Optimising Antibiotic Treatment for Sick Malnourished Children
NCT ID: NCT02746276
Last Updated: 2017-07-02
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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UNKNOWN
PHASE2
81 participants
INTERVENTIONAL
2016-04-01
2017-09-30
Brief Summary
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Detailed Description
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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.
Conditions
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Study Design
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NA
SINGLE_GROUP
TREATMENT
NONE
Study Groups
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Ceftriaxone and metronidazole
Pharmacokinetic study of ceftriaxone and metronidazole in malnourished children
Ceftriaxone
Ceftriaxone is active against a broad spectrum of gram positive and gram negative bacteria, including intracellular bacteria (e.g. Salmonellae, Staphylococci). Its antibacterial effect is dependent on time above the minimum inhibitory concentration(MIC). Ceftriaxone is highly protein-bound and elimination depends on glomerular filtration rate. In severely ill adults, elimination is highly variable. Alteration in plasma proteins, volume of distribution and renal function in sick severely malnourished children could significantly alter pharmacokinetics (PK). Despite several published studies on the PK of ceftriaxone in children, none have included severe malnutrition.
Metronidazole
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. However, metronidazole can cause nausea and anorexia, potentially impairing recovery from malnutrition and may also cause liver and neurological toxicity. Changes in body composition as well as metabolic and drug elimination mechanisms may alter the potential toxicity or effective dose.
Interventions
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Ceftriaxone
Ceftriaxone is active against a broad spectrum of gram positive and gram negative bacteria, including intracellular bacteria (e.g. Salmonellae, Staphylococci). Its antibacterial effect is dependent on time above the minimum inhibitory concentration(MIC). Ceftriaxone is highly protein-bound and elimination depends on glomerular filtration rate. In severely ill adults, elimination is highly variable. Alteration in plasma proteins, volume of distribution and renal function in sick severely malnourished children could significantly alter pharmacokinetics (PK). Despite several published studies on the PK of ceftriaxone in children, none have included severe malnutrition.
Metronidazole
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. However, metronidazole can cause nausea and anorexia, potentially impairing recovery from malnutrition and may also cause liver and neurological toxicity. Changes in body composition as well as metabolic and drug elimination mechanisms may alter the potential toxicity or effective dose.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* Children aged 6 to 59 months with kwashiorkor; or Mid-Upper Arm Circumference (MUAC) \<11.5cm; or weight-for height Z score \<-3;
* Children aged 2 to 5 months with kwashiorkor; or MUAC \<11cm; or weight-for height Z score \<-3; and weight \>2.5 kilograms(kg);
* Eligible to receive intravenous antibiotics according to current national guidelines
For faecal carriage: children aged 2 to 59 months with and without SAM (as defined above) who are admitted to hospital with a syndrome requiring antimicrobial treatment under current national guidelines.
Exclusion Criteria
* Known ceftriaxone or metronidazole administration within the previous 7 days (pharmacokinetics(PK) study only).
* Known allergy or contraindication to ceftriaxone or metronidazole (including penicillin allergy) (PK study only).
* A specific clinical indication for another class of antibiotic (PK study only).
* Concurrent participation in a clinical trial (PK study only).
* Attending clinician's judgement that the child is so severely ill that adequate communication about the study with the parent or legal guardian is not possible.
* Refusal of consent
2 Months
59 Months
ALL
No
Sponsors
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KEMRI-Wellcome Trust Collaborative Research Program
OTHER
Centre for Research in Therapeutic Sciences, Strathmore University, Nairobi Kenya
UNKNOWN
University College, London
OTHER
Centre for Microbiology Research, Kenya Medical Research Institute
UNKNOWN
Centre for Clinical Research, Kenya Medical Research Institute
UNKNOWN
University of Oxford
OTHER
Responsible Party
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James Berkley
Professor
Principal Investigators
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James A Berkley, Paediatrics
Role: PRINCIPAL_INVESTIGATOR
KEMRI Wellcome Trust Research Programme and University of Oxford
Locations
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KEMRI WT Clinical Trials Facility
Kilifi, , Kenya
Countries
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References
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Blomberg B, Manji KP, Urassa WK, Tamim BS, Mwakagile DS, Jureen R, Msangi V, Tellevik MG, Holberg-Petersen M, Harthug S, Maselle SY, Langeland N. Antimicrobial resistance predicts death in Tanzanian children with bloodstream infections: a prospective cohort study. BMC Infect Dis. 2007 May 22;7:43. doi: 10.1186/1471-2334-7-43.
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Related Links
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World Health Organization (2013) Pocket Book of Hospital Care for Children. Geneva.
Other Identifiers
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KEMRI/SERU/CGMR-C/023/3161
Identifier Type: OTHER
Identifier Source: secondary_id
OXTREC 47-15
Identifier Type: -
Identifier Source: org_study_id
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