Thu Thuy Nguyen (1,2), Elisabeth Chachaty (3), Clarisse Huy (4), Carole Cambier (5), Jean de Gunzburg (4), Antoine Andremont (1,6,7), France Mentré (1,2,7)
(1) University Paris Diderot, Paris, France; (2) INSERM, UMR 738, Paris, France ; (3) Institut Gustave-Roussy, Paris, France; (4) Da Volterra, Paris, France; (5) University of Liège, Belgium; (6) EA3964, “Emergence de la résistance bactérienne in vivo”, Paris, France; (7) AP-HP, Hospital Bichat, Paris, France
Objectives: The colonic flora is where antibiotic residues select resistant commensal bacteria during treatment [1]. In this prospective randomised study in piglets, we aimed to develop a pharmacokinetic/pharmacodynamic (PK/PD) model to characterize the link between ciprofloxacin (CIP) concentrations and amounts of CIP resistant Enterobacteriaceae (EB) in feces.
Methods: 29 piglets were randomly assigned to oral treatment with placebo (n = 9), CIP 1.5 mg/kg/day (n = 10) or 15 mg/kg/day (n = 10) from day D1 to D5. Fecal samples were recovered at D1, D3, D5, D7, D9, D12, D16 and D27. Fecal concentrations were measured with a microbiological assay. Fecal resistant EB were counted on selective agar with 2 µg/ml of CIP. The fecal PK model of CIP was assimilated to a one compartment model with intravenous infusion and first order elimination. The infusion rate was the daily dose of CIP with a duration of 5 days. The PD model described the fecal amount of resistant EB as the result of a saturable growth and a natural elimination. The drug effect was supposed to inhibit the elimination rate of resistant EB through an Imax model. These models were written with MLXTRAN in MONOLIX 4.1.1 [2]. The joint modeling of data from 20 piglets receiving CIP was performed by nonlinear mixed effect model. Parameters and their variability were estimated using the SAEM algorithm [3] and model evaluation was performed via goodness-of-fit plots.
Results: The proposed PK/PD model adequately described jointly CIP fecal concentrations and resistant EB counts for the 3 treatment groups. Parameters were well estimated with good precision. From the model, predictions with various CIP doses can be provided to investigate the link between doses, concentrations and amounts of resistant EB excreted. Indeed, CIP fecal concentrations increase sharply with doses and resistant EB amounts increase nonlinearly with concentrations.
Conclusion: The proposed model adequately described the data. To our knowledge, this is the first model developed on in vivo data to study the dynamic of resistance in colonic flora. This modeled relationship suggests that removing residual colonic quinolone can help control the spread of resistance [4]. The next step will be to model these data jointly with the susceptible EB counts.
References:
[1] Donskey, C. (2004) The role of the intestinal tract as a reservoir and source for transmission of nosocomial pathogens, Clinical Infectious Diseases, 39:219-226.
[2] www.monolix.org/
[3] Kuhn, E., Lavielle, M. (2005) Maximum likelihood estimation in nonlinear mixed effects model, Computational Statistics and Data Analysis, 49:1020-1038.
[4] Khoder, L., 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, European Journal of Pharmaceutical Sciences, 41:281-288.
Reference: PAGE 21 () Abstr 2425 [www.page-meeting.org/?abstract=2425]
Poster: Infection