Optimising Antibiotic Treatment for Sick Malnourished Children (FLACSAM-PK)
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| ClinicalTrials.gov Identifier: NCT02746276 |
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Recruitment Status : Unknown
Verified June 2017 by James Berkley, University of Oxford.
Recruitment status was: Active, not recruiting
First Posted : April 21, 2016
Last Update Posted : July 2, 2017
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| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Malnutrition | Drug: Ceftriaxone Drug: Metronidazole | Phase 2 |
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 |
| Allocation: | N/A |
| 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 |
|---|---|
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Ceftriaxone and metronidazole
Pharmacokinetic study of ceftriaxone and metronidazole in malnourished children
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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 |
- 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.
- 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.
- 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 |
Inclusion Criteria:
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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
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
| Kenya | |
| KEMRI WT Clinical Trials Facility | |
| Kilifi, Kenya, 80800 | |
| Principal Investigator: | James A Berkley, Paediatrics | KEMRI Wellcome Trust Research Programme and University of Oxford |
Publications:
| Responsible Party: | James Berkley, Professor, University of Oxford |
| ClinicalTrials.gov Identifier: | NCT02746276 |
| 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. |
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malnutrition antibiotics antimicrobial resistance pharmacokinetics |
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Malnutrition Nutrition Disorders Metronidazole Ceftriaxone |
Anti-Infective Agents Anti-Bacterial Agents Antiprotozoal Agents Antiparasitic Agents |