TÜBERKÜLOZ HASTALARINDAN 2014-2022 YILLARI ARASINDA İZOLE EDİLEN MİKOBAKTERİLERİN ANTİ-TÜBERKÜLOZ İLAÇ DUYARLILIKLARI

Öz

Anti-tüberküloz (anti-TB) ilaç direnci, tedavi başarısını etkileyen başlıca faktörlerden olup bölgesel direnç eğilimlerinin analizi etkili veremle savaş politikalarının geliştirilmesine olanak sağlamaktadır. Bu çalışmada, bölgemizde son dokuz yılda tüberküloz (TB) hastalarından izole edilen mikobakterilerin anti-TB ilaç duyarlılıklarının araştırılması amaçlanmıştır. Malatya TB Tanı Laboratuvarında 2014-2022 yılları arasında çalışılan klinik örneklerin TB kültüründe üretilen izolatların ilaç duyarlılık verileri geriye yönelik olarak ilgili laboratuvarın elektronik veri kaynağından toplanıp analiz edildi. Tüberküloz kültürü Lowenstein Jensen besiyeri ve VersaTrek otomatize TB kültür ve duyarlılık cihazında (TREK Diagnostic Systems, ABD) yapıldı. İzolatların izoniazid (INH), rifampisin (RIF), pirazinamid (PZA), streptomisin (STR) ve etambutol (ETH) duyarlılıkları aynı otomatize sistemde çalışıldı. Dokuz yıllık çalışma süresince 415’i Mycobacterium tuberculosis kompleks (MTBC) ve 14’ü tüberküloz dışı mikobakteri (TDM) olmak üzere toplam 429 mikobakteri izolatının ilaç duyarlılık özellikleri incelendi. Çalışılan MTBC suşlarının 329’u (%79.2) tüm ilaçlara duyarlıydı ve yıllara göre bu oran %63 ila %86.4 arasında değişiyordu. Soyutlanan MTBC suşlarında en yüksek direnç 42 (%10.1) izolatla PZA ve 33 (%8) izolatla INH’a karşı iken, en düşük direnç 1 (%0.2) izolat ile EMB’ye karşı idi. Saptanan 14 TDM izolatının tamamı PZA ve INH direnci gösterirken, en düşük direnç 9 (%64.3) izolatla yine EMB’ye karşı oldu. On (%2.4) MTBC izolatı iki, 5 (%1.2) izolat ise üç anti-TB ilaca dirençli bulundu. Bu çalışmada, bölgemizin anti-TB ilaç direncinin ulusal direnç sıklığına göre daha düşük olduğu saptanmıştır. PZA direnç oranı yüksek bulunmakla birlikte, bu ilacın test edilmesinde bilinen teknik sorunlar ve intrinsik dirençli Mycobacterium bovis türünün ayrılmamış olması dikkate alınmalıdır. Gereksiz antimikrobiyal kullanımını, tedavinin erken terk edilmesini ve dirençli fenotiplerin toplumda yayılımını engelleyici önlemlerin güçlendirilmesi TB tedavisinin en önemli bileşeni olan anti-TB ilaç etkinliğinin korunmasına katkı sunacaktır.

Anahtar Kelimeler

• Antimikrobiyal direnç
• Anti-TB ilaç
• İzoniazid
• Rifampisin
• Tüberküloz

Anti-Tuberculosis Drug Susceptibility of the Mycobacteria Isolated from the Patients with Tuberculosis between 2014 and 2022

Öz

Anti-tuberculosis (anti-TB) drug resistance is one of the main factors affecting the success of treatment, and the analysis of regional resistance trends allows the development of effective tuberculosis (TB) control policies. In this study, it was aimed to investigate the anti-TB drug susceptibility of mycobacteria isolated from TB patients in our region in the last nine years. Drug susceptibility data of isolates grown in TB culture of clinical samples studied in Malatya TB Diagnostic Laboratory between 2014-2022 were collected retrospectively from the electronic data source of the relevant laboratory and analyzed. Tuberculosis culture was performed on Lowenstein Jensen medium and VersaTrek automated TB culture and susceptibility device (TREK Diagnostic Systems, USA). The isoniazid (INH), rifampicin (RIF), pyrazinamide (PZA), streptomycin (STR) and ethambutol (ETH) susceptibilities of the isolates were studied in the same automated system. During the nine-year of study period, drug susceptibility characteristics of a total of 429 mycobacteria strains including 415 Mycobacterium tuberculosis complex (MTBC) and 14 non-tuberculous mycobacteria (TDM) were investigated. Of the studied MTBC isolates, 329 (79.2%) were susceptible to all drugs and, the ratio varied between 63% and 86.4% during the study years. A total 42 (10.1%) of the isolated MTBC strains showed PZA and 33 (8%) INH resistance, the lowest resistance was detected against EMB with 1 (0.2%) isolate. While all 14 TDM isolates were resistant to PZA and INH, the lowest resistance was also against EMB with 9 (64.3%) isolates. Ten (2.4%) MTBC isolates were resistant to two and 5 (1.2%) isolates were resistant to three anti-TB drugs. In this study, it was determined that the anti-TB drug resistance of our region was lower than the national resistance frequency. Although the PZA resistance rate is high, known technical problems in testing this drug and the fact that the intrinsically resistant Mycobacterium bovis species have not been differentiated should be taken into consideration. Strengthening measures to prevent unnecessary antimicrobial use, early discontinuation of treatment and the spread of resistant phenotypes in the community will contribute to the preservation of the effectiveness of drugs, which are the most important components of TB treatment, for many years.

Anahtar Kelimeler

• Antimicrobial resistance
• Anti-TB drug
• Isoniazid
• Rifampicin
• Tuberculosis

Kaynakça

1. Ankrah AO, Glaudemans AWJM, Maes A, Van de Wiele C, Dierckx RAJO, Vorster M, Sathekge MM. Tuberculosis. Semin Nucl Med. 2018;48(2):108-30.
2. Conradie F, Diacon AH, Ngubane N, Howell P, Everitt D, Crook AM, et al. Treatment of highly drug-resistant pulmonary tuberculosis. N Engl J Med. 2020;382(10):893-902.
3. Dookie N, Rambaran S, Padayatchi N, Mohamed S, Naidoo K. Evolution of drug resistance in Mycobacterium tuberculosis: a review on the molecular determinants of resistance and implications for personalized care. J Antimicrob Chemother. 2018;73(5):1138-51.
4. Dorman SE, Nahid P, Kurbatova EV, Phillips PPJ, Bryant K, Dooley KE, et al. Four-month rifapentine regimens with or without moxifloxacin for tuberculosis. N Engl J Med. 2021;384(18):1705-18.
5. Glasauer S, Altmann D, Hauer B, Brodhun B, Haas W, Perumal N. First-line tuberculosis drug resistance patterns and associated risk factors in Germany, 2008-2017. PLoS One. 2019;14(6):e0217597.
6. Global Tuberculosis Report 2021. Geneva: World Health Organization; (2021).
7. Global Tuberculosis Report 2022. Geneva: World Health Organization; (2022).
8. Kalır N, Özkütük AA, Esen N, Özkütük N. Pyrazinamide monoresistance in clinical isolates. Turkish J Med Sci. 2013;43(1):163-7.

9. Poirel L, Yakupoğullari Y, Kizirgil A, Dogukan M, Nordmann P. VIM-5 metallo-beta-lactamase-producing Pseudomonas putida from Turkey. Int J Antimicrob Agents. 2009;33(3):287.
10. Reach the 3 Million. Find. Treat. Cure TB. World Health Organization 2014, Geneva. http://www.stoptb.org Ulaşım Tarihi: 03.08.2023)
11. Rocha DMGC, Magalhães C, Cá B, Ramos A, Carvalho T, Comas I, et al. Heterogeneous streptomycin resistance level among Mycobacterium tuberculosis strains from the same transmission cluster. Front Microbiol. 2021;12:659545.
12. Rocha DMGC, Viveiros M, Saraiva M, Osório NS. The neglected contribution of streptomycin to the tuberculosis drug resistance problem. Genes (Basel). 2021;12(12):2003.
13. Shi J, Su R, Zheng D, Zhu Y, Ma X, Wang S, et al. Pyrazinamide resistance and mutation patterns among multidrug-resistant Mycobacterium tuberculosis from Henan Province. Infect Drug Resist. 2020;13:2929-41.
14. The Global Plan to End TB 2023-2030. World Health Organization (2023). https://www.stoptb.org Ulaşım Tarihi: 03.08.2023
15. Tüberküloz Tanı ve Tedavi Rehberi, TC Sağlık Bakanlığı. Yayın No: 1129, Ankara, (2019).
16. Türkiye’de Verem Savaşı 2020 Raporu, T.C. Sağlık Bakanlığı Halk Sağlığı Genel Müdürlüğü. Yayın No: 1205. Ankara, (2021).
17. Unissa AN, Subbian S, Hanna LE, Selvakumar N. Overview on mechanisms of isoniazid action and resistance in Mycobacterium tuberculosis. Infection, Genetics and Evolution. 2016;45:474-92.
18. Yakupogullari Y, Ermis H, Kazgan Z, Otlu B, Bayindir Y, Gulbas G, et al. Diagnostic and treatment outcomes of patients with pulmonary tuberculosis in the first year of COVID-19 pandemic. East Mediterr Health J. 2022;28(9):682-9.
19. Whitfield MG, Soeters HM, Warren RM, York T, Sampson SL, Streicher EM, et al. A global perspective on pyrazinamide resistance: Systematic review and meta-analysis. PLoS One. 2015;10(7):e0133869.
20. WHO Consolidated Guidelines on Tuberculosis. Module 4: Treatment. Drug-Susceptible Tuberculosis Treatment. Geneva: World Health Organization; (2022).
21. Xu G, Liu H, Jia X, Wang X, Xu P. Mechanisms and detection methods of Mycobacterium tuberculosis rifampicin resistance: The phenomenon of drug resistance is complex. Tuberculosis (Edinb). 2021;128:102083. 81