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.

Figure 1.

Ciprofloxacin concentration measurements in 52 children with malnutrition following oral doses of 10 mg/kg. Samples were measured after the first dose in all patients and after a second dose 12 h later in 16 patients.

Figure 2.

Observed versus population (a) and individual (b) predicted concentrations of ciprofloxacin in malnourished infants based on the final population model. The thin line represents the line of identity; the thick line represents the linear regression line.

Figure 3.

Prediction-corrected visual predictive check of the final model describing the pharmacokinetics of oral ciprofloxacin in infants with malnutrition. The solid line represents the median of the raw data, the dotted lines are the 10th and 90th percentiles of the raw data, and the shaded areas are the 90% confidence intervals of the 10th, 50th and 90th percentiles of the 1000 simulations based on the final model.

Figure 4.

Percentage probability of achieving a target AUC_0–24/MIC ratio ≥125.