In vivo therapeutic efficacy of cefdinir (FK482), a new oral cephalosporin, against Staphylococcus aureus and Haemophilus influenzae in mouse infection models.

Cefdinir (FK482), a new oral cephalosporin, displayed potent oral activity versus induced infections in mice. In studies using beta-lactamase-nonproducing (beta LAC-) and -producing (beta LAC+) Staphylococcus aureus strains, respective PD50s (in mg/kg) were 11 and 24 for preventing subcutaneous abscess and 2.7 and 2.3 for preventing lethal systemic infection. In studies using beta LAC- and beta LAC+ Haemophilus influenzae, respective PD50s were 5.8 and 3.1 for preventing lethal systemic infection. Time-kill studies versus H. influenzae showed that 6- to 12-mg/kg dosing was effective in reducing viable counts of these strains in blood by > or = 100-fold by 24 h after challenge. This in vivo performance was comparable to or exceeded values generated by cefaclor, cefpodoxime proxetil, and ampicillin.

Fluoroquinolones: relationships between structural variations, mammalian cell cytotoxicity, and antimicrobial activity.

Fluoroquinolones are potent inhibitors of bacterial topoisomerase II (DNA gyrase). They can also inhibit eukaryotic topoisomerases, which could possibly lead to clastogenicity and/or cellular toxicity. Recent studies have demonstrated a correlation between mammalian cell cytotoxicity of the fluoroquinolones and the potential of these compounds to induce micronuclei, a genetic toxicity endpoint. In an effort to identify potent nontoxic quinolone antibacterials, we have examined the structural features of the fluoroquinolones associated with mammalian cell cytotoxicity. An investigation of a wide variety of substituents at the 1, 5, 7, and 8 positions of a quinolone nucleus was conducted. The results indicate that no one position has a controlling effect on the observed cytotoxicity. Instead, a combination of the various substituents contributes to the effects seen. Certain trends were apparent, such as the fact that compounds with pyrrolidines at the R-7 position were more cytotoxic than those with piperazines, and halogens at R-8 (X-position) were associated with more cytotoxicity relative to hydrogen. A general trend also existed between the cytotoxicity of the compounds and their Gram-positive antibacterial activity. A detailed comparison between the various groups and positional variations as they controlled the cytotoxicity and antibacterial activity is presented.

In vitro activity of sparfloxacin (CI-978, AT-4140, and PD 131501). A quinolone with high activity against gram-positive bacteria.

Sparfloxacin (CI-978, AT-4140 and PD 131501) is a new antimicrobial agent of the piperazinyl quinolone class. Relative to other quinolones, it is a potent antistaphylococcal and antistreptococcal drug in vitro: The microbroth 90% minimum inhibitory concentration (MIC90) (in microgram/ml) was 0.25 vs 26 methicillin-resistant and -sensitive coagulase-positive and -negative staphylococci and 20 Streptococcus pneumoniae; 0.5 vs 20 strains each of S. pyogenes, S. agalactiae, and Enterococcus faecalis. The data indicate sparfloxacin to be generally superior to ciprofloxacin, ofloxacin, oxacillin, cefazolin, doxycycline, amikacin, and vancomycin against these Gram-positive bacterial groups. Additional MIC90s were determined for Haemophilus influenzae, Moraxella (Branhamella) catarrhalis, and Neisseria gonorrhoeae (less than or equal to 0.03); Enterobacteriaceae (0.5); and Listeria monocytogenes (1). Activity was generally unchanged with light, 50% human serum, aerobic-anaerobic atmosphere, 5% sodium cholate, cation supplementation, and 100-fold increased or decreased inoculum; as with other quinolones, potency was measurably diminished with decreasing pH (pH less than or equal to 6.0) and in 100% urine. Naturally occurring resistant mutants occurred at frequencies of 10(-8) or lower.

In vitro antibacterial activities of the fluoroquinolones PD 117596, PD 124816, and PD 127391.

Three new aminopyrrolidine-substituted fluorocyclopropyl quinolones--PD 117596, PD 124816, and PD 127391--were tested for in vitro antibacterial activity against 349 bacterial strains, which are primarily clinical isolates. The minimum inhibitory concentrations (MIC) in micrograms/ml required for greater than or equal to 90% of strains were 0.03-0.06 for staphylococci (26 strains); 0.06-0.25 for Streptococcus pyogenes, S. agalactiae, S. pneumoniae, and Enterococcus faecalis (80); less than or equal to 0.015 for Branhamella catarrhalis, Haemophilus influenzae, and Neisseria gonorrhoeae (42); 0.06 for Enterobacteriaceae (97); 0.125-0.25 for Acinetobacter spp. (14); 0.5 for Pseudomonas aeruginosa (20); 0.125-1.0 for Bacteroides fragilis (13); and 0.25-0.5 for anaerobic cocci (11). These activities were generally superior to that of ciprofloxacin, imipenem, ampicillin, penicillin G, oxacillin, cefazolin, ceftazidime, cefoxitin, cefsulodin, aztreonam, piperacillin, amikacin, spectinomycin, doxycycline, erythomycin, clindamycin, metronidazole, and vancomycin. The activities of the new quinolones were generally unchanged with light, 50% human serum, aerobic/anaerobic atmosphere, 5% sodium choate, cation supplementation, and 100-fold increased or decreased inoculum; as with other quinolones, potency was measurably diminished with decreasing pH (pH less than or equal to 6.0) and in 100% urine.

In vitro antibacterial activities of PD 131628, a new 1,8-naphthyridine anti-infective agent.

PD 131628 is a new aminopyrrolidine-substituted fluorocyclopropyl naphthyridine quinolone which possesses high in vitro activity against a wide spectrum of bacterial species. The MICs for greater than or equal to 90% of strains were 0.125 to 0.25 microgram/ml for staphylococci, Streptococcus pyogenes, and S. pneumoniae; 0.5 micrograms/ml for S. agalactiae and Enterococcus faecalis; 0.125 micrograms/ml for members of the family Enterobacteriaceae and Acinetobacter spp.; 0.5 micrograms/ml for Pseudomonas aeruginosa; and less than or equal to 0.03 micrograms/ml for Haemophilus influenzae, Moraxella (Branhamella) catarrhalis, and Neisseria gonorrhoeae. In these in vitro comparisons with ciprofloxacin, PD 131628 is more active against gram-positive organisms, approximately equivalent against gram-negative organisms, and, like most other quinolones, relatively inactive against gram-negative anaerobes. In most instances, the in vitro potency of PD 131628 exceeded those of widely used compounds: ciprofloxacin, imipenem, ampicillin, penicillin G, oxacillin, cefazolin, ceftazidime, cefoxitin, cefsulodin, aztreonam, piperacillin, amikacin, spectinomycin, doxycycline, erythromycin, metronidazole, and vancomycin.