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

Abstract

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 g/ml for ciprofloxacin and gatifloxacin and 0.25 g/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 fluoroquinolonetreated patients.

Fluoroquinolone Susceptibility Testing of Salmonella enterica: Detection of Acquired Resistance and Selection of Zone Diameter Breakpoints for Levofloxacin and Ofloxacin

“…In the present study, the new breakpoints resulted in the highest category agreement (94%) when plotted against ciprofloxacin MICs. In addition, the susceptibility breakpoint for levofloxacin (S Յ 0.125 g/ ml) is supported by the work of Booker et al (30). They used an in vitro infection model and Monte Carlo simulations to determine pharmacokinetic-pharmacodynamic (PK-PD)-based susceptibility breakpoints for levofloxacin.…”

Epidemiology, Clinical Presentation, Laboratory Diagnosis, Antimicrobial Resistance, and Antimicrobial Management of Invasive Salmonella Infections

“…It became clear that a subset of strains of Salmonella serovars Typhi and Paratyphi A had emerged that were less susceptible to the fluoroquinolones. They showed decreased susceptibility to ciprofloxacin (MICs of 0.125 to 0.5 g/ml, compared with the wild-type MIC of Յ0.03 g/ml), and the decreased susceptibility is most commonly mediated by point mutations in genes encoding DNA gyrase, the target enzyme for the drug (486,513,514,(520)(521)(522). Isolates that have this decreased-susceptibility phenotype were not defined as resistant by the existing ciprofloxacin interpretive criteria for disk diffusion but were usually found to be nalidixic acid resistant.…”

Effect of Differences in MIC Values on Clinical Outcomes in Patients with Bloodstream Infections Caused by Gram-Negative Organisms Treated with Levofloxacin

“…One can anticipate that slightly lower concentrations are needed when free drug is considered. As predicted, lower AUC 0-24 /MIC ratios are required when only free-drug values are used in calculations, and extrapolating free-drug concentrations from the data in the aforementioned clinical studies results in an optimal free-drug AUC 0-24 /MIC ratio between 61 and 105 (2,5,14).As currently defined by the Clinical and Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing, the MIC breakpoint of levofloxacin for aerobic and facultative gram-negative organisms is 2 mg/liter (8, 16a; Levaquin package insert [http://www.levaquin.com]). The…”