Background: CNS aspergillosis is the most frequent and devastating manifestation of dissemination and mortality is high. Methods: CNS infection was started in cyclophosphamide-suppressed CD-1 mice by intracerebral inoculation of 5x 106 conidia of Aspergillus fumigatus. Therapy began 1d later for 10 days. Preliminary studies showed 1 mg/kg of micafungin (MICA) and 40 mg/kg voriconazole (VCZ) were effective, but not curative. For combination, suboptimal doses were chosen as ABLC (4 mg/kg) Â± MICA or CAS (1 mg/kg), itraconazole (ICZ, 100 mg/kg) or VCZ (40 mg/kg). Regimens also included conventional amphotericin B (AMB, 1 mg/kg), high dose ABLC at 10 or 12 mg/kg and D5W treatment was the control. Results: All D5W treated died and all treatment regimens significantly prolonged survival. No monotherapy regimen proved clearly superior to another at the doses tested. All dosages of ABLC tested proved equivalent to each other and to AmB in prolonging survival. Significantly enhanced efficacy over montherapy was found only with the combination of ABLC + VCZ. For other combinations (i.e., ABLC + ICZ, MICA or CAS), none were better than ABLC alone. ABLC + CAS or MICA trended toward significant enhancement of survival. Recovery of CFU from the brains and kidneys of survivors showed no regimen was curative. ABLC + VCZ was the most effective regimen in the brain, showing significantly enhanced efficacy over VCZ alone, but not ABLC alone. Other combinations showed nonsignificant enhancement over both drugs alone, but trended to lower CFU than after monotherapy. Dose escalation of ABLC alone did not increase reduction of CFU. Recovery of A. fumigatus from the kidneys showed nonsignificant reduction of CFU by the combinations vs. the monotherapies. Conclusion: Overall, each of the drugs tested had significant efficacy against CNS aspergillosis and ABLC in combination with VCZ had enhanced efficacy. Additional studies are warranted.
Full conference title:
42nd Annual Meeting Infectious Diseases Society of America
- Infectious Diseases Society of America 42nd