Dynamics of clarithromycin and azithromycin efficacies against experimental Haemophilus influenzae pulmonary infection

Abstract

The dynamics of clarithromycin and azithromycin efficacy against pulmonary Haemophilus influenzae infection in rats were evaluated. Efficacy was measured by reduction in pulmonary H. influenzae burden on days 3 and 7 postinoculation. Clarithromycin therapy was effective on day 3 or 7 of therapy, while azithromycin was effective on day 7 but not on day 3 of therapy. Both macrolides produced marked efficacy against all six strains of H. influenzae tested, including four strains for which MICs were above the susceptible breakpoint (8 microgram/ml) concentration of clarithromycin. The two macrolides demonstrated markedly different pharmacokinetic characteristics, with clarithromycin present in both blood and tissue, while azithromycin was concentrated primarily in tissue. During pulmonary infection in rats, H. influenzae was found in both intracellular locations and an extracellular location in the lung. Blood concentrations of clarithromycin and azithromycin approximated human pharmacokinetics, and the blood concentrations for either macrolide rarely exceeded MICs for H. influenzae. At dosages producing blood concentrations similar to values achieved clinically, clarithromycin produced efficacy on day 3 of therapy, while both clarithromycin and azithromycin were equally effective on day 7. The different dynamics of clarithromycin and azithromycin suggest that length of therapy should be considered as a key parameter in evaluations of drug efficacy.

FIG. 1

(A) Plasma and lung concentrations of clarithromycin in rats following multiple oral dosages at 150 or 100 mg/kg, b.i.d. × 5. Clarithromycin was administered every 12 h, with a total of five dosages over 48 h. The MIC at which 90% of the isolates are inhibited (MIC₉₀) for H. influenzae (16 μg/ml) is indicated in relation to concentrations in plasma and lungs. (B) Concentrations of azithromycin in plasma and lungs in rats following multiple oral dosages at 50 mg/kg on day 0 and 25 mg/kg on days 1 and 2 or 25 mg/kg on day 0 and 12.5 mg/kg on days 1 and 2. Azithromycin was administered every 24 h, with a total of three dosages over 48 h. The MIC₉₀ for H. influenzae (4 μg/ml) is indicated in relation to concentrations in plasma and lungs.

FIG. 2

(A) Reductions of H. influenzae correlated to AUC/MIC ratios at day 3 of therapy with clarithromycin or azithromycin. (B) Reductions of H. influenzae correlated to AUC/MIC ratios at day 7 of therapy with clarithromycin or azithromycin.