Combination Therapy for TB | 09 Dec 2019

Researchers from Bengaluru have made an important discovery of the mechanism used by Tuberculosis (TB) bacteria to tolerate TB drugs.

Macrophages (a type of white blood cell), when infected with pathogens (such as bacteria or virus), as a first-line of defence, reduce the pH range in the body, i.e. making pH acidic.
The researchers found that instead of controlling the TB bacteria, the mildly acidic pH was actually facilitating a fraction of the bacteria to continue multiplying and develop drug tolerance.
- Anti-TB drugs induce oxidative stress to kill bacteria inside macrophages.
- However, the drug tolerant bacteria have a remarkable ability to counter oxidative stress.
- The bacteria uses the acidic pH of macrophages as a cue to specifically increase its capacity to deal with oxidative stress.
- The bacteria also induce efflux pumps (to expel antibiotics) as an additional mechanism to reduce antibiotic efficacy.
This is against the common notion that only the non-replicating or slowly metabolising TB bacteria become tolerant to anti-TB drugs.
The mechanism was found responsible for longer TB treatment of six-nine months.
The drug-tolerant bacteria were found in macrophages that were more acidic (pH 5.8) while the drug-sensitive bacteria were seen in macrophages that were less acidic (pH 6.6).

The researchers used already approved anti-malaria drug chloroquine in combination with a TB drug isoniazid in mice and guinea pigs.
The chloroquine drug neutralised the pH within the macrophages. This prevented the bacteria from inducing the mechanism to protect themselves from oxidative stress. So no drug-tolerant TB bacteria emerged.
Once the pH was neutralised, the isoniazid drug was able to eradicate TB from animals.
The two-month treatment was able to completely sterilise mouse lungs and a near-complete eradication was observed from the lungs of guinea pigs.
In addition, it was found that the drug combination also reduces the chances of TB relapse.

Tuberculosis

TB is caused by bacteria (Mycobacterium tuberculosis) that most often affect the lungs.
Transmission: TB is spread from person to person through the air. When people with lung TB cough, sneeze or spit, they propel the TB germs into the air.
Symptoms: Cough with sputum and blood at times, chest pains, weakness, weight loss, fever and night sweats.
Treatment: TB is treatable and curable disease. It is treated with a standard 6 month course of 4 antimicrobial drugs that are provided with information, supervision and support to the patient by a health worker or trained volunteer.
Anti-TB medicines have been used for decades and strains that are resistant to 1 or more of the medicines have been documented in every country surveyed.
- Multidrug-resistant tuberculosis (MDR-TB) is a form of TB caused by bacteria that do not respond to isoniazid and rifampicin, the 2 most powerful, first-line anti-TB drugs. MDR-TB is treatable and curable by using second-line drugs.
- Extensively drug-resistant TB (XDR-TB) is a more serious form of MDR-TB caused by bacteria that do not respond to the most effective second-line anti-TB drugs, often leaving patients without any further treatment options.