Azithromycin (CP-62,993), a new
acid-stable 15-membered-ring
macrolide, was well absorbed following
oral administration in mice, rats, dogs, and cynomolgus monkeys. This compound exhibited a uniformly long elimination half-life and was distributed exceptionally well into all tissues. This extravascular penetration of
azithromycin was demonstrated by tissue/plasma area-under-the-curve ratios ranging from 13.6 to 137 compared with ratios for
erythromycin of 3.1 to 11.6. The significance of these pharmacokinetic advantages of
azithromycin over
erythromycin was shown through efficacy in a series of animal
infection models.
Azithromycin was orally effective in treating middle ear
infections induced in gerbils by transbulla challenges with
amoxicillin-resistant Haemophilus influenzae or susceptible Streptococcus pneumoniae;
erythromycin failed and
cefaclor was only marginally active against the H. influenzae challenge.
Azithromycin was equivalent to
cefaclor and
erythromycin against Streptococcus pneumoniae. In mouse models, the new
macrolide was 10-fold more potent than
erythromycin and four other
antibiotics against an anaerobic
infection produced by Fusobacterium necrophorum. Similarly,
azithromycin was effective against established tissue
infections induced by Salmonella enteritidis (liver and spleen) and Staphylococcus aureus (thigh muscle);
erythromycin failed against both
infections. The oral and subcutaneous activities of
azithromycin,
erythromycin, and
cefaclor were similar against acute systemic
infections produced by Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus viridans, or S. aureus, whereas
azithromycin was more potent than
erythromycin and
cefaclor against the intracellular pathogen Listeria monocytogenes. The pharmacokinetic advantage of
azithromycin over
erythromycin in half-life was clearly demonstrated in prophylactic treatment of an acute mouse model of S. aureus
infection. These properties of
azithromycin strongly support the further evaluation of this new
macrolide for use in
community-acquired infections of skin or soft tissue and
respiratory diseases.