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

Anti-TB Anti-TB MedicationMedication

9595 年度北區醫師結核病診治課程年度北區醫師結核病診治課程20062006 年年 55 月月 77 日日

衛生署桃園醫院內科加護病房主任衛生署桃園醫院內科加護病房主任莊子儀醫師莊子儀醫師

OutlineOutline

TB MicrobiologyTB Microbiology Basic ConceptBasic Concept Treatment of TBTreatment of TB Drug-Resistant TBDrug-Resistant TB

TB MicrobiologyTB Microbiology

M. tuberculosisM. tuberculosis is an is an aerobicaerobic, non-spore , non-spore forming, non-motile bacillus with a forming, non-motile bacillus with a high high cell wall content of high-molecular cell wall content of high-molecular weight lipidsweight lipids ( (up to 60% dry weight up to 60% dry weight content)content)..

Cell division occurs from 15-20 hoursCell division occurs from 15-20 hours Share the staining characteristic Share the staining characteristic

known a acid-fastness: red stain known a acid-fastness: red stain seen upon application of seen upon application of acid-acid-alcohol stainalcohol stain

TB MicrobiologyTB Microbiology The rigid core of the cell The rigid core of the cell

wall is composed of threwall is composed of three STRUCTURAL COMPOe STRUCTURAL COMPONENTSNENTS Peptidoglycan, ArabinogaPeptidoglycan, Arabinoga

lactan, Mycolic acidslactan, Mycolic acids External to the peptidoglExternal to the peptidogl

ycan and the arabinogalycan and the arabinogalactan are the mycolic acactan are the mycolic acids, which together with ids, which together with free lipids act as a free lipids act as a hydrohydrophobic permeability barphobic permeability barrierrier

TB MicrobiologyTB Microbiology

Actively multiplying/growing organisms Actively multiplying/growing organisms (susceptible to chemotherapy)(susceptible to chemotherapy)

Slowly growing and metabolically inactive Slowly growing and metabolically inactive (relatively poor response to antibiotics) (relatively poor response to antibiotics)

Intracellular bacilli slowly growing in Intracellular bacilli slowly growing in macrophages (difficult to treat due to macrophages (difficult to treat due to poor accessibility for antibiotics )poor accessibility for antibiotics )

Dormant population (resistant to Dormant population (resistant to chemotherapy)chemotherapy)

Basic ConceptBasic Concept

All drugs as a single dose on empty All drugs as a single dose on empty stomachstomach

The use of a single drug should be The use of a single drug should be avoided (except for prophylaxis)avoided (except for prophylaxis)

In multiple drug regimens at least In multiple drug regimens at least one drug should be bactericidalone drug should be bactericidal


Use multiple drugs to which the Use multiple drugs to which the organisms susceptibleorganisms susceptible Mutation rate about 10Mutation rate about 10-7-7

Patient with TB may have 10Patient with TB may have 101010 organismsorganisms

Never add single drug to failing Never add single drug to failing regimenregimen

Ensure adherence to therapyEnsure adherence to therapy Duration of therapy: 6-9 monthsDuration of therapy: 6-9 months


TB Case

標準初次治療

照會專業醫師

Y

N

過去治療史

新案

•Return after default•Relapse•Failure•Chronic case

Basic ConceptBasic Concept 新案新案 (new case)(new case) ：不曾接受過抗結核藥治療或：不曾接受過抗結核藥治療或

曾接受少於曾接受少於 4 4 週抗結核藥治療之病人。週抗結核藥治療之病人。復發復發 (relapse)(relapse) ：曾接受一個完整療程之抗結核：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藥治療並經醫師宣告治癒而再次痰塗片陽性之病人。人。

失敗復治失敗復治 (treatment after failure)(treatment after failure) ：治療五個：治療五個月後依然痰塗片陽性的病人，或者治療前痰塗片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。陰性、治療二個月後變成痰塗片陽性的病人。

失落復治失落復治 (Treatment after default)(Treatment after default) ：中斷治：中斷治療兩個月以上而再次痰塗片陽性之病人。療兩個月以上而再次痰塗片陽性之病人。

慢性病人慢性病人 (chronic case)(chronic case) ：在監督下接受完整之：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。復治處方治療後依然痰塗片陽性之病人。

Treatment of TBTreatment of TB

First-line agents:First-line agents: Isoniazid (INH)Isoniazid (INH) Rifampin (RIF)Rifampin (RIF) Ethambutol (EMB)Ethambutol (EMB) Pyrazinamide (PZA)Pyrazinamide (PZA) Streptomycin (SM)Streptomycin (SM)

Second-line agents:Second-line agents: Rifabutin, p-Aminosalicylic acid (PAS), ARifabutin, p-Aminosalicylic acid (PAS), A

mikacin, Ciprofloxacin/Levofloxacin, Protmikacin, Ciprofloxacin/Levofloxacin, Prothionamide (TBN)hionamide (TBN)


Cell Wall BiosynthesisCell Wall Biosynthesis:: Isoniazid (INH)Isoniazid (INH) Ethambutol (EMB)Ethambutol (EMB)

Protein Synthesis:Protein Synthesis: Streptomycin (SM), AmikacinStreptomycin (SM), Amikacin

Transcription/DNA Replication:Transcription/DNA Replication: Rifampin (RIF)Rifampin (RIF) Ciprofloxacin/LevofloxacinCiprofloxacin/Levofloxacin

Treatment of TBTreatment of TB Four drugs should be given initially -- Four drugs should be given initially -- Isoniazid, RIsoniazid, R

ifampicin, Pyrazinamide, and Ethambutolifampicin, Pyrazinamide, and Ethambutol -- for at -- for at least two months.least two months.

Where sensitivity tests are awaited, they should bWhere sensitivity tests are awaited, they should be continued until the results are available.e continued until the results are available.

4 months of Isoniazid and Rifampicin are require4 months of Isoniazid and Rifampicin are required to prevent relapse in the fully drug-sensitive patid to prevent relapse in the fully drug-sensitive patient. ent.

If resources are scarce -- 6 months of Isoniazid anIf resources are scarce -- 6 months of Isoniazid and Ethambutol can replace 4 months of Isoniazid ad Ethambutol can replace 4 months of Isoniazid and Rifampicin.nd Rifampicin.

Streptomycin may be substituted for EthambutolStreptomycin may be substituted for Ethambutol

IsoniazidIsoniazid Resembles Resembles B-vitaminB-vitamin and nicotinic acid and nicotinic acid Need supplementation with the vitamin during Need supplementation with the vitamin during

Rx Rx Soluble in water - penetrates readily into all Soluble in water - penetrates readily into all

body fluids, cells (MF), and tissues including the body fluids, cells (MF), and tissues including the CSF (similar to concentrations as in plasma).CSF (similar to concentrations as in plasma).

Bactericidal at most concentrations (Bactericidal at most concentrations (rapidly kills rapidly kills the actively dividing bacilli and reduces the the actively dividing bacilli and reduces the active bacterial count in the sputum initially by active bacterial count in the sputum initially by at least an order of magnitude for every day of at least an order of magnitude for every day of treatment)treatment)

IsoniazidIsoniazid INH is a prodrug activated by bacterial cINH is a prodrug activated by bacterial c

atalase-peroxidase (atalase-peroxidase (katGkatG gene) gene) The main mechanism of INH resistance The main mechanism of INH resistance

is deletion or point mutation in is deletion or point mutation in katG katG gegene (catalase). ne (catalase).

Strains with deletion of Strains with deletion of katGkatG are highly are highly Isoniazid-resistant.Isoniazid-resistant.

Resistance to INH (9% of all clinical isolates!)

IsoniazidIsoniazid Daily Dose

Adults 5 mg/kg; maximum dose: 300 mg/d

Children 10-20 mg/kg; maximum: 300 mg/d

IsoniazidIsoniazid Common adverse effect:Common adverse effect:

HepatitisHepatitis is the most common adverse effect: 12-15% is the most common adverse effect: 12-15% patients on INH may have elevated transaminase levepatients on INH may have elevated transaminase levels in the blood. This does not preclude the use of INHls in the blood. This does not preclude the use of INH

Less common adverse effect:Less common adverse effect: Cutaneous HypersensitivityCutaneous Hypersensitivity (2%) (2%) Peripheral neuropathyPeripheral neuropathy (1%) – Caused by elimination o (1%) – Caused by elimination o

r inhibition of pyridoxine (a cofactor in the synthesis r inhibition of pyridoxine (a cofactor in the synthesis of synaptic neurotransmitters). Concomitant administof synaptic neurotransmitters). Concomitant administration of pyridoxine is recommended (10-50 mg daily).ration of pyridoxine is recommended (10-50 mg daily).

IsoniazidIsoniazid Alcohol (especially daily use) increases hepAlcohol (especially daily use) increases hep

atic hazards of INH atic hazards of INH Inhibits metabolism of the following drugs:Inhibits metabolism of the following drugs:

Phenytoin Phenytoin Carbamazepine Carbamazepine Primidone Primidone Warfarin Warfarin

These medicines may increase the chance of liver damage if taken with Isoniazid

Should be closely monitored and adjusted

RifampinRifampin Bactericidal drug, penetrates various Bactericidal drug, penetrates various

tissues and cells for intracellular tissues and cells for intracellular killing (kills slowly dividing persistent killing (kills slowly dividing persistent organisms and is important in organisms and is important in “sterilizing” TB infection).“sterilizing” TB infection).

Well absorbed after oral administrationWell absorbed after oral administration Excreted mainly by the liverExcreted mainly by the liver Always used in a combination with Always used in a combination with

other drugs to prevent resistanceother drugs to prevent resistance

RifampinRifampin Daily Dose

600 mg/d (10 mg/600 mg/d (10 mg/kg/d) for TB treatkg/d) for TB treatment gives 5-7 mgment gives 5-7 mg/mL serum conce/mL serum concentrationntration

RifampinRifampin Common adverse effect:

Orange-red color stains tissues, secretions, urine etc.

Less common adverse effect: Hepatitis, cutaneous hypersensitivity, gast

rointestinal reactions, thrombocytopenic purpura, febrile reactions, “flu syndrome”.

RifampinRifampin Rifampin may decrease the effects of:Rifampin may decrease the effects of:

Methadone; Clofibrate, Digitoxin; CyclosporiMethadone; Clofibrate, Digitoxin; Cyclosporine, Propranolol, Metoprolol, oral contraceptine, Propranolol, Metoprolol, oral contraceptives and anticoagulants, Quinidine, and Ketocves and anticoagulants, Quinidine, and Ketoconazole.onazole.

Rifampin increases the chance of liver daRifampin increases the chance of liver damage if taken with:mage if taken with: Estrogens (female hormones) or oral contracEstrogens (female hormones) or oral contrac

eptives containing estrogen eptives containing estrogen PhenytoinPhenytoin

EthambutolEthambutol Synthetic water-soluble drugSynthetic water-soluble drug No effect on bacteria other than mycoNo effect on bacteria other than myco

bacteria -- inhibits synthesis of compobacteria -- inhibits synthesis of component of mycobacterial cell wall -- arabinent of mycobacterial cell wall -- arabinogalactan nogalactan

EMB is EMB is bacteriostaticbacteriostatic but useful in pre but useful in preventing the emergence of resistanceventing the emergence of resistance

EthambutolEthambutol Daily Dose

15-25 mg/kg peaking 15-25 mg/kg peaking serum level of 2-5 serum level of 2-5 mg/ml in 2-4 hrsmg/ml in 2-4 hrs

Widely distributed in Widely distributed in the body including the body including CSFCSF

Primarily excreted in Primarily excreted in urine – urine – accumulates accumulates if renal failureif renal failure – – must monitor and must monitor and adjust the doseadjust the dose

EthambutolEthambutol 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

PyrazinamidePyrazinamide Activated in acidic pH environment (pH Activated in acidic pH environment (pH

< 5.5) in intracellular compartments< 5.5) in intracellular compartments Exhibits activity against intracellular Exhibits activity against intracellular

M.tuberculosisM.tuberculosis residing in macrophages residing in macrophages (kills semi-dormant bacilli)(kills semi-dormant bacilli)

PZA kills more slowly dividing persistent PZA kills more slowly dividing persistent organisms. Used as “organisms. Used as “sterilizingsterilizing” agent in ” agent in a combination with INH and RIF in short-a combination with INH and RIF in short-course protocols.course protocols.

PyrazinamidePyrazinamide Daily Dose

Oral dose of 25 Oral dose of 25 mg/kg/d gives mg/kg/d gives serum serum concentration concentration range of 30-50 range of 30-50 mg/ml in 1-2 hrsmg/ml in 1-2 hrs

PyrazinamidePyrazinamide Common adverse effect:

Anorexia, nausea, flushing, hyperuricemia

Less common adverse effect: Hepatitis, vomiting, arthralgia, cutaneous

hypersensitivity

Fixed Dose CombinationFixed Dose Combination Rifater (RFT, Rifater (RFT, 衛肺特衛肺特 ) = INH 80 mg + RMP 12) = INH 80 mg + RMP 12

0 mg + PZA 250 mg0 mg + PZA 250 mg 成人依體重每增加十公斤，則加服一錠，最多每成人依體重每增加十公斤，則加服一錠，最多每

日五錠。日五錠。 Rifinah 300 (RFN 300, Rifinah 300 (RFN 300, 樂肺寧樂肺寧 300) = INH 150 300) = INH 150

mg + RMP 300 mgmg + RMP 300 mg Rifinah 150 (RFN 150, Rifinah 150 (RFN 150, 樂肺寧樂肺寧 150) = INH 100 150) = INH 100

mg + RMP 150 mgmg + RMP 150 mg 體重五十公斤以上者，每日服用體重五十公斤以上者，每日服用 RFN 300RFN 300 兩錠；兩錠；

而體重未滿五十公斤者，每日服用而體重未滿五十公斤者，每日服用 RFN 150RFN 150 三錠。三錠。

Fixed Dose CombinationFixed Dose Combination

StreptomycinStreptomycin

Streptomycin is Streptomycin is bactericidalbactericidal antibiotic antibiotic Penetrates the blood-brain barrierPenetrates the blood-brain barrier Active against extracellular bacilli only Active against extracellular bacilli only

since poorly penetrates into macrophasince poorly penetrates into macrophagege

Use in a combination with other drugs Use in a combination with other drugs due to resistancedue to resistance

StreptomycinStreptomycin

Daily Dose IV dose of 10 - IV dose of 10 -

15 mg/kg/d15 mg/kg/d

StreptomycinStreptomycin Common adverse effect: Common adverse effect:

Cutaneous hypersensitivity, Cutaneous hypersensitivity, dizzinessdizziness, numbness,, numbness, tinnitustinnitus ("ringing in the ears“) ("ringing in the ears“)

Uncommon adverse effect:Uncommon adverse effect: VertigoVertigo, ataxia, deafness, ataxia, deafness

Rare adverse effect:Rare adverse effect: Renal damage, aplastic anemia, agranulocytosisRenal damage, aplastic anemia, agranulocytosis Renal toxicity (needs to adjust the dose)Renal toxicity (needs to adjust the dose)

Toxicity is Toxicity is age- and dose-dependentage- and dose-dependent. . Limit StLimit Streptomycin therapy for reptomycin therapy for no more than 6 monno more than 6 monthsths


HRZ (2M) + HR (4M)HRZ (2M) + HR (4M) HERZ (2M) + HER (4M) HERZ (2M) + HER (4M) HR 9MHR 9M HE 18M, if R cannot be usedHE 18M, if R cannot be used RE 18M, if H cannot be used RE 18M, if H cannot be used HRZS 2M + HR 4MHRZS 2M + HR 4M

Treatment of TBTreatment of TB 　　

Liver disease (AST, ALT 3-5x in recent one year; liver cirrhosis Child C)Liver disease (AST, ALT 3-5x in recent one year; liver cirrhosis Child C)

YesYes NoNo

F/U AST/ALT q1-2w q4w x 3m, then q2mF/U AST/ALT q1-2w q4w x 3m, then q2m

↑↑AST/ALTAST/ALT

YesYes NoNo HERZ(2M) + HER(4M) HERZ(2M) + HER(4M)

E ± SME ± SM E + FQN ± SME + FQN ± SM (SM for smear(+) or advance d (SM for smear(+) or advance diseaseisease

RechallengeRechallenge RechallengeRechallenge

No recurrent- No recurrent- HER x 6-9m HER x 6mHER x 6-9m HER x 6mCausing agent (+)Causing agent (+) ohters x 9m ohters x 9m Causing agentCausing agent (+) others + FQN (+) others + FQN


INH 50 mg/dINH 50 mg/d PZA 250 mg/dPZA 250 mg/d

INH 300 mg/dINH 300 mg/d PZA 1000 mg/dPZA 1000 mg/d

RMP 75 mg/dRMP 75 mg/d < 50kg: PZA 1500 mg/d< 50kg: PZA 1500 mg/d ≧ ≧ 50kg: PZA 2000 50kg: PZA 2000

mg/dmg/dRMP 300mg/dRMP 300mg/d

< 50kg: RMP 450 mg/d< 50kg: RMP 450 mg/d ≧ ≧ 50kg: RMP 600 mg/d50kg: RMP 600 mg/d BTS guideline, 1998

Treatment of TBTreatment of TB 65-y/o65-y/o 男性，男性， liver cirrhosis Child B – C, pneliver cirrhosis Child B – C, pne

umoconiosisumoconiosis 因因 UGI bleedingUGI bleeding 住院後發現住院後發現 open TBopen TB

2004/11: RFT(HRZ) + EMB2004/11: RFT(HRZ) + EMB 2004/11: EMB + Cravit + SM (Petechiae, jaundice, 2004/11: EMB + Cravit + SM (Petechiae, jaundice,

prolonged PT, normal GOT/GPT)prolonged PT, normal GOT/GPT) 2004/12: EMB + Cravit + SM + Rifabutin (Acceptab2004/12: EMB + Cravit + SM + Rifabutin (Acceptab

le jaundice and PT, normal GOT/GPT)le jaundice and PT, normal GOT/GPT) 2005/2: EMB + Cravit + Rifabutin2005/2: EMB + Cravit + Rifabutin

Drug-Resistant TBDrug-Resistant TB

Causes of drug-resistant TB: Causes of drug-resistant TB: Prescription of anti-TB medicationPrescription of anti-TB medication Management of drug supplyManagement of drug supply Case managementCase management Process of drug deliveryProcess of drug delivery

Definition of multi-drug resistant TB Definition of multi-drug resistant TB (MDR-TB): Resistance to both INH (MDR-TB): Resistance to both INH and RIFand RIF


The prescription of The prescription of inadequate chemotinadequate chemotherapyherapy to the multibacillary pulmonar to the multibacillary pulmonary tuberculosisy tuberculosis

The addition of The addition of one extra drugone extra drug in the c in the case of failure, and repeating the additiase of failure, and repeating the addition of a further drug when the patient ron of a further drug when the patient relapses after what amounts to monothelapses after what amounts to monotherapyerapy


Drug resistant rate: Drug resistant rate: RIF: 10RIF: 10-8-8

INH, PZA, EMB, SM: 10INH, PZA, EMB, SM: 10-6-6 PAS: 10PAS: 10-3-3

No. oNo. of durf dur

gsgs

RR Number of AFB in lesionNumber of AFB in lesion

101022 101044 101066 101088 10101010

OneOne 1010-6-6 0.010.01%%

1%1% 63%63% 100100%%

100100%%

TwoTwo 1010-12-12 00 00 00 0.010.01%%

1%1%

ThreThreee

1010-18-18 00 00 00 00 00

Treatment of MDR-TBTreatment of MDR-TB 21-y/o21-y/o 越南新娘越南新娘在北部某醫學中心治療在北部某醫學中心治療

2003/7: RFT(HRZ) + EMB2003/7: RFT(HRZ) + EMB 2003/9: RFT(HRZ) + EMB + 2003/9: RFT(HRZ) + EMB + CiproCipro (Resistance to HR) (Resistance to HR) 2003/12: HER + Cipro (2003/11 CXR improved)2003/12: HER + Cipro (2003/11 CXR improved) 2004/8: HERZ + Cipro (2004/6, 2004/8 CXR worsen)2004/8: HERZ + Cipro (2004/6, 2004/8 CXR worsen) 2004/10: RFT(HRZ) + Cipro (2004/10 CXR worsen)2004/10: RFT(HRZ) + Cipro (2004/10 CXR worsen)

No sputum F/U during treatmentNo sputum F/U during treatment MDR-TB should never be treated without expeMDR-TB should never be treated without expe

rt consultation.rt consultation.

Thank You for Your Thank You for Your AttentionAttention

In memory of NTUH Dr.In memory of NTUH Dr. 廖永祥廖永祥 for profor providing excellent slides.viding excellent slides.

Reference: Reference: ATS guideline 2003.ATS guideline 2003. Murray and Nadel’s Textbook of RespiraMurray and Nadel’s Textbook of Respira

tory Medicine, 4th ed.tory Medicine, 4th ed.

Documents

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

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