Optimising Antibiotic Treatment for Sick Malnourished Children
Klíčová slova
Abstraktní
Popis
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.
Termíny
| Poslední ověření: | 05/31/2017 |
| První předloženo: | 04/03/2016 |
| Odhadovaná registrace vložena: | 04/17/2016 |
| První zveřejnění: | 04/20/2016 |
| Poslední aktualizace byla odeslána: | 06/29/2017 |
| Poslední aktualizace zveřejněna: | 07/01/2017 |
| Aktuální datum zahájení studie: | 03/31/2016 |
| Odhadované datum dokončení primární: | 09/29/2016 |
| Odhadované datum dokončení studie: | 09/29/2017 |
Stav nebo nemoc
Intervence / léčba
Drug: Ceftriaxone and metronidazole
Drug: Ceftriaxone and metronidazole
Fáze
Skupiny zbraní
| Paže | Intervence / léčba |
|---|---|
| Other: Ceftriaxone and metronidazole Pharmacokinetic study of ceftriaxone and metronidazole in malnourished children | Drug: Ceftriaxone and metronidazole 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. |
Kritéria způsobilosti
| Věky způsobilé ke studiu | 2 Months Na 2 Months |
| Pohlaví způsobilá ke studiu | All |
| Přijímá zdravé dobrovolníky | Ano |
| Kritéria | 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 |
Výsledek
Primární výsledná opatření
1. Area under the curve (AUC) of ceftriaxone [24 hours]
2. Trough level of metronidazole [8, 24, 48 and 72 hours]
Měření sekundárních výsledků
1. Prevalence of faecal carriage of extended spectrum beta-lactamase (ESBL) [Through study completion, an average of 5 days]
