Clinical studies on cefmenoxime (CMX) concentration in prostatic tissue and bladder wall were made and the following results were obtained.
1. In 40 patients undergoing operation, 1g of CMX was administered intravenously by bolus technique and CMX levels in peripheral blood, prostatic tissue and bladder wall were examined.
The maximum level of prostatic tissue was 35μg/g after 0.41 hour and bladder wall was 62μg/g after 0.37 hour, and T1/2 was 1.41 hours both.
2. CMX, a new broad spectrum cephalosporin, can be considered as one of the highly useful antibiotics for the treatment of postoperative infection.

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The in vitro activity of cefmenoxime (CMX) was determined using agar dilution at inoculum level of 10⁶cfu/ml against 333 clinical bacterial isolates. CMX was highly active against Escherichia coli, Klebsiella pneu-moniae, Proteus mirabilis, Enterobacter aerogenes and Haemophilus influenzae and also Streptococcus Pyogenes and Streptococcus pneumoniae with MIC values in the range of 0.024 to 3.13μg/ml. Against Staphylococci and Serratia marcescens, CMX showed the antimicrobial activity with MIC₉₀ 6.25μg/ml. However, CMX was not active against Pseudomonas aeruginosa and Acinetobacter anitratus and exhibited no useful activity against Streptococcus faecalis. Reliability of CMX disc diffusion susceptibility test for quantitative estimation of the antimicrobial activity was also investigated, using 8mm diameter disc (Showa) and 6 mm diameter disc (Wako), both of them containing 30μg of CMX. These disc susceptibility test results were well correlated with MICs, capable of utilizing CMX disc susceptibility test for the estimation of proper administra-tive dose of CMX.
Using 6mm diameter disc containing 30μg CMX, FucHs et al.14) have proposed the following tentative zone size break points: ≥22mm=MIC 8μg/ml, susceptible; 15 to 21mm=MIC 16-32μg/ml, moderately susceptible (intermediate); and≤14mm=MIC≥32μg/ml, resistant. In this investigation, the following zone size break points have preferred:≥25mm=MIC≤3μg/ml (+++); 20 to 24mm=MIC>3-15μg/ml (++); 16 to 19mm=MIC>15-60μg/ml (+) and≤15mm=MIC≥60μg/ml (-). Based on CMX pharmacokinetic data currently available, MIC break points proposed,≤53μg/ml and≤15μg/ml, would be useful for estimating the administrative dose of this antibiotic to obtain the effective blood level (e.g. the bacteriostatic activity in serum 1:≥8 for treatment of severe infection).

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Netilmicin (NTL), a new semisynthesized aminoglycoside, was evaluated in 11 episodes of infection in 10 patients, who had severe underlying diseases, such as acute myocardial infarction, cerebral infarction, malig-nancy and hepatic cirrhosis.
The infection was bacteremia in 3 cases, urinary tract infections in 3 cases and respiratory tract infections in 5 cases.
NTL was administered intramuscularly at a dose of 100mg twice a day for 3 to 14 days.
Overall clinical efficacy was only 40%, including excellent in 2 cases, good in 2 cases, fair in 3 cases and poor in 3 cases.
Bacteriologically, 2 episodes of E. colt, 2 of S. marcescens and 1 of K. pneumoniae were eradicated, whereas, 2 of P.aeruginosa were decreased, and 1 of K. pneumoniae and 1 of P. rettgeri were persisted.
Transient eosinophilia was observed in 1 case, and also nephrotoxicity was encountered in 1 case

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Clinical investigation of combination use of cefotiam (CTM), aminoglycoside, or (and) penicillin against complicated infections with hematopoietic disorders was performed, and the results were as follows.
1. Fifty-one patients were administered CTM in combination with aminoglycoside or (and) penicillin. The clinical response was excellent 19.6%, good 27.4%, fair 21.6%, and poor 31.4% showing efficacy rate of 47.1%. The combined therapy of CTM and aminoglycoside was clinical effective in 70% of 10 patients with complicated sepsis. Therefore, combination use of CTM and aminoglycoside is considered to be the first choise for the treatment of complicated sepsis with hematopoietic disorders.
2. The clinical effectiveness of CTM was not influenced by the number of mature neutrophil at the first phase of CTM treatment, but was influenced at the end phase of CTM treatment.
3. Gram-negative bacilli were dominantly isolated from the patients. Pseudomonas sp. was isolated from 70% of the patients with sepsis.
4. No remarkable side effects were observed in this investigation.

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Ceftizoxime (CZX), a parenteral cephalosporin derivative belonging to the so-called third generation cephalosporin is reported to have a broad antibacterial activity, particularly against Gram-negative aerobic bacilli and some anaerobes, such as Bacteroides fragilis and a good stability to is-lactamases.
Clinical study was performed on a total of 20 cases, 9 females (1 case had urinary tract infection 3 times) and 11 males, aged from 27 to 82 years.
All patients had the underlying diseases. They were bronchial asthma in 3 cases, influenza in 1, chronic pulmonary emphysema in 1, pulmonary fibrosis in 1, chronic bronchitis with strongyloidiasis in 1, lung cancer in 3, esophagus cancer in 2, stomach cancer in 1, hepatoma with urolithiasis in 1, liver cirrhosis with diabetes mellitus in 1, alcoholism with strongyloidiasis in 1, cholelithiasis in 1 and congestive heart failure in 1, respectively.
Clinical diagnoses for infections were 2-acute bronchitis, 2-exacerbation of chronic bronchitis, 2-bronchopneumonia, 2-pneumonia including one suspected case, 1-obstructive pneumonia, 2-secondary pulmonary infection, 1-pulmonary infection, 3-urinary tract infection (UTI), 1-UTI with sepsis, 1-sepsis, 1-sepsis with purulent meningitis, 1-biliary tract infection and 1-infected bronchoesophageal fistula.
CZX was given by intravenous drip infusion, at a dose of 1 to 2 g, twice daily for 3 to 15 days. Because of severity in infections and underlying diseases, some cases were treated either steroid, r-globulin preparations or other antibiotics in combination with CZX.
Twelve out of 15 cases assessed clinically responded satisfactorily to the treatment and efficacy rate was 80.0%. From the microbiological point of view, 3 strains of Haemophilus influenzae, 3 of Escherichia coli, 4 of Klebsiella pneumoniae, 2 of Enterobacter cloacae, and 1 of Proteus mirabilis were eradicated. One out of 2 strains of Acinetobacter calcoaceticus was also eradicated. Two strains of Pseudomonas aeruginosa, 1 of Pseudomonas maltophilia and 1 of Enterobacter aerogenes were still persistent after treatment.
One strain of Streptococcus pneumoniae was eliminated. Staphylococcus aureus was decreased in number after CZX therapy in 1 case. Streptococcus faecalis was not changed in number in 1 case.
Effectiveness of CZX was clinically evaluated as good or excellent in 4 (66.7%) out of 6 cases who had responded unsatisfactorily to other antibiotics treatment, such as cephalexin, minocycline, ampicillin, piperacillin, cefotiam and AC-1370.
Decreased values of hemoglobin and hematocrit in 3 cases seemed to be due to underlying DIC and malignancies. Thrombocytopenia in 1 case was due to DIC.
Elevations of S-GOT and S-GPT values were noted in 7 cases, and 6 of them were also due to underlying diseases or combination drug. Remainder was transient.
From the above mentioned results, this drug is considered to be one of the useful antibiotics for the treatment of Gram-negative bacterial infections developed in immunocompromised hosts.

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Cefoperazone (CPZ) has a broad antibacterial spectrum against Gram-positive,-negative aerobic and anaerobic organisms, it is also highly active against Pseudomonas sp. and Enterobacter sp. which are hardly susceptible to current cephalosporins.
The clinical studies on CPZ were performed in postoperative wound infections and abdominal cavity infections, and the following results were obtained.
1. Overall clinical effect: The rates of effectiveness were 100% in postoperative wound infections and 71.4% in abdominal cavity infections.
2. Bacteriological effect: The rates of eradication were 90% in postoperative wound infections and 80% in abdominal cavity infections.
3. Side effects: Any side effects on marked changes in laboratory findings were not observed in any of the cases treated with CPZ.
Based on the above results, we considered that CPZ is a highly useful antibiotic for the treatment of postoperative infections.

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Carbenicillin (CBPC) was evaluated in 4 patients with chronic airway infections and 2 with infections secondary to lung cancer.
The daily dose of CBPC was 10g for all patients.
The following results were obtained.
1. Three out of 4 patients with chronic airway infections showed good response. Both cases with infection secondary to lung cancer showed good response. The overall effectiveness rate was 83.3%.
2. There were no side effects or abnormal laboratory values related to carbenicillin therapy.
3. CBPC is still considered to be a drug of choice for the initial acute exacerbation of chronic airway infection and for infections secondary to lung cancer.

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For the purpose of studying the pharmacokinetic profile of sisomicin (SISO) and the proper conditions for its administration to children, SISO was administered intramuscularly to 10 infants aged less than 1 year, 16 young children and 18 school children at doses of 1.0, 1.5 and 2.0mg/kg and its serum and urine levels were determined by bioassay.
1. The mean peak levels of SISO in serum appeared at 1/4 hour in the infants, irrespective of the dose; the mean peak levels were 2.27, 3.05 and 4.83μg/ml after the 1.0, 1.5 and 2.0mg/kg doses, respectively. In the young children, the mean peak levels appeared at 1/4 hour after the 1.0mg/kg dose and at 1/2 hour after both the 1.5mg/kg and 2.0mg/kg doses. The mean peak levels were 2.82, 3.80 and 6.43μg/ml, respectively. In the school children, the mean peak levels appeared at 1/2 hour after all the doses and were 4.34, 5.31 and 6.87μg/ml, respectively. The mean peak levels were in the order of school children> young children> infants and were dose-dependent.
2. In the infants, the mean urinary recovery was 43.7% for the 1.0 mg/kg dose and 31.2% for the 1.5mg/kg dose; in the young children, 50.5, 35.9 and 65.6% for the 1.0, 1.5 and 2.0mg/kg doses, respectively; and in the school children, 54.2, 50.2 and 56.7%.
3. Using the observed serum levels, the pharmacokinetic parameters were calculated according to the one-compartment open model theory.
(1) The mean elimination rate constants (K) were calculated at 0.60, 0.67 and 0.56 hr^-1 for the infants, young children and school children, respectively. There were found no great differences among the above 3 age groups. The mean absorption rate constants (ka) were 18.5, 7.6 and 5.9 hr^-1 and the apparent volumes ofdistribution per kg body weight, Vd (L/kg), 0.44, 0.26 and 0.22 L/kg, respectively. These 2 parameters were significantly greater in the infants than in the young children and school children.
(2) The maximum serum concentration (C_max) and the time when the concentration reaches a maximum (T_max) were substantially in agreement with the observed values. The half-lives (T1/2) were 1.16, 1.03 and 1.23 hours for infants, young children and school children, respectively, and did not differ significantly among the 3 groups.
(3) A serum level simulation curve constructed by plotting the mean values for K, ka and Vd did not reveal any substantial deviation from the observed values.
4. Based on the MICso values against different clinical isolates and the bactericidal curves, the clinically effective serum concentration of SISO was estimated to be 1.56μg/ml and the dose required for sustaining the effective serum level at least for one hour was regarded as a usual dose. Estimation of the duration of the effective serum level from the simulation curve revealed that the usual single dose of SISO is 1.5mg/kg for infants and 1.0mg/kg for young children and school children. Serum SISO levels at 8 hours after administration in these doses suggested that 2 to 3 doses per day are required. Depending on the kind and severity of the disease and MIC values against causative organisms, the single dose of SISO may be increased up to 2.0 mg/kg for infants and 1.5mg/kg for young children and school children.

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Acute toxicities of MT-141 were studied in mice and rats to obtain the following results.
1. LD₅₀ value of MT-141 by i. v. administration was 6, 100mg/kg for male mice and 5,200mg/kg for female mice. The LD₅₀ value by i. m. administration was 8,200mg/kg for the males and 8,600mg/kg for the females, respectively.
2. The mice administered with a lethal dose of MT-141 showed abnormal syndromes such as decreased spontaneous movement, decreased rate of respiration, ataxic gait, sedative state and loss of righting reflex, followed by a decrease of body weight.
3. Gross inspection revealed no remarkable change in the organs and tissues of mice after a treatment with a lethal dose of MT-141.
4. LD₅₀ value of this compound was 6,600mg/kg for male rats and 5,700mg/kg for female rats by i. v. administration, 8,600mg/kg for the males and 8,550mg/kg for the females by i. p. administration, 9,600mg/kg for the males and 9,700mg/kg for the females by i. m. administration and more than 15,000mg/kg for both sexes by s. c. or p. o. administration, respectively.
5. The rats given a lethal dose of MT-141 showed abnormal syndromes such as steppage gait, face-down position, decreased rate of respiration, ataxic gait, decreased spontaneous movement and loss of righting reflex, followed by a decrease of body weight. The rats exhibited streching behavior when given MT-141 through i. p. route and manifested vocalization when given it through s. c. and i. m. routes.
6. The results of gross inspection and histopathological observation suggested that high doses of MT-141 induced slight renal toxicity in rats.
7. The high concentration of MT-141 caused locally slight irritating effect on the sites of its injection.
8. These results suggest that the death of mice and rats may be due to the paralysis of their respiration when injected MT-141 through i. v. route and due to the deterioration of general physiological conditions when given it through the other routes.

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In this subacute study, male and female rats were administered with 100, 200, 400, 800 and 1,600mg/kg/day of MT-141 through an intramuscular (i. m.) route or with 50, 100, 200, 400 and 800mg/kg/day through an intravenous (i. v.) route for 30 days.
1. MT-141 did not cause lethal effect on male and female rats even at the high dosage of 1,600mg/kg/day i. m.(approx. one-6th of LD₅₀) and 800mg/kg/day i. v.(approx. one-8th of LD₅₀).
2. Histopathological findings revealed that MT-141 induced slight local irritation at the sites of i. m. and i. v. injection.
3. Only at a high dose of 1,600mg/kg/day i. m., MT-141 reduced significantly the gain of body weight in male rats, which was closely related to the decrease of food intake. A slight decrease in serum Cr. and Glc. was observed in male rats at the doses more than 200mg/kg/day i. m. and a slight decrease of liver weight at the doses more than 800mg/kg/day i. m., while a slight increase of serum CPK, GOT, Al-P and LDH was perceived at the doses more than 800mg/kg/day i. m. The distention of cecum was induced by the doses more than 400mg/kg/day i. m. but histopathological findings revealed no abnormality in the cecum. These results suggest that MT-141 at the dosage level of 1,600mg/kg/day i. m. causes nonspecific slight toxicity based on the disturbance of nourishment in male rats.
In female rats given 100 to 1,600mg/kg/day i. m., MT-141 at the high doses induced a slight increase of serum GOT, LDH and CPK and distention of the cecum. It is assumed from these results that MT-141 at the dosage level of 1,600mg/kg/day causes nonspecific slight toxicity in female rats.
4. In male rats given 50 to 800mg/kg/day through an i. v. route, the level of serum Glc. and Cr. and the liver weight slightly decreased at the doses more than 200mg/kg/day i. v. The cecum distended at the doses more than 100mg/kg/day i. v. The dose of 800mg/kg/day i. v. increased the activity of LDH and CPK in the WHIM In female rats, MT-141 raised slightly the level of serum GOT, Al-P, LDH and CPK even at the doses more than 400mg/kg/day i. v., reduced the liver weight at the dose of 800mg/kg/day i. v. and distended the cecum at the all doses. These results suggest that MT-141 at the dosage level of 800mg/kg/day i. v. induces nonspecific slight toxicity in male and female rats.
5. The MT-141-induced changes in many observations on male and female rats were not so much correlated with the dosage levels and fluctuated within the range of the physiological variations. It is deduced from these results that the maximal “no effective” dose of MT-141 is 800mg/kg/day i. m. and 400mg/kg/day i. v., much greater than the daily dose of humans.

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The chronic toxicity of MT-141 was studied in male and female Wistar rats with 182-time intramuscular injections of 50, 100, 200, 400, 800 and 1,600mg/kg/day and the following results were obtained.
1. MT-141 at all dosage levels caused no lethal effect on rats. However, it induced local inflammatory changes at the site of injection, such as hemorrhage, infiltration of round cells and fibrosis particularly at high doses.
2. MT-141 at a high dose of 1,600mg/kg/day decreased the gain of body weights in male rats but not in female rats.
3. MT-141 increased the water intake in male and female rats from 8th day till last day after treatments with the doses more than 800mg/kg/day. This compound also softened the feces and distended the cecum.
4. MT-141 at the highest dosage level of 1,600mg/kg/day increased the weight of kidney in male and female rats. Electron-microscopic findings revealed dissociation of basal infolding and dilatation of endoplasmic reticulum in renal epithelial cells of rats treated with the doses more than 800mg/kg/day. These results suggest that MT-141 may induce renal toxicity in rats at these doses.
5. The administration of MT-141 changed some toxicological parameters in gross and histopathological examinations and analyses of blood, serum and urine. However, the changes were accidental, independent on the dose and within physiological variations.
6. It is concluded from above-mentioned results that the maximal “no effective” dose of MT-141 is 400mg/kg/day in male and female rats.

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Mutagenicity of MT-141, a new cephamycin, was evaluated by in vitro and in vivo assays.
MT-141 did not induce mutations of the test strains, Escherichia coli WP2 (uvr A) and Salmonella typhimurium TA1535, TA1537, TA1538, TA100 and TA98, with and without metabolic activation in vitro. In bone marrow micronucleus assay with male mice, MT-141 showed no induction of micronucleated polychromatic erythrocyte at 6 hours and 30 hours after administration.
In addition MT-141 was found not to cause any dominant lethal effects on male mice for 8 weeks after administration.

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The distribution, metabolism and excretion of the radioactivity were studied in male rats after the bolus intravenous administration of ¹⁴C-MT-141.
1. The biological half-lives obtained from the blood concentration-time curve were 0.43 hour for the data in the first 4 hours and 16.5 hours for the data from 6 hours to 24 hours after the intravenous administration of ¹⁴C-MT-141.
2. The radioactivity was excreted mainly into urine, and the cumulative urinary and fecal excretion of the radioactivity were 75.2% and 24.1% of the dose, respectively, within 120 hours after the intravenous administration of ¹⁴C-MT-141.
3. The cumulative biliary excretion of the radioactivity was 18% of the dose within 48 hours after the intravenous administration, and 35% of the radioactivity excreted into bile (about 6% of the dose) was reabsorbed from the intestine.
4. The highest concentration of the radioactivity was observed in the kidneys, and also the relatively high concentrations were observed in the liver, plasma and intestine, while the concentrations in the brain, fat and muscle were low. Within 24 hours after the intravenous administration of ¹⁴C-MT-141, the radioactivity in the highly distributed organs or tissues was decreased to less than 3% of the values at 5 minutes after the intravenous administration.
5. A small amount of N-acetyl-MT-141 was found in urine and feces as a metabolite.

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The distribution and tissue accumulation of the radioactivity were studied in male rats after the multiple intravenous administration of ¹⁴C-MT-141. The distribution and the placental transfer were also studied using pregnant rats or lactating rats after the single intravenous administration of ¹⁴C-MT-141.
1. The radioactive concentration in the fetus was low and the radioactivity was distributed almost uniformly through the fetus body.
2. The peak time of the milk level was 2 hours after the administration and the radioactivity in milk decreased gradually thereafter. The milk levels decreased more slowly than the blood levels did.
3. The blood level after the last dose administered daily for 7 days tended to decrease more slowly, when compared with the single administration. However the blood concentration at 48 hours after the last administration was less than 3 times as high as that after the single administration.

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