Evaluation of CP-99,219, a new fluoroquinolone, for treatment of experimental penicillin- and cephalosporin-resistant pneumococcal meningitis

Abstract

CP-99,219 is a new fluoroquinolone that has excellent activity against gram-positive organisms including penicillin-and cephalosporin-resistant Streptococcus pneumoniae strains. In our well-established rabbit model of meningitis, we conducted experiments to determine the concentrations of CP-99,219 in cerebrospinal fluid (CSF) after intravenous administration and its ability to eradicate two penicillin-resistant pneumococcal isolates. The peak and trough concentrations of CP-99,219 in the CSF were from 19 to 25% of the concentrations simultaneously obtained in serum and were unaffected by concomitant dexamethasone administration. Compared with untreated (control) animals, three doses of CP-99,219 given 5 h apart significantly reduced the bacterial count in CSF by 5 to 6 log 10 CFU at 10 h. Although 47% of the dexamethasone-treated animals and 18% of those not given the steroid had positive cultures at 24 h (14 h after administration of the last antibiotic dose), the mean bacterial counts did not change from those observed at 10 h. Additionally, only results for animals infected with one of the two pneumococcal strains appeared to be affected by concomitant dexamethasone therapy.CP-99,219, a new investigational fluoroquinolone, is an azabicyclo-naphthyridone that has excellent in vitro activity against several organisms such as penicillin-resistant pneumococci and vancomycin-resistant enterococci (1,5,8). Because of the increase in penicillin-and cephalosporin-resistant pneumococcal isolates worldwide, new antibiotics with improved activities against these organisms are needed, especially to treat infections in which the level of penetration of many antibiotics is reduced, such as in acute otitis media and bacterial meningitis.We conducted experiments in a pneumococcal meningitis model to determine the penetration of CP-99,219 into cerebrospinal fluid (CSF), the effect of dexamethasone therapy on the concentrations of this drug in CSF, and the bacteriologic effect of CP-99,219 against two penicillin-and cephalosporinresistant Streptococcus pneumoniae strains.(This study was presented in part at the 34th Interscience Conference on Antimicrobial Agents and Chemotherapy, Orlando, Fla., 4 to 7 October 1994.) MATERIALS AND METHODSS. pneumoniae strains. Two pneumococcal isolates from children with meningitis who failed standard therapy were used (6, 7). The inoculum was prepared as described previously (14). All experiments with these pneumococcus-resistant strains were conducted during a 6-month period in which each study evaluating an antimicrobial agent had at least two untreated control animals to be certain that the virulence of the organism had not changed, and the inocula in all the experiments ranged from 9 ϫ 10 4 to 4 ϫ 10 5 /ml. Experimental meningitis model. We used our well-characterized meningitis model (9, 10, 12, 18), modified from the original description of Dacey and Sande (2). CSF samples (100 to 200 l) were withdrawn before and at 5, 10, and 24 h after the antibiotic was given. After dilution of CSF ...

In vivo efficacy of trovafloxacin (CP-99,219), a new quinolone with extended activities against gram-positive pathogens, Streptococcus pneumoniae, and Bacteroides fragilis

“…The S. pneumoniae strains used in the acute infection and pneumonia models were susceptible to penicillins and macrolides, but it is expected that trovafloxacin will have equivalent activity against strains resistant to these antibiotics since recent in vitro data have shown trovafloxacin to be equally potent against penicillin-macrolide-susceptible and -resistant S. pneumoniae strains (19,25). When trovafloxacin was evaluated for therapy of experimental meningitis caused by a penicillin-and cephalosporin-resistant S. pneumoniae strain, the effectiveness of the compound was comparable to that of other antibiotics, such as vancomycin and ceftriaxone, and therapy with trovafloxacin resulted in a significant reduction of bacterial populations of penicillin-resistant organisms in cerebrospinal fluid (26).…”

Management of meningitis caused by penicillin-resistant Streptococcus pneumoniae

“…Experimental agents such as the fluoroquinolones, CP-99,219 (13,51) and clinafloxacin (29), and biapenem (57) have been shown to have excellent in vitro activities against penicillin-resistant strains. Clinafloxacin and CP-99, 219 were effective in reducing rapidly the bacterial concentrations in CSF in a model of experimental meningitis (17,49). No clinical data are available to confirm these observations.…”

BMS-284756 in Experimental Cephalosporin-Resistant Pneumococcal Meningitis

“…Because of their excellent antibacterial activity and favorable CSF penetration, the new fluoroquinolones (e.g., trovafloxacin, gatifloxacin, and moxifloxacin) have been shown to be effective for treatment of resistant pneumococcal meningitis in rabbits (9,12,15). We demonstrated that BMS-284756 is highly active against cephalosporin-resistant S. pneumoniae in this meningitis model.…”