2. Learning objective
• Classify first line & second line anti tubercular
drugs
• Enumerate the MOA, ADR, USES , DI of anti
tubercular drugs
• Enumerate newer drugs used in management
of TB
4. Natural History of TB Infection
Exposure to TB
No infection
(70-90%)
Infection
(10-30%)
Latent TB
(90%)
Active TB
(10%)
Untreated
Die within 2 years Survive
Treated
Die Cured
Never develop
Active disease
5. Latent TB vs. Active TB
Latent TB (LTBI) (Goal = prevent future active disease)
= TB Infection
= No Disease
= NOT SICK
= NOT INFECTIOUS
Active TB (Goal = treat to cure, prevent transmission)
= progress to TB Disease
= SICK
= INFECTIOUS if PULMONARY
= NOT INFECTIOUS if not PULMONARY
6. Why treatment complicated
• Mycobacteria resistant to most AB
• Grow slowly
• Dormant
• Lipid rich cell wall impermeable
• Intracellular pathogens – inacessable
• Notorious – resistance
• Response to drug therapy is slow
• Treatment for months
• Chronic nature of disease
• Patients compliance
7. Drugs for TB
• First line drugs – highly efficacious, less toxic
• INH ,RFM, PYZ,EHM, SM
8. • Second line drugs –less efficacious, more toxic
, expensive, reserve drug
• Fluoroquinolones , amikacin,
capreomycin,Kanamycin, ethionamide,
prothionamide, PAS, clarithromycin,
cycloserine, thiacetazone, rifabutin
• Others – linezolid, clofazimine, Amx/ Clv
11. ISONIAZID (INH) : First line / Primary anti T.B drug.
Chemistry: Synthetic analog of pyridoxine.
Small molecule,MW-137
12. INH
• Bactericidal for actively growing TB bacilli
• Penetrates macrophages /cell
• Active – EC & IC
• Less effective – atypical MTB
13. • blocks biosynthesis of mycolic acids
• Mycolic acid -long chain β –hydroxylated fatty
acids
• Decreased Mycolic acid synthesis - loss of acid
fastness.
14. • Isoniazid is a pro-drug
• INH enters mycobacteria – convert
active metabolite catalaseperoxidase (KatG)
enzyme
• Metabolite interacts with NAD and inhibits
“InhA”and “KasA”
• Also adducts with NADP– DHFRase
inhibition – no DNA
20. 2. Liver damage :
Metabolite--- Acetyl hydrazine - Fast
acetylators
Loss of appetite, nausea, vomiting, pain in
right upper quadrant of abdomen &
jaundice.
• Risk > in Alcoholics , pregnancy &
postpartum period.
22. Drug interactions
• Antacids – Al(OH)2 – inhibit absorption
• Inhibit metabolism of Phenytoin, diazepam
carbamazepines, warfarin
23. Clinical use
For treatment of active TB
Used in combination with other Anti T.B drugs
in different regimens.
For prophylaxis in latent TB, as a single agent.
24. Rifampicin / Rifampin
• Semisynthetic derivative Rifamycin--
streptomyces mediterranei
• Members – rifabutin, rifapentin,
• Effective for persisters
25. • Bactericidal.
• Strongly binds - bacterialDNA-dependent RNA
Polymerase.(rpoB)
• Inhibits the RNA synthesis
• Resistance develops - mutations in the gene
(rpoB)
26. Anti Bacterial Spectrum
• Bactericidal for :
Mycobacteria: M T.B & Leprae
G+ve bacteria --- Staphylococcus aureus,
MRSA
G-ve bacteria --- Meningococci & H.Influenzae
27. Pharmacokinetics
• Given orally. Well absorbed from GIT.
• Distribution wide - body fluids & tissues,
CSF, caseous material, reddish orange
• Enterohepatic circulation
• Excreted in bile & faeces
40. Streptomycin
• First drug – exhibit anti tubercular activity
• First Aminoglycoside antibiotic.
• Streptomyces griseus.
• First line Anti TB drug, given by injection
• Bactericidal – only extracellular
42. Clinical uses
Mycobacterium TB Infections
severe life threatening form of infection:
• Disseminated Tuberculosis
• Tuberculous Meningitis
• Infections resistant to other drugs.
43. Adverse effects
• Ototoxicity—vertigo & hearing loss ,may be
permanent.
• Nephrotoxicity—dose related ,more in elderly.
• Dosage adjustment according to Creatinine
CL.
50. Capreomycin
• streptomyces capreolus
• protein synthesis inhibitor
• Poorly absorbed orally, no penetrationBBB
• treatment – MDR TB
• Resistant to SM, AM
51. Capreomycin
Adverse drug reactions
• Nephrotoxicity
• Ototoxicity – tinnitus, deafness, vestibular
disturbance may occur.
• Local pain & sterile abscesses due to inject
62. Learning objective
• Enumerate drugs used as per RNTCP
• Describe MDR-TB & DOTS plus
• Enumerate TB management during pregnancy,
lactation, AIDS etc
• Enumerate the use of Corticosteroids in TB
63. Treatment of TB
• Diagnosis made by symptoms& lab findings
• Preantibiotic era
• Understanding of infection
• Challenge in treatment
64. Goals of drug therapy
• To kill multiplying bacilli
• To kill persisters – prevent relapse
• To prevent resistance development
• To prevent treatment failure
• But poor compliance – relapse, resistant org,
spread
65. Why multiple drugs
• Prevent resistance
• Reduce duration of therapy
• Reduce drug toxicity
• Kill the bacteria
66. WHO guidelines
• Dose is standardized & modified as per BW
• All regimen 2 phase
• Sputum +ve/-ve
• Severity of disease – site & extent of disease
• Type of disease – pulmonary &
extrapulmonary
• H/O previous treatment
67. Reasons for failure of treatment
• Poor patient compliance
• Organism peristers, semidormant, dormant
• Wrong choice of drug
• Associated with uncontrolled DM, AIDS
69. RNTCP
objective
• To implement WHO guidelines for TB
• DOTS therapy /strategy in Indian scenario
classified into 5 groups
to facilitate proper management of the disease
72. MDR TB
• Resistance to INH and RFM /any other first
line drug
• Disease progression rapid
• DOTS plus guidelines
• Treatment for 24-27months
• Cause – HIV/AIDS, DM, steroids
73. DOTS plus
• Programme includes component for MDRTB
• Diagnosis
• Management
• Treatment
• Began in 2000 by WHO
• Implemented in India 2010
74.
75. XDR TB
• Extensively resistant TB
• 2% of MDR are XDR
• INH +RFM + Resistant to all FQ + injectable
second line drugs (km,Am,Cm)
• with or without any other drugs
• Failure to MDR-TB regimen
• Difficult to treat
• Rapid course & high mortality
76.
77. Childhood TB
• Children rarely sputum +ve
• Mc extrapulmonary TB- Lymphadenitis
• TST/ MX positive
• Loss of weight/ failure to thrive
78. Tuberculosis in pregnant women
• Treatment continued
• isoniazid, rifampin - safe during pregnancy.
• SM – CI
• PYZ – safety not clear
• Ethambutol - avoid in early pregnancy.
• HRE-2M, RH-7M
79. MDR-TB & Pregnancy
• Child bearing age -birth control measures,
barrier methods, IUD
• <20 Weeks – MTP, unwilling – mod catIV
• >20 weeks – modified catIV
• Avoid Km, add PAS till delivery
80. Treatment of breast feeding women
• safe – to be continued
• Infant should receive BCG vaccination &
isoniazid prophylaxis.
81. TB with AIDS
• highly lethal
• ART + ATT
• IP – HRZE -2M DAILY
• CP –HR - (6-9m)
• Cotrimoxazole prophylaxis
• Rifabutin – less E. inducer
• MDR TB /HIV – 18-24m
82. Chemoprophylaxis
• Close Contact with TB pts
• Subjects -MX positive – but no active disease
• Immunocompromised HIV, CS, Leukaemia
• Neonate of tubercular mother
• Old not active presently
• HIV Pts exposed to MDR-TB
• INH –300mg /day -6-9m
• RFM -600mg/day 4M
83. Role of corticosteroid
• Used -adequate therapeutic cover
• TB induced adrenocortical insufficiency
• Miliary TB ,severe pul TB
• TB Meningitis –prevent adhesion & hydrocephalus
• Prevent GU, ocular, pericardial, pleural adhesion ,
fibrosis
• Prevent bronchial stenosis
• Gradually withdrawn
• CI – intestinal TB
