PMID- 35078765
OWN - NLM
STAT- MEDLINE
DCOM- 20220822
LR  - 20230308
IS  - 1468-2044 (Electronic)
IS  - 0003-9888 (Print)
IS  - 0003-9888 (Linking)
VI  - 107
IP  - 9
DP  - 2022 Sep
TI  - Randomised controlled trial of fosfomycin in neonatal sepsis: pharmacokinetics 
      and safety in relation to sodium overload.
PG  - 802-810
LID - 10.1136/archdischild-2021-322483 [doi]
AB  - OBJECTIVE: To assess pharmacokinetics and changes to sodium levels in addition to 
      adverse events (AEs) associated with fosfomycin among neonates with clinical 
      sepsis. DESIGN: A single-centre open-label randomised controlled trial. SETTING: 
      Kilifi County Hospital, Kenya. PATIENTS: 120 neonates aged </=28 days admitted 
      being treated with standard-of-care (SOC) antibiotics for sepsis: ampicillin and 
      gentamicin between March 2018 and February 2019. INTERVENTION: We randomly 
      assigned half the participants to receive additional intravenous then oral 
      fosfomycin at 100 mg/kg two times per day for up to 7 days (SOC-F) and followed 
      up for 28 days. MAIN OUTCOMES AND MEASURES: Serum sodium, AEs and fosfomycin 
      pharmacokinetics. RESULTS: 61 and 59 infants aged 0-23 days were assigned to 
      SOC-F and SOC, respectively. There was no evidence of impact of fosfomycin on 
      serum sodium or gastrointestinal side effects. We observed 35 AEs among 25 SOC-F 
      participants and 50 AEs among 34 SOC participants during 1560 and 1565 
      infant-days observation, respectively (2.2 vs 3.2 events/100 infant-days; 
      incidence rate difference -0.95 events/100 infant-days (95% CI -2.1 to 0.20)). 
      Four SOC-F and 3 SOC participants died. From 238 pharmacokinetic samples, 
      modelling suggests an intravenous dose of 150 mg/kg two times per day is required 
      for pharmacodynamic target attainment in most children, reduced to 100 mg/kg two 
      times per day in neonates aged <7 days or weighing <1500 g. CONCLUSION AND 
      RELEVANCE: Fosfomycin offers potential as an affordable regimen with a simple 
      dosing schedule for neonatal sepsis. Further research on its safety is needed in 
      larger cohorts of hospitalised neonates, including very preterm neonates or those 
      critically ill. Resistance suppression would only be achieved for the most 
      sensitive of organisms so fosfomycin is recommended to be used in combination 
      with another antimicrobial. TRIAL REGISTRATION NUMBER: NCT03453177.
CI  - (c) Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published 
      by BMJ.
FAU - Obiero, Christina W
AU  - Obiero CW
AUID- ORCID: 0000-0002-9321-0183
AD  - Clinical Research Deptartment, KEMRI-Wellcome Trust Research Programme, Kilifi, 
      Kenya.
AD  - Department of Global Health, University of Amsterdam, Amsterdam, The Netherlands.
FAU - Williams, Phoebe
AU  - Williams P
AD  - Clinical Research Deptartment, KEMRI-Wellcome Trust Research Programme, Kilifi, 
      Kenya.
AD  - Nuffield Department of Medicine, University of Oxford, Oxford, UK.
FAU - Murunga, Sheila
AU  - Murunga S
AD  - Clinical Research Deptartment, KEMRI-Wellcome Trust Research Programme, Kilifi, 
      Kenya.
FAU - Thitiri, Johnstone
AU  - Thitiri J
AD  - Clinical Research Deptartment, KEMRI-Wellcome Trust Research Programme, Kilifi, 
      Kenya.
FAU - Omollo, Raymond
AU  - Omollo R
AD  - Global Antibiotic Research and Development Partnership, Nairobi, Kenya.
FAU - Walker, Ann Sarah
AU  - Walker AS
AD  - MRC Clinical Trials Unit, University College London, London, UK.
FAU - Egondi, Thaddaeus
AU  - Egondi T
AD  - Global Antibiotic Research and Development Partnership, Nairobi, Kenya.
FAU - Nyaoke, Borna
AU  - Nyaoke B
AD  - Global Antibiotic Research and Development Partnership, Nairobi, Kenya.
FAU - Correia, Erika
AU  - Correia E
AD  - Global Antibiotic Research and Development Partnership, Geneva, Switzerland.
FAU - Kane, Zoe
AU  - Kane Z
AD  - Great Ormond Street Institute of Child Health, University College London, London, 
      UK.
FAU - Gastine, Silke
AU  - Gastine S
AD  - Great Ormond Street Institute of Child Health, University College London, London, 
      UK.
FAU - Kipper, Karin
AU  - Kipper K
AD  - Institute of Chemistry, University of Tartu, Tartu, Estonia.
AD  - Analytical Services International (ASI) Ltd, St George's - University of London, 
      London, UK.
FAU - Standing, Joseph F
AU  - Standing JF
AD  - Great Ormond Street Institute of Child Health, University College London, London, 
      UK.
FAU - Ellis, Sally
AU  - Ellis S
AD  - Global Antibiotic Research and Development Partnership, Geneva, Switzerland.
FAU - Sharland, Mike
AU  - Sharland M
AD  - Paediatric Infectious Diseases Research Group, Institute for Infection and 
      Immunity, University of London, London, UK.
FAU - Berkley, James Alexander
AU  - Berkley JA
AUID- ORCID: 0000-0002-1236-849X
AD  - Clinical Research Deptartment, KEMRI-Wellcome Trust Research Programme, Kilifi, 
      Kenya jberkley@kemri-wellcome.org.
AD  - Nuffield Department of Medicine, University of Oxford, Oxford, UK.
AD  - The Childhood Acute Illness & Nutrition (CHAIN) Network, Nairobi, Kenya.
CN  - NeoFosfo Study Group
LA  - eng
SI  - ClinicalTrials.gov/NCT03453177
GR  - MR/M007367/1/MRC_/Medical Research Council/United Kingdom
GR  - MR/M008665/1/MRC_/Medical Research Council/United Kingdom
GR  - M008665/MRC_/Medical Research Council/United Kingdom
GR  - 203077/WT_/Wellcome Trust/United Kingdom
GR  - WT_/Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20220125
PL  - England
TA  - Arch Dis Child
JT  - Archives of disease in childhood
JID - 0372434
RN  - 0 (Anti-Bacterial Agents)
RN  - 0 (Gentamicins)
RN  - 2N81MY12TE (Fosfomycin)
RN  - 9NEZ333N27 (Sodium)
SB  - IM
MH  - Anti-Bacterial Agents/adverse effects
MH  - Child
MH  - *Fosfomycin/adverse effects
MH  - Gentamicins
MH  - Humans
MH  - Infant
MH  - Infant, Newborn
MH  - *Neonatal Sepsis/drug therapy
MH  - *Sepsis/drug therapy
MH  - Sodium/therapeutic use
PMC - PMC9411916
MID - EMS152547
OTO - NOTNLM
OT  - neonatology
OT  - pharmacology
OT  - sepsis
COIS- Competing interests: None declared.
EDAT- 2022/01/27 06:00
MHDA- 2022/08/23 06:00
PMCR- 2022/08/26
CRDT- 2022/01/26 05:28
PHST- 2021/05/18 00:00 [received]
PHST- 2021/12/24 00:00 [accepted]
PHST- 2022/01/27 06:00 [pubmed]
PHST- 2022/08/23 06:00 [medline]
PHST- 2022/01/26 05:28 [entrez]
PHST- 2022/08/26 00:00 [pmc-release]
AID - archdischild-2021-322483 [pii]
AID - 10.1136/archdischild-2021-322483 [doi]
PST - ppublish
SO  - Arch Dis Child. 2022 Sep;107(9):802-810. doi: 10.1136/archdischild-2021-322483. 
      Epub 2022 Jan 25.