In Vivo Comparison of the Pharmacodynamic Targets for Echinocandin Drugs against Candida Species

Abstract

Previous pharmacodynamic studies using in vivo candidiasis models have demonstrated that the 24-h area under the concentration-time curve (AUC)/MIC is a good descriptor of the echinocandin exposure-response relationship. Further studies investigating the 24-h AUC/MIC target for a stasis endpoint identified free-drug 24-h AUC/MIC against Candida albicans and were similar for two echinocandins, anidulafungin and micafungin. The current studies expand investigation of a third echinocandin (caspofungin) and compare the pharmacodynamic target among C. albicans, Candida glabrata, and Candida parapsilosis. Treatment studies were conducted with six C. albicans, nine C. glabrata, and 15 C. parapsilosis strains with various MICs (anidulafungin, 0.015 to 4.0 g/ml; caspofungin, 0.03 to 4.0 g/ml; and micafungin, 0.008 to 1.0 g/ml). Efficacy was closely tied to MIC and the 24-h AUC/MIC. Therapy against C. parapsilosis required more of each echinocandin on a mg/kg basis. Caspofungin required less drug on a mg/kg basis for efficacy against all of the organisms than did the other two drugs. However, the 24-h AUC/MIC targets were similar among the echinocandins when free drug concentrations were considered, suggesting the relevance of protein binding. The targets for C. parapsilosis (mean, 7) and C. glabrata (mean, 7) were significantly lower than those for C. albicans (mean, 20) for each echinocandin. The results suggest that current susceptibility breakpoints and the consideration of organism species in these determinations should be reexplored.Experimental antifungal pharmacodynamic investigations have been important for the design of optimal dosing strategies and the development of susceptibility breakpoints (1, 2, 5, 17). Several studies have begun to focus on the most recently approved antifungal drug class, the echinocandins (9,11,14,21,22,34,57). Results of these pharmacodynamic experiments have demonstrated concentration-dependent killing and have shown prolonged postantifungal effects. Both concentrationassociated pharmacodynamic indices, the 24-h area under the concentration-time curve (AUC)/MIC and the C max /MIC, have been linked to treatment efficacy. More recently, investigations have attempted to identify the pharmacodynamic target or the drug exposure relative to the MIC needed for treatment efficacy (9, 14). Several observations were made in studies with two echinocandins in experimental models of disseminated Candida albicans. The pharmacodynamic targets were similar between the two echinocandins as long as free drug concentrations were considered, suggesting the relevance of protein binding. However, only a few "high" MIC organisms were available for investigation at the time, and the studies did not include the species demonstrating the least susceptibility in vitro, Candida parapsilosis. The present studies expand evaluation to include all three FDA-approved echinocandins as well as in depth exploration of the pharmacodynamic target for C. parapsilosis. The results from these experiments provide pharmacodyna...

Dose escalation studies with caspofungin against Candida glabrata

“…In agreement with other studies (Andes et al, 2010;Fernández-Silva et al, 2014;Gil-Alonso et al, 2015;Lepak et al, 2012;Pfaller et al, 2011;Spreghini et al, 2012;Szilágyi et al, 2012), caspofungin showed excellent in vitro activity against WT clinical isolates as well as against the ATCC 90030 type strain. However, in RPMI 1640, caspofungin killing activity decreased at 16-32 mg l 21 when compared with the killing at 0.25-1 mg l 21 (Table 3).…”

“…to allow the fungi to establish tissue infection (Berényi et al, 2014;Földi et al, 2012b;Kovács et al, 2014a, Spreghini et al, 2012Wiederhold et al, 2007). This dosing strategy was based on previous pharmacokinetic studies (Andes et al, 2010;Cornely et al, 2011;Flattery et al, 2011;Migoya et al, 2011;Stone et al, 2002), on previous results from our study group (Berényi et al, 2014;Földi et al, 2012b;Kovács et al, 2014a) and on the findings of Howard et al (2011) At the beginning of therapy (day 1), the fungal kidney burden was determined after dissection of four untreated mice for each isolate (day 1 control burden) (Berényi et al, 2014). On day 6 p.i., all mice were sacrificed; both kidneys were removed, weighed and homogenized aseptically.…”

“…and thus higher doses may hypothetically produce better outcomes (Andes et al, 2010;Chen et al, 2011;Howard et al, 2011;Perlin, 2014;Wiederhold et al, 2011). Based on findings with the echinocandin-susceptible C. glabrata ATCC 2001 strain, Howard et al (2011) suggested that echinocandin dose escalation combined with early treatment [5 h post-infection (p.i.)]…”

Killing Rates for Caspofungin Against Candida albicans After Brief and Continuous Caspofungin Exposure in the Presence and Absence of Serum

“…Killing 23 rates (k values) in time-kill and PAFE experiments 24 were determined for each strain and concentration. In 25 time-kill experiments, colony count decreases were 26 isolate-and concentration-dependent at 0.25, 1,4,8,27 16 and 32 mg/L in RPMI-1640, but concentration-28 independent at 1,4,8,16 …”

“…99 For time-kill assays (continuous 24-h caspofungin 100 exposure), test solutions were not centrifuged or 101 washed. We used 0.25, 1,4,8,16 and 32 mg/L 102 caspofungin. In case of isolate DPL20, we used 4, 8, 103 16 and 32 mg/L caspofungin.…”