SABATELLI F; Interscience Conference on Antimicrobial Agents and Chemotherapy (43rd: 2003: Chicago, Ill.).

Abstr Intersci Conf Antimicrob Agents Chemother Intersci Conf Antimicrob Agents Chemother. 2003 Sep 14-17; 43: abstract no. M-990.

Schering-Plough Research Institute, Kenilworth, NJ.

BACKGROUND: POS (SCH 56592), a triazole in Phase III trials, has broad-spectrum antifungal activity and inhibits ergosterol synthesis. CSP is an echinocandin which inhibits fungal cell wall synthesis. The different mechanisms of action suggest they could be effective in combination. We evaluated the interactions between POS and CSP against Aspergillus in vitro and in vivo. METHODS: In vitro interaction against 57 isolates of Aspergillus spp. was assessed by checkerboard microdilution using M38-A MIC methodology (NCCLS). Drug interactions were synergistic, additive, or antagonistic based on the fractional inhibitory concentration (FIC) index. For in vivo studies, immunocompetent mice were infected IV with ca. 5.5x10[6] conidia/mouse of A. fumigatus ND158, ND231 or A. flavus ND83. Treatment with water or 0.9% NaCl (controls), POS alone (PO), CSP alone (IP) or concomitant POS+CSP began 4 h postinfection and continued QD for 4 or 8 days, using 3 dose levels of each drug in all possible combinations (checkerboard); 8 mice/group. Dose levels ranged from 0.1 to 25 mg/kg for POS,and from 0.05 to 10 mg/kg for CSP. Survival was observed for 15 days and analyzed by Log-rank tests. RESULTS: In Vitro: Synergy, defined as FIC 0.5-1.0, was observed in 70.2% of the interactions. Indifferent, defined as FIC >1.0-2.0, was observed in 3.5% of interactions. No antagonism was observed. In Vivo: Of 32 POS+CSP combinations, 78% showed greater survival than one or both drugs alone, and 22% were similar to both drugs alone. No combinations were less effective than either drug alone. CONCLUSION: In Vitro and in vivo combinations of POS+CSP were more efficacious against Aspergillus spp. than one or both drugs alone. No antagonism was observed.

Publication Types:

• Meeting Abstracts

Keywords:

• Animals
• Antifungal Agents
• Aspergillus
• Drug Interactions
• Fungi
• In Vitro
• Mice
• Microbial Sensitivity Tests
• Peptides, Cyclic
• Triazoles
• caspofungin
• posaconazole

Other ID:

• GWAIDS0025279

UI: 102264903

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