Amphotericins selective toxicity

Flucytosine Interferes with DNA and RNA synthesis selectively in fungi Synergistic with amphotericin systemic toxicity in host due to DNA and RNA effects Cryptococcus and chromoblastomycosis infections Oral duration, hours renal excretion Toxicity Myelosuppression... 

Juliano RL, Grant CW, Barber KR, Kalp MA. Mechanism of the selective toxicity of amphotericin B incorporated into liposomes. Mol Pharmacol 1987 31(1) 1-11. 

Kotler-Brajtburg J, Price HD, Medoff G,etal. Molecular basis for the selective toxicity of amphotericin B for yeast and filipin for animal cells. Antimicrob Agents Chemother 1974 5 377-82. 

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 ... 

Don t harm innocent bystanders The primary goal of antimicrobial therapy is to kill bacteria without harming tissues of the host (Fig. 7.1). Drugs like penicillin, which are effective against certain bacteria, but cause few side effects, have high selective toxicity (i.e., good therapeutic index). In contrast, drugs like amphotericin, which are toxic to human cells at therapeutic doses, have poor selective toxicity. 

Janoff AS, et al. Unusual lipid structures selectively reduce the toxicity of amphotericin B. Proc Natl Acad Sci USA 1988 85 6122. 

Selective distal tubular epithelial toxicity by amphotericin can cause hypokalemia, and hypokalemia can cause further tubular damage. There is some evidence that hypokalemia due to amphotericin is mitigated by both spironolactone (83) and amiloride (84). 

Amphoteridn is a complex amphoteric polyene antibiotic that binds to cell membranes and forms a pore through which ions can pass, with consequences that include loss of potassium ions from within the cell. Since the antibiotic binds more readily to fungal cell membranes than mammalian, its action is relatively selective. It can potentiate the action of certain other antifungals. and it may be used with flucytosine. Also, it confers antifungal activity on rifampicin (normally antibacterial). As it has an appreciable renal toxicity, it needs to be used with caution in some patients. Nystatin is a polyene antibiotic similar in structure to amphotericin, often used for local treatment. 

R. A. Zager, C. R. Bredl and B. A. Schimpf, Direct amphotericin B-mediated tubular toxicity assessments of selected cytoprotective agents. Kidney Int., 1992, 41, 1588-1594. 

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