted at Kilifi County Hospital, Coast General Hospital, Mbagathi Hospital in Kenya and Mbale Regional Referral Hospital in Uganda. The trial will assess antimicrobial resistance that is carried by children in their intestines and in invasive bacterial isolates. The relative costs of care for SAM for health facilities and for families, including antimicrobial usage will also be assessed. Clear data on the benefits, risks and costs of these antimicrobials will influence policy on case management and antimicrobial stewardship in this vulnerable population.