The in vitro antibacterial activity of grepafloxacin (GPFX), a new fluoroquinolone, was compared with that of sparfloxacin (SPFX), ciprofloxacin (CPFX) and ofloxacin (OFLX), The results are summarized as follows:
1) GPFX showed a broad spectrum of activity against gram-positive and gram-negative bacteria. The activity of GPFX against gram-positive bacteria was comparable to that of SPFX, and superior to that of CPFX and OFLX.
GPFX was less active than CPFX against most gram-negative bacteria but comparable to SPFX and OFLX.
2) GPFX showed bactericidal action at concentrations near the MIC against a variety of bacteria.
3) The activity of GPFX was decreased by several culture conditions such as acidic pH and a high concentration of magnesium ions.
4) The activity of GPFX was decreased when the inoculum size was increased.
5) The frequency of spontaneous mutants resistant to GPFX was low.
6) GPFX strongly inhibited the supercoiling activity of DNA gyrase of Escherichia coli.

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Grepafloxacin (GPFX) is a 4-quinolone possessing cyclopropyl, methyl and 3-methyl-piperazinyl moieties at the 1, 5 and 7 positions, respectively. The MIC₉₀ of GPFX for 14-50 clinical isolates of Staphylococcus aureus, methicillin-resistant Staphylococcus aureus (MRSA), coagulase-negative staphylococci (CNS), Streptococcus pyogenes, β-streptococci, 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 (ABPC)-resistant Haemophilus influenzae and Bacteroides fragilis were 0.1, 0.2, 0.2, 0.39, 0.39, 0.39, 0.78, 6.25, 0.78, 0.1, 0.39, 0.78, 1.56, 12.5, 6.25, 1.56, 3.13, 12.5, 1.56, 0.78, 6.25, <0.013 and 6.25μg/ml, respectively. GPFX possesses almost the same strong activity against gram-positive bacteria as tosufloxacin, and against gram-negative bacteria as ofloxacin (OFLX) except for P. aeruginosa, A. calcoaceticus and ABPC-resistant H. influenzae. GPFX is more effective than ciprofloxacin and OFLX.
GPFX at 10μg/ml inhibited 50% of the growth of cultured CHO-Kl, HeLa and IMR32 cells, but it had no influence on the axon dendrites of IMR32 neuroblastoma cells. No synergy in bactericidal effect was found between GPFX and serum complement. However, the cells of E. coli NIHJ JC-2 were well engulfed and rapidly digested by mouse macrophages in the presence of higher than 1/8 MIC of GPFX.

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To investigate antibacterial spectrum and antibacterial activity of grepafloxacin (GPFX), MICs of GPFX as well as other antibiotics were determined against standard strains of gram-positive and grampositive bacteria clinically isolates obtained in 1993.
The results obtained are summarized as follows:
1. Antibacterial high activity of GPFX was suggested by MICs against gram-positive bacteria. MIC₉₀ of GPFX against methicillin (DMPPC)-resistant Staphylococcus aureus subsp. aureus, and benzylpenicillininsensitive or-resistant Streptococcus pneumoniae was lowest as compared with reference drug. It was studied that MIC of GPFX against ofloxacin-resistant strains of DMPPC-susceptible S. aureus and Corynebacterium spp. were going up, and suggested that fluoroquinolone-resistant gram-positive bacteria could get cross resistance to GPFX.
2. As antibacterial activity of GPFX against gram-positive bacteria was high, suggesting that it was selected antibiotic at first in community-acquired infection.

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The in vitro and in vivo antimicrobial effects of a new quinolone antimicrobial drug, grepafloxacin (GPFX), were examined and compared with those of ofloxacin (OFLX), enoxacin (ENX), ciprofloxacin (CPFX) and tosufloxacin (TFLX) with the following results.
GPFX had a wide antimicrobial spectrum and the antimicrobial activities against Staphylococcus, including methicillin-resistant Staphylococcus aureus (MRSA), Enterococcus and Streptococcus, were almost equal to those of TFLX. The antimicrobial effects of GPFX against various strains of intestinal flora were slightly weaker than those of CPFX and TFLX but were strongest against gram-negative bacteria including Haemophilus influenzae and Neisseria gonorrhoeae.
The therapeutic effect of GPFX in a mouse systemic infection model was slightly inferior to that of TFLX against S. aureus Smith, S. aureus TMS 33 and Streptococcus pneumoniae, but superior to the control drugs against Escherichia coli C-11, Klebsiella pneumoniae 3K25 and Pseudomonas aeruginosa. In a transnasal pulmonary infection model using K. pneumoniae 3K25, S. pneumoniae TMS 3 and S. aureus Smith as infective strains, the therapeutic effect of GPFX was superior to that of TFLX. In a urinary infection model (P. aeruginosa KU-1), the therapeutic effect of GPLX was equal to that of CPFX.
When the concentrations of GPFX in mouse serum, lung and kidney were examined, the drug was found to be distributed at higher levels in the lung and kidney, although the serum concentration was lower than when other drugs were used.

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The in vitro activity of grepafloxacin (GPFX), a novel quinolone, was compared with that of lomefloxacin, ciprofloxacin (CPFX), ofloxacin (OFLX) and norfloxacin against 49 reference strains and recent clinical isolates of anaerobic bacteria and Gardnerella vaginalis. The MIC was determined by an agar dilution method. GPFX had broad antibacterial activity against anaerobic gram-positive andnegative cocci and gram-positive and-negative rods. Fifty and ninety percent of Bacteroides fragilis isolates were susceptible to 1.56 and 25μg/ml of GPFX, respectively; the activity of GPFX against the organism was comparable to that of OFLX and CPFX. Against Bacteroides thetaiotaomicron and other members of the B. fragilis group, GPFX was the most potent agent tested (MIC for 50% of the isolates, ≤3.13μg/ml). GPFX demonstrated activity similar to that of OFLX and CPFX against gram-positive cocci: Peptostreptococcus anaerobius, Peptostreptococcus magnus and Peptostreptococcus asaccharolyticus. Although GPFX showed modest activity against Clostridium difficile, the MIC₉₀ was 25μg/ml. The compound was the most active agent tested against Clostridium perfringens, Mobiluncus spp. and G. vaginalis with MIC₉₀ of 0.39, 0.10 and 3.13μg/ml, respectively.

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The in vitro and in vivo antibacterial activities of grepafloxacin (GPFX), a new synthetic antimicrobial agent, were compared with those of norfloxacin (NFLX), ofloxacin (OFLX) and ciprofloxacin (CPFX), and the following results were obtained.
1) GPFX had a broad antibacterial spectrum against gram-positive and -negative bacteria including anaerobic bacteria. The antibacterial activity of GPFX was superior to that of any other quinolone against gram-positive and anaerobic bacteria, and superior to those of OFLX and NFLX against gram-negative bacteria.
2) The MICs of GPFX for clinical isolates were lower than those of other quinolones for gram-positive bacteria, Moraxella catarrhalis, Acinetobacter calcoaceticus and Haemophilus influenzae, and almost equal to those of NFLX for gram-negative bacteria other than Proteus spp.
3) The kind of medium, addition of horse serum, addition of metal ions and inoculum size did not affect the antibacterial activity of GPFX against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and A. calcoaceticus. The antibacterial activity of GPFX against those bacteria was enhanced in an alkaline condition.
4) The antibacterial activity of GPFX against S. aureus, E. coli and P. aeruginosa was dose-dependently bactericidal over the MIC.
5) In a morphological examination by phase-contrast microscope, GPFX induced swollen cells in S. aureus, elongated cells in E. coli, and swollen and elongated cells in A. calcoaceticus. The elongation of P. aeruginosa was hardly noted, and the spheroplast-like structure and lysis of P. aeruginosa were observed.
6) The therapeutic effect of GPFX against experimental systemic infections in mice was superior to that of other quinolones against S. aureus, Streptococcus pneumoniae and A. calcoaceticus, similar to that of CPFX against E. coli, Klebsiella pneumoniae and P. aeruginosa, and superior to those of NFLX and OFLX against infections caused by the bacteria tested.
7) The therapeutic effect of GPFX against experimental pneumonia caused by S. pneumoniae in mice was superior to those of other quinolones. The therapeutic effect of GPFX against experimental pneumonia caused by K. pneumoniae in mice was comparable to that of OFLX.

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The in vitro activities of new quinolones against three standard strains (D, E, and F) and 40 clinical isolates of Chlamydia trachomatis obtained from patients with nongonococcal urethritis were compared with those of minocycline (MINO). Monolayer cultures of McCoy cells (3 to 5 × 10⁴cells/well) in flatbottomed plates with cover glasses were infected with 5, 000 to 10, 000 inclusion-forming units of each Chlamydia stock solution. After 72 h of incubation with each antibiotic dilution, the cells were stained with fluorescent monoclonal antibody and examined by fluoresceuce microscope to determine the presence of inclusions. The minimum inhibitory concentration (MIC) of each drug which completely inhibited the formation of the inclusion bodies was determined. The ranges for the MIC against the clinical isolates were as follows: MINO, 0.03 to 0.06μg/ml; grepafloxacin (GPFX), 0.06 to 0.125 μg/ml; temafloxacin (TMFX) and tosufloxacin (TFLX), 0.125 to 0.25μg/ml; ofloxacin (OFLX), 0.5 to 1.0μg/ml and levofloxacin (LVFX), 0.25 to 0.5μg/ml.
Among the five new quinolones, GPFX was the most active antichlamydial agent, followed by TMFX and TFLX, LVFX and OFLX.
These new quinolones should prove to be promising drugs for the treatment of Chlamydia infections.

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The in vitro and in vivo antibacterial activities of grepafloxacin (GPFX), a new synthetic antimicrobial agent, were compared with those of norfloxacin (NFLX), ofloxacin (OFLX), enoxacin (ENX) and ciprofloxacin (CPFX). GPFX showed a broad spectrum of antibacterial activity against gram-positive and gram-negative and aerobic and anaerobic bacteria. GPFX was superior to reference compounds in activity against all gram-positive clinical isolates, including Staphylococcus aureus and Streptococcus pneumoniae. The antibacterial activity of GPFX against Escherichia coli, Citrobacter diversus, Klebsiella pneumoniae and Enterobacter aerogenes was similar to that of CPFX and superior to those of NFLX, ENX and OFLX. The activity of GPFX against Klebsiella oxytoca, Enterobacter cloacae, Serratia marcescens, Pseudomonas aeruginosa and Pseudomonas putida was slightly less than that of CPFX but more active than those other reference drugs. The activity was similar to that of ENX against Citrobacter freundii, Proteus vulgaris, Proteus mirabilis, Providencia rettgeri and Morganella morganii. GPFX was superior to the reference compounds in activity against Haemophilus influenzae, Xanthomonas maltophilia, Acinetobacter calcoaceticus, Moraxella (Branhamella) catarrhalis and Bacteroides fragilis. Neither the medium, variation in medium pH, inoculum size, nor the addition of cations or horse serum had any major effect on its activity. But the activity of GPFX was slightly reduced in the acidic condition and of a high concentration of cations. GPFX acted bactericidally over the MIC, and differences were very small between the MIC and MBC.
Frequencies of mutants resistant to GPFX were low. GPFX strongly inhibited the supercoiling activity of DNA gyrase purified from E. coli K-12. But inhibition of the relaxing activity of topoisomerase II from calf thymus was very low. GPFX produced excellent postantibiotic effects (PAE) against S. aureus and E. coli, and those effects were 2 and 1.6 hours, respectively. The therapeutic effect of these quinolones was evaluated against systemic infections in mice. GPFX was the most active against all the gram-positive bacterial infections. In gram-negative bacterial infections, GPFX was similar in activity to CPFX against E. coli and P. aeruginosa infections and was most active against H. influenzae infection. These results indicate that GPFX may be useful for various kinds of infections in humans.

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A microbiological assay procedure and high-performance liquid-chromatography (HPLC) procedure have been developed for determining grepafloxacin (GPFX) in human plasma and urine.
In the bioassay method drug concentrations were determined by the thin-layer cup method, using Bacillus subtilis ATCC6633 as the test strain and nutrient agar as the test medium. Calibration curves of GPFX were made in human plasma and 1/15M phosphate buffer (P. B.) pH 7.4 for plasma samples and in 1/15M P. B. pH 7.0 for urine samples. The lowest detectable concentration of GPFX by the method was 0.012-0.025 μg/ml.
In HPLC GPFX was extracted from plasma and urine by chloroform. The extracts were analyzed using a reverse-phase analytical column and detected by the fluorescence method. The intra-assay coefficient of variation for plasma was less than 4.6% at 0.01-1.00, μg/ml and less than 3.5% at 0.025-5.00 μg/ml, whereas for diluted urine it was less than 4.0% at 0.25-50.00 μg/ml. Plasma and urine samples in phase I studies were analyzed by HPLC and the bioassay method. A good corelation was observed between them.

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The absorption, distribution and excretion of grepafloxacin (GPFX), a new quinolone antibacterial agent, after oral and intravenous administration were investigated in rats, mice, monkeys, dogs and rabbits.
1. The maximum plasma concentrations (Cmax) of GPFX after a single oral administration of 20 mg/kg in rats, mice, monkeys and dogs and of 18.6μg/kg in rabbits were 1.36, 1.11, 2.28, 2.61 and 0.68μg/ml, respectively, indicating the highest value in dogs, followed by monkeys, and similar values for rats and mice. The absolute bioavailabilities were respectively, 54%, 69%, 76%, 81% and 16%, indicating the highest value in dogs, followed by monkeys. The value in rabbits was lower than that in the other species.
2. The Cmax and AUC of GPFX after a single oral administration of 10, 20 and 40 mg/kg in rats and mice and of 5, 10 and 20 mg/kg in monkeys showed good dose-dependency.
3. There was no delay in the elimination of GPFX after repeated oral administration of 40 and 10 mg/kg once daily for 7 consecutive days in rats and monkeys, respectively.
4. GPFX was administered to dogs by intravenous bolus-infusion, and when the concentrations of GPFX in plasma and cerebrospinal fluid (CSF) had each reached a steady state, the two concentrations were measured. The results showed that the ratio of the CSF concentration to that in plasma was 0.30 at all measurement times, indicating a low transfer to the central nervous system.
5. The concentrations of GPFX in all tissues other than brain were higher than the plasma concentration, indicating high tissue distribution. In particular, high distribution was found in liver, kidneys and lungs.
6. The urinary excretion rates of GPFX at 48 hours after a single oral administration of 20 mg/kg in rats, monkeys and dogs and of 18.6 mg/kg in rabbits were 8.09%, 10.15%, 6.93% and 3.09%, respectively, of the administered dose.

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The absorption, distribution and excretion of radioactivity after single and repeated oral administrations of [¹⁴C] grepafloxacin (GPFX) at 40 mg/kg were investigated in rats.
1. The blood concentration of radioactivity after single oral administration in fasted male rats reached a maximum at 1 hour, indicating rapid absorption. The concentration in fasted rats was higher than that in non- fasted rats. There was no delay in the elimination of radioactivity after repeated administration.
2. The concentrations of radioactivity in almost all tissues after single oral administration in fasted male rats reached a maximum at 0.5-2 hours. The concentrations in almost all tissues were higher than the plasma concentration, indicating high tissue distribution. No radioactivity was detected in almost any tissues at 96 hours after the final dose of the repeated administration. This finding was similar to the results of whole-body autoradiograms.
3. There were no sex differences in the pharmacokinetics of [¹⁴C] GPFX.
4. The in vitro binding rates of [¹⁴C] GPFX to rat, rabbit and human plasma were 38%-52%, indicating no concentration- dependency. The in vivo binding rates of radioactivity to rat plasma were 41.8%-43.0%, similar to the in vitro binding rates.
5. The administered radioactivity was primarily excreted in the feces via the bile. It was also suggested that entero-hepatic circulation was likely to be observed. There were no changes in the excretion of radioactivity during repeated administration.
6. The radioactivity was primarily excreted in the urine in bile duct-ligated male rats.
7. Placental transfer was suggested in pregnant rats. High distribution in the milk was also observed in lactating rats.
8. Radioactivity remained in the hair and eyeballs at 168 hours after administration in pigmented rats.

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The absorption and excretion of radioactivity after a single oral administration of [¹⁴C] grepafloxacin (GPFX) at 20 mg/kg were investigated in monkeys and dogs.
1. The mean plasma concentration of radioactivity reached a maximum of 3.29μg eq./g at 2 hours in monkeys, and declined thereafter with a biological half-life of 5.9 hours. The AUC during the period of 0-48 hours was 39.6μg eq. h/g. The blood concentration was higher than 0.8-1.3 times the plasma concentration.
2. The mean plasma concentration of radioactivity reached a maximum of 4.80μg eq./ml at 2 hours in dogs, and declined thereafter with a biological half-life of 3.8 hours. The AUC during the period of 0-24 hours was 38.3μg eq. h/ml. The blood concentration was higher than 0.9-1.2 times the plasma concentration.
3. The in vitro binding rates of [¹⁴C] GPFX to monkey and dog plasma were 41%-48%, with no concentration-dependency. The in vivo binding rates of GPFX to monkey and dog plasma were 45.7% 47.5%, similar to the in vitro rates.
4. The urinary and fecal excretion rates of radioactivity during the period of 0-120 hours in monkeys were 13.1% and 54.1%, respectively, of the administered dose.
5. In dogs, the urinary and fecal excretion rates of radioactivity during the period of 0-168 hours were 16.0% and 80.3%, respectively, of the administered dose.

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The metabolism after oral administration of grepafloxacin (GPFX) or [¹⁴C] GPFXwas investigated in rats, monkeys and humans.
1. The metabolites of GPFX identified using human urine and rat urine and bile were two GPFX glucuronic acid conjugates (3-glucuronide and 4'-glucuronide), one GPFX sulfate conjugate (4'-sulfate), four metabolites with a metabolized 3-methylpiperazinyl ring (DM-1704, DM-1705, DM-1706 and DM-1725) and two 5-hydroxymethyl-type metabolites (DM-1722 and DM-1723).
2. The main metabolite of GPFX in human plasma was DM-1705. The metabolites excreted in urine during the period of 0-72 hours after dosing were 3-glucuronide (4.0% of the administered dose), 4'-glucuronide (3.5%), DM-1705 (3.0%), DM-1704 (1.3%), 41-sulfate (1.0%) and DM-1706 (0.2%). The metabolites excreted in feces during the period of 0-72 hours after dosing were DM-1705 (2.6%), DM-1704 (2.1%), DM-1725 (1.9%), DM-1706 (1.8%) and 4'-sulfate (1.3%).
3. The main metabolite of GPFX in plasma in both male and female rats was 3-glucuronide. The main metabolite in urine was DM-1723 in male rats and 3-glucuronide in female rats. The main metabolite in feces in both sexes was 4'-sulfate. The main metabolite in bile in male rats was 3-glucuronide. GPFX in male rat lungs accounted for more than 90.5% of the total radioactivity in the lungs, and other metabolite was detected.
4. The main metabolites in monkey plasma, urine and feces were DM-1704, DM-1704 and 4'-sulfate, respectively.

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Fluoroquinolones have been reported to have potent convulsant activity. We have reported that fluoroquinolones inhibited the receptor binding of γ-aminobutyric acid (GABA), an inhibitory transmitter in the central nervous system, and suggested that the onset of the convulsions induced by fluoroquinolones might be related to the inhibition of the receptor binding. Grepafloxacin (GPFX) is a newly developed fluoroquinolone. We studied the effect of GPFX and other fluoroquinolones on GABA receptor binding. GPFX, as well as other fluoroquinolones, inhibited GABA receptor binding in a concentrationdependent manner. The inhibitory activity of the compound was moderate among the fluoroquinolones tested in this study. However, the inhibitory activity of GPFX was hardly enhanced in the presence of NSAIDs. These in vitro results suggest that GPFX might have moderate convulsant activity, but that concurrent administration with NSAIDs might hardly enhance this activity.

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A Phase I study of grepafloxacin (GPFX), a new synthetic antibacterial agent, was conducted to determine the safety and pharmacokinetics of the compound in healthy adult male volunteers.
GPFX was administered orally to fasted volunteers in single doses of 10, 25, 50, 100, 200, 300 and 400mg and in 7-day multiple doses of 200 mg twice daily and 300 mg once daily. The effect of a meal was also investigated at 200 mg.
In 47 healthy adult male volunteers, the subjective and objective symptoms observed were headache in 3 volunteers, dull headache in 1 volunteer, light-headed feeling in 1 volunteer and bitter tasete in 1 volunteer. Abnormal laboratory test values were slightly increased BUN and GPT in one volunteer each. However, all of these symptoms and changes were mild and transient. No GPFX-related abnormalities were observed in any other parameters.
The plasma concentrations of GPFX increased dose-dependently after single oral administration, indicating maxima of 0.41, 0.66, 0.99 and 1.62 μg/ml at 100, 200, 300 and 400 mg, respectively, in fasting volunteers. The elimination half-life (T_1/2) of the plasma concentration in the β phase was 11.0- 12.5 hours. The cumulative urinary excretion during the the first 0-72 hours was 10.0%-12.6%. The fecal excretion of unchanged GPFX during the period of 0-72 hours was 31.5% of the administered dose. The meal had no effect on the absorption of GPFX by the digestive tracts. The change in the saliva concentration after single administration at 200 mg was similar to that in the plasma concentration, and the transfer ratio (ratio of the plasma concentration to the saliva concentration) at 1.5-4 hours was about 0.4-0.6. The plasma concentration in repeated administration at 200 mg twice daily and 300 mg once daily for 7 days reached a steady-state on the fourth day of multiple dosing, and no accumulation was found. These results suggested that, from the safety point of view, it is possible to perform further clinical evaluation.

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Grepafloxacin (GPFX) is a newly developed quinolone derivative. Fecal flora were studied in six healthy volunteers after the administration of 200 mg GPFX b. i. d. for seven days. Fecal samples were taken prior to and several times after administration, and quantitative and qualitative analyses of microorganisms in feces were performed. The total bacterial counts of aerobic and anaerobic bacteria did not change significantly.
Enterobacteriaceae and Enterococcus spp. were strongly suppressed during and after administration but these changes in fecal flora were temporary, and fecal flora returned to their former levels within 28 days after administration.
Transient appearance of Clostridium difficile was observed in some volunteers.

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The effect of a new oral synthetic quinolone antibacterial agent, grepafloxacin (GPFX), on the serum level of theophylline was studied in 5 healthy male adult volunteers. A slow-release preparation of theophylline at a daily dose of 400 mg was given orally for 4 days prior to GPFX administration. The serum level of theophylline was determined on the 4th day and used as the control level. GPFX was then given orally at 200 mg once daily in the morning for 5 days with concomitant administration of theophylline at the same dose as above. The mean Cmax and AUC values of theophylline on the 3rd day with GPFX were, respectively, 1.29 and 1.31 times the control values, and total body clearance was decreased to 0.76 times the control value. On the 5th day with GPFX, the above parameters were 1.28, 1.33 and 0.74 times the control values, respectively, indicating no marked difference from the 3rd day. One volunteer complained of hand and finger tremor and slight aggravation of hot flushes after administration of theophylline alone from the 1st day of concomitant administration, but this did not necessitate discontinuation of the concomitant administration. From the above results, GPFX was considered to increase the serum level of concomitantly administered theophylline, indicating an increase similar to that for ciprofloxacin and tosufloxacin.

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The pharmacokinetics of grepafloxacin (GPFX) were studied in patients with impaired renal function. Patients were classified into 3 groups according to creatinine clearance (Ccr). 7 patients in group I (90 ≥Ccr>60), 10 patients in group II (60≥Ccr>30) and 7 patients in group III (30 Ccr).
The maximum plasma concentration achieved after a single oral administration of 200 mg of GPFX was 0.46μg/ml at 4.3 h in group I, 0.54μg/ml at 4.4 h in group II and 0.37μg/ml at 5.9 h in group M. The plasma elimination half-life was 11.2, 12.8 and 13.0 h, and AUC was 6.31, 7.51 and 5.96μg·h/ml, respectively. There were no significant differences in half-life and AUC between the 3 groups. The urinary recovery rates within 72 h of administration were 6.86%, 7.43% and 3.03% in groups I, II and III, respectively, indicating low values in group III. No drug-related adverse reactions were observed.
These results sμggested that GPFX is mainly excreted into the bile and that little dose adjustment is necessary even in patients with impaired renal function.

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The antimicrobial activity and clinical effects of a new quinolone antimicrobial drug, grepafloxacin (GPFX), were investigated.
Minimum inhibitory concentrations (MICs) of the drug against 209 strains of 7 clinically isolated species were determined to examine the antibacterial activity of the drug. GPFX showed minimum 50% inhibitory concentration (MIC₅₀) levels of 0.09μg/ml, 0.09μg/ml, 0.09μg/ml, 1.56μg/ml, 0.19μg/ml, 0.09μg/ml, and 0.78μg/ml against Staphylococcus aureus, Escherichia coli, Klebsiella pneumaniae, Serratia marcescens, Proteus mirabilis, Morganella morganii, and Pseudomonas aeruginosa, respectively. Minimum 90% inhibitory concentration (MIC₉₀) levels were 0.09μg/ml against E. coli, 0.19μg/ml against K. pneumoniae, 0.19μg/ml against M. morganii, and 0.39μg/ml against P. mirabilis. Thus, GPFX exerted good antibacterial activity against these four species.
GPFX was also administered to 13 patients with respiratory infectious diseases (8 with bronchitis, 2 with acute aggravation of chronic bronchitis, and 3 with secondary airway infection) at a daily dose of 100-300mg for 7-14 days, and the clinical effects were investigated. The drug was effective in 11, slightly effective in 1, and unknown in 1 because the patient did not visit the hospital after administration. None of the patients had side effects or abnormalities on clinical laboratory tests, excluding the patient who was lost to follow-up.

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The antimicrobial effects of a new quinolone antimicrobial drug, grepafloxacin (GPFX), on respiratory pathogens as well as its clinical effects and utility were assessed as follows:
The measured MICs of GPFX of 82 isolated strains in respiratory infections were: 0.1 μg/ml for 10 strains of Staphylococcus aureus, 0.39 μg/ml for 17 strains of Streptococcus pneumoniae and 12 strains of Streptococcus sp., 0.78 μg/ml for 6 strains of Klebsiella pneumoniae, 0.78 μg/ml for 4 strains of Acinetobacter calcoaceticus, ≤0.006 μg/ml for 16 strains of Haemophilus sp., 0.012 μg/ml for 4 strains of Moraxella catarrhalis and 3.13 μg/ml for 13 strains of Pseudomonas aeruginosa.
GPFX was administered at a dose of 200 or 300 mg once/day for 7-14 days to 17 patients, including 3 cases of acute pneumonia, 4 cases of mycoplasma pneumonia, 1 case of acute bronchitis, 5 cases of chronic bronchitis, 1 case each of secondary infection to bronchiectasis and bronchial asthma, and 2 cases of secondary infection to pulmonary emphysema.
The clinical results were excellent in 2 cases, effective in 12 cases, and slightly effective in 2 cases (excluding 1 patient who did not visit after the first consultation). Regardingthe dose distribution, all 6 cases in the 200 mg/day group and 8 of 10 cases in the 300 mg/day group responded effectively.
The bacteriological results were as follows: 2 strains of isolated H. influenzae, 1 strain each of M.catarrhalis, S. pneumoniae, and S. aureus disappeared, and 1 strain of P. aeruginosa decreased.
No side effects were observed in any of the patients. Abnormal laboratory findings were observed in 3 patients: a decrease in WBC in one and elevation of eosinophils in two.

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The in vitro antimicrobial activity, serum and sputum concentrations of grepafloxacin (GPFX), a newquinolone agent for oral use developed in Japan, and its therapeutic efficacy in the treatement of respiratory tract infections were evaluated. The minimum inhibitory concentrations (MICs) of GPFX, ofloxacin (0FLX), ciprofloxacin (CPFX), tosufloxacin (TFLX), sparfloxacin (SPFX) and rifampicin (REP) against 20 strains each of mechicillin-susceptible Staphylococcus aureus (MSSA), methicilinresistant S.aureus (MRSA), Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens, Pseudomonas aeruginosa and Mycobacterium avium, and 18 strains each of Haemophilus influenzae and Mycobacterium tuberculosis were determined by the micro-broth dilution method using the Dynatech MIC 2000 system. As shown by MICs, GPFX was more active than OFLX against all the species tested except for S. marcescens, against which it was as active as OFLX. The ratio of the concentration of GPFX in sputum to that in serum after oral administration of 200mg was 161%. Twenty-two patients received a daily dose of 200mg to 300mg of GPFX per os for 7-14 days (mean: 11.1 days): 4 with chronic bronchitis, 3 with infection associated with bronchial asthma, 6 with infection associated with bronchiectasis and 9 with pneumonia. The clinical effects were excellent in 6, good in 12, fair in 2 and poor in 2. Twelve strains were identified as causative organisms. Eleven strains were eradicated and one strain (P.aeruginosa) was decreased in number by administration of GPFX. No clinical adverse effcts were observed during treatment with GPFX. Eosinophilia and a transient elevation of serum transaminase were observed in one patient each. These adverse effects disappeared after the completion of therapy. We conclude from the above results that GPFX is one of the most useful quinolone agents for oral use as a drug of first choice in the treatment of respiratory infections, especially in outpatient clinics.

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Grepafloxacin (GPFX) was studied basically and clinically with the following results:
In the basic study, the MICs of GPFX on gram-positive bacilli (GPB; methicillin-susceptible Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes, Streptococcus pneumoniae, Enterococcus faecalis) and gram-negative bacilli (GNB; Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Acinetobacter calcoaceticus, Moraxella catarrhalis, Haemophilus influenzae) were compared with those of other new quinolone antibacterial drugs (ofloxacin, ciprofloxacin, tosufloxacin, sparfloxacin), clavulanic acid/amoxicillin, cefixime, and cefteram pivoxil. The MICs of GPFX on GPB ranged from ≤0.05-1.56μg/ml with the MIC₉₀ below 0.78μg/ml, indicating excellent antibacterial activity. On the other hand, the MICs of GPFX on GNB ranged from ≤0.05-3.13 except for ≤0.05-12.5μg/ml for E.coli and 0.2-100μg/ml for P.aeruginosa, and the effect of GPFX was almost equal or inferior to those of other control drugs. The MIC₉₀ were all below 0.78μg/ml except for 25μg/ml for P.aeruginosa, indicating a superior effect.
In the clinical study, GPFX was administered to 20 patients with respiratory infections at a dose of 150mg once or twice a day for 3-7 days. The result was remarkably effective in 6 cases, effective in 8, slightly effective in 3, and ineffective in 3 (efficacy rate: 70%). As for adverse reactions, thirst and constipation were observed in 1 case each, but disappeared spontaneously after withdrawal. No abnormal laboratory changes were observed throughout this study. Thus GPFX was confirmed to be a very safe, useful drug.

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The antimicrobial effects of a new quinolone antimicrobial drug, grepafloxacin (GPFX), were examined by means of an in vitro pharmacokinetic system together with its clinical efficacy in respiratory infections, as follows:
1. Using an in vitro pharmacokinetic system, the drug hemodynamic status during GPFX administration at doses of 200 and 300mg was simulated to examine its antimicrobial activities against Staphylococcus aureus FDA 209 P JC-1, Streptococcus pneumoniae IID55 3, Escherichia coli, NIHJ JC-2, Haemophilus influenzae IID984 and Pseudomonas aeruginosa IFO 3445.
The viable bacterial counts for individual strains decreased within 2-8 hours, resulting in no reproliferation in the 200 and 300 mg models of S.pneumoniae and H.influenzae and in the 300mg model of E.coli. As for P.aeruginosa, more viable bacteria were decreased with retarded reproliferation in the 300mg model as compared with the 200mg model, suggesting dose-dependent activity.
2. GPFX was administered at a daily dose of 100-600mg to 30 patients with respiratory infections to examine its efficacy and safety. The clinical result according to the type of disease was effective in the only case of pharyngitis, all 4 cases of pneumonia (incluiding 1 case of mycoplasma pneumonia), both cases of acute bronchitis, 18 out of 20 cases of chronic bronchitis, and all 3 cases of diffuse panbronchiolitis, for an overall efficacy rate of 93.3%(28 out of 30 cases).
The pathogen was determined in 7 cases, and 9 strains of 4 species were identified. Bacteriologically, all 5 strains of increased S.pneumoniae, the only strain each of Enterobacter cloacae and H. influenzae, and neither of 2 strains of P.aeruginosa disappeared completely.
Subjective and objective side effects included 1 case each of dizziness and dizziness-vertigo, both of which, however, disappeared, one during the administration period and the other after withdrawal.
Abnormal laboratory values included eosinophilia in 1 case, increased GOT in 2 cases and increased GPT in 2 cases. All were temporal and mild in nature.

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A clinical study on grepafloxacin, a new sythetic antimicrobial quinolone derivative, was performed with the following results:
1. Pharmacokinetics
In order to examine the renal elimination mechanism of GPFX, the pharmacokinetics were compared between single-dose and probenecid-combined groups in 6 adult male volunteers using a cross-over method. It was found that the plasma and urinary concentrations of GPFX were not influenced by probenecid. The renal elimination mechanism of GPFX was thus estimated to depend mainly on glomerular filtration.
2. Clinical results
The efficacy and safety of GPFX were examined in 7 outpatients, including 3 cases of urinary infection and 4 cases of respiratory infection. The clinical result was excellent in all 3 cases of urinary infection and 2 cases of respiratory infection. The remaining 2 cases of respiratory infection responded effectively. Although no adverse reaction was noted, slightly increased GOT and GPT levels were observed as abnormal laboratory values in 1 case only.

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We evaluated the clinical efficacy and safety of grepafloxacin (GPFX) in a phase 2 study in a total of seven patients with respiratory infections. GPFX was administered orally at a dose of 150 to 300mg daily. The time course of the serum and sputum concentrations was evaluated after administering a 300mg dose to one patient, and pharmacokinetic analysis was also performed. The subjects included one case each of bronchial asthma and diffuse panbronchiolitis, and five cases of bronchiectasis. Clinical response was good in three cases, fair in one and poor in two. Two strains of Haemophilus influenzae were eradicated, while three strains of Pseudomonas aeruginosa persisted in spite of their susceptibility to GPFX. One patient had headache and lumbago as well as chest discomfort four hours after taking GPFX. No abnormal laboratory findings were observed.
The peak concentration of GPFX in sputum (four hours after administration) was 2.31μg/ml, almost two-fold that in serum, suggesting its efficacy in respiratory infections.

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The administration method of a new quinolone antibiotic, grepafloxacin (GPFX), was examined in a neutropenic mouse thigh-infection model. As compared with ofloxacin (OFLX), GPFX showed a stronger antibacterial effect and longer effective regrowth time against Staphylococcus aureus infections. The antibacterial effect of OFLX on Klebsiella pneumoniae was superior to that of GPFX, but regrowth was soon observed due to its short half-life (T_1/2). GPFX, in spite of differences in administration times, did not cause an extremely increased or decreased number of bacteria, and showed a slightly better result after 24 hours than OFLX. Concerning its pharmacokinetics in mice, GPFX had a lower Cmax and longer T_1/2 in plasma than OFLX. In addition, GPFX showed less AUC in plasma but almost equal AUC in muscle tissues as compared with OFLX. These results indicate that GPFX has a long T_1/2 in plasma and excellent penetration into tissue.

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Antibacterial and clinical studies were performed on grepafloxacin (GPFX), a newly developed quinolone antibacterial drug, and the following results were obtained.
The antibacterial activity of GPFX was compared with those of norfloxacin (NFLX), ofloxacin (OFLX), and ciprofloxacin (CPFX). Against methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA), Escherichia coli, and Klebsiella pneumoniae, the effect of GPFX was superior to those of NFLX, OFLX, and CPFX, but the effect of GPFX against Pseudomonas aeruginosa was about one rank inferior to that of CPFX but superior to NFLX and OFLX.
In the clinical study, 10 patients (including 1 case of acute pharyngolaryngitis, 4 of acute bronchitis, 2 of acute pyelonephritis, 1 of acute cystitis, and 2 of chronic complicated urinary infection) were administered GPFX at a dose of 200-300 mg once or twice daily for 3-15 days. The clinical result was excellent in 1 case, effective in 5 cases, ineffective in 2 cases and unevaluable in 2 cases.
In regard to its safety, adverse reactions were noted in 2 cases: nausea and headache in 1 case and thirst in the other. Abnormal laboratory values were observed only in 1 case as slightly increased GPT and Al-p. These side effects and abnormal laboratory values were, however, mild in degree with no problem from the clinical standpoint.

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The in vitro activity of grepafloxacin (GPFX), a newly developed quinolone for oral use, was studied by determining minimum inhibitory concentration by an agar two-fold dilution method. GPFX was not active against 16 of 39 strains of Staphylococcus aureus with the mecA gene but showed excellent activity against strains of S. aureus without the mecA gene, against which the MIC of this drug ranged from 0.025 to 0.1 μg/ml. GPFX was more active than norfloxacin, ofloxacin and fleroxacin but less active than tosufloxacin against not only S. aureus but also Escherichia coli and Klebsiella Pneumoniae. The MICs of GPFX ranged from 0.006 to 0.2μg/ml against E. coli and from 0.025 to 0.2μg/ml against K. pneumoniae. Among 3 patients with acute laryngitis and 2 with acute bronchitis, 4 were successfully treated by administration of 200 mg once a day of GPFX. Neither significant side effects nor abnormalities of laboratory data were detected after administration of GPFX.

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We studied the penetration into plueral fluid of grepafloxacin (GPFX) and evaluated its clinical efficacy for respiratory tract infections. The penetration rate of GPFX into pleural fluid (ratio of maximum pleural fluid concentration to peak serum concentration) determined by theHPLC method in 3 patients with pleural fluid was 33.3-50.5%(mean: 43.5%). A similar result was obtained by bioassay.
The efficacy rate (more effective) for 24 cases with respiratory infection was 95.7% after oral administration of GPFX.
Bacteriologically, 19 strains were isolated, including 5 strains of Staphylococcus aureus, 3 strains of Haemophilus influenzae, 1 strain of Klebsiella pneumoniae, 3 strains of Pseudomonas aeruginosa, 1 strain of Xanthomonas maltophilia and 1 strain of Corynebacterium sp. and so on. Sixteen strains (except for 2 strain of S. aureus and 1 strains of P. aeruginosa) were eradicated, an eradication rate of 84.2%. No side effect was observed in any of the cases examined. In the laboratory tests, however, slightly elevated s-GOT and s-GPT were observed in 1 case.
Based on the above results, GPFX is considered a useful new quinolone derivative for the treatment of respiratory tract infections.

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The antimicrobial effect of grepafloxacin (GPFX), a newly developed quinolone derivative for oral use, on clinicaly isolated strains was examined in comparison with those of ofloxacin (OFLX), ciprofloxacin (CPFX), sparfloxacin (SPFX), and fleroxacin (FLRX). The antimicrobial effects of GPFX on MSSA, MRSA and Streptococcus pneumoniae among gram-positive bacilli were, like SPFX, superior to those of other tested drugs. In the case of gram-negative bacilli, the antimicrobial effect of GPFX was sufficient on Klebsiella pneumoniae although slightly inferior to CPFX, almost equal to those of other drugs on Haemophilus influenzae, and superior to those of other drugs on Moraxella (Branhamella) catarrhalis, similar to the findings for SPFX. Against Pseudomonas aeruginosa, the antimicrobial effect was superior to that of the others but was slightly inferior to CPFX.
GPFX was orally administered to 20 patients with respiratory infection, mainly consisting of chronic airway infection, to examine its clinical efficacy and safety. The clinical result was effective in 17 cases and slightly effective in 3 cases, an efficacy rate of 85.0%. Bacteriologically, 13 pathogenic strains (P.aeruginosa, S. pneumoniae, H. influenzae, K. pneumoniae, Aeromonas hydrophila, Proteus vulgaris, K. pneumoniae and Xanthomonas maltophilia) were specified from 12 cases. Based on the bacteriological effect of GPFX on these 13 strains, the elimination rate was calculated as 53.8%. Side effects were observed in 3 cases (incidence: 15.0%): vertigo, drowsiness/numbness and wheal in 1 case each. Abnormal laboratory values were observed in 2 cases (incidence: 10.0%): increased serum GOT/GPT/Al-P and increased urinary urobilinogen in 1 case each.

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Basic and clinical studies on grepafloxacin (GPFX), a new oral sythetic quinolone antimicrobial, were performed, and the following results were obtained.
1. The MIC₉₀ range of GPFX against methicillin-sensitive Staphylococcus aureus, Klebsiella pneumoniae, Escherichia coli and Acinetobacter calcoaceticus was distributed from 0.025 to 0.2μg/ml, and was superior to those of ofloxacin (OFLX) and norfloxacin, and equivalent to or better than those of tosufloxacin (TFLX) and ciprofloxacin (CPFX).The MIC₅₀ of CPFX against methicillin-resistant S.aureus was 0.2 μg/ml, thebest, while the MIC₉₀ was 25μg/ml, inferior to that of TFLX, The MIC₅₀ and MIC₉₀ of GPFX against Pseudomonas aeruginosa showed antimicrobial activities of 0.78μg/ml and 3.13 μg/ml, respectively, equivalent to CPFX even though inferior to TFLX.
2. The MIC range of GPFX against Chlamydia pneumoniae, Chlamydia psittaci and Chlamydia trachomatis was distributed from 0.03 to 0.125 μg/ml, showing results superior to alreadyexisting new quinolone preparations such as TFLX and OFLX.
3. In the study on the clinical effects of GPFX, the results for 13 cases with respiratory diseases, including pneumonia and chronic respiratory tract infections, were markedly effective in 3 cases, effective in 5 cases, slightly effective in one case, ineffective in 3 cases and unevaluable in one case, an efficacy rate of 67%(8/12).
In the bacteriological study, the results for 10 cases in which causative bacteriawere isolated were as follows: eradicated in 4 cases, decreased or partially eradicated in 4 cases, unchanged in 1 case, and replaced in 1 case, an eradication rate of 50%. Of 4 strains of S. aureus, 3 were eradicated and 1 unchanged. Of 2 strains of S. pneumoniae, 1 was eradicated and 1 unchanged. One strain of E. coli and 3 strains of H. influenzae were all eradicated. Of 2 strains of K. pneumoniae, 1 was eradicated and 1 unchanged. The 2 strains of P. aeruginosa were both unchanged.
No side effects were observed, and the only abnormal laboratory finding was eosinophilia in one case.

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A newly developed pyridone carboxylic acid antimicrobial drug, grepafloxacin (GPFX), was studied basically and clinically.
1) The minimum inhibitory concentrations (MICs) of GPFX against 242 strains of 10 clinically isolated species were determined, and the MICs of ofloxacin (OFLX), ciprofloxacin (CPFX) and tosufloxacin (TFLX) were determined as controls. The antibacterial activity of GPFX was better by 1-4 grades than the control drugs against gram-positive cocci. The antibacterial activity against gramnegative bacilli was superior to that of OFLX, although it was slightly inferior to those of CPFX and TFLX. Against Proteus spp., however, GPFX was inferior to the control drugs.
2) GPFX was orally administered to 12 patients consisting of 3 with pneumonia, 5 with acute bronchitis, and 4 with chronic bronchitis at a dose of 100-300 mg once or twice a day for 4-25 days. GPFX was effective in 9 patients, slightly effective in 1, and ineffective in 2, the rate of efficacy being 75.0%. All of 7 strains isolated from 5 patients were eradicated. Adverse reactions were observed in three patients; one had nausea and anorexia, one had dizziness, and the other had dizziness, nausea and anorexia. Elevations of GOT and GPT were observed in one patient, and eosinophiliawas observed in another on clinical laboratory tests.

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A new quinolone antimicrobial drug, grepafloxacin (GPFX), was studied basically and clinically, with the following results:
1. Antibacterial activity: Minimum inhibitory concentrations (MICs) of the drug against 515 strains of 16 clinically isolated species were determined, and compared with those of three other drugs, ciprofloxacin (CPFX), norfloxacin (NFLX) and ofloxacin (OFLX).
GPFX was found to have the best antimicrobial activity for gram-positive bacteria among the drugs tested. Its antimicrobial activity against gram-negative bacteria was approximately equal to that of CPFX, and superior to NFLX and OFLX.
2. Concentrations of GPFX in blood and sputum: The concentrations of GPFX in blood and sputum were determined by high-performance liquid chromatography in 4 patients with chronic respiratory tract infection. The maximum blood level reached 0.20-1.63 μg/ml and the maximum sputum level 0.70-4.02 μg/ml at 3-4 hours and 5-6 hours after oral administration of 300 mg and 200 mg, respectively. The penetration rate into sputum was 235.5-371.4%.
3. Clinical study: GPFX was administered to 17 patients with respiratory tract infection, and the clinical and bacteriological efficacy and side effects were investigated. GPFX was excellent in 2 patients, good in 10, poor in 4 and unevaluable in 1. The overall efficacy rate was 75.0%. Eight of the 12 strains isolated from 10 patients were eradicated, showing a 66.7% eradication rate. Although none of the patients had side effects, elevation of transient Al-P or transient eosinophilia was observed in two patients on clinical laboratory tests.

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A new quinolone antimicrobial drug, grepafloxacin (GPFX), was studied basically and clinically.
Its antimicrobial activity (50% minimum inhibitory concentration: MIC₅₀) against major respiratory pathogens was 0.39 μg/ml against Staphylococcus aureus, 0.39 μg/ml against Streptococcus pneumoniae, less than 0.003 μg/ml against Haemophilus influenzae, 0.025 μg/ml against Branhamella catarrhalis, and 0.78 μg/ml against Pseudomonas aeruginosa.
In one of the 2 patients with respiratory infectious disease, the maximum sputum and serum levels of GPFX after a single administration of 100 mg were 1.56 μg/ml and 0.85 μg/ml, and the peak ratio (maximum sputum level/maximum blood level × 100) was 183.5%. In the other patient, the maximum sputum and serum levels of GPFX after a single administration of 200 mg were 1.68 μg/ml and 1.13 μg/ml, respectively, and the peak ratio was 148.7%.
Fifteen patients with respiratory tract infections were studied for the clinical evaluation of GPFX. The rate of clinical efficacy was 100%(13/13; unknown in 2 patients). Although 2 strains of P. aeruginosa were not eradicated, all other bacteria (2 strains of S. pneumoniae, 5 strains of H. influenzae, and 3 strains of B. catarrhalis) were eradicated. The rate of bacterial elimination in sputum samples was 83.3%. No reversed effect was observed.
The results suggest that GPFX can be expected to exert excellent clinical effects on respiratory infectious diseases due to bacteria including S. pneumoniae, when it is administered once or twice a day.

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The in vitro antibacterial activity of a new quinolone antimicrobial drug, grepafloxacin (GPFX), was determined, and the clinical effects were investigated, with the following results:
1. Antibacterial activity: Minimum inhibitory concentrations (MICs) of GPFX against 270 strains of 7 genera clinically isolated were determined according to the method defined by the Japan Society of Chemotherapy, and compared with MICs of three other drugs, ofloxacin (OFLX), ciprofloxacin (CPFX) and fleroxacin (FLRX).
GPFX showed potent antibacterial activity against gram-positive bacteria. The growth of methicillinsensitive Staphylococcus aureus was completely inhibited at the MIC of 0.10μg/ml, as was that of Streptococcus pneumoniae at 0.39μg/ml. Against gram-negative bacteria, GPFX showed more potent or similar antibacterial activity compared with CPFX, FLRX and OFLX.
2. Clinical results: GPFX was orally administered to 8 patients with respiratory infectious diseases (2 patients with pneumonia, 4 with chronic bronchitis, 1 with diffuse panbronchiolitis, 1 with bronchiectasis on infection) at a dose of 100-300 mg once a day for 3 to 14 days. The drug was clinically effective in 6 patients and fair in 2.
Side effects occurred in three patients: mild numbness of the extremities and dull headache were found in 1 patient who received theophylline with the administration of GPFX, nausea was found in 1 patient and diarrhea was found in 1 patient. Elevation of the total bilirubin level was observed in 1 patient on clinial laboratory tests.

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We carried out laboratory and clinical studies on grepafloxacin (GPFX), a new oral pyridone carboxylic acid, antimicrobial drug.
1) Laboratory activity
The minimum inhibitory concentrations (MICs) of GPFX for a total of 334 clinically isolated strains and 40 standard strains were determined and compared with those of tosufloxacin (TFLX), ofloxacin (0FLX), ciprofloxacin (CPFX), enoxacin (ENX), norfloxacin (NFLX), sparfloxacin (SPFX) and erythromycin (EM).
GPFX proved to have a broad antibacterial spectrum, and its in vitro activity against gram-positive cocci was the same as that of TFLX, and more potent than that of the other five reference quinolones. Against gram-negative bacilli except Legionella pneumophila, the in vitro activity of GPFX was the same or lower than that of TFLX, and more potent than that of the other drugs. The MIC₉₀ of GPFX for clinical isolates of L. pneumophila was almost equal to that of SPFX, and superior to those of the other drugs. The MIC₉₀ of GPFX for standard strains of Legionella spp. was slightly inferior to those of TFLX and SPFX, and the same as that of CPFX.
2) Clinical efficacy
We administered GPFX to five patients with respiratory tract infection at a dose of 200-300 mg daily for 7 to 14 days. The clinical results were good in 5 cases, yielding an efficacy rate of 100%. In all cases, neither side effects nor abnormal laboratory findings were observed.

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We determined the minimum inhibitory concentration (MIC) of grepafloxacin (GPFX), a newly developed quinolone-derivative antibacterial agent, against clinical isolates of various bacterial species from enteritis patients, and compared them with those of norfloxacin (NFLX), ofloxacin (OFLX), enoxacin (ENX), ciprofloxacin (CPFX) and nalidixic acid (NA). The MIC₉₀ of GPFX against 37 strains of Shigella spp., 23 strains of Salmonella spp., 15 strains of Campylobacter spp., 11 strains of Vibrio spp., and 9 strains of Escherichia coli were 0.1, 0.2, 0.39, 0.78 and 0.1μg/ml, respectively. The MIC ranges against total clinical isolates (100 strains) were GPFX, ≤0.006 to 1.56μg/ml; NFLX, 0.025 to 3.13μg/ml; OFLX, 0.0125 to 3.13μg/ml; ENX, 0.025 to 6.25μg/ml; CPFX, ≤0.006 to 1.56μg/ml and NA, 0.2 to 50μg/ml. Among the six quinolones, GPFX was 1/2 as active as CPFX, followed by OFLX and NFLX, ENX and NA. GPFX is a newly developed quinolone-derivative antibacterial agent that should prove promising for the treatment of infectious enteritis.

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The efficacy, safety and usefulness of grepafloxacin (GPFX) for patients with acute infectious enteritis, and the carriers mainly of bacillary dysentery, were investigated. The drug was administered at a daily dose of 200 mg once a day for 3 days to patients with cholera, 7 days to patients with Salmonella enteritis and 5 days to patients with other conditions of infectious enteritis including dysentery.
1. The global clinical efficacy was analyzed in 77 of the 113 patients who received administration.
2. The drug was markedly effective or effective for symptoms in 39 patients, and the rate of efficacy was 100%.
3. Bacteriologically, the drug was effective for dysentery bacillus in 41 (97.6%) of 42, Salmonella in 7 of 9, Campylobacter in 5 of 9 and enteropathogenic Escherichia coli in 9 of 9.
4. The global clinical efficacy for 72 cases (excluding 4 cases: 1 with bacillary dysentery, 2 with Salmonella enteritis and 1 with Campylobacter enteritis) was 94.8%(72/76).
5. None of the patients (n=112) had side effects. Abnormal findings were observed in 8 (8%) of the patients (n 100) on laboratory tests. Elevations of s-GOT and s-GPT were the main findings, but they were mild.
6. As to usefulness, 52.6% of the patients (n=78) were very satisfied, and 89.7% were satisfied or very satisfied.
7. The influence of GPFX administration on fecal level and intestinal bacterial flora was investigated in one patient with bacterium-negative enteritis. Results approximately equivalentto those in healthy subjects were obtained.
The above results suggest that GPFX is highly useful for infectious enteritis conditions such as bacillary dysentery.

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Clinical evaluation of grepafloxacin in the treatment of various infectious diseases in the field of internal medicine.
The clinical usefulness of grepafloxacin (GPFX), a new quinolone synthesized as an oral antibacterial agent, in various infections in the field of internal medicine was investigated by collaborative research at 62 institutions nationwide. GPFX was administered primarily to patients with respiratory tract infections (RTI), mostly at daily doses of 100-300 mg once or in 2 divided doses. Clinical efficacy was evaluated in 509 of a total of 525 patients for analysis and efficacy was observed in 443 (87.0%) of the 509, including 432 (87.1%) of 496 patients with RTI and 11 (84.6%) of 13 patients with urinary tract infections (UTI). In RTI by disease, clinical efficacy was observed in 19 (86.4%) of 22 patients with pharyngolaryngitis or pharyngitis, 17 (94.4%) of 18 with tonsillitis, 53 (91.4%) of 58 with acute bronchitis, 104 (87.4%) of 119 with pneumonia, 17 (89.5%) of 19 with mycoplasmal pneumonia, 5 (100%) of 5 with atypical pneumonia, 117 (87.3%) of 133 with chronic bronchitis, 48 of 63 with bronchiectasis, 17 (89.5%) of 19 with diffuse panbronchiolitis, and 35 (87.5%) of 40 with secondary infection with chronic respiratory disease. Bacteriological efficacy in RTI was evaluated in 233 patients. Bacteriological eradication was observed in 154 (78.2%) of 197 patients with monomicrobial infection and 22 (61.1%) of 36 with polymicrobial infection. For monomicrobial infection, bacteriological efficacy was higher in patients infected with gram-positive bacteria (48 of 53, 90.6%) than in patients infected with gram-negative bacteria (105 of 142, 73.9%). The MIC₈₀ of GPFX was 0.39μg/ml in 115 strains of causative organisms in which the MIC₈₀ was determined in RTI, and the MIC₈₀ of norfloxacin (NFLX), ofloxacin (0FLX), enoxacin (ENX) and ciprofloxacin (CPFX) were 6.25, 1.56, 6.25 and 0.78μg/ml, respectively, in 97 strains. Adverse drug reactions were observed in 26 (5.0%, 38 cases) of 519 patients, including mostly gastrointestinal symptoms, CNS symptoms and hypersensitive symptoms. Abnormal clinical laboratory test values were observed in 49 (10.0%) of 490 patients. Major changes included increased eosinophil and transaminase. None of the reported symptoms or abnormal changes were serious. Based on clinical efficacy, adverse drug reactions and abnormal clinical laboratory test values, GPFX was judged to be useful in 432 (84.7%) of a total of 510 patients, 422 (84.9%) of 497 with RTI and 10 (76.9%) of 13 with UTI. From these results, GPFX was considered to be useful in the treatment of various infectious diseases, particularly RTI, in the field of internal medicine.

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A new quinolone antimicrobial agent, grepafloxacin (GPFX), was studied basically and clinically, with the following results.
1) Basic assessment: Minimum inhibitory concentrations (MICs) of GPFX against 559 strains of 12 isolated species from urinary tract infection (UTI) were compared with those of ofloxacin (OFLX), ciprofloxacin (GPFX) and norfloxacin (NFLX). The minimum 90% inhibitory concentrations (MIC₉₀) of GPFX against gram-positive cocci, i. e., Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis and Enterococcus faecium, were generally less than 8μg/ml. GPFX exhibited excellent antibacterial activity in comparison with other antibiotics. On the other hand, the MIC₉₀ of GPFX against gramnegative bacilli were lower than 0.5μg/ml, with the exception of 32μg/ml for Pseudomonas aeruginosa and Serratia marcescens, and 8μg/ml for Enterobacter spp., showing excellent antibacterial activity. The MIC range of GPFX against Chlamydia trachomatis standard strain (D strain) was equivalent to that of a tetracycline preparation.
2) Clinical assessment: GPFX was administered to 3 patients with acute uncomplicated cystitis and 7 patients with complicated UTI. Clinical efficacy as rated by the Japanese UTI Committee criteria was excellent in all 3 patients with acute uncomplicated cystitis, and the efficacy by physician's evaluation was excellent or effective in all 3 patients. Bacteriologically, all 3 strains were eradicated by the treatment. Clinical efficacy was evaluable by the Japanese UTI Committee criteria in 5 of the 7 patients with complicated UTI. According to the evaluation at 5 days after treatment, the result was excellent in 1, good in 3, and poor in 3, and the efficacy rate was 2/5. The patients in whom the result was poor included 2 patients with infection with at least two bacteria including Escherichia coli and P. aeruginosa.
No abnormal changes in clinical laboratory test values or subjective or objective side effects were observed in any of the 10 patients.

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We investigated the antimicrobial activity of grepafloxacin (GPFX) in human urine and the influence of GPFX on the bactericidal activity of leukocytes in a basic study, and examined its clinical efficacy and safety for urinary tract infections, in order to clarify its usefulness.
1. Fundamental study: We measured minimum bactericidal concentrations of GPFX against Escherichia coli NIHJ JC-2 and Pseudomonas aeruginosa 18s in urine media with different pH. The MBCs of GPFX were low when the urine pH was high. We also investigated the influence of GPFX on the bactericidal activity of neutrophils and monocytes, comparing their superoxide generation in the presence or absence of GPFX by means of the chemiluminescence method. The superoxide generation of neutrophils was significantly enhanced in the presence of 10μg/ml or 100μg/ml of GPFX. On the other hand, the superoxide generation of monocytes was significantly enhanced in the presence of 1.0μg/ml or 10μg/ml of GPFX; however, it was reduced in the presence of 100μg/ml of GPFX.
2. Clinical study: We administered GPFX 200 mg to 600 mg daily, for 5 days to 6 patients with chronic complicated urinary tract infections. Clinical efficacy was evaluated according to the criteria proposed by the Japanese UTI Committee or by doctors. The overall effectiveness rate according to the criteria proposed by the Japanese UTI Committee was 4/6 (excellent in 2, moderate in 2, and poor in 2 patients), and the efficacy rate as evaluated by doctors was 4/6 (excellent in 1, good in 3, and poor in 2 patients). No side effects or laboratory abnormalities were seen in any patients after the administration of GPFX.
These results indicate that GPFX has moderate efficacy, and the alkalization of urine might enhance its efficacy.

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Grepafloxacin (GPFX) was administered to 40 male patients with urethritis who visited the Department of Urology, Municipal Taito Hospital, from August 1991 to January 1992. The subjects consisted of 24 cases of gonococcal urethritis, 5 cases of non-gonococcal Chlamydia urethritis, and 11 cases of nongonococcal non-Chlamydia urethritis. GPFX was administered at a dose of 200 or 300mg/day for 2-16 days. In addition, MICs were determined for 23 strains of Neisseria gonorrhoeae from the patients with gonococcal urethritis.
N. gonorrhoeae disappeared in 22 of 24 cases (91.2%) of gonococcal urethritis. In diminished cases, the MIC of GPFX was 0.20μg/ml or below, while 2 strains showed MIC values of 0.39 and 0.78μg/ml, respectively. Since some N. gonorrhoeae have recently been found to be resistant to many new quinolone drugs, reexamination of the clinical application of GPFX to gonococcal urethritis seems necessary in the near future.
In 5 patients with non-gonococcal Chlamydia urethritis, the pathogen disappeared. Furthermore, 10 of 11 cases of non-gonococcal non-Chlamydia urethritis responded effectively, suggesting the possible application of GPFX to non-gonococcal urethritis. In addition, no adverse reaction was observed in any of the 40 patients treated with GPFX. Thus the drug was considered to be very safe.

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The antimicrobial effect of grepafloxacin (GPFX), a new quinolone derivative, on 40 strains of Neisseria gonorrhoeae (including penicillinase-producing N. gonorrhoeae: PPNG) and 8 strains of Chlamydia trachomatis as well as its clinical utility in urinary infections were assessed with the following results:
1. Antimicrobial effects As for the antimicrobial effects of GPFX on 40 stock strains of N. gonorrhoeae, MICs ranged from 0.012-1.56μg/ml and the MIC of GPFX was 0.2μg/ml; its value was equal to that of ciprofloxacin (CPFX) and levofloxacin (LVFX) but less than that of tosufloxacin (TFLX) and sparfloxacin (SPFX). The MIC₅₀ was, however, as low as 0.025μg/ml.
Against 8 strains of C. trachomatis, the antimicrobial effects of GPFX were superior to those of other drugs tested, with an MIC range of 0.08-0.31μg/ml and MIC₅₀ and MIC₉₀ of 0.016 and 0.03 μg/ml, respectively, almost equal to those of SPFX.
2. Clinical utility
In 5 of 10 cases of acute uncomplicated cystitis satisfying the UTI evaluation criteria for drug efficacy, the result was assessed as excellent in 3 cases and effective in 2 cases, an efficacy rate of 100%(all 5 cases). There were 3 excellent, 3 effective, and 3 ineffective cases among 9 cases of complex urinary infections, an efficacy rate of 66.7%(6 of 9 cases). The bacteriological examination revealed that 15 of 17 strains from 6 species disappeared, and the rate of elimination was 88.2%.
As for side effects, only 1 patient complained of upper abdominal discomfort, but this was not a problem clinically.
The results mentioned above indicate that GPFX is useful for the treatment of urinary infections.

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A new oral quinolone antibacterial drug, grepafloxacin (GPFX), was administered to a total of 52 patients, including 51 cases of urinary tract infections (UTI) and 1 case of chronic prostatitis, to examine its therapeutic efficacy and safety. In addition, its concentration in prostatic fluid was measured. GPFX was administered to patients with uncomplicated cystitis at a dose of 100 mg once a day for 3-5 days, and for patients with complicated UTI, the drug was given at a doses of 200-300 mg once a day or divided into 2 doses a day for 5 days.
According to the criteria proposed by the Japanese UTI Committee, the efficacy rate was 100%(11/11) in uncomplicated cystitis, while it was 44.4%(12/27) in complicated UTI. In complicated UTI, the bacterial eradication rate was 10/15 (66.7%) for gram-positive cocci and 15/24 (62.5%) for gramnegative bacteria.
The prostatic fluid concentration of GPFX at 1-4 hours after oral administration at doses of 200-300 mg was 0.03-0.53μg/ml, with a serum ratio of 0.12-1.71. In regard to safety, subjective adverse reactions included 2 cases of GI disorder, 3 cases of CNS disorder and 1 case of allergic skin eruption. Abnormal laboratory findings included 1 case of slight elevation of sGOT, increase of neutrophils and lymphocytopenia.

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The in vitro antimicrobial activity of grepafloxacin (GPFX), a new oral quinolone, against bacteria from urinary tract infection was compared with that of the other quinolones. The in vitro anti-Ureaplasma urealyticum activity of this drug was also studied. The antimicrobial activity of GPFX was similar to that of ciprofoxacin, and superior to those of norfloxacin and ofloxacin (OFLX). The anti-U. urealyticum activity of this drug, based upon the final MIC, was superior to those of minocycline and OFLX.
The penetration of GPFX into prostate, testis and epididymis when given preoperatively to patients undergoing prostatectomy or bilateral orchiectomy was studied. The results indicated effective penetration of GPFX into these organs.
The clinical efficacy of GPFX for various urogenital infections was also investigated. Five patients with acute uncomplicated cystitis and 20 patients with complicated urinary tract infection were treated with GPFX at 50 100 mg/once a day for 3 days and 100, 200 or 300 mg/once a day for five days, respectively. According to the criteria proposed by the Japanese UTI Committee, the overall efficacy rates in acute uncomplicated cystitis and complicated urinary tract infection were 100% and 100%, respectively. Furthermore, in two cases of chronic prostatitis, four of urethritis and one of acute epididymitis, 7 days or 14 days of treatment with GPFX showed excellent clinical efficacy. In conclusion, GPFX is useful in the treatment of various infections.
An adverse reaction, skin eruption, was experienced in only one patient. Abnormal laboratory findings, eosinophilia, elevation of GOT and elevation of GPT, were noted in three patients. Both clinical and laboratory adverse reactions were mild and transient.
It is concluded that GPFX is useful and safe in the treatment of urogenital infection.

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We studied the antibacterial activity and clinical usefulness of grepafloxacin (GPFX), a new quinolone, in the urological field.
1) Antibacterial activity: The MICs of GPFX were measured against 210 clinical isolates of 14 species from urinary tract infection and compared with those of ofloxacin (OFLX), ciprofloxacin (CPFX) and norfloxacin (NFLX). In general, the antibacterial activity of GPFX was inferior to CPFX, but equal or superior to those of other control drugs.
2) Clinical efficacy: Although the clinical efficacy in acute uncomplicated cystitis and chronic bacterial prostatitis was good, the overall clinical efficacy rate according to the criteria of the UTI Committee was 36.4%(8/22) in chronic complicated UTI.
Fifteen of 25 (60%) strains isolated were eradicated.
3) Side effects: Temporary discomfort of the left side of the body was observed in one case. Mild elevation of eosinophils or GOT·GPT was observed in one case.

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We investigated the clinical efficacy of grepafloxacin (GPFX) in the treatment of urinary tract infection (UTI) and prostatitis, and its penetration into human cerebrospinal fluid (CSF). GPFX was given to 8 patients at a single dose of 200 mg 3 hours before lumbar anesthesia. All 8 patients underwent endoscopic surgery for bladder and prostate diseases. The concentration of GPFX in CSF was 0.100±0.011μg/ml and the CSF/serum concentration ratio was 0.136±0.015.
GPFX was given to 11 patients with uncomplicated UTI at daily doses of 100-150 mg, and to 15 patients with complicated UTI or prostatitis at daily doses of 200-300 mg. According to the criteria proposed by the Japanese UTI Committee, the clinical efficacy in 3 patients of acute uncomplicated UTI was excellent in all patients, an overall efficacy rate of 100%. In 12 patients of complicated UTI, the efficacy was excellent in 4, moderate in 2 and poor in 6, an overall efficacy rate of 50%.
Subjective adverse reactions were dizziness or pyrosis, noted in 2 of 26 patients treated with GPFX. A slight decrease in the white blood cell count in peripheral blood was observed in one patients.

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A multi-center clinical study on the efficacy and safety of grepafloxacin (GPFX) was carried out in the treatment of genitourinary tract infections.
Patients received 50 mg to 600 mg of oral GPFX for 3 to 14 days. The most common dose regimen was 300 mg once daily.
Clinical efficacy, assessed by the attending doctors, was obtained in 72.6% of 394 patients with genitourinary tract infections.
The overall clinical efficacy rate and the rate of bacteriological eradication, evaluated by the criteria of the Japanese UTI Committee for 255 evaluable patients, were 100%(53/53) and 96.4%(54/56) for uncomplicated cystitis, 59.8%(104/174) and 71.4%(157/220) for complicated urinary tract infection, 90.0%(18/20) and 90.0%(18/20) for gonococcal urethritis and 100%(6/6) and 100%(6/6) for nongonococcal chlamydial urethritis.
Adverse clinical and laboratory reactions were experienced in 4.3%(18/414) and 3.2%(9/280) of the patients, respectively. Most of these reactions, however, were slight or moderate in degree and similar in kind to those seen in the other fluoloquinolones.
We concluded that GPFX, although not so effective for complicated urinary tract infection, is useful in the treatment of uncomplicated cystitis, gonococcal urethritis and nongonococcal chlamydial urethritis.

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Basic and clinical studies of a new quinolone antimicrobial drug, grepafloxacin (GPFX), were performed. The minimum inhibitory concentrations (MICs) of GPFX, norfloxacin (NFLX), ofloxacin (OFLX), ciprofloxacin (CPFX), lomefloxacin (LFLX), tosufloxacin (TFLX), sparfloxacin (SPFX), and temafloxacin (TMFX) for clinically isolated stock strains, including methicillin-resistant Staphylococcus aureus (MRSA), coagulase-positive staphylococci (CPS), coagulase-negative staphylococci (CNS), Enterococcus faecalis, Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae and Pseudomonas aeruginosa, were determined.
GPFX showed no effective antimicrobial activity against MRSA, similar to the 3 control drugs. Against CPS, however, GPFX completely inhibited the growth of almost all strains up to 0.2μg/ml, showing a superior antimicrobial effect to the other 6 drugs. Although GPFX also showed an excellent antimicrobial effect on CNS, the sensitivity distribution had 2 peaks with many resistant strains, similar to the other comparative drugs. A similar trend was also observed in E. faecalis. GPFX was very effective against gram-negative bacilli, especially E. coli and K. pneumoniae. The growth of E. cloacae except for resistant strains was completely inhibited by GPFX of 0.4μg/ml or below. The MIC of GPFX for P. aeruginosa was 0.8 6.25μg/ml, indicating superior antimicrobacterial activity with no evidence of highly resistant strains.
GPFX was administered to 23 patients with surgical infections and the result was assessed in 22 cases (excluding 1 patients who received no readministration after the first examination). There were 3 excellent, 14 effective, 4 slightly effective and 1 ineffective cases, for an efficacy rate of 77.3%. The ineffective case suffered from MRSA. In all 16 strains in which the bacteriological effect was evaluable, the pathogenic bacteria disappeared completely. One patient complained of a bitter taste in the oral cavity, which, however, required no treatment. No adverse reaction or abnormal laboratory finding was observed in any other case. As mentioned above, GPFX seems to be very useful against surgical infection.

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The purpose of the present study was to evaluate the influence on biliary excretion and provide a clinical evaluation of grepafloxacin (GPFX), a new synthetic, oral quinolone antimicrobial agent. The 31 patients who were operated on for biliary tract disease were examined for biliary excretion of GPFX and bile acid in bile, and given clinical examinations. Every patient was administered 200 mg orally. The concentrations of GPFX in serum, bile and gallbladder tissue were measured by HPLC. The peaks of GPFX in serum ranged from 0.06 to 1.15 μg/ml, in gallbladder bile from 0 to 26.27 μg/ml, in bile duct bile from 0.80 to 18.12 μg/ml and in gallbladder tissue from 0.22 to 6.56 μg/g. The biliary excretion of GPFX indicated that there was enough drug to treat biliary infection.
The clinical efficacy of GPFX was evaluated in 19 patients with cholangitis. Effective clinical response without any clinical adverse effect was recognized in all 19 patients.
In summary, the concentration of GPFX in bile and gallbladder tissue was sufficient for the treatment of biliary tract infection, and the clinical result of GPFX for patients with cholangitis was good or excellent.

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