ANTIFUNGAL ACTIVITY OF THE PRADIMICIN DERIVATIVE BMS-181184 IN THE TREATMENT OF EXPERIMENTAL PULMONARY ASPERGILLOSIS IN PERSISTENTLY NEUTROPENIC RABBITS

The activity of the pradimicin derivative EMS 181184 was evaluated in a model of invasive pulmonary aspergillosis in persistently neutropeni c rabbits and compared with that of amphotericin B deoxycholate. EMS 1 81184 at total daily doses of 50 and 150 mg/kg of body weight was at l east as effective as amphotericin B at 1 mg/kg once a day in conferrin g survival and had comparable activity in reducing organism-mediated t issue injury and excess lung weight. Although treatment at all dosing regimens of EMS 181184 resulted in significant reductions in fungal ti ssue burden compared to untreated controls, equivalence to amphoterici n B occurred only at the higher dosage level. Similar observations wer e made in bronchoalveolar lavage fluid cultures obtained postmortem. M onitoring of the animals through ultrafast computerized tomography sca n revealed a marked resolution of pulmonary lesions during treatment w ith EMS 181184. The compound was well tolerated at all dosing regimens , and no toxicity was noted. Pharmacokinetic studies revealed nonlinea r drug disposition with increased clearance at higher dosages and some evidence for extravascular drug accumulation. EMS 181184 had excellen t activity in the treatment of experimental invasive pulmonary aspergi llosis in persistently neutropenic rabbits, thus underscoring the pote ntial of pradimicin derivatives in therapy of invasive aspergillosis i n the neutropenic host.