In vitro and in vito antibacterial activity of DL-8280, a new pyridone carboxylic acid derivative synthesized in the Research Institute of Daiichi Seiyaku Co., Ltd., was examined using various species of clinical isolates.
1) DL-8280 showed a broad spectrum of antibacterial activity against gram-positive and gram-negative bacteria, including obligate anaerobes.
2) DL-8280 had greater activity against staphylococci, streptococci, P. maltophilia, Acinetobacter spp., B. fragilis and clostridia than did norfloxacin, pipemidic acid and nalidixic acid.
3) The activity of DL-8280 against Enterobacteriaceae, P. aeruginosa, H. inftuenzae and N. gonorrhoeae was roughly comparable to that of norfloxacin and far exceeded that of pipemidic acid and nalidixic acid.
4) Most nalidixic acid-resistant Enterobacteriaceae, ampicillin-resistant N. gonorrhoeae and clindamycin-resistant anaerobes were susceptible to DL-8280.
5) DL-8280 displayed bactericidal action at its minimal inhibitory concentrations against various bacteria.
6) Appearance rate of natural resistrant mutants against DL-8280 was very low.
7) When administered orally to mice which were infected experimentally with E. coil, K. pneumoniae, P. mirabilis, S. marcescens and P. aeruginosa, DL-8280 was 2 to 4 times more effective than norfloxacin and 8 to more than 40 times more effective than pipemidic acid.

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Antibacterial activity of DL-8280 was studied in comparison with that of other antibacterial agents against 224 strains of Streptococcus and 292 strains of glucose-non-fermentative bacilli isolated from various clinical materials in 1982.
Antibacterial activity of DL-8280 against Streptococcus was almost equal to that of NFLX, and DL-8280 was highly active against enterococci many strains of which were resistant to antibacterial agents of common use.
Antibacterial activity of DL-8280 against glucose-non-fermentative bacilli, many strains of them were resistant to antibacterial agents of common use, such as Pseudomonas, Acinetobacter, Flavobacterium, Achromobacter and Cornamonas was superior to that of NFLX, PPA and NA, and the growth of more than 90% strains of these bacilli was inhibited at a concentration of 12.5μg/ml, except A. xylosoxidans and Alcaligenes.

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The in vitro and in vivo antibacterial activity of DL-8280, a new pyridone carboxylic acid derivative, was compared with that of norfloxacin (NFLX), plpemidic acid (PPA) and nalidixic acid (NA).
DL-8280 showed a broad soectrum of antibacterial activity against gram-positive and gram-negative bacteria including obligate anaerobes. The activity of DL-8280 against Enterobacteriaceae, Pseudomonas aeruginosa and Haemophilius influenzae was almost comparable to that of NFLX and far higher than that of PPA and NA.
DL-8280 was more active than NFLX, PPA and NA against glucose non-fermentive gramnegative bacteria, gram-positive cocci and obligate anaerobes. Thus, DL-8280 showed a broader spectrum and higher antibacterial activity than the related agents. Gentamicin-resistant (GM^r)-Serratia marcescens and GM^r-P. aeruginosa were also susceptible to DL-8280.
The activity of DL-8280 was not signficantly affected by inoculum size, klnd of medium and addition of horse serum, though it decreased at pH5. The in vitro resistance of bacteria to DL-8280 developed slower than that to NFLX, PPA and NA. Bacterocidal action of DL-8280 was also confirmed.
The oral absorbability of DL-8280 in mice was greater than that of NFLX and PPA.
The above properties reflected on the higher protective effect of DL-8280 against systemic infections in mice, including mixed infections with Escherichia coli and other bacteria, than that of other agents. DL-8280 was also potent in the therapy of urinary tract infections in mice due to E. coli or P. aeruginosa.

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MICs of DL-8280 were determined against clinically isolated E. coli, K. oxytoca and Salmonella sp., 50 strains of each from pediatric patients and compared with those of CMZ, CPZ, ABPC and CP.
The results were as follows:
1) MICs of DL-8280, CMZ and CPZ against E. coli were≤0.05μg/ml (100%), 0.39 to 0.78μg/ml (82%) and 0.05 to 0.78μg/ml (90%), respectively. All these agents were active against ABPC-resistant strains of MIC value of 100≤μg/ml.
2) MICs of DL-8280, CMZ and CPZ against K. oxytoca were ≤0.20μg/ml (100%), 0.39 to 0.78μg/ml (92%) and 0.05 to 0.78μg/ml (100%), respectively. All these agents were active against ABPC-resistant strains of MIC value of 25≤μg/ml.
3) MICs of DL-8280, CPZ, CP and ABPC against Salmonella sp. were 0.1 to 0.20μg/ml (100%), 0.20 to 0.78μg/ml (98%), 3.13 to 6.25μg/ml (78%) and 0.20 to 1.56μg/ml (60%), respectively, and DL-8280 was active against CP-resistant strains of MIC value of 25≤μg/ml.

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Antibacterial activity of DL-8280, a synthetic antibacterial agent of oxazine derivative, against anaerobes was compared with those of pipemidic acid, nalidixic acid and norfloxacin. All of these agents have structural similarities.
DL-8280 was far more active against all the test organisms of Gram-positive and Gramnegative anaerobes than other agents tested. MIC is different in respective bacteria. MIC of DL-8280 against B. fragilis group was 1.56-6.25μg/ml, and against B. melaninogenicus group was 0.78-1.56μg/ml. MICs of other agents against these organisms were 25-400μg/ml, showing superiority of DL-8280 to other agents. MIC of DL-8280 against anaerobic cocci was 0.20-6.25μg/ml. MIC of DL-8280 against C. perfringens was 0.39-0.78μg/ml, but the MIC against C. difficile was 12.5-25μg/ml.
MIC and MBC of DL-8280 against B. fragilis were the same value suggesting strong bactericidal activity.

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In vivo antibacterial activity of DL-8280 against anaerobes was compared with its chemically related agents, norfloxacin (NFLX) and nalidixic acid (NA).
After intraperitoneal challenge of B. fragilis to mouse, DL-8280, NFLX or NA, was administered orally in doses of 4, 2, 1 or 0.5 mg and the mice were observed for 3 days. Survival rates in DL-8280 treated groups were 100% in both 4 and 2 mg groups, 60% in 1mg group and 10% in 0.5 mg group. All mice in NFLX 4 mg group survived, 20% in 2 mg group and 10% in 1 mg group. Whereas 20% of NA 4 mg group survived, all of NA 2 mg group died.
Following 7 days administration of DL-8280, NFLX or NA to mice, change of C. difficile in cecum contents was examined. Significant increase in C. difficile was observed in all mice received NA. In NFLX treated mice, only small number of C. difficile was isolated. No C. difficile was observed in all mice received DL-8280.

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Bacteriological effect of DL-8280, a new synthetic antimicrobial agent for oral use, was investigated comparing with that of pipemidic acid (PPA) and norfloxacin (NFLX). The results were as follows:
1. DL-8280 had broad-spectrum antimicrobial activity against gram-positive and gram-negative bacteria. The activity of DL-8280 was superior to that of PPA and almost the same as that of NFLX.
2. The sensitivity of clinical isolates of Proteus and Pseudomonas to DL-8280 was lower than that to NFLX, and that of other isolates to DL-8280 was the highest, followed in decreasing order by NFLX, and PPA.
3. The addition of equine serum to the medium and inoculum size did not affect the antimicrobial activity of DL-8280 against Staphylococcus aures, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa. The antimicrobial activity of DL-8280 against these bacteria enhanced in alkaline medium.
4. The bactericidal activity of DL-8280 against E. coli, K. pneumoniae, P. aeruginosa and S. aureus was dose-dependent.
5. As for morphological alterations of bacteria treated with DL-8280, the elongation and lysis of E. coli were observed but the elongation of P. aeruginosa was hardly noted.
6. DL-8280 showed superior therapeutic effect than NFLX or PPA on experimental infection model in mice by S. aureus, E. coli, K. pneumoniae, Serratia marcescens, P. aeruginosa and Acinetobacter calcoaceticus.

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The in vitro activity of DL-8280 was compared with the activities of norfloxacin (NFLX), pipemidic acid (PPA), piromidic acid (PA) and nalidixic acid (NA) against clinical bacterial isolates. DL-8280 was found to be 10-100 times more active than PPA, PA or NA against S. aureus and S. faecalis. NFLX was also active, but slightly less active than DL-8280.
Against E. coli, P. aeruginosa and S. marcescens, DL-8280 was more active than PPA, PA or NA, but slightly less active than NFLX. The growth of N. gonorrhoeae including penicillin resistant strains were completely inhibited by≤0.10μ/ml of DL-8280.

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DL-8280, (±)-9-fluoro-2, 3-dihydro-3-methyl-10-(4-methy-1-piperaziny)-7-oxo-7H-pyrido [1, 2, 3-de][1, 4]benzoxazine-6-carboxylic acid, is a new nalidixic acid analog with a broad spectrum of anitibacterial activity against gram-negative and gram-positive bacteria, including obligate anaerobes. The activity of DL-8280 against Enterobacteriaceae, Pseudomonas aeruginosa, Haemophilus sp., Neisseria gonorrhoeae and Clostridium sp. was roughly comparable to that of norfloxacin and far exceeded that of pipemidic acid. DL-8280 had greater activity against staphylococci, streptococci, Pseudomonas maltophilia, Pseudomonas cepacia, Pseudomonas putida, Acinetobacier anitratus and Bacteroides fragilis than did norfloxacin and pipemidic acid. Ampicillin-resistant gonococci and clindamycin-resistant obligate anaerobes were also susceptible to DL-8280. Administered orally to mice experimentally infected with Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Serratia marcescens or Pseudomonas aeruginosa, DL-8280 was 3 to 8 times more active than norfloxacin and 12 to more than 50 times more active than pipemidic acid.

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To clarify the safety of DL-8280 as a chemotherapeutic, the cytotoxicity was investigated on tumor-type cells, Chinese hamster ovary CHO-Kl cells, human HeLa cells and mouse neuroblastoma 18 cells, and on normal type cells, mouse fetal fibroblasts, comparing with norfloxacin (NFLX) nalidixic acid (NA) and pipemidic acid (PPA).
Although DL-8280 exhibited a stronger cytotoxicity than NFLX on the CHO-Kl cells with a short generation time, the cytotoxicity of DL-8280 was found to be weaker than NFLX on the Hela, neuroblastoma 18 and mouse fibroblast cells that possess rather long generation times. Thecytotoxicity of DL-8280, however, was stronger than that of NA in the every cases. It was suggested that careful studies should be completed on the cytotoxicity of DL-8280 if the drug is planned to be developed for parenteral use that will give a high serum concentration.

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A new antibacterial agent of the pyridone-carboxylic acid derivative DL-8280 (Daiichi Seiyaku Co., Ltd.) was administered to five volunteers (healthy adult males) orally (3 doses of 200mg per day) for 6 days. Changes in the fecal microflora and their correlation to the fecal drug concentrations were investigated.
1. DL-8280 caused drastic suppression of the members of aerobic bacterial groups. In particular, the bacteria belonging to Enterobacteriaceae were eliminated within 2 days of drug administration, and more than one week was required for recovery to normal level.
2. Among anaerobic bacteria, lecithinase-negative clostridia increased after drug administration, although C. difficile was not detected, while lecithinase-positive clostridia were eliminated. The other anaerobes remained unchanged.
3. The total viable count remained unchanged during the experimental period.
4. Recovery of the microflora that had changed by drug administration to normal levels seemed to require 4 to 5 weeks.
5. Degrees of alteration in the flora correlated well to concentrations of the drug in the fecal concentrations of the drug in the fecal contents. DL-8280 caused reduction and elimination of the sensitive bacteria in parallel with its increase in the fecal contents.
6. Mild diarrhoea was observed in two subjects during the period of study.

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Phase I study on DL-8280, a new synthetic antimicrobial agent, was carried out in healthy male volunteers and the following results were obtained.
1) Serum concentration of DL-8280 increased in a dose dependent manner after a single oral administration at doses of 100, 300 and 600 mg. The peak value ofabout 3μg/ml was achieved 2 hours after administration of 300 mg and the biological half lives were 3-5 hours.
2) More than 90% of the dose was excreted into urine as unmetabolized form within 48 hours after administration at single doses of 100, 300 and 600 mg.Doseresponse relationship was found in urinary concentration of DL-8280. The maximum concentration of about 290μg/ml was achieved at 4-6 hours after administration of 300 mg ofDL-8280 and the urinary concentration of about 130 μg/ml was found at 12-24 hours later.
3) From the time course of serum concentration and urinary excretion of DL-8280, no accumulation of the drug was found after repeated doses of 600 mg daily for 3days, 600 mg daily for 14 days and slight accumulation of the drug was found after1, 200 mg daily for 3 days.
4) No subjective and/or objective symptoms of adverse reactions and no abnormal changes in clinical laboratory tests related to DL-8280 administration were notedat single doses of 100, 300 and 600 mg and at repeated doses of 600 mg daily for 3 or 14 days, 1, 200 mg daily for 3 days.

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DL-8280, a new pyridone-carboxylic acid derivative, has been investigated to give following results.
1. Antibacterial activities
MICs of DL-8280 against 373 strains of E. coli, K. pneumoniae, P mirabilis, P. morganii, P. aeruginosa and S. marcescens isolated clinically were determined, using plate dilution method inoculum size in 10⁶ cells/ml. The peak of the MIC values was ≤ 0.1 μg/ml for E. coli, K. pneumoniae, P. mirabilis and P. morganii, 1.56μg/ml for P. aeruginosa. Two peaks of the MIC values were 0.39 and 6.25μg/ml for S. marcescens.
2. Absorption and excretion
Serum concentration and urinary excretion of DL-8280 after single oral dose of 200 mg with food were measured in 6 healthy volunteers. The mean peak serum concentration at 4 hours after ingestion of the drug was detected 1.92μg/ml. The half-life in serum was calculated 3.1 hours and AUC was 15.2μghr/ml. The mean urinary excretion rate within 24 hourswas 83.9%.
3. Clinical results
Thirty one patients with various infections were treated with 150-600 mg daily dose of DL-8280 for 5-14 days. Clinical effect was excellent in 17 cases, good in 10 cases, fair in 1 case and poor in 3 cases. It was 87% of the efficacy rate of the drug. No side effects and abnormal laboratory findings were observed.

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To evaluate the clinical efficacy of DL-8280, the treatment was made with the drug in 45 patients including 7 with pneumonia, 2 with acute bronchitis, 6 with chronic bronchitis, 4 with acute purulent tonsillitis, 7 with acute cystitis, 8 with chronic cystitis, 5 with acute pyelitis, 1 with chronic pyelitis, 2 with acute cholecystitis, 1 with chronic cholangitis and 2 with acute enteritis. Responses were excellent in 20 patients, good in 23 and fair in 2. The efficacy rate of DL-8280 was 95.6%. As side effect, dizziness and photophobia were observed in 1 out of 47 patients. Six patients showed the following abnormal laboratory findings after treatment; temporal elevation of GOT, GPT, Al-P and γ-GTP in 1 case, temporal elevation of BUN in 3 cases and temporal eosinophilia in 2 cases.

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A new nalidixic acid analog, DL-8280 was applied to 14 patients with respiratory tract infections, and good responses were obtained in 5 of 13 patients (38.5%).
Among the isolated bacteria from sputum, DL-8280 was effective for H. influenzae, Pmaltophilia, P. morganii and B. catarrhalis but not effective for P. aeruginosa and S. pneumoniae. One case which was E. coli infection was changed to Candida by DL-8280.
As the side effects of DL-8280, epigastralgia, nausea and appetiteloss were noted in two cases and eosinophilia was noted in one case.

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Recently, a new oral antibiotic agent, structurally related to nalidixic acid, was synthesized in laboratory of Daiichi Seiyaku Co., Ltd., in Japan. It was shown that this new agent possessed a broad antimicrobial spectrum covering gram-negative 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. The growth of all the tested strains of S. aureus was inhibited at 0.39 μg/ml of the agent. At a concentration of 0.78 μg/ml, this agent inhibited 95, 90 and 85 per cent of the strains of S. marcescens, E. coli and E. cloacae, respectively. A concentration of 1.56 μg/ml was required to inhibit 80 per cent of the strains of P. aeruginosa.
Sixteen patients suffering from respiratory tract infections received orally 300 to 600 mg of the drug a day. 3 patients who visited only once at the start of the treatment was omitted from the evaluation of therapeutic efficacy of the drug. In remaining 13 patients, 2 showed an excellent response, 9 a good response and 2 a fair response. No undesirable symptoms and signs due to administration of the drug was observed. No abnormality in laboratory findings was noted during and after the treatment with the drug.

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Clinical efficacy and safety of DL-8280, a new antimicrobial agent, studied in 19 patients with mainly respiratory tract infection.
The drug was administered at a daily dose of 200-400 mg orally for seven to 14 days.
Clinical responses were excellent in four cases, good in 14 cases and fair in one case, showing an efficacy rate of 94.7%.
Eradication of bacteria was noted in 13 of 14 strains (92.9%).
Rash was seen in one case.

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DL-8280 was administered to 7 cass with pneumonia and 2 cases with bronchitis, which was given orally 600 mg per day for 14 days.
The results were as follows:
1) Abnormal shadows in X-ray disappeared in 6 cases and markedly improved in 1 case within 14 days.
2) Both cough and sputum disappeared in 8 cases and markedly-improved in 1 casewithin 14 days.
3) Nobody complained of gastrointestinal disturbance and no abnormal change in hematological and biochemical examination after the treatment was observed.
Therefore all cases were determined as good responses about the therapeutic effect.
It was suggested that DL-8280 was useful drug for respiratory infectious diseases.

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Antimicrobiological and clinical effects of DL-8280 were investigated and the following results were obtained.
Antimicrobiological effect: MIC₈₀ against clinically isolated Staphylococcus and Streptococcus faecalis was 0.78 μg/ml and this value was superior to that of NFLX. MICs against gram negative bacteria were 0.10 μg/ml for Escherichia coli and Klebsiella pneumoniae, 0.20 μg/ml for Proteus, 3.13 μg/ml for Serratia, 0.39 μg/ml for Citrobacter freundii and these values were almost the same to NFLX and superior to those of PPA and AMPC.
Clinical effect: DL-8280 was administered to 23 patients of respiratory tract infection, 12 patients of urinary tract infection and 6 patients of intestinal tract infection in a total of 41 patients. The results showed 6 cases of excellent, 26 cases of good, 8 cases of fair and poor, 1 case of unevaluable and the effective rate was 80%. As a side effect, 1 case with diarrhea and stomach discomfort, 1 case with anorexia and bitter taste and 1 case with vertigo were observed. Laboratory examinations revealed 1 case with an increase in S-GOT and S-GPT, 1 case with an increase in S-GPT, 1 case with an increase in the number of eosinophil but these were slight.
From these results, it was concluded that DL-8280 is a useful drug for the treatment of respiratory tract infection, urinary tract infection and intestinal tract infection.

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DL-8280 was orally administrated to 5 patients with urinary tract infection and 8 patients with respiratory tract infection. The patients received the drug for 7 to 21 days in dose of 300 to 600 mg/day. All patients with urinary tract infection and respiratory tract infection responded well to the therapy.
No side effect of DL-8280 was recognized.

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DL-8280, 200 to 900 mg/day, was administered orally to 20 patients with respiratory tract infection. Clinical effects were excellent in 2 patients, good in 12, fair in 2, and undetermined in 4, thus overall efficacy being 87.5%. A headache, an eruption, or an epigastralgia occurred individually in 3 cases as side effects. However, those symptomes disappeared immediately after discontinuation of the administration without any special treatments. No abnormal findings were disclosed by laboratory examination as well.

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DL-8280 was administered to 12 cases consisting of 2 cases with pneumonia, 1 case with secondary respiratory tract infection by lung cancer, 2 cases with acute colitis, 1 case with chronic cystitis, 2 cases with asymptomatic bacteriuria, 3 cases with acute pyelonephritis, 1 case with acute cholecystitis. Efficacy was evaluated to be excellent in 1 case, good in 9 cases, fair in 1 case, poor in 1 case. DL-8280 was effective in 10 out of 12 cases in total and the effectiveness rate was 83.3%.
No distinct side effect was observed.

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1. MICs of DL-8280 against 9 strains of N. gonorrhoeue including strains resistant to ABPC distributed between 0.006 μg/ml and 0.012 μg/ml.
2. MICs of DL-8280 against 13 strains of H. influenzae including strains resistant to ABPC distributed between 0.012 μg/ml and 0.048 μg/ml.
3. Clinical results of DL-8280 for 2 cases of urinary tract infection caused by E. coli were excellent in 1 and good in 1.
4. Clinical results of DL-8280 for 1 case of right-middle lobe pneumonia caused by S. pneumoniae was excellent.
5. No side effect was observed in 3 cases described above.

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Bacteriological and clinical studies on DL-8280, a new synthetic antimicrobial agent of benzoxazine derivative, were performed and the following results were obtained.
MICs of DL-8280 against clinically isolated strains of E. coli, C. freundii, S. marcescens, P. aeruginosa were almost the same as those of NFLX and were significantly superior to those of NA, PPA and MLX.
DL-8280 was orally administered to healthy adult male volunteers at a dose of 200 mg. The maximum serum concentration of 2.83 μg/ml was obtained at 1 hour after administration. The half life of serum concentration was 3.13 hours. The maximum serum concentration of DL-8280 was higher than that of NFLX at the same dose level and bioavailability of DL-8280 was superior to that of NFLX. Serum concentration increased dose dependently. Urinary recovery of DL-8280 during 24 hours after administration was between 77.2 and 92.2%. In comparison with this high recovery rate of DL-8280, that of NFLX was only 35.4% during 24 hours after administration.
DL-8280 was administered to 21 patients with various infections in the field of internal medicine at daily doses of 150-600 mg for 5-21 days. The clinical result was “excellent” in 3, “good” in 16, “fair” in 2 and the efficacy rate was 90.5%. Twelve out of 13 bacterial strains were eradicated and the eradication rate was 92.3%.
Slight increase in serum alkaline-phosphatase was noted in one patient.
From these results, it is concluded that DL-8280 is the extremely useful synthetic antimicrobial agent for the treatment of the infections in the field of internal medicine.

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Clinical investigation of DL-8280, a new synthetic antimicrobial agent of oxazine derivative, was performed.
Eleven inpatients and 1 outpatient entered into this study. Eleven patients were suffered from urinary tract infections (cystitis, 6 patients ; pyelonephritis, 5 patients) and the remaining 1 patient was suffered from chronic bronchitis.
Causative pathogens isolated from urinary tract infections were E. coli 2 cases, S. marcescens 2 cases, S. faecalis 2 cases, P. aeruginosa 1 case, P mirabilis 1 case, P. morganii 1 case and S. epidermidis 1 case.H. influenzae was isolated from the patient of chronic bronchitis.
DL-8280 was administered orally twice or three times a day. The daily does ranged from 200 to 600 mg and the administration period was 3 to 15 days.
Clinical efficacy on urinary tract infections was “marked” in 3, “effective” in 4, “slightly effective” in 2 and “failure” in 2 and in chronic bronchitis “effective” was observed as a result.
Neither side effect nor abnormal change in laboratory test value was observed.

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DL-8280 is an oxazine agalogue antibacterial drug for oral administration, which was first synthesized by Daiichi Seiyaku Co., Ltd. in 1980. Clinical effects and basic natures of this drug were examined in this study.
1. The antibacterial activity of DL-8280 was compared with that of NFLX and PPA. Each 25 strains of clinically separated S. aureus, E. coli, K. neumoniae, E. cloacae, S. marcescens, P. vulgaris, P. mirabilis and P. aeruginosa were inoculated at the concentration of 10⁶ CFU/ml. DL-8280 and NFLX showed much higher antibacterial activities than PPA for all the strains studied. The comparison between DL-8280 and NFLX showed that their activities were similar, except that the former was slightly superior for S. aureus and K. pneumoniae and the latter for P. mirabilis and P. aeruginosa.
2. Serum concentrations and urinary excretion of DL-8280 were examined in the fasting state and after a meal of 600 Cal. Three hundred mg of this drug was orally administered to 6 healthy adult male volunteers. No significant difference was observed between the peak serum concentrations in the fasting (2.63 μg/ml) and fed (2.46 μg/ml), although the peak time of them was slightly different: one versus two hours on the average. Urinary excretion within 24 hours after the administration was above 90% under both the conditions.
3. Clinical effects of DL-8280 were examined in 38 patients: acute bronchopneumonia (1), acute bronchitis (18), acute tonsillitis (9), secondary infection of bronchiectasis (4), chronic bronchitis (4), acute pyelonephritis (1), and acute cystitis (1). Excepting two cases, they all received 300 mg/day of this drug, which was divided into three times a day. For the mild acute infection of the respiratory system and urinary tract, DL-8280 with the dose duration within 7 days was effective in 27 cases out of 29. For chronic respiratory infections, this drug was effective in only 3 cases out of 8, when the dose duration was between 7 and 14 days. It was not effective in one patient with acute bronchopneumonia. Bacteria were eradicated by the administration in 25 cases out of 28, in which bacteria had been detected before the administration.
4. As a side effect, anorexia was observed in three cases. No abnormality was recognized in the findings of blood examinations and hepatic functions before and after the administration.

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DL-8280 was administered to 15 patients with various infectious diseases (RTI 7, UTI 7, BTI 1). DL-8280 was given orally 100-600 mg/day for 1-39 days.
Clinical efficacy was excellent in 1 case, good in 8, fair in 2, poor in 3 and unknown in 1.
Side effect, hotness and sleeplessness, was observed in 1 case.

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Clinical effects and adverse effects of DL-8280, a new antimicrobial agent, were studied in 36 patients with respiratory tract infections receiving orally 100 mg to 300 mg b. i. d. or t. i. d. Among them, 35 cases were lower respiratory tract infections, one case was lung abscess.
The clinical effects were excellent in 2 cases, good in 15 cases, fair in 6 cases and poor in 12 cases, and one case was not evaluated because of adverse effect. The efficacy rate was 49%.
As for adverse effects, glossitis, diarrhea and stomach sickness were observed in 1 case, and appetite loss was observed in 2 cases.

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DL-8280, a newly developed oral antibacterial agent, is a new nalidixic acid analog. DL-8280 has a broader spectrum and more potent antibacterial activity than other drugs of the nalidixic acid type. DL-8280 has higher antibacterial activity against grain-negative bacteria including Pseudomonas aeruginosa than gentamicin.
DL-8280 was used in the treatment of 20 cases of respiratory infectious disease: 9 cases of acute bronchitis, 4 cases of bronchiectasis, each 2 cases of acute tonsillitis, acute pharyngitis and chronic bronchitis, and one case of pneumonia. DL-8280 was administered orally at a dose of 200mg twice daily for 3 to 14 days and results obtained were excellent in one case, good in 16 cases, fair in one case and poor in 2 cases.
Adverse reaction such as drug eruption, drug fever, nausea, vomiting, diarrhea and dizziness were not observed.
From the above clinical experience, DL-8280 would be a clinically usefull drug against respiratory infectious disease and is worth further studies.

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Antimicrobial activity of DL-8280 was determined on 100 multiresistant S.aureus strains. Ninety-eight out of 100 S.aureus strains were inhibited at the concentration of 1.56μg/ml or less.
Clinical evaluation was performed on 4 patients with RTI and 6 patients with UTI of the aged. Excellent response was observed in 5, good in 3, fair in 1 and poor in 1. No adverse effect was observed.

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A new oxazine derivative, DL-8280, is an oral anti-bacterial agent with broad spectrum (gram positive bacteria, gram negative bacteria, anaerobic bacteria).
DL-8280 was administered orally to 29 patients (pneumonia 1 case, acute bronchitis 13 cases, cholecystitis 2 cases, enteritis 1 case, acute pyelonephritis 5 cases and acute cystitis 7 cases) at daily doses of 200-300mg, and good response were obtained in 27 cases (93.1%).
DL-8280 was effective in a patient with bronchitis due to P.aeruginosa. It was also effective in all cases with urinary tract infection (causative organims were E.coli in 11 cases and P.mirabilis in 1 case).
Epigastralgia was noted in 1 case. No abnormal findings were noted in hematological, renal and hepatic function.

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DL-8280 was used in 23 patients with broncho-pulmonary infections. Daily doses of DL-8280 ranged from 0.2 to 0.6g.
Clinical effects in 9 cases of acute pneumonia were assessed as excellent in 5 cases and good in 4. In 3 cases of acute bronchitis, all were good. In 4 cases of chronic bronchitis, all were good. In 3 cases of bronchiectasis, excellent response was observed in 1 case and good in 2. In 3 cases of diffuse panbronchiolitis, clinical response was good in 2 cases and fair in 1. In 1 case of lung abscess, clinical response was good.
Causative organisms were S.aureus (1 cases), S.pneumoniae (3), K.pneumoniae (2), P.aeruginosa (2) and H.influenzae (2). After DL-8280 treatment, S.aureus, S.pneumoniae, K.pneumoniae and H.influenzae were eradicated, and P.aeruginosa was suppressed in 1 case and persisted in 1.
No side effect was noted, but laboratory findings revealed slight GOT and GPT elevation in 1 case and GPT elevation in 1.

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The in vitro activity of DL-8280, a new pyridone-carboxylic acid derivative, was compared with that of pipemidic acid (PPA), norfloxacin (NFLX), nalidixic acid (NA), aminobenzyl penicillin (ABPC) and kanamycin (KM) against 170 strains isolated during the clinical study of DL-8280.
Clinical study of DL-8280 was performed on 258 patients with acute infectious diarrhea. DL-8280 was orally administered at the doses of 400-600mg for 5-7 days. The efficacy was evaluated in 177 patients.
The results are summarized as follows:
1. The in vitro activity of DL-8280 against Shigella spp., Campylobacter spp., V.parttimemolyticus and enteropathogenic E.coli as same as that of NFLX. And the activity was superior to that of PPA, NA, ABPC and KM.
2. The efficacy rate of DL-8280 on symptoms of acute infectious diarrhea was 100%, exclusive of Campylobacter enteritis.
3. The bacteriological effect of DL-8280 in a dosage of 600mg/day on bacillary dysentery seemed to be superior to that in a dosage of 400mg/day.
4. Bacteriologically, the efficacy rate was 100% in Shigella spp., 100% in enteropathogenic E.coli, 100% in V.parahaemolyticus, 79.2% in Salmonella spp. and 76.9% in Campylobacter spp.
5. Side effects were observed in 8 out of 248 patients (3.2%). Abnormal laboratory finding was seen in 13 patients.
6. From these results, DL-8280 is considered to be very useful medicine in the treatment of acute infectious diarrhea.

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The clinical effects of DL-8280, a new synthetic antimicrobial agent for oral use of oxazine derivative, on respiratory tract infections were studied.
DL-8280 was administered 200mg, t.i.d. for 4 to 21 days to 45 patients of chronic respiratory tract infections and 5 patients of pneumonia.
Therapeutic effective rate was 84.4% in chronic respiratory tract infections and 80.0% in pneumonia.
Pathogens isolated were as follows; S.pneumoniae, K.pneumoniae, H.influenzae, S.marcescens, E.coli and P.aeruginosa. All the isolates were eradicated except 7 strains out of 12 strains of P.aeruginosa and 1 strain out of 2 strains of S.marcescens.
As for side effects, there were 1 case with headache, 1 case with headache and vertigo, 1 case with stomach discomfort and diarrhea, 1 case with elevation of GOT and GPT, 1 case with elevation of GPT and 1 case with eosinophilia. But these cases were slight and none of patients was stopped medication.
From these results, DL-8280 was considered to be highly effective against lower respiratory tract infections including refractory cases.

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A new antibacterial drug, DL-8280, was administered for 5-12 days at daily doses of 600mg to 25 patients, including 1 case of bronchopneumonia, 2 cases of acute bronchitis, 1 case of acute tonsillitis, 7 cases of acute pyelonephritis, 6 cases of acute cystitis and 7 cases of chronic cystitis.
The results obtained were effective in 24 cases and ineffective in 1 case. The total efficacy rate was 96.0%.
Side effect observed was skin eruption in 1 case. As the results of laboratory findings, elevation of S-GPT in 1 case, elevation of S-GOT, S-GPT and Al-P in 1 case, elevation of BUN in 1 case and increase of eosinophile in 1 case were found.

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DL-8280 was investigated for its antibacterial activity and clinical effects and the following results were obtained.
1) Bacteriological examinations: DL-8280 had more potent activity against strains of E. coli, K. pneumoniae, S. marcescens, P. aeruginosa and A. calcoaceticus than nalidixic acid. The MIC peaks of each strains were≤0.2μg/ml, ≤0.2μg/ml, 0.39μg/ml, 3.13μg/ml and 1.56μg/ml, respectively.
2) Clinical effectiveness: Three patients with pyelonephritis, 2 patients with colitis, 2 patients with bronchitis, 1 patient with pneumonia, 1 patient with bronchiectasis and 1 patient with sepsis (suspected) were evaluated for daily 200-600mg of DL-8280. The therapeutic responses were good in 9 cases and not determined in 1 case with sepsis (suspected). Thus, the rate of efficacy was 90%. No abnormal laboratory findings nor side effects due to the drug were observed.
The above results suggest the usefulness of DL-8280 for the treatment of infections.

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Forty patients with respiratory tract infections were treated with DL-8280, a new synthetic antimicrobial agent. The drug was administered orally at daily doses of 400-600mg divided into 2-3 for 3-63 days. The clinical effects were excellent in 18, good in 13, fair in 5, poor in 3, unknown in 1. The efficacy rate was 79.5%. Side effects were observed in 4 cases (incidence 10.0%). Three cases were nausea, and 1 case was edematous feeling.

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A new synthetic antibacterial agent, DL-8280 was administered to a total of 26 patients with variety of infectious diseases, that is, 15 of repiratory, 1 of biliary and 10 of urinary tarct infections.
Clinically, one case was judged as excellent, 23 were good, one was recrudescent andone was poor. At 12 patients to whom bacteriological effect was evaluable, causative organisms were eradicated in 10, and remained unknown in other two cases.
No adverse effects were observed at all. Abnormal laboratory findings were described in 4 cases, but the reciprocal relations were uncertain in every case.

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The studies on antimicrobial activity, absorption, excretion and clinical evaluation of DL-8280 were performed, and following results were obtained.
1) Antibacterial activity: DL-8280 showed an excellent antibacterial activity against gram-negative rods and gram-positive cocci. In the case of S. aureus, DL-8280 completely inhibited the growth at the concentration of 1.56μg/ml and the growth of about 90% of clinically isolated strains of gram-negative rods such as E. coli, K. pneumoniae, P. mirabilis, P. aeruginosa, S. marcesens were inhibited at the concentration of 1.56μg/ml, lower than the MIC value.
2) Peak serum concentration of 2.21μg/ml of DL-8280 in healthy adult volunteer was attained at 2 hours after a single oral administration of 200mg. The half life of DL-8280 in serum was calculated to be 5.3 hours and serum concentration was still more than 0.77μg/ml at 10 hours after dosing. The peak urinary concentration of DL-8280 was 346.5μg/ml which was found in urine collected during 4 to 6 hours after administration and urinary recovery rate was 60.6% within 10 hours.
3) Clinical efficacy rate in 12 patients with respiratory tract infection was 91.7%, and all of 12 patients with urinary tract infection were responded successfully to DL-8280 therapy. As for the untoward reaction of DL-8280, vertigo was observed in one patient, and slight elevation of S-GOT, S-GPT and Al-Pase was observed in 1 patient out of 24 patients.
It was concluded that DL-8280 was a useful synthetic oral antimicrobial agent for the treatment of not only UTI but also RTI.

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The antibacterial activity of DL-8280 was compared to that of norfloxacin (NFLX), pipemidic acid (PPA) and nalidixic acid (NA) in a total of 168 clinically isolated strains of S. aureus, S. faecalis, E. coil, K. pneumoniae, E. cloacae, S. marcescens, Proteus and P. aeruginosa.
DL-8280 exhibited far greater antibacterial activity against S. aureus and S. faecalis than did NFLX, PPA and NA, on the other hand it was proved to be almost the same antibacterial activity as NFLX against gram-negative bacilli.
DL-8280 was then administered to a total of 22 patient, among whom there were 15 cases of respiratory tract infections (RTI) and 7 cases of urinary tract infections (UTI). The results obtained were good in 10 (66.0%) out of 15 RTI cases, excellent and good in 6 (85.7%) out of 7 UTI cases.
As an adverse reaction, leucopenia was observed in 1 case who, however, returned to normal within 7 days after discontinuation of administration.

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Antibacterial activity and the clinical effect of DL-8280 were investigated and the following results were obtained:
1) Antibacterial activity: Antibacterial activity of DL-8280 was investigated against 138 clinical isolates of gram negative bacillus such as E. coli, K. pneumoniae, S. marcescens, P. aeruginosa or Proteus comparing with that of NFLX, PPA and NA. DL-8280 was superior to NFLX against E. coil, K. pneumoniae and S. marcescens, but was inferior to NFLX against P. aeruginosa and Proteus. DL-8280 was by far superior to PPA and NA against these bacteria.
2) Clinical effect: DL-8280 was administered to 31 patients consisting of 3 cases of pneumoniae, 2 cases of acute bronchitis, 8 cases of acute exacerbation of chronic respiratory tract infection, 3 cases of acute tonsillitis, 2 cases of acute laryngitis, 2 cases of acute urinary tract infection and 1 case of lung tuberculosis. Clinical efficacy was judged on 30 patients excluding 1 case of lung tuberculosis. Therapeutic response was “excellent” in 5, “good” in 18, “fair” in 6, “poor” in 1 and efficacy rate was 76.7%. Bacteriological examination revealed that “eradicated” and/or “decreased” in 2 with P. aeruginosa from respiratory tract infection and “eradicated” in 2 with E. coli from urinary tract infection. As side effects, 1 case of increase in eosinophiles and 1 case of increase in GOT were observed, but these values returned to normal level immediately after the cessation of medication.

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Clinical effectiveness of a new antibacterial drug, DL-8280 was evaluated in respiratory tract and urinary tract infections. The drug was administered for 14 days at daily doses of 300mg to 6 cases with pneumonia, 1 case with acute bronchitis and 5 cases with cystitis. It was effective in 4 cases of pneumonia and all cases of cystitis.
No side effect was observed in any case.

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DL-8280, a new orally active antimicrobial agent, was applied to the treatment of 42 patients with respiratory infections.
The drug was administered orally, 300-400mg/day mainly, divided into 2-4 doses, for 5-35 days.
The results were as follows; excellent in 14 cases, good in 18 cases, slightly good in 7 cases, ineffective in 2 cases. Effective rate was 78%. One case was excluded due to obscurity of infection.
Side effects were observed in 3 cases (epigastrial distress, insomnia and diarrhea).
Abnormal elevation of GOT value in one case and BUN value in one case were observed after treatment.

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The bacteriological and clinical studies on DL-8280, a new oxazine derivative for oral use, were performed and the following results were obtained.
All the clinical isolates of S. aureus, E. coli, K. pneumoniae, P. mirabilis and P. vulgaris were inhibited at 0.78μg/ml or lower concentration of DL-8280. All the strains of P. aeruginosa were inhibited at 6.25μg/ml or lower concentration of DL-8280.
Antibacterial activity of DL-8280 was compared with that of NFLX, PPA and NA. DL-8280 showed the highest activity against S. aureus among these agents. Antibacterial activity of DL-8280 against E. coli, K. pneumoniae and P. vulgaris was equal or slightly superior to NFLX and antibacterial activity against P. mirabilis and P. aeruginosa was a little inferior to that of NFLX. DL-8280 showed higher antibacterial activity against these bacteria than PPA or NA.
DL-8280 was administered to 8 patients with chronic bronchitis (2 patients), infected bronchiectasis (3 patients), infected lung fibrosis (1 patient), pneumonia (1 patient) or chronic cystitis (1 patient) at daily doses of 300 mg to 1, 200 mg for 7 to 49 days. The clinical effect was “excellent” in 1, “good” in 5 and “poor” in 2. A transient decrease in neutrophiles was noted in 1 patient. No other side effect or abnormal change in laboratory examiation was observed.

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DL-8280, a newly synthetic antibacterial agent, was studied on its antibacterial activity as well as on its clinical effectiveness. The results obtained were as follows:
1) Antimicrobial activity: Minimal inhibitory concentrations of DL-8280 against standard strains kept in our laboratory as well as against newly isolated strains were determined. DL-8280 was found to be similarly active against gram-negative bacilli and against S. aureus as norfloxacin and remarkably superior to pipemidic acid and nalidixic acid.
2) Clinical trials: Out of seventeen patients (R. T. I. 10, U. T. I. 3, colitis 3 and lymphadenitis 1) treated orally with DL-8280 (100-200mg×2/day), thirteen responded well to the therapy. In one case with chronic bronchitis, the therapy was stopped due to side effects (thirsty, numbness and weakness), which disappeared soon after the cessation of the dosage. No abnormal laboratory findings attributable to the drug were found in these patients.

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Clinical effect of DL-8280, a new synthetic antimicrobial agent for oral use, was investigated on 28 patients with chronic respiratory tract infection (diffuse panbronchiolitis; 19 patients). Clinical efficacy rate was 86% and also a favorable effect was noted bacteriologically.
Long-term administration of DL-8280 was performed against 11 patientsand all the patients responded well.
From these results, it is concluded that DL-8280 is a useful agent for the treatment of chronic respiratory tract infections including diffuse panbronchiolitis.

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Bacteriological and clinical studies on DL-8280, a synthetic antibacterial agent of pyridone-carboxylic acid derivative developed originally by Daiichi Seiyaku Co., Ltd., were performed and the following results were obtained.
1) DL-8280 showed far more superior antibacterial activity to that of PPA against all the bacterial strains clinically isolated from the sputum. The activity of DL-8280 against E. coli, Klebsiella spp., S. marcescens, Proteus spp., P. aeruginosa and P. cepacia were almost equal to that of NFLX, but DL-8280 was much more active than NFLX against S. aureus and Acinetobacter spp.
2) DL-8280 inhibited M. tuberculosis and M. fortuitum at 0.39μg/ml and 1.56μg/ml, respectively, but the activity against other atypical mycobacteria was weak.
3) Serum peak level of 2.06μg/ml was observed at 4 hours and 1.40μg/ml at 2 hours after the administration of 100mg and 200mg of DL-8280 after the breakfast, respectively. Mean urinary excretion rate of DL-8280 during 6 hours after the administration of 100mg and 200mg was 38.5% and 44.9%, respectively.
After repeated dosings, the sputum concentration of DL-8280 was more than 2.0μg/ml.
4) DL-8280 was administered to 64 patients with respiratory tract infections and the efficacy evaluated in 62 patients. Clinical effect was “excellent” in 6, “good” in 44, “fair” in 6, “poor” in 6 and the efficacy rate was 80.6%. Side effects were observed in 4 patients (6.3%) but they were very slight.
From these results, it was concluded that DL-8280 was extremely useful agent against chronic respiratory tract infections and relatively safe agent.

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Antimicrobial activities of DL-8280 were compared with those of NFLX, PPA and NA for various clinically isolated strains described as below in inoculum size of 10⁶ cell/ml.
Gram positive strain: S. aureus, S. epidermidis, S. pneumoniae, α-Streptococcus, β-Streptococcus and Enterococcus
Gram negative strain: E. coli, S. typhi, other Salmonella, Shigella, K. pneumoniae, K. oxytoca, P. vulgaris, P. mirabilis, P. rettgeri, P. inconstans, P. morganii, Serratia, Citrobacter, Enterobacter, P. aeruginosa, P. cepacia, P. maltophilia and Acinetobacter
Against gram positive strains DL-8280 showed superior action to the other antimicrobial agents. For grain negative strains DL-8280 showed almost the same strong activities as NFLX with the exception of Serratia and Pseudomonas. PPA and NA showed much less antimicrobial activities than DL-8280 and NFLX in all strains tested.
DL-8280 was administered to 3 patients with respiratory tract infection, 5 patients with alimentary tract infection including a case of persistent healthy excreter of S. typhi and 2 cases of FUO. Causative organisms were isolated in onecase of respiratory tract infection (H. influenzae) and 4 cases of alimentary tract infection (K. oxytoca, S. litchfield, V. parahaemolyticus and S. typhi).
Good clinical effects were observed in one of respiatory tract infection, in all cases of alimentary tract infection and in one case of FUO. Bacteriologically good effects were observed in all cases which the causative organisms were isolated.
The adverse reactions were occurred in two cases. One of them was a severe vertigo and the other was a granulocytopenia.

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Chemotherapeutic efficacy of DL-8280 was studied in 14 cases. These cases consisted of 9 cases of acute or chronic respiratory tract infection, 4 cases of acute or chronic urinary tract infection and 1 case of bile duct infection.
DL-8280 was given orally to the patients at the dose of 200 to 300 mg per day for 6 to 16 days.
The clinical effectiveness was determined routinely. That was excellent in 5 cases (35.7%), good in 7 cases (50%) and poor in 2 cases (14.3%). The rate of effectiveness of DL-8280 in our studies was 85.7%.
There was no side effect in these cases.

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Laboratory and clinical studies were performed on DL-8280, a new oxazine derivative, and the results were as follows.
1) Antimicrobial activity
MICs of DL-8280 against various clinical isolates were determined with an inoculum size of 10⁶cells/ml. Percentages of strains susceptible to 3.13μg/ml or less were 100% for S. aureus, S. faecalis, E. coli, K. pneumoniae, E. cloacae, E. aerogenes and P. mirabilis, 83% for indole (+) Proteus, 85% for S. marcescens and 87% for P. aeruginosa. Especially, most strains of Enterobacteriaceae were inhibited by 0.20μg/ml or less.
2) Serum concentrations and urinary recovery rates
Serum concentrations of DL-8280 were measured in four healthy adults given 200mg of DL-8280. Serum concentrations were maintained at the levels of about 1.8μg/ml from 0.5 to 3 hours after the administration and diminished gradually to 1.0μg/ml at 8 hours. Mean values of T_1/2 and AUC were 5.9 hr and 20.5μg·hr/ml, respectively. Mean urinary recovery rate was 53% at 8 hours after the administration.
3) Clinical efficacy
One patient with bronchopneumonia, 3 with bronchitis, 1 with chronic tonsilitis, 2 with pyelonephritis, 7 with cystitis, 1 with lymphadenitis and 2 complications (pharyngitis and infected atheroma) were treated with DL-8280 in daily doses of 0.15-0.6g for 4-42 days. Clinical response was excellent in 2, good in 11, fair in 2 and poor in 2 patients. Bacterial effect was good except P. cepacia infection. As the side effect, sleeplessness was observed in 2, and exhaustion, exanthema, diarrhea and nausea in each one patient. GOT and GPT elevation was seen in one patient.

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