Table 1.
Abbreviation of TB drugs tested in the study.
Table 2.
Screening of combinatorial drugs in macrophage model of M. tuberculosis infection.
Fig 1.
In vivo short-term efficacy screen of experimental regimens identified in macrophage studies using the PRS platform.
M. tuberculosis infected mice were sham treated (Treatment Group A) or treated with the Standard Regimen (Treatment Group B), PRS Regimen II (Treatment Group C) or one of the top 4-drug combinations (Treatment Groups D-Q) identified from macrophage screening using the PRS platform starting from a pool of 15 TB drugs 5 days per week for 3 weeks. Three days after the last treatment, mice were euthanized to determine bacterial number in the lung. Standard Regimen is comprised of INH, RIF, EMB and PZA at 25, 10, 100 and 150 mg/kg, respectively. PRS Regimen II is comprised of CFZ, BDQ, PZA and EMB at 25, 30, 450 and 100 mg/kg, respectively. Drug doses used in the top 4-drug experimental regimens are as follows: 200–50 mg/kg for AC, 30 mg/kg for BDQ, 25 mg/kg for CFZ, 2.5 mg/kg for DLM, 100 mg/kg for PA824, 450 mg/kg for PZA, 10 mg/kg for RPT and 25 mg/kg for SQ109.
Fig 2.
Optimization of PRS Regimens IV and V.
(A) Lung burdens of M. tuberculosis in 10 groups of mice were determined after treatment 5 days per week for 3 weeks with PRS Regimen IV (top left) or PRS Regimen V (top right); the individual drugs were administered in high dose (H), middle dose (M) or low dose (L) as indicated below the horizontal axis. Sham-treated mice or mice treated with either the Standard Regimen (SR) or dose-optimized PRS Regimen II (PRS II) served as controls. The Standard Regimen comprised INH, RIF, EMB and PZA at 25, 10, 100 and 150 mg/kg, respectively. PRS Regimen II comprised CFZ, BDQ, PZA and EMB at 25, 30, 450 and 100 mg/kg, respectively. For PRS Regimen IV, the high doses for CFZ, BDQ, PZA and AC were 25, 50, 450 and 600–150 mg/kg, respectively. For PRS Regimen V, the high doses for CFZ, BDQ, PZA and DLM were 25, 50, 450 and 7.5 mg/kg, respectively. The middle dose of each drug was 1/3rd that of the high dose and the low dose was 1/3rd that of the middle dose. (B) Drug-dose efficacy response surface shown as drug-drug doses on the x- and z-axes and the projected lung log10 CFU on the y-axis.
Table 3.
EBA14 study.
Fig 3.
Treatment efficacy of PRS Regimens in BALB/c mice.
(A) Time course of the bacterial burden in the lung over the infection and treatment period. (B) Lung burden of M. tuberculosis after treatment 5 days per week for 3, 4, 5, and 6 weeks in sham-treated mice or mice treated with the Standard Regimen (SR) or one of the PRS Regimens (III–VI). Mice with zero CFU in the lungs are plotted as log 0 CFU on the scale and indicated by a semi-open circle symbol.
Table 4.
Assessment of relapsea.