ENHANCEMENT OF THE INVITRO AND INVIVO ACTIVITIES OF CLARITHROMYCIN AGAINST HAEMOPHILUS-INFLUENZAE BY 14-HYDROXY-CLARITHROMYCIN, ITS MAJOR METABOLITE IN HUMANS
ENHANCEMENT OF THE INVITRO AND INVIVO ACTIVITIES OF CLARITHROMYCIN AGAINST HAEMOPHILUS-INFLUENZAE BY 14-HYDROXY-CLARITHROMYCIN, ITS MAJOR METABOLITE IN HUMANS
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DOI：
10.1128/aac.34.7.1407
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发表时间：
1990-07-01
影响因子：
4.9
通讯作者：
CLEMENT, JJ
中科院分区：
文献类型：
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作者：
HARDY, DJ;SWANSON, RN;CLEMENT, JJ
克拉霉素及其主要人体代谢物14-羟基克拉霉素联合治疗流感嗜血杆菌的mic与单独使用每种化合物的mic相比降低了2至4倍。血清使母体化合物和代谢物的mic比无血清培养基中的mic降低了2 - 4倍。在以临床相关浓度克拉霉素和14-羟基克拉霉素按4:1的固定比例加标的血清中，1.2和0.3 .mu的组合抑制和杀死16株菌株中的15株（94%）。分别g / ml。在时间杀灭实验中，母体化合物和代谢物的组合分别在其个体mic的四分之一和二分之一的水平上减少了细菌计数，减少了0.5 log CFU。克拉霉素与14-羟基克拉霉素联用的抗生素后效果是单独使用克拉霉素的2倍。当给患有流感嗜血杆菌中耳炎的沙鼠口服时，14-羟基代谢物在减少中耳细菌计数方面明显比克拉霉素更有活性。这两种化合物的体内活性组合是协同或添加剂，取决于在治疗开始时存在的流感嗜血杆菌的水平。当剂量为50或100 mg/kg体重的克拉霉素与剂量为12 mg/kg或更高的14-羟基克拉霉素联合使用时，观察到细菌数量显著减少，治愈率显著提高。体外和体内联合试验结果表明，单独使用克拉霉素的常规药敏试验和动物疗效研究可能低估了其对流感嗜血杆菌的潜在疗效。
MICs of clarithromycin and its major human metabolite, 14-hydroxy-clarithromycin, for Haemophilus influenzae in combination were reduced two- to fourfold compared with the MICs of each compound alone. Serum reduced the MICs of the parent compound and metabolite two- to fourfold compared with the MICs in medium without serum. In serum spiked with clinically relevant concentrations of clarithromycin and 14-hydroxy-clarithromycin at a fixed ratio of 4:1, 15 of 16 strains (94%) were inhibited and killed by combinations containing 1.2 and 0.3 .mu.g/ml, respectively. In time kill experiments, the combination of parent compound and metabolite at one-fourth and one-half of their individual MICs, respectively, reduced bacterial counts by >5 log CFU. The postantibiotic effect of clarithromycin combined with 14-hydroxy-clarithromycin was twice that of clarithromycin when tested alone. When orally administered to gerbils with H. influenzae otitis media, the 14-hydroxy metabolite was significantly more active than clarithromycin in reducing bacterial counts from the middle ear. The in vivo activity of the two compounds in combination was synergistic or additive, depending on the level of H. influenzae present at the time treatment was initiated. Significant reductions in bacterial counts and increases in cure rates were observed when clarithromycin at 50 or 100 mg/kg of body weight was combined with 14-hydroxy-clarithromycin at 12 mg/kg or higher. Results from in vitro and in vivo combinations suggest that routine susceptibility tests and animal efficacy studies with clarithromycin alone may underestimate its potential efficacy against H. influenzae.