Anti-TB Medication

1
Anti-TB Medication

• 95?????????????
• 2006?5?7?
• ???????????????
• ?????

2
Outline

• TB Microbiology
• Basic Concept
• Treatment of TB
• Drug-Resistant TB

3
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

4
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

5
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)

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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

7
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

8
Basic Concept
9
Basic Concept

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• ?? (relapse)????????????????????????????????????
• ???? (treatment after failure)????????????????,??
  ??????????????????????????
• ???? (Treatment after default)???????????????????
  ??
• ????(chronic case)???????????????????????????

10
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)

11
Treatment of TB

• Cell Wall Biosynthesis
• Isoniazid (INH)
• Ethambutol (EMB)
• Protein Synthesis
• Streptomycin (SM), Amikacin
• Transcription/DNA Replication
• Rifampin (RIF)
• Ciprofloxacin/Levofloxacin

12
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

13
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)

14
Isoniazid

• INH is a prodrug activated by bacterial
  catalase-peroxidase (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!)

15
Isoniazid

• Daily Dose
• Adults 5 mg/kg maximum dose 300 mg/d
• Children 10-20 mg/kg maximum 300 mg/d

16
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).

17
Isoniazid

• Alcohol (especially daily use) increases hepatic
  hazards of INH
• Inhibits metabolism of the following drugs
• Phenytoin
• Carbamazepine
• Primidone
• Warfarin
• These medicines may increase the chance of liver
  damage if taken with Isoniazid

Should be closely monitored and adjusted
18
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

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Rifampin

• Daily Dose
• 600 mg/d (10 mg/kg/d) for TB treatment gives 5-7
  mg/mL serum concentration

20
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.

21
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

22
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

23
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

24
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

25
Pyrazinamide

• Activated in acidic pH environment (pH lt 5.5) in
  intracellular compartments
• Exhibits activity against intracellular
  M.tuberculosis residing in macrophages (kills
  semi-dormant bacilli)
• PZA kills more slowly dividing persistent
  organisms. Used as sterilizing agent in a
  combination with INH and RIF in short-course
  protocols.

26
Pyrazinamide

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

27
Pyrazinamide

• Common adverse effect
• Anorexia, nausea, flushing, hyperuricemia
• Less common adverse effect
• Hepatitis, vomiting, arthralgia, cutaneous
  hypersensitivity

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Fixed Dose Combination

• Rifater (RFT, ???) INH 80 mg RMP 120 mg PZA
  250 mg
• ???????????,?????,???????
• Rifinah 300 (RFN 300, ??? 300) INH 150 mg RMP
  300 mg
• Rifinah 150 (RFN 150, ??? 150) INH 100 mg RMP
  150 mg
• ?????????,????RFN 300????????????,????RFN 150???

29
Fixed Dose Combination
30
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

31
Streptomycin

• Daily Dose
• IV dose of 10 - 15 mg/kg/d

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Streptomycin

• Common adverse effect
• Cutaneous hypersensitivity, dizziness, numbness,
  tinnitus ("ringing in the ears)
• Uncommon adverse effect
• Vertigo, ataxia, deafness
• Rare adverse effect
• 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

33
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

34
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 HER
  x 6m
• Causing agent () ohters x 9m
  Causing agent () others FQN
  

35
Treatment of TB

• INH 50 mg/d PZA 250 mg/d
• INH 300 mg/d PZA 1000 mg/d
• RMP 75 mg/d lt 50kg PZA 1500 mg/d
• ? 50kg PZA 2000 mg/d
• RMP 300mg/d
• lt 50kg RMP 450 mg/d
• ? 50kg RMP 600 mg/d

BTS guideline, 1998
36
Treatment of TB

• 65-y/o??,liver cirrhosis Child B C,
  pneumoconiosis
• ?UGI bleeding?????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

37
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 (MDR-TB)
  Resistance to both INH and RIF

38
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

39
Drug-Resistant TB

• Drug resistant rate
• RIF 10-8
• INH, PZA, EMB, SM 10-6
• PAS 10-3

No. of durgs R Number of AFB in lesion Number of AFB in lesion Number of AFB in lesion Number of AFB in lesion Number of AFB in lesion
No. of durgs R 102 104 106 108 1010
One 10-6 0.01 1 63 100 100
Two 10-12 0 0 0 0.01 1
Three 10-18 0 0 0 0 0
40
Treatment of MDR-TB

• 21-y/o????
• ??????????
• 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.

41
Thank You for Your Attention

• In memory of NTUH Dr.??? for providing excellent
  slides.
• Reference
• ATS guideline 2003.
• Murray and Nadels Textbook of Respiratory
  Medicine, 4th ed.