Amphotericin B - Antifungals

Antifungal

Amphotericin B

Amphotericin B is a polyene macrolide antibiotic obtained from Streptomyces nodosus, and is one of the earliest systemic antifungals to be introduced into clinical practice.

Uses

·              Amphotericin B is administered as an IV infusion for the treatment of systemic fungal infections caused by Candida,Aspergillus, Cryptococcus, Neoformans, and Mucor species.In other words, it is effective for the treatment of serious infections including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, cryptococcosis, histoplasmosis, mucor-mycosis, paracoccidioidomycosis and sporotrichosis. Due to its significant toxicity, amphotericin B is reserved for life-threatening infections. Intrathecal administration can be done for fungal meningitis (especially due to Coccidioides). Bladder irrigation with amphotericin B in sterile water is effective for candida cystitis.

·              Less toxic formulations of amphotericin B have been intro-duced recently: amphotericin B lipid complex, amphotericin B cholesteryl sulfate complex, and amphotericin B liposome.

Mode of Action

Amphotericin B acts by combining with the ergosterol of the cytoplasmic membrane of the fungus, thereby creating porous cell membranes. This is followed by leakage of cellular organ-elles and cell lysis. Since human cells have cholesterol instead of sterols in their cell membranes, they are less affected.

Toxicokinetics

Amphotericin B is absorbed very poorly from the GI tract. After IV administration, more than 90% of the drug is bound to proteins. Approximately 2 to 5% of each dose is excreted in the urine.

Adverse Effects

■■   Common adverse effects include fever, chills, arthralgia, myalgia, and tachypnoea, which are usually self-limiting.

■■  Cardiovascular effects comprise tachycardia, hypo/hyper-tension, and ventricular fibrillation.

■■  Other reported effects include renal impairment, red man syndrome rash (erythema of the hands, soles, face, and neck), hepatic damage, haematologic abnormalities (anaemia, leukopenia, thrombocytopenia), phlebitis, pulmo-nary distress, hyperkalaemia, vomiting, and diarrhoea.

■■  Intrathecal administration has caused paraesthesia, delirium, temporary psychosis, and parkinsonism.

■■  A few cases of painful cyanotic Raynaud’s phenomenon after intravenous administration or inhalation of ampho-tericin B have been reported.

Drug Interactions

Amphotericin B potentiates potassium loss by corticosteroids, enhances digitalis toxicity, and aggravates renal toxicity when given concomitantly with other nephrotoxic drugs. It is antago-nistic to ketoconazole.

Toxic (Clinical) Features

Several cases of overdose with amphotericin B have been reported, and even a few fatalities. Main features include vomiting, diarrhoea, abdominal distension, hypokalaemia, and cardiac arrest. Overdose cases have resulted in mild renal damage, thrombocytopenia, fever, and chills. Children and infants tolerate comparable dosages of amphotericin B better than adults.

Treatment

Overdose patients should be monitored for altered renal func-tion (BUN, creatinine, creatinine clearance), altered electrolytes (especially hyperkalaemia), and have a complete blood count.

Ingestions of large amounts of ointment, creams, or lozenges may necessitate gastrointestinal decontamination.

·      Admit acutely overdosed patients to intensive care unit and monitor cardiac function. Supportive measures are indicated. Haemodialysis is not beneficial.

·      Amphotericin-induced fever and chills can be prevented/ managed by ibuprofen, hydrocortisone, or pethidine.

·      Amiloride (5 mg twice daily) can help minimise hypoka-laemia.

·      Nephrotoxicity can be minimised by infusing 1 litre of normal saline every day.

·      Amphotericin B is highly protein bound. Therefore, exchange transfusion in infants has been recommended as a treatment for overdose.