In vitro activities of PD 117,596 and reference antibiotics against 448 clinical bacterial strains

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%

Section: Discussionmentioning

confidence: 99%

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

Miller

Madu

Samathanam

et al. 1992

“…Members of this drug class possess a high degree of activity against aerobic gram-negative organisms but are generally less active against aerobic gram-positive cocci, particularly streptococci and enterococci (19). The recently developed quinolones tosufloxacin (1), sparfloxacin (12), CI-934 (2,8), PD 117596 (3,15), WIN 57273 (5), and PD 127391 (CI-960) (7,8,14,15,18), however, have good antimicrobial activity against these organisms. PD 127391 appears to be one of the most active of these agents.…”

mentioning

confidence: 99%

Comparative in vitro activity of PD 127391, a new fluoroquinolone agent, against susceptible and resistant clinical isolates of gram-positive cocci

Miranda¹,

Wanger²,

Singh³

et al. 1992

We examined the in vitro activity of PD 127391, an investigational fluoroquinolone antibacterial agent, against staphylococci (including methicillin-resistant Staphylococcus aureus), enterococci (including beta-lactamase-producing and highly gentamicin-resistant isolates), and streptococci. The compound was active against all organisms tested and compared favorably with antimicrobial agents routinely used to treat infections with these organisms. On the basis of MICs for 90% of the strains tested, PD 127391 was 32-fold more active against all staphylococci, 16-fold more active against methicillin-resistant S. aureus, 8-fold more active against all streptococci, and 4-fold more active against all enterococci than ciprofloxacin. PD 127391 was shown to be more active than sparfloxacin, which in turn was shown to be more active than ciprofloxacin, against these gram-positive cocci. PD 127391 shows promise for the treatment of infections with gram-positive cocci, including organisms which are resistant to other commonly used antimicrobial agents.

“…Proteus vulgaris (10) Providencia rettgeri (10) Providencia stuartii (10) (3,4,6,15,16). However, most clinically studied fluoroquinolones possess excellent potency against gram-negative organisms, especially members of the family Enterobacteriaceae, pathogenic Neisseria spp., H. influenzae, and B. catarrhalis (1,2,5,7,8,17).…”

mentioning

confidence: 99%

“…In addition, few of these compounds have exhibited a usable clinical potency for anaerobic organisms such as the Bacteroides spp. (3,4,15,16). The newer fluoroquinolones that do possess significant activity against gram-positive cocci and/or anaerobic bacteria generally contain a pyrrolidinyl or pyrrolyl group replacing the most commonly used 7-piperazinyl side chain (3,4,6,15,16).…”

mentioning

confidence: 99%

In vitro evaluation of WIN 57273, a new broad-spectrum fluoroquinolone

Jones¹,

Barry²

1990

WIN 57273 is a new fluoroquinolone that has an expanded spectrum of activity against Staphylococcus spp.(MIC for 90% of isolates [MIC9J, 0.008 ,ug/ml), Enterococcus faecalis (MIC90, 0.06 ,Lg/ml), Bacillus spp. (MIC90, 0.03 ,Ig/ml), Listeria monocytogenes (MICso, 0.06 ,ug/ml), Streptococcus spp. (MIC,0, 0.03 ,ug/ml), and Bacteroidesfragilis group strains (MIC90, 0.5 ,ig/ml). Like other fluoroquinolone compounds, WIN 57273 was active against members of the family Enterobacteriaceae (97% of strains inhibited by <2 ,ug/ml), Haemophilus, BranhameUa, and Neisseria strains (100% susceptible), Acinetobacter spp. (100% susceptible), and Pseudomonas aeruginosa (68% susceptible). We observed that WIN 57273 was very active against cephalosporin-or aminoglycoside-resistant gram-negative strains but shared cross-resistance with other fluoroquinolones. Increasing inoculum concentrations had minimal effects on WIN 57273 MICs, and the drug was considered to be bactericidal based on reference MBC and kill curve analyses. Unlike most previously studied drugs in this class, WIN 57273 had increased activity (three-to fourfold) at low pH. Rates of mutation to WIN 57273 resistance at eight times its MIC were in the range of 5.6 x 10-8 to >1.4 x 10-9. This new compound possesses a wide potential spectrum of use, and it should be evaluated further by in vitro and in vivo studies.The halogenated 4-quinolones have generally shown expanded activity against members of the family Enterobacteriaceae and staphylococci compared with that of nalidixic acid, but they have been more variable in their activity against Streptococcus spp., enterococci, and Pseudomonas aeruginosa (7, 17). In addition, few of these compounds have exhibited a usable clinical potency for anaerobic organisms such as the Bacteroides spp. (3,4,15,16). The newer fluoroquinolones that do possess significant activity against gram-positive cocci and/or anaerobic bacteria generally contain a pyrrolidinyl or pyrrolyl group replacing the most commonly used 7-piperazinyl side chain (3,4,6,15,16).WIN 57273 is an investigational fluoroquinolone with the structural formula 1-cyclopropyl-7-(2,6-dimethyl-4-pyridinyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolonecarboxylic acid (Fig. 1). This structure resembles those of previously described compounds having greater in vitro utility against anaerobic bacteria and gram-positive species. Also, since WIN 57273 seems to possess antimicrobial activity similar to those of a number of recently studied 4-quinolones (data on file, Sterling-Winthrop Research Institute), we chose to compare this drug in vitro with other fluoroquinolones (1, 2, 5), including the most active clinically available agent, ciprofloxacin (2). The study of WIN 57273 included (i) an MIC comparison with five quinolones and three penicillins against over 700 stock culture strains; (ii) a series of tests to determine WIN 57273 activity against antimicrobial agentresistant bacteria; (iii) a study of WIN 57273 MBCs and effects of inoculum, pH, or medium on MICs; (iv) the quantitation o...