TB drugs, treatment regimen

1. PHARMACOTHERAPY
OF
TUBERCULOSIS
Dr Siddiqui Waseem Akram (PGY- 3)9-Sep-15
1M.I.M.E.R.Medical College

2. INTRODUCTION
 Chronic granulomatous
disease caused by
Mycobacterium tuberculosis
 Attacks lungs mainly, but can
affect other parts of body
 Spread through cough, sneeze,
or respiratory fluids
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3. GLOBAL BURDEN OF TB
 2 billion infected (1 in 3 of global population)
 9.4 million new cases in 2008
 4 million new sm+ve PTB cases in 2008
 Global incidence of TB peaked in 2004 & is
declining
 1.77mn deaths in 2007, 98% in low-income
countries
 MDR-TB -prevalence in new cases around
3.6% Ref: WHO Global Report, 2006
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4. 9-Sep-154 M.I.M.E.R.Medical College

5. TB IN INDIA
 India has highest burden of TB
 40% population infected
 Annual risk of infection 1.5%
 Lifetime risk 10%
 Incidence- 2.1 million of global incidence of 9 mn
 TB prevalence- 2.6 million
 Sputum +ve cases/yr- 0.8 million
 Death due to TB- 0.37 million
“Global Tuberculosis Control, WHO, Geneva, 2014
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6. PHARMACOTHERAPY OF TB
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7. CLASSIFICATION
 Isoniazid (H)
 Rifampicin (R)
 Pyrazinamide (Z)
 Ethambutol (E)
 Streptomycin (S)
 Ethionamide (Eto)
 Cycloserine (Cs)
 Terizidone (Trd)
 Para Aminosalicylic
acid (PAS)
 Rifabutin
 Rifapentine
FIRST LINE SECOND LINE
Fluoroquinolones
 Moxifloxacin (Mfx)
 Levofloxacin (Lvx)
 Ofloxacin (Ofx)
 Ciprofloxacin (Cfx)
 Amikacin (Am)
Injectable
 Capreomycin (Cm)
 Amikacin (Am)
 Kanamycin (Km)
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Newer drugs
Bedaquiline
Pretomanid

8. GROUPING OF ANTI-TB DRUGS
Group 1:First-line oral
agents
•Isoniazid (H)
• Pyrazinamide (Z)
• Ethambutol (E)
• Rifampin (R)
Group 2:Injectable agents
• Streptomycin (S)
• Kanamycin (Km)
• Amikacin (Am)
• Capreomycin (cm)
Group 3:Fluoroquinolones
• Levofloxacin (lfx)
• Moxifloxacin (mfx)
• Ofloxacin (ofx)
Group 4:Oral bacteriostatic
second-line agents
• Para-aminosalicylic acid (pAS)
• Cycloserine (cs)
• Terizidone (Trd)
• Ethionamide (eto)
• Protionamide (pto)9-Sep-15
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9. Group 5: Agents with unclear role in treatment of drug
resistant-TB
• Clofazimine (cfz)
• Linezolid (lzd)
• Amoxicillin/clavulanate (Amx/clv)
• Thioacetazone (Thz)
• Imipenem/ Cilastatin (ipm/cln)
• Clarithromycin (clr)
GROUPING OF ANTI-TB DRUGS
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10. FIRST LINE DRUGS
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11. ISONIAZID
 Active only against M.tuberculi
 Cheapest drug
 Inhibits resting microbes
(bacteriostatic), kills multiplying
(bactericidal)
 Effective against extracellular &
intracellular organisms
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12. MOA
Prodrug
↓
Mycobacterial catalase-peroxidase(KatG) (activated)
↓
Covalent complex with acyl carrier protein (AcpM) & KasA
↓
Blocks mycolic acid synthesis & kills bacteria
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13. Mechanism of Resistance
 Inherent resistance-Primary
 Mutation of catalase peroxidase gene
 Mutation of inh A gene
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14. Pharmacokinetics
 Rapidly & completely absorbed
 Widely distributed
 Penetrates & accumulates into caseous lesion
 Minimum tuberculostatic concentration is 25 – 30 ng/ml
 Metabolized through N-acetylation
Slow acetylator t1/2 3 hour (Drug causes toxicity,
peripheral neuropathy )
Rapid acetylator t1/2 1 hour (Metabolite causes toxicity,
hepatotoxicity) 9-Sep-15
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15. ADR
 Peripheral neuropathy
 Structurally analogue to pyridoxine & form hydrazone (highly
water soluble) with pyridoxal & rapidly excreted in urine
 Rx- Pyridoxine 10 mg/day prophylaxis &100mg/day-for
toxicity
 Hepatitis (elderly & liver disease)
 Because of CYP2E1 induced hepatotoxic metabolite
generation
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16. Drug interactions
 Isoniazid reduces metabolism of phenytoin,
Carbamazepine, Diazepam, Theophylline &
Warfarin by inhibiting CYP2C19 & CYP3A4
 Al- hydroxide inhibits INH absorption
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17. RIFAMPICIN
 Semi synthetic derivatives of Rifamycin B (Streptomyces
mediterranei)
 Most active agent
 Active against gram +ve & -ve cocci, some enteric bacteria,
mycobacteria & chlamydia
 Extra & intra- cellular organisms
 Slow dividing (main)
 Sterilizing agent & prevents resistance 9-Sep-15
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18.  MOA:
Binds to subunit of bacterial DNA-dependent RNA
polymerase & inhibits RNA synthesis.
 Resistance
Mutation to β subunit of bacterial RNA polymerase
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19. Pharmacokinetics:
 Oral & IV formulations available
 Well absorbed
 Food ↓ absorbtion
 Widely distributed (80 – 90% protein bound)
 t½ 3 hours
 Metabolized & excreted by liver (enterohepatic circulation)
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20. ADR
 Red discoloration of Body fluids
(urine, tear & sputum )
 Fatal hepatitis (Existing liver
disease)
 Flu like syndrome
 Nausea, Vomiting
 Dizziness & Confusion
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21. Drugs interaction
 Powerful enzyme inducer -  own metabolism as
well as other drugs like
 Phenytoin,
 OCP,
 Glucocorticoids,
 Clarithromycin,
 Ketoconazole,
 Theophyllline
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22. TB & atypical
mycobacterial
infections
Leprosy
Prophylaxis in
H. influenza
Resistant staph
infections
Brucellosis
Pneumococcal
meningitis
To eradicate
carrier state
Uses
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23. PYRAZINAMIDE
 Synthetic, orally effective, bactericidal
 Used with INH & Rifampicin
 Prodrug, converted to pyrazinoic acid (pyrazinamindase of
m. tuberculosis)
 Inactive at neutral pH
 Bactericidal to dividing organisms (Intracellular)
 Sterilizing agent 9-Sep-15
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24. Inhibition of synthesis of mycolic acids
pncA gene-enzyme-activates pyrazinamide-
pyrazinoic acid
Lipid content of mycobacteria is reduced
Interacts with a different fatty acid synthase encoding gene
Mechanism of acation
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25. Resistance
 Mutation of pncA gene
 Impaired uptake
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26.  Widely distributed
 CSF (TB meningitis)
 Safe in pregnancy
 Metabolised in liver
 Excreted in urine
 T ½=6-10h
 Dosage: 25- 35 mg/kg/day
Pharmacokinetics
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27. ADR
 Hepatotoxicity (C/I in liver ds)
 Hyperuricaemia, may precipitate gout
 Fever, Malaise, Urticaria, Skin rash
 Arthralgia
 GI upset – Anorexia, Nausea, Vomiting
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28. ETHAMBUTOL
 Tuberculostatic
 Fast multiplying organisms are affected
 Atypical mycobacteria
 Taken up by the erythrocytes & slowly released
 Hasten sputum conversion and prevent development of resistance
 Resistance emerges rapidly if drug is used alone
 Used as alternative to streptomycin
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29.  MOA:
Inhibits mycobacterial arabinosyl transferase,
involved in polymerization reaction of
arabinoglycan, essential component of
mycobacterial cell wall
 Mechanism of resistance: Mutation of emb
gene
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30. Pharmacokinetics
 75-80% absorbed from GIT
 Wide distribution
 Crosses the blood brain barrier only if the meninges are inflamed
 Excreted by GF & TS
 t ½ =4h
 Dosage: 15-30 mg/kg/day
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31. ADR
 Optic neuritis: dose related, initially Red/ Green
color blindness followed by a  in visual acuity
(disappear following withdrawal of drug)
 Hypersensitivity: skin rash, fever, itching
 Other adverse effects: Arthralgia, GI disturbance,
Headache & mental disturbance
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32. STREPTOMYCIN
 First clinically useful antitubercular
drug
 Streptomyces griseus
 Active mainly against extracellular
bacilli
 Supplimental 1st line drug
 Dosage : 1g/day or 15mg/kg/day
i.m or i.v
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33. MOA
 Interference with initiation complex of peptide
formation
 Misreading of mRNA→ Incorporation of incorrect
AA into peptide→Nnonfunctional or toxic protein
 Breakup of polysomes into nonfunctional
monosomes
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34. Mechanism of resistance
1. Production of transferase enzyme, inactivates
aminoglycosides by acetylation, adenylylation or
phosphorylation (Major action)
2. Impaired entry of drug
3. Receptor protein on 30s ribosomal subunit deleted
or altered (Mutation)
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35. ADR
Dose related, & risk is  in elderly
 Ototoxicity
 Nephrotoxicity
 Rash
 Fever
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36. Summary
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DRUGS MOA
Isoniazid (INH) Inhibits synthesis of mycolic acid, an essential
component of bacterial cell wall
Rifampin (RMO) &
Rifabutin
Binds to & inhibits DNA dependant RNA
polymerase (no new RNA synthesis)
Ethambutol (ETB) Inhibits arabinosyl transferase enzyme &
prevents polymerisation of arabinoglycans
(essential component of mycobacterial cell
wall)
Pyrazinamide (PZA) Inhibits mycobacterial fatty acid synthase-1
enzyme & disrupts mycolic acid synthesisM.I.M.E.R.Medical College

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38. Drug Clinical setting Daily dose
Rifampicin Children 10-20 mg/kg
Adults weighing >50 kg 600 mg
Isoniazid Children 10 mg/kg
Adults 200 – 300 mg
Ethambutol Children & adults: Initial 8
weeks
25 mg/kg
Children & adults:
Subsequently
15 mg/kg
Pyrazinamide Children & adults 20-35 mg/kg
Streptomycin Children 30 mg/kg
Adult 1 gm
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39. SECOND LINE DRUGS
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40. CONSIDER SECOND-LINE DRUG, If
 Resistance to first-line agents
 Failure of clinical response to conventional therapy
 Serious treatment-limiting ADR
 Expert guidance available for toxic effects
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41. ETHIONAMIDE
 Chemically related to isoniazid
 Poorly water soluble (Only oral preparation)
 Both extra and intracellular
Mechanism of action:
 Ethionamide blocks synthesis of mycolic acids in
susceptible organisms.
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42. Pharmacokinetics
 Metabolized by the liver
 Dosage : 500 - 750mg/day
 Start with 250mg daily, ↑ up to 1g/day or
15mg/kg/day.
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43. ADR
 Intense gastric irritation
 Optic neuritis (alleviated by pyridoxine)
 Hepatotoxicity
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44. CAPREOMYCIN
 Obtained from Streptomyces capreolus
Mechanism of action :
 Peptide protein synthesis inhibitor
 Important agent for drug resistant tuberculosis
 Strains resistant to Amikacin, susceptible to Capreomycin
 Dosage : 15mg/kg/day im
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45. ADR
 Nephrotoxicity
 Ototoxicity – Tinnitus, Deafness, Vestibular disturbance
 Local pain & sterile abscesses at injection site
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46. CYCLOSERINE :
 Streptomyces orchidaceus
 Structural analog of D- alanine
Mechanism of action :
 Inhibits incorporation of D- alanine into
peptidoglycan pentapeptide & inhibits mycobacterial
cell wall synthesis
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47. ADR
 CNS dysfunction, including depression & psychosis
 Peripheral neuropathy
 Seizures
 Tremors
Pyridoxine 150mg/day should be given with cycloserine because this
ameliorates neurologic toxicity.
Dosage: 0.5 - 1g/day in two or three divided doses
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48. AMINOSALICYLIC ACID (PAS)
 Folate synthesis antagonist, active exclusively
against mycobacterium tuberculosis
 Structurally similar to p-aminobenzoic
acid(PABA) and the sulfonamides
 Dosage: 4 -12g/day PO (adult)
300mg/kg/day for children PO
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49. Pharmacokinetics & Adverse
effects
 Readily absorbed from GIT
 Widely distributed
 Excreted in urine
Adverse effects :
 Hypersensitivity reactions (fever, joint pain,
hepatosplenomegaly, hepatitis,granulocytopenia, adenopathy)
 Peptic ulcer & gastric hemorrhage
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50. FLUOROQUINOLONES
 Active against typical & atypical mycobacteria
 Moxifloxacin is the most active against M
tuberculosis
 Ciprofloxacin, Levofloxacin, Moxifloxacin
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51.  Important drugs, especially for strains resistant to
first line agents
 Dosage :
 Ciprofloxacin 750mg BD,PO
 Levofloxacin 500mg OD.PO
 Moxifloxacin 400mg OD. PO
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52. MOA
 Inhibit bacterial DNA synthesis by inhibiting
bacterial Topoisomerase II (DNA Gyrase) &
topoisomerase IV
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53. ADR
 Nausea, Vomiting, Diarrhea (MC)
 Headache, Dizziness
 Skin rash, Photosensitivity.
 Damage growing cartilage
 Tendinitis & Tendon rupture
 Insomnia 9-Sep-15
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54. KANAMYCIN & AMIKACIN
 Kanamycin, streptomycin – resistant strains, but the
availability of less toxic alternatives (eg capreomycin and
amikacin) has renderd it obsolete
 Prevalence of Amikacin resistant is low & most MDR
remain Amikacin susceptible
 Amikacin is active against atypical mycobacteria.
 Dosage : 15mg/kg IV infusion
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55. LINEZOLID
 Used in combination with Second & Third line
drugs for MDR strains
 Dosage : 600mg/day
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56. ADR
 Bone marrow depression
 Irreversible peripheral neuropathy
 Optic neuropathy
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57. RIFABUTIN/ RIFAPENTINE
 Derived from rifamycin & related to rifampin
 Significant activity against M.tuberculosis , M
avium & M.fortuitum
 Dosage 300mg/day
Mechanism of action:
 Bacterial RNA polymerase inhibitor
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58.  Effective in prevention & treatment of atypical
mycobacterial infection in AIDS
 Weak enzyme inducer of cyt P450 enzymes.
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59. NEWER DRUGS
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60. BEDAQUILINE (SIRTURO, TMC207, R207910)
 First new 40 years
 Approved on 28 December 2012 to treat resistant TB
 Binds to oligomeric & proteolipic subunit-c of
mycobacterial ATP synthase leads to inhibition of ATP
synthesis & death
 ↑ QT interval, abnormal & fatal heart rhythm
(Increased risk of death)
 Nausea, Joint pain, Headache & ↑ liver enzyme
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61. PRETOMANID (PA-824)
 Bicyclic nitroimidazole-like molecule
 Active against both replicating & non-replicating organisms
 Cell wall inhibition (like isoniazid) & respiratory poisoning
(like cyanide)
 Inhibits mycolic acid biosynthesis through unknown molecular
mechanism
 Respiratory poisoning through NO release
 Safe, Well tolerated, & efficacious at doses of 100–200 mg
daily
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62. DOTS
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63. DOTS
 DOTS, to ensure cure by
providing medicine &
confirming it’s taken
 INTENSIVE PHASE- pt
swallows drug in presence of
health worker
 CONTINUATION PHASE- 1
wk medicine in multiblister
combipack (1st dose in presence
of health worker)
 Next week medicine only after
return of empty blister 9-Sep-15
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64. Advantages
 High cure rate
 ↓ Drug resistance
 ADR can be monitored
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65. PHASES OF CHEMOTHERAPY
INITIATION PHASE
• 2-3 months
• 4-5 drugs
• Rapidly kills bacilli
• INH
• Rifampicin
• Ethambutol
• Pyrazinamide
CONTINUATION PHASE
• 4-6 months
• 2-3 drugs
• Eliminates remaining
bacilli
• Prevents relapse
• INH+Pyridoxine
• Rifampicin
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66. CLASSIFICATION OF PATIENTS
Category Type of Patient Regimen Duration
in months
Category I New Sputum Positive Seriously ill
sputum negative,
Seriously ill extra pulmonary,
Sputum Negative,
extra pulmonary not Seriously ill
2 (HRZE)3,
4 (HR)3
6
Category II Sputum Positive relapse,
Sputum Positive failure,
Sputum Positive treatment after default
2 (HRZES)3,
1 (HRZE)3
5 (HRE)3
8
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67. DRUG-RESISTANT TB: Definitions
 Mono-resistant: Resistance to a single drug
 Poly-resistant: Resistance to more than one drug, but
not the combination of isoniazid and rifampicin
 Multidrug-resistant (MDR): Resistance to at least
isoniazid and rifampicin
 Extensively drug-resistant (XDR): MDR plus
resistance to fluoroquinolones and at least 1 of the 3
injectable drugs (amikacin, kanamycin, capreomycin)9-Sep-15
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68. RNTCP’S regimen for MDR-TB
Intensive phase (6-9 months) Continuation phase (18 months)
1. Kanamycin
2. Ofloxacin/ Levofloxacin
3. Ethionamide
4. Cycloserine
5. Pyrazinamide
6. Ethambutol
1. Ofloxacin/ Levofloxacin
2. Ethionamide
3. Cycloserine
4. Ethambutol
+Pyridoxine 100 mg/ day
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69. SPECIAL CASES
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70. TB IN PREGNANT WOMEN
 H, R, Z, E are safe
 Z is not recommended in US
 9 months (2HRE+ 7HR)
 Pyridoxine
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71. TB IN AIDS PATIENTS
 5% of TB pts are HIV +ve
 HIV +ve pts have higher incidence
of extra pulmonary, sever & more lethal TB
 Duration of therapy 6-9 months (2HRZE + 4-7 HR)
 Rifabutin → Rifampin (9-12 months), if pts is on ART
 MDR-TB with HIV should be Rx like in non- HIV pts
 Pyridoxine
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72. TB Meningitis
 Long duration
 5 drugs in continuation phase
 Continuation phase- extended by 3 months
 Higher dose
 Glucocorticoid
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73. Chemoprophylaxis
 Prevent progression of latent infection to active TB
 INH- 300mg (10mg/kg) daily for 6 months
 In case of INH resistance,
INH (5mg/kg) + R (10mg/kg) daily for 3 months
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