In vitro activity of CP-99,219, a new fluoroquinolone, against clinical isolates of gram-positive bacteria

This investigation compared the effect of ethanol on fluoroquinolone antibiotic efficacy and pharmacodynamics in an ethanol-fed rat model of pneumococcal pneumonia. Male Sprague-Dawley rats received a liquid diet containing 36% of total calories as ethanol. Paired controls (pair-fed controls) were fed a liquid diet without ethanol or received rat chow. Diets began 7 days before and continued for 10 days after transtracheal infections with 10 times the 50% lethal dose of type 3 Streptococcus pneumoniae. Beginning 18 h after infection, the rats received once daily subcutaneous phosphate-buffered saline, levofloxacin, moxifloxacin, or trovafloxacin at 50 or 100 mg/kg of body weight. White blood cell counts were determined, blood samples were collected for culture, and mortality was recorded. Additional rats were killed on day 5 for pharmacodynamic studies and quantitative cultures of bronchoalveolar lavage fluid. Bacteremia occurred by day 3 in 20 of 22 untreated rats. All 22 untreated rats died by day 9. Moxifloxacin treatment was effective in all diet groups at both the 50-and 100-mg/kg doses. In contrast, 50-mg/kg doses of levofloxacin and trovafloxacin improved survival in ethanol-fed rats but were ineffective in chow-fed rats. High-dose trovafloxacin at 100 mg/kg was associated with increased mortality in pair-fed rats. The free-fraction area under the concentration-time curve/MIC ratio exceeded 50 with all antibiotics in the ethanol group but dropped below 30 with levofloxacin and trovafloxacin in the pairand chow-fed rats, with higher mortality. Achievement of adequate antibiotic-free fraction area under the concentration-time curve/MIC ratios helps overcome ethanol-induced immune defects induced in experimental pneumococcal pneumonia.

mentioning

confidence: 99%

Effect of Ethanol on Fluoroquinolone Efficacy in a Rat Model of Pneumococcal Pneumonia

Olsen

Gentry-Nielsen

Yue³

et al. 2006

“…The 1-N substitution of CP 99,219 is a difluorinated structure identical to that of tosufloxacin that produces enhanced activity against some ciprofloxacinresistant strains. CP 99,219 possesses a broad spectrum of activity against gram-positive and -negative organisms, including those resistant to ciprofloxacin (9,10,13,14,18,21 …”

mentioning

confidence: 99%

Activity of CP 99,219 compared with those of ciprofloxacin, grepafloxacin, metronidazole, cefoxitin, piperacillin, and piperacillin-tazobactam against 489 anaerobes

Spangler

Jacobs

Appelbaum

1994

100

Agar dilution was used to compare the in vitro activity of CP 99,219 with those of ciprofloxacin, grepafloxacin, metronidazole, cefoxitin, piperacillin, and piperacillin-tazobactam against 489 anaerobes. CP 99,219 yielded a MIC for 50%6 of the strains tested (MIC..) of 0.25 ,ug/ml and a MIC90 of 1.0 pg/ml, with 99.6% of the strains susceptible at a breakpoint of 2.0 ,ug/ml. Ciprofloxacin and grepafloxacin were less active (MIC50, 4.0 ,ug/ml; MIC90, 32.0 ,ug/ml and 2.0 and 16.0 ,ug/ml, respectively). Metronidazole was active against all gram-negative rods (MIC%0, 4.0 ,ug/ml), but 31% of the gram-positive anaerobes were resistant at >8.0 ,ug/ml. Cefoxitin was active against 84% of all strains at <16.0 ,g/mli, with a MIC50 of 4.0 ,ug/ml and a MIC90 of 32.0 ,ug/ml. Tazobactam enhanced the activity of piperacillin against >95% of the j-lactamase-producing gram-negative anaerobic rods (MIC90, 16.0 ,ug/ml).Anaerobes are becoming increasingly resistant to 13-lactams because of P-lactamase production and other mechanisms.Metronidazole resistance in organisms other than non-sporeforming gram-positive rods has been described previously, as has clindamycin resistance in anaerobic gram-negative rodsCommercially available quinolones, such as ciprofloxacin, ofloxacin, fleroxacin, pefloxacin, enoxacin, and lomefloxacin, are inactive or marginally active against anaerobes, with MICs either higher than or clustering around breakpoints. Experimental quinolones with increased anti-anaerobic activity include (i) those with slightly increased activity (sparfloxacin, OPC 17116 [grepafloxacin], tosufloxacin, temafloxacin [now discontinued], CI-990, AM-1155, and levofloxacin) and (ii) those with significantly improved anti-anaerobic activity (Win 57273, Bay y3118, clinafloxacin, and DU-6859a) (6-8, 12, 19, 24, 25). Development of both Win 57273 and Bay y3118 has been discontinued because of toxicity.CP 99,219 is a novel investigational trifluoronaphthyridone with a structure differing from those of norfloxacin, ciprofloxacin, and enoxacin. It contains the C-7 moiety 7-(3-azabicyclo [3.1.0.]hexyl) on a basic naphthyridone configuration (9). The bicyclo C-7 substitution has been previously evaluated and described for 667 (17). The 1-N substitution of CP 99,219 is a difluorinated structure identical to that of tosufloxacin that produces enhanced activity against some ciprofloxacinresistant strains. CP 99,219 possesses a broad spectrum of activity against gram-positive and -negative organisms, including those resistant to ciprofloxacin (9,10,13,14,18,21

“…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.…”

mentioning

confidence: 99%

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

Paris

Hickey

Trujillo

et al. 1995

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 ...