Toxicity and efficacy differences between liposomal amphotericin B formulations in uninfected and Aspergillus fumigatus infected mice.

Because of the reduced toxicity associated with liposomal amphotericin B preparations, different amphotericin B liposome products have been made. In the present study, we compared the amphotericin B liposomal formulations, AmBisome(®) (AmBi) and Lambin(®) (Lbn), in uninfected and Aspergillus fumigatus infected mice, using several in vitro and in vivo toxicity and efficacy assays. The results showed that the formulations were significantly different, with Lbn 1.6-fold larger than AmBi. Lbn was also more toxic than AmBi based on the RBC potassium release assay and intravenous dosing in uninfected mice given a single 50 mg/kg dose (80% mortality for Lbn vs. 0% for AmBi). Renal tubular changes after intravenous daily dosing for 14 days were seen in uninfected mice given 5 mg/kg Lbn but not with AmBi. Survival following A. fumigatus challenge was 30% for 10 mg/kg Lbn and 60% for 10 mg/kg AmBi. When the BAL and lungs were collected 24 h after the second treatment, AmBi at 10 or 15 mg/kg or 15 mg/kg Lbn lowered the BAL fungal burden significantly vs. the controls (P ≤ 0.05), while there was no difference in lung fungal burden amongst the groups. In contrast, lung histopathology at this same early timepoint showed that AmBi was associated with markedly fewer fungal elements and less lung tissue damage than Lbn. In conclusion, given the differences in size, toxicity, and efficacy, AmBi and Lbn were not physically or functionally comparable, and these differences underscore the need for adequate testing when comparing amphotericin B liposome formulations.

Differences in efficacy and cytokine profiles following echinocandin or liposomal amphotericin B monotherapy or combination therapy for murine pulmonary or systemic Aspergillus flavus infections.

Given the recent increase in aspergillosis caused by species other than Aspergillus fumigatus, micafungin, caspofungin, and liposomal amphotericin B (L-AmBi) were investigated as monotherapy or combination therapy for murine systemic or pulmonary Aspergillus flavus infection. Treatment for 3 or 6 days was begun at 24 h (intravenous [i.v.], 2.8 × 10(4) conidia) or 2 h (intranasal, 4.1 × 10(6) to 6.75 × 10(6) conidia) postchallenge as follows: 5 or 10 mg/kg L-AmBi, 10 mg/kg caspofungin, 15 mg/kg micafungin, L-AmBi plus echinocandin, L-AmBi on days 1 to 3 and echinocandin on days 4 to 6, or echinocandin on days 1 to 3 and L-AmBi on days 4 to 6. Mice were monitored for survival, fungal burden, serum or tissue cytokines, and lung histopathology. In the systemic infection, micafungin or caspofungin was more effective than L-AmBi in prolonging survival (P < 0.05), and L-AmBi was associated with significantly elevated serum levels of interleukin-6 (IL-6), macrophage inflammatory protein 1α (MIP-1α), and IL-12 (P < 0.05). In contrast, L-AmBi was significantly more effective than the echinocandins in reducing fungal growth in most tissues (P < 0.05). Concomitant therapies produced significantly enhanced survival, reduction in fungal burden, and low levels of proinflammatory cytokines, while antagonism was seen with some sequential regimens. In comparison, in the pulmonary infection, L-AmBi was significantly better (P < 0.05) than caspofungin or the combination of L-AmBi and caspofungin in prolonging survival and reducing lung fungal burden. Caspofungin stimulated high lung levels of IL-1α, tumor necrosis factor alpha (TNF-α), and IL-6, with extensive tissue damage. In summary, systemic A flavus infection was treated effectively with L-AmBi plus micafungin or caspofungin provided that the drugs were administered concomitantly and not sequentially, while pulmonary A. flavus infection responded well to L-AmBi but not to caspofungin.