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Totally drug resistant TB | or Extremely, XXDR, TDR

What is totally or extremely drug resistant TB (XXDR TB)?

Totally drug resistant TB (usually abbreviated to XXDR TB), which is sometimes referred to as extremely drug resistant TB, is TB which is resistant to all the first and second line TB drugs.1Migliori, G “125 years after Robert Koch’s discovery of the tubercle bacillus: the new XDR-TB threat. Is “science” enough to tackle the epidemic?”, European Respiratory Journal, March 1 2007http://erj.ersjournals.com This makes it almost but not totally impossible to treat.

When was the term extremely drug resistant TB (XXDR TB) first used?

The term extremely drug resistant TB (XXDR TB), was first used in 2007.2Migliori, G “125 years after Robert Koch’s discovery of the tubercle bacillus: the new XDR-TB threat. Is “science” enough to tackle the epidemic?”, European Respiratory Journal, March 1 2007http://erj.ersjournals.com

What is the difference between XDR TB and XXDR TB?

The term XDR TB, is used to refer to strains of TB that are resistant not only to rifampicin and isonizaid, two of the main first line TB drugs, but strains that are also resistant to a fluoroquinolone and to at least one of the second line injectable TB drugs. Totally, or extremely drug resistant TB, or XXDR TB, refers to strains that are resistant to all the first line drugs as well as all the second line TB drugs.

When were the first cases of totally drug resistant TB (XXDR TB) 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.3“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.4(Moll, A “Identification of a Multi-Drug Resistant Tuberculosis Cluster as a Cause of Death Among HIV Coinfected Patients in Rural South Africa”, Poster Presentation CROI 2006, February 2006http://retroconference.org/2006/Abstracts/27209.htm
It was then reported in 2007 that two cases of XXDR TB had occurred in Italy in 2003.5Migliori, G. “First tuberculosis cases in Italy resistant to all tested drugs”, Euro Surveill. 2007www.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 dying 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 or extremely drug resistant TB in the U.S.

A. G. Holley State hospital

A. G. Holley State hospital

The first case of totally drug resistant (XXDR) TB in the U.S., 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 XXDR TB.6Mendoza, M, “First U.S. case of extremely drug resistant strain of tuberculosis diagnosed”, Associated Press 2009 www.msnbc.msn.com/

Amongst 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 (XXDR) TB in Iran

In 2009 it was reported that totally drug resistant TB had been identified in Iran, with most of the cases being 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

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, 2012http://articles.timesofindia.indiatimes.com

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/

Although the number of known cases in India is small they are geographically dispersed. In addition to those at the Hinduja hospital in Mumbai there had been six cases at the St. John’s National Academy of Health Sciences in Bangalore and a further two at the All India Institute of Medical Sciences in New Delhi.12Anand, G “India in Race to Contain Untreatable Tuberculosis”, The Wall Street Journal, Jun 19, 2012//online.wsj.com/article/

It is also understood that at least one of these people is HIV positive but they are not yet receiving antiretroviral therapy.13Sumitra, Deb “Man with deadly TB strain is HIV+”, The Times of India, Jan 27, 2012http://articles.timesofindia.indiatimes.com/2012-01-27 The current international guidelines are that people with HIV and TB co infection, should start antiretroviral therapy between two and eight weeks after starting their TB treatment.14“Antiretroviral Therapy for HIV Infection in Adults and Adolescents: Recommendations for a public health approach 2010 revision”, WHO, Geneva, 2010, 45 www.who.int/hiv/topics/treatment/en/index.html

Further developments with these patients include the fact that 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, although two patients from Mumbai were sensitive to one second line drug.15“TB institute confirms 8 patients resistant to all known TB drugs”, Hindustan Times,www.hindustantimes.com/India-news/Mumbai/TB-institute-confirms-8-patients-resistant-to-all-known-TB-drugs/Article1-848739.aspx

In May 2012 it was reported that five of the nine TB patients at Hinduja hospital who were detected as being resistant to all TB drugs were responding well to treatment. They were being treated with a ‘salvage regime’ of four antibiotics used in the treatment of other diseases.16“Five drug-resistant TB patients responding well to treatment, say docs”, Hindustan Times,www.hindustantimes.com/India-news/Mumbai/Five-drug-resistant-TB-patients-responding-well-to-treatment-say-docs/Article1-849285.aspx It was reported that the doctors at Hinduja continued to believe that this form of TB is different to XDR TB as there are fewer treatment options. In June 2012 it was reported that one of the eight patients whose sample was sent to Bangalore had died.17“13-year-old girl who died was among 8 with XXDR-TB”, Hindustan Times, www.hindustantimes.com/India-news/Mumbai/13-year-old-girl-who-died-was-among-8-with-XXDR-TB/Article1-865556.aspx

In July 2012 the death occurred of one of the 12 patients originally diagnosed in Mumbai with extremely drug resistant (XXDR) TB, and in December it was reported that a second resident had died of extremely drug resistant TB (XXDR-TB) in Navi Mumbai.18“29-yr-old multi-drug resistant TB patient dies at Sewree Hospital”, Hindustan Times,www.hindustantimes.com/India-news/Mumbai/29-yr-old-multi-drug-resistant-TB-patient-dies-at-Sewree-Hospital 19“Drug-resistant TB death in Navi Mumbai”, Hindustan Times, December 5th 2012www.hindustantimes.com/India-news/Mumbai/
In April 2013 it was reported that of the original 12 patients six had since died. The other six had responded to medication, and as a result 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, or XXDR TB.20“No cases of deadliest TB strain in Mumbai”, The Times of India, April 17th 2013http://articles.timesofindia.indiatimes.com/

Totally drug resistant TB returns to Mumbai

In September 2013 it was reported that a recent study conducted at the Kokilaben Hospital in Andheri, had shown that out of 21 children with TB, a number had MDR TB, and one of them had Totally drug resistant TB. Also, 72% of the 21 children with TB had contracted the disease from their community and not their immediate family.21“Children with drug resistant tuberculosis has experts worried”, India.com, September 24th 2013http://health.india.com/news/children-with-drug-resistant-tuberculosis-has-experts-worried

Which terms are recognized by the World Health Organization (WHO)?

Although the terms XXDR, extremely drug resistant, and totally drug resistant have all been widely used in the public media, and to a lesser extent in the medical literature, none of these terms are currently recognized by WHO. WHO considers all these cases of drug resistant TB to be varying forms of XDR TB, as 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, but decided that because of the current lack of drug susceptibility testing for some of the TB drugs, that they would not have any new terms but would continue to consider all these other strains to be XDR TB.22“‘Totally Drug Resistant’ tuberculosis: a WHO consultation on the diagnostic definition and treatment options”, WHO, Geneva, 2012 www.who.int/tb/challenges/xdr 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.”23Anand, G “India in Race to Contain Untreatable Tuberculosis”, The Wall Street Journal, Jun 19, 2012//online.wsj.com/article/

This is indeed true, but what is practical for describing a clinical situation is not necessarily appropriate when defining a term to be used for global monitoring of resistant TB. Defining the term totally drug resistant by reference to the testing that has been done, is very unsatisfactory when so few laboratories are able to test for second line and other TB drugs.24Cegielski, P “Challenges and Controversies in Defining Totally Drug-Resistant Tuberculosis”, Emerg Infect Dis., November 2012, 18(11) wwwnc.cdc.gov/eid/article/

A more satisfactory way forward clearly needs to be found with these definitions, and one possibility is to call this type of TB “XDR plus” TB, meaning TB which satisfies the criteria for XDR TB, but where there is additional resistance.


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