First Line Antimicrobials in Complicated Severe Acute Malnutrition (FLACSAM)

Lead Research Organisation: University of Oxford
Department Name: Tropical Medicine

Abstract

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.

Technical Summary

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.

Planned Impact

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.

Publications

10 25 50
 
Description Review of antibiotics for bacterial infections in paediatrics (WHO Department of Maternal, Newborn, Child and Adolescent Health)
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guideline committee
Impact In order to minimize child mortality for common bacterial infections, especially in the low-income setting, the World Health Organization has issued guidelines on the antibiotic treatment of children suffering from pneumonia, sepsis, dysentery (shigellosis), cholera, or severe acute malnutrition (SAM, often associated with bacterial infection). Several of these recommendations are, however, already over 10 years old. In the light of changing microbial epidemiology and emerging bacterial resistance to antimicrobial agents, the MCA department considered it important to update these guidelines and the WHO recommendations on the use of antibiotics for treatment of children with selected infections. Such a review became especially relevant in the latter part of 2016, when both scientists and regulatory authorities published some new concerns about the safety of two drugs that the WHO was recommending for dysentery treatment: fluoroquinolones and azithromycin (if used in combination with antimalarial drugs). In order to maintain the validity of its guidelines and to make updates where necessary, the WHO, through its Department of Maternal, Newborn, Child and Adolescent Health, decided to undertake a review of its existing guidelines. For this purpose, technical experts from the MCA department first agreed on the process with experts at the WHO's Essential Medicines Program, then solicited five systematic reviews on the current evidence on the safety, efficacy, and feasibility of various antibiotic treatment options for selected bacterial infections among children, shared the reviews in advance with a group of 14 international experts, and finally convened a 3-day meeting in Geneva, where the same experts reviewed the existing guidelines, the solicited literah1re reviews and any other evidence and came up with recommendations.
URL http://www.who.int/selection_medicines/committees/expert/21/applications/s6_paed_antibiotics.pdf
 
Description Institutional Strategic Support Fund: Establishing a meta-genomics platform to support clinical research at KWTRP
Amount £75,800 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 06/2015 
End 05/2016
 
Description One-off grant: The CHAIN Network (Building the evidence base for appropriate care of the sick, undernourished child in limited resource settings)
Amount $16,068,075 (USD)
Funding ID OPP1131320 
Organisation Bill and Melinda Gates Foundation 
Sector Charity/Non Profit
Country United States of America
Start 10/2015 
End 09/2019
 
Description Project Grant
Amount $128,471 (USD)
Organisation World Health Organization (WHO) 
Department Special Programme for Research and Training in Tropical Disease
Sector Public
Country Switzerland, Swiss Confederation
Start 01/2016 
End 06/2017
 
Description Economic analysis 
Organisation Medical Research Council (MRC)
Department MRC International Nutrition Group
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Public 
PI Contribution We are undertaking the economic and cost-benefit analysis. Dr Julie Jemutai, postdoctoral health economist is funded from this award.
Collaborator Contribution Professor Anna Vassall is providing design and analysis support. LSHTM hosted Julie Jemutai for 6 weeks in early 2017 to develop methodology and finalize economic data collection for the main trial.
Impact Methodology, SOP, data collection tools so far.
Start Year 2016
 
Description GOSH/UCL London 
Organisation Great Ormond Street Hospital (GOSH)
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Hospitals 
PI Contribution We designed the PK study together with Joseph Standing and undertook the clinical study.
Collaborator Contribution Dr Joseph Standing, MRC Fellow in Antimicrobial Pharmacy, led design ad analysis of our PK study of ceftriaxone & metronidazole, and provided training.
Impact PK study and building capacity, will lead to two publications: Methods paper PK results, not previously undertaken in malnourished children, with direct policy relevance as well as guiding dosing for the main trial.
Start Year 2016
 
Description Mbale trial site 
Organisation Mbale Regional Hospital
Country Uganda, Republic of 
Sector Hospitals 
PI Contribution We will be funding Mbale as a trial site for the main trial in place of one of the smaller Kenyan sites, Malindi, in order to increase generalisability and complete the trial more quickly.
Collaborator Contribution Hosting the main trial, obtaining scientific and ethical approval, recruiting and following up participants, and sample storage for secondary analyses.
Impact ongoing Agreement in the process of being set up.
Start Year 2016
 
Description Molecular microbiology 
Organisation University of Oxford
Department Centre for Statistics in Medicine
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution We provided rectal swabs from our phase 1 survey of antimicrobial resistance carriage at FLACSAM trial sites during one year, and lab technologist Joseph Waichungo's time, to undertake antimicrobial resistance metagenomic sequencing.
Collaborator Contribution Sample shipping, training & capacity building, nucleic acid extraction, high-throughput sequencing & bioinformatics.
Impact Ongoing
Start Year 2016
 
Description PK assay development 
Organisation St George's Hospital
Department Courtyard Clinic
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Hospitals 
PI Contribution The award funded pharmacologist Mr Martin Ongas to develop and undertake PK assays.
Collaborator Contribution Dr Karin Kipper provided time and visited Kenya to develop and optimize PK assays , and provide capacity building at Strathmore University, Nairobi
Impact The PK results are now ready and have informed main trial dosing. Two papers are being written: methods paper and the results. These will inform policy.
Start Year 2016
 
Description PK assays 
Organisation Strathmore University
Country Kenya, Republic of 
Sector Academic/University 
PI Contribution We provided funding for this award for developing the PK assays with training and support from UCL & St. George's, London. Then, providing consumables and samples to undertake the assays.
Collaborator Contribution Undertook assay development and the assays themselves.
Impact PK assay results were generated to a high standard and analysed with Joseph Standing at GOSH to generate the dosing for the main trial and policy relevance.
Start Year 2015
 
Description BBC World Interview 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Interview about the impact of antimicrobial resistance in Africa shown on BBC World TV.
Year(s) Of Engagement Activity 2016
 
Description CHAIN Network international annual meeting (Malawi) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact The CHAIN annual meeting brought together researchers from Malawi, Uganda, Kenya, Pakistan & Bangladesh; and senior advisors and observers from the WHO, Médecins Sans Frontières and the Gates Foundation. Inpatient and post discharge survival in relation to undernutrition was discussed, questioning the likely effectiveness of interventions and key socio-economic limitations. Plans for study harmonisation and integration made.
Year(s) Of Engagement Activity 2016
URL http://www.chainnetwork.org
 
Description Coast General Hospital Mombas pre-trial engagement 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact 26 people attended a presentation on antibiotic usage, resistance and the FLACSAM trial. Specific discussion and feedback arose on second and third line antibiotic strategy that informs the SOP during the PK phase and main trial phase.
Year(s) Of Engagement Activity 2016
 
Description Consultants meeting IAEA (Vienna) 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact Nine people attended a high-level forum on "Growth in children recovering from acute undernutrition" where issues of infection were presented and discussed, raising debate on the role of intestinal inflammation and microbiota.
Year(s) Of Engagement Activity 2016
 
Description Hospital & County Health Team Enagement (Nairobi) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact 28 nurses, medical interns, pediatricians and health administrative staff attended a presentation on antimicrobial resistance and pharmacokinetics in relation to the FLACSAM study. There was debate on prescribing practice, lack of knowledge of local resistance situation and infection control.
Year(s) Of Engagement Activity 2016
 
Description New site presentation (Mbale, Uganda) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Eight people attended a presentation and discussion about the study aims and practical considerations. Discussions about the relationships between nutrition, infection and mortality. Debate on the challenges of nosocomial infections in African hospitals.
Year(s) Of Engagement Activity 2016
 
Description Nutrition & infection presentation ICDDR,B (Dhaka, Bangladesh) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact About 40 scientists and students from ICDDR,B attended a presentation on the problems of undernutrition and infection, sparking discussion about regional differences and similarities. Future plans made.
Year(s) Of Engagement Activity 2016
 
Description Presentation at the Bill & Melinda Gates Foundation 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Supporters
Results and Impact 31 people, including scientists, from WHO and from the BMGF attended a 'malnutrition convening' at the BMGF to discuss next steps in efforts to reduce mortality acute illness in the context of moderate and severe malnutrition. Outputs directed a funding call for a network of sites collecting common data and harmonisation of clinical trials, including FLACSAM.
Year(s) Of Engagement Activity 2015
 
Description WHO Expert Meeting on Antibiotics Against Childhood Infections (Geneva) 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact 14 experts and policymakers attended presentations and discussion on the use of antibiotics among children with severe acute malnutrition: Current WHO guidelines, review of relevant recent literature.

Output: recommendations on updates to the WHO guidelines and WHO Essential Medicines list. Application to include selected antibiotics to the Essential Medicines List for Children (EMLc), for use among children with pneumonia, sepsis, dysentery, cholera or severe acute malnutrition made.

Severe acute malnutrition: http://www.who.int/entity/selection_medicines/committees/expert/21/applications/s6_paed_antibiotics_appendix7_sam.pdf
Year(s) Of Engagement Activity 2016
URL http://www.who.int/selection_medicines/committees/expert/21/applications/antibacterials-mch_rev/en/