Granulocyte Colony Stimulating Factor (GCSF) and Azole Antifungal Therapy in Murine Aspergillosis: Surprises



GCSF is frequently given to neutropenic patients to prevent mycotic infections or as an adjunct to antifungal therapy. Clinical evidence of benefit is unclear. In the present studies we explored GCSF alone or combined with an antifungal triazole SCH56592 (SCH) in treatment of murine aspergillosis. For these studies groups of 7-10 mice were immune suppressed with cyclophosphamide and 5-fluorouracil (neutropenic) or hydrocortisone (steroid). Some groups of mice were given daily GCSF intraperitoneally (ip) at 125 to 600 mcg/kg, beginning day 3 before intranasal infection with Aspergillus fumigatus conidia, and continuing through day 5 after infection. SCH was given by gavage, alone or with GCSF, in doses from 1 through 25 mg/kp-/day. Neutropenic mice had a sublethal infection, with reduced lung tissue counts when given SCH at >=5 mg/kg/day or GCSF at 2:250 mcg/kg/day. Combined therapy was superior to either agent alone. Histopathologic studies showed no hyphae in treated groups. Steroid treated mice had a lethal infection. SCH at >5 mg/kg/day prolonged survival, but GCSF shortened survival compared with controls. GCSF, when given with SCH abrogated the benefits of SCH. Similar effects were seen in studies of lung tissue counts. Histopathologic studies showed that mice given SCH alone had few hyphae compared with controls, but mice given GCSF alone or with SCH had large abscesses with PMN and abundant hyphae. These studies indicate 1) predisposing factors may weigh heavily on the outcome of aspergillosis and 2) GCSF may not always be beneficial, and may antagonize potent antifungal drugs.

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38th Interscience Conference on Antimicrobial Agents and Chemotherapy
    • ICAAC 38th