In vitro activity of fleroxacin against Gram-positive and-negative bacteria was determined. Fleroxacin showed potent activity against most enterobacteriaceae, Neisseria spp., and Haemophilus influenzae and good activity against staphylococci, Pseudomonas aeruginosa, and Branhamella catarrhalis. Against these bacteria, its activity was roughly comparable to that of norfloxacin and ofloxacin, but slightly less than that of ciprofloxacin. It also showed good activity against methicillin-resistant Staphylococcus aureus and gentamicin-resistant P. aeruginosa. Neither the medium, variation in medium pH, inoculum size, nor the addition of cations or human serum, had any major effect on its activity. It was bactericidal at concentrations around the MIC. It also strongly inhibited the supercoiling activity of DNA gyrase purified from Escherichia coli and P. aeruginosa. Fleroxacin produced an excellent postantibiotic effect (PAE) against E. coli, P. aeruginosa and S. aureus.

View full abstract

We compared the in vitro and in vivo antibacterial activity of fleroxacin with those of other new quinolones. The results are summarized as follows:
1. Fleroxacin had a broad spectrum, with potent antibacterial activity against both Gram-positive and-negative bacteria. Against these bacteria, the activity of fleroxacin was roughly comparable to that of norfloxacin, ofloxacin, enoxacin, and lomefloxacin.
2. Most nalidixic acid-resistant Gram-negative bacteria, gentamicin-resistant Gram-negative bacteria and methicillinresistant Staphylococcus aureus were susceptible to fleroxacin.
3. Fleroxacin displayed bactericidal action at concentrations around the MIC against various bacteria.
4. The appearance rate of mutants spontaneously by resistant to fleroxacin was very low.
5. Fleroxacin strongly inhibited the supercoiling activity of DNA gyrase purified from Escherichia coli.
6. The protective effects of a single oral dose of fleroxacin in mice was greater than that of norfloxacin and comparable to or greater than that of ciprofloxacin, ofloxacin or lomefloxacin against systemic infections.

View full abstract

The MIC_90S of fleroxacin, a new quinolone, against 20 to 52 clinical isolates of Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), coagulase-negative staphylococci (CNS), Streptococcus pyogenes, Streptococcus pneumoniae, Enterococcus faecalis, Enterococcus faecium, Escherichia coli CS2 (R⁺), Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris, Morganella morganii, Providencia rettgeri, Citrobacter freundii, Enterobacter cloacae, Serratia marcescens, Pseudomonas aeruginosa, Pseudomonas cepacia, Xanthomonas maltophilia, Acinetobacter calcoaceticus, ampicillin-resistant Haemophilus influenzae and Bacteroides fragilis were 0.78, 3.13, 0.78, 6.25, 12.5, 12.5, 12.5, 1.56, 0.2, 0.39, 0.2, 0.39, 1.56, 0.39, 1.56, 3.13, 3.13, 12.5, 1.56, 0.78, 0.05, and 6.25 μg/ml, respectively. The antibacterial activity of fleroxacin was similar to that of ofloxacin (OFLX).
Fleroxacin proved to have an ID₅₀ of more than 100 μg/ml against CHO-Kl, HeLa and human neuroblastoma IMR-32 cells, namely, a low cytotoxicity as compared to OFLX.
Synergy of bactericidal effect between fleroxacin and serum complement was not confirmed, although cells of E. coli NIHJ JC-2 and S. pneumoniae 4 were engulfed and well digested by mouse cultured macrophages in the presence of 1/8 MIC and 1/2 MIC of fleroxacin.
Some parts of axon dendrites of redifferentiated human neuroblastoma IMR-32 cells were withdrawn within 3 h by the addition of 5 μg/ml of fleroxacin.

View full abstract

We compared the in vitro and in vivo antibacterial activity of fleroxacin, a new quinolone, with those of ciprofloxacin, ofloxacin, enoxacin and norfloxacin.
1. Fleroxacin proved to have a broad antibacterial spectrum, and its in vitro activity against Staphylococcus spp., including MRSA, was the same as those of ciprofloxacin and ofloxacin, and stronger than those of the other two drugs. Against the family of enterobacteriaceae and glucose-nonfermenting bacteria, including Pseudomonas aeruginosa, fleroxacin was slightly less potent than ciprofloxacin, but the same or more potent than the reference drugs.
2. In systemic infection (Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Serratia marcescens and P. aeruginosa), intranasal respiratory infection (K. pneumoniae) and urinary tract infection (E. coli and S. marcescens) models, the therapeutic efficacy of fleroxacin was the same as that of ciprofloxacin or ofloxacin.
3. In serum, lung and kidney levels of fleroxacin, the maximum concentration was a little higher and the retention time a little longer than for the other four drugs.

View full abstract

The in vitro. activity of fleroxacin, a new quinolone, against anaerobic bacteria was evaluated in comparison with ofloxacin, norfloxacin and pipemidic acid. In antibacterial spectrum study using 35 reference anaerobic strains (34 species), fleroxacin was more potent than norfloxacin and pipemidic acid.
Against clinical isolates of anaerobic bacteria, the activity of fleroxacin was slightly less active than ofloxacin, but more so than norfloxacin, and superior to pipemidic acid. Fleroxacin had potent bactericidal activity against Bacteroides fragilis.
Contents of mouse caecum after ceasing oral administration of fleroxacin showed negative cultures for Clostridium difficile.

View full abstract

We investigated the in vitro and in vivo antibacterial activity of fleroxacin, a synthetic antimicrobial agent, by comparing it with those of ciprofloxacin (CPFX), enoxacin (ENX), ofloxacin (OFLX), norfloxacin (NFLX) and pipemidic acid (PPA). The results were as follows:
1. Fleroxacin showed a broad spectrum against Gram-positive and-negative bacteria, including anaerobes. The antibacterial activity of fleroxacin was almost equal to those of ENX and NFLX against Gram-positive bacteria, those of ENX, OFLX and NFLX against Gram-negative bacteria, and those of CPFX and OFLX against anaerobes. Fleroxacin showed higheractivity than PPA against all species tested.
2. The antibacterial activity of fleroxacin was not affected by the kind of medium, the pH of the medium or inoculum size. The addition of horse serum enhanced the MIC values against some species.
3. The bactericidal activity of fleroxacin was dose-dependent.
4. As for morphological alterations in bacteria treated with fleroxacin, elongation and lysis were observed in Escherichia coli. InPseudomonas aeruginosa, however, scarcely any elongation was noted, though spheroplast-like structures and lysis were observed. Fleroxacin caused the formation of elongated swollen cells in Acinetobacter calcoaceticus.
5. The therapeutic efficacy of fleroxacin was equal or superior to those of CPFX, ENX, OFLX and NFLX against all the experimental systemic infections tested in mice.

View full abstract

We evaluated the in vitro antimicrobial activity of fleroxacin [6, 8-difluoro-1-(2-fluoroethyl)-1, 4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid] and ofloxacin against representative pathogenic mycobacteria by the agar dilution method, using 7H11 agar medium. Fleroxacin showed appreciable antimicrobial activity against Mycobacterium tuberculosis (MIC₉₀=6.25 μg/ml), Mycobacterium kansasii (MIC₉₀=3.13 μg/ml), and Mycobacterium fortuitum (MIC₉₀=6.25μg/ml), whereas Mycobacterium marinum, Mycobacterium scrofulaceum, Mycobacterium avium, Mycobacterium intracellulare, and Mycobacterium chelonae substantially resisted the agent. The activity of fleroxacin was comparable or slightly inferior to that of ofloxacin. Fleroxacin showed antimicrobial activity against M. intracellulare phagocytosed in murine peritoneal macrophages at a concentration of 10 μg/ml in the culture medium, but its activity was considerably lower than that of ofloxacin. In contrast, the therapeutic activity of fleroxacin against M. fortuitum infection induced in mice was higher than that of ofloxacin. Neither fleroxacin nor ofloxacin was efficacious against M. intracellulare infection. Administration of fleroxacin significantly depressed the growth of Mycobacterium leprae in the footpad.

View full abstract

In vivo antibacterial activity of fleroxacin was compared with those of norfloxacin (NFLX), ofloxacin (OFLX) and ciprofloxacin (CPFX).
1. Fleroxacin showed greater activity than NFLX, OFLX and CPFX against systemic infection with Staphylococcus aureus, Escherichia coli, Serratia marcescens and Pseudomonas aeruginosa in mice. The efficacy of fleroxacin in neutropenic mice was almost the same as that in normal mice. Furthermore, the prophylactic effect of fleroxacin was superior to that of OFLX and CPFX.
2. In ascending urinary tract infection with E. coli, Klebsiella pneumoniae and P. aeruginosa in mice, the therapeutic effect of fleroxacin was equal or superior to that of OFLX and CPFX.3. In experimental pneumonia with K. pneumoniae and P. aeruginosa in mice, the therapeutic effect of fleroxacin was about two times greater than that of OFLX and CPFX.
4. In biliary tract infection with E. coli in rabbits, the therapeutic effect of fleroxacin was about eight times greater than that of NFLX.
5. Tissue distribution and urinary recovery of fleroxacin after oral adniinistration in mice were better than with OFLX and CPFX.
The excellent in vivo efficacy of fleroxacin may be due to its good oral absorption and tissue penetration.

View full abstract

Fleroxacin, a new quinolone derivative, was synthesized by Kyorin Pharmaceutical Co., Ltd. It is characterized by a broad antibacterial spectrum and a potent antibacterial effect against Gram-positive and Gram-negative bacteria.
Intrauterine infection was induced in rabbits inoculated with Escherichia coli KH-8908 and/or Bacteroides fragilis GAI-0558, and the therapeutic effects of fleroxacin were assessed.
The MICs of fleroxacin against E. coli and B. fragilis strains were 0.10μg/ml and 6.25μ/ml. Twenty mg/kg of fleroxacin was orally administered once a day five times from the 4th day after mono-infection or mixed infection with both bacteria.
Inflammatory changes of the uterus in the therapeutic groups were milder than those of either infected control group.
These findings suggest that fleroxacin is a useful compound for the treatment of intrauterine infections in obstetrics and gynecology.

View full abstract

We examined the effects of treatment schedules of fleroxacin on experimental Klebsiella pneumaniae B54 pneumonia in mice and obtained the following results.
1. Fleroxacin, administered t. i. d. orally, showed high efficacy against the pneumonia, being about twice as effective as ofloxacin and ciprofloxacin, and more than 15 times more active than norfloxacin, pipemidic acid or cefaclor.
2. Once or twice daily administration of fleroxacin also showed outstanding therapeutic effect.
3. These results may be primarily attributed to better absorption and higher serum and lung levels of fleroxacin thanwith the other new quinolones.

View full abstract

We studied the biological disposition and fate of fleroxacin in rats and rabbits using ¹⁴C-labeled fleroxacin.
Fleroxacin was absorbed from the small intestine almost completely, but hardly at all from the stomach. The absorbed fleroxacin was well distributed in various tissues, especially in the bladder, kidney and liver; but poorlydistributed in the central nervous system and ocular tissues. In rats, approximately 50% of ¹⁴C-activity excreted in bile was reabsorbed from the intestine, indicating an enterohepatic circulation. In rats and rabbits, fleroxacin was excreted mainlyin urine. The plasma protein binding rates of ¹⁴C were 36%-60%.
In rats, the degree of transfer of fleroxacin to the fetus through the placenta and to milk was relatively high. The distribution of fleroxacin in otorhinolaryngological tissues of rabbit suggests that the drug would be useful in otorhinolaryngology.
In rats, after repeated oral administration of 10 mg/kg of ¹⁴C-fleroxacin once daily for 21 days, whole blood and tissue levels, and urinary and fecal excretion were similar to those after a single oral administration. There was no accumulation of the drug in tissues nor delay of excretion by multiple dosing.

View full abstract

We investigated the ocular pharmacokinetics of fleroxacin in rabbits to evaluate its clinical applicability in ocularinfections:
1. The concentrations of fleroxacin reached a peak at 1 or 2 h, and had declined at 8 h in most ocular tissues after a single oral administration of 20 mg/kg. The peak concentrations were 2.22 μg/ml in serum, 0.92 μg/g (cornea) to 2.21 μg/g (extraocular muscle) in the outer tissues, and 0.17 μg/g (lens) to 0.82 μg/g (retina and choroid) in the inner tissues.
2. No change in elimination of fleroxacin in the ocular tissues were observed after repeated oral administration at 20mg/kg once a day for 4 days.
3. During repeated oral dosing, the concentration of fleroxacin in tear was 0.32-0.55 μg/ml 2 h after every dose, corresponding to one-forth or one-third of that in serum.
4. After topical instillation of two drops of 0.3% fleroxacin ophthalmic solution 5 times at 5-min intervals, theconcentration of the drug reached a peak at 4 h in eyelid, and within 1 h in other ocular tissues, and had declined at 6 h. The peak concentrations were 1.32, μg/g (extraocular muscle) to 19.2 μg/g (cornea) in the outer tissues, and 0.03 μg/ml (vitreous body) to 4.29 μg/g (iris and ciliary body) in the inner tissues.
5. In alloxane-induced diabetic rabbits, the ocular distribution of fleroxacin was similar to that in normal rabbits.These results indicate that fleroxacin is effective in the treatment of ocular infections by oral and topical administration.

View full abstract

Metabolites of fleroxacin in urine of dogs and rabbits wereisolated and identified using TLC, UV, HPLC, NMR and mass spectrometry. Fleroxacin and its major metabolites in serum and urine of humans were determined by HPLC:
1. Two metabolites together with the unchanged fleroxacin were identified in urine of dogs and rabbits: demethyl fleroxacin and fleroxacin N-oxide. In rabbit urine, two other metabolites were also identified: demethyl-3-oxo fleroxacin and demethyl-4-formyl fleroxacin
2. In humans, plasma concentrations of the major metabolites, demethyl fleroxacin and fleroxacin N-oxide were only about 1% of the unchanged fleroxacin at the peak level.
3. The total urinary recovery over 72 h after dosing in humans was 83% of the dose. About 90% of the urinary excretion was unchanged fleroxacin. Urinary excretion of four metabolites, demethyl fleroxacin, fleroxacin N-oxide, demethyl-3-oxo fleroxacin and demethyl-4-formyl fleroxacin, were found to be 5, 5, 0.3 and 0.2% of the dose, respectively.
4. It was clarified that fleroxacin was scarcely metabolised in vivo in humans and animals except rabbits, and was metabolically most stable in humans.
5. It is suggested that the antibacterial activity after oral administration of fleroxacin in humans was mainly due to the unchanged drug.

View full abstract

We performed an acute toxicity study on fleroxacin in mice, rats and dogs.
The results obtained' are summarized as follows:
1. The LD₅₀ values of fleroxacin were more than 4000mg/kg in mice and rats and more than 1000mg/kg in dogs by oraladministration; more than 1500 mg/kg in mice and rats by subcutaneous and intraperitoneal injection; and 217mg/kg (male) and 237mg/kg (female) in mice, 205mg/kg (male) and 261mg/kg (female) in rats by intravenous injection.
2. As toxic signs, prone position, ptosis of the eyelids and sedation were found in mice who were given the drug orally, intraperitoneally or intravenously, and in rats injected intraperitoneally or intravenously. Vomiting, reluctance to rise and walk, and abnormal gait due to arthropathy were found in all dogs given the drug orally.
3. An increase in blood sedimentation rate, a slight increase in total serum protein and a slight decrease in the albumin/globulin-ratio were found in dogs. Blisters and erosions on the surface of articular cartilages were found in several joints of all dogs. Histologically, the changes were found to be cavitation and desquamation of the upper cartilage layers.

View full abstract

A subacute toxicity study on fleroxacin was carried out in rats. Fleroxacin was given orally at daily doses of O (control), 45, 135, 400 and 1200mg/kg for 13 weeks, followed by a 5-week recovery period in the control, 400 and 1200mg/kggroups. The following results were obtained.
1. In the 1200mg/kg group, 18 of 20 males and females died during the test period. In the dead animals, a decrease inbody weight, food and water intake, piloerection, diarrhea and marked emaciation were noted.
2. In the survivors of the 1200mg/kg group, a decrease in body weight or suppression of weight gain was noted. A slightly reduced body weight gain was also observed in the males of the 400mg/kg group within the administration period.
3. In both males and females given 135mg/kg or more, minor changes were found in some parameters in the hematological, serum biochemical and urinary examinations.
4. In some males receiving 135mg/kg or more, the epididymides showed a decrease in weight, and contained necrotic sperm or eosinophilic cells, considered to degenerative spermatogenic cells, in the lumen.
5. In males receiving 135mg/kg and more and females receiving 400mg/kg, increased cecum weights were seen. There were, however, no marked histopathological changes.
6. Blister-like lesions were seen on the articular cartilage surfaces in the 400 and 1200mg/kg groups.7. The above-mentioned changes induced by fleroxacin normalized or decreased during the recovery period, except injuries of the articular cartilage.
8. From the above results, the maximum non-effect dose of fleroxacin in this study was estimated to be 45mg/kg/day.

View full abstract

We performed a subacute toxicity study of fleroxacin in 5-month old beagles. Fleroxacin was given orally at daily doses of 0 (control), 8, 20 and 50 mg/kg for 13 weeks. The following results were obtained.
1. In the 50 mg/kg group, reduced food and water consumption, body weight loss, vomiting and salivation were seen immediately after the beginning of fleroxacin administration. Subsequently, one male showed clonic convulsion, reduced body temperature and spontaneous motor activity and was killed on study week 6 because of deterioration in general condition. In the other animals, the changes mentioned above normalized or showed a tendency to recover after 2 to 3 weeks.
2. In the 50 mg/kg group, some changes were found in the clinical examination and organ weight measurements. These were considered to be due to dehydration, malnutrition and body weight loss. In the survivors, however, most of these changes tended to improve together with a recovery in food consumption, water intake and body weight gain. In the 8 mg/kg and 20 mg/kg group, no abnormalities of body weight, food and water consumption or other parameters were seen apart from some minor deviations in the 20 mg/kg group.
3. In the dogs given 20 mg/kg or more, reluctance to stand or walk and abnormal gait were seen as a clinical manifestation of arthropathy. At autopsy, blistering and erosions on the articular cartilage surfaces were found in all dose groups.
4. In the histopathological examination, the seminiferous tubules, epididymal ducts and prostatic epithelia showed immature patterns in the killed animals. Further histopathological findings thought to be due to malnutrition in these animals were atrophy of the lymph nodes, thymus, pancreas and skeletal muscle and vacuolar degeneration of the chief cells of the stomach, hepatocytes and renal distal tubules as well as reduced hematopoiesis in the bone marrow.
5. As mentioned above, the main toxic changes induced by fleroxacin were reduced food and water consumption, body weight loss and injuries of the articular cartilage. Most of the other changes were considered to be due to dehydration and malnutrition.

View full abstract

We investigated the general pharmacological properties of fleroxacin with the following results.
1. Central nervous system: fleroxacin, at an oral dose of 100mg/kg, showed an anti-nociceptive effect and decrease in body temperature in mice; at 300 mg/kg or more it showed antipyretic action, suppressed spontaneous motor activity, prolonged thiopental-induced sleeping time and promoted reserpin-induced hypothermia in mice; and at 1000 mg/kg it showed muscle relaxation. A transient EEG arousal pattern was evoked in conscious, unrestrained cats at over 5mg/kg, intravenously.
2. Respiratory and cardiovascular system: fleroxacin decreased blood pressure in anesthetized dogs at an intravenous dose of 10mg/kg. But it showed little effect on any parameters at an intravenous dose of 10mg/kg in anesthetized rabbits, and on blood pressure at an infusion of 10mg/kg/10 min in unanesthetized, unrestrained cats.
3. Smooth muscles and autonomic nervous system: fleroxacin slightly suppressed the contractile response of isolated rat was deferens to noradrenaline and slightly enhanced the contractile response of isolated guinea pig trachea to histamine. It also slightly inhibited the spontaneous motility of isolated rabbit ileum and uterus at concentrations of 10^-4g/ml and more. It inhibited the motility of urinary bladder at over 10mg/kg i. v., and of rabbit stomach at an i. v. dose of 30 mg/kg, but hadlittle effect on the motility of uterus.
4. Miscellaneous: fleroxacin, at oral doses above 100 mg/kg, increased bile secretion, free fatty acid levels in serum, and ketone bodies in rat urine. It produced a transient decrease in urine volume and blood glucose, showed anti-inflammatory and anti-ulcer effect, and suppressed reticuloendothelial function at oral doses of 300 mg/kg or more. It had no effect on ERG pattern and blood coagulation ability, and no hemolytic action.

View full abstract

Using various methods, we investigated the antigenicity of fleroxacin in guinea pigs, rabbits and mice.
1. For sensitization, fleroxacin was injected subcutaneously and intramuscularly with Freund's complete adjuvant (FCA) to guinea pigs once a week for three weeks. The sensitized guinea pigs showed neither active systemic nor active cutaneous anaphylaxis. The results of the guinea pig maximization test of fleroxacin were also negative.
2. Rabbits were sensitized intradermally and intramuscularly with fleroxacin+ FCA or a fleroxacin-bovine γ-globulin (BGG) mixture+ FCA once weekly for four weeks. Anti-fleroxacin antibodies were not detected by Ouchterlony's test, passive hemagglutination test or 4 h guinea pig passive cutaneous anaphylaxis (PCA) test.
3. In mice, fleroxacin or fleroxacin-BGG mixture was injected intraperitoneally with Al (OH)₃ gel once, twice or four times. Anti-fleroxacin antibodies were not detected by Ouchterlony's test, 1 h mouse PCA or 4 h rat PCA test.
These results suggest that fleroxacin has no antigenicity in guinea pigs, rabbits or mice under the experimental conditions used.

View full abstract

Using various short-term assays, we tested the mutagenicity of fleroxacin in bacteria, mammalian cells andmice, and obtained the following results.
1. DNA-repair test (rec-assay): at levels from 0.4-3.2 μg/disk, fleroxacin showed a difference in inhibition zone between the two strains of Bacillus subtilis; the DNA-repair-deficient strain (M45) and the wild type strain (H17).
2. Reverse mutation test with bacteria (Ames' test): fleroxacin exhibited no mutagenicity against Salmonella typhimurium TA-strains and Escherichia coli WP2uvrA at levels from 0.0005-0.1 μg/plate, in the absence and presence of a microsomal preparation (S-9) derived from rat liver.
3. Mutagenicity test with cultured mammalian cells (V-79 cells): no mutagenicity shown by the increase in 6-thioguanine resistant mutants was observed at levels from 63-499 μg/ml of fleroxacin for 3 h in the absence and presence of S-9.
4. Chromosomal aberration test with cultured mammalian cells (CHL cells): the chromosomal aberrations of cells treated with 50-400 μg/ml of fleroxacin for 24 or 48 h were not significantly different from those of untreated cells. In the presence of S-9, negative results were also obtained from cells treated with the same levels of fleroxacin for 3 h.
5. Micronucleus test with mice: male and female ICR-mice were given a single oral dose of fleroxacin from 1000-4000mg/kg. No statistically significant differences in the frequency of micronuclei 24 h after administration were found between fleroxacin and control groups.
In the rec-assay, fleroxacin caused DNA damage to B. subtilis, but mutagenicity nor clastogenicity were neither observed in bacteria, mammalian cells or mice.

View full abstract

We conducted a fertility study on fleroxacin in Crj: Wistar rats. Fleroxacin was orally administered at doses of 20, 80 and 320 mg/kg/day to the male rats for 61 days before mating and until fertility was confirmed and to the females for 14 days before mating and up to the day 7 of gestation.
1. In the 320 mg/kg male group, as general symptoms, an increase in unkempt fur was observed from the start of treatment. Sedation was also noted.
2. In the 320 mg/kg male group, transient suppression of body weight gain was observed at the start of treatment, but afterwards, this was recovered.
3. In the 320 mg/kg male group, the organ weight of epididymis and prostate significantly decreased. In histological findings of testes and epididymis, disappearance or reduction in spermatozoa and atrophy of seminiferous tubules were observed.
4. The mating performance of fleroxacin-treated groups was the same as that of the control group.
5. The number of implantations, the implantation rate and number of surviving fetuses significantly decreased in the 320mg/kg group, but no effect on growth or external defects in fetuses were observed.
The maximum no-effect dose of fleroxacin was considered to be 80 mg/kg for Fo rats and fetuses.

View full abstract

Fleroxacin was administered orally to pregnant rabbits during fetal organogenesis at daily doses of 25, 50 and 100mg/kg, and the following results were obtained.
1. In pregnant rabbits, abortions were observed in one and four cases of the 25 mg and 100mg/kg groups, respectively. Body weight gain was suppressed in the 100mg/kg group. Transient reduction in food intake was noted in the early days of treatment. Dilatation of stomach and caecum was observed in three cases of the 100 mg/kg group at autopsy on day 29 of gestation, but the other drug-treated groups were unaffected.
2. As to the effect on fetuses, the mean number of live fetuses was less in the 25mg/kg group, but there were no significant differences in the number of resorptions or dead fetuses between the control and drug-treated groups. Moreover, there were no effects of fleroxacin on fetal development or any occurrence of teratogenicity.
From the above results, we consider the maximum no-effect dose of fleroxacin to be 50mg/kg in dams, and 100mg/kg or more in fetuses.

View full abstract

We studied the tolerance and pharmacokinetics of fleroxacin in healthy male adult volunteers.
The peak serum concentrations of unchanged fleroxacin were 1.6, 2.9 and 5.1μg/ml at 1-2 h after a single oral dose of 100, 200 or 400 mg. The apparent serum elimination half-life was about 10 h, independent of the dose.
Fleroxacin, demethyl fleroxacin and fleroxacin N-oxide excreted in urine over 3 days accounted for about 75%, 6% and 5% of the doses, respectively. The urine concentrations of unchanged drug were dose-related; the mean concentrations, sustained over 24 h, were about 50, 100 and 150μg/ml after 100, 200 and 400 mg doses, respectively.
Food intake scarcely influenced the pharmacokinetic parameters and urinary excretion.
Steady state serum concentrations were achieved from day 3 onwards by repeated doses twice daily and were 2-4 and 5-9μg/ml after 200 and 400 mg b.i.d., respectively. The mean concentrations of unchanged drug in urine were about 200 and 300 tig/ml at the respective dosages. The pattern of urinary metabolites was not changed by repeated doses and about 86% of the total dose was recovered in urine, including metabolites. The serum protein binding of fleroxacin was 32%.
The saliva concentration was 40% of the total serum concentration or 60% of the free serum concentration.
The fecal recovery over 3 days was 3% of the dose following a single 200 mg dose after a meal. No severe dose-related side-effects were observed.

View full abstract

We studied the pharmacokinetics and tolerance of fleroxacin in healthy male volunteers given 200mg and 300mg of the drug once daily for 7 days.
Serum and urinary concentrations of unchanged drug reached a steady-state after 2-3 days with both doses. During the steady-state, mean serum concentrations of unchanged drug at 2 h after administration of 200 and 300 mg were 1.9-2.8 (n=4) and 3.7-4.2μg/ml (n= 5), and those at 24 h after administration were 0.4-0.5 and 0.7-0.9μg/ml. Serum half-life was 8.3-8.7h, independent of the dose and multiple administration.
Fleroxacin concentrations in urine for 24h at steady-state were about 120 and 170μg/ml on average at 200 and 300mg. Mean urinary fleroxacin concentrations at 24 h after the first administration of 200 and 300 mg were 54 and 87μg/ml. The amounts of the drug excreted in urine up to 72 h after the last administration were 77-78% of the total dose on average, independent of the dose. Total urinary excretion, including metabolites, amounted to 87-88% of the total dose.
No side-effects related to the drug were observed during the study.

View full abstract

Fleroxacin is a newly developed quinolone derivative, with a broad spectrum of activity against Gram-negative and-positive bacteria, including aerobes and anaerobes. It has the longest serum half-life of all the new quinolones.
Fecal flora were studied in five healthy adult male volunteers after the administration of 400mg fleroxacin b.i.d. for seven days. Stool samples were taken prior to and several times after the initiation of therapy, and qualitative and quantitative analyses of microorganisms were performed.
Enterobacteriaceae were eliminated in all volunteers by the end of therapy. No resistant Enterobacteriaceae were observed. The number of CFU of the Bacteroides fragilis group remained unchanged or changed only slightly during the trial. There was no selective growth of Clostridium difficile and resistant B. fragilis group organisms.

View full abstract

We performed an experimental study on fleroxacin, a new synthetic antimicrobial agent for oral use, in the field of oral surgery.
Fleroxacin was administered to 6 healthy volunteers before and after meals at 200 mg and the serum and salivary concentrations were determined periodically. A pharmacokinetic study was performed using a one-compartment model and moment analysis. The parameters of pharmacokinetic analysis were as follows.
Blood Saliva
Fasting Non-fasting Fasting Non-fasting
Tmax(h) 3.92 2.62 3.39 2.60
Cmax(μg/ml) 2.05 2.41 1.84 2.02
T_1/2 7.11 8.73 5.45 6.16
AUC (μg·h/ml) 29.35 32.25 20.65 21.26

View full abstract

We investigated the effect of aluminum hydroxide, an antacid, on the gastrointestinal absorption of fleroxacin in six healthy male volunteers. Two hundred milligrams of fleroxacin was given orally to fasting subjects with and without 1g of dried aluminum hydroxide gel.
The peak serum concentrations of unchanged drug were slightly reduced from 2.37 to 1.81μg/ml by concurrent administration of aluminum hydroxide, but no significant changes were found in the area under the serum concentration-time curve, time at which peak serum concentrations were achieved, and elimination half-life in serum. Furthermore, urinary excretion of fleroxacin and total drug over 48 h slightly decreased from 67.2 and 77.6 to 60.3 and 68.3%, respectively. We therefore concluded that the effect of aluminum hydroxide on the gastrointestinal absorption of fleroxacin was less than on other quinolonecarboxylic acid antimicrobial agents.

View full abstract

We investigated fleroxacin, a newly developed synthetic pyridonecarboxylic acid antibacterial agent, for its antibacterial activity, absorption, excretion and tissue penetration, and obtained the following results.
1. Antibacterial activity: the MICs of fleroxacin against 247 strains of 14 species of clinical isolates from obstetric and gynecologic infections were examined and compared with those of norfloxacin, ofloxacin, enoxacin, ciprofloxacin and cefaclor.
The MICso of fleroxacin against Gram-positive bacteria was 0.39-3.13μg/ml and against Gram-negative rods 0.05-6.25μg/ml.
2. Absorption and excretion: the serum concentration of the drug reached a peak level of 4.38μg/ml at 1h after administration of 200mg, 0.5μg/ml at 12h, and 4.92±0.38μg/ml after administration of 300mg. The excretion rate within 12h was 33.7-59.1%.
3. Tissue penetration: tissue penetration of the drug into the intrapelvic genital organs was good. The maximum tissue level (C_max) was 3.92μg/g after administration of 200mg and 6.14μg/g after administration of 300mg, and the half-life was 8.7-9.0 h.
Our results suggest that fleroxacin is effective in treating gynecological infections.

View full abstract

We performed a pharmacokinetic study on fleroxacin in biliary tract and soft tissue infections. After administration of fleroxacin to 21 preoperative patients at 200mg, we determined the concentrations in peripheral blood, portal blood, gallbladder, muscle, fat tissue, gallbladder bile and choledochal bile. After 2h, the mean concentrations in these samples were 2.10μg/ml, 2.34μg/ml, 2.16μg/g, 3.09μg/g, 0.50μg/g, 4.74μg/ml, and 6.01μg/ml, respectively.
After 6 h, they were 3.64μg/ml, 3.68μg/ml, 4.30μg/g, 4.06μg/g, 0.82μg/g, 6.91μg/ml, and 9.85μg/ml. And after 14h, 1.76μg/ml, 1.79μg/ml, 2.56μg/g, 2.14μg/g, 0.45μg/g, 12.31μg/ml, 4.13μg/ml. Fleroxacin showed good biliary excretion and sufficient concentration in muscle and gallbladder.
We consider that fleroxacin is an useful drug for the treatment of skin and soft tissue and biliary infections.

View full abstract

We studied the effect of fleroxacin, a new oral pyridone-carboxylic acid derivative, on the serum concentration of theophylline in five healthy male volunteers.
In advance, theophylline alone was given for four days at a dose of 200 mg b. i. d. and serum samples were obtained as a control. After 5 days, concomitant administration of fleroxacin at 200mg b. i. d. was started. Blood samples were taken and on days 3 and 5 of concomitant administration, and the serum concentration was compared with that of the control. At the same time, urinary excretion of theophylline and its metabolites was measured.
Fleroxacin caused no significant difference in maximum serum concentration values, the area under the curve and the total body clearance of theophylline from the control on days 3 and 5 of concomitant administration. Urinary excretion of theophylline and its metabolites also showed little change on these days.
These results suggest that fleroxacin has no effect on serum theophylline concentration and can be used safely with theophylline.

View full abstract

We tested the antibacterial activity of fleroxacin, a new synthetic pyridon carboxylic acid antibacterial agent, against 7 species of 182 clinical isolates at 10⁶ cells/ml. The MIC range and MIC₉₀ of fleroxacin were 0.39-25μg/ml and 3.13μg/ml for Staphylococcus aureus; Escherichia coli (<0.10-3.13, 1.56); Klebsiella sp.(<0.10-3.13, 0.78); Proteus mirabilis (<0.10-0.39, 0.39); Morganella morganii (<0.10-0.78, 0.39); Serratia marcescens (<0.10-12.5, 6.25); and Pseudomonas aeruginosa (1.56-25, 12.5). These values were about the same as those for norfloxacin, ofloxacin, enoxacin and ciprofloxacin, which were examined for the comparison.
Clinical efficacy was examined by dosing 100-200mg of fleroxacin twice a day for 2-15 days in principle to 36 patients with various infections (1 case of pneumonia, 2 of acute pharyngitis, 7 of acute tonsillitis, 2 of acute bronchitis, 12 of chronic bronchitis and 12 of cystitis). Clinical efficacy was assessed as excellent in 9 and good in 25 cases with an efficacy rateof 100% for the evaluable cases. All bacteria detected in the focus totally disappeared. As to side effects, diarrhea and stomachache were observed in one patient each, but no abnormal laboratory findings were noted.

View full abstract

We measured the in vitro antimicrobial activity, and serum and sputum concentrations of fleroxacin, a new quinolone agent for oral use, and evaluated its therapeutic efficacy in respiratory infections. The minimum inhibitory concentrations (MICs) of fleroxacin and ofloxacin (OFLX) against 20 strains each of Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens and Pseudomonas aeruginosa were determined by a microbroth dilution method using the Dynatech MIC-2000 system. As shown by the MICs, fleroxacin was somewhat less active than OFLX against all these species. The concentrations of fleroxacin in the serum of three patients with respiratory infections were highest at 2h after oral administration of 300mg (7.41, 2.82 and 3.93μg/ml). The penetration rate of fleroxacin from serum at 2 h after oral administration into the sputum collected during 2h thereafter was 91%, 66% and 52% in these 3 patients. Thereafter, the concentrations of fleroxacin in their serum and sputum decreased gradually: at 24h after administration, the concentrations of fleroxacin in serum were 1.66, 0.72 and 0.537mu;g/ml and those in sputum were 1.63, 0.53 and 0.23μg/ml. A daily dose of 200-300mg of fleroxacin was given orally for 5-14 days (mean: 7.8 days) to 10 patients: 4 with acute bronchitis, 1 with infection supervening on bronchiectasis and 5 with acute pneumonia. The clinical efficacy was assessed as excellent in 1, good in 6, fair in 1 and poor in 2. Six strains were identified as causative organisms, five of which were eradicated by fleroxacin. Mild epigastric pain and elevation of eosinophils were each observed in one patient. From the above results, we conclude that fleroxacin is one of the most useful quinolone agents for oral use in the treatment of respiratory infections.

View full abstract

We carried out basic and clinical studies on fleroxacin, a new oral pyridonecarboxylic acid, and obtained the following results.
The in vitro antibacterial activity of fleroxacin was tested against 275 strains of clinical isolates of 15 species and compared with those of norfloxacin, ofloxacin, ciprofloxacin, enoxacin, cefixime, cefaclor, ampicillin and minocycline. Fleroxacin and other new pyridonecarboxylic acids were very active against Gram-negative bacilli.
We administered fleroxacin to 12 patients with respiratory infections at a dose 200-300mg daily for 7-14 days. The clinical response obtained was excellent in 1 and good in 11 cases. The organisms isolated from two cases, one of Streptococcus pneumoniae and Escherichia coli, were eradicated. Neither side effects nor remarkable worsening of laboratory findings was observed.

View full abstract

Twenty-one patients with lower respiratory tract infection were treated in a phase II study with fleroxacin, and its clinical efficacy and safety were evaluated. We also evaluated the sputum and serum concentrations of the drug after administering a single dose of 200mg or 300mg in patients with copious mucopurulent sputum. The underlying diseases were bronchiectasis (14 cases), diffuse panbronchiolitis (5), sequelae of pulmonary tuberculosis (1) and bronchial asthma (1). A dose of 100mg or 200mg of fleroxacin was administered orally twice daily in most cases. Clinical response was excellent in 3, good in 10, fair in 4 and poor in 3 cases. One case was unevaluable. The overall clinical response (excellent and good) rate was 65%. Of 7 strains of Haemophilus influenzae, 5 were eradicated, 1 was replaced by Streptococcus pneumoniae and 1 persisted. Branhamella catarrhalis was eradicated in one case. Of 3 strains of S. pneumoniae, 2 persisted and 1 was replaced by Staphylococcus aureus. There was no eradication in 2 cases of Klebsiella pneumoniae, 2 of Escherichia coli and 1 of Pseudomonas aeruginosa. No adverse effect was observed except for one case of slight eosinophilia. At a dose of 300mg, the average peak concentration of serum (from 1-4 h) was 4.55±1.42μg/ml and that of sputum 4.62±1.46μg/ml. The mean sputum/serum concentration ratio was 101±3%. Our results indicate that fleroxacin penetrates well into bronchial secretions and seems to be useful in the treatment of respiratory tract infection.

View full abstract

We tested the in vitro antibacterial activity of seven new quinolones-fleroxacin, norfloxacin, ofloxacin, enoxacin, ciprofloxacin, lomefloxacin and tosufloxacin tosilate-against 100 strains of clinically isolated Staphylococcus aureus.
Fifty-eight of the strains (58%) showed multidrug resistance, and 45 of 67 strains (67.2%) from inpatients and 13 of 33 strains (39.4%) from outpatients were MRSA.
The MRSA strains were isolated mainly from sputum (48.9%) in inpatients and from otorrhea (37.5%) in outpatients.
Against MSSA, tosufloxacin tosilate showed the lowest MICs and fleroxacin, ofloxacin and ciprofloxacin showed good MICs. Against MRSA, tosufloxacin tosilate also showed the lowest MICs and fleroxacin ranged from 0.39-100μg/ml. Cross-resistance against MRSA was seen in all new quinolones.
Clinical evaluation of fleroxacin was performed in 14 patients with respiratory tract infection: 4 males and 10 females, 26-65 years old. Fleroxacin was given orally in doses of 100mg (6 cases) or 200mg (8 cases) once or twice daily.
A total of eight strains, comprising four of Haemophilus influenzae, and one each of β-streptococcus, Streptococcus pneumoniae, Streptococcus pyogenes and Klebsiella pneumoniae were isolated from sputum of patients.
All of these were eradicated after treatment. The clinical efficacy rate was also 100%: excellent in five and good in seven cases. Side effects (insomnia, dizziness) were observed in two cases.
From the above results, we consider fleroxacin to be an effective, safe and useful new quinolone on respiratory tract infection.

View full abstract

We investigated the antibacterial activity and clinical efficacy of fleroxacin. The results were as follows.
1. Antibacterial activity: fleroxacin was good against all 10 clinical isolates of S. aureus, methicillin-resistant S. aureus, S. pyogenes, E. faecalis, E. coli, K. pneumoniae, E. cloacae, P. mirabilis, S. marcescens and P. aeruginosa. The MIC₉₀ (10⁶ cells/ml) was 1.56, 3.13, 6.25, 6.25, 0.39, 0.39, 3.13, 0.39, 25, and 25μg/ml, respectively.
2. Clinical results: the efficacy of the drug, administered at 100-200mg, once or twice daily to 14 patients with respiratory tract infection (13) and urinary tract infection (1), was good in 13 and fair in 1. Bacteriologically, S. aureus (2) and E. coli (1) were isolated and all strains eradicated.
As adverse reactions, dizziness was observed in one case, but there were no abnormal laboratory findings related to fleroxacin.

View full abstract

We performed laboratory and clinical studies on fleroxacin, a new quinolone, with the following results.
1. The MICs of fleroxacin against methicillin-sensitive Staphylococcus aureus (MSSA), Escherichia coli, Acinetobacter calcoaceticus, Serratia marcescens, Proteus mirabilis, Proteus vulgaris and Morganella morganii were 0.025-1.56μg/ml, which were inferior to those of tosufloxacin tosilate and CPFX and almost equal to those of OFLX. The peak MICs against methicillin-resistant Staphylococcus aureus (MRSA), Klebsiella sp., Enterobacter cloacae and Pseudomonas aeruginosa were less than 3.13μg/ml.
2. Twentrsix patients with respiratory tract infections and one with acute cystitis were treated with fleroxacin at 100-200mg, once or twice daily. The clinical efficacy rate was 95.7%.
As side effects, nausea and vomiting were observed in two patients, nausea and abdominal fulness were observed in one patient, and insomnia and abdominal fulness in another. Slight elevation of S-GPT was also noted in one patient.

View full abstract

We performed basic and clinical studies on fleroxacin, a newly developed pyridonecarboxylic acid derivative, in respiratory infections, and obtained the following results.
1. Antimicrobial activity: minimum inhibitory concentrations (MICs) of the present agent, norfloxacin (NFLX), ofloxacin (OFLX), enoxacin (ENX) and ciprofloxacin (CPFX) against 644 clinical isolates (13 species and 18 strains, including Gram-positive cocci, Gram-negative rods, and anaerobes) were measured and compared. The antimicrobial activity of fleroxacin was about the same as that of NFLX against Gram-positive cocci, Gram-negative rods and anaerobes.
2. Clinical results: fleroxacin was given for 2.5-7 days at a daily dose of 200-400mg to four patients with respiratory infections. Clinical efficacy was assessed as fair in both of two cases. Side effects were observed in three cases: central nervous system effects in two cases and gastrointestinal in another. All were, however, mild and disappeared after discontinuation or the end of administration. No change was noted in the laboratory findings.

View full abstract

We carried out basic and clinical studies on fleroxacin (FLRX), a new antimicrobial agent, with the following results.
1. Antibacterial activity: the in vitro activity of fleroxacin was determined against 30 standard strains and 567 clinical isolates of 16 different species by a microbroth dilution method and compared with those of norfloxacin (NFLX), ofloxacin (OFLX), enoxacin (ENX), ciprofloxacin (CPFX), and pipemidic acid (PPA).
Fleroxacin showed excellent activity against Gram-positive cocci and Gram-negative bacilli of standard strains. Furthermore, it was 8 to 512 times more effective than PPA and almost the same as NFLX, ENX, OFLX, but 2 to 16 times less effective than CPFX.
2. Serum and sputum levels in chronic respiratory infections: four patients with chronic respiratory infection were given various doses of fleroxacin (150-300mg) orally, and its concentrations in serum and sputum were measured by HPLC. Peak levels of fleroxacin in serum (2.06-7.747mu;g/ml) were higher than those of OFLX, and high concentrations were observed even 8 h after administration (1.58-4.94μg/ml). Furthermore, since the sputum levels were higher than serum levels in all patients, fleroxacin seems to transfer easily into lung tissue and sputum. Our results suggest that fleroxacin should be useful in patients with acute and chronic respiratory infection.
3. Clinical effects and adverse reactions: twenty-one patients with respiratory infection were tested with fleroxacin. The overall efficacy rate was 84.2% (excellent 3, good 13, fair O, poor 3, unevaluable 2). As side effects, auditory hallucinations, dizziness and a heat sensation were observed in one patient each. Transient slight elevation of BUN was observed in one patient.

View full abstract

Fleroxacin is a new quinolone derivative structurally related to norfloxacin. We evaluated its utility in chronic respiratory infections. Its antimicrobial activity (50% minimum inhibitory concentration: MIC50) against major respiratory pathogens was 12.5μg/ml against Streptococcus pneumoniae, 0.39μg/ml against Haemophilus influenzae, 0.39μg/ml against Branhamella catarrhalis, 6.25μg/ml against Staphylococcus aureus, and 6.25μg/ml against Pseudomonas aeruginosa.
The maximum sputum level of fleroxacin in one patient with chronic bronchitis during oral administration of 200mg once and twice per day was 1.29μg/ml and 1.40μg/ml. The maximum serum peak level and serum half-life in one patient with bronchiectasis was 3.67μg/ml, and 13.2 h after a single oral dose of 300mg, while the ratio of maximum sputum to serum peak level was 50.4%.
In 21 cases of chronic respiratory infections, fleroxacin was clinically evaluated. The drug was given orally at 200-400mg per day for 5-7 days. Causative organisms were S. pneumoniae (8 cases), B. catarrhalis (7), H. influenzae (9), P. aeruginosa (4) and others. The rate of clinical response was 68.4%. The bacteriological response against all isolated pathogens was 84.8%. A side-effect (erythema) occurred in only one patient.
These results support that fleroxacin is one of the most useful oral antimicrobial agents in the treatment of chronic respiratory infections.

View full abstract

We performed laboratory and clinical studies on fleroxacin, a new synthetic fluorinated quinolone antimicrobial agent, with the following results.
1. Antimicrobial activity The minimum inhibitory concentrations (MICs) of fleroxacin against 13 species and 303 clinically isolated strains, were determined and compared with those of ofloxacin and ciprofloxacin, using the MIC-2000 system (Dynatech Laboratories).
Fleroxacin had broad-spectrum antimicrobial activity against clinically isolated strains except Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus faecalis and Pseudomonas aeruginosa.
2. Clinical efficacy
Fleroxacin (200 or 300 mg/day) was given to 17 patients with infections (2 with bacterial pneumonia, 10 with chronic bronchitis, 4 with acute bronchitis and one with urinary tract infection) for 4-9 days.
Clinical response was excellent in 2, good in 11, and ineffective in 3 patients with respiratory infections. Overall clinical efficacy was 81.3%.
Three strains of Haemophilus influenzae and one each of Klebsiella pneumoniae and Streptococcus pyogenes were eradicated. One strain of S. pneumoniae was eradicated, but another was not evaluable. One strain of Escherichia coli, isolated from UTI, was eradicated.
As a side effect, nausea was noted in one patient, but no altered laboratory findings were observed in any of the patients.

View full abstract

To objectively evaluate the appropriate clinical dose of fleroxacin, a new quinolone antibacterial agent, in the treatment of chronic respiratory tract infections, we carried out a dose-finding comparative study using ofloxacin (OFLX) as the control drug.
Patients were given fleroxacin at a single daily dose of 200 mg or 300mg or 600mg of OFLX (t. i. d.) for 14 days in principle. The following results were obtained.
1. The clinical efficacy rates (including excellent and good) as judged by the committee were 62.2%(28/45) in the fleroxacin 200 mg group, 90.0%(36/40) in the fleroxacin 300 mg group and 77.3%(34/44) in the OFLX group. There was a significant difference between the 200 mg and 300 mg fleroxacin groups.
2. Bacteriologically, the eradication rates were 65.4%(17/26) in the fleroxacin 200 mg group, 73.9%(17/23) in the fleroxacin 300 mg group and 75.9%(22/29) in the OFLX group.
3. The incidence of side effects was 8.5%(4/47) in the fleroxacin 200 mg group, 9.5%(4/42) in the fleroxacin 300 mg group and 4.3%(2/46) in the OFLX group. They were not serious in degree.
4. The incidence of abnormal changes in laboratory test values was 7.1%(3/42) in the fleroxacin 200 mg group, 8.3%(3/36) in the fleroxacin 300 mg group and 25.6%(11/43) in the OFLX group. All changes were mild in degree.
5. The utility rates (including markedly useful and useful) as judged by the committee were 62.2%(28/45) in the fleroxacin 200 mg group, 85.4%(35/41) in the fleroxacin 300 mg group and 75.6%(34/45) in the OFLX group. There was a significant difference between the 200mg and 300 mg fleroxacin groups.
Our results suggest that a daily dose of 300mg of fleroxacin is a suitable clinical dosage in treating chronic respiratory tract infections.

View full abstract

We investigated the antibiotic and clinical effects of fleroxacin.
The MICs against bacteria isolated from urinary tract infections were measured. Fleroxacin showed excellent antibiotic action against Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, indole-positive Proteus spp. and Enterobacter spp., with MIC₉₀ values of 3.13μg/ml or less. In contrast, against Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Enterococcus faecium, Serratia marcescens and Pseudomonas aeruginosa, the values were 6.25μg/ml or more. However, MIC₅₀ values of fleroxacin against these bacteria were all 3.13μg/ml or less, except against E.faecium (6.25μg/ml). The antibiotic activity of fleroxacin was about the same as these of norfloxacin, ofloxacin and enoxacin, though weaker than that of ciprofloxacin. Thus its efficacy against urinary tract infections was expected.
A clinical study was conducted on 9 patients with acute uncomplicated cystitis (AUC) and 19 with chronic complicated cystitis (CCC). Efficacy was judged according to the criteria of the Japanese UTI Committee. In the 7 AUC cases, the efficacy rate was 100% on day 3 of medication. Bacteriologically, all seven bacterial strains disappeared (eradication rate 100%). In the 13 CCC cases, the treatment was effective in 9 and ineffective in 4 on day 5 (efficacy rate was 69%) and 18 of 20 strains disappeared (eradication rate 90%). Side effects were one case each of stomach discomfort and rash. There were no abnormalities in laboratory data of 27 cases.

View full abstract

We studied the antibacterial activity and clinical efficacy of fleroxacin, a new quinolonecarboxylic acid.
1. Antibacterial activity
he in vitro activity of fleroxacin was tested against clinical isolates of Escherichia coli, Citrobacter freundii, Serratia marcescens, Pseudomonas aeruginosa and Neisseria gonorrhoeae and compared them with the in vitro activity of norfloxacin (NFLX), enoxacin (ENX), ofloxacin (OFLX), ciprofloxacin (CPFX) and pipemidic acid (PPA). Against E.coli, non-penicillinase producing N.gonorrhoeae and penicillinase producing N.gonorrhoeae, the MIC_90s of fleroxacin were 3.13μg/ml, 0.2μg/ml and 0.4μg/ml. But the MIC_90s against C. freundii, S. marcescens and P.aeruginosa were high. The antibacterial activity of fleroxacin against all tested strains was slightly inferior to that of CPFX, similar to those of NFLX, ENX and OFLX, and superior to that of PPA.
2. Clinical study
In 9 patients with acute uncomplicated cystitis, the clinical efficacy of fleroxacin was excellent in 8 and moderate in 1, with an overall efficacy rate of 100%. In 28 patients with complicated urinary tract infection, clinical efficacy was excellent in 4, moderate in 17 and poor in 7 cases, and the overall efficacy rate was 75.0%. Bacteriologically, 24 of 34 strains isolated from urine were eradicated, with an eradication rate of 70.6%. The clinical efficacy rate in gonococcal and non-gonococcal urethritis was 100%.
Abnormal clinical findings were shown in one case, namely, elevation of GOT and GPT. There were no noteworthy objective or subjective side effects.

View full abstract

Fleroxacin, a new oral quinolone, has been developed by Kyorin Pharmaceutical Co., Ltd., Japan. We evaluated the penetration of the drug into cerebrospinal fluid (CSF) and its clinical efficacy in urinary tract infections.
Fleroxacin was administered orally at a single dose of 200 mg, and its concentration in serum and CSF determined 4 h afterwards. The concentration in CSF ranged from 0.22-1.26μg/ml. The ratio of CSF to serum concentration ranged from 0.10-0.51.
Fleroxacin was administered to 24 patients with urinary tract infections. In 13 cases of acute uncomplicated urinary tract infections, the overall clinical efficacy rate according to the Japanese UTI Committee's criteria was 100%, and all 15 strains isolated from patients were bacteriologically eradicated. In five cases of chronic complicated urinary tract infections, the overall efficacy rate was 80% according to the same criteria, and 5 of 8 strains (63%) were eradicated.

View full abstract

We performed a clinical study on fleroxacin, a newly developed quinolone derivative, with the following results.
1. Diffusion into prostatic fluid (PF)
The concentration of fleroxacin in PFs, which were collected 1.0-1.5h after a 200 mg administration, ranged from 0.04-0.21μg/ml (4 specimens from 2 patients).
2. Clinical results
Fleroxacin was used in treating 40 patients at doses of 200-600mg a day (400mg, in 2 divided doses, as a rule) for 3-28 days (in many cases 5-14 days).
1) Urinary tract infection
(a) Acute uncomplicated cystitis: all five patients, assessed by the Japanese UTI Committee's criteria, were completely cured after 3 day's administration.
(b) Chronic complicated diseases: of 21 cases, efficacy in 14 (66.7%) was evaluated as excellent or moderate according to the Japanese UTI Committee's criteria.
(c) Genital infection: efficacy in two cases of chronic prostatitis was good and poor. Of two cases of chronic epididymitis (non-chlamydial), the response was good in both after 10-14 day's treatment.
3. Side effects
1) Clinical abnormal values: a transient, mild elevation of BUN and s-Cr was observed in one case.
2) Subjective side effects: there were four cases (six incidences) of side effects probably due to the drug administration: vomiting, headache, disturbed sleep/irritating feeling, and disturbed sleep/light-headed feeling, in one case each.
Except in the case of vomiting, administration was continued. After therapy was completed these side effects spontaneously disappeared within 1-2 days.
We consider that fleroxacin's long half life (about 10 h) makes it useful in treating UTI and genito-urinary tract infections with once daily administration.

View full abstract

We compared the in vitro antibacterial activity of fleroxacin, a new oral quinolone, against both Gram-positive cocci and Gram-negative rods from urinary tract infections and compared it with those of the control drugs, norfloxacin, ofloxacin and ciprofloxacin.
The antibacterial activity of fleroxacin was inferior to that of ciprofloxacin, though it was similar to those of norfloxacin and ofloxacin.
Four patients with acute uncomplicated cystitis and 15 with complicated urinary tract infections were treated with fleroxacin at 200 mg/once daily for 3 days and 200-300 mg/once daily for 5 days. According to the criteria of the Japanese UTI Committee, the overall efficacy rate of fleroxacin in acute uncomplicated cystitis and complicated urinary tract infection was 100% and 91%.
No adverse reactions were experienced and no abnormal laboratory findings noted.
We conclude that fleroxacin is useful in the treatment of urinary tract infection.

View full abstract

We studied fleroxacin, a new fluoroquinolone derivative, for rational treatment in an in vitro bladder model, pharmacokinetics in patients with impaired renal function and clinical efficacy in urinary tract infection. The results were as follows.
1. In the bladder model, a single cycle exposure to fleroxacin suppressed the growth of E. coli for longer than did double cycle exposure. From the results obtained, once daily treatment appeared rational in treating urinary tract infections.
2. In 11 patients with impaired renal function, blood levels and urinary excretion after oral administration were investigated. Fleroxacin is a drug of the renal excretion type, as are other new quinolone derivatives, and clear differences were observed between patients with impaired renal function and healthy volunteers.
3. The efficacy rate of fleroxacin in two cases of acute uncomplicated cystitis was 100%. In 14 cases of chronic complicated urinary tract infection, it was 71%. No clinical or laboratory adverse reactions were observed.

View full abstract

We studied the antibacterial activity and clinical utility of fleroxacin, a new oral fluoroquinolone, in urological infections.
1. Antibacterial activity: the MICs of fleroxacin against clinical isolates (185 strains of 12 species) from urinary tract infections, were compared with those of ofloxacin (OFLX) and norfloxacin (NFLX). Except against P.aeruginosa, the overall antibacterial activity of fleroxacin was excellent and similar to that of NFLX.
2. Clinical efficacy: the overall clinical efficacy according to the criteria of the Japanese UTI Committee was 100%(1/1) in acute uncomplicated cystitis and 75.6%(31/41) in chronic complicated UTI. Bacteriologically, 36 of 45 strains (80.0%) were eradicated.
3. Side effects: facial hot flushes were noted in one patient, but the symptom was mild and transient. With regard to laboratory findings, slight and transient elevations of GOTand GPT and of BUN and s-Cr were seen in one patient.

View full abstract

Fleroxacin, a novel new-quinolone, was administered to 17 patients and the results described below were obtained.
1. Of 11 patients with complicated urinary tract infection (UTI), excellent results were observed in 2, moderate in 4 and poor in 5. The overall clinical efficacy rate was 54.5%.
2. In bacteriological response, 9 of 14 strains (64.3%) were diminished.
3. As classified by dose and timing, clinical efficacy rates were 40% in the 100mg once daily group, 66.7% in the 200mg once daily group and 66.7% in the 200mg twice daily group.
4. Clinical efficacy in one case of acute uncomplicated cystitis was excellent.
5. Side effects were stomach discomfort and diarrhea in one case, and abnormal elevation of GOT, GPT and ALP in another.

View full abstract

We performed antimicrobial and clinical studies on fleroxacin, a new oral fluoroquinolone, and obtained the following results.
1. Antimicrobial activity of fleroxacin
The antimicrobial activity of fleroxacin against 10 species isolated from urine was compared with that of norfloxacin (NFLX) and ofloxacin (OFLX). Against Pseudomonas aeruginosa, fleroxacin was less active than the others. Against Escherichia coli, Citrobacter freundii, Klebsiella pneumoniae, Enterobacter cloacae, Proteus mirabilis, Proteus vulgaris and Serratia marcescens, fleroxacin showed comparable activity. Against Staphylococcus sp. and Enterococcus faecalis, the activity of fleroxacin was superior to that of NFLX, but inferior to that of OFLX.
2. Clinical efficacy
Fleroxacin was administered to 31 patients with urinary tract infections (UTI) at 200-400 mg, once daily or b.i.d. for 5 days. The overall clinical efficacy rate was 61.1%(11/18) according to the Japanese UTI Committee's criteria.
3. Bacteriological response
Sixteen of 21 strains (76.2%) isolated from patients with UTI, including 6 Gram-positive cocci and 15 Gram-negative rods, were eradicated.
4. Adverse reactions
Nausea and cold sweat, nausea and vomiting, and eruption occured transiently in one case each. No abnormal laboratory findings induced by the drug were observed.

View full abstract