Pharmacokinetic and pharmacodynamic assessment of co-amoxiclav in the treatment of melioidosis

Objectives: We conducted a prospective pharmacokinetic study of oral co-amoxiclav in patients with melioidosis to determine the optimal dosage and dosing interval in this potentially fatal infection. Patients and methods: Serial plasma concentrations were measured after administration of two 1 g tablets of Augmentin® (1750 mg of amoxicillin and 250 mg of clavulanate) to 14 adult patients with melioidosis. Monte Carlo simulation was used to predict the concentration of each drug following multiple doses of co-amoxiclav at different dosages and dose intervals. The proportion of the dose-interval above MIC (T > MIC) was calculated from 10 000 simulated subject plasma concentration profiles together with chequerboard MIC data from 46 clinical isolates and four reference strains of Burkholderia pseudomallei. Results: The median (range) observed maximum plasma concentrations of amoxicillin and clavulanate were 11.5 (3.3–40.2) mg/L and 5.1 (0.8–12.1) mg/L, respectively. The median (range) elimination half-lives were 94 (73–215) and 89 (57–140) min, respectively. Simulation indicated that co-amoxiclav 1750/250 mg given at 4, 6, 8 or 12 hourly dosing intervals would be associated with a T > MIC of ≤50% in 0.7%, 2.8%, 8.6% and 33.2% of patients, respectively. Corresponding proportions for T > MIC of ≥90% were 95.8%, 78.6%, 50.2% and 10.8%, respectively. Conclusions: The dosing interval for co-amoxiclav (750/250 mg) in melioidosis should not be greater than 6 h.