In vitro pharmacodynamic characteristics of flucytosine determined by time-kill methods

Two Candida albicans isolates, three non-albicans Candida isolates (Candida glabrata, Candida krusei, and Candida tropicalis), and one Cryptococcus ne oformans isolate were evaluated by time-kill methods to characterize the re lationship of flucytosine concentrations to antifungal activity and the dur ation of the post-antifungal effect (PAE). Against Candida and Cryptococcus isolates, flucytosine at concentrations > 1 x MIC exhibited fungistatic (l ess than or equal to 99% reduction in CFU) activity over a 24-h time-period . The rate and extent of fungistatic activity of flucytosine against all is olates was generally not increased when 5-FC concentrations exceeded 4 X MI G. A notable PAE was detected for flucytosine against both Candida and Cryp tococcus species that persisted 2 to 4 h. These in vitro data suggest that flucytosine is predominately a concentration-independent fungistatic agent at clinically achieved serum concentrations. This pharmacodynamic character istic coupled with the persistent PAE and the relatively long half-life of flucytosine in humans (>5 h), suggests lower daily dosing may possible with out loss of antifungal efficacy. (C) 2000 Elsevier Science Inc. All rights reserved.