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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)
[]
.
-
.
1966 , 2005 4
.
.
,
(Private-Public Mix, PPM) PPM .
PPM , ,
.
.
,
2011 (Korean guidelines for tuberculosis)
, 2014 .
,
.
(PPM) ,
,
3 .
,
.
2017 5
(PPM)
-
. 1
3
23 .
2013 1
(2013-2017) 2020 (
10 50) , ,
.
, ,
.
. . 2011
.
2014 2
, ,
3
.
,
.
2017 5
-
i
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
OECD
.
.
, ,
(Korean guidelines
for tuberculosis) 2011 , 2014 2
.
2
2016 PPM
3 .
1)
2014 2
(adaptation)
.
, , , , ,
.
5 (, ,
, , ) .
,
.
, 3
-
ii
,
3 .
, .
5(, 2009)
.
2)
(quality of evidence)
(strength of the recommendation)
. (ATS)
.
(Quality of evidence supporting the recommendation)
I.
(At least one properly randomized trial with clinical end point)
II.
(Clinical trials that either are not randomized or were conducted in other populations)
III. (Expert opinion)
(Strength of recommendation)
A. (Preferred: should generally be offered)
B. (Alternative: acceptable to offer)
C. .
(Offer when preferred or alternative regimens cannot be given)
D. (Should generally not be offered)
E. (Should never be offered)
-
iii
3)
3 .
3 .
.
.
4)
3 2016 .
, , .
2017 5
-
iv
| |
(, )
(, )
(, )
(, )
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(, )
(, )
(, )
(, )
()
(, )
(, )
(, )
( , )
()
(PPM , )
-
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)
(antiretroviral therapy, ART)
Adenosine deaminase (ADA)
Private-public mix (PPM)
-
1
.
,
. X , ,
, , ,
.
.
1.
. 2-3 (IIIA).
. , (IIIA).
.
. ,
, (night sweat), , , .1
, .
.
. , 2-3
I.
-
2
.2,3
, .
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).
. X (IIIA).
X . X
, .
X .
X .
1-2 ( ) X
(lower lung zone disease) , , ,
( )
,
(upper lobe cavitary
disease).1,2
X
.
, .3,4
1/3 ,
. X X
.
-
4
X X
. X (
) X
.
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)
.
(acid fast bacilli, AFB) .
carbol fuchsin Ziehl-Neelsen (ZN) Kinyoun
. ZN 1,000 . auramine O auramine-
rhodamine 200-250 400-450 .
ZN 10%
. LED (Light-emitting diode)
.1 25-80%
. 3 83-87%
10-12% 3-5% .2
2 ,
, 2
,3,4 2 3 ( , 1
) .
.
. .
, .
.
-
6
. ,
. .
(induced sputum) ,
( ).
, 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
2.
. (IA).
. (IIA).
. (IIIA).
.1 ,
1) , 2) , 3)
, .
,
.
,
. (normal flora)
, ,
, , .
.2
.
.
Lowenstein-Jensen Ogawa .
, 3-8
. BACTEC MGIT960 (BD) BacT/ALERT (bioMerieux)
. 2
,
.
.3-5
.
,
-
8
.
. 6
.
, 6 .
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.
. (IIIA).
(M. tuberculosis-polymerase chain reaction, TB-PCR)
(DNA) .
, ,
.1
.
-
9
.
.1
90-100% ,
.2 ,
,
.
(.
).
.
, ,
.3
. (indeterminate) . (kit)
, ,
.
.
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
4.
(spontaneous mutation) 104-
108 .1
(selective pressure) .
(acquired resistance) ,
(primary resistance) .2
1 1
.2
3% .3
2004 2.7% 2008 2.9% 3% .4,5
2004 9.9%, 24.1% .4
.
.
.
.
1)
. (IA).
. 3 (IA).
., Xpert MTB/RIF , (IIIA).
(critical concentration)
.
1% .5 (proportion method),
(absolute concentration method), (resistant ratio method) ,
-
11
.
3-4 .
2 . (first-line drug)
(second-line drug)
.
. . , Xpert MTB/RIF
2 .
.
.
.
.
.
(minimal inhibitory concentration, MIC) .6,7
. 3
.
2)
. (IA).
. (IIB).
2-4
.
.
.
-
12
.
.
,
10 20 2%
1 , ,
(human immunodeficiency virus, HIV)
.8
.9
, line probe assay (LPA)
.
, .
rpoB , 95% rpoB
(hot spot)
.1 katG (50-95%), inhA (20-35%), ahpC (10-15%)
.10
. rpoB
S531L .
.11 inhA
.
(interpretative reporting) .
.
.12
25-33% ,
.
.
-
13
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.
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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%
. 94% 98% .3
Xpert (positive
predictive value) . 15% Xpert
90% 5% 70% .1
Xpert
.2
.1
-
15
Xpert
. 10 20
2% 1
, , HIV
.4
Xpert .5
Xpert .
Xpert .
Xpert .
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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.
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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
.1-8
X
CT
X . , CT X
( ; tree-in-bud appearance)
, , , (bronchopleural fistula) X
. CT
.2 CT . CT
CT
,
.1,8-10 , ,
CT X . CT
.
-
18
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radiographic features of pulmonary tuberculosis. AJR Am J Roentgenol 1986;146:497-506.
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1993;186:653-60.
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in miliary lung disease. J Comput Assist Tomogr 1992;16:384-90.
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lymphadenitis: CT manifestations. Radiology 1987;164:115-9.
2. ( )
. (ID).
. (IB).
-
19
(tuberculin skin test, TST)
(interferon-gamma releasing assay, IGRA) .1
HIV 10%
. TST IGRA
. 1%
.
.2,3 TST IGRA .4,5 IGRA
22 IGRA
.6
.
1)
TST purified protein derivatives (PPD)
T .
TST Mantoux . .
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
-
20
ESAT-6 CFP-10 enzyme-linked immunospot (ELISPOT)
spot .
TST IGRA , TST 48-72 IGRA
. , TST
IGRA TST .
IGRA TST
. TST .8,9
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assays for active tuberculosis. Exp Ther Med. 2015;10(1):345-51
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Sci Rep. 2015;5:15284.
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Mycobacterium tuberculosis infection. JAMA 2001;286:1740-7.
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Dis Primers 2016;2:16076.
-
21
6.
X
.
1.
.
Xpert MTB/RIF ,
.
.
2.
(. ).
3.
.
.
.
4.
,
, ,
.
. ,
-
22
.
X ( X )
.
(broad-spectrum
antibiotics) .
.
CT, , ,
.
.
.
1. . TB-PCR = M. tuberculosis-polymerase chain reaction, AFB = acid-fast bacilli, NTM = nontuberculous mycobacteria.
2 , 3(TB-PCR)
AFB (+)TB-PCR (+)
AFB (+)TB-PCR ( )
AFB ( )TB-PCR (+)
AFB ( )TB-PCR ( )
NTM
-
23
. 10
.
.
.
6
.
.
1) ,
2) 3) .
1.
1940 (streptomycin, S), (p-aminosalicylic acid, PAS)
, (isoniazid, H), (pyrazinamide, Z), (ethambutol, E)
(rifampin, R)
.
(first-line drug) (second-line drug) .
,
I I .
-
24
.1 , , ,
( 1). , (WHO)
(extensively drug-resistant tuberculosis, XDR-TB)
. ,
(multidrug-resistant tuberculosis, MDR-TB)
(aminoglycosides) (capreomycin, Cm) ,
, .2
,
2016 4 (A-D, D D1, D2, D3
1. *
()
1
(Isoniazid, INH, H)
(Rifampin, RIF, R)
(Ethambutol, EMB, E)
(Pyrazinamide, PZA, Z)
(Rifabutin, RFB*)
2 (Kanamycin, Km)
(Amikacin, Am)
(Capreomycin, Cm)
(Streptomycin, S)
3 (Levofloxacin, Lfx)
(Moxifloxacin, Mfx)
4 (Prothionamide, Pto)
(Cycloserine, Cs)
(p-aminosalicyclic acid, PAS)
5
(Linezolid, Lzd)
(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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pulmonary tuberculosis. N Engl J Med 2012; 366:2151-2160
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Drug Regimens for Treatment of Pulmonary Tuberculosis in Two High TB-Burden African
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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 .
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.
3 ,
.
2 . ,
, .
.10
9, 6 .
18 .
1. 3
()
H (S) R,E, Z ( FQ) 6-9 FQ .
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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
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. , 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).
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-
59
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60
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62
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66
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clavulonate amoxicillin/clavulanate .
-
67
5.
. 8 (IIIA).
. 20 (IIIA).
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,
. 1994 2003
120 g .6 WHO
, 1997 3 , 2006 2008
6 4 . 2011
8 .
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