Optimising Antibiotic Treatment for Sick Malnourished Children

NCT02746276 | Unknown Phase 2

• 2 other identifiers: OXTREC 47-15KEMRI/SERU/CGMR-C/023/3161
• Study Type: interventional
• Target: 81
• Locations: 1 country
• Sites: 1

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.

Conditions

Malnutrition

Keywords

malnutrition; antibiotics; antimicrobial resistance; pharmacokinetics

Outcome Measures

Primary Outcomes (2)

• Area under the curve (AUC) of ceftriaxone

  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

  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 Outcomes (1)

• Prevalence of faecal carriage of extended spectrum beta-lactamase (ESBL)

  Through study completion, an average of 5 days

Study Arms (1)

Ceftriaxone and metronidazole

OTHER

Pharmacokinetic study of ceftriaxone and metronidazole in malnourished children

Drug: Ceftriaxone; Drug: Metronidazole

Interventions

Ceftriaxone DRUG

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.

Also known as: Rocephin

Ceftriaxone and metronidazole

Metronidazole DRUG

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.

Also known as: Flagyl

Ceftriaxone and metronidazole

Eligibility Criteria

• Age: 2 Months - 59 Months
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Oxford: lead
• KEMRI-Wellcome Trust Collaborative Research Program: collaborator
• Centre for Research in Therapeutic Sciences, Strathmore University, Nairobi Kenya: collaborator
• University College, London: collaborator
• Centre for Microbiology Research, Kenya Medical Research Institute: collaborator
• Centre for Clinical Research, Kenya Medical Research Institute: collaborator

Study Sites (1)

KEMRI WT Clinical Trials Facility

Kilifi, 80800, Kenya

Location

Related Publications (22)

• Black RE, Victora CG, Walker SP, Bhutta ZA, Christian P, de Onis M, Ezzati M, Grantham-McGregor S, Katz J, Martorell R, Uauy R; Maternal and Child Nutrition Study Group. Maternal and child undernutrition and overweight in low-income and middle-income countries. Lancet. 2013 Aug 3;382(9890):427-451. doi: 10.1016/S0140-6736(13)60937-X. Epub 2013 Jun 6.

  PMID: 23746772 BACKGROUND

• Bejon P, Mohammed S, Mwangi I, Atkinson SH, Osier F, Peshu N, Newton CR, Maitland K, Berkley JA. Fraction of all hospital admissions and deaths attributable to malnutrition among children in rural Kenya. Am J Clin Nutr. 2008 Dec;88(6):1626-31. doi: 10.3945/ajcn.2008.26510.

  PMID: 19064524 BACKGROUND

• Talbert A, Thuo N, Karisa J, Chesaro C, Ohuma E, Ignas J, Berkley JA, Toromo C, Atkinson S, Maitland K. Diarrhoea complicating severe acute malnutrition in Kenyan children: a prospective descriptive study of risk factors and outcome. PLoS One. 2012;7(6):e38321. doi: 10.1371/journal.pone.0038321. Epub 2012 Jun 4.

  PMID: 22675542 BACKGROUND

• Heikens GT, Bunn J, Amadi B, Manary M, Chhagan M, Berkley JA, Rollins N, Kelly P, Adamczick C, Maitland K, Tomkins A; Blantyre Working Group. Case management of HIV-infected severely malnourished children: challenges in the area of highest prevalence. Lancet. 2008 Apr 12;371(9620):1305-7. doi: 10.1016/S0140-6736(08)60565-6. No abstract available.

  PMID: 18406865 BACKGROUND

• Chimhuya S, Kambarami RA, Mujuru H. The levels of malnutrition and risk factors for mortality at Harare Central Hospital-Zimbabwe: an observation study. Cent Afr J Med. 2007 May-Aug;53(5-8):30-4. doi: 10.4314/cajm.v53i5-8.62612.

  PMID: 20355679 BACKGROUND

• Fergusson P, Tomkins A. HIV prevalence and mortality among children undergoing treatment for severe acute malnutrition in sub-Saharan Africa: a systematic review and meta-analysis. Trans R Soc Trop Med Hyg. 2009 Jun;103(6):541-8. doi: 10.1016/j.trstmh.2008.10.029. Epub 2008 Dec 5.

  PMID: 19058824 BACKGROUND

• Trehan I, Goldbach HS, LaGrone LN, Meuli GJ, Wang RJ, Maleta KM, Manary MJ. Antibiotics as part of the management of severe acute malnutrition. N Engl J Med. 2013 Jan 31;368(5):425-35. doi: 10.1056/NEJMoa1202851.

  PMID: 23363496 BACKGROUND

• Berkley JA, Lowe BS, Mwangi I, Williams T, Bauni E, Mwarumba S, Ngetsa C, Slack MP, Njenga S, Hart CA, Maitland K, English M, Marsh K, Scott JA. Bacteremia among children admitted to a rural hospital in Kenya. N Engl J Med. 2005 Jan 6;352(1):39-47. doi: 10.1056/NEJMoa040275.

  PMID: 15635111 BACKGROUND

• Tansarli GS, Poulikakos P, Kapaskelis A, Falagas ME. Proportion of extended-spectrum beta-lactamase (ESBL)-producing isolates among Enterobacteriaceae in Africa: evaluation of the evidence--systematic review. J Antimicrob Chemother. 2014 May;69(5):1177-84. doi: 10.1093/jac/dkt500. Epub 2014 Jan 6.

  PMID: 24398340 BACKGROUND

• Babirekere-Iriso E, Musoke P, Kekitiinwa A. Bacteraemia in severely malnourished children in an HIV-endemic setting. Ann Trop Paediatr. 2006 Dec;26(4):319-28. doi: 10.1179/146532806X152845.

  PMID: 17132297 BACKGROUND

• Acquah SE, Quaye L, Sagoe K, Ziem JB, Bromberger PI, Amponsem AA. Susceptibility of bacterial etiological agents to commonly-used antimicrobial agents in children with sepsis at the Tamale Teaching Hospital. BMC Infect Dis. 2013 Feb 18;13:89. doi: 10.1186/1471-2334-13-89.

  PMID: 23419199 BACKGROUND

• 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.

  PMID: 17519011 BACKGROUND

• Aiken AM, Mturi N, Njuguna P, Mohammed S, Berkley JA, Mwangi I, Mwarumba S, Kitsao BS, Lowe BS, Morpeth SC, Hall AJ, Khandawalla I, Scott JAG; Kilifi Bacteraemia Surveillance Group. Risk and causes of paediatric hospital-acquired bacteraemia in Kilifi District Hospital, Kenya: a prospective cohort study. Lancet. 2011 Dec 10;378(9808):2021-2027. doi: 10.1016/S0140-6736(11)61622-X. Epub 2011 Nov 29.

  PMID: 22133536 BACKGROUND

• Garot D, Respaud R, Lanotte P, Simon N, Mercier E, Ehrmann S, Perrotin D, Dequin PF, Le Guellec C. Population pharmacokinetics of ceftriaxone in critically ill septic patients: a reappraisal. Br J Clin Pharmacol. 2011 Nov;72(5):758-67. doi: 10.1111/j.1365-2125.2011.04005.x.

  PMID: 21545483 BACKGROUND

• Lazzerini M, Tickell D. Antibiotics in severely malnourished children: systematic review of efficacy, safety and pharmacokinetics. Bull World Health Organ. 2011 Aug 1;89(8):594-607. doi: 10.2471/BLT.10.084715. Epub 2011 May 20.

  PMID: 21836758 BACKGROUND

• Woerther PL, Angebault C, Jacquier H, Hugede HC, Janssens AC, Sayadi S, El Mniai A, Armand-Lefevre L, Ruppe E, Barbier F, Raskine L, Page AL, de Rekeneire N, Andremont A. Massive increase, spread, and exchange of extended spectrum beta-lactamase-encoding genes among intestinal Enterobacteriaceae in hospitalized children with severe acute malnutrition in Niger. Clin Infect Dis. 2011 Oct;53(7):677-85. doi: 10.1093/cid/cir522.

  PMID: 21890771 BACKGROUND

• Paterson DL. "Collateral damage" from cephalosporin or quinolone antibiotic therapy. Clin Infect Dis. 2004 May 15;38 Suppl 4:S341-5. doi: 10.1086/382690.

  PMID: 15127367 BACKGROUND

• Jones KD, Hunten-Kirsch B, Laving AM, Munyi CW, Ngari M, Mikusa J, Mulongo MM, Odera D, Nassir HS, Timbwa M, Owino M, Fegan G, Murch SH, Sullivan PB, Warner JO, Berkley JA. Mesalazine in the initial management of severely acutely malnourished children with environmental enteric dysfunction: a pilot randomized controlled trial. BMC Med. 2014 Aug 14;12:133. doi: 10.1186/s12916-014-0133-2.

  PMID: 25189855 BACKGROUND

• Ignatius R, Gahutu JB, Klotz C, Steininger C, Shyirambere C, Lyng M, Musemakweri A, Aebischer T, Martus P, Harms G, Mockenhaupt FP. High prevalence of Giardia duodenalis Assemblage B infection and association with underweight in Rwandan children. PLoS Negl Trop Dis. 2012;6(6):e1677. doi: 10.1371/journal.pntd.0001677. Epub 2012 Jun 12.

  PMID: 22720102 BACKGROUND

• Heikens GT, Schofield WN, Christie CD, Gernay J, Dawson S. The Kingston Project. III. The effects of high energy supplement and metronidazole on malnourished children rehabilitated in the community: morbidity and growth. Eur J Clin Nutr. 1993 Mar;47(3):174-91.

  PMID: 8458315 BACKGROUND

• Lares-Asseff I, Cravioto J, Santiago P, Perez-Ortiz B. A new dosing regimen for metronidazole in malnourished children. Scand J Infect Dis. 1993;25(1):115-21.

  PMID: 8460335 BACKGROUND

• Ribbing J, Jonsson EN. Power, selection bias and predictive performance of the Population Pharmacokinetic Covariate Model. J Pharmacokinet Pharmacodyn. 2004 Apr;31(2):109-34. doi: 10.1023/b:jopa.0000034404.86036.72.

  PMID: 15379381 BACKGROUND

Related Links

• World Health Organization (2013) Pocket Book of Hospital Care for Children. Geneva.

MeSH Terms

Conditions

Malnutrition

Interventions

Ceftriaxone; Metronidazole

Condition Hierarchy (Ancestors)

Nutrition Disorders; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Cefotaxime; Cephacetrile; Cephalosporins; beta-Lactams; Lactams; Amides; Organic Chemicals; Thiazines; Sulfur Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Nitroimidazoles; Nitro Compounds; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring

Study Officials

• James A Berkley, Paediatrics

  KEMRI Wellcome Trust Research Programme and University of Oxford

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Model Details: Sparse sample pharmacokinetics study

Study Record Dates

• First Submitted: April 4, 2016
• First Posted: April 21, 2016
• Study Start: April 1, 2016
• Primary Completion: September 30, 2016
• Study Completion: September 30, 2017
• Last Updated: July 2, 2017

Record last verified: 2017-06

Data Sharing

• IPD Sharing: Will share

Locations

KE (1)