Review of Respiratory Medicine - Volumen 22, Número 2 - June 22

Review Article

Practical Pharmacological Aspects of Drugs Used for the Treatment of Drug-Resistant Tuberculosis in Adults and Children

Aspectos farmacológicos prácticos de las drogas para el tratamiento de la tuberculosis drogorresistente en adultos y pediatría

ABSTRACT

The emergence of resistant strains of Mycobacterium tuberculosis to multiple drugs and the difficulties of their diagnosis and treatment constitute a challenge to global public health. To face this challenge, new anti-tuberculosis drugs, such as bedaquiline, pretomanid, and delamanid, as well as replacement drugs, such as fluoroquinolones, linezolid and clofazimine, are used. Based on the evidence provided by multicenter studies, drugs associated with a better prognosis of drug-resistant tuberculosis have been discovered and, recently, a new classification has been proposed, as well as new totally oral regimens. In this review, we describe current treatment regimens and practi­cal pharmacological aspects required when prescribing new drug-resistant tuberculosis treatment regimens.

Key words: Tuberculosis, Drug-resistance, MDR-TB, Pharmacology

RESUMEN

La emergencia de cepas resistentes de Mycobacterium tuberculosis a múltiples dro­gas, las dificultades de su diagnóstico y tratamiento constituyen un desafío a la salud pública mundial. Para afrontar esta situación, se emplean nuevas drogas antituber­culosis, como bedaquilina, pretomanid y delamanid, así como drogas repropuestas, como fluoroquinolonas, linezolid y clofazimina. Con base en la evidencia brindada por estudios multicéntricos, se han descubierto fármacos asociados a un mejor pronóstico de la tuberculosis drogorresistente y, recientemente, se ha propuesto una nueva clasifi­cación, así como nuevos esquemas totalmente orales. En esta revisión, describimos los esquemas de tratamiento actuales y los aspectos farmacológicos prácticos necesarios a la hora de la prescripción de los nuevos regímenes de tratamiento de la tuberculosis drogorresistente.

Palabras clave: Tuberculosis, Drogorresistencia, TB-MDR, Farmacología

Recibido: 12/09/2021

Aceptado: 02/12/2022

INTRODUCTION

The global threat of drug-resistant tuberculosis (DR-TB) has promoted the research of new treat­ment regimens, new drugs, and repurposed drugs¹ (not originally sold for TB, such as fluoroquino­lones, linezolid and clofazimine) together with the traditionally called “second-line drugs” for the purpose of improving the efficacy of treatment of these forms of the disease.

The objective of this review is to briefly analyze current treatment regimens according to interna­tional rules, and to describe dosages in adults and children, mechanisms of action, adverse reactions, and use in cases of renal and liver failure, preg­nancy and tuberculous meningitis, of available drugs to treat drug-resistant TB. Thorough review on DR-TB found in².

There are different DR-TB categories^3-5: mono­resistant TB, caused by strains of Mycobacterium tuberculosis (Mtb) and resistant to only one drug, the most concerning being monoresistance to isoniazid (Hr) and rifampicin (Rr); multidrug-resistant TB (MDR-TB), which shows resistance to at least isoniazid (H) and rifampicin (R); pre-extensively drug resistant TB (pre-XDR-TB), which is MDR and also shows resistance to one of the antituberculous fluoroquinolones (levofloxacin or moxifloxacin); and at last, extensively resistant (XDR-TB), which apart from being pre-XDR-TB, is also resistant to at least bedaquiline or linezolid (group A of the World Health Organization, WHO).

In 2018, the WHO published a new classifica­tion of drugs to be used for DR-TB, updated in 20206 (Table 1) and based on the meta-analysis of individual MDR-TB patients data published by Ahmad et al⁷.

Treatment regimens of Hr-TB, Rr-TB and MDR-TB

The treatment recommended by the international guidelines for Hr-TB is a 6-month regimen with four drugs, without initial phase: levofloxacin, pyrazinamide, rifampicin and ethambutol. Treat­ment duration is determined by the need to com­plete 6 months of levofloxacin^{6, 8}.

Rr-TB is a category that arose from the advent of the rapid molecular method for diagnosis called Xpert Mtb RIF, which detects in Mtb, with almost 100% specificity, the presence of the five most common mutations of the RpoB gene that explain resistance to R⁹. Given the fact that approximately 80% of the Rr strains show additional resistance to H¹⁰ and that a first-line drug for the treatment of TB has been lost, Rr-TB should be treated as MDR-TB^{6, 8}.

According to new recommendations, MDR-TB can be treated with a 100% oral regimen including the three drugs of the WHO Group A (bedaquiline, linezolid, fluoroquinolone), together with one or two drugs from Group B (cycloserine or clofazi­mine). Bedaquiline is administered the first 6 months (see Table 2), and the other three or four drugs are given throughout the whole treatment, which lasts 18 months (it may be shortened in mild cases). Group C drugs would be left as replacement of Groups A and B if they can’t be used due to resistance or adverse reactions^{6, 8}.

Alternatives to isoniazid and rifampicin for the treatment of DR-TB

Tables 2 and 3 show every drug, mechanisms of action, dosage in adults and children, most common adverse reactions, use in renal and liver failure and pregnancy and passage into CSF (ce­rebrospinal fluid), a fundamental element in the treatment of tuberculous meningitis.

Treatment of XDR-TB^11-13

As seen in its definition, it implies resistance to at least H, R, one fluoroquinolone (levo or moxi­floxacin) and bedaquiline or linezolid. From that minimum base of the definition (which already cre­ates a complicated situation but still leaves other therapeutic options), resistance can be extended practically to all anti-TB drugs. Also, the antibio­gram of multi-treated patients doesn’t correlate very well with the clinical picture, as in MDR-TB, and it is more common to find differences between the phenotypic and genotypic methods. So, it is important to ask the patients detailed questions regarding their previous treatments and clinical and bacteriological responses. To sum up, the design of a regimen for XDR-TB is individualized, and no guidelines can be provided as in other forms of DR-TB. Regimens are indicated with drugs that show persistent antibiogram sensitivity plus those that weren’t previously used, trying to get a minimum number of potentially effective drugs (3 or 4). In an effort to improve the diagnosis of these patients, the bedaquiline-delamanid combi­nation has been used, as well as bedaquiline alone, for one year of treatment. New regimens such as BPaL (bedaquiline, pretomanid and linezolid) will provide evidence on the efficacy of the new drug, pretomanid, under these circumstances¹⁴. The prognosis of these patients is worse than in other forms of DR-TB.

CONCLUSIONS

In this brief review of the practical pharmacologi­cal aspects of drugs for the treatment of DR-TB in adults and children, we show drugs (such as bedaquiline, delamanid and pretomanid) that have been specifically studied as antituberculosis drugs, something that hadn’t occurred since the discovery of rifampicin, half a century ago. This is an auspicious fact, together with the evidence showing the activity of drugs that allow a 100% oral treatment in children and adults. There is availability of regimens based on published evidence for the treatment of monoresistant and multi-drug resistant TB. Unfortunately, XDR-TB, the most severe mycobacterial resistance situation, is still a complex problem in terms of therapeutic and prognostic aspects.

Conflict of interest

Authors declare there isn’t any conflict of interest in rela­tion to this publication.

REFERENCES

1. Rossato Silva D, Dalcolmo M, Tiberi S, et al. New and repurposed drugs to treat multidrug- and extensively drug-resistant tuberculosis. J Bras Pneumol. 2018; 44: 153-60. https://doi.org/10.1590/S1806-37562017000000436

2. Palmero DJ, Lagrutta L, Inwentarz SJ, Vescovo M, Aidar OJ, González Montaner PJ. Tratamiento de la tuberculosis drogorresistente en adultos y niños. Revisión narrativa. Medicina (Buenos Aires). 2021. E-pub: https://www.me­dicinabuenosaires.com/adelantos/

3. Organización Mundial de la Salud (OMS). Definiciones y marco de trabajo para la notificación de Tuberculosis-revisión 2013 (actualizado en diciembre de 2014). WHO/ HTM/TB/2013.2. ISBN 978 92 4 350534 3.

4. World Health Organization (WHO). Meeting report of the WHO expert consultation on the definition of extensively drug-resistant tuberculosis, 27-29 October 2020. Geneva: World Health Organization; 2021. CC BY-NC-SA 3.0 IGO. En: https://www.who.int/publications/i/item/meeting-report-of-the-who-expert-consultation-on-the-definition-of-extensively-drug-resistant-tuberculosis

5. Roelens M, Migliori GB, Rozanova L, et al. Evidence-based Definition for Extensively Drug-resistant Tuberculosis. Am J Respir Crit Care Med. 2021; 204): 713-22. https://doi.org/10.1164/rccm.202009-3527OC.

6. WHO. Consolidated guidelines on tuberculosis. Mod­ule 4: treatment - drug-resistant tuberculosis treat­ment. Geneva: World Health Organization; 2020. CC BY-NC-SA 3.0 IGO. En: https://www.who.int/publications/i/item/9789240007048

7. Ahmad N, Ahuja SD, Akkerman OW, et al. Collaborative Group for the Meta-Analysis of Individual Patient Data in MDR-TB treatment–2017. Treatment correlates of successful outcomes in pulmonary multidrug-resistant tuberculosis: an individual patient data meta-analysis. Lancet. 2018; 392: 821-34. https://doi.org/10.1016/S0140-6736(18)31644-1

8. Nahid P, Mase SR, Migliori GB, et al. Treatment of Drug- Resistant Tuberculosis. An Official ATS/CDC/ERS/IDSA Clinical Practice Guideline. Am J Respir Crit Care Med. 2019; 200: e93-e142. https://doi.org/10.1164/rccm.201909-1874ST.

9. WHO. WHO consolidated guidelines on tuberculosis. Module 3: diagnosis – rapid diagnostics for tuberculosis detection. 2020. CC BY-NC-SA 3.0 IGO. En: https://www.who.int/publications/i/item/9789240029415

10. WHO. Global tuberculosis report 2021. Geneva: World Health Organization; 2021. CC BY-NC-SA 3.0 IGO. En: https://www.who.int/publications/i/item/9789240037021

11. Hewison C, Bastard M, Khachatryan N, et al. Is 6 months of bedaquiline enough? Results from the compassion­ ate use of bedaquiline in Armenia and Georgia. Int J Tub Lung Dis. 2018;22:766-72. https://doi.org/10.5588/ijtld.17.0840

12. Conradie F, Diacon AH, Ngubane N, et al. Nix-TB Trial Team. Treatment of Highly Drug-Resistant Pulmonary Tuberculosis. N Engl J Med. 2020; 382: 893-902. https://doi.org/10.1056/NEJMoa1901814

13. Pecora F, Dal Canto G, Veronese P, Esposito S. Treatment of Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis in Children: The Role of Bedaquiline and Delamanid. Microorganisms. 2021; 9: 1074. https://doi.org/10.3390/microorganisms9051074

14. Conradie F, Everitt D, Olugbosi M, et al. High rate of successful outcomes treating highly resistant TB in the ZeNix study of pretomanid, bedaquiline and alternative doses and durations of linezolid. Abstract OALB01LB02. 11th IAS Conference on HIV Science Abstract Supplement JIAS 2021;24(S4):e25755-Page 70 En: https://onlinelibrary.wiley.com/doi/epdf/10.1002/jia2.25755; consultado octubre 2021.

15. Sentinel project. Management of Drug-Resistant Tuberculosis in Children: A Field Guide. Boston, USA: The Sentinel Project for Pediatric Drug-Resistant Tuberculosis; November 2018, Fourth edition. En: http://sentinel-project.org/2019/04/10/sentinel-field-guide/; consultado octubre 2021.

16. Dheda K, Gumbo T, Maartens G, et al. The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incur­able tuberculosis. Lancet Respir Med. 2017; S2213-2600: 30079-6. v https://doi.org/10.1016/S2213-2600(17)30079-6

17. WHO. Companion Handbook to the WHO Guidelines for the Programmatic Management of Drug-Resistant Tuber­culosis. Geneva: World Health Organization; 2014. WHO/ HTM/TB/2014.11. En: https://apps.who.int/iris/bitstream/handle/10665/130918/9789241548809_eng.pdf; consultado octubre 2021.

18. Lange C, Dheda K, Chesov D, Mandalakas AM, Udwadia Z, Horsburgh CR Jr. Management of drug-resistant tuber­culosis. Lancet. 2019; 394: 953-66. https://doi.org/10.1016/S0140-6736(19)31882-3.

19. Huynh J, Marais BJ. Multidrug-resistant tuberculosis infection and disease in children: a review of new and re­purposed drugs. Ther Adv Infect Dis. 2019; 6: 1-16. https://doi.org/10.1177/2049936119864737.

20. WHO. Rapid communication on updated guidance on the management of tuberculosis in children and adolescents. Geneva: World Health Organization; 2021. Licence: CC BY-NC-SA 3.0 IGO. En: https://www.who.int/publications/i/item/9789240033450

21. Seddon JA, Wilkinson R, van Crevel R, et al. Knowledge gaps and research priorities in tuberculous meningitis. Wellcome Open Res. 2019; 4: 188. https://doi.org/10.12688/wellcomeopenres.15573.1

22. Wilkinson RJ, Rohlwink U, Misra UK, et al. Tuberculous Meningitis International Research Consortium: Tubercu­lous meningitis. Nat Rev Neurol. 2017; 13: 581-98. https://doi.org/10.1038/nrneurol.2017.120.

23. Palmero D, González Montaner P, Cufré M, García A, Vesco­vo M, Poggi S. First series of patients with XDR and pre- XDR TB treated with regimens that included meropenen-clavulanate in Argentina. Arch Bronconeumol. 2015; 51: e49-52. https://doi.org/10.1016/j.arbres.2015.03.012

24. Tiberi S, D’Ambrosio L, De Lorenzo S, et al. Ertapenem in the treatment of multidrug-resistant tuberculosis: first clinical experience. Eur Respir J. 2016; 47: 333-6. https://doi.org/10.1183/13993003.01278-201