In vitro and in vivo antibacterial activities of cefotiam (SCE-963), a new cephalosporin antibiotic, were studied and the following results were obtained.
1) Cefotiam showed a broad antibacterial spectrum against both gram-positive and gram-negative bacteria. Cefotiam was more potent than cefazolin (CEZ) against gram-negative bacteria, but was less active against gram-positive bacteria.
2) P.morganii, P.inconstans and Enterobacter were more susceptible to cefotiam than to CEZ.
3) Cefotiam was as stable as other cephalosporins to penicillinase-type β-lactamase. However, cefotiam, as well as CEZ, was hydrolysed by cephalosporinase-type β-lactamase.
4) Cefotiam showed more potent bactericidal activities against E.coli than CEZ, but regrowth of the organism was observed.
5) Cefotiam was more effective than CEZ against experimental infections caused by E.coli in mice. In addition, cefotiam exhibited good therapeutic effects against mice infections due to CEZ-resistant E.coli.
6) With heavy inoculum (1.9×10⁹cells/mouse) of E.coli, the therapeutic effect of cefotiam against experimental infections was inferior to that of CEZ. This would be because of the higher serum level of CEZ than that of cefotiam in mice.

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In vitro antibacterial activities of cefotiam (SCE-963) against 835 strains of Staph.aureus, E.coli, Klebsiella, Enterobacter, 2 species of Citrobacter, 5 species of Proteus, Serratia marcescens, 4 species of Pseudomonas, Fl.meningosepticum, Achr. zylosoxidans and Bacteroides, which were isolated from clinical materials in 1976 and 1977, were determined comparing with those of other cephalosporins.
1) Cefotiam showed potent antibacterial activities against Staph.aureus, E.coli, Klebsiella, Cit.diversus and Pr.mirabilis. Especially, against these 4 species of gram-negative bacteria, no conventional cephalosporins were comparable to cefotiam.
2) Most organisms tested except Bacteroides were more susceptible to cefotiam than to cefazolin (CEZ). However, cross-resistance between cefotiam and CEZ were observed to some extent.

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The antibacterial activities of cefotiam (SCE-963), cefazolin and cephalothin against 31 strains of Escherichia coil, 16 strains of Klebsiella pneumoniae and 16 strains of Enterobacter cloacae were studied by the twofold agar dilution method. All strains were isolated from bloods of patients admitted to Keio-University Hospital from 1973 to 1977. The antibacterial activity of cefotiam showed to be definitely stronger against Escherichia coli and Klebsiella pneumoniae than cefazolin and cephalothin. None of the 3 tested antibiotics could inhibit the growth of 16 strains of Enterobacter cloacae even at 400μg/ml, when overnight cultures in heart infusion broth were used as inocula suspensions. However, cefotiam at 0.78μg/ml inhibited the growth of 2 strains of E.cloacae when 100 fold dilutions of overnight cultures were used. The cefazolin-inactivating activity of these 2 strains was obviously lower than the other strains.

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Laboratory studies were made on cefotiam (SCE-963), a new antibiotic of cephalosporins. The summarized results are as follows.
1. The MICs against Enterobacter cloacae and Vibrio cholerae biotype eltor were much lower than those of the other cephalosporins which have been available so far.
2. Antimicrobial effects against Streptococcus faecalis were inferior to those of the other cephalosporins.
3. Cefotiam showed bactericidal activities against gram-positive and gram-negative bacteria.
4. Bactericidal activities of cefotiam and drug-inactivating activities of organisms were in inverse proportion.
5. Cefotiam was a heat-labile antibiotic. 100μg/ml cefotiam solution in saline was inactivated 50% and more than 90%, in 5 minutes and 30 minutes respectively, at 70°C

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Present paper described results of the following studies on cefotiam (SCE-963), a new cephalosporin.:(1) Antibacterial activity against stock cultures of anaerobes (86 stiains).(2) Influence of medium used, medium pH, and inoculum size on antimicrobial activity of anaerobes.(3) Resistance to hydrolysis of β-lactamase derived from Bacteroides fragilis.(4) Chemotherapeutic effect on experimental anaerobic infections in mice due to Fusobacterium necrophorum.(5) Antibacterial activity against stock cultures of aerobes (174 strains).
From the results, cefotiam was inferior to cefazolin (CEZ) according to antibacterial activity against anaerobes but superior to CEZ according to antibacterial activity against aerobes, especially strains of E.coli, K.pneumoniae and P.mirabais. Cefotiam was more resistant to hydrolysis of β-lactamase extracted from B.fragilis than CEZ and cephalothin but less resistant than cefoxitin

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Bacteriological evaluation was made on cefotiam (SCE-963), a new broad-spectrum cephalosporin antibiotic, and the following results were obtained.
1) Cefotiam showed potent antibacterial activities against gram-positive and gram-negative bacteria. It was especially more potent than commercially available cephalosporins against gram-negative bacteria including indole-positive Proteus. S.marcescens and P.aeruginosa were almost insusceptible to cefotiam.
2) MICs of cefotiam against a great majority of clinical isolates of S.aureus (51 strains), N.gonorrhoeae (21 strains), E.coli (60 strains), K.pneumoniae (41 strais) and P.mirabilis (24 strains) distributed from 0.2 to 3.13μg/ml with inoculum size of 10⁸cells/ml and from 0.1 to 0.78μg/ml with 10⁶cells/ml. Sixtythree % of indole-positive Proteus (67 strains) were inhibited by cefotiam at 6.25μg/lm and lower.
3) MICs of cefotiam varied with inoculum sizes especially against gram-negative bacteria.
4) Cefotiam was as stable as cefazolin and cephalothin to PCase-type β-lactamse. It was, however, hydrolysed by CSase-type β-lactamase, but cefotiam was slightly more stable than cefazolin and cephalothin.
5) Cefotiam showed bactericidal action against E.coli and K.pneumoniae at 1.56-6.25μg/ml or higher. At lower concentrations, cefotiam showed bacteriostatic action.
6) Cefotiam was more effective than cefazolin and cephalothin against experimental infection in mice caused by intraperitoneal challenge of E.coli and K.pneumoniae. In mice infection with K.pneumoniae, total ED₅₀ of cefotiam in 4-6 divided administrations was less than 1/10 of ED₅₀ in single administration.

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Cefotiam (SCE-963), a new semisynthetic cephalosporin, is about tenfold more active than cefazolin (CEZ) against Escherichia coli.
The action mechanism of cefotiam was compared with that of CEZ, which is structurally related to cefotiam.
Both antibiotics displayed nearly identical inhibitory activity for peptidoglycan synthesis catalized by membrane enzyme system from E.coli. Increase in the antibacterial activity by ethylenediaminetetraacetic acid (EDTA) was not observed with cefotiam whereas detectable increase was found with CEZ.
These results suggest that the marked high antibacterial activity of cefotiam against E.coli may be attributed, at least in part, to its high permeability of the outer membrane.

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Cefotiam (SCE-963) showed excellent antibacterial activities against gram-positive and gram-negative bacteria including Haemophilus influenzae, indol-positivo Proteus, Enterobacter cloacae, and Citrobacter freundii. The MICs of cefotiam against most strains of clinically isolated Escherichia coli, Klebsiella pneumoniae, H.influenzae and Proteus mirabilis were within the range of 0.2 to 0.78μg/ml. These activities were about 10 times or more than 10 times as potent as that of cefazolin, cephaloridine, cephalothin, cefuroxime, cefoxitin and cefmetazole. Variations of MICs in medium pH, addition of horse serum and kind of growth medium had no significant effects on the activity of the cephalosporin, but the inoculum size elicited a considerable effect on the activity of β-lactamase-producing strains of bacteria. Cefotiam exerted bactericidal and bacteriolytic effects on Staphylococcus aureus and E.coli. The pronounced in vitro activity was reflected in the remarkable protection in mice infected with a wide range of gram-negative bacteria, such as E.coli, K.pneumoniae, P.mirabilis, Proteus vulgaris, Proteus morganii and Proteus rettgeri. The protective effects of cefotiam in mice infected with E.coli, K.pneumoniae and P.vulgaris varied according to the challenge dose. The activity of cefotiam in parenteral administration was far more potent than that in oral administration.

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The rate of hydrolysis of cefotiam (SCE-963) by cephalosporin β-lactamases from various bacteria except Proteus vulgaris, was smaller than that of cefazolin, cephaloridine and cephalothin. Cefotiam as well as cefazolin and cephalothin, was hydrolysed more slowly than cephaloridine by penicillin β-lactamases. When incubated with intact cells in the medium, cefotiam was more stable to degradation than cephaloridine and cefazolin but less stable than cephalothin. The ability of cefotiam to penetrate the outer membrane of Escherichia coli TN 713 and Klebsiella pneumoniae TN 1698 was estimated to be ten and two times greater than that of cephalothin and cefazolin, respectively, but smaller thanthat of cephaloridine. The calculated concentration of cefotiam inside the outer membrane of Escherichza coli TN 713 and Klebsiella pneumoniae TN 1698 was 35 to 37% and 10 to 17% of the concentration outside the cells, respectively, and was three to seventy times higher than that of cefazolin, cephaloridine and cephalothin.

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A microbiological method for the quantitative determination of Cefotiam (CTM, SCE-963)(7β-[2-(2-aminothiazol-4-y1) acetamido]-3-[[[1-(2-dimethylaminoethyl)-1H-tetrazol-5-yl] thio] methyl]-ceph-3-em-4-carboxylic acid) in biological specimens is described. This method is essentially a cylinder-plate technique using Proteus mirabilis ATCC 21100 as the test organism grown in the DST agar medium (Oxoid), pH 8.0. As low as 0.1μg (potency)/ml of CTM in 0.1M phosphate buffer (pH 7.0), or 0.2μg (potency)/ml in human serum specimens, can be measured. A method for the qualitative detection of CTM in biological specimens is also presented. The procedure involves a thin-layer chromatography on silica gel plate combined with a bioautography using P.mirabilis ATCC 21100 as the test organism grown in the same medium as described above.

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Fundamental studies were made on cefotiam (CTM, SCE-963), a new cephalosporin antibiotic, and the following results were obtained.
1) MIC of CTM to 14 strains of Staphylococcus aureus was equal to or twice as high as that of cefa-solin, consequently showing no significant difference. This antibiotic exhibited far superior antibacterial activity to cefazolin against 9 strains of E. coli, 3 strains of Salmonella typhi, one strain of Proteus mirabilis and 3 strains of Klebsiella pneumoniae. As to one strain of Proteus morganii and one of 3 strains of Entero-bacter, MIC of 0.8 μg/ml was obtained when the inocula size was decreased, but as to other Enterobacters, Pseudomonas aeruginosa, it was higher than 100 μg/ml, irrespective of the inocula size.
2) Distribution of MIC to 41 strains of Klebsiella pneumoniae biovar. oxytoca showed the following results. With cefazolin, it was higher than 100 μg/ml in half the strains and 1.6 μg/ml in all.With CTM, however, it exhibited a wider distribution between lower than 1μg/ml and higher than 100 μg/ml, strains with higher than 100 μg/ml being almost one quarter.
3) Concentrations of this antibiotic in serum (μg/ml), CSF (μg/ml) and CSF/serum ratio (%) were determined at the indicated time after one shot intravenous injection of 100 mg/kg in Staphylococcus aureus meningitis in 6 rabbits; 55.0, 6.6, and 12.2 (30 min), 13.3, 4.2, 31.6 (1 hr) and 2.0, 1.4, and 70.0 (2 hr), respectively. Although these values were superior to those with ampicillin, individual differences were larger than ampicillin in passage into CSF.
4) Based on the above results, it appears likely that CTM can pass into CSF more easily than other cephalosporin and penicillins. Further detailed studies will be needed to obtain the conclusion.

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Serum and skin concentrations of cefotiam (SCE-963) were determined after intramuscular injection to male Wistar rats at the dose of 20 mg/kg and compared with those of cefazolin.
Both drugs were absorbed rapidly and reached the peak levels at 15 minutes in both skin and serum concentrations. Serum and skin levels of cefotiam decreased more rapidly than cefazolin. Serum/skin concentration ratio at the peak was about 3 in both drugs.

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A single dose of 20 mg/kg of cefotiam (SCE-963)[7β-[2-(aminothiazol-4-yl) acetamido]-3--[[[1-(2-dimethylaminoethyl)-1H-tetrazol-5-yl] thio] methyl]-ceph-3-em-4-carboxylic acid] was administered subcutaneously to mice, intramuscularly to rats, rabbits, and dogs. Plasma and tissue levels of cefotiam reached the peak in 15 to 30 min. after administration. In mice, rats and dogs, cefotiam distributed at high concentration in the descending order to the kidney, liver, plasma, lung and spleen; and in rabbits, to the kidney, plasma, lung, liver and spleen. The cefotiam levels in the liver of mice, rats and dogs were higher than those of cefazolin, cephaloridine and cephalothin. The plasma and tissue levels of cefotiam in mice and rats diminished rapidly, but those in rabbits and dogs declined gradually. In dogs, the biological half. lives were 0.6 to 0.84 h. by intravenous administration of cefotiam of 2.5 to 20 mg/kg and 0.69 to 0.96h. by intramuscular administration of the same doses. Cefotiam was mainly excreted in the urine. The excretion of cefotiam in the bile was two to three times higher than that of cefazolin.

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Cefotiam (SCE-963) was administered to ten patients suffered from cholelithiasis with T-tube placed in common bile duct. Concentration in blood and excretion in bile and urine were studied.
In 7 cases to whom 500 mg of cefotiam was given intravenously, the concentration in blood showed 27.69 ±7.50 μg/ml after 30 minutes, and 1.16±0.71 μg/ml after 4 hours. The concentration in bile was 199.14 ± 116.47 μg/ml 30 minutes after injection, with peak concentration of 325.97 ±128.34 after one hour.
In 3 cases to whom 1 gram of cefotiam was given by intravenous drip infusion within an hour, the concentration in blood was 67.0-100.7 μg/ml at the end of administration.
The concentration in bile was studied too. Two out of these 3 cases revealed 281.7 μg/ml and 87.3 μg/ml at the end of administration and reached to peak one hour later and the values were 490.7 μg/ml and 436.4 μg/ml respectively.
However, in another case who had been suffered from obstructive jaundice for more than 2 weeks with persistent elevated S-GOT and S-GPT (more than 300 u), the peak concentration was 1.9 μg/ml at the end of intravenous drip infusion.
The recovery rate in urine was 50.1-85.4% after 8 hours.

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One g of cefotiam (SCE-963) was administered by one-shot intravenous injection preceding a surgery of the proximal area of the femur. The bone marrow blood was taken as a specimen and gentrifuged, then supernatant was separated and kept frozen. After thawing concentration of this antibiotic was assayed by agar-well method using Proteus mirabilis ATCC 21100 and compared with that of serum obtained at the same time of sampling.
Twenty-four cases of clinical material were examined. The most high concentration in serum was detected as high as 190.2μg/ml at ten min. after injection, at which time, that of bone marrow was 133.0μg/ml. The lowest concentration was 1.2μg/ml in serum and 1.3μg/ml in bone marrow at 180min. after injection.
Comparing the concentration of bone marrow blood with that of serum, both were almost the same level. However, it is interested that the level in bone marrow exceeded the level in serum in 23 samples among 39 samples. This is 59% in ratio. Further, this phenomenon tended to appear to late stage after injection.
It will be concluded that cefotiam can easily infiltrated into the skeletal tissue and not only suitable antibiotic agent for treatment of infections disease of bone, but also advantageous drug as particularly prophylactic use for infection at the time of surgery.

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The general pharmacological studies on the new semi-synthetic cephalosporin antibiotic, cefotiam (SCE-963), showed the following. 1The agent had no muscle-relaxant, anticonvulsant, hypnosis-potentiating, anti-inflammatory, analgesic, hypothermic, antipyretic, intestinal motility-disturbing, diuretic or antidiuretic activity in mice or rats at a subcutaneous dose of 250 or 1, 000 mg/kg. Nor was there any appreciable effect on the spinal reflex, neuromuscular junction, blood pressure, heart rate, respiration or autonomic nervous system in anesthetized cats at an intravenous dose of 250 mg/kg, The blood pressure of anesthetized monkeys, rabbits, guinea pigs or rats was hardly affected by the intravenous administration of cefotiam 300 mg/kg, but that of anesthetized and unanesthetized dogs was markedly depressed by the intravenous administration of cabotiam 100 mg/kg or higher. In anesthetized dogs, the hypotension started with a marked rise in the portal vein pressure but not in the central vein pressure ; the blood flow in the common carotid artery increased markedly and the ear temperature rose. Repeated administrations caused diminishing responses, and a slow intravenous infusion of cefotiam 100 mg/kg over a period of 60 minutes (1.67 mg/kg per minute), produced no effect on blood pressure. The depressor response to cefotiam was not blocked by pretreatment with atropine but reduced by that with antihistaminics. The results on the cardiovascular effects of the agent indicate that the hypotension is species-specific to the dog and is due to a release of endogenous histamine. In unanesthetized, paralyzed cats, cefotiam at an intravenous dose of 100 mg/kg produced spikes and at 250 mg/kg seizure discharges in the electroencephalogram ; these effects were similar in action and potency to cefazolin. In in vitro experiments, no effect on spontaneously beating atria of guinea pigs or various smooth muscle preparations was found at a concentration of 100 μg/ml.

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Cefotiam (SCE-963) is a new cephalosporin derivative with a broad antimicrobial spectrum and its activity against gram-negative bacteria is more potent than other cephalosporin antibiotics such as CET, CEZ and CER. Its subacute and chronic toxicity was examined in rats, dogs and monkeys and the results are summarized as follows:
1. In rats which were treated intramuscularly with high doses for 1 or 6 months, there were slight to moderate local lesions at the injection sites and, perhaps related, anemia and a decrease in serum albumin. A minimal increase in SGPT and/or SGOT was also seen in some of these animals but none of them showed treatment-related histopathological changes in the liver. There was a dose-related increase in weights of the kidney and, histologically, a prominence of lysosomes in the proximal tubular epithelium. However, no degenerative change was seen in these epithelial cells and the prominence of lysosomes disappeared after a 1-3 months recovery period.
The rats which received intramuscular dosing of CET at 1000mg/kg/day showed similar pathological changes and a similar process of recovery as those treated with the same dose of cefotiam.
2. In beagle dogs treated intramuscularly with high doses for 1 month, local lesion and related changes similar to those in the rat study were seen. Prominence of lysosomes in the kidney was also revealed in this and other dog studies (iv, 1 and 6 months). Species-specific changes in the dog were transient flush and/or swelling of the skin due to vasodilation at the time of injection. A separate examination revealed that mast cells of the dog are particularly susceptible to the agent and that their histamine-containing granules are released after each treatment with cefotiam at high doses.
3. Nephrotoxicity of cefotiam was found in cynomolgus monkeys at 1000mg/kg intramuscular and intravenous 1-month dosings. Some of the animals were sacrificed due to a moribund condition during the dosing period. Histopathological examination of these monkeys revealed degeneration (and regeneration) of proximal tubules in the kidney and, in some cases, a slight change in the liver such as accumulation of fat or brown granules in hepatocytes. At 300mg/kg (im or iv), a slight change in the kidney was seen in some of the animals.
Intramuscular dosing of CET at 1000mg/kg/day induced the similar pathological changes in monkeys as that of cefotiam at the same dosage.
4. From these results, it was concluded that toxicity of cefotiam was quite comparable to that of CET and that its maximum non-toxic dose in these animals was at least 100mg/kg/day.

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A total of 26 normal adult volunteers were given cefotiam (SCE-963) in a single dose of 125, 250 and 500mg i.m.; twice a day at a 6-hour interval with each doses of 250mg i.m. for 2 and 5 days; in a single dose of 500mg by i.v. drip infusion ; twice at a 6-hour interval with doses of 500mg and 1000 mg by i. v. injection as a bolus and twice at a 6-hour interval with each dose of 2000mg by i. v. drip infusion to study the safety and the absorption and excretion of drug:
(1) No significant changes were noted as to subjective and objective symptoms, blood pressure, heart rate, respiratory rate, ECG and hematological examinations. The pain at the site of intramuscular injection was mild and neither swelling nor induration was observed.
(2) The only finding that was caused by the administration of cefotiam was an apparent elevation of the serum CPK, though within normal range, following intramuscular injection of 500mg, suggesting a damage to the muscle at the site of injection. It would, therefore, be advisable to avoid consecutive intramuscular injections of 500mg at one site.
(3) In the subjects receiving two doses of 2000mg by i.v. drip infusion, urinalysis showed traces of protein two to four hours after the start of the infusion, associated with a tendency toward very mild, transient increases in hyaline casts and white blood cells in the urinary sediments. In one of these subjects, S-GPT was elevated above the normal range two weeks after the infusion. These abnormalities could not immediately be related to the administration of cefotiam, but it appears necessary to pay attention to the effects of the drug on kidneys and liver when large doses are repeated.
(4) Cefotiam, when administered intramuscularly, was rapidly absorbed, reaching its maximum serum levels in 0.5-1 hour. The maximum serum level was about 10μg/ml after 250mg about 20μg/ml after 500mg i. m. and also after i. v. drip infusion of 500mg over 2 hours, and about 80μg/ml after i.v drip infusion of 2000mg over 1 hour. The serum levels were about 65μg/ml and 115μg/ml five, minutes after 500mg i.v. and 1000mg i.v., respectively. Thus, the serum levels were high in proportion to doses with the same route of administration. The biological half-life was about 0.8 hours in every case, the serum level falling below 1μg/ml six hours after the administration. The 24-hour urinary excretion rates remained in the range of from about 70 to 80% in all cases and the major portion was excreted within six hours giving very high urinary levels.
With the administration routes and doses studied, repeated administration of cefotiam at a 6-hour interval did not given rise to a tendency for drug accumulation in the body.

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A phase I study on cefotiam (SCE-963), a new injectable cephalosporin, was carried out on total 15 healthy adult volunteers. Cefotiam was administered in a single shot at doses of 125, 250 and 500 mg intravenously (i. v.), 1000mg/2 hr. by intravenous drip infusion (i. v. d.), twice 1000 mg/30min. i. v. d. at a 6-hour interval and 2000 mg/lhr. i. v. d. 1000 mg cefotiam/2hr. i.v.d. study was performed following double blind crossover design against physiological saline solution for comparison.
Subjective and objective symptoms, blood pressure, heart rate, ECG, respiratory rate, hematological examination, blood chemistry tests, urinalysis were examined before and after administration at regular time intervals for attesting the safety of the drug. Serum concentrations and urinary excretion of cefotiam were also examined.
1. As to subjective and objective symptoms as well as other test results including liver and renal function tests, no significant change attributable to the drug were noted.
2. High serum concentration of cefotiam in proportion to the administered doses was obserevd. Elimination of the drug was rapid and its biological half-life was about 40 minutes in i.v. administration. 65-70 % of the administered doses was excreted into the urine by 6 hours after the administration, giving urinary high concentration. Following excretion, however, was scanty. Two repeated doses of 1000 mg/30min. i.v.d. at a 6-hour interval did not show any tendency of the drug accumulation in the body.

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Cefotiam (SCE-963), a new cephalosporin antibiotic, has been investigated to give the following results.
As to the pharmacokinetics, serum concentrations and urinary recoveries of cefotiam were measured in 6 healthy male volunteers following intravenous administration of 500 mg. The mean serum concentration was 25.3μg/ml after 15 minutes, 11.7 after 30 minutes, 4.4 after 1 hour and 1.45 after 2 hours, respectively. The mean half life in blood was 0.72 hour. Urinary recovery was 78.8% within 6 hours. The serum concentration and the half life in blood in 3 patients with mild renal impairment was determined following 500 mg of intravenous administration. The serum concentration was higher than normal volunteers and the half life was 1.03 to 1.15 hours.
As to the clinical evaluation, 34 patients with various infections (14 respiratory, 5 biliary and 15 urinary tract infections) were treated with cefotiam in daily doses of 1 to 4 g for 7 to 16 days. Clinical responses were excellent in 9 cases, good in 17, fair in 6 and poor in 2. The effective rate was 76 5%. As for the bacteriological effect, organisms disappeared in 23 of 34 cases, and the rate of disappearance was 67 6%.
No side effect was observed clinically. On the laboratory finding, GOT elevation in 3 cases and both GOT and GPT elevation in 1 case were observed.

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Cefotiam (SCE-963), a new cephalosporin antibiotic, was given to 6 cases with respiratory tracd infections (4 pneumonia including 1 PAP, 1 bronchiectasis and 1 pulmonary abscess). Dosage of cefotiam was 1.0-3.0 g twice a day by intravenous drip infusion.
Clinical responses were excellent in 3 cases, good in 1 and failure in 2 (PAP and bronchiectasis).
Skin test for hypersensitivity to cefotiam demonstrated no positive reactions but itching was observed as a side effect in 1 case.

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To evaluate the clinical efficacy of cefotiam (SCE-963), the treatment was made with the drug in 16 patients including 1 with pulmonary abscess, 5 with acute pneumoniae, 2 with cholecystitis and 8 with tuinary tract infections. Responses were excellent in 7 patients and good in 9. All cases with acute pneumonia satisfactorily responded to the treatment.
The MICs of cefotiam against in E. coli and Kiebsiella, which were isolated from urine and duodesal juice of patients with cystitis, pyelitis and cholecystitis, were considerably lower than those of cefasolin and cephalothin.
Side effect noted was GOT and GPT elevation in 1 patient.

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The antibacterial activity of cefotiam (SCE-963) was measured by MIC (Standard Method of Japanese Society of Chemotherapy) against many kinds of strains isolated from clinical materials. Clinically, cefotiam was administered intravenously or intramuscularly at daily dose of 1-3 g for 8-23 days to two cases of respiratory tract infections and one case of sepsis.
1) MIC of cefotiam against clinical isolates of Staphylococcus aureus, Klebsiella pneumoniae and Escherichia coli were in the range of ≤0.20-0.78 μg/ml (Inoculum size of 10⁶ cells/ml).
2) Serratia marcescens and Pseudomonas aeruginosa were not susceptible to cefotiam.
3) Clinical response to treatment with cefotiam was excellent in a case with pneumonia, poor in a case with primary atypical pneumonia and good in a case with sepsis.
4) No side effect was observed.

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Laboratory and clinical investigations on cefotiam (SCE-963) were performed and the results were obtained as follows;
1) Susceptibility of clinically isolated strains to cefotiam was tested by agar plate dilution method. Minimum inhibitory concentrations (MICs) of cefotiam against 64 strains of Klebsiella and 61 strains of Haemophilus influenzae were 0.2 μg/ml (70.3%) and 0.78 μg/ml (75.4%) respectively. And MICs of cefotiam against three β-lactamase-producing ABPC-resistant strains of Haemophilus influenzae were very excellent values, which were 0.29 μg/ml, 0.78 μg/ml and 3.13μg/ml.
2) Nine out of 11 patients with respiratory tract infections (Klebsiella 2 cases, Staphylococcus 2 cases, Haemophilus influenzae 7 cases) showed effective clinical results. The effect of cefotiam on the acute exacervation of chronic bronchiolitis due to β-lactamase-producing Haemophilus influenzae was remarkable.
3) Transient leukopenia was found in 2 cases.

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Antibacterial activity and clinical effect in respiratory tract infection on cefotiam (SCE-963) were studied with following results.
1. Antibacterial activity
1) The antibacterial activity of cefotiam against Klebsiella pneumoniae was two-fold more potent than cefazolin (CEZ), four to five-fold than cephalothin (CET), and one-fold than dibekacin (DKB).
2) The antibacterial activity against Klebsiella ozaenae was three to five-fold more potent than CEZ or CET.
3) The antibacterial activity against Enterobacter aerogenes was four-fold more potent than CEZ or CET.
4) Against Enterobacter cloacae, cefotiam showed good MIC when inoculum size was small.
5) Against Escherichia coil, it showed three to five-fold more potent activity than CEZ or CET.
6) Against Staphylococcus aureus, the antibacterial activity was similar to CEZ or CET.
2. Clinical responses
Cefotiam was given in daily doses of 2.0g to 18 cases with respiratory tract infections consisted of 3 cases with suppurative lung infection, one case with mycoplasma pneumonia, 9 cases with acute pneumonia, 3 cases with secondary infection complicated in chronic lung disease, and 2 cases with secondary infection complicated in lung cancer. Clinical responses were excellent in 10 cases, good in 4, fair in 2 and poor in 2 with efficacy of 77.8%(14 out of 18 cases).
Bacteriological study in 17 strains of isolates including 8 strains of gram-negative bacteria resulted in 13 strains of disappearance and 4 strains of persistence. Out of 18c ases, 3 cases showed elevation of transaminase, However, it was returned to nomal limit during or after completion of administration.

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Cefotiam (SCE-963) was given to 19 patients with urinary tract infections and 1 patient with bronchopneumonia in daily doses of 0.5-2g for 5-14 days. Responses were good in 13 patients, fair in 1 and poor in 6. Eight patients out of 11 with chronic urinary tract infections showed satisfactory citnical responses.
Seven strains out of 10 isolates of E. coli, 2 out of 3 Streptococcus faecalis, 1 out of 2 Proteus mirabilis, 1 out of 2 Klebsiella and 1 isolates of Enterobacter were eradicated by cefotiam therapy.
As side effects, exanthem was observed in 2 patients and transient elevation of GPT and blood platelets was noted.

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Basic and clinical investigations on cefotiam (SCE-963), a new cephalosporin antibiotic were performed and the following results were obtained.
1. The sensitivity of a variety of gram-negative bacilli isolates from clinical specimens against cefotiam exceeded in comparison with that of cefazolin.
2. In the groups of rats injured liver acutely or chronically with CCl₄, serum level was somewhat lower than the healthy control, showing higher urinary excretion than that. Biliary excretion of the group acutely injured decreased comparing with chronically injured and control groups.
3. Cefotiam was administered to five patients with a variety of infectious diseases. Two patients showed good responses and the others failed to respond. No side effect was noticed.

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Antibacterial activities, absorption and excretion and clinical responses on cefotiam (SCE-963) were studied to give the following results.
1. In vitro antibacterial activities
Antibacterial activities of cefotiam against clinically isolated E. coli and K. pneumoniae were 4-8 times as potent as those of cefazolin. Six strains out of 10 isolates of S. marcescens were susceptible to 50 μ g/ml or less of cefotiam.
2. Absorption and excretion
After i.v. administration of 250mg, serum levels reached 33 μ g/ml within 5 minutes and declined with a half-life of 0.66 hours. Levels of cefotiam in urine for first 1 hour after administration was 720 μ g/ml, and 6 hour urinary recovery was 60%.
3. Clinical responses
Twenty patients with respiratory tract infections, biliary tract infections and urinary tract infections were treated with cefotiam. Responses were good in 13 patients, fair in 3, poor in 3 and unassessable in 1. Side effects noted were eruption in 1 patient and GOT elevation in 2 patients. Eruption disappeared 3 days after cessation of dosing. The relation of GOT elevation and drug administration was not clear.

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Basic and clinical studies on cefotiam (SCE-963) were carried out and the following results were obtained.
1) In vitro antibacterial activities
Antibacterial activities of cefotiam against clinical isolates of E. coli and Klebsiella were potent and especially, with smaller inoculum, its activities were prominent.
2) Absorption and excretion
Three healthy adults were given 1 g of cefotiam by i.v. drip infusion over 1 hour. The same subjectswere also given 1 g and 2 g of cefazolin and pharmacokinetic parameters were calculated. The serum level of cefotiam was lower than that of cefazolin and the half-life of cefotiam in serum was shorter. However, the volume of distribution of cefotiam was larger than that of cefazolin. The mean 6-hour urinary recovery of cefotiam was 67%.
3) Clinical responses
Four patients with respiratory tract infections, 4 patients with urinary tract infections and 2 patients with biliary tract infections were treated with cefotiam. Of them, 9 patients showed good responses to therapy. The optimum dosage of cefotiam was considered 1-2 g per day in 2 divided doses. No side effects were observed.

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In the basic and clinical studies on cefotiam (SCE-963), a newly developed cephalosporin, the following results were obtained.
1) In vitro antibacterial activities of cefotiam against clinically isolated S. aureus, E. coli, Klebsiella, Proteus mirabilis and Enterobacter cloacae were compared with those of cefazolin Cefotiam showed more potent antibacterial activities than cefazolin against gram-negative bacilli. S. aureus were, however, as susceptible to cefotiam as to cefazolin. MICs of cefotiam were varied with inoculum sizes, while those of cefazolin were less influenced by inoculum sizes.
2) Serum level, urinary recovery and biliary recovery of cefotiam were determined in one case with cholecystectomy. After 1 g i. v. drip infusion over 2 hours, serum level reached 40μg/ml. Urinary recovery for 6 hours after administration was 76.5%. Biliary recovery for 6 hours was 0.1% and peak bile level reached 20.4μg/ml.
3) Four cases with respiratory tract infections, 5 with urinary tract infections and one with cholangitis were given cefotiam in daily doses of g for about 2 weeks. 50% of the cases with respiratory tract infections and all cases with other infections showed good clinical responses to therapy.
4) No side effects were observed.

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Cefotiam (SCE-963), a new cephalosporin, was evaluated in five elderly patients (two with urinary tract infection, two with cholangitis and one with septicemia). All but a patient with septicemia had some compromized defense mechanisms.
Two patients with UTI and one with cholangitis showed satisfactory clinical responses, Septicemia was eradicated by combination of cefotiam and amikacin. No adverse effect was noted.

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1. Cefotiam (SCE-963) was given to 4 aged patients with respiratory tract infections caused by Streptococcus pneumoniae, Haemophilus influenzae and Proteus mirabilis, which were resistant to other antibiotics. All patients satisfactorily responded to therapy with cefotiam.
2. The optimum dosage of cefotiam was considered to be lg twice a day by i.v. drip infusion.
3. Side effects noted were leukopenia and eosinophilia in 1 patient. The abnormal laboratory findings were normalised immediately after finishing treatment.

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1. Antimicrobial activity of cefotiam (SCE-963) against clinically isolated S. aureus, E. coil, Klebsiella and Enterobacter was compared with that of cefazolin (CEZ) and cephalothin (CET). As the result, cefotiam showed better antimicrobial activity against E. coli, Klebsiella and Enterobacter than CEZ and CET.
2. Cefotiam was administered to 13 cases including pneumonia (7 cases), pyelonephritis (4 cases), bacteremia from cholecystitis (1 case) and bacteremia from liver abscess (1 case). The clinical results were as follows: excellent in 6, good in 3 and fair in 4 cases.
3. No side effect was found including laboratory findings of urine, peripheral blood, renal and hepatic functions.

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Bacteriological and clinical studies on cefotiam (SCE-963), a new cephalosporin antibiotic, were carried out and the following results were obtained.
1. In vitro antibacterial activities of cefotiam were more potent than cefazolin against clinical isolates of E. coil and K. pneumoniae.
2. Five patients with respiratory tract infections and 3 with sepsis were treated with cefotiam. One patient with infectious bronchial asthma and 1 with sepsis showed good clinical response. The other patients failed to respond to the therapy.
3. No side effects were observed and no abnormal findings were demonstrated with laboratory tests.

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Clinical application of cefotiam (SCE-963) was attempted in nine patients with various infections.
In four patients with respiratory infection (one with acute exacerbation of chronic tonsillitis and three with pneumonia), therapeutic effects of cefotiam were excellent in one patient, good in two, and fair in one.
In both of two patients with complicated urinary tract infection, clinical responses were good. Regarding 3 patients with cholecystitis including two accompanying septicemia (case 5 and 6), the first patient (case 5) with septicaemia due to E. coil (MIC of cefotiain: 0.1μg/ml) responded excellently to therapy with cefotiam in i.m. doses of 1 g every 8 hours. The second patient (case 6) with septicaemia due to Klebsiella (MIC of cefotiam: 0.39μg/ml) also showed good response to cefotiam therapy by i.v. drip infusion of 2 g every 8 hours, though the patient failed to respond to i.m. administration of 1 g of cefotiam and concomitant use of 60 mg of tobramycin every 8 hours. In the third patient (case 7), good response was obtained by i.m. injection of 1 g of cefotiam every 8 hours.
No side effects were observed in any of the cases.

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1) Clinical pharmacological studies of cefotiam (SCE-963) were conducted in patients with various renal function. The serum concentrations of cefotiam in the patients 1, 3, 5, 8 and 24 hours after an intravenous injection of 1000mg are shown in Table 1 and Fig. 1. The serum half-lives of cefotiam were 0.5 hour (Ccr 76.3 ml/min.), 0.8 hour (Ccr 50.6 ml/min.), 1.8 hours (Ccr 28 ml/min.), 8 hours (Ccr less than 5 ml/min.) and 1.5 hours (Ccr less than 5 ml/min., during hemodialysis).
2) Cefotiam was used in 13 cases. The results are shown in Table 2 and 3. Two cases (Case 1, 3) were proved to be tuberculosis and one case (Case 5) was considered to be too serious to be evaluated for drug effect. These three cases (Case 1, 3, 5) were excluded from the effect evaluation. Clinical effects were excellent in 1 case, good in 5 cases, fair in 1 cases, and poor in 3 cases As a side effect, eosinophilia was observed in 1 case (Case 9).

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Laboratory and clinical investigations were carried out on cefotiam (SCE-963), a semisynthetic cephalosporin antibiotic, and following results were obtained.
1. Cefotiam exhibited a wide-spectrum growth inhibitory action against gram-positive cocci and gramnegative bacilli, and its antibacterial activity was stronger than those of cephalothin and cephaloridine against E. coli, Klebsiella and Proteus.
2. The antimicrobial activity of cefotiam against Klebsiella and Proteus seems to be decreased by increasing the inoculum size.
3, Cefotiam was administered by intravenous drip infusion to 13 patients with respiratory tract infections and 7 patients with urinary tract infections. Responses were excellent in 1 patient and good in 9 out of 13 patients with respiratory tract infections, and excellent in 2 and good in 3 out of 7 patients with urinary tract infections.
4. As a side effect, eosinophilia was observed in 2 patients a week after the start of cefotiam administration.

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Three patients with acute leukemia developed septicemia due to E. coli or Klebsiella or both during remission-induction therapy. They were promptly placed on cefotiam (SCE-963)(1 gram 4 times a day by 2-hour intravenous infusion) in combination with gentamicin or amikacin. The 2 patients who achieved complete remission of acute leukemia made a rapid recovery from septicemia, while the other one with E. coli septicemia died on the 4th day of such therapy because of the severity of the underlying disease. Cefotiam proved to be more active against the causative organisms isolated from the blood than cefazolin. It was suggested that in E. coli and Klebsiella septicemia associated with acute leukemia the therapeutic efficacy of cefotiam may compare favorably with that of cefazolin.

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Laboratory and clinical studies on cefotiam (SCE-963) were carried out and the following results were obtained.
1. The biliary excretion of cefotiam in the perfusing isolated liver of rat was strikingly higher than other cepharosporins (cephalothin, cephaloridine, cefazolin, cephacetrile, ceftezol, cephalexin, cephradine, cefatrizine).
2. Cefotiam was given to 6 patients with moderate or severe biliary tract infection (5 patients) and respiratory tract infection (1 patient). Responses were excellent in 2 patients, good in 3 and poor in 1, As a side effect, anemia was observed in 1 case.

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Celotiam (SCE-963), a new cephalosporin derivative developed by Takeda Chemical, was examined on its antibacterial activity, as well as on its distribution in rats. Some clinical trials were also carried out. The results obtained were as follows:
1) Antibacterial activity: The MIC distribution of cefotiam against clinical isolates of S. aureus was similar to cephaloridine, cephalothin, and cefazolin. Clinical isolates of E. coli were found to be much more sensitive to cefotiam than to other cephalosporins, especially when the inoculums were diluted to 10⁶ cells/ml. Out of thirteen strains of Klebsiella only one was highly resistant (MIC≥100 μg/ml) to cefotiam
while four to cefazolin, six to cephalothin, and seven to cephaloridine. Although MIC of cefotiam against Proteus mirabilis were distributed in a wide range (0.1-100 μg/ml), most of them shifted to lower concentrations (0.1-0.4 μg/ml) by diluting the inoculum to 10⁶/ml. Similar phenomenon was also observed on the s ensitivity of P. vulgaris and P. rettgeri, but these strains were essentially insensitive to the drug.
2) Tissue concentrations in rats: Tissue levels of cefotiam after i. m. administration of 10 mg/kg rankedin order of kidneys, liver, serum, lungs and spleen. The drug was undetectable in muscles as well as in the brain. In vitro recovery of the drug from organ emulsions of rats was found to be almost 100%.
3) Clinical trials: Nine patients with infections (4 with U. T. I., 3 with pulmonary infections, 1 with cholecystitis, and another with F. U.O.) weie treated with the drug. Five of the patients well responded to the therapy. Although no severe side effects were observed, rash was encountered in two of the patients, and disorder of liver function was observed in two of them.

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1. In vitro antibacterial activities
Cefotiam (SCE-963) showed more potent antibacterial activities against clinically isolated E. coli, K.pneumoniae and P. mirabilis than cefazolin, cephaloridine and cefmetazole. Cefotiam was, however, less active against P. vulgaris and S. marcescens than cephamycin antibiotics.
2. Experimental infections
Cefotiam was effective against experimental pneumonia caused by K. pneumoniae in mice. Daily doses of 120mg/kg divided into 3 were more effective than single daily dose of 120mg/kg.
3. Absorption and excretion
Peak serum level of 27.0μ/ml appeared at the end of lg i.v. drip infusion over 2 hours. Six-hour urinary recovery was 69%.
4. Clinical responses
Cefotiam was given to 8 patients. Responses were good in 3 patients, fair in 1, poor in 3 and unassessable in 1. No side effects were observed.

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Cefotiam (SCE-963), a new cephalosporin antibiotic, was administered intravenously to the patients with respiratory tract or urinary tract infections in daily doses of 2.0 to 4.0 g and their clinical responses were investigated.
All the 9 patients had the underlying diseases other than the infections. Good clinical responses were obtained in 2 of 7 cases with respiratory tract infections and in one of 2 cases with urinary tract infections.
Side effects noted were skin eruption in a case with acute bronchitis and bronchial asthma, but improved by be cessation of the drug and administration of β-methasone.
Cefotiam is seemed to be a effective antibiotic for the respiratory tract as well as urinary tract infections if it was administered to appropriate patients.

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Basic and clinical studies were carried out on cefotiam (SCE-963), a new cephalosporin antibiotic.
1) In vitro antibacterial activities
MICs of cefotiam against various clinical isolates were determined. With 10⁶cells/ml inoculum size, MICA against Staphylococcus aureus distributed from 0.78 to 1.56μg/ml. None of isolates of Streptococcus faecalis were susceptible to 25 μg/ml. Most isolates of E. coli were susceptible to 12.5 μg/ml or less. Almost all of strains of Klebsiella pneumoniae were susceptible to 6.25 μg/ml or less. None of isolates of Enterobacter, Serratia marcescens and Pseudomonas aeruginosa were susceptible to 100 μg/ml. MICs of cefotiam with inoculum size of 10⁶ cells/ml were considerably lower than those with 10⁸ cells/mi. Antibacterial activities of cefotiam against gram-negative bacilli were more potent than those of cefazolin and cephaloridine.
2) Absorption and excretion
Three healthy adults were given 1 g of cefotiam intramuscularly. Peak serum level of 33.1 μg/ml occurred 30 minutes after administration and this declined 2.7 μg/ml 4 hours after dosing. The same subjects were given 1 g of cefotiam by i.v. drip infusion over 1 hour. Serum level reached 40.0 μg/ml as peak at the end of drip infusion and it was 4.2, 0.8 and 0.2 μg/ml at 2, 4 and 6 hours after the end of infusion, respectively. Mean 6-hour urinary recovery was 66% by i.m. administration and 64% by i.v. drip infusion.
3) Clinical responses
Two patients with sepsis, 5 with bronchopneumonia and 3 with acute pyelonephritis were treated with cefotiam in daily doses of g for 2-21 days. Responses were good in 5, fair in 1, poor in 3 and unassessable in 1. All patients with urinary-tract infections and 2 with respiratory infections showed good responses, while patients with sepsis failed to respond to therapy. Side effects noted were slight GOT and GPT elevation in 2 patients.

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Cefotiam (SCE-963) is a newly developed broad spectral cephalosporin which is reported to be stable to β-lactamases. Clinical and laboratory investigation on this drug was carried out and the results were as follows:
1) Antibacterial activity
Susceptibility of 22 standard strains and 803 clinical isolates (Staphylococcus aureus 54, Salmonella spp. 36, Citrobacter freundii 38, C. amalonatica 10, Escherichia coli 53, Shigella spp. 45, Kkbsiella aerogenes 53, Enterabacter aerogenes 54, E. cloacae 54, Serratia marcescens 54, Proteus vulgaris 12, P. mirabilis 41, P.rettgeri 22, P. inconstans 16, P. morganii 43, Pseudomonas aeruginosa 54, P. putida 30, P. maltophilia 33, P. putrefaciens 14, Flavobacterium spp. 50 and Acinetobacter anitratus 7) were tested to cefotiam in comparison with cefazolin (CEZ) by using plate agar method. The inoculum size was 10⁶ CFU/ml. Cefotiam and CEZ had almost same activity against gram-positive standard strains. MIC, s of cefotiam against gram-negative standard strains except for P. aeruginosa were about 2 times lower than those of CEZ.
In regards to the clinical isolates, against Stabhylococcus aureus, CEZ had more active than cefotiam. Cefotiam was 2 to 4 times more active than CEZ against Salmonella spp., C. freundii, C. diversus, E. aerogenes, P. mirabilis, P. inconstans and P. putrefaciens. Against C. amalonatica, E. cloacae, S. marcescens, P. vulgaris, P. rettgeri, P. morganii, P. aeruginosa, P. putida, P. maltophilia, Flavobacterium spp. and A. anitratus, both drugs had almost same activity.
2) Serum levels in man.
A 52-year-old male and a 58-year-old female patients having normal renal function were administered 1 gram of cefotiam by intravenous drip infusion over one hour. Peak serum levels were 30 and 56 Pgiml at the end of infusion respectively. Six hours after injection, 2 or 3μg/ml of drug was detected.
Two grams of cefotiam was injected to a 64-year-old male patient and a peak serum level was 60μg/ml at the end of infusion. At 6 hours after injection, serum level was 4 μg/ml.
3) Urinary recovery in man Urinary recoveries of cefotiam after intravenous drip infusion at a dose of 1-2 grams were 50-60% within two hours and 64-70% within 6 hours after injection.
4) Sputum level of cefotiam and transition of bacteria in sputum
A patient with cystic bronchiectasis infected with E. coli was administered 1 gram of cefoiam intravenously. A peak sputum level of 0.2 μg/ml was assayed five hours after injection. Viable count of E. coli, which was 10⁷/ml in number initially, decreased to about 10⁵/ml 8-9 hours after the start of treatment. E. coli was not eliminated from the sputum in spite of 7-day treatment. MIC of cefotiam against E. coli isolated from sputum was 0.4-0.78μg/ml.
5) Clinical evaluation and adverse reaction
Twenty-one patients (pneumonia 10, bronchiectasis 1, pulmonary abscess 2, chronic bronchitis, 1, P.T.B. 1, acute pyelonephritis 3, chronic pyelonephritis 1, acute cystitis 1 and cholecystitis 1, ) were treated with cefotiam in doses of 0.5-2.0 grams 1-2 times per day for 4-16 days parenterally. Out of twenty patients, 18 showed satisfactory responses. One patient had a slight elevation of serum transaminase, but value of transaminase became normal with continuation of therapy.

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The laboratory and clinical studies on cefotiam (SCE-963), a new derivative of cephalosporin, were performed with following results.
1) Antibacterial activities against respiratory pathogens were measured as the MIC values. MIC values against 61 strains of Streptococcus pneumoniae ranged from 0.013 to 0.20μg/ml, being slightly superior to cefazolin. MICs against 55 of 57 strains of Haemophilus influenzae ranged 0.20 to 0.78 μg/ml, and 2 strains of β-lactamase non-productive ampicillin-resistant Haemophilus influenzae were resitant to cefotiam (MIC: 12.5μg/ml). But 6 strains of β-lactamase productive ampicillin-resistant Haemophilus isolated in England were sensitive to cefotiam (MIC: 0.39μg/ml). MICs against 19 strains of Klebsiella pneumoniae ranged from 0.10 to 0.20 μg/ml, and against 7 strains of E. coli ranged from 0.05 to 0.39μg/ml. Cefotiam is 32 times as active as cefazolin against these gram-negative bacilli.
2) After intramuscular administration of cefotiam 20 mg/kg in rats, tissue concentrations reached peak value in 15 minutes. Tissue levels in order of concentrations were in kidney, liver, serum and lung. The drug disappeared rapidly from serum.
3) In 6 healthy adults, serum levels and urinary recovery of cefotiam were measured after 1. v. instillation comparing with cefazolin. After i.v. instillation of 1 g dose over 1 hour, serum peak level of cefotiam was 47.0 μg/ml and that of cefazolin was 77.0μg/ml, and half lives in serum were 47 minutes and 91 minutes. But the ratios of serum levels of cefotiam to the median values of MICs of cefotiam against respiraotry pathogens were extremely higher than those of cefazolin.
4) The kinetics of the transport of cefotiam into respiratory tract was studied in 7 patients (acute bronchitis; 1, pneumonia ; 1, chronic bronchitis ; 5). The ratios of sputum peak levels of cefotiam to serum peak levels were 2.3 to 10.5%(mean; 4.6%), and this value is higher than those of other cephalosporins.
5) Fifty-eight patients with respiratory tract infections (acute pneumonia; 41, acute bronchitis; 2, chronic bronchitis; 8, chronic bronchiolitis; 1, bronchiectasis; 1, lung abscess; 4, empyema; 1) were treated with cefotiam 0.25 g to 2.0 g b.i.d. for 3 to 45 days. The clinical responses were excellent in 11 patients, good in 38, fair in 3, poor in 4, and undecided in 2 patients. In 51 patients administered cefotiam 1 or 2 g as a daily dose, the clinical effectiveness was 92%.
6) Mild eosinophilia was observed in a patients in whom eosinophilia had occurred three times by penicillins. Another patient with Grawitz's tumor complained of nausea and chest pain after i.v. instillation of cefotiam but it was difficult to decide the cause of them because of the severity of underlying disease.
From above results, it is concluded that cefotiam is superior to other cephalosporins on the market, and that cefotiam should be one of the first choice for respiratory tract infections.

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1. In vitro antibacterial activities
Antibacterial activities of cefotiam (SCE-963) against clinically isolated S. aureus was slightly weeker than that of cefazolin. However, cefotiam showed more potent activities than cefazolinagainst E. coli, K. pneumoniae, Proteus and Serratia.
2. Clinical responses
Cefotiam was given to 12 patients with respiratory tract infections. Responses were excellent in 3 patients, good in 5, fair in 3 and poor in 1. No side effects were observed and no abnormal findings were demonstrated with laboratory test.

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Efficacy and safety of cefotiam (SCE-963) 2g/day and cefazolin 4g/day in the 14-day treatment of bacterial pneumonia and pulmonary suppuration were compared by a randomized, double-blind method.
1) Treatment was done on 122 patients in total, 59 on cefotiam and 63 on cefazolin.
2) The overall therapeutic efficacy of cefotiam and cefazolin was 94% and 74%, respectively. Cefotiam was significantly superior to cefazolin (p<0.01).
3) Cefotiam showed significantly better bacteriological effect than cefazolin (p<0.05).
4) The judgement of clinical usefulness significantly favored cefotiam over cefazolin (p<0.05).
5) The incidence of side effects was less by the cefotiam treatment (6 cases) than the cefazolin treatment (14 cases).
The results indicate that cefotiam is more useful for therapy of bacterial pneumonia and pulmonary suppuration than cefazolin.

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Clinical studies were made on 24 patients including 8 postoperative wound infections, 5 postoperative infections fistulas and 11 subcutaneus abscesses. Cefotiam (SCE-963) was given in daily doses of 1.0-4.0g by intravenous administration for 5-12 days.
Clinical responses were excellent in 20 cases, good in 1 case and fair in 3 cases, and the effectiveness rate was 87.5%. Thirteen patients with infections due to S. aureus satisfactorily responded to therapy in 92.3% and 8 patients due to E. coli responded in 87.5%. Two patients with mixed infections with S. aureus and E. coli showed excellent responses in 100%.
No side effects were observed.

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Basic and clinical studies on cefotiam (SCE-963) were performed and following results were obtained,
1) Antibacterial activity
Antibacterial activities of cefotiam and cefazolin was examined against E. coli and Klebsiella, and cefotiam was found to be more active than cefazolin.
2) Biliary excretion In a patient with obstructive jaundice due to cholangiocarcinoma, the biliary excretion of cefotiam was examined. Peak bile level (2.43μg/ml) appeared 2-3 hours after 250 mg Lin. administration.
3) Clinical effectiveness
Cefotiam was administered to 13 patients with surgical infections, and the results were excellent in 2 cases, good in 5, fair in 3 and poor in 3. No side effects were observed.

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Biliary excretion and clinical efficacy of cefotiam (SCE-963), a new cephalosporin antibiotic, were studied and the following results were obtained
1) In 26 cholecystectomized patients, 2 grams of cefotiam was injected intravenously, followed by determination of concentration in bile and gallbladder tissue two hours after administration. In 14 cases without obstructive cystic duct, the mean concentration in gallbladder bile was 622±132μg/Ml, and the mean concentration in the gallbladder tissue was 24.5±7.4μg/g. In 12 obstructive cases, the values were 23.7±14.8μg/ml and 11.2±5.4μg/g, respectively. The mean concentration in commn duct bile was 434.9±148.7μg/ml.
2) Bile concentration of cefotiam was compared with those of other cephalosporins by cross-over method in 6 cases. The peak bile concentration of cefotiam was 745.1μg/ml 2 hours after 2g intravenous administration.
Cefotiam showed extremely higher concentraion in bile than cefazolin, cefoxitin and cefuroxime in any time.
3) The mean recovery in bile for six hours after administration was 0.662% in cefotiam, 0.082% in cefazolin, 0.132% in cefoxitin, and 0.083% in cefuroxime. It was evidently shown that cefotiam revealed an incomparably higher excretion in bile than other cephalosporins.
4) The clinical effect was studied in 48 cases. Seven cases showed markedly effective and 30 cases showed effective with efficacy rate of 77.1%. Even among 14 cases which were non-responsive to other cephalosporins, cefotiam was effective in 10 cases (71.4%).
5) Cefotiam was given to 65 cases including prophylactic use for postoperative infection. Drug eruption and fever were observed in each one case. These adverse reactions were subsided when medication was discontinued. GOT and GPT elevated in 2 cases, but they returned to normal limits by discontinuation of the administration.

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