Practical Issue in the Management of Tuberculosis

.. 2554

.. 2554

 (Abbreviation)
AFB

Acid-fast bacilli ()

AIDS

Acquired immunodeficiency syndrome ()

ART

Antiretroviral therapy ()

Cs
CSF
DOT

D-cycloserine
Cerebrospinal fluid ()
Directly observed treatment ()

DST

Drug susceptibility testing ()

DR-TB

Drug-resistant tuberculosis ()

E, EMB

Ethambutol

Eto

Ethionamide

EPTB

Extrapulmonary tuberculosis ()

FLDST

First-line drug susceptibility test ()

FDC

Fixed-dose combination ()

H, INH

Isoniazid

HIV

Human immunodeficiency virus ()

INF
IGRA
Km

Interferon
interferon-gamma release assay
Kanamycin

Lfx

Levofloxacin

MDR-TB

Multi-drug-resistant tuberculosis ()

NNRTI

Non-nucleoside reverse transcriptase inhibitor

NRTI

Nucleoside reverse transcriptase inhibitor

NTM
NTP

Non-tuberculous mycobacterium
National tuberculosis control programme

PAS
PI
PTB

P-aminosalicylic acid
Protease inhibitors
Pulmonary tuberculosis ()

Rapid DST

Rapid drug susceptibility test ( H / R )

R, RMP

Rifampicin

SLDST

Second-line drug susceptibility test ()

S, SM

Streptomycin

SSC
TB

Standard short-course (, 2HRZE/4HR)

Tuberculosis ()

TB/HIV

HIV-related TB

TST
WHO
XDR-TB

Tuberculin skin test

World health organization ()
Extensively drug-resistant tuberculosis ()

Z, PZA

Pyrazinamide


(Strength of Recommendation)
++
(strongly recommend)

(Cost effective)
+
(recommend)

+/ (neither recommend nor against)

(against)

- (strongly against)

 (Quality of Evidence)
I
1) (systematic review)
(randomize-controlled clinical trials)
2) (welldesigned, randomize-controlled, clinical trial) 1
II
1) (systematic review)
(non-randomized, controlled, clinical trials)
2) (welldesigned, non-randomized, controlled clinical trial)
3) (cohort)
(case control analytic studies)
/
4) (multiple time series)

..2480

III
1) (descriptive studies)
2)
clinical trial)

(fair-designed,

controlled

IV
1) (consensus)

2) 2
V
(Anecdotal report)


(incidence)
10 . 2552
30 , (new
case) (relapse) 9.4 1.7

9 17 22

.2558

Genus; Mycobacterium M. tuberculosis

complex M. tuberculosis (), M. africanum (), M. bovis (/
), M. canetti M. microti (), M.
pinnipedii, M. caprae M. mungi 3 species DNA sequence
M. tuberculosis (M. TB)

airborne-transmitted infectious disease

(TB
infection)
30 (tuberculin skin test;
TST) interferon gamma ()
interferon-gamma release assay (IGRA)

(latent TB infection; LTBI)
10 LTBI (
) (reactivated TB)
(primary TB) 4-6

10-15
(Standard short-course; SSC) 2

o 2
(++, I)
o 2
SSC (++, II)
o () 2
SSC

(++, III)
o
(++, II)

 2
2.1
,

2.1.1


rales stethoscope
(post-tussive rales)

o 2
( 2.1)
2.1.2
reticulonodular cavity

o
(++, I)
o
( 2.2)
2.1.3
2.1.3.1 ,

o
(true sputum)
() 1 (++, II)
o 2 (spot sputum)
(collected sputum) (++, II)
o / (++, IV)
o
()

 2.1

2.2

. (3% saline via nebulization) (

) (+/-, IV)
. (biopsy)
/ (+/-, I)
2.1.3.2
(Gold standard) (Nontuberculous Mycobacterium; NTM)

o
(DR-TB) (++,II)
-
- 2 (default),
(relapse) ()
- (treatment failure) (
2.2.3 )
-
NTM
, bronchiectasis (++,II)
o (PTB SS pos.)

o (PTB SS neg.)

2.1.3.3 (nucleic acid amplification test; NAAT)
PCR, real-time PCR,

o NTM
(*)
2.1.3.4 tuberculin skin test, Interferon gamma-released assays (IGRA)

2.2
2.2.1

o >60


o nephritic syndrome
Aminoglycosides
2.2.2
(..2552) Category 1 4
3
1: New patient regimen 1
- 2HRZE / 4HR

( 2.1.3.2 )
1 (++, I)
(delay treatment response)
(continuation phase) SSC 9-12
, 6
, ,

2: Re-treatment regimen with first-line drugs

- 2HRZES / 1HRZE / 5HRE
default relapse

3: MDR regimen
(MDR-TB)
- > 6Km5LfxEtoCs+PAS / > 12 LfxEtoCs+PAS
treatment failure

:
Kanamycin 5 4
3 (intensive phase)
Kanamycin Streptomycin

10

 3 MDR-TB regimen (++, II)

o
o
o

1 4

o
2 (culture conversion) 4
6

18 2

3
2 3
( 2.1)
2.1

Treatment after failure

Empirical MDR-TB regimen:

> 6Km5LfxEtoCs+PAS /
> 12 LfxEtoCs+PAS

DST

Treatment after
relapse or default

Retreatment regimen:
2HRZES/1HRZE/5HRE

( 2)

2.2.3
(2 )

11

 1: New patient regimen ( 2.3)

1)
( 2.1.3.2 )
2) ( 2 )

o 2 HR
PTB (SS+) 5

PTB (SS neg.)

o 2 *
(
)


HR HRZE 1


3
2
-
- (drug-to-drug / drug-to-food interaction)

-
(immuno-compromised host)
-
- NTM
-
3) 3 2
o 3
HR 2

o 3
( 2)

12

( 2)
HR
5

MDR-TB treatment failure

MDR-TB (
2)

2.3

4) 5 ()
o
HR

13

treatment failure MDR-TB

( 2)
( )

2: Re-treatment regimen with first-line drugs ( 2.4)

1)

2) ( 3 )

o 3
HRE

5
o 3

HRE

MDR-TB treatment failure
MDR-TB
( 2)

5
4) 5 ()
o 5
HRE
2
3

14



o 5


treatment failure MDR-TB empirical regimen

( 2)
( )

2.4 (Re-treatment regimen with 1st line drugs)

2.2.4 (Treatment after interruption)

( 4
4.5)


2.5

15

 Treatment after interruption (++, IV)

o *



o
o
DOT
o
2.5

* ,

16

 3
3.1
primary reactivated TB


3.1

3.1

()
5 -44
30 -50
32
20 - 28

(biopsy) ( 3.2)
tuberculin skin test (TST)
3.2

()
< 10

()
<1

()
5 37

12 - 70

25 - 60

40 -80

1.
exudate lymphocyte ADA
2.
3.

17



(CSF)
3.4
o (
)




o
NTM
o immunodiagnostics non-conventional diagnostics PCR

3.4
Characteristic
Appearance
pH

usually straw colored straw colored or serosanguinous clear early, turbid with chronicity
rarely < 7.3, never > 7.4
not well described
not well described

cell count
cell differential

1,000 - 5,000
lymphocytes 5090%,
eosinophils < 5%,
few mesothelial cells

not well described

increased lymphocytes,
PMN preponderant early, later
up to mononuclear cells
predominate

100 - 500
PMN preponderant early, later
up to 95% mononuclear cells

protein
glucose

usually > 2.5 g/dl

usually < serum conc.

usually high
low

cytology

no malignancy cell

no malignant cell

usually high (100-500 mg/dl)

usually 40-50 mg/dl
(50% of blood glucose)
no malignant cell

3.2

3.5 systemic corticosteroid
3.6

18

 3.5 (Standard short-course, SCC)

()

Rating

(Tuberculoma)

6
6
6
> 12

++, I
++, II
++, II
+, II

9 12
6

++, I
++, II
-

o
(++, II)
o
(*)
AFB (*)
AFB NTM

(*)
incision and drainage
o systemic
corticosteroid 3.6
o Obstructive hydrocephalus
A-P shunt (*)
o surgical debridement radical operation
(*)

1. (*)
2. cord compression persistence recurrence of neurological deficit (*)
3. instability of spine (*)
o nephrectomy nonfunctioning or poorly functioning kidney
(continuous flank pain) (*)

19

 3.6 corticosteroid

Corticosteroid

*
*

Rating (corticosteroid)
-, IV
-, I
++, I
++, I
-, IV
-, IV
-, IV

Prednisolone 40-60 mg/d 2-4 wk 30 mg/d x 2 wk 15 mg/d x 2 wk 5 mg/d x 1 wk

20

 4
(first-line anti-tuberculosis drugs, FLD)
4.1
( 14 ) 4.1
4.1

(.)
30 40 *
40 - 50
> 50

H (.)
5-10
././

R (.)
8-12
././

Z (.)
20-30
././

300
300
300

300
450
600

1,000
1,250
1,500

E (.)
15-20
././

S (.)
15-18
././

600
800
1,000

500
750
1,000

* < 30 .

o (FDC) HR, HRZ, HRZE

(*)
o Ethambutol / (*)
o Streptomycin (*)
o Streptomycin (> 60 ) 750 ./
750 ./ (*)
o

4.2
(standard short-course; SSC)
100%

4.2.1

(initial phase intensive phase)

21

4.2.2

4.2.3 6 12

4.2.4

directly observed treatment (DOT)

o (*)
(daily package) (fixed-dose drug combination; FDC)
(*)
o
, (*)
o
DOT 4.1 (*)

4.3


2 (major side-effects) (minor sideeffects) 4.2
4.3.1
3

o
o

o
prednisolone

22

 4.1 (DOT)

4.2

(vertigo nystagmus)

purpura

S
S
H, R, Z

E
R
S
Z, R, H
Z>E
H
H
R

aspirin, NSAIDS paracetamol

pyridoxine 50-75 .

intermittent

23

o systemic steroid
prednisolone 40-60 .

o
o
- H R E Z
- 1/3 1/2 2-3

4.3.2 /





. H, R Z bilirubin
AST/ALT R

o >60 ,
, , , ,

o 5

o
AST/ALT total bilirubin (TB)
o
AST/ALT TB 1-2 1

o
o AST/ALT > 3
H, R Z
o AST/ALT < 3
3

24


o TB > 3 ./ AST/ALT 3
R
o AST/ALT < 5
1
o AST/ALT > 5
H, R Z
re-challenge
o fulminant hepatitis
o AST/ALT < 2 TB < 1.5 ./.
o H, R Z
o 1
o
o AST/ALT TB 1

o re-challenge AST/ALT TB

4.3.3 (Optic neuritis, Retrobulbar neuritis)

ethambutol isoniazid
(dyschromatopsia, - -)
(central scotoma)


50
ethambutol
o
o (visual acuity)
ethambutol
o ethambutol 15 ././ 20 ././
o
o
o
o
o isoniazid isoniazid

25

4.4
Rifampicin (R) estrogen,
, , , ,

4.5 (Organization of tuberculosis treatment unit, TB Clinic)

4.5.1

-
4.5.2
(
1-2 5-7 )

4.5.3
(daily package) (FDC)
Bioavailability

4.5.4
4.5.5

4.5.6
(DOT)

4.5.7

4.5.8
(
)

26

 5
5.1 /


1.

2. ( CD4 < 200 cells/L)

, ,

3.
4. (Stevens-Johnson syndrome; SJS
toxic epidermal necrolysis; TEN )
5. RMP
Protease inhibitor (PI), azole ( Itraconazole, Ketoconazole),
Macrolides
6. paradoxical reaction immune restoration inflammatory syndrome (IRIS)

Constitutional symptoms



NTM CD4 < 50 cells/L
AFB CD4
2
1. (CD4 > 350 cells/L)

2. (CD4 < 200 cells/L) 50

( CD4 > 350 cells/L 28)

CD4
(typical CXR) CD4 CD4 < 200
cells/L interstitial
infiltration military infiltration

27


o
o
o NTM
(*)
o (*)
-
(needle aspiration) (tissue biopsy)
(bone marrow aspiration) pancytopenia
(CSF)
- (
) ( therapeutic diagnosis)
2
-

(SSC)
o 2
6 9
o RMP RMP sputum conversion

o 6 (pyridoxine) 50100 mg
(++, II)
o CD4
(++, I) ( 5.1)
o RMP Nucleoside revese
transcriptase inhibitors (NRTIs) Non-nucleoside reverse transcriptase inhibitors (NNRTs)
(++, I)
o Protease inhibitors (PIs) (--, I)
(
.. 2553)
o
(++, II)

28

 5.1 (Primary prophylaxis)

CD4
CD4

(Primary prophylaxis)

>200 - 350

2 NRTI + 1 NNRTI
()

>100 - 200

Co-trimoxazole
( 1 )

2 NRTI + 1 NNRTI
( 2 - 2 )

< 100

Co-trimoxazole
( 2 )
Fluconazole
( 2 )

2 NRTI + 1 NNRTI
()

5.2

SSC
o ALT > 3
()
2
9 HRE (*)
2 SHRE / 7HR (*)
6-9 RZE (*)
1
2 SHE/10-16 HE (*)

18-24 HE + Fluoroquiniolone (*)
o 1 2 - 3 2
2
(*)

29

o (
) (*)
o INH 6 (pyridoxine) 50100 mg
(++, II)
o 4.3.2

5.3
o
o

o
o
o

INH RMP
EMB metabolites PZA creatinine
clearance < 30
(concentration dependent bactericidal)
5.2
SM (*)
(hemodialysis) PZA
hemodialysis
INH 6 (pyridoxine) 50100 mg
(++, II)

5.2 creatinine clearance < 30

(hemodialysis)

INH
RMP
EMB
PZA
SM

15-20 mg/day, 3 days/week

25-35 mg/day, 3 days/week

5.4

o SCC

o INH 6 (pyridoxine) 50100 mg

(++, II)

30

o


o SM
o fluoroquinolone

1. Havlir DV, Barnes PF. Tuberculosis in patients with human immunodeficiency virus infection. N Engl J
Med 1999; 340: 367-73.
2. Barnes PF, Lakey DL, Burman WJ. Tuberculosis in patients with HIV infection. Infect Dis Clin North Am
2002; 16: 107-26.
3. Jones BE, Young SM, Antoniskis D. Relationship of the manifestations of tuberculosis to CD4 cell counts in
patients with human immunodeficiency virus infection. Am Rev Respir Dis 1993; 148: 1292-7.
4. Abouya L, Coulibaly IM, Coulibaly D, Kassim S, Ackah A, Greenberg AE, et al. Radiologic manifestations
of pulmonary tuberculosis in HIV-1 and HIV-2-infected patients in Abidjan, Cote d'Ivoire. Tuber Lung Dis
1995; 76(5):436-40.
5. . Mycobacteria : ,
, , , , , .
, 1 : , 2548, 1177-91.
6. American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of
America. Treatment of tuberculosis. Am J Respir Crit Care Med 2003; 167:602-62.
7. Marries A, Maher D, Graham S, editors. TB/HIV a clinical manual, 2nd ed., WHO 2004.

31


1
1.1
(2009) 4
1.1.1
1.1.2 ()
1.1.3
1.1.4

1.1.1. 1.1.2 ( 2.1)

(Pulmonary Tuberculosis: PTB)
( 2)
- (PTB SS+)
1
- (PTB SS neg.)
1)
- 2 ( collect sputum 1 )
- active TB
- ( Fluoloquinolone
)
2)
(M. tuberculosis) WHO
1 5
( )
- (PTB SS not done)

(Extrapulmonary Tuberculosis: EPTB)

/
( 3) (Mediastinal
and/or hilar lymph nodes) (Pleural effusion)

32

 2.1

(, )

(, )

(,
)

PTB, SS- *

(
)

(
)

PTB, SS+ *

PTB, SS not done

EPTB

*
1.1.3
2.2

1.1.4.

1.2
2.3

33

 2.2

1
Defaulted **

+ neg.

(New)

Treatment success **

Treatment failed **

+ neg.

+ neg.

TAD

Relapse **
(Previously
TAF
treated)
(Transfer in)

(Other)

* + M. tuberculosis
neg. M. tuberculosis

** 2.3

34

 2.3

(Cure)

(Treatment completed)

(Treatment success)
(Treatment failure)

(Died)
(Default)
(Transfer out)

1
-
(
)
-

-
- (
) 5
- DST MDR-TB

-
- / 2
-

35