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.

Autor:	Walter K; Division of Infection Immunology, Research Center Borstel, Leibniz Lung Center, Borstel, Germany.; German Center for Infection Research, Partner Site Hamburg-Lübeck-Borstel-Riems, Borstel, Germany., Te Brake LHM; Department of Pharmacy, Radboud Institute of Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands., Lemm AK; Division of Infection Immunology, Research Center Borstel, Leibniz Lung Center, Borstel, Germany., Hoelscher M; Institute of Infectious Diseases and Tropical Medicine, University Hospital, LMU Munich, Munich, Germany.; German Center for Infection Research, Partner Site Munich, Munich, Germany.; Fraunhofer Institute ITMP, Immunology, Infection and Pandemic Research, Munich, Germany.; Unit Global Health, Helmholtz Zentrum Munich, German Research Center for Environmental Health (HMGU), Neuherberg, Germany., Svensson EM; Department of Pharmacy, Radboud Institute of Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.; Department of Pharmacy, Uppsala University, Uppsala, Sweden., Hölscher C; Division of Infection Immunology, Research Center Borstel, Leibniz Lung Center, Borstel, Germany.; German Center for Infection Research, Partner Site Hamburg-Lübeck-Borstel-Riems, Borstel, Germany., Heinrich N; Institute of Infectious Diseases and Tropical Medicine, University Hospital, LMU Munich, Munich, Germany.; German Center for Infection Research, Partner Site Munich, Munich, Germany.; Fraunhofer Institute ITMP, Immunology, Infection and Pandemic Research, Munich, Germany.
Jazyk:	angličtina
Zdroj:	The Journal of antimicrobial chemotherapy [J Antimicrob Chemother] 2024 Aug 07. Date of Electronic Publication: 2024 Aug 07.
DOI:	10.1093/jac/dkae266
Abstrakt:	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.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu