In vitro and in vivo antibacterial activities of AT-4140, a new broad-spectrum quinolone

Abstract

AT-4140, 5-amino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(cis-3,5-dimethyl-1-piperazinyl)-4-oxoquinoline-3-carboxylic acid, showed broad and potent antibacterial activity. Its MICs for 90% of the strains tested were 0.1 to 0.78 ,ug/mi against gram-positive organisms, such as members of the genera Staphylococcus, Streptococcus, and Enterococcus, and 0.0125 to 1.56 ,ug/ml against gram-negative organisms, such as members of the family Enterobacteriaceae and the genera Pseudomonas, Branhamella, Campylobacter, Haemophilus, and Neisseria. Its MICs were 0.025 to 0.78 ,ig/ml against glucose nonfermenters, such as members of the genera Xanthomonas, Acinetobacter, Alcaligenes, Moraxella, Flavobacterium, and Brucella; 0.2 to 0.78 ,ug/mi against anaerobes, such as Clostridium perfringens and Bacteroides fragilis; 0.0125 to 0.05 p.g/ml against Legionella spp.; 0.0125 to 0.2 ,ug/ml against Mycoplasma spp.; 0.031 to 0.063 ,u.g/ml against Chlamydia spp.; and 0.1 to 0.3 ,ig/ml against Mycobacterium spp. The potencies of AT-4140 against gram-negative organisms were comparable to those of ciprofloxacin and higher than those of ofloxacin, enoxacin, and norfloxacin. The potencies of AT-4140 against gram-positive organisms, glucose nonfermenters, anaerobes, Mycoplasma spp., Chlamydia spp., and Mycobacterium spp. were generally higher than those of the quinolones with which AT-4140 was compared. AT-4140 showed good oral efficacy against systemic infections with Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, Escherichia coli, and Pseudomonas aeruginosa in mice. Its efficacy was better when a daily dose was given once than when it was given in two doses. Good efficacies of the orally administered drug were also observed in pulmonary, dermal, and urinary tract infection models in mice. The in vivo efficacies of AT-4140 were equal to or better than those of ciprofloxacin, ofloxacin, enoxacin, and norfloxacin.New quinolones used clinically these days have a broad spectrum of activity against both gram-positive and gramnegative organisms. However, some important pathogens, such as streptococci, enterococci, Mycoplasma spp., Chlamydia spp., and Mycobacterium spp., are not sufficiently susceptible to the quinolones. To improve this point, we screened of this group of compounds and found a new compound called AT-4140 (Fig. 1) with a broader antibacterial spectrum. This paper describes the in vitro and in vivo antibacterial activities of AT-4140 compared with those of ciprofloxacin, ofloxacin, enoxacin, and norfloxacin.(

In vitro susceptibility of Mycobacterium avium complex to the new fluoroquinolone sparfloxacin (CI-978; AT-4140) and comparison with ciprofloxacin

“…In the absence of ethambutol, the combination of sparfloxacin plus rifampin appeared to be antagonistic against three of the MAC strains. (7,8,10). To examine the in vitro activity of this new agent against MAC, we tested sparfloxacin against 30 strains of MAC isolated at San Francisco General Hospital from patients with acquired immune deficiency syndrome (AIDS) and compared this activity with that of ciprofloxacin.…”

“…Ciprofloxacin and WIN 57273 are among the most active compounds in this group of agents (2,4), with ciprofloxacin showing inhibitory activity against approximately 30o of MAC strains (11). Sparfloxacin (CI-978; AT-4140) is a new agent in the fluoroquinolone class of antimicrobial agents (7,8,10). To examine the in vitro activity of this new agent against MAC, we tested sparfloxacin against 30 strains of MAC isolated at San Francisco General Hospital from patients with acquired immune deficiency syndrome (AIDS) and compared this activity with that of ciprofloxacin.…”

Penetration of sparfloxacin and ciprofloxacin into alveolar macrophages, epithelial lining fluid, and polymorphonuclear leucocytes

“…However, they are less potent against some common respiratory pathogens, particularly Streptococcus pneumoniae, Mycoplasma pneumoniae and some intracellular organisms. Sparfloxacin is a novel quinolone derivative with comparable activity to ciprofloxacin and ofloxacin against gram-negative organisms, but it possesses greater activity than these quinolones against Gram-positive cocci (including S. pneumoniae), Mycoplasma spp., Chlamydia spp., Mycobacteria spp., and some anaerobes [1][2][3][4][5][6][7][8][9][10]. The pharmacokinetics of sparfloxacin are characterized by: good absorption after oral administration; good penetration into many tissues and body fluids; and a long plasma elimination half-life, ranging 16-24 h [11][12][13][14].…”

Parenteral sparfloxacin compared with ceftriaxone in treatment of experimental endocarditis due to penicillin-susceptible and -resistant streptococci

“…These bacteria were greater than or equal to eight times more susceptible to growth inhibition by sparfloxacin than by the other quinolones tested. Such good activity of sparfloxacin against gram-positive cocci was also reported by others in the literature (5,14,24).…”