Drugs online research references
Antimicrob Agents Chemother. 2003 Mar;47(3):1017-22.
Effects of an efflux mechanism and ribosomal mutations on macrolide susceptibility of Haemophilus influenzae clinical isolates.
Peric M, Bozdogan B, Jacobs MR, Appelbaum PC.
Department of Pathology, Hershey Medical Center, Pennsylvania 17033, USA.
This study investigated macrolide resistance mechanisms in clinical Haemophilus influenzae strains with different levels of susceptibility to macrolides. A total of 6,382 isolates were collected during the Alexander Project from 1997 to 2000. For 96.9% of these isolates, the azithromycin MICs were 0.25 to 4 micro g/ml, and these were defined as baseline strains. For 1.8% of the isolates, the azithromycin MICs were lower (<0.25 micro g/ml), and for 1.3% of the isolates, the MICs were higher (>4 micro g/ml). These isolates were defined as hypersusceptible and high-level macrolide-resistant strains, respectively. To identify the mechanisms associated with these three susceptibility patterns, representative strains were studied for the presence of macrolide efflux pumps and for ribosomal alterations. Macrolide efflux was studied by measuring the accumulation of radioactive azithromycin and clarithromycin in the presence or absence of carbonyl cyanide m-chlorophenylhydrazone (CCCP), a protonophore. Treatment with CCCP increased the accumulation of macrolides in baseline as well as high-level resistant strains, demonstrating the presence of an efflux mechanism, but not in the 20 hypersusceptible strains tested. Among the 31 strains studied that showed high-level resistance to both azithromycin and clarithromycin, 28 had ribosomal alterations, 7 had mutations in ribosomal protein L4, 11 had mutations in L22, 2 had mutations in 23S rRNA, 8 had multiple mutations, and 3 had no mutations. From these results, we conclude that the vast majority (>98%) of H. influenzae strains have a macrolide efflux mechanism, with a few of these being hyperresistant (1.3%) due to one or several ribosomal mutations. Occasional hypersusceptible strains (1.8%) were found and had no macrolide resistance mechanisms and appeared to be the only truly macrolide-susceptible variants of H. influenzae.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12604536&dopt=Abstract
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Antimicrob Agents Chemother. 2003 Mar;47(3):1047-51.
Influence of P-glycoprotein inhibitors on accumulation of macrolides in J774 murine macrophages.
Seral C, Michot JM, Chanteux H, Mingeot-Leclercq MP, Tulkens PM, Van Bambeke F.
Unite de Pharmacologie Cellulaire et Moleculaire, Universite Catholique de Louvain, Brussels, Belgium.
The influence of inhibitors of P-glycoprotein (verapamil [VE], cyclosporine [CY], and GF120918 [GF]) on the cell handling of macrolides (erythromycin [ERY], clarithromycin [CLR], roxithromycin [ROX], azithromycin [AZM], and telithromycin [TEL]) was examined in J774 murine macrophages. The net influx rates of AZM and TEL were increased from 2- to 3.5-fold in the presence of these inhibitors, but their efflux was slowed only marginally. At 3 h, the inhibitors increased the levels of AZM, ERY, and TEL accumulation approximately three- to fourfold (the effect of VE, however, was lower) but did not influence CLR accumulation (the inhibitors had an intermediate behavior on ROX accumulation). The effect was concentration dependent (half-maximal increases in the level of accumulation of AZM were obtained with GF, CY, and VE at 0.5, 5, and 10 micro M, respectively). ATP depletion also caused an approximately threefold increase in the level of accumulation of AZM. Two inhibitors of MRP (probenecid [2.5 mM] and gemfibrozil [0.25 mM]) had no effect. Monensin (a proton ionophore) completely suppressed the accumulation of AZM in control cells as well as in cells incubated in the presence of VE, demonstrating that transmembrane proton gradients are the driving force causing the accumulation of AZM in both cases. Yet, VE did not alter the pH of the lysosomes (approximately 5) or of the cytosol (approximately 7.1). P-glycoprotein was detected by immunostaining at the cell surface as well as in intracellular vacuoles (endosomes and lysosomes). The data suggest that the influx of AZM, ERY, TEL, and ROX is adversely influenced by the activity of P-glycoprotein in J774 macrophages, resulting in suboptimal drug accumulation.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12604540&dopt=Abstract
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Antimicrob Agents Chemother. 2003 Mar;47(3):1135-6.
In vitro activities of rifamycin derivatives ABI-1648 (Rifalazil, KRM-1648), ABI-1657, and ABI-1131 against Chlamydia trachomatis and recent clinical isolates of Chlamydia pneumoniae.
Roblin PM, Reznik T, Kutlin A, Hammerschlag MR.
Division of Infectious Diseases, Department of Pediatrics, State University of New York Downstate Medical Center, Brooklyn 11203-2098, USA.
ABI-1648 (rifalazil) is a semisynthetic rifamycin with potent bactericidal activity against intracellular respiratory bacteria, including Mycobacterium tuberculosis, and a long half-life (approximately 60 h) and thus can be administered once weekly. We therefore tested the in vitro activities of ABI-1648, its derivatives ABI-1657 and ABI-1131, azithromycin, and levofloxacin against 10 strains of Chlamydia trachomatis and 10 recent clinical isolates of Chlamydia pneumoniae. The MICs at which 90% of the isolates were inhibited and the minimal bactericidal concentration at which 90% of the isolates were killed for ABI-1648, ABI-1657, and ABI-1131 were 0.0025 micro g/ml for C. trachomatis and 0.00125 to 0.0025 micro g/ml for C. pneumoniae. ABI-1648, ABI-1657, and ABI-1131 were 10- to 1,000-fold more active than azithromycin and levofloxacin.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12604555&dopt=Abstract
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