First Line Antimicrobials in Complicated Severe Acute Malnutrition (FLACSAM)

Severe acute malnutrition (SAM) causes 1 million deaths in children annually by making children susceptible to common infections. The World Health Organisation (WHO) recommends that children with SAM should receive antibiotics together with nutritional rehabilitation. Children with SAM and complications including signs of infection or severe metabolic disturbance are referred for hospital admission. However, most admissions with SAM present directly to hospital because of severe illness, and their SAM is only detected during clinical assessment. At the four hospital sites for the proposed trial, between 15% and 18% of paediatric admissions between the ages of 2 and 59 months have SAM. In sub-Saharan Africa, up to 30% of children admitted to hospital with complicated SAM die, usually from severe infection. Mortality is highest amongst those who also have HIV infection.

There are reports that bacteria isolated from children with SAM, when tested in the laboratory, are often not susceptible to the recommended first-line antibiotics. In Kenya we have conducted long term surveillance of bacterial infections. Amongst children with SAM, non-susceptibility has risen: in the last 5 years, more than one third of bacteria isolated at admission to hospital are non-susceptible to the recommended antibiotics. Because children with SAM are vulnerable to infection, this to result in death rather than simply a prolonged hospital stay.

An alternative antibiotic, ceftriaxone, is cheaper the currently recommended combination and only has to be given once a day instead of four times. Much less resistance to ceftriaxone is reported. Ceftriaxone would be used as first line treatment if such a child were admitted to hospital in the UK. At first sight, it seems that ceftriaxone would be a more appropriate antibiotic, and it could reduce deaths. However, a significant concern is that ceftriaxone is known to rapidly induce resistance to multiple classes of antibiotics. This could mean that subsequent infections could be harder, and more expensive, to treat. Furthermore, studies have not shown a clear relationship between laboratory susceptibility testing and actual outcomes. In determining policy for empiric antimicrobials for this vulnerable population, potential benefits of reduced mortality, quicker recovery and reduced costs must be weighed against potential risks of infections that are difficult and expensive to treat. There is currently no evidence to inform this decision.

A second question in the antibiotic treatment of SAM is the value of metronidazole. Current WHO guidelines suggest that metronidazole may be optionally used although it has never been tested in a clinical trial. It is effective against bacteria that cause abnormal overgrowth in the small bowel, and against gut parasites such as Giardia. These conditions are common amongst children with SAM and may cause malabsorption of nutrients and diarrhoea. Treating them improve nutritional recovery. Results of small studies suggest this may be the case. However, metronidazole can cause nausea, vomiting and other toxicities which could impede nutritional recovery.

We propose an efficiently designed trial to test both ceftriaxone and of metronidazole against standard care for the outcomes of mortality and nutritional recovery. First we will determine the optimal dosing for the drugs in malnourished children. We will carefully investigate children for infections and the antibiotic susceptibility of bacteria isolated determined. An economic analysis will measure the cost-benefit ratio of each strategy and overall costs of treatment for SAM. The trial will be run at 2 rural and 2 urban hospitals in Kenya. The results are expected to have direct impact on antibiotic policy for the management of SAM in hospitals in Africa and will provide unique information that will contribute to global efforts to combat the threat of antimicrobial resistance.

The WHO currently recommends all children with severe acute malnutrition (SAM) receive broad-spectrum antibiotics. At the four hospitals for the proposed trial, 15-18% of admissions aged 2-59 months have SAM, of whom 20-25% have HIV. SAM dramatically increases the case fatality of all common clinical syndromes with overall case fatality up of to 30%. Non-susceptibility to the recommended first-line empiric antimicrobials (penicillin plus gentamicin) is widespread. Our long-term surveillance in Kenya suggests that 38% of bacterial isolates from children with SAM are non-susceptible to this combination, compared to <14% to ceftriaxone. There are no tests that accurately indicate the presence of invasive bacterial infection or non-susceptibility within the vital first few days.

Ceftriaxone is a potential alternative first-line antibiotic. Some centres are already changing policy without data on susceptibility or outcomes. Ceftriaxone is given once rather than four times daily, and is now inexpensive. However, a significant concern is the induction of resistance to multiple antibiotic classes, increasing costs and threatening our ability to treat serious infections. Any benefits of reduced mortality must be weighed against potential risks of infections that are difficult and expensive to treat.

A second outstanding question in the management of SAM is the use of oral metronidazole. It is active against anaerobic bacteria that cause small bowel overgrowth, and against Giardia. Small cohort studies suggest growth benefits However, metronidazole can cause nausea, anorexia and hepatic toxicity, potentially impairing recovery. Importantly, the one pharmacokinetic study in SAM, reported delayed elimination.

We propose a 2x2 factorial trial of ceftriaxone and metronidazole versus standard care, with primary outcomes of mortality and anthropometric recovery. We will examine pharmacokinetics; predictors of infection; antimicrobial resistance; and cost-effectiveness.

The project aims to directly inform national actors (e.g. Ministries of Health) and international (e.g. WHO) bodies responsible for guidelines and policy. The project will generate: i) a basis for dosing antimicrobials in children with severe malnutrition; ii) high quality evidence for the efficacy, risks and costs of empiric ceftriaxone and metronidazole compared to current standard care; iii) knowledge of the types and risks of invasive bacterial infections, and of the prevalence, types and risks factors for antimicrobial resistance that will inform prescribing; iv) knowledge of the costs of healthcare, including those due to antimicrobial resistance; and v) data on nosocomial infection that informs policies for infection control and antimicrobial stewardship.

Ultimately, the beneficiaries will be undernourished children, who will receive treatment that has a firmer evidence base. Impact will be ensured by: i) existing committee membership by the investigators, including within the Kenyan Ministry of Health, Pharmacy and Poisons Board, Kenya Paediatric Association, World Health Organisation expert advisory groups on malnutrition and antimicrobials, International Malnutrition Task Force, networks on antimicrobial resistance, and collaborative activities with UNICEF, MSF and other humanitarian agencies; ii) workshops and conferences in Kenya ; and iii) open-access publication.

Benefits to the wider public will include raised awareness and data to support rational antimicrobial prescribing. Hospital services may be improved by more cost and time-efficient antimicrobial regimens.

Data on pharmacokinetics amongst children with severe acute malnutrition will be available after the first year of the project and will be published in open access journals along with dosing recommendations. Data on the efficacy of the trial interventions will be made available once the trial is complete, along with data on the predictive value of clinical signs for infection, the frequency and types of community and hospital acquired bacterial infections, information relating to infection control and cost-benefit analyses. These will be shared at a national workshop, international conferences, at international advisory committees and published in open-access journals. Impact will be assessed by output being included in systematic reviews and being considered by committees that set guidelines and policies.

Project staff will all be trained in GCP/GCLP, ethics communication and consent, data entry, project management, and GPS mapping. Clinical staff at all of the hospital sites will be trained on best practises for management of severe acute malnutrition. A Kenyan paediatrician will run clinical aspects of the trial and will be trained in clinical trials and become an expert in infection in relation to undernutrition. Staff at Strathmore University will gain further skills in pharmacokinetic analysis and mathematical modelling techniques. A research assistant in microbiology at the KWTRP will receive specific training in the laboratory evaluation of antimicrobial resistance, focussing on ESBL-producing Enterobacteriaceae. A Kenyan health economist will be mentored by Dr Griffiths at the LSHTM in order to build further capacity on evaluation and analysis in Kenya. Academic trial staff will be encouraged to publish in peer-reviewed journals, present at international meetings and write proposals to use data and samples.