Efficacy of Abelcet alone, or in combination therapy, against experimental central nervous system aspergillosis.
BACKGROUND
CNS aspergillosis is the most frequent and devastating manifestation of dissemination and mortality is high.


METHODS
Cyclophosphamide-suppressed CD-1 mice were infected intracerebrally with conidia of Aspergillus fumigatus and treated for 10 days with suboptimal doses of Abelcet (4 mg/kg) plus micafungin (1 mg/kg), caspofungin (1 mg/kg), itraconazole (100 mg/kg) or voriconazole (40 mg/kg) and compared with monotherapy. Other groups included conventional amphotericin B (1 mg/kg), Abelcet at 10 or 12 mg/kg or 5% dextrose water (diluent control).


RESULTS
All controls died and all treatment regimens significantly prolonged survival. No monotherapy regimen was superior to another. All dosages of Abelcet and conventional amphotericin B tested were equivalent. Significant enhancement of survival over the respective monotherapies was found only with the combination of Abelcet and voriconazole. Other combinations were not better than Abelcet alone. Recovery of cfu from the brains and kidneys of survivors showed that no regimen was curative. Abelcet and voriconazole showed significantly enhanced efficacy in reducing brain infection. Other combinations showed lower cfu, but no significant enhancement over either drug alone. Dose-escalation of Abelcet alone did not increase reduction of cfu. Recovery from the kidneys showed non-significant reduction of cfu by combinations compared with monotherapies.


CONCLUSIONS
Each of the drugs tested had significant efficacy against CNS aspergillosis and Abelcet in combination with voriconazole had enhanced efficacy. Additional studies are warranted.
Clemons
Karl V
KV
California Institute for Medical Research, San Jose, CA 95128, USA. clemons@cimr.org
Parmar
Rachana
R
Martinez
Marife
M
Stevens
David A
DA
D000666:Amphotericin B / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001228:Aspergillosis / Q000188:drug therapy* / Q000382:microbiology; D001232:Aspergillus fumigatus / Q000187:drug effects*; D001921:Brain / Q000382:microbiology; D002494:Central Nervous System Infections / Q000188:drug therapy* / Q000382:microbiology; D015169:Colony Count, Microbial; D004195:Disease Models, Animal; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D007668:Kidney / Q000382:microbiology; D051379:Mice; D010713:Phosphatidylcholines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D010715:Phosphatidylglycerols / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines / Q000008:administration & dosage / Q000627:therapeutic use; D016019:Survival Analysis; D014230:Triazoles / Q000008:administration & dosage / Q000627:therapeutic use; D065819:Voriconazole
D000935:Antifungal Agents; D004338:Drug Combinations; D010713:Phosphatidylcholines; D010715:Phosphatidylglycerols; D011743:Pyrimidines; D014230:Triazoles; C068538:liposomal amphotericin B; D000666:Amphotericin B; D065819:Voriconazole