Antimycobacterials-Antifungals - Slides 2024.pdf

Antimycobacterials Antifungals Lecture Objectives Review the indications, contraindications, and interactions for the use of antimycobacterial agents for tuberculosis and leprosy. 2. Discuss the mechanism of physiological action, most common unintended effects, and mechanisms of acquired drug resist...

Antimycobacterials Antifungals Lecture Objectives Review the indications, contraindications, and interactions for the use of antimycobacterial agents for tuberculosis and leprosy. 2. Discuss the mechanism of physiological action, most common unintended effects, and mechanisms of acquired drug resistance for antimycobacterials. 3. Review the indications, contraindications, and interactions for the use of antifungal agents. 4. Discuss the mechanism of physiological action, most common unintended effects, and mechanisms of acquired drug resistance for antifungals. 1. Antimycobacterial Drugs Tuberculosis A leading cause of death worldwide due to infectious disease Increased prevalence among immunosuppressed Multi-drug treatment Reduce development of resistant strains Streptomycin, Isoniazid, p-aminosalicylic acid Rifampin, Pyrazinamide, Ethambutol, Cycloserine, Ethionamide Antimycobacterial Drugs Tuberculosis Mycobacterium tuberculosis Mycobacteria most commonly found in lungs Resistance is common to a single drug Multi-drug therapy First-line drugs Rifampin, Isoniazid, Pyrazinamide and Ethambutol Treatment continued well after disappearance of clinical symptoms Isoniazid Isoniazid Pyridoxine analog Most potent agent vs. Mycobacterium tuberculosis Always given with other antitubercular agents Mechanism of action Inhibits assembly of mycolic acids into mycobacteria Mycolic acids are unique to mycobacteria Selective against mycobacteria Isoniazid Antibacterial spectrum Intracellular and extracellular mycobacteria Mycobacterium tuberculosis Resistance Reduced accumulation Alteration in or excessive target site No cross resistance Isoniazid Pharmacokinetics Well-absorbed orally Metabolized in liver by acetylation Widely distributed → Crosses BBB Metabolite excreted by glomerular filtration Doses reduced in chronic hepatic disease Isoniazid Adverse effects Dose-related Peripheral neuritis Most common Relative pyridoxine (vitamin B6) deficiency Corrected by supplementation Fatal hepatitis Most serious → Due to toxic metabolite Increased incidence among elderly, alcoholics, patients on rifampin Rifampin (Rifadin) Mechanism of action Inhibits bacterial DNA-dependent RNA polymerase Inhibits bacterial mRNA synthesis Inhibits transcription Specific for procaryotes Rifampin Antimicrobial spectrum Bactericidal for intracellular and extracellular mycobacteria Mycobacterium tuberculosis, Mycobacterium leprae, atypical mycobacteria Given in combination for leprosy Resistance Alteration in target protein (reduced affinity for RNA polymerase) Decreased permeability Rifampin Pharmacokinetics Adequately absorbed orally Metabolized in liver Widely distributed → Crosses BBB Induces hepatic microsomal enzymes Excreted in bile/feces and urine Urine, feces and other secretions → Orange-red color Rifampin Adverse effects Hypersensitivity Skin rash and drug fever GI Nausea, vomiting and diarrhea Jaundice In elderly, alcoholics, patients with chronic liver disease Rifampin Drug interactions Induction of cytochrome P-450 isoenzymes Increase metabolism of other drugs Warfarin, oral contraceptives, corticosteroids, sulfonylurea OHA Contraindications HIV protease inhibitors Darunavir Pyrazinamide Pyrazinamide Mechanism of action Must be hydrolyzed to active compound Pharmacokinetics Used p.o. in combo with Isoniazid and Rifampin Mycobacterium tuberculosis Enters CNS, macrophages, lysosomes, metabolized Adverse effects May contribute to hepatotoxicity Ethambutol (Myambutol) Ethambutol Pharmacokinetics Active p.o. against Mycobacterium tuberculosis, Mycobacterium kansasii and MAI complex Used in combo with other first-line agents Well distributed and enters CNS during inflammation Metabolized and excreted by kidneys Adverse effects Optic neuritis → Reduced visual acuity/color vision disturbances Second-Line Drugs Alternative agents More adverse effects Streptomycin Capreomycin Cycloserine Multi-drug resistant Mycobacterium tuberculosis Amikacin Ciprofloxacin and Levofloxacin Capreomycin (Capastat) Mechanism of action Pharmacokinetics Inhibits protein synthesis Administered i.m., i.v. Eliminated in urine → Doses reduced in renal insufficiencies Adverse effects Ototoxicity Nephrotoxicity Cycloserine Mechanism of action Inhibits bacterial cell wall synthesis Pharmacokinetics Well-absorbed p.o., widely distributed, crosses BBB Metabolized and eliminated in urine Doses reduced in renal insufficiencies Adverse effects Peripheral neuropathies, CNS disturbances, seizures Chemotherapy of Leprosy Leprosy Mycobacterium leprae Treated with triple-drug therapy Rifampin Dapsone Clofazimine Resistant Mycobacterium leprae Clarithromycin Levofloxacin Dapsone Dapsone Sulfonamide analog PABA antagonist Inhibits synthesis of folic acid Clinical uses Mycobacterium leprae Pneumocystis pneumonia Acne (topical) Dapsone Pharmacokinetics Well absorbed p.o. Well distributed Metabolized in liver Excreted in urine Adverse effects Peripheral neuropathy Hemolytic anemia Methemoglobinemia Clofazimine Clofazimine Antibacterial spectrum Mycobacterium leprae MAI complex Pharmacokinetics Inhibits bacterial DNA template function Well absorbed p.o., does not enter CNS Adverse effects Eosinophilic enteritis and skin discoloration Antifungal Agents Fungal infections Mycoses Superficial mycotic infections Skin Subcutaneous mycotic infection Recurrent in nature Beneath skin Systemic mycotic infections Life threatening Most difficult to treat Antifungal Agents Incidence of mycoses Increased along with number of immunosuppressed patients Opportunistic fungal infections Aspergillosis Cryptococcal meningitis Antifungal Agents Systemic/subcutaneous infection Amphotericin B Flucytosine Fluconazole Itraconazole Voriconazole Posaconazole Echinocandins (Caspofungin, Micafungin, Anidulafungin) Mechanisms of Antifungal Action Drugs for Systemic/Subcutaneous Mycoses Amphotericin B (Abelcet, AmBisome) Polyene macrolide antimicrobial DOC for treatment of most systemic mycoses Mechanism of action Binds to ergosterol (within fungal membrane) Disrupts fungal membrane function Increased membrane permeability → Cell death Synergistic with flucytosine Amphotericin B Antifungal spectrum Broad spectrum Candida albicans Histoplasma capsulatum Cryptococcus neoformans Coccidioides immitis Aspergillus Paracoccidioides Blastomyces dermatitidis Sporothrix schenckii (Sporotrichosis) Amphotericin B Pharmacokinetics Administration (poor oral absorption) I.V. infusion → Systemic use/combo w/ flucytosine Intrathecal → Coccidioidal meningitis Distribution (crossed BBB poorly) Toxic effects CTI = 2 Anaphylaxis, hypersensitivity reactions, convulsions Fever, chills, hypotension, anemia, nephrotoxicity Drugs for Systemic/Subcutaneous Mycoses Flucytosine (5-FC, Ancobon) Fluorinated pyrimidine antimetabolite Employed synergistically with Amphotericin B Meningitis due to Cryptococcus neoformans Mechanism of action Converted to antimetabolite within fungal cells Flucytosine → 5-Fluorouracil Cytosine deaminase Drugs for Systemic/Subcutaneous Mycoses Mechanism of action Converted to antimetabolite within fungal cells (not mammals) 5-FU → 5-Fluorodeoxyuridine monophosphate Flucytosine → 5-Fluorouracil Inhibits thymidylate synthase Inhibits synthesis of thymidine monophosphate Inhibits fungal DNA and RNA synthesis Synergistic with Amphotericin B Flucytosine Antifungal spectrum Cryptococcosis (meningitis and pneumonia) Synergistically with Amphotericin B Immunosuppressed and immunocompetent patients Candida infections Synergistically with Amphotericin B Additive with azole antifungals Flucytosine Pharmacokinetics Well absorbed p.o. Enters CSF Excreted by glomerular filtration Unintended effects GI upset Bone marrow depression Hepatic impairment Drugs for Systemic/Subcutaneous Mycoses Fluconazole (Diflucan) Itraconazole (Sporanox, Onmel) Voriconazole (Vfend) Posaconazole (Noxafil) Mechanism of action Inhibits conversion of lanosterol to ergosterol Disrupts fungal membrane function → Cell death 1. Additive with flucytosine 2. Antagonistic to amphotericin B Fluconazole Antifungal spectrum/primary indications (Broad spectrum) Candida infections Candidemia, candidiasis, candiduria Pneumonia Vulvovaginal and mucosal candidiasis Cryptococcus neoformans infections (including meningitis) Prophylaxis/treatment (Immunosuppressed/immunocompetent) Coccidioidomycosis (Coccidioides) (including meningitis) Fluconazole Pharmacokinetics Administered p.o. and i.v. Crosses BBB (meningitis) Eliminated via urine, accumulates in reduced renal function Unintended effects GI upset, hypersensitivity reactions, teratogenic CI: Pregnancy Potential drug interactions: Inhibitor of CYP2C19 Itraconazole Antifungal spectrum/primary indications (Broad spectrum) Blastomycosis (Blastomyces) Paracoccidioidomycosis (Paracoccidioides) Histoplasmosis (Histoplasma) Effective vs. AIDS-associated histoplasmosis Itraconazole Pharmacokinetics Administered p.o. Metabolized by CYP3A4 Half-life decreased by rifampin, phenytoin, phenobarbital Eliminated via bile, accumulates in reduced hepatic function Unintended effects GI upset, hypersensitivity reactions Potential drug interactions: Inhibitor of CYP3A4 Voriconazole Antifungal spectrum/primary indications (Broad spectrum) Aspergillus (Aspergillosis) Candida infections Pharmacokinetics Administered p.o. and i.v. Metabolized by CYP2C19, accumulates in reduced renal function Unintended effects GI upset, hypersensitivity rxns, elevated hepatic enzymes, visual disturbances Potential drug interactions: Inhibitor of CYP3A4, CYP2C9 Posaconazole Antifungal spectrum/primary indications Broadest spectrum systemic azole antifungal agent Aspergillus prophylaxis → Immunosuppressed patients Aspergillus salvage therapy Candida prophylaxis (candidiasis) Immunosuppressed patients Candida infections (oropharyngeal) → Azole resistant Posaconazole Pharmacokinetics Administered p.o. Eliminated via bile, accumulates in reduced hepatic function Unintended effects GI upset, myelosuppression, elevated hepatic enzymes Potential drug interactions: Inhibitor of CYP3A4 Drugs for Systemic Mycoses Echinocandins Newest class of systemic antifungals Mechanism of action Inhibits glucan synthase Inhibiting b-glucan synthesis Disruption of fungal cell wall Cell death Echinocandins Echinocandins → Lipopeptides Caspofungin (Cancidas) Micafungin (Mycamine) Anidulafungin (Eraxis) Primarily employed in treatment of Candida infections Candidemia and esophageal candidiasis Candida prophylaxis (Micafungin) Bone marrow transplants Echinocandins Pharmacokinetics Distribution Widely distributed Does not cross BBB Metabolism Administered i.v. Hepatic non-P450 process Elimination Feces/urine → Accumulates in severe hepatic dysfunction Echinocandins Unintended effects N & V, vomiting, diarrhea, constipation, abdominal pain Anemia, neutropenia, thrombocytopenia Elevated hepatic enzymes Stimulates histamine release Anaphylaxis, flushing, vasodilation Drugs for Superficial Mycoses Dermatophytes Fungi that cause superficial skin infections Epidermophyton Microsporum Trichophyton Tinea corporis, tinea capitis, tinea pedis, tinea versicolor Griseofulvin (Grifulvin) Mechanism of action Binds to fungal microtubules Disrupts mitotic spindle Inhibits fungal mitosis Antifungal spectrum Systemic treatment of dermatophytes Diseases of skin, hair and nails Severe tinea infections Griseofulvin (Grifulvin) Pharmacokinetics Administered p.o. Distributes to infected keratinized tissue Glucuronidated and eliminated by kidney Unintended effects Allergic reactions, GI upset, headache Hepatotoxic, teratogenic Terbinafine (Lamisil) Mechanism of action Clinical uses Treatment of tinea infections (onychomycosis) Pharmacokinetics Inhibits squalene epoxidase → Inhibits ergosterol synthesis Administered p.o. and topically, distributes to keratinized tissue Hepatic metabolism and renal excretion Unintended effects GI upset, increased hepatic enzymes, CI: Hepatic dysfunction Nystatin (Bio-Statin) Mechanism of action Clinical uses Oral treatment of oral thrush (swish) & intestinal candidiasis (swallow) Pharmacokinetics Binds to ergosterol → Disrupts fungal membrane function Poor p.o. absorption Excreted in feces Unintended effects GI upset Other Topical Antifungals Ketoconazole (Nizoral, Extina) Imidazole → Inhibits synthesis of ergosterol Disrupts fungal membrane function Primarily used today for superficial mycotic infections Cutaneous candidiasis/tinea infections Other Topical Antifungals Miconazole (Monistat, Lotrimin AF) Clotrimazole (Gyne-Lotrimin, Lotrimin AF) Terconazole (Terazol 3, Terazol 7, Zazole) Tioconazole (Vagistat 1) Tolnaftate (Tinactin) Topically active antifungal agents → VVC, AF, Tinea infections Not given systemically due to toxicity Mechanism of action Inhibits ergosterol synthesis → Other azole antifungals Tolnaftate (Tinactin)