The term XDR appears to have been used for the first time in March 2006. A report was published jointly by the US CDC and the World Health Organisation (WHO), describing strains of TB that were resistant not only to isoniazid and rifampicin (that is they were MDR-TB) but they were also resistant to at least three of the six classes of second line anti TB drugs.1“Emergence of Mycobacterium tuberculosis with Extensive Resistance to Second-Line Drugs — Worldwide, 2000–2004”, CDC MMWR, March 24 2006 www.cdc.gov/mmwr 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 2007 http://erj.ersjournals.com
This definition was subsequently modified at a meeting of the WHO XDR TB Task Force in October 2006. The revised definition is strains of TB that are resistant to at least rifampicin and isoniazid (which means that it is MDR-TB), and also resistant to a fluoroquinolone and to at least one of the three injectable TB drugs, capreomycin, kanamycin and amikacin.3“Extensively drug-resistant tuberculosis (XDR-TB): recommendations for prevention and control”, Weekly epidemiological record, WHO, Geneva, 2006, 81 www.who.int/
XDR is sometimes referred to as extensively drug resistant TB.4“Global Tuberculosis Report 2015”, WHO, Geneva, 2015 www.who.int/tb/publications/global_report/ There is more about the different types of drug resistant TB.
By the end of 2016 XDR had been reported by 121 Member States of the World Health Organisation. Combining the data, the average proportion of MDR-TB cases with XDR-TB was 6.2%. The best estimate was lower than those based on data available in previous years (9.5% in 2015, 9.7% in 2014). This decrease can be explained partly by a larger quantity of routine surveillance data. Among the 40 countries with a high TB or MDR-TB burden, 22 have data on resistance to second line anti TB drugs.
The proportion of MDR-TB/RR-TB cases with resistance to any fluoroquinolone for which testing was done was 20%.
The notified cases of XDR TB, or extensively drug resistant TB, by World Health Organisation (WHO) region for 2016 are given below 5“Global Tuberculosis Report 2017”, WHO, Geneva, 2017 www.who.int/tb/publications/global_report/
|Region||Notified Cases of XDR-TB|
|Global Total for XDR-TB||8,014|
Globally, 8,511 patients were enrolled in treatment in 68 countries and territories in 2016. This was a 17% increase compared with 2015. However in 29 countries the number enrolled on treatment was less than the number of cases notified to WHO.
Among 6,904 patients started on treatment in 2014, in 52 countries and territories for which outcomes were reported, 30% completed treatment successfully. Treatment failed for 21%, 28% died and 20% were either lost to follow up or their treatment outcome was not evaluated.
India, the Russian Federation, and Ukraine, accounted for 68% of the 2014 cohort. Cohorts are groups of people who started treatment at a particular time (in this case 2014), and who are then followed for a number of years. Among seven countries with cohorts of more than 100 individuals mortality was highest (42%) in India and South Africa.
In South Africa there were over 1,000 cases of XDR-TB diagnosed in the province of KwaZulu-Natal between August 2011 and November 2014. This gives an indication of the level of drug resistant TB in South Africa. It is however believed that many cases are never diagnosed due to a lack of laboratory capacity to test for resistance to second line drugs. Many people may also die from what is thought to be multi drug resistant TB. It may be believed that they were not taking their drugs properly, when they actually had XDR-TB and they needed to be given different second line drugs.
A study in KwaZulu-Natal which evaluated the social networks as well as clinical data from people with XDR-TB concluded that transmission, in both hospitals and households, had been the primary driver of the XDR-TB epidemic in the province.6Auld, S, “South Africa’s XDR-TB epidemic is due to transmission rather then evolution of resistant strains”, CROI, March 2016, www.aidsmap.com This confirms what it is believed happened when the outbreak occurred earlier at Tugela Ferry.
In 2005 South African and US clinicians and researchers identified a large number of cases of extensively drug resistant TB at the Church of Scotland Hospital in Tugela Ferry. Tugela Ferry is a rural and desperately poor part of KwaZulu-Natal province in South Africa.7“Tugela Ferry, KwaZulu Natal, South Africa” ysmwebsites.trafficmanager.net/intmed/global/sites/southafrica.aspx It was discovered that of 221 patients with multi drug resistant TB, 53 had XDR-TB.8“The tuberculosis X factor”, The Lancet Infectious Diseases, Vol 6, November 2006, 679 www.thelancet.com/journals/ All the patients with XDR-TB had both TB and HIV.
Of the 53 patients with XDR-TB diagnosed during the first year of surveillance only one survived. The average survival rate from time of diagnosis was just 16 days among the 42 patients with confirmed dates of death. More than half the patients with XDR-TB had never been previously treated for TB. An additional third had either been cured or had completed treatment for previous TB illness.
So it is believed that transmission of XDR-TB strains between individuals had occurred. It was also believed that transmission of TB had occurred in the hospital as two thirds of the patients were recently hospitalised before the onset of XDR-TB. At least two health care workers died. These findings were considered to be particularly worrying for resource limited settings where many patients admitted to hospital are HIV positive, and effective TB infection control facilities and practices are extremely limited.9Gandhi, N. “Extensively drug resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa”, The Lancet, Vol 368, 4 November 2006, 1575-1580 www.thelancet.com
By 2009 there had been 820 patients with drug resistant TB at the Tugela Ferry hospital, and 57% had XDR-TB.10Heysell, S. “The Quiet Storm”, JAMA Network, July 1 2009 The Quiet Storm
It is not just in South Africa that the consequences of what happened at Tugela Ferry are still being seen. Many years later a South African born health care worker died in England of drug resistant TB and he was also infected with HIV. He had worked at the Tugela Ferry hospital during 1996-2002, and it is believed that this is the most likely place that he became infected. It has been said that:
“there were several missed opportunities for diagnosis of TB and HIV that could have prevented this patient’s death.” 11Cooke, G. “International Spread of MDR TB from Tugela Ferry, South Africa”, Emerg Infect Dis, Volume 17, November 2011, 1575-1580 http://wwwnc.cdc.gov/eid/article/17/11/11-0291_article.htm
When XDR first came to public attention in 2006 it was generally portrayed as a new and virtually incurable disease. The outbreak at Tugela Ferry led many people to believe that being diagnosed with XDR was effectively a death sentence.12“Studies confirm XDR-TB can be cured”, www.pih.org/news/entry/studies-confirm-xdr-tb-can-be-cured/ However a number of studies subsequently published have shown that with intensive and specialised care many people diagnosed with XDR-TB can not only be treated but can be cured.
In Peru care was provided to patients with XDR who were not infected with HIV. However they had received numerous previously unsuccessful anti TB treatments. The TB treatment they were provided with was aggressive, with the patients being given many drugs, at the highest doses they could tolerate. In most patients treatment lasted for more than two years.
Drug susceptibility testing was used to decide which regimes were likely to be effective. Some patients were provided with surgery as treatment for their TB. The patients were treated on an outpatient basis and more than half of them were cured.13Mitnick, C. “Comprehensive Treatment of Extensively Drug Resistant Tuberculosis”, N Engl J Med, August 2008, 563-574 www.nejm.org/
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Global Tuberculosis Report 2017, WHO, Geneva, 2017 www.who.int/tb/publications/global_report/en/
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|1.||↑||“Emergence of Mycobacterium tuberculosis with Extensive Resistance to Second-Line Drugs — Worldwide, 2000–2004”, CDC MMWR, March 24 2006 www.cdc.gov/mmwr|
|2.||↑||Migliori, 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 2007 http://erj.ersjournals.com|
|3.||↑||“Extensively drug-resistant tuberculosis (XDR-TB): recommendations for prevention and control”, Weekly epidemiological record, WHO, Geneva, 2006, 81 www.who.int/|
|4.||↑||“Global Tuberculosis Report 2015”, WHO, Geneva, 2015 www.who.int/tb/publications/global_report/|
|5.||↑||“Global Tuberculosis Report 2017”, WHO, Geneva, 2017 www.who.int/tb/publications/global_report/|
|6.||↑||Auld, S, “South Africa’s XDR-TB epidemic is due to transmission rather then evolution of resistant strains”, CROI, March 2016, www.aidsmap.com|
|7.||↑||“Tugela Ferry, KwaZulu Natal, South Africa” ysmwebsites.trafficmanager.net/intmed/global/sites/southafrica.aspx|
|8.||↑||“The tuberculosis X factor”, The Lancet Infectious Diseases, Vol 6, November 2006, 679 www.thelancet.com/journals/|
|9.||↑||Gandhi, N. “Extensively drug resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa”, The Lancet, Vol 368, 4 November 2006, 1575-1580 www.thelancet.com|
|10.||↑||Heysell, S. “The Quiet Storm”, JAMA Network, July 1 2009 The Quiet Storm|
|11.||↑||Cooke, G. “International Spread of MDR TB from Tugela Ferry, South Africa”, Emerg Infect Dis, Volume 17, November 2011, 1575-1580 http://wwwnc.cdc.gov/eid/article/17/11/11-0291_article.htm|
|12.||↑||“Studies confirm XDR-TB can be cured”, www.pih.org/news/entry/studies-confirm-xdr-tb-can-be-cured/|
|13.||↑||Mitnick, C. “Comprehensive Treatment of Extensively Drug Resistant Tuberculosis”, N Engl J Med, August 2008, 563-574 www.nejm.org/|