Direct evidence for antipseudomonal activity of macrolides: Exposure-dependent bactericidal activity and inhibition of protein synthesis by erythromycin, clarithromycin, and azithromycin
Direct evidence for antipseudomonal activity of macrolides: Exposure-dependent bactericidal activity and inhibition of protein synthesis by erythromycin, clarithromycin, and azithromycin
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DOI：
10.1128/aac.40.10.2271
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发表时间：
1996-10-01
影响因子：
4.9
通讯作者：
Yamaguchi, K
中科院分区：
文献类型：
--
作者：
Tateda, K;Ishii, Y;Yamaguchi, K
以前的几位研究人员曾报道，长期服用某些大环内酯类抗生素对持续性肺部铜绿假单胞菌感染是有效的，即使这些药物的临床可达浓度远低于他们的MIC。在本研究中，我们研究了大环内酯类抗生素亚MIC如何影响几种铜绿假单胞菌的生存能力和蛋白质合成。我们报告，在含有临床可达浓度的阿奇霉素(0.5微克/毫升，1/128MIC)的琼脂上生长48小时，而不是12或24小时，显著降低了菌株PAO-I的活力。红霉素和克拉霉素在2 mU g/ml(分别为MIC的1/128和1/)下也有类似的作用，而交沙霉素、奥兰霉素、头孢他啶、妥布霉素、米诺环素和氧氟沙星对活性没有影响，即使在代表其MIC相对较高的浓度下孵育48h后，阿奇霉素的杀菌活性也不仅限于PAO-1菌株，而且对14株临床分离株中的13株也有杀菌活性，包括粘液型和非粘液型菌株，尽管48h之前活性没有下降。我们还发现，铜绿假单胞菌在12~36h内持续积累阿奇霉素。这些结果表明，当细菌较长时间地接触这些抗生素时，某些大环内酯亚MIC对铜绿假单胞菌具有杀菌作用，抗生素在细胞内的暴露依赖性积累和蛋白质合成的抑制可能是大环内酯类抗生素在相对较长的潜伏期内抗假单胞菌活性的部分原因。
Several previous investigators have reported that long-term administration of certain macrolides is efficacious in patients with persistent pulmonary Pseudomonas aeruginosa infections, even though the clinically achievable concentrations of these medications are far below their MICs, In the present study, we examined how sub-MICs of macrolide antibiotics affect the viability of and protein synthesis in several strains of P. aeruginosa, We report that 48 h, but not 12 or 24 h, of growth on agar containing a clinically achievable concentration of azithromycin (0.5 mu g/ml, 1/128 the MIC) significantly reduces the viability of strain PAO-I, Similar effects were seen with erythromycin and clarithromycin at 2 mu g/ml (1/128 and 1/64 the respective MICs), whereas josamycin, oleandomycin, ceftazidime, tobramycin, minocycline, and ofloxacin had no effect on viability, even following 48 h of incubation with concentrations representing relatively high fractions of their MICs, The bactericidal activity of azithromycin seen following 48 h of incubation was not limited to strain PAO-1 but was also seen against 13 of 14 clinical isolates, including both mucoid and nonmucoid strains, Although viability was not decreased prior to 48 h, we found that 4 mu g of azithromycin per mi inhibits protein synthesis after as little as 12 h and that protein synthesis continues to decrease in a time-dependent manner, We likewise found that P. aeruginosa accumulates azithromycin intracellularly over the period from 12 to 36 h, These results suggested that sub-MICs of certain macrolides are bactericidal to P. aeruginosa when the bacteria are exposed to these antibiotics for longer periods, Exposure-dependent intracellular accumulation of the antibiotic and inhibition of protein synthesis may partially account for the antipseudomonal activity of macrolides over relatively prolonged incubation periods.