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This document discusses various classes of antifungal drugs including polyenes, echinocandins, azoles, and allylamines. It provides details on specific drugs in each class like amphotericin B, fluconazole, terbinafine, and caspofungin. It also covers the mechanisms of action, indications, dosing considerations, toxicities and interactions for many of these antifungal agents. Finally, it discusses several topical antifungal drugs and their uses in treating superficial fungal infections.
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- 2. CLASSIFICATION1. Antibiotics A. Polyenes:Amphotericin B (AMB), Nystatin, Hamycin B. Echinocandins:Caspofungin, Micafungin, Anidulafungin C. Heterocyclic benzofuran: Griseofulvin 2. Antimetabolite Flucytosine (5-FC) 3. Azoles A. Imidazoles Topical: Clotrimazole, Econazole, Miconazole, Oxiconazole Systemic: Ketoconazole B. Triazoles: Fluconazole, (systemic) Itraconazole, Voriconazole, Posaconazole 4. Allylamine Terbinafine 5. topical agents Tolnaftate, Undecylenic acid, Benzoic acid,Quiniodochlor, Ciclopirox olamine, Butenafine, Sod. thiosulfate.
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- 5. •Amphotericin B deoxycholate(C-AMB) nephrotoxicity •Amphotericin B colloidal dispersion (ABCD) (not available in the U.S.) Associated with acute reactions, including infusion-related fever and chills •Liposomal amphotericin B (L-AMB) •Amphotericin B lipid complex (ABLC)
- 6. • Invasive candidiasis •Invasive aspergillosis • Blastomycosis • Histoplasmosis • Coccidioidomycosis Cryptococcosis • Mucormycosis • Sporotrichosis • Empirical therapy in immunocompromised host
- 7. ACUTE REACTION •each infusionand chills, fever, aches and pain all over, nausea, vomiting and dyspnoea lasting for 2–5 hour, •When the reaction is severe—the dose should be increased gradually. Usually the intensity of reaction decreases with continued medication. •Injection of hydrocortisone 0.6 mg/ kg with the infusion may reduce the intensity of reaction. Thrombophlebitis .
- 8. LONG-TERM TOXICITY •Nephrotoxicity .dose-related. azotemia, reduced g.f.r., acidosis, hypokalaemia and inability to concentrate urine. • reverses slowly and often incompletely after stoppage of therapy. Anaemia: develop progressing anaemia due to bone marrow depression. reversible. •CNS toxicity: occurs only on intrathecal injection—headache, vomiting, nerve palsies, etc.
- 9. FLUCYTOSINE • Cryptococcosis (withamphotericin B) Has broad activity but emergence of resistance limits usefulness as single- agent therapy • ↓ Dosage in patients with ↓ renal function • Toxicity more frequent in patients with AIDS or azotemia • depress bone marrow, leukopenia and thrombocytopenia
- 12. KETOCONAZOLE •decreases androgen productionfrom testes •displaces testosterone from protein binding sites. •Gynaecomastia, loss of hair and libido, and oligozoospermia •Menstrual irregularities occur in some women due to suppression of estradiol synthesis. •dose-dependent decrease in serum hydrocortisone due to synthesis inhibition has also been noted
- 13. •Orally administered KTZis effective in dermatophytosis because it is concentrated in the stratum corneum. •It is an alternative to griseofulvin, but use is restricted due to potential adverse effects. Used as a lotion or shampoo, KTZ is quite effective in seborrhoea of scalp and dandruff. •effective in monilial vaginitis, oral therapy (for 5–7 days) with KTZ is reserved for recurrent cases or those not responding to topical agents. •Administered orally, KTZ is effective in several types of systemic mycosis, but triazoles, being more active with fewer side effects, have largely replaced it for these indications. •occasionally used in dermal leishmaniasis and in kala azar. •High-dose used in Cushing’s syndrome to decrease corticosteroid production.
- 14. FLUCONAZOLE • Invasive candidiasis •Cryptococcosis • Coccidioidomycosis • Prophylaxis and empirical therapy in immunocompromised host • Plasma concentrations are essentially the same whether the drug is given orally or intravenously. • Concentrations in CSF = 50%–90% of CP • Inhibitor of CYP3A4 and CYP2C9 • Contraindicated during pregnancy
- 15. ITRACONAZOLE • Invasive aspergillosis •Blastomycosis • Coccidioidomycosis • Histoplasmosis • Pseudallescheriasis • Sporotrichosis • Ringworm • Onychomycosis • Substrate for and potent inhibitor of CYP3A4 • Hepatotoxic • Contraindicated in pregnancy and in women considering becoming pregnant
- 16. VORICONAZOLE • Invasive aspergillosis •Invasive candidiasis • Pseudallescheriasis • Oral bioavailability is 96%. • Metabolized by CYPs 2C19/2C9 /3A4 • prolong the QTc interval • Transient visual or auditory hallucinations are frequent after the first dose. • Contraindicated in pregnancy
- 17. POSACONAZOLE • Oropharyngeal candidiasis •Prophylaxis in immunocompromised host against aspergillosis and candidiasis • Oral bioavailability enhanced by food • Drugs that ↓ gastric acid ↓ posaconazole exposure • Inhibits CYP3A4 • Can prolong the QTc interval • headache and GI disorders
- 18. ISAVUCONAZOLE • Invasive aspergillosis •Mucormycosis • Oral bioavailability is 98%. • Substrate of and inhibitor of CYP3A4 • Does not appear to prolong QTc
- 19. ECHINOCANDINS Caspofungin • ↓ Dosein moderate hepatic impairment Micafungin • Reduction of micafungin dose in moderate hepatic failure is not required. Anidulafungin • No dose adjustment is needed for hepatic or renal failure
- 21. GRISEOFULVIN: Inhibits microtubule function,disrupts assembly of the mitotic spindle • Ringworm • Onychomycosis • Absorption is reduced by barbiturates • Induces hepatic CYPs
- 22. ALLYLAMINES Inhibit fungal squaleneepoxidase and reduce ergosterol biosynthesis Terbinafine • Ringworm • Onychomycosis • Bioavailability is ∼ 40% due to first-pass metabolism in the liver. • accumulates in skin, nails, and fat. • initial t1/2 is ~ 12 h but extends to 200–400 h at steady state.
- 23. AGENTS ACTIVE AGAINST MICROSPORIDIAAND PNEUMOCYSTIS Albendazole • Microsporidia infection • Anthelmintic • Inhibitor of α-tubulin polymerization
- 24. Fumagillin • Microsporidia infection •Used in immunocompromised individuals with intestinal microsporidiosis due to Enterocytozoon bieneusi unresponsive to albendazole • Not approved for human use in the U.S.
- 25. Pentamidine • Pneumocystis jirovecipneumonia • Prophylaxis use to prevent PJP in at-risk individuals who cannot tolerate trimethoprim-sulfamethoxazole
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- 33. Topical Antifungal Agents-Nystatin •Too toxic for systemic use •Candidal infection of mucosa, skin, GIT, vagina •Not absorbed so toxicity rare •Bitter and foul taste
- 34. Topical Antifungal Agents-Azoles •Clotrimazole, miconazole , ketoconazole,butaconazole, econazole , oxiconazole , sulconazole , terconazole, tioconazole , sertaconazole •Superficial mycosis •Tinea pedis , tinea corporis, tinea cruris, tinea versicolor, cutaneous , oropharyngeal , vulvoginal candidiasis •Skin oitments, cream , lotion, vaginal cream, vaginal tablet •Shampoo for seborrheic dermatitis •Topical azoles +corticosteroid FDC
- 35. Topical Antifungal Agents-Tolnaftate •tineacruris and tinea corporis •Because of poor penetrability, it is less effective in tinea pedis and other hyperkeratinized lesions. ineffective in tinea capitis (involving scalp) and tinea unguium (involving nails). •Symptomatic relief occurs early, but if applications are discontinued before the fungus bearing tissue is shed—relapses are common. Resistance does not occur. •Salicylic acid can aid tolnaftate by keratolytic action. Tolnaftate causes little irritation, but is inferior in efficacy to imidazoles.not effective in candidiasis or other types of superficial mycosis.
- 36. Topical Antifungal Agent-Ciclopirox Olamine •tineainfections, pityriasis versicolor and dermal candidiasis. •High cure rates are reported. It penetrates superficial layers and reaches hair roots but systemic absorption is negligible. •Local tolerance without irritation is good. Sensitization occurs occasionally. •Formulated as nail lacquer, it has been used in onychomycosis. •Vaginal candidiasis can be treated by 1% ciclopirox vaginal cream
- 37. Topical Antifungal Agents-Allylamines •Naftifine 1%cream, cutaneous dermatophytosis , candida infections Effcetive as topical azoles •Butenafine 1% cream ,superficial dermatophytosis, •Terbenafine 1% cream tinea pedis , tinea cruris , tinea corporis , tinea versicolor
- 38. Topical Antifungal Agents-BenzoicAcid •antifungal and antibacterial property in slightly acidic medium. •Fungistatic action is weaker than tolnaftate; eradication of the fungus needs prolonged application till infected keratin is totally shed. • hyperkeratotic lesions, as Whitfield’s ointment: benzoic acid 5%, salicylic acid 3%. its keratolytic action, helps to remove the infected tissue and promotes the penetration of benzoic acid into the lesion. •Irritation and burning sensation
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Editor's Notes
- #4 Amphotericin B and other polyenes (e.g., nystatin) bind to ergosterol in fungal cell membranes and increase membrane permeability. imidazoles and triazoles (itraconazole, etc.) inhibit 14-α-sterol demethylase, prevent ergosterol synthesis, and lead to accumulation of toxic 14-α-methylsterols. allylamines (e.g., naftifine and terbinafine) inhibit squalene epoxidase and prevent ergosterol synthesis. echinocandins (e.g., caspofungin) inhibit the formation of glucans in the fungal cell wall. Metabolites of 5-fluorocytosine can disrupt fungal RNA and DNA synthesis. Griseofulvin inhibits microtubule assembly, thereby blocking fungal mitosis.
- #5 The antifungal activity of amphotericin B depends on its capacity to bind ergosterol in the fungal cell membrane. B. Ergosterol, here depicted as a green rod, decorates both bilayers of the fungal membrane. C. Amphotericin B appears to form aggregates that sequester and effectively extract ergosterol from lipid bilayers, much like a selective sponge, disrupting membrane structure and resulting in fungal cell death.
- #6 Associated with significant nephrotoxicity, including azotemia, renal tubular acidosis, and hypochromic, normocytic anemia C-AMB is tolerated by premature neonates much better than older children and adults; as a result, it remains an important part of the antifungal formulary in the critical care nursery. Infusion-related reactions typically decrease with subsequent infusions. While less toxic, the lipid formulations are much more costly than C-AMB, making them unavailable in many countries and dictating prudent use in the U.S. and other resource-rich areas.
- #7 Invasive candidiasis is an infection caused by a yeast (a type of fungus) called Candida. Unlike Candida infections in the mouth and throat (also called “thrush”) or vaginal “yeast infections,” invasive candidiasis is a serious infection that can affect the blood, heart, brain, eyes, bones, and other parts of the body. Blastomyces dermatitidis HISTOPLASMA CAPSULATUM Coccidioides. immitis or Coccidioides posadasii fungi. Cryptococcus neoformans and Cryptococcus gattii. MUCORMYCESES / ZYGOMYCESES Mucor, Rhizopus, Absidia, and Cunninghamella genera also termed rose gardener's or rose handler's disease) is an infection caused by the fungus Sporothrix schenckii
- #8 probably due to release of cytokines (IL, TNFα).
- #9 Azotemia is an elevation of blood urea nitrogen (BUN) and serum creatinine levels.
- #11 All susceptible fungi are capable of deaminating flucytosine to 5FU, a potent antimetabolite that is used in cancer chemotherapy. Fluorouracil is metabolized first to 5FUMP) by the enzyme UPRTase. uracil phosphoribosyltransferase .5FUMP is then either incorporated into RNA (via synthesis of 5-fluorouridine triphosphate) or metabolized to 5FdUMP, a potent inhibitor of thymidylate synthase, ultimately inhibiting DNA synthesis. The selective action of flucytosine is due to the lack of cytosine deaminase in mammalian cells, which prevents metabolism to fluorouracil.
- #12 A. Fungal ergosterol synthesis proceeds via a series of enzymic steps that include Erg11, a 14-α-sterol demethylase. The completed ergosterol is then inserted into both leaflets of the membrane bilayer. B. Imidazole and triazole antifungals inhibit the activity of 14-α-sterol demethylase, thereby reducing the biosynthesis of ergosterol and leading to the accumulation of 14-α-methylsterols. These methylsterols are toxic, disrupting the close packing of acyl chains of phospholipids, impairing the functions of certain membrane-bound enzyme systems, and thus inhibiting growth of the fungi.
- #16 Pseudallescheriasis is a fungal infection caused by Pseudallescheria species, such as Pseudallescheria boydii Ringworm, also known as dermatophytosis, dermatophyte infection, or tinea, is a fungal infection of the skin. Onychomycosis, also known as tinea unguium, is a fungal infection of the nail. Symptoms may include white or yellow nail discoloration, thickening of the nail, and separation of the nail from the nail bed. Toenails or fingernails may be affected, but it is more common for toenails to be affected. Itraconazole is a triazole that lacks the corticosteroid suppression associated with ketoconazole while retaining most of ketoconazole’s pharmacological properties and extending the antifungal spectrum. Importantly, itraconazole has activity against Aspergillus spp. While imidazoles do not.
- #20 • Invasive candidiasis • Empirical therapy in the immunocompromised host Prophylaxis in the immunocompromised host
- #21 The strength of the fungal cell wall is maintained by fibrillar polysaccharides, largely β-1,3-glucan and chitin, which bind covalently to each other and to proteins. A glucan synthase complex in the plasma membrane catalyzes the synthesis of β-1,3-glucan; the glucan is extruded into the periplasm and incorporated into the cell wall. Echinocandins inhibit the activity of the glucan synthase complex, resulting in loss of the structural integrity of the cell wall. The Fks1p subunit of glucan synthase appears to be the target of echinocandins, and mutations in Fks1p cause resistance to echinocandins.
- #28 Tinea capitis
- #29 Tinea versicolor
- #30 Tinea pedis
- #31 Tinea corporis
- #32 Tinea cruris
- #33 tinea unguium