แนวทางการบริหารจัดการผู้ป่วยวัณโรคดื้อยา พ.ศ. 2558

Guideline for Programmatic Management of Drug-Resistant Tuberculosis

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2558

2,500

116 ()

. 10120

/.

New Funding Model

ISBN 978-616-11-2512-7


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(Abbreviation)

1

1.1

1.2

1.3

2

2.1

2.2

3 :Mono-,Poly-Multi-drugresistantTB

3.1

3.2

3.3

4

4.1

4.2 /

4.3

4.4

4.5

4.6

5 XDR-TB

5.1 Pre-XDR-TB XDR-TB

5.2 (Palliative cares)

6

6.1 HIV

6.2

6.3

6.4

6.5

i

jm1

2

3

5

778

17

17

20

25

29

29

30

34

37

44

47

51

51

54

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7

7.1

7.2

7.3 (Multidisciplinary care)

(DOT)

7.4

7.5

7.6

7.7 .

8

8.1

8.2

8.3

8.4

8.5

8.6

1

2 XDR-TB

3 molecular assay

4 (DST)

solid media liquid media

5 solid media liquid media

6 PMDT

75

75

78

78

83

84

85

86

89

89

90

92

93

94

94

99

101

105

109

114

115

119


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1.1

2.1 X-pert

MTB/RIF R

3.1

3.2

3.3

3.4

4.1 /

4.2 Mycobacterium

tuberculosis

4.3

4.4

6.1

6.2

6.3

6.4 paradoxical IRIS

6.5

6.6 Anti-TB drug U.S. FDA class

6.7

7.1

4

9

19

23

24

26

31

35

38

44

60

61

61

63

69

71

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2.1 MDR-TB

2.2

4.1

4.2

6.1

6.2 (MDR-TB)

7.1

12

13

30

34

67

68

83


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1.

1.1

1.2

1.3 .

1.4

1.5

1.6

1.7

1.8 .

1.9

1.10

1.11

1.12

1.13

1.14

1.15

2.

2.1

2.2

2.3

2.4

2.5

2.6

2.7

2.8

2.9

2.10

2.11 ()

2.12

2.13

2.14

2.15 .

2.16


k

2.17 .

2.18

2.19

2.20

2.21

2.22

2.23

2.24

2.25

2.26 .

2.27 .

2.28

2.29

2.30

2.31

2.32 . /

2.33 /

2.34 /

2.35 /

2.36 /

3.

3.1

3.2

1)

2) .

3.3

1)

2)

3) .

4)

5)

6)

7)

8)

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9)

10)

11)

12)

13)

14)

15) 11


m

3TC lamivudine

ABC abacavir

AFB acid-fast bacilli

AFRIMS Armed Forces Research

Institute of Medical Science

ALT alanine transaminase

Am amikacin

Amx amoxicillin

Amx/Clv amoxicillin/clavulanate

ART antiretroviral therapy

ATV atazanavir

AUC area under the curve

AZT zidovudine

Bdq bedaquiline

CBC complete blood count

CD4 cluster of differentiation 4

CD8 cluster of differentiation 8

CDC-US Centers for Disease Control

and Prevention (USA)

Cfx clofazimine

Clr clarithromycin

Cm capreomycin

Cr creatinine

CrCl creatinine clearance

CRP c-reactive protein

Cs cycloserine

CSF cerebrospinal fluid

CXR chest x-ray

CYP 450 cytochrome P450

d4T stavudine

ddI didanosine

ddC zalcitabine

DHFS dihydrofolate synthase

DHHS Department of Health and

Human Service

Dlm delamanid

DOT directly observed therapy

DR-TB drug resistant tuberculosis

DRV darunavir

DST drug susceptibility testing

E ethambutolECG electrocardiography

EFV efavirenz

Eto ethionamide

FDA Food and Drug Administra-

tion

FL-DST first-line drug susceptibility

testing

FLDs first-line anti-tuberculosis

drugs

FQs fluoroquinolones

FTC emtricitabine

(Abbreviation)

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H, INH isoniazid

HIV human immunodeficiency

virus

IC infection control

IDV indinavir

IFN- interferon gammaIGRA interferon gamma release

assay

IL interleukin

INR international normalized

ratio

INSHI International Network for

the Study of HIV associated

IRIS

IOM International Organization

for Migration

Ipm/Cln imipenem/cilastatin

IRIS immune reconstitution

inflammatory syndrome

IRS immune recovery syndrome

K, Km kanamycin

LAMP loop-mediated isothermal

amplification assay

LED light-emitting diode

Lfx levofloxacin

LTBI latent tuberculosis infection

LPA line probe assay

LPV liponavir

Lzd linezolid

MDR-TB multidrug resistant tubercu-

losis

Mer/Clv meropenem/clavulanate

Mfx moxifloxacin

MIC minimum inhibitory

concentration

MODS microscopic observation

drug susceptibility

NA not available

NNRTIs non-nucleoside reverse

transcriptase inhibitors

NRTIs nucleoside reverse

transcriptase inhibitors

NSAIDs nonsteroidal anti-inflammatory

drugs

NTM nontuberculous

mycobacterium

NTP national tuberculosis

control programme

NTRL national tuberculosis reference

laboratory in bangkok,

Thailand

NVP nevirapine

O, Ofx ofloxacin

P, PAS para-aminosalicylic acid

PCR polymerase chain reaction

PIs protease inhibitors

PPIs proton pump inhibitors

PMDT programmatic management of

drug resistant tuberculosis

Pre-XDR-TB pre-extensive drug resistant

tuberculosis

PT prothrombin time

PTC provincial TB coordinator

Pto prothionamide


o

R rifampicin

RNA ribonucleic acid

RTC regional TB coordinator

RTV ritronavir

S, Sm streptomycin

SL-DST second-line drug susceptibility

testing

SLDs second-line anti-tuberculosis

drugs

SLIs second-line injectable drugs

SQV saquinavir

TAD treatment after default

TB tuberculosis

TDF tenofovir

TDR-TB total drug resistant

tuberculosis

Thz thiacetazone

TNF tumor necrosis factors

Trd terizidone

TST tuberculin skin test

UV ultraviolet

VL viral load

WHO World Health Organization

XDR-TB extensive drug resistant

tuberculosis

Z, PZA pyrazinamide

ZN Ziehl Neelsen

.

..

.

.

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1

(multidrug resistant tuberculosis, MDR-TB)

isoniazid (H, INH) rifampicin (R) .. 1970 (.. 2513)

fluoroquinolones (FQs) .. 1990 (.. 2533)

(extensive drug resistant tuberculosis, XDR-TB)

(directly observed therapy, DOT)

DOT ..1996 (.. 2539)

(cure) (relapse) (drug resistance)

1 (first-line anti-tuberculosis drugs, FLDs)

2,000-4,000

2 (second-line anti-tuberculosis drugs, SLDs) MDR-TB

200,000 XDR-TB 1,000,000

HIV

98-100 MDR-TB 60-80

XDR-TB 44-50 HIV

MDR-TB XDR-TB 1 MDR-TB

71 XDR-TB 83 (1)

1.1

1.2

1.3

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1.1(2,3,4)

Primary drug resistant TB

Acquired drug resistant TB

fall and rise phenomenon

acquired drug resistant TB

susceptible resistant

Drug resistance among new TB cases

1

acquired drug resistant TB primary drug resistant TB

Drug resistance among previously treated TB cases

3 1)

2) acquired drug resistant TB 3)

(re-infection with resistant bacilli)

acquired drug resistant TB

Combined drug resistant TB

combined drug resistant TB

Mono-resistant TB

Poly-resistant TB MDR-TB

H R H ethambutol (E), R streptomycin (S), E S, H

E S

Multi-drug resistant TB (MDR-TB) H R

H R

Pre-extensive drug resistant TB (Pre-XDR-TB)

MDR-TB FQs second-line injectable drugs (SLIs)

Extensive drug resistant TB (XDR-TB)

MDR-TB FQs SLIs kanamycin, amikacin capreomycin


3

(totaldrugresistantTB(TDR-TB)WHO

)

1.2

(5) 3.5

(95%CI 2.2-3.5%) MDR-TB 20.5

(95%CI 13.6-27.5%) 9 (95%CI 6.5-11.5%) MDR-TB

(XDR-TB) .. 2013

(.. 2556) XDR-TB 100 (5)

.. 2013 (.. 2556) 480,000

210,000 (5)

MDR-TB .. 2013 (.. 2556)

MDR-TB 45

8.5 17

71 48 (median:

59.5%) ( .. 2011)(5)

4 MDR-TB

MDR-TB 2 MDR-TB

20 4

1 .. 2540-41 (.. 1997-1998)(6)

2 .. 2544-45 (.. 2001-2002)(7)

3 .. 2549-50 (.. 2006-2007)(8)

4 .. 2555-56 (.. 2012-2013)(9)

4 1.1

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1.1 (nationalanti-TBdrugresistance

surveillance)(6-9)

Drugresistance

1

(..1997-

1998)

2

(..2001-

2002)

3

(..2006-

2007)

4

(..2012-

2013)

Drugresistanceamong

newcases

- Any resistance 25.4 14.8 15.7 16.83

- Mono H resistance NA 5.3 5.65 6.54

- Mono R resistance NA 0.3 0.87 0.12

- Any H resistance 12.4 9.5 9.7 12.21

- Any R resistance 5.72 1.4 2.6 2.22

- MDR 2.01 0.93 1.65 2.03

Drugresistanceamongprevi-

ouslytreatedcases

- Any resistance NA 39 51.0 39.29

- Mono H resistance NA 4.1 5.2 9.69

- Mono R resistance NA 1.7 0.5 3.57

- Any H resistance NA 30.8 44.3 29.59

- Any R resistance NA 22.7 35.1 23.98

- MDR NA 20.35 34.5 18.88

NA = not available ()

MDR-TB 5-7(2,3,10) MDR-TB

.. 2012(11) (.. 2555) MDR-TB

1,760 800 960

300-400

MDR-TB

126 MDR-TB


5

248, 327 366 2550, 2551 2552 XDR-TB

5-8 40-50(12)

(genetic mutation)

(man-made phenomenon)

(clinical practice) (programmatic TB management)

(4)

.

(DOT)

.

(mal-absorption)

.

1.3

MDR-TB 2.03

1)

(previously treated patient) relapse, after failure of first treatment with

FLDs after failure of retreatment regimen with FLDs after loss to follow-up(3)

2) 3 3)

MDR-TB MDR-TB

rapid test R HR /

(standardized

MDR-TB regimen)

(individualized regimen) (strictly DOT)

(13)

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. 70

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1. Chang KC, Yew WW. Management of difficult multi-drug resistant tuberculosis and

extensively drug resistant tuberculosis: update 2012. Respirology 2013; 18: 8-21.

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

resistant tuberculosis 2013. Paris, France: International Union against Tuberculosis

and Lung Diseases 2013, 15-9.

3. World Health Organization. Companion handbook to the WHO guidelines for the

programmatic management of drug-resistant tuberculosis. Geneva, Switzerland:

WHO; 2014: 17-22.

4. World Health Organization. Guidelines for the programmatic management of

drug-resistant tuberculosis, emergency update 2008. Geneva, Switzerland: WHO;

2008.

5. World Health Organization. Global tuberculosis report 2014. Geneva, Switzerland:

WHO; 2014: 54-73.

6. Payanandana V, Rienthong D, Rienthong S, Ratanavichit L, Kim SJ, Sawert H.

Surveillance for anti-tuberculosis drug resistance in Thailand: result from a

national survey. Thai J Tuberc Chest Dis 2000; 21: 1-8.

7. World Health Organization. Anti-tuberculosis drug resistance in the world: report

No.3. Geneva, Singapore: WHO; 2004.

8. , , .

3 .. 2549-50

1 .. 2540-41 2 .. 2544-45.

2551; 34: 30-9.

9. .

4 .. 2555-2556.

10. Chuchottaworn C. Extensively drug resistant tuberculosis (XDR-TB) in chest disease

institute, 1997-2005. J Med Assoc Thai 2010; 93: 34-7.

11. World Health Organization. Global tuberculosis report 2013. Geneva, Switzerland:

WHO; 2014: 132.

12. .

2550-2552.

13. . .

: , 2554.


7

(drug susceptibility testing, DST)

(priority setting)

(cost effectiveness) (quality) (reliability)

2.1

(any drug resistance) (MDR-TB)

MDR-TB 3

MDR-TB

(1)

2

2.1

-(Previouslytreatedpatients)

-3

-(Newpatients)

2.2

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2.1.1 (previously treated patients)

- (after failure of retreatment

regimen with FLDs)(2)

(chronic case) retreatment

(DOT) MDR-TB 85

- (after failure of first

treatment with FLDs)(2)

5 MDR-TB

50 10-90

DOT

(extent of disease)

- (relapse)

(early

relapse) retreatment MDR-TB

50 MDR-TB

10

- (after loss to follow-up)(2)

2.1.2 1 3

MDR-TB

2.1.3 (new patients) MDR-TB

- MDR-TB MDR-TB index

case MDR-TB

index case MDR-TB

- MDR-TB /

- MDR-TB

MDR-TB

2.2

2.2.1 (smear microscope)

ZiehlNeelsen (ZN) (light microscope)

(fluorescent microscope)

light-emitting diode (LED) smear


9

5,000-10,000 /(3,4)

2.2.2 screening test real-time PCR

Xpert MTB/RIF

rifampicin 100

smear 131 /

(5,6) R

(follow up specimen)

meta-analysis(7) Xpert MTB/RIF

(sensitivity) 95 (specificity) 98

R 2.1(7)

2.1 X-pertMTB/

RIFR(7)

TypeofanalysisMedian(%)pooled

sensitivity(95%CrI)

Median(%)pooled

specificity(95%CrI)

Xpert MTB/RIF

R (

sensitivity 17 555

specificity 24 2,414 )

95 (90-97) 98 (97-99)

Xpert MTB/RIF

smear (22

9,008 )

88 (84-92) 99 (98-99)

Xpert MTB/RIF

smear (23

7,151 )

68 (61-74) 99 (98-99)

CrI (credible interval) = the CrI is the Bayesian equivalent of the confidence interval

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meta-analysis(7) X-pert MTB/RIF R

pooled sensitivity 86% (95% CrI, 53-98) pooled specificity 98% (95% CrI,

94-100)

pleural fluid pooled sensitivity 43.7% (95% CI, 24.8-64.7%) pooled specificity

98.1% (95% CI, 95.3-99.2%)(7) CSF pooled sensitivity 79.5% (95% CI, 62.0-90.2%)

pooled specificity 98.6% (95% CI, 95.8-99.6%)(7)

2.2.3 (gold standard)

2.2.3.1 (culture and drug

susceptibility testing)

- (culture)

(gold standard)

(non-tuberculous mycobacteria, NTM)

10-1,000 /

(8,9,10) 2

. (solid media)

ogawa Lowenstein-Jensen 6-8

(contamination rate) 2-5

. (liquid media)

BACTEC-MGIT 960 2-3 100

/(9) yield solid media 10

contamination rate 10

smear (no

growth) digestion & decontamination

identification M. tuberculosis

- (DST)

. 1 (first-line DST, FL-DST)

4-5 H, R, E, S pyrazinamide (Z) ()

(MTB isolates) indirect test (gold standard)

proportion method 3-4

1-3


11

DST R H

S, E Z

R

(strain)

(reproductive fitness)

strain (10-20 mutate strains) conventional DST

molecular technique

R ( FQs SLIs) molecular technique

conventional DST(11)

. 2 (second-line DST,

SL-DST) solid

automated liquid system amionoglycosides, polypeptides, FQs

para-aminosalicylic acid

(PAS), ethionamide (Eto), cycloserine (Cs)

1 (FL-DST) MDR-TB

2 (SL-DST)

2.2.3.2 Line probe assay (LPA) genotype MTB-DR plus

H R

2

(gold standard) MDR-TB

160 cells(12) smear

(culture isolated) (13)

LPA R 91.7 96.6

H 70.6 99.1

MODS (microscopic observation drug susceptibility)(14, 15) LAMP (loop-mediated

isothermal amplification) assay(16)

MDR-TB

smear 24

solid media 9-12

liquid media 3-5 LPA smear

MDR-TB 1-2 smear

liquid media 2.1(17)

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2.1MDR-TB(goldstandard)(17)

1. MDR diagnosis with soild culture & DST

2. MDR-TB diagnosis with liquid culture & DST

3. MDR-TB diagnosis with line prode assay, liquid culture & DST

Microscopy24 hours

Microscopy24 hours

Microscopy24 hours

Solid culture6-8 weeks

FL-DST3-4 weeks

FL-DST1-3 weeks

FL-DST1-3 weeks

MDR-TB diagnosisAfter 9-12 weeks



MDR-TB diagnosisAfter 1-2 days

Line probe assay +24 hours

Line probe assay -24 hours

Liquid culture2-3 weeks

liquid culture2-3 weeks

MDR-TB

3

MDR-TB

molecular test LPA Xpert MTB/RIF ( molecular test

culture DST)

- LPA MDR-TB 1

MDR-TB MDR-TB

FLDs SLDs

- Xpert MTB/RIF R

culture DST

2

Xpert MTB/RIF

. MTB detected, R resistance R MDR-TB

MDR regimen

. MTB detected, R resistance not detected

MDR-TB 1

. MTB detected, R resistance indeterminate

R () 1

DST


13

. MTB not detected NTM culture

identification 1

. invalid or error X-pert

MTB/RIF invalid/error 1

DST

conventional DST

(individualized MDR regimen)

(migrant worker)

liquid solid culture FL-DST 4 ( LPA

)

2.2

2.2

Assess the risk of MDR-TB

1) all retreatment TB cases (TAF, TAD, relapse)2) during TB treatment, smear+ at M3, M53) new TB cases, contact with MDR-TB

new TB cases with HIV+,prisoners, migrants, HCWs

individualized drug regimen (depend on DST result)

Culture & DST (or LPA if possible)

Start FLD regimenwhile waiting for DST

result

LPA X-pert MTB/RIF* Culture & DST*

Non MDR MDRMTB, RR

MDR regimenRepeat

X-pert MTB/RIF**Start or continue

FLD regimen

invalid/error-MTB, R not resist-MTB, R indeteminate-MTB not detect

Molecular test

* 2 2

** repeat FLD regimen

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DST (transient

resistance)(11)

H 4-5

colony

DST

smear

culture DST

MDR-TB

1. . ,

2. :

; 2556.

2. World Health Organization. Companion Handbook to the WHO Guidelines for the

Programmatic Management of Drug-Resistant Tuberculosis. Geneva, Switzerland: WHO;

2014: 17-22.

3. Toman K. How many bacilli are present in a sputum specimen found positive by smear

microcopy? In: Frieden TR, ed. Tomans tuberculosis: case detection, treatment and

monitoring, 2nd ed. China: World Health Organization; 2004: 11-3.

4. Toman K. How reliable is smear microcopy? In: Frieden TR, ed. Tomans tuberculosis:

case detection, treatment and monitoring, 2nd ed. China: World Health Organization;

2004: 14-22.

5. World Health Organization. Policy statement: automated real-time nucleic amplification

technology for rapid and simultaneous detection of tuberculosis and rifampicin

resistance: Xpert MTB/RIF system. WHO; 2011 (WHO/HTM/TB/2011.4).

6. World Health Organization. Rapid implementation of the Xpert MTB/RIF diagnostic test:

technical and operational How-to practical considerations. Geneva, Switzerland:

World Health Organization; 2011: 6.

7. World Health Organization. Xpert MTB/RIF assay for diagnosis of pulmonary and

extrapulmonary TB in adults and children. Policy update. France: WHO; 2013.


15

8. World Health Organization. Laboratory services in tuberculosis control, part III: culture. Geneva, Switzerland: WHO; 1998: 9.

9. Yeager H Jr, Lacy J, Smith LR, LeMaistre CA. Quantitative studies of mycobacterial population in sputum and saliva. Am Rev Respir Dis 1967; 95: 998-1004.

10. DeunAV.What is the roleofmycobacterialculture indiagnosisandcasefinding?

In: Frieden TR, ed. Tomans tuberculosis: case detection, treatment and monitoring, 2nd ed. China: World Health Organization; 2004: 35-43.

11. Caminero JA, ed. Guidelines for clinical and operational management of drug-resistant tuberculosis. Paris, France: International Union Against Tuberculosis and Lung Diseases; 2013: 13-70.

12. Hain Lifescience GmbH. GenoType MTBDR plus, instructions for use. Germany; 2014.13. Luetkemeyer AF, Kendall MA, Wu X, Loureno MC, Jentsch U, Swindells S, et al.

Evaluation of two line probe assays for rapid detection of Mycobacterium tuberculosis, tuberculosis (TB) drug resistance, and non-TB Mycobacteria in HIV-infected individuals with suspected TB. J Clin Microbiol 2014; 52: 1052-9.

14. Pandey B D, Poudel A, Yoda T, et al. Development of an in-house loop mediated isothermalamplification(LAMP)assayfordetectionofMycobacteriumtuberculosis

and evaluation in sputum samples of Nepalese patients. J Med Microbiol 2008; 57: 439-43.

15. World Health Organization. Implementing tuberculosis diagnosis: policy framework. Geneva, Switzerland: WHO; 2015 (WHO/HTM/TB/2015.11).

16. Moore DA, Mendoza D, Gilman RH, ed al. Microscopic observation drug susceptibility assay, a rapid, reliable diagnostic test for multidrug-resistant tuberculosis suitable for use in resource-poor setting. J Clin Microbiol 2004; 42: 44327.

17. World Health Organization. Policy framework for implementing new tuberculosis diagnosis. Geneva, Switzerland: WHO; 2010.

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3.1

1

5 3.1(1,2,3,4)

1: 1 (first-line oral anti-tuberculosis agents)

isoniazid (INH, H), rifampicin (R), pyrazinamide (Z), ethambutol (E)

(drug susceptibility testing, DST)

2: (injectable anti-tuberculosis agents) capreomycin

(Cm) aminoglycosides kanamycin (Km), amikacin (Am) streptomycin

(S) Km Am S

Km Am (ototoxicity) S

Km Am cross-resistance

Km Am

Cm Km

aminoglycosides

3: (fluoroquinolones) levofloxacin

(Lfx), moxifloxacin (Mfx) ofloxacin (Ofx)

MDR-TB Lfx Mfx Ofx ciprofloxacin

3:

Mono-, Poly- Multi- drug resistant TB

3.1

3.2

3.3

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drug-susceptible drug-resistant TB

cross-resistance

4 : 2 (oral bacteriostatic second-line

anti-tuberculosis agents) para-aminosalicylic acid (PAS, P), cycloserine (Cs), terizidone

(Trd), ethionamide (Eto) prothionamide (Pto) Eto

MDR-TB 2

Eto PAS 3 Eto, PAS Cs Pto

Eto Trd Cs

5: (anti-tuberculosis agents with unclear

efficacy in treatment of drug resistant TB) clofazimine (Cfz), linezolid (Lzd), amoxicillin/

clavulanate (Amx/Clv), thioacetazone (Thz), meropenem/clavulanate (Mer/Clv), imipenem/

cilastatin (Ipm/Cln), high-dose isoniazid (16-20 mg/kg/day) clarithromycin (Clr)

MDR-TB

1 4

4 XDR-TB

Lzd MDR-TB

XDR-TB 80 MDR-TB

50 XDR-TB(5,6)

Pre-XDR-TB XDR-TB linezolid (600 ) 1

XDR-TB

()

1) Lzd, 2) Cfz,

3) Ipm/Cln, 4) Clr, 5) Amx/Clv, 6) Thz 7) high-dose INH

MDR-TB, Pre-XDR-TB XDR-TB bedaquiline

(Bdq)(7) delamanid (Dlm)(8) Interim policy Bdq

Dlm MDR-TB, Pre-XDR-TB XDR-TB

5

. (proper patient inclusion)

18 /

/ Dlm

Bdq 65

. (informed consent)

.


19

.

. (active pharmacovigilance)

3.1(1,2,3,4)

(//)(/)**

1:

First-line oral

agents

- Isoniazid (H, INH) 5 300

- Rifampicin (R) 10 450-600

- Pyrazinamide (Z) 20-30 1,000-2,000

- Ethambutol (E) 15-20 800-1,200

2:

Injectable agents

- Streptomycin (S) 15 750-1,000

- Kanamycin (Km, K) 15 750-1,000

- Amikacin (Am) 15 750-1,000

- Capreomycin (Cm) 15 750-1,000

3:

Fluoroquinolones (FQs)

- Levofloxacin (Lfx) 15 500-750

- Moxifloxacin (Mfx) 7.5-10 400

4:

Oral bacteriostatic

second-line agents

- Ethionamide (Eto) 15 500-750

- Prothionamide (Pto) 15 500-750

- Para-aminosalicylic acid (PAS, P) 150-200 8,000-12,000

- Cycloserine (Cs) 15 500-750

5:

Agents with

unclear efficacy in

treatment of drug

resistant-TB

- Linezolid (Lzd) - 600

- Clofazimine (Cfz) - 100

- Imipenem/cilastatin (Ipm/Cln) - 500-1000 b.i.d.

- Clarithromycin (Clr) - 500 b.i.d.

- Amoxicillin/clavulanate (Amx/Clv) - 875/125 b.i.d.

- High-dose isoniazid (High-dose H)* 16 600-800 OD

- Bedaquiline (Bdq) - 400 OD

2

200 OD (3

)

22 ***

- Delamanid (Dlm) - 100 b.i.d.

24

* High-dose isoniazid (High-dose H) INH (>1% 0.2 / 1 / INH) High-dose H INH (>1% 1 / INH)***** prolong QT Cfz, FQs, Dlm, azole, anti-fungal drugs

additive QT prolongation

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3.2(1,2,9)

1 Sm

2 1

H, R, Z Sm bactericidal activity E bacteriostatic activity

2 bactericidal activity FQs,

aminoglycosides polypeptide

1

2

(intensive phase) (maintenance phase)

3 4

2 3

MDR-TB

(intensive phase) 3 4 (maintenance

phase) 2 3

MDR-TB

(drug resistance survey)

standardized MDR-TB regimen of NTP

individualized regimen

20

MDR-TB

.

.

(standardized MDR-TB regimen of NTP)

6 4 5

3

20 18

.

. 1


21

. high quality DOT

. (AFB smear)

(culture) 6 8

2

.

.

4 2 3

18 24

3.2.1

MDR-TB(buildingregimenformono/polyDR-TB)(1,2,9)

1 : 1 (H, R, Z, E)

2: FQs 1 (Lfx, Mfx, Ofx)

3: 4 1 2

injectable agent 1 (Km, Am, Cm, S)

3.2.2 (buildingregimenfor

MDR-TB)(1,2,3,6,10,11,12)

1 : 1 (Z, E)

2: FQs 1 (Lfx, Mfx) injectable agents 1 (Km, Am,

Cm, S) Lfx Km

3: 2 (Eto, Cs, PAS)

2 4 6 ( 1)

4 : 4 6 2 3

5 (Lzd, Cfz, Mer/Clv, Ipm/Cln, Clr, Amx/Clv, Thz, High-dose H)

5 Lzd

1 (6)

3.2.3

(buildingregimenforPre-XDR-TBandXDR-TB)(1,2,4)

1: FQs 1 (Lfx, Mfx) injectable agents 1 (Km, Am,

Cm) XDR-TB FQs FQs

Mfx FQs Pre-XDR-TB injectable agents

Cm

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2: 2 (Eto, PAS, Cs)

4

3: 5 (Lzd, Cfz, Mer/Clv, Ipm/Cln, Clr, Amx/

Clv, Thz, High-dose H) 2 4

Lzd 1 (6)

bedaquiline(7)

XDR-TB

FQs injectable agents

treatment after failure (TAF)

>6Km5LfxEtoPCs/>14LfxEtoPCs

treatment after relapse treatment after default (TAD)

2HRZES/1HRZE/5HRE

3.2 3.3


23

3.2(1,2,3,4)

**

E H, R, Z 6 2HRZ/4HRH R, Z, E 6-9

12

6-9RZE

2RZE/10RE

H S R, Z, E 6-9

12

6-9RZE

2RZE/10RE

H E (S) R, Z, FQs 6-9

12

12

6-9RZLfx (Ofx)

2RZLfx (Ofx)/10RLfx (Ofx)

2RZLfx (Ofx)/10RZ

Z H, R, E 9

9

2HRE/7HR

2HRES/7HR

H Z R, E, FQs 9-12

12

12

9-12RELfx (Ofx)

2RELfx (Ofx)/10RLfx (Ofx)

2RELfx (Ofx)/10RE

H Z

E

R, FQs, Injectable ( 3-6

), Plus X*18 >3K

5RLfx (Ofx)P(Eto, Cs)/

12-18 RLfx(Ofx)P(Eto, Cs)

R H, E, Z, FQs 18 2HEZLfx (Ofx)/16HLfx (Ofx)

2HEZLfx (Ofx)/16HE

R Z (

E)

H, E ( Z), FQs, Injectable

( 3 )

18 >3K5HLfx (Ofx)E(Z)/12-18 HLfx-

(Ofx)E(Z)

R Z

EH, FQs, Injectable ( 3-6

), Plus X*18 >3K

5HLfx (Ofx)P(Eto, Cs)/

12-18 HLfx(Ofx)P(Eto, Cs)

MDR with

any drug

resistance

Injectable, FQs, Eto, P, Cs 20-24 >6K5LfxEtoPCs/>14LfxEtoPCs***

(

)

FQs Lfx Ofx

X* Eto, PAS Cs

** rifampicin resistance ofloxacin rifampicin

efflux pump resistance ofloxacin

*** vitamin B6 100-300 mg/day second line drug Cs

Gu

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3.3(13)

Treatmentafterrelapseor

defaultTreatmentafterfailure

MDR-TB

2HRZES/1HRZE/5HRE >6K5LfxEtoPCs/>14Lfx

EtoPCs

DST* individualized regimen

*DST = drug susceptibility testing

DST FLDs SLDs

2

DST DST

DST 3-4 DST

. (transient resistance) H

H

H

H colony

H

. (functionally receiving only one drug)

4 H R, E, Z, S maintenance phase

HR R 2

R rapid test Xpert MTB/RIF R

MDR-TB regimen mono-resistant regimen


25

3.3(1,2)

.

. (sputum AFB smear)

. (sputum culture)

2

. 3

6 6

Sputumsmearconversion

sputumcultureconversion

sputumconversion 2

2 30 sputum conversion

MDR-TB culture conversion

culture conversion

4 culture conversion

18 6 8

20 3.4

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3.4(2)

,

2-3

,

culture conversion 4

2

(

3 )

3 6 6

Serum creatinine ( 1-3

HIV )

Serum potassium ( 1-3

HIV ) Cm Dlm

Thyroid stimulating

hormone (TSH)

3 ethionamide/protionamide

/ PAS ( thyroid hormone )

Liver enzymes 1-3 pyrazinamide

HIV Bdq

HIV

CBC Lzd CBC 2

HIV AZT

Lipase Lzd, d4T, ddI, ddC

Lactic acidosis Lzd ART

E 2

ECG Mfx, Cfz, Bdq, Dlm

2, 12, 24 (

hypothyroidism electrolyte imbalance)


27

1. . .

2. : ; 2556.

2. World Health Organization. Guidelines for the programmatic management of drug-

resistant tuberculosis. Geneva, Switzerland: World Health Organization; 2008 (WHO/

HTM/TB/2008.402).

3. Chang KC, Yew WW. Management of difficult multidrug-resistant tuberculosis and

extensively drug-resistant tuberculosis: Update 2012. Respirology 2013; 18: 8-21.

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

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

2013: 13-70.

5. Cox H and Ford N. Linezolid for the treatment of complicated drug-resistant tuberculosis:

a systematic review and meta-analysis. Int J Tuberc Lung Dis 2012; 16: 447-54.

6. Sotgiu G, Centis R, DAmbrosio L, Alffenaar JW, Anger HA, Caminero JA, et al. Efficacy,

safety and tolerability of linezolid containing regimens in treating MDR-TB and XDR-TB:

systematic review and meta-analysis. Eur Respir J 2012; 40: 1430-42.

7. World Health Organization. The use of bedaquiline in the treatment of multidrug-

resistant tuberculosis: interim policy guidance. Geneva, Switzerland: World health

organization; 2013 (WHO/HTM/TB/2013.6).

8. World Health Organization. The use of delamanid in the treatment of multidrug-resistant

tuberculosis: interim policy guidance. France: World health organization; 2014 (WHO/

HTM/TB/2014.23).

9. World Health Organization. Guidelines for the programmatic management of drug-

resistant tuberculosis 2011 update. Geneva, Switzerland: World health organization;

2011 (WHO/HTM/TB/2011.6).

10. Chaiprasert A, Srimuang S, Tingtoy N, Makhao N, Sirirudeeporn P, Tomnongdee N, et al.

Eleven-year experience on anti-TB drugs direct susceptibility testing from Siriraj Hospital,

Thailand. Diagn Microbiol Infect Dis 2013; 77: 241-4.

11. Chang KC, Yew WW, Tam CM, Leung CC. WHO group 5 drugs and difficult multidrug-

resistant tuberculosis: a systematic review with cohort analysis and meta-analysis.

Antimicrob Agents Chemother 2013; 57: 4097-104.

12. Reechaipichitkul W. Multidrug-resistant tuberculosis at Srinagarind Hospital. Southeast

Asian J Trop Med Public Health 2002; 33: 570-4.

13. World Health Organization. Treatment of tuberculosis guidelines. 4th ed. Geneva,

Switzerland: World health organization; 2010 (WHO/HTML.2009.420).

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29

4.1

(M. tuberculosis) 2 1

log phase

107-108 2

dormant phase ( 4.1)

(1,2)

INH Sm

4

4.1

4.2 /

4.3

4.4

4.5

4.6

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30

(solid caseous material) (semi-dormant)

R

PZA PZA

(intensive phase) (105

)

(continuous phase)

(1,2)

4.1(1,2)

High

Speed of

Continuous

growth

DormantAcid

inhibition

Spurts of

metabolism

Bacterial growth

Low

INH(R, S)

PZA R

B C

A

D

4.2/(3)

4.1


31

4.1

/

(

3)

Dru

gAbso

rption

Cmax

g/ml

MIC

g/ml

Distribution

Metab

olis

mEx

cretion

Ison

iazi

d

(H)

(

)

,

Cmax

1-2

5.4+

2.0

(rapi

d

met

abol

ism

)

7.1+

1.0

(slo

w

met

abol

ism

)

0.02

-0.2

acet

ylat

ion

(

auto

som

al d

omin

ant):

slow

ace

tyla

tors

, rap

id a

cety

lato

rs

sl

ow a

cety

lato

rs

2-4.

5

r

apid

ace

tyla

tors

0.75

-1.8

75-

95

Rifa

mpi

cin

(R)

90

-95,

Cmax

1.5

-3

(

)

14.9

10.

05-1

80

ent

eroh

epat

ic c

ircul

a-

tion,

dea

cety

latio

n,

activ

e m

etab

olite

,

hepa

tic e

nzym

e in

duce

r

2-5

(

)

30

65

Pyra

zina

mid

e

(Z)

,

Cmax

2

38.7

+5.9

16-5

0

(pH

5.5

)

5

hydr

olys

ed

hydr

oxyl

ated

5-hy

drox

ypyr

a-

zino

ic a

cid

9.5

3

Etha

mbu

tol

(E)

70

-80,

Cmax

2-4

0.97

21-

5

40

15

alde

hyde

dic

arbo

xylic

met

abol

ites

3-4

,

75

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32

Dru

gAbso

rption

Cmax

g/ml

MIC

g/ml

Distribution

Metab

olis

mEx

cretion

Stre

ptom

ycin

(S)

,

Cmax

< 1

25-5

02-

8

34

2.3

-4

,

90

Oflo

xaci

n

(Ofx

)/

Levo

floxa

cin

(Lfx

)

Mox

iflox

ain

(Mfx

)

,

Cmax

< 2

3.0

6.21

+1.3

4

4.34

+1.5

1

0.5-

2.5

Ofx

, Lf

x

M

fx

/

Ofx

5-7

.5

, Lfx

6-8

,

Mfx

12-

13

,

Cycl

oser

ine

(Cs)

,

Cmax

3-4

10.0

35-

20

pep

tidog

lyca

n sy

nthe

sis

10

Ethi

onam

ide

(Eto

)

,

Cmax

1-1

.5

2.16

2.5-

10

m

ycol

ic a

cid

H

1

.92


33

Dru

gAbso

rption

Cmax

g/ml

MIC

g/ml

Distribution

Metab

olis

mEx

cretion

Para

amin

o-

salic

ylic

aci

d

(PAS

)

60-6

5,

Cmax

6

21.4

1-10

fo

lic

acid

1

Kana

myc

in

(Km

)/

Amik

acin

(Am

)

Capr

eom

y-

cin

(Cm

)

IM

Cm

ax 1

-2

35-4

52-

4

Km, A

m

2.3-

4

Cm

4-6

Line

zolid

(Lzd

)

Cmax

1-2

12.5

1-4

oxid

atio

n

m

orph

olin

e rin

g

4.9

Beda

quili

ne

(Bdq

)

Cmax

5

400

mg

1

Cmax

= 5

.5

0.03

CYP3

A4

a

ctiv

e

N-d

esm

ethy

l m

etab

olite

(M2)

173

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4.3

R 1 108 H, S, E, PAS,

Km 1 106 Eto, Cm Cs 1 103

108 S 10-100

(4)

(5) 4.2 (6,7)

4.2 rifampicin subunit RNA polymerase RNA 95

-subunit rpo B gene

4.2(5)


35

4.2 Mycobacterium

tuberculosis(6,7)

Minimal

inhibitory

concen-

trations

(MICs)

(/

)

H mycolic

acid

0.02-0.2 katG

inhA

catalase-

peroxidase

enoyl ACP

reductase

50-95

8-43

R RNA polymerase

RNA

0.05-1 rpoB -subunit of RNA polymerase

95

Z

16-50

(pH 5.5)

pncA nicotinamidase/ pyrazinamidase

72-97

E arabinosyl transferase

arabinogalactan

1 -5 embB arabinosyl transferase

47-65

S ribosome 30S

subunit ribosomal S12

protein 16S rRNA

mRNA

2-8 rpsLrrs

gidB

S12 ribosomal

protein

16S rRNA

rRNA

methyltransferase

52-59

8-21

Am/

Km/

Cm

ribosome 30S

subunit 16S rRNA

mRNA

2-4 rrs 16S rRNA 76

FQs DNA gyrase

(topoisomerase II)

topoisomerase IV

chromosomal

replication

0.5-2.5 gyrA

gyrB

DNA gyrase

subunit A

DNA gyrase

subunit B

-subunit of RNA polymerase

75-94

Gu

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Minimal

inhibitory

concen-

trations

(MICs)

(/

)

Eto mycolic

acid

2.5-10 etaA/ethAinhA

flavin

monooxygenase

37

56

PAS PAS folate

synthesis antagonist

folic acid

0.5-2 enzyme

dihydrofo-

rate (DHFS)

mutation

inhibits DHFS

enzymatic

Unknown

Cs cell wall synthesis

cycloserine

D-alanine

cell wall synthesis

peptidoglycan

synthesis

L-alanine

D-alanine

D-alanine 2

D-alanine-D-alanine

5-30 D-alanine

mutation

inhibition of

alanine racemase

and D-alanyl-D-

alanine synthetase

Unknown

Lzd 23S RNA

50S ribosomal

subunit

0.125-0.5 23S RNA

mutation

ribosomal

inhibition

Unknown

Bdq proton pump

mycobacterial ATP

synthase

ATP

0.03 AtpE gene

mutation

ATP

synthase subunit C

Unknown

Dlm mycolic

acid

0.006-0.024 Rx3547

gene

mutation

unknown Unknown


37

4.4

( ) ( )

( )

(8) 4.3

- aminoglycosides

serum creatinine

- (electrolyte wasting) Cm

serum potassium

Cm

- (hypothyroidism) PAS Eto

10 TSH

TSH 3

3 6

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4.3

(8)

*

1. Seizure

()

Cs(3%)(9),

H, Lfx, Mfx, Ofx

1.

2.

- Phenytoin loading

dose 1

maintenance dose 300 ./

- Vaproic acid

initial dose 10-15

././ maintenance

dose 20-30 ././(10)

- Phenobarbital

loading dose 10-20 ./.

20 (maximum dose

30 ./.) loading

dose 12

maintenance dose

1-3 ././

1 2

(11)

( phenytoin INH)

3. pyridoxine 200

./

4.

5.

6.

1.

MDR-TB

2.

/

3.

MDR-TB


39

*

2. Hepatitis

(

)

PZA(1%)(9),H

(0.1-0.6%)(12),R

(0-1.6%)(12),

Eto (2%)(8), Pto,

PAS, E

1.

2.

3.

4.

1.

2.

3. Renal

toxicity

(

)

Cm(20-25%)(9),

Km (3.4%)(9), Am

(3.4%)(9), Sm

(2%)(9)

1.

2. 3

(

)

3.

4.

1.

2.

4. Optic

neuritis

(

)

E(

30./

./

18%)(9)H, Eto, Pto

1.

2.

3.

1. etham-

butol

5. Bone

marrow

suppression

(

)

Lzd(12.5%)(13) 1. Lzd

2.

CBC

300 ./

3.

CBC 2

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*

6. Hearing

loss and

vestibular

disturbance

(

)

Sm(1.5%)(9),

Km(1.5%)(9),

Am(1.5%)(9)

1 .

()

2. Cm

3. 3

4.

5.

1. amio-

glycoside

baseline

2.

3.

7. Hypo-

thyroidism

(

)

PAS,Eto,Pto 1. thyroid

hormone (levothyroxine)

50-100

/ 6-8

(maximum: 300 /

) euthyroidism

2.

1.

2. PAS Eto

Pto

8.Gastritis

(

)

PAS,Eto, Pto 1. H2-blockers

ranatidine 150 . 2 ,

PPIs omeprazole 20 .

(antacid)

2.

3.

1.

2.

2

3

3.


41

*

9. Peripheral

neuropathy

(

)

INH( 500 ms

2.

- ECG

- Bdq QTc

> 500 ms

- QT

prolongation

- potassium,

calcium magnesium

-

QT prolongation

1. QTc < 440 ms

QTc > 440 ms

(cardiac arrhythmias )

torsades de pointes

QTc

> 500 ms

2. FQs

QT prolongation

Mfx

Lfx

Ofx

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44

4.5(importantdruginteractions)

1-5 MDR-,

Pre-XDR-, XDR-TB 4.4

4.4

1:First-lineoralanti-tuberculosisagents

INH(16,17) - INH carbamazepine CYP 2C9 CYP

3A4 - INH phenytoin

CYP 2C9

- carbamazepine, phenytoin

-

INH

R(17,18,19) - single protease inhibitor (PI) atazanavir (ATV), lopinavir (LPV), ritonavir (RTV) PI AUC 80

- dual PIs 1. saquinavir (SQV)/ritonavir (RTV)

2. lopinavir (LPV)/ritonavir (RTV) (Kaletra)

3. super-boosted LPV/RTV (Kaletra)

-

- 1. SQV 400 mg + RTV 400 mg 2

2. LPV/RTV (Kaletra)

4 (200 . LPV 50 . RTV) 2

3. super-boosted LPV/RTV (Kaletra) 2 (200 . LPV 50 . RTV) + 300 . RTV 2

- efavirenz (EFV) - EFV1. 50 . 600

./2. 50 . 800

./

- nevirapine (NVP) -

- azole (ketoconazole, itraconazole)

- - fluconazole


45

R(17,18,19) - warfarin - INR prothrombin time (PT) warfarin

- digoxin - digoxin digoxin

- - high dose estrogen (50 )

- sulfo- nylurea (glyburide, glimepiride,

glipizide) (20)

-

R FQs efflux pump (21)

2:Injectableanti-tuberculosisagents(16,19)

SmKmAmCm

- amphoteri-cin B, cephalosporin, cyclospo-rin, cisplatin, furosemide vancomycin

-

Cm - neuromuscular blocking agents non-depolarizing muscle relaxant vecuronium

- non-depolarizing muscle relaxant neuromuscular function

3:Fluoroquinolones(22)

Ofx LfxMfx

- didanosine (ddI) aluminium, magnesium FQs

- 2

- warfarin - INR PT

- theophylline - theophylline

4:Oralbacteriostaticsecond-lineagents

PAS(8,16) - digoxin - Eto

- hypothyroidism

Eto- acetylation

isoniazid isoniazid

- digoxin - liver enzymes

- thyroid hormone (levothyroxine)- INH

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Eto

Pto(16)- Cs

neurotoxicity

-

- PAS

- B6 (200 ./)

-

- liver enzymes hypothy-

roidism Eto

PAS

Cs(16) - Eto INH

CNS Cs

- Cs

- B6

-

5:Agentswithunclearroleintreatmenttodrugresistance

Cfz(8) - Cfz weak inhibitor CYP

3A4

- Cfz R

time to Cmax

drug interactions

dapsone, estrogen A

-

Lzd(8,16) - buspirone,

mereridone, fluoxetine

serotonin 5-HT1 antagonists

serotonin syndrome

-

Clr(18,23) - EFV, NVP

clarithromycin

-

:NewdrugsforMDR-,Pre-XDR-,MDR-TB

Bdq(24) -

CYP3A4

ketoconazole LPV/RTV

Bdq

toxicity

R enzyme inducer

Bdq

drug interactions

-


47

HIV HIV

Bdq

Dlm(25) - drug-drug interaction

Dlm TDF, EFV

LPV/RTV

Dlm

HIV

MDR-TB Dlm

ART

-

4.6(newdrugsintuberculosis)

linezolid (Lzd), bedaquiline

(Bdq), delamanid (Dlm), sutezolid (PNU-100480), PA-824(15)

MDR-, Pre-XDR-, XDR-TB

4.6.1 Linezolid (Lzd)

Lzd oxazolidinones

(Food and Drug Administration, FDA) Enterococcus faecium

vancomycin

M. tuberculosis 23S RNA 50S ribosomal subunit MIC

0.125-0.5 ./. 600 ./

300 ./

()

(15)

4.6.2 Bedaquiline (Bdq)

Bdq diaryquinolones

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(MDR-TB) .. 2555

ATP 5.5

concentration dependent killing

AUC/MIC

400 . 1 2 200 . 3

/ 22

QTc interval QT

interval prolongation (24)

4.6.3 Delamanid (Dlm)

Dlm nitroimidazoles Otsuka

Pharmaceutical delamanid M.tuberculosis MIC M.tuberculosis 0.006-0.024 / post-antibiotic effect QT interval

prolongation electrolyte disturbances(25)

1. Mitnick CD, McGee B, Peloquin CA. Tuberculosis pharmacotherapy: strategies to

optimize patient care. Expert Opin Pharmacother 2009; 10: 381-401.

2. Mitchison MA. Basic mechanism of chemotherapy. Chest 1979; 76: 771-81.

3. Douglas JG and McLeod MJ. Pharmacokinetic factors in the modern drug treatment

of tuberculosis. Clin Pharmacokinet 1999; 37: 127-46.

4. Canetti G, Froman S, Grosset J, Hauduroy P, Langerova M, Mahler HT, et al. Myco-

bacteria: laboratory methods for testing drug sensitivity and resistance. Bull World

Health Organ. 1963; 29: 565-78.

5. Courtesy of CDC/Dr.R Butier; Janice Carr, NIAID/Krista Townsend. Available from:

http://www3. Niaid.nih.gov/topics/tuberculosis/whatis TB/Scientific illustrations/

multidrug Resistant illustration.htm [Cited 2014 August 5].

6. Zhang Y, Yew W. Mechanisms of drug resistance in Mycobacterium tuberculosis.

Int J Tuberc Lung Dis 2009; 13: 1320-30.

7. Telenti A and Iseman M. Drug-resistant tuberculosis: what do we do now?. Drugs

2000; 59: 171-9.

8. World Health Organization. Guidelines for the programmatic management of

drug-resistant tuberculosis. Geneva, Switzerland: World Health Organization; 2008

(WHO/HTM/TB/2008.402).


49

9. American Thoracic Society, CDC, and Infectious Diseases Society of America.

Treatment of tuberculosis, MMWR 2003; 52 (RR11): 1-77.

10. Leong WF, Judi C, Leean JA eds. Mims. 124thed. Thailand: Tims (Thailand) Ltd;

2011.

11. Phenobarbital [Internet]: Drug.com. Available from: http://www.drugs.com/dosage/

phenobarbital.html#Usual_Adult_Dose_for_Seizures [Cited 2014 August 5].

12. . :

(antituberculosis drug-induced hepatotoxicity: incidence, mechanism and

management). 2555; 7: 197-204.

13. Roongruangpitayakul C, Chuchottaworn C. Outcomes of MDR/XDR-TB patients

treated with linezolid: experience in Thailand. J Med Assoc Thai 2013; 96: 1273-82.

14. Riddle RW, Bignall JR, Citron KM, Somner AR, Shera M, Stewart ME, Schonell A.

A Comparison of the toxicity of prothionamide and ethinamide: a report from the

research committee of the british tuberculosis association. Elsevier Inc., Tubercle

1968; 49: 125-35.

15. World health organization. Companion handbook to the WHO guildelines

programmatic management of drug-resistant tuberculosis. Geneva, Switzerland:

World Health Organization; 2014 (WHO/HTM/TB/2014.11).

16. Charles F, Lora L, Morton P, Leonard L. Drug information Handbook 15th ed.

United states of America. Lexi-comp; 2007-2008: 96-7, 431-2, 664, 942-4.

17. World Health Organization. Treatment of tuberculosis: guidelines for national

programmes. 4th ed.; 2009. Available from: http://whqlibdoc.who.int/publica-

tions/2010/9789241547833_eng.pdf. [Cited 2010 May 1].

18. (). : .

: ; 2555: 198-209.

19. CDC. Managing drug interactions in the treatment of HIV-related tuberculosis;

2007. Available from: http://www.cdc.gov/tb/TB_HIV_Drugs/default.htm [Cited

2014 July 1].

20. Yew WW. Clinically significant interactions with drugs used in the treatment of

tuberculosis [online]. 2002. Available from: http://www.ncbi.nlm.nih.gov/

pubmed/11888353 [Cited 2014 July 1].

21. Louw GE, Warren RM, Gey van Pittius NC, Leon R, Jimenez A, Hernandez-Pando

R, et al. Rifampicin reduces susceptibility to ofloxacin in rifampicin-resistant

Mycobacterium tuberculosis through efflux. Am J Respir Crit Care Med 2011; 184:

269-76.

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50

22. Oliphant CM and Green GM. Quinolones: a comprehensive review. Am Fam

Physician 2002; 65: 455-64.

23. Coyne KM, Pozniak AL, Lamorde M, Boffito M. Pharmacology of second-line

antituberculosis drugs and potential for interactions with antiretroviral agents.

AIDS 2009; 23: 437-46.

24. World Health Organization. The use of bedaquiline in the treatment of multidrug-

resistant tuberculosis: interim policy guidance. Geneva, Switzerland: World Health

Organization; 2013 (WHO/HTM/TB/2013.6).

25. World Health Organization. The use of delamanid in the treatment of multidrug-

resistant tuberculosis: interim policy guidance. France: World Health Organization;

2014 (WHO/HTM/TB/2014.23).


51

5.1Pre-XDR-TBXDR-TB

(extensive drug resistant tuberculosis,

XDR-TB)

(World Health Organization, WHO)

(Centers for Disease Control and Prevention, CDC-USA) .. 2006 (.. 2549)

(MDR-TB)

aminoglycoside FQs

..

2549 .. 2549(1)

5.1.1 (Pre-XDR-TB)

(XDR-TB)

(XDR-TB)

( H R) FQs (Ofx, Lfx, Mfx)

second line injectable drugs (SLIs) Km, Am, Cm

(Pre-XDR-TB)

( H R) FQs (Ofx, Lfx, Mfx)

second line injectable drugs (SLIs) Km, Am, Cm

5.1.2 (Pre-XDR-TB) (XDR-TB)

H, R, Ofx Km Am

molecular technique line probe assays (LPA)

5 XDR-TB

5.1 Pre-XDR-TBXDR-TB

5.2 (Palliativecares)

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LPA

Ofx / Km

LPA Ofx / Km

5.1.3 (Pre-XDR-TB)

(XDR-TB)

Pre-XDR-TB XDR-TB

Cs Eto

Pre-XDR-TB second line injectable drugs (SLIs) / FQs

(Pre-XDR-TB)

(XDR-TB)

4 20

(Pre-XDR-TB)

(XDR-TB)*

1: /

- aminoglycosides Km, Am, Cm /

- FQs Lfx, Mfx /

- second line oral anti-tuberculosis drugs Eto, Cs , PAS

2:

4

- Lzd 300-600 ./ /

- Cfz 100 ./ /

- Ipm/Cln 500-1000 . 2 /

- Clr 500 . 2 /

- Amx/Clv 875/125 . 2 /

- High-dose H** 16 ././ 800 ./

3: Bdq Dlm

- Bdq 400 .(4 100 .) 14

200 .(2 100 .) 3 22

- Dlm 100 . 2 24 :

*

** high-dose H INH (>1% 0.2 /

1 / INH) high-dose H INH (>1%

1 / INH)


53

(Pre-XDR-TB)fluoroquinolone

1. Mfx Mfx 400 ./

Mfx

Mfx

2. Lzd 600 ./

600 ./ 300 ./(2,3)

3. Cfz 100 ./ (4,5)

4. Km 15 ././ 1,000 ./

5. 3

Bdq Dlm

(Pre-XDR-TB)aminoglyoside

1. Lfx 500-750 ./

2. Cfz 100 ./ (4,5)

3. Cm 15 ././ 1,000 ./

4. 3 Lzd

Bdq Dlm

(XDR-TB)

1. Mfx Mfx 400 ./

Mfx

Mfx

2. Lzd 600 ./

600 ./ 300 ./ (2,3)

3. Cfz 100 ./ (4,5)

4. Cm 15 ././ 1,000 ./

5. 3

Bdq Dlm

5.1.4

3

Lzd CBC 2

(optic neuritis)

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Cm BUN, Cr

electrolyte potassium

Cm

Cfz

Bdq Dlm

active pharmacovigilance

5.2(palliativecare)(6,7)

MDR/XDR-TB

MDR/XDR-TB

(quality of life)

5.2.1 MDR/XDR-TB

4

. DOT

.

1

.

1 smear

() smear

.

.


55

. HIV

HIV

5.2.2

MDR/XDR-TB

. smear 8 10

.

. 2

. (respiratory insufficiency)

5.2.3.

.

. 2

.

.

.

5.2.4

MDR/XDR-TB (palliative cares)

.

.

.

.

.

.

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. (disused atrophy)

.

5

1. Revised definition of extensively drug-resitant tuberculosis. MMWR Weekly 2006;

55: 1176.

2. Sotgiu G, Centis R, DAmbrosio L, Alffenaar JW, Anger HA, Caminero JA, et al.

Efficacy, safety and tolerability of linezolid containing regimens in treating MDR-TB

and XDR-TB: systematic review and meta-analysis. Eur Respir J 2012; 40: 1430-42.

3. Roongruangpitayakul C, Chuchottaworn C. Outcomes of MDR/XDR-TB patients

treated with linezolid: experience in Thailand. J Med Assoc Thai 2013; 96: 1273-82.

4. Cholo MC, Steel HC, Fourie PB, Germishuizen WA, Anderson R. Clofazimine: current

status and future prospects. J Antimicrob Chemother 2012; 67: 290-8.

5. Dey T, Brigden G, Cox H, Shubber Z, Cooke G, Ford N. Outcomes of clofazimine

for the treatment of drug resistant TB: a systematic review and meta-analysis. J

Antimicrob Chemother 2013; 68: 284-93.

6. World Health Organization. Guideline for the Programmatic management of

drug-resistant tuberculosis. Italy: WHO; 2006 (WHO/HTM/TB/2006.361).

7. World Health Organization. Palliative care: symptom management and end-of-life

care. Geneva: World Health Organization; 2004 (WHO/CDS/IMAI/2004.4).


57

6.1HIV

6.1.1

CD4

immune reconstitution inflammatory syndrome (IRIS)

6 (1-7)

CD4

6

6.1 HIV

6.2

6.3

6.4

6.5

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367 /..

IRIS

Department of Health and Human Services (DHHS)

guidelines .. 2557

CD4 CD4 50

/.. 2

CD4 50 /..

Karnofsky score (body mass index,

BMI) 2-4

8-12

CD4

CD4 50 /.. 2

CD4

50 /.. 2

2-8

CD4

2-4

6.1.2

R

CYP 450 efflux multi-drug transporter p-glycoprotein

non-nucleoside reverse transcriptase inhibitors (NNRTIs) protease

inhibitors (PIs) Eto CYP 450

Eto aminoglycoside

tenofovir (TDF) 6.1

.

HIV TDF + emtricitabine (FTC) + efavirenz (EFV) TDF + lamivudine (3TC) +EFV

.

. TDF nucleotide reverse transcriptase inhibitor (NRTI)

creatinine clearance

. TDF +

lamivudine (3TC) + EFV


59

. Abacavir (ABC) + 3TC + EFV NRTIs

zidovudine (AZT) TDF

ABC hypersensitivity reaction

nevirapine (NVP) ABC NVP

. AZT + 3TC NRTIs

EFV NVP

. Efavirenz (EFV) NNRTI

NVP

EFV

. NVP NNRTI

AZT + 3TC

CD4 250

/.. CD4 400 /..

. Lopinavir (LPV)/ritonavir (RTV) PIs

800/200 .

24 . 400/100 . 12 .

. Darunavir (DRV)/ritonavir (RTV)

800/100 . 24 .

. NVP EFV NRTIs

2-4 NVP EFV

NNRTIs

. R

NNRTIs PIs TDI aminoglycoside Cm

renal toxicity AZT Lzd anemia d4T

Lzd peripheral neuropathy LPV/RTV Bdq

toxicity TDF, EFV LPV/RTV Dlm Dlm

. aminoglycoside FQs

TDI renal toxicity, AZT anemia

d4T peripheral neuropathy first line ART MDR-TB, Pre-XDR-TB

XDR-TB AZT+3TC+EFV

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6.1

NRTIs

+

NNRTIs

NNRTIs

Tenofovir/emtriciabine*

Tenofovir/lamivudine

Efavirenz Lopinavir/

ritonavir

Abacavir/lamivudine

Zidovudine/ lamivudine

Rilpivirine

Nevirapine

Atazanavir/

ritonavir

Darunavir/

ritonavir

Raltegravir

Elvitegravir

*

6.1.3

rifampicin (R)

6.1.3.1 R

6.1.3.2 R

R CYP 450

efflux multi-drug transporter p-glycoprotein NNRTIs PIs

. NNRTIs EFV NVP

. PIs

- PIs NNRTIs EFV NVP

integrase inhibitor ( raltegravir)

- NNRTIs integrase inhibitor

R

R R

MDR-TB, Pre-XDR-TB

XDR-TB AZT+3TC+EFV


61

6.1.4

CD4

CD4 6.2

6.3

6.2

CD4 6

12

6 12 CD4

> 350 cells/mm3 VL < 50

copies/mL 1

.

2

(viral load, VL)

3

6

VL < 50 copies/mL

1 VL > 50

copies/mL

6.3

ALT

- 3

Creatinine (Cr) 15-20

15-30

15-30

1

-

50

50 . indinavir

(IDV) 6

- TDF IDV

6

Total Cholesterol,

Triglyceride,

Fasting blood

sugar

1

1

- < 35

1 /

- < 35

2 /

- < 35 2

/

( .)

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Urinalysis 1

1

-

50

IDV 6

- TDF IDV

6

6.1.5 (immune reconstitution

inflammatory syndrome, IRIS)

CD4 CD8

immune reconstitution inflammatory syndrome (IRIS)

immune recovery syndrome (IRS)

paradoxical IRIS

unmasking IRIS

paradoxical IRIS

International Network for the Study of HIV-associated

IRIS (INSHI) paradoxical IRIS (8)

6.4

prednisolone placebo

TB paradoxical IRIS prednisolone 1.5

./. 2 0.75 ./. (9)


63

prednisolone

placebo

prednisolone

c-reactive protein (CRP) cytokines interleukin (IL)-6,

IL-10, IL-12, interferon-gamma (IFN), tumor necrosis factor (TNF) chemokines prednisolone paradoxical IRIS

1.5 ./. 2

4 unmasking TB IRIS

6.4 paradoxicalIRIS(8)

I. 2

1.

2.

2

II.

3

1 2

1.

2.

3.

4. (serositis)

1.

2.

3. (peritonitis)

III.

1.

2.

3.

4.

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6.2

primary tuberculous infection

() AFB

(primary drug resistance TB)

acquired drug resistance TB

MDR-TB (10)

28 34

MDR-TB 5.7 3.8 (11,12)

6.2.1

1 3

2

(index caes)

80-90(13)

80 AFB

(rapid drug susceptibility testing)

line probe assay Xpert MTB/RIF

(14-16)

(17)

.

.

. 1

.

6.1(17)

AFB

6.2.2

6.2.2.1

MDR-TB 15-18

(18,19)

5 (20) INH


65

R INH

INH R(21) (MDR-TB)

6.2(21)

6.2.2.2 (17)

6.2.2.2.1 1 MDR-TB (monoresistant

polyresistant-TB)

INH 6-9 RZE 2RZE/10RE

FQs

R 2 4 INH,

E, FQs ( Lfx Ofx) PZA 2 INH E INH FQ

12-18

1 MDR-TB

FQs / 1 2

12-18 (22)

6.2.2.2.2 MDR-TB

6.1

4 1

6.5(17,23)

4 (1) 1

(2) 2 Am Km (3) 3

FQs Lfx Mfx Ofx ciprofloxacin (4) 4 2

1 4

4

5

1 MDR-TB

Km5LfxEtoCs (PAS) (Km

5 = kanamycin 5 , Lfx = levofloxacin, Eto

= etionamide, Cs = cycloserine, PAS = para-aminosalicylic acid) PAS

MDR-TB PAS(23) PAS

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4 (17)

6

4

6

(17,23,24)

3-4

18

20

(23,24)

.

. Directly observed therapy (DOT)

.

.

PAS

2

6.5


67

6.1 (17)

()

Xpert MTB/RIF

RIF Inconclusive

//

1

()

* 1

( ) /

/

* Xpert MTB/RIF rifampicin

1

( )

2

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6.2 (MDR-TB)(21)

MDR-TB

?- - -

- TST IGRAs- /-

- ( 1 )- -

12

1-2 6 2 (

)

- -


69

6.5 (17,23)

././

/

1

1

Isoniazid

Rifampicin

7-15

10-20

300 .

600 .

hepatotoxicity

hepatotoxicity, rash, flu-like

symptom

Ethambutol

Pyrazinamide

15-25

30-40

1.2

2

optic neuritis (rare)

hepatotoxicity,

arthralgia, rash

2

Amikacin

Kanamycin

Capreomycin

15-20

15-30

15-30

1

1

1

ototoxicity,

nephrotoxicity

3

Fluorquino-

lone

Ofloxacin

Levofloxacin

Moxifloxacin

15-20

7.5-10*

7.5-10

800 .

750 .

400 .

insomnia

arthralgia

4

2

Ethionamide 15-20 1 hepatotoxicity, hypothyroidism

Cyclocerine 10-20 1 psychosis, convulsion,

paraesthesia, depression

PAS 150-200

(

2-3 )

1.2 diarrhea, hypothyroidism

5

3

(

)

Linezolid 10-12** (1 ) - myelosuppression,

peripheral neuropathy,

lactic acidosis

Clofazimine 3-5 (1 ) - skin discoloration, xerosis

Amoxi/clavulanate

- gastrointestinal intolerance

Thioacetazone 5-8 (1 ) - gastrointestinal intolerance,

dermatitis, thrombocytopenia,

agranulocytosis

Imipenem

- drug rash, convulsion

High-dose INH 15-20 (1 ) - hepatitis, peripheral

neuropathy

Clarithromycin 7.5-15 ( 2 ) - gastrointestinal intolerance,

prolonged QT syndrome

* 5 Levofloxacin 7.5-10 ./. 2

** Linezolid 10 10-12 ./. 2

GI disturbance

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6.3(managementduringpregnancyandbreast-feeding)

urine pregnancy test

second trimester

(22)

FLDs SLDs class C FDA Class

( 6.6)(25)

aminoglycosides Sm, Km Am ototoxic teratogenic effect

Cm ototoxic teratogenic effect

FQs, Eto unclear efficacy teratogenic effect

SLDs 4 FQs 1 Cm

Km second trimester

first trimester 3

B6 150 ./ B6

FQs

B6 withdrawal


71

6.6 Anti-TBdrugsU.S.FDAclass(25)

Safetyclass Drug

A -

B ethambutol, amoxicillin/clavulanate

C

isoniazid, rifampicin, pyrazinamide, fluoroquinolones, ethionamide, prothion-

amide, para-amionosalicylic acid, cycloserine, capreomycin, linezolid, clarithro-

mycin, clofazimine

D streptomycin, kanamycin, amikacin

X -

(22) guidelines(25)

6.4(liverdysfunction)

( PZA) hepatotoxicity E aminoglycosides hepatotoxicity

FQs hepatotoxicity hepatotoxic effect

4 PZA

PZA

6.5(renalinsufficiency)

6.7(22)

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6.7 (22)

CrCl2 6

6. (transferred out)

6

7.1.2.1 (final outcome)

PMDT 08

1. (cured)

3 30

2. (treatment completed)

3

3. (treatment failed)

2

.

(culture conversion)

. (culture reversion)

. FQs SLIDs

.

4. (died)

5. (lost to follow-up) >2

6. (transfer out)

7. (on treatment)

8. (not evaluated, NE)

* 8

** (treatment success)

AFB

2 3 6

6 2

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7.2

DR- TB

(TB03)

1 . . . .

2 PMDT 03

2 TB 03 DR-TB center (./

./.)

.

DR-TB center

3

6

1. PMDT 07 3 (detection)

(enrolment ) DR-TB 1

6-9

2. PMDT 07/1 (interim results) 3

6 2

PMDT 07 15-18

3. PMDT 08 (final outcomes) 12

2 PMDT 07 ( 4 cohort/)

36-48

7.3(multidisciplinarycare)

(DOT)(2,3)

2


79

DR-TB

7.3.1

1.

2.

3.

4.

5.

1.

2. (unit dose)

3.

4.

5.

()

1.

2.

3. HIV

4. /

5. (DOT)

6.

7.

/

1.

2.

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80

3.

4.

(infectioncontrol,IC)

1.

2.

3.

4.

1

5. IC

1.

2.

3.

4.

5.

(ProvincialTBcoordinator,PTC)

1.

2.

DOT

3.

4.

(PMDT 07, 07/1, 08) (./.)


81

(RegionalTBCoordinator,RTC)

1.

2.

3.

4. (PMDT 07, 07/1, 08)

7.3.2 (case management)

2

1. second line drugs

(DOT)

2.

(on the job training)

(DOT)

3.

7.3.3 (DOT)

DOT (directly observed therapy)

2 4

6 20

(DOT)

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7.3.3.1 (DOT watcher)

1. (accountability)

2. (accessibility)

3. (acceptance)

(patient support)

7.3.3.2

(DOT corner)

(packet)

(initial phase) ( 6 )

(DOT)

.

.

.

(treatment card/DOT card)

. 10-15

.

.

.

.

. ( 1 )

(maintenance phase)

14 (DOT)


83

7.4

2

4

6 20

2

10 30

DOT DR-TB

DR-TB

DOT

7.1

7.1

./ .

.

../

./

./.

./.

./.

(comprehensive)

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. 2

./.. DOT

.

.

(refer/transfer) case conference

./. ./..

DOT ./.

./.. (.)

DR-TB

DR-TB

2 team approach

community based clinic based

(patient center)

7.5

2 20

1.

(true sputum) 2 . () 2-5 .

2. ()

1


85

3. 2 (spot

sputum) 2 (collected

sputum)

4.

()

- (3% normal saline nebulization)

(

)

- /

(biopsy)

5.

(ice pack)

7.6(2,3)

(close contact)

(indoor living space)

..

2

.

.

.

.

. DR-TB

.

DST 2.2 ( 2)

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. DR-TB

tuberculin skin test (TST)

IGRA Test

2 smear,

culture DST Xpert MTB/RIF

(AFB smear) rifampicin

.

DR-TB DR-TB

. 2

.

7.7 . .

2550 2558 .

(4) 13

1.

- FLD: H 100 , R 300 , R 450 , Z 500 , E 400

, E 500 , S 1

- FDC: H 100 + R 150 , H 150 + R 300 H 75

+ R 150 + Z 400 + E 275

- SLD: Km 1 , Ofx 200 , Lfx 500 , Eto 250 , P 1 ,

Cs 250

XDR-TB .

.

2.

- AFB 6 3 () course

- 5 course

- Standard package Alternative

package 7.1(4)


87

7.1 *

Package &

Remark

Standard package

Solid/Liquid

culture & DST

Alternative package

molecular assay

+ Solid culture

(DST)

Re-treatment

group

Relapse All case

(AFB + or -)

AFB +ve only

Package

Treatment after

default

On-treatment

group

3

AFB +ve only AFB +ve only

Pre-treatment

group with

risk factors

Household MDR TB All case

(AFB + or -)

AFB +ve only

Prisoner

TB with HIV positive

: * 3-3[4] 89 . 2558 (4)

.. 1 course ( .

)

- . solid liquid culture

( DST) 16 course .

. molecular assay

3. . . .

4. . . .

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1. .

.. 2556. 2. :

; 2556.

2. .

.. 2556. 2. :

; 2556.

3. World Health Organization. Companion handbook to the WHO guidelines for the

programmatic management of drug-resistant tuberculosis, Geneva, Switzerland:

World Health Organization; 2014 (WHO/HTM/TB/2014.11).

4. .

2558:

. 1. : ; 2557.


89

(1)

MDR-TB 1.65

MDR-TB 34.5 .. 2549 XDR-TB .. 2550(2)

.. 2536

68-85(3-6)

39.4-86.4(7-8)

(9-11)

(11)

8.1

2-10

(12)

.

.

8

8.1

8.2

8.3

8.4

8.5

8.6

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.

(13-17)

8.1.1

(18)

(sputum induction) (bronchoscopy)

(endotracheal intubation) aerosolized pentamidine

(wound irrigation) (

)(19)

8.1.2

(20)

8.2

3 (21)

8.2.1 (administrative measures)

.


91

(13)

(21)

.

.

smear 24

. (21)

(22)

1-3

.

(bronchoscopy)

.

(airborne droplet nuclei)(23)

(21)

.

tuberculin skin test (TST)

interferon gamma release assay (IGRA)

.

.

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8.2.2 (engineering controls)

12

(21)

(12)

(smoke tube tracer test)

(24)

8.2.3 (respiratory protection)

1 particulate respirator(22) N95, N99

8.3

. (triag

Documents

แนวทางการบริหารจัดการผู้ป่วยวัณโรคดื้อยา พ.ศ. 2558