1. 항결핵제 감수성시험의 정도관리 2009 년 7 월 3 일 결핵연구원 김창기

2. 배경 Emergence of resistant tuberculosis –Multidrug-resistant tuberculosis (MDR-TB) Resistant to INH and RIF –Extensively drug-resistant tuberculosis (XDR-TB) MDR-TB, resistant to any member of the quinolone family and at least one of the following second-line anti-TB injectable drugs: kanamycin, capreomycin, or amikacin

3. 국내 결핵의 내성 현황 Anti-Tuberculosis Drug Resistance in the World. 4 th global report, WHO/HTM/TB/2008.394

4. Given the underlying HIV epidemic in Africa, drug-resistant TB could have a major impact on mortality and requires urgent action on care and prevention XDR-TB related to district hospital, KwaZulu-Natal South Africa 2006 KZN 70% TB patients are HIV infected 53 of 544 TB patients defined as XDR-TB cases 44 tested, all were HIV (+) 52/53 patients died on average within 25 days, including those on ART 2 healthcare workers affected XDR-TB likely in bordering African countries

5. Czech Republic Ecuador Georgia Argentina Bangladesh Germany Republic of Korea Armenia Russian Federation South Africa Portugal Latvia Mexico Peru USA Brazil UK Sweden Thailand Chile Spain Islamic Republic of Iran China, Hong Kong SAR France Countries with XDR-TB confirmed cases

6. Of 17,690 isolates from 49 countries during 2000-2004 20% were MDR; 2% XDR XDR found in: USA: 4% of MDR Latvia: 19% of MDR S Korea: 15% of MDR XDR found in Southern Africa associated with HIV XDR-TB: extensively drug-resistant TB

7. Treatment Outcomes and Long-term Survival in Patients with Extensively Drug-resistant Tuberculosis Treatment OutcomesXDR-TB (n = 75) Other MDR-TB (n = 1,332) Total (n = 1,407) P Value Cure9 (12.0)416 (31.2)425 (30.2)<0.001 Treatment completion4 (5.3)89 (6.7)93 (6.6)0.647 Short-term treatment completion 9 (12.0)110 (8.3)119 (8.5)0.257 Failure12 (16.0)53 (4.0)65 (4.6)<0.001 Transfer out9 (12.0)99 (7.4)108 (7.7)0.148 Default12 (16.0)441 (33.1)453 (32.2)0.002 Death20 (26.7)124 (9.3)144 (10.2)<0.001 Treatment success22 (29.3)615 (46.2)637 (45.3)0.004 Relapse (n = 637) * 3/22 (13.6)54/615 (8.8)57/637 (8.9)0.436 Am J Respir Crit Care Med. 2008;178:1075-82

8. 항결핵제 감수성시험의 외부정도관리 해외 외부정도관리 프로그램 –College of American Pathologist (CAP) –WHO/IUATLD Supranational Reference Laboratory Network –US CDC Model Performance Evaluation Program 국내 외부정도관리 프로그램 – 항결핵제 감수성 정도관리 프로그램 운영 질병관리본부 용역과제임 2008 년부터 시행하고 있음.

9. CAP 항결핵제 정도관리

10. WHO/IUATLD 정도관리 프로그램 Supranational Reference Laboratory Network (SRLN) was formed in 1994 –To ensure optimal performance of the laboratories participating in the global project. The network has expanded since 2004; it now includes 26 laboratories in 6 WHO regions. Coordinating center: –The Prince Leopold Institute of Tropical Medicine in Antwerp, Belgium. A panel of 30 pretested and coded isolates is exchanged annually within the network for proficiency testing.

15. Format of the raw data for one round verified by the laboratory Strain identity known to Antwerp laboratory

16. Technical procedure to determine analysis set -Combine data from all rounds and laboratories -Sum number of valid results for each drug and round -Determine proportion with resistant vs susceptible result -Determine judicial result (sensitivity, specificity, efficiency): - >=80% identical result: gold standard - <80% identical result: strain excluded -Reproducibility: - Determine pairs with valid result - Determine proportion concordant

17. Definitions SensitivityProportion with true resistant results among those with a judicially defined resistant result SpecificityProportion with true susceptible results among those with a judicially defined susceptible result EfficiencyProportion with true resistant plus true susceptible results among the total with judicial results ReproducibilityProportion of pairs with an identical result among all pairs of results including discordant results, irrespective of the judicial result

18. ANTI-TUBERCULOSIS DRUG RESISTANCE IN THE WORLD Fourth Global Report WHO/HTM/TB/2008.394 The WHO/IUATLD Global Project on Anti-tuberculosis Drug Resistance Surveillance 2002-2007

19. PROFICIENCY TESTING ROUND 13 WITHIN THE SUPRANATIONAL LABORATORY NETWORK.

20. AVERAGE PERFORMANCE OF SRL NETWORK LABORATORIES OVER 5 ROUNDS

23. EMB INH RMP SM

24. Sensitivity in detecting resistance

25. Specificity in detecting resistance

26. Efficiency in detecting resistance

27. Reproducibility in detecting resistance

28. Comparative performance: 16 continuously participating vs 11 other laboratories

29. Comparison of trends in sensitivity, specificity, efficiency, and reproducibility among 16 continuously participating laboratories

30. Conclusions oThe judicial criterion has weaknesses: except for isoniazid, 10% or more of strains failed the criterion oThe performance is best for isoniazid and rifampicin. Results for streptomycin, and particularly for ethambutol are frequently unreliable oContinuously collaborating laboratories show persistent and reliable performance for isoniazid and rifampicin, some other laboratories perform dismally poor oAn alternative approach to the current judicial system must be identified oReplacing phenotypic with genotypic testing for rifampicin susceptibility must be given consideration

31. CDC 정도관리 Model Performance Evaluation Program (MPEP) –Since 1986, HIV and Tuberculosis test –DST 128 participants 80 (62.5%) health departments, 35 (27.3%) hospitals, 10 (7.8%) independent laboratories, and 3 (2.3%) other type of laboratories –Biosafety Levels BSL-3: 75 participants, BSL-2 facilities with level 3 containment practices: 42 BSL-2, 11 participants.

32. Figure 1: Distribution of the Annual Volume of M. tuberculosis Isolates Tested for Drug Susceptibility by Participating Laboratories in 2007.

33. Figure 2: Procedures Used by the Participating Laboratories for M. tuberculosis Drug Susceptibility Testing

34. Participant Results for M. tuberculosis, resistant to INH at 0.2 and 1.0 μg/ml and to SM at 2.0 and 10.0 μg/ml.

35. Participant Results for M. tuberculosis, resistant to RMP at 1.0 μg/ml

36. 결핵 감수성시험 정도관리 질병관리본부 용역과제로 2008 년부터 시작됨. 국내 7 개 기관을 대상으로 proficiency test 를 시행함. – 결핵연구원이 coordinating center 임 – 녹십자 의료재단, 서울의과학 연구소, 네오딘, 국립마산병원, 국립목포병 원, 서울서북병원 WHO SRLN 의 정도관리 체계를 따름. –30 개의 panel strain 을 발송함. –20 개는 중복균주임. 1 차 약제 4 종과 2 차 약제 중 kanamycin, amikacin, capreomycin, ofloxacin 결과를 분석하였음.

37. 감수성 정도관리 결과 Institute Drugs INHRMPSMEMBKMAMKCPMOFL A Sensitivity100 94.410072.7N/A 75 specificity10089.510089.5100N/A 100 B Sensitivity100 88.9100 81.875 specificity10089.510089.510095.8100 C Sensitivity100 72.245.590.910090.975 specificity100 D Sensitivity100 88.9100 N/A90.975 specificity100 94.7 N/A100 E Sensitivity100 90.9 N/A63.675 specificity100 89.5100N/A100

38. 결론 지속적인 내성의 증가로 정확한 감수성 시험의 중요성이 커지고 있음. 세계적으로 감수성시험의 정도관리에 많은 노력을 기울 이고 있음. 국내에서도 결핵에 대한 관심이 커지고 있고 검사분야에 서도 많은 변화가 있음. 국내 감수성시험 시행기관의 정도관리 및 교육 훈련이 강 화되어야 함. 향후 분자유전학적 방법을 이용한 신속내성검사와 액체 배지 감수성 시험에 대한 정도관리로 확대되어야 함.