Kinetic disposition of temafloxacin and ciprofloxacin in a murine model of pneumococcal pneumonia. Relevance for drug efficacy.
The authors studied whether pharmacokinetic parameters could explain differences in the in vivo antipneumococcal activity of temafloxacin and ciprofloxacin in a mouse model of pneumonia. The effects of infection on the disposition and clearance mechanisms of the two drugs were evaluated after a single administration (100 mg/kg s.c.) relative to noninfected controls. Effective drug concentrations and possible drug inactivation at sites of infection were assessed using both microbiological (active drug levels) and high-performance liquid chromatography (total drug levels) procedures and by recording bacterial clearance in blood and lung homogenates. Pulmonary bacterial clearance was correlated more closely to concentrations in serum than to those in lung homogenates, probably because they better reflect interstitial fluid concentrations. Neither the serum and lung concentrations nor the clearance of ciprofloxacin were modified greatly by infection. Ciprofloxacin was not inactivated at sites of infection. Temafloxacin exhibited higher serum concentrations and tissue penetration than ciprofloxacin. The differences between the two drugs in noninfected controls were accentuated, with apparent retention of temafloxacin in infected mice resulting in more persistent activity in lung and serum. The renal failure observed in infected mice did not apparently account for the reduction in the total clearance of temafloxacin, suggesting its probable trapping at sites of infection. The observation that serum (and tissue) concentrations of temafloxacin exceeded the minimal inhibitory concentration of the test organism over the whole dosing interval (12 hr), could account for its efficacy in severe pneumococcal disease.
Vallée
E
E
Institut National de la Santé et de la Recherche Médicale U 13, Hôpital Claude Bernard, Paris, France.
Azoulay-Dupuis
E
E
Bauchet
J
J
Pocidalo
J J
JJ
D000818:Animals; D000890:Anti-Infective Agents / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D002939:Ciprofloxacin / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D005260:Female; D024841:Fluoroquinolones; D007279:Injections, Subcutaneous; D008168:Lung / Q000378:metabolism; D008657:Metabolic Clearance Rate; D051379:Mice; D008810:Mice, Inbred C57BL; D011018:Pneumonia, Pneumococcal / Q000378:metabolism*; D015363:Quinolones / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*
D000890:Anti-Infective Agents; D024841:Fluoroquinolones; D015363:Quinolones; C054745:temafloxacin; D002939:Ciprofloxacin