Ketoconazole Amphotericin

What is it about fungal cells that is different to human cells and allows selective toxicity of antifungal drugs such as amphotericin, ketoconazole and terbinafine ... 

Ketoconazole. For treatment of systemic mycoses with amphotericin B or miconazole, the patient must be admitted to a hospital. This is not always possible, particularly in areas where systemic mycoses occur frequently, nor is it always desirable, because of the expense. For these reasons, it was desirable to find an antimycotic that combined safety and broad-spectmm activity with oral adraiinistration. Ketoconazole (10), which is orally active, met most of these requirements. This inhibitor of the ergosterol biosynthesis is an A/-substituted imidazole, that differs from its precursors by the presence of a dioxolane ring (6,7). Ketoconazole is rapidly absorbed in the digestive system after oral adrninistration. Sufficient gastric acid is required to dissolve the compound and for absorption. Therefore, medication that affects gastric acidity (for example, cimetidine and antacids) should not be combined with ketoconazole. 

Treatment fluconazole, itraconazole, ketoconazole, Amphotericin B Consider liposomal products decrease or stop CSA or TAC to minimize nephrotoxicity Remember to adjust doses of renally eliminated drugs (e.g., acyclovir, ganciclovir, TMP-SMX)... 

Two to three weeks of fluconazole or itraconazole solution are highly effective and demonstrate similar clinical response rates.32 Doses of 100 to 200 mg are effective in immunocompetent patients but doses up to 400 mg are recommended for immunocompromised patients. Due to variable absorption, ketoconazole and itraconazole capsules should be considered second-line therapy. In severe cases, oral azoles may prove ineffective, warranting the use of amphotericin B for 10 days. Although echinocandins and voriconazole are effective in treatment of esophageal candidiasis, experience remains limited. 

Mucocutaneous candidiasis is generally not life-threatening nor invasive and can be treated with topical azoles (clotrimazole troches), oral azoles (fluconazole, ketoconazole, or itraconazole), or oral polyenes (such as nystatin or oral amphotericin B). Orally administered and absorbed azoles (ketoconazole, fluconazole, or itraconazole solution), amphotericin B suspension, intravenous caspofungin, or intravenous amphotericin B are recommended for refractory or recurrent infections.20... 

The answer is d. (Hardman, pp 1183-1184.) Mucocutaneous infections, most commonly Candida albicans, involve the moist skin and mucous membranes. Agents used topically include amphotericin B, nystatin, miconazole, and clotrimazole. Ketoconazole and fluconazole are administered orally in pill form for treatment of chronic infections... 

Selfiimited disease Amphotericin Bc 03-0.5 mg/kg/day x 2-4 weeks (total dose 500 mg) or ketoconazole 400 mg orally daily x 3-6 months can be... 

Itraconazole and ketoconazole (200-800 mg/day orally for 1 year) are effective in 74% to 86% of cases, but relapses are common fluconazole 200-400 mg daily is less effective (64%) than ketoconazole or itraconazole, and relapses are seen in 29% of responders Severe disease Amphotericin B 0.7 mg/kg/day for a minimum total dose of 35 mj kg is effective in 59% to 100% of cases and should be used in patients who require hospitalization or are unable to take itraconazole because of drug interactions, allergies, failure to absorb drug or failure to improve clinically after a minimum of 12 weeks of itiaconazole therapy... 

Disseminated histoplasmosis Acute (Infantile) Subacute Progressive histoplasmosis (immunocompetent patients and immunosuppressed patients without AIDS) 0.02-0.05 Disseminated histoplasmosis Untreated mortality 83% to 93% relapse 5% to 23% in non-AIDS patients therapy is recommended tor all patients Nonimmunosuppressedpatients Ketoconazole 400 mj day orally x 6-12 months or amphotericin B 35 mg/kg IV Immunosuppressed patients (non-AIDS) or endocarditis or CNS disease Amphotericin B >35 mg/kg x 3 months followed by fluconazole or itraconazole 200 mg orally twice daily x 12 months Life-threatening disease Amphotericin B 0.7-1 mg/kg/day IV for a total dosage of 35 mj kg over 2-4 months once the patient is afebrile, able to take oral medications, and no longer requires blood pressure or ventilatory support therapy can be changed to itraconazole 200 mg orally twice daily for 6-18 months Non-life-threatening disease Itraconazole 200-400 mg orally daily for 6-18 months fluconazole therapy 400-800 mg daily should be reserved for patients intolerant to itraconazole, and the development of resistance can lead to relapses... 

Patients with mild, self-limited disease, chronic disseminated disease, or chronic pulmonary histoplasmosis who have no underlying immunosuppression can usually be treated with either oral ketoconazole or IV amphotericin B. 

All patients with disseminated blastomycosis and those with extrapulmonary disease require therapy (ketoconazole, 400 mg/day orally for 6 months). CNS disease should be treated with amphotericin B for a total cumulative dose greater than 1 g. 

Mucocutaneous infections caused primarily by the fungus Candida albicans occm in regions of moist skin and mucous membranes (i.e. gastrointestinal tract, perianal, and vulvovaginal areas). Amphotericin B, miconazole, clotrimazole, and nystatin are used topically to treat such infections. For chronic infections, ketoconazole is taken orally. 

Fluconazole is very effective in the treatment of infections with most Candida spp. Thrush in the end-stage AIDS patient, often refractory to nystatin, clotrimazole, and ketoconazole, can usually be suppressed with oral fluconazole. AIDS patients with esophageal candidiasis also usually respond to fluconazole. A single 150-mg dose has been shown to be effective treatment for vaginal candidiasis. A 3-day course of oral fluconazole is effective treatment for Candida urinary tract infection and is more convenient than amphotericin B bladder irrigation. Preliminary findings suggest that Candida endophthalmitis can be successfully treated with fluconazole. Stable nonneutropenic patients with candidemia can be adequately treated with fluconazole, but unstable, immunosuppressed patients should initially receive... 

Blastomycosis, histoplasmosis, sporotrichosis, paracoccidioidomycosis, and chromomycosis are better treated with itraconazole than ketoconazole, although ketoconazole remains an alternative agent. Ketoconazole is ineffective in the treatment of cryptococcosis, aspergillosis, and mucormycosis. Candidemia is best treated with fluconazole or amphotericin B. 

Candida species amphotericin B fluconazole ketoconazole itraconazole... 

Miconazole, oxiconazole, ketoconazole, sulconazole, clotrimazole (along with betamethasone dipropionate), terbinafine (SEBIFIN), naftifine, butenafine, tolnaftate, nystatin, amphotericin B, cyclopirox... 

Leishmaniasis Skin mucocutaneous tissues viscera Amphotericin B Itraconazole, ketoconazole pentamidine, sodium stibogluconate... 

Coccidioides immitis Amphotericin B Fluconazole, itraconazole, ketoconazole... 

The drugs used in the treatment of subcutaneous and systemic mycoses are amphotericin B, flucytosine, and the new group of azoles, ketoconazole, fluconazole and itraconazole. 

Mode of action Ketoconazole interacts with C-14 a-demethylase (a cytochrome P-450 enzyme) to block demethylation of lanosterol to ergosterol, the principal sterol of fungal membranes Figure 34.4). This inhibition disrupts membrane function and increases permeability. Ketoconazole acts in an additive manner with flucytosine against Candida, but antagonizes amphotericin B s antifungal activity. 

Self-limited disease Amphotericin 6 0.3-0.5 mg/kg/day x 2-4 weeks (total dose 500 or ketoconazole 400 mg orally daily x 3-6 months can be beneficial in patients with severe hypoxia following inhalation of large inocula Antifungal therapy generally not useful for arthritis or pericarditis NSAIDs or corticosteroids can be useful in some cases Most lesions resolve spontaneously surgery or antifungal therapy with amphotericin B 40-50 mg/dayx2-3 weeks or itraconazole 400 m day orally x 6-12 months can be beneficial in some severe cases mild to moderate disease can be treated wHh itraconazole for 6-12 months Amphotericin B 0.7 mg/k day, for a total dose of SSm kg (or 3 rng/k day of one of the lipid preparations) prednisone 60 mg daily tapered over 2 weeks/ followed by itraconazole 200 rng twice daily for 6-12 weeks in patients who do not require hospitalization, itraconazole 200 mg once or twice daily for 6-12 weeks can be used... 

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