The in vitro antibacterial activity of gatifloxacin (GFLX), a new fluoro-methoxy-quinolone agent, was studied and compared with that of other new quinolones.
GFLX showed a broad spectrum of potent antibacterial activity against Gram-positive bacteria, Gram-negative bacteria, anaerobic bacteria, and Mycobacterium spp.
The antibacterial activity of GFLX was superior to that of norfloxacin (NFLX), ciprofloxacin (CPFX), and levofloxacin (LVFX), and comparable to that of tosufloxacin (TFLX) and sparfloxacin (SPFX) against clinical isolates of Gram-positive bacteria, including Staphylococcus aureus subsp. aureus and Streptococcus pneumoniae. Against clinical isolates of Gram-negative bacteria, including the family Enterobacteriaceae and glucose-nonfermentative rods, GFLX possessed the same antibacterial activity as NFLX, SPFX, and LVFX, and only slightly lower activity than CPFX and TFLX. Against Haemophilus infiuenzae, the antibacterial activity of GFLX was superior to that of NFLX, CPFX, TFLX, and SPFX, and comparable to that of LVFX. GFLX showed higher antibacterial activity than CPFX and the same antibacterial activity as SPFX against clinical isolates of Mycoplasma pneumoniae and Ureaplasma urealyticum.
The in vitro antibacterial activity of GFLX was not influenced by the type of medium, inoculum size, pH of medium, or addition of human serum or human urine. However, the activity of GFLX decreased in the presence of Mg⁺⁺, similar to the decrease in activity of CPFX in the same condition.

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In vivo antibacterial activity of gatifloxacin (GFLX) on experimental infections was compared with that of sparfloxacin (SPFX), levofloxacin (LVFX), ciprofloxacin (CPFX), and metronidazole.
1.In systemic infection in mice, the protective effect of GFLX against Staphylococcus aureus subsp. aureus, (S.aureus) including a CPFX-resistant strain, was superior to that of LVFX and CPFX and similar to that of SPFX.Against Streptococcus pneumoniae infection, GFLX was the most effective of the quinolones tested. The efficacy of GFLX on Escherichia coli infection was inferior to that of SPFX, but comparable to those of LVFX and CPFX.GFLX showed efficacy similar to the other quinolones against Pseudomonas aeruginosa infection.
2. The therapeutic effect of GFLX on pneumonia caused by S.pneumoniae in mice was more than three times superior to that of the other quinolones.Against pneumonia with Klebsiella pneumoniae subsp. pneumoniae, GFLX showed efficacy about three times higher than CPFX, and similar to LVFX and SPFX.
3. In urinary tract infection with E. coli in mice, the efficacy of GFLX was comparable to that of other quinolones tested.
4. The therapeutic efficacy of GFLX on skin infection with S. aureus in mice was similar or superior to that of SPFX, LVFX, and CPFX.
5. In rat inflammatory pouch infections, GFLX was more effective than CPFX against S. aureus, and more effective than CPFX and metronidazole against Bacteroides fragilis.
These results indicate that GFLX may be useful against infections caused by various pathogens, including gram-positive cocci and anaerobes.

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The bactericidal activity of gatifloxacin (GFLX) against Staphylococcus aureus subsp. aureus (S. aureus), Streptococcus pneumoniae, Escherichia coli, and Pseudomonas aeruginosa was determined using an in vitro pharmacokinetic model simulating serum levels of the drug in humans after oral administration of 200 mg.
1. GFLX showed potent bactericidal activity against S.aureus Smith, S. pneumoniae Type III, and E.coli ML4707. P. aeruginosa IID1210 was also killed in the model of GFLX, but regrowth was observed 4 h after addition of the drug.
2. The bactericidal activity of GFLX in the in vitro pharmacokinetic model was due to its antibacterial activity and pharmacokinetic properties.
3. The bactericidal activity of GFLX against S.aureus, S. pneumoniae, and P. aeruginosa was equal or superior to that of levofloxacin, sparfloxacin, and tosufloxacin.

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In vitro and in vivo antibacterial activity of gatifloxacin (GFLX), and its S and R isomers were examined.
1.The two optical isomers showed a broad spectrum of antibacterial activity which was as potent as that of GFLX.
2.The efficacy of the optical isomers by oral administration on systemic infections in mice was comparable to that of GFLX.
These results indicate that there is no difference in antibacterial activity between GFLX and its optical isomers.

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In order to evaluate the antibacterial spectrum and antimicrobial activity of gatifloxacin (GFLX), minimum inhibitory concentrations (MICs) of GFLX and control drugs were determined against standard strains and clinical isolates that were obtained by our laboratory in 1995.
Results are summarized as follows:
1.Antimicrobial activity of GFLX against Streptococcus spp.(including Streptococcus pneumoniae and Streptococcus pyogenes) and Peptostreptococcus spp.was equal to or stronger than that of tosufloxacin (TFLX), and was stronger than that of levofloxacin (LVFX) and ciprofloxacin (CPFX).
2.Antimicrobial activity of GFLX against the Bacteroides fragilis group and Prevotella spp.was clearly stronger than that of TFLX, LVFX and CPFX.
3.The results of antimicrobial activity against Staphylococcus spp., Enterococcus spp.and quinolonesresistant Enterobacteriaceae suggest that GFLX shows strong antimicrobial activity against fluoroquinolone-resistant strains.
4.Antimicrobial activity of GFLX against Pseudomonas aeruginosa was approximately equal to that of other fluoroquinolones, and its antimicrobial activity against other glucose-nonfermentative Gram-negative rods was strong.

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Gatifloxacin (GFLX) is a new quinolone with potent and broad antibacterial activity against Gram-positive and Gram-negative bacteria. Pharmacokinetic studies have shown that GFLX has a serum elimination half-life of approximately 7 hours, and a urinary recovery rate of 80% within 24 hours after various single oral doses.
In this study, the responses of two strains of Escherichia coli to GFLX, fleroxacin (FLRX), ofloxacin (OFLX), ciprofloxacin (CPFX), and norfloxacin (NFLX) were investigated in an in vitro model of the urinary bladder simulating the dynamic conditions in which bacteria are exposed to antibiotics in the treatment of bacterial cystitis.
Two types of concentration profile, single cycle (100mg once a day) and double cycle (50mg twice a day), were employed.
In the conditions of the bladder model, GFLX suppressed the growth of two strains of E.coli for the longest period among the five agents tested. Although single cycle exposure to FLRX suppressed the growth of E.coli for a longer period than did double cycle exposure, no significant difference of growth inhibition period was observed between a single and double cycle exposure to GFLX. During exposure of two strains to five agents, no emergence of resistance was observed under the present conditions of this bladder model.
From the results obtained in this study, oral administration of GFLX once or twice a day appears to be appropriate in the treatment of the urinary tract infections.

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The MIC values of the newly synthesized quinolone antibiotic gatifloxacin (GFLX)(Kyorin Pharmaceutical Co., Ltd., Tokyo) were determined with various bacterial species, and were compared with five other 4-quinolone antibiotics-ciprofloxacin, norfloxacin, ofloxacin, tosufloxacin, and sparfloxacin. MIC₉₀ values (μg/mL) of GFLX against various species or groups of bacteria (number of isolates in parentheses) were as follows: 3.13, Staphylococcus aureus subsp. aureus (66); 0.2, methicillinresistant S. aureus subsp. aureus (MRSA)(47, isolated in 1981); 6.25, MRSA (64, isolated in 1987); 0.2, coagulase-negative staphylococci (41); 0.39, Streptococcus pneumoniae (33); 0.39, penicillin-insensitive S. pneumoniae (17); 0.39, Streptococcus pyogenes (47); 0.78, Enterococcus faecalis (37); 1.56, Enterococcus, faecium (41); 0.39, Escherichia coli (43); 0.2, Klebsiella pneumoniae subsp. pneumoniae (47); 0.39, Proteus mirabilis (48); 0.39, Proteus vulgaris (54); 0.78, Morganella morganii (49); 25, Providencia rettgeri (47); 1.56, Serratia marcescens (50); 0.78, Enterobacter cloacae (50); 1.56, Citrohacter freundii (48); 0.39, Acinetobacter spp.(41); 6.25, Pseudomonas aeruginosa (32); 6.25, Burkholderia cepacia (33); 0.78, Stenotrophomonas maltophilia (47);≤0.013, Haemophilus influenzae (54); 1.56, Bacteroides fragilis (38). GFLX had an antibacterial spectrum similar to sparfloxacin, and had a better activity than the other 4-quinolones, especially against Gram-positive bacteria, including MRSA and penicillin-insensitive S. pneumoniae. In vitro activity against 30 MRSA strains isolated from 19 different countries during the period 1961 to 1986 was compared with that of five other 4-quinolones. MIC₉₀ of GFLX to MRSA from the various countries was 0.2μg/mL, 2-16-fold less than OFLX, NFLX, and CPFX, and 2-fold greater than SPFX and TFLX. To test the degree of cross-resistance to GFLX, we obtained isogenic sets of NFLX-resistant, and NFLX-OFLX resistant mutants from susceptible S. aureus strains. GFLX showed strong activity (MIC, 0.2μg/mL) against the NFLX-resistant mutants and also fairly good activity (MIC, 3.13μg/mL) against NFLX-OFLX-resistant mutants which harbored a mutation of the gyrA gene. Therefore, mutants resistant to NFLX and NFLX-OFLX showed incomplete cross-resistance to GFLX. GFLX selected the spontaneous resistant subclones from quinolone-susceptible and NFLX-OFLX-resistant MRSA at a low mutation rate. The selective toxicity of GFLX was determined by measuring growth inhibitory concentrations of this agent in cultured mammalian cells. At concentrations higher than 50μg/mL, GFLX manifested cytostatic activity to mammalian cells which was relatively stronger than that of OFLX.

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Gatifloxacin (GFLX) is a newly synthesized 6-fluoro-8-methoxy quinolone with a wide spectrum of antibacterial activity against various bacteria. The in vitro activity of GFLX was compared with that of sparfloxacin (SPFX), tosufloxacin (TFLX), ofloxacin (GFLX), and norfloxacin (NFLX), against 2, 178 strains, including streptococci (S.pyogenes, S.agalactiae, S.intermedius, group C and Gstreptococci, and S.pneumoniae), enterococci (E.faecalis, E.faecium and others), Branhamella catarralis, Haemophilus influenzae, Helicobacter pylori, Gardnerella vaginalis, Serratia marcescens, Enterobacter (E.cloacae and E.aerogenes), Pseudomonas aeruginosa, and anaerobes (Peptostreptococcus spp., Lactobacillus spp., Propionibacterium acnes, Eubacterium spp., Clostridium (C. perfringens and C.difficile), Veillonella, Bacteroides fragilis group, and other Gram-negative bacilli), which had been isolated from clinical materials during the period 1990 to 1995.
GFLX showed a broad spectrum of antibacterial activity against Gram-positive and Gramnegative bacteria, and its activity was almost equal to that of SPFX and TFLX, and superior to that of OFLX and NFLX. GFLX was especially potent against β-haemolytic streptococci, penicillin-resistant Streptococcus pneumoniae, enterococci (except for Enterococcus faecalis and Enterococcus faecium), and Haemophilus influenzae (including ampicillin-resistant strains).
The antibacterial activity of GFLX was weak against Bacteroides thetaiotaomicron, Prevotella bivia, and Fusobacterium spp.

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The in vitro and in vivo antimicrobial activities of a new quinolone antimicrobial agent, gatifloxacin (GFLX), were examined and compared with those of sparfloxacin (SPFX), tosufloxacin (TFLX), ciprofloxacin (CPFX), and ofloxacin (OFLX).
GFLX had a broad antimicrobial spectrum, and its antimicrobial activity against Staphylococcus (including methicillin-resistant Staphylococcus aureus subsp. aureus (MRSA)), Streptococcus, and Enterococcus was higher than that of CPFX and OFLX, and almost equal to that of SPFX and TFLX. Against members of the family Enterobacteriaceae and glucose-nonfermentative Gram-negative rods (except for Pseudomonas aeruginosa), the antimicrobial activity of GFLX was the same as that of SPFX, TFLX, CPFX, and OFLX. The activity of GFLX for P.aeruginosa was similar to that of SPFX and OFLX. The antibacterial effect of GFLX against Bacteroides fragilis was the most active among all the drugs tested.
The therapeutic effects of GFLX in a mouse systemic infection model were almost equal to those of SPFX against S.aureus subsp.aureus Smith, Streptococcus pneumoniae TMS3, Escherichia coli C11, and Pseudomonas aeruginosa E7. In a transnasal pulmonary infection model using S.pneumoniae TMS3 as the infective strain, the therapeutic effect of GFLX was superior to that of CPFX and OFLX.
Peak levels of GFLX in murine serum, lungs, and kidneys after a single oral administration of 50 mg/kg were 3.86±0.61μg/mL (15min after administration), 7.80±6.58μg/g (2 hours) and 16.49±4.69μg/g (30 min), respectively.The peak concentration of GFLX was less than that of OFLX except in kidneys, but 2-6 times higher than that of CPFX and TFLX and equal to that of SPFX. The excellent therapeutic effects of GFLX can be attributed to its potent antibacterial activity and favorable tissue distribution.

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The in vitro activity of gatifloxacin against two standard strains and 40 clinical isolates of Chlamydia trachomatis was compared with that of three other fluoroquinolones and of minocycline.
Minimal inhibitory concentrations (MICs, μg/mL) against the isolates were as follows: gatifloxacin, 0.06 to 0.25;tosufloxacin, 0.125 to 0.25;levofloxacin, 0.25 to 0.5;ofloxacin, 0.5 to 1.0;and minocycline, 0.03 to 0.06.
Results for the two standard strains were similar.

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Gatifloxacin (GFLX) is a newly developed quinolone derivative. Fecal flora were studied in six healthy male volunteers after the oral administration of two doses of 300 mg of GFLX for seven days.Fecal samples were taken prior to and several times after administration, and quantitative and qualitative analyses of microorganisms in the feces were performed.
Counts of aerobic and anaerobic bacteria were depressed during the administration period. Total bacterial counts decreased in two of the six volunteers.
Fecal bacteria returned to their former levels within 14 days after administration.
Transient appearance of Clostridium difficile was observed in two volunteers.

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Since quinolones are known to have potent convulsant activity, we studied the convulsant activity of gatifloxacin (GFLX), a newly developed quinolone, and its effect on the receptor binding of γ-aminobutyric acid (GABA), an inhibitorytransmitter in the mammalian central nervous system (CNS). Intraventricular injection of GFLXinduced convulsions in mice in a dose-dependent manner. The potency of convulsant activity was between norfloxacin and fleroxacin. GFLX inhibited GABA receptor binding at high concentrations. Biphenylacetate and flurbiprofen moderately enhanced its inhibitory activity. These results suggest that GFLX might induce convulsions at unusually high concentrations in the brain.

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In vitro and in vivo postantibiotic effects (PAE) of gatifloxacin (GFLX) were compared with that of ofloxacin.
1. In vitro PAE of GFLX for 4 MIC at 1 hour exposure to Staphylococcus aureus Smith, Streptococcus pneumoniae IID552, Enterococcus faecalis IID682 and Klebsiella pneumoniae BK were 2.1-4.1 hours. In vitro PAE of GFLX against S.aureus and S.pneumoniae was comparable to that of ofloxacin, whereas that of GFLX against E.faecalis and K.pneumoniae BK was more than that of ofloxacin.
2. In vivo PAE of GFLX and ofloxacin with a dose of 4mg/kg against K.pneumoniae thigh infection in neutropenic mice were 4.5 and 1.2 hours, respectively.
3. Effective regrowth times (ERT) of GFLX with doses of 4 and 8 mg/kg against K.pneumoniae BK were more than 12 hours and more than 16 hours, respectively. That of ofloxacin with a dose of 4mg/kg was 6.6 hours.

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We developed high-performance liquid chromatographic (HPLC) methods for the determination of gatifloxacin (GFLX), a new quinolone, in plasma and urine. The assay method for plasma was based on on-line deproteinization with BSA-ODS column and separation with ODS column, using a column-switching system, followed by detection with fluorescence monitor. The assay method for urine was based on separation with ODS column only, followed by detection with fluorescence monitor.
Plasma and urine samples were directly injected into the HPLC system after addition of the internal standard (AM-1202). The chromatograms exhibited no interfering blank peak. Calibration curves were linear in the concentration ranges of 0.05 to 2.5μg/mL and 0.5 to 250μg/mL, in plasma and urine respectively. The limits of detection and quantification were 0.01 and 0.05μg/mL respectively in plasma, and 0.1 and 0.5μg/mL in urine. GFLX was stable for at least 1 day in plasma, urine, and their analytical mixtures at room temperature, and for at least 3 months in plasma and urine, both at-40°C and after three freeze-thaw cycles. In conclusion, these HPLC methods should be useful for the routine analysis of GFLX in biological fluids because they are rapid and simple, and show excellent reproducibility of the chromatograms and the measured values.

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We investigated the pharmacokinetics of gatifloxacin (GFLX), a new quinolone, and its enantiomers (S-and R-isomers) following intravenous and oral administration of each compound singly to mice, rats, rabbits, dogs, and monkeys.GFLX was rapidly absorbed, and the bioavailability of GFLX ranged from 87% to 116% in rats, dogs, and monkeys, indicating that GFLX is almost completely absorbed in these species.The volume of distribution at steady state, which was found to be about 2L/kg in all the species tested, suggested the extensive distribution of this drug. Species with larger body weight tended to show a smaller total body clearance and a longer half-life: half-lives in mice, rats, rabbits, dogs, and monkeys were 1.1, 1.6, 1.9, 6.0, and 2.2h, respectively. Serum protein binding was low, 15% to 27%. The unchanged drug was excreted almost completely within 24 h in all species. Cumulative urinary recovery was more than 40% in rats, dogs, and monkeys, and ranged from 20% to 30% in mice and rabbits. GFLX was also excreted into bile in rats: GFLX was excreted predominantly as a glucuronide conjugate in bile, and as an unchanged drug in urine. No large differences were found among GFLX, S-isomer, and R-isomer in concentrations in serum, oral absorption, serum protein binding, or excretion in urine and bile in laboratory animals.

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Gatifloxacin (GFLX), a new quinolone with a chiral center in its structure, has been developed as a racemate because its two enantiomers have almost the same antimicrobial activity. An enantioselective high-performance liquid chromatographic (HPLC) method was developed for the simultaneous determination of two enantiomers of GFLX in biological samples. This method was based on the derivation of R-and S-isomers in plasma (or serum) and urine with optically active L-valinamide, followed by the separation of these diastereomers by reversed-phase HPLC. The pharmacokinetics of GFLX and its two enantiomers were investigated in animals using this method.No interconversion of the enantiomers of GFLX was observed on chromatograms of serum following intravenous administration of single enantiomers in rats, dogs, and monkeys. Furthermore, there was no difference between the two enantiomers following oral administration of GFLX in monkeys with respect to disposition in serum and urinary excretion. These results indicate that R-and S-isomers of GFLX have similar pharmacokinetic profiles in laboratory animals.

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The present study was conducted to investigate the absorption, distribution, and excretion of [¹⁴C] gatifloxacin (GFLX) after a single oral administration of 10 mg/kg in rats.Placental transfer and secretion into milk of [¹⁴C] GFLX in pregnant and lactating rats, respectively, were also investigated.
1) Radioactivity in the blood reached a peak of 1.93μgeq./mL within 1 hour after oral administration in male rats, and had declined to 0.05μg eq./mL at 24 hours, with a half-life of 2.46 hours.
2) When [¹⁴C] GFLX was administered to loops of stomach, duodenum, jejunum, and ileum, radioactivity was absorbed well from the entire small intestine, but not from the stomach.
3) Radioactivity showed its highest level at 1 hour in major tissues such as digestive tract, bladder, kidney, pancreas, prostate, and liver, and then rapidly declined to undetectable levels in most tissues by 72 hours.However, distribution of [¹⁴C] GFLX in the brain and cerebrospinal fluid was minimal.This finding coincided with the results of radioluminograms.
4) Urinary and fecal excretion of radioactivity amounted to 43.1% and 57.6%, respectively, over the 192 hours after dosing.Most of this excretion occurred within the first 24 hours.
5) Biliary, urinary, and fecal excretion of radioactivity in bile duct-cannulated rats amounted to 34.4%, 43.1%, and 20.4% of dose, respectively, within 48 hours after dosing.
6) Rats were intraduodenally dosed with an aliquot of bile collected from other rats up to 4 hours after a single oral dose of [¹⁴C] GFLX.Recovery of radioactivity from the bile and urine indicated that 37.1% of the radioactivity was reabsorbed.
7) Radioactivity in the fetus was nearly equal to that in the maternal blood at 1 hour after oral administration, and it declined to a level below the detection limit by 24 hours after administration.
8) Radioactivity in milk was 3 to 7 times higher than that in blood throughout the 8 hours after administration, and it decreased along with the decrease in blood.

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We investigated the absorption, distribution, and excretion of [¹⁴C] gatifloxacin (GFLX) during and after repeated oral administration at a once-daily dose of 10 mg/kg for 14 days in rats.
1) Radioactivity in the blood 1 hour after each oral administration ranged from 0.63 to 0.88μg ea./mL.and radioactivity at 24 hours reached a steady state, 0.04μg eq./mL, after the 6th dose.There was no significant change in pharmacokinetic parameters between the first and last days.
2) One hour after the 14th administration, radioactivity in the kidney, spleen, and liver were higher than in other tissues: 7.55, 4.17, and 3.77μg eq./g, respectively.On the other hand, radioactivity in the brain, eyeball, and fat tissues were less than half of that in the blood. Radioactivity in almost all tissues except the bone decreased to the limit of detection (below 0.01μg eq./g) by 192 hours after the final dosing.
3) The daily excretion of radioactivity into urine and feces during repeated dosing ranged from 22.2 to 34.7% and from 68.2 to 84.3% of the daily dose, respectively.Nearly all of the excretion of the total dose in urine and feces was 28.4% and 78.6%, respectively, within 192 hours after the last dosing.

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We investigated the metabolism of gatifloxacin (GFLX), a new quinolone, in rats, rabbits, and dogs.The results were as follows:
1.We identified an unchanged drug, an ester-type glucuronide of GFLX (M-1) and three metabolites possessing cleaved 3-methylpiperazinyl moiety, -ethylenediamine (M-2), 2-methylethylenediamine (M-3) and amino (M-4) forms-, in rat bile and urine collected after oral administration of GFLX.
2.The radioactivity excreted from the body amounted to 99.9%, 83.6% and 70.5% of the dose up to 24 h following oral administration of ¹⁴C-labelled GFLX ([¹⁴C] GFLX) in rats, rabbits, and dogs, respectively.The respective urine-to-feces excretion ratios of radioactivity were 34: 66, 40: 60, and 69: 31.
3.GFLX accounted for about 90% of the total radioactive excreta in urine of rats, rabbits, and dogs.In addition, 3% of M-1, 1% to 2% of M-4, and 1% each of M-2 and M-3 were also detected.No marked species differences were found in the metabolic profiles of GFLX in urine.Furthermore, most of the radioactivity in feces of these animals was unchanged GFLX. One to two percent each of the total fecal radioactivity was also excreted as M-2, M-3, and M-4.
4.In bile-duct-cannulated rats, 96.1% of the total radioactivity was excreted from the body up to 24 h following oral administration of [¹⁴C] GFLX.The excretion ratios of radioactivity in urine, bile and feces were 41: 45: 14, respectively.In rat bile, 54% of M-1, 18% of GFLX, and also small amounts of M-2, M-3 and M-4 were quantitated.
5.GFLX and M-1 accounted for 82%, 91% and 89% of the total radioactivity in 24 h urine and feces following oral administration of [¹⁴C] GFLX in rats, rabbits, and dogs, respectively.
6.Radioactivity in serum existed mostly as an unchanged form following oral administration of [¹⁴C] GFLX in rats.
7.The in vitro antibacterial activity of M-2, M-3 and M-4 against a number of reference strains were 4 to 256 times less active than that of GFLX.

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The intestinal absorption characteristics of gatifloxacin (GFLX), a new fluoro-methoxy-quinolone, were investigated in rats using the in situ ligated loop method.
1. GFLX was absorbed well from duodenum, jejunum, ileum, and colon, but not from the stomach.
2. This drug was rapidly absorbed from jejunum and ileum, and tissue accumulation was minimal.
3. The absorption of quinolones from jejunum loops increased with the increase of lipophilicity. GFLX was completely absorbed in the same manner as fleroxacin, ofloxacin, and sparfloxacin.
4. The high concentrations of amino acids and peptides did not inhibit the absorption of GFLX from jejunum loops. On the other hand, the absorption of cephalexin, which was transferred by a dipeptide carrier-mediated system in the small intestine, was found to be inhibited by glycylglycine but not by glycine. This fact suggests that the common amino acid-or peptidemediated active transport system dose contribute to the absorption of GFLX in the small intestine.

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We investigated the affinity to melanin of gatifloxacin (GFLX), a new quinolone, comparing it with that of other related quinolones, and chloroquine and befunolol.Furthermore, we evaluated the disposition of GFLX in pigmented rabbit eyes, using a high-performance liquid chromatographic (HPLC) method.
1. The rank order of affinity to acid-insoluble melanin (0.1 mg/mL) extracted from bovine eyes was as follows: chloroquine, befunolol, ciprofloxacin, norfloxacin and pefloxacin, ofloxacin, lomefloxacin or GFLX, fleroxacin.The binding to melanin of GFLX was 66.9% and 36.9% at 1 and 10μg/mL, respectively.
2. A HPLC method was developed for the determination of GFLX in melanin-containing tissues. This method is based on pretreatment with solid-extraction after homogenization of tissues with 6 M potassium hydroxide, then separation by HPLC. The recovery and stability of GFLX during this analytical procedure were excellent, and the measured values by this method coincided with those from radio assay.
3. Concentrations of GFLX in ocular tissues were measured for 8 weeks after oral administration of 30 mg/kg GFLX once daily for 14 consecutive days in pigmented rabbits. GFLX was rapidly eliminated from tissues not containing melanin. By contrast, GFLX reached peaks of 214μg/g at 24h after the last dosing in iris and ciliary body, and 268μg/g at 2 h in choroid-pigmented epithelium, and then was eliminated from these melanin-containing tissues with half-lives of 10.7 and 12.2 days, respectively.
In conclusion, GFLX has a melanin-affinity like other quinolones, and it shows a high distribution to melanin-containing ocular tissues in pigmented rabbits. Though this drug is retained for a longer time in these tissues than in ones not containing melanin, the binding to melanin might be reversible.

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A Phase I study of gatifloxacin (GFLX), a new quinolone, was conducted to evaluate its safety and pharmacokinetics in healthy male volunteers.Each volunteer received a single oral dose of 20, 50, 100, 200, 400, or 600 mg.At the 200 mg dose level, the effects of food intake and a concurrent dose of probenecid were also tested.
Throughout the study period, GFLX was well tolerated by all of the 40 subjects. No abnormal change was found in subjective and objective symptoms, blood pressure, pulse rate, body temperature, ECG, blood chemistry, blood biochemistry, or urinalysis.Furthermore, no crystalluria attributable to the drug and no abnormal change in audiometry, opthalmological, or balance tests were observed at the doses of 400 and 600 mg.
Concentrations in serum reached a peak between 1.41 and 2.28 hours, and the peak concentrations (Cmax) were 0.873, 1.71, 3.35, and 5.41μg/mL at doses of 100, 200, 400, and 600 mg, respectively. The respective areas under the serum concentration-time curve from time zero to infinity (AUC_0-∞) were 7.00, 14.5, 32.4, and 53.5μg·h/mL. Elimination half-lives (T_1/2β) were 6.93 to 8.41 hours, independent of dose.Cmax and AUC_0-∞ increased in proportion to the dose.The unchanged drug was excreted mainly in the urine, with 81.6 to 87.9% of the dose appearing within 72 hours.Fecal recovery of the unchanged drug amounted to 5.7% within 72 hours after a single oral administration of 400 mg. Serum protein binding was 20%, independent of the concentrations in serum.Concentrations in saliva were approximately 80% of those in serum.
Food intake had little effect on pharmacokinetic parameters and urinary excretion of GFLX, except the slight decrease in AUC from 14.5 to 12.7μg·h/mL; Cmax, Tmax, and T_1/2β were 1.65μg/mL, 1.86 hours, and 6.52 hours, respectively.The concurrent administration of 1.5 g probenecid prolonged the elimination half-life to 10.2 hours, and increased AUC_0-∞ to 20.6μg·h/mL. Furthermore, it decreased the apparent total body clearance from 235 to 164 mL/min, renal clearance from 197 to 122 mL/min, and the excretion ratio (intrinsic renal clearance of GFLX/creatinine clearance) from 2.28 to 1.35.These results suggest that tubular secretion contributed to the renal clearance of GFLX.
In conclusion, there do not appear to be any safety problems with GFLX and, taking into consideration its favorable pharmacokinetics and potent antibacterial activity, a positive clinical evaluation seems warranted.

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A Phase I study of gatifloxacin (GFLX), a new quinolone, was conducted to evaluate its safety and pharmacokinetics in healthy adult male volunteers. Six volunteers received 13 total oral doses of 300 mg twice daily on seven consecutive days at 10/14-hour intervals. One subject showed a transitory elevation of glutamic pyruvic transaminase (GPT) on the day after the last dosing, but it returned to normal on the 4th day and later. Except for that, blood biochemistry, subjective and objective symptoms, vital signs, hematology, blood chemistry, urinalysis, ECG, electroencephalogram, audiometry, ophthalmological test, and balance test all showed no abnormal changes attributable to the trial medication. No crystalluria was observed. No significant change was found in disposition in serum on Day 1, 4 and 7 with the succession of doses. Furthermore, the measured concentrations in serum fitted the simulation curve well. The drug was rapidly excreted: within 72 hours after the last dose, 78.8 % of the total dose was eliminated renally unchanged. Concentrations of GFLX in serum and urine reached a steady state within 2 to 3 days. These findings indicate the persistence of linear pharmacokinetics and no accumulation of GFLX in serum during multiple dosing.
In conclusion, GFLX was tolerated well by healthy subjects. This drug is expected to be clinically useful against various infections because of its potent and broad spectrum of antibacterial activity, and its favourable pharmacokinetics.

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We investigated the effects of dried aluminum hydroxide gel [Al (OH)₃] and cimetidine on the pharmacokinetics of gatifloxacin (GFLX), a new quinolone, in six healthy male volunteers. Fasting subjects ingested 200 mg of GFLX alone, 200 mg of GFLX with 1 g of Al (OH)₃, and 200 mg of cimetidine followed by 200 mg of GFLX one hour later. The serum and salivary concentrations and the urinary excretion of GFLX were analyzed pharmacokinetically.
The peak serum concentration and the area under the serum concentration-time curve of GFLX were reduced by the concurrent administration of Al (OH)₃ from 1.71 to 0.75μg/mL, and from 14.4 to 7.79μg·h/mL respectively. The salivary peak concentration and the area under the salivary concentration-time curve also decreased, from 1.35 to 0.36μg/mL, and from 6.55 to 3.88μg·h/mL, respectively. This change in salivary profile thus closely corresponded to the serum profile. Furthermore, urinary excretion of GFLX over 48 h decreased from 72.5% to 42.3%. On the other hand, no reduction of these pharmacokinetic parameters was found when cimetidine was ingested prior to GFLX. These results indicate that Al (OH) ₃ reduced the absorption of GFLX by half, but that cimetidine had no effect on the pharmacokinetics of GFLX.
In conclusion, in clinical use GFLX can be co-administered with cimetidine, but not with an antacid containing aluminum.

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We investigated the effects of concomitant medication of 160 mg of ferrous sulfate (FeSO₄), and drug intake with green tea or milk on the pharmacokinetics of 200 mg of gatifloxacin (GFLX) in six healthy male volunteers. The peak serum concentration of unchanged drug and the area under the serum concentration-time curve (AUC_0-∞) decreased from 1.97 to 1.00 μg/mL and from 14.2 to 10.1 μg·h/mL, respectively, and the urinary excretion of GFLX over 48 h decreased from 80.8% to 65.2% of dose with FeSO₄ On the other hand, these parameters were not changed with green tea and milk, except for the slight reduction of AUC_0-∞ to 12.0 μg·h/mL with milk. These results indicated that concomitant medication of FeSO₄ decreased the absorption of GFLX, but that intake with green tea and milk had little effect on the pharmacokinetics of GFLX in humans.

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We investigated the pharmacokinetics of gatifloxacin (GFLX), a new quinolone, in five elderly patients with infectious disease, aged 74 to 86 years.Concentrations of unchanged drug in serum rapidly reached peaks (0.91 to 1.36 μg/mL) at 0.39 to 4.74 h following oral administration of 100 mg of GFLX, and declined with elimination half-lives (T_1/2β) of 10.4 to 17.0 h. Urinary recovery amounted to 44.4% to 67.6% of dose over 48 h. The area under the serum concentrationtime curve (AUC_0-∞) had a tendency to increase with the decrease of creatinine clearance in all five patients.On the contrary, the apparent body clearance (CL_T/F), renal clearance (CL_R), and urinary recovery of GFLX decreased.The AUC_0-∞ and T_1/2β values of elderly patients were larger than those of healthy volunteers aged 21 to 38 years. Elongation of T_1/2β in elderly patients was attributed to the reduction of CL_R and also of CL_T/F. The dosage regimen of 100 mg of GFLX twice daily may be adequate for elderly patients with impaired renal function. In conclusion, GFLX should be cautiously administered in elderly patients, and their renal function should be considered.

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The pharmacokinetics of gatifloxacin (GFLX) were studied in patients with impaired renal function after a single oral administration of 100 mg of GFLX. Patients were classified into three groups according to creatinine clearance (Ccr): six patients in Group I (60<Ccr≤90 mL/min), five patients in Group II (30<Ccr≤60 mL/min), and seven patients in Group III (10≤Ccr≤30 mL/min). Blood and urine samples were collected at different times from 0 to 72 hours after administration, and serum and urinary concentrations of GFLX were determined by HPLC.
Mean peak serum concentrations were 1.29 μg/mL at 1.0 hour in Group I, 1.22 μg/mL at 1.8 hours in Group II, and 1.37 μg/mL at 1.9 hours in Group III. Mean elimination half-lives (T_1/2) were 9.0, 15.7, and 30.2 hours and the mean areas under the curve (AUC_0-∞) were 13.4, 20.2, and 48.7 μg·h/mL, respectively. Cumulative urinary recovery within 72 hours was 62.7%, 50.8%, and 36.3%, respectively. Prolonged T_1/2 increased AUC_0-∞, and reduced urinary excretion were observed depending on the degree of renal impairment. No findings of clinical or laboratory adverse reactions were observed in any case.
Based on the results of this study, we recommend the following dosages of GFLX for patients with impaired renal function: 100 mg every 12 hours for patients with Ccr of 30 to 90 mL/min, and 100 mg every 24 hours for patients with Ccr of 10 to 30 mL/min.

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We investigated the penetration of gatifloxacin (GFLX), a new quinolone derivative, into human cerebrospinal fluid (CSF). Patients who needed to undergo urological surgery under lumbar spinal anesthesia, and who had no central nervous system diseases which interfered with the study, were given GFLX, and then CSF and serum were collected by dura puncture about 3 hours after dosing. Concentrations of GFLX in CSF and serum were determined by the HPLC method.
Mean CSF and serum concentrations of the drug after a single oral dose of 200 mg GFLX were 0.21±0.16 and 1.67±0.43 μg/mL, respectively. The mean ratio of CSF/serum concentration was 0.11±0.07.
In the multiple-dose group, to whom 200 mg GFLX was given orally twice a day for 3 days, the mean CSF concentration of GFLX was 0.82 ±0.31/μg/mL, and the mean serum concentration was 2.47±0.96μg/mL. The mean ratio of CSF/serum concentrations was 0.35±0.10, about 3 times greater than that in the single-dose group.
The ratio of CSF/serum concentration of GFLX in both the single-and multiple-dose groups was similar to those of other quinolones.
No clinically significant adverse reactions and no abnormal laboratory test findings were observed.

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Gatifloxacin (GFLX) is a newly developed fluoroquinolone derivative for oral use. We examined the clinical efficacy and safety of GFLX in 6 patients with eye infections. The following cases were studied: 3 cases of meibomitis, and 1 each of blepharitis, hordeolum, and conjunctivitis. GFLX was administrated b. i. d. at a dose of 200mg for 3 to 8 days. Its clinical efficacy was excellent in 4, case good in 1, and fair in 1. No side effects and no clinical abnormal findings were observed. The drug was judged useful in 5 cases and fairly useful in 1.
After a single oral administration of 200mg of GFLX in 9 fasting healthy volunteers, GFLX levels in both tear fluid and serum were determined. The peak level of GFLX in tear fluid reached 1.22±0.90 μg/mL at 0.5 h after administration and the tear/serum ratio was 0.85±0.34 at the same time.

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We investigated the clinical and bacteriological efficacy, safety, usefulness and fluid concentrations of gatifloxacin (GFLX) for the treatment of infections in the field of internal medicine.
The subjects were 170 patients with respiratory tract infection and 2 with urinary tract infection. GFLX was administered in once-daily or twice-daily doses of 100, 150 or 200mg for 3 to 14 days.
The results were as follows:
1. Clinical efficacy was evaluated in 172 cases, and the majority had received twice-daily doses. The overall clinical efficacy rate (excellent or good) was 94.2%(162/172).
2. Bacteriological efficacy was evaluated in 72 cases of identified bacteria. The eradication rate was 90.3%(65/72).
3. Side effects were evaluated in 192 cases, and their incidence was 4.2%(8/192). Laboratory test findings were evaluated in 156 cases, and the incidence of abnormal findings was 10.3%(16/156).
4. Clinical usefulness was evaluated in 175 cases. The usefulness rate (very useful or useful) was 90.9%(159/175).
5. Serum and sputum concentrations of GFLX were measured after the first dose of 200mg twice daily, and the maximum sputum concentration was 2.13μg/mL. The sputum to serum concentration ratio was 1.09μg/mL. These results suggest the favorable penetration of GFLX.
The results indicate good clinical and bacteriological efficacy of GFLX, as well as, its satisfactory penetration into sputum. Therefore, it was concluded that GFLX would be a useful antimicrobial drug and that the dosage of 100 to 200 mg twice daily is well tolerated and satisfactory for the treatment of infections in the field of internal medicine.

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We investigated the clinical and bacteriological efficacy, safety, usefulness, and fluid concentrations of gatifloxacin (GFLX) in respiratory tract infections. GFLX was administered in once-daily or twice-daily doses of 100, 150, or 200 mg for up to 7 days in cases of acute bronchitis and for up to 14 days in cases of chronic respiratory infection and pneumonia.
The results were as follows:
1. Clinical efficacy was evaluated in 87 cases, of whom 83 received twice-daily and 4 once-daily doses. The overall clinical efficacy rate (excellent or good) was 92.0%(80/87).
2. Bacteriological efficacy was evaluated in 34 cases of identified bacteria. The eradication rate was 91.2%(31/34).
3. Side effects were evaluated in 97 cases, and their incidence was 6.2%(6/97). Laboratory test findings were evaluated in 84 cases, and the incidence of abnormal findings was 11.9%(10/84).
4. Clinical usefulness was evaluated in 89 cases. The usefulness rate (very useful or useful) was 84.3%(75/89).
5. Serum and sputum concentrations of GFLX were measured in one case of chronic respiratory-tract infection after the 5th and 9th doses of 200mg twice daily. The sputum to serum concentration ratios were 1.60 and 2.38, respectively.
These results indicate good clinical and bacteriological efficacy for GFLX and suggest a satisfactory penetration into sputum. Therefore, it was concluded that GFLX, 100 to 200mg twice daily, is a useful and satisfactory antimicrobial drug for the treatment of respiratory tract infections.

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To evaluate the clinical efficacy, safety, and tissue penetration of gatifloxacin (GFLX) in urinary tract infections (UTI), we performed a multi-center clinical open study.
Patients with either uncomplicated UTI (acute pyelonephritis and acute cystitis) or complicated UTI were admitted to the study and received mainly 100 mg to 300 mg of GFLX once or twice a day for 3 to 14 days. The most common dose regimen was 100 mg b. i. d.
Clinical efficacy, as assessed by the doctors in charge, was obtained in 96.4% of 55 patients with uncomplicated UTI and 80.2% of 197 patients with complicated UTI. The overall clinical efficacy and bacteriological eradication rates, evaluated according to the criteria of the Japanese UTI Committee, were 100% of 34 patients and 100% of 47 strains in acute uncomplicated cystitis, and 84.1% of 164 patients and 86.2% of 239 strains in complicated UTI.
The incidence of clinical adverse reactions was 1.8%(5 in 271 patients) and of laboratory adverse reactions, 3.1%(7 in 223 patients). None of the findings in adverse reactions were serious.
In prostate and epididymis, the concentration ratios of tissue to serum were 1.0 or higher, suggesting good penetration of GFLX into these tissues.
From the results of this study, we conclude that GFLX is well tolerated and effective in the treatment of urinary tract infections at a dose of 100 mg to 200 mg at once or twice a day.

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To evaluate the clinical efficacy, safety, and tissue penetration of gatifloxacin (GFLX) in genitourinary tract infections, we performed a multi-center clinical open study.
Patients with uncomplicated urinary tract infections (acute pyelonephritis and acute cystitis), complicated urinary tract infections, urethritis, prostatitis, and epididymitis were admitted to the study and received 150 mg to 400 mg of GFLX daily for 3 to 14 days.Common dose regimens were 150 mg b. i. d., 200 mg once a day, and 200 mg b. i. d.
Clinical efficacy, assessed by the doctors in charge, was obtained in 96.6% of 29 patients with uncomplicated urinary tract infections (UTI), 68.8% of 32 patients with complicated UTI, 97.1% of 35 patients with urethritis, 86.7% of 15 patients with prostatitis, and 87.5% of 8 patients with epididymitis. Overall clinical efficacy and bacteriological eradication, evaluated according to the criteria of the Japanese UTI Committee, were 100% of 21 patients and 100% of 33 strains in uncomplicated UTI; 70.0% of 30 patients, 87.7% of 57 strains in complicated UTI; 88.9% of 9 patients, 88.9% of 9 strains in gonococcal urethritis; 100% of 10 patients, 100% of 10 strains in chlamydial urethritis;and 100% of 9 patients and 100% of 14 strains in chronic prostatitis.
The incidence of clinical adverse reactions was 3.3%(4 in 122 patients) and of laboratory adverse reactions, 3.9%(3 in 76 patients). None of the findings in adverse reactions were serious.
In prostate and epididymis, the concentration ratios of tissue to serum were 1.0 or higher, suggesting good penetration of GFLX into these tissues.
From the results of this study, we conclude that GFLX is well tolerated and effective in the treatment of genitourinary tract infections.

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Basic and clinical studies of a new quinolone antimicrobial drug, gatifloxacin (GFLX, AM-1155), in the field of surgery were performed, with following results:
1) A single dose of GFLX was orally administered to six patients in the amount of 150, 200, or 300 mg. Levels in serum reached a peak four hours after administration. GFLX levels in bile were higher than those in serum at all the times measured up to 24 hours, so biliary excretion seemed to be good.
2) Clinical responses were excellent in 37 cases, good in 23 cases, fair in two cases, and poor in six cases, an efficacy rate of 88.2%. Bacteriological efficacy rate was 89.5%(51/57). Eradication rate for 129 strains identified was 90.0%(45/50) for gram-positive bacilli, 93.1%(27/29) for gram-negative bacilli, and 100%(50/50) for anaerobes, overall 94.6%(122/129). MIC₉₀ of GFLX against clinical isolates were 3.13, μg/mL against 53 strains of gram-positive bacilli, 0.78 μg/mL against 28 strains of gram-negative bacilli, and 1.56 μg/mL against 51 strains of anaerobes. Against gram-positive bacilli and anaerobes, GFLX showed higher antibacterial activity than other quinolones tested.As for adverse reactions, a slight gastric discomfort was observed in one case. No abnormal changes were observed on clinical laboratory tests.
In summary, GFLX seems to be a useful drug for the treatment of surgical infection.

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We performed a multi-center clinical trial of gatifloxacin (GFLX), a new fluoroquinolone, to examine its skin penetration and its clinical efficacy and safety in the field of dermatology. Results were as follows:
Concentrations of skin tissue and serum were 1.22-1.39μg/g and 0.85-1.13μg/mL, respectively, at 2 h after a single oral administration of 100mg of GFLX. Ratios of skin concentration to serum concentration were 1.23-1.44.
Minimum inhibitory concentrations (MICs) of GFLX against 22 clinical isolates of Staphylococcus aureus ranged from ≤ 0.025 to 0.20μg/mL, with MICs inhibiting 50% and 90% of the strains, both at 0.10μg/mL.
GFLX was administered to 110 patients at dosages of 100mg, 150mg, or 200mg once or twice daily.
The clinical efficacy rate classified by disease groups was 100%(5/5), 100%(2/2), 87.8%(36/41), 90.9%(20/22), 78.4%(29/37), and 33.3%(1/3) for groups Ia, Ib, IIa, IIb, III, and IV, respectively. The overall clinical efficacy rate was 84.5%(93/110).The bacteriological response rate was 91.1 %(82/90).
Adverse reactions and abnormal laboratory findings were observed in 2.5%(3/122) and 7.5%(8/106) of the cases, respectively.All of the findings of adverse reaction and abnormal laboratory tests were slight.
These results suggest that GFLX will be a useful antibacterial agent for dermatological infections.

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We performed a cliniclal study on gatifloxacin, a new oral fluoroquinolone antimicrobial agent, to evaluate its clinical efficacy, safety and utility in obstetrical and gynecological infections. In addition to clinical utility, its penetration into genital tissues was also examined.
1. Examination of tissue penetration:
After oral administration of 100, 150, and 200 mg of gatifloxacin, the concentration was determined in serum and endometrium, myometrium, cervix uteri, portio vaginalis, ovary, and oviduct. The ratio of serum concentrations were 0.69-3.07 times in each tissue. These results suggest good tissue penetration with gatifloxacin.
2. Examination of clinical effect, bacteriological effect, and safety:
Gatifloxacin at 100, 150, and 200 mg was administered to 121 patients with intrauterine infection, adnexitis, externalia infection, cervicitis, and mastitis, in once or twice a day doses.
(1) Clinical effect: Of 121 cases treated with gatifloxacin, 80 qualified for efficacy evaluation and 41 were excluded.The clinical effect of intrauterine infection, adnexitis, externalia infection, cervicitis, and mastitis was 97.2%(35/36), 92.3%(12/13), 100%(13/13), 100%(12/12), 6/6, resnectively.Total clinical effects were 97.5 %.
(2) Bacteriological effect: The bacteriological effects were evaluated in 45 cases.The overall eradication rate was 88.9%, and the eradication rate against 74 isolated strains was 93.2%.
(3) Safety: Adverse reactions were observed in 2 cases, which were nausea in 1 case and heaviness in the head/systemic fatigue in 1 case.Laboratory findings were noted in cases evaluated.
(4) Utility: Utility was evaluated in 82 cases as follows: markedly useful, 7 cases;useful, 71 cases;slightly useful, 1 case;and useless, 3 cases. The utility rate was 95.1%.
The results of this study indicate that gatifloxacin is clinically useful against obstetric and gynecological infections such as intrauterine infection, adnexitis, externalia infection, cervicitis and mastitis.

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Pharmacokinetic and clinical studies were carried out with gatifloxacin (GFLX) in otorhinolaryngological infections.The results were as follows:
1. The concentration of GFLX in the mucous membrane of the middle ear was 2.68-3.64μEg/g, in the mucous membrane of paranasal sinuses was 0.30-2.49μEg/g, and in the tonsils, 0.06-3.12μg/g.
2. Clinical efficacy rates were 77.8%(28/36) in otitis media, 96.4%(27/28) in paranasal sinusitis, and 81.8%(18/22) in tonsillitis.Overall clinical efficacy was assessed as excellent in 48 cases, good in 33, fair in 10 and poor in 5, the efficacy rate being 84.4%(81/96).
Bacteriological elimination rates were 85.7%(60/70) for Gram-positive bacteria and 88.9%(24/27) for Gram-negative bacteria. The rate for anaerobes was 100%(11/11).
Side effects were observed in eight of 138 cases (5.8 %), but they were slight.
Abnormal laboratory findings were recorded in 2 cases (2.1 %). All were mild in degree.
From the above results, we conclude that GFLX is a useful drug for the treatment of otorhinolaryngological infections.

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Studies of the fundamental characteristics and clinical usefulness of gatifloxacin, a newly developed fluoroquinolone antibacterial drug, were performed in the field of ophthalmology.
1) Antibacterial activity: The antibacterial activity of gatifloxacin (GFLX) was found to be similar to tosufloxacin (TFLX) and sparfloxacin (SPFX), and superior to ofloxacin (OFLX).
MICs of GFLX against standard strains (35 strains) were below concentration (1.71μg/mL), rising to 200mg oral administration of GFLX except for a single strain of Pseudomonas aeruginosa.
Against Staphylococcus aureus stored in our laboratory, MIC₉₀ of GFLX was 0.10μg/mL, a value similar to that of TFLX and SPFX.
MIC₉₀ of GFLX was 3.13μg/mL against Pseudomonas aeruginosa stored in our laboratory, a level
2) Ocular penetration: After 200 mg oral administration, concentrations of GFLX in human aqueous humor, tarsus gland tissue, and conjunctiva were 0.04-0.22μg/mL (at 2.37-24.03h, 0.09-0.60 times the serum level), 4.36-6.02μg/g (at 1.87-2.5h, 2.71-3.17 times the serum level), and 2.273.46μg/g (at 2.00-2.37h, 1.22-1.48 times the serum level), respectively. of antibacterial activity between SPFX and TFLX against these strains.
3) Clinical study: In a clinical study, GFLX was administered orally once or twice a day at daily doses of 200mg, 300mg, or 400mg to forty-four cases evaluated for clinical efficacy. Clinical response was excellent in 34 cases, good in 7 cases, fair in 2 cases, and poor in 1 case, with an efficacy rate of 93.2%(41/44).
As to bacteriological efficacy, the eradication rate was 92.0%(23/25) for the twenty-five cases evaluated.
Side effects were evaluated in 46 cases, and one case of discomfort epigastric was found, an appearance rate of 2.2%(1/46).
In the 18 cases evaluated for abnormal laboratory findings, there was one case of elevation of LAP, making the appearance rate of abnormal laboratory findings 5.6%(1/18).
Finally, the usefulness rate was 93.2%(41/44).

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We performed experimental and clinical studies on gatifloxacin, a new synthetic antimicrobial agent, for oral use in the field of oral surgery.
1. A single dose of 150 mg of gatifloxacin (GFLX) was administered to 16 patients.Concentrations of GFLX in gingiva were 0.97-7.28 μg/g 1.1-12 hours after administration in 14 subjects; those in alveolar bone were 0.13 μg/g at 3.5-12 hours in 2 subjects; and those in cyst, 3.51μg/g at 2.6 hours in 1 subject; and in palatine mucosa, 1.67 μg/g at 12 hours in 1 subject.
2. A single dose of 100 mg of GFLX was administered to 45 patients, and concentrations found in tooth extraction wounds 0.2-5.6 hours later were < 0.01-1.59 μg/g.
3. A clinical study was conducted in 104 patients with odontogenic infections. The efficacy rate judged by comparative score evaluation was 85.1% for 67 patients, while that by doctors was 82.9 % for 76 patients.
4.Side effects were observed in eight cases (diarrhea, rash, sleepiness, nausea, discomfort, dizziness, headache, dullness). Abnormal laboratory findings were recognized in two cases (mild increase in eosinophils and slight elevation of S-GPT, Al-p).
Based on these results, we conclude that gatifloxacin is a useful antimicrobial agent for the treatment of odontogenic infections at a dose of 200-400 mg/day.

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We performed a double-blind, randomized, multi-center dose-finding study of gatifloxacin (GFLX) to determine the optimal dose regimen for chronic respiratory tract infections. The daily dosage of vatifloxacin was 100 mg b.i.d.(Group L), 150 mg b.i.d.(Group M), or 200 mg b. i. d.(Group H).
The results were as follows:
1. Clinical efficacy was evaluated in 104 cases. The clinical efficacy rates (excellent or good) in Groups L, M, and H were 97.1%(33/34), 87.5%(28/32), and 94.7%(36/38), respectively, with no significant differences among the groups. “Excellent” response rates were 5.9%(2/34) in Group L, 6.3%(2/32) in Group M, and 21.1%(8/34) in Group H, significantly higher than the former two.
2. Bacteriological efficacy was evaluated in 59 cases of identified bacteria.Eradication rates in Groups L, M, and H were 75.0%(18/24), 76.5%(13/17), and 72.2%(13/18), respectively, with no significant differences among the groups.
3.Side effects were evaluated in 114 cases; 5.1%(2/39) in Group L, 2.9%(1/35) in Group M, and 7.5%(3/40) in Group H.Laboratory test findings were evaluated in 106 cases, and the incidences of abnormal findings were 14.7%(5/34) in Group L, 0%(0/34) in Group M, and 5.3%(2/38) in Group H.
4.Clinical usefulness was evaluated in 107 cases.The usefulness rates (very useful or useful) were 94.3%(33/35) in Group L, 84.9%(28/33) in Group M, and 92.3%(36/39) in Group H.
These results indicate that no significant differences in clinical or bacteriological efficacy among the three dosage groups were found, and that there were no dose-dependent side effects or abnormal laboratory findings, nor dose-related differences in type or severity of side effects. However, since clinical efficacy rates in bronchiectasis-related infections and in moderate-type infections were significantly higher in Group H, as well as the clinical “excellent” rating, the daily dosage of 200 mg b. i. d. of gatifloxacin is considered optimal for treatment of chronic respiratory tract infections.

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A dose-finding clinical trial, a double-blind, randomized, comparative study of gatifloxacin (GFLX), a new oral 8-methoxyquinolone derivative antimicrobial agent, was performed to determine the optimal dosage in complicated urinary tract infections.
100mg, 150mg, and 200mg of GFLX b. i. d. for 7 days (called L, M, and H groups, respectively) were administered to 143 patients who had no indwelling catheters.Clinical efficacy was evaluated according to the criteria of the Japanese UTI Committee, and the following results were obtained:
1. The number of patients evaluated for clinical efficacy was 37, 39, and 37 in L, M, and H groups, respectively.Among the three groups, there was no significant difference in background characteristics of patients.
2. Overall clinical efficacy rates were obtained in 86.5% of 37 patients in L group, 82.1% of 39 patients in M group, and 94.6% of 37 patients in H group. These differences were not statistically significant.
3. Overall bacteriological eradication rates obtained in L, M, and H groups were 90.7 % of 54 strains, 90.3% of 62 strains, and 96.4% of 55 strains, respectively, with no significant differences.
4. Incidence of clinical adverse reactions in L, M, and H groups were 2.1%(1/48 patients), 6.5%(3/46), and 2.1%(1/48), and of laboratory adverse reactions, 4.5%(2/44), 2.2%(1/45), and 2.3%(1/44), respectively, the differences being not significant.None of the findings in adverse reactions were serious.
5. There was also no significant difference in clinical value among the three groups.
From the results of this study, we conclude that 200 mg b.i.d.of GFLX is the optimal dosage for treatment of complicated urinary tract infections.

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