Pharmacokinetic/pharmacodynamic modelling of the bactericidal activity of free lung concentrations of levofloxacin and gatifloxacin against Streptococcus pneumoniae.

The aim of this work was to compare the pharmacological properties of levofloxacin and gatifloxacin against Streptococcus pneumoniae by pharmacokinetic/pharmacodynamic (PK/PD) modelling of the time-kill curves employing an E(max) model. An in vitro infection model was used to simulate free pulmonary fluctuating concentrations expected after multiple dosing regimens of both drugs in humans or constant multiples of the minimum inhibitory concentration. PK/PD parameters and PK/PD indices of the simulated dosing regimens were compared. The levofloxacin EC(50) (concentration producing 50% of the maximum effect) (mean ± standard deviation 3.57±2.16 mg/L) was higher than that for gatifloxacin (0.95±0.56 mg/L) when simulating multiple dosing regimens as well as constant concentrations (EC(50,levofloxacin)=2.75±0.45 mg/L; EC(50,gatifloxacin)=1.03±0.52 mg/L). The maximum killing rate constant (k(max)) was not statistically different for both drugs independent of fluctuating (k(max,levofloxacin)=0.40±0.19 h(-1); k(max,gatifloxacin)=0.48±0.15 h(-1)) or constant concentrations (k(max,levofloxacin)=0.34±0.06 h(-1); k(max,gatifloxacin)=0.39±0.23 h(-1)). The PK/PD model was able to describe the effect of levofloxacin and gatifloxacin against S. pneumoniae in vitro for all the simulations investigated. Gatifloxacin was more potent than levofloxacin, but both presented equivalent efficacy. The model can be used for simulating alternative regimens and optimising therapy to treat streptococcal infextions.