Investigating the treatment shortening potential of a combination of bedaquiline, delamanid and moxifloxacin with and without sutezolid, in a murine tuberculosis model with confirmed drug exposures.

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  • Additional Information
    • Source:
      Publisher: Oxford University Press Country of Publication: England NLM ID: 7513617 Publication Model: Print Cited Medium: Internet ISSN: 1460-2091 (Electronic) Linking ISSN: 03057453 NLM ISO Abbreviation: J Antimicrob Chemother Subsets: MEDLINE
    • Publication Information:
      Publication: 1997- : London : Oxford University Press
      Original Publication: London, New York, Academic Press.
    • Subject Terms:
      Nitroimidazoles*/therapeutic use ; Nitroimidazoles*/administration & dosage ; Nitroimidazoles*/pharmacology ; Antitubercular Agents*/therapeutic use ; Antitubercular Agents*/pharmacokinetics ; Antitubercular Agents*/administration & dosage ; Antitubercular Agents*/pharmacology ; Diarylquinolines*/therapeutic use ; Diarylquinolines*/pharmacology ; Mice, Inbred BALB C* ; Disease Models, Animal* ; Mycobacterium tuberculosis*/drug effects ; Oxazoles*/therapeutic use ; Oxazoles*/administration & dosage ; Oxazoles*/pharmacology ; Moxifloxacin*/therapeutic use ; Moxifloxacin*/administration & dosage ; Moxifloxacin*/pharmacology ; Drug Therapy, Combination*; Animals ; Mice ; Female ; Tuberculosis, Multidrug-Resistant/drug therapy ; Tuberculosis, Multidrug-Resistant/microbiology ; Oxazolidinones/therapeutic use ; Oxazolidinones/administration & dosage ; Oxazolidinones/pharmacokinetics ; Pyrazinamide/therapeutic use ; Pyrazinamide/administration & dosage ; Treatment Outcome ; Isoxazoles
    • Abstract:
      Background: New and shorter regimens against multi-drug resistant tuberculosis (TB) remain urgently needed. To inform treatment duration in clinical trials, this study aimed to identify human pharmacokinetic equivalent doses, antimycobacterial and sterilizing activity of a novel regimen, containing bedaquiline, delamanid, moxifloxacin and sutezolid (BDMU), in the standard mouse model (BALB/c) of Mycobacterium tuberculosis (Mtb) infection.
      Methods: Treatment of mice with B25D0.6M200U200, B25D0.6M200, B25D0.6M200(U2003) or H10R10Z150E100 (isoniazid, rifampicin, pyrazinamide, ethambutol, HRZE), started 3 weeks after Mtb infection. Bactericidal activity was assessed after 1, 2, 3 and 4 months of treatment and relapse rates were assessed 3 months after completing treatment durations of 2, 3 and 4 months.
      Results: B25D0.6M200U200 generated human equivalent exposures in uninfected BALB/c mice. After 1 month of treatment, a higher bactericidal activity was observed for the B25D0.6M200U200 and the B25D0.6M200 regimen compared to the standard H10R10Z150E100 regimen. Furthermore, 3 months of therapy with both BDM-based regimens resulted in negative lung cultures, whereas all H10R10Z150E100 treated mice were still culture positive. After 3 months of therapy 7% and 13% of mice relapsed receiving B25D0.6M200U200 and B25D0.6M200, respectively, compared to 40% for H10R10Z150E100 treatment showing an increased sterilizing activity of both BDM-based regimens.
      Conclusions: BDM-based regimens, with and without sutezolid, have a higher efficacy than the HRZE regimen in the BALB/c model of TB, with some improvement by adding sutezolid. By translating these results to TB patients, this novel BDMU regimen should be able to reduce treatment duration by 25% compared to HRZE therapy.
      (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)
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    • Grant Information:
      TTU 02.710 German Center for Infection Research; PanACEA 2; German Ministry for Education and Research; Swiss State Secretariat for Education, Research, and Innovation; Nederlandse Organisatie voor Wetenschappelijk Onderzoek
    • Accession Number:
      0 (Nitroimidazoles)
      78846I289Y (bedaquiline)
      0 (Antitubercular Agents)
      0 (Diarylquinolines)
      0 (OPC-67683)
      0 (Oxazoles)
      U188XYD42P (Moxifloxacin)
      0 (Oxazolidinones)
      2KNI5N06TI (Pyrazinamide)
      1199LEX5N8 (terizidone)
      0 (Isoxazoles)
    • Publication Date:
      Date Created: 20240807 Date Completed: 20240930 Latest Revision: 20241003
    • Publication Date:
      20241003
    • Accession Number:
      PMC11441997
    • Accession Number:
      10.1093/jac/dkae266
    • Accession Number:
      39110473