Thu Thuy Nguyen (1,2), Jeremie Guedj (1,2), Elisabeth Chachaty (3), Jean de Gunzburg (4), Antoine Andremont (1,5,6), France Mentré (1,2,6)
(1) University Paris Diderot; (2) INSERM, UMR 738, Paris, France; (3) Institut Gustave-Roussy, Paris, France; (4) Da Volterra, Paris, France; (5) EA3964, “Emergence de la résistance bactérienne in vivo”, Paris, France; (6) AP-HP, Hospital Bichat, Paris, France
Objectives: Environmental dissemination of antibiotic resistant enterobacteria (EB) via fecal excretion upon fluoroquinolone (FQ) treatment is a major public health burden [1]. Modeling approach can provide new insights into this problem and is increasingly performed in in vitro studies [2-5]. However little has been done to gain a precise understanding of the in vivo kinetics of antibiotic sensitive and resistant EB during and after FQ treatment. Here we aimed to characterize by mathematical modeling the relationship between intestinal exposure to ciprofloxacin (CIP) and excretion of resistance for various dosage regimens.
Methods: 29 piglets were randomly assigned (9:10:10) to oral treatment with placebo, CIP 1.5 or 15 mg/kg/day for 5 days. CIP concentrations and counts of resistant and total EB were obtained from fecal samples during and after treatment. A mechanistic model was developed to fit CIP pharmacokinetics (PK) as well as total and resistant EB kinetics, using elements of earlier models from in vitro studies [2-5], with new elements for the intestinal flora. The joint modeling of data from all piglets was performed by nonlinear mixed effect model, using SAEM algorithm [6] in MONOLIX 4.2.0. We also evaluated by simulation the effect of various dosage regimens on fecal excretion of resistance.
Results: The PK model was a one compartment model with first-order elimination and constant rate of CIP during 5 days. In the bacterial model, we assumed that resistant EB were present in absence of treatment due to random mutation and continuously incoming in the digestive tract by ingestion. Initiation of treatment resulted in a concentration-dependent killing rate of sensitive EB through an Emax model. This model described adequately data from all dose groups. CIP concentrations rapidly reached a plateau (8.7 and 87 µg/g in the 1.5 and 15mg/kg groups, respectively) and the C50 was equal to 5 µg/g, well below this plateau. Thus, susceptible EB rapidly decreased with a half-life of 37 minutes. Although resistant EB had a low replicative fitness of 14%, this rapid elimination of susceptible EB allowed with both dosage regimens the inverse expansion of resistance which remained in high counts up to 3 weeks after treatment end.
Conclusions: To our knowledge, this is the first model to characterize the dynamics of resistance to FQ in the intestinal flora. This approach can be used to design strategies to reduce dissemination of resistance during treatments [7].
References:
[1] Carlet J (2012). The gut is the epicentre of antibiotic resistance. Antimicrob. Resist. Infect. Control. 1:39.
[2] Meagher AK, Forrest A, Dalhoff A, Stass H, Schentag JJ (2004). Novel pharmacokinetic-pharmacodynamic model for prediction of outcomes with an extended-release formulation of ciprofloxacin. Antimicrob. Agents Chemother. 48:2061-2068.
[3] Campion JJ, McNamara PJ, Evans ME (2005). Pharmacodynamic modeling of ciprofloxacin resistance in Staphylococcus aureus. Antimicrob. Agents Chemother. 49:209-219.
[4] Nielsen EI, Viberg A, Löwdin E, Cars O, Karlsson MO, Sandström M (2007). Semimechanistic pharmacokinetic/pharmacodynamic model for assessment of activity of antibacterial agents from time-kill curve experiments. Antimicrob. Agents Chemother. 51:128-136.
[5] Bulitta JB, Yang JC, Yohonn L, Ly NS, Brown SV, D’Hondt RE, Jusko WJ, Forrest A, Tsuji BT (2010). Attenuation of colistin bactericidal activity by high inoculum of Pseudomonas aeruginosa characterized by a new mechanism-based population pharmacodynamic model. Antimicrob. Agents Chemother. 54:2051-2062.
[6] Kuhn E, Lavielle M (2005). Maximum likelihood estimation in nonlinear mixed effects model, Comput. Stat. Data Anal., 49:1020-1038.
[7] Khoder M, Tsapis N, Domergue-Dupont V, Gueutin C, Fattal E (2010). Removal of residual colonic ciprofloxacin in the rat by activated charcoal entrapped within zinc-pectinate beads. Eur. Jour. Pharm. Sci. 41:281–288.
Reference: PAGE 22 () Abstr 2769 [www.page-meeting.org/?abstract=2769]
Poster: Other Drug/Disease Modelling