Applied Antifungal Pharmacometrics: Fluconazole and Echinocandins in the Treatment of Candidemia and Invasive Candidiasis

Abstract

In this chapter, we review the application of pharmacometric data to the treatment of invasive candidiasis in adults. Echinocandin antifungals are increasingly recognized as first-choice agents against candidemia and many other types of invasive candidiasis. Fluconazole is the agent of choice against mucosal candidiasis and remains an effective alternative agent against invasive candidiasis. In particular, fluconazole may be preferred for the treatment of patients with prior echinocandin exposure or infections such as urosepsis or endophthalmitis, in which echinocandins are limited by pharmacokinetic considerations. Fluconazole is also a useful step-down agent after a clinical response to treatment with an echinocandin. Data from the mouse model of hematogenously disseminated candidiasis identify fluconazole area under the curve (AUC)/minimum inhibitory concentration (MIC) and echinocandin C _max/MIC as pharmacokinetic–pharmacodynamic (PK–PD) parameters that are most closely associated with successful treatment. Fluconazole AUC/MIC ≥ 25 and ≥ 75 are acceptable and optimal targets, respectively, for achieving successful outcomes in mouse models and humans. Simulation models predict that acceptable and optimal AUC/MIC will be reliably achieved in patients if daily fluconazole dose/MIC ratio is ≥ 50 and ≥ 100, respectively. Echinocandins are more active than fluconazole against Candida albicans and C. glabrata strains in the mouse model. Echinocandin MICs are higher against C. parapsilosis than other species, but PK–PD targets are lower and echinocandins have been used successfully against C. parapsilosis candidemia in clinical trials. PK–PD data suggest that echinocandins will be most effective if administered infrequently at high doses; such regimens must be validated in clinical trials, and the impact on resistance and toxicity must be defined.