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Optimising Antibiotic Treatment for Sick Malnourished Children (FLACSAM-PK)

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ClinicalTrials.gov Identifier: NCT02746276
Recruitment Status : Active, not recruiting
First Posted : April 21, 2016
Last Update Posted : July 2, 2017
Sponsor:
Collaborators:
KEMRI Wellcome Trust Research Program, Kenya
Centre for Research in Therapeutic Sciences, Strathmore University, Nairobi Kenya
University College, London
Centre for Microbiology Research, Kenya Medical Research Institute
Centre for Clinical Research, Kenya Medical Research Institute
Information provided by (Responsible Party):
James Berkley, University of Oxford

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Malnutrition Drug: Ceftriaxone Drug: Metronidazole Phase 2

Detailed Description:

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.


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 81 participants
Intervention Model: Single Group Assignment
Intervention Model Description: Sparse sample pharmacokinetics study
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Pharmacokinetics of Antimicrobials and Carriage of Antimicrobial Resistance Amongst Hospitalised Children With Severe Acute Malnutrition
Actual Study Start Date : April 1, 2016
Actual Primary Completion Date : September 30, 2016
Estimated Study Completion Date : September 30, 2017


Arm Intervention/treatment
Ceftriaxone and metronidazole
Pharmacokinetic study of ceftriaxone and metronidazole in malnourished children
Drug: 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.
Other Name: Rocephin

Drug: 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 Name: Flagyl




Primary Outcome Measures :
  1. Area under the curve (AUC) of ceftriaxone [ Time Frame: 24 hours ]
    To determine the pharmacokinetics of intravenous ceftriaxone given at currently recommended dose and frequency amongst severely malnourished, sick children.

  2. Trough level of metronidazole [ Time Frame: 8, 24, 48 and 72 hours ]
    To determine the pharmacokinetics of oral metronidazole given at currently recommended dose and frequency amongst severely malnourished, sick children.


Secondary Outcome Measures :
  1. Prevalence of faecal carriage of extended spectrum beta-lactamase (ESBL) [ Time Frame: Through study completion, an average of 5 days ]
    To determine the frequency of faecal carriage of ESBL at admission to hospital and at discharge amongst children admitted with and without severe malnutrition.



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Ages Eligible for Study:   2 Months to 59 Months   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Severe acute malnutrition(SAM) defined as:

    • 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:

  • Admitted as a transfer from another hospital.
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02746276


Locations
Kenya
KEMRI WT Clinical Trials Facility
Kilifi, Kenya, 80800
Sponsors and Collaborators
University of Oxford
KEMRI Wellcome Trust Research Program, Kenya
Centre for Research in Therapeutic Sciences, Strathmore University, Nairobi Kenya
University College, London
Centre for Microbiology Research, Kenya Medical Research Institute
Centre for Clinical Research, Kenya Medical Research Institute
Investigators
Principal Investigator: James A Berkley, Paediatrics KEMRI Wellcome Trust Research Programme and University of Oxford

Additional Information:
Publications:

Responsible Party: James Berkley, Professor, University of Oxford
ClinicalTrials.gov Identifier: NCT02746276     History of Changes
Other Study ID Numbers: OXTREC 47-15
KEMRI/SERU/CGMR-C/023/3161 ( Other Identifier: KEMRI Scientific and Ethics Review Unit )
First Posted: April 21, 2016    Key Record Dates
Last Update Posted: July 2, 2017
Last Verified: June 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Yes. Data sharing will be considered by the investigators, then by applying to the Data Governance Committee at CGMR,C who will ensure that appropriate ethical approval is in place for any new analysis.

Keywords provided by James Berkley, University of Oxford:
malnutrition
antibiotics
antimicrobial resistance
pharmacokinetics

Additional relevant MeSH terms:
Malnutrition
Severe Acute Malnutrition
Nutrition Disorders
Metronidazole
Anti-Infective Agents
Ceftriaxone
Anti-Bacterial Agents
Antiprotozoal Agents
Antiparasitic Agents