Liposomal nystatin (Nyotran)

1. Nystatin

Nystatin is a polyene antibiotic derived from Streptomyces noursei and is closely related in structure to amphotericin B.

 

Nystatin possesses a broad spectrum including Candida, Torulopsis, Cryptococcus, Trichosporon, Geotrichum, Aspergillus, Mucor, Rhizopus, Penicillium, Histoplasma, Blastomyces, Coccidioides, Sporothrix and some Fusarium. The mechanism of action has been attributed to the binding of nystatin to ergosterol in fungal membranes resulting in an altered membrane permeability. Although nystatin-resistant fungi have been created in the laboratory, resistance to nystatin in humans is rare and is not clinically significant. However, resistance in a small number of clinical cases has been reported. Fungi resistant to amphotericin B are not always resistant to nystatin, suggesting that in some fungi the mechanism of action of these polyenes may be different.

 

Nystatin has been used for 30 years for the treatment of oropharyngeal, cutaneous and vaginal fungal infections. Its use has been limited to topical applications, due to the lack of significant absorption following oral administration that is necessary for the treatment of systemic fungal infections. Although nystatin demonstrated antifungal activity in humans in early attempts to use the drug intravenously, use of the intravenous nystatin in humans was short lived because of its toxicity (thrombophlebitis, fever, chills and nausea) and insolubility.

 

II. Liposomal nystatin

 

Nyotran® is a lyophilised liposomal formulation containing nystatin, dimyristoyl phosphatidyl choline and dimyristoyl phosphatidyl glycerol. It is manufactured by Aronex Pharmaceuticals Inc., 8707 Technology Forest Place, The Woodlands, Texas 77381-1191, USA. Nyotran is supplied as a 50 mg deliverable nystatin in a 50 ml vial or a 100 mg deliverable nystatin in a 100 ml vial. After reconstitution Nyotran® contains 1 mg/ml of nystatin.

 

1. In vitro activity

 

Nyotran® has been shown to be active against the following species of fungi : Allescheria sp., Alternaria sp., Aspergillus flavus, Aspergillus fumigatus, Aspergillus niger, Beauvaria sp., Bipolaris sp., Candida albicans, Candida famata, candida glabrata, candida guittlermondil, Candida kefyr, Candida krusei, Candida lusitaniae, Candida parapsilosis, Candida rugosa, Candida tropicalis, Candida wiswanathii, Chrysosporium sp., Cladosporium sp., Cryptococcus laurentii, Cryptococcus neoformans, Cunninghamella elegans, Curvularia sp., Fonsecaea sp., Geotrichum sp., Hansenula anomala, Issatchenkia orientalis, Mucor sp., Penicillium sp., Rhizopus sp., Rhodotorulla rubra, Sporothrix sp. and Trichosporon sp. Nyotran® is active in vitro against most, but not all, Fusarium isolates, and is not active against Scedosporium prolificans. In addition, Nyotran® is active against all yeasts that are resistant in vitro to fluconazole, itraconazole and lipid amphotericin B drugs.

 

2. In vivo activity

 

Nyotran® demonstrated efficacy in experimental candidiasis in normal and neutropenic mice. It was also active against Aspergillus in both neutropenic mice and neutropenic rabbits. The effective dose in experimental studies ranged from 2 to 8 mg/kg.

 

3. Toxicology

 

In vitro, Nyotran® causes substantially less hemolysis than free nystatin or amphotericin B.

 

The LD 50 value in rats is 10.6 mg/kg for Nyotran® compared to 7.6 mg/kg for free nystatin and 4.0 mg/kg for amphotericin B.

 

Subchronic toxicity studies were conducted in rats and dogs for up to 90 days. Rats were given daily intravenous doses of Nyotran® at three dose levels (0.1, 0.4 and 1.6 mg/kg) for 90 days. there was no treatment related clinical signs. The predominant target organ was identified as the kidney and effects were observed primarily at the highest dose level. Histopathological examination revealed nephropathy in rats at the highest dose level group (1.6 mg/kg/d) but serum creatinine and BUN were only marginally increased. Mild regenerative anaemia was also observed in this group.

 

A 90-day study was also conducted in Beagle dogs using daily intravenous doses of Nyotran® at dose levels of 0.2, 1.0 or 2.0 mg/kg. BUN and creatinine rose in dogs receiving 1.0 and 2.0 mg/kg/d. The primary renal changes observed after 90 days were tubular regeneration, tubular dilatation and nephrosclerosis. No histopathological changes were observed in any other tissues.

 

4. Pharmacokinetics

 

Spleen and kidney are the organs in which nystatin was found in the highest concentration following simple or multiple intravenous doses in rats. Smaller amounts could be detected in the liver.

 

The pharmacokinetics of liposomal nystatin in blood has been determined in humans. Liposomal nystatin was administered as an intravenous infusion at 2 ml/min every other day at doses of 1, 2, 3, 4, 5 or 7 mg/kg to HIV-infected patients. Blood concentration versus time profiles were generated after the first administration of liposomal nystatin at doses of 2, 3, 4, or 5 mg/kg to three to four patients per dose group. The concentration at the end of the infusion and blood AUC values increased with increasing dose. The maximal blood concentration was 4.8, 9.5, 24.3 and 24.1 µg/ml for doses of 2, 3, 4 or 5mg/kg, respectively. Therapeutic blood levels ( In vitro MIC = 1 µg/ml) were maintained for several hours following single doses of liposomal nystatin as low as 2 mg/kg. Following repeat doses of liposomal nystatin every other day, little or no nystatin accumulated in the blood at doses up to 5 mg/kg.

 

Excretion of nystatin following administration of Nyotran® has not yet been studied in humans. In rats, 5.5 % of the total dose of nystatin was excreted in the urine after 4 days.

 

5. Clinical activity

 

Nyotran® has been shown to be effective in some patients who have failed therapy with amphotericin B desoxycholate and Abelcet.

 

Nyotran® has also been reported to be effective in at least 60 % of episodes of refractory candidemia, including those treated with amphotericin B, fluconazole and/or flucytosine.

 

Nyotran was reported to have a 67 % success rate in 43 patients with candidemia. In the same study its was reported that Nyotran caused renal toxicity in only 14 % of the patients versus 37 % of the patients in a Fungizone historical control. Although these results have been reported in a small number of patients so far, they are encouraging in the possibility that Nyotran is active in human patients with systemic fungal infections, particularly those who have failed other antifungal drugs.

 

Prepared by Raoul Herbrecht MD, Service d’Onco-Hématologie, Hôpital de Hautepierre, 67098 Strasbourg France. November, 1998

 

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