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May 1, 2004
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Use of an in vitro Pharmacodynamic Model & Monte Carlo Simulation to Characterize the Pharmacokinetics and Pharmacodynamics of Gatifloxacin vs Salmonella Typhi

Abstract

Salmonella enterica serotype Typhi and non-typohoidal Salmonella remain major causes of morbidity and mortality worldwide. Ampicillin, trimethoprim-sulfamethoxazole, and chloramphenicol no longer provide reliable coverage of Salmonella and fluoroquinoloes have emerged as first-line treatment options. Due to mounting evidence of decreased in vitro susceptibility and diminished clinical response to fluoroquinolone therapy, it has been suggested that the NCCLS breakpoints for the salmonellae be re-evaluated. We utilized an in vitro infection model to determine which pharmacokineticpharmacodynamic (PK-PD) measure was most closely linked to fluoroquinolone activity against salmonellae and the magnitude that was predictive of efficacy. Monte Carlo simulation was utilized to determine the probability of attaining potential susceptibility breakpoints for three fluoroquinolones. The free-drug AUC0-24:MIC ratio was the PK-PD measure most predictive of efficacy and a ratio of 105 corresponded to 90% of maximal activity. Simulation results suggest susceptible breakpoints of 0.12 μg/mL for ciprofloxacin and gatifloxacin and 0.25 μg/mL for levofloxacin. These proposed breakpoints correspond to the MIC separating the wild-type susceptible organism population from those strains possessing single-step mutations in the quinolone resistance-determining region (QRDR). These results that integrate PK-PD measures and fluoroquinolone MIC distributions in the genetic context of examined Salmonella, clearly demonstrate the prudent use of a lower susceptibility breakpoint minimizes the probability of clinical failure or delayed response in fluoruqinolone-treated patients.

European Congress of Clinical Microbiology and Infectious Disease (ECCMID), Prague, Czech Republic, May 2004

By B.M. Booker, P.F. Smith,  A. Forrest, J. Bullock, P. Kelchlin, S.M. Bhavnani, R. N. Jones, and P.G. Ambrose

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