Amelia N. Deitchman (1), Johannes Kast (1), Hartmut Derendorf (1)
(1) University of Florida, Gainesville, FL, USA
Objectives: Together, tigecycline (TIG) and tetracycline (TET) have displayed augmented in vitro activity against Pseudomonas aeruginosa [1]. The goal of this research is to develop a PK/PD model that describes the observed effects of TET against P. aeruginosa in in vitro static time-kill experiments incorporating results from resistance testing and accounting for potential drug degradation.
Methods: In vitro static time kill curves of 0.25, 0.5, 1, 2, 4, and 8 XMIC were performed in triplicate for TET (MIC 16 mg/L) against P. aeruginosa. Concentrations of bacteria were quantified at 0, 2, 4, 6, 8, 10, 12, 16, and 24 hours [2]. Resistance testing was performed by plating aliquots on 3X MIC drug-containing agar plates after 24 hours of varying levels of TET exposure. PK/PD modeling of time-kill curves was conducted using NONMEM (Version 7.3.0). Various one- and two- bacterial subpopulation models were fitted and evaluated based on change in objective function value (OFV), goodness of fit plots, and visual predictive checks to explore aspects of drug effect, drug degradation, and delay in drug effect. Models for incorporating resistant subpopulations or adaptive resistance were considered based on experimental results.
Results: TET time kill curve data were best described using a model including susceptible and persistent resting subpopulations of bacteria. A sigmoidal Emax model best described the drug effect (EC50 24.4 mg/L tetracycline HCl, Hill factor 1.22, maximal kill rate constant 3.39 h-1). While delay of drug effect did not improve model fit, drug degradation did allow for better description of the data. Resistance was not considered in the modeling process, as TET resistance was not observed at any tested concentrations at 24 hours.
Conclusions: The developed model describes the effect of TET well against P. aeruginosa over time for various drug exposures and is informed by additional resistance testing. A similar approach will investigate and incorporate resistance for TIG and the combination of TIG and TET. A final model describing the effects of each drug, alone and in combination, will be used, with published clinical PK data/models, to simulate and evaluate potential dosing regimens for the treatment of P. aeruginosa.
References:
[1] Deitchman AN, Singh RP, Mukker JK, Sy SK, Zoehner A, Derendorf H. Exploring In Vitro Antipseudomonal Activity Of Synergistic Tigecycline-Tetracycline Combinations. ASCPT Poster Presentation 2015. New Orleans, LA. Clin Pharmacol Ther. 2015 Feb; 97(S1):S26.
[2] Deitchman A, Singh R, Zoehner A, Derendorf H. In Vitro Pharmacodynamics of Tigecycline and Tetracycline Combinations against Pseudomonas aeruginosa. ECCMID Poster Presentation 2015. Copenhagen, Denmark.
Acknowledgement: This research is funded by a University of Florida Clinical and Translational Science Institute Pilot Project Award.
Reference: PAGE 25 () Abstr 5842 [www.page-meeting.org/?abstract=5842]
Poster: Drug/Disease modeling - Infection