Pharmacodynamic studies of trovafloxacin and grepafloxacin in vitro against Gram-positive and Gram-negative bacteria

Grepafloxacin and trovafloxacin are two novel fluoroquinolones with extende d Gram-positive bacterial spectra compared with older quinolones. The aim o f the present study was to investigate the different pharmacodynamic parame ters of grepafloxacin in comparison with those of trovafloxacin. The follow ing studies were performed against various Gram-positive and Gramnegative b acteria: (i) determination of the rate and extent of killing at a concentra tion corresponding to the 1 h non-protein-bound human serum level following an oral dose of 800 mg grepafloxacin and 300 mg trovafloxacin; (ii) determ ination of the rate and extent of killing of the two quinolones at differen t concentrations; (iii) determination of the post-antibiotic effects (PAEs) ; (iv) determination of the post-antibiotic sub-MIC effects (PA SMEs); (iv) determination of the rate and extent of killing in an in vitro kinetic mod el. It was shown that both grepafloxacin and trovafloxacin exhibited concen tration-dependent killing against both Gram-positive and Gram-negative bact eria. Grepafloxacin exhibited a slower bactericidal effect against all the Gram-positive strains investigated in comparison with trovafloxacin in spit e of a similar C-max/MIC in the static experiments and a similar AUC/MIC ra tio in the kinetic experiments. No major differences in the extent and rate of killing were noted against the Gram-negative strains, which were killed almost completely after 3 h except for Pseudomonas aeruginosa. A PAE of bo th quinolones was noted for all strains investigated. Trovafloxacin induced longer PAEs against the Gram-positive strains but shorter PAEs in comparis on with those of grepafloxacin against the Gram-negative strains. A prolong ing of the PAEs was noted for all bacteria when exposed to sub-MICs in the post-antibiotic phase. With a similar AUC/MIC of 310 for the penicillin-sen sitive strain of Streptococcus pneumoniae and 143 for the penicillin-resist ant strain, the time for 99.9% eradication for bath strains was 2 h for tro vafloxacin and 6 h for grepafloxacin.