News reports of at least a dozen cases of “totally drug resistant” tuberculosis (TB) in India recently have raised various questions, including why India and why now? In a letter to the editor in December’s issue of the journal Clinical Infectious Diseases describing the first cases of TDR-TB that surfaced in India, doctors at Mumbai’s Hinduja Hospital & Research Center argue that the new strain is attributable to poor management of multidrug-resistant (MDR)-TB cases in the private health care sector. The World Health Organization also released a fact sheet on the topic.
Science Speaks briefly interviewed the lead author of that letter, Dr. Zarir F. Udwadia, a consultant chest physician at Hinduja Hospital. He offers clarification on treatment options and outcomes for these patients and how dire the situation is in India.
How is Totally Drug Resistant (TDR)-TB distinctly different from Extensively Drug Resistant (XDR)-TB?
This is a further and final step in the amplification process that started in the 1990s from multidrug-resistant (MDR)-TB (which is resistant to rifampicin and isoniazid – the two most potent drugs in the TB arsenal), to extensively drug-resistant (XDR) TB (resistant to isoniazid, rifampicin, floroquinolones and at least one injectable second-line treatment), and now TDR-TB (resistant to all first- and second-line TB drugs).
What’s the prognosis for these patients? Have any of them died? Are any of them showing improvement?
The prognosis is very bleak. Three out of the 12 patients that have been identified with TDR-TB are dead. Two of them are stable, and the rest are deteriorating gradually.
It would be unconscionable to say, “Sorry you’re doomed. No known anti-TB drug is going to work on you.” So I attempt to treat these patients with a “salvage regimen” that includes everything left to throw at them. We have tried:
- Double-dose isoniazid: Although their TB strain is resistant to isoniazid, the hope is a higher dose would have some in-vivo efficacy.
- Linezolid: This antibiotic is dreadfully toxic (one in two patients has major side effects that demand withdrawal).
- Clofazamine: This is an anti-leprosy drug that has at least some, albeit weak, anti-TB effect.
- Thioridazine: This is an ancient, cheap, anti-psychotic drug that in some promising lab work by an amazing colleague, Professor Len Amaral, has been shown to have some efficacy in TB.
- Meropenem and clavunate: A paper in Science showed these had some effect on TB in mice. They are expensive, and need IV administration, but we are clutching at straws here.
- Finally, and we’ve come a full cycle here, we offer aggressive surgery (if drugs can’t help at least let’s cut out the worst parts!). Sadly most patients are too malnourished and have such advanced TB disseminated in both lungs that even this is not an option. We tried this aggressive surgery in three of the 12 patients, with one death post-op.
What is the process for determining a TB strain is untreatable by culture? How long would this process take? Are there other methods that can be used?
A new molecular test (Gene Xpert MTB/RIF rapid TB diagnostic) can determine the existence of multidrug-resistant TB in 24 hours. Another molecular test (Hain GenoType MTBDRplus Assay) will give first- and some second-line sensitivity in 48 hours. Traditional liquid media still takes four to eight weeks at least. Sadly, India has only 25 labs sanctioned to reliably perform drug sensitivity tests – A drop in the sea of 1.2 billion people living in India.
The tests to diagnose TDR are liquid cultures, which still sadly take too long – six to eight weeks for results.
What is current access to treatment for MDR-TB in the public and private sectors in India? What do you think the implications are for private sector TB care in India?
Less than one percent of people living with MDR-TB in India have access to government/public treatment. Everyone has access to private health care, except the desperately poor, but sadly the quality of the prescriptions are so poor that most only amplify resistance.
Describe for me the training deficits in private sector doctors in India.
Education of private doctors is needed. Guidelines exist but are not followed because when it comes to TB everyone is an “expert”!
Are there any drug combinations in the pipeline that you think might be effective against this new strain?
There are a couple promising drugs in the pipeline: TMC 207 and OPC 67863. Sadly the National Institutes of Health spends more on smallpox and anthrax research than on TB research because the perceived threat of biological terrorism exceeds (in their mind) the very real threat of TB.
What are the implications of these cases for other high burden TB countries?
No other country has thrown around and squandered second-line TB drugs as India has, so no other country will have as much TDR. Of course, if other countries don’t act now they will begin to see a fraction of their XDRs convert to TDR.