Antibiotic Resistance Clinical Trial
Official title:
First Line Antimicrobials in Children With Complicated Severe Acute Malnutrition
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.
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.
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