Korean Guidelines for Tuberculosis

Third Edition, 2017

Joint Committee for the Revision of Korean Guidelines for Tuberculosis

Korea Centers for Disease Control and Prevention

11-1352159-000765-14

ISBN 978-89-6838-340-3(93510)

978-89-6838-341-0(95510)

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iv

(List of abbreviation) vi

I. 1

1. 1

2. X 3

3. 5

3.1. 5

3.2. 7

3.3. 8

3.4. 10

3.4.1. 10

3.4.2. 11

3.5. Xpert MTB/RIF 14

4. 16

5. 17

5.1. 17

5.2. ( ) 18

5.2.1. 19

5.2.2. 19

6. 21

6.1. 21

6.2. 21

6.3. 21

6.4. 21

II. 23

1. 23

1.1. 25

1.2. (isonicotinic acid hydrazide, INH, H) 27

1.3. (rifamycin) 27

1.4. (ethambutol, EMB, E) 28

1.5. (pyrazinamide, PZA, Z) 28

1.6. (injectable drugs) 29

1.7. (fluoroquinolones) 30

1.8. (thioamide) 30

1.9. (cycloserine, CS) 31

1.10. (p-aminosalicyclic acid, PAS) 31

1.11. (linezolid, Lzd) 31

1.12. (delamanid, Dlm) 32

1.13. (bedaquiline, Bdq) 32

1.14. (clofazimine, Cfz) 33

1.15. (amoxicillin-clavulanic acid, carbapenem) 33

1.16. (macrolides) 33

2. 34

3. 35

3.1. 35

3.1.1. 35

3.1.2. 35

3.1.3. 36

3.2. 36

3.2.1. 37

3.2.2. 37

3.2.3. 40

3.2.4. 40

4. 44

4.1. 44

4.2. 45

4.3. 46

4.4. 47

4.5. (drug fever) 47

III. 48

1. (Retreatment) 48

1.1. 48

1.2. 49

1.2.1. 49

1.2.2. 50

1.2.3. 50

2. 51

2.1. 51

2.2. 52

2.3. 53

3. (multidrug-resistant: MDR) 54

3.1. 55

3.2. 56

3.3. 58

3.4. 60

3.5. 67

3.6. 68

3.7. (Shorter MDR-TB treatment regimen) 68

4. 71

4.1. 71

4.2. 72

IV. 80

1. 80

1.1. 80

1.2. 81

2. 83

2.1. 2 84

2.2. 1 84

2.3. 84

3. 86

V. (HIV) 89

1. HIV 90

1.1. 90

1.2. HIV 91

1.3. 91

1.4. (immune reconstitution inflammatory syndrome, IRIS) 92

2. HIV 95

2.1. 95

2.2. 96

VI. 98

1. 98

2. 101

3. 104

4. 106

5. 109

6. 113

7. 115

8. 117

9. 119

10. 120

VII. 122

1. 122

1.1. 123

1.2. 123

1.3. 123

1.4. 124

2. 125

2.1. 125

2.2. 126

2.3. 127

2.4. 128

2.5. Xpert MTB/RIF 128

2.6. ( ) 128

3. 131

3.1. 131

3.2. 132

3.3. 135

3.4. 135

3.5. 136

4. 138

4.1. 138

4.2. 140

4.3. 141

4.4. 146

5. (BCG) 152

5.1. 152

5.2. 152

5.3. 153

5.4. 153

5.5. ( ) 153

5.6. 155

5.7. 156

VIII. 158

1. 158

2. 160

2.1. 160

2.2. 160

3. 165

3.1. 165

3.2. 169

4. 173

4.1. 173

4.2. , X, LTBI 175

4.3. 175

4.4. 176

4.5. 177

4.6. 177

5. TNF 179

5.1. TNF 179

5.2. TNF 181

5.3. TNF 182

6. 184

7. 188

IX. 191

1. 191

2. (contact investigation) 192

2.1. (infectivity) 192

2.2. 193

2.3. 193

2.4. 193

2.5. 194

2.6. 2 195

2.7. 196

2.8. 196

3. 198

3.1. 198

3.2. 198

3.3. - (Private-Public Mix, PPM) 199

4. 201

4.1. 201

4.2. 202

4.3. 203

4.4. 204

206

1. 206

2. () 214

3. 219

4. 3 222

5. 229

i

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vi

(List of abbreviation)

(isoniazid, INH, H)

(rifampin, rifampicin, RIF, R)

(ethambutol, EMB, E)

(pyrazinamide, PZA, Z)

(streptomycin, S)

(kanamycin, Km)

(amikacin, Am)

(cycloserine, Cs)

(prothionamide, Pto)

(p-aminosalicylic acid, PAS)

(levofloxacin, Lfx)

(moxifloxacin, Mfx)

(rifabutin, Rfb)

(rifapentin, RPT)

(capreomycin, Cm)

(linezolid, Lzd)

(delamanid, Dlm)

(bedaquiline, Bdq)

(clofazimine, Cfz)

(imipenem, Ipm)

(meropenem, Mfm)

(amoxicillin/clavulanate, Amx-Clv)

vii

(extensively drug-resistant tuberculosis, XDR-TB)

(multidrug-resistant tuberculosis, MDR-TB)

(immune reconstitution inflammatory syndrome, IRIS)

(nontuberculous mycobacterium, NTM)

(human immunodeficiency virus, HIV)

(interferon-gamma releasing assay, IGRA)

(latent tuberculosis infection, LTBI)

(tuberculin skin test, TST)

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1. Zumla A, Raviglione M, Hafner R, von Reyn CF. Tuberculosis. N Engl J Med 2013;368:745-55.

2. World Health Organization. International standards for tuberculosis care, 3rd edition. 2014.

3. Migliori GB, Zellweger JP, Abubakar I, Ibraim E, Caminero JA, De Vries G, et al. European

union standards for tuberculosis care. Eur Respir J 2012;39:807-19.

3

2. X

. X (IA), X (ID).

. X X (IIA).

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1. Jeong YJ, Lee KS. Pulmonary tuberculosis: up-to-date imaging and management. AJR Am J

Roentgenol 2008;191:834-44.

2. Rozenshtein A1, Hao F, Starc MT, Pearson GD. Radiographic appearance of pulmonary

tuberculosis: dogma disproved. AJR Am J Roentgenol 2015;204:974-8.

3. Jones BE, Ryu R, Yang Z, Cave MD, Pogoda JM, Otaya M, Barnes PF. Chest radiographic

findings in patients with tuberculosis with recent or remote infection. Am J Respir Crit Care

Med 1997;156:1270-3.

4. Geng E, Kreiswirth B, Burzynski J, Schluger NW. Clinical and radiographic correlates of pri-

mary and reactivation tuberculosis: a molecular epidemiology study. JAMA 2005;293:2740-5.

5

3.

1.

. 2, 3 (IA).

. , 24 (IIIA).

(Mycobacterium tuberculosis)

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(induced sputum) ,

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, 24 .

(nontuberculous mycobacteria, NTM)

.

1. World Health Organization. Fluorescent light-emitting diode (LED) microscopy for diagnosis

of tuberculosis: policy statement. Geneva: World Health Organization, 2011.

2. Harries A. What is the additional yield from repeated sputum examinations by microscopy

and culture? In: Frieden TR, editor. Tomans tuberculosis. Case detection, treatment and

monitoring 2nd ed: World Health Organization; 2004.

3. World Health Organization. Same-day diagnosis of tuberculosis by microscopy: WHO policy

statement. Geneva: World Health Organization, 2011.

4. Davis JL, Cattamanchi A, Cuevas LE, Hopewell PC, Steingart KR. Diagnostic accuracy of

same-day microscopy versus standard microscopy for pulmonary tuberculosis: a systematic

review and meta-analysis. Lancet Infect Dis 2013;13:147-54.

7

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.

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1. Long R, Ellis E. Introducing the sixth edition of the Canadian Tuberculosis Standards. Can J

Infect Dis Med Microbiol 2007;18:283-4.

2. Long R. Canadian Tuberculosis Standards. 6th ed. Ottawa: Canadian Lung Association and

Public Health Agency of Canada, 2007.

3. Clinical and Laboratory Standards Institute (CLSI). Laboratory detection and identification of

mycobacteria. Document M48-A. CLSI, Wayne, PA., 2008

4. Leber AL. Clinical microbiology procedures handbook, 4th ed. ASM Press, Washington, DC.,

2016

5. Jorgensen JH, Pfaller MA. Manual of clinical microbiology. 11th ed. ASM Press, Washington

DC., 2016

3.

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(M. tuberculosis-polymerase chain reaction, TB-PCR)

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1. Long R. Canadian Tuberculosis Standards. 6th ed. Ottawa: Canadian Lung Association and

Public Health Agency of Canada, 2007.

2. American Thoracic Society. Diagnostic standards and classification of tuberculosis in adults

and children. Am J Respir Crit Care Med 2000;161:1376-95.

3. British National Institute for Health and Clinical Excellence. Tuberculosis. NICE guideline.

London, UK: NICE, 2016.

10

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(spontaneous mutation) 104-

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1. Zhang Y, Yew WW. Mechanisms of drug resistance in Mycobacterium tuberculosis. Int J

Tuberc Lung Dis 2009;13:1320-30.

2. Caminero JA, ed. Guidelines for the clinical and operational management of drug-resistant

tuberculosis. Paris, France: International Union Against Tuberculosis and Lung Disease, 2013.

3. World Health Organization. Treatment of tuberculosis: guidelines, 4th ed. WHO/HTM/

TB/2009.420, 2010.

4. Bai GH, Park YK, Choi YW, Bai JI, Kim HJ, Chang CL, et al. Trend of anti-tuberculosis drug

resistance in Korea, 1994-2004. Int J Tuberc Lung Dis 2007;11:571-6.

5. Park YS, Hong SJ, Boo YK, Hwang ES, Kim HJ, Cho SH, et al. The national status of

tuberculosis using nationwide medical records survey of patients with tuberculosis in Korea.

Tuberc Respir Dis (Seoul) 2012;73:48-55.

6. Mitchison DA. Drug resistance in tuberculosis. Eur Respir J 2005;25:376-9.

7. Kim SJ. Drug-susceptibility testing in tuberculosis: methods and reliability of results. Eur

Respir J 2005;25:564-9.

8. Lewinsohn DM, Leonard MK, LoBue PA, Cohn DL, Daley CL, Desmond E, et al. Official

American Thoracic Society/Infectious Diseases Society of America/Centers for Disease

Control and Prevention Clinical Practice Guidelines: Diagnosis of tuberculosis in adults and

children. Clin Infect Dis 2017;64:e1-e33.

9. World Health Organization. WHO treatment guidelines for drug-resistant tuberculosis: 2016

updates, 2016.

10. Ramaswamy S, Musser JM. Molecular genetic basis of antimicrobial agent resistance in

Mycobacterium tuberculosis: 1998 update. Tuber Lung Dis 1998;79:3-29.

11. Van Deun A, Aung KJ, Hossain A, de Rijk P, Gumusboga M, Rigouts L, de Jong BC. Disputed

rpoB mutations can frequently cause important rifampicin resistance among new tuberculosis

patients. Int J Tuberc Lung Dis. 2015;19:185-90.

12. World Health Organization. Policy guidance: The use of molecular line probe assays for the

detection of resistance to second-line anti-tuberculosis drugs, 2016.

14

5. Xpert MTB/RIF

. Xpert MTB/RIF (IA).

. HIV Xpert MTB/RIF (IA).

. Xpert MTB/RIF (IIB).

. (IIB).

. Xpert MTB/RIF (IIB).

Xpert MTB/RIF ( Xpert) (real-time PCR) DNA

, 2

.1 Xpert .

. ,

. Xpert

.

, .2

. . Xpert

98%, 68%

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predictive value) . 15% Xpert

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Xpert .

1. Weyer K, Mirzayev F, Migliori GB, Van Gemert W, D'Ambrosio L, Zignol M, et al. Rapid

molecular TB diagnosis: evidence, policy making and global implementation of Xpert MTB/

RIF. Eur Respir J 2013;42:252-71.

2. World Health Organization. Policy update: Automated real-time nucleic acid amplification

technology for rapid and simultaneous detection of tuberculosis and rifampicin resistance:

Xpert MTB/RIF assay for the diagnosis of pulmonary and extrapulmonary TB in adults and

children, 2013.

3. Steingart KR, Schiller I, Horne DJ, Pai M, Boehme CC, Dendukuri N. Xpert MTB/RIF assay

for pulmonary tuberculosis and rifampicin resistance in adults. Cochrane Database Syst Rev

2014 Jan 21;(1):CD009593.

4. Lewinsohn DM, Leonard MK, LoBue PA, Cohn DL, Daley CL, Desmond E, et al. Official

American Thoracic Society/Infectious Diseases Society of America/Centers for Disease

Control and Prevention Clinical Practice Guidelines: Diagnosis of tuberculosis in adults and

children. Clin Infect Dis 2017;64:e1-e33.

5. World Health Organization. WHO treatment guidelines for drug-resistant tuberculosis: 2016

updates, 2016.

16

4.

. (IIA).

,

, .1

. , , ,

.

.

, .

2-6

.2,3

, (paradoxical

response) .

.4

1. Jagirdar J, Zagzag D. Pathology and insights into pathogenesis of tuberculosis. In: Rom WN, Garay

SM, editors. Tuberculosis. 2nd ed. Philadelphia: Lippincott Williams & Wilkins; 2004. p. 323-44.

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diagnosis of pulmonary tuberculosis. Eur Respir J 2010;35:851-7.

3. Lee HS, Park KU, Park JO, Chang HE, Song J, Choe G. Rapid, sensitive, and specific detection

of Mycobacterium tuberculosis complex by real-time PCR on paraffin-embedded human

tissues. J Mol Diagn 2011;13:390-4.

4. Golden MP, Vikram HR. Extrapulmonary tuberculosis: an overview. Am Fam Physician

2005;72:1761-8.

17

5.

1.

. X (IIIB).

. (IIIB).

X . X

,

.1-8 (computed tomography, CT) .1 X

, ,

.1

X .3-5 CT , CT X

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( ; tree-in-bud appearance)

, , , (bronchopleural fistula) X

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CT

,

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CT X . CT

.

18

1. Woodring JH, Vandiviere HM, Fried AM, Dillon ML, Williams TD, Melvin IG. Update: the

radiographic features of pulmonary tuberculosis. AJR Am J Roentgenol 1986;146:497-506.

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early active disease and sequential change with antituberculous therapy. Radiology

1993;186:653-60.

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in miliary lung disease. J Comput Assist Tomogr 1992;16:384-90.

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of miliary tuberculosis. J Comput Assist Tomogr 1994;18:862-6.

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accuracy of chest radiography. Chest 1996;110:339-42.

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children: evaluation with CT. AJR Am J Roentgenol 1997;168:1005-9.

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associated with pulmonary tuberculosis in patients with human immunodeficiency virus

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Br J Radiol 2006;79:999-1000.

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lymphadenitis: CT manifestations. Radiology 1987;164:115-9.

2. ( )

. (ID).

. (IB).

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(tuberculin skin test, TST)

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HIV 10%

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2)

TST . 2000 IGRA

.7 T

.

QuantiFERON-TB Gold In-Tube (Qiagen) T-SPOT.TB (Oxford Immunotec) .

QuantiFERON-TB Gold In-Tube (ESAT-6, CFP-10, TB7.7) ,

(Nil), (Mitogen) 16-24 enzyme-

linked immunosorbent assay (ELISA) . 0.35 IU

(international unit)/ml , 0.5 IU/

ml (indeterminate) . T-SPOT.TB

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spot .

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IGRA TST

. TST .8,9

1. Mazurek GH, Jereb J, Vernon A, LoBue P, Goldberg S, Castro K, et al. Updated guidelines

for using interferon gamma release assays to detect Mycobacterium tuberculosis infection -

United States, 2010. MMWR Recomm Rep 2010;59:1-25.

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performance in pulmonary and extrapulmonary tuberculosis. PLoS One 2012;7:e32652.

3. Fan L, Chen Z, Hao XH, Hu ZY, Xiao HP. Interferon-gamma release assays for the diagnosis

of extrapulmonary tuberculosis: a systematic review and meta-analysis. FEMS Immunol Med

Microbiol 2012;65:456-66.

4. Sester M, Sotgiu G, Lange C, Giehl C, Girardi E, Migliori GB, et al. Interferon-gamma release

assays for the diagnosis of active tuberculosis: a systematic review and meta-analysis. Eur

Respir J 2011;37:100-11.

5. Yan L, Xiao H, Han M, Zhang Q. Diagnostic value of T-SPOT.TB interferon-gamma release

assays for active tuberculosis. Exp Ther Med. 2015;10(1):345-51

6. Zhou XX, Liu YL, Zhai K, Shi HZ, Tong ZH. Body fluid interferon-gamma release assay for

diagnosis of extrapulmonary tuberculosis in adults: a systematic review and meta-analysis.

Sci Rep. 2015;5:15284.

7. Mazurek GH, LoBue PA, Daley CL, Bernardo J, Lardizabal AA, Bishai WR, et al. Comparison

of a whole-blood interferon gamma assay with tuberculin skin testing for detecting latent

Mycobacterium tuberculosis infection. JAMA 2001;286:1740-7.

8. Dheda K, Barry CE 3rd, Maartens G. Tuberculosis. Lancet 2016;387:1211-26.

9. Pai M, Behr MA, Dowdy D, Dheda K, Divangahi M, Boehme CC, et al. Tuberculosis. Nat Rev

Dis Primers 2016;2:16076.

21

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5

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(Delamanid, Dlm)

(Bedaquiline, Bdq)

(Clofazimine, Cfz)

(Imipenem/cilastatin, Ipm), (Meropenem, Mpm)

(Amoxicillin/clavulanate, Amx-Clv)

(High dose isoniazid, Hh#)

* HIV #16-20 mg/kg/day

25

) .2 , WHO

5

( 1).

6

.

,

.

1.

2 .

(ideal body weight) .

.

30 2

.

2. ( )*

( )

Isoniazid 5 mg/kg (300 mg) ,

300 mg

, ,

Rifampin 10 mg/kg (600 mg) ,

450 mg (50 kg)

600 mg (50 kg)

,

(flu-like syndrome),

,

, ,

Rifabutin 5 mg/kg (300 mg) ,

300 mg

,

Ethambutol 15-20 mg/kg

(1,600 mg)

, (

)

Pyrazinamide 20-30 mg/kg

(2,000 mg)

,

1,000 mg (50 kg)

1,500 mg (50-70 kg)

2,000 mg (70 kg)

, ,

26

2. Continued

( )

Kanamycin

Amikacin

Streptomycin

Capreomycin

50

: 15 mg/kg (1,000 mg)

50

: 10 mg/kg (750 mg)

, ,

Levofloxacin

Moxifloxacin

750-1,000 mg

400 mg

, , , ,

Linezolid 600 mg , , ,

,

Clofazimine 100-200 mg 2 200 mg ,

100 mg

,

,

, ,

Cycloserine 15 mg/kg

(1,000 mg)

2,

500 mg (50 kg)

750 mg (50-70 kg)

750-1,000 mg (70 kg)

,

Prothionamide 15 mg/kg

(1,000 mg)

2,

500 mg (50 kg)

750 mg (50-70 kg)

750-1,000 mg (70 kg)

,

Bedaquiline 2 400 mg,

22 200 mg

3

(QT ),

, , ,

Delamanid 200 mg 100 mg 2,

,

(QT ),

PAS (p-amino-

salicylic acid)

150 mg/kg (12 g) 3,

3.3 g (pack), 3

, , ,

,

Imipenem-cilastatin 1,000 mg, 2, , ,

Meropenem 1,000 mg, 2, ,

3-4 125 mg

clavulanate .

, ,

Amoxicilin-

clavulanate

Amoxicillin 1,000 mg

clavulanate 125 mg 2

, , ,

*Modified from reference 2. .

27

2. (isonicotinic acid hydrazide, INH, H)

(bactericidal effect)

. 70% (rapid acetylator)

50 kg , 400 mg ,

400 mg . 300 mg

400 mg 3 300 mg

(IIA).1,4

(pyridoxine: vitamin B6) (peripheral

neuropathy) (tingling sensation) .

(10-50 mg/day) .

, , , , , , .

( ).

3. (rifamycin)

(rifampin, RIF), (rifabutin, Rfb) (rifapentine, RPT) .

.

. .

cytochrome P-450 system (inducer)

.

(therapeutic margin)

.

(quinidine, phenytoin), (warfarin), , (glucocorticoids), ,

(sulfonylurea) .

prothrombin time

, 2-3 .

50%

2 .

28

.

cytochrome P-450 system

7-14 . ,

2 .

HIV

. (80%),

. 100%

.

4. (ethambutol, EMB, E)

(optic neuropathy) .

, (red-green blindness) . 2

.

. 15 mg/kg/day

, (25 mg/

kg/day) (renal insufficiency patient) .

.

5. (pyrazinamide, PZA, Z)

(early inflammatory site) (caseous foci)

(acid environment)

. 2 .

.

40% , ,

29

. 2

(nonsteroid anti-inflammatory drug) (symptomatic therapy) .

.

pyrazinoic acid

(hyperuricemia) (acute gouty arthritis) .

(flushing) (photo-

sensitivity) . ,

.

6. (injectable drugs)

(aminoglycosides) .

(kanamycin), (amikacin), (streptomycin)

. (capreomycin)

(polypeptide)

. , . 4

MIC (minimal inhibitory concentration) .

.

.

( )

.

1 5-7 2-4

1 2-3 .

(cochlear toxicity, vestibular toxicity), (nephrotoxicity) .

(circumoral paresthesia), ,

. , .

30

7. (fluoroquinolones)

DNA .

.

(ciprofloxacin), (ofloxacin)

(levofloxacin)

, .5

, 3

.6,7

, 30%

,

,8 .

,

(IIIB).1 ,

2 .

, .

.5

, QT QT

.

8. (thioamide)

mycolic acid .

(ethionamide) (prothionamide)

.

30% . (metallic taste), , ,

, .

250 mg 250 mg 2

31

. .

, (p-aminosalicylic acid, PAS) . .

9. (cycloserine, CS)

.

, , , .

, , , , .

.

.

(50 mg/250 mg of cycloserine).

10. (p-aminosalicyclic acid, PAS)

, , , .

(granular form)

. 10 g 3 .

11. (linezolid, Lzd)

oxazolidinone

.9-11

600 mg ,

300 mg

.10,12,13 , ,

.

.

32

.

. 10

, , ,

. ,

.

300 mg , 27%

.13 , ,

, , , , .

.

.

12. (delamanid, Dlm)

nitro-dihydro-imidazooxazole mycolic acid

. 2

, 2 .14

.15 100 mg 2, 6(24) . QT

. 2.8 g/dl

cytochrome 3A (carbamazepine, rifampin ) . Cytochrome 3A

.

13. (bedaquiline, Bdq)

diarylquinoline ATP synthase .

2012 FDA , 2013

.16

IIb

. 400 mg 2 200 mg 3 22

6(24) .

33

QT , .

, .

14. (clofazimine, Cfz)

in vitro

. ,

.

.17

, 100 mg/day . ,

(photosensitivity) .

.

15. (amoxicillin-clavulanic acid, carbapenem)

beta-lactamase , beta-lactamase

clavulanic acid ,18

. beta-lactamase

clavulanic acid ,

.19,20 clavulanic acid amoxicillin .

amoxicillin-clavulanic acid .2

16. (macrolides)

,21 (azithromycin)

(clarithromycin) .22

QT , , , ,

, .

.

34

2.

.

.

.

(10-6) .

( , acquired resistance). (

)

.

. , (bactericidal)

.

. ,

. ,

, , .

(intermittent growth).

( )

. 6

.

. (dormant state)

.

. . 1)

3 . 2)

, 1

1 . 3) 6 .

35

3.

. 2HREZ/4HR(E). 2 (IIB).

. X , 2 (IIB).

1.

1)

. 1)

, 2) 1 (new patient) .

2)

2 (initial intensive phase) 4 (maintenance

phase) (2HREZ/4HR(E)). 2 , , ,

(HREZ)

. 4 , , (HRE)

.

, , 9 (9HRE).1,23,24

.

. , , ,

4 (fixed dose combination) , 2

. 4 1 75 mg

, 150 mg , 275 mg , 400 mg .

2 1 150 mg 300 mg ( 1).

25,26

.27

36

1. 4

(75 mg), (150 mg),

(275 mg), (400 mg) (kg)

2

3

4

5

30-37

38-54

55-70

70

3)

6(2HREZ/4HR(E)), .

. 2-3 X

2

3 9 .1 X

2 1

.28 , , 3

. X 2

,

(IIB).

2.

. (compliance)

( ).

37

1)

. (IIIA).

. , , (IIIA).

.

.

. , , .

B C . HIV HIV

, .

. ,

(, ) .

.

2)

,

.

.

38

(1)

. ( ) , 2 ,

(IIIA).

. (IIIA).

. (IIIA).

. (IIIA).

.

( ) 2

1 (IIIA).

.

. (contamination)

(colonizer).29

.

3 ,

. 4

.

2

.1,23 , . ,

. , .

, .

39

(2) X

. X (ID).

X

. (radiologically active tuberculosis)

1-2 X .

X .1,23,24

, (

, , , , )

.

(3) (paradoxical reaction)

. HIV HIV

. , ,

, ,

.

.1 458 16%

2

.30 .

(4)

.

. B

.1

40

3)

,

. .

. , ,

. .

1 6

.

(1)

14

. 14 .

(2)

80% 2

2 . 80%

.

, ( )

. ( )

.

4)

.

(WHO) 31 ( 2)

( 2 ).

(treatment failed) 4

.

41

. , , 1

(cured) . ,

1

(treatment completed) . (treatment success)

. , 2 (lost to follow

up) . , (transferred out) (not

evaluated) .

2.

( )

, ( )

1

4

2

,

1. Blumberg HM, Burman WJ, Chaisson RE, et al. American Thoracic Society/Centers for Disease

Control and Prevention/Infectious Diseases Society of America: treatment of tuberculosis. Am

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Reactions between Isoniazid 300mg and 400mg in Korean Patients with Pulmonary

Tuberculosis. Tuber Lung Dis 2006; 60:5

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review and meta-analysis. Ann Clin Microbiol Antimicrob 2016; 15:41

12. Park IN, Hong SB, Oh YM, et al. Efficacy and tolerability of daily-half dose linezolid in

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58:701-704

13. Koh WJ, Kang YR, Jeon K, et al. Daily 300 mg dose of linezolid for multidrug-resistant

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Chemother 2012; 67:1503-1507

14. Gler MT, Skripconoka V, Sanchez-Garavito E, et al. Delamanid for multidrug-resistant

pulmonary tuberculosis. N Engl J Med 2012; 366:2151-2160

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XDR-TB: a study in China. Eur Respir J 2015; 45:161-170

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lactamase by clavulanate. Biochemistry 2007; 46:11998-12004

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for extensively drug-resistant tuberculosis. Int J Tuberc Lung Dis 2012; 16:558-560

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containing regimens in the treatment of MDR- and XDR-TB. Eur Respir J 2016; 47:1235-

1243

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21. Andini N, Nash KA. Intrinsic macrolide resistance of the Mycobacterium tuberculosis

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1470

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status and future prospects. Int J Tuberc Lung Dis 2015; 19:1417-1427

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December 2014). 2013

44

4.

. 5 3

(IIIA).

.

(IIIA).

. (IIIA).

.

.

,

,

.

.

.

. 2

.

.

1.

. 1

, ,

45

. 30

, , (

) .

30 2

.

2.

.

, , .

, , .

( ).

(alanine aminotransferase, ALT) , ,

(aspartate aminotransferase, AST) .1 ALT

.1

. , ,

, , .

.2

.

5

. 20%

. ALT 5

3

. A, B, C

, ,

. ALT 2 .

ALT ALT .

46

3 (, ,

, ) .

. ALT .

ALT .

3 9 . 1

3 .

( 100 200 300 mg) 300 mg

.

3.

, , , ,

Stevens-Johnson .

.

.

.

. , (Stevens-Johnson

) .

3 . 2-3

. -- .

.

47

4.

2 ,

.

.

.

5. (drug fever)

, .

2 .

,

.

HIV .3

.

. 24 .

.

1. Saukkonen JJ, Cohn DL, Jasmer RM, Schenker S, Jereb JA, Nolan CM, et al. An official

ATS statement: hepatotoxicity of antituberculosis therapy. Am J Respir Crit Care Med.

2006;174:935-52.

2. Singh J, Garg PK, Tandon RK. Hepatotoxicity due to antituberculosis therapy. Clinical profle

and reintroduction of therapy. J Clin Gastroenterol 1996;22:211-4.

3. Narita M, Ashkin D, Hollender ES, Pitchenik AE. Paradoxical worsening of tuberculosis

following antiretroviral therapy in patients with AIDS. Am J Respir Crit Care Med 1998;

158:157-61.

48

1. (Retreatment)

, , 2

.

. 2008

9.3% , 2.9%

.1 ,

.

.

.

, .

1.

. (IIIA).

. 2 3 (IIIA).

. , (IIIA).

(). 3-6

III.

49

.

.

.

1-2 3 (2HRZE/7HR(E)).

.

.

2.

. (IIIA).

. , (IIIA).

. (IIIE).

. (IIIA).

1)

.

( , , ,

, )

.

(paradoxical reaction) . HIV

HIV .

, , ,

.

3

( 4-5 ), 4 ( 5-6 )

50

.

.

2)

,

, ,

, .

(poor compliance).

(

: acquired resistance), ( : primary

resistance).

.

.

3)

. ,

.

.

,

4 .

, (, , , ),

(, , ) .

.

,

.

51

2.

Monoresistance , polydrug resistance 2

.2

. 1 ,

, Curry ,3

.

1.

. , , (REZ) 6-9 (IIIA).

. (IIIB).

. (HREZ) , (RE) 12

(IIIB).

2004 5%,

7%.4 4 95%

,

2

5

, , 6-9 .6

2HREZ/10RE, 2HREZ/4REZ, 2HREZ/7RE

92% (36/39), 8% (3/39) ,

WHO

.6,7

(97.3% vs

84.6%, P=0.007).8

52

, (HREZ) 2 HRE

,

, (RE) 12 .

2.

. , , 12-18 (PZA 2 ) (IIIA).

. (IIIB).

.2

0.8%, 2.1% ,

.

, (,

)

.

, ,

12-18 . 2 .

.

WHO 2016 , polydrug resistance,

.9

.

Xpert

,

. Curry WHO

.3

.

53

3.

1 .

.7

.

3 ,

.

2 . ,

, .

.10

9, 6 .

18 .

1. 3

()

H (S) R,E, Z ( FQ) 6-9 FQ .

H, Z R,E, FQ 9-12

H, E R,Z, FQ 9-12

R H,E,FQ, Z( 2) 12-18 .

R, E (S) H,Z,FQ, ( 2-3) 18 (6)

.

R, Z (S) H,E,FQ, ( 2-3) 18 (6)

.

H, E, Z (S)R, FQ, 2 ,

( 2-3)18

(6)

.

H = isoniazid; R = rifampin; E = ethambutol; Z = pyrazinamide; S = streptomycin, FQ = fluroquinolon

54

3. (multidrug-resistant: MDR)

.

. 2009

62%,11 2015 WHO 50% .12 2011

44-66% ,13-16 1,407

45% 32%

.17 2015 2

(later generation fluroquinolone) .18,19

2016 82.1%

.20

2014 .

,

.

, repurposed drugs

, .

.

WHO 2016 .9

(shorter MDR-TB treatment regimen, ) ,

, (conventional regimen) .

WHO 2016 2011 Ahuja 21

.

, .

,

(availability) ,

.

55

WHO 2016 ,

.

1.

, (conventional,

phenotypic method) (molecular, genotypic method) .9

.

1) (confirmed MDR-TB)

.

2) (presumptive MDR-TB)

,

.

:

.

:

( ), .

:

,

.

, ,

.

(index case) . ,

.

56

2.

, , 1 5 5 (24

, 1. ). WHO 2016 ,9

. WHO 2016 ,

.

WHO 2016

WHO 2016

( 2).9

(core second-line agent) (add-on agent) . A

- , B- , C- , D D1, D2,

D3 .

2014 3 A, 2

B . 5 C

. , 4 D3

. 5 D2 ,

.

,

. , C

D2 , ,

. ,

, .

.

, 2011 100/100

. ,

. ,

57

. endTB

WHO (interime guidance)

.22

2. 9

Group A. Fluoroquinolones Levofloxacin

Moxifloxacin

Gatifloxacin

Group B. Second-line injectable agents Amikacin

Capreomycin

Kanamycin

(Streptomycin)

Group C. Other core second-line agents Ethionamide/prothionamide

Cycloserine/terizidone

Linezolid

Clofazimine

Group D. Add-on agents (not part of the core MDR-TB regimen)

D1 Pyrazinamide

Ethambutol

High-dose isoniazid

D2 Bedaquiline

Delamanid

D3 p-aminosalicylic acid

Imipenem-cilastatin

Meropenem

Amoxicillin-clavulanate

(Thioacetazone)

58

3.

. (IIIA).

. , , , 4, 5 (IIIE).

. (IIIA).

. (IIIA).

. (IIIE).

. (IIIA).

1) .

,

.

. (

) .

, , , 4, 5

.

.

59

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.

.

.

.

. .

WHO 2016 Xpert

.9 ,

.

3) .

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.

. 4 , , ,

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. ,

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.

60

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. 5 , 4( ) (IIIA).

. , 1, 1, , ,

(IIIA).

. 5 (IIIA).

. , (IIIA).

. (IIIA).

1)

2014 , WHO 2011 4

. Ahuja 21

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. ,

.

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, .9

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62

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.

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. ,

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.

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.

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. .

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.

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. ,

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.

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. ,

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.

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. ,

, , .

,

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.

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,

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, , .

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51 .

. ,

, QT

.

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, inhA

.

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-lactamase inhibitor (clavulanate)

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clavulonate amoxicillin/clavulanate .

67

5.

. 8 (IIIA).

. 20 (IIIA).

1) 8 .

,

. 1994 2003

120 g .6 WHO

, 1997 3 , 2006 2008

6 4 . 2011

8 .

8

, .

, 8 . 1 5-7

2-4 1 2-3 . ,

, , .10

3 ,

.

3 .

, .

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WHO 2008 18 , 2011

20 .

.

. ,

.

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. , , 2-3 (IIIA).

. 2-3 (IIIA).

. 12-24 (IIIA).

,

80-90% .56

, ,

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,

.

, 2-3

. 60 ,58

. Fox 59 4,238

. ,

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.

. WHO 2016

.9

7. (Shorter MDR-TB treatment regimen)

. (IIIE).

69

1)

(shorter MDR-TB treatment regimen, ) 2010

.60 206 9

88% ,60 515

84.4% .61

WHO (STREAM 1)

11 .

2015 2018 . 62 63

89.2%, 89% . WHO

1,205 . WHO ,

2016

.

2)

WHO

. 7 4 4

5 . 6

9-12. 3 .

4-6 Km-Mfx-Pto-Cfz-Z-Hhigh-dose-E / 5 Mfx-Cfz-Z-E

3.

DrugWeight group

Less than 30 kg 30 kg to 50 kg More than 50 kg

Gatifloxacin 400 mg 600 mg 800 mg

Moxifloxacin 400 mg 600 mg 800 mg

Claofazimine 50 mg 100 mg 100 mg

Ethambutol 800 mg 800 mg 1,200 mg

Pyrazinamide 1,000 mg 1,500 mg 2,000 mg

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