Table 8.
Summary of treatment efficacy of delamanid and pretomanid within various drug combination regimens in animal models of tuberculosis
| Author | Animal (infection route) | M. tuberculosis strain | Incubation period until start of treatment | Drug combination (dose in mg/kg) | Treatment duration | Route of drug administration | Exposure to DLM or PMD | Outcome | |
|---|---|---|---|---|---|---|---|---|---|
| Bactericidal activity | Relapse rates | ||||||||
| Matsumoto et al. (2006)10 | ICR mice (intratracheal instillation) | Kurono | 28 days | 2 months RIF (5) + DLM (2.5) + PZA (100) and 2 months RIF (5) + DLM (2.5) | 4 months | Oral | AUC0–24 = 4.13 μg·h/mL (monotherapy, single dose of 2.5 mg/kg) | Faster culture-negativity (by at least 2 months) in the lungs compared to the standard regimen (HRZE). | NA |
| Chen et al. (2017)95 | Guinea pigs (intratracheal instillation) | Kurono | 4 weeks | RIF (25) + DLM (100) + PZA (150) | 4 or 8 weeks | Oral | AUC0–24 = 9.45 μg·h/mL (monotherapy, single dose of 100 mg/kg) | Culture-negativity in the lungs was reached after 4 weeks of treatment versus 8 weeks for the standard regimen (HRZ). | NA |
| Nuermberger et al. (2006)108 | BALB/c mice (aerosol) | H37Rv | 19 days | 2 months RIF (10) + PMD (100) + PZA (150) and 4 months RIF (10) + PMD (100) | 6 months | Oral | AUC0–24 = 396.8 μg·h/mL (monotherapy, 2 months treatment, dose 100 mg/kg) | Culture-negativity in the lungs was reached after 4 months of treatment versus 6 months for the standard regimen (HRZ). This difference was not statistically significant. | Relapse rates were comparable to those of the standard HRZ-regimen (2/19 versus 0/46, respectively). |
| Tasneen et al. (2008)106 | BALB/c mice (aerosol) | H37Rv | 2 weeks | RIF (10) + PMD (12.5/25/50/100) + PZA (150) | 2, 4, 5, or 6 months | Oral | AUC 0–∞ = 127.5 μg·h/mL (monotherapy, single dose of 54 mg/kg) | PMD at 50 and 100 mg/kg increased activity of RIF + PZA in a dose-dependent manner. Culture-negativity in the lungs was reached after 2 months of treatment (PMD 100 mg/kg). | No relapse was seen after 4 months of treatment versus a relapse rate of 15% for the regimen (HRZ). |
| Pieterman et al. (2021)93 | BALB/c mice (intratracheal instillation) | Beijing | 2 weeks | BDQ (25) + DLM (2.5) + LZD (100) | 2–6 months | Oral | AUC0–24 = 11.234 μg·h/mL (4 weeks treatment, dose 2.5 mg/kg, BDL combination) | Culture negativity in the lungs was reached after 2 months of treatment versus 20 weeks for the standard regimen (HRZE). | No relapse was seen after treatment duration of 4 months or longer (except for 1 mouse, treated for 5 months). HRZE-treated mice still relapsed after 6 months of treatment (1/3 mice). |
| Tasneen et al. (2016)128 | BALB/c mice (aerosol) | H37Rv | 13–14 days | BDQ (25) + PMD (50) + LZD (100) | 2–4 months | Oral | NA | Two and 3 months of treatment led to a significantly lower mycobacterial load in the lungs compared to the standard regimen (HRZ). | No relapse was seen after 3 months of treatment. Infection still relapsed in HRZ-treated mice after 4 months of treatment. |
| Xu et al. (2019)123 | BALB/c mice (aerosol) | H37Rv | 13 days | BDQ (25) + PMD (100) + LZD (100) | 1–4 months | Oral | NA | Addition of PMD to BDQ + LZD led to a higher mycobacterial load reduction when administered for 1 and 2 months and prevented the emergence of BDQ resistance. | After 2 months of treatment with BPaL, infection relapsed in 7/15 mice. No relapse was seen after 3 months of treatment. |
| Bigelow et al. (2020)121 | BALB/c mice (aerosol) | H37Rv or HN878 | 2 weeks | BDQ (25) + PMD (50 or 100) + different LZD dosing strategies (45 or 90) | 1–3 months | Oral | NA | BDQ + PMD with different dosing strategies for LZD resulted in a higher mycobacterial load reduction compared to the standard regimen (HRZE). LZD’s contribution to BDQ + PMD + LZD regimens was dependent on the M. tuberculosis strain. | Relapse rates were highly variable between the different LZD dosing strategies, LZD (90 mg/kg) dosed every other day leading to the highest relapse rate (11/15 mice) and LZD (90 mg/kg) dosed daily to the lowest relapse rates (1/15 mice) |
| Xu et al. (2021)122 | BALB/c mice (aerosol) | H37Rv | 2 weeks | BDQ (25) + PMD (100) + LZD (100) | 1 month | Oral | NA | Lung cfu were reduced by approximately 2 log10. | NA |
| Mudde et al. (2021)107 | BALB/c mice (intratracheal instillation) | Beijing | 2 weeks | BDQ (25) + PMD (100) + LZD (100) | 6–13 weeks | Oral | AUC0–24 = 104 and 99.13 μg·h/mL (4 weeks treatment, dose 100 mg/kg, BPaMZ combination or BPaL combination, respectively) | NA | Mice treated for the maximum duration of 13 weeks still showed relapse (3/3 mice). |
| Tasneen et al. (2021)137 | BALB/c mice (aerosol) | HN878 (Beijing subfamily) | 7 weeks | BDQ (25) + PMD (100) + LZD (100) | 1 or 2 months | Oral | NA | 1 month of BPaL treatment led to a 3.87 log10 reduction in lung cfu. | After 2 months of treatment with BPaL, infection relapsed in 7/15 mice. After 3 months of treatment with HRZE, infection relapsed in 9/15 mice. |
DLM, delamanid; PMD, pretomanid; RIF, rifampicin; PZA, pyrazinamide; HRZE, isoniazid + rifampicin + pyrazinamide + ethambutol; HRZ, isoniazid + rifampicin + pyrazinamide; BDQ, bedaquiline; LZD, linezolid; BDL, bedaquiline + delamanid + linezolid; BPaMZ, bedaquiline + pretomanid + moxifloxacin + pyrazinamide; BPaL, bedaquiline, pretomanid, linezolid.