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Walter, K.* ; Te Brake, L.H.M.* ; Lemm, A.K.* ; Hoelscher, M. ; Svensson, E.M.* ; Hölscher, C.* ; Heinrich, N.*

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)
Verlagsversion DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Pharmacokinetics; Pretomanid; Metabolite; Regimens; Efficacy; Humans
ISSN (print) / ISBN 0305-7453
e-ISSN 1460-2091
Zeitschrift Journal of Antimicrobial Chemotherapy
Quellenangaben Band: 79, Heft: 10, Seiten: 2607-2610 Artikelnummer: , Supplement: ,
Verlag Oxford University Press
Verlagsort Great Clarendon St, Oxford Ox2 6dp, England
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Research Unit Global Health (UGH)
Förderungen Nederlandse Organisatie voor Wetenschappelijk onderzoek
PanACEA 2
German Ministry for Education and Research
Swiss State Secretariat for Education, Research, and Innovation