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and must be given by i.v. infusion for systemic infection; about 10% remains in the blood and the fate of the remainder is not known but it is probably bound to tissues. The is 15 d, i.e. after stopping treatment, drug persists in the body for several weeks.

Amphotericin is at present the drug of choice for most systemic fungal infections (see Table 14.2). The diagnosis of systemic infection should whenever possible be firmly established because toxicity from conventional amphotericin is significant and the lipid-associated formulations are very expensive; tissue biopsy and culture may be necessary. New molecular diagnostic methods based on the polymerase chain reaction to detect aspergillus DNA may soon revolutionise management of invasive infection. A conventional course of treatment for filamentous fungal infection lasts 6-12 weeks during which at least 2 g of amphotericin is given (usually 1 mg/kg/day), but lower total and daily (e.g. 0.6 mg/kg) doses are used for Candida infections with correspondingly lower rates of adverse drug reactions.

Lipid-associated formulations of amphotericin offer the prospect of reduced risk of toxicity while retaining therapeutic efficacy. In an aqueous medium, a lipid with hydrophilic and hydrophobic properties will form vesicles (liposomes) comprising an outer lipid bilayer surrounding an aqueous centre. The AmBisome formulation incorporates amphotericin in a lipid bilayer (diameter 55-75 ran) from which the drug is released. Amphotericin is also formulated as other lipid-associated complexes, e.g. Abelcet ('amphotericin B lipid complex'), and Amphocil ('amphotericin B colloidal dispersion'). Experience with these formulations is growing; AmBisome is the most established, and it is significantly less toxic but much more expensive than conventional amphotericin. It may be more effective for some indications, probably because higher doses may safely be given more quickly (e.g. 3 mg/kg/day). It is the first choice for patients with impaired renal function, but treatment is often begun with the conventional formulation in those with normal kidneys. Therapy can be transferred to AmBisome if the patient's renal function deteriorates. Further clinical trials are needed to establish the best clinically and cost effective ways to use these drugs.

Adverse reactions. Gradual escalation of the dose limits toxic effects but these may have to be accepted in life-threatening infection if conventional amphotericin is used. Renal impairment is invariable, although reduced by adequate hydration and amphotericin need not be stopped until serum creatinine has risen to 180-200 micromol/1; the same dose may then be resumed after 3-5 days. Amphotericin nephrotoxicity is reversible, at least in its early stages. Hypokalemia (due to distal renal tubular acidosis) may necessitate replacement therapy. Other adverse effects include: anorexia, nausea, vomiting, malaise, abdominal, muscle and joint pains, loss of weight, anaemia, hypomagnesaemia and fever. Aspirin, an antihistamine (Hj receptor) or an antiemetic may alleviate symptoms. Severe febrile reactions are mitigated by hydrocortisone 25-50 mg before each infusion. Lipid-formulated preparations are much less often associated with adverse reactions, but fever, chills, nausea, vomiting, nephrotoxicity, electrolyte disturbance and occasional hepatotoxicity have been reported.

Nystatin

(named after New York State Health Laboratory)

Nystatin is too toxic for systemic use. It is not absorbed from the alimentary canal and is used to prevent or treat superficial candidiasis of the mouth, oesophagus or intestinal tract (as suspension, tablets or pastilles), for vaginal candidiasis (pessaries) and cutaneous infection (cream, ointment or powder).

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