Pharmacokinetic/Pharmacodynamic Modeling of Adaptive Resistance of Gentamicin
A. Mohamed (1), E.I. Nielsen (1), O. Cars(2) and L.E. Friberg(1).
(1) Department of Pharmaceutical Biosciences, Uppsala University, Uppsala; (2) Department of Infectious Diseases, University Hospital, Uppsala, Sweden.
Objectives: Adaptive resistance is a pharmacodynamic process that is characterized by a reversible refractoriness to the bactericidal action of an antibacterial agent [1]. This phenomenon, specific to the aminoglycosides group, is not fully understood but it emerges already at the administration of the first dose, is enhanced by higher doses, and augmented by consecutive doses if administered before the bacteria return to their susceptibility stage [2]. The underlying mechanism is postulated to be a reversible down regulation of the active transport of gentamicin into gram negative bacteria [1]. The aim of this study is to develop a pharmacokinetic/pharmacodynamic model that describes the bactericidal activity of gentamicin and can predict the adaptive resistance.
Methods: In vitro time kill curve experiments were conducted for 24-48 hours on a strain of Escherichia coli. Gentamicin exposure was either at constant concentration ranging between 0.125-16 times the MIC or in a dynamic kinetic system with different dosing regimens; 1-8 times the MIC every 12 or 24 hours with simulated two-compartment kinetics. Bacterial counts were monitored with frequent sampling throughout the experiments. All data were fit simultaneously in NONMEM using a previously developed semi-mechanistic model for antibiotics as the basis [3]. The adaptive resistance was modeled either as an empirical function where Ec50 increased with dose and time [4], or, as a component in a hypothetical compartment that affected Ec50 and accumulated following drug administration and diminished with time.
Results: The data showed that gentamicin has a fast bactericidal effect with clear indication of adaptive resistance in static as well as dynamic experiments. The original semi-mechanistic model [3] could not describe the gentamicin data. The semi-mechanistic model with the added hypothetical component resulted in a better fit to the data (OFV>80 units) and improved goodness-of-fit compared with the model with the empirical component.
Conclusion: The semi-mechanistic model with the added hypothetical component, that allows adaptive resistance to be reversible, was superior to the model with the empirical function earlier described. After further refinement the developed model may be used for improved dosing strategies of gentamicin.
References:
[1] Barclay ML and Begg EJ. Aminoglycoside Adaptive Resistance: Importance for effective dosage regimens. Drugs 2001; 61(6): 713-721.
[2] Barclay ML, Begg EJ, Chambers ST. Adaptive resistance following single doses of gentamicin in a dynamic in vitro model. Antimicrob Agents Chemother 1992; 36: 1951-7
[3] Nielsen EI, Viberg A, Löwdin E, Cars O, Karlsson MO, Sandström M. Semimechanistic pharmacokinetic/pharmacodynamic model for assessment of activity of antibacterial agents from time-kill curve experiments. Antimicrob Agents Chemother. 2007; 51(1):128-136.
[4] Tam VH, Ledesma KR, Vo G, Kabbara S, Lim TP, and Nikolaou M. Pharmacodynamic modeling of aminoglycosides against Pseudomonas aeruginosa and Acinetobacter baumannii: Identifying dosing regimens to suppress resistance development. Antimicrob Agents Chemother 2008; 52(11): 3987-3993.