https://www.merckmanuals.com/professional/infectious-diseases/mycobacteria/tuberculosis-tb
Usually, when you are about to join new job or enroll in a school/university, you are told go through a mandatory health check-up to make sure you have been vaccinated. You may even get a Tuberculosis (TB) skin test. If you were born in the United States, the TB skin test will most likely not result in any reaction. For me, however, I develop a giant, itchy red bump within two days where the nurse had inserted a small fluid known as tuberculin underneath my skin. Looking at my medical history, I have had the BCG vaccine and had been treated for latent TB. The next step for me is to get a chest x-ray which have been normal so far. Although tuberculosis cases in the United States are low, about 2.7 cases per 100,000 persons, nearly 80% of the active TB cases are due to reactivation of latent TB1. These cases can become incredibly serious, if the person with reactivated TB had already been treated with TB previously1. Screening for drug resistance becomes an immediate priority.
To understand the growing concern of drug-resistant Mycobacterium
tuberculosis bacteria, we must understand TB history and how it infects
people. Tuberculosis has been around since antiquity. Mycobacterial DNA has
been found in ancient Egyptian mummied remains dating back to the Middle
Kingdom, 2050 B.C2. During
the 17th and 18th century, many scientists have
documented various pathological signs of tuberculosis. It was not until 1882
when Robert Koch figured out that the cause of tuberculosis was a mycobacterium3.
M. tuberculosis spreads when an infected person coughs, sneezes, spits
or speaks. Most people infected with TB do not have any signs or symptoms of
the disease until the disease is activated. These people have latent TB and
about 10% of persons with latent TB later have active TB if untreated4.
Interestingly, persons who have latent TB are not contagious; only persons with
active TB are4. When the bacteria is activated and grows in the
lungs, it’s known as pulmonary TB4. Extrapulmonary TB affects
tissues such as the lymphatics (tuberculosis lymphadenitis), bones (skeletal
tuberculosis), various tuberculosis of the abdomen, or CNS tuberculosis which
causes meningitis5. However, let us just focus on pulmonary
tuberculosis, which is the most common.
When tuberculosis bacterium is inhaled, the bacteria migrates to the alveolar sacs. Here pulmonary macrophages endocytose the bacterium. The bacteria reside in the phagosome and replicate and evade macrophage digestion6. The infected macrophage attracts other cells of the immune system such as more macrophages, T cells and B cells6. Macrophages fuse around the infected macrophage and T cells form a barrier around the macrophages6. Fibroblasts and collagen that surround the T cells and form a granuloma6. The on-going infection is a constant battle between tissue destruction and healing causing an increasing amounts of scar tissue6. In the chest x-ray, granulomas are the primary characteristic of a TB infection6. TB can become dormant during the granuloma stage and can be reactivated if the immune system is weakened when challenged by other events such as an infection by another pathogen like HIV 6. Therefore, it is essential that persons with latent TB are treated to reduce any chance of activating the infection7. Persons wIsoniazid is a pro-drug that is activated by the catalase-peroxidase enzyme found in M. tuberculosis8. Once activated, isoniazid becomes isonicotinic acyl-NADH which inhibits the synthesis of mycolic acids in the mycobacterial cell wall8. Rifampin, also known as rifampicin, inhibits bacterial RNA polymerase 9. Isoniazid and rifampin are two of the most potent drugs used to treat active and latent TB. From 2018 to 2019, there have been a 10% increase of multi-drug resistant (MDR) TB, where both rifampin and isoniazid no longer have an effect4. Only 57% of MDR TB patients have been successfully treated globally4. MDR TB is diagnosed by detecting growth rate of the bacteria in a sputum sample treated with the rifampin or isoniazid10. This is then followed by a series of PCR tests to check for drug resistant genotypic markers10. Persons with MDR TB are treated with a second line of TB medications which are much more toxic. Other agents used are expensive injectable agents such as amikacin/kanamycin, fluoroquinolone as well as other compounds that might have some activity against the infection like cycloserine10. The side effects vary from nephrotoxicity to drug induced hepatitis depending on the treatment plan10. Although rare, extensively drug resistant (XDR) TB exists as well where the person is not only resistant to the first line of drugs but also resistant to at least one of the second line of drugs10. Scientists are now focusing on generating better antibiotic drugs that better target mycobacteria for patients with MDR TB10.
https://www.who.int/news/item/30-10-2017-who-report-signals-urgent-need-for-greater-political-commitment-to-end-tuberculosis
For the first time in few decades, two new TB drugs have shown to have positive outcomes for persons with MDR-TB as compared to those treated with the usual regime10. Delamanid belongs to a class of nitroimidazoles and was developed by Otsuka Pharmaceutical Development and Commercialization, in Osaka, Japan11. The mechanism of action is similar to isoniazid. It inhibits mycolic acid synthesis11. The side effects are dizziness and QT prolongation, which means the heart takes a longer time to repolarize11. Bedaquiline belongs to the diarylquinoline group and was developed by Janssen Pharmaceuticals in Titusville, NJ11. The drug inhibits mycobacterial ATP synthase and has a long half-life11. More studies need to be conducted regarding bedaquiline’s side effects and toxicity as well as possible resistance11. With two new drugs on the market, there is potential that MDR-TB can be treated and hopefully eradicated in countries where TB is endemic.
By Bhavani Gudlavalleti, A Master’s of Medical Sciences Student at
the University of Kentucky
Literature Cited
1. Schwartz, N. G., Price, S. F., Pratt, R. H., & Langer, A. J. (2020, March 19). Tuberculosis - United States, 2019. Retrieved October 23, 2020, from https://www.cdc.gov/mmwr/volumes/69/wr/mm6911a3.htm
2. Zink, A. R., Sola, C., Reischl, U., Grabner, W., Rastogi, N., Wolf, H., & Nerlich, A. G. (2003). Characterization of Mycobacterium tuberculosis complex DNAs from Egyptian mummies by spoligotyping. Journal of clinical microbiology, 41(1), 359–367. https://doi.org/10.1128/jcm.41.1.359-367.2003
3. Iseman, M. (2013, February 01). Tuberculosis: History. Retrieved October 23, 2020, from https://www.nationaljewish.org/conditions/tuberculosis-tb/history
4. WHO. (2020, October 14). Tuberculosis (TB). Retrieved October 23, 2020, from https://www.who.int/news-room/fact-sheets/detail/tuberculosis
5. Golden, M. P., & Vikram, H. R. (2005). Extrapulmonary tuberculosis: an overview. American family physician, 72(9), 1761–1768.
6. Desai, Rishi. [Medscape]. (2018, Jan. 9). Tuberculosis | Clinical Presentation. [Video]. YouTube. https://www.youtube.com/watch?v=0qFiflLL21U
7. CDC. (2020, February 13). Treatment Regimens for Latent TB Infection. Retrieved October 23, 2020, from https://www.cdc.gov/tb/topic/treatment/ltbi.htm
8. Timmins, G. S., & Deretic, V. (2006). Mechanisms of action of isoniazid. Molecular microbiology, 62(5), 1220–1227. https://doi.org/10.1111/j.1365-2958.2006.05467.x
9. Wehrli W. (1983). Rifampin: mechanisms of action and resistance. Reviews of infectious diseases, 5 Suppl 3, S407–S411. https://doi.org/10.1093/clinids/5.supplement_3.s407
10. Millard, James, Ugarte-Gil, Cesar, and Moore, David A J. "Multidrug Resistant Tuberculosis." BMJ : British Medical Journal 350.Feb26 10 (2015): H882. Web.
11. Migliori, G. B., Pontali, E., Sotgiu, G., Centis, R., D'Ambrosio, L., Tiberi, S., Tadolini, M., & Esposito, S. (2017). Combined Use of Delamanid and Bedaquiline to Treat Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis: A Systematic Review. International journal of molecular sciences, 18(2), 341. https://doi.org/10.3390/ijms18020341ith latent TB are treated with either rifampin for three to four months or isoniazid for six to nine months7. The dosage and drug concentrations vary based on age and body mass. These same drugs are used for persons with active TB7.
Interesting article Bhavani, I did not know that latent TB was not contagious. Have you looked into why it is not contagious in the latent form and what causes it to be activated into active TB?
ReplyDeletePersons with latent tb have the bacterium contained in the granulomas. Active tb persons have unguarded tb bacteria in their lungs and can spread them. Activation of latent tb can be many things such as HIV infection, aging, etc. Anything that engages the immune system, can cause latent tb to become active tb because the granulomas breakdown.
DeleteGreat article, in the past I've had to prepare IV drugs such as Rifampin for patients with TB. I would hear from time to time from other medical staff that it's one of the few drugs that is effective for TB but they are seeing more and more strains resistant to it. So it is good to hear that new medications are being developed help with MDR-TB because it is something that you do see from time to time.
ReplyDeleteThis was a very interesting article, as a pharmacy technician we dispense the capsules from time to time. When I worked in Specialty Pharmacy, my group covered the hepatitis patients, so I found the drug induced heptatis to be interesting as well.
ReplyDeleteThis is a great short article about TB. I also did not know latent TB was not contagious and there are two lines of defense medicine if it has become resistant to the first. Are there any current trials being done with the new two drugs that have been put on the market?
ReplyDeleteLast summer, the FDA approved the two new drugs for MDR-TB. Here is the link that goes more little more in depth! https://www.fda.gov/news-events/press-announcements/fda-approves-new-drug-treatment-resistant-forms-tuberculosis-affects-lungs
DeleteA very interesting article. I was unaware there were new drugs on the market for MDR-TB. Are there plan in place to prevent the development of resistance to them as well? I wonder if they will be used sparingly and as a last resort, or would they be better served as an attempt at eradication where MDR-TB runs rampant?
ReplyDeleteThere are global and nation wide health programs in countries where TB is endemic that have some sort of protocol to ensure people are taking the full course of TB and prevent the rise of MDR-TB. But I am not too sure on the details of those plans
DeleteGreat article Bhavani, tuberculosis is one of those diseases that we often think of as a thing of the past. But, if MDR-TB were to become more widespread it could cause many issues. I am glad to hear that there are new antibiotics being developed to treat this re-emerging threat.
ReplyDeleteVery interesting read. I was very unfamiliar with TB before reading this. What has caused the MDR in TB disease? Just random genetic mutations, or does the over prescription of antibiotics have a role in this disease developing drug resistance?
ReplyDeleteThe rise of MDR-TB has mostly like to due with patients not finishing the full course of antibiotics and some random genetic mutations popping up.
DeleteThis was a great read. I never hear much about TB especially here in the US, but I do know that it is a different story in some other countries. My personal experience with TB is only having to have blood drawn to the TB blood test, off the top of my head I do not remember ever having to get the TB skin test. Are there any specific cases where the blood TB test is better to use than the skin test? I was fascinated to read about the two new drugs being developed to help combat the antibiotic resistant strains of TB. I was curious about Bedaquiline, you wrote that further testing is needed to understand the side effects and toxicity, but you also said that both drugs are on the market. So has Bedaquiline been approved for treating TB?
ReplyDeleteTB blood test is always more accurate than the skin test. Usually you have blood test if you are positive for a skin test. Bedaquiline had been approved by the FDA for MDR-TB treatment only.
DeleteThis was a great and informative read and I especially loved your personal anecdote here! I only have one question-- have the two new drugs proven to be efficacious at treating other bacterial infections?
ReplyDeleteThey are bactericidal however, they are almost always used for M. tuberculosis. Could not find studies where they are used against other types of bacteria.
DeleteVery interesting article Bhavani! The newer drugs seem promising. Do you know what mechanism is being used by TB to cause resistance to Isoniazid and Rifampin? I wonder if the new drugs with similar MOA won’t also result in a resistance even quicker in patients already resistant to Isoniazid?
ReplyDeleteThe resistance to Isoniazid and Rifampin are thought to be mutations developing overtime especially if there's an incomplete regimen. Bedaquilline targets the proton pump of the ATP synthase and Delamanid blocks mycolic acid synthesis, but I am unsure on the exact mechanism.
DeleteThis was a very interesting post, and your person anecdote really draws the reader in! It's crazy to think TB has been around for so long, yet still has not been eradicated. Do you think it has resurged due to the widespread anti-vaccination surge; or do some countries not have access to vaccines? Just curious, great read though!
ReplyDeleteThe BCG vaccine is 70-80% effective against severe forms of TB like TB meningitis for children. It is not as effective for respiratory TB.
DeleteI enjoyed reading this post, as like some others I am not too familiar with TB beyond the skin test I've had to take a few times. I think the history of TB is very interesting though, and I wonder how similar the "ancient" mycobacterial was to the more modern forms before MDR-TB started to develop.
ReplyDeleteVery interesting article, Bhavani. With the medication that causes the qt prolongation does it require further monitoring because of this side effect or is it hesitantly prescribed? I have taken this test for every job I’ve had so far and have never really thought about it, this was a very englightening read and good to know going forward.
ReplyDeleteThis was a cool article about a disease that is not talked about as much anymore, which is a good thing I guess. The TB vaccine is made of a live attenuated (weakened) form of the pathogen, so I wonder if there is any literature relaying anything about the live bacteria reverting to an infectious state, or contributing to a latent form TB. I was unaware of the multi-drug resistant TB, and was curious on what the benefit would be for targeting the mycobacterial ATP synthase over the RNA polymerases.
ReplyDelete