Antifungal Pharmacokinetics and Pharmacodynamics

Abstract

Successful treatment of infectious diseases requires choice of the most suitable antimicrobial agent, comprising consideration of drug pharmacokinetics (PK), including penetration into infection site, pathogen susceptibility, optimal route of drug administration, drug dose, frequency of administration, duration of therapy, and drug toxicity. Antimicrobial pharmacokinetic/pharmacodynamic (PK/PD) studies consider these variables and have been useful in drug development, optimizing dosing regimens, determining susceptibility breakpoints, and limiting toxicity of antifungal therapy. Here the concepts of antifungal PK/PD studies are reviewed, with emphasis on methodology and application. The initial sections of this review focus on principles and methodology. Then the pharmacodynamics of each major antifungal drug class ( polyenes, flucytosine, azoles, and echinocandins) is discussed. Finally, the review discusses novel areas of pharmacodynamic investigation in the study and application of combination therapy. PHARMACOKINETICS

Pharmacodynamic Optimization for Treatment of Invasive Candida auris Infection

“…1D (27). For amphotericin B, the data for C. auris were also remarkably congruent with prior studies, which have shown stasis to occur at C max /MIC exposures of 1 to 2 (27). The stasis C max /MIC for the groups of C. auris strains in this study was near 1.…”

“…The reasons for the enhanced efficacy observed for micafungin against C. auris compared to those of fluconazole and amphotericin B are unknown and an important area for future investigation. Importantly, targets identified in this model with triazoles and echinocandins have correlated well with clinical outcomes in patients with invasive candidiasis (27). Thus, the present findings in this PK/PD study should be useful for forecasting effective treatment regimens for patients and in the development of preliminary susceptibility breakpoints.…”

“…The PK exposures were plotted relative to MIC and the previously defined PK/PD driver. Specifically, AUC/MIC (area under the concentration-time curve over 24 h in the steady state divided by the MIC) was used for fluconazole and micafungin, and C max /MIC (the maximum concentration of drug in serum divided by the MIC) was used for amphotericin B (26,27). The magnitude of the PK/PD index (AUC/MIC or C max /MIC) associated with net stasis and 1-log kill (when achieved) for each strain was calculated with the equation log 10 D ϭ log 10 (E/[E max Ϫ E])/(N ϩ log 10 ED 50 ), where E is the control growth for the static dose (D), E ϩ 1 is the control growth for the 1-log kill dose (D), and ED 50 is the 50% effective dose.…”

In Vivo Pharmacokinetics and Pharmacodynamics of ZTI-01 (Fosfomycin for Injection) in the Neutropenic Murine Thigh Infection Model against Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa

“…This is consistent with AUC/MIC ratio as the pharmacodynamically linked index and supports our findings. The importance of the AUC/MIC ratio index for this compound with concentration-independent killing is reminiscent of PK/PD characteristics of the oxazolidinones and triazoles (24)(25)(26). One reason for this observed outcome in our dose fractionation study could be due to postantibiotic effects (PAEs).…”

A phase 1/1b study of PUR1900, an inhaled formulation of itraconazole, in healthy volunteers and asthmatics to study safety, tolerability and pharmacokinetics

“…Pharmacokinetic data indicate that PUR1900 results in higher and more sustained lung exposure of itraconazole relative to oral dosing, an important factor in the activity of itraconazole against Aspergillus. In addition, plasma exposure following PUR1900 inhalation was substantially lower than that with oral dosing, potentially decreasing risks of systemic itraconazole‐related AEs and drug–drug‐interactions. Finally, the sustained nature of lung exposure and the relatively low accumulation with repeat dosing supports once daily dosing in future clinical trials.…”