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Antifungal Efficacy of Caspofungin (MK-0991) in Experimental Pulmonary Aspergillosis in Persistently Neutropenic Rabbits: Pharmacokinetics, Drug Disposition, and Relationship to Galactomannan Antigenemia
- Source :
- Antimicrobial Agents and Chemotherapy. 46:12-23
- Publication Year :
- 2002
- Publisher :
- American Society for Microbiology, 2002.
-
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.
- Subjects :
- medicine.medical_specialty
Antifungal Agents
Neutropenia
Microbial Sensitivity Tests
Aspergillosis
Peptides, Cyclic
Gastroenterology
Aspergillus fumigatus
Mannans
Echinocandins
Lipopeptides
Galactomannan
chemistry.chemical_compound
Caspofungin
Amphotericin B
Internal medicine
medicine
Animals
Experimental Therapeutics
Pharmacology (medical)
Mycosis
Pharmacology
Lung Diseases, Fungal
biology
Respiratory disease
Galactose
Antibiotic Prophylaxis
biology.organism_classification
medicine.disease
Anti-Bacterial Agents
Disease Models, Animal
Aspergillus
Treatment Outcome
Infectious Diseases
chemistry
Immunology
Female
Rabbits
Peptides
medicine.drug
Subjects
Details
- ISSN :
- 10986596 and 00664804
- Volume :
- 46
- Database :
- OpenAIRE
- Journal :
- Antimicrobial Agents and Chemotherapy
- Accession number :
- edsair.doi.dedup.....d4e59670ac825894163eb60fd54b0764