In vitro and in vivo antibacterial activities of sparfloxacin (SPFX), a new fluoroquinolone, were examined comparing with those of ciprofloxacin (CPFX), ofloxacin (OFLX), and norfloxacin. The results were summarized as follows:
1) SPFX possessed improved activity against gram-positive cocci. It had potent activity against some quinolone-resistant Staphylococcus aureus including methicillin-resistantStaphylococcus aureus.
2) SPFX activity against gram-negative bacteria was generally comparable to that of CPFX.
3) Frequency of spontaneous mutants resistant to SPFX was approximately 10^-9
4) SPFX strongly inhibited the supercoiling activity of DNA gyrase of Escherichia coli.
5) The in vivo efficacy of SPFX by oral administration was higher than that of CPFX and OFLX against mouse systemic infection models with gram-positive and -negative bacteria.

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We compared the in vitro and in vivo antibacterial activities of sparfloxacin, a newly synthesized quinolone, with those of ciprofloxacin, enoxacin, ofloxacin and norfloxacin, and obtained the following results.
1. Sparfloxacin proved to have a broad antibacterial spectrum, and its in vitro activity against Gram-positive cocci of Staphylococcus spp., including methicillin-resistant Staphylococcus aureus (MRSA) and Enterococcus faecalis, was more potent than that of the other four reference quinolones. Against the family of Enterobacteriaceae and glucose-nonfermenting bacteria, Bacteroides fragilis and Clostridium difficile, the in vitro activity of sparfloxacin was the same or lower than that of ciprofloxacin, and more potent than that of the other drugs.
2. The therapeutic efficacy of sparfloxacin was the same as that of ciprofloxacin and ofloxacin against experimental mouse models, i.e. systemic infections with MRSA and Pseudomonas aeruginosa, respiratory infections with Klebsiella pneumoniae and urinary tract infections with Escherichia coli and Serratia marcescens.
3. The maximum concentrations of sparfloxacin in mouse serum and kidneys following oral administration were lower than those of ofloxacin and enoxacin. However, the concentrations of sparfloxacin in lung were the highest among the drugs tested and the time-course levels of sparfloxacin were better than those of the reference drugs, and the T_1/2 and AUC of sparfloxacin revealed high values.

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The MIC₉₀ s of sparfloxacin (SPFX) 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, Serratia marcescens, Enterobacter cloacae, Pseudomonas aeruginosa, Pseudomonas cepacia, Xanthomonas maltophilia, Acinetobacter calcoaceticus, ampicillin-resistant Haemophilus influenzae and Bacteroides fragilis were 0.1, 0.2, 0.2, 1.56, 0.78, 0.39, 0.78, 0.78, 0.39, 0.39, 0.39, 0.78. 1.56, 6.25, 1.56, 1.56, 1.56, 12.5, 1.56, 0.39, 0.39, 0.05, and 3.13μg/ml, respectively. SPFX manifested stronger activities against Staphylococcus aureus, MRSA, CNS, Streptococcus pneumoniae, Enterococcus faecalis and Enterococcus faecium than ciprofloxacin CPFX) and ofloxacin (OFLX), and the same activity against Streptococcus pyogenes as CPFX. SPFX, however, showed slightly weaker activities against Gram-negative bacilli (including Pseudomonas aeruginosa) than CPFX, except Klebsiella pneumoniae, Xanthomonas maltophilia and Acinetobacter calcoaceticus against which the activities of SPFX were prominent. SPFX collaborated with the serum complement in the bactericidal effect on Escherichia coli NIHJ JC-2, and the cells of Escherichia coli NIHJ JC-2 were well engulfed and digested by mouse cultured macrophage in the presence of this agent at 1/4 MIC or higher. The cytostatic activity of SPFX was found to be stronger than that of CPFX and OFLX against HeLa and CHO-Kl cells, and similar to CPFX against human neuroblastoma IMR-32 cells. SPFX withdrew some parts of axon dendrites in redifferentiated IMR-32 cells at 5μg/ml after 3hr incubation.

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We evaluated the antibacterial activity of sparfloxacin (SPFX), a new quinolone, in comparison with temafloxacin (TMFX), ofloxacin (OFLX), ciprofloxacin (CPFX), erythromycin (EM), cefuroxime (CXM), ceftazidime (CAZ), ampicillin (ABPC) and other antimicrobials against 3290 clinical strains isolated in the Clinical Laboratory of Juntendo University Hospital.
Antimicrobial susceptibility was measured by the microbroth two-fold dilution method in the MIC 2000 system using Mueller Hinton broth (Difco). For fastidious organisms and anaerobes, supplemented Trypticase soy broth (BBL) and ABCM broth (Eiken), respectively were used as the test medium.
SPFX had a broad antibacterial spectrum against almost all Gram-positive and Gram-negative organisms. Fifty percent of methicillin-resistant Staphylococcus aureus (MRSA) were inhibited by SPFX at the concentration of less than 0.1μg/ml. The antibacterial activity of SPFX against Streptococcus pneumoniae, Enterobacteriaceae, Flavobacterium meningosepticum, Xanthomonas maltophilia, Acinetobacter anitratus and Bacteroides fragilis was superior to that of OFLX, TMFX and CPFX. Its activity against Haemophilus influenzae and Bacteroides fragilis was also superior to that of CXM, CAZ, ABPC and EM.

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Influence of human albumin and fresh plasma on bactericidal or antibacterial activities of sparfloxacin were examined.
The macro-broth-dilution method was used to determine antibacterial activities. Bactericidal activities were determined using the killing curve method. Used in the broth-dilution method were two media, Mueller Hinton broth (MHB) and the same medium supplemented with 5g human albumin/dl (MHB-A). The first experiment was to compare minimum inhibitory concentrations (MICs) determined in MHB with those in MHB-A, of sparfloxacin against Staphylococcus aureus FDA 209 P JC-1, Escherichia coli ATCC 25922 and Pseudomonas aeruginosa NCTC10490. MICs using MHB-A were equal to MICs using MHB.
In the second experiment, killing curves were determined in the three media, MHB, MHB-A and fresh plasma against three standard strains. The concentrations of the antibiotics used were 1/2×MIC, 1×MIC and 2×MIC. MICs determined in the first experiment were used here. Killing curves determined in MHB-A and fresh plasma reflected killing curves determined in MHB.
Human albumin did not influence antibacterial and bactericidal activities of sparfloxacin. Sparfloxacin retained bactericidal activities in fresh plasma.

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Sparfloxacin is characterized by its long half-life (T_1/2; 16 hours). Based on this feature, its availability as a ‘once a day’ treatment was assessed in an in vitro computer-programmed pharmacokinetic system using a one-compartment open model.
Viable cell counts of Haemophilus influenzae as well as Escherichia coli decreased to undetectable levels at 3 hours after the administration of sparfloxacin in both the ‘300mg once a day’ and ‘150mg twice a day’ simulation models. In Streptococcus pneumoniae and Staphylococcus aureus, sparfloxacin treatments of 300mg once or 150mg twice depressed the cells to more than 2 log levels without marked regrowth until 24 hours. The cell counts of Pseudomonas aeruginosa treated once with 300 mg of sparfloxacin were lower than those with 150mg twice. In the former, no detectable cells were found until 7 hours.
Thus, sparfloxacin showed a sufficient antibacterial activity in a model simulating ‘once a day’ administration.

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The in vitro and in vivo antibacterial activities of sparfloxacin (SPFX), a new quinolone, were compared with those of enoxacin (ENX), ciprofloxacin (CPFX) and ofloxacin (OFLX). The following results were obtained.
SPFX had a broad antimicrobial spectrum against Gram- positive and Gram- negative bacteria, and its antibacterial activity was superior to those of ENX, CPFX and OFLX against Gram- positive bacteria and equal to that of CPFX against Gram-negative bacteria. The antibacterial activity of SPFX against anaerobic bacteria, moreover, was superior to those of ENX, CPFX and OFLX.
In the sensitivity distribution of clinically isolated strains, the activity of SPFX was almost equal to that of CPFX and superior to those of OFLX and ENX against Escherichia coli and Klebsiella pneumoniae, and slightly inferior to that of CPFX and almost the same as that of OFLX against Serratia marcescens, Citrobacter freundii, Pseudomonas aeruginosa, Providencia rettgeri, Morganella morganii, Enterobacter spp. and Proteus spp. However, against all the other isolates tested, SPFX was the highest, followed in decreasing order by CPFX, OFLX and ENX.
The addition of horse serum and inoculum size did not affect the antibacterial activity of SPFX against Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa. Its antibacterial activity against those bacteria was slightly enhanced in an alkaline medium.
SPFX showed potent concentration-dependent bactericidal activity against Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter calcoaceticus.
In a morphological examination by phase-contrast microscope, SPFX induced the formation of swollen cells in Staphylococcus aureus, and filamentous cells in Escherichia coli. In Pseudomonas aeruginosa, SPFX induced spheroplast-like structures and bacteriolysis, but didn' t result in the filamentous forms of the bacteria. In Haemophilus influenzae and Acinetobacter calcoaceticus, SPFX treatment resulted in filamentous forms with swollen parts.
In the systemic infections caused by 3 Gram- positive and 5 Gram-negative strains in mice, SPFX showed good therapeutic efficacies against all the infections tested. Its therapeutic effects were almost equal to those of CPFX and OFLX against Serratia marcescens and superior to those of CPFX, OFLX and ENX against all other strains tested.

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In vitro and in vivo antibacterial activities of a new quinolone, sparfloxacin (SPFX), were compared with those of ciprofloxacin (CPFX), ofloxacin (OFLX), enoxacin (ENX) and norfloxacin (NFLX) with the following results.
1. SPFX was similar to CPFX in activity against gram-negative bacteria and Legionella spp., and more potent than CPFX, OFLX, ENX and NFLX in activity against gram-positive bacteria, glucose-nonfermenters, anaerobes, Mycoplasma spp., Chlamydia spp., and Mycobacterium spp. Most clinical isolates were as susceptible to SPFX as laboratory strains.
2. SPFX was not cross-resistant with ampicillin, cephalexin, tetracycline, chloramphenicol and streptomycin, and inhibited bacteria highly resistant to nalidixic acid (MIC:≥100μg/ml) in a concentration range of 0.025-0.78μg/ml.
3. The MIC values of SPFX were scarcely affected by the addition of horse serum, sodium desoxycholate or divalent cations such as Mg²⁺ and Ca²⁺, but slightly rose when medium pH lowered or inoculum sizes were enlarged. The MICs of SPFX in human urine were no higher than those in sensitivity test broth.
4. SPFX was bactericidal around its MICs.
5. Frequencies of mutants resistant to SPFX were <1.6×10^-9 at selective concentrations of 16 times the MICs.
6. SPFX was more effective than CPFX, OFLX, ENX and NFLX by the oral route in systemic, pulmonry, kidney and dermal infections in mice.
These results indicate that SPFX is a quinolone with broad and potent antibacterial activity in vitro and in vivo, and may be useful for various kinds of infections in humans.

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Antichlamydial activity of sparfloxacin (SPFX) was examined in comparison with that of ofloxacin (OFLX) and minocycline (MINO) with the following results.
1. The MIC₉₀ of SPFX for 37 clinical isolates of Chlamydia trachomatis was 0.063 μg/ml, while the MIC₉₀s of OFLX and MINO were 1 and 0.031 μg/ml, respectively.
2. The minimum lethal concentration of SPFX for Chlamydia trachomatis D/UW-3/Cx was0.125 μg/ml, twice the MIC (0.063/μg/ml), while that of OFLX was 2μg/ml, twice the MIC (1μg/ml), and that of MINO was 0.25μg/ml, 8 times the MIC (0.031μg/ml).
3. Transmission electron microscopic observation revealed that SPFX and MINO specifically disrupted reticulate bodies but not elementary bodies. The degree of disruption of reticulate bodies was more marked under SPFX treatment (2 MIC) than under MINO treatment (2MIC).
These results indicate that SPFX is as potent as MINO as an antichlamydial agent.

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The in vitro activities of sparfloxacin (SPFX), ofloxacin (0FLX), ciprofloxacin (CPFX) and rifampicin (RFP) against 20 clinical isolates each of Mycobacterium tuberculosis, Mycobacterium auium complex, Mycobacterium kansasii, and 15 clinical isolates of Mycobacterium fortuitum were evaluated by the agar dilution method using Kirchner's liquid medium supplemented with 10% bovine serum and modified Dubos Tween albumin liquid medium. The MIC₉₀ of SPFX against the isolates of Mycobacterium tuberculosis, Mycobacterium avium complex, Mycobacterium kansasii, and Mycobacterium fortuitum were≤0.01, 1.56, 0.20, and≤0.01μg/ml on Kirchner's liquid medium, respectively. Those of RFP were 12.5, 12.5-≥25, 3.13, and 12.5-≥25, respectively. The newly developed quinolone, SPFX, was more active against all four mycobacterial species than the other 2 quinolones and RFP.
This newly developed quinolone (SPFX) is a good candidate antimycobacterial agent for continued in vivo evaluation.

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The in vitro activity of sparfloxacin, a newly developed quinolone, was determined by an agar dilution technique against 33 selective reference strains and 382 clinical strains of anaerobic bacteria. Sparfloxacin inhibited the growth of most reference bacteria of clinical importance, such as Bacteroides fragilis, Bacteroides distasonis, Bacteroides ovatus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Prevotella oris, Prevotella oralis, Prevotella intermedia, Porphyromonas gingivalis, Fusobacterium nucleatum, Veillonella parvula, Peptostreptococcus anaerobius, Peptostreptococcus asaccharolyticus, Peptostreptococcus rnagnus, Propionibacterium acnes and Eubacterium lentum, at a concentration of 1. 56 μg/ml. Sparfloxacin was also very active against selective clinical isolates including Bacteroides fragilis group, Mobiluncus spp. and Gardnerella vaginalis. Its activity was comparable to that of tosufloxacin, and more active than those of ofloxacin and norfloxacin.
Sparfloxacin inhibited 90% of strains of Clostridium difficile at a concentration of 6. 25μg/ml and was able to induce the overgrowth of C. difficile in the caecum although its ability is considerably low.

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As a microbiological assay method used for determining concentrations of sparfloxacin (SPFX) in body fluids, an agar-well method using Escherichia coli Kp as a test organism was found to be sensitive and accurate. Standard solutions of SPFX were made in 1/15 M phosphate buffer, pH 7.0 for urine samples etc. and in human serum for serum or plasma samples. The assay limit of SPFX by the method was ca. 0.01μg/ml. SPFX in human serum or urine were stable for at least 2 weeks at -20°C in a freezer.

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Absorption, distribution and excretion of sparfloxacin (SPFX) were studied in animals given a single oral dose of 5mg/kg.
The plasma C_max of SPFX in mice, rats, dogs and monkeys were 0.25, 0.50, 1.14 and 0.49 μg/ml, respectively, with t_1/2 of 5.0, 3.8, 8.0 and 11.7h. The oral bioavailability of SPFX calculated from the ratio of AUC after oral or intravenous administration was 77% in dogs. The ratios of tissue level/plasma level of SPFX as an index of tissue penetration were 2 to 11 in rats. Such ratios of SPFX in mice were 2 to 3 times higher than those of ciprofloxacin. The 24-h biliary recovery of SPFX in rats was 5.6% of the dose and turned out 21.3% after β-glucuronidase treatment and 30.5% after heating with NaOH. The 48-h urinary recoveries of SPFX in mice, rats, dogs and monkeys were 6.7, 12.9, 8.6 and 12.7% of the dose and were 7.8, 16.3, 8.9 and 18.9% after β-glucuronidase treatment.
These results indicate that SPFX is well absorbed by the oral route, partially metabolized into glucuronide at least in rats and monkeys, and distributed over most parts of body at high concentrations with relatively long half-lives.

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Sparfloxacin (SPFX) was orally administered to New Zealand white rabbits locally infected with bacteria in the mandibular tissues, and its penetration from the blood into the mandibulae was confirmed.
On the basis of the preliminary result, [¹⁴C] SPFX was administered in a single oral dose of 20mg/kg to the similarly infected rabbits and the animals were killed at the time of the peak blood concentrations, 3 or 24 hours after the administration. The penetration of the labelled SPFX into the jaw bone was studied by autoradiography.
1. The pharmacokinetic parameters obtained in the infected animals were as follows: For the sera: T_max, 3.1hours; C_max, 0.82μg/ml; and AUC, 8.79μg·h/ml. For the jaw bones: T_max, 3.4hours; C_max, 0.48μg/g; and AUC, 5.00μg.h/g.
2. Autoradiography revealed that the penetration of [¹⁴C] SPFX into the cortical bones was poor in the control rabbits, whereas distribution in the bone marrow, teeth, dental pulp and peridental membrane in the submaxilla was excellent.
3. In the infected model group, extremely high levels of [¹⁴C] SPFX were observed around the infected foci.
4. The above results indicate that SPFX distributes around the acutely infected tissues rather than the core part of the infected foci, suggesting SPFX's usefulness as an antimicrobial against odontogenic infections.

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The concentration of sparfloxacin in the prostatic tissue and serum was measured in 38 patients with benign prostatic hypertrophy undergoing prostatectomy after preoperative oral administration of 200mg of sparfloxacin. The mean concentrations (μg/ml) of sparfloxacin in the serum were 0.79 at 2 hours, 0.73 at 4 hours, 1.10 at 6 hours, 0.90 at 8 hours 0.78 at 12 hours, and 0.43 at 24 hours after administration. The corresponding concentrations (μg/g) in the prostatic tissue were 0.81, 0.92, 1.35, 0.94, 1.15, and 0.53 respectively. The concentrations of the drug in the prostatic tissue and serum were consistently close (the mean ratio of prostatic tissue concentration to serum concentration: 1.0-1.5). The pharmacokinetic parameters were analyzed by the program MULTI according to the one compartment model in serum and well-stirred model in prostatic tissue. The parameters in the serum were as follows: T_1/2, 14.1 hours; T_max, 5.6 hours; C_max, 0.96μg/ml; AUC_0→24h, 16.76μgh/ml. Those of prostatic tissue were as follows: T_1/2, 13.6hours; T_max, 6.7hours; C_max, 1.14μg/g; AUC_0→24h, 21.362μgh/g. This data suggested an effective penetration of sparfloxacin into the prostatic tissue.

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1) Minimum inhibitory concentrations (MICs)(inoculum 10⁶cells/ml) of sparfloxacin (SPFX), ofloxacin (OFLX) and norfloxacin (NFLX) were determined against 110 isolates of Staphylococcus aureus from skin and skin structure infections. In methicillin-resistant Staphylococcus aureus (MRSA, 28 isolates), SPFX showed a peak of MIC distribution at 0.1μg/ml and 0.2μg/ml, OFLX at 3.13μg/ml, and NFLX showed no peak of MIC distribution.
2) Serum and skin levels of SPFX after oral administration (20mg/kg) were determined in rats. Mean serum levels were 1.27, 2.31, 1.49, 0.97, 1.30, 0.21, and 0.25μg/ml, and the corresponding skin levels were 1.25, 2.04, 2.32, 2.35, 2.85, 0.69, and 0.66μg/g (wet skin weight) at 0.5, 1, 2.4, 6, 12, and 24 hours after administration, respectively.
3) Serum and skin levels of SPFX after oral administration (200mg) were determined in patients. The ratio of skin/serum levels was 1.44 (n=12).

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Penetration of sparfloxacin (SPFX) into the human spinal fluid was examined and compared to that of 5 other fluoroquinolones including norfloxacin (NFLX), enoxacin (ENX), ofloxacin (OFLX), ciprofloxacin (CPFX) and fleroxacin (FLRX). The serum and cerebrospinal fluid (CSF) from 271 patients with urological diseases were collected during operation under lumbar anesthesia 3 hours after giving fluoroquinolones.
They were divided into 2 groups: a single dose group, and consecutive dose group treated for 3 days before operation. SPFX was given to 81 cases. Pharmacokinetics of SPFX after a single 200 or 300mg administration was also studied. Samples were measured by an agar microwell method.
SPFX level in CSF after giving a single dose of 200mg was 0.155±0.039μg/ml (mean±SE) and consecutive dose was 0.403±0.053μg/ml, a single dose of 300mg was 0.240±0.063μg/ml and consecutive dose was 0.561±0.060μg/ml. As a result of Bartlett's test, OFLX, FLRX and SPFX were found competent for Duncan's test in the single dose group. The CSF levels of OFLX and FLRX were higher than that of SPFX (p<0.01). In the consecutive dose group, CSF to serum ratios were available for Duncan's test. There is no statistical difference among the drugs.
Although dose dependency of the CSF level was evident between a single and consecutive dosage of 200mg and 300mg of both FLRX and SPFX, the CSF to serum ratio of SPFX did not change.
In a pharmacokinetic study based on a low flux peripheral compartment model, the CSF level of SPFX reached a peak at approximately 8 hours after the administration and gradually decreased.

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The effect of sparfloxacin on the plasma level of theophylline was investigated in 6 healthy male volunteers. Plasma concentration of theophylline was measured after administration of theophylline preparation alone in a dose of 400mg daily for 5 days, and then together with sparfloxacin in a dose of 300mg daily for 7 days. There was no significant difference in plasma concentration of theophylline between theophylline alone and sparfloxacin with theophylline treatments.

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Many new quinolones have been developed and used for the treatment of infectious diseases. Both old and new quinolones have been reported to have a convulsive activity as one of their side effects. Furthermore, it has been reported that concurrent therapy with enoxacin and fenbufen, one of the non-steroidal anti-inflammatory drugs, might be responsible for the induction of convulsions. Therefore, we studied the effect of sparfloxacin, a newly synthesized quinolone, and other new quinolones on receptor binding of γ-aminobutyric acid (GABA) with or without non-steroidal anti-inflammatory drugs.
Intraventricular injection of sparfloxacin (up to 10 nmol) with 4-biphenylacetate (5 nmol) did not induce convulsions in mice, whereas intraventricular injection of enoxacin with 4-biphenylacetate induced convulsions in mice. Sparfloxacin itself hardly inhibited GABA receptor binding. Furthermore, the inhibitory activity of sparfloxacin in GABA receptor binding was not enhanced even in the presence of non-steroidal anti-inflammatory drugs.
From these results, it was suggested that sparfloxacin might have little convulsant activity even in the presence of non-steroidal anti-inflammatory drugs.

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Sparfloxacin (SPFX), a novel quinolone antibacterial (NQ) was compared with other NQs such as norfloxacin (NFLX), ofloxacin (OFLX), enoxacin (ENX), ciprofloxacin (CPFX), lomefloxacin (LFLX) and tosufloxacin-tosilate (TFLX) on the central nervous system (CNS) exitability in combination with, or without, non-steroidal anti-inflammatory drugs (NSAID) in mice.
Intraperitoneal administration of large doses of NQs except SPFX caused convulsant death. LD₅₀ values (mg/kg) of NQs were 700 for LFLX, 805 for OFLX, 1064 for NFLX, 1165 for CPFX, 3600 for ENX and 3100 for SPFX, respectively. These neuroexcitable effects of NQs were amplified by concomitant administration of 4-biphenylacetic acid (BPAA), an active metabolite of fenbufen, resulting in tonic and clonic convulsions and convulsant death. The rank order was ENX<NFLX<LFLX<CPFX<OFLX<SPFX on the basis of dose. when NQs other than SPFX were orally given in combination with BPAA, ketoprofen or naproxen, convulsions were induced in a dose dependent manner. As to the convulsive effects of NQs with 200mg/kg BPAA: a dose (mg/kg) which caused convulsive death in all animals was 50 for LFLX, 75 for ENX, 200 for NFLX, 400 for CPFX and 1500 for OFLX, respectively. Concomitant use of 1500mg/kg TFLX and 400mg/kg BPAA evoked convulsions in 10% animals. In contrast, no neuroexitable activity and convulsions were observed in the oral intake of SPFX under all experimental conditions. In the presence or absence of BPAA, SPFX showed no affinity against GABA_A receptor. These results suggest that SPFX possesses little neuro-excitability and that SPFX appears to have exceptional ability to avoid the CNS-related adverse reactions induced by concomitant use of NSAID and NQs.

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Acute toxicity study of sparfloxacin was carried out in mice, rats and beagle dogs. Sparfloxacin was administered in a single dose to mice and rats by oral (p. o.), subcutaneous (s. c.) and intraperitoneal (i. p.) routes, and to dogs by p. o. route.
Maximal doses were administered to animals of each species by each route, and no deaths occurred. In mice and rats, the p. o. LD₅₀ values were estimated at 5000mg/kg or more, while the s. c. and i. p. LD₅₀ values were estimated at 2000mg/kg or more. In dogs, the p. o. LD₅₀ value was estimated at 600mg/kg or more.
Major physical signs included diarrhea or loose stool, inactiveness in mice and rats receiving p. o. and i. p. administrations, and crust formation at the injection site in mice and rats receiving s. c. administration. In dogs, physical signs included inactiveness, vomiting, salivation and tremors.
Body weight decreased slightly during the first week of treatment in mice and rats (except rats receiving p. o. administration). In rats, food consumption decreased slightly during the first week. In dogs, there were no changes in body weight and food consumption.
Significant findings included cyst formation of the injection site in mice and rats receiving s. c. administration, and adhesions in various areas of the visceral organs and cyst formation on the serous surface of the visceral organs in mice and rats receiving i. p. administration.

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Sparfloxacin, a synthetic antibacterial agent, was administered orally to Jcl: SD rats at doses of 12. 5, 50, 200 and 800mg/kg for 4 weeks followed by a 2-week recovery period.
Clinical signs attributable to the treatment included soft stool noted in males at 200mg/kg or more and females at 800mg/kg, and blood-like discharges on the anal mucosa noted in both sexes at 800mg/kg. Body weight gain was depressed in males at 800mg/kg. Food consumption was transiently decreased in males at 800mg/kg and females at 200mg/kg or more. Water consumption was increased in both sexes at 200mg/kg or more. Urinalysis exhibited a decreased Na+ level and Na⁺/K⁺ ratio in both sexes at 800mg/kg and decreased urine volume, protein and in males at 800mg/kg. Hematology disclosed increased WBC in both sexes at 800 mg/kg. Cecum weight was increased in males at 50mg/kg or more and females at 200mg/kg or more. Necropsy revealed yellow discoloration of the ileum and mesenteric lymph node in both sexes at 800mg/kg. In histopathological examination, accumulation of macrophages corresponded to the macroscopic alterations. All of the above-described toxic effects reversed or tended to reverse following the withdrawal of administration.
From these results, it is concluded that a maximum no-effect dose is 50mg/kg.

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Four-week oral subacute toxicity study of sparfloxacin was conducted in male and female beagle dogs at dosage levels of 5, 15 and 45mg/kg/day.
Dogs at 45mg/kg/day showed vomiting during the dosing period. A slight suppression of food consumption was observed at 15 and 45mg/kg/day. Electrocardiographic examinations showed prolongation of Q-T intervals at 45mg/kg/day. Biochemical analysis showed elevations in urea nitrogen and creatinine levels at 15 and 45mg/kg/day. Erosion of the articular cartilage surface was noted macroscopically at 45mg/kg/day. The changes described had nearly recovered 2 weeks after the final administration.
There were no effects on body weights, urinalysis, ophthalmology, hematology and organ weights, and no treatment-related histopathological findings.
Based on these results, the no-effect dose level for this study is considered to be 5mg/kg/day. At a dose level of 15mg/kg/day and above, some indications of toxic signs were observed but such changes appeared to be reversible.

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Sparfloxacin (SPFX) is a new pyridonecarboxylic acid antimicrobial agent. We determined its MIC at 10⁶ cells/ml on 7 species, from 209 strains of clinical isolates. Its MIC₉₀ was found to be: Staphylococcus aureus 3. 13μg/ml; Escherichia coli 0.09μg/ml; Klebsiella pneumonrae 0.19μg/ml; Proteus mirabilis 0.19μg/ml; Morganella morganii 0.39μg/ml; Serratia marcescens 25μg/ml; and Pseudomonas aeruginosa 1.56μg/ml. Against almost all strains, it displayed stronger antibacterial activity than other drugs of the same type including norfloxacin (NFLX), enoxacin (ENX), ofloxacin (OFLX). ciprofloxacin (CPFX), tosufloxacin (TFLX) and lomefloxacin (LFLX).
We administered 200mg of SPFX to 6 healthy adult males on an empty stomach, and studied blood concentrations and urine excretion by both bioassay and HPLC. The T_max, was 4.7 hours, the C_max was 0.65μg/ml and T_1/2 was 18.2-19.2 hours; the urine excretion rate up to 72 hours ranged from 11.4-2.3%.
To 18 patients with infections in the field of internal medicine (chronic bronchitis, 9 cases; acute bronchitis, 5 cases; and acute tonsillitis, 4 cases) we orally administered 200-300mg of this drug in two divided doses, and we conducted a study on its clinical efficacy. The efficacy rate was 94%. In regard to its bacteriological effect it was found that in all 15 cases bacteria were no longer detectable. No side effects or abnormal clinical test results were observed. The excellent efficacy and safety of this drug were confirmed.

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Sparfloxacin, a newly synthesized pyridone carboxylic acid antibacterial agent, was administered to 6 patients with respiratory tract infections. Quantitative cultures of the sputum revealed 2 strains of Staphylococcus aureus and one each of Branhamella catarrhalis and Pseudomonas aeruginosa.
The drug was administered orally at a daily dose of 150 to 300mg, distributed once to twice a day, for 5 to 15 days. As a result, one each strain of Staphylococcus aureus and Branhamella catarrhalis was eradicated, and one each of Staphylococcus aureus and Pseudomonas aeruginosa unchanged. Global evaluation including clinical efficacy, such as the relief of symptoms and the improvement of laboratory findings, revealed that 4 of 6 patients had good or excellent responses. The sensitivity distribution of sparfloxacin against 49 strains of Streptococcus pneumoniae, 33 strains of Branhamella catarrhalis, 53 strains of Haemophilus influenzae and 92 strains of Pseudomonas aeruginosa, all clinically isolated in 1988, was compared with that of enoxacin, norfloxacin, ofloxacin and ciprofloxacin. The data revealed that sparfloxacin was the most sensitive to Streptococcus pneumoniae, and almost identically sensitive to others in these drugs.

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The in vitro antimicrobial activity of sparfloxacin, a new quinolone agent for oral use, was measured and its therapeutic efficacy on respiratory infections was evaluated. The minimum inhibitory concentrations (MICs) of sparfloxacin (SPFX), ofloxacin (OFLX) and ciprofloxacin (CPFX) against 20 strains each of Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens and Pseudomonas aeruginosa were determined by a micro-broth dilution method using the Dynatech MIC 2000 system. As shown by MICs, sparfloxacin was the most active of the 3 agents tested against Staphylococcus aureus, Escherichia coli and Enterobacter cloacae. Sparfloxacin was less active than ciprofloxacin, but more active than ofloxacin against Klebsiella pneumoniae, Serratia marcescens and Pseudomonas aeruginosa. A daily dose of 200-300mg of sparfloxacin was given orally for 3-17 days (mean: 11.1 days) to 7 patients: 1 each with acute bronchitis, infected bronchiectasis and infection secondary to pulmonary emphysema, and 4 with acute pneumonia. The clinical effects were excellent in 1, good in 3 and poor in 2 cases. One case of pneumonia was excluded from clinical evaluation because of lack of symptom and sign of infection. Three strains of Haemophilus influenzae were identified as causative organisms. All of them were eradicated by sparfloxacin. Erythema and a transient elevation of the value of GPT were each observed in one patient. These adverse reactions disappeared after completion of the therapy. From the above results, we conclude that sparfloxacin is one of the most useful quinolone agents for oral use, and a first choice in the treatment of respiratory infections, especially in chronic cases.

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We carried out basic and clinical studies on sparfloxacin, a new oral pyridonecarboxylic acid, and obtained the following results.
The in vitro antibacterial activity of sparfloxacin was tested against clinical isolates of 23 species and compared with those of ciprofloxacin, ofloxacin, norfloxacin, enoxacin and cefteram pivoxil. Sparfloxacin showed the best antibacterial activities for Gram-positive bacteria among the tested quinolones, especially for Staphylococcus aureus, methicillin-resistant Staphylococcus aureus and Streptococcus pneumoniae. Sparfloxacin and the other agents were equally active against Gram-negative bacteria.
We administered sparfloxacin to 19 patients with respiratory tract infections at a dose of 200-300mg daily for 3 to 22 days. The clinical responses obtained were excellent in 1, good in 12 and fair in 4, poor in 1 and unknown in 1 case. Neither side effects nor remarkable worsening of laboratory findings was observed.

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We performed basic and clinical studies on sparfloxacin (SPFX), a newly synthesized quinolone, and obtained the following results.
1. Effects of antacid (dried aluminium hydroxide gel, AL) and probenecid on the gastrointestinal absorption and renal excretion of SPFX were investigated by a cross-over design in six healthy male volunteers.
The subjects received orally 200mg of SPFX with and without 1g of AL or 1.5g of probenecid, and the time course of blood levels, urinary concentrations and urinary recovery of SPFX and its pharmacokinetic parameters were determined. SPFX concentrations in the samples were measured by the HPLC method. The obtained pharmacokinetic parameters for SPFX after each of the treatment were as follows: the C_max, T_max, T_1/2 and AUC_0→∞ for SPFX alone were 0.865μg/ml, 5.3h, 14.7h and 21.1μg·h/ml, respectively; those for co-administration with AL were 0.683μg/ml, 4.0h, 14.0h and 13.7μg·h/ml; and those for co-administration with probenecid were 0.810μg/ml, 3.5h, 15.7h and 20.1μg·h/ml. Gastrointestinal absorption of SPFX was inhibited by interaction with AL, but SPFX was the least inhibited among the new quinolones.
2. Twenty-three patients with respiratory infections, 5 with urinary tract infections and one with mastitis were treated orally at a daily dose of 100-300mg of SPFX for 3-4 days. The clinical results were excellent in 8 cases, good in 16 and poor in 5, giving the efficacy rate of 82.8%. We encountered adverse reactions to SPFX in two cases: vertigo, nausea and epigastric pain in one case, and fever and eosinophilia in another case.
These adverse reactions disappeared shortly after completion of the treatment. There were no cases in which the administration of SPFX was discontinued due to adverse effects.

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We evaluated the clinical efficacy and safety of sparfloxacin in a total of nine patients with respiratory tract infections; 6 with bronchiectasis and 3 with diffuse panbronchiolitis. Sparfloxacin was administered orally at a daily dose of 200 or 300mg, once or two divided doses. The time course of the serum and sputum concentrations was evaluated after administering a single dose of 300mg to two patients with copious mucopurulent sputum, and pharmacokinetic analysis was also performed.
The clinical response to the drug was rated as excellent in two cases, good in 5 and fair in one of the 8 evaluable cases, the efficacy rate being 88%. The clinical efficacy on the clinically isolated organisms was excellent in two cases with Haemophilus influenzae, good in two cases with Branhamella catarrhalis, good in one case each with Pseudomonas aeruginosa and glucosenonfermenting Gram-negative rod, and fair in one case with Streptococcus pneumoniae. No adverse reaction was observed except for one case with slight eosinophilia.
The peak concentrations in both the serum and sputum were observed at the same time in the two cases after a single administration of 300mg. The C_max of the sputum was 5.09μg/ml and 3.55μg/ml which compares to the serum concentration as 172 and 204%, respectively. On the third and ninth day of administering 300mg of sparfloxacin in one patient, the average concentrations before and 4 hrs after administration were 0.97μg/ml and 4.68μg/ml in the sputum, and 0.88μg/ml and 3.01μg/ml in the serum, respectively.
Good penetration of sparfloxacin into the sputum suggested the high therapeutic efficacy in respiratory infections.

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Laboratory and clinical studies were performed on a new quinolone derivative, sparfloxacin (SPFX).
The in vitro antibacterial activity of SPFX was evaluated against clinically isolated strains, and compared with those of norfloxacin (NFLX) and ciprofloxacin (CPFX). Against methicillinsensitive Staphylococcus aureus (MSSA; 10 strains), methicillin-resistant Staphylococcus aureus (MRSA; 10 strains), and Escherichia coli (10 strains), SPFX was the most active. Against MRSA, MIC₅₀ and MIC₉₀ of SPFX were 1.6μg/ml, and 6.25μg/ml, respectively. Against Klebsiella pneumoniae, the activity of SPFX was comparable to that of CPFX and higher than NFLX. Against Pseudomonas aeruginosa, SPFX was inferior to CPFX and superior to NFLX. Against Acinetobacter sp. SPFX was almost equal to CPFX, and superior to NFLX.
SPFX was administered to 6 patients (2 with pneumonia, 3 with acute bronchitis and 1 with bronchiectasis) orally at the dose of 150 to 300mg once a day for 7 to 12 days. The results were excellent in 1 case, good in 3, fair in 1 and unevaluable in 1. The causative organism was eradicated in 1 case, persisted in 1 and unevaluable in 4.
As for adverse reactions, a slight headache was observed in 1 case. No abnormal laboratory findings were found in any cases.

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Sparfloxacin (SPFX) is a newly developed oral pyridonecarboxilic acid antimicrobial agent. Among the current quinolone derivatives, SPFX is characterized as the most potent antimicrobial with a broad spectrum of activity and a long plasma elimination life. SPFX has also the advantage of extensive tissue penetration.
1) The in vitro postantibiotic effect of SPFX by exposing isolates at the 2 to 4 fold MIC for 1 to 2 hrs was 0.8 to 2.1 hrs for Escherichia coli, 2. 2 to 3. 2 hrs for Klebsiella pneumoniae, and 1.9 to 2.6 hrs for Pseudomonas aeruginosa. The in vitro effective regrowth time (ERT) of SPFX was longer than that of ofloxacin and enoxacin. In Klebsiella pnemoniae BK in a neutropenic mouse thigh infection model, the change in viable counts at 24 hrs was almost the same with dosage regimens of 2mg/kg twice-a-day, and 4mg/kg once-a-day.
2) SPFX was administered to 12 patients mainly with respiratory tract infections, the efficacy rate being 88% with efficient bacterial eradication. The dose regimen of 300mg once-a-day was better than that of 150mg twice-a-day in terms of the rate of “excellent” and the safety.

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We studied a newly developed oral quinolone antimicrobial agent, sparfloxacin (SPFX), and obtained the following results.
1) Serum and sputum levels of SPFX were determined after oral administration of SPFX 200mg to 2 patients with chronic obstructive pulmonary disease, and serum and urine levels of SPFX were determined after similar administration to 12 patients with various degrees of renal function.
The peak level of the drug in one patient with chronic obstructive pulmonary disease was 1.42μg/ml in serum and 2.05μg/ml in sputum, and in the other patient was 1.71μg/ml in serum and 1.28μg/ml in sputum. Peak sputum to serum level ratio was 144.4% and 74.9% respectively. The patients with renal failure were classified according to creatinine clearance (Ccr) values into Group I (n=5, 50≤Ccr<80ml/min), Group II (n=4, 20≤Ccr<50ml/min), and Group III (n=3, Ccr<20ml/min). The SPFX pharmacokinetic parameters did not differ greatly among the three groups. T., ranged from 4.7 to 7.2h, Cmax from 1.50 to 1.63μg/ml, T_1/2 from 17.3 to 20.2h, and AUC0_-72h from 39.4 to 44.7μg·h/ml. The total urinary elimination rate was 7.86% in Group I, 7.15% in Group II and 2.91% in Group III, indicating a renal function-related decrease in a elimination rate.
2) SPFX was used to treat 34 patients with respiratory tract infections and 1 patient with urinary tract infection. Clinical response was good in 32, fair in 1 and poor in 2 patients. Laboratory tests revealed elevation of GOT and GPT in one case, and eosinophilia in another case. No side effects caused by the drug were observed.

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We evaluated the penetration of sparfloxacin (SPFX), a new oral quinolone, into serum and sputum and its clinical usefulness in respiratory tract infections.
The concentrations of SPFX in the serum of four patients with respiratory tract infections were highest at 2-6 hours after oral administration of 300mg (0.209-1.97μg/ml), and those of the sputum were highest at almost same time (0.219-2.81μg/ml). The penetration of SPFX from serum to the sputum was 63.8-212%.
A daily dose of 300mg of SPFX was given orally for 7-15 days to 27 patients. The clinical efficacy was assessed as excellent in 10, good in 14, fair in 2 and poor in 1 case. The overall clinical efficacy rate was 88.9%, especially that of diffuse panbronchiolitis was 87.5%(as excellent in 4, good in 3 and poor in 1 case).
The bacteriological eradication rate was 94.7% against 19 strains. One strain, Pseudomonas aeruginosa, persisted.
No side effects or abnormal laboratory findings were observed in any of the patients.
The above results suggest that SPFX is a valuable and safe antimicrobial agent for once daily administration against respiratory tract infections.

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We studied clinical efficacy of SPFX and its effect on theophylline clearance.After obtaining an informed consent, SPFX was administered to patients with respiratory tract infections who visited our hospital and a related hospital. A total of 12 patients consisted of 1 with laryngopharyngitis, 4 with pneumonia, 4 with acute exacerbation of chronic bronchitis, and 3 with chronic respiratory tract diseases such as bronchiectasis.
The clinical response was excellent in I case, good in 10, and fair in 1, the efficacy rate being 91.7%. The bacteriological eradication was evaluated in 7 patients infected with 9 strains (5 Haemophilus influenzae, 2 Streptococcus pneumoniae, 1 Haemophilus parainfluenzae and 1 Branhamella catarrhalis), the eradication rate being 100%.
No side effects and abnormal laboratory values were observed.
To six patients who are in a convalescent stage after administration of sustained-release theophylline tablets (400-600mg/day) for a long period. The concentrations of theophylline and its metabolites in plasma and in urine were measured before and after coadministration of SPFX. SPFX slightly raised the theophylline concentrations and reduced the clearance into the urine slightly without any statistical significance. Thus, SPFX will likely find its greatest utility in treating respiratory tract infections without problems of theophylline side effect.

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Sparfloxacin (SPFX), a new orally active pyridonecarboxylic acid antimicrobial agent, was evaluated for its kinetics and clinical efficacy in elderly patients.
1) Pharmacokinetics: Thirty minutes after breakfast, SPFX was orally administered to 3 elderly subjects in a dose of 150mg and its pharmacokinetic parameters were determined. The mean maximum blood concentration (C_max) was 1.72μg/ml and the mean blood elimination half life (T_1/2) was 26.3 hours. Urinary recovery of the unchanged SPFX was 9.7% at 72 hours after administration.
2) Clinical studies: Thirty minutes after breakfast, SPFX was administered (150mg once a day) to 10 elderly patients (mean age 80.4 years) with respiratory tract infection (8 with pneumonia and 2 with lower respiratory tract infection). The clinical response was good in 8 and fair in 2, the efficacy rate being 80%. Bacteriological evaluation revealed eradication in 6 cases, replacement in 2, and unknown in 2.
No adverse reactions related to SPFX were found. Clinical laboratory testing revealed a slight elevation in total bilirubin and GPT values in each case, but the values returned to normal after withdrawal of SPFX.

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Sparfloxacin (SPFX), a new quinolone antimicrobial, was studied for its pharmacokinetics, efficacy and safety.
The results obtained were as follows.
1) SPFX was orally administered to 6 healthy volunteers at a dose of 300mg once daily for 7 days after breakfast. The mean peak plasma concentration was 1.15μg/ml attained 4h after the first dose. The peak was slightly higher after the 2nd dose, and thereafter increased to 1.40 to 1.48μg/ml after the 5th dose.
The urinary excretion recovery in 24 h was 6.03% of the 1st dose. The recovery increased gradually thereafter, and reached 9 to 10% at the 6th day.
2) SPFX was orally administered at a dose of 50 to 150mg twice daily or 300mg once daily for 6.5 to 15 days to a total of 17 patients (2 with chronic bronchitis, 2 with infected bronchiectasis, 2 with infected bronchial asthma, 2 with diffuse panbronchiolitis, 4 with bacterial pneumoni a, 2 with mycoplasmal pneumonia, 1 with bronchiolitis obliterans with organic pneumonia (BOOP), 1 with pyelonephritis, and 1 with acute uncomplicated cystitis). The clinical response in 14 of the 15 cases with respiratory infections excluding the one case with BOOP was excellent in 1 case, good in 10, fair in 1 and poor in 2. The response was good in the 2 cases with urinary tract infections.
Bacterial eradication after the treatment was observed in all strains of Staphylococcus aureus (3), Streptococcus pneumoniae (3), Enterococcus faecalis (1), Branhamella catarrhalis (2), Haemophilus influenzae (5), and Escherichia coli (1). However, only 1 of 3 Pseudomonas aeruginosa strains was eradicated.
Adverse reactions related to SPFX were not observed in any of the patients except in one case with a slight, transient increase in alkaline phosphatase.

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We performed bacteriological and clinical studies on sparfloxacin, a new quinolone derivative, in respiratory tract infections and obtained the following results.
1) The MICs of sparfloxacin against Streptococcus pneumoniae, Staphylococcus aureus, Branhamella catarrhalis, Haemophilus influenzae, Klebsiella pneumoniae, Serratia marcescens, Enterobacter cloacae, Acinetobacter calcoaceticus and Escherichia coli were under 0.1μg/ml, and were collectively superior to those of ciprofloxacin (CPFX), ofloxacin (OFLX) and cefteram pivoxil (CFTM-PI).
The MIC against methicillin-resistant Staphylococcus aureus was superior to that of CPFX, OFLX and CFTM-PI.
The antibacterial activity against Pseudomonas aeruginosa was almost equal to that of OFLX.
2) The MICs against Mycobacterium tuberculosis, Mycobacterium Kansasii, Mycobacterium fortuitum were each 0.1-0.5μg/ml.
3) The MICs against Chlamydia pneumoniae and Chlamydia trachomatis were 0.06μg/ml, which was superior to those of tosufloxacin (TFLX). OFLX, CPFX, fleroxacin (FLRX), lomefloxacin (LFLX) and norfloxacin (NFLX).
4) Ten patients with respiratory tract infections were treated with sparfloxacin and clinical efficacy was evaluated in 9 cases. The clinical efficacy was excellent in 1, good in 7, and fair in 1 case.
Side effects were observed in 2 patients with eruption and fever, and in 1 patient with insomnia.
Abnormal laboratory findings observed were: eosinophilia, thrombocytopenia, and elevation of LDH in one case each, and elevation of GOT in two cases.

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The antimicrobial activities of sparfloxacin (SPFX) against 437 clinically isolated strains of 15 species containing 10 of Gram-negative bacilli and 5 of Gram-positive cocci were compared with those of norfloxacin (NFLX), ofloxacin (OFLX), and ciprofloxacin (CPFX). As to Gramnegative bacilli the antimicrobial activities of SPFX were superior to the other drugs in general, but against some species the activities of SPFX was equal to CPFX. As to Gram-positive cocci the antimicrobial activities of SPFX were the strongest among the other drugs.
SPFX was administered to 22 cases with respiratory tract infections consisting of 15 cases with pneumonia, 2 with mycoplasma (MP) pneumonia, 2 with chronic bronchitis, one with diffuse panbronchiolitis (DPB), one with bronchiectasis, one with acute bronchitis and one Salmonella carrier. Good response against the drug was observed clinically in 13 cases with pneumonia, 2 with MP pneumonia, one with chronic bronchitis, and one with acute bronchitis.
The causative organisms were recognized in 9 cases including 4 of Staphylococcus aureus, 2 of Haemophilus influenzae and one each of Haemophilus parainfluenzae, Pseudomonas aeruginosa and Salmonella hadar. Bacteriological survey after the cessation of the treatment in all cases mentioned above with the exception of a case of staphylococcal pneumonia. Though one Pseudomonas aeruginosa strain remained, the other strains were eradicated after the treatment.
As to adverse reactions, nausea, eruption or thirstiness were observed in three cases. The abnormal laboratory findings observed in two cases were eosinophilia with renal dysfunction, and decrease of RBC count, respectively.

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We performed basic and clinical studies on sparfloxacin (SPFX), a new oral pyridonecarboxylic acid, in respiratory infections, with the following results.
1. The MICs of SPFX for causative organisms were measured using the agar dilution method with an inoculum size of 10⁶CFU/ml.
The MICs for 20 strains of Haemophilas influenzae were under 0.05μg/ml; for 25 strains of Streptococcus pneumoniae, 0.2-0.39μg/ml; for 20 strains of Branhamella catarrhalism, 0.025-0.1μg/ml; for 20 strains of Staphylococcus aureus, 0.1-12.5μg/ml; for 14 strains of Pseudomonas aeruginosa, 0.2-6.25μg/ml.
2. Clinical evaluation of SPFX in 7 patients with respiratory infections was excellent in 2, good in 4 and unknown in 1, the efficacy rate being 100%. In all cases, neither side effects nor abnormal laboratory findings were observed.
These results suggest that SPFX is a useful oral antibacterial agent in respiratory infections.

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We performed laboratory and clinical studies on sparfloxacin (SPFX), a new oral pyridonecarboxylic acid antimicrobial, with the following results.
1) Bacteriological evaluation
The MIC₉₀ values of SPFX determined for the clinical isolates were as follows: Staphylococcus aureus 0.39; Enterococcus faecalis 0.78; Escherichia coli ≤0.05; Citrobacter freundii 1.56; Klebsiella pneumoniae 0.39; Enterobacter cloacae 0.10; Enterobacter aerogenes 0.78 Serratia marcescens 12.5; Proteus uulgaris 0.39; Proteus mirabilis 3.13; Pseudomonas aeruginosa 100; Acinetobacter calcoaceticus 0.20μg/ml. These values of SPFX were lower as compared with the other 3 quinolones for Gram-positive cocci and Acinetobacter calcoaceticus except for Proteus spp. In contrast, the values of SPFX were equal or slightly higher than those of CPFX, but lower than the other 2 quinolones for the other Gram-negative rods.
2) Clinical evaluation
The clinical efficacy of SPFX was evaluated for a total of 25 patients, 4 with pneumonia, 6 with bronchitis, 1 with bronchitis and cystitis, 3 with pharyngitis, 2 with lymphadenitis (suspected), 1 with infectious atheroma, 6 with cystitis and 2 with bacillary dysentery. The patients consisted of 5 males and 20 females aged 20 to 92 years, and most of them had underlying diseases. The main isolated pathogens were Haemophilus influenzae in respiratory diseases and Escherichia coli in urinary tract infections. The clinical efficacy of SPFX in the dosage regimen of 50 to 300mg, once to 2 times daily for 2 to 25 days, was: excellent in 15 cases, good in 9, poor in 1, and unknown in 1, the efficacy rate being 96.0%. The side effects observed in 3 cases were soft stool, anorexia and diarrhea/headache/diaphoresis. An increase in eosinophil count was observed in two cases in the laboratory testing.

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Clinical efficacy of sparfloxacin (SPFX), a new quinolone antimicrobial, was evaluated in 8 patients with respiratory infections. The blood concentrations of the agent in elder patients were also measured.
The patients were aged from 26 to 80 years and consisted of 4 males and 4 females. Three had pneumonia, 3 had chronic bronchitis and the rest 2 had chronic bronchiectasis. SPFX was orally administered in a single daily dose of 200 mg for 7 to 28 days.
The clinical response was excellent in 1 case, good in 5, fair in 1, and poor in 1, the efficacy rate being 75%.
One strain each of Staphylococcus aureus and Pseudomonas aeruginosa was clinically isolated, but the strains were eradicated by treatment with the agent.
The side effect related to the agent could not be found except a slight elevation in alkaline phosphatase in one case.
To determine the pharmacokinetics in the elderly, 200mg of SPFX was orally administered to 6 patients aged 66 to 84 years with chronic respiratory diseases, and the blood concentrations were measured periodically after meals. The following pharmacokinetic parameters were obtained: C_max, 0.90±0.25μg/ml;T_max, 6.0±1.3 hours: T_1/2, 17.8±5.1 hours, and AUC_0→∞ 23.6±6.1μg·h/ml.

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We measured in vitro antimicrobial activity of sparfloxacin (SPFX) against clinical isolates and evaluated its clinical efficacy for respiratory infections. The obtained results were as follows:
1. Antimicrobial activity: Using the agar dilution method, the MICs were measured for 925 clinically isolated strains of 27 species (192 strains of Gram-positive cocci, 26 Branhamella catarrhalis, 452 enterobacteria, 232 glucose non-fermenting Gram-negative rods, 23 Bacteroides fragilis), and compared with those of norfloxacin (NFLX), enoxacin (ENX), ofloxacin (OFLX) and ciprofloxacin (CPFX). SPFX was excellent in its antimicrobial activity against MRSA (methicillin-resistant Staphylococcus aureus), Streptococcus pneumoniae and Pseudomonas aeruginosa, being the most potent except against a few species.
2. Clinical results: SPFX was administered to 6 patients with respiratory tract infections in a dose of 200mg or 300mg once or twice daily for 7 to 10 days. The clinical efficacy was assessed as excellent in 1, good in 3 and fairly good in 2 cases.
No subjective and objective side effects and no abnormalities in laboratory values were observed

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We have performed a clinical study on sparfloxacin, . a new broad-spectrum quinolone, in patients with respiratory tract infections. In addition, we have studied penetration of this agent into sputum. The results obtained were as follows.
1. A dose of 300mg of sparfloxacin was administered to 8 patients once a day for 7-14 consecutive days. On the 7 th day, venous blood and sputum were obtained 4 hr after administration. In these samples, the sputum concentration of sparfloxacin was 2.39±1.26μg/ml (mean±SD, n=8) and the serum concentration was 1.81±1.35μg/ml (mean±SD, n=8). The penetration ratio of this agent into sputum was 1.49±0.45 (mean±SD, n=8).
2. Antibacterial activity of sparfloxacin against clinical isolates was tested. The MICs of this agent against 18 strains of causative organisms were 0.013-0.78μg/ml for Haemophilus influenzae (9 strains), 0.39-1.56μg/ml for Streptococcus pneumoniae (5 strains), 0.10μg/ml for Branhamella catarrhalis (2 strains), 0.78μg/ml for Pseudomonas aeruginosa (1 strain) and 0.39μg/ml for Pasteurella multocida (1 strain). After administration of sparfloxacin, on the other hand, the MICs aginst two strains of Haemophilus influenzae increased from 0.05 to 1.56μg/ml and from 0.78 to 3.13μg/ml, respectively.
3. The clinical effects of sparfloxacin were evaluated in 24 patients with respiratory tract infections: 6 with acute bronchitis, 4 with pneumonia, 7 with bronchiectasis, 4 with diffuse panbronchiolitis and 3 with chronic bronchitis. The overall efficacy rate was 91.7% and 17 of 20 clinical isolates (85%) were eradicated with administration of sparfloxacin. And there were no serious side effects of this agent. Only one patient had stomatitis and glossitis after three days administration, but he recovered quickly without treatment for these symptoms.

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The newly developed broad-spectrum fluoroquinolone, sparfloxacin (SPFX). was evaluated in vitro and in vivo in comparison with ciprofloxacin, ofloxacin, enoxacin and norfloxacin. The results were as follows;
1. Antimicrobial activity: Minimal inhibitory concentrations (MICs) against 225 clinical isolates including 7 different species were determined by the microbroth dilution method.
Sparfloxacin showed excellent antimicrobial activity against Gram-positive and negative bacteria. The MIC values of sparfloxacin for Gram-positive bacteria including MRSA were superior to those of the other quinolones tested. The MIC values of sparfloxacin for Gramnegative bacteria were comparable to those of ciprofloxacin and superior to those of ofloxacin, enoxacin and norfloxacin. The MIC value of sparfloxacin for Mycoplasma pneumoniae was superior to ofloxacin.
2. Sparfloxacin concentration in serum and sputum: Sparfloxacin was orally administered in a single dose of 200mg or 300mg to five patients with chronic lower respiratory diseases, and its concentrations in serum and sputum were measured at intervals by HPLC or bioassay. The mean peak concentrations of sparfloxacin in the serum and sputum of patients administered 200mg were 0.54 and 0.88μg/ml, respectively, and those of patients administered 300mg were 2.59 and 2.67μg/ml, respectively. From these data, it was suggested that sparfloxacin had good penetration into the lung.
3. Clinical efficacy and adverse reactions: Thirty-five patients with respiratory tract infections were treated with sparfloxacin, and the overall efficacy ratio was 85.7%(excellent in 8 cases, good in 22, fair in 3, and poor in 2). As the side effect, heart burn in one case was observed. Although the eosinophilia in 3 cases, the elevation of GOT and GPT in 2 cases, the elevation of GPT and LDH in 1, and the elevation of amylase in 1 were observed as laboratory abnormal findings, they were mild and transient, and improved rapidly after completion of sparfloxacin treatment.

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We evaluated the usefulness of sparfloxacin, a new quinolone derivative, in lower respiratory infections. Its antimicrobial activity (90% minimum inhibitory concentration: MIC₉₀) against major respiratory pathogens was 0.39μg/ml against Streptococcus pneumoniae, 3.13μg/ml against methicillin-sensitive Staphylococcus aureus, 12.5μg/ml against methicillin-resistant Staphylococcus aureus, 0.025μg/ml against Haemophilus influenzae, 0.025μg/ml against Branhamella catarrhalis, 0.39μg/ml against Klebsiella pneumoniae, and 6.25μg/ml against Pseudomonas aeruginosa.
The maximum serum and sputum level of sparfloxacin in four patients with chronic respiratory tract infections during oral administration of 300mg once per day was 1.50±0.52μg/ml and 1.29±0.37μg/ml, respectively. The peak ratio (maximum sputum level/maximum serum level) was determined to be 0.99±0.55. The maximum serum and sputum level of sparfloxacin in one patient with chronic respiratory tract infection during oral administration of 200mg once per day was 0.66, and 1.60μg/ml. Urinary excretion rate of sparfloxacin within 24 hours was 4.55%. The serum half-lives of sparfloxacin in three patients were as long as 10.8-13.4 hours.
In 17 cases of lower respiratory tract infections, sparfloxacin was clinically evaluated. The drug was given orally at 200-300mg per day for 7-14 days. Causative organisms were Streptococcus pneumoniae (5 cases), Staphylococcus aureus (1 case), Branhamella catarrhalis (4 cases), Haemophilus influenzae (4 cases), Pseudomonas aeruginosa (3 cases). The rate of clinical response was 88.2%. The rate of bacterial elimination in sputum samples was 82.4%. No reversed effect was observed.
In a neutropenic mouse model of Pseudomonas aeruginosa pneumonia, oral administration of sparfloxacin (MIC against challenge strain: 0.39μg/ml) at a dose of 10mg/kg, twice per day, protected 100% of mice against an otherwise uniformally fatal outcome. The maximum plasma and lung level of sparfloxacin in neutropenic mice with Pseudomonas aeruginosa pneumonia during oral administration of 5mg/kg was determined to be 0.9±0.1μg/ml, and 3.3±0.2μg/ml, respectively. A high penetration of sparfloxacin into the infected lung parenchyma of mice was documented.
These results support that sparfloxacin is a very useful oral antimicrobial agent in the treatment of lower respiratory infections.

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We performed laboratory and clinical evaluations of sparfloxacin, a new oral quinolone, with the following results.
1) Antimicrobial activity
The minimum inhibitory concentrations (MICs) of sparfloxacin for a total of 309 clinically isolated strains were determined and compared with those of tosufloxacin, ofloxacin, and ciprofloxacin, using the MIC-2000 system.
Sparfloxacin had wide antimicrobial activities to clinically isolated strains except methicillinsensitive Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa. Especially, sparfloxacin showed better MICs to Streptococciig pneumoniae than the compared antimicrobial agents.
2) Clinical efficacy
Sparfloxacin (300 mg/day) was administered to 1 patient with bacterial pneumonia and 1 patient with chronic bronchitis two times per day. Four patients with chronic bronchitis were treated with sparfloxacin (300 mg) in once a day medication.
Clinical responses were excellent in 1 patient, and good in 5 patients. Clinical efficacy rate was 100%. One strain of Haemophilus influenzae was isolated and eradicated.
Side effects, and abnormally altered laboratory findings were not observed in all patients.

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A dose-finding study on sparfloxacin (SPFX: AT-4140), a new quinolone antimicrobial, was conducted by the double blind comparative design in patients with chronic respiratory tract infections. The patients were classified into three groups. Namely, SPFX 200 group was administered SPFX in a daily dose of 200mg, SPFX 300 group received a daily dose of 300mg SPFX, and ENX group received enoxacin (ENX), as a control, in a daily dose of 600mg (200mg×3).
The total number of patients enrolled in the trial was 148, of which 138 cases (48, 48, and 42 in SPFX 200, SPFX 300, and ENX groups, respectively), and 146 cases (52, 49 and 45 as grouped and ordered above), were evaluable by the committee for clinical efficacy and side effects, respectively.
1) The backgrounds of patients were well-balanced among the three groups.
2) The clinical efficacy rates were 72.9% for SPFX 200, 72.9% for SPFX 300, and 71.4% for ENX, In patients with only chronic bronchitis, the efficacy rate was 69.6%, 82.8% and 77.8%, respectively. The efficacy rate was highest in SPFX 300 group, but there was no significant difference among the three groups.
3) The bacterial eradication rates were 85.7%. 79.2% and 66.7%, without any significant difference in the three groups.
4) In the safety evaluation, the side effect rates were 7.7%, 12.2% and 11.1%, and the abnormal laboratory findings rates were 13.0%, 10.6% and 11.9%. There were no significant differences in the two safety evaluations.
5) The usefulness rates were 68.2%, 69.6% and 70.0%, without any significant difference among the three groups.
These results indicate that SPFX in a daily dose of 200mg and 300mg, and 600mg daily ENX in three 200mg doses, are almost equivalent in both efficacy and safety for patients with chronic respiratory tract infections.
However, among the three groups tested, a 300mg dosage of SPFX was most excellent in patients with only chronic bronchitis. Therefore, the 300mg daily dose was considered to be an appropriate medication for such intractable chronic respiratory tract infections.

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Sparfloxacin (SPFX), a new oral quinolone antibacterial, was evaluated for efficacy, safety and usefulness in patients with chronic respiratory tract infections by the randomized double blind comparative study using ofloxacin (OFLX) as a control drug. The patients were given either SPFX (300 mg once daily) or OFLX (200 mg three times daily) for 14 days, in principle. The results obtained were as follows:
1) A total of 185 patients (SPFX 97, OFLX 88) were enrolled in the trial. The number of evaluable cases according to the criteria proposed by the committee was 157 for clinical efficacy (SPFX 84, OFLX 73), 174 for side effects (SPFX 94, OFLX 80), 162 for laboratory findings (SPFX 87, OFLX 75), and 163 for usefulness (SPFX 86, OFLX 77). There was no significant difference in the rate of background factors of the patients, except in the distribution of pretreatment with antimicrobial agents, between the two groups.
2) The clinical efficacy rate judged by the committee was 82.1%(69/84) in the SPFX group and 83.6N (61/73) in the OFLX group, and judged by the doctor in charge was 76.2%(64/84) and 79.5%(58/73), respectively, without any significant difference between the two groups.
3) The bacteriological eradication rate was 84.2% (32/38) in the SPFX group and 77.4% (24/31) in the OFLX group, without any significant difference between the two groups.
4) The incidence of side effects was 13.8% (13/94) in the SPFX group and 15.0% (12/80) in the OFLX group, and that of abnormal laboratory findings was 13.8% (12/87) in the SPFX group and 16.0% (12/75) in the OFLX group, the difference between the two groups being without any significance.
5) The usefulness rate judged by the committee was 70. 9%(61/86) in the SPFX group and 77. 9%(60/77) in the OFLX group, and judged by the doctor in charge was 70.9%(61/86) and 72.7%(56/77), respectively, without any significant difference between the two groups.
The above results indicate that SPFX (300 mg once daily) is as useful as OFLX (200mg three times daily) in the treatment of patients with chronic respiratory tract infections.

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Sparfloxacin (SPFX), a new oral quinolone antibacterial, was evaluated for efficacy, safety and usefulness in patients with bacterial pneumonia by the randomized double blind comparative study using ofloxacin (OFLX) as a control drug. The patients were given either SPFX (300mg once daily) or OFLX (200mg three times daily) for 14 days, in principle. The results obtained were as follows:
1) A total of 173 patients (SPFX 86, OFLX 87) were enrolled in the trial. The number of evaluable cases according to the criteria proposed by the committee was 149 for clinical efficacy (SPFX 72, OFLX 77), 164 for side effects (SPFX 82, OFLX 82), 160 for laboratory findings (SPFX 78, OFLX 82), and 150 for usefulness (SPFX 72, OFLX 78). There was no significant difference in the rate of background factors of the patients except in the distribution of severity of the disease between the two groups.
2) The clinical efficacy rate judged by the committee was 93. 1%(67/72) in the SPFX group and 90.9%(70/77) in the OFLX group, and judged by the doctor in charge was 93.1%(67/72) and 92.2%(71/77), respectively, without any significant difference between the two groups.
3) The bacteriological eradication rate was 100%(22/22) in the SPFX group and 96.6%(28/29) in the OFLX group, without any significant difference between the two groups.
4) The incidence of side effects was 6.1%(5/82) in both groups, and that of abnormal laboratory findings was 19. 2%(15/78) in the SPFX group and 19, 5%(16/82) in the OFLX group, the difference between the two groups being without any significance.
5) The usefulness rate judged by the committee was 90.3%(65/72) in the SPFX group and 88.5%(69/78) in the OFLX group, and judged by the doctor in charge was 88.9%(64/72) and 87.2%(68/78), respectively, without any significant difference between the two groups.
The above results indicate that SPFX (300mg once daily) is as useful as OFLX (200mg three times daily) in the treatment of patients with bacterial pneumonia.

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We performed basic and clinical studies of sparfloxacin (SPFX), a new pyridonecarboxylic acid derivative, on 108 patients with acute infectious enteritis and carriers. SPFX was orally administered at a once a day dose of 200mg for 7 days in salmonellosis and for 5 days in other infections.
A total of 82 cases was evaluated: 43 cases with shigellosis, 17 with Salmonella enteritis, 5 with Campylobacter enteritis, 2 with enteropathogenic Escherichia coli (EPEC) enteritis, 6 with polymicrobial infectious enteritis and 9 with acute enteritis from undetected infectious pathogens.
The clinical efficacy for symptoms was 1009 in 43 cases. On the bacteriological response, the eliminated rate was 93.0% in 43 strains of Shigella spp. and 86.7% in 15 of Salmonella spp. All strains consisting of Campylobacter spp.(n=7), Vibrio parahaemolyticus (n=2), EPEC (n=2) and one each of Aeromonas hydrophila and Plesiomonas shigelloides were eliminated. The overall clinical efficacy rate was 93.0% in 43 cases with shigellosis and 88.2% in 17 with Salmonella enteritis. Excellent and/or good responses were observed in 5 cases with Campylobacter enteritis, in 2 with EPEC enteritis, in 6 with polymicrobial infectious enteritis and in 9 with acute enteritis from undetected infectious pathogens.
As side effects, eruption and abdominal discomfort were observed in one each (1.9%) out of the 108 cases. Deteriorations in laboratory findings were noted in 9 (9.8%) out of 92cases, which included the elevation of s-amylase, GOT, GPT, LDH or eosinophili and WBC decrease.
The MIC₉₀ value of SPFX on Shigella spp. and Salmonella spp. were 0.05μg/ml and 0.1μg/ml, respectively. The values were similar to those of ciprofloxacin and superior to those of enoxacin, ofloxacin, norfloxacin, pipemidic acid and nalidixic acid (NA). The MIC value on Campylobacter spp. was lowest among the pyridonecarboxilic acid derivatives.
Seven of the 43 strains of Shigella were high NA-resistant strains (MIC;>100μg/ml) and 3 poor responders to SPFX were infected by these strains.

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