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Totally Drug Resistant Tuberculosis

By Amesh A. Adalja MD, FACP, January 20, 2012

The treatment of tuberculosis (TB), once the leading cause of death from an infectious disease, is now complicated by antimicrobial resistance. Following the identification of single drug resistance, multidrug resistance (MDR) emerged in the 1990s, followed by extreme drug resistance (XDR) in 2001. Most recently, totally drug resistant (TDR) TB* emerged in 2007. A recent report in Clinical Infectious Diseases details 4 cases of TDR TB in India; this is the third report of TDR TB since 2007.1

TB Drug Resistance Categories

The specific number and class of antimicrobial drugs to which Mycobacterium tuberculosis bacterium displays resistance determines its classification:

  • MDR-TB: Resistant to both isoniazid (INH) and rifampin
  • XDR-TB: MDR + resistant to any fluoroquinolone + 1 of 3 injectable drugs (amikacin, capreomycin, kanamycin)
  • TDR-TB: XDR-TB that is resistant to all tested drugs (preliminary definition)
     

First Cases

Despite media attention to the most recent cases of TDR-TB in publications such as the Los Angeles Times, the first cases of TDR-TB were recognized several years ago when 2 Italian women died from TB after being treated for several years with failing regimens to which their isolates were totally resistant.3 The report of those cases was published in 2007. In 2009, 15 patient isolates submitted to Iran’s national TB reference laboratory were classified as TDR-TB after resistance testing. The Iranian isolates were further identified (spoligotyped) and discovered to belong to 4 separate M. tuberculosis families, suggesting that TDR-TB developed independently from MDR-TB after drug exposure in patients. Additionally, when compared to MDR and XDR isolates, the TDR-TB patients in Iran were statistically more likely to be male and younger. The clinical outcome of the Iranian cases was not provided.4

Indian Case Patients

In the most recent report, 4 Indian patients ranging in age from 20 to 57 years were identified as having TDR-TB. Of those patients, 3 were noted to have received “erratic, unsupervised second-line drugs, added individually and often in incorrect doses.”1 Drug resistance was determined using standard culture-based drug susceptibility testing; genotype testing was performed in 3 of the cases. Their clinical outcomes were not provided.1

TDR-TB Resulting from Treatment

Based on the limited case histories provided for the 21 cases reported thus far, it appears that this pattern of resistance is the result of selection pressure on MDR-TB arising from treatment with anti-mycobacterial drugs. Practices that may forestall development of resistance include the following:

  • Ensuring full adherence with the treatment regimen, which may require directly observed therapy (DOT)
  • Incorporating results of resistance testing into treatment decisions
  • Changing more than one drug in a regimen when resistance develops, as single drug changes foster resistance

Outcome Data Needed

Reporting outcome data on the cases of TDR-TB is essential for determining the level of mortality that can be expected in cases that are not medically treatable. Extrapolating from reports of XDR-TB cases in HIV infected patients, a high case fatality rate would be expected, but we do not have the data necessary to determine whether the same is true for patients who are not HIV coinfected.

Outcome data will also help to identify potential interventions. When feasible, one intervention that may prove effective in managing XDR- and TDR-TB cases is surgical resection of affected tissue: in one of the fatal Italian cases, surgical resection was employed to treat a patient’s daughter who presumably contracted a nonfatal (presumed TDR) TB strain from her mother who succumbed to the infection.2

Cases of TDR-TB—indeed, all instances of antimicrobial resistance—underscore the need for novel therapies to treat infectious diseases, which may include traditional antimicrobials, monoclonal antibody based treatments, or even bacteriophages. TDR-TB also highlights the need for greater emphasis on antimicrobial stewardship. For clinicians, the specter of TDR-TB translates into treating one of the historically most fatal infectious diseases without the benefit of antimicrobial therapy—a nearly insurmountable challenge.

* The European Centers for Disease Control (ECDC) does not advocate the use of the term “TDR- TB” as there is no official definition, and use of the term is relative, based on the drugs that are locally available for resistance testing in a given area.2

References

  1. Udwadia ZF, Amale RA, Ajbani KK, et al. Totally drug-resistant tuberculosis in India. Clin Infect Dis. Advance Access published December 21, 2011. http://cid.oxfordjournals.org/content/early/2011/11/24/cid.cir889.full. Accessed January 17, 2012.
  2. ECDC. New drug resistant form of tuberculosis reported in India. http://ecdc.europa.eu/en/activities/sciadvice/Lists/ECDC%20Reviews/ECDC_DispForm.aspx?List=512ff74f-77d4-4ad8-b6d6-bf0f23083f30&ID=1240. Accessed January 17, 2012.
  3. Migliori GB, De Iaco G, Besozzi G, Centis R, Cirillo DM. First tuberculosis cases in Italy resistant to all tested drugs. Euro Surveill. 2007. http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=3194. Accessed January 17, 2012.
  4. Velayati AA, Masjedi MR, Farnia P, et al. Emergence of new forms of totally drug-resistant tuberculosis bacilli: super extensively drug-resistant tuberculosis or totally drug-resistant strains in Iran. Chest 2009;136:420–5.