Liposomal nystatin against experimental pulmonary aspergillosis in persistently neutropenic rabbits: efficacy, safety and non-compartmental pharmacokinetics

The activity of liposomal nystatin against invasive pulmonary aspergillosis was investigated in persistently neutropenic rabbits. Treatment groups inc luded liposomal nystatin at dosages of 1,2 and 4 mg/kg/day intravenously, o r amphotericin B deoxycholate 1 mg/kg/day administered intravenously after normal saline loading. As compared with untreated controls, liposomal nysta tin administered at 2 and 4 mg/kg/day prolonged survival and reduced fungus -mediated tissue injury and excess lung weight at post-mortem in a similar manner to amphotericin B. Although amphotericin B was superior in clearing infected lung tissue, treatment with all regimens of liposomal nystatin led to a significant reduction in pulmonary fungal tissue burden. During treat ment, ultrafast CT-scan demonstrated ongoing resolution of pulmonary lesion s at 2 and 4 mg/kg/day, but not at 1 mg/kg/day. With the exception of mild increases in blood urea nitrogen (BUN) and serum creatinine values during t reatment at 2 and 4 mg/kg/day, which were similar to those found in amphote ricin B-treated rabbits, liposomal nystatin was well tolerated. Preliminary pharmacokinetic studies in non-infected animals established linear drug di sposition of liposomal nystatin in plasma over the investigated dosage rang e and peak plasma levels above the MIC for the test strain after multiple d aily dosing for 7 days. Liposomal nystatin increased survival and provided reduced tissue injury, effective microbiological clearance and tolerable si de effects in experimental pulmonary aspergillosis in persistently neutrope nic rabbits, thus providing a rational basis for further investigations in clinical trials.