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

June 30, 2017 updated by: James Berkley, University of Oxford

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.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

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

Enrollment (Actual)

81

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Kenya
      • Kilifi, Kenya, 80800
        • KEMRI WT Clinical Trials Facility

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

3 years to 1 year (Child)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Other: 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 Names:
  • 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 Names:
  • Flagyl

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
24 hours
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.
8, 24, 48 and 72 hours

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
Through study completion, an average of 5 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Oxford

Collaborators

University College, London
KEMRI-Wellcome Trust Collaborative Research Program
Centre for Research in Therapeutic Sciences, Strathmore University, Nairobi Kenya
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

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 1, 2016

Primary Completion (Actual)

September 30, 2016

Study Completion (Anticipated)

September 30, 2017

Study Registration Dates

First Submitted

April 4, 2016

First Submitted That Met QC Criteria

April 18, 2016

First Posted (Estimate)

April 21, 2016

Study Record Updates

Last Update Posted (Actual)

July 2, 2017

Last Update Submitted That Met QC Criteria

June 30, 2017

Last Verified

June 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • OXTREC 47-15
  • KEMRI/SERU/CGMR-C/023/3161 (Other Identifier: KEMRI Scientific and Ethics Review Unit)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Yes

IPD 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.

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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