In vitro and in vivo antibacterial activity of ATAT-2266, a new pyridonecarboxylic acid derivative developed by Dainippon Pharmaceutical Co., Ltd.(Osaka, Japan) was examined using various species of clinical isolates.
The results were summarized as follows.
1) ATAT-2266 had a broad and potent antibacterial activity against clinical isolates of gram-positive and gramnegative bacteria. The in vitro antibacterial activity of ATAT-2266 was in general comparable to that of NFLX but much higher than that of PPA and NA.
2) NA- resistant Enterobacteriaceae was also inhibited by ATAT-2266 at relatively low concentrations.
3) The MIC values of ATAT-2266 were scarely affected by the addition of horse serum and sodium cholate, medium pH and inoculum size.
4) The action of ATAT-2266 was bactericidal at concentrations of around its MIC value.
5) Spontaneous mutants resistant to ATAT-2266 as well as those of NFLX were not detected in various bacteria.
6) The in vivo efficacy of ATAT-2266 by oral route was uniformly higher than that of NFLX, PPA, and NA against mouse systemic infections with gram- positive and gram- negative bacteria including NA- resistant ones.

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In vitro and in vivo antibacterial activities of ATAT-2266, a new pyridonecarboxylic acid antibacterial agent, were compared with those of the same class of antibacterial agents, norfloxacin and pipemidic acid, and the following results were obtained.
ATAT-2266 was active against gram-positive and gram- negative organisms, especially E. coli, Shigella, Salmonella, Klebsiella (K. pneumoniae, K. oxytoca), Proteus sp.(P. mirabilis, P. vulgaris, P. morganii), E. cloacae and S. epidermidis. It was more active than pipemidic acid and as active as or slightly less active than norfloxacin.
ATAT-2266 was as active as norfloxacin against P. aeruginosa and S. marcescens, and more active than norfloxacin or pipemidic acid against fermentative organisms, such as P. maltophilia, P. cepacia, A. faecalis and F. meningosepticum.
It was found that ATAT-2266 had a more potent bactericidal activity against E. coli than did norfloxacin and pipemidic acid.
ATAT-2266 was superior to norfloxacin and pipemidic acid in protecting infections with K. pneumoniae, P. vulgaris, P. aeruginosa and A. calcoaceticus in experimental infections in mice.

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ATAT-2266 was evaluated bacteriologically in comparison with Norfloxacin (NFLX), Pipemidic acid (PPA) and Nalidixic acid (NA) and the following results were obtained.
1. ATAT-2266 had a broad spectrum of antibacterial activity against gram- positive and gram- negative anaerobic bacteria (except for C. difficile and C. ramosum) and the antibacterial activity of ATAT-2266 was stronger those of PPA and NA. The activity of ATAT-2266 against anaerobic bacteria was same activity those of NFLX.
2. Bactericidal effect of ATAT-2266 against Bacteroides was same to that of NFLX and was strong.
3. ATAT-2266 exhibited an excellent chemotherapeutic effect against polymicrobial subcutaneously infections in mice due to β- lactamase producing E. coli and B. fragilis.

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Bacteriological evaluation of AT-2266, a new synthetic chemotherapeutic agent, was carried out compared with pipemidic acid (PPA) and norfloxacin (NFLX), and the following results were obtained.
1. AT-2266 showed a broad antibacterial spectrum covering gram-positive, gram-negative and anaerobic bacteria, with antibacterial potencies similar to those of NFLX.
2. The MICs of AT-2266 for clinical isolates were lower than those of PPA for all tested bacteria, equal to those of NFLX for Staphylococcus aureus, Serratia marcescens and Klebsiella pneumoniae, about 2 times higher than those of NFLX for Streptococcus pyogenes, Escherichia coli, Enterobucter spp., Proteus mirabilis, indolepositive Proteus spp., Haemophilus influenzae and Pseudomonas aeruginosa, and about one half those of NFLX for Acinetobacter calcoaceticus.
3. The MIC values of AT-2266 were lowered in alkaline medium pH or with smaller inoculum sizes, but not affected by the addition of horse serum into medium.
4. The viable cells of S. aureus, E. coli, S. marcescens, K. pneumoniae, P. aeruginosa and A. calcoaceticus decreased during exposure to AT-2266 at 1 MIC.
5. Phase-contrast microscopy revealed that AT-2266 induced morphological changes of bacteria; swollen cells of S. aureus at 0.78μg/ ml, elongated cells of E. coli at 0.05μg/ ml, elongated cells having vacuoles of P.aeruginosa at 1.56μg/ ml, and elongated swollen cells of A. calcoaceticus at 1.56μg/ ml.
6. In the experimental systemic infections with one gram-positive and eight gram-negative bacteria in mice, AT-2266 showed excellent therapeutic activities superior to those of PPA and NFLX. The ED50 values of AT-2266 were lowered by increasing medication times or decreasing challenge bacterial inocula, and they were alwayslower than those of PPA and NFLX.
7. In the experimental urinary-tract infections in mice, viable bacteria in kidney decreased by dosing AT-2266 at the doses smaller than those of PPA or NFLX.
8. In the experimental pulmonary infections in mice, AT-2266 made survival days of infected mice longer with the decrease of viable bacteria in lung. Such effects were superior to those of PPA and NFLX.
9. The lung levels of AT-2266 in mice with a pulmonary infection was about 2 times higher than the plasma levels, but not so the lung levels of NFLX. The plasma and lung levels of AT-2266 were about 4 and 7 times higher than those of NFLX, respectively.

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In vitro and in vivo antibacterial activities of AT-2266, were compared with those of norfloxacin (NFLX), pipemidic acid (PPA), nalidixic acid (NA) and gentamicin (GM), with the following results.
1. AT-2266 as well as NFLX showed broad and potent antibacterial activities against gram-positive bacteria, gram-negative bacteria, glucose nonfermenters and Mycoplasma pneumoniae, whose activities were higher than those of PPA and NA. Most of clinical isolates were similar to laboratory strains in susceptibility to AT-2266.
2. AT-2266 was not cross-resistant with antibiotics and most NA-resistant bacteria were inhibited by AT-2266 at 0.78-6.25μg/ml.
3. The MIC values of AT-2266 were scarcely affected by the addition of horse serum or sodium cholate, but slightly rose with lowering medium pH or employing higher inoculum sizes.
4. AT-2266 was bactericidal at MIC.
5. Spontaneous mutants resistant to AT-2266 (10 μg/ml) were not detected in all the tested bacteria.
6. AT-2266 showed excellent oral effects in various experimental infections (systemic, pulmonary, dermal and urinary tract infections) in mice, whose ED₅₀ values were 1-1/9 those of NFLX, 1/2-1/27 those of PPA and 1/4-1/160 those of NA. The oral effects of AT-2266 were comparable to subcutaneous GM in urinary tract infections but inferior to the latter in the other infections. AT-2266 was also effective against infections with GM-resistant and NA-resistant bacteria.
The results indicate that AT-2266 is similar to NFLX in in vitro antibacterial properties but superior to NFLX, PPA and NA in in vivo antibacterial activities.

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Oral absorption, distribution, excretion and metabolism of AT-2266 were examined in mice, rats, dogs and monkeys partially compared with norfloxacin (NFLX).
The peak plasma levels of AT-2266 after single oral administration to mice (50mg/kg), rats (50mg/kg) and dogs (25mg/kg) were 2.39, 1.63 and 4.99μg/ml with half-lives of 2.24, 2.81 and 5.76 h, and those of NFLX were 0.514, 0.411 and 0.694μg/ml with half-lives of 1.40, 2.35 and 6.06 h. In dogs receiving 5 repeated doses (25mg/kg) of AT-2266 every 12 h, the peak plasma level after the third dose (5.33μg/ml) was almost equal to that after the fifth dose (5.00μg/ml) and about 1.4 times higher than that after the first dose (3.79μg/ml). The protein binding rates of AT-2266 in animal plasma and human serum ranged between 27.6 and 40.3%, which were independent of drug concentration, and significantly decreased upon dilution of serum.
The peak levels of AT-2266 in plasma, brain, heart, lung, liver, kidney, and muscle of rats given a 50mg/kg dose were 2. 43, 0.164, 6. 65, 4.60, 21.3, 33.9 and 5. 35μg/ml or g, and those of NFLX in plasma, lung, muscle and kidney were 0.226, 0.390, 0.272 and 2.05μg/ml or g. Similar tissue distribution was observed in dogs and monkeys repeatedly given AT-2266.
The peak urine levels of AT-2266 in mice, rats, dogs and monkeys given a single oral dose of 50mg/kg were 991, 1, 270, 1, 280 and 1, 110μg/ml and those of NFLX in mice, rats and dogs were 64.2, 99.5 and 78.4μg/ml. The 24h urinary recoveries of AT-2266 ranged from 40.6 to 64.7%, and those of NFLX from 2.90 to 5.67%. The peak bile level of AT-2266 in rats given a single oral dose of 50mg/kg was 27.2μg/ml and the 24-h biliary recovery was 2.47%.
The bioautographic study of plasma and urine of animals given AT-2266 revealed that main active principle in vivo was unchanged AT-2266.
The results indicate that AT-2266 is well absorbed by the oral route, distributed over most parts of body at high concentrations and excreted mainly into urine as it is.

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Metabolism of a new synthetic antibacterial agent AT-2266 [1-ethyl-6-fluoro-1, 4-dihydro-4-oxo-7-(1-pi. perazinyl)-1, 8-naphthyridine-3-carboxylic acid] was investigated in rats, dogs, monkeys and man following single oral administration of AT-2266. Metabolites in 24-hour urine were identified by comparison with authentic materials using high-performance liquid chromatography and mass spectrometry. The results were as follows.
1. Five metabolites together with the unchanged AT-2266 were identified in urine of rats, dogs, monkeys and man: 7-amino-1-ethyl-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid (M-1); 1-ethyl-6-fluoro-1, 4-dihydro-4-oxo-7-(3-oxo-1-piperazinyl)-1, 8-naphthyridine-3-carboxylic acid (M-2); 1-ethyl-6-fluoro-7-(4-formyl-1-piperazinyl)-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid (M-3); 7-(4-acetyl-1-piperazinyl)-1-ethyl-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid (M-4) and 7-(2-aminoethylamino)-1-ethyl-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid (M-5). In rat urine, the glucuronic acid conjugate of the unchanged drug was also detected.
2. The amounts of the metabolites excreted in urine was less than that of the unchanged drug as judged by the chromatograms.
3. All metabolities except for the glucuronide showed a similar antibacterial spectrum to AT-2266, but their potency was about 3-10 times lower than that of AT-2266.

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Plasma levels and urinary excretion of AT-2266 and its metabolites in mice, rats, cats, dogs and monkeys following single oral administration of 20 mg/kg of AT-2266 were determined by high-performance liquid chromatography with the following results.
1. The unchanged AT-2266 and its metabolite M-2 were found in plasma of all animals examined, but other metabolites were not detected.
2. AT-2266 was rapidly absorbed, and mean plasma levels were maximal 0.5-2 h after dosing with levels of 0.8, 0.6, 4.2 and 4.2μg/ml in mice, rats, dogs and monkeys, respectively, and declined with apparent half-lives of 2.0, 2.8, 5.0 and 4.2 h, respectively. Mean plasma levels of M-2 in mice, rats and dogs were less than 0.03 μg/ml, but was 2.5 μg/ml in monkeys (about 60% of the unchanged drug).
3. Other 4 metabolites M-1, M-3, M-4 and M-5 were excreted together with the unchanged drug and M-2 in urine of all animals. In addition, the glucuronide of the unchanged drug was also detected in rat urine.
4. Mean urinary excretion in mice, rats, cats, dogs and monkeys for 24 h after dosing were found to be 30.8, 19.4, 43.0, 28.9 and 55.9% of the dose, respectively. A large portion of the urinary excretion was the unchanged drug (>90% in mice, cats and dogs, 76% in monkeys and 65% in rats). Urinary excretion of the metabolites were less than 1.5% of the dose except for M-2 in monkeys (12.0%) and the glucuronide in rats (6.2%).
5. Mean biliary excretion in rats for 24 h after dosing was accounted for 25.3% of the dose, and the major excreta was the conjugates of the unchanged drug.
6. The results suggest that the antibacterial activity after oral administration of AT-2266 is mainly due to the unchanged drug.

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AT-2266, a new Synthetic antibacterial agent, was administered orally to male healthy volunteers. Plasma levels and urinary excretion of AT-2266 and its metabolites were determined by high-performance liquid chromatography after single dosing (100, 200, 400 and 800 mg, each of 6 subjects) or consecutive dosings (400 mg twice a day for 7 days, 6 subjects). The results were as follows.
1. The unchanged AT-2266 and its metabolite M-2 were found in plasma, and other 4 metabolites M-1, M-3, M-4 and M-5 together with the unchanged drug and M-2 were detected in urine.
2. Mean plasma levels of the unchanged drug were maximal 1-2h after single dosing of 100, 200, 400 and 800 mg of AT-2266 with levels of 0.5, 1.6, 2.7 and 6.0μg/ ml, respectively, in a dose-related manner, followed by a biphasic decrease with an apparent terminal elimination half-life of 5.4-5.8h. Mean plasma levels of M-2 were one tenth of those of the unchanged drug.
3. An average of 32.0% of the unchanged drug was bound to plasma protein.
4. A total amount of urinary excretion for 24h after single dosing was 53-59% of the dose. More than 80% of the urinary excretion was the unchanged AT-2266. Urinary excretion of the major metabolite M-2 was 1/5 or less of that of the unchanged drug, and those of other 4 metabolites M-1, M-3, M-4 and M-5 were less than 1.1% of the dose.
5. Plasma levels and urinary excretion were not significantly changed with or without food.
6. Mean peak level of the unchanged drug after consecutive dosings was 1.6 times higher than that after first dosing, but there were no significant changes in the elimination half-life and the ratios of M-2 to the unchanged drug in plasma and urine.
7. The results indicate that the antibacterial activity in man after single and consecutive oral administration of AT-2266 is mainly due to the unchanged drug.

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Absorption, distribution, metabolism and excretion of [¹⁴C] AT-2266, a novel antibacterial agent, were investigated after oral administration at 50mg/kg in rats in partial comparison with those of [¹⁴C] norfloxacin.
1. Blood levels of [¹⁴C] AT-2266 radioactivity reached maximum as early as 1 hr after oral administration. Plasma level of unchanged AT-2266 was 2.3μg/ ml at 1 hr. Blood levels of [¹⁴C] norfloxacin radioactivity also reached maximum 1 hr after oral administration but were about 1/ 10 level of [¹⁴C] AT-2266.
2. It was suggested that AT-2266 was mainly absorbed in the whole region of the small intestine but scarecely in stomach. Extent of absorption of AT-2266 from digestive tracts was estimated to be 50-60% based on the urinary excretion ratio and blood level AUC ratio after oral to parenteral administration and on the sum of urinary and biliary excretion of [¹⁴C] AT-2266 radioactivity. Estimate of norfioxacin absorption was around several per cent.
3. Tissue radioactivity reached maximum 1 hr after oral administration of [¹⁴C] AT-2266. Higher tissue levels were seen in the kidney and liver than all tissues examined, except for digestive tracts. Levels in many other tissues were roughly equal to, or higher than plasma levels. When estimated by TLC, levels of unchanged [¹⁴C]. AT-2266 in the heart, lung, liver and kidney were 2.0-6.0 times as high as that of plasma at 1 hr. In contrast, levels of radioactivity in the testicle and fat were lower than plasma levels and in the brain no radioactivity was detected. Levels in the fetus of [¹⁴C] AT-2266 radioactivity were found much lower than maternal blood level in the whole body autoradiograms of pregnant rats.
The distribution pattern of [¹⁴C] norfloxacin radioactivity in rats was seemingly similar to that of [¹⁴C] AT-2266 although the autoradiograms were rather hard to observe exactly due to poor absorption of norfioxacin.
4. Levels of [¹⁴C] AT-2266 in plasma and many tissues were decreased with t1/2 of 2-3 hr and practically nil 24 hr after oral administration.
5. Binding of AT-2266 to rat plasma and human serum was around 35% and reversibly lowered by dilution. Binding to albumin was suggested to be rather weak.
6.[¹⁴C] AT-2266 radioactivity was excreted in urine in about 30% of dose and in feces, about 70%, respectively, within 24 hr after oral administration. About 30% of dose was excreted in bile within 24 hr.
Excretion of [¹⁴C] norfloxacin radioactivity amounted to about 3% in urine about 95% in feces.
7. Major radioactive urinary component was unchanged [¹⁴C] AT-2266. Glucuronide of AT-2266 was also found in urine together with some other minor metabolites. The unchanged and glucuronide AT-2266 were also found in bile.

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Disposition and metabolism of [¹⁴C] AT-2266 were studied after 7 oral consecutive daily dosings in rats.
1. Blood levels of [¹⁴C] AT-2266 radioactivity after the initial and final administration were essentially similar to each other. Levels 1 hr after each dosing were around 2.5μg eq./ml. Unchanged [¹⁴C] AT-2266 accounted for about 60% of total radioactivity in plasma 1 hr after the last administration.
2. Tissue levels of [¹⁴C] AT-2266 radioactivity 1 hr after the last administration were the highest in the digestive tract, liver, kidney, seminal vesicle and prostate among organs examined (the latter two, however, being mostly attributed to artifact caused by urine contamination after sacrifice of animals for autopsy). Most of tissue levels were higher than blood level but were lower in such tissues as testicle and fat. The brain level was under reliable limit of detection. Unchanged [¹⁴C] AT-2266 accounted for> 70% of total radioactivity in the liver and kidney, and >90%, in lung and heart. Levels in most tissues were not detected or<1μg eq./g 24 hr after the last administration. Autoradiographic findings agreed with above radiometric findings.
3. About 30 and 60% of dosed radioactivity were excreted in urine and feces, respectively, during and after repeated administration.
4. About 67% of urinary radioactivity were derived from the unchanged [¹⁴C] AT-2266 and about 21%, its glucuronide.
5. Disposition and metabolism of [¹⁴C] AT-2266 after repeated administration were thus essentially similar to those after single administration reported previously. The results suggest that none of any significant accumulation of [¹⁴C] AT-2266 radioactivity in tissues, any delay in excretion and metabolic alteration occurs even after repeated administration, implying its safety in long term administration.

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1.[Ethyl-1-¹⁴C] AT-2266, a novel antimicrobial agent, was orally administered in guinea pigs at a dose of 50mg/ kg and distribution of radioactivity was i vestigated in otorhinolaryngological tissues by autoradiography.[Ethyl-1-¹⁴C] norfloxacin was also studied for comparison.
2. Blood levels of both [¹⁴C] AT-2266 and [¹⁴C] norfloxacin radioactivity reached maximum at 1 hr, but the level of the former was about 4 times as high as that of the latter due to the difference of absorption.
3. At 1 hr after administration, [¹⁴C] AT-2266 radioactivity was far more significant in the septum cartilage, turbinates and ethmoid cells than in blood. Their surface tissues (nasal mucosa) contained the similar level of radioactivity to blood level. No appreciable radioactivity was seen in the brain and most of optic tissues.
4. Petrosal bone contained higher level of radioactivity than blood level, to which levels in outer surface of external auditory canal and mucosa of tympanic cavity were similar. Level of radioactivity in the tympanic membrane was lower. Radioactivity was extremely low or not appreciable in cochlea and its lymph fluid.
5. Soft palate and pharynx levels of radioactivity were most significant, and tongue level, more significant relative to blood level.
6. In contrast, levels of [¹⁴C] norfloxacin radioactivity were so low that the exact distribution was hardly observable. This was thought to be due to its poor absorption from digestive tracts.
7. Based on the distribution of [¹⁴C] AT-2266 radioactivity observed above, the usefulness of the agent was discussed in relation to its promising application for chemotherapy in otorhinolaryngological field.

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[Ethyl-1-¹⁴C] AT-2266 was synthesized for the disposition and metabolism studies.
An excessive amount (one third molar excess) of ethyl 7-(4-acetyl-1-piperazinyl)-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylate [I-a] was [¹⁴C] ethylated with commercially available [1-¹⁴C] ethyl iodide (185 MBq, 5.0mCi). The resultant mixture of [1-¹⁴C] ethyl-I-a (II-a-¹⁴C) and unreacted I-a was then ethylated completely with an excess amount of non-labeled ethyl iodide. These two steps of ethylation (hot and cold runs) advantageously made the subsequent purification and isolation procedure and finally gave pure II-a-¹⁴C in a good yield (130.6 MBq, 3.53 mCi)(70.6%). Hydrolysis of II-a-¹⁴C with diluted hydrochloric acid gave 107.3 MBq (2.9 mCi) of [ethyl-1-14] AT-2266 in 82.2% yield. The overall radiochemical yield was 58.0%.
[Ethyl-1-¹⁴C] norfloxacin was prepared by the similar procedure described above and 44.4 MBq (1.2 mCi) of [ethyl-1-¹⁴C] norfloxacin was obtained from 111 MBq (3.0 mCi) of [1-¹⁴C] ethyl iodide (overall radiochemical yield 40.0%).
Radiochemical purities of both [ethyl-1-¹⁴C] AT-2266 and [ethyl-1-¹⁴C] norfloxacin were found to be more than 99%.

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Mechanism of renal excretion of ATAT-2266, a new chemotherapeutic agent, was investigated in anesthetized dogs using renal clearance and stop- flow methods. Results were compared with those of pipemidic acid.
(1) Renal clearance rate of ATAT-2266 was lower than that of pipemidic acid.
(2) ATAT-2266 differed from pipemidic acid in stop- flow study in which ATAT-2266 showed a similar pattern with creatinine.
These results suggested that the renal excretion of ATAT-2266 took place mainly by glomerular filtration. The longer biological half life time of ATAT-2266 than that of pipemidic acid might derive from the above characteristic in renal excretion.

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ATAT-2266 or ampicillin (ABPC) was orally administered to rabbits at a dose of 50mg/ kg per dose, twice a day for 5 days, and their general symptoms and fecal flora were checked before and after administration.
ABPC administration caused the decrease of body weight and fecal amount, and a marked change of fecal flora, i. e. the remarkable increase in the number of Enterobacteriaceae and the significant decrease in that of Strepto coccus. The increased Enterobacteriaceae were mainly Escherichia coli, and the MIC values of ATAT-2266 and ABPC for them were 0.2 and 3.13-> 100μg/ ml respectively.
ATAT-2266 administration did not affect body weight nor fecal amount, but decreased the number of Enterobacteriaceae, a minor component of rabbit fecal flora, without affecting the number of Bacteroidaceae and Streptococcus.
These results indicate that ATAT-2266 being different from ABPC is a drug not affecting major components of rabbit fecal flora.

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Pharmacological properties of AT-2266, a new antibacterial agent, were investigated with the following results.
(1) By oral administration, AT-2266 did not show significant pharmacological effects except for a few experi. mental items such as potentiation in hexobarbital narcosis in mice and a slight decrease in acid output in rats.
(2) By intravenous administration, AT-2266 caused hypotension, decrease in heart rate and inhibition in respiration in anesthetized cats. In addition, minor changes were observed in ECG pattern and carotid blood flow in anesthetized dogs.
(3) EEG pattern, responses of blood pressure and heart rate induced by autonomic substances in cats were slightly affected by intravenous administration of AT-2266. Moreover minor changes were observed in respiration, ECG pattern, tone of nictitating membrane. But no appreciable effects was observed in contraction on skeletal muscle.
(4) In the experiments with isolated organs, AT-2266 did not show appreciable effects except for a slight changes in rabbit ileum, rabbit ear vessel, guinea-pig atrium and rat uterus.
From these results, it could be considered that pharmacological properties of AT-2266 closely resembles those of piromidic acid (PA) and pipemidic acid (PPA).

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Antigenicity (immunogenicity and allergenicity) of ATAT-2266 was examined in rabbits, guinea pigs and mice.(1) Production of the antibody specific to ATAT-2266 hapten in rabbits and guinea pigs (mainly IgG type) or in mice (IgE type) was observed when animals were immunized with ATAT-2266 conjugated to bovine serum albumin (BSA) or ovalbumin (OVA), but was not observed when immunized with ATAT-2266.(2) PCA reaction could not be elicited by a challenge of ATAT-2266 in animals sensitized with both types of the antibody. (3) In guinea pigs immunized with ATAT-2266- BSA, both immediate type of systemic anaphylaxis and delayed type of skin reaction were elicited by a challenge of ATAT-2266- OVA, but could not be elicited by that of ATAT-2266.
From these results, it could be concluded that ATAT-2266 lacks the antigenicity as far as it is given in a form of free hapten.

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Acute toxicities of ATAT-2266, a newly synthesized antibacterial agent, were assessed using mice, rats, dogs and monkeys.
The results obtained were summarized as follows:
1) The LD₅₀ values in intravenous administration were 327mg/kg in male and 391mg/kg in female of mice and 236mg/kg in male and 294 mg/kg in female of rats ; in subcutaneous administration, 1, 237mg/kg in male and 1, 320 mg/kg in female of mice and 2, 000mg/kg or more in rats ; in oral administration, 5, 000mg/kg or more in mice and rats and 1, 600mg/kg or more in dogs and monkeys, respectively.
2) As for the toxic signs in nearly lethal intravenous and subcutaneous doses, mice and rats developed ataxia, ptosis and sedation. The dead animals showed further myoclonus and tonic convulsion.
3) With regard to oral administration, mice and rats developed no toxic sign; however, there found vomiting in a few dogs receiving the lower dose (25mg/kg) and in a few monkeys receiving the relatively higher dose (400mg/kg), respectively.
4) Necropsy findings revealed that parenteral doses elicited not only irritable responses in the injected area but also, in subcutaneous route of mice, peritonitis due probably to deposition of the compound-like crystal in the abdominal cavity; however, the other systemic alterations could not be detected in all administration routes.

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ATAT-2266, a newly synthesized antibacterial agent, was administered orally to rats at dose levels of 120, 600 and 3, 000 mg/ kg/ day in one- month subacute toxicity study, and of 60, 300 and 1, 500 mg/ kg/ day in six- month chronic toxicity study, respectively.
The results obtained were as follows:
1) In both toxicity studies, there found no animal death due to administration of the compound and, as for the toxic signs, the animals receiving the high dose in chronic study and receiving the moderate dose or more in subacute study developed soft stool.
2) The high dose of both studies caused the depression of growth rate.
3) Cecum weight increased dose-dependently in both studies.
4) Blister- like change at the intermediate zone of the articular cartilage was noted in a few animals receiving the moderate dose or more in both studies.
5) Slight desquamation and hydropic degeneration of the uriniferous tubules were observed in a few animals of the high dose group in subacute toxicity study.
6) There found atrophic testis and degenerated spermatids in ductus epididymides only in the high dose group of both studies.
7) With regard to increased cecum weight and atrophic testis, the changes were recognized to recover or to alleviate, after the cessation period for one month in chronic toxicity study.
From the results mentioned above, the safaty dose of AT-2266 was estimated to be 120 mg/ kg/ day in subacute toxicity and 60 mg/ kg/ day in chronic toxicity, respectively.

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ATAT-2266, a newly synthesized antibacterial agent, was administered intragastrically via nose to female monkeys (Macaca fascicularis) once a day for 6 weeks at dose levels of 20, 40 and 80 mg/ kg.
The results obtained were as follows:
1) As for the changes related to administration of ATAT-2266, all monkeys developed loose or solid stool which was essentially due to antibacterial effects of the compound.
2) In 20 and 40 mg/ kg dose groups, there found no abnormal findings in body weight, food consumption, urinalysis, hematology, blood biochemistry, BSP excretion test, organ weight, necropsy and histopathology.
3) One of 4 monkeys given 80 mg/ kg developed anorexia, vomiting and candidiasis (oral cavity and esophagus), followed by moribund state and then, was sacrificed at the 29 th day of dosing. At the moribund state, various abnormalities related to starvation were observed but, grossly or histopathologically, alterations attributable to the direct effects of the compound were scarcely observed in all organs. The survivors given 80 mg/ kg, on the other hand, showed no toxicological effects except for slight elevation of neutrophil and slight renal failure.
From the results mentioned above, the maximum safety dose of ATAT-2266 in monkeys was estimated to be 40 mg/kg/day.

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ATAT-2266, a newly synthesized antibacterial agent, was administered orally to beagle dogs twice a day for 6 months at daily dose levels of 30, 60 and 120 mg/kg.
The results obtained were as follows:
1) In 30 and 60 mg/kg dosing groups, there found no abnormal findings in body weight, food consumption, urinalysis, hematology, blood biochemistry, BSP excretion test, organ weight, necropsy and histopathology.
2) As for changes related to the administration of the compound, 2 of 3 females of 120 mg/kg dosing group developed decrease or loss of appetite, followed by emaciation due to continual anorexia for 3 weeks or more. In 1 female sacrificed in extremis on the 23 rd day of dosing, various changes associated with limophthisis and dehydration were observed grossly and histopathologically, while alterations attributable to direct effects of the compound were scarcely observed in all organs examined. The other female recovered by the discontinuation of dosing for 4 days, thereafter, no remarkable changes took place following the resumption of dosing. In the survivals of 120 mg/kg dosing group, there found slight anemia on and after 5th month of dosing and proliferative changes of erythroid cells in the bone marrow which might be a compensatory change to anemia. Furthermore, atrophic changes of seminiferous tubules which might suggest an inhibition of latter stage of spermatogenesis were observed histopathologically in all males of 120 mg/kg dosing group.
From the results mentioned above, the maximum safety dose of ATAT-2266 in dogs was estimated to be 60 mg/kg/day.

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The purpose of this study was to evaluate the effects of ATAT-2266, a new antibacterial agent, on the fertility and early fetal development in the Jcl: SD rats. The compound was administered daily by gavage at doses of 100, 300 and 1, 000 mg/kg/ day to the males from 63 days before mating until completion of reproductive performance and to the females from 14 days before mating until day 7 of gestation.
Male fertility impairment resulting in non- pregnancy or decreased implantations in partner females occurred in the 1, 000mg/kg dose group after 63- day treatment. One half of males in each group were autopsied on day 112 or 113 of treatment and examined for their testes and epididymides microscopically. Although no apparent changes were detected in the testes for any group, degenerate germinal cells were observed in the lumen of the epididymal ducts in the males treated with 1, 000mg/kg of the compound. The observations suggest that the dose of 1, 000mg/kg impairs spermatogenesis. The remaining half males in each group were examined for their fertility again after 63- day cessation of treatment. The fertility of the males in the 1, 000mg/ kg dose group recovered to normal and no microscopical changes in the epididymis were observed. Therfore, the male fertility impairment was reversible.
No markedly abnormal changes were observed in the adult females or their fetuses.
It is concluded that the maximum non-toxic dose is 300mg/ kg/ day in this study.

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It has been reported that treatment with 1, 000mg/kg/ day of ATAT-2266, a new antibacterial agent, to male rats for 63 days resulted in non- pregnancy or decreased implantations in mated females. The male fertility impairment was considered due to spermatogenesis disturbance. The purpose of the present study was to examine the mechanism of the effect on male fertility.
ATAT-2266 was administered daily by gavage at a dose of 1, 000mg/kg/ day to Jcl: SD male rats for 13 weeks. Each male rat was paired with two non- treated virgin females per week from 1 week prior to initiation of treatment until 10 weeks after cessation of treatment. Mated females were cesarean- sectioned on day 14 of gestation and implantation rates as an index of male fertility were recorded. During the mating period, a part of males were additionally mated with non- treated females and eggs from the females were examined for fertilization.
Lower implantation rates were observed in the 1, 000 mg/ kg dose group from week 6 of treatment until week 4 after cessation of treatment. The result suggests that spermatogenesis is disturbed when germinal cells are continuously exposed to the compound from spermatocyte phase to spermatid phase. Egg examinations revealed that the lower implantation rate was due to lower rate of egg fertilization. Therefore, the lower implantation rate is not due to dominant lethality.

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ATAT-2266, a new antibacterial agent, was evaluated for teratogenic potential in the Jcl: SD rats. The compound was administered daily by gavage to the mated females at doses of 100, 300 and 1, 000mg/kg/ day from days 7 through 17 of gestation. Twenty- five mated females in each group were cesarean- sectioned on day 21 of gestation and their fetuses were examined for external, visceral and skeletal abnormalities. Fifteen mated females in each group were allowed to deliver and their offspring were examined for growth and functional development.
In 1, 000mg/ kg dose group dams, soft feces were consecutively observed and body weight gain was decreased duringestation. An increased cecum weight was noted in cesarean- sectioned females in all drug- treated groups and also in females allowed to deliver in the 300 and 1, 000mg/ kg dose groups. No drug- related variations were found in delivery or maternal behavior.
In the fetal examination, decreased body weight, decreased incidence of 14th ribs and retarded ossification were observed in the 1, 000mg/ kg dose group. But drug- treated and control group offspring were comparable in survival rate, growth, physical and behavioral development, spontaneous activity, learning ability and reproductive performance.
It is concluded that ATAT-2266 has no teratogenic potential in the rat at a dose of 1, 000mg/ kg/ day and that the non- toxic maximum dose of the compound is 300 mg/ kg/ day in this study.

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ATAT-2266, a new antibacterial agent, was administered daily by gavage to the pregnant female rats of the Jcl: SD strain (18 to 20 rats per group) at doses of 100, 300, and 1, 000mg/ kg/ day from day 17 of gestation through day 21 of lactation. The dams were allowed to deliver and their offspring were examined for growth and functional development.
In the 1, 000 mg/ kg dose group, all dams showed soft feces consecutively. An increased cecum weight and enlarged cecum were noted in dams in all drug- treatment groups, but these reactions are common to many of antibacterial agents. No drug- related abnormalities were found in delivery or maternal behavior.
Drug- treated and control offspring were comparable in the survival rate, growth, physical and behavioral development, spontaneous activity, learning ability and reproductive performance.
It is concluded that ATAT-2266 does not affect parturition or maternal behavior, or the growth, behavior or function of offspring. In the dams, persistent soft feces occurred at 1, 000 mg/kg/ day. This suggests that the maximum non- toxic dose of the compound for dams is 300mg/ kg/ day in the present study. In the offspring, no evidence of toxicity was obtained, so the maximum non- toxic dose for offspring may be 1, 000 mg/kg/ day or more.

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The purpose of this study was to evaluate the effects of AT-2266, a new antibacterial agent, on the dams and their fetuses in beagle dogs. AT-2266 was administered by gavage to pregnant animals at doses of 15, 30 and 60mg/kg/day on days 14 through 35 of gestation.
No maternal deaths occurred during the study. Physical sign, pregnancy and food consumption were not affected by treatment. Maternal body weight was slightly decreased in the 60mg/kg dose group on and after day 45 of gestation because one 60mg/kg dose group dam had fetal deaths (7 of 8 fetuses died in the uterus) and did not put on weight during gestation.
Fetal body weight was slightly decreased in the 60mg/kg dose group. At 60 mg/kg, slight increase of fetal mortality was observed because one dam in that group had intrauterine fetal death as mentioned above.
One control and four 60mg/kg dose group fetuses had external abnormalities. The abnormalities, however, were not considered to be related to treatment since the incidence was not significantly different between the two groups and was similar to that in one of the previous dog teratogenicity studies conducted in our laboratory. No drug-related visceral or skeletal abnormalities were observed in fetuses.
Therefore, it is concluded that AT-2266 is not teratogenic to dogs at 60 mg/kg. A dose of 30 mg/kg is the maximum non-toxic dose in this study.

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The phase I study of AT-2266, a new synthetic antibacterial agent of pyridonecarboxylic acid class, was performed on 22 healthy male volunteers to investigate its pharmacokinetics and safety. In the single dose group, the drug was administered orally in a dose of 200, 400 or 800mg after the meal. In the repeated-dose group, the daily dose of 800mg was orally administered into two equally divided doses, i. e. after breakfast and after supper for 7 days.
With regard to subjective symptoms, 1 patient each in the single 800mg dose group reported face flush and heavy feeling of stomach and 1 patient each in the repeated-dose group reported constipation and thirst. All of these side effects were mild and transient. No abnormal findings which were definitely attributable to AT-2266 were found in other subjective and objective symptoms, blood pressure, heart rate, respiratory rate, body temperature, ECG, hematology, blood chemistry, urinalysis, equilibrium test or audiometry. Slight elevation of GPT was fond in 1 patient given a single dose of 200mg. However, elevated GPT was not found in patients given single doses of 400 or 800mg or those given repeated doses of 800mg. Therefore, it appears that this elevation was not attributed to AT-2266. In future studies, attention will be required to be given to the liver function.
The plasma concentration of AT-2266 after administration of single doses of 100, 200, 400 and 800mg reached a peak 1 to 2 hours after administration and the peak values were 0.403, 1.68, 3.14 and 6.98μg/ml, respectively. The elimination half-life from the blood ranged from 4.87 to 6.35 hours. The urinary recovery within 24 hours after administration ranged form 54.4-64.3%. The effect of meals was investigated in a crossover design using the 400mg group. It was found that meals had no appreciable effect on the absorption of this drug. Even when a daily dose of 800mg was orally administered for 7 consecutive days, there was no tendency for this drug to accumulate in the blood.

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ATAT-2266 is a new synthetic pyridonecarboxylic acid antimicrobial agent. The peak MICs of this drug against clinical isolates were 0.2μg/ml against 54 strains of E. coli, 0.4μg/ml against 54 strains of K. pneumoniae, 1.6 μg/m l against 54 strains of P. mirabilis, 0.2μg/ml against 54 strains of P. morganii, 0.8 and 25μg/ml, i.e. biphasic, against 53 strains of S. ntarcescens, and 1.6μg/ml against 104 strains of P. aeruginosa. ATAT-2266 was superior by a few dilution factors to PA and PPA but inferior by one dilution factor to NFLX. When 300 mg of AT-2266 was administered orally to 6 healthy adult males in fasting state, the blood concentration of the drug reached apeak of 2.29μg/ml at 1 hour and declined gradually to 1.15μg/ml at 4 hours, 0.45μg/ml at 8 hours, 0.25μg/mlat 12 hours and below the detection limit at 24 hours. The blood half- life was 4.31 hours. The area under the curve (AUC) was 12.0 hr·μg/ml. The urinary excretion of the drug was 55% in 24 hours. HPLC revealed a trace of oxo form in the blood; the percentage of the oxo form increased in the urine. The drug was administered in a daily dose of 600mg or 300mg in 3 divided doses to a total of 32 patients, i. e. 20 patients with respiratory tract infections and 12 patients with urinary tract infections for 4 to 14 days to evaluate its clinical efficacy. The clinical results were: excellent in 17 cases, good in 13, fair in 1, and unknown in 1. The success rate was 96.8%. Bacteriologically, marked effect was found, i. e. S. aureus, E. coli, P. mirabilis, and H. influenzae were eradicated. No noticeable side effects were encountered, nor was found any abnormal laboratory value.

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ATAT-2266, a synthetic oral antimicrobial agent, was administered (600mg/ day in 3 divided doses) to three patients with acute pneumonitis, 2 with biliary tract infections, and 3 with acute cystitis to evaluate its antibacterial activity, clinical efficacy and absorption and elimination.
In 3 cases of acute pneumonitis, the causative organisms, i. e. S. aureus, K. pneumoniae, K. oxytoca were eradicated after administration of ATAT-2266. Both in biliary tract infections (P. aeruginosa, A. hydrophila, S. faecalis, A. anitratus, K. pneumoniae) and acute cystitis (Streptococcus sp., K. pneumoniae, A. lwoji, E. colt), the causative organisms were eradicated. The MICs of the drug were 0.39μg/ml against K. pneumoniae (2 strains), 0.78μg/ml against P. aeruginosa, 0.10μg/ml against A. hydrophila and 1.56μg/ml against A. lwoffi. The clinical response was excellent in 1 case, good in 6 cases, and poor in 1 case, which was pneumonitis with the underlying disease of lung cancer.
The absorption and elimination of ATAT-2266 was rapid.(The concentrations of the drug in the blood, sputum, bile and urine were determined in 3, 1, 1 and 1 cases, respectively.) Over the period of 24 hours, the concentration of the drug was 2μg/ml or more in blood, 1μg/ml or more in sputum, 10μg/ml or more in bile, and 300μg/ml or more in urine.

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AT-2266, a synthetic pyridonecarboxylic acid antibacterial agent, was administered to 12 patients with respiratory tract infections, mostly, secondary to some underlying disease.
In 10 of the 12 patients, quantitative cultures of the sputum revealed significant causative organisms. AT-2266 was administered orally in doses of 200-300 mg two to four times daily for treatment of bacterial infection. Out of 10 patients (2 patients had shown normal flora.), the original organisms were eradicated in 6 patients, the type and amount of bacteria remained unchanged in 3 patients, and microbial substitution took place in 1 patient. Global evaluation including clinical efficacy, such as relief of symptoms and improvement in laboratory findings, evealed that 6 of 12 patients had good or excellent responses.

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Recently, a new oral antimicrobial agent, structurally related to nalidixic acid, was synthesized in laboratory of Dainippon Pharmaceutical Co., Ltd. in Japan. It was shown that this new agent possessed a broad antimicrobial spectrum covering gram-positive cocci and gram-negative bacilli.
Minimal inhibitory concentrations (MICs) of the agent against each 20 clinical isolates of S. aureus, E. coli, K. pneumoniae, S. marcescens, E. cloacae and P. aeruginosa were determined by use of Dynatech MIC 2000 system. At a concentration of 0.78μg/ ml, this agent inhibited 65, 85, 95, 90, 80 and 70% of the strains of S. aureus, E. coli, K. pneumoniae, S. marcescens, E. cloacae and P.aeruginosa, respectively.
Nine patients suffering from respiratory tract infections received orally 600 mg of the drug a day.
Seven showed a good response and two a fair response.
No undesirable symptoms and signs due to administration of the drug were observed. No abnormality in laboratory findings was noted during and after the treatment with the drug.

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The concentration in sputum and plasma and clinical investigations against respiratory tract infections were performed on AT-2266, a new pyridonecarboxylic acid derivative.
200 mg of AT-2266 was administered to the patients 3 times a day.
The concentration in plasma kept 1 to 2μg/ ml through a day and that in sputum increased to 1 to 2μg/ ml after 2 to 3 hours and kept through a day.
AT-2266 was administered to a total of 27 patients with respiratory tract infections including 5 cases of pneumonia, 15 cases of exacerbation of chronic bronchitis, 4 cases of acute bronchitis and 3 cases of panbronchiolitis.
The drug was administered at a daily dose of 600 mg (5 cases) or 800 mg (22 cases) for 7 to 14 days.
The drug was discontinued after four times' therapy in 1 case because of a taste of bitter and after three days' therapy in 1 case because of a slight feeling of insomnia.
The following 20 potential pathogens were recovered from the sputum at a start of the treatment with AT-2266 and 17 pathogens were eradicated during the treatment (eradication ratio=85%).
The clinical response to the treatment with AT-2266 was excellent in 10 cases, good in 14 cases, fair in 2 cases and not valuable in 1 case (efficiency=92.3%).
The slight feeling of insomnia was observed in 1 case and the other side effects were not observed.<BR.From the above results, it is concluded that AT-2266 is one of effective and useful antimicrobial agent.

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AT-2266, a newly developed pyridonecarboxylic acid derivative, was administered to 7 patients with respiratory tract infections and 2 patients with urinary tract infections. The dosage was 600 to 900 mg/ day given in divided doses three times daily for 5 to 14 days. The clinical response was excellent in 1 case, good in 6 cases, and fair in 2 cases. The success rate was 77.8%.
Neither side effects nor abnormal laboratory findings were found.

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A clinical study of AT-2266, a new pyridonecarboxylic acid derivative, was performed in the field of internal medicine.
Three inpatients and 2 outpatients, or a total of 5 patients were admitted to the study. The diseases under study were classified as 3 cases of urinary tract infection (2 cases of acute pyelonephritis and 1 case of chronic cystitis) and 2 cases of chronic bronchitis.
The causative organism was E. coil or P. inconstans in urinary tract infections and H. influenzae in chronic bronchitis.
The drug was administered in doses of 200 mg three times daily for 6 -12 days.
The clinical response was excellent in 2 cases and good in 1 case for urinary tract infection and excellent in 1 case and fair in 1 case for chronic bronchitis.
No particular side effects were encountered. As for clinical laboratory findings, moderately elevated GOT, GPT and Al-p were found in 2 cases, but the causal relationship with this drug was unknown.

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We investigated the antibacterial activity, absorption and excretion, and clinical efficacy of AT-2266, a new p yridone carboxylic acid antimicrobial agent.
The results obtained were as follows.
1) Antibacterial activity
The antibacterial activity of the drug against clinical isolates, i. e. E. coli, K. pneumoniae, and P. aeruginosa, was investigated. AT-2266 was more active against E. coli than NFLX, MLX, PPA andNA; it was comparable to NFLX but more active than MLX, PPA and NA against K. pneumoniae and P. aeruginosa.
2) Absorption and excretion
After oral administration of a single dose of 200 mg of AT-2266, the blood level reached a peak concentration having an average of1.34 μg/ml at 1 hour and decreased gradually with half-life of 6.40 hours to 0.04μg/ml on the average at 24 hours. The urinary recovery rate within 24 hours was 69.1% on the average. No appreciableeffect of probenecid was found.
3) Clinical response
The drug was administered to 16 patients with infections in the field of internal medicine. The clinical response was rated excellent in 1 patient, good in 9 and fair in 2.
Subjective side effects were found in 4 patients.

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The effect of AT-2266 was clinically evaluated in 29 cases of lower respiratory infections (23 cases of chronic bronchitis, 4 cases of diffuse panbronchiolitis and 2 cases of pneumonia). 200mg of AT-2266 was orally administered 3 times a day.
Clinical responses were excellent in 1 case, good in 15 cases, fair in 1 case and poor in 6 cases among 23 cases of chronic bronchitis, and good in 2 cases, poor in 2 cases among 4 cases of diffuse panbronchiolitis and good in 2 cases of pneumonia. 69.0% of the efficacy rate was given.
As to the side effects, headache, the elevation of GPT and Al-p were observed in each 1 case.
From the results, it was considered that AT-2266 would be expected to be useful for the treatment of patients with lower respiratory tract infection including faradvanced or intractable cases.

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AT-266, a new antipseudomonal agent structurally related to pipemidic acid, was administered to 5 patients with respiratory tract infection. AT-2266 was given orally 600mg/day for 7-21 days.
Clinical efficacy was good in 4 and fair in 1 case. No side effect was observed.

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AT-2266 200mg was given t. i. d. to 10 aged patients (mean 73.2 years old). Of 4 patients with respiratory infection, 3 responded satisfactorily. Of 6 patients with urinary tract infection, 5 showed satisfactory response. Transient elevation of BUN and serum creatinine was observed in 1 patient with chronic renal disease.

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Basic studies of AT-2266, a newly developed oral antibacterial agent, were performed and the drug was used in the treatment of 19 patients with infections.
1. Staphylococcus aureus, E. coli, Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens, Proteus mirabilis, Proteus vulgaris and Pseudomonas aeruginosa were isolated from the clinical materials. The antibacterial activity of AT-2266 was compared with that of NFLX at an inoculum size of 10⁶ CFU/ml against 25 strains each of these isolated organisms. AT-2266 was comparable to NFLX in antibacterial activity against S. aureus, S. marcescens and P. aeruginosa but slightly inferior to NFLX against other organisms.
2. A single dose of 500 mg of AT-2266 was administered to 8 healthy male adults, i. e. 4 men in the fasting state and another 4 men who had taken 600 calories of food just before. In both groups, peak blood levels were achieved two hours after administration. The peak level was 3.31μg/ ml in the fasting state and 3.09μg/ml in the satiation state. In the fasting state, the absorption of the drug was slightly more rapid and the peak level was slightly higher. However, the differences were not significant. There was little effect of a meal. The urinary recovery up to 8 hours was about 54%.
3. A clinical trial was performed on 19 patients, i. e. 17 patients with respiratory tract infections and 2 patients with urinary tract infections. The dosage was 600 mg daily for all patients. In acute respiratory tract infections, the drug was clinically effective in 13 of 14 cases; bacteriologically, the causative organisms were eradicated in 11 cases and unknown in 2 cases. In chronic respiratory tract infections, the drug was effective in 1 of 3 cases. Both patients with acute cystitis responded to the drug.
4. No appreciable side effects were encountered in any of the cases.
From these results, it is concluded that AT-2266 is a useful drug as an oral antibacterial agent.

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A clinical study of AT-2266 was performed on 18 patients during the period from June to October 1982.
11 men and 7 women, aged 36 to 88 years (mean±S. E. 64.7±12.5 years) were admitted to the study. There were 5 cases of acute pneumonia, 3 cases of bronchiectasis, 3 cases of chronic bronchitis, 2 cases of acute bronchitis, 2 cases of middle lobe syndrome, 1 case of pulmonary abscess, 1 case of acute pharyngitis, and 1 case of acute cystitis.
Bacteriological examination was performed on 16 patients. Six patients had normal flora. A single causative organism was detected in 8 patients and plural organisms were detected in 2 patients. The isolated organisms were P. aeruginosa in 4 cases, S. pneumoniae in 2, E. coli in 1, H. influenzae in 1, K. pneumoniae in 1, S. aureus in 1, P. vulgaris in 1, and P. maltophilia in 1.
AT-2266 was administered in doses of 200 mg and 300 mg three times daily to 12 and 6 patients, respectively for 3 to 35 days. The total dose ranged from 1.8 to 31.5 g (mean±S.E. 9. 6±7.4g).
The clinical response was rated excellent in 3 cases, good in 12, fair in 1, and poor in 2. The success rate was 83.3%. The; bacteriological response was rated elimination in 6 cases, reduction in 0, no change in 3, microbial substitution in 0, and unknown in 9. The bacterial elimination rate was 66.7%. Three persistent organisms comprosed 2 P. aeruginosa and 1 S. pneumoniae.
Side effects or abnormal laboratory values were found in 3 cases. They were granulocytopenia, abdominal distension and thrombocytopenia.

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Clinical study was made on AT-2266, a new pyridonecarboxylic acid derivative and the following results were obtained.
1) AT-2266 was found effective in 40.0% of 30 patients with respiratory infection.
2) AT-2266 was found effective in 50% of 14 patients with lower respiratory tract infection except bronchiolitis and pulmonary emphysema.
3) AT-2266 was found effective in 31.2% of 16 patients with so called small airways diseases which include di. ffuse panbronchiolitis and pulmonary emphysema.
4) Bacteriological study showed that AT-2266 had good effect in respiratory tract infection due to Haemophilus influenzae but that it had no effect in streptococcal infection.
5) AT-2266 caused headache in 2 patients, loss of appetite in 1 patient, eosinophilia in 2 patients and elevation of GOT in 1 patient, but these findings were alleviated rapidly following cessation of AT-2266.

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A new drug, AT-2266, was given orally to a total of 37 patients with infectious diseases (1 case with acute tonsillitis, 6 cases with acute pharyngitis, 20 cases with acute bronchitis and 10 cases with exacerbation of chronic bronchitis), and following results were obtained.
The daily dose of this drug ranged from 600 to 900 mg.
1) Clinical effectiveness:
The clinical response in acute tonsillitis was evaluated as good in 1 case. In acute pharyngitis is was evaluated as good in 3 cases and poor in 2. The clinical response in acute bronchitis was evaluated as good in 12 cases, air in 3 and poor in 5. In exacerbation of chronic bronchitis it was evaluated as excellent in 1 case, good in 6, fair in 2 and poor in 1.
The overall efficacy rate in 36 cases was 63.9%.
2) Bacteriological effectiveness: The 3 strains of S. pneumoniae, H. influenzae and β-Streptococccus was isolated from sputa and the mucous of pharynx in the patients with respiratory tract infection. All these strains excepting 1 strain of S. pneumoniae were eliminated by this drug.
3) Side effecst:
One adverse reaction due to this drug was observed.
In 2 cases, nausea was observed. However, this disappeared soon after ceasing the administration of the drug.

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The antibacterial activity of AT-2266, its absorption and excretion in patients with chronic renal failure and its clinical efficacy were investigated. The results were as follows.
1) Antibacterial activity: The antibacterial activity of AT-2266 against all 6 clinical isolates, i. e. S. aureus, E. coli, K. pneumoniae, P. mirabilis, P. aeruginosa, and S. marcescens, was nearly equal to that of Norfloxacin, except P. aeruginosa. At a concentration of 1.56μg/ml or less, 80% or more of strains of these 6 organisms were inhibited.
2) Absorption and excretion inpatients with chronic renal failure: When a single dose of 200 mg of AT-2266 was administered orally to patients with impaired renal function (Ccr 2.4-4.2ml/min) in fasting state, the blood concentration of AT-2266 reached a peak of 1.39-1.85μg/ml at 1 to 2 hours. The urinary recovery within 12 hours was 3.4 to 7.7%.
3) Clinical results: The drug was administered to 20 patients with respiratory tract infections. The clinical response was good in 16 cases, fair in 1 case, poor in 2 cases, and unassessable in 1 case. The success rate was 80%.
As regards side effects, dizziness was found in 1 case. No abnormal laboratory values were found.
From these results, it is considered that AT-2266 is a useful drug in the treatment of respiratory tract infection.

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AT-2266 a new antimicrobial agent developed by Dainippon Pharmaceutical Co., Ltd., was administered to 40 patients with respiratory tract infections. The dosage was 600 to 900 mg in divided doses taken 3 times daily for 3 to 28 days.
The disease under study was chronic respiratory tract infection (28 cases)(chronic bronchitis 18, bronchiectasia 10), acute respiratory tract infection (11 cases)(acute bronchitis 4, acute pharyngolaryngitis 7), and middle lobe syndrome (1 case). The causative organisms were demonstrated in 17 patients. As regards cocci, 2 strains of S. pneumoniae were found. As for bacilli, there were 6 strains of H. influenzae, 1 strain of E. coli, 2 strains of Klebsiella sp., 1 strain of P. mirabilis, 4 strains of P. aeruginosa, and 1 strain of Serratia sp.
After administration of the drug, S. pneumoniae, H. influenzae, E. coli, Klebsiella sp. and Serratia sp. were eradicated, P. mirabilis was replaced by other organisms, and some strains of P. aeruginosa were eradicated and other strains of P. aeruginosa were persistent.
Out of 40 patients, 15 had excellent clinical responses and 19 had good clinical responses; the rate of excellent responses was 37.5% and the success rate was 85.0%. In 28 cases of chronic respiratory tract infection, which accounted for 70% of all cases, 12 were rated excellent and other 12 good ; the rate of excellent response was 42.9% and the success rate was 85.7%.
Side effects occurred in 7 (17.5%) of 40 cases. All side effects found were gastrointestinal symptoms, such as nausea, anorexia, heartburn, diarrhea, stomatitis and angular stomatitis. No serious side effects were encountered.
No appreciable abnormality was found in laboratory data.
These results suggest that AT-2266 is expected to be a drug of first choice for the treatment of exacerbation of chronic respiratory tract infection.

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AT-2266 was orally administered to 10 patients with urinary tract infection and 10 patients with respiratory tract infection. The patients received the drug for 4 to 49 days in doses of 300 to 1, 200 mg/day. All patients except for a patient with chronic cystitis and urethral stricture responded well to the therapy. No side effect of AT-2266 was recognized.

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Clinical studies on AT-2266, a newly synthesized antimicrobial compound, were carried out in this clinic and the following results were obtained.
1. AT-2266 was administered to a total of 30 patients: 26 with respiratory tract infection, 3 with urinarytract infection and 1 with biliary tract infection.
2. Clinical responses were excellent in 1 patient, good in 23, fair in 4, poor in 2.
3. Each patient suffered from one of the adverse reaction: eruption, epigastralgia and anorexia. Laboratory test revealed eosinophilia in 1 case. No severe side effects were observed in all cases.

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One hundred miligrams of AT-2266 was administered twice a day to six patients having a total of seven episodes of urinary tract infections associated with neurogenic disorders due to cerebrovascular disease. The MICs of AT-2266 against E. coil, Proteus mirabilis, Klebsiella and Citrobacter isolated from their urine ranged from 0.1 to 0.39μg/ml. Clinical and bacteriological effects were good in six episodes except in one episode in a patient who also had insulin dependent diabetes. No side effect and abnormality oflaboratory data in relation to administration of AT-2266 were found, in all cases. AT-2266 was useful in the treatment and presumably in the prevention of relapse of urinary tract infection.

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The antibacterial activity and clinical efficacy of AT-2266 were investigated. The results obtained were as follows.
1) Antibacterial activity: AT-266 and the same class of antibacterial agent, i. e. NFLX, PPA and NA were compared with each other in terms of antibacterial activity against 138 clinical isolates of gram-negative bacilli, such as E. coil, K. pneumoniae, S. marcescens, P. aeruginosa, P. mirabilis, P. morganii and P. vulgaris.The MICs of AT-2266 for clinical isolates were 4 to 6 times lower than those of PPA and NA for all tested bacteria, 2 times higher than those of NFLX for E. coli, K. pneumoniae and Proteus, equal to those of NFLX for S.marcescens and P. aeruginosa.
2) Clinical results: AT-2266 was administered to 4 patients with pneumonia, 15 with acute bronchitis, 1 with acute tonsillitis, 1 with acute laryngitis, 10 suffering from an acute exacerbation of chronic respiratory tract infection, 1 with acute urinary tract infection and 1 with chronic urinary tract infection, or a total of 33 patients. One patient who discontinued treatment during the course of the study owing to side effect was excluded from efficacy evaluation and the remaining 32 patients were included in it. The clinical response was rated excellent in 1 case, good in 19 cases, fair in 5 cases and poor in 7 cases. The success rate was 60.0%. The success rate was higher in patients with acute respiratory tract infections such as pneumonia and acute bronchitis but lower in patients suffering from an acute exacerbation of chronic respiratory tract infection. Bacteriological examination revealed the following: S. pneumoniae, which was detected in acute bronchitis, was eradicated ; P. mirabilis, which was detected in acute exacerbation of chronic respiratory tract infection, was replaced by S. epidermidis; S. marcescens persisted; P. aeruginosa persisted in 1 case and was replaced by E. agglomerans in another case. In 2 cases of urinary tract infections, multiple bacteria were detected, i. e. C. freundii plus E. aerogenes and P. vulgaris plus Fravobacterium plus C. freundii, and all these bacteria were eradicated. Side effects observed were eruption in 1 case, elev ated GPT in 1 case, decreases in the number of leucocytes in 1 case, increased eosinophile in 1 case, and positive coombs test in 1 case.

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The authors report the results of clinical investigations of AT-2266, 1-ethyl-6-Auoro-1, 4-dihydro-4-oxo-7-(1-piperazinyl)-1, 8-naphthyridine-3-carboxylic acid, is a new antipseudomonal agent structurally related to Pipe.midic acid (PPA).
The antibacterial activity of ATAT-2266 was compared to that of Norfloxacin (NFLX), Pipemidic acid (PPA), Nalidixic acid (NA) and Gentamicin (GM) in a total of 156 clinical isolated strains of S. aureus, E. coli, K. pneu. moniae, E. cloacae, S. marcescens, Proteus sp. and P. aeruginosa.
AT-2266 was somewhat inferior to GM against S. aureus but stronger than that of NFLX, PPA and NA, meanwhile AT-2266 showed almost the same activity as NFLX against gram- negative bacilli. Clinical evaluation was carried out in 14 patients with respiratory tract infection (RTI) and 5 patients with urinary tract infection (UTI). Response was good in 9 (64.3%) out of 14 RTI cases and excellent and good in all cases of UTI.
As a side effect, eosinophilia observed in 1 case, but adverse reaction returned to normal within one week following completion of administration.

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AT-2266, a new synthesized antimicrobial agent for oral administration, was applied to the clinical trial in treatment of respiratory tract infections.
The drug was administered orally, 600mg-800mg/ day, divided into three to four doses, for the period of five to eighteen days.
The results were as follows, of seven trial cases, good in five cases, slightly good is one case, and one case was excluded in violation of the protocol.
No side effects were observed. No significant laboratory data were observed.
Usefulness of the drug was suggested for treatment of respiratory tract infections.

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