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

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 B<inf>25</inf>D<inf>0.6</inf>M<inf>200</inf>U<inf>200</inf>, B<inf>25</inf>D<inf>0.6</inf>M<inf>200</inf>, B<inf>25</inf>D<inf>0.6</inf>M<inf>200</inf>(U<inf>200</inf>³ ) or H<inf>10</inf>R<inf>10</inf>Z<inf>150</inf>E<inf>100</inf> (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: B<inf>25</inf>D<inf>0.6</inf>M<inf>200</inf>U<inf>200</inf> generated human equivalent exposures in uninfected BALB/c mice. After 1 month of treatment, a higher bactericidal activity was observed for the B<inf>25</inf>D<inf>0.6</inf>M<inf>200</inf>U<inf>200</inf> and the B<inf>25</inf>D<inf>0.6</inf>M<inf>200</inf> regimen compared to the standard H<inf>10</inf>R<inf>10</inf>Z<inf>150</inf>E<inf>100</inf> regimen. Furthermore, 3 months of therapy with both BDM-based regimens resulted in negative lung cultures, whereas all H<inf>10</inf>R<inf>10</inf>Z<inf>150</inf>E<inf>100</inf> treated mice were still culture positive. After 3 months of therapy 7% and 13% of mice relapsed receiving B<inf>25</inf>D<inf>0.6</inf>M<inf>200</inf>U<inf>200</inf> and B<inf>25</inf>D<inf>0.6</inf>M<inf>200</inf>, respectively, compared to 40% for H<inf>10</inf>R<inf>10</inf>Z<inf>150</inf>E<inf>100</inf> 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.