Tb

• Tuberculosis


  An ancient disease, the discovery of Spinal Tuberculosis among Egyptian Mummies has dated back 1550 – 1080 BC
• Mycobacterium TB complex


  • M. tuberculosis
  • M. bovis
  • M. Africanum
  • M. microtii
  • M. canetti
• All belong to the order Actinomycetales and the family Mycobacteriaceae. M. tuberculosis is the most important cause of tuberculosis disease in humans.
• Mycobacterium tuberculosis


  • Obligate aerobes
• Transmission


  • Droplet
  • Ingestion
  • Inoculation
  • Transplacental
• Tuberculosis disease


  • Acid-fast smear of sputum
  • Extensive upper lobe infiltrate or cavity
  • Copious production of thin sputum
  • Severe and forceful cough
• Environmental factors


  Poor air circulation
• Bacteriological status


  • Bacteriologically confirmed
  • Clinically diagnosed
• Anatomical site


  • Pulmonary TB (PTB)
  • Extrapulmonary TB (EPTB)
• Treatment regimens for drug sensitive DS-TB

  • Regimen 1: 2HRZE/4HR
  • Regimen 2: 2HRZE/10HR
• Basic principles of treatment

  • Adherence to therapy
  • Never add single drug to failing regimen
  • Susceptible to multiple drugs
  • Safest, most effective
• Drugs for tuberculosis


  • Isoniazid (H)
  • Rifampicin (R)
  • Pyrazinamide (Z)
  • Ethambutol (E)
  • Streptomycin
  • Quinolones
  • Thionamides
  • Aminoglycosides
  • PAS
  • Cycloserine
• Isoniazid (INH)


  • Primary drug for the chemotherapy of tuberculosis
  • Bacteriostatic for "resting" bacilli but is bactericidal for rapidly dividing microorganisms
  • Penetrates cells with ease and is just as effective against bacilli growing within cells as it is against those growing in culture media
• Isoniazid (INH)


  • Mechanism of action: Inhibits the biosynthesis of mycolic acids
  • A competitive antagonist in pyridoxine-catalyzed reactions
  • Well absorbed from the gut
  • Readily diffuses in all body tissues and body fluids (CSF)
  • Metabolism by N-acetyltransferase (prodrug)
  • Rapid acetylator- hepatotoxicity
  • Slow acetylator- neuropathy
  • Increase plasma concentration of phenytoin and carbamazepine
• Untoward effects of Isoniazid


  • Rash during the first week of treatment
  • Fever
  • Jaundice
  • Peripheral neuritis - *pyridoxine*
  • Hematological reactions
  • Vasculitis associated with ANA
  • Arthritic symptoms
  • Convulsions
  • Optic neuritis
• Rifampicin


  • Inhibits growth of most gram-positive bacteria, as well as many gram-negative microorganisms
  • Inhibits DNA-dependent RNA polymerase of mycobacteria and other microorganisms
  • Suppression of initiation of chain formation in RNA synthesis
• Rifampicin


  • Absorbed from the GIT in the fasting state
  • Rapidly eliminated in the bile with enterohepatic circulation
  • Distributed throughout the body
  • Resistance rapidly develops
  • Adequate level with meningeal irritation
• Untoward effects of Rifampicin

  • Rash
  • Fever
  • Nausea and vomiting; GI disturbances
  • Jaundice
  • Flu like syndrome
  • Orange discoloration of urine, tears, saliva and sputum
• Rifampicin drug interactions


  Decreases plasma half-life of prednisone, digitoxin, quinidine, ketoconazole, propranolol, metoprolol, and reduces efficacy of oral anticoagulants
• Pyrazinamide (PZA)


  • Synthetic pyrazine analog of nicotinamide
  • Bactericidal activity in vitro only at a slightly acidic pH
  • Well absorbed from GIT
  • Widely distributed throughout the body
  • Excreted by renal GFR
• Untoward effects of Pyrazinamide

  • Injury to the liver
  • Arthralgia particularly of shoulders
  • Anorexia
  • Nausea and vomiting
  • Dysuria
  • Malaise and fever
  • Hyperuricemia
• Ethambutol


  • Suppresses the growth of most INH-and streptomycin-resistant tubercle bacilli
  • Mechanism of action is unknown
  • Absorbed from GIT
  • Excreted, unchanged in urine, dose reduction needed if with renal disease
  • Should not be given to children <6y.o.or in patient where visual acuity cannot be reliably monitored
• Untoward effects of Ethambutol


  • Diminished visual acuity
  • Rash
  • Drug fever
  • Pruritus
  • Joint pain
  • GI upset
  • Malaise, headache, dizziness, mental confusion, disorientation, hallucination
  • Peripheral neuritis
• Streptomycin


  • First clinically effective drug available for the treatment of TB
  • Bactericidal for tubercle bacillus in vitro
  • Inhibit protein synthesis and decrease the fidelity of translation of mRNA
  • Nephrotoxic, ototoxic
• Second-line drugs


  • Ethionamide
  • Aminosalicylic acid
  • Cycloserine
  • Kanamycin
  • Amikacin
  • Capreomycin
• Ethionamide


  • Bacteriostatic
  • Nicotinic derivatives related to INH
  • Complete absorption - oral
  • Bioavailability almost 100%
  • Hepatic metabolism→ active metabolite sulfoxide
  • Drug-drug interactions with INH, cycloserine, MgOxide, citric acid
• Cycloserine


  • Broad spectrum antibiotic
  • Inhibits reactions in which D-alanine is involved in bacterial cell-wall synthesis
  • Absorbed from the GIT
  • Used exclusively for resistant TB
  • CSF concentration = plasma concentration
  • Drug-drug interactions with Ethionamide, INH, MgO, citric acid
• Para-amino salicylic acid (PAS)

  • Folic acid antagonist
  • Structurally similar to PABA and sulfonamide
  • Renal elimination -80% (50% in acetylated form)
  • Forms crystals in acidic urine
• Other second-line drugs


  • Kanamycin
  • Amikacin
  • Fluoroquinolones
  • Capreomycin
• The alternative drugs are usually considered only in case of resistance to first-line agents, failure of clinical response to conventional therapy, or serious treatment-limiting adverse drug reactions.
• Dosage of drugs


  • Isoniazid (H): 5 mg/kg/day, max 400 mg/day (children 10 mg/kg/day, max 300 mg)
  • Rifampicin (R): 10 mg/kg/day, max 600 mg/day (children 10-20 mg/kg/day, max 600 mg)
  • Pyrazinamide: 20-30 mg/kg/day
• Ethionamide


  Bacteriostatic, Nicotinic derivatives related to INH, Complete absorption –oral, Bioavailability almost 100%, Hepatic metabolism→ active metabolite sulfoxide, DDI- INH, cycloserine, MgOxide, citric acid
• Cycloserine


  Broad spectrum antibiotic, Inhibits reactions in which D-alanine is involved in bacterial cell-wall synthesis, Absorbed from the GIT, Used exclusively for resistant TB, CSF conc = plasma conc, DDI : Ethionamide, INH, MgO, citric acid
• Para-amino salicylic acid


  FA antagonist, Structurally similar to PABA and sulfonamide, Renal elimination -80% ( 50% in acetylated form), Forms crystals in acidic urine
• Other drugs


  • Kanamycin
  • Amikacin
  • Fluoroquinolones
  • Capreomycin
• For therapy of "resistant" or treatment-failure tuberculosis when given with ethambutol or isoniazid
• Drugs and dosages


  • Isoniazid (H) - Adult 5 max 400 mg/day, Children 10 max 300
  • Rifampicin (R) - Adult 10 max 600 mg/day, Children 10-20 (15) max 600
  • Pyraziamide - Adult 20-30 max 2g /day, Children 30-40 (35)
  • Ethambutol - Adult 15-20 max 1.2 g, Children 14-25 (20)
  • Amikacin - 15-30 max 1 g
  • Kanamycin - 15-30 max 1 g
  • Streptomycin - 20-40 max 1 g
  • Capreomycin - 15-30 max 1 g
• Pregnancy and Lactation treatment

  • INH (9 months if with latent TB)
  • Rifampicin
  • Ethambutol
  • Pyrazinamide (for 2 months although safety is not well established)
• Pyridoxine 25 mg/day recommended for all taking INH
• Treatment Options


  • 2HRZE/4HR
  • 2HRE/7RH