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  • American Society for Microbiology  (2)
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  • American Society for Microbiology  (2)
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  • 1
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 58, No. 6 ( 2014-06), p. 3496-3503
    Kurzfassung: BMS-791325 is a nonnucleoside inhibitor of hepatitis C virus (HCV) NS5B polymerase with low-nanomolar potency against genotypes 1a (50% effective concentration [EC 50 ], 3 nM) and 1b (EC 50 , 7 nM) in vitro . BMS-791325 safety, pharmacokinetics, and antiviral activity were evaluated in a double-blind, placebo-controlled, single-ascending-dose study in 24 patients (interferon naive and experienced) with chronic HCV genotype 1 infection, randomized (5:1) to receive a single dose of BMS-791325 (100, 300, 600, or 900 mg) or placebo. The prevalence and phenotype of HCV variants at baseline and specific posttreatment time points were assessed. Antiviral activity was observed in all cohorts, with a mean HCV RNA decline of ≈2.5 log 10 copies/ml observed 24 h after a single 300-mg dose. Mean plasma half-life among cohorts was 7 to 9 h; individual 24-hour levels exceeded the protein-adjusted EC 90 for genotype 1 at all doses. BMS-791325 was generally well tolerated, with no serious adverse events or discontinuations. Enrichment for resistance variants was not observed at 100 to 600 mg. At 900 mg, variants (P495L/S) associated with BMS-791325 resistance in vitro were transiently observed in one patient, concurrent with an observed HCV RNA decline of 3.4 log 10 IU/ml, but were replaced with wild type by 48 h. Single doses of BMS-791325 were well tolerated; demonstrated rapid, substantial, and exposure-related antiviral activity; displayed dose-related increases in exposure; and showed viral kinetic and pharmacokinetic profiles supportive of once- or twice-daily dosing. These results support its further development in combination with other direct-acting antivirals for HCV genotype 1 infection. (This trial has been registered at ClinicalTrials.gov under registration no. NCT00664625.)
    Materialart: Online-Ressource
    ISSN: 0066-4804 , 1098-6596
    RVK:
    Sprache: Englisch
    Verlag: American Society for Microbiology
    Publikationsdatum: 2014
    ZDB Id: 1496156-8
    SSG: 12
    SSG: 15,3
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 2
    Online-Ressource
    Online-Ressource
    American Society for Microbiology ; 2019
    In:  mSphere Vol. 4, No. 4 ( 2019-08-28)
    In: mSphere, American Society for Microbiology, Vol. 4, No. 4 ( 2019-08-28)
    Kurzfassung: Staphylococcus aureus bacteria form biofilms and distinctive microcolony or “tower” structures that facilitate their ability to tolerate antibiotic treatment and to spread within the human body. The formation of microcolonies, which break off, get carried downstream, and serve to initiate biofilms in other parts of the body, is of particular interest here. It is known that flow conditions play a role in the development, dispersion, and propagation of biofilms in general. The influence of flow on microcolony formation and, ultimately, what factors lead to microcolony development are, however, not well understood. The hypothesis being examined is that microcolony structures form within a specific range of levels of shear stress. In this study, laminar shear flow over a range of 0.15 to 1.5 dynes/cm 2 was examined. It was found that microcolony structures form in a narrow range of shear stresses around 0.6 dynes/cm 2 . Further, measurements of cell density as a function of space and time showed that shear dependence can be observed hours before microcolonies form. This is significant because, among other physiologic flows, this is the same shear stress found in large veins in the human vasculature, which, along with catheters of similar diameters and flow rates, may therefore play a critical role in biofilm development and subsequent spreading of infections throughout the body. IMPORTANCE It is well known that flow plays an important role in the formation, transportation, and dispersion of Staphylococcus aureus biofilms. What was heretofore not known was that the formation of tower structures in these biofilms is strongly shear stress dependent; there is, in fact, a narrow range of shear stresses in which the phenomenon occurs. This work quantifies the observed shear dependence in terms of cell growth, distribution, and fluid mechanics. It represents an important first step in opening up a line of questioning as to the interaction of fluid forces and their influence on the dynamics of tower formation, break-off, and transportation in biofilms by identifying the parameter space in which this phenomenon occurs. We have also introduced state-of-the-art flow measurement techniques to address this problem.
    Materialart: Online-Ressource
    ISSN: 2379-5042
    Sprache: Englisch
    Verlag: American Society for Microbiology
    Publikationsdatum: 2019
    ZDB Id: 2844248-9
    Standort Signatur Einschränkungen Verfügbarkeit
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