IN-VIVO EFFICACY OF TROVAFLOXACIN (CP-99,219), A NEW QUINOLONE WITH EXTENDED ACTIVITIES AGAINST GRAM-POSITIVE PATHOGENS, STREPTOCOCCUS-PNEUMONIAE, AND BACTEROIDES-FRAGILIS

The interesting in vitro antimicrobial activity and pharmacokinetics o f the new quinolone trovafloxacin (CP-99,219) warranted further studie s to determine its in vivo efficacy in models of infectious disease. T he significance of the pharmacokinetic and in vitro antimicrobial prof iles of trovafloxacin was shown through efficacy in a series of animal infection models by employing primarily oral therapy, Against acute i nfections, trovafloxacin was consistently more effective than temaflox acin, ciprofloxacin, and ofloxacin against Streptococcus pneumoniae an d other gram-positive pathogens while maintaining activity comparable to that of ciprofloxacin against gram-negative organisms. In a model o f murine pneumonia, trovafloxacin,vas more efficacious than temafloxac in, while ciprofloxacin failed against S. pneumoniae (50% protective d oses, 2.1, 29.5, and >100 mg/kg, respectively). In addition to its inh erent in vitro potency advantage against S. pnenmoniae, these data wer e supported by a pharmacokinetic study that showed levels of trovaflox acin in pulmonary tissue of S. pneumoniae-infected CF1 mice to be cons iderably greater than those of temafloxacin and ciprofloxacin (twice t he maximum drug concentration in serum; two to three times the half-li fe, and three to six times the area under the concentration-time curve ). Against localized mixed anaerobic infections, trovafloxacin was the only agent to effectively reduce the numbers of recoverable CFU of Ba cteroides fragilis (>1,000-fold), Staphylococcus aureus (1,000-fold), and Escherichia coil (>100-fold) compared with ciprofloxacin, vancomyc in, metronidazole, clindamycin, cefoxitin, and ceftriaxone. The in vit ro and in vivo antimicrobial activities of trovafloxacin and its pharm acokinetics in laboratory animals provide support for the ongoing and planned human phase II and III clinical trials.