Rastogi N, Labrousse V
Unité de la Tuberculose et des Mycobactéries, Institut Pasteur, Paris, France.
Antimicrob Agents Chemother. 1991 Mar;35(3):462-70. doi: 10.1128/AAC.35.3.462.
Mycobacterium avium complex bacteria are opportunistic human pathogens, and their chemotherapy remains a challenge since these organisms are resistant to a majority of routine antituberculous drugs. Recently, a wide range of new macrolide antibiotics has been developed, among which the drug clarithromycin appears to have a selective action against M. avium bacteria. In the present study, we have investigated the action of clarithromycin alone (MIC and MBC determinations) and in association with the routine antimycobacterial drugs ethambutol and rifampin at sublethal concentrations (1 micrograms/ml; below concentrations obtainable in human serum) against M. avium. Our viable count data showed that clarithromycin was bactericidal against all 10 strains of M. avium studied and that its activity was enhanced by ethambutol (in 8 of 9 strains) and rifampin (in 3 of 9 strains). The use of all three drugs in association resulted in higher bactericidal effects than found with any of the drugs used alone or in two-drug combinations in seven of nine strains. The bactericidal effects of various drugs used alone and in combination at concentrations obtainable in human serum were investigated against the type strain ATCC 15769 by using 7H9 broth and BACTEC radiometry (extracellular action) and a J-774 macrophage cell line (intracellular action). A good agreement between the extracellular and intracellular activities was found. Electron microscopy using a ruthenium red cytochemical staining of the bacteria showed that clarithromycin disorganized the outer wall layer and the cytoplasmic membrane in the mycobacterial cell envelope and resulted in formation of large vacuoles inside the cytoplasm, with solubilization of ribosomal structures and consequent plasmolysis. Its association with ethambutol and rifampin resulted in more drastic alterations in the bacterial morphology than were seen with any of the drugs used alone, leading to the removal of the bacterial outer layer, homogenization of cytoplasm, complete cell lysis, and formation of ghosts.
鸟分枝杆菌复合群细菌是人类机会性致病菌，由于这些微生物对大多数常规抗结核药物耐药，其化疗仍然是一项挑战。最近，已开发出多种新型大环内酯类抗生素，其中克拉霉素似乎对鸟分枝杆菌有选择性作用。在本研究中，我们研究了克拉霉素单独作用（MIC和MBC测定）以及与亚致死浓度（1微克/毫升；低于人血清中可达到的浓度）的常规抗分枝杆菌药物乙胺丁醇和利福平联合使用时对鸟分枝杆菌的作用。我们的活菌计数数据表明，克拉霉素对所研究的所有10株鸟分枝杆菌均有杀菌作用，并且乙胺丁醇（9株中的8株）和利福平（9株中的3株）可增强其活性。在9株中的7株中，三种药物联合使用比单独使用任何一种药物或两种药物联合使用产生更高的杀菌效果。通过使用7H9肉汤和BACTEC放射测量法（细胞外作用）以及J-774巨噬细胞系（细胞内作用），研究了单独使用和联合使用各种药物在人血清可达到的浓度下对标准菌株ATCC 15769的杀菌作用。发现细胞外和细胞内活性之间有良好的一致性。使用钌红细胞化学染色对细菌进行电子显微镜观察表明，克拉霉素使分枝杆菌细胞包膜的外壁层和细胞质膜紊乱，并导致细胞质内形成大液泡，核糖体结构溶解并随之发生质壁分离。它与乙胺丁醇和利福平联合使用导致细菌形态的改变比单独使用任何一种药物时更为剧烈，导致细菌外层去除、细胞质均质化、细胞完全裂解并形成菌影。
