Amphotericin antifungal action

Clotrimazole and other azole derivatives have a different mode of action than the polyenes, eg, amphotericin B. The latter biad to the ergosterol present ia the membranes of yeasts and fungi, but azole derivatives inhibit the cytochrome P-450 dependent biosynthesis of ergosterol (8—11). This inhibition not only results in a reduction of ergosterol, but also in an accumulation of C-14 methyl sterols. They disturb membrane permeabiUty, inhibit cell rephcation, and are basically responsible, in combination with the reduction of ergosterol levels, for the antifungal action. 

It is obtained from Streptomyces noursei. It has similar antifungal action as amphotericin but is highly toxic and used topically only. It is effective against Candida, Histoplasma, Trichophyton, Blastomyces, Microsporum audouini etc. It is indicated in Candida albicans especially oral moniliasis. 

Furthermore, the antifungal actions of amphotericin B are enhanced by flucytosine, minocycline, or rifampin, agents otherwise devoid of antifungal activity. 

Various polyene—ion complexes have been developed. Water-soluble complexes of amphotericin B with calcium and oxalic or succinic acids have been described [382]. Stable water-soluble borate complexes of amphotericin B, candidin, candicidin, pimaricin have been developed [383]. An advantage of producing stable water-soluble iron(Fe(II) and Fe(III))—polyene complexes was that complexes retained the in vitro antifungal properties of the parent compound [384] while water-soluble calcium complexes showed enhanced antifungal action [385] and it has been suggested that amphotericin B—meglumine complexes were less toxic when used intravenously than desoxycholate complexes [386]. 

Hoeprich and Huston [117] assessed the stability of miconazole and three other antifungal agents under conditions encountered in bioassay and susceptibility testing in vitro. Although the amphotericins were labile as compared with other drugs, tests should be reliable with all four drugs in view of the rapid action of the polyenes and the relatively slow action of miconazole and 5-fluorocytosines. 

Amphotericin B Cholesteryl (Amphotec) [Antifungal/Polyene Mocrollde] Uses AspCTgillosis if intolCTant/refractory to conventional amphotericin B, systemic candidiasis Action Binds ceU membrane sterols, alters permeability Dose Adults Peds. Test dose 1.6—8.3 mg, over 15-20 min, then 3-4 mg/kg/d 1 mg/kg/h inf w/ renal insuff Caution [B, ] Disp Inj SE Anaphylaxis fever, chills, HA, nephrotox, -1- BP, anemia Notes Do not use in-line filter Interactions See Amphotericin B EMS See AmphotCTicin B OD May cause cardiac arrest s ptomatic and supportive... 

Nystatin (Mycostatin) is a polyene antifungal drug with a ring structure similar to that of amphotericin B and a mechanism of action identical to that of amphotericin B. Too toxic for systemic use, nystatin is limited to the topical treatment of superficial infections caused by C albicans. Infections commonly treated by this drug include oral candidiasis (thrush), mild esophageal candidiasis, and vaginitis. 

It is used orally for intestinal candidiasis, topically for oral, vaginal and cutaneous candidiasis and hospital treatment of progressive and potentially fatal systemic fungal infections. It is the gold standard of antifungal therapy. Flucytosine has supraadditive action with amphotericin B if the fungi is sensitive to both. It is also potentiated by rifampicin and minocycline. 

Flucytosine (5-FC) was discovered in 1957 during a search for novel antineoplastic agents. Though devoid of anticancer properties, it became apparent that it was a potent antifungal agent. Flucytosine is a water-soluble pyrimidine analog related to the chemotherapeutic agent fluorouracil (5-FU). Its spectrum of action is much narrower than that of amphotericin B. 

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. 

Finally, there remain some effects of ansamycins of which the significance and the biochemical targets are as yet unknown these include the combined action of rifamycin and amphotericin B on fungal cells, and the antibacterial and antifungal activity of naphthomycin and geldanamycin. 

Nystatin was discovered in 1950 and exhibits the same mode of action as amphotericin B but tends to be of lower solubility, which has restricted its use to the treatment of topical infections. While nystatin was effective for the treatment of conditions such as oral and vaginal candidosis its use has been overtaken by the introduction of azole antifungal drugs. 

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. 

---