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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. More than eight million people develop active tuberculosis (TB) every year, and about two million die. Incidence of TB (WHO 2008) Treatment Problems (WHO) 1. Co-infection with HIV significantly increases the risk of developing TB. 2. Mycobacterium avium complex is associated with AIDS-related TB. 3. Multidrug resistance, which is caused by poorly managed TB treatment, is a growing problem of serious concern. Multidrug-Resistant TB (WHO 2008) Extensively Drug-Resistant TB Extensively drug-resistant tuberculosis (XDR TB) is a relatively rare type of multidrugresistant tuberculosis (MDR TB). It is resistant to almost all drugs used to treat TB. Treatment Problems Slowly growing organisms Lipid-rich mycobacterial cell wall Intracellular organism Ability to develop resistance to single drug G(-) bacteria Mycobacteria Drug Used in TB First-line agents: Isoniazid (INH) Rifampin (RIF) Pyrazinamide (PZA) Ethambutol (EMB) Streptomycin (SM) Approach in TB Treatment INH + rifampin (9 months) 95 - 98% cure rate Plus PZA (first 2 months) reduce total duration to 6 months TB Treatment Regimen 1. Initiation of therapy INH + rifampin + PZA + ethambutol (or streptomycin) for 2 months 2. Continuation phase INH + rifampin for 4 (or 7) months 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 Isoniazid Structural similarity to pyridoxine Bactericidal for actively growing bacilli Active against both extra- and intra-cellular organisms Isoniazid Mechanism of action A prodrug activated by catalase-peroxidase (KatG) Inhibits synthesis of mycolic acids. Isoniazid Resistance Frequency about 1:106 Most commonly results from mutations in different genes such as KatG (high-level resistance) Isoniazid Pharmacokinetics Readily absorbed Well distributed (including CNS) Extensive metabolism (rapid & slow acetylation) Average half-lives are less than 1h (rapid) & 3h (slow) Isoniazid Clinical uses A. Treatment of TB (300 mg once daily or 900 mg twice weekly; pyridoxine is recommended for patients predisposing to neuropathy) B. Prevention of active TB in people with latent tuberculosis (eg, a positive tuberculin test) as a single agent for 9 months Adverse Reaction of Isoniazid Allergic reactions A. – – – B. Fever skin rashes drug-induced SLE Direct toxicity 1) Hepatitis with greater risk in alcoholics and possibly during pregnancy & postpartum (1% of isoniazid recipients) 2) Peripheral & central neuropathy Adverse Reaction of Isoniazid Peripheral neuropathy infrequently seen with the standard 300 mg adult dose Is due to a relative pyridoxine deficiency Rifampin Effective in vitro against: G(+) & G(-) cocci Some enteric bacteria Mycobacteria Chlamydia Bactericidal for mycobacteria including intracellular organisms Rifampin Antimicrobial activity Binds firmly to b-subunit of DNA-dependent RNA polymerase & inhibits RNA synthesis Rifampin Resistance Polymerase gene mutations (1:106) Pharmacokinetics Well absorbed & excreted mainly into the bile (enterohepatic circulation). Distributed widely (crosses BBB if inflammation present). Rifampin Clinical uses (600 mg/d or twice weekly) A. Mycobacterial infections (also for prophylaxis) B. Other indications Rifampin Clinical uses B. Other indications: 1) Elimination of meningococcal carriage 2) Elimination of staphylococcal carriage (with a second agent) 3) Staphylococcal prosthetic valve endocarditis Rifampin Adverse reactions a) A harmless orange color b) Cholestatic jaundice & hepatitis c) Flu-like syndrome (< twice weekly) fever, chills, myalgia hemolytic anemia, thrombocytopenia e) Induction of cytochrome P450 isoforms 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. Ethambutol Clinical use Treatment of TB (single daily dose or twice weekly) Tuberculous meningitis (with higher dose) Ethambutol Adverse reactions Optic neuritis resulting in: a) loss of visual acuity b) red-green color blindness Contraindicated in very young children Pyrazinamide Is converted to pyrazinoic acid (active form) by mycobacteria pyrazinamidase. Drug target & mechanism of action is unknown Resistance a) Impaired uptake of drug b) Mutations in pyrazinamidase gene Pyrazinamide Clinical uses An important drug used in short-course of TB treatment (active against intracellular organisms) Adverse reactions Hepatotoxicity Hyperuricemia Streptomycin Active mainly against extracellular bacilli Is indicated in injectable drug needed severe TB eg, meningitis & disseminated disease Second-Line Drugs a) b) c) d) 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 Second-Line Drugs Less effective and more toxic effects Include (in no particular order): Amikacin Kanamycin Capreomycin p-amino salicylic acid Streptomycin Ethionamide Fluoroquinolones Third-Line Drugs least effective and most toxic Linezolid Rifabutin Rifapentine Antifungal Agents Licensed Antifungal Agents: The Pace Quickens ravuconazole anidulafungin posaconazole 20 micafungin Caspofungin voriconazole Nyotran AmBisome 10 Griseofulvin ketoconazole miconazole 5-flucytosine Amphotec Abelcet itraconazole fluconazole terbinafine Amphotericin B Nystatin 1950 1960 1970 1980 1990 2000 What are the targets for antifungal therapy? Classification of Antifungal Agents A. Systemic drugs for systemic infections (oral or parenteral) B. Oral drugs for mucocutaneous infections C. Topical drugs for mucocutaneous infections Systemic Drugs for Systemic Infections Amphotericin B A polyene macrolide Pharmacokinetics Poorly absorbed from the GI Serum t1/2 is approximately 15 days Amphotericin B Mechanism of action Binds to ergosterol & alters the permeability Exerts fungicidal effect Mode of Action of Polyenes Ergosterol Aqueous pore Hydrophobic side Hydrophilic side OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH Cytoplasmic membrane Amphotericin B Polyenes Form Non-Specific Pores in The Membrane Extracellular medium Ergosterol Amphotericin B Aqueous pore Cytoplasm Amphotericin B A. B. C. 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 Amphotericin B Adverse effects A. Infusion-related toxicity B. 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) 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. Properties of Conventional Amphotericin B & Some Lipid Formulations Drug Dosing (mg/kg/d) Conventional formulation: 1 Fungizone Lipid formulations: AmBisome Amphotec Abelcet Nephrotoxicity _ 3-5 5 5 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 Flucytosine (5-FC) Mechanism of action cytosine permease 5-FC into the cell 2) 5-FC → 5-FU (5-fluorouracil) → phosphorylated derivatives → inhibits DNA & RNA synthesis Synergy with amphotericin B 1) Flucytosine (5-FC) Clinical uses Cryptococcal meningitis (+ amphotericin B) Chromoblastomycosis (+ itraconazole) Adverse effects Metabolism by intestinal flora (5-FC → 5-FU) bone marrow toxicity Azoles (Imidazoles & Triazoles) Imidazoles: Ketoconazole Miconazole Clotrimazole Triazoles: Itraconazole Fluconazole Voriconazole Posaconazole Azoles Mechanism of action Decrease in ergosterol synthesis by inhibition of fungal cytochrome P450 enzymes Acetyl CoA Squalene Squalene epoxidase Allylamine drugs Squalene-2,3 oxide Lanosterol Azoles 14-a-demethylase Ergosterol Azoles Adverse effects (selective toxicity) Clinical uses (a broad spectrum of action) Ketoconazole Less selectivity for fungal enzymes Interferes with biosynthesis of adrenal & gonadal steroids Interaction with metabolism of other drugs Itraconazole Less interaction with human enzymes than ketoconazole Does not affect mammalian steroid synthesis. Interacts with hepatic microsomal enzymes, though to a lesser degree than ketoconazole. Itraconazole Azole of choice for treatment infections due to dimorph fungi such as histoplasma. Is used extensively in the treatment of dermatophytoses and onychomycosis. Fluconazole The least effect on hepatic microsomal enzymes The broadest therapeutic index of the azoles Fluconazole Azole of choice in the treatment and secondary prophylaxis of cryptococcal meningitis Prophylactic use against fungal disease in bone marrow transplant & AIDS patients Fluconazole IV fluconazole equivalent to amphotericin B in candidemia in ICU patient with normal WBC counts. Commonly used in mucocutaneous candidiasis Voriconazole Well absorbed orally Low inhibition of mammalian P450 Toxicities include rash, elevated hepatic enzyme & transient visual disturbances Azole of choice for aspergillosis Voriconazole Excellent activity against candida (including fluconazole-resistant species) Less toxic & probably more effective than amphotericin B in aspergillosis Posaconazole Drug interactions have been documented. The broadest spectrum member of azoles. Currently is approved for: Salvage therapy in invasive aspergillosis Prophylaxis of fungal infections during chemotherapy Echinocandins (Caspofungin) The newest class of antifungal agents Active against both candida and aspergillus Caspofungin Mechanism of action Inhibition of b(1-3) glucan synthesis This results in disruption of cell wall and cell death Adverse effects extremely well tolerated A scheme of the structure of the yeast cell wall S Mannoprotein 40% S GPI Anchor b1-3 glucan 50% Transmembrane Protein b1-6 glucan 8% Chitin 2% Caspofungin Licensed for: disseminated and mucocutaneous candida infections empiric antifungal therapy during febrile neutropenia Oral Drugs for Mucocutaneous Infections Griseofulvin Clinical uses Systemic treatment of dermatophytoses Mechanism of action Deposited in newly forming skin (fungistatic) Adverse effects Allergic syndrome Hepatitis Terbinafine Available in oral form Mechanism of action Inhibits the fungal enzyme squalene epoxidase (fungicidal) Clinical uses Dermatophytoses esp. onychomycosis Acetyl CoA Squalene epoxidase Squalene Allylamine drugs Squalene-2,3 oxide Lanosterol Azoles 14-a-demethylase Ergosterol Topical Drugs for Mucocutaneous Infections Nystatin A polyene macrolide ONLY used topically Active against most candida species Topical azoles Clotrimazole & Miconazole Effective in: Vulvovaginal candidiasis Dermatophytic infections Topical Allylamines Terbinafine & Naftifine Available as topical creams Effective in tinea cruris, …