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A semi-mechanistic pharmacokineticpharmacodynamic model with adaptation development for invitro activity of ciprofloxacin against Pseudomonas aeruginosa

Abstract number: P1609

Grégoire N., Raherison S., Grignon C., Comets E., Marliat M., Ploy M.C., Couet W.

Objective: To implement pharmacokinetic–pharmacodynamic (PK-PD) model to describe over time the effects of ciprofloxacin (CIP) against P. aeruginosain vitro.

Methods: Time-kill curves were generated over 24 h with an inoculum of 5×106 CFU/mL at concentrations from 0.5 to 16×MIC. P. aeruginosa susceptibility to CIP was assessed before and after 24 h exposure to CIP: (i) modifications of the DNA gyrase and topoisomerase IV enzymes caused by mutations in Quinolone Resistance Determining Region of gyrA and parC subunit genes, were investigated using PCR, (ii) CIP efflux pumps activation was tested by addition of Phenyl Arginine b-naphthylamide, a known inhibitor of Mex multidrug efflux system implicated in fluoroquinolones active efflux in P. aeruginosa. A previously described PK-PD model (1), in which the concentration necessary to achieve 50% maximal kill rate (EC50) increased as a function of antibiotic concentration and time, to account for bacteria adaptation, was fitted to the time-kill data. A population approach was used with Nonmem® software.

Results: At intermediate CIP concentrations, microbial regrowth was observed after initial killing. Sub-inhibitory CIP concentrations (leqslant R: less-than-or-eq, slant MIC) favoured the emergence of mutants with increased but moderate resistance to CIP (MIC 8 fold increase), only by over-expression of Mex efflux pumps. The selected PK-PD model with adaptation adequately described the microbial response to CIP in the range of concentrations investigated.

Conclusion: Susceptibility of P. aeruginosa to CIP may rapidly decline after multidrug efflux pump activation. This phenomenon was adequately described by a PK-PD model with adaptation. Resistance development over longer period of time should now be investigated using dynamic approaches (hollow-fiber model) to mimic multiple dosing treatments.

References

1. V.H. Tam et al., J. Antimicrob. Chemother. 55: 699–706 (2005)

Session Details

Date: 10/04/2010
Time: 00:00-00:00
Session name: Abstracts 20th European Congress of Clinical Microbiology and Infectious Diseases
Subject:
Location: Vienna, Austria, 10 - 13 April 2010
Presentation type:
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