The bacteriological and clinical effect of tinidazole (TDZ) was evaluated in 16 cases of intrauterine, intrapelvic and vulvar infection caused by anaerobic organisms and the following results were obtained.
1. Anaerobes were detected in 16 cases, including 1 case with anaerobes alone and 15 cases with mixed anaerobes and aerobes.Eight different species and 24 strains were detected.A single species was isolated from 9 cases, 2 species from 6 cases and 3 species from 1 case.The main species detected were Bacteroides fragilis and Peptostreptococcus spp.of which 9 strains (37.5%) each were isolated. Escherichia coli and B.fragilis was the most frequently occurring combination.
2. The peak MIC values of TDZ were 0.78μ/ml for B.fragilis and 1.56μ/ml for Peptostreptococcus spp.Most other organisms were also sensitive to TDZ.
3. The bacteriological response of the anaerobic infections to TDZ was 87.5% and overall clinical efficacy was 87.5%.
4. Few side effects were observed.

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Forty-one male patients with gonorrheal urethritis were treated with ceftizoxime (CZX) administered concomitantly probenecid at the urological ward of Tokyo Metropolitan Taito Hospital during the period from October, 1982 to February, 1983, and clinically evaluated.Eighty strains of Neisseria gonorrhoeae isolated from the clinical specimens of these patients were bacteriologically studied.
Of the 80 strains, 12 (15%) were PPNG strains and the other 68 strains were non-PPNG strains.
MICs of PCG to the 12 PPNG strains were 3.13-25μg/ml and to the 68 non-PPNG strains were 0.0122-3.13μg/ml.While MICs of CZX to the PPNG strains were<0.003-0.024μg/ml and to the non-PPNG strains were <0.003-0.05μg/ml.
Those patients with gonorrheal urethritis were given a single 0.5g intramuscular dose of CZX and a single 1g oral dose of probenecid.
The following clinical findings were obtained:
1. The clinical efficacy rate of 41 cases was 98%;excellent in 24, good in 16, poor in 1 case.
2. All 3 patients with gonorrheal urethritis caused by PPNGs were cured with the treatment.
3. No subjective side effects were found.

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Cefbuperazone, a new cephamycin antibiotic, was used in 13 complicated UTI cases.The drug was given at a dose of 1g in 100ml of physiological saline solution twice a day for 5-44 days and judged for its clinical effect in 11 cases on days 5-7 according to the criteria of the UTI committee.
Overall clinical efficacy was excellent in 3 cases, moderate in 2 cases and poor in 6 cases, the effectiveness rate was 45.5%.
In laboratory findings, slightly elevated transaminase and Al-P were observed in 2 cases and 1 case, respectively.

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In order to compare the antibacterial activity with Acyl-Lys-Lys (Thr)-Glu-OH (I), already reported, 3 kinds of Acyl-Lys-Lys (Glu)-Thr-OH (9a-, c) and corresponding tetrapeptide (10), which were exchanged Thr for Glu on I, were synthesized by dicyclohexylcarbodiimide method.
It was proved the (+)-6-Methyloctanoyl-Lys-Lys (Glu)-Thr-OH (9a) shows antibacterial activity against 5 kinds of Gram-negative bacteria and against 2 kinds of Gram-positive bacteria, but that the others (9b),(9c), only have the weak one, and that tetrapeptide has against Gram-positive bacteria; and that those compounds have almost the same one as Acyl-Lys-Lys (Thr)-Glu-OH (I) has.

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In our previous study on aminoglycoside antibiotic-induced skeletal neuromuscular blockades, we have reported that kanamycin sulfate (KM) has more preferential presynaptic antireleasing action of acetylcholine than gentamicin and neomycin 1-3) and the calcitonin-induced hypocalcemia potentiates presynaptically KM-induced neuromuscular blockade2, 4).In the train of these studies, we noticed that there was a discrepancy between the total infused dose of KM and the strength of its pharmacological actions.When continually and intravenously infused a solution of lower concentration of KM, much higher infused dose was required to induce the same extent of neuromuscular blockade than that of higher concentration.Although this might be explained by the rapid renal elimination rate of the infused KM, there arised a question of KM pharmacokinetics in its plasma levels and its tissue levels probably implicating its properpharmacological actions (neuromuscular and cardiovascular depressions): The plasma level can directly express the tissue level in continual infusion of KM? This question led us to examine the interrelations of the infusion rate, the concentration of infused solutions, the plasma level and the neuromuscular blocking action of KM.

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The efficacy and safety of tobramycin (TOB) administration at 90mg twice a day (90mg group) to patients with respiratory tract infections (RTI) were objectively investigated by means of a well-controlled comparative study.The results in this 90mg group were compared with the case of administering 3 times a day of 60mg each (60mg group) as the control.In both of these patient groups, TOB was administered by intramuscular injection for 10 consecutive days.
This study included 85 patients (90mg group: 43 patients;60mg group: 42 patients).The Committee, however, excluded 19 patients consisting of 13 cases of infection other than RTI and 6 cases of out of protocol drug administration.Thus, 66 patients (90mg group: 32 patients; 60mg group: 34 patients) were used for the efficacy analysis.All 85 patients were used, however, for the evaluation of the safety of TOB and for the usefulness of TOB as judged by the physicians in charge.A brief summary of the results is presented below.
1.The cases employed by the Committee consisted of 8 and 17 cases in the 90 mg and 60mg groups, respectively, with bacterial pneumonia and lung abscess, and 24 and 17 cases in the 90mg and 60mg groups, respectively, with chronic RTI.There was a tendency for the distribution of disease cases in the 2 drug groups to be significant.Within the chronic RTI disease classification, the number of patients with chronic bronchitis was almost equal in the 2 drug groups;16 cases in the 90mg group and 15 cases in the 60 mg group.However, secondary infections were diagnosed in 8 cases in the 90mg group and 2 cases in the 60mg group.
2. The clinical efficacy judged for all cases investigated by the Committee showed efficacy ratios of 56.3% for the 90mg group and 70.6% for the 60mg group. The difference between the 2 drug groups was not statistically significant.
In the treatment of bacterial pneumonia and lung abscess, the efficacy rate in the 90mg group was 87.5%, while it was 88.2% in the 60 mg group;these high values were practically identical. Against chronic RTI, the efficacy rates were 45.8% in the 90mg group and 52.9% in the 60 mg group;within that disease classification, the efficacy rates against the chronic bronchitis cases were nearly the same at 43.8% and 46.7%, respectively. These data showed no statistically significant differences between the 2 drug administration groups.
3. The investigation of the bacteriological efficacy revealed no statistically significant differences between the 2 drug administration groups.
4. With regard to the safety of these drug administration regimens, there were no cases of side effects in either of the drug groups. In addition, there were only 2 patients found to develop abnormal variations in the laboratory test values, both in the 60mg group;1 patient with RBCs in the urine, and 1 patient with elevated GOT and GPT values. There was again no statistically significant difference observed between the 2 administration groups.
5. Concerning the usefulness of the drug regimens as judged by the Committee, an evaluation of quite useful or useful was given to 56.3% of the cases in the 90mg group and 70.6% of the cases in the 60mg group. This difference between the 2 administration groups was not statistically significant. In addition, the results for the usefulness as judged by the physicians in charge for all of the patients showed a pattern similar to that obtained by the Committee, with no statistically significant difference between them.
Based on the above results, the 90mg and 60mg TOB administration regimens were concluded to be equivalent in terms of their efficacy and safety.

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Male Wistar rats received 20mg/kg/day of amikacin (AMK) with or without 200mg/kg/day of fosfomycin (FOM) for 5 days.Accumulation of AMK in renal lysosome-containing fraction was inhibited by FOM.FOM was reported to interfere with the nephrotoxic properties of aminoglycosides. Our observation supports the finding.

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The frequency and severity of side effects, above all, phlebitis, associated with an intravenous use of cephapirin (CEPR) or cephalothin (CET) was compared in 69 patients with infections.
Two grams of each drug were administered intravenously twice a day with a 21-G vein needle in one of the two arms of the patients.CEPR was administered to 32 patients, and CET to 37 patients respectively. After treatment, the status of the veins was checked, and laboratory findings and other side effects were evaluated daily.
Each drug appeared to be equally efficacious in the treatment of infections.The administration of CEPR was associated with a slightly lower rate of phlebitis and other side effects, but the difference between the 2 drugs was not significant (0.05<P<0.10).Phlebitis was observed in 1 patient (3.1%) of CEPR group and in 3 patients (8.1%) of CET group.Side effects, including phlebitis, were observed in 4 patients (12.5%) of CEPR group and in 12 patients (32.4%) of CET group.In CET group, drug exanthema.(3 cases), drug fever (3 cases), and abnormalities in liver function (4 cases) were observed.
These findings, together with the results of other reports, suggest that CEPR is a safe and useful drug in the treatment of infection as compared with CET.

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Chronological variation in blood isolates obtained from 1968 to 1982 was studied.Escherichia coli was the most frequent isolates followed by Klebsiella species, glucose-non-fermentative Gram-negative rods (excluding Pseudomonas aeruginosa), Enterobacter-Serratia group, and Staphylococcus aureus. The isolation of glucose-non-fermentative Gram-negative rods, about half of which being Achromobacter xylosoxidans, increased greatly in number from 1980.
A total of 113 strains of blood isolates was examined for susceptibility to various antibiotics.Although there was a significant increase in S.aureus resistant to GM, these strains were susceptible to cephalosporins.In the 9 strains of GM-resistant aerobic Gram-negative rods (2 strains of Kkbsiella, 2 strains of Enterobacter, 4 strains of Serratia and 1 strain of P.aeruginosa), 3 strains of Serratia species were also resistant to AMK.Two strains of LCM-resistant Bacteroides fragilis were susceptible to LMOX, but 1 strain was not inhibited by 100μg/ml of CFX.
Among the clinical specimens, differences were found in the rate of isolation of resistant strains, particularly in the case of Serratia and P.aeruginosa.Antibiotic resistant strains were isolated more frequently from urine and the least frequently from sputum.
Since the frequency of isolation of resistant strains varied according to organism, clinical material and year of isolation, microbiological laboratories should develop their own data base from which clinicians can make rational therapeutic decisions.

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Serum concentrations of dibekacin (DKB), sisomicin (SISO) and gentamicin (GM) were measured in 3 rabbits after intratracheal administration through the transtracheal teflon tube. The peak serum levels (average) were 106μg/ml (administrated 100mg DKB for injection), 148μg/ml (administrated 100mg DKB solution), 166μg/ml (administrated 100mg SISO solution) and 80μg/ml (administrated 80mg GM solution).
Serum concentrations and urine excretions of DKB were measured in 3 volunteers after aerosol administration using ultrasonic nebulizer.The peak serum levels (average) were 4.6μg/ml (administrated 100 mg DKB for in jection) and 3.1μg/ml (administrated 100mg DKB solution).The urine excretions (average) were 3.7mg and 4.3mg respectively during 6 hours.Before and after administration of DKB aerosol the spirogram and flow-volume curve were examined in the volunteers.But the examinations showed no changes.
Sputum concentrations were measured in 1 patient with chronic bronchobronchiolitis after administration of DKB aerosols using the ultrasonic nebulizer.The highest sputum concentration was acquired immediately after nebulization and the sputum levels decreased gradually while time passed.
Six patients with the lower respiratory tract infections were treated with DKB aerosol therapy and the utility rate was 80%.

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Concentrations of cefotiam (CTM) in the exudate after abdominal operation were studied. The exudates were collected by 6 mm paper discs and the antibiotic concentrations were determined by the paper disc method using Proteus rettgeri ATCC 9250 as test organism. Comparison between agar well and paper disc assay for CTM in ascites specimens showed good correlation. Two grams of CTM was intravenously given to the patients after abdominal operations. The concentration of CTM in the exudate for 6 hours after injection was 0.4-14.2μg/ml and this value exceeded the antibacterial level of CTM.It is, therefore, concluded that CTM will be effective for the postoperative prophylaxis.

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Various antibiotics are widely used for the purpose of protection against postoperative infections. Neurosurgeon must select the effective antibiotics to bacterium, that which penetrated enough to the intracranial organ through the blood-brain barrier.Eighteen cases with ventriculo-peritoneal shunt received intravenous drip infusion of cefotiam (CTM) and the concentration of CTM in blood and cerebrospinal fluid (CSF) was measured.The conclusion drawn from this study on penetration of CTM is summarized as follows:
1. The concentration of CTM in CSF and its ratio to that of serum (CSF/serum%) showed the values of 0.543μg/ml (3.66%) in the group of 1g CTM injection and 0.900μg/ml (4.02%) in the group of 2g CTM injection, 2 hours after an intravenous administration.
2. The concentration of CTM in CSF were gradually decreased in comparison with antibiotic levels in the blood.
3. The most cases of 1g or 2g intravenous administration were able to get the sufficient concentration in the CSF, which exceeds MIC (minimal inhibitory concentration) against Gram-positive cocci and Gram-negative bacilli.
4. As a result of penetration of CTM into cerebrospinal fluid, we recommend the intermittent intravenous injection of 2g CTM for prophylaxis of postoperative infections.

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Twelve infants having undergone extrahepatic cholangiojejunostomy (SURUGA's procedure II) after portal hepaticojejunostorny as a radical operation for congenital biliary atresia received prophylactic cefotiam (CTM) against biliary tract infection, 50mg/kg by intravenous drip in 1 hour, followed by serial determinations of bile and serum CTM levels.
The patients were evaluated as to degree of CTM excretion into the bile, by classification into 4 groups according to success or failure in establishing the anastomosis, bile outflow and persistence of jaundice.Patients with an established anastomosis, satisfactory bile flow and no longer jaundice showed high biliary antibiotic concentrations whereas lower biliary antibiotic levels were seen in those with failure in anastomosis, poor bile flow and persistent jaundice.In both cases, nevertheless, the antibiotic concentration in bile sufficiently exceeded the MICH values of CTM against principal bacterial pathogens causative of biliary tract infections, thus demonstrating clinical significance of the use of CTM for this purpose.The antibiotic excretion into the bile improved with normalization of liver function in an infant displaying satisfactory bile outflow from an early postoperative stage.The bile and serum CTM assay data obtained by the agar well method showed a high degree of correlation with those by high performance liquid chromatography.

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The in vitro antibacterial activities of cefoperazone (CPZ) against clinical isolates including various-lactamase-producing strains were studied and compared with those of cefotiam (CTM).CPZ βhad a broad spectrum against Gram-negative and Gram-positive bacteria. Especially, CPZ showed apparently more potent antibacterial activities than CTM against Enterobacter cloacae, Serratia marcescens, and Pseudomonas aeruginosa.However, CPZ was less active than CTM against Staphylococcus aureus and Proteus mirabilis.
The stability and affinity of CPZ for various types of β-lactamase were also studied.CPZ was more resistant to hydrolysis by typical cephalosporinase (CSase) and cefuroximase (CXase) than CTM, but was less stable to penicillinase (PCase).CPZ often showed higher affinity to β-lactamases than CTM.The study for the inducer-activity revealed that CPZ hardly induced CSase production in E. cloacae and Proteus vulgaris while CTM highly induced in both strains.
CPZ was more active against CSase-producers than CTM, especially against strains which inducibly produced the enzyme.It was speculated that this activity was responsible for the superior stability to CSase and low inducer-activity for CSase production.

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The in vivo antibacterial activity of cefoperazone (CPZ) against systemic infections was studied in comparison with that of cefotiam (CTM) using p-lactamase non-producing bacteria and producing bacteria. In vitro antibacterial activity of CPZ against Gram-positive bacteria was slightly inferior to that of CTM, but there was no significant difference between their in vivo activities.On the other hand, the therapeutic effect of CPZ against Gram-negative bacteria was nearly parallel to in vitro antibacterial activity and particularly was superior to that of CTM against cephalosporinase (CSase) producing bacteria. The ascitic levels of CPZ in mice infected with CSase producing bacteria were persisted longer, but those of CTM disappeared quickly after administration.This result appeared to reflect on the therapeutic effects of both drugs.

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The in vivo antibacterial activity and the penetration into inflammatory tissues of cefoperazone (CPZ) were compared with those of cefotiam (CTM) in local infection systems using mouse subcutaneous abscess and rat granuloma pouch.The serum levels of CPZ in subcutaneous abscess in mice caused by Staphylococcus aureus F-230 (penicillinase producing strain) were lower than that of CTM, but there was no significance between the therapeutic effects of both drugs.The same results were obtained using Staphylococcus aureus F-196 (penicillinase non-producing strain).When infected with Enterobacter cloacae H-27 (cephalosporinase producing strain) in rat granuloma pouch, the exudate levels of CTM were lower than those of CPZ.Judging from these results, it was suggested that CPZ was a useful antibiotic for the treatment of bacterial-inflammatory tissues.

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Patients with bronchopulmonary infections were treated with cefoperazone (CPZ), and the serum and pleural effusion concentrations were determined after 2 g CPZ drip infusion.The following results were obtained:
1. Eight of 10 patients treated with CPZ responded with a significant clinical improvement.
2. Side effects were found in 4 cases; eruption in 1 case, fever and granulocytopenia in 1 case, elevation of GPT in 1 case, and thrombocytopenia in 1 case.But these side effects disappeared immediately after cessation of CPZ treatment.
3. Intravenous drip infusion of 2g CPZ yielded a peak serum concentration of 112.0-210.0μg/ml immediately after the end of drip infusion, and a peak pleural effusion concentration of 8.8-43.0μg/ml at 2-6 hours after the end of drip infusion.
4. The ratio of peak pleural effusion concentration to peak serum concentration was 4.4-26.9%.

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Ceftazidime (CAZ), a new cephalosporin antibiotic, was studied in the field of obstetrics and gynecology, and the following results were obtained.
1.The absorption and tissue penetration of CAZ into intrapelvic genital organs were good after a single drip infusion of 1.0g for 30-60 minutes.The maximum level of 76.4μg/ml was obtained in uterine artery serum at 8 minutes after administration.The high concentrations were also obtained in genital tissues;the maximum concentrations ranged from 46.8-62.1μg/g at 20 minutes after administration and the levels were as high as 2.1-7.7μg/g at 5 hours and 40 minutes after administration. The concentration curves in tissues were consistent with those of serum levels.
2.The concentrations of CAZ in retroperitoneal dead space exudate were determined after intravenous drip infusion of 1g.The peak levels ranged from 26 to 32μg/ml after 30 minutes of administration and the level of 8.53μg/ml was sustained even 6 hours later.
3.Good response was obtained in cases of gyneco-obstetric infections such as intrauterine infection, intrapelvic infection and external genital infection with daily dose of 2-4g.CAZ was effective in 13 out of 14 cases (the efficacy ratio;92.9%).As to side effects, gastric discomfort and vomiting were observed in 1 case.

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To study concentrations in the gynecological organs, ceftazidime (CAZ) was given intravenously by one shot of 0.5g to 1 patient and of 1.0g to 10 patients who underwent simple hysterectomy because of uterine myoma.Also, clinical effect of the drug was studied in 3 cases.The levels of CAZ in sera in uterine artery and elbow vein, and tissue concentrations in various sites of the gynecological organs obtained during 50 to 425 minutes after administration were determined by the paper-disc method with P.mirabilis ATCC 21100 strain.
Concentrations of CAZ at 92 minutes after administration of 1.0g i.v. were 39.8mcg/ml in serum of uterine artery, 47.6mcg/ml in serum of elbow vein, 20.5mcg/g (tissue/serum ratio 0.43) in the ovary, 18.0mcg/g (0.38) in the fallopian tube, 16.1mcg/g (0.34) in the endometrium, 34.5 mcg/g (0.72) in the myometrium, 30.8mcg/g (0.65) in the uterine cervix, 36.4mcg/g (0.76) in the portio vaginalis and then gradually decreased time-dependently.Tissue concentrations were higher than those in serum in the endometrium, uterine cervix and portio vaginalis at 147 minutes after administration.CAZ concentrations of adipose tissue between 353 and 365 minutes after injection of 1.0g were lower than 0.8mcg/g.
The clinical responses to CAZ in intrapelvic infections were good in all cases.Slight elevation of total bilirubin, to 1.5mg/dl, was observed in a case.In the light of these clinical findings, CAZ appears to be a potent antibiotic effective in the clinical application.

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Ceftazidime (CAZ) was administered to patients with obstetrical and gynecological infectious diseases and we studied its clinical effect: CAZ was administered to 24 patients at a dose of 2-4g per day (twice a day) by drip infusion over a period of 3-11 days (total 6-32g).The subjects included 19 cases of intrauterine infection, 4 of adnexitis, and 1 of infection of the external genital organs. The overall clinical results were excellent in 6 cases and good in 18 cases, the efficacy rate being 100%. For bacteriological study, 26 strains were isolated from 16 patients.These included Gram-positive bacteria (10 strains), Gram-negative bacteria (6 strains) and anaerobes (10 strains). After CAZ treatment, 4 strains (S.mitis 1, E.coli 1, P.anaerobius 1, B.melaninogenicus 1) were eliminated, but as to the other 22 strains, the results were unknown, because we could not examine microbiology after administration. No clinial side effect or abnormality in laboratory findings was observed.

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Ceftazidime (CAZ) was studied for its transference into adnexa uteri and uterine tissues as well as for its effects and safety on gynecological infections.The results obtained are as follows:
1. Peak levels of CAZ were obtained in the tissues of adnexa uteri and uteri at 15-30 minutes after one shot intravenous injection of CAZ 1g, and relatively high concentrations were maintained for several hours.
2. In the treatment of 33 cases of gynecological infections, the clinical efficacy of CAZ was assessed as excellent in 13 cases and effective in 20 cases.
3. As for the bacteriological effects of CAZ, 95.5% of clinically isolated organisms were eradicated.
4. The laboratory tests performed before and after administration of CAZ revealed rise in GOT, GPT values in 2 cases and eosinophilia in 1 case. However, these cases were all mild and required no particular measures.

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Clinical effect and safety of ceftazidime (CAZ) in the obstetrics and gynaecology were studied in 7 cases of intrauterine infections, 8 cases of parametritis, 1 case of BARTHOLIN'S abscess, and 4 cases of intrapelvic infections totalling 20 cases.CAZ was administered at a dose of 2g per day by intravenous drip infusion, for 4-9 days depending on severity of the disease.The results showed that CAZ was effective in 13 out of 20 cases (overall efficacy rate 65%), and especially in intrauterine infections, it was effective in all the cases.However, effects were not satisfactory in 8 cases of parametritis and 4 cases of intrapelvic infections for various reasons such as influences of underlying diseases including cancer.Neither adverse reactions nor abnormal laboratory findings attributable to CAZ were observed during the treatment.

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