Pharmacodynamics of Trovafloxacin, Ofloxacin, and Ciprofloxacin against Streptococcus pneumoniae in an In Vitro Pharmacokinetic Model

Abstract

An in vitro pharmacokinetic model was used to simulate the pharmacokinetics of trovafloxacin, ofloxacin, and ciprofloxacin in human serum and to compare their pharmacodynamics against eightStreptococcus pneumoniae strains. The MICs of ofloxacin and ciprofloxacin ranged from 1 to 2 μg/ml. Trovafloxacin was 8- to 32-fold more potent, with MICs of 0.06 to 0.12 μg/ml. Logarithmic-phase cultures were exposed to peak concentrations of trovafloxacin, ofloxacin, or ciprofloxacin achieved in human serum after 200-, 400-, and 750-mg oral doses, respectively. Trovafloxacin was dosed at 0 and 24 h, and ofloxacin and ciprofloxacin were dosed at 0, 12, and 24 h. Human elimination pharmacokinetics were simulated, and viable bacterial counts were measured at 0, 2, 4, 6, 8, 12, 24, and 36 h. Trovafloxacin was rapidly and significantly bactericidal against all eight strains evaluated, with viable bacterial counts decreasing at least 5 logs to undetectable levels. Times to 99.9% killing were only 1 to 3 h. Although the rate of killing with ofloxacin was substantially slower than that with trovafloxacin, ofloxacin was also able to eradicate all eight strains from the model, despite a simulated area under the inhibitory curve/MIC ratio (AUC/MIC) of only 49. In contrast, ciprofloxacin eradicated only five strains (AUC/MIC = 44) from the model. Against the other three strains (AUC/MIC = 22), the antibacterial activity of ciprofloxacin was substantially diminished. These data corroborate clinical data and suggest that trovafloxacin has a pharmacodynamic advantage over ciprofloxacin and ofloxacin against S. pneumoniae in relation to its enhanced antipneumococcal activity.

Pharmacodynamic evaluation of tosufloxacin against Streptococcus pneumoniae in an in vitro model simulating serum concentration

“…21,22 Pharmacodyamic studies with various fluoroquinolones against S. pneumoniae using in vitro pharmacokinetic models have shown that an AUC/ MIC ratio in the range of approximately 30 to 60 is sufficient to achieve eradication. [23][24][25][26][27] For quinolone-susceptible strain ATCC49619, tosufloxacin showed bactericidal activity, given that the AUC 0-24h /MIC ratios at 150 mg t.i.d. and 300 mg b.i.d.…”

The effect of pharmacokinetic/pharmacodynamic (PK/PD) parameters of gatifloxacin on its bactericidal activity and resistance selectivity against clinical isolates of Streptococcus pneumoniae

“…It was suggested that AUC/MIC ratios of 30-60 were sufficient to eradicate S. pneumoniae. [5][6][7][8][9] However, because fluoroquinolones kill bacteria in a concentration-dependent manner, 4 not only the AUC/MIC but also the C max /MIC might affect their pharmacodynamics. Therefore, it was important to consider the effect of the AUC/MIC ratio and the C max /MIC ratio on the pharmacodynamics of fluoroquinolones against S. pneumoniae.…”

“…Our results agreed with the ideas from previous PK/PD studies in which AUC/MIC ratios of approximately 30 to 60 were sufficient for the eradication of S. pneumoniae. [5][6][7][8][9] Resistance selectivity is one of the important PD factors in antibacterial agents. Pharmacokinetic parameters, as well as the target preference of quinolones, are thought to be associated with their resistance selectivity.…”

“…The 24h area under the concentration-time curve (AUC) 24h /minimum inhibitory concentration (MIC) ratios have been identified as possible predictors of the bactericidal effect of quinolones. [5][6][7][8][9] The optimal efficacy of quinolones has been observed at AUC 24h /MIC ratios of 30-60. [5][6][7][8][9] Some investigators have also suggested that maximum concentration in serum (C max )/MIC ratios ranging from 2 to 10 are required to prevent the selection of resistance to quinolones.…”

“…[5][6][7][8][9] The optimal efficacy of quinolones has been observed at AUC 24h /MIC ratios of 30-60. [5][6][7][8][9] Some investigators have also suggested that maximum concentration in serum (C max )/MIC ratios ranging from 2 to 10 are required to prevent the selection of resistance to quinolones. 5,[10][11][12] In this study, we investigated the effect of pharmacokinetic/pharmacodynamic (PK/PD) parameters of gatifloxacin on its bactericidal activity and resistance selectivity against S. pneumoniae, and compared its efficacy with those of levofloxacin and ciprofloxacin by simulating the serum concentration according to the Japanese clinical regimen.…”