Do current oral ciprofloxacin regimens achieve pharmacokinetic/pharmacodynamic targets within safe exposure limits in older adults with Pseudomonas aeruginosa infection? A population pharmacokinetic analysis

BACKGROUND: Ciprofloxacin is one of the few orally available antibiotics with activity against Pseudomonas aeruginosa. This study developed a population pharmacokinetic (popPK) model for oral ciprofloxacin in older adults and evaluated whether standard regimens achieve the pharmacokinetic/pharmacodynamic (PK/PD) target of 24 h area under the concentration-time curve over minimal inhibitory concentration (AUC0-24/MIC) ≥ 125. METHODS: This was a prospective pilot study in patients ≥75 years taking oral ciprofloxacin at the McGill University Health Centre, Canada. Plasma samples were collected at steady state (peak, mid-interval, trough) and data fitting was performed using NONMEM with stochastic approximation expectation-maximization. Monte Carlo simulations (n = 1000) assessed the probability of target attainment (PTA) for standard dosing regimens of 250-750 mg q12h across MICs of 0.125-2 mg/L. RESULTS: Fifteen patients (median age 82 years, weight 75 kg, creatinine clearance 46 mL/min) contributed 42 plasma concentrations to the analysis. A one-compartment model with first-order absorption and elimination best described the data. Population mean apparent clearance and volume of distribution were 14.3 L/h and 247 L, respectively (resulting in a 12 h half-life), with high interindividual variability (IIV: 75.2% and 36.0%). The absorption rate constant was fixed to 2.5 h-1. No covariate effects were retained in the final model. At the P. aeruginosa clinical MIC breakpoint of 0.5 mg/L, standard regimens achieved PTAs of 18.7% (250 mg q12h), 56.6% (500 mg q12h), and 76.5% (750 mg q12h). CONCLUSIONS: This first popPK model for oral ciprofloxacin specifically in older adults demonstrates that simulated standard dosing regimens fail to achieve PK/PD targets for P. aeruginosa. The large IIV, increased drug exposure and low target attainment support implementation of therapeutic drug monitoring in this population.