Sandra Gil-Alonso (1), Nerea Jauregizar (1), Ignacio Ortega (2), Elena Eraso (3) and Guillermo Quindós (3)
(1) Department of Pharmacology, Faculty of Medicine, University of the Basque Country (UPV/EHU), Spain. UFI11/25 “Microbios y Salud”. (2) Research Development and Innovation Department, Faes Farma S.A. Leioa. Spain. (3) Department of Immunology, Microbiology and Parasitology, Faculty of Medicine, University of the Basque Country (UPV/EHU), Spain. UFI11/25 “Microbios y Salud”
Objectives: In vitro time-kill studies are commonly used in the assessment of efficacy of antimicrobial agents. The aim of the present study was to develop a general semi-mechanistic pharmacokinetic/pharmacodynamic mathematical model that fits three echinocandins time-kill data against Candida isolates in vitro.
Methods: Time-kill curve data from static in vitro experiments with Candida albicans, Candida glabrata and other emerging species exposed to constant concentrations of three echinocandins (caspofungin, micafungin and anidulafungin) were used for model development. The concentrations ranged from 0.06 to 2 µg/mL and samples for viable counts were taken at time points 0, 2, 4, 6, 24 and 48 h after start of experiments. Data was modeled using NONMEM V7.2.0 [1] with first order conditional estimation method. Diagnostic plots and precision of parameter estimates were evaluated to assess model performance.
Results: Time-kill data were best fit by using an adapted sigmoidal Emax model that corrected for delay in the growth of Candida and the onset of the three drugs activity, steepness of the concentration-response curve, and saturation of the cell number of Candida. Time-kill curves of all investigated strains, drugs and concentrations were well predicted by the model.
Conclusions: The activity of the three echinocandins against Candida isolates can be accurately described using this semi-mechanistic mathematical model. The developed model allowed the estimation of pharmacodynamic parameters (EC50: concentration of echinocandin necessary to produce 50% of maximum effect; Kmax: maximum killing rate constant and delay in the onset of killing) for the comparison of the three echinocandins.
References:
[1] Beal SL, Sheiner LB, Boeckmann AJ & Bauer RJ (Eds.) NONMEM Users Guides. 1989-2011. Icon Development Solutions, Ellicott City, Maryland, USA.
Reference: PAGE 22 () Abstr 2795 [www.page-meeting.org/?abstract=2795]
Poster: Infection