LOUIE A, DEZIEL M, LIU W, DRUSANO M, GUMBO T, DRUSANO GL; 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. A-1573.

Ordway Research Institute, Albany, NY.

BACKGROUND: C is an echinocandin antifungal agent whose PD-linked variable is AUC/MIC ratio. Given the prolonged (2X) T1/2 of C in the K relative to serum (S) in mice, we wished to demonstrate the primacy of infection compartment concentrations in a non-neutropenic mouse model using a strain of C albicans - ATCC 36082. METHODS: The C MIC was determined by NCCLS macrobroth dilution method in RPMI-1640 with MOPS. In vitro post-antibiotic effect (PAE) determination for C at 5 x MIC and 10 x MIC was performed by standard methods. The serum PK of 0.4 mg/kg of C (given IP) was determined in mice and the time that the serum concentration declined below the MIC was identified. Then, in a separate study, 0.4 mg/kg of C or saline was given IP to treatment and control (CON) groups of mice at Time = 0h. Infection by tail vein injection of C albicans occurred at T = 48h for both CON and C groups. Sacrifice occurred at 72h. Drug was assayed serially in both S and K by HPLC. Statistical testing (Student t-test) was performed between groups. RESULTS: The MIC for C was 0.2 mg/L. S concentrations of C were below the MIC at T = 24, 48 and 72h (C = 0.17, 0.053, 0.033 mg/L, respectively). K concentrations of C at these times were 1.26, 0.582, 0.13 mg/L. At time of infection (48 h), K colony counts (Log[10] (CFU/g)) were 5.01 +/- 0.13 (CON group) and 4.99 +/- 0.14 (C group). At 72h, these were 5.78 +/- 0.48 and 4.32 +/- 0.26. This difference was statistically significant (p = 0.005). PAE at 5 x MIC and 10 x MIC were 14 h and between 36 and 48 h, respectively. CONCLUSIONS: The C concentrations in the effect site (K) were important in determining the outcome. A significant decline in Candida counts in K was seen between groups, even though S concentrations of C had been below the MIC for > 24 h at the time of fungal inoculation. Thus the decline in fungal density in K could not be due to S-induced PAE. A concentration-dependent in vitro PAE was seen that may account for part of the difference in colony counts between groups as K concentrations declined below the MIC between 48 & 72h.

Publication Types:

• Meeting Abstracts

Keywords:

• Animals
• Anti-Bacterial Agents
• Antifungal Agents
• Area Under Curve
• Candida
• Candidiasis
• Cesium
• Chromosomes
• Female
• In Vitro
• Kidney
• Menstruation
• Mice
• Microbial Sensitivity Tests
• Peptides, Cyclic
• caspofungin
• genetics
• pharmacokinetics
• pharmacology

Other ID:

• GWAIDS0026210

UI: 102265834

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