title: Dosing regimens of oral ciprofloxacin for children with severe malnutrition: a population pharmacokinetic study with Monte Carlo simulation.
abstract: BACKGROUND
  Severe malnutrition is frequently complicated by sepsis, leading to high case fatality. Oral ciprofloxacin is a potential alternative to the standard parenteral ampicillin/gentamicin combination, but its pharmacokinetics in malnourished children is unknown.
  
  
  METHODS
  Ciprofloxacin (10 mg/kg, 12 hourly) was administered either 2 h before or up to 2 h after feeds to Kenyan children hospitalized with severe malnutrition. Four plasma ciprofloxacin concentrations were measured over 24 h. Population analysis with NONMEM investigated factors affecting the oral clearance (CL) and the oral volume of distribution (V). Monte Carlo simulations investigated dosage regimens to achieve a target AUC(0-24)/MIC ratio of ≥125.
  
  
  RESULTS
  Data comprised 202 ciprofloxacin concentration measurements from 52 children aged 8-102 months. Absorption was generally rapid but variable; C(max) ranged from 0.6 to 4.5 mg/L. Data were fitted by a one-compartment model with first-order absorption and lag. The parameters were CL (L/h) = 42.7 (L/h/70 kg) × [weight (kg)/70](0.75) × [1 + 0.0368 (Na(+) - 136)] × [1 - 0.283 (high risk)] and V (L) = 372 × (L/70 kg) × [1 + 0.0291 (Na(+) - 136)]. Estimates of AUC(0-24) ranged from 8 to 61 mg·h/L. The breakpoint for Gram-negative organisms was <0.06 mg/L with doses of 20 mg/kg/day and <0.125 mg/L with doses of 30 or 45 mg/kg/day. The cumulative fraction of response with 30 mg/kg/day was ≥80% for Escherichia coli, Klebsiella pneumoniae and Salmonella species, but <60% for Pseudomonas aeruginosa.
  
  
  CONCLUSIONS
  An oral ciprofloxacin dose of 10 mg/kg three times daily (30 mg/kg/day) may be a suitable alternative antibiotic for the management of sepsis in severely malnourished children. Absorption was unaffected by the simultaneous administration of feeds.
authors.affiliation: KEMRI-Wellcome Trust Research Programme, Centre for Geographic Medicine Research (Coast), PO Box 230, 80108 Kilifi, Kenya.
authors.forename: Nahashon
authors.initials: N
authors.lastname: Thuo
authors.forename: Wanchana
authors.initials: W
authors.lastname: Ungphakorn
authors.forename: Japhet
authors.initials: J
authors.lastname: Karisa
authors.forename: Simon
authors.initials: S
authors.lastname: Muchohi
authors.forename: Alex
authors.initials: A
authors.lastname: Muturi
authors.forename: Gilbert
authors.initials: G
authors.lastname: Kokwaro
authors.forename: Alison H
authors.initials: AH
authors.lastname: Thomson
authors.forename: Kathryn
authors.initials: K
authors.lastname: Maitland
mesh_terms: D000284:Administration, Oral; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D016470:Bacteremia / Q000150:complications / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D002939:Ciprofloxacin / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D003681:Dehydration; D024901:Drug Resistance, Multiple, Bacterial; D004926:Escherichia coli / Q000187:drug effects; D005260:Female; D006801:Humans; D007223:Infant; D007711:Klebsiella pneumoniae / Q000187:drug effects; D008297:Male; D044342:Malnutrition / Q000150:complications / Q000378:metabolism*; D008826:Microbial Sensitivity Tests; D009010:Monte Carlo Method; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D012475:Salmonella / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D002939:Ciprofloxacin