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Original Research |

Predictors of Extensively Drug-Resistant Pulmonary Tuberculosis

Kai Kliiman, MD; and Alan Altraja, MD, PhD
[+] Article, Author, and Disclosure Information

From the University of Tartu, Tartu, Estonia.

Acknowledgment: The authors acknowledge the valuable and professional assistance of Dr. Vahur Hollo and Tiina Kummik in data collection.

Financial Support: By the Estonian Health Insurance Fund.

Potential Financial Conflicts of Interest: None disclosed.

Reproducible Research Statement:Study protocol: Available from Dr. Kliiman (e-mail, kai.kliiman@kliinikum.ee) or Dr. Altraja (e-mail, alan.altraja@kliinikum.ee). Statistical code: Available from Dr. Altraja (e-mail, alan.altraja@kliinikum.ee). Data set: Available from Dr. Kliiman (e-mail, kai.kliiman@kliinikum.ee).

Requests for Single Reprints: Kai Kliiman, MD, Department of Pulmonary Medicine, University of Tartu, Riia 167, 51014 Tartu, Estonia; e-mail, kai.kliiman@kliinikum.ee.

Current Author Addresses: Drs. Kliiman and Altraja: Department of Pulmonary Medicine, University of Tartu, Riia 167, 51014 Tartu, Estonia.

Author Contributions: Conception and design: K. Kliiman, A. Altraja.

Analysis and interpretation of the data: K. Kliiman, A. Altraja.

Drafting of the article: K. Kliiman.

Critical revision of the article for important intellectual content: K. Kliiman, A. Altraja.

Final approval of the article: K. Kliiman, A. Altraja.

Provision of study materials or patients: K. Kliiman.

Statistical expertise: A. Altraja.

Administrative, technical, or logistic support: A. Altraja.

Collection and assembly of data: K. Kliiman.

Ann Intern Med. 2009;150(11):766-775. doi:10.7326/0003-4819-150-11-200906020-00004
Text Size: A A A

Background: About 40 000 cases of extensively drug-resistant tuberculosis emerge worldwide annually, but the predictors of extensive drug resistance are unclear.

Objective: To identify risk factors for extensively drug-resistant tuberculosis and multidrug-resistant but non–extensively drug-resistant tuberculosis in patients with culture-confirmed pulmonary tuberculosis.

Design: Cross-sectional, countrywide study.

Setting: Estonia, a country with 1 of the world's highest rates of extensively drug-resistant and multidrug-resistant tuberculosis.

Patients: All patients with culture-confirmed pulmonary tuberculosis with clinical or radiologic evidence of active disease detected from January 2003 to December 2005.

Measurements: Risk determinants from patients' demographic characteristics, socioeconomic variables, and tuberculosis-related data or HIV status.

Results: Of 1163 patients, 60 (5.2%) had extensively drug-resistant tuberculosis and 196 (16.9%) had multidrug-resistant but non–extensively drug-resistant tuberculosis. Previous antituberculosis treatment (adjusted odds ratio [OR], 10.54 [95% CI, 5.97 to 18.62]), HIV infection (OR, 3.12 [CI, 1.31 to 7.41]), homelessness (OR, 2.73 [CI, 1.15 to 6.48]), and alcohol abuse (OR, 1.98 [CI, 1.08 to 3.64]) increased risk for extensive drug resistance. Previous treatment (OR, 4.11 [CI, 2.77 to 6.08]) and age 24 years or younger (OR, 2.57 [CI, 1.09 to 6.06]), 25 to 44 years (OR, 2.64 [CI, 1.35 to 5.16]), and 45 to 64 years (OR, 2.06 [CI, 1.06 to 3.99]) were determinants of multidrug resistance. In patients age 24 years or younger, female sex (OR, 6.23 [CI, 1.02 to 37.99]) and birth outside of Estonia (OR, 82.04 [CI, 3.46 to 1945.47]) increased risk for multidrug resistance.

Limitation: patients' comorbid conditions and drug abuse history were not incorporated into analyses because of inconsistent source data.

Conclusion: Previous treatment is a common risk factor for extensively drug-resistant and multidrug-resistant tuberculosis. Reducing relapses; screening persons younger than 65 years and immigrants; and combating against HIV infection, alcoholism, and homelessness are key issues for decreasing the spread of highly drug-resistant tuberculosis.

Primary Funding Source: Estonian Health Insurance Fund.


Grahic Jump Location
Figure 2.
Standardized OR results.

Odds ratios with 95% CIs divided by their standard errors are derived from full multinomial logistic regression model and are adjusted for all other variables in the respective subset of covariates. Age ≥65 years and university education were used as reference categories when analyzing the effect of age and education, respectively, versus the comparator. MDR = multidrug-resistant tuberculosis; nMDR = non–multidrug-resistant tuberculosis: nXDR = non–extensively drug-resistant tuberculosis; OR = odds ratio; XDR = extensively drug-resistant tuberculosis. * P < 0.05. † P < 0.01. ‡ P < 0.001.

Grahic Jump Location




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Submit a Comment/Letter
Pharmacological Modalities for the Treatment of Drug Resistant Tuberculosis: New Horizon
Posted on July 8, 2009
Rajakrishnan Vijayakrishnan
Saint Vincent Hospital, Worcester, Massachusetts
Conflict of Interest: None Declared


I read with interest the article by Kliiman et al (1). The authors state that: "Any new drug developed to treat tuberculosis (which is rarely done) will rapidly become unusable because of developing resistance against it if public health does not ensure the drugs are correctly used. ....... the key issues are reducing relapses through proper detection and more successful treatment of new cases with adequate drug regimens and a patient-oriented approach to ensure adherence." This statement holds true for conventional anti-tuberculous drugs which develop resistance after non -judicial use. We have conducted structure-based studies to design lead compounds which can be developed into drugs, to counter the resistance to Isoniazid (INH) "“ one of the key drugs in treatment of tuberculosis (2). The NADH"“dependent Enoyl-ACP reductase (InhA), which is encoded by the Mycobacterium gene inhA, is a key enzyme in the biosynthesis of mycolic acids. It is now well established that InhA is the primary molecular target of Isoniazid (3).

Isoniazid is a prodrug, which must first be activated by KatG, a catalase-peroxidase, to an acyl radical which covalently binds to the co- substrate for InhA, NADH (4). Resistance to INH is mediated mainly through mutations in the KatG gene (5). Therefore, direct inhibitors of InhA, which do not require activation, are suitable candidates for the development of new drugs against tuberculosis. Using a structure-based approach, we have identified a tripeptide inhibitor (100 times more potent than the existing inhibitors) which is a potential lead compound for the development of new anti-tuberculous drugs (2).

The significance of such drug discovery lies in the fact that even when drug resistant M tuberculi, is identified it can be effectively treated by using these novel agents. There is a need for increased research at the molecular mechanisms of drug resistance in tuberculosis. Such novel drugs which can overcome drug resistance are a new horizon in the treatment of multi-drug resistant tuberculosis which still holds the largest morbidity and mortality caused by a single bacterial agent in the world.


1. Kliiman K, Altraja A. Predictors of extensively drug-resistant pulmonary tuberculosis. Ann Intern Med 2009;150(11):766-75.

2. Subba Rao G, Vijayakrishnan R, Kumar M. Structure-based design of a novel class of potent inhibitors of InhA, the enoyl acyl carrier protein reductase from Mycobacterium tuberculosis: a computer modelling approach. Chem Biol Drug Des 2008;72(5):444-9.

3. Banerjee A, Dubnau E, Quemard A et al. inhA, a gene encoding a target for isoniazid and ethionamide in Mycobacterium tuberculosis. Science 1994;263:227-30.

4. Zhang Y, Heym B, Allen B, Young D, Cole S. The catalase-peroxidase gene and isoniazid resistance of Mycobacterium tuberculosis. Nature 1992;358:591-3.

5. Escalante P, Ramaswamy S, Sanabria H et al. Genotypic characterization of drug-resistant Mycobacterium tuberculosis isolates from Peru. Tuber Lung Dis 1998;79(2):111-8.

Conflict of Interest:

None declared

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