The reformulation of amphotericin B (AMB) into a lipid complex (AMB lipid complex [ABLC]) or liposomal carrier (liposomal AMB [L-AMB])changes the rate and extent of drug distribution to the lung. The importance of pharmacokinetic differences among the various lipid AMB formulations in the treatment of invasive pulmonary aspergillosis (IPA) remains unknown. We compared the kinetics of AMB lung accumulation and fungal clearance of ABLC-and L-AMB-treated mice with acute IPA. BALB/c mice were immunosuppressed with cyclophosphamide and cortisone before intranasal inoculation with 1.5 ؋ 10 6 Aspergillus fumigatus 293 conidia. ABLC or L-AMB was administered in daily intravenous doses (1, 5, or 10 mg/kg of body weight), starting 12 h after infection and continuing until day 5. At predetermined times (0, 24, 72, and 120 h), mice were euthanized, and lungs were harvested for determinations of lung fungal burdens (quantitative PCR) and total AMB lung tissue concentrations. Both ABLC and L-AMB were effective at reducing lung fungal burdens at doses of >5 mg/kg/day. Clearance of A. fumigatus during the first 24 h was associated with AMB tissue concentrations of >4 g/g. At 5 mg/kg/day, ABLC produced a more rapid fungal clearance than did L-AMB, but at the end of therapy, fungal burden reductions were similar for both formulations and were not improved with higher dosages. These data suggest that ABLC delivers active AMB to the lung more rapidly than does L-AMB, resulting in faster Aspergillus clearance in an experimental model of IPA. However, pharmacodynamic differences between the two formulations were less apparent when mice were dosed at 10 mg/kg/day.Despite the availability of new treatment options, lipid formulations of amphotericin B (AMB) continue to play a central role in the management of invasive pulmonary aspergillosis (IPA) due to their broad spectrum and low potential for cross-resistance with other antifungals (5). Currently, the following three lipid formulations are approved for the treatment of IPA in patients who have failed or are intolerant to other therapies: AMB colloidal dispersion, AMB lipid complex (ABLC), and liposomal AMB (L-AMB). All three AMB formulations differ in terms of their lipid composition and particle size, resulting in different pharmacokinetic characteristics when the drugs are administered in vivo. For example, L-AMB consists of small unilamellar particles (60 to 70 nm) that avoid uptake by cells of the reticuloendothelial system (RES) (7,8,14,25). Hence, intravenous administration of L-AMB results in sustained, high concentrations of encapsulated AMB in the serum, with a somewhat delayed distribution of free drug to tissues. Conversely, intravenous administration of ABLC results in relatively low serum AMB concentrations due to the rapid RES cell uptake of the large lipid complex (1,600 to 11,000 nm) (1). Extensive RES cell uptake of ABLC is thought to account for the more rapid distribution of ABLC to certain organs, such as the lungs, than that of other formulations (18,19). The cl...