Tuesday, March 10, 2015

The Search for New Treatments for Drug-Resistant Tuberculosis

            The discovery of the first antibiotics during the early stages of the 20th century forever changed the world of medicine. Many diseases that plagued mankind for millennia were now curable with a simple course of antibiotic treatment. Despite the discovery of several novel antibiotics over the course of the century, over-prescription as well as misuse of antibiotics has led to the creation of “superbugs” that have gained resistance to most of the drugs used to treat them. This development is particularly terrifying given that fact that current drug development has not been able to keep pace with the development of resistance in many different strains of bacteria. Part of this problem stems from little interest by pharmaceutical companies to invest in R&D for these drugs because antibiotics generally end up not being very lucrative investments. Additionally, the process of moving a drug from the discovery and optimization stages to large phase 3 clinical trials takes several years and several promising drugs are often screened out during this process.

Tuberculosis is an example of a bacterial disease that has caused considerable amounts of human suffering. The discovery of Streptomycin in 1944 changed this disease from being a death sentence to curable. However, there have been no new antibiotics developed to treat Tuberculosis since the early 1980s.  The lack of novel antibiotics coupled with the misuse of current drugs has led to a significant rise in the prevalence of multi-drug and extensively-drug resistant strains of Tuberculosis. The World Health Organization estimates that 450,000 people worldwide were infected with antibiotic resistant strains of Tuberculosis in 2012. This number is expected to be even larger now due the highly infectious nature of the resistant strains as well as the continued misuse of antibiotic treatments in areas where Tuberculosis remains prominent.

Source: Dr. Gwendolyn Marriner NIH/NIAID

Bedaquiline (Siruto) is the first novel antibiotic approved by the FDA for the treatment of Tuberculosis in over 30 years. It is a diarylquinoline that has a mechanism of action that is unlike any other TB treatments currently on the market. Many traditional antibiotics work by disrupting the bacteria’s ability to synthesize its cell walls. Bedaquiline, on the other hand, acts by inhibiting the ATP-sythase of the Tuberculosis, which kills the bacteria by disrupting its major mechanism for generating energy. Due to bedaquiline’s novel mechanism of action against TB, it appears to be a promising new treatment for MDR and XDR-TB because resistance to other drugs would not decrease bedaquiline’s efficacy.

Source: http://en.wikipedia.org/wiki/Tuberculosis_management

Multidrug-Resistant Tuberculosis and Culture Conversion with Bedaquiline, by Diacon et al. highlights the results of a phase 2B clinical trial that sought to evaluate the efficacy and safety of bedaquiline. In this clinical trial, patients were divided into either placebo or treatment groups. The placebo group was given a regiment of five traditional antibiotics plus a placebo. The treatment group received the same five antibiotics as well as bedaquiline. The primary endpoint of the study was designated as the time to sputum culture conversion for the patients. This method collects sputum from the patients at regular time points during the clinical trial. Their sputum is then cultured and researchers are able to evaluate whether or not there are living Tuberculosis cells in the culture. For this particular study, patients needed to have two consecutive negative sputum cultures at least 25 days a part to be considered cured. Tuberculosis treatment often has considerable rates of treatment relapse due partly to the development of hypoxic lung legions. As a result of this, this study chose to evaluate clinical outcomes after both 24 weeks and 120 weeks.  120 weeks is considered the gold standard for treatment length to prevent relapse. After the 24-week period, both the placebo and treatment group only received the five-drug background regiment. The study found that after both the 24-week and 120-week periods the treatment group had statistically significant higher rates of sputum culture conversion than the placebo group.

After this paper was published, many physicians were worried by fact that the treatment group had 10 patients die, while the placebo group only experienced 2 fatalities. In the discussion section of the paper, the researchers do some hand waving and say that the reason for the higher mortality rate is unclear and the placebo group appeared to have a lower than normal mortality rate for its patients. Additionally, it appears that bedaquiline treatment results in a prolonged the QT interval, which is the length of time between the start of the Q wave and end of the T wave in the heart's electrical circuit. This induced heart arrhythmia may result in heart attacks. Despite the higher mortality rate in the treatment group, the FDA decided to approve bedaquiline for public use. However, it is suggests that bedaquiline is only to be used when no other treatment options are available. Bedaquiline appears to have some problems as a new treatment for Tuberculosis, which is why we need to invest much more heavily in drug discovery before Tuberculosis and other bacterial diseases become completely resistant to all conventional forms of treatment.

1. Diacon AH, Pym A, Grobusch MP, de los Rios, Jorge M, Gotuzzo E, Vasilyeva I, Leimane V, Andries K, Bakare N, De Marez T. Multidrug-resistant tuberculosis and culture conversion with bedaquiline. N Engl J Med. 2014, 371(8):723-32.
2. World Health Organization. Global tuberculosis report 2013. 2013. World Health Organization.
3. Andries K, Verhasselt P, Guillemont J, Gohlmann HW, Neefs JM, Winkler H, Van Gestel J, Timmerman P, Zhu M, Lee E, et al. A diarylquinoline drug active on the ATP synthase of mycobacterium tuberculosis. Science. 2005, 307(5707):223-7.
4. Huitric E, Verhasselt P, Andries K, Hoffner SE. In vitro antimycobacterial spectrum of a diarylquinoline ATP synthase inhibitor. Antimicrob Agents Chemother. 2007, 51(11):4202-4.


  1. Nice post, Drew. This is some scary stuff: having 450,000 people infected worldwide with any deadly, contagious and untreatable pathogen seems like a recipe for disaster. You mention in the beginning of you post that big pharma has little motivation to get into the antibiotic-development game today. Is there some way that we can construct an incentive system to motivate antibiotics research? Is this something in which the government should be taking a more aggressive role?

  2. I was thinking, as Joe was, that the government may need to step in to help get this process of drug development going. Perhaps they could offer subsidies or other financial incentives to pharmaceutical companies to motivate them to search for new antibiotics, although this would probably be extremely expensive.
    On a different note, was there any investigation done to determine the cause of death of the 10 people in the treatment group? If most died from cardiac problems, this would support the idea the bedaquiline played a role in these deaths. There certainly is some room for hand-waving because 120 weeks is quite a while, and it is conceivable that a few people would die during this time. Still, more research should have been done to determine what caused the deaths of these people before the drug is released. The FDA must have been desperate to release a new drug. And if you have XDR-TB, there's not much hope anyways.

  3. I think this post shows a lot of the difficulties to trying to find new treatments. A company spent years developing this new treatment, and although it was approved, it still has some very dangerous flaws. It is very difficult to develop a successful drug, and even after putting years in and copious amount of money, you can still fail. Additionally, even if a drug is successful and approved, resistance can develop taking the drug out of the market. Developing new antibiotics is crucial, yet it is understandable why companies don't want invest in such a risky venture. I feel it is necessary to some how remedy this issue, yet there is not a clear solution. Perhaps public funding could be one possibility.