First Line Antimicrobials in Children With Complicated Severe Acute Malnutrition
- Conditions
- Antibiotic ResistanceMalnutrition SevereAntibiotic Toxicity
- Interventions
- Registration Number
- NCT03174236
- Lead Sponsor
- University of Oxford
- Brief Summary
Children with severe malnutrition who are admitted sick to hospitals have a high mortality(death rate), usually because of infection. All children with severe malnutrition admitted to hospitals are treated with antibiotics(medication used to kill bacteria). However, the current antibiotics used in hospitals may not be the most effective. It is possible that the antibiotics that are currently used after initial antibiotics should be used first. No studies have been carried out to determine if the current antibiotics used for treating malnourished children who are sick and admitted in hospital are the most appropriate. The aim of this study is to find out if a changed antibiotic system for children with malnutrition is safe, reduces the risk of death and improves nutritional recovery.
- Detailed Description
Children with complicated severe acute malnutrition (SAM) admitted to hospital in sub-Saharan Africa have a case fatality(death rate) between 12% and more than 20%. Because children with SAM may not exhibit the usual signs of infection, WHO guidelines recommend routine antibiotics(medication used to kill bacteria). However, this is based on "low quality evidence". There is evidence that because of bacterial resistance to the currently recommended first-line antibiotics (gentamicin plus ampicillin or penicillin) could 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.
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 multi-centre 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, additional pharmacokinetic data for the dosing schedule used in the trial will be collected from 120 participants in a sub-study. 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. A further sub-study will examine 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.
Recruitment & Eligibility
- Status
- UNKNOWN
- Sex
- All
- Target Recruitment
- 2000
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- FACTORIAL
- Arm && Interventions
Group Intervention Description Benzyl penicillin plus gentamicin Benzyl penicillin Arm 2 IV Benzyl penicillin plus gentamicin (usual care): Participants in this group receive 50 000 U/kg IV benzyl penicillin every six hours for a minimum of two days and a maximum of seven days. Placebo Placebo Arm 2 Placebo: Participants receive an oral placebo dose to match that for Metronidazole twice a day for seven days. Benzyl penicillin plus gentamicin Gentamicin Arm 2 IV Benzyl penicillin plus gentamicin (usual care): Participants in this group receive 50 000 U/kg IV benzyl penicillin every six hours for a minimum of two days and a maximum of seven days. Ceftriaxone Ceftriaxone Arm 1 IV Ceftriaxone: Participants in this group receive 80mg/kg IV ceftriaxone once a day for a minimum of 48 hours and a usual maximum of seven days. Metronidazole Metronidazole Arm 1 Metronidazole: Participants receive 10 to 16 mg/kg oral metronidazole twice a day for seven days.
- Primary Outcome Measures
Name Time Method Mortality 90 days after enrolment. Mortality is measured using source documents from medical records, verbal autopsy, or death or burial certificates in the community.
- Secondary Outcome Measures
Name Time Method Grade 4 toxicity Up to 7 days following enrolment Grade 4 toxicity events are measured according to the Division of AIDS Tables for Grading the Severity of Adverse Events using medical records.
Mortality during the first 7 days 7 days Mortality during the first 7 days
Mortality during the first 30 days 7 days Mortality during the first 30 days
Serious adverse events 90 days after enrolment. Serious adverse events are measured using inpatient and outpatient medical records.
Tolerability - relevant side effects during the first 7 day 7 days Vomiting, diarrhoea, NG tube in place and convulsions during the first 7 days
Re-admission to hospital. From discharge from hospital to 90 days after enrolment Re-admission to hospital defined as at least one overnight stay in a hospital or health facility are measured using inpatient records.
Duration of hospitalisation. 90 days after enrolment. Total duration of hospitalisation is measured in days using inpatient records at the start and end of each admission to hospital.
Index admission inpatient mortality Through index hospital admission, an average of 7 days. Mortality during the index hospitalisation, measured using inpatient records.
Change in nutritional status 90 days after enrolment. Change in nutritional status is measured using mid-upper arm circumference, weight-for-length, weight-for-age and length-for-age compared to at enrollment.
Faecal carriage of bacteria expressing Extended Spectrum Lactamase (ESBL) Through study completion an average of 90 days. Faecal carriage of bacteria expressing Extended Spectrum Lactamase (ESBL) is measured using microbial culture and sensitivity testing of rectal swabs.
Mortality after discharge from index admission. 90 days after enrolment Mortality occurring after discharge from the index hospital admission is measured using inpatient medical records, verbal autopsy, or death or burial certificates in the community.
Causes of death. 90 days after enrolment Causes of death, as determined by an endpoint review committee.
Duration of administration of antibiotics. 90 days after enrolment. Duration of administration of intravenous antibiotics measured using inpatient records.
Trial Locations
- Locations (7)
Mbagathi Hospital
🇰🇪Nairobi, Kenya
Coast General Hospital - Study site
🇰🇪Mombasa, Kenya
Mbagathi District Hospital
🇰🇪Nairobi, Kenya
Mbale Regional Referral Hospital
🇺🇬Mbale, Uganda
Kemri Wellcome Trust Research Programme
🇰🇪Kilifi, Coast Province, Kenya
Kilifi County Hospital
🇰🇪Kilifi, Kenya
KEMRI WT Clinical Trials Facility
🇰🇪Kilifi, Kenya