L-701,677, L-708,299 and L-708,365 are novel azalide derivatives of erythromycin that exhibit improved acid stability over erythromycin, azithromycin 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 hours 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 > azithromycin = clarithromycin > erythromycin. In a disseminated Streptococcus pyogenes mouse infection model, azithromycin and L-708,365 were slightly more efficacious than clarithromycin, L-701,677 and L-708,299; all 5 compounds being more active than erythromycin. In a Klebsiella pneumoniae pulmonary challenge mouse model, azithromycin, L-701,677, L-708,299 and L-708,365 were all equal in efficacy and at least four-fold more active than clarithromycin and erythromycin. Clarithromycin, L-708,365 and interestingly erythromycin, showed greater bacterial clearance than azithromycin, L-701,677 and L-708,299 in a localized infection model 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.