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The multiple-dose pharmacokinetics and safety of amifloxacin, a new fluoroquinolone antibacterial agent, were evaluated in healthy male volunteers. Amifloxacin was administered orally at 200, 400, or 600 mg every 12 h (q12h) and 400, 600, or 800 mg every 8 h (q8h) for 10 days. An additional dose was administered on day 11. Concentrations of amifloxacin in plasma and urine were measured on days 1, 5, and 11 by high-performance liquid chromatography. Steady-state amifloxacin concentrations were reached by day 5. Mean +/- standard deviation maximum observed amifloxacin concentrations in plasma were 2.52 +/- 1.12, 4.98 +/- 1.44, 5.40 +/- 2.02, 4.59 +/- 2.17, 6.53 +/- 2.44, and 8.01 +/- 3.00 micrograms/ml after the initial dose and 2.30 +/- 0.98, 5.41 +/- 0.74, 8.05 +/- 1.68, 6.87 +/- 2.81, 9.53 +/- 0.50, and 11.9 +/- 1.92 micrograms/ml on day 11 of the study for the 200-, 400-, and 600-mg q12h and 400-, 600-, and 800-mg q8h regimens, respectively. Amifloxacin was rapidly absorbed, as evidenced by the mean time to the maximum observed amifloxacin concentration of 0.98 h. Mean values for the terminal amifloxacin half-life in plasma ranged from 3.58 to 5.78 h. Mean amifloxacin concentrations in urine on day 11 in samples collected 0 to 2 h after dosing were 105, 417, 376, 336, 518, and 464 micrograms/ml for the 200-, 400-, and 600-mg q12h and 400-, 600-, and 800-mg q8h regimens, respectively. The mean amount of the dose excreted in the urine as amifloxacin was 53.9%. Amifloxacin was generally well tolerated, although there was a tendency for the subjects who received amifloxacin to experience more gastrointestinal, central nervous system, and cutaneous complaints than did those who received placebo. Clinically significant adverse reactions, including pruritus and transaminase elevations, occurred only at doses of 1,200 mg/day or above. Clinical and pharmacokinetic data suggest that orally administered amifloxacin may have utility in the treatment of urinary tract infections.

In preliminary in vitro susceptibility tests Ro 24-6392 (desacetylcefotaxime with a 3'-ciprofloxacin substitution) demonstrated activity against a wide spectrum of aerobic bacteria, 98.6% of strains being inhibited by less than or equal to 8 mg/l. Of the commonly isolated species tested, only enterococcal strains were resistant (MICs greater than or equal to 32 mg/l). The potency of Ro 24-6392 was generally between that observed for the two hydrolysis components, except in the case of Providencia stuartii and penicillin-resistant pneumococci isolates which were more susceptible to Ro 24-6392. This new dual-action compound appears to be slightly more active than the previously studied peer drug Ro 23-9424, principally because of the superior activity of the fluoroquinolone component, ciprofloxacin.

Thirteen patients with cystic fibrosis and 12 healthy control volunteers received a single oral 800 mg dose of fleroxacin and 800 mg every day for 5 days. Interstitial fluid penetration was studied by the suction-induced blister technique. Fleroxacin and its two major metabolites, N-demethyl and N-oxide, were analyzed in plasma and urine by HPLC. Single-dose absorption parameters (absorption rate constant, normalized peak plasma drug concentration, and time to reach peak concentration) and total urinary excretion indicated that fleroxacin was absorbed more slowly and more completely in patients with cystic fibrosis than in control subjects. Fleroxacin volume of distribution tended to be smaller in patients with cystic fibrosis and it reached statistical significance after a single dose when normalization for lean body mass was applied. When normalized for lean body mass, the formation clearance of N-demethyl fleroxacin and N-oxide fleroxacin was significantly greater in patients with cystic fibrosis than in control subjects (p less than 0.05). These data concur with those of others showing an induction of drug-metabolizing enzymes in cystic fibrosis. Renal clearances of fleroxacin and its metabolites were significantly increased in cystic fibrosis (p less than 0.05), and this seems to be explained by a decreased tubular reabsorption of these compounds. The differences seen in the pharmacokinetics of fleroxacin in cystic fibrosis support the theories of generalized induction of drug metabolism and of a defective renal tubular reabsorptive process of drugs in cystic fibrosis.

A new "dual action" cephalosporin (Ro 24-6778), representing an ester-linked desacetylcefotaxime and desmethylfleroxacin was tested against 287 aerobic bacteria. Ro 24-6778 was found to be very active (minimal inhibitory concentrations [MIC90], less than or equal to 0.5 micrograms/ml) against Enterobacteriaceae, Streptococcus spp., and Aeromonas hydrophila. Moderate Ro 24-6778 activity (MIC90, 1-8 micrograms/ml) was demonstrated against Bacillus spp., Staphylococcus spp. (including oxacillin-resistant strains), Flavobacterium spp., Enterococcus durans, and Acinetobacter anitratus. More Ro 24-6778-resistant strains (MIC90, 16- greater than 32 micrograms/ml) were usually found among the enterococci, Xanthomonas hydrophila, Pseudomonas spp., and Achromobacter xyloxidans isolates. These preliminary Ro 24-6778 MIC test results show a spectrum superior (93.4% of strains susceptible at less than or equal to 8 micrograms/ml) to the comparison drugs (cefotaxime or fleroxacin) and possible clinical utility for therapy of many fluoroquinolone- or cephalosporin-resistant strains.

The histologic and histochemical features of quinolone-induced arthropathy were studied using 14 skeletally immature Beagle dogs (3 to 4 months old) dosed orally with difloxacin at 300 mg/kg body weight once daily for 1, 2, 5, or 7 days. A placebo was given to eight other age-matched Beagle dogs that served as controls. A scoring technique that included lesion size and histologic features was used to determine the progression of lesions. Articular-epiphyseal cartilage complexes on the femoral and humeral heads and tibial tarsal bone were identified as predilection sites. Within predilection sites on femoral and humeral heads, lesions developed in specific areas. Lesions appeared within 2 days of the onset of treatment, and lesion scores increased with time. Grossly, the lesions were raised, fluid-filled vesicles on the articular surface. Histologic changes included vesicle formation with loss of proteoglycan, clumping of unmasked collagen, and degeneration and necrosis of chondrocytes. In lesions with higher scores, chondrocytes were often in clusters or they were undergoing metaplasia toward spindle-shaped cells. Although dissolution of matrix and necrosis of chondrocytes were typical of all lesions, smaller lesions had histologically normal chondrocytes adjacent to small vesicles. In sections stained with toluidine blue, proteoglycan was aggregated with collagen fibrils or was absent from the matrix adjacent to vesicles. Unique features, such as biomechanical forces, may predispose specific areas of articular cartilage to develop lesions.

Amifloxacin pharmacokinetics after a single oral dose in healthy elderly subjects were determined. Five males and five females aged 65 to 79 years and having creatinine clearances of 39.3 to 87.2 ml/h per kg of body weight were given a 200-mg amifloxacin caplet following an overnight fast. Mean (standard deviation) pharmacokinetic parameters for amifloxacin were as follows: maximum observed concentration in plasma, 1.13 (0.48) and 1.95 (0.52) micrograms/ml; half-life, 5.37 (0.96) and 4.47 (0.87) h; total plasma clearance (unadjusted for fraction absorbed), 259 (53) and 199 (55) ml/h per kg; renal clearance, 113 (20) and 86 (26) ml/h per kg; Varea/F (Varea is volume of distribution; F is fraction absorbed), 2.05 (0.75) and 1.28 (0.39) liter/kg; and amifloxacin excreted in the urine, 42.5% (14.5%) and 42.8% (10.6%) for males and females, respectively. There were no statistically significant differences in pharmacokinetic parameters between sexes that could not be attributed to differences in body weight. Except for a modest 23% reduction in renal clearance and the suggestion of reduced bioavailability, mean values of pharmacokinetic parameters for elderly male subjects were similar to those previously determined for younger male volunteers. Therefore, a modification in amifloxacin dosage regimen based solely on age may not be necessary.

Steady-state pharmacokinetics of oral fleroxacin were studied in six males who had skin or skin structure infections and who were receiving 400 mg of fleroxacin once a day. Blood samples (n = 10) and total urine output were collected during a 24-h dosing interval. Fleroxacin concentrations in serum and urine were determined by high-performance liquid chromatography. The maximum concentration in serum and the time to achieve that maximum were 6.2 +/- 2.2 micrograms/ml and 0.94 +/- 0.62 h, respectively. The absorption half-life, alpha half-life, beta half-life, apparent steady-state volume of distribution, apparent total body clearance, and renal clearance were 0.56 +/- 0.37 h, 0.78 +/- 0.51 h, 10.56 +/- 1.40 h, 0.85 +/- 0.31 liters/kg, 129.2 +/- 19.6 ml/min, and 53.3 +/- 16.7 ml/min, respectively. Fleroxacin disposition in this patient population was similar to that in noninfected volunteers with normal renal function.

The effect of the O2-dependent antimicrobial systems of the human neutrophil on the intraphagocytic activity of difloxacin, ciprofloxacin, pefloxacin and fleroxacin was determined by use of a radioassay with Staphylococcus aureus as the test organism. The fluoroquinolones exhibited good intraphagocytic activity with normal neutrophils. However the intracellular bioactivities of the four antimicrobial agents were substantially less in tests with neutrophils from two patients with chronic granulomatous disease. These observations suggest a synergic interaction between fluoroquinolones and the O2-dependent antimicrobial systems of phagocytes in the eradication of intracellular microbial pathogens.

A high-performance liquid chromatographic method is described for the determination of the new fluoroquinolone fleroxacin and its metabolites in plasma and urine. Plasma samples are deproteinized with acetonitrile, and, after evaporation and reconstitution of the supernatant, samples are analysed on a reversed-phase column. The limit of quantification is 10-20 ng/ml for the parent drug and 10 ng/ml for the metabolites, using a 0.2-ml sample. Urine samples are diluted with the mobile phase. An aliquot is then injected directly onto the column. The limits of quantification are 1 micrograms/ml for the parent drug and 0.5 micrograms/ml for the metabolites, using a 0.1-ml sample. The method has been successfully applied to pharmacokinetic studies of human volunteers and patients.

7-(2-Aminoethoxy)-, 7-(2-aminoethylthio)-, and 7-(2-aminoethylamino)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoq uin oline-3- carboxylic acids and their derivatives (11a--f, h, j, k, 12a--f, and 13a--f) were synthesized and their antibacterial activities were tested. Among them, compounds (13a, d) having a primary amino group at the terminal position of alkoxy and alkylthio groups were found to have excellent in vitro and in vivo antibacterial activity comparable to those of ciprofloxacin (5). Structure-activity relationship of these compounds was also stated.

The in vitro and in vivo interaction of fleroxacin with amphotericin B (Amph B), flucytosine (5-FC) and azoles against Candida albicans strains was tested. In vitro the interaction between fleroxacin and various antifungals was not dependent on the incubation time. Fleroxacin neither enhances nor antagonizes the in vitro activity of Amph B at high concentration (50-100 micrograms/ml). Fleroxacin has a synergistic effect with ketoconazole (KETO), but this is not observed with itraconazole (ITRA) or fluconazole (FLU). In no instance antagonism was observed. The activity of 5-FC was antagonized by fleroxacin being generally reduced by 2-4 dilution steps. In murine candidosis the efficacies of all antifungal drugs were not influenced by addition of 100 mg/kg fleroxacin. Therefore, the effects seen in in vitro tests are most probably not relevant for the clinical use of a combination of fleroxacin with antifungal drugs.

We conducted a randomized controlled trial of orally administered amifloxacin versus trimethoprimsulfamethoxazole (TMP-SMX) as treatments of acute uncomplicated urinary tract infection in women. Amifloxacin at a dosage of 200 mg twice a day appeared as safe and effective as TMP-SMX, but amifloxacin at 400 mg twice a day tended to cause adverse events more frequently than did TMP-SMX.

Ciprofloxacin analogs with various substitutions on the piperazine nitrogen were tested against several mycobacteria. In contrast to what has been found with other gram-positive and gram-negative bacteria, alkyl analogs such as N-isopropylciprofloxacin were shown to be significantly more active than ciprofloxacin. MICs of 0.125 microgram/ml against Mycobacterium tuberculosis were found.

In a double-blind randomized trial, we evaluated the efficacy and safety of three oral dosage regimens of fleroxacin, a new fluoroquinolone, once daily in 62 patients for the treatment of complicated urinary tract infections. The regimens compared were 200 mg for 10 days (n = 20), 400 mg for 10 days (n = 21), and 600 mg for 10 days (n = 21). Forty-five patients were evaluable for efficacy. A clinical cure was reached in 78% of the patients. Overall, a favorable bacteriological response (negative culture or reinfection at 4 to 6 weeks) was obtained in 36 of 45 (80%) patients. No significant difference could be found among the three dosage groups. During therapy, one Klebsiella ozaenae strain became resistant and one Pseudomonas aeruginosa strain became less susceptible to fleroxacin. In 13 patients, therapy had to be discontinued due to major adverse events (oliguria [n = 1], psychosis [n = 1], photosensitivity [n = 1], insomnia [n = 1], and nausea [n = 9]). Minor side effects were seen in 13 other patients. Increased dosage correlated significantly (P less than 0.01) with total number of adverse events.

The in vitro activity of Ro 23-9424, which is desacetyl-cefotaxime linked to fleroxacin, was compared with the activities of cefotaxime, desacetyl-cefotaxime, fleroxacin, ofloxacin, and ciprofloxacin. It inhibited the majority of members of the family Enterobacteriaceae, except for some Serratia marcescens, Citrobacter freundii, and Enterobacter cloacae strains, at less than or equal to 0.25 microgram/ml and had an MIC for 90% of strains tested (MIC90) of 8 micrograms/ml against Pseudomonas aeruginosa. Most group A, B, C, and G streptococci and Streptococcus pneumoniae were inhibited at less than or equal to 0.25 microgram/ml. Ninety percent of the staphylococci were inhibited at less than or equal to 4 micrograms/ml, except for some methicillin-resistant Staphylococcus aureus isolates. The MIC90S of Ro 23-9424 for Enterococcus faecalis and Listeria monocytogenes were greater than or equal to 16 micrograms/ml. Ninety percent of Clostridium perfringens isolates were inhibited by less than or equal to 2 micrograms/ml, whereas Bacteroides fragilis had an MIC90 of 32 micrograms/ml. There was a minimal inoculum size effect. The MICs and MBCs were either identical or within a twofold dilution. The MICs of Ro 23-9424 for Escherichia coli, Klebsiella pneumoniae, Serratia marcescens, Enterobacter cloacae, Citrobacter freundii, Pseudomonas aeruginosa, and Staphylococcus aureus increased 16- to 128-fold after 2 weeks of transfer in the presence of Ro 23-9424, showing that the presence of two agents does not prevent resistance.

Tosufloxacin (A-60969 HCl), a new quinolone with broad activity against gram-positive and anaerobic organisms, was compared in vitro with other quinolones against bacterial pathogens of diarrhea. Tosufloxacin was the most active agent against Salmonella spp., Shigella spp., Campylobacter spp., Aeromonas hydrophila, and Vibrio spp. Temafloxacin (A-62254) also demonstrated good activity against these organisms.

Quinolone-resistant clones were selected from clinical Escherichia coli, Citrobacter freundii and Serratia marcescens isolates in a frequency ranging from 10(-8) to 10(-6). The outer membrane proteins of quinolone-resistant E. coli clones remained unaltered, as was the case for 10 of 11 C. freundii and 4 of 11 S. marcescens clones ('nal B' type). There was no strong relation between alterations of outer membrane proteins and cross-resistance with chemically unrelated compounds such as tetracycline or chloramphenicol; however, tetracycline resistance was observed in some C. freundii clones with unaltered outer membrane proteins ('mar A'). Most of the quinolone-resistant S. marcescens clones can be considered 'nor B' or 'nor C' mutants due to their cross-resistance with other compounds, their altered outer membrane proteins and changes of lipopolysaccharide. In a few cases, subinhibitory quinolone concentrations caused alterations of outer membrane proteins in S. marcescens during mid log phase without development of resistance.

A rapid technique for sample preparation and HPLC was developed to study in vitro the erythrocyte binding and plasma protein binding of fleroxacin in the concentration range 0.2-15 micrograms ml-1. The red blood cell partition coefficient of fleroxacin was 1.45 +/- 0.18 at 25 degrees C and was independent of concentration, incubation time and temperature. The in vitro plasma protein binding of fleroxacin in humans, determined by two independent methods, was 47-51%. Partition studies using erythrocytes as a simple in vitro model may be useful to predict the degree of tissue uptake and the volume of distribution.

Single-dose administration of fleroxacin was evaluated as a means of preventing foreign body infection due to staphylococci. Tissue cages were implanted into guinea pigs and subsequently infected (100% rate) with 10(2) or more CFU of Staphylococcus aureus Wood 46. When a single dose of 30 mg of fleroxacin or vancomycin per kg of body weight was administered intraperitoneally, bactericidal levels of the antimicrobial agent were found in the tissue cage fluid after 3 h (when guinea pigs were inoculated with S. aureus) and during the next 24 h. Either fleroxacin or vancomycin successfully prevented experimental infection in all tissue cages challenged by 10(2) CFU of S. aureus Wood 46. When tissue cages were challenged with 10(4) CFU of S. aureus Wood 46, however, fleroxacin was more effective than vancomycin (P less than 0.05) in reducing colony counts below the detection limit of 10 CFU/ml in the inflammatory fluid of all tissue cages during the initial 48 h. In contrast to their initially different actions, the effects of the antibiotics were similar after 7 days, mostly because bacterial regrowth occurred more frequently in the fleroxacin-treated than in the vancomycin-treated tissue cages. These data show that experimental infections of subcutaneous tissue cages are a useful model for studying the prophylaxis of foreign body infections with antimicrobial agents.

Fleroxacin (Ro 23-6240, AM-833), a new fluoro-4-quinolone, was tested in vitro against 273 gram-positive clinical isolates. Norfloxacin, a quinolone mostly used in urinary tract infections, was included as a standard. Overall, in vitro activities of fleroxacin and norfloxacin were superposable, but interestingly, fleroxacin was two- to fourfold more active against Staphylococcus aureus, and 1 mg/l of fleroxacin inhibited all 5 multiply resistant Corynebacterium jeikeium tested. While both quinolones were similarly active weight by weight, fleroxacin with its more favorable pharmacokinetic properties harbors the added promise of clinical usefulness in systemic infections against susceptible isolates.

The dual-action antibacterial R 23-9424 (desacetylcefotaxime linked to the quinolone fleroxacin) is a new antibacterial agent with excellent in vitro activity. It was evaluated for in vivo efficacy in comparison with the cephalosporin cefotaxime and the quinolone component, fleroxacin. Ro 23-9424 demonstrated significant activity against all strains tested in systemic infections, including those strains resistant in vivo to cefotaxime (Staphylococcus aureus 753, Serratia marcescens SM and Pseudomonas aeruginosa 8780) and fleroxacin (Streptococcus pneumoniae 6301 and Streptococcus pyogenes. In prophylactic studies, Ro 23-9424 compared favorably with fleroxacin against Escherichia coli and with cefotaxime against S. pyogenes, but Ro 23-9424 was considerably more active than cefotaxime against E. coli and more active than fleroxacin against S. pyogenes. In a murine pneumonia model, Ro 23-9424 was equivalent in activity to cefotaxime against S. pneumoniae and more active than cefotaxime against Klebsiella pneumoniae. Fleroxacin was inactive against S. pneumoniae and about 20-fold more active than Ro 23-9424 against K. pneumoniae. In a murine meningitis infection caused by S. pneumoniae, Ro 23-9424 was 3 times as active as cefotaxime, while fleroxacin was inactive. When meningitis was induced by K. pneumoniae, Ro 23-9424 was as active as the quinolone, while cefotaxime was inactive. In a neutropenic (immunocompromised) model, Ro 23-9424 was more active than cefotaxime against P. aeruginosa and 5-fold less active than fleroxacin. In the control normal (immunocompetent) mouse infection, Ro 23-9424 was 3-fold more active than cefotaxime, but 10-fold less active than fleroxacin.

The renal handling of fleroxacin was studied by renal clearance and stop-flow techniques in rabbits and dogs and by analyzing the pharmacokinetics with and without probenecid in humans. In rabbits the excretion ratios (fleroxacin intrinsic renal clearance/glomerular filtration rate) were greater than unity (2.01) without probenecid and were decreased to a value below unity (0.680) with probenecid. In dogs, on the other hand, the excretion ratios were less than unity (0.608 and 0.456) both without and with probenecid, and so were not affected by probenecid. This fact suggested that fleroxacin was excreted into urine by both glomerular filtration and renal tubular secretion in rabbits, but only by glomerular filtration in dogs, accompanied by partial renal tubular reabsorption in both species; these mechanisms were also supported by stop-flow experiments. In humans probenecid treatment induced increases in the elimination half-life and area under the serum concentration-time curve and decreases in apparent serum clearance, renal clearance, and urinary recovery of fleroxacin. The excretion ratio without probenecid was 1.13, which was significantly decreased to 0.750 with probenecid. These results indicated that both renal tubular secretion and reabsorption contributed to renal excretion of fleroxacin in humans. The contribution of tubular secretion was species dependent and was extensive in rabbits, minimal in dogs, and moderate in humans. Renal tubular reabsorption was commonly found in every species. The long elimination half-life of fleroxacin in humans might be explained by its small total serum clearance and small renal clearance, which are attributed to less tubular secretion and more tubular reabsorption.

The broad antimicrobial spectrum of Fleroxacin RO 23-6240 was tested on a panel of bacterial and several mycobacterial species. Staph. aureus strains, gramnegative bacteria E. coli, Kl. pneumoniae, Salmonella spp. were found to be rather susceptible to the tested preparation in vitro. The same was true of those species which are known to feature strong natural resistance, e.g. Ps. aeruginosa and Acinetobacter calcoaceticus. As regards mycobacteria, complete susceptibility was recorded for 10 M. tuberculosis strains, 17 M. kansasii strains and 4 strains of M. fortuitum. Only two of the eleven tested strains of the complex M. avium-intracellulare were found to be susceptible and one M. chelonae strain tested proved resistant. Due to their broad spectrum and strong bactericidal effects, chinolone preparations can be anticipated to assume an everincreasing significance in the future.

According to the generally accepted mechanism by which bacterial enzymes react with cephalosporins, opening of the beta-lactam ring can lead to the expulsion of a 3'-substituent. A series of dual-action cephalosporins was prepared in which antibacterial quinolones were linked to the cephalosporin 3'-position through an ester bond in the expectation that, in addition to exerting their own beta-lactam activity, these cephalosporins would act as prodrugs for the second antibacterial agent. Compared to parent cephalosporins in which the 3'-substituent was acetoxy, the bifunctional cephalosporins exhibited a broadened antibacterial spectrum, suggesting that a dual mode of action may indeed be operative.

The activity of amifloxacin, a new quinolone carboxylic acid compound, against 147 strains of microorganisms was studied and was compared with the activities of cinoxacin, trimethoprim, amikacin, and four beta-lactam antimicrobials. The minimal concentration at which 90% of strains were inhibited by amifloxacin was lowest for Escherichia coli and Klebsiella sp (less than or equal to 0.125 microgram/ml), followed by Proteus sp (less than or equal to 0.25 microgram/ml), Enterobacter sp and Citrobacter sp (less than or equal to 0.5 microgram/ml), Providencia sp (less than or equal to 2 micrograms/ml), and Pseudomonas aeruginosa, Serratia sp, and Acinetobacter calcoaceticus var anitratus (less than or equal to 8 micrograms/ml). When compared with the ranges of activity of seven reference antimicrobials, the range of amifloxacin activity was lowest for P aeruginosa, Citrobacter sp, Proteus sp, and A calcoaceticus var anitratus and similar to aztreonam's activity against Enterobacter sp. For amikacin-resistant P aeruginosa, the minimal inhibitory concentrations (MICs) of amifloxacin ranged from 1 to 16 micrograms/ml. The MICs and minimal bactericidal concentrations (MBCs) of amifloxacin were similar. For all strains tested, microbial susceptibilities to amifloxacin were greater than those to currently available oral antimicrobial drugs, such as cinoxacin and trimethoprim.

Two quinolones, fleroxacin and ofloxacin were used as oral treatment in a model of experimental pyelonephritis in rats. The infecting strains were Escherichia coli, Klebsiella oxytoca and Pseudomonas aeruginosa. Compared to untreated control rats, the rats treated with the quinolones showed a great reduction in bacterial counts in kidney tissue and urine. At lower dosages, fleroxacin had a greater bacterial killing effect than ofloxacin.

The in vitro activity of the dual-action antibacterial agent Ro 23-9424 was compared with those of cefotaxime, ceftazidime, ciprofloxacin, fleroxacin, imipenem, and amikacin against 358 aerobes and anaerobes. The MIC ranges, MICs for 50 and 90% of the strains (MIC50s and MIC90s), and percentage of strains susceptible for each agent at the recommended susceptible MIC breakpoint were determined for each genus. The MIC90s (micrograms per milliliter) of the agents against members of the family Enterobacteriaceae were as follows: ciprofloxacin, 0.063; Ro 23-9424, fleroxacin, and imipenem, 0.5; ceftazidime, 2; amikacin, 4; and cefotaxime, 16. The MIC90s (micrograms per milliliter) against Pseudomonas and Acinetobacter spp. were as follows: ciprofloxacin, 2; ceftazidime and imipenem, 8; Ro 23-9424, 16; fleroxacin, 32; amikacin, 64; and cefotaxime, 128. Against gram-positive bacteria, excluding the enterococci, the MIC90s (micrograms per milliliter) were as follows: ciprofloxacin, 1; imipenem, 4; Ro 23-9424 and fleroxacin, 8; amikacin, 64; and ceftazidime and cefotaxime, greater than 128. Against gram-positive bacteria, including the enterococci, the MIC90s changed only for the following agents: Ro 23-9424, 16 micrograms/ml; and amikacin, 128 micrograms/ml. Strains of Branhamella catarrhalis, Haemophilus influenzae, and Neisseria gonorrhoeae were 100% susceptible to Ro 23-9424, cefotaxime, ciprofloxacin, and fleroxacin, while the other three agents showed somewhat less activity only against N. gonorrhoeae. Against anaerobes, imipenem was the most effective agent, while the activities of the other six agents were variable.

Ro 23-9424 is a broad-spectrum antibacterial agent composed of a cephalosporin and a quinolone moiety. Its biological properties were compared with those of its two components and structurally related cephalosporins and quinolones. Like ceftriaxone and cefotaxime but unlike its decomposition product, desacetyl cefotaxime, Ro 23-9424 bound at less than or equal to 2 micrograms/ml to the essential penicillin-binding proteins 1b and 3 of Escherichia coli and 1, 2, and 3 of Staphylococcus aureus. In E. coli, Ro 23-9424 produced filaments exclusively and decreased cell growth; cefotaxime produced both filaments and lysis. Like its decomposition product fleroxacin but unlike quinolone esters, Ro 23-9424 also inhibited replicative DNA biosynthesis in E. coli. In an E. coli strain lacking OmpF, growth continued after addition of Ro 23-9424, decreased after addition of cefotaxime, and stopped immediately after addition of fleroxacin. The results, together with the chemical stability of Ro 23-9424 (half-life, approximately 3 h at pH 7.4 and 37 degrees C), suggest that in E. coli the compound acts initially as a cephalosporin with intrinsic activity comparable to that of cefotaxime but with poorer penetration. Subsequent to the decomposition of Ro 23-9424 to fleroxacin and desacetyl cefotaxime, quinolone activity appears. The in vitro antibacterial activity reflects both mechanisms of action.

Several 3-formylquinolone derivatives (8a-c) were synthesized to assay the antibacterial activity both in vitro and in vivo. In vitro, all of the compounds 8a-c showed lower activity than that of the corresponding 3-carboxyl compounds 1a-c, and in vivo, they showed higher activity than that of compounds 1a-c. After oral administration of 3-formyl compounds 8a-c to mice, the compounds were rapidly metabolized into 3-carboxyl compounds 1a-c. In particular, the 3-formyl derivative (8a) of norfloxacin (NFLX, 1a) gave a 2-fold higher serum level than that of NFLX and functioned as a prodrug of NFLX.

The killing kinetics of fleroxacin against four strains of Bacteroides fragilis were investigated. Viable counts were determined from 0 to 24 h after exposure to fleroxacin at multiples of the MIC. A one to three log reduction in viable count was observed after 2 h at 8 mg/l fleroxacin, and a more rapid rate of killing was seen at greater concentrations of the antimicrobial agent. An increase in cell length was observed at concentrations at and above the MIC from 2 h after exposure. The presence of a bacteriostatic concentration of chloramphenicol had negligible influence on viability but inhibited cell elongation.

A-56619 and A-56620 are two new quinolone compounds that are currently being studied. They were found to be active against multi-resistant and routine isolates of Staphylococcus aureus, enterobacteria, aminoglycoside-sensitive and resistant strains of Pseudomonas aeruginosa. Most of the enterobacteria were inhibited by 0.5-1 mg/l of A-56620. A-56619 was less active, concentrations of 1-4 mg/l being needed for 90% inhibition. Both the compounds were active at concentrations of 0.5-1 mg/l against staphylococci, including multi-resistant S. aureus. The MIC90 for P. aeruginosa was 1-2 mg/l for A-56620 and 8 mg/l for A-56619.

A series of novel arylfluoroquinolones has been prepared. These derivatives are characterized by having a fluorine atom at the 6-position, substituted amino groups at the 7-position, and substituted phenyl groups at the 1-position. Structure-activity relationship (SAR) studies indicate that the in vitro antibacterial potency is greatest when the 1-substituent is either p-fluorophenyl or p-hydroxyphenyl and the 7-substituent is either 1-piperazinyl, 4-methyl-1-piperazinyl, or 3-amino-1-pyrrolidinyl. The electronic and spatial properties of the 1-substituent, as well as the steric bulk, play important roles in the antimicrobial potency in this class of antibacterials. As a result of this study, compounds 45 and 41 were found to possess excellent in vitro potency and in vivo efficacy.

The pharmacokinetics of a single 400 mg oral dose of fleroxacin and pefloxacin were evaluated in ten healthy male volunteers in a randomized cross-over study. There were no significant differences in Tmax (0.9 vs. 1.3 h) and in plasma elimination half-life (11.9 vs. 10.8 h) between fleroxacin and pefloxacin. Cmax and AUC of fleroxacin were statistically significantly greater (P less than 0.05) compared to pefloxacin (Cmax: 5.62 vs. 4.09 mg/l, AUC0-48: 65.9 vs. 48.7 mg/l.h, AUC0-infinity: 70.7 vs. 51.5 mg/l.h). Renal clearances of fleroxacin and pefloxacin were 51.8 and 11.7 ml/min respectively. The 48-h urine recovery was 48.6% for fleroxacin, 8.6% for pefloxacin, 7.1% and 17.4% for the N-demethyl metabolites, and 3.8% and 16.6% for the N-oxide metabolites of fleroxacin and pefloxacin respectively. Urinary concentrations of both the microbiologically active parent drug and the N-demethyl metabolite of fleroxacin were, at all intervals up to 48 h post dose, two to three times higher than those of pefloxacin.

Ro 23-9424 is a novel ester-linked codrug of fleroxacin (Ro 23-6240; AM-833) and the cefotaxime metabolite desacetylcefotaxime. Its potency was determined against over 1,000 organisms and found to be intermediate between those of the two components. More than 99% of members of the family Enterobacteriaceae were inhibited by greater than or equal micrograms of Ro 23-9424 per ml; its MIC for 50% of strains tested ranged from greater than or equal to 0.06 to 1 micrograms/ml. Staphylococci, streptococci, Branhamella catarrhalis, Corynebacterium jeikeium, Bacillus spp., Haemophilus influenzae, Listeria monocytogenes, and the pathogenic Neisseria spp., including oxacillin-resistant Staphylococcus aureus, beta-lactamase-producing strains, and penicillin-resistant pneumococci, were also inhibited by Ro 23-9424. Pseudomonas aeruginosa, Enterococcus spp., and Bacteroides fragilis group isolates were more refractory to Ro 23-9424 (the MIC for 90% of strains tested was less than or equal to 32 micrograms/ml). Overall, Ro 23-9424 inhibited 97% of the aerobic strains, compared with 90% for ceftazidime and 92% for cefoperazone. Ro 23-9424 was bactericidal, was relatively stable to inoculum effects on MICs at 10(7) CFU/ml, and was determined to be highly active against organisms resistant to fluoroquinolones or ceftazidime. Preliminary quality control guidelines were determined, and a 30-micrograms disk concentration appears to be the most usable form.

The in-vitro activity of Sch 34343, a new penam antibiotic, was tested against 257 Gram-positive isolates from cancer patients, and compared with that of imipenem and amifloxacin. Sch 34343 was extremely active against beta-haemolytic streptococci (Lancefield groups A, B and G) with MIC90s ranging from 0.025 to 0.05 mg/l. It was also active against methicillin-susceptible Staphylococcus aureus and had variable activity against coagulase-negative staphylococci. MIC90 for Listeria monocytogenes was 0.78 mg/l and 84% of enterococcal isolates were inhibited by 6.25 mg/l.

Chancroid is gaining importance as a sexually transmitted disease because of its association with transmission of human immunodeficiency virus type 1 (HIV-1). Effective, simply administered therapy for chancroid is necessary. Fleroxacin is effective against Haemophilus ducreyi in vitro. We performed an initial randomized clinical trial to assess the efficacy of fleroxacin for treatment of chancroid in Nairobi, Kenya. Fifty-three men with culture-positive chancroid were randomly assigned to receive either 200 mg (group 1) or 400 mg (group 2) of fleroxacin as a single oral dose. Groups 1 and 2 were similar with regard to severity of disease, bubo formation, and HIV-1 status. A satisfactory clinical response to therapy was noted in 23 of 26 patients (88%) in group 1 and 18 of 23 patients (78%) in group 2. Bacteriological failure occurred in 1 of 26 evaluable patients (4%) in group 1 and 4 of 23 evaluable patients (17%) in group 2. Two of 37 HIV-1-seronegative men (5%) and 3 of 11 HIV-1-infected men (27%) were bacteriological failures. Fleroxacin, 200 or 400 mg as a single oral dose, is efficacious therapy for microbiologically proven chancroid in patients who do not have concurrent HIV-1 infection. Among HIV-1-infected men, a single dose of 200 or 400 mg of fleroxacin is inadequate therapy for chancroid.

The new aryl fluoroquinolones, Abbott 56619 and Abbott 56620, were compared to ciprofloxacin, norfloxacin and newer beta-lactam agents in standardized microtiter testing versus multidrug-resistant gram-negative bacilli. Ciprofloxacin, followed by Abbott 56620, was generally the most active quinolone and imipenem the most active beta-lactam agent.

Constant infusion experiments with amifloxacin, a quinoline carboxylic acid derivative, were performed in five anesthetized dogs to determine the drug concentrations in prostatic secretion (PS), prostatic interstitial fluid (PIF), prostatic tissue, and plasma (P). The experiments were carried out under steady-state conditions. Amifloxacin concentrations in PS and PIF were lower than the corresponding P concentrations, as might be expected for an acid compound. There was no significant difference between the PS/P and PIF/P concentration ratios of the drug, and none exceeded 1.0. The concentrations of amifloxacin in PS, PIF, and prostatic tissue were above the minimal inhibitory concentration values of most gram-positive bacteria causing chronic bacterial prostatitis. Clinical trials of amifloxacin seem justified.

Ro 23-6240 is a new fluoroquinolone displaying pronounced activity against a wide range of Gram-positive and Gram-negative pathogens. In order to obtain information about the absorption, distribution and excretion of this quinolone in man, six healthy volunteers received in cross-over an intravenous infusion of 100 mg Ro 23-6240 and an oral dose of two tablets corresponding to 400 mg Ro 23-6240. Serial plasma and urine samples were assayed for unchanged substance by HPLC with subsequent fluorescence or UV detection. Pharmacokinetics were evaluated from these data assuming a two-compartment open model. Characteristic of this new antibacterial are the high plasma levels following oral administration (Cmax: 4.5 micrograms/ml) and the long elimination half-lives (8-12 h). Both these parameters are favourable kinetic prerequisites for a once-a-day dosage regimen. In addition, the volume of distribution at steady state clearly exceeds 1 l/kg and points to good tissue penetration. Total systemic clearance was 122 ml/min and total renal clearance reached 89 ml/min. Within 96 h, 60-70% of the administered dose was recovered from urine as unchanged drug. The absolute bioavailability (extent of absorption) of the tablet amounted to 96%, indicating a complete absorption of this galenic formulation.

The efficacy of fleroxacin versus that of vancomycin was assessed by using the rabbit model of methicillin-resistant Staphylococcus aureus endocarditis. Animals were treated with fleroxacin (30 mg/kg of body weight every 8 h) or vancomycin (17.5 mg/kg every 6 h) for 4 days. These antimicrobial agents were equally effective in clearing bacteremia, reducing bacterial counts in vegetations and tissues, and curing endocarditis. However, resistance to fleroxacin at fivefold the MIC arose in the test strain of S. aureus in 8% of animals that received the drug. We conclude that fleroxacin is as efficacious as vancomycin in this model of a serious systemic S. aureus infection, but modest resistance to fleroxacin may develop during therapy.

The in vitro activity of S-25930 and S-25932, two new 4-quinolones, against 450 aerobic gram-negative organisms isolated from cancer patients was evaluated and compared with the activity of ciprofloxacin, enoxacin, difloxacin (A-56619), and A-56620. Both agents inhibited most members of the family Enterobacteriaceae at concentrations of less than or equal to 2.0 micrograms/ml, but their activity against Pseudomonas aeruginosa was inferior to that of other quinolones. Although considerably less active than ciprofloxacin and A-56620, S-25930 was frequently two- to eightfold more active than S-25932 and was comparable to difloxacin and enoxacin against most isolates.

The in-vitro activity of Ro 23-6240, a new quinolone, was tested in comparison with that of other quinolones against 486 recent clinical isolates. Ro 23-6240 displayed the typical features of the new quinolones: highest activity against Gram-negative bacilli, MBCs close to the MICs, minimum inoculum effect and rapid killing. Against Gram-negative organisms (Enterobacteriaceae, non-fermenters, Haemophilus influenzae and gonococci) the activity of Ro 23-6240 was between that of ofloxacin and norfloxacin; against staphylococci its activity was between that of ciprofloxacin and ofloxacin, and against streptococci it was similar to that of norfloxacin.

The in vitro activities of A56619 (difloxacin) and A-56620, two newer quinolones, have been compared with the activities of ciprofloxacin, ofloxacin, ceftazidime and netilmicin. A total of 782 clinical, bacterial isolates were employed. Minimal inhibitory concentrations (MICs) were determined under standard conditions with all isolates and, for 100 isolates against difloxacin and A-56620, with variation of agar pH and bacterial inoculum size. On a weight-for-weight basis, ciprofloxacin and A-56620 were the most active agents against Enterobacteriaceae (MIC90 = 0.03 and 0.12 mg/l, respectively). Difloxacin was the least active quinolone, particularly against Proteus, Morganella and Providencia spp. Except for ceftazidime, all agents were highly active against staphylococci, but difloxacin and ofloxacin were somewhat less active against Staphylococcus saprophyticus. The streptococcal isolates were moderately sensitive to the quinolones, difloxacin being least active. Haemophilus influenzae and Neisseria gonorrhoeae were extremely susceptible to all the quinolones; nearly all isolates were inhibited by the lowest concentrations of the agents that were employed in the study (0.03 mg/l). The quinolones all showed moderate activity against Bacteroides fragilis. The activities of difloxacin and A-56620 were affected little by inoculum size. Difloxacin showed lower activity against most isolates at pH 8.0 as compared to the activity at pH 7.4 and 6.8. A-56620 was minimally influenced by pH variation.

The pharmacokinetics of fleroxacin after oral administration of 400 mg fleroxacin in twelve healthy volunteers were investigated. All drug analysis was carried out by HPLC. Pharmacokinetic analysis was done by non-compartmental methods. We found that fleroxacin achieves high plasma levels of 5.2 +/- 1.1 mg/l after 1.2 +/- 0.7 h. The high AUC-value of 60.4 +/- 8.4 mg.h/l is the result of complete absorption and the long half-life of 10.8 +/- 1.6 h. The total, renal and non-renal clearance of fleroxacin were 107.9 +/- 15.1, 67.6 +/- 11.8 and 40.3 +/- 14.5 ml/min respectively. The volume of distribution Vd beta/F was 101.4 +/- 21.9 or 1.32 +/- 0.28 l/kg. Fleroxacin penetrated well into saliva (66%), nasal secretions (223%), tears (69%) and sweat (43%). On the basis of these findings once a day administration deserves consideration in the further clinical development of fleroxacin.

Irloxacin (E-3432) is a new quinolone derivative. In this study, the activity of irloxacin was compared with that of nalidixic acid, norfloxacin and ciprofloxacin against strains of clinical isolates. Irloxacin showed greater in vitro activity than nalidixic acid, similar activity to norfloxacin and lower activity than ciprofloxacin. Against Staphylococcus, the MIC range of E-3432 was 0.06-1 mg/l, better than the other compounds studied.

A series of polyfluoro-3-quinolonecarboxylic acids have been synthesized and their in vitro antibacterial activity evaluated. The desired 7-(substituted amino) derivatives were prepared from the 5,6,7,8-tetrafluoroquinolone acids. Conversely, amine displacement occurred primarily at the 5-position when the ester was used. Structure-activity studies indicated that the antibacterial activity was greatest when the N-1 substituent was cyclopropyl and the 7-substituent was 4-methyl-1-piperazinyl. All 5-(substituted amino) derivatives showed poor in vitro activity.

An analytical method for the quantitation of amifloxacin, 6-fluoro-1,4-dihydro-1-(methylamino)-7-(4-methyl-1-piperazinyl)-4-oxo-3- quinolinecarboxylic acid, in plasma and urine has been developed. The method involves extraction with chloroform, back-extraction into 0.1 M sodium hydroxide, and subsequent analysis by reverse-phase high-pressure liquid chromatography with UV detection. The precision of the assay calculated as the overall standard deviation was +/- 4.9% in plasma and +/- 1.1% in urine. The range of mean percent differences from the nominal values was used as an estimate of accuracy and was 93.6 to 103% of the nominal values in plasma and 95.2 to 107% of the nominal values in urine. The minimum quantifiable levels were 0.032 micrograms/ml in plasma and 2.7 micrograms/ml in urine. The methods were employed in a pharmacokinetic analysis of amifloxacin after intravenous administration to rhesus monkeys. The decline in drug plasma levels was described by a biexponential process with mean rates of 8.4 h-1 and 0.32 h-1 with corresponding half-lives of ca. 5 min and 2.2 h. Amifloxacin was rapidly excreted, with ca. 53% of the dose appearing in the urine within 48 h after medication. The mean renal clearance +/- standard deviation was 4.4 +/- 1.0 ml X kg-1 X min-1 and is compatible with passive glomerular filtration in this species.