A newly developed pyridone carboxylic acid antimicrobial drug for oral use in surgery, grepafloxacin GPFX), was studied basically and clinically, with the following results:
1) Antibacterial activity: Minimum 50% inhibitory concentration/minimum 90% inhibitory concentration (MIC₅₀/MIC₉₀)(μg/ml) against Staphylococcus aureus (20 strains), Escherichia coli (20 strains), Klebsiella pneumoniae (12 strains) and Pseudomonas aeruginosa (20 strains), which were isolated from surgical lesions, were 0.39/3.13, ≤0.2/3.13, ≤0.2/≤0.2, and 0.78/3.13, respectively. There were any sensitive strains of P. aeruginosa.
2) Results of clinical use: In 21 patients with surgical infectious diseases, the drug was markedly effective in 9, effective in 6, slightly effective in 1, ineffective in 4, and unevaluable in 1. Bacteriologically, 23 of the 27 strains were eradicated, and the eradication rate was 85.2%. As an objective adverse reaction, exanthema appeared in one patient with lymphadenitis. After the discontinuation of administration, the exanthema disappeared. No abnormal changes were observed on clinical laboratory tests.

View full abstract

In order to assess the utility of a new quinolone carboxylic acid synthetic antimicrobial drug, grepafloxacin (GPFX), on biliary infections, fundamental and clinical studies were performed using 20 patients whose informed consent was obtained prior to initiation of the study.
1) GPFX was orally administered at a dose of 300 mg once a day, starting 3 days before surgery, to 6 patients who were to undergo cholecystectomy. During laparotomy, blood, gallbladder tissue, and gallbladder bile samples were collected to determine the respective levels of GPFX. It was found that the gallbladder tissue and gallbladder bile levels of GPFX were 9.6 and 189.3 μg/ml, respectively, higher than the blood level of 1.8μg/ml, and exceeded the MICs for almost all isolated organisms.
2) GPFX was orally administered to 1 patient with PTCD at a dose of 150 mg once on the first day, and after 24 hours, the drug was administered at a single dose of 300 mg once a day to investigate dosedependence. AUCs of bile GPFX and metabolites were 20.7 and 72.1μg·h/ml, respectively, during 150 mg administration and 47.7 and 199.1μg·h/ml, respectively, during 300 mg administration, showing dose-dependence.
3) GPFX was administered at a dose of 300 mg to 2 patients under PTCD treatment for lower bile duct cancer, and the bile levels of GPFX, metabolites, glucuronic acid conjugate, and serum levels of GPFX were determined by HPLC. The bile levels of GPFX were 13.8 μg/ml (for 2-4 hours) and 2.85μg/ml (for 4-8 hours), which were higher than the levels of metabolites, in these patients.
4) GPFX was orally administered at a single dose of 300 mg to 2 patients under PTCD treatment for obstructive jaundice due to gastric and colonic cancers to determine the bile and urine levels of GPFX and metabolites together with the recovery rates. In these patients, the bile levels of GPFX were 2.85 and 3.13μg/ml, the urine levels were 19.8 and 24.9 μg/ml, and the recovery rates were 11.3 and 17.6%.
5) GPFX was orally administered at a dose of 150 mg twice a day for 5 days to 9 patients with cholangitis. The drug was very effective in 2 patients, effective in 5 patients, and slightly effective in 1 patient. The drug was very effective at a dose of 300 mg once a day in all patients.
The bacteriological results included decreased or partially eliminated bacteria in 2 patients, no change in 3 patients, bacterial replacement in 1 patient, and undeterminable results in 3 patients. There were no subjective/objective side effects or abnormal laboratory test values.
GPFX was suggested to be useful for the treatment of biliary infections.

View full abstract

The clinical effects of a newly developed quinolone antimicrobial drug for oral use, grepailoxacin (GPFX), on infectious diseases in the surgical field were investigated by 13 collaborating organizations and 4 related institutions throughout the country. The results were as follows. GPFX was administered to 183 patients at a dose of 150-400 mg once or twice a day for 3 14 days. Eight patients were excluded or dropped out, leaving 177 patients to be evaluated for clinical effects.
The efficacy rate was 85.9% in the patients with superficial purulent diseases, 66.7% in those with mastitis, 93.8% in those with periproctal abscess, 81.8% in those with secondary infections (19/23 for postoperative wound, 3/3 for wound, 1/1 for burn, and 4/6 for others), and 94.7% in those with cholecystitis and cholangitis. The total efficacy rate was 85.3%.
The efficacy rate in 116 patients in whom bacteria were isolated before the start of administration was 85.3%. Eradication of bacteria could be assessed in 99 patients. The isolates were eradicated or superinfection was observed in 83 patients. The eradication rate was 83.8%. The eradication rate in the 170 strains whose eradication was confirmed was 91.7%(11/12 strains) for Staphylococcus aureus, 92.9%(13/14) for coagulase-negative staphylococci, 100%(13/13) for Staphylococcus epidermidis, 73.3%(11/15) for Escherichia coli and 100%(11/11) for Peptostreptococcus spp. The total rate was 86.5%(147/170).
With regard to safety, slight and transient adverse reactions, mainly of bitter taste in the oral cavity, were observed in 7 of the 179 subjects. Abnormal change in s-GPT was observed in one patient on clinical laboratory tests.
The above results suggest that GPFX is highly useful for infectious diseases in the surgical field.

View full abstract

In a multicenter clinical trial, grepafloxacin (GPFX), a new fluoroquinolone, was examined in terms of its skin penetration and its clinical efficacy in the treatment of skin and skin structure infections. Patients were enrolled in the trial, after informed consent was obtained.
Skin samples were obtained from the normal portions of excised materials in 22 skin surgery patients who received a single oral dose of 200mg of GPFX. The excision was done 51 to 266 min after drug administration in 20 patients and 24 h after drug administration in two patients. The blood samples were drawn about the same time as the skin excisions. The skin and blood levels were 0.12 to 2.35.μg/g and 0.06 to 1.07.μg/ml, respectively, where levels lower than the detectable limits (3 cases for skin and one for serum) were omitted. The skin concentration and serum concentration ratios varied from 14.6% to 343.3%. The skin and serum levels in two patients after 24 h were (0.72, 0.72.μg/g) and (0.10, 0.18.μg/ml), respectively. The skin concentration and serum concentration ratios were 720% and 400%. Minimum inhibitory concentrations (MICs) of GPFX against 63 clinical isolates of Staphylococcus aureus ranged from 0.024 to 12.5.μg/ml, with MIC inhibiting 50% of the strains at 0.05.μg/ml and MIC inhibiting 90% of the strains at 0.2.μg/ml.
GPFX was administered to 179 patients. Clinical efficacy was evaluated in 169 patients. The daily dosages were 100 mg once a day in 43 patients, 200mg once a day in 39 patients, and 100mg twice a day in 87 patients. Clinical evaluation was done in less than 9 days except for infected atheroma and miscellaneous abscesses in which evaluation was done in less than 12 days. The overall clinical efficacy rate was 89.3%(151/169). The rates were 83.7%(36/43) in the group given 100mg once a day, 92.3%(36/39) in the group given 200mg once a day, and 90.8%(79/87) in the group given 100mg twice a day. The bacteriologic response rate was 81.1%(82.1% for S.aureus). Adverse reactions were seen in 4 out of 175 patients. Skin eruption was seen in 2 patients, but phototoxicity was not observed. Minor abnormalities of laboratory findings were seen in 7 out of 146 patients.
We concluded that GPFX is worthy of further investigation in the dermatological field and that the dose of 200mg once a day will be useful in terms of compliance. Phototoxicity should be carefully monitored.

View full abstract

We performed a clinical study on grepafloxacin (GPFX), a new oral quinolone antimicrobial agent, to evaluate its clinical efficacy, safety and utility in obstetrical and gynecological infections. Its penetration into genital tissues was also examined.
1) After oral administration of 200 or 300 mg of GPFX, the concentration was measured in serum and intrapelvic genital tissues. The serum concentrations in the uterine artery blood and peripheral vein blood were almost equal, and the maximum levels of GPFX were 0.61.μg/ml (200 mg dose) and 1.25.μg/ml (300 mg dose) within 4-5 hours after administration.
The maximum levels of the 300 mg dose were 6.44μg/g in endometrium, 4.21μg/g in cervix uteri, 2.60μg/g in portio vaginalis, 5.22μg/g in ovary and 3.63μg/g in oviduct. The ratio of maximum levels for Cmax were 2.1-5.2 times in each tissue.
2) GPFX at 200 mg or 300 mg was administered to 62 patients with intrauterine infection, adnexitis, Bartholin's abscess, cervicitis and mastitis once a day for 3-14 days.
(1) Clinical effect: Among 62 cases treated with GPFX, 53 qualified for efficacy evaluation and 9 were excluded. The clinical effects were segregated in 3 cases for excellent, in 47 for good and in 3 for poor. The efficacy rate was 93.5%(50/53).
(2) Bacteriological effect: The bacteriological effects were evaluated in 43 cases, revealing an eradication rate of 93.0%(40/43). The eradication rate against 77 strains isolated from 43 cases was 94.8%(73/77).
(3) Safety: The adverse reaction was observed: nausea in 1 (1.6%) of 62 cases, and no abnormal laboratory findings were noted in 58 cases evaluated.
(4) Utility: The utility for 54 cases evaluated were segregated in 3 cases for markedly satisfactory, in 47 for satisfactory, in 1 for intermediate, in 3 for unsatisfactory. The utility rate was 92.6%(50/54).
The results of this study indicated that GPFX was clinically useful against obstetric and gynecological infections such as intrauterine infection, adnexitis, Bartholin's abscess, cervicitis and mastitis.

View full abstract

A new quinolone antimicrobial drug, grepafloxacin (GPFX), was investigated basically and clinically in otorhinolaryngology, with the following results.
As the basic study, the serum concentration and concentration in tissues from various parts were determined 2-5 hours after the administration of 100 mg of GPFX in 7 patients who had undergone otorhinolaryngological surgery. Concentrations in the mucous membrane of the maxillary sinus (n=6) were 0.24-1.51g/g (mean, 0.61μg/g), concentrations in the nasal polyp (n=2) were 0.26-0.56μg/g (mean, 0.41μg/g), and serum concentrations (n=7) were 0.21-0.51μg/g (mean, 0.33μg/ml). Penetration rate of tissue concentration/serum concentration ranged from 0.96 to 3.78 (mean, 1.79), showing favorable tissue penetration.
The clinical usefulness of GPFX administered at a dose of 100-300 mg once or twice a day was investigated in 15 patients with otorhinolaryngological infectious diseases (8 with otitis media and 7 with sinusitis). The drug was markedly effective in 5, effective in 8 and slightly effective in 1 of the patients (excluding one in whom infection with fungus was clarified). The overall rate of efficacy (excellent + good) was 92.9%(13/14).
Bacteriologically, a total of 10 strains were specified from 9 patients as pyogenic bacteria, and the eradication rate of the strains, excluding 2 in which eradication of pyogenic bacteria could not be confirmed, was 7/8.
With regard to safety, stomach ache and diarrhea were observed in one patient as side effects, and elevation of GPT was observed as an abnormal change on clinical laboratory tests in one patient. All of these reactions were mild.
These results suggest that the drug is useful for infectious diseases in otorhinolaryngology.

View full abstract

Grepafloxacin (GPFX), a newly developed oral antibacterial quinolone derivative, was used for the treatment of infections in the otorhinolaryngological field to examine its efficacy and safety. In addition, its tissue distribution was investigated fundamentally.
1. Materials and methods
In the fundamental study, GPFX, at a dose of 100 mg, was orally administered preoperatively to 42 patients with sinusitis, congential auricular fistula and tonsillar hypertrophy, and tissue and blood samples were taken 2-6 hours later to determine plasma and tissue concentrations. In the clinical study, the drug was orally administered at a dose of 100-300 mg at time, 1-2 times a day (100-300 mg/day) for 4-14 days to 45 patients consisting of 25 cases of otitis media (8 acute, 2 chronic, 15 acute exacerbation of chronic), 6 cases of sinusitis (5 acute, 1 acute exacerbation of chronic), 3 cases of acute tonsillitis, 10 cases of acute external otitis and 1 case of acute submaxillitis.
2. Results
The mean serum concentration was 0.22μg/ml (N=42), while the mean tissue concentration (μg/g) was generally high: 1.92 (N=17) in tonsil, ND-1.55 (N=8) in middle ear mucosa, ND-2.19 (N=8) in maxillary sinus mucosa, 0.27-0.88 (N=2) in parotid gland and 2.24-5.74 (N=2) in submandibular gland.
The clinical results were then evaluated in 44 patients except for 1 patient with sinusitis who did not revisit the hospital after the first examination. An effective response was observed in 23 of 24 cases (95.8%) with otitis media, all 6 cases with sinusitis, 2 of 3 cases with tonsillitis, 8 of 10 cases with external otitis and in 1 case with submandibular sialoadenitis. The overall efficacy rate was thus 90.9%. Bacteriologically, 42 of 45 strains consisting of 33 gram-positive and 12 gram-negative bacteria were completely diminished, for an elimination rate of 93.3%. As for side effects, mild abdominal distention/stagger and stomachache were observed in 2 of 44 patients. As abnormal laboratory value, a slight elevation of s-GPT was observed in 1 case.
From the results mentioned above, GPFX was considered to be an excellent drug for treating infections in the otorhinolaryngological field.

View full abstract

The usefulness of a new quinolone antimicrobial drug for oral use, grepafloxacin (GPFX), was studied basicallly and clinically. The results were as following:
1. Tonsillar and serum levels of GPFX administered orally at 200 mg were determined by highperformance liquid chromatography. At 2-3 hours after administration, the tonsillar level was 1.48-5.37 peg and the serum level was 0.36-0.98 μg/ml. The tissue transfer rate was 251-590%, showing excellent results.
2. GPFX was administered to 31 patients with otorhinolaryngological infections. The drug was markedly effective in 13 patients, effective in 10, slightly effective in 1, ineffective in 3, and unevaluable in 4. The drug was thus markedly effective or effective in 23 of the 27 patients in whom the effects were evaluable. The efficacy rate was 85.2%. Bacteriologically, 24 of the 26 strains isolated were eradicated, and its eradication rate was 92.3%. Diarrhea was observed as an objective adverse reaction in one patient, and discomfort in the oral cavity after administration was observed in another. Elevation of GPT was observed as an abnormal change on clinical laboratory tests in one patient. None of these reactions was serious.
These results suggest that the drug is useful for infectious diseases in otorhinolaryngology.

View full abstract