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

The impact of the pharmacokinetic/pharmacodynamic (PK/PD) parameters (the 24h area under the concentration-time curve AUC_24h]/minimum inhibitory concentration MIC] and maximum concentration in serum C_max]/MIC ratio) after single oral dosing of gatifloxacin on its bactericidal activity and resistance selectivity against quinolone-susceptible clinical isolates of Streptococcus pneumoniae J-69 was investigated using an in vitro PK model. The MICs of gatifloxacin, levofloxacin, and ciprofloxacin were 0.25, 1, and 1µg/ml, respectively. When the range of AUC_24h/MIC ratios was varied from 9.0 to 36 with a constant C_max/MIC ratio of 3.4, the bactericidal activity was correlated with the AUC_24h/MIC ratios. Eradication was observed at an AUC_24h/MIC ratio of 36. On the other hand, the resistance selectivity was associated with the C_max/MIC ratio. Mutant strains were selected at a C_max/MIC ratio of 0.84, but not 1.7 with a constant AUC_24h/MIC ratio of 9.0. These results suggested that an AUC_24h/MIC ratio of 36 and a C_max/MIC ratio of 1.7 might be possible benchmarks to show enough bacterial eradication and prevention of emergence of resistant strains to gatifloxacin, respectively. When the serum concentrations after clinical oral dosing of gatifloxacin (200mg b.i.d.), levofloxacin (100mg t.i.d.), and ciprofloxacin (200mg t.i.d.) were simulated, the bactericidal activity of gatifloxacin was higher than those of levofloxacin and ciprofloxacin. Moreover, no resistant strain was obtained by the exposure to gatifloxacin and levofloxacin, whereas ciprofloxacin selected resistant strains. The clinically relevant oral dosage of gatifloxacin was anticipated to result in a high AUC_24h/MIC₉₀ ratio of 81 and a C_max/MIC₉₀ ratio of 4.4, suggesting that this agent is clinically effective in the treatment of pneumococcal infections.