Table 7.
Summary of treatment activity of delamanid and pretomanid as a monotherapy in various animal models of tuberculosis
| Author | Animal (inoculation route) | M. tuberculosis strain | Time until start of treatment | Drug treatment (dose, mg/kg) | Treatment duration | Route of drug administration | Drug exposure | Outcome |
|---|---|---|---|---|---|---|---|---|
| Gengenbacher et al. (2017)117 | Nos2−/− mice (intradermal) | H37Rv | 42 days (control) or 56 days (hypoxic lung lesions) | DLM (1); PMD (75) | 70–84 days | Oral | NA | DLM and PMD were both active against non-replicating and replicating bacilli, and had comparable bactericidal activity in hypoxic necrotic lesions. |
| Tasneen et al. (2015)120 | BALB/c mice (aerosol) | H37Rv | 13–14 days | DLM (3–100); PMD (10–600) | 2–8 weeks | Oral | NA | DLM and PMD showed time-dependent and dose-dependent bactericidal activity. DLM was approximately 10-fold more active than PMD. |
| Upton et al. (2015)63 | BALB/c mice (aerosol) | Erdman | 10 days | DLM; PMD (100) | 3 weeks | Oral | NA | DLM was significantly more active than PMD in this model of acute infection. DLM led to a 1 log10 reduction in lung cfu. PMD inhibited mycobacterial growth, but did not reduce lung cfu. |
| BALB/c mice (aerosol) | Erdman | 70 days | DLM; PMD (100) | 3 weeks | Oral | NA | DLM was significantly more active than PMD in this model of chronic infection. DLM led to a 2 to 3 log10 reduction in lung cfu. PMD led to a 2 log10 reduction in lung cfu. | |
| Kmentova et al. (2010)119 | BALB/c mice | 70 days | DLM; PMD (100) | 3 weeks | Oral | NA | DLM was 10-fold more active than PMD, with 3 log10 versus 2 log10 reduction in lung cfu, respectively. | |
| Matsumoto et al. (2006)10 | ICR mice (intravenous) | Kurono | 4 weeks | DLM (0.156–40); PMD (1.25–40) | 4 weeks | Oral | AUC0–24 = 4.13 μg·h/mL (single dose of 2.5 mg/kg DLM) | DLM led to a dose-dependent reduction in lung cfu. For PMD, RIF and INH higher doses were needed to equal the load reduction by DLM. |
| BALB/c (nude) mice (intravenous) | Kurono | 1 day | DLM (0.313–10) | 10 days | Oral | AUC0–24 = 4.13 μg·h/mL (single dose of 2.5 mg/kg) | DLM led to a dose-dependent reduction in lung cfu, which was equal in immunodeficient and immunocompetent mice. | |
| Sasaki et al. (2006)11 | ICR mice (intravenous) | Kurono | 1 day | DLM (0.5–10) | 10 days | Oral | NA | DLM led to a 2.5 log10 to >4.4 log10 reduction in lung cfu, which was superior to RIF (5 mg/kg). |
| ICR mice (intravenous) | Kurono | 1 day | DLM (0.078–2.5) | 28 days | Oral | NA | DLM led to a dose-dependent reduction in lung cfu. DLM activity (0.313 mg/kg) was similar to RIF (5 mg/kg). | |
| Hariguchi et al. (2020)118 | ICR mice (intratracheal inoculation) | Kurono | 4 weeks | DLM (2.5) | 4 weeks | Oral | NA | DLM led to a significant 1.5 log10 reduction of lung cfu, which was similar to RIF (5 mg/kg) |
| Pieterman et al. (2021)93 | BALB/c mice (intratracheal instillation) | Beijing | 2 weeks | DLM (1.25, 2.5 or 5) | 3 weeks | Oral | AUC0–24 = 11.234 μg·h/mL (4 weeks treatment, dose 2.5 mg/kg, combined with BDQ 25 mg/kg + LZD 100 mg/kg) | DLM led to a 2 log10 reduction in lung cfu for all tested doses. |
| Chen et al. (2017)95 | Guinea pig (intratracheal inoculation) | Kurono | 4 weeks | DLM (100) | 4 or 8 weeks | Oral | AUC0–24 = 9.45 μg·h/mL (single dose of 100 mg/kg) | DLM led to a 3 log10 reduction in lung cfu after 4 weeks of exposure. No cfu were retrieved after 8 weeks of exposure. DLM showed bactericidal activity in hypoxic lesions. |
| Stover et al. (2000)12 | BALB/c mice (intravenous) | H37Rv | 4 days | PMD (25, 50, or 100) | 10 days | Oral | NA | PMD led to a dose-dependent reduction in lung cfu. PMD activity (25 mg/kg) was similar to INH activity (25 mg/kg). |
| Tyagi et al. (2005)124 | BALB/c mice (aerosol) | H37Rv | 20 days (initial phase), 8 weeks (continuation phase) | PMD (3.125–200) | 4–16 weeks | Oral | NA | PMD activity (100 mg/kg) was comparable to that of INH (25 mg/kg). PMD was active during both the initial and continuation phase of therapy. |
| Lenaerts et al. (2005)66 | C57BL/6 mice (aerosol) | Erdman | 19 days | PMD (50, 100, or 300) | 9 days | Oral | NA | PMD showed dose-dependent activity. PMD activity (100 mg/kg) was similar to that of RIF (20 mg/kg) and INH (25 mg/kg). |
| C57BL/6 mice (aerosol) | Erdman | 19 days | PMD (100) | 12 weeks | Oral | NA | PMD (100 mg/kg) was as active as INH (25 mg/kg). | |
| Lakshminarayana et al. (2014)105 | BALB/c mice (intranasal) | H37Rv | 4 weeks | PMD (25 or 100) | 4 weeks | Oral | AUC0–24 = 50.9 μg·h/mL (dose 25 mg/kg) | At 25 mg/kg PMD led to a 1.48 log10 reduction in lung cfu, and to a 2.3 log10 reduction at 100 mg/kg. |
| Nuermberger et al. (2006)108 | BALB/c mice (aerosol) | H37Rv | 19 days | PMD (100) | 2 months | Oral | AUC0–24 = 396.8 μg·h/mL (2 months treatment, dose 100 mg/kg) | PMD led to a 2 log10 reduction in lung cfu. |
| Tasneen et al. (2008)106 | BALB/c | H37Rv | 2 weeks | PMD (100) | 2 months | Oral | AUC0–∞ = 127.5 μg·h/mL (single dose of 54 mg/kg) | PMD led to a 2.7 log10 reduction in lung cfu, which was slightly inferior to the 3.1 log10 reduction by RIF (10 mg/kg). |
| Sala et al. (2010)71 | BALB/c mice (intravenous) | 18b without streptomycin | 4 weeks | PMD (100) | 8 weeks | Oral | NA | PMD led to a 1.5 log10 reduction in lung cfu, which was superior to INH (25 mg/kg), but inferior to RIF (10 mg/kg). |
| Lanoix et al. (2014)125 | BCG-immunized-BALB/c mice (aerosol) | H37Rv | 6 weeks | PMD (50) | 8 weeks | Oral | NA | PMD led to a 1 log10 reduction in lung cfu, which was similar to INH (10 mg/kg), but inferior to RIF (10 mg/kg) |
| BCG-immunized-C3HeB/FeJ mice (aerosol) | H37Rv | 6 weeks | PMD (50) | 8 weeks | Oral | NA | PMD led to a 0.75 log10 reduction in lung cfu, which was similar to INH (10 mg/kg), but inferior to RIF (10 mg/kg) | |
| Dutta et al. (2014)126 | BCG-immunized-C3HeB/FeJ mice (aerosol) | H37Rv | 6 weeks | PMD (50) | 1–4 months | Oral | NA | PMD led to a 2.7 log10 reduction in lung cfu, which was comparable to INH (10 mg/kg), but inferior to RIF (10 mg/kg). The relapse rate of PMD (assessed 3 months after completion of a 4-month treatment duration) was 100%, which was equal to INH, and higher than RIF (33%). |
| Stover et al. (2000)12 | Guinea pig (aerosol) | H37Rv | 4 weeks | PMD (40) | 4 weeks | Oral | NA | PMD led to a 1 log10 reduction in lung cfu, which was comparable to INH (25 mg/kg). |
| Garcia-Contreras et al. (2010)127 | Guinea pig (aerosol) | H37Rv | 4 weeks | PMD (inhaled: 180 or 360 mg; oral: 40 mg/kg) | 4 weeks | Inhaled or oral | NA | PMD led to a significant reduction of the mycobacterial load. Higher PMD activity was observed for oral administration versus inhaled doses. |
DLM, delamanid; PMD, pretomanid; NA, not assessed; cfu, colony forming units; RIF, rifampicin; INH, isoniazid; BDQ, bedaquiline; LZD, linezolid.