Activity of E-3846, a new fluoroquinolone, in vitro and in experimental cystitis and pyelonephritis in rats

Abstract

The in vitro antibacterial activity of E-3846, a new fluoroquinolone carboxylic acid derivative with a pyrrol ring substituent at position 7, was evaluated in comparison with norfloxacin and ciprofloxacin. E-3846 was more active than the reference quinolones against Staphylococcus species, including methicillin-resistant strains. E-3846 was similar to ciprofloxacin and more active than norfloxacin against Streptococcus (Enterococcus) faecalis. In general, E-3846 was more active than norfloxacin against members of the family Enterobacteriaceae, but less active than ciprofloxacin. For Pseudomonas aeruginosa, the MICs giving 90% inhibition for E-3846, norfloxacin, and ciprofloxacin were 2, 1, and 0.25 ,ug/ml, respectively. The activity of E-3846 increased at acid pH; in contrast, acid pH caused a pronounced decrease in the activity of norfioxacin and ciprofloxacin. In vivo, E-3846 demonstrated excellent therapeutic efficacy in treating experimental S. faecalis, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Pseudomonas aeruginosa cystitis and pyelonephritis in rats.The newer DNA gyrase subunit A inhibitors, such as amifloxacin (6, 14, 22), ciprofloxacin (1,8,23, 31), difloxacin (9, 26), enoxacin (4, 18, 20), irloxacin (5, 17), norfloxacin (3, 12, 13, 15), ofloxacin (10, 24), and perfloxacin (11, 27) are distinguished from earlier compounds such as nalidixic acid or oxolinic acid by modifications at positions 6, 7, and 8 on the ring structure. The addition of a fluorine atom to position 6 and modifications at position 7 resulted in an enormous increase in the antibacterial activity of these compounds (25).E-3846 (6-fluoro-1-cyclopropyl-1,4-dihydro-4-oxo-7[pyrrol-1-yl]-quinolone-3-carboxylic acid [ Fig. 1]) is a new fluoroquinolone antibacterial agent with a pyrrol ring at position 7 of the molecule. Other compounds with a 7-pyrrol ring substituent are irloxacin (17) and E-3604 (29).In this report, we describe E-3846 and compare its in vitro antibacterial activity with those of norfloxacin and ciprofloxacin against a wide variety of organisms. We also examined the in vivo efficacy of E-3846 in the treatment of experimental urinary tract infections in rats.

In vitro and in vivo antibacterial activities of E-4497, a new 3-amine-3-methyl-azetidinyl tricyclic fluoroquinolone

“…(This work was presented in part at the 7th Mediterranean Congress of Chemotherapy, Barcelona, Spain, 1990 [13a] (1,5, and 10 mM, respectively).…”

Discovery and development of new antimicrobial agents

“…An integral part of the program, then, was to find the most potent dehydropeptidase I inhibitors and attempt to modify them chemically so that they would have a pharmacokinetic profile similar to that of imipenem, as assessed experimentally in the chimpanzee (86 More complex animal protection experiments are designed to test the efficacy of new antimicrobial agents for clearing infecting organisms from specific tissues. Infection models that represent abscess formation, pneumonia, pyelonephritis, meningitis, osteomyelitis, and endocarditis have been developed in mice, rats, and rabbits (27,58,62,105). Furthermore, with the increased incidence of immunosuppressed patients seen in hospitals today, there is a major need for new antimicrobial agents that provide adequate therapy in patients lacking an intact immune system (57,98,134).…”

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

“…Unlike the case with most other quinolones, low pH increased the WIN 57273 activity (1,8,17). Only a few fluoroquinolones (E-3846, E-3604 and irloxacin) containing pyrrol side chains have demonstrated this effect (6). This feature would increase the potency of WIN 57273 at urine pHs.…”

“…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).…”

“…(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).…”