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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.
J. Antimicrob. Chemother. 79, 2607-2610 (2024)
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.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Pharmacokinetics; Pretomanid; Metabolite; Regimens; Efficacy; Humans
ISSN (print) / ISBN
0305-7453
e-ISSN
1460-2091
Quellenangaben
Volume: 79,
Issue: 10,
Pages: 2607-2610
Publisher
Oxford University Press
Publishing Place
Great Clarendon St, Oxford Ox2 6dp, England
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Research Unit Global Health (UGH)
Grants
Nederlandse Organisatie voor Wetenschappelijk onderzoek
PanACEA 2
German Ministry for Education and Research
Swiss State Secretariat for Education, Research, and Innovation
PanACEA 2
German Ministry for Education and Research
Swiss State Secretariat for Education, Research, and Innovation