Abstract
OBJECTIVE: To characterize the population pharmacokinetics and pharmacodynamics of oral grepafloxacin in patients with acute bacterial exacerbations of chronic bronchitis (ABECB), with particular attention to the speed of bacterial killing. This was possible because the study design incorporated daily cultures of the patients’ sputum.PATIENTS AND METHODS: The study group included 76 patients (43 male, 33 female) between 23 and 81 years of age who were part of a multicentre, randomized, double-blind, dose-response study. Patients were randomly assigned to receive oral regimens of grepafloxacin - 200, 400 or 600 mg - each administered once daily for 14 days. Daily cultures and quantitative Gram stains from serial 24 h collections of sputum were used to determine the days to eradication of each strain of bacteria. Grepafloxacin plasma concentration profiles were best fit by a pharmacokinetic model with first order absorption following a lag time between administration of the dose and onset of systemic absorption. Pharmacodynamic analysis was performed for three measures of antibacterial response: probability of bacteriological cure and probability of clinical cure, and time to eradication.RESULTS: All three measures of response were strongly related to the 24 h area under the inhibitory curve (AUIC) (area under the curve/minimum inhibitory concentration). At an AUIC below of 75/serum inhibiting titre (SIT) x 24 h, the percentage probability of clinical cure was 71 %; at an AUIC between 75 and 175, it was 80% (P<0.05); and, at an AUTC above 175, it was 98% (P<0.01).CONCLUSION: The speed of bacterial killing for grepafloxacin in ABECB patients was highly related to AUIC; values below 75 appear inadequate, and values greater than 175 were optimal.