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Pathogenicity of Antifungals due to: microtoxin production, allergenicity, and/or tissue invasion. Systemic drugs for Systemic Infections Polyene antibiotics (amphotericin B), cytosine analogs (flucytosine), azoles: imidazoles and triazoles (itraconazole, ketconazole - replaced by itraconazole for the treatment of all mycoses except when cost is the primary deterrent), echinocandins (caspofungin), and other antibiotics (trimethoprim-sulfamethoxazole, pentamidine, clindamycin-primaquine) Amphotericin B (AmBisome) polyene macrolide antibiotic. BROAD SPECTRUM ANTIFUNGAL AGENT against pathogenic yeasts and molds, and fungi causing endemic mycoses. useful agent for life threatening mycotic infections, but may be replaced by less toxic drugs. IV administration. drug >90% bound to plasma protein. t1/2 ~15 days. little CSF penetration. intrathecal inj in cases of fungal meningitis. POORLY ABSORBED FROM GI, thus oral prep are effective only on fungi within the lumen of the tract. ergosterol a cell membrane sterol present in fungi cholesterol predominant cell membrane sterol on bacteria and human cells Amphotericin B MOA, MOR binds to fungi membrane ergosterol altering cell permeability by forming pores. - allows leakage of intracell. ions and macromolecules leading to cell death. some binding to human cell membrane sterols does occur - ACCOUNTING FOR THE DRUG SERiouS TOXICITITY. MOR: alterations in ergosterol binding may lead to resistance. Amphotericin B regime can be toxic to human cell membranes. initial induction regime for serious fungal infections, then replaced by an azole drug. VERY IMPORTANT for immunosuppressed patients or with severe fungal pneumonia or cryptoccocal meningitis LOCAL ADMINISTRATION effective for mycotic corneal ulcers and keratitis. otheruses- fungal arthritis and candiduria. Amphotericin B AE Immediate AE: toxicity - immediate reactions; also reactions occuring more slowly. acute hypersensitivity reactions. CNS Side effects - hypokalemia, hypomagnesemia, occasional abnormal liver enzymes. Intrathecal therapy - seizures and chemical arachnoiditis. IMMEDIATE - fever, chills, muscle spasms, hypotension. BEFORE TREATMENT STARTS TEST PATIENTS RESPONSE WITH A 1mg IV INJECTION. severity of side effects can be diminished by slowing drug infusion rate, decreasing its daily dose, or using some premedication regimen (antihistamines, antipyretics) cumulative toxicity: RENAL IMPAIRMENT MOST IMPORTANT OCCURS IN NEARLY ALL PATIENTS. azotemia, dec renal perfusion (rev) and renal tubular injury (irrever). anemia - due to reduced erythropoietin. RENAL TOXICITY - tubular acidosis and significant K and Mg losses. PNEUMOCYSTIS (CARINII) JIROVECI PNEUMONIA (PCP) Fungal pneumonia, PCP does not respond to antifungal treatment. Recommended duration of treatment is 21 days in HIV patients and 14 days for all other patients. HIV patients tend to have a higher organism burden and respond to treatment slower than other patients (4-5 days vs 8 days) Up to 10% of mild-to-moderate PCP cases fail to respond to antibiotic treatment because of lack of drug efficacy Adding additional PCP medications to a current regimen only increases the risk of adverse drug reactions without improving the likelihood of a good outcome Treatment of PCP recommendations Antibiotics are primarily recommended for treatment of PCP Trimethoprim-sulfamethoxazole (TMP-SMX) is as effective as IV pentamidine and more effective than other alternative treatment regimens (preferred during pregnancy - watch for hyperbilirubinemia and kernicterus) Clindamycin-primaquine comination is likely to be more effective than IV pentamidine in the treatment of infections resistant to TMP-SMX FLUCYTOSINE (5-Fluorocytosine) Pyrimidine anolog, narrow spectrum of action. water soluble. well absorbed from GI, peak plasma level after 1-2hrs. widely distributed including CSF. renal excretion, t.5 ~3-4hours. Toxicity: associated with RENAL INSUFFICIENCY and aids, removed by dialysis. Toxic to fungal cells only after it is transported by the enzyme cytosine permease into the fungal cell, where is deaminated by fungal cytosine deaminase to 5-fluorouracyl (5-FU) 5 Fluorocytosine MOA 5-FU is either converted and incorporated into RNA, or converted into a potent inhibitor of thymidylate synthase. 5-FUTP inhibits RNA synthesis F-dUMP inhibits DNA synthesis Human cells are unable to convert this drug to active metabolites. 5 Fluorocytosine MOR resistance can result from loss of the permease enzyme necessary for cytosine transport. decreased activity of uracyl phosphoribosyl transferase (UPRTase) or cytosine deaminase. (URPTase converts fluorouracil to 5-fluorouracil-ribose monophosphate) Conversions of 5-Flucytosine: transported into fungal cell and deaminated to 5-FLUCYTOSINE..................5-FLUOROURACIL (5-FU) converted to 5-FU .......5-FLUOROURACIL-ribose monophosphate (FUMP) converted to converted to FUMP...5-FUDP...5-FUTP which is incorporated into RNA converted to 5-FUMP...-FdUMP (potent inhibitor of thymidylate synthase) 5-FdUMP inhibits thymidylate synthase 5-dUMP........................dTMP (DNA synthesis inhibition) 5-FC synergy with? Synergy with amphotericin B due to enhanced flucytosine fungal cell penetration through amphotericin B-damaged cell membranes. so used with amphotericin B for treating ctyptococcal meningitis or with itraconazole for chromoblastomycosis. 5- FC AEs AE results from metabolism, possibly by intestinal flora to toxic 5-FU GI alterations, leucopenia, thrombocytopenia. A form of toxic enterocolitis may occur, azotemia in AIDS patients. AZOLES MOA synthetic compounds. 2 nitrogen atoms = imidazole, 3 nitrogen atoms in azole ring = triazoles. MA: Inhibit 14-alpha-sterol demethylase, a microsomal CPY enzyme essential for ergosterol biosynthesis. This results in the accumulation of 14-alpha-methylsterols that disrupt the packing of acyl chains of phospholipids and impair the functions of membrane-bound enzymes such as ATPase and those of electron transport systems, resulting in inhibited fungal growth Specificity of azoles results from their greater affinity for fungal than for human cytochrome P-450 enzymes Common Imidazoles Ketoconazole, Miconazole, Clotrimazole exhibit a lesser degree of specificity than triazoles, explaining for their higher incidence of drug interactions and side effects. Common Triazoles Itraconazole, Fluconazole, Voriconazole AZOLE MOR Accumulation of mutations in the gene encoding 14-alpha-sterol demethylase is the main mechanism of resistance to azoles in C. albicans; resulting in cross-resistance to all azoles Increasing number of resistant fungal strains are being reported, probably due to the increase use of these drugs for prophylaxis and treatment AZOLE uses Useful in superficial and systemic fungal infections Broad spectrum: candida species, endemic mycoses, C neoformans, the dermatophytes, aspergillus infections. Amphotericin-B resistant pseudallescheria boydii As a group these drugs are relatively nontoxic, with the most common side effect been minor GI upset and changes in liver enzymes, which very rarely results in hepatitis All azoles affect mammalian cytochrome P450 enzymes to some extent, consequently they administration may result in various drug interactions Azole interactions Interaction of itraconazole and other azoles with a significant number of drugs metabolized by the CPY3A4 enzymatic system has been reported. These interactions may lead to serious toxicity including fatal cardiac arrhythmias These interactions may also result in significant changes in azole bioavailabity, including decreasing their concentration to below therapeutic levels ITRACONAZOLE (SPORANOX) DOC for treatment of the dimorphic fungi histoplasma, blastomyces, and sporothrix has replaced ketoconazole for treatment of all mycoses (except if going by cost). Effective after oral or IV administration, absorption increased by food and low gastric pH, poor CSF penetration interacts with hepatic microsomal enzymes and its bioavailability is significantly REDUCED when taken with RIFAMYCINS!! does not affect mammalian steroid synthesis. use limited by bioavailabity. (new forms with cyclodextran as carrier to increase solubility) FLUCONAZOLE (DIFLUCAN) DOC: treatment and secondary prophylaxis of C meningitis. IV treatment equivalent to the use of amphotericin B in candidemia in ICU patients with normal white cell blood counts. well abosrbed from GI and good CSF penetration. effective orally or IV. Little effect on hepatic enzymes and better GI tolerance. FLUCONAZOLE has WIDEST THERAPEUTIC INDEX among azoles allowing for more aggressive dosing in fungal infections. Prophylactic use reduce fungal disease in bone marrow transplant and AIDS patients. Concern for the emergence of fluconazole-resistant fungi VORICONAZOLE use and AE Effective as oral and IV preparations. Similar spectrum activity than itraconazole (DOC for treatment of the dimorphic fungi histoplasma, blastomyces, and sporothrix ). Use leads to visual disturbances e.g., blurring and changes in color brightness or vision in up to 30% of patients. These symptoms appear soon after taking the medication and disappear after ~ 30 min ECHINOCANDINS MOA Inhibit the synthesis of Beta(1,3)D-glucan, thus disrupting fungal cell wall structure leading to cell death Newer class of antifungal agents with a novel chemical structure consisting of large cyclic peptides linked to a long chain fatty acid. Drugs effective against CANDIDA and ASPERGILLUS infections Caspofungin, micafungin and anidulafungin ECHINOCANDINS MOR Resistance develops in C albicans by mutation in one of the genes encoding B(1,3)D-glucan synthase Azole resistant isolates of c albicans remains susceptible to echinocandins ECHINOCANDINS uses only IV, t.5 ~10h. hydrolysis and N-acetylated products eliminated in urine and feces. Useful in the treatment of esophageal candidiasis, candidemia and salvage therapy of aspergillosis Generally well tolerated, echinocandins may produce minor GI side effects, some flushing also reported. As with any relatively new drugs physician should be alert to unexpected side effects SYSTEMIC ANTIFUNGAL DRUGS FOR MUCOCUTANEOUS INFECTIONS GRISEOFULVIN (GRIFULVIN, FULVICIN) TERBINAFINE (LAMISIL) Azoles: Ketoconazole, Itraconazole, Fluconazole, Voriconazole GRISEOFULVIN (GRIFULVIN, FULVICIN) Uses and MOA Fungistatic antibiotic. Only current use is for the systemic treatment of DERMATOPHYTOSIS. poor solubility, its GI absorp enhanced when given in microcrystalline form and fatty foods. DEPOSITED IN NEWLY FORMING SKIN, IT BINDS TO KERATIN PROTECTING SKIN FROM NEW INFECTION! 2-6 weeks treatment for skin, hair. NAIL infections may require therapy for months! TERBINAFINE (LAMISIL) uses Treatment dermatophytoses, particularly ONYCHOMYCOSIS, which is cured in 90% of patients 1 tablet/d/12 weeks. KERATOphillic medication, acts as a FUNGICIDAL agent. Terbinafine MOA and AE FUNGICIDAL Similar to the azoles, it interferes with ergosterol biosynthesis, but rather that interacting with the P450 system, it inhibits the fungal enzyme squalene epoxidase, leading to accumulation of the sterol squalene which is toxic to the fungi Adverse effects are rare e.g., GI, headaches TOPICAL DRUGS FOR MUCOCUTANEOUS INFECTIONS AZOLES: CLOTRIMAZOLE, MICONAZOLE POLYENE ANTIBIOTICS: NYSTATIN ALLYLAMINES: TERBINAFINE, NAFTIFINE When are topical drugs recommended? Recommended for various superficial fungal infections e.g., those confined To the stratum corneum, squamous mucosa, or cornea e.g., candidiasis, Tinea versicolor, fungal keratitis, etc Preferred preparations are creams and solutions Powder are used for the feet and moist lesions of the groin and other intertriginous areas TOPICAL drugs for mucocutaneous infections are unsuccessful for what treatment? Generally unsuccessful for treating mycosis of the nails and hair or subcutaneous fungal infections Considerations for TOPICAL drug efficacy Efficacy depends on type of lesion and drug; also on viscosity, hydrophobicity and acidity of preparation. Penetration of hyperkeratotic lesions is often poor, and removal of thick infected keratin is an useful adjunct therapy TOPICAL clotrimazole, miconazole (azoles) preprations used in: dermatophytic infections (tinea pedis, corporis, cruris), seborrheic dermatitis (shampoo form) and vaginal candidiasis. specifically: NySTATIN same mechanism of action as Ampthotericin B (binds to fungi membrane ergosterol altering cell permeability by forming pores) and present cross resistance. NOT absorbed from GI, SKIN or VAGINA. ONLY USED against muscocutaneous candidal infections, stomatitis, vaginitis etc. ALLYLAMINES. Terbinafine and naftifine USES creams used for TINEA CRURIS and CORPORIS BROAD SPECTRUM antifungal agents MOA: block ergosterol biosynthesis by inhibiting squalene 2,3-epoxidase enzyme. REVIEW: SYSTEMIC DRUGS: TREATING SYSTEMIC INFECTIONS POLYENE ANTIBIOTICS: Amphotericin B OTHER ANTIBIOTICS: Trimethoprim-sulfamethoxazole; pentamidine; clindamycin-primaquine CYTOSINE ANALOGS: Flucytosine AZOLES: Itraconazole Ketoconazole: replaced by Itraconazole for the treatment of all mycoses except when cost is the primary determinant ECHINOCANDINS: Caspofungin REVIEW: SYSTEMIC drugs for treatment of MUCOCUANEOUS infections Griseofulvin Terbinafine Azoles: Ketoconazole, Itraconazole, Fluconazole, Voriconazole REVIEW: TOPICAL drugs for treatment of MUCOCUTANEOUS INFECTIONS Polyene antibiotics: Nystatin Azoles: Clotrimazole, Miconazole Allylamines: Terbinafine, Naftifine REVIEW AZOLE MOA inhibit cytochrome P450 -> impaired synthesis of ergosterol -> impaired fungal cell membrane formation. REVIEW POLYENES MOA bind to ergosterol in fungal cell membrane and disrupt membrane integrity REVIEW Flucytosine MOA anti-metabolite, inhibits RNA and DNA synthesis. REVIEW echinocandins MOA inhibit synthesis of B (1,3)-D-glucan (cell wall component) REVIEW Griseofulvin anti-mitotic REVIEW Terbinafine inhibits squaline epoxidase, blocks ergosterol synthesis