Antifungal Efficacy of Caspofungin (MK-0991) in Experimental Pulmonary Aspergillosis in Persistently Neutropenic Rabbits: Pharmacokinetics, Drug Disposition, and Relationship to Galactomannan Antigenemia

Abstract

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 < 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 >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.

Longitudinal, in vivo assessment of invasive pulmonary aspergillosis in mice by computed tomography and magnetic resonance imaging

“…In previous studies, a similar scoring system was used to obtain semiquantitative information on the development of pulmonary lesions based on ultrafast CT lung images of rabbits suffering from IPA. [40][41][42] However, radiological skills are mandatory and the method is to some extent observer-dependent. To obtain an objective read-out for the developing infection, multiple lung parameters were quantified based on a VOI covering the entire lung.…”

“…[40][41][42] At day 1 after infection, an initial score of zero was assigned to the CT/MRI lung data set of each individual animal. Subsequently, four coronal image slices were selected from each data set at four different, predefined positions within the lungs.…”

Contributions of Human Tumor Xenografts to Anticancer Drug Development

“…The basis for this dispute lies in an insufficient predictive power of the traditionally explored tumor model systems for how actual human beings will respond to the treatment in the clinic (1,2). This is in contrast to other disease areas (e.g., fungal infections), where evidence of a protective preclinical effect in rabbits readily translates into clinically active agents, assuming that human pharmacology and toxicology can be optimized (3).…”

Characterization and Comparison of Galactomannan Enzyme Immunoassay and Quantitative Real-Time PCR Assay for Detection of Aspergillus fumigatus in Bronchoalveolar Lavage Fluid from Experimental Invasive Pulmonary Aspergillosis

“…These curves were then used to define cutoff, sensitivity, and specificity values that optimized the test performance of each assay. Both methods were studied using a well-established persistently neutropenic rabbit model of IPA (11,28,42). We further investigated the impact of different antifungal modalities, including ravuconazole, micafungin, and deoxycholate amphotericin B, on the sensitivity and specificity of each assay.…”