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Epidemiology

Antimycobactrial Drugs Parvaneh Rahimi-Moghaddam MD PhD Department of Pharmacology Iran University of Medical Sciences. Epidemiology. Nearly up to 1/3 of the global population is infected with M tuberculosis and at risk of developing the disease.

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Epidemiology

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  1. Antimycobactrial DrugsParvanehRahimi-Moghaddam MD PhDDepartment of PharmacologyIran University of Medical Sciences

  2. Epidemiology • Nearly up to 1/3 of the global population is infected with M tuberculosis and at risk of developing the disease. • More than eight million people develop active tuberculosis (TB) every year, and about two million die.

  3. Incidence of TB (WHO 2008)

  4. Treatment Problems (WHO) • Co-infection with HIV significantly increases the risk of developing TB. • Mycobacterium aviumcomplex is associated with AIDS-related TB. • Multidrug resistance, which is caused by poorly managed TB treatment, is a growing problem of serious concern.

  5. Multidrug-Resistant TB (WHO 2008)

  6. Extensively Drug-Resistant TB • Extensively drug-resistant tuberculosis (XDR TB) is a relatively rare type of multidrug-resistant tuberculosis (MDR TB). • It is resistant to almost all drugs used to treat TB.

  7. Treatment Problems • Slowly growing organisms • Lipid-rich mycobacterial cell wall • Intracellular organism • Ability to develop resistance to single drug Mycobacteria G(-) bacteria

  8. Drug Used in TB • First-line agents: • Isoniazid (INH) • Rifampin (RIF) • Pyrazinamide (PZA) • Ethambutol (EMB) • Streptomycin (SM)

  9. Approach in TB Treatment • INH + rifampin(9 months)  95 - 98% cure rate • Plus PZA (first 2 months)  reduce total duration to6 months

  10. TB Treatment Regimen • Initiation of therapy INH + rifampin + PZA + ethambutol(or streptomycin)for 2 months • Continuation phase INH + rifampin for 4 (or 7) months

  11. Treatment Failure • Defined as positive cultures after 4 months of treatment in patients for whom medication ingestion was ensured • Single new drug should never be added to a failing regimen; it may lead to acquired resistance to the added drug

  12. Isoniazid • Structural similarity to pyridoxine • Bactericidal for actively growing bacilli • Active against both extra- and intra-cellular organisms

  13. Isoniazid • Mechanism of action • A prodrug activated by catalase-peroxidase (KatG) • Inhibits synthesis of mycolic acids.

  14. Isoniazid • Resistance • Frequency about 1:106 • Most commonly results from mutations in different genes such as KatG (high-level resistance)

  15. Isoniazid • Pharmacokinetics • Readily absorbed • Well distributed (including CNS) • Extensive metabolism (rapid & slow acetylation) • Average half-lives are less than 1h (rapid) & 3h (slow)

  16. Isoniazid • Clinicaluses • Treatment of TB (300 mg once daily or 900 mg twice weekly; pyridoxine is recommended for patients predisposing to neuropathy) • Prevention of active TB in people with latent tuberculosis (eg, a positive tuberculin test) as a single agent for 9 months

  17. Adverse Reaction of Isoniazid • Allergic reactions • Fever • skin rashes • drug-induced SLE • Direct toxicity 1) Hepatitiswith greater risk in alcoholics and possibly during pregnancy & postpartum (1% of isoniazid recipients) 2) Peripheral & central neuropathy

  18. Adverse Reaction of Isoniazid • Peripheral neuropathy infrequently seen with the standard 300 mg adult dose • Is due to a relative pyridoxine deficiency

  19. Rifampin • Effective in vitro against: • G(+) & G(-) cocci • Some enteric bacteria • Mycobacteria • Chlamydia • Bactericidal for mycobacteria including intracellular organisms

  20. Rifampin • Antimicrobial activity • Binds firmly to b-subunit of DNA-dependent RNA polymerase & inhibits RNA synthesis

  21. Rifampin • Resistance • Polymerase gene mutations (1:106) • Pharmacokinetics • Well absorbed & excreted mainly into the bile (enterohepatic circulation). • Distributed widely (crosses BBB if inflammation present).

  22. Rifampin • Clinical uses(600 mg/d or twice weekly) • Mycobacterial infections (also for prophylaxis) • Other indications

  23. Rifampin • Clinical uses • Other indications: 1) Elimination of meningococcalcarriage 2) Elimination of staphylococcalcarriage (with a second agent) 3) Staphylococcalprosthetic valve endocarditis

  24. Rifampin • Adverse reactions • A harmless orange color • Cholestatic jaundice & hepatitis • Flu-like syndrome (< twice weekly) • fever, chills, myalgia • hemolytic anemia, thrombocytopenia • Induction of cytochrome P450 isoforms

  25. Ethambutol • Inhibits synthesis of arabinoglycan via inhibition of arabinosyl transferases. • Resistance is due to mutations in the enzyme gene. • Pharmacokinetics • Well absorbed& excreted about 50% in urine in unchanged form. • Crosses BBB if inflammation is present.

  26. Ethambutol • Clinical use • Treatment of TB (single daily dose or twice weekly) • Tuberculous meningitis (with higher dose)

  27. Ethambutol • Adverse reactions • Optic neuritis resulting in: • loss of visual acuity • red-green color blindness • Contraindicated in very young children

  28. Pyrazinamide • Is converted to pyrazinoic acid (active form) by mycobacteria pyrazinamidase. • Drug target & mechanism of action is unknown • Resistance • Impaired uptake of drug • Mutations in pyrazinamidase gene

  29. Pyrazinamide • Clinical uses • An important drug used in short-course of TB treatment (active against intracellular organisms) • Adverse reactions • Hepatotoxicity • Hyperuricemia

  30. Streptomycin • Active mainly against extracellular bacilli • Is indicated in injectable drug needed severe TB eg, meningitis & disseminated disease

  31. Second-Line Drugs • Usually considered only in case of: • resistance to first-line agents • failure of clinical response to conventional therapy • serious treatment-limiting adverse drug reactions • expert guidance is available to deal with the toxic effects

  32. Second-Line Drugs • Less effective and more toxic effects • Include (in no particular order): • Amikacin • Kanamycin • Capreomycin • p-amino salicylic acid • Streptomycin • Ethionamide • Fluoroquinolones

  33. Third-Line Drugs least effective and most toxic • Linezolid • Rifabutin • Rifapentine

  34. Antifungal Agents

  35. Licensed Antifungal Agents:The Pace Quickens ravuconazole anidulafungin 20 posaconazole micafungin Caspofungin voriconazole Nyotran AmBisome Amphotec Abelcet 10 itraconazole fluconazole ketoconazole terbinafine miconazole Griseofulvin 5-flucytosine AmphotericinB Nystatin 1950 1960 1970 1980 1990 2000

  36. What are the targets for antifungal therapy?

  37. Classification of Antifungal Agents • Systemic drugs for systemic infections (oral or parenteral) • Oral drugs for mucocutaneous infections • Topical drugs for mucocutaneous infections

  38. Systemic Drugs for Systemic Infections

  39. Amphotericin B • A polyene macrolide • Pharmacokinetics • Poorly absorbed from the GI • Serum t1/2 is approximately 15 days

  40. Amphotericin B • Mechanism of action • Binds to ergosterol & alters the permeability • Exerts fungicidal effect

  41. OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH Mode of Action of Polyenes Ergosterol Aqueous pore Cytoplasmic membrane Hydrophobic side Hydrophilic side Amphotericin B

  42. Polyenes Form Non-Specific Poresin The Membrane Extracellular medium Ergosterol Amphotericin B Cytoplasm Aqueous pore

  43. Amphotericin B • Antifungal activity • The broadest spectrum of action • Clinical uses • Drug of choice for all life-threatening mycotic infections • Empiric therapy if a systemic fungal infection is suspected • Topical use eg, mycotic corneal ulcers

  44. Amphotericin B • Adverse effects • Infusion-related toxicity • Cumulative toxicity 1) Renal damage (reversible & irreversible) 2) Anemia (due to reduced erythropoietin production) 3) Abnormalities in liver function tests 4) Seizures & chemical arachnoiditis (after intrathecal therapy)

  45. Liposomal Amphotericin B • Advantages • Lipid packaged drug will bind to the mammalian membrane less readily. • Furthermore, some fungi contain lipases that may liberate free drug directly at the site of infection.

  46. Properties of Conventional Amphotericin B & Some Lipid Formulations

  47. Flucytosine (5-FC) • A pyrimidine analog • Narrower spectrum of action than amphotericin B • Pharmacokinetics • Is well absorbed • Penetrates well into all tissues including CNS • Eliminated by glomerular filtration with a half-life of 3-4 hours

  48. Flucytosine (5-FC) • Mechanism of action • 5-FC into the cell • 5-FC → 5-FU (5-fluorouracil) → phosphorylated derivatives → inhibits DNA & RNA synthesis • Synergy with amphotericin B cytosine permease

  49. Flucytosine (5-FC) • Clinical uses • Cryptococcal meningitis (+ amphotericin B) • Chromoblastomycosis (+ itraconazole) • Adverse effects • Metabolism by intestinal flora (5-FC → 5-FU)  bone marrow toxicity

  50. Azoles (Imidazoles & Triazoles) • Imidazoles: • Ketoconazole • Miconazole • Clotrimazole • Triazoles: • Itraconazole • Fluconazole • Voriconazole • Posaconazole

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