Pharmacodynamics of trovafloxacin in a mouse model of cephalosporin-resistant Streptococcus pneumoniae pneumonia.
Trovafloxacin is a potentially useful agent for treatment of infections caused by cephalosporin-resistant Streptococcus pneumoniae. We studied the effectiveness of trovafloxacin therapy and examined the correlation between pharmacodynamic indices in serum and lung, and bacterial killing. Immunocompetent Balb/c mice were infected by intranasal inoculation of a cephalosporin-resistant S. pneumoniae isolate (MIC of ceftriaxone and trovafloxacin 2 and 0.06 mg/L, respectively). Trovafloxacin 10-30 mg/kg/day in one or three divided doses was started 15 h after infection. Serum and lung drug concentrations were measured at multiple time points for 24 h. Serum concentrations peaked at 30-60 min and lung concentrations approximately 30 min later. The serum T1/2 was approximately 9 h and lung T1/2 varied from 5 to 9 h. Lung AUC and Cmax values were 2-3 times greater than those in serum. At the start of therapy lung bacterial concentrations were 8.4 +/- 0.3 log10 cfu/mL and 24 h later had decreased by 3.5 +/- 0.2, 4.0 +/- 0.2, 0.8 +/- 0.3 and 1.0 +/- 1.2 log10 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 dosage regimens were not significant. Trovafloxacin serum AUC/MIC ratio correlated best with bacterial killing in the lungs over 24 h. Trovafloxacin is likely to be useful in the treatment of cephalosporin-resistant S. pneumoniae pneumonia.
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University of Texas Southwestern Medical Center, Dallas 75235, USA.
Lutsar
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Wubbel
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Ghaffar
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Jafri
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McCracken
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Friedland
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D000704:Analysis of Variance; D000818:Animals; D000890:Anti-Infective Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D018550:Cephalosporin Resistance / Q000502:physiology; D002511:Cephalosporins; D004195:Disease Models, Animal; D005260:Female; D024841:Fluoroquinolones; D008168:Lung / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D009287:Naphthyridines / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D011018:Pneumonia, Pneumococcal / Q000097:blood / Q000188:drug therapy*; D013296:Streptococcus pneumoniae / Q000187:drug effects
D000890:Anti-Infective Agents; D002511:Cephalosporins; D024841:Fluoroquinolones; D009287:Naphthyridines; C080163:trovafloxacin