Optimizing Echinocandin Dosing and Susceptibility Breakpoint Determination via In Vivo Pharmacodynamic Evaluation against Candida glabrata with and without fks Mutations

Abstract

cEchinocandins are a preferred therapy for invasive candidiasis due to their potency and broad spectrum. Resistance, especially in Candida glabrata, is an emerging threat to their use. Pharmacodynamic (PD) studies examining reduced susceptibility secondary to fks mutations in C. glabrata are lacking. The current study explored PD targets for anidulafungin, caspofungin, and micafungin in an in vivo invasive candidiasis model against 11 C. glabrata isolates with known or putative fks mutations. The PD targets were compared to those of 8 wild-type (WT) isolates. The MIC ranges in the WT group were 0.03 to 0.25 mg/liter for anidulafungin, 0.03 to 0.25 mg/liter for caspofungin, and 0.01 to 0.06 mg/liter for micafungin. The MIC ranges for mutants were 0.06 to 4, 0.25 to 16, and 0.13 to 8 mg/liter for the same compounds, respectively. The mean free drug 24-h area under the concentration-time curve (AUCf)/MIC ratio associated with a stasis endpoint for the WT group was 13.2 for anidulafungin, 2.04 for caspofungin, and 6.78 for micafungin. Comparative values for mutants were 3.43, 2.67, and 0.90, respectively. Pharmacokinetic data from patients suggest that the C. glabrata PD targets needed for success in this model could be achieved based on MIC values of 0.25 mg/liter for anidulafungin, 2 mg/liter for caspofungin, and 0.5 mg/liter for micafungin. These values are higher than recently identified epidemiology cutoff values (ECVs). The results suggest that drug-specific MIC breakpoints could be increased for caspofungin and micafungin against C. glabrata and could include organisms with mutations in fks-1 and fks-2. While identification of genetic mutants is epidemiologically important, the phenotype (MIC) provides a better predictor of therapeutic efficacy.

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).…”

“…In accordance with other authors (Andes et al, 2010;Fernández-Silva et al, 2014;Lepak et al, 2012;Spreghini et al, 2012;Wiederhold et al, 2007), WT C. glabrata clinical isolates were highly susceptible in vivo to caspofungin even at 1 mg kg 21 in mice (corresponding to a 35 mg daily dose in humans) (Cornely et al, 2011;Flattery et al, 2011;Migoya et al, 2011). Moreover, as observed previously with Candida albicans, Candida krusei and Candida inconspicua, increasing the drug dose further did not yield better efficacy (Berényi et al, 2014;Kovács et al, 2014a), i.e.…”

“…This study confirmed the clinical experience that the efficacy of echinocandins is not enhanced by higher doses against echinocandin-susceptible clinical isolates (Betts et al, 2009;Pappas et al, 2007), and even higher doses are inefficient against isolates with prominent FKS-mediated resistance (Berényi et al, 2014;Fernández-Silva et al, 2014;Lepak et al, 2012;Spreghini et al, 2012). As C. glabrata rapidly develops resistance to echinocandins, even during short treatment periods (Alexander et al, 2013;Beyda et al, 2014;Lepak et al, 2012;Perlin, 2014;Shields et al, 2013), rapid detection of the most common FKS mutations would best be achieved by FKS sequencing in C. glabrata isolates, as published for C. albicans (Dudiuk et al, 2015).…”

“…The delay in treatment allowed the establishment of high tissue fungal burden in the deeply neutropenic host, modelling the most probable clinical situation; in some cases, the unfavourable therapeutic response may be the result of delayed antifungal treatment (Colombo et al, 2014;Pappas et al, 2009;Pfaller et al, 2012). The importance of early treatment against disseminated candidasis was elegantly demonstrated by MacCallum & Odds (2004) for C. albicans in an immunocompetent murine model and by Howard et al (2011) and Lepak et al (2012) for C. glabrata in neutropenic murine models. These ) treatment was started at 24 h p.i.…”

“…As C. glabrata rapidly develops resistance to echinocandins, even during short treatment periods (Alexander et al, 2013;Beyda et al, 2014;Lepak et al, 2012;Perlin, 2014;Shields et al, 2013), rapid detection of the most common FKS mutations would best be achieved by FKS sequencing in C. glabrata isolates, as published for C. albicans (Dudiuk et al, 2015). As mutations in the FKS genes are not equal in terms of the level of resistance provided (Beyda et al, 2014;Fernández-Silva et al, 2014;Lepak et al, 2012), and non-FKS-related mechanisms may also emerge over time (Perlin, 2014), MIC testing in RPMI 1640 with or without 50% serum is still useful to detect isolates with decreased susceptibility (Farmakiotis et al, 2014;Perlin, 2014;Wang et al, 2015). Finally, the fitness and virulence of echinocandin-susceptible and -resistant isogenic isolates should be compared in future studies to obtain relevant data on the relationship between echinocandin resistance and virulence.…”