The in vitro antibacterial activity of balofloxacin (BLFX), a new fluoroquinolone, was compared with that of tosufloxacin (TFLX), ciprofloxacin (CPFX), ofloxacin (OFLX), sparfloxacin (SPFX) and norfloxacin (NFLX). The results are summarized as follows:
1) BLFX had a broad spectrum of antibacterial activity against Gram-positive and-negative bacteria.
2) Against Gram-positive bacteria, the activity of BLFX was higher than those of CPFX and OFLX and comparable to those of TFLX and SPFX. Against Gram-negative bacteria, the activity of BLFX was two-to eightfold less than those of reference fluoroquinolones, but the MIC of BLFX against 90% of Haemophilus influenzae, Neisseria gorwrrhoeae, Moraxella catarrhalis and enteric bacteria except Citrobacter freundii, Serratia marcescens and Providencia rettgeri was lower than 3.13μg/ml.
3) Methicillin-resistant Staphylococcus aureus was susceptible to BLFX.
4) BLFX yielded low-frequency mutation rates, the same as reference fluoroquinolones.
5) The 50% inhibitory concentration of BLFX for DNA gyrases isolated from S. aureus, Escherichia coli and Pseudomonas aeruginosa were 36.7, 0.70 and 3.30μg/ml, respectively.

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The MIC₉₀s of balofloxacin (BLFX) for 18-66 clinical isolates of Staphylococcus aureus, methicillinresistant S. aureus, coagulase-negative staphylococci, Streptococcus pneumoniae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcus faecium, Escherichia coli CS2 (R+), Klebsiella pneumoniae, Proteus vulgaris, Proteus mirabilis, Morganella morganii, Providencia rettgeri, Citrobacter freundii, Enterobacter cloacae, Serratia marcescens, Pseudomonas aeruginosa, Pseudomonas cepacia, Xanthomonas maltophilia, Acinetobacter calcoaceticus, ampicillin-resistant Haemophilus influenzae, Campylobacter coli, Campylobacter jejuni and Bacleroides fragilis were 3.13, 6.25, 0.39, 0.39, 0.39, 0.78, 3.13, 1.56, 1.56, 1.56, 1.56, 1.56, 25, 6.25, 12.5, 6.25, 100, 25, 6.25, 3.13, 0.025, 0.78, 1.56 and 1.56μg/ml, respectively. BLFX collaborated with serum complement in its bactericidal effect on E. coli NIHJ JC-2, and the cells of E. coli NIHJ JC-2 were well engulfed and digested by mouse cultured macrophages in the presence of this agent at 1/8 NIIC or higher. BLFX at up to 10μg/ml, did not affect the growth of cultured CHO-K1 or HeLa cells, indicating that this agent is a rather weakly cytotoxic new quinolone.

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Balofloxacin (BLFX), a new fluoroquinolone, was evaluated for its in vitro and in vivo antibacterial activities in comparison with those of ciprofloxacin (CPFX), lomefloxacin (LFLX), ofloxacin (OFLX), sparfloxacin (SPFX) and tosufloxacin (TFLX). BLFX showed in vitro antibacterial activity against both gram-positive and gram-negative bacteria. The MIC for 90% of methicillin-resistant Staphylococcus aureus (MRSA)(MIC₉₀) was 8.0μg/ml, and was two-fold more active than SPFX. The MIC₉₀ for methicillinsusceptible S. aureus, Staphylococcus epidermidis, Streptococcus pneumoniae and Streptococcus pyogenes were 0.25, ≤0.063, ≤0.063 and 0.125μg/ml, respectively. These values indicate that the drug was two-fold or more active than CPFX and LFLX, but was similar in activity to SPFX and TFLX. Against other gramnegative bacteria, BLFX was 2-to more than 4-fold (in some cases) less active than the reference quinolones. In experimental septicemia, the in vivo activity of BLFX was reflected its in vitro antibacterial activity. In respiratory tract infections in mice with S. pneumoniae TMS-3, in which OFLX showed only slight effect, BLFX showed a therapeutic effect similar to SPFX and TFLX. BLFX showed almost the same activity as OFLX in mice with pyelonephritic infection due to Escherichia coli TMS-3. The peak levels of BLFX in murine serum, lungs and kidneys after a single oral administration of 50 mg/kg were 3.35±0.95μg/ml (15 min after administration), 9.57±2.67μg/g (15 min) and 11.64±2.43μg/g (30 min), respectively.

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The in vitro activity of balofloxacin (BLFX), a new quinolone, was compared with that of sparfloxacin (SPFX), tosufloxacin (TFLX), fleroxacin (FLRX) and ofloxacin (OFLX) against 66 reference strains (19 genera, 62 species), 334 fresh isolates of anaerobic bacteria, and 22 fresh isolates of Gardnerella vaginalis. MICs were determined by an agar dilution method. BLFX had a broad spectrum against reference anaerobic bacteria, with MICs of 6.25μg/ml or less, mostly less than 1.56μg/ml. In general, BLFX was more active than FLRX and OFLX against reference strains of anaerobes. BLFX was more active than FLRX and OFLX but less active than SPFX and TFLX against clinical isolates of the Bacteroides fragilis group; the MICs for 50% of these organisms were 12.5μg/ml or less. BLFX inhibited beta-lactam-resistant B. fragilis at 12.5μg/ml or less. BLFX was the most active against Prevotella bivia, Prevotella intermedia, Porphyromonas gingivalis, Peptostreptococcus magnus, Peptostreptococcus asaccharolyticus, Peptostreptococcus anaerobius, Clostridium difficile, and G. vaginalis. Increase in inoculum size and lower medium pH had little influence on the activity of BLFX and resulted in slightly higher MICs. A 5-day administration of BLFX caused slight overgrowth of C. difficile in a mouse cecum model.

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The in vitro and in vivo antibacterial activities of a newly synthesized oral quinolone antimicrobial drug, balofloxacin (BLFX), were compared with those of ofloxacin (OFLX), ciprofloxacin (CPFX), tosufloxacin (TFLX), lomefloxacin (LFLX) and sparfloxacin (SPFX), and the following results were obtained.
BLFX showed a broad antimicrobial spectrum against gram-positive and gram-negative bacteria and anaerobes. With regard to the antibacterial activity of BLFX against the following clinical isolates, the minimum 90% inhibitory concentrations of BLFX for methicillin-sensitive Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), Staphylococcus epidermidis, Streptococcus pneumoniae and Streptococcus pyogenes were 0.2, 6.25, 0.2, 0.39 and 0.39μg/ml, respectively, all of which were 4-16 times higher than those of OFLX, CPFX and LFLX and approximately equal to those of TFLX and SPFX. BLFX exhibited the highest antibacterial activity against clinical isolates of quinolone-resistant staphylococci. The antibacterial activity of BLFX against gram-negative bacteria, in contrast, was slightly inferior to that of OFLX but approximately equivalent to that of LFLX. The antibacterial activity of BLFX against anaerobes was superior to those of OFLX, CPFX and LFLX.
The antibacterial activity of BLFX was not affected by the type of medium, addition of serum or the quantity of the bacterial inoculate, as was the case with the drugs used for comparison, though the pH of the medium was decreased in the acid state. BLFX exerted bactericidal effects on the proliferation curve at levels higher than the minimum inhibitory concentration (MIC). Morphological changes in bacteria while the drug was exerting its effects were observed with a differential interference microscope. Marked elongation of Escherichia coli, slight elongation of Pseudomonas aeruginosa and swelling of S. aureus were observed at the sub-MIC of BLFX. At levels higher than the MIC, bacteriolysis was also observed.
The inhibitory effect of BLFX on the target enzyme, DNA gyrase, was equivalent to that of other drugs on E. coli and P. aeruginosa, whereas the effect on S. aureus was the highest among the comparative drugs.
The therapeutic effects of BLFX on experimentally induced systemic infectious diseases in mice were investigated. Although the effects on gram-negative bacterial infections were inferior to those of other comparative drugs, the effects on gram-positive bacteria were superior to those of OFLX, CPFX and LFLX. The therapeutic effets of BLFX on murine subcutaneous abscess due to quinolone-resistant MRSA were the highest among the comparative drugs.

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The antimicrobial activity of balofloxacin (BLFX), a new quinolone agent, was compared with those of seven other new quinolones (norfloxacin, ofloxacin, levofloxacin, ciprofloxacin, fleroxacin, tosufloxacin and sparfloxacin). Susceptibility testing was carried out by the agar dilution method in 297 strains of Enterobacteriaceae, 148 strains of glucose non-fermentative gram-negative rods, 270 strains of grampositive cocci and 54 strains of anaerobes. Among the agents tested, BLFX exhibited the highest activities against strains of streptococci and most of the gram-positive cocci. The MIC₉₀ of BLFX against Streptococcus pneumoniae, Streptococcus pyogenes and Streptococcus agalactiae were 0.39μg/ml and that against Enterococcus faecium was 3.13μg/ml. The MIC₉₀ against staphylococci, including methicillinresistant (MIC>25μg/ml) Staphylococcus aureus, were less than 6.25μg/ml. BLFX also exhibited equivalent or superior activity against most Enterobacteriaceae strains. The MIC₉₀ against Pseudomonas aeruginosa was 3.13μg/ml.
Resistance to BLFX was induced in a stepwise fashion in broth cultures of S. aureus, Enterococcus faecalis and Escherichia coli strains, indicating that the rate was very slow and the increased level of resistance did not exceed fourfold.

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Balofloxacin (BLFX, Q-35) is a new oral quinolone in which the 7 position of the fluoroquinolone ring is replaced by a methylaminopiperidine group and its 8 position is modified with a methoxy group. BLFX was investigated for its in vitro antibacterial activities in comparison with ofloxacin (OFLX), norfloxacin (NFLX), ciprofloxacin (CPFX), tosufloxacin (TFLX) and lomefloxacin (LFLX). The MIC₉₀ of BLFX ranged from 0.05 to 3.13μg/ml for clinically isolated methicillin-susceptible Staphylococcus aureus (MSSA), S. epidermidis, streptococci, enterococci, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris, Morganella morganii, Providencia stuartii, Haemophilus influenzae, Xanthomonas maltophilia, Bacteroides fragilis. Against methicillin-resistant S. aureus (MRSA), BLFX inhibited the growth of all strains tested at a concentration of 6.25μg/ml and was superior to the reference quinolones. BLFX was not affected by several media, the addition of horse serum into the medium or inoculum size in the expression of antibacterial activity. The activity of BLFX was influenced by the pH of the medium and the addition of metal ion into the medium, as was that of the reference quinolones. The minimum bactericidal concentration (MBC) of BLFX against all of the strains tested was equal to the MIC. BLFX acted bactericidally on S. aureus, S. pneumoniae, E. coli and P. aeruginosa at higher concentrations than the MIC for the respective bacteria. BLFX showed an excellen postantibiotic effect (PAE) against S. aureus and E. coli.

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Balofloxacin (BLFX, Q-35) is a new oral quinolone in which the 8 position of the fluoroquinolone ring is modified with a methoxy group. BLFX was investigated for its in vivo antibacterial activities in comparison with norfloxacin (NFLX), ofloxacin (OFLX), ciprofloxacin (CPFX), tosufloxacin (TFLX) and lomefloxacin (LFLX).
1. BLFX was more effective than reference quinolones against intraperitoneal infections due to methicillin-susceptible and-resistant Staphylococcus aureus and streptococci in mice. With infections due to Escherichia coli, Klebsiella pneumoniae, Salmonella typhimurium and Pseudomonas aeruginosa, BLFX was inferior to OFLX and CPFX but was equal or superior to NFLX. The efficacy of BLFX in leukopenic mice was almost the same as that in normal mice.
2. In experimental respiratory tract infection caused by Streptococcus pneumoniae in mice, BLFX was as effective as TFLX and more effective than the other reference quinolones.
3. In mice with mixed infection in the urinary tract, BLFX was more effective than reference quinolones against Enterococcus faecalis and equal or superior to CPFX and NFLX against E. coli in reducing the number of viable bacteria in the kidneys.
4. In a subcutaneous abscess model caused by MRSA in mice, the therapeutic effect of BLFX was equal to that of TFLX.
5. The serum levels of BLFX in mice after oral administration were higher than those of NFLX and CPFX and lower than those of OFLX and LFLX.

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A highly-sensitive quantitative method of evaluating a newly synthesized quinolone antimicrobial drug, balofloxacin (BLFX)(±)-1-cyclopropyl-6-fluoro-1, 4-dihydro-8-methoxy-7-(3-methylaminopiperidin-1-yl)-4-oxoquinoline-3-carboxylic acid dehydrate, in human vital specimens by HPLC was established.
Human vital specimens without BLFX were diluted in 100 mM phosphate buffered solution (pH 7.4). After an internal standard had been added, organic solvent extraction was performed with dichloromethane. The resultant was dissolved in the mobile phase of HPLC for the concentration determination. A calibration curve was prepared by using serum, plasma and urine samples without BLFX, and phosphate buffered solution was used for other specimens. The calibration curve showed favorable linearity within the range from 0.01μg/ml to 1.0μg/ml. Reproducibility was determined in each of the specimens with BLFX at concentrations of 0.05 and 0.5μg/ml. Both diurnal and daily variations were 0.61-15.48%, showing favorable results. The quantitative concentration determination method established is precise and has the favorable accuracy. It was also procedurally easy, suggesting that this method could be useful for the determination of concentrations in human vital specimens.

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A microbiological assay procedure has been developed for determining the newly synthesized quinolone balofloxacin (BLFX) in biological body fluids. Drug concentrations were determined by means of the paper disk method, using Bacillus subtilis ATCC6633 as the test organism. The standard solutions were prepared with M/15 phosphate buffer solution (pH 8.0), normal urine and serum for each sample, respectively. The standard curve prepared by M/15 phosphate buffer could be to utilized when the urine sample was diluted with more than 10 times of phosphate buffer. The lower limits of quantification in plasma and in urine were approximately 0.2μg/ml. The repeatability and intermediate precision (CV%) were 2.0-7.8% and 4.0-10.1%, respectively.
BLFX solution in human serum and urine was stable at-20°C for at least 2 months.

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The absorption and excretion of ¹⁴C-labeled balofloxacin (BLFX)[±-1-cyclopropyl-6-fluoro-1, 4-dihydro-8-methoxy-7-(3-methyl-aminopiperidine-1-yl)-4-oxoquinoline-3-carboxylic acid], a new fluoroquinolone antimicrobial agent, was studied in mice and dogs.
1. ¹⁴C-BLFX was absorbed rapidly after an oral administration in mice and dogs. However, there were species differences in the disposition of radioactivity after ¹⁴C-BLFX administration. The elimination halflife in plasma was shorter in dogs than in mice, and the ratio of AUC for dose (AUC/dose) in dogs was greater (>20 times) than that in mice.
2. A large portion of the urinary excretion was unchanged BLFX in mice and dogs, and small amounts of BLFX glucuronide (BLFX glu.) and N-desmethyl-BLFX were found as metabolites. On the other hand, a large portion of the biliary or fecal excretion was BLFX glu. in dogs, and large amounts of unknown metabolites in addition to BLFX glu. were found in mice.
3. After an oral administration of ¹⁴C-BLFX, almost all administered radioactivity was excreted into the urine and feces in mice and dogs. Species differences were observed in the excretion routes of radioactivity after an intravenous administration of ¹⁴C-BLFX; the urinary excretion rate in dogs was similar to the fecal excretion rate, however, the urinary excretion rate in mice was much lower than the ecal excretion rate.

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We examined the phototoxic potential of balofloxacin (BLFX), a newly developed fluoroquinolone antibacterial agent in which a methoxy group is substituted at the 8 position of the quinoline nucleus, using BALB/c mice under irradiation with long-wave UV light (UVA).
When mice were dosed orally with a single dose of 800 mg of BLFX per kg of body weight, the maximum dose given, and exposed to UVA light, no inflammatory lesions were observed in their ears. Ear redness was marked in mice given a single oral dose of more than 200 mg of ofloxacin (OFLX) and nalidixic acid (NA) per kg, and exposed to UVA light. Histopathological changes, edema, and infiltration of neutrophils were also observed microscopically in groups receiving NA but not in groups receiving OFLX nor BLFX. Similar inflammatory reactions were observed to occur in a dose-dependent manner with consecutive dosing of OFLX and NA.
From these results, it could be concluded that BLFX lacks phototoxic potential in mice as long as it is given under the present conditions.

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We examined the photoallergenic potential of balofloxacin (BLFX), a newly developed fluoroquinolone antibacterial agent in which a methoxy group is substituted at the 8 position of the quinoline nucleus, using Hartley guinea pigs under irradiation with long-wave UV light (UVA).
When guinea pigs which had been sensitized cutaneously by administration of an 8-fluorinated analog of BLFX (8-F analog) and given UVA irradiation for 5 consecutive days were challenged orally and intradermally by the 8-F analog, positive reactions were observed in 3 of 5 animals in each group. Furthermore, in the case of oral elicitation of the photoallergic reaction in guinea pigs given the 8-F analog orally with UVA irradiation once a day for 5 consecutive days, skin redness were observed at irradiation sites of UVA in 2 of 5 animals.
On the other hand, no positive reactions were observed in guinea pigs orally sensitized with BLFX and UVA irradiation for two weeks.
From these results, it could be concluded that BLFX lacks photoallergenic potential in guinea pigs under the present conditions.

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Since quinlones are well known to have potent convulsant activity, we studied the effect of balofloxacin (BLFX, Q-35), a newly synthesized quinolone, on the receptor binding of γ-aminobutyric acid (GABA), an inhibitory transmitter in mammalian central nervous system. BLFX, as well as norfloxacin (NFLX), enoxacin (ENX) and ciprofloxacin (CPFX), inhibited GABA receptor binding in a concentration-dependent manner. The inhibitory activity of BLFX was not affected in the presence of nonsteroidal anti-inflammatory drugs (NSAIDs). In contrast, the inhibitory activity of NFLX, ENX and CPFX was remarkably enhanced. The intraventricular injection of BLFX and ENX induced convulsions in mice in a dose-dependent manner. However, concurrent administration of biphenyl acetate did not affect the convulsant activity of BLFX, whereas concurrent administration enhanced the convulsant activity of ENX. These results suggest that BLFX induced convulsions when present at high concentrations in the central nervous system, and that NSAIDs did not enhance the convulsant activity of BLFX.

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Balofloxacin (BLFX) was orally administered to healthy male volunteers, and its safety and pharmacodynamics were investigated.
A preliminary test was performed on two patients at each dose of 10mg, 20mg and 50mg during fasting by single administration.
Subsequently, oral administration was initiated at 100mg, then gradually increased to 200 and 400 mg, as the test. The drug was administered at a dose of 200mg twice, before and after breakfast, to the same subject by the cross-over method in which a one-week drug-cessation period was included for the purpose of investigating the influence of meals. One patient in the group to which 200mg was administered postprandially had mild and transient dull headache, and one in the group to which 400mg was administered had symptoms resembling dizziness that disappeared about 10 minutes later. All the symptoms subsided rapidly without any specific treatment. No other problematic symptoms or findings were observed.
The blood concentration increased in proportion to dose after the administration of BLFX. The maximum concentration (Cmax) was about 1μg/ml with the administration of 100mg, and about 2μg/ml with the administration of 200mg. The time of maximum concentration (Tmax) was 1.0-1.2 hours, and the half-life (T_1/2) was 7.0-8.3 hours, showing rapid intestinal absorption and relatively long duration in the blood. Tmax was prolonged and Cmax was decreased by postprandial administration, but there seemed to be no influence on absorption, because the cumulative rate of urinary excretion was approximately equal to that with administration during fasting.
Regardless of dose, the cumulative rate of urinary excretion was 70-80%. Glucuronic conjugated material was detected at about 4% and demethylated substance at about 0.4%. The rate of unchanged bodies recovered in the spontaneously excreted feces was 2.8-10.7%, showing a tendency for the urinary excretion rate to be low in the subjects who showed a high recovery rate.
These results suggest that BLFX can be clinically administered in patients with infectious diseases, because it is safe and shows excellent pharmacodynamics.

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Balofloxacin (BLFX) was orally and repeatedly administered to healthy male volunteers at a dose of 200 or 300mg every 12 hours, and its safety, pharmacodynamics, and influence on intestinal bacterial flora were investigated.
Slight feelings of physical disorder of the abdominal region (rumbling of bowels, abdominal distension) appeared in two subjects each in every administration group (each consisting of six subjects). Subjective symptoms began to appear 3-4 days after administration, but they subsided with defecation on the day after administration or the following day. One subject in the 200mg repeated administration group had mild, transient constipation. This also resolved with defecation on the day after administrtion. Extremely slight elevation of GPT was observed in clinical laboratory testing, but it was rapidly restored to the level before administration when administration ceased. There were no other abnormal changes.
The actually determined levels of blood concentration were in good accordance with the simulation curve, and showed no phenomena suggestive of accumulation. The cumulative urinary excretion rate was 71.9% with the 200mg repeated administration and 86.3% with the 300mg repeated administration. The number of aerobic bacteria in feces was reduced to less than the limit of determination. The number of anaerobic, bacteria was also decreased by about 1/10, but at least 10⁹ cfu/g still remained. When the administration finished, however, the number of each type of bacteria was rapidly restored to that before administration.

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The effects of a newly developed pyridone carboxylic acid antibacterial agent, balofloxacin (BLFX), were investigated in six healthy male volunteers. BLFX was given orally in two doses of 400mg each for 7 days. BLFX did not decrease the total bacterial count in feces. The impact on aerobic and facultative aerobic components was more marked than that on anaerobic components. BLFX caused a decrease in Bifidobacterium, Eubacterium, and Clostridium spp., but not in Bacteroides fragilis group organisms. Members of Enterobacteriaceae, Streptococcus/Enterococcus and Lactobacillus decreased markedly during treatment and returned to normal within 10 days after the cessation of administration.
Clostridium difficile was recovered from only one volunteer.

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We studied the effect of balofloxacin (BLFX), a new oral quinolone derivative, on the serum concentration of theophylline (TP) in 5 healthy male volunteers.
In advance, TP alone was given orally for four days at a daily dose of 400mg b. i. d., then the serum samples were obtained as a control. From the 5th day of TP administration, concomitant administration of BLFX at a daily dose of 200 mg b.i.d. was started.
Blood was drawn on the 3rd and 5th days of concomitant administration, and the serum concentrations of TP were compared with those of the control.
On the 3rd and 5th days of concomitant administration, no significant differences were observed in any pharmacokinetic parameters, including AUC, Cmax and Cl_TB, of TP. No objective or subjective side effects were observed throughout the experimental period.
According to the above results, we concluded that BLFX is safe when administered concomitantly with TP.

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The in vitro antibacterial activity of a newly developed oral quinolone, balofloxacin (BLFX), and its clinical effects on respiratory infectious diseases were investigated. The antibacterial activity of BLFX against 236 strains of 8 species of clinical isolates tended to be greater for gram-positive bacteria and less for gram-negative bacteria than existing quinolone preparations. When BLFX was orally administered at a dose of 100mg or 200mg twice a day for 6-14 days to 15 patients with respiratory infectious diseases, the clinical efficacy was excellent in 2 and good in 13, for an efficacy rate of 100%. Four strains of gram-positive cocci and 8 strains of gram-negative bacteria were isolated from 10 patients as the causative organisms, and all 12 strains were eradicated. No abnormal changes in clinical laboratory test values and no side effects were observed in any of the patients.
Although BLFX exhibited no marked in vitro antibacterial activity, it exerted clinical efficacy equivalent to existing quinolone. It had no problem with safety. These results suggest that BLFX is useful for the treatment of respiratory infectious diseases.

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We evaluated the penetration of balofloxacin (BLFX), a new oral 8-methoxy fluoroquinolone, and its clinical usefulness in respiratory tract infections. A daily oral dose of 200 or 400mg of BLFX was administered to 13 patients for 7-14 days. Four of the patients had pneumonia, 1 acute bronchitis, 3 chronic bronchitis, 2 bronchiectasis and 3 secondary infection to chronic respiratory disease. Clinical efficacy was excellent in 2 patients and good in 11, for an efficacy rate of 100%. Two strains of Streptococcus pneumoniae, 2 strains of Haemophilus influenzae and 1 strain of Haemophilus spp. were identified as causative organisms, and all were eradicated by treatment with BLFX. No problems with safety or abnormal laboratory values were found.
Concentrations in serum and sputum were determined using a diffuse panbronchiolitis patient receiving repeated oral administration of 200mg BLFX. The sputum levels reached at 2-3μg/ml 2-4 hours laters as same as the serum levels.

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Balofloxacin (BLFX), a newly synthesized pyridone carboxylic acid antibacterial agent, was administered to 13 patients with respiratory tract infections. Quantitative cultures of the sputum revealed one case each of Moraxella (Branhamella) catarrhalis and Streptococcus pneumoniae as causative organisms.
The drug was administered orally at a daily dose of 100 to 200mg, distributed twice a day, for 7 to 21 days. As a result, one strain each of S. pneumoniae and M.(B.) catarrhalis were eradicated, and one stran of Pseudomonas aeruginosa emerged.
Global evaluation including clinical efficacy, such as the relief of symptoms and improvement of laboratoy findings, revealed that 7 of 10 patients had good or excellent responses. The sensitivity distribution of BLFX against 83 strains of S. pneumoniae, 52 strains of M.(B.) catarrhalis, 52 strains of Haemophilus influenzae and 52 strains of P. aeruginosa, all clinically isolated in 1988, was compared with that of ofloxacin, tosufloxacin and ciprofloxacin. The data revealed that BLFX was almost identical to these drugs in sensitivity to S. pneumoniae and H. influenzae.

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The in vitro antimicrobial activity and serum and sputum concentrations of balofloxacin (BLFX: Q-35), a new-quinolone agent for oral use developed in Japan, and its therapeutic efficacy in the treatment of respiratory tract infections were evaluated. The minimum inhibitory concentrations (MICs) of BLFX, ofloxacin (OFLX), ciprofloxacin (CPFX), tosufloxacin (TFLX), sparfloxacin (SPFX), cefaclor (CCL) and rifampicin (RFP) against 20 strains each of methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant S. aureus (MRSA) Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens, and Pseudomonas aeruginosa, 18 strains each of Haemophilus influenzae and Mycobacterium intracellulare, and 22 strains each of Mycobacterium tuberculosis and Mycobacterium avium were determined by the micro-broth dilution method using the Dynatech MIC 2000 system. As shown by MICs, BLFX was as active as OFLX against all the species tested except for Mycobacteriaceae. BLFX was less active than OFLX against Mycobacteriaceae, but more active than OFLX against RFP-resistant M. tuberculosis. Twenty-one patients received a daily dose of 100 mg or 200 mg of BLFX per os for 3 to 21 days (mean; 10.7 days): 2 patients with acute bronchitis, 10 patients with acute pneumonia, 1 patient with Mycoplasma pneumoniae pneumonia, 2 patients with infection associated with bronchiectasis, 4 patients with chronic bronchitis and 1 patient with infection associated with pulmonary emphysema and 1 patient with infection associated with old pulmonary tuberculosis. Two cases were excluded from clinical evaluation. The clinical effects were excellent in 5 and good in 14 patients (efficacy rate: 100%). Five strains were identified as causative organisms: 3 strains of H. influenzae, one strain of K. pneumoniae and one strain of P. aeruginosa. All strains were eradicated.
In one case of chronic bronchitis, the maximum concentration of BLFX in serum (1.57μg/ml) was achieved 3 hours after oral administration of 200 mg and that in sputum (2.29μg/ml) 5 to 6 hours after administration. The ratio of the concentration of BLFX in sputum to that in serum was 146%.
No adverse reactions were observed during treatment with BLFX. Eosinophilia was observed in three patients and a transient elevation of serum transaminase was observed in two patients. These adverse effects disappeared after the completion of therapy.
We conclude from the above results that BLFX is one of the most useful quinolone agents for oral administration as a drug of first choice in the treatment of respiratory infections.

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A new oral fluoroquinolone, balofloxacin, was basically and clinically investigated as follows.
The drug exhibited excellent antibacterial activity against gram-positive bacteria, which was comparable to that of sparfloxacin. The antibacterial activity against gram-negative bacteria was, however, slightly inferior to that of other quinolone drugs.
The clinical efficacy was rated as excellent in 2, effective in 9 and slightly effective in 2, among a total 13 patients with respiratory tract infections, for an efficacy rate of 84.6%. Neither side effects nor abnormal changes in clinical laboratory test values were observed.

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A new quinolone drug for oral use, balofloxacin (BLFX), was studied basically and clinically, with the following results:
1. Influence of combined use with aluminum hydroxide gel: The plasma maximum concentration (Cmax), the time when the plasma concentration reached the maximum (Tmax), and the area under the curve (AUC), which are pharmacodynamic parameters, were 1.95±0.39μg/ml, 1.75±0.51 hours, and 18.0±21.67μg·h/ml, respectively, when BLFX was administered at a single dose of 200 mg. When aluminum hydroxide gel was administered at 1000 mg, simultaneously with BLFX, Cmax was 0.41±0.05μg/ml, Tmax 4.50±0.72 hours, and AUC 6.09±0.61, μg·h/ml. These results indicate marked inhibition of absorption, in a manner similar to that of other quinolone drugs.
2. Influence of combined use with cimetidine: When cimetidine was administered at a dose of 200 mg postprandially, simultaneously with BLFX or one hour before the administration of BLFX, the pharmacodynamics of BLFX were essentially unchanged. However, when cimetidine was administered with BLFX while fasting, one hour before administration, absorption of BLFX was markedly inhibited.
3. Influence of combined use of probenecid: When probebecid was administered at 1000 mg 2 hours before administration of BLFX, the cumulative urinary excretion rate of BLFX was decreased from 86±1.9% to 51±4.4%, and the half time (T_1/2) was prolonged from 6.0±0.5 hours to 9.6±1.0 hours. These results suggest that urinary tubular excretion is involved in the mechanism of renal excretion of the drug.
4. General clinical tests: BLFX was orally administered to one patient with acute bronchitis, two with tonsillitis and four with pneumonia (one each with mycoplasma pneumonia and chlamydial pneumonia) at a dose of 100 mg or 200 mg, two or three times a day, for 3-14 days. The clinical efficacy was rated as excellent in three and effective in four. Thus, the symptoms improved in all seven patients. No side effects were observed. Slightly elevated GOT and GPT were observed in two patients as abnormal changes inclinical laboratory test values.

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Pharmacodynamics of a new oral quinolone, balofloxacin (BLFX), and its clinical effects were investigated, with the following results.
The drug was administered as a single dose of 100 mg or 200 mg to patients with infectious diseases, who had renal hypofunction, and blood and urinary levels were determined over time. Twelve hours after administration, the blood level was increased due to the decreased renal function, the half time in blood (T_1/2) was delayed, and urinary excretion was reduced.
The sputum level was determined over time in 2 patients with infection, who had normal renal function.The level peaked (2.5-2.7μg/ml) at 4-6 hours after administration, and this maximum exceeded thatof the blood level (1.6-2.5μg/ml).
The drug was also orally administered at a dose of 100 mg or 200 mg, once or twice a day, to 24patients including 8 with pneumonia, 3 with mycoplasma pneumonia, 2 with acute bronchitis, 7 with chronic bronchitis, 1 with tonsillitis and 3 with cholecystitis. Two, in whom drug efficacy could not be evaluated because of underlying diseases, were excluded from the study group. Clinical efficacy was rated as excellent or effective in all 22 remaining patients. The pyogenic bacteria isolated from 4 patients included 3 Staphylococcus aureus strains, 1 Klebsiella pneumoniae strain, and 1 Pseudomonas aeruginosa strain. All strains of S. aureus were eradicated, and the remaining 2 strains were not evaluable because bacterial testing was not done after administration. Neither side effects nor abnormal changes in clinical laboratory test values were observed.

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Balofloxacin (BLFX: development code Q-35) was orally administered at 200 mg once a day for 7 days to 3 elderly patients with varying degrees of renal dysfuntion. The curve simulated from the plasma concentration of BLFX on the first day was generally consistent with the subsequent changes in plasma concentration, showing no accumulation. As renal dysfunction progressed, T_1/2was prolonged, and the area under the curve (AUC) increased. In contrast, the rate of recovery from urine accumulated up to 168 hours was decreased.
Clinical efficacy was investigated in 27 patients: 22 with various respiratory infectious diseases, 4 with cholecystocholangitis and 1 with urinary tract infection. BLFX was administered to the patients with respiratory infectious diseases at a dose of 200 mg once a day for 7 days. BLFX was administered to the patients with cholecystocholangitis at a dose of 100 mg twice a day for 11-14 days. BLFX was administered to the patient with urinary tract infection at a dose of 100 mg once a day for 7 days. Clinical efficacy was good in 26 patients, for an efficacy rate of 96.3%. Although no particular side effects were observed, slight elevations of GOT and GPT were observed in 1, a slight elevation of GPT in 1, and a slight elevation of BUN in 1 on clinical laboratory tests.

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A new oral quinolone drug, balofloxacin, was orally administered at a single dose of 100 mg to an elderly patient with bronchiectasis. The serum level increased with time from 0.26 μg/ml at 2 hours after administration to 1.54 μg/ml at 12 hours after administration. The sputum level also rose in approximately parallel with the serum level.
The drug was also repeatedly administered, at a dose of 200 mg (in 2 divisions) or 400 mg (in 2 divisions), to 24 patients with respiratory infectious diseases. The efficacy was rated as excellent in 9 and good in 13, all of whom showed improvement in infectious symptoms (efficacy rate, 91.7%). The drug was particularly useful for 17 patients with pneumonia, who included 6 with mycoplasmal pneumonia; efficacy was excellent or good in all 17.
Four of 5 pyogenic bacterial strains isolated were eradicated.
Mild headache appeared in one patient as a side effect after 6 days of administration at 400 mg (in 2 divisions). Abnormal changes in clinical laboratory test values included elevated transaminases in 4, thrombocytosis in 1, and eosinophilia in 1, all of which were mild.
These results suggest that this new quinolone drug, for oral use, is useful for treating respiratory infectious diseases, particularly pneumonia.

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The antibacterial activity of a new quinolone drug for oral use, balofloxacin (BLFX), against fresh clinical isolates (between November 1992 and March 1993) was investigated. Sensitivities of Staphylococcus aureus, Staphylococcus epidermidis and Streptococcus pneumoniae to BLFX were distributed in the 0.1-1.56μg/ml range, and the activity was more potent than that of ofloxacin (OFLX), by 2-4 times, and those of norfloxacin (NFLX) and enoxacin (ENX), by 4-8 times. BLFX exhibited activity against Haemophilus influenzae which was 4 times stronger than those of OFLX and ENX. Although the activity of BLFX against Klebsiella pneumoniae was inferior to those of OFLX and ENX, by 2-4 times, it was equivalent to that of NFLX.
The clinical effects of BLFX on respiratory infectious diseases were investigated in 14 patients. The clinical efficacy was excellent in 4 and effective in 7, all of whom showed improvement in infectious symptoms. In 5 patients with pneumonia, including one with mycoplasma pneumonia and 2 with acute bronchitis particularly, the symptoms were markedly improved. Ten pyogenic bacterial strains were isolated from 10 patients, and all were eradicated in the 7 patients in whom bacteriological evaluation was possible.
Mild loss of apetite and elevated S-GPT and BUN were observed, but no specific problematic side effects appeared.
This new quinolone drug, for oral use, was considered to be a safe and useful in chemotherapy for respiratory infectious diseases.

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We performed bacteriological and clinical studies on balofloxacin (BLFX), a new quinolone derivative, in respiratory tract infections and obtained the following results.
1) The MICs of balofloxacin against methicillin-susceptible Staphylococcus aureus (MSSA), Streptococcus pneumoniae, Haemophilus influenzae, Branhamella catarrhalis and Klebsiella pneumoniae ranged from 0.01 to 4μg/ml, equal to those of sparfloxacin (SPFX) and levofloxacin (LVFX). The MIC₉₀ against methicillin-resistant S. aureus (MRSA) was 4μg/ml, which was superior to those of SPFX and LVFX. The MIC₉₀ against Pseudomonas aeruginosa was 64μg/ml, inferior to those of SPFX and LVFX.
2) The MICs against Chlamydia pneumoniae, Chlamydia psittaci and Chlamydia trachomatis were 0.25-0.5μg/ml, equal to those of ofloxacin and ciprofloxacin but inferior to those of tosufloxacin and SPFX.
3) Ten patients with respiratory tract infection were treated with BLFX. Efficacy was rated as excellent in 2, good in 7, and poor in 1 case. The overall clinical efficacy was 90%. No adverse side effects were seen, but there was 1 patient with mild liver dysfunction.

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Clinical and bacteriological studies on balofloxacin (BLFX), a newly developed fluoroquinolone, were carried out, and the following results were obtained.
The antimicrobial activity of BLFX was measured against 378 clinically isolated strains of 24 species, and compared with those of ofloxacin (OFLX) and ciprofloxacin (CPFX). The activity of BLFX against Staphylococcus spp., Streptococcus spp. and Enterococcus faecalis was superior to those of OFLX and CPFX. Against Enterobacteriaceae and other gram-negative bacteria, CPFX showed the most potent activity, and BLFX was less active than OFLX.
A daily dose of 400 mg of BLFX was given orally to 5 patients with respiratory tract infection, 2 with pneumonia and one each with chronic bronchitis, infected bronchiectasis and infected pulmonary emphysema, for 9 to 15 days. Clinical responses were excellent in both cases of pneumonia and good in the other 3 cases. Strains isolated before the treatment, including Streptococcus pneumoniae, Haemophilus influenzae and Staphylococcus aureus, were eradicated. No adverse reactions were observed in any cases.

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A new quinolone drug for oral use, balofloxacin (BLFX), was investigated basically and clinically. The following results were obtained:(1) Minimum inhibitory concentration (MIC) of BLFX for the grampositive bacteria; Staphylococcus aureus and Enterococcus faecalis, among 247 strains of 11 species isolated from inpatients of the First Department of Internal Medicine, Faculty of Medicine, Kyushu University, was approximately equivalent to that of a control drug, tosufloxacin, and superior to those of ofloxacin and ciprofloxacin by at least two test tubes. The concentration of BLFX needed for gram-negative rods such as Escherichia coli, Citrobacter freundii, Klebsiella pneumoniae, Enterobacter spp. and Proteus spp. was slightly inferior to that of the control drugs, the minimum 90% inhibitory concentration (MIC₉₀) being lower than 3.13 μg/ml for all of these rods. The MIC₅₀ and MIC₉₀ for Pseudomonas aeruginosa were 6.25 and 50 μg/ml, respectively, showing BLFX to be slightly inferior to the controls.(2) BLFX was orally administered at a dose of 100-200 mg, twice a day, for 4-21 days to 10 patients (2 of whom were the same person). The clinical efficacy was rated as excellent in one, good in five and fair in one of 7 patients with respiratory infectious diseases. The clinical efficacy was effective for one with colitis, and excellent and good in each one of the patients with cystitis. Neither side effects nor abnormal changes in clinical laboratory test values, likely to be attributable to the drug, were observed in any of the patients.

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A newly developed antimicrobial agent, balofloxacin (BLFX), was evaluated in vitro and in vivo The results were as follows:
1) Antimicrobial activity: Minimal inhibitory concentrations (MICs) against 602 clinical isolates of 17 different species were determined and compared with those of five other drugs, ciprofloxacin (CPFX), tosufloxacin (TFLX), ofloxacin (OFLX), sparfloxacin (SPFX) and norfloxacin (NFLX). BLFX showed excellent antimicrobial activities against gram-positive and-negative bacteria.
2) Clinical efficacy and adverse reactions: Eight patients with respiratory tract infection were treated with BLFX. Overall efficacy was excellent in 2 cases, good in 2, fair in 2, and not evaluated in 2. Side effects were not observed in any patients. As abnormal laboratory findings, elevation of GPT in one case and decreased hematocrit in another were observed. These changes were mild and improved rapidly after the completion of treatment, indicating that BLFX is a safe agent.

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Balofloxacin (BLFX) is a newly developed antibacterial agent derived from fluorinated quinolone. We carried out laboratory and clinical studies to evaluate its usefulness in respiratory infections. The in vitro antibacterial activity of BLFX against 217 isolates of 5 major respiratory pathogens was compared with that of other inhibitors of DNA gyrase, The MIC₅₀ and MIC₉₀ at 10⁶CFU/ml were 0.025 μg/ml and 0.05 μg/ml of BLFX against Haemophilus influenzae (33 strains), 0.39 μg/ml and 0.78 ug/ml against Streptococcus pneumoniae (49 strains), 0.2 μg/ml and 0.2 itig/ml against Moraxella (Branhamella) catarrhalis (39 strains), 12.5 μg/ml and 25 μg/ml against Pseudomonas aeruginosa (43 strains) and 0.78μg/ml and 12.5 μg/ml against Staphylococcus aureus (53 strains). These MICs were the same as or better than those of other inhibitors of DNA gyrase. The maximal concentration in sputum ranged from 0.3 to 3.3 μg/ml. These results were almost the same as those of other inhibitors of DNA gyrase.
Eleven patients with 12 episodes of respiratory infections were studied for the clinical evaluation of BLFX administered orally at a dose of 200 mg or 400 mg daily for 3.5-14 days. The therapeutic efficacy rate was 100% in acute respiratory infections and 66.7% in chronic respiratory infections. The overall efficacy rate was 75% for both respiratory infections. At a dose of 200 mg daily, the efficacy rate was 100%; at a dose of 400 mg daily, it was 62.5%. The causative organisms were H. influenzae (3 strains), S. pneumoniae (2 strains), M (B). catarrhalis (2 strains) Shewanella (Pseudomonas) putrifaciens (1 strain), and P. aeruginosa (1 strain). Except for a strain of P. aeruginosa, these eight strains were eradicated. The eradication rate was 88.9%.
From these results, we concluded that BLFX was an effective, useful and safe oral antibacterial agent for the treatment of respiratory infections, especially those caused by S. pneumoniae, H. influenzae and M (B). catarrhalis.

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The antibacterial activity of a new quinolone drug, balofloxacin (BLFX), against clinical isolates and its clinical effects on respiratory infectious diseases were investigated. The following results were obtained.
1. Antibacterial activity: Minimum inhibitory concentration (MIC) was determined, using the method established by the Japan Society of Chemotherapy, in 516 strains of 12 species. Levels of ofloxacin (OFLX), lomefloxacin (LFLX) and tosufloxacin (TFLX), which were simultaneously determined, were compared with those of BLFX. Ingeneral, BLFX was approximately equivalent to TFLX and superior to OFLX and LFLX by 2-5 test tubes in terms of activity against gram-positive bacteria. Although activity against gram-negative bacteria was slightly inferior to that of control drugs, adequate clinical efficacy was demonstrated by the results.
2. Transfer to serum and sputum: The serum concentration peaked (1.22μg/ml) 2 hours after the oral administration of BLFX at a dose of 100 mg. The sputum concentration peaked (0.84μg/ml) 3-4 hours after administration. The maximum sputum concentration to maximum serum concentration ratio was 0.69.
3. Clinical results: The clinical efficacy was rated as excellent in one, good in nine, fair in two and poor in one of 13 patients in whom the clinical effects could be evaluated (1 with acute bronchitis, 8 with chronic bronchitis, 3 with bronchiectasis, and 1 with secondary infection of chronic respiratory disease), for an efficacy rate of 76.9%(10/13). The drug was bacteriologically effective in 2/3 isolates (1/2 for Pseudomonas aeruginosa and 1/1 for Haemophilus influenzae). Headache was observed in one and nausea and vomiting were observed in one, of the 15 patients to whom BLFX was administered, and these symptoms were mild. No abnormal changes in clinical laboratory test values, likely to be attributable to administration, were observed in any of these patients.

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We performed measured laboratory and clinical studies on balofloxacin (BLFX), a new oral pyridonecarboxylic acid derivative.
1) Laboratory activity
The minimum inhibitory concentrations (MICs) of BLFX for a total of 397 strains clinically isolated and 41 standard strains of Legionella spp. were determined and compared with those of tosufloxacin (TFLX), ofloxacin (OFLX), ciprofloxacin (CPFX), and sparfloxacin (SPFX). BLFX proved to have a broad antibacterial spectrum, and its in vitro activity against gram-positive cocci, especially MRSA, was more potent than that of the other four reference quinolones. Against gram-negative bacilli, the in vitro activity of BLFX was the same or slightly lower than that of the other drugs.
2) Clinical efficacy
We administered BLFX to ten patients with respiratory tract infections (bronchopneumonia: 3 cases, acute exacerbation of COPD: 4 cases, acute exacerbation of bronchiectasis: 1 case, mycoplasmal pneumonia: 2 cases) at a dose of 200-400 mg daily for 7 to 14 days.
The clinical efficacy was excellent in 3 cases and good in 7.
Causative bacteria were Streptococcus pneumoniae (2 cases), Haemophilus influenzae (1 case), Klebsiella pneumoniae (1 case), Enterobacter cloacae (1 case). All 5 strains were eradicated.
No side effects were observed in any patient, for an efficacy rate of 100%. As for abnormal laboratory findings, elevation of eosinophillia, transaminase and transaminase and ALP were observed in 1 case, 2 and 1 respectively but they were all mild and transient.

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Microbiological and clinical studies of balofloxacin (BLFX), a new quinolone antimicrobial agent, were carried out.
The MICs of BLFX against 581 strains of 12 species of clinical isolates from urinary tract infection (UIT) were determined, and compared with the antimicrobial activities of ofloxacin (OFLX), tosufloxacin (TFLX) and ciprofloxacin (CPFX). The MIC₉₀ of BLFX against gram-positive cocci was 8-16μg/ml. BLFX exhibited more powerful activity against gram-positive cocci than the reference drugs. On the other hand, the MIC₉₀ of BLFX against gram-negative rods was 0.125-64μg/ml. The antimicrobial activities of BLFX against gram-negative rods were similar or inferior to those of the reference drugs.
In the clinical study, BLFX was administered to 10 female patients with acute uncomplicated cystitis, 6patients with complicated UTI and a patient with chlamydial urethritis, 17 patients in all. In 3 patients with acute uncomplicated cystitis who were evaluable according to the criteria of the Japanese UTI Committee, the clinical efficacy was excellent in all three. In 4 patients with complicated UTI, the clinical efficacy was excellent in 2 patients and good in 2. In one patient with chlamydial urethritis, the clinical efficacy was excellent.
Subjective side effects were observed in 3 of 17 patients; they were nausea and gastralgia, headache and palpitation, and eruption, respectively. All side effects were eliminated, in some cases by discontinuation of BFLX. No abnormal laboratory findings were observed.
In conclusion, we believe that BFLX is highly useful in treating UTI.

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We investigated the antimicrobial activity of balofloxacin (BLFX) in human urine and the influence of BLFX on the bactericidal activity of leukocytes, fundamentally, and its clinical efficacy and safety for urinary tract infections, clinically, in order to clarify its usefulness for urinary tract infections.
1. Fundamental study: We measured the minimum bactericidal concentrations of BLFX against Escherichia coli NIHJ JC-2 and Pseudomonas aeruginosa 18s in urine media with different pH and different magnesium and calcium concentrations. The MBCs of BLFX were low when urine pH was high or magnesium concentration was low. We also investigated the influence of BLFX on bactericidal activities of neutrophils and monocytes, comparing their superoxide generation in the presence or absence of BLFX by means of the chemiluminescence method. The superoxide generation of neutrophils was significantly enhanced in the presence of 10 μg/ml or 100 μg/ml of BLFX. On the other hand, the superoxide generation of monocytes was significantly enhanced in the presence of 10 μg/ml of BLFX; however, it was reduced in the presence of 100 μg/ml of BLFX.
2. Clinical study: We administered BLFX 200 mg daily, for 3 days to 2 patients with acute uncomplicated cystitis, and 200 mg or 400 mg daily, for 5 days to 5 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 of BLFX against acute uncomplicated cystitis according to the criteria proposed by the Japanese UTI Committee was excellent in both patients. That against chronic complicated urinary tract infections was excellent in 2, and poor in 3 patients. No side effects or laboratory abnormalities were seen in any patients after the administration of BLFX.
These results indicate that BLFX has moderate efficacy, and the alkalization or dilution of urine might enhance its efficacy.

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The clinical effects of an oral quinolone preparation, balofloxacin (BLFX), on urethritis were investigated. The subjects were 20 patients with gonococcal urethritis, 4 with gonococcal chlamydial urethritis, 17 with chlamydial urethritis, and 26 with non-gonococcal non-chlamydial urethritis. The drug was orally administered at a dose of 200 mg twice a day to the patients with gonococcal urethritis, and at a dose of 100 mg twice a day, for 2-14 days, in the other patients.
Among the 35 patients in whom clinical efficacy could be evaluated according to the Japanese Urinary Tract Infection Drug Evaluation, clinical efficacy was rated excellent in 9 and effective in 8 of the patients with gonococcal urethritis, effective in 3 patients with gonococcal chlamydial urethritis, and excellent in 13 and effective in 2 of the patients with chlamydial urethritis.The efficacy rate was 100%.
The efficacy by investigator's evaluation was excellent in 24 and effective in 2 of the patients with nongonococcal non-chlamydial urethritis, for an efficacy rate of 100%. The antibacterial activity of the drug against 21 gonococcus strains isolated before administration was equivalent or slightly superior to that of ofloxacin, norfloxacin and ciprofloxacin. No side effects were observed in any of the patients.
The results suggest that BLFX is safe and useful for gonococcal and chlamydial urethritis.

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A newly developed quinolone antimicrobial drug, balofloxacin (BLFX), was investigated basically and clinically to clarify its usefulness for treating urinary tract and urogenital infections, with the following results.
BLFX was administered to 5 patients with gonococcal urethritis, 7 with chlamydial urethritis, 21 with non-gonococcal and non-chlamydial urethritis, 2 with prostatitis, and 2 with epididymitis at a dose of 100-200 mg twice a day for 3-14 days. The clinical efficacy was rated as excellent or good in all patients with gonococcal urethritis and chlamydial urethritis, among the 29 patients with urethritis in whom the effects could be evaluated. The efficacy rate for non-gonococcal and non-chlamydial urethritis was 84.2%.The clinical efficacy was good in both cases with prostatitis and both with epididymitis. No subjective or objective side effects were observed.
The minimum 90% inhibitory concentration (MIC₉₀) of BLFX for Neisseria gonorrhoeae was 0.39 μg/ml, which was approximately equivalent to that of the control drugs ofloxacin (OFLX) and ciprofloxacin (CPFX). The MIC₉₀ of BLFX for Chlamydia trachomatis was 0.063 μg/ml, showing excellent antibacterial activity, which was superior to those of OFLX and CPFX though inferior to that of sparfloxacin (SPFX).
The mean concentration of BLFX in prostate tissue and the mean tissue concentration to serum ratio were 2.68 μg/g and 1.95, respectively, 2 hours after a single administration of 200 mg, and the corresponding levels 13 hours post-administration were 1.35 μg/g and 1.88, respectively.

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Balofloxacin (BLFX), one of the newer quinolones, was investigated for its in vitro activity, diffusion into prostatic fluid (PF) and clinical efficacy in the treatment of urinary tract infection (UTI). The results obtained were as follows.
1. In vitro activity: Against 80 strains of Enterococcus faecalis isolated from UTI, the MIC of BLFX ranged from 0.20-25μg/ml, and the MIC₅₀ and MIC₉₀ were 0.78μg/ml and 12.5μg/ml, respectively, roughly comparable to sparfloxacin. The drug appeared to be superior to other reference drugs such as norfloxacin, ofloxacin and ciprofloxacin. However, BLFX was less potent against 50 strains of Pseudomonas aeruginosa, for which the MIC₅₀ and MIC₉₀ were as much as 25μg/ml and >100μg/ml.
2. Diffusion into PF: The concentration in PF at 1 hr after administration of 200 mg reached 0.01-0.94μg/ml, with an average of 0.35μg/ml (n=7), while that in serum, ranged from 0.06-1.96μg/ml, with an average of 0.79μg/ml. The ratio for PF/serum was 0.35.
3. Clinical assessment: A total of 38 UTI patients were given BLFX at doses of 100-200 mg, once or twice a day for 3-14 days. The patients included 14 cases of acute uncomplicated UTI, 23 cases of chronic complicated UTI and one case of acute prostatitis. According to the evaluation by the doctor (s) in charge, 30 of 38 evaluable cases, 78.9%, were assessed as effective (excellent/good), while according to the Japanese UTI criteria, 28 of 34, 82.4%(excellent/moderate), were determined to be effective. The bacteriological response rate was 13 of 14, 92.9%, in uncomplicated UTI, and 17 of 23, 73.9%, in complicataed UTI.
As for the safety profile, 3 of 39 patients treated with BLFX experienced adverse reactions (CNS) disturbance/GI disorder 1, CNS 1, GI disorder 1, however they were mild and transient, and disappeared after the completion of therapy without any treatment. No clinical abnormal values were detected in laboratory tests in any of the patients.

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We studied the antimicrobial activity of balofloxacin (BLFX), a new fluoloquinolone antibiotic drug, and its clinical usefulness in urinary tract infection (UTI).
1. The MICs of BLFX and control quinolones [norfloxacin (NFLX), ofloxacin (OFLX) and ciprofloxacin (CPFX)] were measured using the plate dilution method against clinical isolates from the urinary tract. The MIC₉₀s of BLFX against methicillin-sensitive Staphylococcus aureus, methicillin-resistant S. aureus, Staphylococcus epidermidis and Enterococcus faecalis were 1.56, 6.25, 1.56 and 12.5μg/ml, respectively. These results were superior to all of the control drugs. Those against Enterobacteriaceae were approximately equal to NFLX and OFLX and inferior to CPFX.
2. Four patients with acute uncomplicated cystitis were treated with 100 mg or 200 mg of BLFX twice a day for 3 days, and 19 patients with complicated UTI were treated with 100 mg, 200 mg or 300 mg of BLFX twice a day for 5 or 7 days. The therapeutic efficacy was evaluated by the criteria proposed by the Japanese UTI Committee. Of the 4 patients with acute uncomplicated cystitis, clinical efficacy was excellent in all patients. Of the 17 patients with complicated UTI, it was excellent in 13, moderate in 1 and poor in 3 patients.
Side effects were observed in 3 patients. These were upper abdominal discomfort in 1 case, dyspnea and eruption in 1 case and cold sweating and insomnia in 1 case. Also, laboratory adverse reactions were observed in 3 patients.
Therefore, this study demonstrated that BLFX to be a useful quinolone in the treatment of UTI.

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We studied the antimicrobacterial activity and clinical efficacy of balofloxacin (BLFX), a new quinolone, in the urological field.
1) Antibacterial activity: The MICs of BLFX were measured against 210 clinical isolates of 14 species from urinary tract infections and compared with those of ofloxacin (OFLX) and norfloxacin (NFLX). In general, the antibacterial activity of BLFX was inferior to that of OFLX, but almost equal to that of NFLX.
2) Clinical efficacy: According to the criteria of the Japanese UTI Committee, the overall efficacy rate was 80.0%(4/5) for chronic complicated UTI. Bacteriologically, eleven of the 12 strains isolated (91.7%) were eradicated.
3) Side effects: No clinical adverse reactions and no abnormal laboratory findings were observed.

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We studied the in vitro activity, penetration to cerebrospinal fluid and clinical usefulness of balofloxacin (BLFX), a new oral fluoroquinolone.
The in vitro activity of BLFX against 30 strains each of 11 species isolated from patients with urinary tract infections (UTI) was measured by the agar dilution method with an inoculum size of 10⁶ CFU/ml. The drug showed activity superior to those of ofloxacin and tosufloxacin against gram-positive cocci and comparable with those against gram-negative bacteria.
The mean ratio of cerebrospinal fluid level to serum level 2 hours after a single 200 mg oral dose in 4 patients who underwent transurethral surgery was 0.05.
Six patients with acute uncomplicated cystitis (AUC) and 10 with chronic complicated UTI were treated with a daily dose of 100 mg to 400 mg of the drug for 3 to 5 days. The clinical efficacy rates of the drug against 6 cases of AUC and 7 cases of chronic complicated UTI as judged by the criteria proposed by the Japanese UTI Committee were 100% and 43%, respectively. No adverse reactions were observed in any of the 16 patients. Slight elevation of alkaline phosphatase was observed in one case.
We conclude that BLFX is a useful drug in the treatment of UTI, especially that caused by grampositive cocci.

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Pharmacokinetics and clinical effects of a new oral quinolone, balofloxacin (BLFX), in the field of surgery were investigated.
The pharmacodynamic study was performed on five patients with cholelithiasis, two with choledocholithiasis, one with acute gangrenous appendicitis, and two with peritonitis derived from acute appendicitis. BLFX was orally administered at a single dose of 200 mg preoperatively, and body fluids and tissue specimens were collected during surgery. The gallbladder bile concentration to plasma concentration ratio was 0.15 to 33.4, and the bile concentration in the common bile duct to plasma concentration ratio was 11.71 to 31.11, and the gallbladder wall concentration to plasma concentration ratio was 0.93 to 2.10. These results indicate good transfer to bile. The concentration in intraperitoneal exudate was 0.86 to 2.73μg/ml, and the appendicular tissue concentration to plasma concentration ratio was 1.32 to 1.96.
The drug was administered to 10 patients, including seven with infectius atheroma, one with subcutaneous abscess, one with mastitis, and one with infection secondary to operative wound. The clinical efficacy was rated as excellent in six and good in four, for an efficacy rate of 100%. No side effects were observed in any of the patients. Slightly elevated GPT was observed in one patient, but no abnormal changes in other clinical laboratory tests occurred.

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A new oral quinolone, balofloxacin (BLFX), was orally administered 200 mg to a patient who had undergone gallstone extraction. Serum concentrations 1, 3, and 5.5 hours later were 1.11μg/ml, 1.27μg/ml, and 1.11μg/ml, respectively. Bile concentrations 3 and 5.5 hours later were 16.52μg/ml and 20.07μg/ml, respectively. These levels showed higher transfer, as compared to blood levels, by 13-18 times.
The gallbladder tissue concentration was 1.92μg/ml at 3 hours after administration. The antibacterial activity of BLFX against clinical isolates was equivalent or superior to that of cefaclor, tosufloxacin and ofloxacin.
When seven patients with surgical infectious diseases (four with perirectal abscess, one with cholangitis, one with mastitis and one with hypogastric furuncle) were given at a dose of 200mg twice a day, the clinical efficacy was excellent in two and good in five. Two Peptostreptococcus anaerobius strains, two Escherichia coli strains, one Clostridium sp. and one Bacteroides sp. isolated from four patients, were eradicated by the therapy. Side effects, were observed gastric fullness in one and epigastralgia in one. No abnormal changes in clinical laboratory test values were founnd.

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The clinical effects of a new quinolone drug for oral use, balofloxacin (BLFX), on surgical infectious diseases, particularly those of the skin and soft tissues, were investigated. The study included 13 patients with mastitis, wound infection, subcutaneous abscess, periproctal abscess, phlegmon, hidradenitis suppurativa and pilar antritis. The severity of the diseases was mild in eight and moderate in five.
The drug was administered at a dose of 100 mg or 200 mg once or twice a day for 7-12 days, and clinical usefulness was investigated. The clinical efficacy, by physician's evaluation, was excellent in five, effective in four, slightly effective in two and ineffective in two, for an efficacy rate of 69.2%.
The clinical efficacy against pyogenic bacteria was rated as excellent in five, effective in four, and ineffective in one, for an efficacy rate of 90.0%.
Bacteriologically, 16 strains were isolated from 10 patients. The bacteria were eradicated in nine of the 10 patients and partially eradicated in one, as shown by the clinical isolates. The eradication rate was 90%. Mild diarrhea and headache appeared in one patient as side effects, but disappeared during treatment by reducing the daily dose (given in 2 divisions) from 400 mg to 200 mg.

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In 24 patients with biliary tract diseases, balofloxacin (BLFX) was orally administered at a single dose of 200 mg. The plasma concentration was 1μg/ml 1-4 hours after administration, 2.6-3.0μg/ml being the maximum level. In contrast, the bile concentration reached a plateau of 4-18μg/ml 6-8 hours after administration, and this level persisted until 12 hours after administration. The gallbladder tissue concentration of BLFX was equivalent to or slightly higher than the blood concentration (ratio: 0.2-4.1). The bile in gallbladder contained glucuronic acid conjugation metabolites at 3.8-90.0%, suggesting the possibility of enterohepatic circulation.

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A newly developed oral quinolone, balofloxacin (BLFX), was investigated basically and clinically in the field of surgery. The results were as follows.
1) The drug was orally administered at a dose of 100 mg preoperatively to 3 patients with biliary tract diseases. Transfer to tissue and humor 2 hours after administration was investigated. Two patients in whom the levels could be determined showed serum concentrations of 0.05 and 0.98μg/ml, respectively, and gallbladder wall concentrations of 0.05 and 1.52μg/g, gallbladder and bile concentrations of 0.06 and 8.74μg/ml, bile duct and bile concentrations of 0.66 and 17.34μg/ml, subcutaneous fat concentrations of 0 and 0.31μg/g, and ascites concentrations of 0.07 and 1.16μg/ml, respectively.
2) The clinical efficacy of the drug was excellent in 3, good in 13, fair in 4, and poor in 1 of the patients with surgical infections, for an efficacy rate of 76.2%(16/21).
3) No side effects or abnormal changes in clinical laboratory test values probably attributable to the drug were observed in any of the 27 patients who received the administration.
The results suggest that BLFX is useful for surgical infections.

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As part of a two-part investigation, a pharmacokinetic study was performed with four patients during bile drainage as the subjects.
Two tablets (200 mg) of balofloxacin (BLFX), a new oral quinolone, was administered and serial samples of blood and bile were taken. The peak levels of BLFX in the plasma were 1.01-1.54μg/ml at 4-6h after the start of administration, and the peak levels in the bile were 4.61-23.13μg/ml at 2-6h.
In the second part of the study, 51 patients were treated.
Clinical efficacy was excellent in 18 infections, good in 24 infections, fair in 6 infections, and poor in 3 infections with an efficacy of 82%.
The bacteriological response of 50 strains of 21 bacterial species isolated was evaluated. Forty-seven strains were eradicated and three strains persisted, with an eradication rate of 94%. The bacteriological response of the host was evaluated in 33 infections.
Bacteria were eradicated in 29 infections, decreased in one, were replaced in two and persisted in one with an eradication rate of 94%.
The MIC was calculated for 54 strains isolated, and 28 strains of them required the MIC of 0.39μg/ml or more to be inhibited. The bacteriological response of 42 strains of MIC were calculated was evaluated. All 22 strains, which required the MIC of 0.20μg/ml or less to be inhibited, were eradicated.
Two patient of diarrhea and one patient of skin eruption were reported. No abnormal changes in laboratory test results which might be caused by this drug, was found. BLFX seemed to be effective for skin and soft tissue infections and bile duct infections.

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The excretion into bile and penetration into gallbladder tissue of a new quinolone, balofloxacin (BLFX), were evaluated in 5 patients who had given informed consent.
In 3 patients undergoing cholecystectomy, the gallbladder tissue concentrations of BLFX ranged from 0.97 to 3.67 μg/g at 3.5-4.5 hours after a single oral dose of 100 mg, although the serum concentrations were 0.4 to 1.23 μg/ml.
In 2 patients with an indwelling T-tube or PTCD-tube, bile was collected after a single oral dose of 200 mg BLFX. The peak concentrations of free BLFX in bile were 15.6 and 5.84μg/ml at 4 and 6 hours after dosing, respectively. The glucuronide form was detected at a proportion of 20 to 50% of BLFX in bile.

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