Date Published: May 10, 2019
Publisher: Public Library of Science
Author(s): Daniel L. Clemens, Bai-Yu Lee, Aleidy Silva, Barbara Jane Dillon, Saša Masleša-Galić, Susana Nava, Xianting Ding, Chih-Ming Ho, Marcus A. Horwitz, Olivier Neyrolles.
Shorter, more effective treatments for tuberculosis (TB) are urgently needed. While many TB drugs are available, identification of the best regimens is challenging because of the large number of possible drug-dose combinations. We have found consistently that responses of cells or whole animals to drug-dose stimulations fit a parabolic response surface (PRS), allowing us to identify and optimize the best drug combinations by testing only a small fraction of the total search space. Previously, we used PRS methodology to identify three regimens (PRS Regimens I–III) that in murine models are much more effective than the standard regimen used to treat TB. However, PRS Regimens I and II are unsuitable for treating drug-resistant TB and PRS Regimen III includes an experimental drug. Here, we use PRS methodology to identify from an expanded pool of drugs new highly effective near-universal drug regimens comprising only approved drugs.
We evaluated combinations of 15 different drugs in a human macrophage TB model and identified the most promising 4-drug combinations. We then tested 14 of these combinations in Mycobacterium tuberculosis-infected BALB/c mice and chose for PRS dose optimization and further study the two most potent regimens, designated PRS Regimens IV and V, consisting of clofazimine (CFZ), bedaquiline (BDQ), pyrazinamide (PZA), and either amoxicillin/clavulanate (AC) or delamanid (DLM), respectively. We then evaluated the efficacy in mice of optimized PRS Regimens IV and V, as well as a 3-drug regimen, PRS Regimen VI (CFZ, BDQ, and PZA), and compared their efficacy to PRS Regimen III (CFZ, BDQ, PZA, and SQ109), previously shown to reduce the time to achieve relapse-free cure in mice by 80% compared with the Standard Regimen (isoniazid, rifampicin, PZA, and ethambutol). Efficacy measurements included early bactericidal activity, time to lung sterilization, and time to relapse-free cure. PRS Regimens III–VI all rapidly sterilized the lungs and achieved relapse-free cure in 3 weeks (PRS Regimens III, V, and VI) or 5 weeks (PRS Regimen IV). In contrast, mice treated with the Standard Regimen still had high numbers of bacteria in their lungs after 6-weeks treatment and none achieved relapse-free cure in this time-period.
We have identified three new regimens that rapidly sterilize the lungs of mice and dramatically shorten the time required to achieve relapse-free cure. All mouse drug doses in these regimens extrapolate to doses that are readily achievable in humans. Because PRS Regimens IV and V contain only one first line drug (PZA) and exclude fluoroquinolones and aminoglycosides, they should be effective against most TB cases that are multidrug resistant (MDR-TB) and many that are extensively drug-resistant (XDR-TB). Hence, these regimens have potential to shorten dramatically the time required for treatment of both drug-sensitive and drug-resistant TB. If clinical trials confirm that these regimens dramatically shorten the time required to achieve relapse-free cure in humans, then this radically shortened treatment has the potential to improve treatment compliance, decrease the emergence of drug resistance, and decrease the healthcare burden of treating both drug-sensitive and drug-resistant TB.
Tuberculosis (TB) is a health problem of global proportions. Almost one quarter of the world’s population is tuberculin-positive and potentially latently infected with Mycobacterium tuberculosis and these people have a 10% life-time risk of developing active TB . In 2017, ten million people developed active TB and 1.3 million died of TB, making it the leading cause of death from a single infectious agent . The current standard treatment for drug sensitive TB requires 6–9 months and is often complicated by problems with adherence, toxicity, and the development of antibiotic resistance. Treatment of drug-resistant TB is even more problematic, often requiring 20–26 months treatment with second and third line drugs  and is complicated by drug toxicities, treatment failure and non-completion .
We have demonstrated two new TB treatment regimens, one comprising 4 drugs (CFZ, BDQ, PZA, and DLM–PRS Regimen V) and one comprising 3 drugs (CFZ, BDQ, and PZA–PRS Regimen VI) that achieve relapse-free cure in the BALB/c mouse model with only 3 weeks of treatment, and a fourth regimen (CFZ, BDQ, PZA, and AC, PRS Regimen IV) that does so in 5 weeks. The 4-drug regimens should be effective against MDR-TB because the only first line drug utilized is PZA. In addition, because these regimens do not include a fluoroquinolone, or an aminoglycoside or other injectable agent, they should also be effective against many cases of XDR-TB. While PRS Regimen IV was two weeks slower to achieve relapse-free cure than PRS Regimens III, V, and VI, this difference was relatively minor, since only two out of 10 PRS Regimen IV mice had detectable CFU after 3 weeks treatment and only one out of 10 had a single CFU at 4 weeks.