Effect of dosing intervals on efficacy of clarithromycin and erythromycin in mouse infection models

Clarithromycin is a new macrolide with a serum half-life which is at least twice that of erythromycin. In order to select the appropriate dosing intervals, the in vitro post-antibiotic effect (PAE) of clarithromycin and erythromycin were compared and the efficacies of clarithromycin and erythromycin when administered once (q.d.), twice (b.i.d.) and three (t.i.d.) times a day in mouse protection tests were measured. The doses were selected from achievable peak serum concentrations in man and were 18 mg/kg for clarithromycin which gave a peak blood level of 2.0 micrograms/ml and a serum half-life of 0.82 h, and 10 mg/kg for erythromycin which gave a peak blood level of 0.9 microgram/ml and a serum half-life of 0.46 h. The PAE of clarithromycin for Staph. aureus is 6.25 h compared to 2.35 h for erythromycin. Clarithromycin was effective against Staph. aureus, Strep. pyogenes and Strep. pneumoniae when administered q.d., b.i.d. and t.i.d. and there was no difference in the cumulative mortalities in the three treatment groups. For erythromycin, there was also no difference in the survival of Strep. pyogenes and Strep. pneumoniae-infected mice, but when tested against Staph. aureus it was more effective when administered t.i.d. than b.i.d., and b.i.d. was more effective than q.d. Clarithromycin administered q.d. was more effective than erythromycin administered t.i.d. against Staph. aureus.