title: Rapid evaluation in whole blood culture of regimens for XDR-TB containing PNU-100480 (sutezolid), TMC207, PA-824, SQ109, and pyrazinamide.
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.
authors.affiliation: Pfizer, Groton, Connecticut, United States of America. robert.wallis@pfizer.com
authors.forename: Robert S
authors.initials: RS
authors.lastname: Wallis
authors.forename: Wesley
authors.initials: W
authors.lastname: Jakubiec
authors.forename: Mark
authors.initials: M
authors.lastname: Mitton-Fry
authors.forename: Lynn
authors.initials: L
authors.lastname: Ladutko
authors.forename: Sheldon
authors.initials: S
authors.lastname: Campbell
authors.forename: Darcy
authors.initials: D
authors.lastname: Paige
authors.forename: Annette
authors.initials: A
authors.lastname: Silvia
authors.forename: Paul F
authors.initials: PF
authors.lastname: Miller
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D000995:Antitubercular Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D064687:Diarylquinolines; D016903:Drug Monitoring / Q000379:methods*; D004359:Drug Therapy, Combination; D005029:Ethylenediamines / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D054908:Extensively Drug-Resistant Tuberculosis / Q000097:blood* / Q000188:drug therapy; D006801:Humans; D008826:Microbial Sensitivity Tests / Q000379:methods; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000254:growth & development; D009593:Nitroimidazoles / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D023303:Oxazolidinones / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D011718:Pyrazinamide / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D011804:Quinolines / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D015203:Reproducibility of Results; D013997:Time Factors
chemical_list: D000995:Antitubercular Agents; D064687:Diarylquinolines; D005029:Ethylenediamines; C506841:N-geranyl-N'-(2-adamantyl)ethane-1,2-diamine; D009593:Nitroimidazoles; D023303:Oxazolidinones; C543015:PNU-100480; D011804:Quinolines; C410767:pretomanid; D011718:Pyrazinamide; C493870:bedaquiline; D000218:Adamantane