Replication Data for: Dosing of ceftriaxone and metronidazole for children with severe acute malnutrition.

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Standing, Joseph F.; Ongas, Martin O.; Ogwang, Caroline; Kagwanja, Nancy; Murunga, Sheila; Mwaringa,Shalton; Ali, Rehema; Mturi, Neema; Timbwa, Moline; Manyasi, Christine; Mwalekwa, Laura; Bandika, Victor L.; Ogutu, Bernhards; Waichungo, Joseph; Kipper, Karin; Berkley, James A.; FLACSAM‐PK Study Group, 2020, "Replication Data for: Dosing of ceftriaxone and metronidazole for children with severe acute malnutrition.", https://doi.org/10.7910/DVN/YBRNXC, Harvard Dataverse, V1, UNF:6:xbfwNn54224wmyZxmCxuvQ== [fileUNF]

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Description	This study forms the initial stage of the First Line Antimicrobials in Complicated Severe Acute Malnutrition (FLACSAM) trial (http://clinicaltrials.gov NCT03174236), which will compare ceftriaxone (±metronidazole) with standard‐of‐care antimicrobials (±metronidazole) in a 2 × 2 factorial design for outcomes including mortality and nutritional recovery. Infants and young children with severe acute malnutrition (SAM) are treated with empiric broad‐spectrum antimicrobials. Parenteral ceftriaxone is currently a second‐line agent for invasive infection. Oral metronidazole principally targets small intestinal bacterial overgrowth. Children with SAM may have altered drug absorption, distribution, metabolism, and elimination. Population pharmacokinetics of ceftriaxone and metronidazole were studied, with the aim of recommending optimal dosing. Eighty‐one patients with SAM (aged 2–45 months) provided 234 postdose pharmacokinetic samples for total ceftriaxone, metronidazole, and hydroxymetronidazole. Ceftriaxone protein binding was also measured in 190 of these samples. A three‐compartment model adequately described free ceftriaxone, with a Michaelis–Menten model for concentration and albumin‐dependent protein binding. A one‐compartment model was used for both metronidazole and hydroxymetronidazole, with only 1% of hydroxymetronidazole predicted to be formed during first‐pass. Simulations showed 80 mg/kg once daily of ceftriaxone and 12.5 mg/kg twice daily of metronidazole were sufficient to reach therapeutic targets.
Subject	Medicine, Health and Life Sciences
Related Publication	Standing, J.F., Ongas, M.O., Ogwang, C., Kagwanja, N., Murunga, S., Mwaringa, S., Ali, R., Mturi, N., Timbwa, M., Manyasi, C. and Mwalekwa, L., 2018. Dosing of ceftriaxone and metronidazole for children with severe acute malnutrition. Clinical Pharmacology & Therapeutics, 104(6), pp.1165-1174.doi: 10.1002%2Fcpt.1078
Notes	Access to the dataset is restricted. Accompanying documentation is available under open access. For more detailed information beyond the metadata and documentation provided, there is a process of managed access requiring submission of a request form for consideration by our Data Governance Committee [dgc@kemri-wellcome.org). Click to download Data Request Form
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	FLACSAM_PK_data_manip_V03_final.pdf Adobe PDF - 606.1 KB Published Feb 20, 2020 4 Downloads MD5: 1f639d5e1dcd9b2fa618dbf4536cebcb Output generated using 'FLACSAM_PK_data_manip_V03_final.Rmd' Documentation	Preview "FLACSAM_PK_data_manip_V03_final.pdf" Access File File Access Public Download Options Adobe PDF Download Metadata Data File Citation Download EndNote XML Download RIS Download BibTeX
	FLACSAM_pk_cef_170102.tab Tabular Data - 40.3 KB Published Feb 20, 2020 2 Downloads 20 Variables, 620 Observations UNF:6:WjzOThwkZFkzYo02lwfj1w== Contains Ceftriaxone related data Data	Access File File Access Restricted Users may not request access to files. Download Metadata Data File Citation Download EndNote XML Download RIS Download BibTeX
	FLACSAM_pk_met_170104.tab Tabular Data - 113.4 KB Published Feb 20, 2020 2 Downloads 23 Variables, 1362 Observations UNF:6:3SfuTv46VIWiiYP+GaXRgQ== Contains Metronidazole related data Data	Access File File Access Restricted Users may not request access to files. Download Metadata Data File Citation Download EndNote XML Download RIS Download BibTeX
	FLACSAM_PK_data_manip_V03_final.Rmd Unknown - 52.6 KB Published Feb 20, 2020 2 Downloads MD5: 9ee52d5e27bf3e69ad4bd2c8cd13534f R script Code	Access File File Access Public Download Options Original File Format Download Metadata Data File Citation Download EndNote XML Download RIS Download BibTeX

Citation Metadata

Persistent Identifier	doi:10.7910/DVN/YBRNXC
Publication Date	2020-02-20
Title	Replication Data for: Dosing of ceftriaxone and metronidazole for children with severe acute malnutrition.
Author	Standing, Joseph F.Great Ormond Street Institute of Child Health, University College London, London, UK; Paediatric Infectious Diseases Research Group, Institute for Infection and Immunity, St. George's, University of London, London, UK Ongas, Martin O.Center for Research in Therapeutic Sciences, Strathmore University, Nairobi, Kenya; KEMRI‐Centre for Clinical Research, Nairobi, Kenya Ogwang, CarolineKEMRI‐Wellcome Trust Research Programme, Kilifi, Kenya Kagwanja, NancyKEMRI‐Wellcome Trust Research Programme, Kilifi, Kenya Murunga, SheilaKEMRI‐Wellcome Trust Research Programme, Kilifi, Kenya Mwaringa,ShaltonKEMRI‐Wellcome Trust Research Programme, Kilifi, Kenya Ali, RehemaKEMRI‐Wellcome Trust Research Programme, Kilifi, Kenya Mturi, NeemaKEMRI‐Wellcome Trust Research Programme, Kilifi, Kenya Timbwa, MolineKEMRI‐Wellcome Trust Research Programme, Kilifi, Kenya; Mbagathi County Hospital, Nairobi, Kenya Manyasi, ChristineKEMRI‐Wellcome Trust Research Programme, Kilifi, Kenya; Mbagathi County Hospital, Nairobi, Kenya Mwalekwa, LauraKEMRI‐Wellcome Trust Research Programme, Kilifi, Kenya; Coast General Hospital, Mombasa, Kenya Bandika, Victor L.Coast General Hospital, Mombasa, Kenya Ogutu, BernhardsCenter for Research in Therapeutic Sciences, Strathmore University, Nairobi, Kenya; KEMRI‐Centre for Clinical Research, Nairobi, Kenya Waichungo, JosephKEMRI‐Wellcome Trust Research Programme, Kilifi, Kenya Kipper, KarinAnalytical Services International, St George's University of London, London, UK; Institute of Chemistry, University of Tartu, Tartu, Estonia Berkley, James A.KEMRI‐Wellcome Trust Research Programme, Kilifi, Kenya; The Childhood Acute Illness & Nutrition (CHAIN) Network, Nairobi, Kenya; Centre for Tropical Medicine & Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK FLACSAM‐PK Study Group
Point of Contact	Use email button above to contact. Berkley, James A. (KEMRI-Wellcome Trust Research programme;)
Description	This study forms the initial stage of the First Line Antimicrobials in Complicated Severe Acute Malnutrition (FLACSAM) trial (http://clinicaltrials.gov NCT03174236), which will compare ceftriaxone (±metronidazole) with standard‐of‐care antimicrobials (±metronidazole) in a 2 × 2 factorial design for outcomes including mortality and nutritional recovery. Infants and young children with severe acute malnutrition (SAM) are treated with empiric broad‐spectrum antimicrobials. Parenteral ceftriaxone is currently a second‐line agent for invasive infection. Oral metronidazole principally targets small intestinal bacterial overgrowth. Children with SAM may have altered drug absorption, distribution, metabolism, and elimination. Population pharmacokinetics of ceftriaxone and metronidazole were studied, with the aim of recommending optimal dosing. Eighty‐one patients with SAM (aged 2–45 months) provided 234 postdose pharmacokinetic samples for total ceftriaxone, metronidazole, and hydroxymetronidazole. Ceftriaxone protein binding was also measured in 190 of these samples. A three‐compartment model adequately described free ceftriaxone, with a Michaelis–Menten model for concentration and albumin‐dependent protein binding. A one‐compartment model was used for both metronidazole and hydroxymetronidazole, with only 1% of hydroxymetronidazole predicted to be formed during first‐pass. Simulations showed 80 mg/kg once daily of ceftriaxone and 12.5 mg/kg twice daily of metronidazole were sufficient to reach therapeutic targets.
Subject	Medicine, Health and Life Sciences
Related Publication	Standing, J.F., Ongas, M.O., Ogwang, C., Kagwanja, N., Murunga, S., Mwaringa, S., Ali, R., Mturi, N., Timbwa, M., Manyasi, C. and Mwalekwa, L., 2018. Dosing of ceftriaxone and metronidazole for children with severe acute malnutrition. Clinical Pharmacology & Therapeutics, 104(6), pp.1165-1174. doi 10.1002%2Fcpt.1078 https://dx.doi.org/10.1002%2Fcpt.1078
Notes	Access to the dataset is restricted. Accompanying documentation is available under open access. For more detailed information beyond the metadata and documentation provided, there is a process of managed access requiring submission of a request form for consideration by our Data Governance Committee [dgc@kemri-wellcome.org). Click to download Data Request Form
Depositor	Berkley, James A.
Deposit Date	2020-02-17
Data Type	Clinical Trial

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