coli and Klebsiella spp. [2, 10–12]. Several studies have assessed the ability of FQs to select for resistance by subculturing bacteria at concentrations close to MICs. However, the antimicrobial concentrations used in these studies were quite different from those actually acquired at the site of infection [13–16]. For these reasons, we have recently modified the methodologies used to assess in vitro the selection for resistance Tipifarnib by testing antimicrobial concentrations reported to occur in vivo [17]. The aim of the present study was to compare the ability of levofloxacin, ciprofloxacin and prulifloxacin to in vitro select for resistance in E. coli and Klebsiella spp. clinical isolates

at peak (Cmax) and trough (Cmin) plasma concentrations. Results

Susceptibility to fluoroquinolones Basal MICs of E. coli strains ranged from 0.016 learn more mg/L to 1 mg/L, from 0.004 mg/L to 0.5 mg/L and from 0.016 mg/L to 0.125 mg/L for levofloxacin, ciprofloxacin and prulifloxacin, respectively. MICs of Klebsiella spp. ranged between 0.03 mg/L and 1 mg/L, 0.016 mg/L and 0.5 mg/L, and 0.03 and 0.25 mg/L for levofloxacin, ciprofloxacin and prulifloxacin, respectively. Frequency of mutation Levofloxacin, 500 and 750 mg, and ciprofloxacin 500 mg limited bacterial growth with median frequencies of mutations below 10-11 at plasma Cmax. Median frequencies of mutations for prulifloxacin were generally higher than comparators ranging from 10-7 to 10-8 and from 10-8 to 10-9 at plasma Cmax in E. coli and Klebsiella spp., respectively

(Table 1). Table 2 shows MIC values of the strains that were able to grow in the presence of the above mentioned concentrations of all tested antimicrobials. While no strain was able to grow at Cmax for NU7441 levofloxacin and ciprofloxacin, 3 and 5 strains grew at prulifloxacin Cmax. These strains showed increments in MICs from 32 to 128 times for E. coli and from selleck compound 32 to 128 times for Klebsiella spp. with respect to the basal values. Since in some instances, Cmin for all the study drugs, except for levofloxacin at 750 mg dosage, were below MIC values, some strains were able to diffusely grow on the agar plate. For these strains, in order to detect any change in bacterial susceptibility, MICs were evaluated for randomly sampled colonies (Table 2). Table 1 Frequency of mutation at plasma antimicrobial concentrations in E. coli and Klebsiella spp. Drug Frequency of mutation   E. coli (n = 20) Klebsiella spp . (n = 20)   Cmax Cmin * Cmax Cmin* LVX 500 mg         Range <10-11 < 10-11 – 1.0 × 10-7 <10-11 <10-11 – 7.4 × 10-5 median <10-11 2.0 × 10-11 <10-11 7.9 × 10-8 LVX 750 mg         Range <10-11 <10-11 – 2.7 × 10-5 <10-11 <10-11 – 7.7 × 10-6 median <10-11 <10-11 <10-11 2.2 × 10-8 CIP 500 mg         Range <10-11 <10-11 – 6.3 × 10-6 <10-11 3.2 × 10-8 – 8.5 × 10-5 median <10-11 <10-11 <10-11 1.5 × 10-7 PRU 600 mg         Range <10-11 – 2.4 × 10-6 < 10-11 – 4.1 × 10-6 <10-11 – 1.7 × 10-5 6.3 × 10-9- 2.2 × 10-5 median 4.3 × 10-8 2.4 × 10-7 6.