Polyene antibiotics toxicity

How do antibiotics act Some, like penicillin, block specific enzymes. Peptide antibiotics often form complexes with metal ions (Fig. 8-22) and disrupt the control of ion permeability in bacterial membranes. Polyene antibiotics interfere with proton and ion transport in fungal membranes. Tetracyclines and many other antibiotics interfere directly with protein synthesis (Box 29-B). Others intercalate into DNA molecules (Fig. 5-23 Box 28-A). There is no single mode of action. The search for suitable antibiotics for human use consists in finding compounds highly toxic to infective organisms but with low toxicity to human cells. 

This primary mode of action of tomatine, that involves the formation of complexes with membrane sterols is similar to that described for polyene antibiotics [2, 4], and results in pore formation and loss of membrane integrity. This mode of action is supported by the reduced activity of tomatine on sterol-free bacteria and Oomycete fungi such as Pythium and Phytophthora [15, 28], and the strongly reduced toxicity of hydrolysis products of the glycoalkaloid which fail to bind sterols [57]. 

Amphotericin B is the only polyene antibiotic given parenterally. When the intravenous route is contemplated, amphotericin B is dispersed fresh, as discussed, and infused slowly. Amphotericin B should not be administered rapidly because this causes cardiac toxicity. Heparin (1000 units) is often added to the infusion suspension to avert the risk of thrombophlebitis. Amphotericin B can also precipitate normocytic or normochromic anemia, leukopenia, and thrombocytopenia. 

Nystatin [nye STAT in] is a polyene antibiotic its structure, chemistry, mode of action, and resistance resemble those of amphotericin B. Its use is restricted to topical treatment of Candida infections because of its systemic toxicity. The drug is negligibly absorbed from the gastrointestinal tract, and it is never used par-enterally. It is administered as an oral agent ( swish and swallow ) for the treatment of oral candidiasis. Excretion in the feces is nearly quantitative. Adverse effects are rare because of its lack of absorption, but occasionally nausea and vomiting occur. 

Ulcerogenic effect of alprenolol salts Relative toxicities of quinapyramine salts Toxicity of aspirin salts Toxicity of polyene antibiotics... 

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. 

In the early 1960s, studies showed that polyene antibiotics induced changes in cellular permeabihty that resulted in the leakage of important ceUular constituents, followed by lysis and death [42-46]. It was also discovered that the toxic effect of the drugs on cells was dependent on the presence of sterols in the cell membranes, and that addition of sterols to the growth media of certain fungi prevented the polyene-induced... 

The extent to which the polyene antibiotics with clinical usefulness have tolerable human toxicities is based on a selectivity, which may in turn be due to different sterols in these two types of membranes having different affinities for a particular polyene. The pri-... 

The high mammalian toxicity and low aqueous solubility of polyene antibiotics has led to a seardi for derivatives with reduced toxicity, increased solubility and... 

Polyene antibiotics which possess a free amino group, e.g. amphotericin B, react with carbohydrates or their derivatives under appropriate conditions, yielding A -glycosyl derivatives. These derivatives formed water-soluble salts. The N-glucosyl and -glucuronyl derivatives showed similar antifungal activity to the parent compound but reduced systemic toxicity [398,399] and proved effective when administered intraperitoneally in the treatment of experimental candidiasis in mice [400]. 

Table 3.7. TOXICITY OF POLYENE ANTIBIOTICS IN SMALL MAMMALS...

M. Laasonen, T. Harmia-Pulkkinen, C. Simard, M. Rasanen, and H. Vuorela, Relationship between Acute Toxicity in Mice and Polymorphic Forms of Polyene Antibiotics, Eur.. Pharm. Sci., 21,493 (2004). 

Polyene antibiotics are used clinically as fungicides for internal infections. They are rather toxic to the patient, but are the best drugs available. The two most clinically useful members are (a) nystatin (14.14), whose complex composition was worked out by Birch et ah (1964), and Chong and Rickards... 

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