Biomaterial Database

Extracellular and intracellular activities of clarithromycin used alone and in association with ethambutol and rifampin against Mycobacterium avium complex. 1991

N Rastogi, and V Labrousse

Unité de la Tuberculose et des Mycobactéries, Institut Pasteur, Paris, France.

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.

UI	MeSH Term	Description	Entries
D008826	Microbial Sensitivity Tests	Any tests that demonstrate the relative efficacy of different chemotherapeutic agents against specific microorganisms (i.e., bacteria, fungi, viruses).	Bacterial Sensitivity Tests,Drug Sensitivity Assay, Microbial,Minimum Inhibitory Concentration,Antibacterial Susceptibility Breakpoint Determination,Antibiogram,Antimicrobial Susceptibility Breakpoint Determination,Bacterial Sensitivity Test,Breakpoint Determination, Antibacterial Susceptibility,Breakpoint Determination, Antimicrobial Susceptibility,Fungal Drug Sensitivity Tests,Fungus Drug Sensitivity Tests,Sensitivity Test, Bacterial,Sensitivity Tests, Bacterial,Test, Bacterial Sensitivity,Tests, Bacterial Sensitivity,Viral Drug Sensitivity Tests,Virus Drug Sensitivity Tests,Antibiograms,Concentration, Minimum Inhibitory,Concentrations, Minimum Inhibitory,Inhibitory Concentration, Minimum,Inhibitory Concentrations, Minimum,Microbial Sensitivity Test,Minimum Inhibitory Concentrations,Sensitivity Test, Microbial,Sensitivity Tests, Microbial,Test, Microbial Sensitivity,Tests, Microbial Sensitivity
D008854	Microscopy, Electron	Microscopy using an electron beam, instead of light, to visualize the sample, thereby allowing much greater magnification. The interactions of ELECTRONS with specimens are used to provide information about the fine structure of that specimen. In TRANSMISSION ELECTRON MICROSCOPY the reactions of the electrons that are transmitted through the specimen are imaged. In SCANNING ELECTRON MICROSCOPY an electron beam falls at a non-normal angle on the specimen and the image is derived from the reactions occurring above the plane of the specimen.	Electron Microscopy
D009162	Mycobacterium avium	A bacterium causing tuberculosis in domestic fowl and other birds. In pigs, it may cause localized and sometimes disseminated disease. The organism occurs occasionally in sheep and cattle. It should be distinguished from the M. avium complex, which infects primarily humans.
D002455	Cell Division	The fission of a CELL. It includes CYTOKINESIS, when the CYTOPLASM of a cell is divided, and CELL NUCLEUS DIVISION.	M Phase,Cell Division Phase,Cell Divisions,Division Phase, Cell,Division, Cell,Divisions, Cell,M Phases,Phase, Cell Division,Phase, M,Phases, M
D002478	Cells, Cultured	Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others.	Cultured Cells,Cell, Cultured,Cultured Cell
D004338	Drug Combinations	Single preparations containing two or more active agents, for the purpose of their concurrent administration as a fixed dose mixture.	Drug Combination,Combination, Drug,Combinations, Drug
D004917	Erythromycin	A bacteriostatic antibiotic macrolide produced by Streptomyces erythreus. Erythromycin A is considered its major active component. In sensitive organisms, it inhibits protein synthesis by binding to 50S ribosomal subunits. This binding process inhibits peptidyl transferase activity and interferes with translocation of amino acids during translation and assembly of proteins.	Erycette,Erymax,Erythromycin A,Erythromycin C,Erythromycin Lactate,Erythromycin Phosphate,Ilotycin,T-Stat,Lactate, Erythromycin,Phosphate, Erythromycin,T Stat,TStat
D004977	Ethambutol	An antitubercular agent that inhibits the transfer of mycolic acids into the cell wall of the tubercle bacillus. It may also inhibit the synthesis of spermidine in mycobacteria. The action is usually bactericidal, and the drug can penetrate human cell membranes to exert its lethal effect. (From Smith and Reynard, Textbook of Pharmacology, 1992, p863)	Dexambutol,EMB-Fatol,EMB-Hefa,Etambutol Llorente,Ethambutol Hydrochloride,Etibi,Miambutol,Myambutol,EMB Fatol,EMB Hefa,Hydrochloride, Ethambutol,Llorente, Etambutol
D012293	Rifampin	A semisynthetic antibiotic produced from Streptomyces mediterranei. It has a broad antibacterial spectrum, including activity against several forms of Mycobacterium. In susceptible organisms it inhibits DNA-dependent RNA polymerase activity by forming a stable complex with the enzyme. It thus suppresses the initiation of RNA synthesis. Rifampin is bactericidal, and acts on both intracellular and extracellular organisms. (From Gilman et al., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th ed, p1160)	Rifampicin,Benemycin,Rifadin,Rimactan,Rimactane,Tubocin
D017291	Clarithromycin	A semisynthetic macrolide antibiotic derived from ERYTHROMYCIN that is active against a variety of microorganisms. It can inhibit PROTEIN SYNTHESIS in BACTERIA by reversibly binding to the 50S ribosomal subunits. This inhibits the translocation of aminoacyl transfer-RNA and prevents peptide chain elongation.	6-O-Methylerythromycin,A-56268,Biaxin,TE-031,A 56268,A56268,TE 031,TE031