(From the WHO 2011 TB Progress Report)
# 6896
The existence of TDR-TB (Totally Drug Resistant Tuberculosis) has been fraught with controversy since the term first sprang into the headlines a little more than a year ago (see Crofsblog India: New TB strain is "totally drug-resistant" (updated)).
The story concerned at least 12 patients treated at an Indian hospital that had been diagnosed with `TDR-TB’.
Not - as has been seen in the past - MDR-TB (multi-drug resistant tuberculosis), and XDR-TB (extensively drug resistant Tuberculosis), but tuberculosis that was supposedly resistant to all known drugs.
Varyingly resistant forms of TB have come about primarily as the result of incomplete, irregular, or inappropriate treatment and management of infected patients. Patient compliance for long-term treatment has consistently been a major obstacle.
Until now – as difficult as treatment might have been - there has always been some combination of antibiotics that could be used to treat even the most resistant of TB cases.
The emergence of a totally resistant form of the disease would be a game-changer, and so these reports began to set off alarm bells around the world.
A few days later, in ECDC Comment On Drug Resistant TB In India, we saw calls to avoid using the term TDR-TB until it could be better defined.
From the ECDC report New drug resistant form of tuberculosis reported in India.
Total drug resistant TB is a relative notion and depends on the local drugs available and tested on. This term/expression should either be avoided or should be defined worldwide. The World Health Organization (WHO) has internationally-endorsed treatment recommendations for the treatment of drug-susceptible, MDR-TB and XDR-TB.
During this time, Maryn McKenna – Flublogia’s favorite scary disease girl – wrote extensively about these developments on her Superbug Blog:
Totally Resistant TB: Earliest Cases in Italy
- By Maryn McKenna January 12, 2012
India Reports Completely Drug-Resistant TB
- By Maryn McKenna January 9, 2012
Totally Drug-Resistant TB: A Patient Is Missing
- By Maryn McKenna January 14, 2012
That same week, in Resistant TB: The Limits Of Surveillance & Reporting, I wrote about the World Health Organization’s initial response to these reports (they did not currently recognize TDR-TB due to reasons stated in their TDR-TB FAQ), along with an article in the Indian Express suggesting that TDR-TB cases may be more widespread than reported.
By the end of January, India’s government was denying the existence of untreatable TB in their country (see Referral: McKenna On India’s Denial Of TDR-TB), a response not dissimilar to their denials of NDM-1.
In March of 2012, the World Health Organization released a statement on the supposed TDR-TB, titled More evidence and better diagnostics needed before redefining severe forms of drug-resistant TB says WHO.
The `TDR-TB’ story simmered quietly for the next few months, that is, until October of 2012, when in EID Journal: Challenges To Defining TDR-TB we looked at an EID Journal article called:
NOTE: Corrected Link
Challenges and Controversies in Defining Totally Drug-Resistant Tuberculosis
Peter Cegielski , Paul Nunn, Ekaterina V. Kurbatova, Karin Weyer, Tracy L. Dalton, Douglas F. Wares, Michael F. Iademarco, Kenneth G. Castro, and Mario Raviglione
(Excerpt)
Susceptibility tests for several drugs are poorly reproducible. Few laboratories can test all drugs, and there is no consensus list of all anti-TB drugs. Many drugs are used off-label for highly drug resistant TB, and new drugs formulated to combat resistant strains would render the proposed category obsolete. Labeling TB strains as totally drug resistant might lead providers to think infected patients are untreatable. These challenges must be addressed before defining a new category for highly drug-resistant TB
All of which brings us to a new EID Journal article (abstract reparagraphed for readability), published yesterday, called:
Emergence and Spread of Extensively and Totally Drug-Resistant Tuberculosis, South Africa
Marisa Klopper, Robin Mark Warren, Cindy Hayes, Nicolaas Claudius Gey van Pittius, Elizabeth Maria Streicher, Borna Müller, Frederick Adriaan Sirgel, Mamisa Chabula-Nxiweni, Ebrahim Hoosain, Gerrit Coetzee, Paul David van Helden, Thomas Calldo Victor, and André Phillip Trollip
Abstract
Factors driving the increase in drug-resistant tuberculosis (TB) in the Eastern Cape Province, South Africa, are not understood. Using a convenience sample of 309 drug-susceptible and 342 multidrug-resistant (MDR) TB isolates, collected July 2008–July 2009, we characterized them by spoligotyping, DNA fingerprinting, insertion site mapping, and targeted DNA sequencing.
Analysis of molecular-based data showed diverse genetic backgrounds among drug-sensitive and MDR TB sensu stricto isolates in contrast to restricted genetic backgrounds among pre–extensively drug-resistant (pre-XDR) TB and XDR TB isolates.
Second-line drug resistance was significantly associated with the atypical Beijing genotype. DNA fingerprinting and sequencing demonstrated that the pre-XDR and XDR atypical Beijing isolates evolved from a common progenitor; 85% and 92%, respectively, were clustered, indicating transmission.
Ninety-three percent of atypical XDR Beijing isolates had mutations that confer resistance to 10 anti-TB drugs, and some isolates also were resistant to para-aminosalicylic acid.
These findings suggest the emergence of totally drug-resistant TB.
For those unfamiliar with para-aminosalicylic acid (PAS), it’s an older drug discovered in 1944, and one of the first drugs to effectively treat TB. Its use as a first-line drug treatment was discontinued when newer antibiotics – like Rifampin - became available.
PAS is still used in treating XDR-TB although its value is limited and there are problems with toxicity.
Whether we should label them XDR-TB or TDR-TB may be debatable, but what is not is that we continue to see an erosion in our arsenal of effective drugs as new, resistant forms of TB emerge and spread.
As reported in last week’s MMWR, getting the best drugs to treat resistant TB can be difficult, even here in the United States (Interruptions in Supplies of Second-Line Antituberculosis Drugs — United States, 2005–2012).
Semantics aside, if you are unlucky enough to be infected by one of these resistant TB strains - and no effective drug is available to you – then the fine distinction over whether it is XDR or TDR TB is of little practical consequence to you.
