Prevalence and genetic profiles of isoniazid resistance in tuberculosis patients: A multicountry analysis of cross-sectional data

Autoři: Anna S. Dean aff001;  Matteo Zignol aff001;  Andrea Maurizio Cabibbe aff002;  Dennis Falzon aff001;  Philippe Glaziou aff001;  Daniela Maria Cirillo aff002;  Claudio U. Köser aff003;  Lice Y. Gonzalez-Angulo aff001;  Olga Tosas-Auget aff001;  Nazir Ismail aff004;  Sabira Tahseen aff005;  Maria Cecilia G. Ama aff006;  Alena Skrahina aff007;  Natavan Alikhanova aff008;  S. M. Mostofa Kamal aff009;  Katherine Floyd aff001
Působiště autorů: Global TB Programme, World Health Organization, Geneva, Switzerland aff001;  Emerging Bacterial Pathogens Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy aff002;  Department of Genetics, University of Cambridge, Cambridge, United Kingdom aff003;  Centre for Tuberculosis, National Institute for Communicable Diseases, Johannesburg, South Africa aff004;  National TB Reference Laboratory, National Tuberculosis Control Programme, Islamabad, Pakistan aff005;  National TB Reference Laboratory, Research Institute for Tropical Medicine, Muntinlupa City, Philippines aff006;  Republican Scientific and Practical Centre for Pulmonology and Tuberculosis, Minsk, Belarus aff007;  Main Medical Department, Ministry of Justice, Baku, Azerbaijan aff008;  National TB Reference Laboratory, Dhaka, Bangladesh aff009
Vyšlo v časopise: Prevalence and genetic profiles of isoniazid resistance in tuberculosis patients: A multicountry analysis of cross-sectional data. PLoS Med 17(1): e32767. doi:10.1371/journal.pmed.1003008
Kategorie: Research Article
doi: 10.1371/journal.pmed.1003008



The surveillance of drug resistance among tuberculosis (TB) patients is central to combatting the global TB epidemic and preventing the spread of antimicrobial resistance. Isoniazid and rifampicin are two of the most powerful first-line anti-TB medicines, and resistance to either of them increases the risk of treatment failure, relapse, or acquisition of resistance to other drugs. The global prevalence of rifampicin resistance is well documented, occurring in 3.4% (95% CI 2.5%–4.4%) of new TB patients and 18% (95% CI 7.6%–31%) of previously treated TB patients in 2018, whereas the prevalence of isoniazid resistance at global and regional levels is less understood. In 2018, the World Health Organization (WHO) recommended a modified 6-month treatment regimen for people with isoniazid-resistant, rifampicin-susceptible TB (Hr-TB), which includes rifampicin, pyrazinamide, ethambutol, and levofloxacin. We estimated the global prevalence of Hr-TB among TB patients and investigated associated phenotypic and genotypic drug resistance patterns.

Methods and findings

Aggregated drug resistance data reported to WHO from either routine continuous surveillance or nationally representative periodic surveys of TB patients for the period 2003–2017 were reviewed. Isoniazid data were available from 156 countries or territories for 211,753 patients. Among these, the global prevalence of Hr-TB was 7.4% (95% CI 6.5%–8.4%) among new TB patients and 11.4% (95% CI 9.4%–13.4%) among previously treated TB patients. Additional data on pyrazinamide and levofloxacin resistance were available from 6 countries (Azerbaijan, Bangladesh, Belarus, Pakistan, the Philippines, and South Africa). There were no cases of resistance to both pyrazinamide and levofloxacin among Hr-TB patients, except for the Philippines (1.8%, 95% CI 0.2–6.4) and Belarus (5.3%, 95% CI 0.1–26.0). Sequencing data for all genomic regions involved in isoniazid resistance were available for 4,563 patients. Among the 1,174 isolates that were resistant by either phenotypic testing or sequencing, 78.6% (95% CI 76.1%–80.9%) had resistance-conferring mutations in the katG gene and 14.6% (95% CI 12.7%–16.8%) in both katG and the inhA promoter region. For 6.8% (95% CI 5.4%–8.4%) of patients, mutations occurred in the inhA promoter alone, for whom an increased dose of isoniazid may be considered. The main limitations of this study are that most analyses were performed at the national rather than individual patient level and that the quality of laboratory testing may vary between countries.


In this study, the prevalence of Hr-TB among TB patients was higher than the prevalence of rifampicin resistance globally. Many patients with Hr-TB would be missed by current diagnostic algorithms driven by rifampicin testing, highlighting the need for new rapid molecular technologies to ensure access to appropriate treatment and care. The low prevalence of resistance to pyrazinamide and fluoroquinolones among patients with Hr-TB provides further justification for the recommended modified treatment regimen.

Klíčová slova:

Antibiotic resistance – Antimicrobial resistance – Drug therapy – Extensively drug-resistant tuberculosis – Genome sequencing – Isoniazid – Multi-drug-resistant tuberculosis – Tuberculosis


1. World Health Organization. Global Tuberculosis Report. 2019.

2. Zignol M, Dean AS, Falzon D, van Gemert W, Wright A, van Deun A, et al. Twenty Years of Global Surveillance of Antituberculosis-Drug Resistance. N Engl J Med. 2016;375: 1081–1089. doi: 10.1056/NEJMsr1512438 27626523

3. World Health Organization. WHO consolidated guidelines on drug-resistant tuberculosis treatment. 2019.

4. World Health Organization. Guidelines for treatment of drug-susceptible tuberculsois and patient care (2017 update). 2017. Available:

5. Getahun H, Matteelli A, Abubakar I, Aziz MA, Baddeley A, Barreira D, et al. Management of latent Mycobacterium tuberculosis infection: WHO guidelines for low tuberculosis burden countries. Eur Respir J. 2015; ERJ-01245-2015. doi: 10.1183/13993003.01245–2015

6. World Health Organization. Latent tuberculosis infection—updated and consolidated guidelines for programmatic management. 2018. Available:

7. Gegia M, Winters N, Benedetti A, van Soolingen D, Menzies D. Treatment of isoniazid-resistant tuberculosis with first-line drugs: a systematic review and meta-analysis. Lancet Infect Dis. 2017;17: 223–234. doi: 10.1016/S1473-3099(16)30407-8 27865891

8. World Health Organization. WHO treatment guidelines for isoniazid-resistant tuberculosis. 2018.

9. World Health Organization. WHO Global Tuberculosis Database. [cited 27 Jun 2019]. Available:

10. World Health Organization. Guidelines for surveillance of drug resistance in tuberculosis - 5th edition. 2015.

11. Zignol M, Dean AS, Alikhanova N, Andres S, Cabibbe AM, Cirillo DM, et al. Population-based resistance of Mycobacterium tuberculosis isolates to pyrazinamide and fluoroquinolones: results from a multicountry surveillance project. Lancet Infect Dis. 2016;16: 1185–1192. doi: 10.1016/S1473-3099(16)30190-6 27397590

12. Alikhanova N, Akhundova I, Seyfaddinova M, Mammadbayov E, Mirtskulava V, Rüsch-Gerdes S, et al. First national survey of anti-tuberculosis drug resistance in Azerbaijan and risk factors analysis. Public Health Action. 2014;4: S17–23. doi: 10.5588/pha.14.0049 26393092

13. Kamal SMM, Hossain A, Sultana S, Begum V, Haque N, Ahmed J, et al. Anti-tuberculosis drug resistance in Bangladesh: reflections from the first nationwide survey. Int J Tuberc Lung Dis. 2015;19: 151–156. doi: 10.5588/ijtld.14.0200 25574912

14. Skrahina A, Hurevich H, Zalutskaya A, Sahalchyk E, Astrauko A, van Gemert W, et al. Alarming levels of drug-resistant tuberculosis in Belarus: results of a survey in Minsk. Eur Respir J. 2012;39: 1425–1431. doi: 10.1183/09031936.00145411 22005924

15. Tahseen S, Qadeer E, Khanzada FM, Rizvi AH, Dean A, Van Deun A, et al. Use of Xpert(®) MTB/RIF assay in the first national anti-tuberculosis drug resistance survey in Pakistan. Int J Tuberc Lung Dis. 2016;20: 448–455. doi: 10.5588/ijtld.15.0645 26970152

16. Lim DR, Dean AS, Taguinod-Santiago MR, Borbe-Reyes A, Maurizio Cabibbe A, Zignol M, et al. Low prevalence of fluoroquinolone resistance among patients with tuberculosis in the Philippines: results of a national survey. Eur Respir J. 2018. doi: 10.1183/13993003.02571–2017

17. Ismail NA, Mvusi L, Nanoo A, Dreyer A, Omar SV, Babatunde S, et al. Prevalence of drug-resistant tuberculosis and imputed burden in South Africa: a national and sub-national cross-sectional survey. Lancet Infect Dis. 2018;18: 779–787. doi: 10.1016/S1473-3099(18)30222-6 29685458

18. Pavlenko E, Barbova A, Hovhannesyan A, Tsenilova Z, Slavuckij A, Shcherbak-Verlan B, et al. Alarming levels of multidrug-resistant tuberculosis in Ukraine: results from the first national survey. Int J Tuberc Lung Dis. 2018;22: 197–205. doi: 10.5588/ijtld.17.0254 29506617

19. World Health Organization. Updated interim critical concentrations for first-line and second-line DST. 2012.

20. Miotto P, Tessema B, Tagliani E, Chindelevitch L, Starks AM, Emerson C, et al. A standardised method for interpreting the association between mutations and phenotypic drug resistance inMycobacterium tuberculosis. Eur Respir J. 2017;50. doi: 10.1183/13993003.01354–2017

21. Zignol M, Cabibbe AM, Dean AS, Glaziou P, Alikhanova N, Ama C, et al. Genetic sequencing for surveillance of drug resistance in tuberculosis in highly endemic countries: a multi-country population-based surveillance study. Lancet Infect Dis. 2018. doi: 10.1016/S1473-3099(18)30073-2 29574065

22. Unitaid. Tuberculosis Diagnostic Technology Landscape. 5th edition. 2017. Available:

23. Isoniazid resistance levels of Mycobacterium tuberculosis can largely be predicted by high-confidence resistance-conferring mutations | Scientific Reports. [cited 7 Jun 2018]. Available:

24. Ghodousi A, Tagliani E, Karunaratne E, Niemann S, Perera J, Köser CU, et al. Isoniazid resistance in Mycobacterium tuberculosis is a heterogeneous phenotype comprised of overlapping MIC distributions with different underlying resistance mechanisms. Antimicrob Agents Chemother. 2019;63.

Článek vyšel v časopise

PLOS Medicine

2020 Číslo 1
Nejčtenější tento týden
Nejčtenější v tomto čísle
Zapomenuté heslo

Nemáte účet?  Registrujte se

Zapomenuté heslo

Zadejte e-mailovou adresu, se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.


Nemáte účet?  Registrujte se