Pharmacokinetic-pharmacodynamic approach to evaluate antimicrobial activity of azithromycin

Abstract

The efficacy of azithromycin in the treatment of infections caused by the common bacteria, using a PK/PD approach which combines in vivo PK data from the free drug concentration versus time profile and in vitro PD from the time-kill curve was studied. The bacterial time-kill curves of azithromycin against four bacterial strains (Streptococcus pneumoniae/penicillin-sensitive, Streptococcus pneumoniae /penicillin-intermediate, Haemophilus influenzae and Moraxella catarrhalis) were determined by in vitro infection models. Twelve different PK/PD models were fitted and compared to the time-kill curve data using software Scientist®. Results show that a simple PK/PD model was not sufficient to describe the pharmacodynamic effects for these four bacterial strains. Appropriate models that gave good curve fits included additional terms for saturation of the number of bacteria (Nmax), delay in the initial bacterial growth phase and/or the onset of anti-infective activity (1-e-zt) as well as a Hill factor (h) that captures the steepness of the concentration-response profile. The determined PD parameters from the curve fit of bacterial time-kill curves showed that azithromycin was highly effective against S. pneumoniae strains and M. catarrhalis while the efficacy of azithromycin against H. influenzae was poor. The pharmacokinetic of azithromycin was obtained from eight healthy volunteers after once-daily oral administration of 2x250 mg of azithromycin capsules for 3-day regimen. The mean values of Cmax, AUClast, AUCinf, and AUMC were decreased approximately by 50% from 525.94 to 292.21 ng/mL, 7873.84 to 3755.02 h.ng/mL, 9636.96 to 4572.99 h.ng/mL, and 447865.88 to 194602.11 h.h.ng/mL for total plasma drug and free drug, respectively. These pharmacokinetic parameters indicated that the effect of protein binding should be taken into consideration. Therefore, PK profile from free plasma of azithromycin was properly fitted with appropriate PK/PD models. Simulated kill curves with the PK profile of free plasma concentration of azithromycin into the PK/PD models predicted that 2x250 mg of azithromycin capsules orally once-daily showed a good bactericidal effect for S. pneumoniae (both penicillin-sensitive and penicillin-intermediate) whereas the same dose appeared to be insufficient to decrease bacterial counts for H. influenzae and M. catarrhalis. Therefore, PK/PD approach based on time-kill curve could be a suitable method to evaluate antimicrobial activity of azithromycin.