EFFICACY OF ABT-719, A 2-PYRIDONE ANTIMICROBIAL, AGAINST ENTEROCOCCI,ESCHERICHIA-COLI, AND PSEUDOMONAS-AERUGINOSA IN EXPERIMENTAL MURINE PYELONEPHRITIS

ABT-719 is a 2-pyridone antimicrobial which inhibits DNA gyrase activi ty. It has considerable subcutaneous (sc) and oral efficacy in the tre atment of experimental pyelonephritis induced in carrageenan-treated m ice by clinical isolates of Enterococcus faecalis, Enterococcus faeciu m, Escherichia coli, and Pseudomonas aeruginosa. Therapeutic ED(50)s, defined here as producing a 2 log(10) reduction in kidney bacterial bu rden, provide a reliable end point for comparison of drug efficacy in this experimental infection. Therapeutic ED(50)s for ABT-719 against t hese infections were equal to or up to ten-fold lower than those for c iprofloxacin, used as a reference because of similarity in mode of act ion. Against E. faecalis, the therapeutic ED(50)s for ABT-719 were 4.5 -13.6 mg/kg.day for sc administration and 6.8-8.9 mg/kg.day for oral a dministration. ABT-719 was more potent than ciprofloxacin and vancomyc in against the E. faecalis strains, which showed ciprofloxacin and van comycin resistance covering a range of MICs. Against E. faecium, the t herapeutic ED(50)s for ABT-719 were 8.8 mg/kg.day (sc) and 9.4 mg/kg.d ay (oral). Against an isolate of E. faecium showing ciprofloxacin and vancomycin resistance the ED(50) for ABT-719 to achieve a 1 log,, redu ction in kidney bacterial burden was 17.9 mg/kg.day by sc administrati on. While ABT-719 had lower efficacy against this isolate than against others, ciprofloxacin and vancomycin failed to show efficacy. Against E. coli, the therapeutic ED(50) for ABT-719 was 1.1 mg/kg.day (oral), and against P. aeruginosa, this value was 2.7 mg/kg.day (oral) with v alues against both of these pathogens similar to those for ciprofloxac in. ABT-719, which represents the new 2-pyridone compound class, has p romise for the treatment of urinary tract infections, as suggested by the significant efficacy seen against experimental pyelonephritis caus ed by E. coil, P. aeruginosa and susceptible and resistant enterococci .