Tuberculosis (TB)

Drug-resistant TB: Totally drug-resistant TB FAQ

Totally drug-resistant TB

Is the term “totally drug resistant” clearly defined? Is it recognised by the WHO?

The term “totally drug resistant” has not been clearly defined for tuberculosis. While the concept of “total drug resistance” is easily understood in general terms, in practice, in vitro drug susceptibility testing (DST) is technically challenging and limitations on the use of results remain: conventional DST for the drugs that define MDR and XDR-TB has been thoroughly studied and consensus reached on appropriate methods, critical drug concentrations that define resistance, and reliability and reproducibility of testing.[9]

Data on the reproducibility and reliability of DST for the remaining SLDs are either much more limited or have not been established, or the methodology for testing does not exist.

Most importantly, correlation of DST results with clinical response to treatment has not yet been adequately established. Thus, a strain of TB with in vitro DST results showing resistance could in fact, in the patient, be susceptible to these drugs.

The prognostic relevance of in vitro resistance to drugs without an internationally accepted and standardised drug susceptibility test therefore remains unclear and current WHO recommendations advise against the use of these results to guide treatment.[10]

Lastly, new drugs are under development, and their effectiveness against these “totally drug resistant” strains has not yet been reported.

For these reasons, the term “totally drug resistant” tuberculosis is not yet recognised by the WHO. These cases are defined as extensively drug resistant tuberculosis (XDR-TB), according to WHO definitions.

What is extensively drug resistant tuberculosis?

Extensively drug-resistant tuberculosis (XDR-TB) is an even more severe form of drug resistant TB than multidrug-resistant TB (MDR-TB). In 2006, the first reports of XDR-TB began to appear. [1,2]

MDR-TB is defined as resistance to isoniazid and rifampicin, with or without resistance to other first-line drugs (FLD). XDR-TB is defined as resistance to at least isoniazid and rifampicin, and to any fluoroquinolone, and to any of the three second-line injectables (amikacin, capreomycin, and kanamycin). Within a year of the first reports of XDR-TB, isolated cases were reported in Europe that had resistance to all first-line anti-TB drugs (FLD) and second-line anti-TB drugs (SLD) that were tested.[3,4,5] In 2009, a cohort of 15 patients in Iran was reported which were resistant to all anti-TB drugs tested.[6]

The terms “extremely drug resistant” (“XXDR-TB”) and “totally drug-resistant TB” (“TDR-TB”) were given by the respective authors reporting on this group of patients. Recently, a further 4 patients from India with “totally drug resistant” tuberculosis (“TDR-TB”) were described [7], with subsequent media reports of a further 8 cases.[8]

Why are these terms not yet recognised by WHO?

Terms such as “totally drug resistant” have not been clearly defined for tuberculosis. While the concept of “total drug resistance” is easily understood in general terms, in practice, in vitro drug susceptibility testing (DST) is technically challenging and limitations on the use of results remain: conventional DST for the drugs that define MDR and XDR-TB has been thoroughly studied and consensus reached on appropriate methods, critical drug concentrations that define resistance, and reliability and reproducibility of testing.[9] Data on the reproducibility and reliability of DST for the remaining SLDs are either much more limited or have not been established, or the methodology for testing does not exist. Most importantly, correlation of DST results with clinical response to treatment has not yet been adequately established. Thus, a strain of TB with in vitro DST results showing resistance could in fact, in the patient, be susceptible to these drugs. The prognostic relevance of in vitro resistance to drugs without an internationally accepted and standardised drug susceptibility test therefore remains unclear and current WHO recommendations advise against the use of these results to guide treatment.[10]

Lastly, new drugs are under development, and their effectiveness against these “totally drug resistant” strains has not yet been reported.

For these reasons, the term “totally drug resistant” tuberculosis is not yet recognised by the WHO. For now these cases are defined as extensively drug resistant tuberculosis (XDR-TB), according to WHO definitions.

For more information, please contact:

Monica Dias Global TB Programme WHO/Geneva Email: diash@who.int

References

1.Centers for Disease Control and Prevention. Emergence of Mycobacterium tuberculosis with extensive resistance to second-line drugs worldwide. MMWR Morb Mortal Wkly Rep 2006; 55: 301-305.

2.World Health Organization (WHO). Extensively drug-resistant tuberculosis (XDR.TB): recommendations for prevention and control. Weekly Epidemiol Record 2006; 81: 430-432.

3.GB Migliori, R Loddenkemper, F Blasi and MC Raviglione. 125 years after Robert Koch’s discovery of the tubercle bacillus: the new XDR-TB threat. Is “science” enough to tackle the epidemic? Eur Respir J 2007; 29: 423-427.

4.Migliori GB, De Iaco G, Besozzi G, Centis R, Cirillo DM. First tuberculosis cases in Italy resistant to all tested drugs. Euro Surveil. 2007; 12(20): pii=3194.

5.Migliori GB, Ortmann J, Girardi E et al. Extensively drug-resistant tuberculosis, Italy and Germany. Emerging Infectious Diseases, 2007;13: 780-782.

6.Velayati AA, Masjedi MR, Farnia P, et al. Emergence of new forms of totally drug-resistant tuberculosis bacilli: super extensively drug-resistant tuberculosis of totally drug-resistant strain in Iran. Chest 2009; 136: 420-425.

7.Zarir F Udwadia, Rohot A Amale, Kanchan K Ajbani, Camilla Rodrigues. Correspondence: Totally Drug-Resistant Tuberculosis in India. Clin Infect Dis, published online December 21, 2011 doi:10.1093/cid/cir889 8.Times of India. New deadlier form of TB hits India. Jan 7, 2012.

9.World Health Organization. Policy guidance on drug susceptibility testing (DST) of second-line anti-tuberculosis drugs. WHO/HTM/TB/2008.392

10.WHO. Guidelines for the programmatic management of drug-resistant tuberculosis: Emergency Update 2008. WHO/HTM/TB/2008.402. Geneva, Switzerland: WHO, 2008.