We conducted fundamental and clinical studies on the efficacy ofcefmetazole (CMZ) for postoperative infections with the following results:
1) Patients with postoperative infections were divided into groups A and B and used for evaluation of the clinical effect of CMZ.In group A CMZ was administered immediately after development of postoperative infections and in group B the drug was applied after other cephem antibiotics had been proved to be ineffective.In group A CMZ was evaluated to be clinically effective in 22 (85.7%) out of 28 patients with postoperative wound infection and 4 (57.1%) out of 7 with postoperative peritonitis. In group B the drug was effective in 8 (61.5%) out of 13 patients with postoperative wound infection and in 8 (72.7%) out of 11 with postoperative peritonitis.
2) Eruption occurred in one case. Thus, the incidence of side effects was 1.5%.
3) The kinds of bacteria isolated frequently before CMZ treatment were S. epidermidis, E. coli, and Klebsiellasp. in group A and Klebsiella sp.in group B. Pseudomonas sp. was frequently isolated after CMZ treatment in both groups.
4) MIC's of CMZ and cefazolin (CEZ) and β-lactamase activity were determined for the bacteria isolated from patients with postoperative infections. MIC's indicated that gram-negative and anaerobic bacteria tended to be more sensitive to CMZ than to CEZ. In addition, CMZ was more resistant than CEZ with respect to β-lactamase activity. The specific activity was below 1μ/mg protein in all strains.
5) CMZ levels in the serum and peritoneal exudate were determined after an intravenous injection of 1g of the drug in 2 stomach cancer patients who had been operated on 2 days previously. The peak CMZ level in the peritoneal exudate was 20.2 and 26.7μg/ml, respectively. Its ratio to the serum CMZ level was 52.2 and 47.5%, respectively.

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Antimicrobial susceptibility of 101 strains of Acinetobacter calcoaceticus subsp. anitratus isolated from clinical specimens during 1979-4980 were investigated against 11 drugs, i. e., 7 aminoglycoside antibiotics, ampicillin, tetracycline, chloramphenicol and mercuric chloride. Production of aminoglycoside-modifying enzyme among resistant strains to aminoglycoside antibiotics was tested by bioassay.
The results were as follows.
(1) Almost all of test strains of Acinetobacter calcoaceticus subsp.anitratus were resistant to ABPC and CP, but were sensitive to 5 aminoglycosides (KM, DKB, AMK, GM and NTL) and TC.
(2) Four strains resistant to SM and SPC showed enzymatic modification of these antibiotics in the presence of adenosine-5'-triphosphate and magnesium ion. But no strain with resistance to GM, NTL, KM, DKB, and AMK had aminoglycoside-modifying enzyme activity.

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Cefmetazole (CMZ) was administered to the thirty three cases of infectious diseases of bone and joint. In most of cases, 2.0g of CMZ was solved in 500ml of saline or the similar and intravenously dripped twice a day, taking one or two hrs. Ten cases of acute suppurative osteomyelitis completely healed by mainly general chemotherapy.
Ten of recurrence of chronic osteomyelitis of which symptom was acute inflammation, effectively healed as well. In five cases of chronic osteomyelitis, one case failed in healing because of infection with resistant Serratia, which was finally amputated being due to sinus carcinoma. Five cases of acute suppurative arthritis was similarly treated and effectively healed by mainly chemotherapy. In three cases of chronic arthritis, one individual had hepatitis due to toxicosis by anesthetic drug, so that chemotherapy had to be discontinued. In general, 31 cases of bone and joint infection was satisfactorily healed out of 33 with administration of CMZ.
In this series of infections, causative microorganisms were found to be positive in twenty cases, in which majority of organism was S. aureus as fourteen cases. One case of Serratia was sufficiently suppressed by CMZ, but the other case of Serratia was resistant to CMZ.
Twenty four cases out of all were hematogenous infection and nine were exogenous following to open fracture or iatrogenic disorder. CMZ is known to have broad spectrum antibacterial action and thought to be advantageous as a therapeutic drug of first choice for particularly early treatment of hematogenous osteomyelitis and suppurative arthritis.

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Fundamental studies on the effects of ceftizoxime (CZX) was made on the tissue concentration of ovarium, fallopian tube and various parts of uterine tissue. Following the intravenous drip infusion of 1g CZX with constant rate of 1 hour duration, abdominal simple hysterectomy was performed on 20 cases of uterine myoma and endometriosis.The patients were allotted to 6 groups, according to the interval between the finish of CZX infusion and the bilateral ligation of uterine artery ranging from 1 to 6 hours.
Tissue concentration of CZX was measured by disc bioassay method utilizing Bacillus subtilis ATCC 6633, and the obtained data was simulated by a simple linear model consisting from one compartment of constant diffusion rate.
The correlation coefficient between the model and data was calculated as 0.858 to 0.752 except for that of endometrium.
The efficacy of tissue penetration was estimated as the ratio between the concentration of various tissue and that of venous sera, resulted in the range of 0.4 to 0.6 (myometrium 0.42, cervix 0.48, portio vaginalis 0.52, ovarium 0.58, and fallopian tube 0.41). While minimum value of 0.2 was observed in endometrium.
Estimated half life of CZX was as follows; 1.98 hours in cubital vein, 1.91 in uterine artery, 2.09 hours in endometrium, 1.95 hours in myometrium, 1.78 hours in ovarium, and 1.89 hours in fallopian tube, respectively.
The recovery rate of CZX was also estimated on 2 cases of hysterectomy, following 10μg/g addition to the excised tissues, revealing from 9.80 μg/g portio vaginalis to 10.6 μg (uterine cervix), in good correspondence with the preliminary measurements of 9.70 to 9.96 μg in rat liver and kidney.

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To evaluate the efficacy and safety of AM-715 for the treatment of acute simple cystitis, a double blind clinical study comparing AM-715 with pipemidic acid (PPA) was carried out. Patients received either 300mg/day of AM-715 or 750 mg/day of PPA three times a day for 3 days by oral route and the following results were obtained.
1) Of the 241 patients (121 cases treated with AM-715 and 120 cases with PPA), clinical efficacies were evaluated in 197 cases (AM-715 100 cases, PPA 97 cases) excepting 44 cases those excluded or dropped out. Side effect was evaluated in 226 cases (AM-715 115 cases, PPA 111 cases). There was no significant difference in the back-ground characteristics between the two treatment groups.
2) The overall clinical efficacy of treatment was excellent in 80%, moderate in 19%, and the effectiveness rate was 99% in the AM-715 group.It was excellent in 68%, moderate in 26.8%, and the effectiveness rate was 94.8% in the PPA group.Significantly higher efficacy was obtained in the AM-715 group (P<0.05). There was no significant difference in the effects on subjective symptoms and pyuria between the groups.Effect on bacteriuria was “Eliminated” in 91% of the cases in the AM-715 group and in 79.4% of the cases in the PPA group, and a significant difference was observed between the groups (P<0.03).
3) Bacteriological response was “Eradicated” in 106 strains (98.1%) out of 108 strains (GNR 89, GPC 19) in the AM-715 group and in 100 strains (90.8%) out of 110 strains (GNR 86, GPC 24) in the PPA group.Significantly higher efficacy was obtained in the AM-715 group (P<0.02).But there was no significant difference between the groups with respect to the eradication rate of GNR.
4) The overall clinical efficacy on patients with GNR infections was evaluated in 85 cases out of the AM-715 group and 83 cases out of the PPA group, respectively.The efficacy was excellent in 78.8%, moderate in 20%in the AM-715 group, excellent in 73.5% and moderate in 24.1% in the PPA group.There was no significant difference between the groups in the effects on subjective symptoms and pyuria and bacteriuria.
5) Evaluation by the attending physician was excellent in 76%, excellent or good in 93.0% of the cases in the AM-715 group, excellent in 62.9%, excellent or good in 90.8% of the cases in the PPA group, and there was no significant difference between the groups.In the evaluation by the attending physician for the GNR cases, there was no significant difference between the groups.
6) In the evaluation of usefulness, “Satisfied” rate was 89% in the AM-715 group and 85.6% in the PPA group.There was no significant difference between the groups.
7) Side effects were observed in 5 cases (4.3%) in the AM-715 group and in 3 cases (2.7%) in the PPA group.Most of the side effects were slight gastrointestinal disorders.No abnormal change in laboratory findings due to treatment with AM-715 or PPA was observed.
It is considered that the treatment in dose of 300 mg of AM-715 may be same or more effective than the treatment in dose of 75) mg of PPA, safe and useful for patients with acute simple cystitis.

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To evaluate the efficacy, safety and utility of AM-715 for the treatment of complicated urinary tract infections, a double blind study comparing AM-715 with pipemidic acid (PPA) was carried out. Patients received either 800mg/day of AM-715 or 2, 000mg/day of PPA four times a day for 5 days by oral route, and the following results were obtained.
1. Of the 339 patients, clinical efficacies were evaluated in 265 cases (AM-715 128 cases, PPA 137 cases) excepting 74 cases those excluded or dropped out. Side effect was evaluated in 334 cases (AM-715 165 cases, PPA 169 cases). There was no significant difference in the back-ground characteristics between the two treatment groups.
2. Overall clinical efficacy was excellent in 30.5%, moderate in 40.6%, and the effectiveness rate was 71.1%in the AM-715 group.It was excellent in 21.2%, moderate in 37.2%, and the effectiveness rate was 58.4%in the PPA group.Significantly higher efficacy was obtained in the AM-715 group (P<0.03).
3. Pyuria was cleared in 38.3% of the cases treated with AM-715 and in 28.5%of the cases treated with PPA. The effect of AM-715 on pyuria seemed superior to that of PPA.Bacteriuria was eliminated in 63.3% of the cases treated with AM-715 and in 48.2%of the cases treated with PPA. The effect of AM-715 on bacteriuria was superior to that of PPA with significant difference (P<0.04).
4. With respect to the classification by the type of infection, overall clinical efficacy in the 5 th group (polymicrobial infection with catheter indwelt) was excellent in 22.2%and moderate in 22.2%(the effectiveness rate 44.4%) in the AM-715 group.It was only moderate in 10%(the effectiveness rate 10%) in the PPA group. No significant difference was observed between the effects of AM-715 and PPA in other 5 groups.
5. The clinical efficacy evaluated by the attending physician was excellent in 36.2%, excellent or good in 66.9%in the AM-715 group. It was excellent in 22.1%, excellent or good in 58.6% in the PPA group. Significant difference was observed between the two groups.
6. In evaluation of GNR cases, the overall clinical efficacy was excellent in 29.3%, moderate in 41.4%and poor in 29.3% in the AM-715 group It was excellent in 16.3%, moderate in 39.0% and poor in 44.7% in the PPA group. Significantly higher efficacy was obtained in the AM-715 group.
7. Side effects were observed in 2 cases (1.2%) in the AM-715 group and in 7 cases (4.1%) in the PPA group. No significant difference was observed between the groups. No severe change in laboratory findings was observed.
8. day of PPA, safe and useful for the treatment of complicated urinary tract infections. It was considered that 800 mg/day of AM-715 might be same or more effective than 2, 000 mg/day of PPA, safe and useful for the treatment of complicated urinary tract infections.

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Antibacterial activities of norfloxacin (AM-715) against clinically isolated 77 strains of Shigella sp. were compared with those of nalidixic acid (NA) and pipemidic acid (PPA). The MICs of AM-715 for 83.1% of the strains distributed at concentrations less than 0.2μg/ml, and all of the strains were inhibited by AM-715 at 1.56 μg/ml or less.The distribution of MICs of PPA showed a peak at 1.56μg/ml, but there existed 2 strains resistant to PPA and the MICs of PPA for these 2 strains were 25μg/ml or more.Most of the MICs of NA distributed at 1.56 and 3.13μg/ml, and 14 out of 77 strains were resistant to NA.Antibacterial activity of PPA against Shigella sp.seemed superior to that of NA, but some cross resistance to PPA and NA was observed.While the strains resistant to NA and/or PPA were susceptible to AM-715.
The therapeutic effects of AM-715 on 6 cases with bacillary dysentery and 9 carriers of Shigella sp. were examined.AM-715 was orally administered at a daily dose of 800 mg for 5 days. Bacteriological effect was evaluated in 9 cases in whom Shigella sp.was detected on the first day of administration of AM-715.Eradication was observed in 8 out of 9 cases on the second day and in the remaining one case on the 4 th day of the administration.Thus, this drug was effective in all of these 9 cases.
In the other 6 cases, Shigella sp.was detected before hospitalization but not detected after hospitalization. Recurrent excretion of Shigella sp.did not occur in these 6 cases after the administration.
No side effect was observed.

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The topical consecutive administration of a 1% isoconazole nitrate cream for two weeks resulted in a marked therapeutic effect on cutaneous infection of guinea pigs with a Trichophyton mentagrophytes strain, in terms of improvement of lesions and of negative culture of the inoculated organisms, in a degree similar to clotrimazole.
The oral or intraperitoneal administration of 20 mg/kg/day of isoconazole nitrate for two weeks also caused a considerable suppressive effect against a systemic lethal infection of mice with a Candida albicans strain in a degree similar to miconazole nitrate.
A complete elimination of the organisms from the kidneys was not attained in any animals, but a more or less considerable decrease in number of the organisms was observed in the majority of the animals.

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The serum concentrations following intravenous drip infusion of 90mg TOB fur 1 hour, its clinical effects for respiratory tract infections and side effects were studied.The average age, body weight and creatinine clearance (C_er) of the 10 subjects were 59 years, 48.5 kg and 77ml/min, respectively. Serum concentrations were determined on the first and last day of TOB administration.Peak serum concentrations of the first and last day were 6.7±2.0μg/ml (mean±S. D.) and 6.6±1.0μg/ml, respectively. The half lives of TOB of the first and last day were 2.3 hours and 2.8 hours, respectively. In 9 subjects with C_cr more than 50ml/min, the serum concentration curves of the last day were similar to that of the first day. But in one subject with C_er less than 50ml/min, the half life of the last day was markedly prolonged. The actual serum concentrations during drip infusion were higher than that calculated by one-compartment model analysis, though they fitted well to calculated values after drip infusion. So, one-compartment model analysis was considered to be useful to predict serum concentrations in clinical practice. The clinical effect of 6 cases was evaluated good and that of 4 cases was fair. No side effects were observed except one case with prolonged half life. we conclude that drip infusion of 90mg TOB is safe and effective in patients with normal and slightly reduced renal function, but serum concentrations should be often determined in patients with impaired renal function.

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Therapeutic effects of pyridonecarboxylic acid agents (norfloxacin, pipemidic acid and nalidixic acid) against experimental urinary tract infections in mice induced by gram negative bacilli were studied with comparing the reduction of renal viable bacterial number.
The marked therapeutic effect was obtained when therapy with norfloxacin was initiated against the relatively mild and acute experimental urinary tract infection in mice before renal gross lesion being observed, that is 48, 24 and 24 hrs after infection with E. coil KU 3, K. pneumoniae KU 2 and P.aeruginosa KU 1, respectively.In mice infection with S. marcescens KU 21, therapeutic effect was sufficiently observed when therapy was initiated at 48 hrs after infection, at that time, renal gross lesion was limited. But little therapeutic effect was observed when therapy was initiated after renal lesion expanded. The results of these experiments suggested that primary therapy was essential.
In these experiments, norfloxacin showed best therapeutic effect than others did against experimental urinary tract infection in mice induced by every four gram negative bacillus.

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Although various experimental infection model systems have been presented for evalution of antibiotics, there is considered that bacterial species and strains make differences in infection ability using varied infection routes and varied animal species.
In this report, Nye compared infection ability of every fifteen strains of clinical isolated gram negative bacilli, E. coli, K. pneunoniae, S. marcescens and P. aeruginosa in mice experimental urinary tract infection model to evaluate the difficulty for establishment of infection model.
In mice groups which were allowed access to water adlib, it appeared that strains detected from kidneys of infected mice more than three fifth were 14 (93%) in K.pneumoniae, 11 (73%) in P.aeruginosa, 6 (40%) in E.coli and 1 (7%) in S.marcescens. On the other hand, in mice groups which were restricted water intake for 20 hrs before inoculation of bacteria, that of strains v.ere 15 (100%) in K. pneumoniae, 13 (87%) in P. aeruginosa and E. coli and 9 (60%) in S. marcescens, and then infection ability was increased.
Using every one strain from each four bacterial species, experimental urinary tract infections were induced in mice. There were different variation patterns in viable cells of kidneys by infecting bacterial strains, but gross lesion was observed at 2 to 3 days after infection. No infected bacteria were detected from blood, lung, liver and spleen. This model was the relatively mild ascending urinary tract infection without instance of death, consequently useful for evaluation of antibiotics on the acute stage of that infection.

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