Malnutrition Clinical Trial
Official title:
Pharmacokinetics of Antimicrobials and Carriage of Antimicrobial Resistance Amongst Hospitalised Children With Severe Acute Malnutrition
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, policymakers 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. Finding this out will need a large trial comparing different antibiotics. To prepare for such a trial the investigators first want to make sure that the doses given are correct for malnourished children. The investigators also want to check whether malnourished children more commonly carry resistant bacteria in their feces than well-nourished children. The study is important because the types of antibiotics and the doses needed to fight infection may be different in malnourished children because of the changes in their body due to malnutrition and the types of bacteria present.
Children with complicated severe acute malnutrition (SAM) admitted to hospital in sub-Saharan
Africa have an inpatient case fatality of 10 to 20%. Because children with SAM may not
exhibit the usual signs of infection, World Health Organization (WHO) guidelines recommend
routine antibiotics. However this is based on "low quality evidence". There is evidence from
Centre for Geographic Medical Research - Coast (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 a problem. It is possible that because of
frequent illness and antibiotic exposure, malnourished children may be more likely to have
resistant bacteria. 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 further problems with
antimicrobial resistance, including inducing extended spectrum beta-lactamase (ESBL) and
other classes of resistance.
A further area where evidence for policy is lacking is on 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 Giardia, which is common amongst children with SAM; and against other anaerobic
infections, including small bowel bacterial overgrowth and Clostridium difficile colitis.
Small cohort studies suggest there may be benefits for nutritional recovery. In Jamaica, half
of the children admitted for nutritional rehabilitation had evidence of small bowel anaerobic
bacterial overgrowth and this was improved by metronidazole. However, metronidazole can cause
nausea and anorexia, potentially impairing recovery from malnutrition and may also cause
liver and neurological toxicity. One small study of metronidazole in children with SAM
conducted in in Mexico reported significantly prolonged clearance in SAM, without symptomatic
toxicity, but suggesting a dosing frequency reduction. Overall, very few pharmacokinetic
studies have been done in malnourished children. Changes in body composition as well as
metabolic and drug elimination mechanisms may alter the potential toxicity or effective dose.
The investigators are planning a large clinical trial to assess the efficacy of ceftriaxone
and metronidazole on mortality, nutritional recovery and antimicrobial resistance in sick,
severely malnourished children. This preparatory work aims to determine the pharmacokinetics
of ceftriaxone and metronidazole in 80 severely malnourished children who are admitted to
three hospitals in Kenya in order to ensure dosing for the main trial is safe and in the
therapeutic range. The study will also determine the frequency of faecal carriage of
antimicrobial resistant enteric bacteria at presentation to hospital and at discharge
following exposure to antibiotics and the hospital environment, comparing 360 children with,
and 360 children without severe malnutrition at three different hospitals. Clear data on the
benefits, risks and pharmacokinetics of these antimicrobials will influence policy on case
management and antimicrobial stewardship in this vulnerable population.
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