Girard A E, Girard D, English A R, Gootz T D, Cimochowski C R, Faiella J A, Haskell S L, Retsema J A
Central Research Division, Pfizer Inc., Groton, Connecticut 06340.
Antimicrob Agents Chemother. 1987 Dec;31(12):1948-54. doi: 10.1128/AAC.31.12.1948.
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.
阿奇霉素（CP - 62,993）是一种新型的酸稳定型15元环大环内酯类抗生素，在小鼠、大鼠、犬和食蟹猴口服给药后吸收良好。该化合物的消除半衰期一致较长，且在所有组织中的分布都非常好。阿奇霉素的这种血管外渗透表现为组织/血浆曲线下面积比在13.6至137之间，而红霉素的该比值为3.1至11.6。通过在一系列动物感染模型中的疗效，显示了阿奇霉素相对于红霉素这些药代动力学优势的重要性。阿奇霉素口服可有效治疗由耐阿莫西林的流感嗜血杆菌或敏感的肺炎链球菌经鼓泡攻击诱导的沙鼠中耳感染；红霉素治疗失败，而头孢克洛仅对流感嗜血杆菌攻击有微弱活性。阿奇霉素对肺炎链球菌的疗效与头孢克洛和红霉素相当。在小鼠模型中，这种新型大环内酯类抗生素对坏死梭杆菌引起的厌氧菌感染的效力比红霉素和其他四种抗生素高10倍。同样，阿奇霉素对肠炎沙门氏菌（肝脏和脾脏）和金黄色葡萄球菌（大腿肌肉）引起的已建立的组织感染有效；红霉素对这两种感染均治疗失败。阿奇霉素、红霉素和头孢克洛对肺炎链球菌、化脓性链球菌、草绿色链球菌或金黄色葡萄球菌引起的急性全身感染的口服和皮下活性相似，而阿奇霉素对细胞内病原体单核细胞增生李斯特菌的效力比红霉素和头孢克洛更强。在金黄色葡萄球菌感染的急性小鼠模型的预防性治疗中，清楚地证明了阿奇霉素相对于红霉素在半衰期方面的药代动力学优势。阿奇霉素的这些特性有力地支持了对这种新型大环内酯类抗生素用于社区获得性皮肤或软组织感染及呼吸道疾病的进一步评估。
