In vitro antimicrobial activity of CP-99,219, a novel azabicyclo-naphthyridone

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

supporting

confidence: 79%

“…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

“…Many investigators (8,13,14,23) have reported that trovafloxacin (CP-99,219) has potent in vitro activity against grampositive bacteria, including streptococci, such as S. pneumoniae and Streptococcus pyogenes, and enterococci (i.e., Enterococcus faecalis). This enhanced in vitro activity against gram-positive pathogens has not diminished the compound's gram-negative antimicrobial spectrum.…”

mentioning

confidence: 99%

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

Girard

Gootz

et al. 1995

The interesting in vitro antimicrobial activity and pharmacokinetics of the new quinolone trovafloxacin (CP-99,219) warranted further studies to determine its in vivo efficacy in models of infectious disease. The significance of the pharmacokinetic and in vitro antimicrobial profiles of trovafloxacin was shown through efficacy in a series of animal infection models by employing primarily oral therapy. Against acute infections, trovafloxacin was consistently more effective than temafloxacin, ciprofloxacin, and ofloxacin against Streptococcus pneumoniae and other gram-positive pathogens while maintaining activity comparable to that of ciprofloxacin against gram-negative organisms. In a model of murine pneumonia, trovafloxacin was more efficacious than temafloxacin, while ciprofloxacin failed against S. pneumoniae (50% protective doses, 2.1, 29.5, and >100 mg/kg, respectively). In addition to its inherent in vitro potency advantage against S. pneumoniae, these data were supported by a pharmacokinetic study that showed levels of trovafloxacin in pulmonary tissue of S. pneumoniae-infected CF1 mice to be considerably greater than those of temafloxacin and ciprofloxacin (twice the maximum drug concentration in serum; two to three times the half-life, 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 Bacteroides fragilis (>1,000-fold), Staphylococcus aureus (1,000-fold), and Escherichia coli (>100-fold) compared with ciprofloxacin, vancomycin, metronidazole, clindamycin, cefoxitin, and ceftriaxone. The in vitro and in vivo antimicrobial activities of trovafloxacin and its pharmacokinetics in laboratory animals provide support for the ongoing and planned human phase II and III clinical trials.

“…As trovafloxacin demonstrates a broad spectrum of activity against gram-positive and gram-negative aerobes and anaerobes (2,7,10,12,19), treatment of a wide range of serious pediatric infections is possible. In particular, the in vitro activity of trovafloxacin against S. pneumoniae is excellent, with the drug having similar activity against both penicillin-susceptible and nonsusceptible strains (11,17,19).…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of a Fluoronaphthyridone, Trovafloxacin (CP 99,219), in Infants and Children following Administration of a Single Intravenous Dose of Alatrofloxacin

Bradley

Kearns

Reed

et al. 2000

The pharmacokinetics of trovafloxacin following administration of a single intravenous dose of alatrofloxacin, equivalent to 4 mg of trovafloxacin per kg of body weight, were determined in 6 infants (ages 3 to 12 months) and 14 children (ages, 2 to 12 years). There was rapid conversion of alatrofloxacin to trovafloxacin, with an average ؎ standard deviation (SD) peak trovafloxacin concentration determined at the end of the infusion of 4.3 ؎ 1.4 g/ml. The primary pharmacokinetic parameters (average ؎ SD) analyzed were volume of distribution at steady state (1.6 ؎ 0.6 liters/kg), clearance (151 ؎ 82 ml/h/kg), and half-life (9.8 ؎ 2.9 h). The drug was well tolerated by all children. There were no age-related differences in any of the pharmacokinetic parameters studied. Less than 5% of the administered dose was excreted in the urine over 24 h. On the basis of the mean area under the concentration-time curve of 30.5 ؎ 10.1 g ⅐ h/ml and the susceptibility (<0.5 g/ml) of common pediatric bacterial pathogens to trovafloxacin, dosing of 4 mg/kg/day once or twice daily should be appropriate.