Alder J D, Ewing P J, Nilius A M, Mitten M, Tovcimak A, Oleksijew A, Jarvis K, Paige L, Tanaka S K
Experimental Therapeutics and Pharmacology, Abbott Laboratories, Abbott Park, Illinois, USA.
Antimicrob Agents Chemother. 1998 Sep;42(9):2385-90. doi: 10.1128/AAC.42.9.2385.
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.
评估了克拉霉素和阿奇霉素对大鼠肺部流感嗜血杆菌感染的疗效动态。通过接种后第3天和第7天肺部流感嗜血杆菌负荷的降低来衡量疗效。克拉霉素治疗在治疗的第3天或第7天有效，而阿奇霉素在第7天有效，但在治疗的第3天无效。两种大环内酯类药物对所有六种测试的流感嗜血杆菌菌株均产生显著疗效，包括四种对克拉霉素的最低抑菌浓度（MIC）高于敏感断点（8微克/毫升）的菌株。这两种大环内酯类药物表现出明显不同的药代动力学特征，克拉霉素存在于血液和组织中，而阿奇霉素主要集中在组织中。在大鼠肺部感染期间，在肺的细胞内和细胞外位置均发现了流感嗜血杆菌。克拉霉素和阿奇霉素的血药浓度接近人体药代动力学，两种大环内酯类药物的血药浓度很少超过流感嗜血杆菌的MIC。在产生与临床实际达到的值相似的血药浓度的剂量下，克拉霉素在治疗的第3天产生疗效，而克拉霉素和阿奇霉素在第7天同样有效。克拉霉素和阿奇霉素不同的疗效动态表明，在评估药物疗效时，治疗时长应被视为一个关键参数。
