Pharmacodynamics of trovafloxacin in a mouse model of cephalosporin-resistant Streptococcus pneumoniae pneumonia

Trovafloxacin is a potentially useful agent for treatment of infections cau sed by cephalosporin-resistant Streptococcus pneumoniae. We studied the eff ectiveness of trovafloxacin therapy and examined the correlation between ph armacodynamic indices in serum and lung, and bacterial killing. Immunocompe tent Balb/c mice were infected by intranasal inoculation of a cephalosporin -resistant S. pneumoniae isolate (MIC of ceftriaxone and trovafloxacin 2 an d 0.06 mg/L, respectively). Trovafloxacin 10-30 mg/kg/day in one or three d ivided doses was started 15 h after infection. Serum and lung drug concentr ations were measured at multiple time points for 24 h. Serum concentrations peaked at 30-60 min and lung concentrations approximately 30 min later. Th e serum T-1/2 was approximately 9 h and lung T-1/2 varied from 5 to 9 h. Lu ng AUC and C-max values were 2-3 times greater than those in serum. At the start of therapy lung bacterial concentrations were 8.4 +/- 0.3 log(10) cfu /ml and 24 h later had decreased by 3.5 +/- 0.2, 4.0 +/- 0.2, 0.8 +/- 0.3 a nd 1.0 +/- 1.2 log(10) cfu/mL with 30 mg/kg x 1, 10 mg/kg x 3, 10 mg/kg x 1 and 3.3 mg/kg x 3 regimens, respectively. Although the larger dosages were more effective (P < 0.001) the differences between divided and single dosa ge regimens were not significant. Trovafloxacin serum AUC/MIC ratio correla ted best with bacterial killing in the lungs over 24 h. Trovafloxacin is li kely to be useful in the treatment of cephalosporin-resistant S. pneumoniae pneumonia.