Transcript Treatment of TB

Anti-TB Medication
95年度北區醫師結核病診治課程
2006年5月7日
衛生署桃園醫院內科加護病房主任
莊子儀醫師
Outline




TB Microbiology
Basic Concept
Treatment of TB
Drug-Resistant TB
TB Microbiology
M. tuberculosis is an aerobic, non-spore
forming, non-motile bacillus with a high cell
wall content of high-molecular weight lipids
(up to 60% dry weight content).
 Cell division occurs from 15-20 hours

 Share
the staining characteristic known a
acid-fastness: red stain seen upon
application of acid-alcohol stain
TB Microbiology

The rigid core of the cell wall
is composed of three
STRUCTURAL
COMPONENTS


Peptidoglycan, Arabinogalactan,
Mycolic acids
External to the peptidoglycan
and the arabinogalactan are
the mycolic acids, which
together with free lipids act
as a hydrophobic
permeability barrier
TB Microbiology




Actively multiplying/growing organisms
(susceptible to chemotherapy)
Slowly growing and metabolically inactive
(relatively poor response to antibiotics)
Intracellular bacilli slowly growing in
macrophages (difficult to treat due to poor
accessibility for antibiotics )
Dormant population (resistant to chemotherapy)
Basic Concept



All drugs as a single dose on empty stomach
The use of a single drug should be avoided
(except for prophylaxis)
In multiple drug regimens at least one drug
should be bactericidal
Basic Concept




Use multiple drugs to which the organisms
susceptible
 Mutation rate about 10-7
 Patient with TB may have 1010 organisms
Never add single drug to failing regimen
Ensure adherence to therapy
Duration of therapy: 6-9 months
Basic Concept
TB Case
過去治療史
Y
•Return after default
•Relapse
•Failure
•Chronic case
N
新案
標準初次
治療
照會專業醫師
Basic Concept





新案 (new case)：不曾接受過抗結核藥治療或曾接
受少於 4 週抗結核藥治療之病人。
復發 (relapse)：曾接受一個完整療程之抗結核藥治
療並經醫師宣告治癒而再次痰塗片陽性之病人。
失敗復治 (treatment after failure)：治療五個月後依
然痰塗片陽性的病人，或者治療前痰塗片陰性、
治療二個月後變成痰塗片陽性的病人。
失落復治 (Treatment after default)：中斷治療兩個
月以上而再次痰塗片陽性之病人。
慢性病人(chronic case)：在監督下接受完整之復治
處方治療後依然痰塗片陽性之病人。
Treatment of TB

First-line agents:
Isoniazid (INH)
 Rifampin (RIF)
 Ethambutol (EMB)
 Pyrazinamide (PZA)
 Streptomycin (SM)


Second-line agents:

Rifabutin, p-Aminosalicylic acid (PAS), Amikacin,
Ciprofloxacin/Levofloxacin, Prothionamide (TBN)
Treatment of TB

Cell Wall Biosynthesis:
Isoniazid (INH)
 Ethambutol (EMB)


Protein Synthesis:


Streptomycin (SM), Amikacin
Transcription/DNA Replication:
Rifampin (RIF)
 Ciprofloxacin/Levofloxacin

Treatment of TB





Four drugs should be given initially -- Isoniazid,
Rifampicin, Pyrazinamide, and Ethambutol -- for at
least two months.
Where sensitivity tests are awaited, they should be
continued until the results are available.
4 months of Isoniazid and Rifampicin are required to
prevent relapse in the fully drug-sensitive patient.
If resources are scarce -- 6 months of Isoniazid and
Ethambutol can replace 4 months of Isoniazid and
Rifampicin.
Streptomycin may be substituted for Ethambutol
Isoniazid




Resembles B-vitamin and nicotinic acid
Need supplementation with the vitamin during Rx
Soluble in water - penetrates readily into all body fluids,
cells (MF), and tissues including the CSF (similar to
concentrations as in plasma).
Bactericidal at most concentrations (rapidly kills the
actively dividing bacilli and reduces the active bacterial
count in the sputum initially by at least an order of
magnitude for every day of treatment)
Isoniazid




INH is a prodrug activated by bacterial catalaseperoxidase (katG gene)
The main mechanism of INH resistance is
deletion or point mutation in katG gene
(catalase).
Strains with deletion of katG are highly
Isoniazid-resistant.
Resistance to INH (9% of all clinical isolates!)
Isoniazid

Daily Dose
Adults 5 mg/kg;
maximum dose: 300
mg/d
 Children 10-20 mg/kg;
maximum: 300 mg/d

Isoniazid

Common adverse effect:


Hepatitis is the most common adverse effect: 12-15%
patients on INH may have elevated transaminase levels in the
blood. This does not preclude the use of INH
Less common adverse effect:


Cutaneous Hypersensitivity (2%)
Peripheral neuropathy (1%) – Caused by elimination or
inhibition of pyridoxine (a cofactor in the synthesis of
synaptic neurotransmitters). Concomitant administration of
pyridoxine is recommended (10-50 mg daily).
Isoniazid


Alcohol (especially daily use) increases hepatic
hazards of INH
Inhibits metabolism of the following drugs:
Phenytoin
 Carbamazepine
Should be closely monitored
and adjusted
 Primidone
 Warfarin
These medicines may increase the chance of liver
damage if taken with Isoniazid


Rifampin




Bactericidal drug, penetrates various tissues and
cells for intracellular killing (kills slowly dividing
persistent organisms and is important in
“sterilizing” TB infection).
Well absorbed after oral administration
Excreted mainly by the liver
Always used in a combination with other drugs
to prevent resistance
Rifampin

Daily Dose

600 mg/d (10
mg/kg/d) for TB
treatment gives 5-7
mg/mL serum
concentration
Rifampin

Common adverse effect:


Orange-red color stains tissues, secretions, urine etc.
Less common adverse effect:

Hepatitis, cutaneous hypersensitivity, gastrointestinal
reactions, thrombocytopenic purpura, febrile
reactions, “flu syndrome”.
Rifampin

Rifampin may decrease the effects of:


Methadone; Clofibrate, Digitoxin; Cyclosporine,
Propranolol, Metoprolol, oral contraceptives and
anticoagulants, Quinidine, and Ketoconazole.
Rifampin increases the chance of liver damage
if taken with:
Estrogens (female hormones) or oral contraceptives
containing estrogen
 Phenytoin

Ethambutol



Synthetic water-soluble drug
No effect on bacteria other than mycobacteria -inhibits synthesis of component of
mycobacterial cell wall -- arabinogalactan
EMB is bacteriostatic but useful in preventing
the emergence of resistance
Ethambutol

Daily Dose



15-25 mg/kg peaking
serum level of 2-5 mg/ml
in 2-4 hrs
Widely distributed in the
body including CSF
Primarily excreted in
urine – accumulates if
renal failure – must
monitor and adjust the
dose
Ethambutol

Common adverse effect:
Optic neuritis (reversible) - Dose related: Occurs in
15% of patients receiving 50 mg/kg/d and 5% with
25 mg/kg/d.
 Decreases visual acuity and promote red/green color
blindness.


Less common adverse effect:

Chills; difficult breathing; dizziness; fever; headache;
itching; muscle and bone pain; shivering; skin rash
and redness
Pyrazinamide



Activated in acidic pH environment (pH < 5.5)
in intracellular compartments
Exhibits activity against intracellular
M.tuberculosis residing in macrophages (kills semidormant bacilli)
PZA kills more slowly dividing persistent
organisms. Used as “sterilizing” agent in a
combination with INH and RIF in short-course
protocols.
Pyrazinamide

Daily Dose

Oral dose of 25
mg/kg/d gives serum
concentration range
of 30-50 mg/ml in 12 hrs
Pyrazinamide

Common adverse effect:


Anorexia, nausea, flushing, hyperuricemia
Less common adverse effect:

Hepatitis, vomiting, arthralgia, cutaneous
hypersensitivity
Fixed Dose Combination
 Rifater (RFT, 衛肺特) = INH 80 mg + RMP 120 mg +
PZA 250 mg
 成人依體重每增加十公斤，則加服一錠，最多每
日五錠。
 Rifinah 300 (RFN 300, 樂肺寧 300) = INH 150 mg +
RMP 300 mg
 Rifinah 150 (RFN 150, 樂肺寧 150) = INH 100 mg +
RMP 150 mg
 體重五十公斤以上者，每日服用RFN 300兩錠；而
體重未滿五十公斤者，每日服用RFN 150三錠。
Fixed Dose Combination
Streptomycin




Streptomycin is bactericidal antibiotic
Penetrates the blood-brain barrier
Active against extracellular bacilli only since
poorly penetrates into macrophage
Use in a combination with other drugs due to
resistance
Streptomycin

Daily Dose

IV dose of 10 - 15
mg/kg/d
Streptomycin

Common adverse effect:


Uncommon adverse effect:


Vertigo, ataxia, deafness
Rare adverse effect:



Cutaneous hypersensitivity, dizziness, numbness, tinnitus
("ringing in the ears“)
Renal damage, aplastic anemia, agranulocytosis
Renal toxicity (needs to adjust the dose)
Toxicity is age- and dose-dependent. Limit
Streptomycin therapy for no more than 6 months
Treatment of TB






HRZ (2M) + HR (4M)
HERZ (2M) + HER (4M)
HR 9M
HE 18M, if R cannot be used
RE 18M, if H cannot be used
HRZS 2M + HR 4M
Treatment of TB
Liver disease (AST, ALT 3-5x in recent one year; liver cirrhosis Child C)
Yes
No
F/U AST/ALT q1-2w
q4w x 3m, then q2m
↑AST/ALT
Yes
No HERZ(2M) + HER(4M)
E ± SM
E + FQN ± SM (SM for smear(+) or advance disease
Rechallenge
Rechallenge
No recurrent- HER x 6-9m
Causing agent (+) ohters x 9m
HER x 6m
Causing agent (+) others + FQN
Treatment of TB
INH 50 mg/d
PZA 250 mg/d
INH 300 mg/d
PZA 1000 mg/d
RMP 75 mg/d
< 50kg: PZA 1500 mg/d
≧ 50kg: PZA 2000 mg/d
RMP 300mg/d
< 50kg: RMP 450 mg/d
≧ 50kg: RMP 600 mg/d
BTS guideline, 1998
Treatment of TB


65-y/o男性，liver cirrhosis Child B – C,
pneumoconiosis
因UGI bleeding住院後發現open TB




2004/11: RFT(HRZ) + EMB
2004/11: EMB + Cravit + SM (Petechiae, jaundice,
prolonged PT, normal GOT/GPT)
2004/12: EMB + Cravit + SM + Rifabutin (Acceptable
jaundice and PT, normal GOT/GPT)
2005/2: EMB + Cravit + Rifabutin
Drug-Resistant TB

Causes of drug-resistant TB:
Prescription of anti-TB medication
 Management of drug supply
 Case management
 Process of drug delivery


Definition of multi-drug resistant TB (MDRTB): Resistance to both INH and RIF
Drug-Resistant TB


The prescription of inadequate chemotherapy to
the multibacillary pulmonary tuberculosis
The addition of one extra drug in the case of
failure, and repeating the addition of a further
drug when the patient relapses after what
amounts to monotherapy
Drug-Resistant TB

Drug resistant rate:



RIF: 10-8
INH, PZA, EMB, SM: 10-6
PAS: 10-3
No. of
durgs
R
One
Two
Three
10-6
10-12
10-18
Number of AFB in lesion
102
104
106
108
1010
0.01% 1%
63% 100% 100%
0
0
0
0.01% 1%
0
0
0
0
0
Treatment of MDR-TB


21-y/o越南新娘
在北部某醫學中心治療







2003/7: RFT(HRZ) + EMB
2003/9: RFT(HRZ) + EMB + Cipro (Resistance to HR)
2003/12: HER + Cipro (2003/11 CXR improved)
2004/8: HERZ + Cipro (2004/6, 2004/8 CXR worsen)
2004/10: RFT(HRZ) + Cipro (2004/10 CXR worsen)
No sputum F/U during treatment
MDR-TB should never be treated without expert
consultation.
Thank You for Your Attention


In memory of NTUH Dr.廖永祥 for providing
excellent slides.
Reference:
ATS guideline 2003.
 Murray and Nadel’s Textbook of Respiratory
Medicine, 4th ed.
