First Line Antimicrobials in Children With Complicated Severe Acute Malnutrition

Antibiotic Resistance Clinical Trial

— FLACSAM  

Official title:

First Line Antimicrobials in Children With Complicated Severe Acute Malnutrition

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03174236
• Other study ID #: KEMRI/SERU/CGMR-C/063/3399
• Secondary ID: 1-17105431/Z/14/
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: September 4, 2017
• Est. completion date: December 31, 2020

Study information

• Verified date: May 2020
• Source: University of Oxford
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Children with severe malnutrition who are admitted sick to hospitals have a high mortality(death rate), usually because of infection. All children with severe malnutrition admitted to hospitals are treated with antibiotics(medication used to kill bacteria). However, the current antibiotics used in hospitals may not be the most effective. It is possible that the antibiotics that are currently used after initial antibiotics should be used first. No studies have been carried out to determine if the current antibiotics used for treating malnourished children who are sick and admitted in hospital are the most appropriate. The aim of this study is to find out if a changed antibiotic system for children with malnutrition is safe, reduces the risk of death and improves nutritional recovery.

Description:

Children with complicated severe acute malnutrition (SAM) admitted to hospital in sub-Saharan Africa have a case fatality(death rate) between 12% and more than 20%. Because children with SAM may not exhibit the usual signs of infection, WHO guidelines recommend routine antibiotics(medication used to kill bacteria). However, this is based on "low quality evidence". There is evidence that because of bacterial resistance to the currently recommended first-line antibiotics (gentamicin plus ampicillin or penicillin) could be less effective than potential alternatives. 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 increased antimicrobial resistance, including inducing extended spectrum beta-lactamase (ESBL) and other classes of resistance.

A further area where evidence for policy is lacking is 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 anaerobic bacteria, small bowel bacterial overgrowth, Clostridium difficile colitis and also Giardia, which is common amongst children with SAM. Small cohort studies of metronidazole usage suggest there may be benefits for nutritional recovery in malnourished children. However, metronidazole can cause nausea and anorexia, potentially impairing recovery from malnutrition and may also rarely cause liver and neurological toxicity.

This multi-centre clinical trial will assess the efficacy of two interventions, ceftriaxone and metronidazole, on mortality and nutritional recovery in sick, severely malnourished children in a 2x2 factorial design. There will also be an analysis of antimicrobial resistance and an economic analysis. To extend our understanding of metronidazole and ceftriaxone pharmacokinetics, additional pharmacokinetic data for the dosing schedule used in the trial will be collected from 120 participants in a sub-study. The trial will be conducted at Kilifi County Hospital, Coast General Hospital, Mbagathi Hospital in Kenya and Mbale Regional Referral Hospital in Uganda. The trial will assess antimicrobial resistance that is carried by children in their intestines and in invasive bacterial isolates. A further sub-study will examine the relative costs of care for SAM for health facilities and for families, including antimicrobial usage will also be assessed. Clear data on the benefits, risks and costs of these antimicrobials will influence policy on case management and antimicrobial stewardship in this vulnerable population.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 2000
• Est. completion date: December 31, 2020
• Est. primary completion date: January 31, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Months to 13 Years

Eligibility

Inclusion:

• Age 2 months to 13 years inclusive

• Severe malnutrition defined as:

• kwashiorkor at any age or:

• for children between 2 to 5 months: MUAC <11cm or weight-for length Z score <-3

• for children between 6 to 59 months: MUAC <11.5cm or weight-for length Z score <-3

• for children between 5 to 13 years: MUAC <11.5cm or BMI-for-age Z score <-3

• Admitted to hospital and eligible for intravenous antibiotics according to WHO guidelines

• Planning to remain within the hospital catchment area and willing to come for specified visits during the 90 day follow up period

• Informed consent provided by the parents/guardian

Exclusion:

• Known allergy or contraindication to penicillin, gentamicin, ceftriaxone or metronidazole

• A specific and documented clinical indication for another class of antibiotic

• Previously enrolled in this study

Related Conditions & MeSH terms

• Antibiotic Resistance
• Antibiotic Toxicity
• Malnutrition
• Malnutrition Severe
• Severe Acute Malnutrition

Intervention

Drug:
• Ceftriaxone
Ceftriaxone a third-generation cephalosporin. Ceftriaxone is active against a broad spectrum of Gram positive and Gram negative bacteria.
• Benzyl penicillin
The currently recommended first-line antibiotics for the treatment of severe acute malnutrition are gentamicin plus ampicillin or penicillin.
• Metronidazole
The WHO guidelines recommend that Metronidazole may be given in addition to broad-spectrum antibiotics, "however, the efficacy of this treatment has not been established in clinical trials."

Other:
• Placebo
Suspension manufactured to match metronidazole

Drug:
• Gentamicin
The currently recommended first-line antibiotics for the treatment of severe acute malnutrition are gentamicin plus ampicillin or penicillin.

Locations

Country	Name	City	State
Kenya	Kemri Wellcome Trust Research Programme	Kilifi	Coast Province
Kenya	KEMRI WT Clinical Trials Facility	Kilifi
Kenya	Kilifi County Hospital	Kilifi
Kenya	Kilifi County Hospital	Kilifi	Coast
Kenya	Coast General Hospital - Study site	Mombasa
Kenya	Mbagathi District Hospital	Nairobi
Kenya	Mbagathi Hospital	Nairobi
Uganda	Mbale Regional Referral Hospital	Mbale

Sponsors (6)

Lead Sponsor	Collaborator
University of Oxford	KEMRI-Wellcome Trust Collaborative Research Program, Kenya Medical Research Institute, London School of Hygiene and Tropical Medicine, Swansea Trials Unit, University College, London

Countries where clinical trial is conducted

Kenya,  Uganda, 

References & Publications (25)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Berkley JA, Ngari M, Thitiri J, Mwalekwa L, Timbwa M, Hamid F, Ali R, Shangala J, Mturi N, Jones KD, Alphan H, Mutai B, Bandika V, Hemed T, Awuondo K, Morpeth S, Kariuki S, Fegan G. Daily co-trimoxazole prophylaxis to prevent mortality in children with complicated severe acute malnutrition: a multicentre, double-blind, randomised placebo-controlled trial. Lancet Glob Health. 2016 Jul;4(7):e464-73. doi: 10.1016/S2214-109X(16)30096-1. Epub 2016 Jun 2. — View Citation

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. Review. Erratum in: Lancet. 2013. 2013 Aug 3;382(9890):396. — View Citation

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. — View Citation

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. — View Citation

Dubray C, Ibrahim SA, Abdelmutalib M, Guerin PJ, Dantoine F, Belanger F, Legros D, Pinoges L, Brown V. Treatment of severe malnutrition with 2-day intramuscular ceftriaxone vs 5-day amoxicillin. Ann Trop Paediatr. 2008 Mar;28(1):13-22. doi: 10.1179/146532808X270635. — View Citation

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. Review. — View Citation

Haybittle JL. Repeated assessment of results in clinical trials of cancer treatment. Br J Radiol. 1971 Oct;44(526):793-7. — View Citation

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. Review. — View Citation

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. — View Citation

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. — View Citation

Jones KD, Hünten-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. — View Citation

Moïsi JC, Gatakaa H, Berkley JA, Maitland K, Mturi N, Newton CR, Njuguna P, Nokes J, Ojal J, Bauni E, Tsofa B, Peshu N, Marsh K, Williams TN, Scott JA. Excess child mortality after discharge from hospital in Kilifi, Kenya: a retrospective cohort analysis. Bull World Health Organ. 2011 Oct 1;89(10):725-32, 732A. doi: 10.2471/BLT.11.089235. Epub 2011 Jul 13. — View Citation

Ongas M, Standing J, Ogutu B, Waichungo J, Berkley JA, Kipper K. Liquid chromatography-tandem mass spectrometry for the simultaneous quantitation of ceftriaxone, metronidazole and hydroxymetronidazole in plasma from seriously ill, severely malnourished children. Wellcome Open Res. 2017 Jun 19;2:43. doi: 10.12688/wellcomeopenres.11728.2. eCollection 2017. — View Citation

Paterson DL. "Collateral damage" from cephalosporin or quinolone antibiotic therapy. Clin Infect Dis. 2004 May 15;38 Suppl 4:S341-5. — View Citation

Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV, Mantel N, McPherson K, Peto J, Smith PG. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. I. Introduction and design. Br J Cancer. 1976 Dec;34(6):585-612. — View Citation

Standing JF, Ongas MO, Ogwang C, Kagwanja N, Murunga S, Mwaringa S, Ali R, Mturi N, Timbwa M, Manyasi C, Mwalekwa L, Bandika VL, Ogutu B, Waichungo J, Kipper K, Berkley JA; FLACSAM-PK Study Group. Dosing of Ceftriaxone and Metronidazole for Children With Severe Acute Malnutrition. Clin Pharmacol Ther. 2018 Dec;104(6):1165-1174. doi: 10.1002/cpt.1078. Epub 2018 Apr 19. — View Citation

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. — View Citation

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. — View Citation

Williams PCM, Berkley JA. Guidelines for the treatment of severe acute malnutrition: a systematic review of the evidence for antimicrobial therapy. Paediatr Int Child Health. 2018 Nov;38(sup1):S32-S49. doi: 10.1080/20469047.2017.1409453. — View Citation

Williams PCM, Isaacs D, Berkley JA. Antimicrobial resistance among children in sub-Saharan Africa. Lancet Infect Dis. 2018 Feb;18(2):e33-e44. doi: 10.1016/S1473-3099(17)30467-X. Epub 2017 Oct 9. — View Citation

Woerther PL, Angebault C, Jacquier H, Hugede HC, Janssens AC, Sayadi S, El Mniai A, Armand-Lefèvre L, Ruppé E, Barbier F, Raskine L, Page AL, de Rekeneire N, Andremont A. Massive increase, spread, and exchange of extended spectrum ß-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. — View Citation

* Note: There are 25 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Mortality	Mortality is measured using source documents from medical records, verbal autopsy, or death or burial certificates in the community.	90 days after enrolment.
Secondary	Mortality during the first 7 days	Mortality during the first 7 days	7 days
Secondary	Mortality during the first 30 days	Mortality during the first 30 days	7 days
Secondary	Index admission inpatient mortality	Mortality during the index hospitalisation, measured using inpatient records.	Through index hospital admission, an average of 7 days.
Secondary	Mortality after discharge from index admission.	Mortality occurring after discharge from the index hospital admission is measured using inpatient medical records, verbal autopsy, or death or burial certificates in the community.	90 days after enrolment
Secondary	Grade 4 toxicity	Grade 4 toxicity events are measured according to the Division of AIDS Tables for Grading the Severity of Adverse Events using medical records.	Up to 7 days following enrolment
Secondary	Serious adverse events	Serious adverse events are measured using inpatient and outpatient medical records.	90 days after enrolment.
Secondary	Tolerability - relevant side effects during the first 7 day	Vomiting, diarrhoea, NG tube in place and convulsions during the first 7 days	7 days
Secondary	Causes of death.	Causes of death, as determined by an endpoint review committee.	90 days after enrolment
Secondary	Re-admission to hospital.	Re-admission to hospital defined as at least one overnight stay in a hospital or health facility are measured using inpatient records.	From discharge from hospital to 90 days after enrolment
Secondary	Duration of hospitalisation.	Total duration of hospitalisation is measured in days using inpatient records at the start and end of each admission to hospital.	90 days after enrolment.
Secondary	Duration of administration of antibiotics.	Duration of administration of intravenous antibiotics measured using inpatient records.	90 days after enrolment.
Secondary	Change in nutritional status	Change in nutritional status is measured using mid-upper arm circumference, weight-for-length, weight-for-age and length-for-age compared to at enrollment.	90 days after enrolment.
Secondary	Faecal carriage of bacteria expressing Extended Spectrum Lactamase (ESBL)	Faecal carriage of bacteria expressing Extended Spectrum Lactamase (ESBL) is measured using microbial culture and sensitivity testing of rectal swabs.	Through study completion an average of 90 days.

External Links

•   Pocket book of hospital care for children Guidelines for the management of common illnesses with limited resources Author: World Health Organization