In vitro and in vivo activities of a new quinolone, WIN 57273, possessing potent activity against gram-positive bacteria

Although composite data from separate subjects can be used to generate single-subject estimates, intersubject variation precludes rigorous ocular pharmacokinetic analysis. Therefore, a rabbit model in which sequential aqueous and vitreous humor samples were obtained following the administration of the quinolone fleroxacin was developed. Mean data from individual animals were used for pharmacokinetic analysis. Following direct intravitreal or systemic drug administration, sequential paracenteses did not alter pharmacokinetic constants or ocular penetration and were not associated with an increase in ocular protein; contamination of vitreous humor with blood was minimal (<0.1%). Following direct injection or intravenous administration, vitreous humor concentration-time data were best described by one-and two-compartment models, respectively. The maximum concentration and the penetration into the aqueous and vitreous humors were 1.54 and 0.5 ,ug/ml and 27 and 10%, respectively. Elimination rates from aqueous and vitreous humors and serum were similar following parenteral drug administration. Drug elimination following direct injection was rapid, and the elimination rate from the vitreous humor was not prolonged by the coadministration of probenecid. Our animal model provides a new approach to the rigorous examination of the ocular pharmacokinetics of quinolone antimicrobial agents in the eye.

Section: Discussionsupporting

confidence: 74%

Fleroxacin pharmacokinetics in aqueous and vitreous humors determined by using complete concentration-time data from individual rabbits

Miller

Madu

Samathanam

et al. 1992

“…Win 57273 is a new broad-spectrum 7-dimethylpyridinyl quinolone with greater activity against gram-positive organisms than the activity of ciprofloxacin or ofloxacin; the compound is also active against Legionella species (10,19,20,31). Pharmacokinetic data in rats revealed maximum VOL.…”

mentioning

confidence: 99%

Susceptibilities of penicillin-susceptible and -resistant strains of Streptococcus pneumoniae to RP 59500, vancomycin, erythromycin, PD 131628, sparfloxacin, temafloxacin, win 57273, ofloxacin, and ciprofloxacin

Spangler

Jacobs

Appelbaum

1992

The MICs of four new quinolones, sparfloxacin (AT4140, CI-978), PD 131628 (the active form of the prodrug Susceptibility to RP 59500, a new streptogramin, was also tested and compared with those to the quinolones, erythromycin, and vancomycin. All MICs were determined by a standardized agar dilution method by using Mueller-Hinton agar supplemented with sheep blood. Quinolone, vancomycin, and RP 59500 susceptibilities were not affected by susceptibility or resistance to penicillin. For Win 57273, the MICs for 50%o (MIC50) and 90%YO (MIC90) of strains tested were 0.015 and 0.03 JLg/ml, respectively. MIC,Os of both sparfloxacin and PD 131628 were 0.25 pg/ml, and MIC,0s were 0.5 jag/ml. The MIC. of temafloxacin was 0.5 ,ug/ml, and the MIC,, was 1.0 pg/ml. By comparison, ofloxacin and ciprofloxacin both yielded MIC-.s of 1.0 jag/ml and MIC90s of 2.0 pLg/ml. RP 59500 yielded an MIC. of 0.5 zg/ml and an MIC90 of 1.0 pg/ml and was only 1 doubling dilution less active against 17 erythromycin-resistant strains. Vancomycin was active against all strains (MIC50, 0.25 iag/ml; MIC90, 0.5 jag/mI). All four experimental quinolones as well as RP 59500 show promise for therapy of infections with penicillin-resistant and -susceptible pneumococci.

“…Additionally, the widespread use of ciprofloxacin has resulted in resistance to this quinolone among gentamicin-resistant enterococci (16). A number of novel fluoroquinolones, including WIN 57273 (6,7,17), PD (10) were performed in triplicate with each strain to determine the extents and rates of killing by WIN 57273 alone or with penicillin and by penicillin with and without an aminoglycoside. Antibiotics were tested at the following concentrations: penicillin, 10 U/ml; WIN 57273, 2 jig/ml; gentamicin, 5 ,ug/ml; and streptomycin, 25 p,g/ml.…”

mentioning

confidence: 99%

Bactericidal activity of the fluoroquinolone WIN 57273 against high-level gentamicin-resistant Enterococcus faecalis

Noskin

Mehl

Warren

1993

The fluoroquinolone WIN 57273 showed identical bactericidal activities (MBC for 90%v of the strains = 0.25 ug/ml) for bacteremic strains ofEnterococcusfaecalis with and without high-level gentamicin resistance. WIN 57273 was bactericidal in time-kill measurements with highly gentamicin-resistant, ciprofloxacin-susceptible strains of E. faecalis. However, WIN 57273 was indifferent with penicillin for gentamicin-resistant E. faecalis and was not bactericidal for ciprofloxacin-resistant E. faecalis. antimicrobial agent which inhibits visible growth. The MBC is defined as the lowest concentration of antibiotic that kills .99.9% of the original inoculum. For our study, MBCs were determined by subculturing clear culture broths onto antibiotic-free Mueller-Hinton agar plates. Three E. faecalis strains were used for time-kill measurements: LS-31, which demonstrated high-level gentamicin resistance, high-level streptomycin resistance, and ciprofloxacin susceptibility (Gmr Smr Cips); LS-45, which demonstrated high-level gentamicin resistance, streptomycin susceptibility, and ciprofloxacin susceptibility (Gmr Sms Cips); and LS-49, which demonstrated high-level gentamicin resistance, streptomycin susceptibility, and ciprofloxacin resistance (Gmr Sm, Cipr). Time-kill measurements (10) were performed in triplicate with each strain to determine the extents and rates of killing by WIN 57273 alone or with penicillin and by penicillin with and without an aminoglycoside. Antibiotics were tested at the following concentrations: penicillin, 10 U/ml; WIN 57273, 2 jig/ml; gentamicin, 5 ,ug/ml; and streptomycin, 25 p,g/ml. Antibiotic carryover was eliminated by the use of a minimum dilution factor of at least 100. Organisms were diluted in 20 ml of cation-supplemented Mueller-Hinton broth to give a final inoculum of 5 x 105 CFU/ml and incubated with mechanical shaking at 35°C. At 0, 4, 8, and 24 h after inoculation, 0.5-ml samples were taken from the broth and passed through serial 10-fold dilutions. From each dilution, a 0.1-ml sample was spotted and spread over the entire surface of antibiotic-free agar. A 0.1-ml sample of undiluted broth was also directly inoculated to antibioticfree agar. Colonies were counted after 24 h of incubation. The minimum accurately countable bacterial population was 50 CFU/ml. Bactericidal activity in time-kill measurements is defined as a .3 log10 increase in bacterial killing at 24 h of incubation. Synergy is defined as a .2 logl0 increase in killing by a combination of two antibiotics compared with the killing by the active antibiotic alone, with the other antibiotic present in a concentration which does not affect the growth curve of the organism. If the result of using two drugs in time-kill measurements equals the effect of the more active antibiotic used alone (s1 loglo increase), the antibiotic combination is considered to be indifferent (2).The activity of WIN 57273 was compared with those of other fluoroquinolones, as shown in