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Totally drug resistant TB – XDR TB, WHO, curing TDR, India

What is the difference between Totally drug resistant TB and XDR TB?

Totally drug resistant TB (also known as extremely & TDR TB), is used to refer to strains that are resistant to all the first line drugs as well as all the second line TB drugs that can be tested for. Different countries and indeed regions vary in which second line drugs they can test for. In other words they are strains resistant to everything that can be tested for.

The term XDR TB, is used to refer to more limited drug resistance. XDR TB refers to strains of TB that are resistant to rifampicin and isonizaid, two of the main first line TB drugs. The strains are also resistant to a fluoroquinolone and to at least one of the second line injectable TB drugs.

Is Totally drug resistant TB recognized by the World Health Organization (WHO)?

The term totally drug resistant TB is not currently recognized by WHO. This is despite the fact that the terms totally drug resistant, TDR and extremely drug resistant have all been widely used in the public media. To a lesser extent they have also all be used in the medical literature. WHO considers all these cases of drug resistant TB to be varying forms of XDR TB. This is because they do all satisfy the definition of XDR TB.

In March 2012 WHO convened a meeting to discuss whether there should be a new definition. They decided however that because of the current lack of drug susceptibility testing for some of the second line TB drugs, that they would not have any new terms. They would continue to consider all these other strains to be XDR TB.1“‘Totally Drug Resistant’ tuberculosis: a WHO consultation on the diagnostic definition and treatment options”, WHO, Geneva, 2012 www.who.int/tb/areas-of-work/drug-resistant-tb/totally-drug-resistant-tb-faq/en/ However, as Camilla Rodrigues the lab chief at the Hinduja hospital where most of India’s cases of “totally drug resistant TB” have been found, said:

“the strain’s total drug resistance was indeed difficult to confirm in a lab. But, .. it was easily confirmed in clinical practice.”2Anand, G “India in Race to Contain Untreatable Tuberculosis”, The Wall Street Journal, Jun 19, 2012 //online.wsj.com/article/

This is certainly true. But what is appropriate for describing a clinical situation is not necessarily appropriate when defining a term to be used for global monitoring of certain types of drug resistant TB.

The problem of a new definition

In general with drug resistant TB, the type of resistance is described by referring to the testing that has been done.  This is though very unsatisfactory when so few laboratories are able to test for second line and other TB drugs.3Cegielski, P “Challenges and Controversies in Defining Totally Drug-Resistant Tuberculosis”, Emerg Infect Dis., November 2012, 18(11) wwwnc.cdc.gov/eid/article/

WHO does not recognise the term “totally drug resistant” because this has not been clearly defined. It says that:

“While the concept of “total drug resistance” is easily understood in general terms, in practice, in vitro (laboratory) drug susceptibility testing is technically challenging and limitations on the use of results remain”

However, in respect of worldwide monitoring this leaves no distinction between XDR TB where the resistance is exactly the minimum required by the definition (resistant to isoniazid and rifampicin and three of the six classes of second line anti TB drugs), and the resistance that has been encountered in India. This included resistance to all three injectable TB drugs.

At the same time that WHO has refused to consider an additional definition for this situation, it would appear that they have defined a new term of “uncomplicated MDR TB”. This is TB that satisfies the criteria for MDR TB but also where it is known that there is no resistance to any other (unspecified) second line drugs.

So maybe there could be a definition of “uncomplicated XDR” which is XDR without additional resistance, in a similar way as it defines “uncomplicated MDR” as being MDR without additional resistance. Either way a new definition would seem to be needed in order that the worldwide level of “uncomplicated XDR” and XDR can be monitored.

Can Totally drug resistant TB be cured?

In the Indian hospital where twelve cases of totally drug resistant TB were found in 2012, they have a cure rate of about 70%, which is similar to some other hospitals. But they have found that it is essential that there is individualized therapy and that this is based on reliable drug sensitivity testing.

When were the first cases of totally drug resistant TB (TDR) reported?

From the time in 2006 that the term XDR was first used, it was clear that there were some strains of TB that were not only resistant to one of the second line drugs, but were possibly resistant to at least several if not all of them.4“Emergence of Mycobacterium tuberculosis with Extensive Resistance to Second-Line Drugs — Worldwide, 2000–2004”, CDC MMWR, March 24 2006 www.cdc.gov/mmwr  However, the lack of drug susceptibility testing often made it unclear whether it was just some or all of the second line drugs that these strains were resistant to.

It was then reported in 2007 that two cases of totally drug resistant TB had occurred in Italy in 2003.5Migliori, G. “First tuberculosis cases in Italy resistant to all tested drugs”, Euro Surveill. 2007 www.eurosurveillance.org Both cases were young women who were born in Italy and they were initially diagnosed and treated in non specialised TB facilities. They both received several different courses of TB treatment, before being admitted to a specialist TB facility with suspected multi drug resistant TB.

The first woman had acquired TB from her mother, who was known to have MDR TB. Over the course of several treatments the woman received at least a dozen different drugs before she died of TB in 2003. Drug susceptibility testing was carried out on almost all the drugs, and resistance was found to all the tested drugs. The second woman also received a large number of different drugs and the last treatment regime was followed for 60 months, before she also died. Resistance was found to all the drugs with known anti TB activity. In both cases resistance to new TB drugs had been acquired over quite an extended time.

Totally drug resistant TB in the United States

A. G. Holley State hospital where patients with totally drug resistant TB were treated

A. G. Holley State hospital where patients with totally drug resistant TB were treated

The first case of totally drug resistant  TB in the United States, was in a young Peruvian man called Oswaldo Juarez who was visiting the United States to study English. His illness originally puzzled the doctors he saw as he had never had TB before.

Then in December 2007 he was sent to A.G. Holley State hospital, the last TB sanatorium in the U. S. which has now closed down. Oswaldo Juarez went there voluntarily, and he was then treated with high doses of drugs, some of which are not normally used for TB. But when he left the hospital nineteen months later he was cured of extremely TB.6Mendoza, M, “First U.S. case of extremely drug resistant strain of tuberculosis diagnosed”, Associated Press 2009 www.msnbc.msn.com/

Among those people who are diagnosed with multi drug resistant TB in the U.S., many were born in other countries. However, as a leading U.S. TB expert has said:

“You’re really looking at a global issue .. It’s not a foreign problem, you can’t keep these TB patients out. It’s time people realize that.”
Dr Lee Reichman 7Mendoza, M, “First U.S. case of extremely drug resistant strain of tuberculosis diagnosed”, Associated Press 2009 www.msnbc.msn.com/

Totally drug resistant TB in Iran

In 2009 it was reported that totally drug resistant TB had been identified in Iran. Most of the cases were people who had a previous history of TB. It was suggested that further research was required to determine the level of totally drug resistant TB, not only in Iran, but also in nearby countries such as Pakistan and the former Soviet Union.8Udwadia, Zarir “Emergence of New Forms of Totally Drug-Resistant Tuberculosis Bacilli”, Chest, April 6 2009 www.ncbi.nlm.nih.gov/pubmed/

Totally drug resistant TB in India

Totally drug resistant TB in Mumbai

In early January 2012 it was reported that twelve cases of TB had been diagnosed in Mumbai which were referred to as totally drug resistant (TDR) TB. It was said that in all twelve cases the strain of TB was resistant to twelve TB drugs. The doctors were pessimistic saying that:

“We have little to offer these patients except for drastic surgery and medication for some relief,”
Dr Zarir Udwadia9Malathy, Iyer “New, deadlier form of TB hits India”, The Times of India, Jan 7, 2012 http://articles.timesofindia.indiatimes.com

There is more about surgery as treatment for TB.

It was also said that totally drug resistant TB had emerged because of the failure of the overall health system as:

“These patients have received erratic, unsupervised second line drugs, added individually and often in incorrect doses, from multiple private practioners.”

However, within a couple of weeks the Indian health authorities had rejected these claims, saying that all the cases were in fact extensively drug resistant, that is XDR TB infections.10“India rejects ‘total drug resistant TB’ claim”, BBC, Jan 20, 2012 www.bbc.co.uk/news/ In April though the government apparently quietly confirmed the strain.11Anand, G “India in Race to Contain Untreatable Tuberculosis”, The Wall Street Journal, Jun 19, 2012 //online.wsj.com/article/

The National Tuberculosis Institute at Bangalore confirmed that all eight patients whose sputum samples were sent to it for retesting, showed resistance to all known first and second line TB drugs. However two patients from Mumbai were sensitive to one second line drug.12“TB institute confirms 8 patients resistant to all known TB drugs”, Hindustan Times, www.hindustantimes.com/mumbai/tb-institute-confirms-8-patients-resistant-to-all-known-tb-drugs/story-Q7BJ34Kuhk5EVrQMZUVJVI.html

By April 2013 some of these patients had responded well to treatment whereas others had died. As a result the remaining patients` had been downgraded to having XDR, or extensively drug resistant TB. As a result there were not considered to be any patients in the city with totally drug resistant TB.13“No cases of deadliest TB strain in Mumbai”, The Times of India, April 17th 2013 http://articles.timesofindia.indiatimes.com/

Since then there have been a few other cases of totally drug resistant TB elsewhere in India, and there have also been some cases in children.

You can read more about:

MDR TB

Ending TB

TB in India

References

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1. “‘Totally Drug Resistant’ tuberculosis: a WHO consultation on the diagnostic definition and treatment options”, WHO, Geneva, 2012 www.who.int/tb/areas-of-work/drug-resistant-tb/totally-drug-resistant-tb-faq/en/
2. Anand, G “India in Race to Contain Untreatable Tuberculosis”, The Wall Street Journal, Jun 19, 2012 //online.wsj.com/article/
3. Cegielski, P “Challenges and Controversies in Defining Totally Drug-Resistant Tuberculosis”, Emerg Infect Dis., November 2012, 18(11) wwwnc.cdc.gov/eid/article/
4. “Emergence of Mycobacterium tuberculosis with Extensive Resistance to Second-Line Drugs — Worldwide, 2000–2004”, CDC MMWR, March 24 2006 www.cdc.gov/mmwr
5. Migliori, G. “First tuberculosis cases in Italy resistant to all tested drugs”, Euro Surveill. 2007 www.eurosurveillance.org
6. Mendoza, M, “First U.S. case of extremely drug resistant strain of tuberculosis diagnosed”, Associated Press 2009 www.msnbc.msn.com/
7. Mendoza, M, “First U.S. case of extremely drug resistant strain of tuberculosis diagnosed”, Associated Press 2009 www.msnbc.msn.com/
8. Udwadia, Zarir “Emergence of New Forms of Totally Drug-Resistant Tuberculosis Bacilli”, Chest, April 6 2009 www.ncbi.nlm.nih.gov/pubmed/
9. Malathy, Iyer “New, deadlier form of TB hits India”, The Times of India, Jan 7, 2012 http://articles.timesofindia.indiatimes.com
10. “India rejects ‘total drug resistant TB’ claim”, BBC, Jan 20, 2012 www.bbc.co.uk/news/
11. Anand, G “India in Race to Contain Untreatable Tuberculosis”, The Wall Street Journal, Jun 19, 2012 //online.wsj.com/article/
12. “TB institute confirms 8 patients resistant to all known TB drugs”, Hindustan Times, www.hindustantimes.com/mumbai/tb-institute-confirms-8-patients-resistant-to-all-known-tb-drugs/story-Q7BJ34Kuhk5EVrQMZUVJVI.html
13. “No cases of deadliest TB strain in Mumbai”, The Times of India, April 17th 2013 http://articles.timesofindia.indiatimes.com/