EVALUATION OF ANTIMICROBIAL ACTIVITIES OF CLARITHROMYCIN AND 14-HYDROXYCLARITHROMYCIN AGAINST 3 STRAINS OF HAEMOPHILUS-INFLUENZAE BY USING AN IN-VITRO PHARMACODYNAMIC MODEL

An in vitro pharmacodynamic model was used to simulate the in vivo pha rmacokinetics of clarithromycin and 14-hydroxyclarithromycin in order to generate time-kill curves for three clinical isolates of Haemophilu s influenzae (isolates 2019, 91-183, and 1746). Representative concent rations in serum or lung tissue and the pharmacokinetic parameters of clarithromycin and the 14-hydroxy metabolite, separately and in combin ation, were simulated for the time-kill studies. Amoxicillin-clavulani c acid was used as a control drug. The simulation of typical concentra tions of the macrolides in serum in time kill studies resulted in magn itudes of bacterial killing that were less than (for strains 2019 and 91-183, MICs = 4 mg/liter for clarithromycin and 14-hydroxyclarithromy cin) or equal to (for strain 1746, MIC = 1 mg/liter for clarithromycin and 14-hydroxyclarithromycin) those observed in amoxicillin-clavulani c acid studies. When typical concentrations in lung tissue were simula ted, total log decreases in bacterial counts were greater than those a chieved with typical concentrations in serum and, in the case of strai n 1746, exceeded the magnitude observed with the control drug. In each case, the time to 3-log-unit killing was longer for the macrolides th an for amoxicillin-clavulanic acid. Time-kill curve analyses demonstra ted the presence of synergy (defined as a 2-log-unit decrease in the C FU per milliliter between the combination and the most active constitu ent at any time point) for the combination of clarithromycin and 14-hy droxyclarithromycin at simulated concentrations in serum for one strai n of H. influenzae (isolate 91-183). Synergism is likely bacterial str ain specific, and the presence of synergy may be dependent on the anti biotic concentrations that are tested. Evaluation of the kill curve ki netics in terms of bactericidal rate fbr the various starting concentr ations of clarithromycin did not result in a clear demonstration of ei ther concentration-dependent or concentration-independent bactericidal activity.