IN-VIVO EVALUATION OF 3 ACID-STABLE AZALIDE COMPOUNDS, L-701,677, L-708,299 AND L-708,365 COMPARED TO ERYTHROMYCIN, AZITHROMYCIN AND CLARITHROMYCIN

L-701,677, L-708,299 and L-708,365 are novel azalide derivatives of er ythromycin that exhibit improved acid stability over erythromycin, azi thromycin and clarithromycin. The half-life in aqueous solution at pH= 2.1 of these compounds ranged from 0.3 hour for erythromycin to 16.2 h ours for L-708,299. The rank order of half-life in acid solution from most to least stable was L-708,299 > L-701,677 > L-708,365 > azithromy cin = clarithromycin > erythromycin. In a disseminated Streptococcus p yogenes mouse infection model, azithromycin and L-708,365 were slightl y more efficacious than clarithromycin, L-701,677 and L-708,299; all 5 compounds being more active than erythromycin. In a Klebsiella pneumo niae pulmonary challenge mouse model, azithromycin, L-701,677, L-708,2 99 and L-708,365 were all equal in efficacy and at least four-fold mor e active than clarithromycin and erythromycin. Clarithromycin, L-708,3 65 and interestingly erythromycin, showed greater bacterial clearance than azithromycin, L-701,677 and L-708,299 in a localized infection mo del that measured clearance of Staphylococcus aureus from mouse thigh tissues. Our results indicate that L-701,677, L-708,299 and L-708,365 exhibit improved acid stability and were at least equally efficacious as presently marketed macrolide/azalide antibiotics.