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Antitubercular Agents

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  • 1. Antitubercular Agents
  • 2. Tuberculosis
    • Agent: Mycobacterium tuberculosis ALSO: M. africanum & M. bovis
    • Route of Infection:
      • Primary: inhalation of infectious particles (droplet nuclei) ALSO: spread by lymphatics
    • Incubation: 2-10 weeks; risk of progressive disease greatest in first 2 years (HIV decreases both)
    • Cell-mediated immune response  tubercle formation
    • Culture takes 6 weeks
    • Dx relies on AFB smear (Acid-Fast Bacillus)
      • BUT threshold of detection 5-10,000 organisms/mL
  • 3. Tb Infection may not cause disease
    • A good example of difference between infection and infectious disease
    • Tb skin test converters have been infected,
    • but are not sick. They are at risk of developing disease
  • 4. Tuberculosis: Types
    • Sites:
      • Pulmonary (most common)
      • Bone
      • Urinary tract
    • Primary
      • Initial infection with the disease
    • Reactivation
      • Patient infected in past has reactivation of disease
  • 5. Tuberculosis: Risk Factors
    • HIV infection
    • Close contacts of persons with infectious Tb
    • Persons with medical conditions that decrease resistance to infection
    • Persons who inject drugs
    • Foreign-born persons where Tb is endemic
    • Medically underserved, low-income populations
    • Residents & employees of LTC facilities
    • Local high prevalence groups (e.g., migrants)
    • Healthcare workers at risk of exposure in workplace
  • 6. Antitubercular Agents Trecator Ethionamide Seromycin Cycloserine Streptomycin (SM) Myambutol Ethambutol HCl (EMB) Pyrazinamide (PZA) Rifandin, Rimactane Rifampin (RIF) Laniazid Isoniazid (INH) TRADE GENERIC
  • 7. Indications for drug therapy
    • Prevention & treatment of tuberculosis
    • No prototype – each drug differs from the others
    • TB:
      • Highly contagious
      • Reportable disease
      • Treatment initiated by specialist
      • Refer for initial work-up & treatment
    • PCP ROLE:
      • Follow patient while on therapy
      • Prophylaxis
  • 8. Patient Variables
    • Geriatrics
      • Increased risk for toxic effects, esp. liver & CNS
    • Pediatrics
      • INH, RIF, PZA commonly used
      • EMB NOT recommended for children < 13
      • Streptomycin NOT recommended for use in children
      • Cycloserine & ethionamide: safety NOT established
    • Pregnancy
      • Category C: prescribe only when necessary
      • Category D: Aminoglycosides (SM) & Ethionamide (teratogenicity in animals)
    • Lactation
      • INH, RIF, PZA, EMB, cycloserine all appear in breast milk
  • 9. Prophylaxis
    • Recent skin test converters
      • Positive PPD, nL CXR & no evidence of active Tb
    • Close contacts of individuals with infectious, clinically active Tb
    • Evaluate to r/o active Tb
    • Assess for Hx hepatitis, heavy alcohol ingestion, liver disease, age > 35
      • If Hx positive  obtain LFTs to evaluate any contraindications to therapy
    • Must weigh risk vs. benefit
    • Prophylaxis: INH 300mg PO QD
    • Length of Tx:
      • Children < 18: 9 mo
      • Adults: 6 mo
      • Immunocompromised or abnL CXR(NOT active Tb): 12 mo
    • Dispense: 1 mo supply – monitor Qmo
  • 10. Treatment of active disease
    • Direct Observed Treatment (DOT)
      • Standard of care in MD & NYC
      • Every dose of anti-Tb medication observed and supervised by a h/c worker
      • Compliance is KEY
      • Noncompliant may be sent to prison to assure compliance (has been shown to reduce prevalence of multidrug resistance
    • Increased prevalence of resistance  4 drug regimen
      • INH, RIF, PZA & (EMB OR SM)
  • 11. Tuberculosis: Resistance
    • Reasons for development
      • Inadequate treatment
      • Discontinuance of treatment prematurely
    • Many organisms resistant to standard Tx
      • INH, RIF, & EMB
    • Some strains resistant to all known Tb drugs
    • Patterns of resistance determine local treatment
  • 12. Patient Monitoring
    • INH Prophylaxis
      • Seen Q month & assess for
        • s/s of liver damage or other toxic effects, anorexia, n/v, fatigue, weakness, paresthesias of hands/feet, persistent dark urine, icterus, rash, elevated temp
      • Routine LFTs (Q mo) for patients at high risk for developing INH hepatitis (age >35, daily drinkers, concomitant medications toxic to liver, hx of liver disease)
      • D/C INH immediately if s/s of toxicity
  • 13. Patient Monitoring
    • Active Tb Treatment
      • CXR at baseline & 6 mo
      • Sputum smear & culture at baseline and monthly until negative
      • Measure: liver enzymes, bilirubin, serum creatinine, CBC, PLTs, serum uric acid at baseline & monthly
        • INH  periodic ophthalmologic exam
        • PZA  blood glucose levels
        • EMB  color vision for red/green at baseline & 2-3 months
        • SM  audiogram prior to Tx & 2-3 months; serum SM levels
        • Cycloserine  weekly blood levels in reduced renal function
  • 14. Isoniazid (INH)
    • Mechanism of Action
      • Bacteriostatic for resting organisms
      • Bactericidal for dividing organisms
      • Interferes with lipid and nucleic acid biosynthesis
    • Contraindications
      • Known contact with INH-resistant Tb case
      • Previous INH-associated adverse effect
      • Acute liver disease, severe chronic liver disease
  • 15. INH Pharmacokinetics
    • Half-life
      • Variable
    • Distribution
      • Widely distributed to all body tissues
    • Metabolism
      • Acetylation & dehydrazination
      • Rate of acetylation genetically determined 50% of blacks & whites are “slow acetylators” majority of Eskimos & Asians are “rapid acetylators”
    • Excretion
      • Renal
  • 16. Isoniazid (INH)
    • Adverse Effects
      • Most frequent: liver & nervous system effects
      • Stains urine orange-red
      • Fever, rash, vasculitis
      • N/V
      • Agranulocytosis, thrombocytopenia
      • Peripheral neuropathy, numbness & tingling of extremities
      • Jaundice, abnormal LFTs
  • 17. Isoniazid (INH)
    • Drug Interactions
      • P450 1A2 inhibitor & 2C inhibitor
      • Concomitant use of alcohol associated with higher incidence of hepatitis
      • Higher rate of hepatotoxicity with RIF
      • Aluminum containing antacids decrease absorption
      • Some MAOI activity (tyramine containing foods)
    • Overdose
      • EARLY: N/V, dizziness, slurring of speech, blurring of vision, visual hallucination
      • LATE: respiratory distress, CNS depression (may be fatal)
  • 18. INH: Patient Education
    • Take on empty stomach 1 hr before or 2 hrs after meal
    • Minimize alcohol consumption
    • Avoid foods containing tyramine (wine, hard cheese, liver) and histamine (tuna, sauerkraut)
    • Notify provider if fatigue, weakness, n/v, loss of appetite, yellowing of skin or eyes, darkening of urine, numbness/tingling of hands / feet
  • 19. Pharmacokinetics Renal: active drug & metabolites Hepatic 80% & rapid Ethionamide Renal Hepatic Well absorbed Cycloserine Renal: Glomerular Filtration Hepatic PO: poor IM: rapid SM Renal: 80% Feces: 20% Hepatic-oxidation 75-80% EMB Renal Hepatic Well absorbed PZA Bile: 70% Urine: 30% Hepatic Readily RIF Renal Hepatic-acetylation genetic Interference with food INH EXCRETION METABOLISM ABSORPTION DRUG
  • 20. Pharmacokinetics Wide Wide Well distributed Most tissues Most tissues Wide distribution 80% protein bound Diffuses to all body tissue DISTRIBUTION & PROTEIN-BINDING 3 hr Ethionamide 25-30 mcg/ml 12 hr 4-8 hr Cycloserine 25-50 mcg/ml 5-6 hr 1 hr SM Requires special assay 24 hr 2-4 hr EMB 9-12 mcg/ml 9-10 hr 2 hr PZA 4-32 mcg/ml 2-3 hr varies RIF 24 hr 1-2 hr varies INH THERAPEUTIC SERUM LEVEL ½-LIFE PEAK DRUG
  • 21. Tuberculosis: Symptoms
    • Sx:
      • Cough, pain in chest when breathing or coughing, cough productive of sputum or blood
      • Weight loss, fatigue, malaise, fever, & night sweats
    • Assume contagious if:
      • Cough is present
      • Undergoing cough inducing procedures
      • Sputum smear is positive until 3 negative
      • Until patient on Tx at least 1 week
      • Showing poor response to Tx
  • 22. Tuberculosis: Exposure Testing
    • Purified Protein Derivative (PPD) or Mantoux Test
      • Mantoux – preferred, more accurate
      • Tine test – no longer used
    • 0.1 mL of PPD with 5 TU injected intradermally – pale elevation 6-10 mm read 48-72 hours after injection
    • Only induration (hardness) is measured
  • 23. Criteria for Positive Tb Skin Test
    • Negative does NOT r/o
      • Person may be anergic
    • > 5 mm induration
      • Children <1 year of age
      • X-ray or clinical evidence of disease
      • Close contact of person with active disease
      • Evidence of old healed Tb
      • Persons with risk factors for HIV infection
      • Persons who inject drugs
    • > 10 mm induration
      • Children between 1 & 4 years old
      • Foreign-born persons from high prevalence countries
      • HIV seronegative IV drug users
      • Persons with medical risk factors (DM, ETOH, drug abuse)
      • Employees / residents of LTC facilities
    • > 15 mm induration
      • All others
  • 24. Testing for Tb Exposure
    • Skin testing for person with history of BCG vaccine
      • WAS: never give PPD to person who had received BCG
      • NOW: BCG status should NOT influence need for Tb skin testing – may see boosted reaction
    • Two-step Tb skin testing (PPD  2nd PPD in 1-3 wks)
      • Distinguishes boosted reaction (b/c hypersensitivity reaction wanes with time) vs. reaction d/t new infection
      • Recommended for elderly patients and high-risk employees
  • 25. Testing for Tb Exposure
    • Chest X-ray
      • AP & LAT for all persons with positive PPD
      • Very sensitive (not a lot of false negatives): nL CXR  Tb unlikely
      • Detected abnormalities  biopsy showing caseation granulomas to confirm diagnosis
      • Policies on annual CXR vary for positive skin test most are considered cleared of Tb if CXR clear & F/U CXR only required if s/s of Tb
    • Sputum
      • Direct examination shows presence of AFB
      • Positive smear  considered contagious
      • Classic Dx made by culture (takes 6 weeks)
      • Mycobacterium tuberculosis Direct Test results in 4-5 hours BUT misses 5% of cases (requires culture)
  • 26. Diagnosis of Active Tb
    • PRESUMPTIVE (report w/in 24 hr to HD):
      • Recent conversion to positive PPD associated with characteristic s/s
      • Positive sputum (or other body fluid) smear
      • Characteristic CXR
      • Bx showing caseating granulomas
      • HIV/AIDS (d/t high rate of concurrent infection)
    • CONFIRMED (report w/in 24 hr to HD):
      • Positive culture (any body fluid or Bx specimen)
      • Also tests for drug susceptibility
  • 27. Rifampin
    • Mechanism of Action
      • Inhibits DNA-dependent RNA polymerase activity  suppressing RNA synthesis
      • May be bacteriostatic or bactericidal
      • Most active against bacteria undergoing cell division
    • Contraindications
      • Hypersensitivity
  • 28. Rifampin
    • Warnings / Precautions
      • Hepatotoxicity with fatality – monitor LFTs & adjust dose with impaired liver fxn
      • Hyperbilirubinemia
      • Porphyria exacerbation
      • Meningococci resistance may emerge
      • Hypersensitivity reaction if intermittent or interrupted therapy
      • May be associated with carcinogenesis
      • Monitor CBC & LFTs
      • Urine, feces, saliva, sputum, sweat, & tears may be colored red-orange. Soft contact lenses may be permanently stained
      • Thrombocytopenia – usu. reversible but may be fatal
  • 29. Rifampin
    • Adverse Effects
      • Common: GI Sx’s & rash
      • High doses  flulike syndrome, hematopoietic reactions
    • Drug Interactions
      • P450 1A2 substrate, 2C inducer, 2D6 inducer, 3A4 inducer and substrate
      • Decreases effectiveness of many drugs including oral anticoagulants & oral contraceptives
      • Decreases serum digoxin concentrations
    • Overdose – requires hospitalization
      • N/V, lethargy
      • Liver toxicity
  • 30. Rifampin: Patient Education
    • Take on an empty stomach, 1 hr before or 2 hrs after meals
    • Avoid missing doses
    • May cause red-orange discoloration of body fluids
    • Notify provider if “flulike” Sx’s, yellow discoloration of skin or eyes, skin rash or itching
  • 31. Pyrazinamide (PZA)
    • Mechanism of Action
      • Unknown
      • Bacteriostatic vs. bactericidal activity dose-dependent
    • Contraindications
      • Hypersensitivity, liver damage, acute gout
  • 32. Pyrazinamide (PZA)
    • Warning / Precautions
      • Inhibits renal excretion of urates – may cause hyperuricemia and gout
      • Use with caution in patient with renal function impairment – reduced dose usually not necessary
      • Monitor patients with hepatic impairment closely
      • In patients with DM, BG control may be more difficult
  • 33. Pyrazinamide (PZA)
    • Adverse Effects
      • Frequent: mild arthralgia & myalgia
      • Most common serious: gout & hepatic toxicity
    • Drug Interactions
      • No known P450
    • Overdose
      • Liver toxicity
  • 34. PZA: Patient Education
    • Report:
      • Fever, loss of appetite, malaise, N/V, darkened urine, yellowish discoloration of skin or eyes, pain or swelling or joints
  • 35. Ethambutol HCl
    • Mechanism of Action
      • Impairs cellular metabolism  stops cell multiplication & causes cell death
      • Bactericidal & active only against mycobacteria
    • Contraindications
      • Hypersensitivity
      • Known optic neuritis
  • 36. Ethambutol HCl
    • Warnings / Precautions
      • Visual testing (on each eye individually & both together) before initiating Tx and periodically including visual acuity, ophthalmoscopy, peripheral fields, & color discrimination
      • Renal impairment requires dose adjustment
  • 37. Ethambutol HCl
    • Adverse Effects
      • Fever, malaise, dizziness, headache
      • Dermatitis, pruritis
      • Thrombocytopenia
      • Common: N/V, anorexia, abdominal pain
      • SEVERE: Optic neuritis, loss of acuity, loss of red-green discrimination
    • Drug Interactions
      • Aluminum salts may delay/reduce absorption
  • 38. EMB: Patient Education
    • May cause GI upset – take with food
    • Aluminum-containing antacids may interfere with absorption  separate administration by several hours
    • Notify provider of
      • Changes in vision: blurring, red-green color blindness
      • Rash
  • 39. Cycloserine
    • Mechanism of Action
      • Inhibits cell wall synthesis
      • May be bacteriostatic or bactericidal
    • Warnings / Precautions
      • D/C if: CNS toxicity, dysarthria, allergic dermatitis
      • Small Therapeutic Index: Toxicity r/t to high blood levels
      • Renal Function Impairment: accumulation & toxicity
      • Anticonvulsants or sedatives may be effective in controlling Sx’s. ALSO, pyridoxine may be helpful in ameliorating neurotoxicity
      • Associated with B12, folic acid deficiency, megaloblastic & sideroblastic anemia
  • 40. Cycloserine
    • Adverse Effects
      • CNS Sx’s: convulsions, psychosis, somnolence, depression, confusion, hyperreflexia, headache, tremor, vertigo, paresis
    • Drug Interactions
      • INH: increase in dizziness
      • Alcohol: increased risk of epileptic episodes
    • Overdose
      • CNS depression
  • 41. Cycloserine: Pt Education
    • Notify provider of:
      • Dizziness, mental confusion, skin rash, tremor
    • Avoid alcohol
    • May cause drowsiness, use caution when operating heavy machinery
  • 42. Ethionamide (when 1st line Tx has failed)
    • Mechanism of Action
      • Inhibits peptide synthesis
      • Bacteriostatic or bactericidal depending on concentration & susceptibility of organism
      • Highly specific for Mycobacterium
      • NOT a first line agent
    • Contraindications
      • Hepatic damage or hypersensitivity
    • Warnings / Precautions
      • Hepatitis occurs more frequently  monitor LFTs
      • Management of DM may be more difficult
    • Drug Interactions
      • Raises serum concentrations of INH
      • May potentiate adverse effects of other antitubercular drugs, esp. cycloserine
      • Avoid alcohol ingestion (may produce psychotic reaction)
  • 43. Ethionamide: Pt Education
    • May cause stomach upset, metallic taste, or loss of appetite
    • Take with food to minimize GI upset
    • Notify provider if effects persist