The in vitro and in vivo properties of a new 1-difluorophenyl-6-fluoroquinolone, temafloxacin hydrochloride (A-62254), were compared with those of difloxacin and ciprofloxacin. Temafloxacin hydrochloride was as active as ciprofloxacin and difloxacin against staphylococci and as active as ciprofloxacin and 2 twofold dilutions more active than difloxacin against streptococci. Against gram-negative enteric bacteria and Pseudomonas aeruginosa, temafloxacin hydrochloride was 2 twofold dilutions more active than difloxacin but 2 to 4 twofold dilutions less active than ciprofloxacin. The MICs of temafloxacin hydrochloride and difloxacin were increased by 2 to 5 twofold dilutions in urine at pH 6.5 compared with 4 to 5 twofold-dilution increases in the MICs of ciprofloxacin. The MICs of temafloxacin hydrochloride, difloxacin, and ciprofloxacin were increased by 1 to 3 twofold dilutions in serum. The MICs of temafloxacin hydrochloride, difloxacin, and ciprofloxacin were the same or within 1 to 2 twofold dilutions at pHs 6.5, 7.2, and 8.0. When administered orally in mouse protection tests, temafloxacin hydrochloride was as active as difloxacin and 5 to 10 times more active than ciprofloxacin against infections with Staphylococcus aureus and streptococci. Against infections with gram-negative enteric bacteria and P. aeruginosa, temafloxacin hydrochloride was as active as difloxacin and ciprofloxacin. Temafloxacin hydrochloride was three times less active than difloxacin but was five times more active than ciprofloxacin against infections with Salmonella typhimurium. Temafloxacin hydrochloride was as active as difloxacin and ciprofloxacin against P. aeruginosa and Proteus mirabilis pyelonephritis in mice. The peak serum concentration and serum half-life of temafloxacin hydrochloride in mice were approximately one-half and one-sixth, respectively, that of difloxacin after oral administration. The peak serum concentration of temafloxacin hydrochloride in mice after oral administration was six times higher than that of ciprofloxacin, and the serum half-life was equal to that of ciprofloxacin.As a class, the aryl-fluoroquinolones exhibit broadspectrum in vitro potency, as well as excellent in vivo activity (2). We have previously described the activity of two of these new quinolones, difloxacin and A-56620 (5, 14). Difloxacin is four-to eightfold less active in vitro than is ciprofloxacin against members of the family Enterobacteriaceae and Pseudomonas spp.; its similar in vivo efficacy in experimental infections, however, is probably due to its higher serum concentration and longer half-life. The mean terminal elimination serum half-life of difloxacin in humans after oral administration is 26 h (7). Temafloxacin hydrochloride (A-62254) was discovered while searching for a new quinolone with improved activity against gram-negative bacteria, higher solubility in water, and a serum half-life shorter than that of difloxacin but longer than that of ciprofloxacin. The structure of this compound, 1-o,p-difluorophenyl-6-fluoro-1 ,4-d...

The in vitro and in vivo antibacterial activity of A-56268 (TE-031), the 6-0-methyl derivative of erythromycin, was compared with those of erythronmycin and other reference drugs. A-56268 A-56268 was more potent than erythromycin against Legionella infection in guinea pigs. The concentration of A-56268 in the serum and lung was higher than that of erythromycin after intraperitoneal administration. In ntice, the peak levels in serum of A-56268 and erythromycin were simnilar after subcutaiieous administration and seven times higher for A-56268 after oral administration. The serum half-life of A-56268 was approximately twice that of erythromycin after administration by both routes.In recent years, interest in macrolides has been renewed because of their spectrum and loW toxicity profile (1,4,12,16,27). Erythromycin, the first useful macrolide, is still widely used in treating respiratory and genital tract infections (25,26). One of the limitations of erythromycin is poor absorption after oral adnministration.A-56268 (TE-031) is a new macrolide which differs from erythromycin chemically in having an 0-methyl substitution at position 6 of the macrolide ring (13). The structures of A-56268 and erythromycin are shown in Fig. 1.The in vitro and in vivo antibacterial activity and spectrum of A-56268 (6-0-methyl erythromycin) were evaluated by using etythromycin as the reference macrolide. Other compounds were also used for reference purposes.In this paper we dfescribe the MICs of A-56268 against a wide variety of aerobic and anaerobic bacteria. MBCs, killing kinetics, and in vitro synergy studies are also described. The relative potency of A-56268 against experimental bacterial infection in rodents was determined and related to its pharmacokinetic properties. MIC determinations. MICs wete determined by the agar dilution mnethod described by the National Committee for Clinical Laboratory Standards with Mueller-Hinton agar at pH 7.3 for nonfastidious aerobic organisms such as staphylococci and enterococcal streptococci (15). Mueller-Hinton agar supplemehted with 5% (vol/vol) lysed horse blood and 0.001% NAD was used for Haemophilus influenzae. Mueller-Hinton agar supplemented with 5% sheep blood was used for Streptococcus pyogenes, other fastidious streptococci, and Listeria monocytogenes. Neisseria gonorrhoeae Was tested on proteose 3 agar supplemented with 1% hemoglobin and 1% (vol/vol) Kelloggs supplement; Legionella pneumophila was tested on buffered charcoal-yeast extract agar. N. gonorrhoeae, L. pneumophila, and some ahaemolytic streptococci were grown in the presence of 5% 865 MATERIALS AND METHODS

A-56619 and A-56620 are two new aryl-fluoroquinolones which are as potent as or more potent than norfloxacin when administered orally and subcutaneously in mouse protection tests against Staphylococcus aureus, Streptococcus pyogenes, and Streptococcus pneumoniae. A-56619 and A-56620 were more potent than norfloxacin when administered orally against Escherichia coli, Proteus mirabiis, Serratia marcescens, and Pseudomonas aeruginosa. A-56620 was as potent or two-to threefold more potent than norfloxacin when administered subcutaneously against members of the family Enterobacteriaceae and Pseudomonas aeruginosa. Infection with SalmoneUa typhimurium was more effectively treated with A-56619 (50% effective dose [EDSO], 1.4 mg/kg per day) than with norfloxacin (ED50, 62.8 mg/kg per day). E. coi or Pseudomonas pyelonephritis in mice was more effectively treated with A-56619 or A-56620 than with norfloxacin. After oral treatment, the ED50S of A-56619 and A-56620 were <12.5 mg/kg per day against E. coli and 62.9 and 38 mg/kg per day against P. aeruginosa pyelonephritis, respectively. Norfloxacin was ineffective at 200 mg/kg per day against E. coli or P. aeruginosa pyelonephritis. A-56619 and A-56620 were also more potent than norfloxacin in treatment of mixed bacterial pyelonephritis caused by E. coli and Streptococcus faecalis. A-56619 was at least 30 times more potent than norfloxacin and A-56620 was 4 to 11 times more potent than norfloxacin when administered against Klebsiella pneumonia in mice. A-56619 and A-56620 were at least 2 to 10 times more potent than norfloxacin against Staphylococcus aureus infections in immunosuppressed mice. A-56619 was equally potent in all in vivo tests when administered orally or subcutaneously, whereas A-56620 was similar to norfloxacin in being more potent when administered subcutaneously. The peak serum levels after subcutaneous and oral administration of A-56619 and A-56620 were higher than that of norfloxacin. The serum half-lives of A-56619 and A-56620 after subcutaneous and oral administration Were longer than the serum half-life of norfloxacin.

A-61827 (A-60969 is the hydrochloric salt of A-61827) is a new aryl-fluoronaphthyridine which is active against aerobic and anaerobic bacteria. The MICs of A-61827 for 90% of strains (MIC90) of staphylococci and streptococci were 1 ,ug/ml and were generally 1 to 4 twofold dilutions less than those of ciprofloxacin for these bacteria. The MIC90s of A-61827 for members of the family Enterobacteriaceae and Pseudomonas aeruginosa were also '1 ,ug/mI. Ciprofloxacin was 1 to 3 twofold dilutions more active than A-61827 against these gram-negative bacteria. Neisseria gonorrhoeae, Campylobacter jejuni, and Haemophilus influenzae were susceptible to <0.06 jig of A-61827 per ml. The MIC90 of A-61827 for Legionella pneumophila was 0.25 ,ug/ml.A-61827 was as potent or 1 to 2 twofold dilutions more potent than ciprofloxacin against these organisms. The MIC90 of A-61827 for all anaerobic bacteria was <4 ,ug/ml compared with .32 ,ug/ml for ciprofloxacin. In mouse protection tests, A-61827 was as active as ciprofloxacin against Escherichia coli, P. aeruginosa, and Salmonella typhimurium and 5 to 10 times more active than ciprofloxacin against Staphylococcus aureus and Streptococcus pyogenes. A-61827 was as active as ciprofloxacin against P. aeruginosa in a mouse pyelonephritis model and more active than ciprofloxacin and metronidazole in a mouse Bacteroides fragilis abscess model.After oral administration of 100 mg/kg to mice, the peak concentrations of A-61827 and ciprofloxacin in serum were 2.3 and 2.4 ,ug/ml and the half-lives in serum were 3.9 and 1.2 h, respectively.Several new fluoroquinolones have been previously described (1; H. C. Neu, Antimicrob. Newsl. 4:9-14, 1987). The quinolones for which most clinical data are available, such as norfloxacin, ofloxacin, enoxacin, and ciprofloxacin, have less than optimal activity against streptococci (1). In addition, they do not have significant activity against many gram-negative anaerobic bacteria (5). A-61827 ( Fig. 1) Chu, 25th ICAAC, abstr. no. 133, 1985). The activity of this compound, relative to ciprofloxacin, is described in greater detail in this paper. MATERIALS AND METHODSBacterial strains. The bacterial strains used in this study were clinical isolates maintained frozen at -60°C.Antibacterial agents. A-61827 and ciprofloxacin were synthesized at Abbott Laboratories, Abbott Park, Ill. Solutions of ciprofloxacin were prepared in water. Since the free base A-61827 is poorly soluble in water, A-60969, the HCl salt, was used for in vitro tests. Stock solutions at a concentration of 100 p.g of base per ml were prepared in water by being heated in a boiling-water bath. For in vivo tests, the sulfate salt of A-61827 was used instead of the HCI salt because of the higher solubility of the former. Stock solutions containing 2 mg of base per ml were prepared for in vivo tests.Metronidazole (G. D. Searle and Co., Skokie, Ill.) was * Corresponding author. dissolved in sterile water to a concentration of 4 mg/ml and was neutralized with 8.5% sodium bicarbonate.Susceptibility tes...

The MICs of difloxacin (A-56619), A-56620 and ofloxacin were similar or within one to two-fold dilutions against a variety of anaerobic bacteria. Ciprofloxacin was slightly less active (two- to four-fold dilutions) than difloxacin, A-56620 and ofloxacin. Norfloxacin was less active than the other fluoroquinolones tested against anaerobic bacteria. The MICs of norfloxacin, A-56620, ciprofloxacin and ofloxacin against most anaerobes, except the Gram-positive cocci, were lower at pH 8.1 than at pH 6.6. MICs of the fluoroquinolones against anaerobic cocci were the same at pH 6.6, 7.3 and 8.1. Norfloxacin and ciprofloxacin were most affected by the acidic pH. Ofloxacin and A-56620 were affected to a lesser extent by an acidic pH than norfloxacin and ciprofloxacin. The potency of difloxacin was similar at the three pHs tested. A subcutaneous anaerobic infection model in mice was used to determine the in-vivo efficacy of the new fluoroquinolones against Bacteroides fragilis. Difloxacin was the most potent compound in this test.