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Antimicrobial Agents and Chemotherapy, May 2005, p. 1775-1781, Vol. 49, No. 5
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.5.1775-1781.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Application of an In Vitro Infection Model and Simulation for Reevaluation of Fluoroquinolone Breakpoints for Salmonella enterica Serotype Typhi

Brent M. Booker,1,2 Patrick F. Smith,1,2* Alan Forrest,1 Julie Bullock,1 Pamela Kelchlin,1 Sujata M. Bhavnani,1,3 Ronald N. Jones,4,5 and Paul G. Ambrose1,3*

The University at Buffalo School of Pharmacy and Pharmaceutical Sciences Applied Pharmacodynamics Laboratory,1 Roswell Park Cancer Institute,2 Cognigen Corporation, Buffalo, New York,3 The JONES Group/JMI Laboratories, North Liberty, Iowa,4 Tuft's University School of Medicine, Boston, Massachusetts5

Received 2 June 2004/ Returned for modification 31 August 2004/ Accepted 12 January 2005

Salmonella enterica serotype Typhi and nontyphoidal 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 reevaluated. We utilized an in vitro infection model to determine which pharmacokinetic-pharmacodynamic (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 area under the concentration-time curve from 0 to 24 h/MIC ratio was the PK-PD measure most predictive of efficacy, and a ratio of 105 corresponded to 90% of maximal activity. Simulation results suggested 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. These results that integrate PK-PD measures and fluoroquinolone MIC distributions in the genetic context of examined Salmonella isolates clearly demonstrate that the prudent use of a lower susceptibility breakpoint minimizes the probability of clinical failure or delayed response in fluoroquinolone-treated patients.

* Corresponding author. Mailing address for Paul G. Ambrose: Division of Infectious Diseases, Cognigen Corporation, Buffalo, NY 14221. Phone: (716) 633-3463, ext. 302. Fax: (716) 633-3465. E-mail: paul.ambrose{at}cognigencorp.com. Mailing address for Patrick F. Smith: University at Buffalo, School of Pharmacy & Pharmaceutical Sciences, 219 Cooke Hall, Buffalo, NY 14260. Phone: (716) 645-2828, ext. 242. Fax: (716) 645-2886. E-mail: pfsmith{at}buffalo.edu.

Antimicrobial Agents and Chemotherapy, May 2005, p. 1775-1781, Vol. 49, No. 5
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.5.1775-1781.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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