Woloch C (1,2,3), Ba B (4), Benay S (1), Marouani H (1), Iliadis A (1)
(1) Laboratory of Pharmacokinetics, Faculty of Pharmacy, Aix-Marseille University, France (2) Laboratory of Pharmacology, Dupuytren Hospital, Limoges, France (3) Laboratory of Pharmacology, European George Pompidou Hospital, Paris, France (4) Laboratory of Pharmacokinetics, Faculty of Pharmacy, Bordeaux, France
Objectives: Multidrug resistant S.maltipholia (Sm) has emerged as an important global opportunistic pathogen associated with high mortality rate [1]. In vitro dynamic PK/PD models, commonly used to assess antibiotic efficacy, could provide valuable information on optimal dosing strategies allowing reducing the emergence of drug resistance [2]. The aim of this study is to develop a mechanistic PK/PD model to characterize Sm resistance against two fluoroquinolones (FQ), ciprofloxacin (CIP) and moxifloxacin (MOX). Performance of the PK/PD model will be compared to two already published semi-mechanistic models (SMM), SMM1 [3], SMM2 [4].
Methods: Human PK profiles of CIP (750mg/12h) and MOX (400mg/24h) were simulated in an in vitro dynamic PK/PD model during a 48h experience on three Sm strains [5]. For each experiment, the PK profile of drugs and the bacterial growth kinetics with or without FQ were fitted simultaneously. PK/PD parameters were estimated using MATLAB (R2011b).
Results: Three bacterial subpopulations were considered in the PD model with sensitive, quiescent and resistant bacteria compartments to describe acquired or innate resistance. A Gompertz model was used for bacterial growth. FQ bactericidal effect was described by a derived Emax model which involves a Heaviside step function to link FQ bactericidal effect with a threshold FQ concentration. To account for the delay of the resistant mutant growth (innate resistance) or emergence (acquired resistance) and to link this delay with FQ concentration, a “time to resistance model” was developed.
Except SMM1 with RMSE up to 50% on the 6 experiments, SMM2 and the model here developed give acceptable bactericidal kinetics fitting (RMSE < 30%) respectively in 3 and 4 experiments. MOX effect delay is shorter and MOX is twice more effective than CIP on sensitive and resistant subpopulation. Moreover, the time to resistant model indicates that growth resistant subpopulation is delayed with MOX.
Conclusions: The PK/PD model here developed seems to be more informative on resistance characterization than previously published models. Flexibility of this model is oriented for pre-clinical phase development of antibiotics.
References:
[1] Falagas ME, Valkimadi PE, Huang YT, Matthaoui DK, Hsueh PR. Attributable mortality rate of Stenotrophomonas maltipholia infections: a systematic review of literature. Future Microbiol. 2009 Nov; 4(9): 1103-9.
[2] Ba BB, Bernard A, Iliadis A, Quentin C, Ducint D, Etienne R, Fourtillan M, Maachi-Guillot I, Saux MC. New approach for accurate simulation of human pharmacokinetics in an in vitro pharmacodynamic model: application to ciprofloxacin. J Antimicrob Chemother. 2001 Feb;47(2):223-7.
[3] Tam V, Kabbara S, Vo G, Schilling A, Coyle E. Comparative pharmacodynamics og gentamicin against Staphylococcus aureus and Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 2006, 50(8) : 2628.
[4] Nielsen E, Cars O, Friberg L. Predicting in vitro antibacterial efficacy across experimental designs with a semimechanistic pharmacokinetic/pharmacodynamics model. Antimicrob Agents Chemother. 2011, 1571-1579.
[5] Ba BB, Feghali H, Arpin C and al. Activities of ciprofloxacin and moxifloxacin against Stenotrophomonas maltipholia and emergence of resistant mutants in an in vitro pharmacokinetic/pharmacodynamics model. Antimicrob Agents Chemother. 2004, 48 (3): 946-953.
Reference: PAGE 24 () Abstr 3514 [www.page-meeting.org/?abstract=3514]
Poster: Drug/Disease modeling - Infection