The antifungal efficacy, pharmacokinetics, and safety of
caspofungin (CAS) were investigated in the treatment and prophylaxis of
invasive pulmonary aspergillosis due to Aspergillus fumigatus in persistently neutropenic rabbits. Antifungal
therapy consisted of 1, 3, or 6 mg of CAS/kg of
body weight/day (CAS1, CAS3, and CAS6, respectively) or 1 mg of
deoxycholate amphotericin B (AMB)/kg/day intravenously for 12 days starting 24 h after endotracheal inoculation. Prophylaxis (CAS1) was initiated 4 days before endotracheal inoculation. Rabbits treated with CAS had significant improvement in survival and reduction in organism-mediated
pulmonary injury (
OMPI) measured by
pulmonary infarct score and total lung weight (P < 0.01). However, animals treated with CAS demonstrated a paradoxical trend toward increased residual fungal burden (log CFU per gram) and increased serum
galactomannan antigen index (GMI) despite improved survival. Rabbits receiving prophylactic CAS1 also showed significant improvement in survival and reduction in
OMPI (P < 0.01), but there was no effect on residual fungal burden. In vitro
tetrazolium salt hyphal damage assays and histologic studies demonstrated that CAS had concentration- and dose-dependent effects on hyphal structural integrity. In parallel with a decline in GMI, AMB significantly reduced the pulmonary tissue burden of A. fumigatus (P < or = 0.01). The CAS1, CAS3, and CAS6 dose regimens demonstrated dose-proportional exposure and maintained
drug levels in plasma above the MIC for the entire 24-h dosing interval at doses that were > or =3 mg/kg/day. As serial
galactomannan antigen levels may be used for therapeutic monitoring, one should be aware that profoundly neutropenic patients receiving
echinocandins for
aspergillosis might have persistent
galactomannan antigenemia despite clinical improvement. CAS improved survival, reduced
pulmonary injury, and caused dose-dependent hyphal damage but with no reduction in residual fungal burden or
galactomannan antigenemia in persistently neutropenic rabbits with
invasive pulmonary aspergillosis.