Liposomal Nystatin in Patients with Invasive Aspergillosis Refractory to or Intolerant of Amphotericin B

Abstract

We assessed the activity and safety of liposomal nystatin, a broad-spectrum antifungal agent, for invasive aspergillosis in patients refractory to or intolerant of amphotericin B. Thirty-three patients were enrolled, received at least one dose of the study drug, and were evaluable for safety. Twenty-six patients had confirmed probable or definite aspergillosis and were fully eligible. Most patients had a hematological malignancy (53.8%) or hematopoietic stem cell transplantation (23.0%), were neutropenic (61.5%), and were refractory to previous amphotericin B (92.3%). The median duration of previous amphotericin B treatment was 16.5 days (range, 5 to 64 days). Aspergillosis was definite in 3 cases and probable in 23 cases. Liposomal nystatin was initiated at a dose of 4 mg/kg of body weight/day. Twenty-five patients were evaluable for response: a complete response was achieved for one patient, and a partial response was achieved for six. Thus, the overall response rate is 7 of 25 (28%; 95% confidence interval, 12 to 49%). Seventeen (68.0%) of the 25 evaluable patients died during therapy or within 1 month after the end of therapy. The primary cause of death was invasive aspergillosis for nine patients and underlying malignancy for eight patients. The most frequent side effects included chills, shivering, and fever, leading to discontinuation of therapy for two patients. Grade 1 decline in renal function was seen for 10 (30.3%) patients, and hypokalemia was seen for 13 (39.4%). We conclude that liposomal nystatin can be effective for salvage therapy of invasive aspergillosis. Infusion-related adverse events have been observed frequently.Mold infections continue to be an important cause of death for patients with leukemia, allogeneic hematopoietic stem cell transplantation, and advanced stages of malignancy. The mortality rate of invasive aspergillosis (IA) ranges from 40 to 90% depending on the degree of underlying immune suppression and the institution of early therapy (5,16).Until the recent approval of voriconazole, standard treatment of IA consisted of intravenous amphotericin B given at doses of at least 1 mg/kg of body weight/day (11, 24). Amphotericin B is associated with considerable toxicity and frequent treatment failure, particularly in the case of advanced disease and prolonged neutropenia. The liposomal formulation of amphotericin B has allowed the administration of more than fivefold doses of the drug with considerable improvement in the safety profile (15,25).The liposomal encapsulation technique can, however, be extended to other antifungal agents that were previously excluded for treatment of systemic fungal infections due to the lack of a well-tolerated intravenous formulation. Nystatin is a naturally occurring product of Streptomyces noursei that has been used as a topical fungicidal drug since the 1950s. It is active against Candida, Cryptococcus, Histoplasma, Blastomyces, and Aspergillus spp. and has a spectrum of antifungal activity similar to that of amphotericin B (1,4,13,22).Early attempt...

Update on antifungal drug resistance mechanisms of Aspergillus fumigatus

“…Nystatin resistance was conferred by mutations affecting membrane sterols, whereas AMB resistance was associated with a mutation affecting cell wall composition (Hapala et al, 2005). Similarly, in a recent multicenter clinical study involving 25 patients with refractory IA -in most of which prior AMB had failed -liposomal nystatin given as salvage therapy resulted in a response rate of 28% (Offner et al, 2004).…”

New antifungal agents

“…Offner et al (9) presented an interesting study of liposomal nystatin at the 2000 meeting of the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). They administered 4 mg/kg/day of the drug to patients who were invasive aspergillosis (IA) refractory or intolerant to polyenes.…”

Invasive Aspergillosis

“…Offner et al reported a case series of 23 IA patients treated with liposomal nystatin as a treatment option for salvage therapy. 59 These authors also reported infusion related events and nephrotoxicity similar to amphotericin B. At this time there is insufficient evidence to recommend liposomal nystatin as initial therapy for IA.…”