In vitro and in vivo antibacterial activity of temafloxacin (TMFX), a new fluoroquinolone, was compared with that of ciprofloxacin (CPFX), ofloxacin (OFLX), and norfloxacin (NFLX). The results are summarized as follows:
1) The potency of TMFX against gram-positive aerobic bacteria was higher or comparable to that of CPFX, OFLX and NFLX.
2) TMFX was less active than CPFX against most gram-negative enteric bacteria and Pseudomonas species, but was generally as active as OFLX and NFLX, except against Proteus species and Morganella morganii.
3) TMFX showed bactericidal action at concentrations near the MIC against a variety of bacteria.
4) The activity of TMFX was unaffected by different media, inoculum sizes, and horse serum, but decreased under acidic conditions and in the presence of magnesium ion.
5) TMFX yielded low-frequency mutation rates, the same as other fluoroquinolones.
6) TMFX strongly inhibited the supercoiling activity of DNA gyrase purified from Escherichia coli.
7) The in vivo efficacy of TMFX after oral administration was higher or comparable to that of CPFX against Staphylococcus aureus, E. coli and Pseudomonas aeruginosa systemic infection models.

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The MIC₉₀ of temafloxacin (TMFX) against 13 to 50 clinical isolates of Staphylococcus aureus, methicillin-resistant S.aureus (MRSA), coagulase-negative staphylococci (CNS), Streptococcus pyogenes, other β-streptococci, Streptococcus pneumoniae, Enterococcus faecalis, Enterococcus faecium, Escherichia coli (R⁺), Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris, Morganella morganii, Providencia rettgeri, Citrobacter freundii, Enterobacter cloacae, Serratia marcescens, Pseudomonas aeruginosa, Xanthomonas maltophilia, Pseudomonas cepacia, Acinetobacter calcoaceticus, ampicillinresistant Haemophilus influenzae and Bacteroides fragilis was 0.2, 0.78, 0.39, 0.78, 1.56, 1.56, 1.56, 6.25, 1.56, 0.78, 0.78, 0.78, 1.56, 12.5, 3.13, 3.13, 6.25, 6.25, 3.13, 6.25, 0.78, ≤0.013, and 3.13 μg/ml, respectively.
TMFX did not manifest cytostatic activity against cultured CHO-K1 HeLa, or human neuroblastoma IMR32 cells up to 10 μg/ml, and its cytotoxicity was the same as that of ofloxacin (OFLX). Synergy between the bactericidal effect of TMFX and serum complement was not confirmed, although living E.coli NIHJ JC-2 cells were often engulfed and digested in mouse cultured macrophages in the presence of higher than 1/8 MIC of TMFX. TMFX caused the withdrawal of axon-dendrites of redifferentiated neuroblastoma IMR32 cells at a concentration of 5μg/ml, however, its neurotoxicity was as low as that of OFLX.

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The in vitro and in vivo antibacterial activity of temafloxacin (TMFX), a new quinolone, was compared with that of ciprofloxacin (CPFX), ofloxacin (OFLX), enoxacin (ENX) and tosufloxacin (TFLX).
TMFX had a broad antimicrobial spectrum similar to those of the reference quinolones.
The in vitro antibacterial activity of TMFX against Staphylococcus spp. including methicillinresistant Staphylococcus aureus (MRSA) and Streptococcus spp. was inferior to that of TFLX and equivalent or superior to that of the other reference drugs. The antibacterial activity of TMFX against Enterobacteriaceae and Pseudomonas spp. was inferior to that of CPFX and TFLX, but equivalent or superior to that of the other reference drugs.
The therapeutic efficacy of TMFX against systemic infection due to Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa in mice was equal to that of TFLX and superior to that of the other reference drugs. The therapeutic efficacy of TMFX against neutropenic mice infected with P. aeruginosa E7 was equivalent to that of CPFX and superior to that of the other reference drugs.
The therapeutic efficacy of TMFX against respiratory tract infections due to K.pneumoniae and S. pneumoniae and urinary tract infections due to P. aeruginosa was superior to that of OFLX and CPFX.
The peak serum concentration of TMFX was lower than that of OFLX, but higher than that of the other reference drugs. The peak concentration of TMFX in the lung and kidneys was lower than that of OFLX, the same as the serum concentration, but higher than that of the other reference drugs. On the other hand, TMFX had the longest serum half-life of all of the test drugs.

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The in vitro activity of temafloxacin (TMFX), a new fluoroquinolone, was evaluated against anaerobic bacteria, and the inducibility of Clostridium difficile overgrowth in murine cecum by 5-day administration of temafloxacin was also studied. The antimicrobial activity of ciprofloxacin, ofloxacin and norfloxacin were compared with that of TMFX. TMFX showed a broad spectrum, and was the most active against 45 reference strains (44 species) tested, although some species of genus Lactobacillus had low susceptibility to this compound. Against all recent clinical isolates tested, TMFX was the most active among antimicrobial agents used; 90% of Bacteroides fragilisisolates were inhibited at 3.13 μg/ml of the compound. TMFX showed strong bactericidal activity against B.fragilis. A 5-day administration of TMFX did not provoke the overgrowth of C. difficile in murine cecum.

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The in vitro and in vivo antibacterial activities of temafloxacin (TMFX), a new synthetic antimicrobial agent, were compared with those of ciprofloxacin (CPFX), ofloxacin (OFLX) and enoxacin (ENX).
TMFX had a broad spectrum of antibacterial activity against gram-positive and gram-negative aerobes and anaerobes. In a comparison of MIC₉₀ against clinical isolates, TMFX was superior to the reference drugs against methicillin-sensitive Staphylococcus aureus and methicillin-resistant S.aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcus faecium, Acinetobacter cakoaceticus, Haemophilus influenzae and Moraxella catarrhalis. But TMFX was slightly inferior to those against Proteus sp. Against other species, TMFX was more active than ENX, almost the same as OFLX and less active than CPFX. TMFX was the most active of the reference drugs against anaerobes.
The antibacterial activity of TMFX was not affected by the kind of medium, addition of horse serum or inoculum size. The activity of TMFX was slightly reduced in acidic or alkaline pH medium.
Kinetic study of the bactericidal effect TMFX showed that the effect was dose-dependent, like those of reference drugs.
Morphological observation by phase-contrast microscope showed that TMFX induced the formation of filamentous cells and lysis of Escherichia coli, and also induced lysis of Pseudomonas aeruginosa and A. calcoaceticus. These effects were observed above 0.5 × MIC. Observation of the nucleus of elongated E. coli treated with TMFX by microscope revealed thet the nucleus was single, thus TMFX inhibited the nuclear reproduction of the elongated cells.
TMFX was the most effective of the reference drugs against experimental systemic infections in six test strains of mice, although the MICs of TMFX were similar to those of OFLX and inferior to those of CPFX.

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The antibacterial activity of a new quinolone, temafloxacin (TMFX), was compared with that of ciprofloxacin (CPFX), enoxacin (ENX), norfloxacin (NFLX) and ofloxacin (OFLX), using clinical isolates. The activity of TMFX against gram-positive bacteria was superior to that of the reference quinolones. The activity of CPFX was superior to that of TMFX against many kinds of gram-negative bacteria, but against Haemophilus influenzae and Moraxella catarrhalis, TMFX was equal to CPFX. Against Bacteroides fragilis, TMFX was superior to the reference quinolones.
The antibacterial activity of TMFX was influenced by the pH of the medium and the addition of Mg²⁺ into the medium, as was that of the reference quinolones.
TMFX acted bactericidally on Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa at higher concentrations than MIC or 2MIC for the respective bacteria. Microscopic observation of E. coli and P. aeruginosa treated with TMFX and OFLX showed that both drugs changed E. coli cells to filamentous form, and some P. aeruginosa cells to a bulging form at higher concentrations than 8MIC. The IC₅₀ (50% inhibitory concentration) of TMFX for DNA gyrase of E. coli KL-16 was the same as that of OFLX.
The frequency of isolation of strains resistant to TMFX at 8MIC was the same as that of the reference quinolones.
It was suggested that TMFX would be effective against many bacterial infections.

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Antimycoplasmal activities of new quinolones were investigated in vitro and in vivo. The in vitro antimycoplasmal activities of new quinolones were compared with those of tetracyclines and macrolides as reference drugs. Among new quinolones, MICs of temafloxacin (TMFX), ofloxacin (OFLX), and ciprofloxacin (CPFX) determind by the agar dilution method were most active against fifty strains of Mycoplasma pneumoniae, but enoxacin and norfloxacin were not active. In the next experiment, MICs and MBCs of antimicrobial agents were determined by the broth microdilution method. Although MICs obtained by the broth dilution method were approximately the same as those of the agar dilution method in the corresponding antimicrobial agents, TMFX, OFLX and CPFX, MBCs were only 15 times higher than their MICs. MBCs of tetracycline, minocycline, erythromycin and josamycin were markedly higher: 1000 times their MICs. These results suggested that TMFX, OFLX and CPFX had more potent mycoplasmacidal activity than macrolides and tetracyclines. To determine the in vivo activity of these drugs against M.pneumoniae, they were orally administered to M. pneumoniae-infected hamsters. In the case of 15 days of daily administrations, TMFX was most active compared with OFLX and CPFX at 200 mg/kg once per day or 100 mg/kg twice per day. At 5 days of daily administrations, none of these drugs (200 mg/kg/day) was active in eliminating M. pneumoniae. These cumulative results suggest that TMFX might be a useful antimicrobial agent in infection with M.pneumoniae, and further investigations on the clinical effects are needed.

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The therapeutic effects of temafloxacin (TMFX) on various experimental infection models in mice were studied in comparison with those of ofloxacin (OFLX), ciprofloxacin (CPFX), norfloxacin (NFLX) and enoxacin (ENX).
1. TMFX was more effective than OFLX, CPFX, NFLX and ENX against intraperitoneal infections due to Staphylococcus aureus and streptococcal species in mice. TMFX was also superior to reference drugs against Pseudomonas aeruginosa infections. With infections due to Enterobacter aerogenes 816 and Citrobacter freundii 916, TMFX was inferior to CPFX and was equal or superior to OFLX, NFLX and ENX. The efficacies of TMFX, OFLX, ENX and NFLX in neutropenic mice were slightly reduced.
2. In experimental pneumonia caused by Klebsiella pneumoniae B-54 in mice, the therapeutic effect of TMFX was equal to those of OFLX and CPFX. However, TMFX showed a more potent therapeutic effect than OFLX, CPFX, NFLX and ENX against experimental pneumonic infections induced by Mycoplasma pulmonis m-53 in mice.
3. In ascending urinary tract infections caused by Escherichia coli 2004 in mice, the therapeutic effect of TMFX was equal to those of OFLX and CPFX. TMFX was more effective than OFLX and CPFX for kidney infections caused by Proteus mirabilis TU-1698 in carrageenan treated mice. Furthermore, the therapeutic effect of TMFX was equal to those of OFLX and CPFX in Enterococcus faecalis 1227 and Pseudomonas aeruginosa 169 infections.
4. In intestinal tract infections caused by Salmonella typhimurium TPRL-10781 in mice, the therapeutic effect of TMFX was equal or superior to that of OFLX and was superior to those of CPFX, ENX and NFLX.
5. In a subcutaneous abscess model caused by Staphylococcus aureus Y-14 (MRSA) and S.aureus CH-91 in mice, the suppressive effect of TMFX was equal to that of OFLX.

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The antibacterial effect of temafloxacin (TMFX) was compared with those of ofloxacin (OFLX) and ciprofloxacin (CPFX) in experimental pneumonia induced by Klebsiella pneumoniae B-54 in mice by means of whole body autobacteriography. Upon treatment with 12.5 mg/kg or 3.13 mg/kg of TMFX in mice with the pneumonia, the bacterial distribution on autobacteriograms was significantly reduced as compared with untreated controls. The antibacterial effects of TMFX observed in the distribution density of the autobacteriograms was comparable to or greater than that of OFLX and remarkably greater than that of CPFX. At 30 minutes after administration of 12.5 mg/kg to mice with pneumonia, the concentration of TMFX in the lung was 1.62 ± 0.35 μg/g which was comparable to that of OFLX. From 1 hour after administration, the concentration of TMFX was considerably higher than that of OFLX. The concentration of TMFX was 0.9 ± 0.29μg/g even at 4 hours after administration. The bactericidal activity in the lungs of mice with pneumonia at the time of treatment with 12.5 mg/kg of TMFX was more potent than that of OFLX. TMFX also showed a good effect in terms of in vitro bactericidal activity against K. pneumoniae B-54.

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An experimental inflammatory pouch infection model was prepared in rats with Staphylococcus aureus Y-14 which shows β-lactamase production and resistance to methicillin. Using this model, the antibacterial effect and exudate concentration of temafloxacin (TMFX) were studied in comparison with those of ofloxacin (OFLX) and ciprofloxacin (CPFX). After a single oral administration at a dose of 100 mg/kg, TMFX showed a more potent antibacterial effect than OFLX and CPFX. The peak exudate concentration of TMFX was similar to that of OFLX and higher than that of CPFX. The exudate concentration of TMFX persisted longer than that of OFLX. The persistent property of TMFX was well reflected in its antibacterial effect. Under twice daily administration for 3 days at a dose of 100 mg/kg, both concentration levels and antibacterial activities of TMFX were equal to OFLX during the treatment period. Furthermore, the peak exudate concentrations of these quinolones in pouches infected with S. aureus Y-14 were higher than those found in uninfected pouches.

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A microbiological assay procedure has been developed for determining temafloxacin (TMFX) in human serum and urine. Drug concentrations were determined by the disk-plate method, using Escherichia coli Kp as the test strain and heart infusion agar as the test medium. The lowest detectable concentration of TMFX was 0.156 μg/ml in serum, diluted urine and 1/15M phosphate buffer (pH7.0).

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A simple and precise high-performance liquid-chromatography procedure has been developed for the determination of temafloxacin in human serum and urine. Pretreatment of serum samples was carried out by ultrafiltration after addition of an internal standard in a displacing reagent containing sodium dodecyl sulfate and acetonitrile. The ultrafiltrates are directly analyzed using a reverse-phase analytical column and fluorescence detection. The mean intra-assay coefficient of variation for serum was less than 2.6% in the 5.0-0.01μg/ml range, whereas for diluted urine it was less than 1.0% in the 4.0-0.02μg/ml range. Serum and urine samples in phase I studies were analyzed by HPLC and the bioassay method to determine the precision of each. A good correlaton was observed between the two.

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The pharmacokinetics of temafloxacin (TMFX) were studied and compared with those of ofloxacin (OFLX), ciprofloxacin (CPFX) and erythromycin (EM) in mice, rats and hamsters.
1. In rats orally dosed with 20 mg/kg, there were no significant differences between males and females in the plasma AUC or in urinary recoveries.
2. In rats, the plasma AUCs were linearly related to oral dose in the range of 10-100 mg/kg.
3. In rats, the oral bioavailability of TMFX was 60% from the p.o./i.v. AUC ratio and 76% from the p.o./i.v. urinary recovery ratio.
4. In mice and rats orally dosed with 20 mg/kg, the peak serum levels were in the order of OFLX, TMFX and CPFX, whereas the serum AUCs were in the order of TMFX, OFLX and CPFX. The peak lung levels were in the order of TMFX and/or OFLX and CPFX, whereas the lung AUCs were in the order of TMFX, OFLX and CPFX.
5. In hamsters orally dosed with 50 mg/kg, the peak serum levels were in the order of OFLX, TMFX, EM and CPFX and the serum AUCs were in the same order. In contrast, the peak lung levels were in the order of TMFX, OFLX, EM and CPFX, whereas the lung AUCs were in the order of TMFX, OFLX, CPFX and EM. The lung-to-serum concentration ratios of TMFX were 2-fold higher than those of OFLX.
6. In rats intravenously dosed with 10 mg/kg, the cerebrospinal fluid (CSF)-to-serum concentration ratios of TMFX were 1/2 to 1/3 of those of OFLX.
7. In rats orally dosed with 20 mg/kg, the recoveries of TMFX in urine and bile were similar to those of OFLX.
8. Binding rates to the serum proteins of mice, rats, rabbits, dogs, monkeys and humans were 29.5, 34.1, 35.8, 25.6, 29.0 and 26.6%, respectively.

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Absorption, distribution and excretion of temafloxacin (TMFX) were studied in rats after oral and intravenous administration of [¹⁴C] TMFX.
1.[¹⁴C] TMFX was absorbed mainly from the upper parts of the rat small intestine, but not from the stomach.
2. Blood levels of radioactivity in fasted rats reached a peak of 5.9μg equiv./ml at 0.7 h after oral administration. The radioactivity concentration in blood declined with a half-life of 2.3 h. In non-fasting rats, there was an appreciable decrease in the absorption of TMFX from the gastrointestinal tract.
3. Tissue radioactivity concentrations after oral administration of [¹⁴C] TMFX were much higher in all tissues, except for the central nervous system, than those in plasma. In most tissues, radioactivity levels reached a peak at 0.5-1 h after dosing: during these times, the highest radioactivity concentrations were observed in the kidney and liver. By 24 h after administration, radioactivity in most of tissues had declined to below 0.2μg equiv./g. There was no tendency for radioactivity to accumulate in particular tissues.
The time-courses of the tissue radioactivity concentrations in female rats were similar to those in male rats, indicating no sex differences in distribution and excretion profiles.
4. In pigmented rats, radioactivity was incorporated into melanin containing tissues such as hair follicles and the uveal tract of eye, and decreased relatively slowly.
5. The binding rate of [¹⁴C] TMFX to human serum albumin (16%) was higher than that to other serum proteins: a1-acid glycoprotein (6%), β-globulin (4%) and bovine β-lipoprotein (6%), indicating that TMFX binds mainly to albumin in plasma.
6. Within 5 days after oral administration of [11C] TMFX to fasted rats, about 47% and 55% of the dose had been excreted in the urine and feces, respectively. Most of the radioactivity was excreted within 24 h.
7. Excretion in the bile after intravenous and oral administration of [¹⁴C] TMFX was approximately 25% of the dose. Some of the radioactivity excreted in the gastrointestinal tract via bile was reabsorbed, and circulated entero-hepatically.

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The absorption, distribution and excretion of temafloxacin (TMFX) were studied in rats after multiple oral administrations of [¹⁴C] TMFX at a once-daily dose of 20 mg/kg for 21 days.
1) The blood levels of radioactivity reached a maximum concentration at 1 h, corresponding to the range of 1.4-1.8 μ equiv./ml (F value=7-9), and a low concentration at 8 h, corresponding to the range of 0.2-0.3 μ equiv./ml (F value=1.0-1.4), after each oral administration. The high and low radioactivity concentrations, respectively, were kept at a steady state level from the 1st to the 21st administration.
2) After 1, 7, 14 and 21 dosings, the radioactivity concentrations in blood declined exponentially with a half-life of 3 h and the areas under the curve were within the range of 5-6 μ equiv. h/ml. There were n o changes in pharmacokinetic parameters with multiple administrations.
3) One hour after the 21st administration, the radioactivity concentrations in the kidney and liver, but not the gastrointestinal tract, were about 9 μ equiv./g (Fvalue=4 5). The radioactivity concentrations in the brain, eye and bone were low being about 0.2-0.6 μ equiv./g (F value=1.0-3.0). The radioactivity concentrations in other tissues were similar to or slightly higher than that in blood (1.6μ equiv./ml). At 48 h after the 21st dosing, the concentrations in most tissues were below 0.2 μ equiv./g, which suggests relatively rapid excretion of the radioactive components from rats. There was no noteworthy change in the radioactivity distribution in organs between the single and the 21 administrations.
4) The daily excretion rates of radioactive components in urine and feces were in the range of 22-24% and 73-78%, respectively, through the 21 dosings. The cumulative excretion rates per total of doses in urine and feces were 23% and 76%, respectively, within 96 h after the final dosing. The remains of radioactivity in the body at 96 h after the final dosing were 0.04% of the total doses.
From these results, it is considered that there was little or no accumulation of drug-related radioactivity in the body and almost no change in the excretion balance of urine and feces during and after multiple dosing with [¹⁴C] TMFX.

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The metabolism of temafloxacin (TMFX) was studied in rats after oral administration of [14C] TMFX (20 mg/kg).
1. In plasma and urine, unchanged TMFX accounted for 94% of total plasma or urinary radioactivity. Metabolites, EDA and MEDA, which were formed by oxidation and cleavage of the piperazine ring of TMFX, were detected with tracer amounts.
2. Two major metabolites together with unchanged TMFX were detected and identified in bile: glucuronic acid conjugate and sulfuric acid conjugate of TMFX. Three other minor metabolites, EDA, MEDA and aminoquinolone derivative (AQ) of TMFX, were also detected and characterized in bile.
3. The main metabolite in bile was the ester glucuronide of TMFX, followed by unchanged TMFX and TMFX N-sulfate. Other metabolites, AQ, EDA and MEDA, accounted for only 0.6 to 2.7% of total plasma, urinary and biliary radioactivity.
These results suggest that TMFX is hardly metabolized in rats, and most orally administered TMFX behaves as unchanged drug.

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Using radioassay, bioassay and HPLC methods, the absorption, metabolism and excretion of temafloxacin (TMFX) were investigated in dogs after oral administration of [14C] TMFX in a dose of 20mg/kg.
1. Plasma radioactivity levels reached a peak concentration of 8.5μg equiv./ml 1.5 h after oral administration and declined with a half-life of 5h.
2. The plasma protein binding rates of the drug metabolites at both 1.5 and 6 h after oral administration were approximately 42%.
3. By 7 days after oral administration, about 53 and 45% of dose was excreted in urine and feces, respectively.
4. In both plasma and urine, unchanged TMFX accounted for more than 80% of the total radioactivity in the corresponding samples, and the ester glucuronide of TMFX represented 9 to 14%. Other metabolites, the ethylenediamine (EDA) and methylethylenediamine (MEDA) derivatives of TMFX, amounted to only both 0.2 to 4%. Thus, TMFX was hardly metabolized in the dog, the same as in the rat, and most of the dose administered remained in its unchanged form.
5. The concentration ratios of the enantiomers of TMFX (SIR) were 1.1 to 1.2 in plasma and 1.3 to 1.4 in urine, and that of the ester glucuronide of TMFX was 0.9 in urine, suggesting that the pharmacokinetics of the enantiomers differ slightly from each other in the dog.

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The placental transfer and secretion into milk of temafloxacin (TMFX) were assessed in rats on the 13th and 19th day of pregnancy, and in lactating rats on the 7th and 13th day after delivery following oral administration of [1AC] TMFX at a dose of 20 mg/kg.
1. Irrespective of the stages of pregnancy, the concentrations of radioactivity in the fetus were nearly equal to the corresponding maternal blood concentrations. The transfer ofradioactivity to the fetus on the 13th and 19th day of pregnancy was less than 0.01 and 0.18%, respectively, of the dose to the dams throughout the observation periods. At 24 h after administration, the radioactivity in the fetus had declined to near background level. There was no tendency to accumulate drug-associated radioactivity in the fetus.
2. After oral administration of [¹⁴C] TMFX to lactating rats on the 7th day after delivery, the concentrations of radioactivity in milk were 2-4 times higher than in blood throughout the observation periods. The elimination half-life of radioactivity in milk was similar to that in blood. Most of the radioactivity in milk 1 and 3 h after administration was accounted for by unchanged TMFX.
3. The transfer of [¹⁴C] TMFX and/or its radioactive metabolites to sucklings via milk was less than 0.08% of the dose to the dams on the 13th day after delivery throughout the observation period.
4. The present whole-body autoradiographic findings using pregnant and lactatingrats confirmed the above results of tissue distribution studies.

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As part of a safety evaluation program for the new synthetic antibacterial agent temafloxacin (TMFX), a 26-week oral toxicity study (0, 100, 200 and 400mg/kg/day) was carried out on rats and followed by a 4-week recovery study. Four rats died during the treatment period and 3 rats receiving 400mg/kg were killed. In the moribund animals, soiled hair, gum, sedation and hypothermia were noted and food consumption and body weight decreased. In the surviving rats, body weight decreased in females receiving 400mg/kg and in males receiving 200mg/kg or more. Water intake increased in rats receiving 400mg/kg. As to clinical pathology, BUN, creatinine and inorganic phosphate were elevated in moribund rats receiving 100mg/kg. Urinary sodium decreased in females receiving 400mg/kg and in males receiving 200mg/kg or more and the serum level of protein decreased in males receiving 200mg/kg or more. The weights of the kidney, adrenal glands and uterus in the 400mg/kg group were higher than those of the control group. Enlarged ceca, atrophy of the thymus and spleen, discoloration of the liver and a white line in the renal medulla were found in rats receiving 400mg/kg. Renal lesions such as tubular dilatation and degeneration or regeneration of the collecting tubular epithelium were observed microscopically. After discontinuation of drug administration, most of the changes detected on clinical observation and laboratory examination disappeared. Thus, the long-term non-toxic dose of TMFX was estimated to be 100mg/kg in rats.

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As part of a safety evaluation program for the new synthetic antibacterial agent temafloxacin (TMFX), a 26-week oral toxicity study (0, 50, 75 and 100mg/kg/day) was carried out on beagle dogs and followed by a 4-week recovery study. No animal died during the treatment period. Transient salivation, vomiting, hyperemia of the skin and visible mucosa were noted in all TMFXtreated groups. One male dog receiving 100mg/kg showed a transient staggering gait. In addition, sedation and transient edema of the eyelids were observed in a female receiving 100mg/kg. Body weight decreased in males receiving 100mg/kg and in females receiving 75mg/kg or more. Food consumption tended to decrease in all TMFX-treated groups. On electroretinography, the a and b wave amplitudes were reduced in the 100mg/kg dogs. As to clinical pathology, GOT activity was slightly elevated in one male dog in the 100mg/kg group. Pathology revealed chondrocyte clusters and fissures in the middle cartilage zone in a few dogs in the 75mg/kg and 100mg/kg groups. After discontinuation of drug administration, the changes detected by clinical observation and laboratory examination disappeared or diminished. Thus, the long-term non-toxic dose of TMFX was estimated as 50mg/kg in dogs.

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The antigenicity (immunogenicity and allergenicity) of temafloxacin (TMFX), a new antibacterial agent, was examined in guinea pigs and mice.
In guinea pigs, immunogenicity (potential of mainly IgG antibody production) and allergenicity (potential of induction of type I allergic reaction) were examined by active systemic anaphylaxis (ASA), homologous 4-h passive cutaneous anaphylaxis (PCA) and diffusion-in-gel precipitin tests. ASA was not elicited by a challenge of TMFX or acetylated TMFX-bovine serum albumin (TMFXBSA) conjugate in guinea pigs treated orally with TMFX or subcutaneously with TMFX with Freund's complete adjuvant (FCA). The antisera obtained from these guinea pigs were shown by PCA and diffusion-in-gel methods to contain no anti-TMFX antibodies. ASA was elicited by a challenge of TMFX-BSA conjugate but not by that of TMFX in the guinea pigs treated subcutaneously with the acetylated TMFX-ovalbumin (TMFX-OVA) conjugate with FCA. In the antisera obtained from these animals, the PCA reaction was elicited by a challenge of TMFX-BSA conjugate, but could not be elicited by that of TMFX.
In mice, immunogenicity (potential of IgE antibody production) and allergenicity were examined by heterologous 24-h PCA test in rats. Similar to the results obtained from the study in guinea pigs, neither immunogenicity nor allergenicity was noted when TMFX was administered alone.
From these results, it was concluded that TMFX lacks antigenicity both in guinea pigs and mice.

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To determine the arthrotoxicity of temafloxacin hydrochloride (TMFX) in immature animals, TMFX was orally administered to 4-week-old rats (12 rats of each group and sex) at doses of 30, 100 and 300mg/kg and 3-month-old dogs (3 dogs of each group and sex) at doses of 10, 30 and 90mg/kg for 7 days.
1) No remarkable clinical or pathological changes were seen in immature rats throughout the treatment or recovery period.
2) In observing the gait of immature dogs, abnormal flexion of the carpal joints was seen in 3 male and 2 female dogs in the 90mg/kg group, and 1 male in the 30mg/kg dose group during the treatment period. This abnormality was observed throughtout the treatment period after its appearance. In the recovery period, this abnormality persisted 2-3 days after withdrawal in 1 male dog in each 30mg/kg and 90mg/kg group, but it disappeared later on.
3) Blister-like lesions or erosions in the articular cartilage were grossly obseeved in all dogs with abnormal gait and 1 female dog with normal gait in the 90mg/kg group.
4) Corresponding to the gross lesions, rarefaction of cartilage matrix and fissuring were histopathologically seen at the end of the treatment period. Chondrocytic regeneration and fibrocartilage-like metaplasia regarded as a process to repair articular cartilage damage were observed in the area surrounding fissures at the end of the recovery period. Edema of subsynovial connective tissue with stratification of synovial lining cells was only observed in dogs in the 90mg/kg group at the end of the treament period.
From the above results, the arthrotoxicity dose of TMFX was considered to be over 300mg/kg in immature rats and 30mg/kg in immature dogs.

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A phase I clinical study on temafloxacin was conducted in healthy male volunteers to evaluate its safety and pharmacokinetics.
In the single-dose study, 100, 200, 400 and 600mg of temafloxacin (TMFX) were administered in the fasting state. In the multiple-dose study, 300mg and 450mg of TMFX were administered twice a day, at 12-hour intervals, after meals, for 7 days. The effects of food intake were investigated at the 200mg dose.
No side effects or abnormal findings attributable to TMFX were observed during this study. The serum concentrations after single oral doses of 100, 200, 400 and 600mg in the fasting group showed dose-dependency, and the peak levels were 0.98, 1.64, 3.20 and 4.07μg/ml, respectively, 1.3-2.3 hours after administration. The elimination half lives were 6.51-7.53 hours, and no dose-dependency was observed. The cumulative urinary excretion rates were about 70%. At the 400mg dose of TMFX 14.8% of TMFX was excreted into feces. Salivary levels were correlated with serum levels and the penetration ratio was approximately 0.7 from 1 to 4 hours after the 600mg dose. The peak serum level in the non-fasting group decreased to about 90% of that in the fasting group, while the urinary excretion rate showed little difference between the two groups. Therefore it appeared that there was no effect of food intake on absorption. The serum protein binding rates were approximately 35%. The serum concentration following multiple dosing reached a plateau after Day 3, and no further accumulation was observed.

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We studied the pharmacokinetics of temafloxacin (TMFX) after a single oral administration of the drug to healthy volunteers at a dose of 600mg.
Average serum levels of TMFX reached the maximum concentration at 2 h after oral dosing, then declined with a half-life of 6.6 h.
When TMFX was administered orally, 65% of the dose was excreted as unchanged TMFX in urine within 48 h after dosing.
In addition to unchanged TMFX, three metabolites (AQ, EDA, MEDA), which were oxidized at the piperazine ring, were found in serum and urine. Glucuronic acid conjugates of TMFX and its metabolites were also found. The amounts of these metabolites were small.
The time-course of the serum level of S (-)·TMFX was similar to that of R (+)·TMFX. The antibacterial activities of metabolites were less potent than those of TMFX. No difference in antibacterial activities between enantiomers was observed.

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The effect of temafloxacin (TMFX), a newly synthesized quinolone antibacterial agent, given orally for 7 days to five healthy male volunteers, on intestinal microflora was investigated. Faecal specimens were cultured quantitatively for aerobic and anaerobic bacteria before, during and after administration.
Marked suppressions of Enterobacteriaceae and Streptococcus, including Enterococcus, were observed during TMFX administration. The anaerobic bacteria, Bacteroides, Eubacterium, Bifidobacterium, Veillonella and Gram-positive cocci were also reduced by TMFX administration in most subjects. Lecithinase-positive Clostridium was eliminated, though, lecithinase-negative Clostridium was not affected. Recovery of the levels and composition of the intestinal microflora was not delayed.

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Temafloxacin (TMFX) is a new pyridonecarboxylic acid antimicrobial agent. We investigated its antimicrobial activity, pharmacokinetics and clinical efficacy.
We determined its MIC at 10⁶cells/ml against 180 strains of 7 species of clinical isolates. The MIC₉₀ values were: Staphylococcus aureus, 3.13μg/ml; Escherichia coli, 0.39μg/ml; Proteus mirabilis, 0.78μg/ml; Morganella morganii, 0.78μg/ml; Klebsiella spp., 0.78μg/ml; Serratia spp. 50μg/ml and Pseudomonas aeruginosa, >100μg/ml. It displayed almost the same antimicrobial activity as other drugs of the same type, including enoxacin (ENX), norfloxacin (NFLX), ofloxacin (OFLX) and ciprofloxacin (CPFX).
We administered 200mg of TMFX and OFLX by the cross-over method to 6 healthy adult male volunteers in the fasting state and determined serum concentrations and urinary excretion using the bioassay method. The C_max values were TMFX 1.72μg/ml; OFLX 2.33μg/ml, and the C_max of OFLX was larger than that of TMFX. The t112 values were 5.51h and 3.99h, respectively, and the AUCO48 values were 15.63μg·h/ml and 13.56μg·h/ml, respectively. The t112 and AUC values of TMFX were significantly larger than those of OFLX. The urinary excretion rates were TMFX 77.93% and OFLX 84.53%.
Seventeen patients with internal medical infections (respiratory disease, 13; urological disease, 4) were treated orally with 200-400mg of TMFX for 4-10 days. The efficacy ratewas 100%(excellent, 6 cases; good, 11). No side effects or abnormal clinical test results were observed.

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We evaluated the penetration of temafloxacin (TMFX), a new oral quinolone, into serum and sputum and its clinical usefulness in respiratory tract infections.
A daily oral dose of 600mg of TMFX was administered to 15 patients for 6-14 days. Five of the patients had pneumonia, 6 bronchitis, 1 mycoplasma pneumonia, 1 diffuse panbronchiolitis and 2 secondary infection to chronic respiratory desease.
A dose of 600mg of TMFX was administered to 2 patients (1 with chronic bronchitis and 1 with diffuse panbronchiolitis).
Venous blood and sputum were collected on day 1, 4 and 7.
Clinical efficacy was excellent in 3 patients, good in 11 and fair in 1, with an efficacy rate of 93.3%.
Four strains of Haemophilus influenzae were identified as causative organisms, and all were eradicated by treatment with TMFX.
As regards safety, 1 case of diarrhea was observed among the 15 patients treated. Abnormal laboratory values was found in 2 cases; one consisted of a slight elevation in eosinophil count and the other a slight elevation of both ALP and γ-GTP.
The concentrations of TMFX in the sputum of the two patients with respiratory infections were highest 2-4 4 hours after oral adminstration on day 1, 4 and 7 (means: 1.60, 3.01 and 3.98μg/ml, respectively).
The penetration of TMFX from serum to sputum was 75-120%.

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Laboratory and clinical studies were performed on a new quinolone derivative, temafloxacin (TMFX).
The bactericidal activity of human polymorphonuclear leukocytes (PMN) against Escherichia coli was increased by the addition of sub-MIC of TMFX. The activity was also augmented by pretreatment with a relatively high concentration of TMFX. These effects of TMFX were more remarkable than those of ofloxacin (OFLX) and norfloxacin (NFLX).
TMFX was administrated to seven patients with respiratory tract infection and one patient with urinary tract infection orally at a dose of 300 mg twice a day for 7 to 14 days. The results were good in 6, fair in 1 and poor in 1. The efficacy rate was 75.0%. One side effect observed was mild urticaria-like exanthema. No abnormal clinical laboratory findings were observed.

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Pharmacokinetic and clinical studies of temafloxacin (TMFX), a new pyridonecarboxylic acid antibacterial agent, were performed, and the results obtained were as follows:
1) Pharmacokinetic study
Serum and sputum levels of TMFX were measured in three patients with chronic pulmonary emphysema treated with 150mg (1 patient) or 300mg (2 patients) orally. The peak serum levels were 1.36, and 2.47 and1.70μg/ml, 4, and 2 and 4 hours, respectively, after administration. The peak sputum levels were 1.33, and 1.79 and 2.43μg/ml, 4, and 2 and 4 hours, respectively, after administration. The ratios of peak sputum levels to peak serum levels were 97.8, and 72.5 and 142.9%, respectively.
2) Clinical study
Eleven patients with respiratory tract infections (RTIs)(acute bronchitis 3, chronic brochitis 2, bronchiectasis 2, acute pharyngitis 1, acute tonsillitis 1, pneumonia 1, chronic pulmonary emphysema 1) were given 300 or 600mg per day orally for 7-17 days. The clinical efficacy rate was 63.6%. Ten of the thirteen causative organisms (3/3 Haemophilus influenzae, 2/2 Moraxella catarrhalis, 1/2 Staphylococcus aureus, 1/2 Streptococcus pneumoniae, 1/2 Pseudomonas aeruginosa, 1/1 Klebsiella oxytoca, 1/1 Enterobacter cloacae) were eradicated.
No subjective side effects were observed, while transient, slight elevations of laboratory test values (GOT, GPT, BUN) were found in 3 patients.
Based on these results, we concluded that TMFX is an effective and useful oral antibacterial agent for the treatment of RTIs, particularly those caused by H. influenzae and M. catarrhalis.

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The in vitro antimicrobial activity of temafloxacin (TMFX), a new quinolone agent for oral use, was measured, and its therapeutic efficacy in respiratory infections was evaluated. The minimum inhibitory concentrations (MICs) of TMFX, ofloxacin (OFLX), ciprofloxacin (CPFX), tosufloxacin (TFLX), sparfloxacin (SPFX) and rifampicin (RFP) against 20 starains each of methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant S. aureus (MRSA), Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens, Pseudomonas aeruginosa and Mycobacterium avium, and 18 strains each of Haemophilus influenzae and Mycobacterium tuberculosis were determined by the micro-broth dilution method using the Dynatech MIC 2000 system. As shown by the MICs, TMFX was as active as OFLX against all of the species tested except S. marcescens, P. aeruginosa and M. avium. TMFX was somewhat less active than OFLX against S. marcescens and P. aeruginosa, and more active than OFLX against M. avium. A daily dose of 300mg (3 cases) or 600mg (5 cases) of TMFX was administered orally for 8-21 21 days (mean: 13.6 days) to 8 patients: 2 with acute bronchitis, one with Mycoplasma pneumoniae pneumonia and 5 with acute pneumonia. The clinical effects were good in all cases. Five strains were identified as causative organisms. Four strains were eradicated and one strain (S. aureus) was decreased in number by administration of TMFX. No clinical adverse effects were observed during treatment with TMFX. Proteinuria was observed in one patient and a transient elevation of serum transaminase in another two patients, in one of whom anemia was also observed. These adverse effects resolved after the completion of therapy. We conclude from the above results that TMFX is one of the most useful quinolone agents for oral use as a drug of first choice in the treatment of respiratory infections, especially in outpatient clinics.

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We performed basic and clinical studies on temafloxacin (TMFX), 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 TMFX were investigated by a cross-over design in six healthy male volunteers.
The subjects received orally 200mg of TMFX with and without 1g of AL or 1.5g of probenecid, and the time course of blood levels, urinary concentrations and urinary recovery of TMFX and its pharmacokinetic parameters were determined. TMFX concentrations in the samples were measured by the HPLC method. The pharmacokinetic parameters for TMFX obtained after each of the treatments were as follows: the Cmax, Tmax, T112, AUC_0→∞ and the urinary excretion rate for TMFX alone were 2.33μg/ml, 1.8h, 5.7 h, 22.9μg·h/ml and 61.5%, respectively; those for coadministration with AL were 0.81μg/ml, 3.3 h, 6.1 h, 9.8μg. h/ml and 29.5%; and those for coadministration with probenecid were 2.33μg/ml, 2.3 h, 8.2 h, 31.9μg·/ml and 49.4%.
Gastrointestinal absorption of TMFX was inhibited by interaction with AL, but the inhibition was middle class (AUC<30%, Cmax>0.2μg/ml) among the new quinolones.
Coadministration of probenecid resulted in increases in serum half-life and AUC0, and decreases in the urinary excretion rate. These data suggest that tubular excretion was involved in the renal excretion of the drug.
2. Four patients with respiratory infections, two with urinary tract infections and one with tonsillitis were treated orally at a daily dose of 300-600 mg of TMFX for 5-10.5 days. The clinical results were excellent in one case, good in five and poor in one. No side effects or abnormal laboratory values were observed.

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Microbiological and clinical studies were carried out with the oral quinolone carboxylic acid antibiotic temafloxacin (TMFX).
The MIC₅₀ and MIC₉₀ of TMFX against 44 clinical isolates of methicillin-sensitive Staphylococcus aureus (MSSA) were 0.5μg/ml, and the MIC₅₀ and MIC₉₀ against 35 clinical isolates of methicillin-resistant S. aureus (MRSA) were 0.5μg/ml and 16μg/ml. These MIC values indicate that TMFX is as effective against MSSA and MRSA as levofloxacin.
Clinical studies were carried out on 38 patients with infections in the field of internal medicine (8 with pneumonia, 4 with acute bronchitis, 20 with chronic bronchitis, 3 with bronchiectasis, and 1 each with diffuse panbronchiolitis, cystitis, and phlegmone).
The clinical response was classified as excellent in 2 cases, good in 30 cases, fair in 3 cases and poor in 3 cases. The efficacy rate was 84.2%(32/38). In the microbiological study, 21 strains were obtained before treatment, and 14 were eliminated after treatment. The rate of elimination of causative pathogens was 66.7%.
TMFX did not induce any side effects in this study, but abnormal laboratory findings were observed: elevated GPT in 1 case and increased erythrocytes in the urine sediment in 1 case.

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The sputum penetration of temafloxacin (TMFX), a novel quinolone synthetic antimicrobial, and its clinical, utility were studied. The mean rate of penetration of TMFX to sputum (the maximum drug concentration ratio of sputum to peak serum concentration) in 4 patients with chronic respiratory infections was as high as 121.8%, with a range of 102% to 145%. TMFX was administered orally to 38 patients with respiratory tract infections in doses of 100 to 300mg in a b.i.d. regimen to evaluate its clinical utility. The response was classified as excellent in 16, good in 20, and fair in 2 patients. The rate of effectiveness was rather high at 94.7%. Two of 4 isolated strains Pseudomonas aeruginosa disappeared after treatment. In one of the remaining 2 patients the bacterial count was decreased, while the other was left with persistent infection. Three strains of isolated Klebsiella pneumoniae were decreased or persisted. On the other hand, all strains of Staphylococcus aureus (3 strains), Streptococcus pneumoniae (3 strains), Haemophilus influenzae (3 strains), and Haemophilus parainfluenzae (2 strains) were eradicated. Mild lightheadness was experienced by 1 of 38 patients as a side effect of the test drug. Biochemical studies revealed abnormal increases in s-GPT and s-GOT in 2 patients and an abnormal decrease in platelet count in 1 patient.

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We carried out in vitro and in vivo studies on temafloxacin (TMFX), a newly-developed quinolone, and obtained the following results. The MICs of 488 clinical isolates of 25 species were compared with those of the other tested antibiotics, ciprofloxacin, ofloxacin, tosufloxacin, lomefloxacin, fleroxacin, sparfloxacin (SPFX), cefteram pivoxil (CFTM-PI), clavulanic acid/amoxicillin (CVA/AMPC) and minocycline (MINO).
Against Gram-positive cocci, the antibacterial activity of TMFX was higher than or almost equal to those of the other antibacterial agents examined. Against Gram-negative rods and cocci, the MICs of TMFX were lower than those of SPFX, CFTM-PI, CVA/AMPC and MINO, and equal to those of the other new quinolones tested.
In the clinical study, TMFX was given to 21 patients with respiratory infections and 4 with urinary tract infections. Clinical efficacy was excellent in 12, good in 12 and poor in 1, with an efficacy rate of 96.0%.
Side effects observed were urticaria in 1 and vomiting in 1, which disappeared while the agent was continued. There were no newly-developed abnormal findings in laboratory examinations.

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We evaluated the clinical efficacy and safety of temafloxacin (TMFX) in a phase II study in a total of twelve patients with respiratory infections. TMFX was administered orally at a dose of 300mg twice daily in most cases. The time course of the serum and sputum concentrations was evaluated after administering a single 300mg dose to two patients with copious mucopurulent sputum, and pharmacokinetic analysis was also performed. The subjects included one case each of pneumonia, mycoplasmal pneumonia, infected bullae, diffuse panbronchiolitis, and eight cases of bronchiectasis. Clinical response was good in eight cases, fair in two and poor in two. The overall clinical response rate was 67%. Two strains of Haemophilus influenzae were eradicated. Two of the 3 strains of Pseudomonas aeruginosa persisted and one decreased. No adverse effects were observed.
The average peak concentration of TMFX in serum was 3.53μg/ml and in sputum 3.72μg/ml. The mean sputum/serum concentration ratio was 106%. The pharmacokinetic parameters in sputum were very similar to those in serum. The results indicate that TMFX penetrates into bronchial secretions well and is useful in the treatment of respiratory infections.

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Bacteriological and clinical studies were krformed on temafloxacin (TMFX), a new quinolone derivative, and the following results were obtained.
The antibacterial activity of TMFX was compared with that of norfloxacin (NFLX) and ciprofloxacin (CPFX).
Minimal inhibitory concentrations of the agent against 10 clinical isolates each of methicillinsensitive Staphylococcus aureus (MSSA), methicillin-resistant S. aureus (MRSA), Escherichia coli, Klebsiella pneumoniae, 20 clinical isolates of Pseudomonas aeruginosa and 9 clinical isolates of Acinetobacter calcoaceticus were determined according to the standard procedure described by the Japan Society of Chemotherapy.
The clinical isolates of MSSA were inhibited at TMFX concentrations of 0.8μg/ml or less.
TMFX showed the highest activity against MSSA among these agents.
The antibacterial activity of TMFX against E. coli and A. calcoaceticus was superior to that of NFLX, its antibacterial activity against K. pneumoniae was equal to that of NFLX, and its antibacterial activity against P. aeruginosa was slightly inferior to that of NFLX.
The antibacterial activity of TMFX against E. coli, P. aeruginosa, and A. calcoaceticus was equal, slightly inferior and inferior, respectively, to that of CPFX. The antibacterial activity of TMFX against MRSA was almost the same as that of NFLX and CPFX.
TMFX was administered orally to 8 patients, 2 with acute enteritis, 1 with acute gastroenteritis, 3 with acute tonsillitis, 1 with acute pneumonia and 1 with acute bronchitis at a daily dose of 150mg to 300mg, 2 times a day for 4 to 9 days. The clinical effect was excellent in 3 cases, good in 4 cases and fair in 1 case.
In regard to the bacteriological effect after treatment, the causative organisms were eradicated in 1 patient, replaced in 1 patient and persisted in 1 patient.
Adverse reactions consisted of transient dizziness in 1 patient, which disappeared in a day without special treatment, and among the laboratory findings, of slight elevations in GOT and GPT in 1 patient.
Based on the above results, TMFX is considered a useful drug for the treatment of infections in the field of internal medicine.

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The antimicrobial activity, absorption, elimination and clinical utility of temafloxacin (TMFX), a newly developed quinoline antimicrobial, were determined, and the following results were obtained.
1) Antimicrobial activity of the test drug against clinically isolated methicillin-susceptible Staphylococcus aureus, methicillin-resistant S. aureus, Escherichia coil, Klebsiella pneumoniae, and Pseudomonas aeruginosa was determined.
2) Absorption and elimination: After the test drug was administered orally once to 2 adults (diabetics without infection) at a dose of 150 or 300mg/day and 3 elderly patients without infections at a dose of 300mg/day after fasting, the drug concentrations in serum and urine were determined. The maximum drug concentrations (C_max) in patients receiving 300mg/day were 3.01μg/ml for the adults and 4.29μg/ml on average for the elderly. The average serum elimination half-times (T_1/2) were 6.32 hours for the former and 7.90 hours for the latter, and the drug concentrations were 1.90 and 2.60μg/ml for the two groups of patients after 10 hours. On the other hand, the C_max for the adults receiving 150mg/day orally was 2.31μg/ml, and the T_1/2 was 5.94 hours. The drug concentration was 0.79μg/ml after 10 hours. The rates of recovery in urine were 50.2% and 54.5% after 12 hours following the administration of 150 and 300mg/day, after fasting, respecitvely, and 72.1% after 48 hours following the administration of 300mg/day after fasting.
3) Laboratory tests: Among 12 patients admitted to the study were 5 with pyogenic tonsillitis, 2 with acute pharyngitis, 2 with acute bronchitis, 2 with bacterial pneumonia, and 1 with pulmonary suppuration.
The test drug was effective in all but 1 patient with pulmonary suppuration, the rate of effectiveness being 91.7%. Streptococcus pneumoniae and Streptococcus pyogenes were isolated from 1 patient with acute bronchitis and 2 with pyogenic tonsillitis. The former disappeared after treatment and the latter disappeared in 1 patient, but the other patient was left with the infection after treatment. No objective or subjective side effects, or abnormal laboratory tests were observed during treatment.
The results of this study suggest that TMFX is of use in the treatment of infections in the field of internal medicine.

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We evaluated the in vitro antimicrobial activity and the clinical efficacy of temafloxacin (TMFX), and obtained the following results.
1. Antimicrobial activity: The MIC₉₀s (inoculum size: 10⁶ CFU/ml) of TMFX against clinically isolated Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Proteusmirabilis, Proteus vulgaris, Morganella morganii (27 strains each), Serratia marcescens (19 strains) and Pseudomonas aeruginosa (27 strains) were 0.2, 1.56, 0.2, 0.78, 6.2 5, 0.78, 25 and >100μg/ml, respectively.
2. Clinical efficacy: TMFX was administered orally to 24 patients with respiratory infections at a dailly dose of 150 or 300 mg divided into two administrations. The clinicalresponse was good in 1 case of acute tonsillitis, and excellent or good in 5 of 9 acute bronchitiscases, in 4 of 5 cases with acute exacerbation of chronic respiratory infections and in 6 of 9 pneumonia cases. One strain each of Streptococcus pneumoniae and Haemophilus influenzae was eradicated, one each of Streptococcus pyogenes and Haemophilus parainfluenzae was unchanged. One patienthad a rash and two patients developed drug fever, but recovered upon withdrawal of the agent. Elevations in GOT and GPT in one patient, eosinophils in two patients and GOT, GPT, ALP, γ-GTP and LDH in one patient were observed.

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We performed bacteriological and clinical studies on temafloxacin (TMFX), a new quinolone derivative, and obtained the following results.
1) The MIC₉₀ of TMFX against Streptococcus pneumoniae, Staphylococcus aureus, Moraxella catarrhalis, Haemophilus influenzae, Klebsiella pneumoniae, Serratia marcescens, Enterobacter cloacae, Acinetobacter calcoaceticus and Escherichia coli were 0.0125-0.39μg/ml, superior to those of ciprofloxacin (CPFX), ofloxacin (OFLX) and cefteram pivoxil (CFTM-PI). The MIC against methicillin resistant S. aureus was superior to those of CPFX, OFLX and CFTM-PI.
The antibacterial activity against Pseudomonas aeruginosa was almost equal to that of OFLX.
2) The MICs against Chlamydia pneumoniae, Chlamydia psittaci and Chlamydia trachomatis were 0.25-0.5μg/ml, superior to those of OFLX, CPFX, fleroxacin, lomefloxacin and norfloxacin.
3) Twelve patients with respiratory tract infection were treated with TMFX. Efficacy was good in 9, fair in 1 and poor in 2 cases. The overall clinical efficacy was 75%.
Side effect was observed in 1 patient, who had fever.
Abnormal laboratory finding was observed in 1 patient, who showed eosinophilia.

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We studied the effect of temafloxacin (TMFX), a new oral pyridone-carboxylic acid derivative, on the serum concentration of theophylline in 6 healthy male volunteers.
Thephylline alone was given for four days at a daily dose of 200mg b. i. d., and the serum samples were obtained as a control. After 5 days, concomitant administration of TMFX at a daily dose of 300mg b. i. d. was started.
Blood was drawn on the third and fifth days of concomitant administration, and the serum concentration of theophylline was compared with that of the control.
On the third day of concomitant administration, C_max and AUC were 4.1% and 4.3% lower than those of the control. On the fifth day they were 12.2% and 9.8% lower than those of the control. Total body clearance of theophylline showed a 7.6% increase from that of the control at day 5.
The above results suggested that TMFX might be a safe drug when administered to patients concomitantly with theophylline.

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We compared the antibacterial activity of temafloxacin (TMFX), a newly developed fluoroquinolone, with that of norfloxacin (NFLX), ofloxacin (OFLX) and ciprofloxacin (CPFX) in vitro, and examined the clinical efficacy of TMFX.
The antibacterial activity of these drugs against 282 clinically isolated strains of gram-negative bacilli and 155 strains of gram-positive cocci was measured. The activity of TMFX was most potent against Acinetobacter calcoaceticus. It was equal to that of CPFX and superior to that of NFLX and OFLX against Haemophilus influenzae. CPFX showed the most potent activity against the other species of gram-negative bacilli, and the activity that of TMFX was equal to that of NFLX and OFLX. The antibacterial activity of TMFX was most potent against Streptococcus pneumoniae and Staphylococcus aureus, and was equal to that of CPFX and superior to that of NFLX and OFLX against the other gram-positive cocci.
TMFX was administered at daily doses of 300-600mg for 4-14 days to eight patients; two with pneumonia, one with Mycoplasma pneumonia, four with acute bronchitis and one with chronic urinary tract infection. Clinical efficacy was good in one of two patients with pneumonia, in all four patients with acute bronchitis and in the patient with urinary tract infection. H. influenzae, Klebsiella spp. and Serratia spp. isolated from these patients were eradicated after treatment with TMFX.
Adverse reactions consisted of anorexia in one patient, but no abnormal laboratory findings were detected.

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We performed basic and clinical studies on temafloxacin (TMFX), a new pyridonecarboxylic acid, in respiratory infections, with the following results.
1. The MICs of TMFX for causative organisms were measured using the agar dilutionmethod with an inoculum size of 10⁶ CFU/ml.
The MICs for 14 strains of methicillin-sensitive Staphylococcus aureus (MSSA) were 0.2-12.5μg/ml; for 28 strains of methicillin-resistant S. aureus, 0.2-25μg/ml; for 21 strains of Streptococcus pneumoniae, 0.2-1.56μg/ml; for 20 strains of Moraxella catarrhalis, 0.025-0.1μg/ml; for 19 strains of Haemophilus influenzae, <0.013-1.56μg/ml; for 16 strains of Pseudomonas aeruginosa, 0.2-12.5μg/ml.
2. Clinical evaluation of TMFX in 12 patients with respiratory infections was excellent in 2, good in 10, the efficacy rate being 100%. No adverse reaction was observed exceptfor one case with mild elevation of GPT.
These results suggest that TMFX is a useful oral antimicrobial agent in respiratory infections.

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We performed laboratory and clinical studies on temafloxacin (TMFX), a new oral pyridonecarboxylic acid, with the following results.
1) Minimal inhibitory concentrations (MIC) of TMFX were measured for 242 clinical isolates of 12 species, and compared with those of ciprofloxacin (CPFX), ofloxacin (OFLX) and enoxacin (ENX). The MIC values of TMFX against gram-positive cocci and Acinetobacter calcoaceticus were equal to those of CPFX, but superior to those of OFLX and ENX. In contrast, those of TMFX against gram-negative bacteria were inferior to those of CPFX, but equal to those of OFLX. Those of TMFX against Proteus spp. were less than those of the other three quinolones.
2) Effects of cimetidine (H₂-blocker) on absorption and excretion of TMFX were investigated in five healthy male volunteers. The time of the maximum TMFX concentration (T_max) was delayed and the 12h-cumulative urinary recovery rates were decreased by cimetidine, but other data were not influenced.
3) The clinical efficacy of TMFX was evaluated in a total 33 patients; 6 with pneumonia, 1 with pneumonia and cystitis, 8 with acute bronchitis, 1 with acute bronchitis and an infected decubitus ulcer, 4 with chronic bronchitis, 1 with infected pulmonary infarction, 3 with pharyngitis and laryngitis, 1 with acute pharyngitis and cystitis, 6 with cystitis, 1 with bacillary dysentery and 1 with acute lymphadenitis. The patients were given a daily dose of 150-300 mg, b. i. d. or t. i. d. for 2-37 days. The clinical response was excellent in 9 cases, good in 22 cases, fair in 2 cases and poor in 3 cases, the efficacy rate being 86.1%. Bacteriologically, 14 of 16 strains isolated from respiratory tract infections and 8 of 9 strains isolated from urinary tract infections were eradicated by treatment with TMFX. The side effects observed in 3 cases were vomiting/epigastralgia, fever/headache and general fatigue. Elevations of GOT and GPT were observed in a case.

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We measured the in vitro antimicrobial activity of temafloxacin (TMFX), a new quinolone antimicrobial, against clinical isolates, evaluated its clinical efficacy in respiratory tract infections, and obtained the following results.
1. Antimicrobial activity
The thinimum inhibitory concentrations (MICs) were measured for 581 clinically isolated strains of 19 species of bacteria (including gram-positive cocci, Moraxella catarrhalis, gramnegative bacilli and anaerobes), and compared with those of ofloxacin (OFLX), ciprofloxacin, tosufloxacin (TFLX). The antimicrobial activity of TMFX was slightly less than that of TFLX and about the same as that of OFLX.
2. Clinical results
Eight patients with respiratory tract infections were given 150mg of TMFX twice daily for 7-14 days. Clinical efficacy was assessed as good in 6 cases and fair in 2. No subjective or objective side effects or any abnormal changes in laboratory findings were observed.

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The newly developed broad-spectrum fluoroquinolone, temafloxacin (TMFX), was evaluated in vitro and in vivo in comparison with ofloxacin (OFLX), ciprofloxacin (CPFX) and norfloxacin (NFLX). The results were as follows:
1. Antimicrobial activity: Minimal inhibitory concentrations (MICs) against 483 clinical isolates including 15 different species were determined by the microbroth dilution method. TMFX showed excellent antimicrobial activity against gram-positive bacteria in particular. The MIC values for 3 species of gram-positive bacteria were superior to those of the other quinolones tested except against Streptococcus pyogenes and Enterococcus faecalis, for which TMFX was equal to CPFX. The MIC values for gram-negative bacteria were below those of CPFX, especially for Morganella morganii, Citrobacter freundii, Proteus vulgaris and Pseudomonas aeruginosa. TMFX, however, showed equal activity to OFLX and NFLX against the other gram-negative bacteria.
2. TMFX concentrations in serum and sputum: TMFX was orally administered at a single dose of 300mg to two patients with chronic lower respiratory diseases, and the concentrations in serum and sputum were measured by HPLC. The peak concentrations of TMFX in the serum and sputum of one patient were 2.98 and 3.38μg/ml, respectively, and those of the other patient were 1.80 and 1.45μg/ml, respectively. From these data, it was suggested that TMFX has good penetration into sputum.
3. Clinical efficacy and adverse reactions: Twenty-six patients with respiratory tract infections were treated with TMFX, and the overall efficacy rate was 76% (exellent in 2 cases, good in 17, fair in 5, poor in 1, and not evaluable in 1). Stomach discomfort was observed as a side effect in one patient. Although the elevation of GPT was observed in one case, leukopenia in 1 case and the elevation of GOT, GPT and ALP in 1 case, these abnormal laboratory findings were mild and improved rapidly after the completion of TMFX treatment.

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We evaluated the usefulness of temafloxacin (TMFX), a new quinolone derivative, in respiratory tract infections. The MIC of TMFX for 70% of methicillin-sensitive Staphylococcus aureus was 0.10μg/ml. It was 50μg/ml for methicillin-resistant S. aureus, 0.78μg/ml for Streptococcus pneumoniae, 0.05μg/ml for Haemophilus influenzae, 0.05μg/ml for Branhamella eatarrhalis, 6.25μg/ml for Pseuaomonas aeruginosa and 0.10μg/ml, for Klebsiella pneummiae 0.10μg/ml. The activity was comparable with or superior to that of ofloxacin (OFLX).
The pharmacokinetics of TMFX were studied in four chronic respiratory patients. The maximum sputum levels in two patients during a 150mg oral administration two times per day were 0.86μg/ml and 1.05μg/ml. The maximum sputum, levels in two patients after an administration of 300mg were 2.40μg/ml and 3.00μg/ml, and the peak ratio (maximum sputum level/maximum serum level) was 100%. The serum elimination half-lives in two patients were 7.1 hours and 9.9 hours.
Nineteen patients with lower respiratory tract infections were studied for clinical evaluation of TMFX. TMFX was given orally at 300-600 mg per day for 3-14 days. The causative organisms were S. pneumoniae (4 cases), H. influenzae (4 cases), B. catarrhalis (6 cases), P. aeruginosa (4 cases) and Escherichia coli (1 case). The rate of clinical response was 78.9%. The rate of bacterial elimination in sputum samples was 76.5% (4 strains of P. aeruginosa were not eliminated). No reverse effect was observed.
The effects of subMlCs of TMFX and OFLX on a fimbriate strain of B. catarrhalis from a patient with chronic respiratory tract infection was observed by transmission electron microscopy. Abnormal fimbriae were observed in 29% of B. catarrhalis at 1/2 MIC of TMFX, 3% at 1/4 MIC and 1% at 1/8 MIC. No abnormal fimbriae were observed at subMlCs of OFLX. We concluded that TMFX is a very useful oral antimicrobial agent for the treatment of respiratory tract infections.

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We performed laboratory and clinical evaluations of temafloxacin (TMFX), a new oral trifluorinated quinolone, with the following results.
1) Antimicrobial activity
The minimum inhibitory concentrations (MICs) of TMFX for a total of 307 clinically isolated strains, were determined and compared with those of ofloxacin, tosufloxacin, ciprofloxacin, enoxacin and norfloxacin using the MIC-2000 system.
TMFX had broad antimicrobial activities against all clinically isolated strains except methicillin-resistant Staphylococcus aureus (MRSA), Serratia marcescens and Pseudomonas aeruginosa.
2) Clinical efficacy
TMFX, 150mg × 2 (300mg/day), was given to 2 patients with chronic bronchitis. Two patients with acute bronchitis and 4 with chronic bronchitis were treated with TMFX, 300mg × 2 (600mg/day).
Clinical responses were good in all 8 patients.
One strain of Haemophilus influenzae was eradicated while one strain of P. aeruginosa was not.
No side effects were observed, but abnormal laboratory findings, including slight elevations in GOT, GPT and eosinophils, were observed in 2 patients.

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We evaluated the clinical effect, safety and usefulness of a new quinolone antimicrobial agent, temafloxacin (TMFX), in patients with acute infectious enteritis, mainly shigellosis, and carriers of enteric pathogens. The daily dose of TMFX was 600mg, twice a day for 7 days in Salmonella enteritis and for 5 days in other infections.
1. Of 127 cases studied, 92 cases were evaluated: 39 cases of shigellosis, 11 of Salmonella enteritis, 9 of Campylobacter enteritis, 5 of Vibrio parahaemolyticus enteritis, 4 of other enteritis, 12 of polymicrobial infectious enteritis and 12 of acute enteritis that were pathogen-negative.
2. The clinical efficacy rate for symptoms was 100% in 49 cases.
3. In terms of bacteriological response, the rate of eradication was 100% in 39, 10 and 6 cases of infections caused by Shigella spp., Campylobacter spp. and EPEC, respectively. It was 81.8% in 11 cases of Salmonella spp.
4. As side effects, skin eruption was observed in 1 (0.8%) of 126 cases, although this symptom disappeared after withdrawal of the drug. Abnormal changes in laboratory findings were noted in 7 (6.8%) of 103 cases, and included mainly the elevation of transaminase (GOT, GPT), although they were all slight in degree.
5. In 93 evaluable cases, the clinical usefulness rates were 58.1 and 95.7% for marked satisfaction, and marked satisfaction and satisfaction, respectively.
6. The antimicrobial activity of TMFX was closest to that of ciprofloxacin, and slightly superior to ofloxacin for Shigella spp., Salmonella spp. and Escherichia coli. For Campylobacter spp., TMFX was superior to the other agents tested.
7. The fecal drug concentrations and effects on fecal microflora were determined in two patients with shigellosis.
TMFX was excreted into feces at a high concentration from 11 hours after the initial administration of TMFX until the day after the final dosage (173.1-646.2 μg/g).
Enterobacteriaceae and Enterococci were well supressed, while the former did not recover to the initial level even after the final dosage. In one case, Bacteroides spp. was also decreased, although the total viable counts of anaerobes remained constant.
From these results, TMFX is considered to be a very useful agent for the treatment of acute enteric infections.

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The clinical effect of temafloxacin (TMFX), a new quinolone antibacterial agent developed by Abbott Laboratories, was investigated in Mycoplasma pneumoniae infections.
Clinical specimens, throat swabs and sputum, were collected from 28 adult patients with acute respiratory tract infections, including infections by M. pneumoniae, in 11 hospitals in Japan. The patients were generally treated by oral administration of TMFX 300mg twice a day for 7-14days.
M. pneumoniae was isolated from 9 patients, and an increase in M. pneumoniae specific antibodies, such as indirect hemagglutinins and complement-fixing antibodies, was observed. An increase in antibodies was observed, in 6 cases, but the attempts at isolation were negative. The clinical evaluation of TMFX in M. pneumoniae infection was conducted in these 15 cases.
The clinical response to TMFX was excellent in 6 patients, good in 8 and fair in 1, and the clinical efficacy rate was 93.3%. Bacteriological studies showed that the clinical specimens from which M. pneumoniae was isolated became nagative within 3-11 days after initiation of TMFX administration.
Side effects were observed in 2 cases; dizziness in one, and dizziness and gastrointestinal complaints in the other. Abnormal laboratory findings consisted of one case each of increase in urinary protein and increase in serum potassium. These side effects were transient in both cases.
On the basis of these results, it may be concluded that TMFX is a promising antimicrobial agent for the treatment of M. pneumoniae infections.

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To determine the optimal dose of temafloxacin (TMFX), a new quinolone antibacterial agent, in respiratory tract infections, a dose-finding study was conducted in patients with chronic lower respiratory tract infections using ofloxacin (OFLX) as the control drug. A TMFX 300 group (150mg b. i. d.) and TMFX 600 group (300mg b. i. d.) were compared by the double blind method. In principle, these drugs were administered for 14 days.
The total number of patients enrolled in the trial was 147, 132 of which (TMFX 300 group: 44, TMFX 600 group: 47, OFLX group: 41) were eligible for evaluation of clinical efficacy. There were no significant differences in the distribution of background factors, but the number of patients previously treated with other antibiotics in the TMFX 600 group was significantly larger than in the other groups (p <0.05).
1) The clincal efficacy rate was 86.4%, in the TMFX 300 group and 85.1% in the TMFX 600 group. The percentages of cases in which clinical efficacy was “excellent”(the “excellent” rate) were 4.5% and 8.5% in the TMFX 300 group and the TMFX 600 group, respectively.
In the patients with chronic bronchitis, the efficacy rates were 88.5% and 89.3%, and the “excellent” rates were 7.7% and 10.7%, in the TMFX 300 group and the TMFX 600 group, respectively. In patients whose infection severity was moderate, the efficacy rates were 88.9% and 90.0%, and the “excellent” rates were 11.1% and 20.0% in the TMFX 300 group and the TMFX 600 group, respectively. The differences between these two groups, however, were not significant.
In the OFLX group, the clinical efficacy rate was 92.7% in the patients as a whole, 94.1% in the patients with chronic bronchitis and 92.9% in the patients whose infection severity was moderate. The “excellent” rates were 2.4%, 5.9% and 7.1%, respectively.
2) The bacterial eradication rate (eradicated ± replaced) was 85.7% in the TMFX 300 group and 87.0% in the TMFX 600 group, with no significant difference between the two groups. The eradication rate in the OFLX group was 81.8%.
3) There were no cases of adverse drug reactions (ADRs) in the TMFX 300 group, but there was one case (2.1%) in the TMFX 600 group. Abnormal laboratory test findings were observed in 6 cases (13.6%) in the TMFX 300 group and in 9 cases (20.5%) in the TMFX 600 group. There were no significant differences between these two groups in incidence of ADRs or abnormal laboratory test findings. In the OFLX group, ADRs were observed in 2 cases (4.5%), and abnormal laboratory test findings were observed in 3 (7.3%).
4) The usefulness rates were 84.1% in the TMFX 300 group and 83.0% in the TMFX 600 group. The percentages of cases in which degree of usefulness was “markedly useful” were 4.5% and 6.4% in the TMFX 300 group and the TMFX 600 group, respectively. There were no significant differences between these two groups. In the OFLX group, the utility rate was 90.5%, and the “markedly useful” rate was 2.4%.
These results indicate that the TMFX 300 group and 600 group were almost equal in terms of both efficacy and safety for chronic lower respiratory tract infections. However, the TMFX 600 group was slightly better than the TMFX 300 group in the “excellent” rate and the bacterial eradication rate. In addition, among the patients with chronic bronchitis, the-TMFX 600 group was superior in terms of both the clinical efficacy rate and the “excellent” rate, as well as among patients whose severity of infection was moderate. Therefore, a daily dose of 600 mg of TMFX was considered necessary to treat respiratory tract infections, including intractable cases.

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