TY - JOUR
T1 - Bactericidal and sterilizing activity of a novel regimen with bedaquiline, pretomanid, moxifloxacin, and pyrazinamide in a murine model of tuberculosis
AU - Li, Si Yang
AU - Tasneen, Rokeya
AU - Tyagi, Sandeep
AU - Soni, Heena
AU - Converse, Paul J.
AU - Mdluli, Khisimuzi
AU - Nuermberger, Eric L.
N1 - Funding Information:
This research was funded by the Global Alliance for TB Drug Development and the National Institutes of Health (grant R01-AI111992 to E.L.N.).
PY - 2017/9
Y1 - 2017/9
N2 - New regimens based on 2 or more novel agents are sought to shorten or to simplify treatment of tuberculosis (TB), including drug-resistant forms. Prior studies showed that the novel combinations of bedaquiline (BDQ) plus pretomanid (PMD) plus pyrazinamide (PZA) and PMD plus moxifloxacin (MXF) plus PZA shortened the treatment duration necessary to prevent relapse by 2 to 3 months and 1 to 2 months, respectively, compared with the current first-line regimen, in a murine TB model. These 3-drug combinations are now being studied in clinical trials. Here, the 4-drug combination of BDQPMDMXFPZA was compared to its 3-drug component regimens and different treatment durations of PZA and MXF were explored, to identify the optimal regimens and treatment times and to estimate the likelihood of success against drug-resistant strains. BDQPMDMXFPZA rendered all mice relapse-free after 2 months of treatment. PZA administration could be discontinued after the first month of treatment without worsening outcomes, whereas the absence of MXF, PZA, or BDQ administration from the beginning necessitated approximately 0.5, 1, or 2 months, respectively, of additional treatment to attain the same outcome.
AB - New regimens based on 2 or more novel agents are sought to shorten or to simplify treatment of tuberculosis (TB), including drug-resistant forms. Prior studies showed that the novel combinations of bedaquiline (BDQ) plus pretomanid (PMD) plus pyrazinamide (PZA) and PMD plus moxifloxacin (MXF) plus PZA shortened the treatment duration necessary to prevent relapse by 2 to 3 months and 1 to 2 months, respectively, compared with the current first-line regimen, in a murine TB model. These 3-drug combinations are now being studied in clinical trials. Here, the 4-drug combination of BDQPMDMXFPZA was compared to its 3-drug component regimens and different treatment durations of PZA and MXF were explored, to identify the optimal regimens and treatment times and to estimate the likelihood of success against drug-resistant strains. BDQPMDMXFPZA rendered all mice relapse-free after 2 months of treatment. PZA administration could be discontinued after the first month of treatment without worsening outcomes, whereas the absence of MXF, PZA, or BDQ administration from the beginning necessitated approximately 0.5, 1, or 2 months, respectively, of additional treatment to attain the same outcome.
KW - Bedaquliine
KW - Mouse
KW - Moxifloxacin
KW - Mycobacterium tuberculosis
KW - Pretomanid
KW - Pyrazinamide
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U2 - 10.1128/AAC.00913-17
DO - 10.1128/AAC.00913-17
M3 - Article
C2 - 28630203
AN - SCOPUS:85028317237
VL - 61
JO - Antimicrobial Agents and Chemotherapy
JF - Antimicrobial Agents and Chemotherapy
SN - 0066-4804
IS - 9
M1 - e00913-17
ER -