NDLI: Rapid Evaluation in Whole Blood Culture of Regimens for XDR-TB Containing PNU-100480 (Sutezolid), TMC207, PA-824, SQ109, and Pyrazinamide

Content Provider	PubMed Central
Author	Wallis, Robert S. Jakubiec, Wesley Mark, Mitton-fry Lynn, Ladutko Campbell, Sheldon Paige, Darcy Silvia, Annette Miller, Paul F.
Editor	Surolia, Avadhesha
Copyright Year	2012
Abstract	There presently is no rapid method to assess the bactericidal activity of new regimens for tuberculosis. This study examined PNU-100480, TMC207, PA-824, SQ109, and pyrazinamide, singly and in various combinations, against intracellular M. tuberculosis, using whole blood culture (WBA). The addition of 1,25-dihydroxy vitamin D facilitated detection of the activity of TMC207 in the 3-day cultures. Pyrazinamide failed to show significant activity against a PZA-resistant strain (M. bovis BCG), and was not further considered. Low, mid, and high therapeutic concentrations of each remaining drug were tested individually and in a paired checkerboard fashion. Observed bactericidal activity was compared to that predicted by the sum of the effects of individual drugs. Combinations of PNU-100480, TMC207, and SQ109 were fully additive, whereas those including PA-824 were less than additive or antagonistic. The cumulative activities of 2, 3, and 4 drug combinations were predicted based on the observed concentration-activity relationship, published pharmacokinetic data, and, for PNU-100480, published WBA data after oral dosing. The most active regimens, including PNU-100480, TMC207, and SQ109, were predicted to have cumulative activity comparable to standard TB therapy. Further testing of regimens including these compounds is warranted. Measurement of whole blood bactericidal activity can accelerate the development of novel TB regimens.
Related Links	http://dx.doi.org/10.1371/journal.pone.0030479
Starting Page	30479
File Format	PDF
ISSN	19326203
e-ISSN	19326203
Journal	PLoS ONE
Issue Number	1
Volume Number	7
Language	English
Publisher	Public Library of Science
Publisher Date	2012-01-01
Access Restriction	Open
Rights Holder	Public Library of Science
Subject Keyword	Biochemistry, Genetics and Molecular Biology(all) Agricultural and Biological Sciences(all) Medicine(all) Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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Sterilizing Activity of Second-Line Regimens Containing TMC207 in a Murine Model of Tuberculosis

Sterilizing Activity of Novel TMC207- and PA-824-Containing Regimens in a Murine Model of Tuberculosis ▿ †

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Rapid Evaluation in Whole Blood Culture of Regimens for XDR-TB Containing PNU-100480 (Sutezolid), TMC207, PA-824, SQ109, and Pyrazinamide

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