MAY 15, 2019 11:44 AM PDT

Researchers Identify Near-Universal Drug Regimens for Treating TB

WRITTEN BY: Dena Aruta

Tuberculosis remains a public health crisis with more than 25% of the world's population having a positive tuberculin skin test and possibly a latent infection with Mycobacterium tuberculosis (MTB). For those who do have a latent infection, approximately 10% will develop active MTB. The Centers for Disease Control estimates that, in 2017, 10 million people worldwide were infected with MTB, and there were 1.3 million deaths. MTB is also the leading cause of mortality in HIV-infected patients. MTB is not a disease found only in developing countries; in the U.S, there were over 9,000 cases in 2017. The standard treatment for MTB is a long and arduous course of drugs that aren't well-tolerated for some making compliance a critical issue in disease-control. The current regimen takes 6-9 months, and people often experience adverse events of drug toxicities. When individuals don't finish the entire course of antibiotics, drug resistance develops. The treatment of drug-resistant MTB is much more difficult requiring 20-26 months with second and third-line drugs that have the same problems with toxicities.

If we are to reduce the burden of tuberculosis globally, shorter and less toxic treatments need to be developed that will encourage compliance and completion of the entire course of antibiotics. Daniel Clemens and colleagues set out to identify new, highly effective near-universal drug regimens from FDA-approved drugs. The method they employed was the parabolic response surface (PRS), which is described by Dr. Clemens as:

The efficacy of drugs at different doses is described by a smooth parabolic surface–in other words there are no abrupt changes in efficacy as dose is altered. Such a smooth parabolic surface is described by a second order algebraic equation. Therefore, to identify optimal drug-dose combinations, one does not need to test billions of possible drug-dose combinations but only to solve this algebraic equation by testing a relatively few drug-dose combinations over the surface in an iterative process. 

The PRS platform allows for considerable savings in time, cost, and effort. The researchers developed an "artificial intelligence enabled parabolic response surface platform to model the drug-dose response surface and identify the most promising drug regimens by testing only a small portion of the total search space." They initially chose 15 drug combinations and evaluated them in a human macrophage TB model--macrophages are the primary targets in MTB infections. From these 15 combinations, they identified the most promising 4-drug combinations to further analyze in "Mycobacterium tuberculosis-infected BALB/c mice."  The two most potent combinations were "designated PRS Regimens IV and V, consisting of clofazimine (CFZ), bedaquiline (BDQ), pyrazinamide (PZA), and either amoxicillin/clavulanate (AC) or delamanid (DLM), respectively." 

Efficacy of the combinations was compared to PRS Regimen III (CFZ, BDQ, PZA, and SQ109) for time to lung sterilization, bactericidal activity, and time to cure with no relapse. PRS Regimens III-VI all resulted in relapse-free cure and rapid sterilization of the lungs within three weeks. The Standard Regimen (isoniazid, rifampicin, PZA, and ethambutol) didn't achieve lung sterilization or relapse-free cure after six weeks.

What do the results of this study mean for the treatment of MTB and individuals who cannot tolerate the standard treatments? Clinical trials will need to be performed, but with the rapid and shortened time required for treatment, there is the potential for increased compliance and reduction in multi-drug resistant MTB. 

Science Daily  quoted the following: "If our findings are replicated in human studies, patients will be cured much faster, be more likely to adhere to the drug regimen, suffer less drug toxicity, and be less likely to develop drug-resistant TB," said Dr. Marcus Horwitz, distinguished professor of medicine and microbiology, immunology & molecular genetics at the David Geffen School of Medicine at UCLA, and the study's senior author.

 

About the Author
  • After earning my Bachelor of Science degree in biology/chemistry from Virginia Polytechnic Institute and State University (aka Va. Tech), I went on to complete clinical rotations in laboratory medicine at Roanoke Memorial Hospital. I spent the next 21 years working in healthcare as a clinical microbiologist. In 2015, I combined my fascination with medicine and passion for writing into a freelance career, and I haven't looked back. Even though my expertise is in microbiology and infectious diseases, I'm adept at writing about any medical topic. Being a freelance writer allows me to pursue a career where I can work at home with my two feline assistants, Luke and Grace. I'm a firm supporter of animal rights and volunteer for a local rescue during my free time. 
You May Also Like
DEC 28, 2020
Immunology
What Happens When Your Immune System Works Against You?!
DEC 28, 2020
What Happens When Your Immune System Works Against You?!
Our immune system is our army against any molecule that wants to invade our bodies like viruses, bacteria, and cancer. I ...
DEC 28, 2020
Drug Discovery & Development
Anti-Diarrhea Drug Kills Aggressive Brain Cancer Cells
DEC 28, 2020
Anti-Diarrhea Drug Kills Aggressive Brain Cancer Cells
Glioblastoma is a very aggressive and lethal form of brain cancer that responds poorly to chemotherapy in children and a ...
JAN 04, 2021
Cannabis Sciences
How Does Cannabis Affect the Liver?
JAN 04, 2021
How Does Cannabis Affect the Liver?
As research on cannabis emerges, what we know about how it interacts with the liver is becoming more and more complex. A ...
JAN 12, 2021
Immunology
Killer Control: Engineered Stem Cells Dodge Transplant Rejection
JAN 12, 2021
Killer Control: Engineered Stem Cells Dodge Transplant Rejection
The first organ transplant—performed over 60 years ago—was a success because the donor and recipient were id ...
JAN 19, 2021
Cardiology
Looking to the Immune System for Help Diagnosing Carotid Stenosis
JAN 19, 2021
Looking to the Immune System for Help Diagnosing Carotid Stenosis
Everyone has seen a commercial about how bad fats can build up into a plaque into a blood vessel. This is called atheros ...
JAN 21, 2021
Health & Medicine
More Evidence Cannabis Can Calm a Cytokine Storm
JAN 21, 2021
More Evidence Cannabis Can Calm a Cytokine Storm
A new study out of Canada lends further evidence to the idea that cannabis components may help to calm the cytokine stor ...
Loading Comments...