Experimental systemic murine aspergillosis: treatment with polyene and caspofungin combination and G-CSF.
OBJECTIVE
In view of the poor therapy outcomes of invasive aspergillosis, the objective of this study was to evaluate the efficacy of combination treatment consisting of the polyene amphotericin-B-intralipid, the echinocandin caspofungin and granulocyte-colony stimulating factor (G-CSF) in experimental murine systemic aspergillosis. With inhibition of synthesis of 1,3-beta-d-glucan in the fungal cell wall by caspofungin and an effect on the cell membrane by amphotericin-B-intralipid, this treatment may result in a synergic effect against Aspergillus fumigatus. Addition of G-CSF may further contribute to therapy of aspergillosis.


METHODS
ICR mice were immunosuppressed by intraperitoneal administration of cyclophosphamide. Three days later, the mice were inoculated intravenously (iv) with A. fumigatus conidia. Infection and treatment were evaluated during an observation period of 30 days in terms of mortality (survival rate and mean survival time) and morbidity (quantitative determination of fungal burden, histopathology, and detection of serum galactomannan).


RESULTS
Combination of caspofungin + G-CSF or addition of G-CSF to the combination of caspofungin + amphotericin-B-intralipid increased the survival rate of infected mice up to 78.9% and prolonged their mean survival time to 25 days. These combinations also resulted in a reduction in fungal burden in organs, and a decrease in serum galactomannan.


CONCLUSIONS
The successful results obtained in the experimental model may possibly open the way to more effective management of aspergillosis in humans.
Sionov
Edward
E
Department of Human Microbiology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, 69978, Israel.
Mendlovic
Sonia
S
Segal
Esther
E
D000666:Amphotericin B / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001228:Aspergillosis / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality; D001232:Aspergillus fumigatus / Q000187:drug effects; D000077336:Caspofungin; D004195:Disease Models, Animal; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D054714:Echinocandins; D005260:Female; D005690:Galactose / Q000031:analogs & derivatives; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage / Q000494:pharmacology*; D016867:Immunocompromised Host; D007668:Kidney / Q000382:microbiology / Q000473:pathology; D055666:Lipopeptides; D008081:Liposomes / Q000008:administration & dosage; D008168:Lung / Q000382:microbiology / Q000473:pathology; D008351:Mannans / Q000097:blood; D051379:Mice; D008813:Mice, Inbred ICR; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000494:pharmacology*; D011090:Polyenes / Q000008:administration & dosage; D015996:Survival Rate
D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D008081:Liposomes; D008351:Mannans; D010456:Peptides, Cyclic; D011090:Polyenes; C012990:galactomannan; D016179:Granulocyte Colony-Stimulating Factor; D000666:Amphotericin B; D000077336:Caspofungin; D005690:Galactose