Aspergillus terreus is an uncommon but emerging fungal pathogen, which causes lethal infections that are often refractory to amphotericin B (AmB). In comparison to Aspergillus fumigatus, A. terreus was resistant to the in vitro fungicidal effects of safely achievable concentrations of AmB. These in vitro findings correlated directly with resistance of A. terreus to AmB in experimental invasive pulmonary aspergillosis. Residual fungal pulmonary burden and galactomannan antigenemia demonstrated persistent infection, despite therapy with deoxycholate AmB or liposomal AmB. By comparison, posaconazole and itraconazole resolved GM antigenemia, reduced residual fungal burden, and improved survival. There were no differences in phagocytic host response to A. terreus versus A. fumigatus; however, the rate of conidial germination of A. terreus was slower. The strain of A. terreus with the highest minimum inhibitory and minimum lethal concentration of AmB also had the lowest membrane ergosterol content. The hyphae of A. terreus in vivo displayed distinctive aleurioconidia, which may be a practical microscopic feature for rapid preliminary diagnosis.

Invasive pulmonary aspergillosis is an important cause of morbidity and mortality in immunocompromised patients. Simultaneous inhibition of fungal cell-wall and cell-membrane biosynthesis may result in synergistic interaction against Aspergillus fumigatus. We studied the antifungal activity of micafungin, a new echinocandin, in combination with ravuconazole, a second-generation triazole, against experimental invasive pulmonary aspergillosis in persistently neutropenic rabbits. This combination led to significant reductions in mortality (P

Micafungin (FK463) is an echinocandin that demonstrates potent in vitro antifungal activities againstCandida and Aspergillus species. However, little is known about its comparative antifungal activities in persistently neutropenic hosts. We therefore investigated the plasma micafungin pharmacokinetics and antifungal activities of micafungin against experimental disseminated candidiasis and invasive pulmonary aspergillosis in persistently neutropenic rabbits. The groups with disseminated candidiasis studied consisted of untreated controls (UCs); rabbits treated with desoxycholate amphotericin B (DAMB) at 1 mg/kg of body weight/day; or rabbits treated with micafungin at 0.25, 0.5, 1, and 2 mg/kg/day intravenously. Compared with the UCs, rabbits treated with micafungin or DAMB showed significant dosage-dependent clearance of Candida albicans from the liver, spleen, kidney, brain, eye, lung, and vena cava. These in vivo findings correlated with the results of in vitro time-kill assays that demonstrated that micafungin has concentration-dependent fungicidal activity. The groups with invasive pulmonary aspergillosis studied consisted of UCs; rabbits treated with DAMB; rabbits treated with liposomal amphotericin B (LAMB) at 5 mg/kg/day; and rabbits treated with micafungin at 0.5, 1, and 2 mg/kg/day. In comparison to the significant micafungin dosage-dependent reduction of the residual burden (in log CFU per gram) of C. albicans in tissue, micafungin-treated rabbits with invasive pulmonary aspergillosis had no reduction in the concentration of Aspergillus fumigatus in tissue. DAMB and LAMB significantly reduced the burdens of C. albicans and A. fumigatus in tissues (P < 0.01). Persistent galactomannan antigenemia in micafungin-treated rabbits correlated with the presence of an elevated burden of A. fumigatus in pulmonary tissue. By comparison, DAMB-and LAMB-treated animals had significantly reduced circulating galactomannan antigen levels. Despite a lack of clearance of A. fumigatus from the lungs, there was a significant improvement in the rate of survival (P < 0.001) and a reduction in the level of pulmonary infarction (P < 0.05) in micafungin-treated rabbits. In summary, micafungin demonstrated concentrationdependent and dosage-dependent clearance of C. albicans from persistently neutropenic rabbits with disseminated candidiasis but not of A. fumigatus from persistently neutropenic rabbits with invasive pulmonary aspergillosis.

This model provides a strategy by which relationships among pathogenesis, immunological effectors, and antifungal drug therapy for invasive pulmonary aspergillosis may be further understood.

Patients with chemotherapy-induced granulocytopenia for neoplastic diseases and those receiving cyclosporin A plus corticosteroids for prevention and treatment of organ transplant rejection are two immunologically distinct patient populations with high risks for development of invasive pulmonary aspergillosis. In order to compare the pathogenesis of aspergillosis in these two high-risk populations and to further characterize the role of cyclosporin A in development of pulmonary aspergillosis, we studied the patterns of infection and inflammation in two clinically applicable rabbit models of invasive pulmonary aspergillosis. There were striking differences in the patterns of infection and inflammation of invasive pulmonary aspergillosis according to the type of underlying immune defect. Among rabbits challenged with the same intratracheal inoculum, there was a 100% mortality for invasive pulmonary aspergillosis in profoundly granulocytopenic rabbits in comparison with a 100% mortality for invasive pulmonary aspergillosis in profoundly granulocytopenic rabbits in comparison with a 100% survival in rabbits immunosuppressed with cyclosporin A plus methylprednisolone (CsA+MP). Lesions of pulmonary aspergillosis in granulocytopenic rabbits consisted predominantly of coagulative necrosis, intraalveolar hemorrhage, and scant mononuclear inflammatory infiltrate. By comparison, pulmonary foci in rabbits immunosuppressed by CsA+MP consisted mainly of neutrophilic and monocytic infiltrates, inflammatory necrosis, and scant intraalveolar hemorrhage. There was extensive infiltration by hyphae with angioinvasion in granulocytopenic rabbits, whereas conidia in various stages of germination predominated in CsA+MP treated animals in which there was a paucity of hyphae or angioinvasion. Extrapulmonary disease predominated in granulocytopenic rabbits. Methylprednisolone was the major immunosuppressive drug in rabbits treated with CsA+MP. Cyclosporin A alone did not increase the progression of pulmonary aspergillosis and did so only when used chronically with methylprednisolone.