Cephacetrile (CEC) shows in vitro antibacterial activity against gram-positive and gram-negative bacteria as well as Cephalothin (CET), Cephaloridine (CER) and Cefazolin (CEZ). CEC exhibits stronger activity against clinical isolates of Proteus mirabilis than that of other cephalosporins. Several antibacterial features of CEC such as the influence of inoculum size, medium pH, effect of addition of horse serum, development of resistance, cross resistance, and bactericidal and bacteriolytic activity were shown to be almost identical to those of other cephalosporins. The antibacterial activity of CEC was stable in solution at pH levels of 2 to 9, especially at pH 4.
The in vivo protective activity of CEC was slightly weak than that of CEZ in mice infected intraperitoneally with certain strains of the gram-positive species, and CEC has similar activity with CET in mice infected with certain strains of the gram-negative species.

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The bacteriological evaluation was performed on Cephacetrile (CEC) using those of the known cephalosporins, Cephalothin (CET) and Cephapirin (CEP), as control.
The following results were obtained.
1) The antibacterial spectrum of CEC was similar to CET and CEP, and the antibacterial activity was slightly less potent than those of CET and CEP against gram-positive bacteria.
2) Desacetyl-7-cyanoacetamido-cephalosporanic acid (Desacety-CEC) which is one of main metabolites of CEC, showed the weaker antibacterial activity against gram-positive bacteria than that of the original substance. While lactone derivatives of Desacetyl-CEC was ineffective against both gram-positive and gram-negative bacteria.
3) The antibacterial activity of CEC against clinically isolated Staphylococci and Proteus was a little less potent than that of CET, but it was superior against E. coli.
4) CEC was stable against β-lactamase extracted from Staphylococcus. It was inactivated as well as CET by β-lactamase extracted from E. coli. As compared with CET, however, CEC seemed to exhibit a little resistance against β-lactamase extracted from E. coli.
5) In the studies with mice experimentally infected with penicillin resistant Staphylococcus, CEC was far superior to CET. With E. coli, both were similar and with Proteus, they were ineffective.

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The effect of antibacterial activity of Cephacetrile was measured against 500 strains of Staphylococcus aureus isolated from clinical materials in our laboratory. The result obtained is as follows :
The MIC values in most of the bacterial strains were within the range between 0.20 and 3. 13μg/ml. This indicates that Staphylococcus aureus has a very strong sensitivity against Cephacetrile.

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Cephacetrile (CEC), 7-cyanoacetamido-cephalosporanic acid, is a new cepharosporin active against many gram-positive and gram-negative bacteria. The antimicrobial evaluation and stability against β-lactamases were performed on CEC using Cefazolin (CEZ) and Cephaloridine (CER) as reference samples.
In in vitro experiments, antimicrobial and bactericidal activity of CEC were found to be of the same order or slighly less to CEZ and CER against P-lactamase producing strains except Escherichia coli GN 5499 possessing Rms 192⁺.
CEC showed approximately 20 and 10 times higher resistance than CEZ and CER against the β-lactamase legradation produced by Citrobacter freundii GN 346, however, no distinguish differences of hydrolysis rate in other β-lactamases were observed.
In the experiments in vivo, the chemotherapeutic trials of experimental infections of Cit. freundii in mice revealed the superiority of CEC to CER, however, the therapeutic effect of CEC against three strains of E.coli was not effective comparing with those of both drug.

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We determined the antibacterial activity of Cephacetrile, Cephalothin, Cephaloridine and Cephapirin against many strains of following various pathogenic bacteria by agar plate dilution method. We used 1, 105 strains of staphylococci, pneumococci, haemolytic streptococci, enterococci, 10 species of Enterobacteriaceae, Pseudomonas aeruginosa and 3 genera of anaerobes isolated from clinical materials in our laboratory during 1973 and the first half of 1974.
We examined and compared the antibacterial activity of Cephacetrile, Cephalothin and Cephaloridine against 1, 105 strains, but for Cephapirin we examined rather few strains of several species of pathogens.
1) For staphylococci, pneumococci and hemolytic streptococci was Cephacetrile least active among cephalosporins tested.
2) Cephalosporins were active to enterococci and Cephacetrile had almost same activity as Cephaloridine, but was less active than Cephalothin.
3) Among the bacteria of Enterobacteriaceae cephalosporins were less active to Enterobacter, Serratia, Citrobacter, Proteus morganii, Proteus rettgeri, Proteus vulgaris and Proteus inconstans excluding E. coli, Klebsiella and Proteus mirabilis. We could not find out the differences of antibacterial activity against E. coli, Klebsiella and Proteus mirabilis among Cephacetrile, Cephalothin and Cephaloridine.
4) Cephalosporins had not the antibacterial activity against Pseudomonas aeruginosa.
5) Cephalosporins have rather good antibacterial activity against Peptococcus, but have very weak activity against Fusobacterium and Bacteroides. Cephacetrile, Cephalothin and Cephaloridine have almost similar antibacterial activity against these three genera of anaerobes.

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The basic and bacteriological studies on Cephacetrile (CEC) were performed in comparison with the other cephalosporin derivatives, and the following results were obtained.
1) The sensitivities of 94% of test strains of Staph. aureus were below 0.78 μg/ml. Mean MIC of CEC tends to be greater than that of CET, CER, smaller than CEG and CEX.
The MIC of 64% of test strains of E. coli was 12.5 μg/ml, 27% was 25 μg/ml and 9% was 100 μg/ml, and these sensitivity pattern were similar to that of CET.
The sensitivities of 93% of test strains of Klebsiella were below 12.5 μg/ml. The sensitivities of 92% of test strains of Enterobacter cloacae were above 100 μg/ml, and nearly the same as CET, CER, CEG and CEX.
The sensitivities of 5 strains of Proteus mirabilis were 25 μg/ml, mean MIC of CEC tends to be greater than CET, and nearly the same as CER and CEG.
The sensitivity distribution curve of Vibrio parahaemolyticus showed similar pattern as that of CET, CER and CEG. The sensitivities of Proteus inconstans, Proteus rettgeri, Proteus morganii and Pseud. aeruginosa were above 100 μg/ml, and the same as other cephalosporin derivatives.
2) Cross resistance was observed between CEC and other cephalosporin derivatives.
3) The changes in inoculum size of Staph. aureus did not show any influence on antibacterial activity of CEC. The antibacterial activity of CEC to E. coli showed definite increase with the decrease in inoculum size.
4) The antibacterial activity of CEC to Staph. aureus and E. coli showed to be more potent at the acid side, and to be less potent at the alkaline side of culture medium pH.
5) CEC showed a considerably high bactericidal action against Staph. aureus and E.coli.
6) The antibacterial activity of CEC showed a remarkably decrease in the alkaline solution.
7) CEC solution showed red colorization in the neutral, and yellow in the alkaline side, but none in the acid at 37-40°C.
8) In the colored substance which was extracted by butanol from the colored solution of CEC, two spots of pink and violet color were observed on the plate of TLC.

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The in vitro activities of Cephacetrile (CEC) against anaerobes were determined by agar dilution method.
Anaerobic cocci were very sensitive to concentration of 3.13μg/ml or less. But many strains of anaerobic rods were relatively insensitive to CEC.
CEC was more active on acidified medium. The activities of CEC were influenced by inoculum size and basal medium.
The in vitro resistance of Peptostreptococcus anaerobius (B-30) and Fusobacterium necrophorum (S-45) developed slowly and step by step.
Among 4 strains tested of Bacteroides fragilis, only one strain, Bacteroides fragilis ss. vulgatus (2514), showed β-lactamase activity. β-Lactamase from this strain inactivated CEC and CET but not PC-G.
The chemoprophylactic and chemotherapeutic effect of CEC was demonstrated in mice with subcutaneous abscess due to Fusobacterium necrophorum (S-45).

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Distribution, fate and excretion of Cephacetrile (CEC) were investigated.
1. Serum and organ levels were rapidly declined after intravenous injection of CEC (50 mg/kg) in the rat. The kidney level was the highest and levels were in the descending order of serum, lung, heart, spleen, liver and muscle. All levels were lowered below a level of 1μg/g 4 hours after administration. Organ levels in the carbon tetrachloride-treated rat and in the E. coli inoculated rat were higher than those of the control group.
2. Total amounts excreted in urine of the rat and rabbit injected CEC intravenously were 38.48% and 52.61%, respectively. Those in the carbon tetrachloride-treated rats were larger in proportion to the doses of its administration.
3. Enzymatic hydrolysis of CEC was confirmed by the manometric technique. The rate of hydrolysis were 0.07 mmol/g/h. in the mouse liver which was considerably lower than those of CEP and CET.
4. The metabolite of CEC in the urine was identified Desacetyl-CEC. The ratios of CEC and Desacetyl-CEC excreted in the urine were 89. 1% in 0-2h. urine and 400% in 2-4h. urine. These ratios in carbon tetrachloried-treated rat were smaller in proportion to the doses of its administration.
5. In vivo formation of CGP-695 (violet-reddish pigment) was not observed in the rat which was inoculated β-lactamase producing E. coli. However, small fomation of CGP-695 was observed when the rat was injected the destructed compound of CEC by β-lactamase.
In in vitro experiment, long term incubation of CEC and CEC-insensitive E. coli produced substantial formation of CGP-695.
6. The rat fetal blood level of CEC was attained to maximum 1 hour after administration, which was lower than placental levels and slightly higher than amniotic fluid levels.
7. The rate of permeability of CEC to rabbit intestine was 54.2%.
8. Approximately 80% of CEC was bound to bovine serum proteins and albumin. Fraction to be tightly bound (rate of inactivation) was approximately a half.
9. Partition coefficients between rat lipid and buffer and those between chloroform and buffer were 0.044 to 0.30 and 0.012 to 0.248, respectively.

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Assay methods for Cephacetrile and its metabolites were studied.
1. For determination of total activity, a cup-plate method, using Bacillus subtilis ATCC 6633 as test organism, was established. Sensitivity of this method for Cephacetrile in human plasma was 0.6μg/ml. The activity of Desacetyl-Cephacetrile measured by this method was about one forth of the activity of Cephacetrile.
2. For differential assay of Cephacetrile in the presence of its desacetyl metabolite, a cup-plate method using Escherichia coli NIHJ was examined. Since the sensitivity of the method being as low as 25μg/ml, it seems not to be sufficient for general use.
3. A thin-layer chromatography-bioautography system was applied to differential assay of Cephacetrile and Desacetyl-Cephacetrile. This method could be also adapted to assay of Cephalothin and its desacetyl metabolite.
4. A violet-reddish pigment (CGP 695) formed from Cephacetrile was determined by spectrophotometry at 550 mμ in n-butanol.

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Immunological specificity of Cephacetrile (CEC) in comparison with Cefazolin (CEZ), Cephalothin (CET), Cephaloridine (CER), Penicillin G (PCG) and Ampicillin (ABPC) was examined. Like several cephalosporins and penicillins, CEC-Human Serum Albumin (HSA) antibody was obtained in the rabbits sensitized with the mixture of CEC-HSA conjugate and FREUND's complete adjuvant. From the quantitative precipitin test, hapten inhibition test, agar-gel precipitation test and passive cutaneous anaphylaxis (PCA) test, reaction between anti-CEC-HSA serum and CEC-Bovine Gamma Globulin (BGG) conjugate, immunologically specific reaction was observed, but no immunological cross-reaction was observed between CEC and other cephalosporins and penicillins. From these results it is suggested that the immunological specificity of cephalosporins seems to be dependent on the acyl side chain of the molecule.

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No nephro-and hepato-toxicity of Cephacetrile (CEC) in mice, rats and rabbits has been confirmed. Cephaloridine (CER) has a strong nephro-toxicity in the experimental animals and a nephro-toxicity of Cefazolin (CEZ) was observed in rabbits. The hepato-toxicity of CER and Cephalothin (CET) in rats were observed.

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The following conclusion could be drawn from our fundamental studies on the antimicrobial activities, absorption, excretion, and levels in various organs of Cephacetrile.
1. Antimicrobial activity
The sensitivities of Escherichia coli and Klebsiella against Cephacetrile were found to be distributed over the range 6. 25-200 μg/ml or more. Although the results were found to be slightly inferior to those of Cefazolin, they were comparable to those of Cephaloridine. Some of the bacterial strains indicating resistance to Cephalothin and Cephalexin equal to or greater than 200 μg/ml showed minimum inhibitory concentrations of 6.25-50 μg/ml to Cephacetrile.
2. Serum concentration and urinary excretion
The peak of the serum concentration of Cephacetrile, following an intravenous injection of 1 g, reached a level as high as 100 μg/ml with serum dilution. Its blood level was lowered therafter relatively quickly with a half-life of 0. 63-0.86 hours. On the other hand, the serum level following its intramuscular injection in the same dose indicated a peak of 25.0-27.5 μg/ml with serum dilution, and its subsequent serum level indicated a trend towards an even slower drop in serum concentration in comparison with that of its intravenous injection. These results may be claimed to represent higher serum levels than those obtained with the same dose of Cephalothin. The serum levels of Cephacetrile with dilution by phosphate buffer, however, remained approximately half of those with serum dilution in both intravenous and intramuscular injection.
The urinary excretion of this drug following its intramuscular or intravenous injections reached a maximum level of more than 1, 000 μg/ml, and the recovery rate from urine, up to 6 hours, amounted to a relatively good level of 52.3-68.4%.
3. Concentration in the tissues
The tissue concentration of Cephacetrile following its single intramuscular injection to rats in a dose of 20 mg/kg was found to be extremely high but its penetration of the liver was poor. The tissue penetration of Cephacetrile was similar to that of Cephalothin and Cephaloridine.

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On a new cephalosporin derivative, Cephacetrile, basic studies were carried out and the following results were obtained.
1. Organ levels 15 minutes after intravenous injection of Cephacetrile to mice ranked in order of the kidneys, serum, lung and liver.
2. The conversion of Cephacetrile to desacetyl-type metabolite was compared with Cephalothin and Cephapirin under the contact with organ homogenates of rat. The speed of conversion of Cephacetrile was the slowest among them.
3. The addition of cephalosporinase to the solution of Cephacetrile accelerated the coloring of wine-red. The coloring was delayed by the prevention of oxygen supply.

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Using a cross-over method, pharmacokinetic study of Cephacetrile (CEC) was carried out on 5 patients. The results were compared with those of Cephalothin (CET) and Cefazolin (CEZ).
1. A solution of CEZ mixed with human serum and a solution of CEC diluted with a phosphate buffer achieved the highest blood levels, while with CET, the lowest levels were attained both with the mixture and the dilution. Regarding the time required for decrease in blood values, CET was the shortest, CEZ the longest, and CEC in between the two.
2. The maximum urinary concentration was attained with CET, while CEZ showed the least. Urine collected 4-6 hours after the administration showed that the highest concentration was obtained with CEZ, CET was the lowest and CEC was in between.
3. Presence of metabolites in the blood and urine was examined using a bioautogram. No metabolite was detected in the blood of patients administered CEC. Approximately 1.7% (average) of desacetyl compound was demonstrated in the urine, but the amount is not expected to affect the potency of CEC as measured by the cup method. CET group demonstrated approximately 40% desacetyl compound in the blood and 39% in the urine. In a patient about 76-86% desacetyl compound was demonstrated in the blood. In view of this data the desacetyl compound may affect the potency of CET as measured by the cup method. any metabolite of CEZ was not detected in both blood and urine of patients administered this drug.
4. Total urinary excretion rates, including metabolites, were as high as 70-80% for all three brugs.
Although CEC demonstrates similar pharmacokinetic behavior to that of CEZ, CEC seems to be evaluated between CET and CEZ.

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The laboratory and clinical investigations were carried out on a new derivative of cephalosporin-Cephacetrile (CEC). and the following results were obtained.
1) In susceptibility test using clinically isolated bacteria, MICs of both CEC and CEZ on 20/21 strains of Staph. aureus were found less than 1.6 μg/ml, and those of 13/14 of E. coli were less than 12.5 and 3.2 μg/ml respectively, whereas most of Klebsiella-Enterobacter and Pseud. aeruginosa were not inhibited at the concentration of 100 μg/ml of these drugs.
2) The activity of desacetylated metabolite of CEC both on Staph. aureus and E. coli decreased to 1/2-1/4 of parent substance. Desacetyl-lactone form did not show the activity practically.
3) In i. m. absorption and excretion study in human subjects using cup plate method, B. subtitis as the test organism, mean blood level attained to peak of 21.3 μg/ml at 1 hour. Calculated half life, in the blood was found to be about 1.8 hours. Twenty-60% of dose was recovered in 8 hours as active substance in urine.
4) In study of protein binding, the bound ratios of CEC and CED were about 38.5-50 and 11-20% respectively by the cellophane bag dialysis.
5) In the study of metabolism using TLC, CEC and its desacetylated metabolites were found in urines of a patient following multiple i. m. administration.
6) In clinical investigation, 25 cases including 9 cases with R. T. I. and 13 cases with U. T. I. were treated daily 2-39 i. m. or i. v. administration of CEC. Twenty-two cases responded well but relapses have occurred in 3 cases. Two cases with biliary tract infection and one with septicemia due to Klebsiella resistant to cephalosporins did not respond. Laboratory values before and after the treatment showed no abnormal fluctuation except for 3 cases with decrease in RBC after the treatment.

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Cephacetrile (CEC) is a new antimicrobial agent of cephalosporins. The therapeutic efficacy of the drug was evaluated in nine patients with urinary tract infections, including a case of renal abscess and in one patient of acute pneumonia. These patients were given 2g of Cephacetrile, twice a day for 2 to 12 days, by means of intramuscular injection (4 patients) and of intravenous administration (6 patients). Organisms, isolated from these patients were E. coli (7), Klebsiella pneumoniae (1) and Staphylococcus epidermidis (2). In 7 patients, the symptoms were improved and the culture of organisms became negative. No therapeutic effect was obtained in 2 patients. In a patient the administration of the drug was discontinued due to side effect of flushing. Serious side effects were not observed.

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Laboratory and clinical studies were made on Cephacetrile with following results :
1) Susceptibility of Streptococcus pneumoniae and Haemophilus influenzae.
MIC values of Cephacetrile against 26 strains of respiratory pathogenic Streptococcus pneumoniae ranged from less than 0.05 μg/ml to 1.56 μg/ml, and their distribution pattern was almost equal to that of Cefazolin.Against 27 strains of respiratory pathogenic Haemophilus influenzae, MIC values of Cephacetrile ranged from 3.13 to 100 μg/ml, and those values were 4 to 8 times higher than those of Cephaloridine.
2) Tissue levels in rats
After intramuscular administration of Cephacetrile 50 mg/kg, Cephacetrile levels attained to the peak levels in any organs at less than 15 minutes.
The peak values were 86 μg/ml in serum, 54 μg/ml in kidney, 11 μg/ml in lung and 2.5 μg/ml in liver.
The half life of Cephacetrile in the tissues was about 30 minutes.
3) Serum and sputum levels in human
Serum levels in a patient (57 years-old man, B. W. 65kg, renal function normal) after intravenous instillation of 5g Cephacetrile dissolved in 500 ml of 5% glucose during 3 hours were measured.
Peak value was 86 μg/ml and half life in serum was about one hour.
In another patient (44 years-old woman, B. W. 44kg, chronic bronchiolitis), concentration in serum, expectorated sputum and intrabronchiolar secretes, collected through KIFA green catheter from 4 different bronchi, after i. v. instillation of 3g Cephacetrile dissolved in 500 ml of 5% glucose during 2 hours were measured. Serum peak level was 86 μg/ml and half life was about one hour. Concentration in expectorated sputum one hour after administration was 0.90 μg/ml (1.1% of serum peak level), and in intrabronchiolar secretes their values ranged from 1.33 to 1.98 μg/ml.
4) Clinical application
Cephacetrile was intravenously administered to 15 patients with pulmonary infection 11 cases, urinary tract infection 3 cases and bacterial endocarditis 1 case at daily dose of 2.0 to 8.0g. Cephacetrile was effective in all patients with pulmonary infection and 2 of 3 patients with urinary tract infection.
CEC that was dissolved in the peritoneal perfusate was administered at dose 4g/day to a patient with peritonitis, and the result was clinically effective.
5) Side effect
Skin eruption was observed in one patient, and violet-colored urine was observed in another patient with urinary tract infection. They disappeared soon after cessation of administration. Hepatic and renal function tests and blood examination showed no abnormalities.

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Cephacetrile (CEC) is a new semi-synthetic derivative of cephalosporin. Its in vitro activities against gram positive bacteria and negative bacilli were examined. Then, therapeutic effects on respiratory tract infectious diseases were evaluated. Cephacetrile was revealed to be effective against gram positive cocci and some of gram negative bacilli. When Cephacetrile was given intravenously at a dose of 4 to 6 g a day, an excellent clinical response was obtained in all 4 cases of pneumonia, and good responses were observed in a case of lung abscess and a case of superinfection to lung cancer. No serious side effect was seen in all these 6 cases.

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1. Metabolites of Cephacetrile in human urine were studied using bioautography. In this study, Desacetyl-Cephacetrile was detected, but Lactone of desacetyl-Cephacetrile was not.
2. Cephacetrile was administered to 11 patients (7 cases of pulmonary infection, 3cases of urinary infection and 1 case of purulent arthritis), and therapeutic results were effective in 7 cases, moderately effective in 2 cases, ineffective in 1 case and undetermined in 1 case. As to side effects, drug eruption was observed in 2 cases, but disappeared rapidly when the administration of Cephacetrile was discontinued.
3. Although 4g per day of Cephacetrile were used for about 50 days in a patient with acute renal failure caused by pyelonephritis, it did not influenced harmfully on the improvement of her impaired renal function.

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A clinical study on Cephacetrile, a new antibiotic belonging to the cephalosporins was carried out with the following results :
1) Comparing the sensitivity of CEC to Staphylococcus aureus, E. coli and Klebsiella isolated from foci with those of CET, CER, and CEZ, Cephacetrile was almost equivalent to CET and CEZ, and slightly inferior to CER against Staphylococcus aureus, and slightly superior to CET and inferior to CER and CEZ against E. coli.
CEC was almost equivalent to CET and CER yet inferior to CEZ against Klebsiella.
2) After a 1-2g i. v. administration of CEC, high blood levels were evident, but the excretion was rapid and this substance could not be identified 6 hours after an i. v. injection of one gram. The recovery rate in urine was about 60%, 4-6 hours after administration. The maximum blood levels after drip infusion in doses of 2 and 4 g were 72.3 μg/ml and 166 μg/ml respectively. Six hours later, the levels were approx. 10 μg/ml. The recovery rates in urine were high.
3) CEC was given to a total of 14 patients including 11 with acute pneumonia, one with secondary infection associated with lung cancer, one acute pyelonephritis, and one acute lymphadenitis.
The results were remarkably effective in 2, effective in 7, unknown in 2, and ineffective in 2 out of 13 cases. In one patient assessment was impossible. The dosage was 2-8 g and the duration was 7-34 days.
4) Allergic reactions such as skin rashes were observed in 5 out of 14 cases and eosinophilia was demonstrated hematologically in one. In some cases elevations of the GOT, GPT, and BUN occurred. Normal levels were reverted to soon after discontinuation of the administration. Disorders in the GOT, GPT, and BUN were nil in patients on the drug more than one month. Thus the efficacy of CEC was clearly demonstrated.

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Cephacetrile was investigated on the basic and clinical examination, and the following results were obtained.
1) The MIC of Cephacetrile (CEC) was measured on 66 strains of various bacteria isolated from lesions to compare with that of CET, CEX and CER. The antibacterial activity of CEC against gram positive bacillus was similar to CEX, but lower than CET and CER, and against E. coli it was similar to CET and CER.
2) When 1 g of CEC was given intravenously to 2 patients, the serum peak level was 36μg/ml and the highest concentration in bile was 13.5 μg/ml in average. In two hours a high concentration in urine was seen in the average of 5225 mg/mi.
3) The total number of clinical cases was 58 as shown in Table 8 and the evaluation was made in 52 cases. Among the 52 cases, excellent effect was found in 9 and good effect in 30, giving a rate of positive effect of 75.0%.
Effectiveness of CEC to pneumonia and furuncle were examined in each 6 cases, and proved in all cases.
As regards side effects, eruptions and local pain at the site of intramuscular injection were seen in 2 cases respectively.
By the laboratory examination, elevation of GOT and GPT was found in 1 case.

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Fundamental and clinical studies with Cephacetrile (CEC) were performed with the following results.
1. The MIC values of CEC were found to be equal to or slightly less than those obtained with other. available cephalosporin derivatives.
2. CEC achieved marked therapeutic results in the treatment of cholecystitis and interstitial pneumonia caused by mixed organisms.
3. CEC was found to have neither an adverse effect on renal and liver function, nor on the peripheral blood.
4. This compound may be a unique antibiotic, the studies suggesting it induces less renal toxicity than Cephalothin.

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Cephacetrile (CEC), a newly synthesized cephalosporin derivative, was examined on its antibacterial activity as well as on its absorption, distribution and excretion after intramuscular administration. Some clinical trials were also carried out. The results obtained were as follows :
1) The MIC of 29 strains of Staph. aureus isolated from human infection foci against CEC were between 0.8 and 3.1gμg/ml, the peak of the MIC distribution curve being located between those of CEP, CET, CEZ and those of CER, CED, CEX. The sensitivity of E. coli strains were similar to those against CET and CEX, that of Klebsiella strains being lower than CET and CEX. All of the Pseudomonas aeruginosa strains examined were resistent (MIC 100μg/ml) to CEC.
2) Serum peak level of 20μg/ml was obtained in normal human adults 30 minutes after single intramuscular injection of 1g CEC, while 10-12g/ml after 0.5g administration. The average urinary recovery of the drug in 8 hours was about 70% of the dose.
3) Distribution into rat organs : The tissue concentration of the antibiotic showed similar pattern to other cephalosporins, i.e. highest in kidney followed by lung, liver and spleen.
4) Protein binding on CEC in human serum examined by ultrafiltration was found to be 11.8% in 50μg/ml concentration, and 15.8% in 10μg/ml.
5) Three patients with various infections (cholangitis, bronchopneumonia or pyelitis) were treated with CEC 2g daily i. m. or i. v.. Favourable results were obtained in all of the three cases, while one patient showed anemia after the therapy, which could not be defined as a side effect of the drug, otherwise no untoward reactions were found in the treated cases.

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Basic and clinical studies on Cephacetrile were conducted and the following results were obtained.
1. Antibacterial activities of Cephacetrile against various clinical isolates were tested.All 31 strains of Staph. aureus were sensitive to Cephacetrile at the concentration of 12.5μg/ml and the isolates showed a peak of distribution at MIC 0.78μg/ml.
Susceptibility of 19 strains of E. coli, 13 strains of Klebsiella and 21 strains Proteus to Cephacetrile was shown with a peak of distribution at MIC 12.5μg/ml.
Six out of the 19 strains of E. coli, 1 out of the 13 strains of Klebsiella and 4 out of the 21 strains of Proteus were resistant to Cephacetrile showing MIC of 100μg/ml and more than 100 μg/ml.
All 9 strains of Pseudomonas were resistant to 100μg/m1 of Cephacetrile.
2. One gram of Cephacetrile given intramuscularly to healthy volunteers showed a peak serum level at 25 to 28μg/ml 30 to 60 minutes after injection. The level reduced gradually to about 1μg/ml 6 hours after administration.
Average urinary recovery in these volunteers was about 90% during 6 hours after administration.
3. Distribution of Cephacetrile in several organs of rats was observed after intramuscular injection of 100 mg/kg. Thirty minutes after administration the Cephacetrile concentrations were higher in the kidney, serum, lung, muscle, liver, heart and spleen in the order.
The concentrations in serum and kidney were about 100μg/ml or g and those in the other organs were less than 10μg/g 30 minutes after injection.
Cephacetrile was not detected 2 hours after injection in the organs except serum and kidney.
4. Cephacetrile was given at daily dosage of 2.0 to 4.0 grams i. m. to 6 patients consisting of 1 case with pneumonia, 2 cases wtih pulmonary cancer with infection, 1 case of sepsis, 1 case with Hodgkin's disease with fever and 1 case with perianal abscess. Clinical responses of the drug obtained in these cases were excellent in one case of pneumonia due to Strept. pneumoniae, but poor in 4 cases and unevaluable in one case.
Side effects observed were skin rash in 2 cases, rise of GOT and GPT in one case and red-coloration of urine in one case.

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Laboratory and clinical investigations were performed on Cephacetrile comparing with Cephalothin, and the results were obtained as follows :
1) The in vitro growth inhibiting activity of Cephacetrile against Staphylococcus, E. coli and Proteus sp, were in the similar grade as Cephalothin.
2) The serum levels of Cephacetrile and Cephalothin administered at an intramuscular dose of 1 g were determined in three patients using cross over method. The higher serum levels were obtained with Cephacetrile than with Cephalothin 2 and 4 hours after injection.
3) Cephacetrile was given to 5 patients with respiratory infections in daily doses of 1 or 2 g for 5 to 14 days. Symptomatic improvements were observed in all cases without detectable side effect. Staphylococci in sputa disappeared after Cephacetrile administration in all cases.

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Cephacetrile (CEC), a new derivative of 7-aminocephalosporanic acid, was administered intravenously to 10 patients of respiratory infection, 4 of urinary tract infection and one of cholecystitis. Minimum inhibitory concentration (MIC) of CEC was examined against clinically isolated bacteria by two fold dilution technique. The following results were obtained.
1) Antibacterial activity of CEC was determined on 50 strains of gram negative bacteria isolated from clinical specimens. Mean value of MIC against
E. coli was 12.5μg/ml. Klebsiella and Proteus sp. were inhibited by 12.5μg/ml. Strains of Enterobacter were not sensitive for CEC.
2) CEC was evaluated in 15 patients with bacterial infection. The effective response was observed in 9 of 15 patients.
3) Transaminases (GOT, GPT), alkaline phosphatase, BUN, RBC and platelet were obtained before and after CEC treatment. Laboratory abnormalities were not observed on the 14 patients, except one of patients who has elevated on GOT during CEC treatment.

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Basic and clinical examinations of Cephacetrile (CEC), a cephalosporin derivative, were performed and the following results were obtained
1. The average blood level of CEC after intramuscular administration of 1g to six patients were 11.7±2.17μg/ml 30 minutes, 12.4±0.64μg/ml one hour, 10.27±1.14μg/ml 2 hours, 4.98±1.41μg/ml 4 hours, and2.02±0.64μg/ml 6 hours.
2. The sputum levels of CEC after intramuscular administration of 1 g were 0.3μg/ml 0 to 2 hours, 0.7μg/ml 2 to 4 hours and 0.8μg/ml 4 to 6 hours.
3. The spinal fluid levels of CEC after intramuscular administration of 1g to two patients with meningitis were 0.2μg/ml and 0.3μg/ml.
4. CEC was used in 8 patients with respiratory infections, and the effectiveness was obserbed in 7 cases (85.7%). No side effects with CEC was found.

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Cephacetrile (CEC), a new derivative of cepharosporin C compounds, was examined basically and clinically in patients with respiratory infectious diseases and the following results were obtained :
1) Antibacterial activity
Various microorganisms were isolated clinically. There were 189 strains of gram positive cocci (Staphylococcus aureus 64, beta-hemolytic Streptococcus 61 and Enterococcus 64) and 380 strains of gram negative bacilli (Salmonella 16, Shigella 16, Escherichia coli 62, Klebsiella pneumoniae 64, Enterobacter cloacae 32, Serratia marcescens 64, Proteus vulgaris 16, Proteus mirabilis 16, Proteus morganii 19, Proteus rettgeri 13 and Pseudomonas aeruginosa 62). Twenty two standard strains were cultured in our laboratory and a total of 591 strains were used to determine the MIC of Cephacetrile. The results were compared with those of Cephalothin (CET). CEC was more effective than CET against Enterococcus, equipotent against E. coli, Klebsiella, Proteus vulgaris and Proteus mirabilis and both drugs were ineffective against Enterobacter, Serratia, Proteus morganii, Proteus rettgeri and Ps. aeruginosa.
2) Blood concentration
Four g of CEC was diluted with 5 % glucose and drip infusion was carried out for two hours in 6 patients with respiratory infections. The antibiotic concentration in the blood was measured at the termination of infusion and the highest average concentration was 111. 3 pg/ml, the average half life was approximately 40, minutes.
3) Excretion of the antibiotic substance into the sputum
Four g of CEC was given by drip infusion over a 2 hour period to patients with bronchiectasis who were expectorating 50-80 ml of pus containing sputum. The maximum concentration of the agent in the sputum was 3.3μg/ml and the concentration ratio to the maximum blood level was 0.035.
4) Levels in rat organs
Wistar strain rats were given intramusculary 20mg/kg of CEC and the distribution of the substance in organs was measured. The highest concentration was observed in the serum, followed next by kidney, lung and liver.
5) Clinical results in respiratory infections
Eleven patients with lower tract pulmonary infections were administered 4g of CEC (60.6-114.3mg/kg) once daily by drip infusion. These eleven included 6 with pneumonia and bronchopneumonia, 3 with pulmonary suppuration, one with middle lobe syndrome and with bronchiectasis.
There was marked improvement in 5, improvement in 2, slight improvement in 3 and no improvement in one patient.
Side effects :
An elevation in S-GOT and S-GPT was observed in one patient, however, levels returned to normal immediately following discontinuation of the administration.

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Basic and clinical studies of Cephacetrile (CEC) were carried out in the pediatric field. Intramuscular and intravenous drip administrations were mainly given and the results are as follows :
1) The peak in the blood level after i. m. injection was observed 30 minutes after the administration and considerably high levels were maintained for 3 hours. Even 6 hours later, levels in the blood were readily demonstrated.
2) The peak in the blood level after a single i. v. injection was also observed 30 minutes after the administration, however, after 3 hours the level could not be determined.
3) The blood levels with intravenous drip infusion were highly maintained from 30 minutes after the start of the administration and continued for 3 hours up to the time of completion of the drip infusion. Such a tendency was marked in the acute stage of pneumonia and was similar to the case of a single i. v. administration. Considerably high blood levels could be demonstrated even one hour after completion of the drip infusion. When CEC and Cephalothin were given by drip infusion in the same dose over the same period of time, the blood levels of CEC were higher.
4) A drip infusion of 300 mg/kg to a newborn over a 24 hour period revealed blood concentrations to be about 110-80pg/ml 3 hours after the starting of the infusion.
5) The recovery rates in urine 6 hours after the intramuscular, single intravenous, or intravenous drip administration, were approx. 34.4-95% of the administered amount, with an average of 40-50% recovery.
6) The subjects of this trial included 20 children who suffered from diseases of the respiratory organs, including acute bronchitis (majority), bronchopneumonia and pyothorax. Clinical results were clearly evident with i. m. administration of daily doses of 50-100 mg/kg, usually in the later stages of the disease.
7) In order to investigate the large border dose of this drug, drip administration was carried out with daily doses of around 100-200 mg/kg to one patient with pyothorax due to Staphylococcus aureus. Satisfactory therapeutic results were obtained in 33 days.
8) A drip infusion of this drug in doses of 100-220 mg/kg was effective in cases of deradenitis with fever and septicemia due to Staphylococcus aureus.
9) The efficacy rate of this drug was 90% in the 20 patients studied herein.
10) The influence on the S-GOT, S-GPT, BUN, and haematological findings etc. was investigated particularly when the administration was over 10 days, however, abnormalities were absent in all cases including those on high dosage administrations, e. g. 38g in 15 days and 305g in 33 days.

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Cephacetrile in a daily dose of approx. 50-100mg/kg was administered to 15 children infections, i. e. one of left recurrent parotitis, one of acute tonsillitis and bronchitis, 2 of tonsillitis, 2 of bronchitis, 4 of bronchial pneumonia, and 5 cases of pneumonia. As a result symptoms almost disappeared in one to 2 days in 8 remarkably effective cases and in 3 to 4 days in 7 effective cases.
No adverse reactions attributable to the Cephacetrile administration were observed in the clinical and laboratory findings of 15 cases.

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The authors have carried out the laboratory and clinical studies of Cephacetrile.The results were as follows; The sensitivity was measured by the plate dilution method with 28 strains of Staph. aureus and 19 strains of E. coli isolated from the patients.
The growth of 71.4% of Staph. aureus was inhibited in concentration of less than 0.78 μg/ml. The growth of 84. 2% of E. coli was inhibited in concentration of 6. 25-25 μg/ml. Cephacetrile were given intramuscular dose of 25-50 mg per kg b. w. to 3 children and intravenous dose of 20 mg per kg b. w. to one child. The maximum blood levels were reached at 30 minutes, 43 μg/ml and at 15 minutes, 92 μg/ml respectively.
And the blood level at 6 hours after injection was not determined.
The excretion rate of Cephacetrile in the urine was 85.0-93.9% up to 6 hours after a single intramuscular dosing.
Cephacetrile was effective in 4 cases with severe bacterial infections (two cases with pneumonia, one case with cellulitis and purulent meningitis respectively).
No side effects were observed except for red coloring of urine.

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Cephacetrile (CEC), a new derivative of cephalosporin C was investigated with the following results :
1) The antibacterial spectrum of this substance resembles that of CET or CEP and is effective against gram positive and negative bacteria. The scope is, however, somewhat narrower than that of CET and CEP.
2) CEC demonstrated antibacterial actions against isolated Staphlococcus aureus, Proteus group, E. coli and Klebsiella, however, compared to CET and CEP, CEC showed a little less sensitive than the former two and a little more sensitive than the latter two.
3) Blood and urine levels
Cephacetrile 500mg was administered i. m. and levels in blood and urine were determined by means of the cup method using a strain of B. subtilis ATCC 6633. The highest levels in blood were obtained 30min. after the administration with the mean value of 14.8 μg/ml. The highest concentration in urine was on an average 2616. 7 μg/ml per hour. The recovery rate was on an average 69.2% until 6 hours after the administration. A renal excretion type was observed.
4) Twenty mg/kg of Cephacetrile given i. m. to SD rats revealed that the tissue levels were the highest in the injected muscle followed by the highest levels in the serum, kidney and lung. Content in the brain, heart, liver, spleen and non-injected muscle were nil. The amount in the bile was one-fifth of that in the serum.
5) Bioautograms of the metabolism in the living body were prepared by means of TLC. Urine tests in humans revealed that CEC is metabolized in a living body and is broken down into CEC and Desacetyl-CEC.
6) Concerning the activation of β-lactamase and isolation of a red pigment in the urine, β-lactamases were extracted from Proteus morganii and Klebsiella pneumoniae resistant to CEC. With the application of CEC, both β-lactamases became completely inactivated in 30min. later and a red pigment was formed from the inactivated substance. Absorption at around 550mμ was observed in the spectrum. This inactivated substance was thus demonstrated to be one of the metabolites of CEC.
7) Cephacetrile was administrated to 32 surgical patients. Results proved effective in 23 (2 later had a recurrence) and ineffective in 9 patients. Adverse reactions were nil in all cases.

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Fundamental and clinical studies were carried out with CEC and the following results were obtained.
i) For measurement of body fluid concentrations, M/15 phosphate buffer solution pH 7.0 was used. Five fold dilution of bile with the buffer solution was sufficient to elucidate the results.
ii) Following intravenous administration of 1g of CEC, 41 and 20μg/ml of blood levels were achieved at 30 and 60 minutes. At 30 minutes concentrations in bile (from choledochus) were equivalent to 1/10 th or higher to those in blood. The transfer in gall bladder bile was 1/10 th of density to bile from choledochus and this compound excreted in equivalent value to gall bladder bile in patients with obturation of bile duct.
iii) Following intramuscular administration of 1 g of CEC, a blood level of 9.0μg/ml was attained in one hour, having half life of three hours. The peak biliary concentration was 1.9μg/ml, which was achieved in two hours.
iv) Following administration of CEC, human sera were collected for electrophoretic examination and the bioautograms were compared with the contrast. One out of the six cases demonstrated a different albumin pattern, having subspot besides main spot which was common to all six cases. The relative mobilities of each spot in the albumin phoresis were 1.5-2.1 and-0.57.
v) CEC was administered either intravenously or intramuscularly to 6 patients with soft tissue infections or postoperative subphrenic abscess. 5 patients achieved a satisfactory result, but one patient with traumatic infection due to Pseudomonas aeruginosa could not respond to the medication.
vi) CEC was given to 13 patients for prophylaxis of post-operative infections and traumatic infection was observed in 2 patients.

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Fundamental and clinical studies on Cephacetrile (CEC) were performed. The antibacterial activity of CEC was tested against various organisms isolated from patients in the surgical field and the results were compared with those of Cephaloridine (CER), Cephalothin (CET), Cefazolin (CEZ) and Cephapirin (CEP), all tested under the same conditions. CEC was shown to have a broad spectrum of antibacterial activity like other cephalosporin derivatives. The antibacterial activity of CEC was similar to that of CET. CEC was well absorbed via the intramuscular route and high blood levels were achieved. A single intramuscular dose of 1g gave a peak blood level of 30.3μg/ml (the mean value of 3 cases), 30 minutes after its administration. Levels were measured after a single intravenous dose of 1g, the study being performed in a crossed over design.
The urinary recovery rate was 73.7% within 6 hours. The bile level in patients (with hepatic disorder) was observed to be approximately one third of serum level concentration.
The clinical effectiveness of CEC was evaluated in 15 patients with infections of mixed aetiology, and 85.7% responded to the drug.
No unwanted effects of CEC were observed in the liver, kidney or haematopoietic system of any patient and in only one case were unwanted symptoms recorded, namely nausea and vomiting.

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Cephacetrile (CEC), a new antibiotic derived from cephalosporin-C, was investigated on serum level, urinary excretion, clinical effectiveness and untoward side effects.
1) Following a single intravenous infusion of 1g Cephacetrile in 3 healthy adult volunteers the mean serum concentration showed a peak of 34.0μg/ml at 15 minutes after administration.
2) In the same subjects, the urinary excretion of Cephacetrile was 652. 2mg (65.22%) within 8 hours.
3) Cephacetrile was administered to 25 patients with infections in the field of surgery, and the result was excellent on 2 cases, good 7, fair 5, poor 8 and unknown 2, the effectiveness rate accounting for 65.2%.
4) Among untoward side effects, only eruption was observed in 3 of the 25 patients (12.0%).

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1) The biliary excretion of Cephacetrile (CEC) was studied in 3 patients with common bile duct drainage after operation for cholelithiasis. The concentration of CEC in bile was determined by cup-method using B. subtilis PCI 219. An average biliary level after single intravenous administration of 2000mg of CEC was 7.5, 3.7, 0.7 and under 0.5μg/ml1 at 1, 2, 4 and 8 hours, respectively. The highest concentration of CEC in pancreatic juice in a case was 0.9μg/ml.
2) The clinical use of CEC was applied to 9 surgical cases. Seven patients in the postoperative application were effective clinically. Two long-standing, hard healed cases with chronic fistula caused by injury of liver and biliary tract, and of pancreas were slightly improved clinically though there was no bacteriologic effectiveness for Klebsiella and Pseudomonas infection that seemed to be appeared by microbisme substitution.

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Cephacetrile (CEC), a new derivative of cephalosporin C was given to twenty-six patients of orthopaedics who had bone and joint infections.
CEC was administered by means of intravenous injection or drip infusion, the routine daily dosage was two grams.
The results were excellent in seven, good in eight, fair in six, and poor in five.
Some discussion was made in these results.

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Cephacetrile, a newly synthesized cephalosporin derivative, has been evaluated by bacteriological, pharmacological and clinical studies. Cephacetrile was active against E. coli, Proteus mirabilis species and also against some of other coli-forms. Minimal inhibitory concentrations of this drug on sensitive strains were 3.13 or 6.25μ/ml on nutrient agar (Difco) plates.
Blood level and urinary recovery studies in healthy adult volunteers showed 1) 2g of drug given intravenously gave blood level of 40μg/ml, at 15 min. and 1 g gave about 25μg/ml, 2) 1 g of Cephacetrile given by intramuscular injection gave maximal. blood level of 10μg/ml, 30 min. after injection, and 3) urinary recovery in these occasions was almost 60% of administered dose in each case.
Clinical efficacy was evaluated in 7 patients in ten occasions. When cultured organism were E. coli, the drug was effective though stones, catheters and calyceal scar were intervening the urinary systems. In one case, superinfection by a Pseudomonas and an Enterobacter species was noticed during prolonged catheter drainage in the ureter following erradication of offending E. coli was done. The drug was ineffective against Enterobacter infections. No side effect was seen except severe pain on injection site even employing xylocaine solution as solvent. However in a volunteer case pre-shock state (dizziness, sensation of fainting, sweating) was induced by 2g intravenous administration (none by previous 1 g).

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Laboratory and clinical investigations were performed on a new semi-synthetic cephalosporin derivative, Cephacetrile (CEC), and the following results were obtained.
1. CEC had a similar antibacterial activity to other cephalosporin antibiotics against gram negative rods isolated from patients with urinary tract infections.
2. CEC showed a higher resistance to cephalosporinase derived from Pseud. aeruginosa than that of CET.
3. CEC is inactivated by sensitive E. coli but the degree of inactivation is less than that of CET.
4. So called inactivation of CEC and CET by sensitive E. coli is due to degradation of bacteria, and mainly due to their β-lactamase
5. CEC was administered to 15 patients with complicated urinary tract infections and achieved improvement in 10 patients, effectiveness of 67%.
6. Only one case was observed to produce nausea and heart burn

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1. Antibacterial activity.
Excellent bacteriological results were obtained against gram positive and negative bacteria, and the drug's potency was observed to be similar to CER.
2. Clinical results.
22 patients with complicated urinary tract infections, including 15 patients of inlying catether, were administered CEC. Marked therapeutic results were observed in 3 patients, good results in 9 and no effect in 10, overall effectiveness being 54.5%.
3. Side effect.
Of 23 cases, only one case was observed to produce skin eruption, but no other abnormalities were noticed in the laboratory data.

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Nine-teen cases with urogenital infections and 4 cases for prophylaxis of postoperative infections were given Cephacetrile (CEC) at a daily dose of 4-6g except one case of child given 2g daily for 4 to 7 days intravenously by dripinfusion.
Of 10 cases with acute pyelonephritis, excellent responses were seen in 5 cases, good in 3 cases and poor in 2 cases.
Of 7 cases with chronic pyelonephritis, 3 were excellent, 2 were good, 2 were poor. Of 2 cases with acute prostatitis, one was good and one was poor. Of 4 cases for prophylaxis of postoperative infection, 1 was excellent, 2 were good, and one was poor.
The antibacterial activity of CEC against E. coli, Klebsiella, Proteus, Pseudomonas was almost the same as that of Cephalothin, but lower than Cefazolin.
Side-effect was experienced with CEC in one case in whom S-GOT and S-GPT elavated slightly.

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1) Cephacetrile (CEC) in a single dose of one gram i. m. was administered to 2 adult men and serum levels and the urine excretion rate were determined. The peak serum concentration was reached in 30 minutes and only a trace of CEC was observed at 6 hours. More than 50% of the drug was excreted in the urine within 3 hours.
2) CEC was administered to 22 patients, some hospitalised, with urinary tract infections at the Urological Clinic of Kyushu University.
a) Six out of 22 patients had acute simple urinary tract infections (cystitis), and received CEC, 2 g i. m.daily for 3-4 days. Good effects were observed in all the cases.
b) Sixteen out of 22 patients with complicated post-operative urinary tract infections received CEC for the duration of 3 to 8 day in a dose regime as follows :
8 cases : 3 g i. v. infusion morning 1 gi. m. evening
6 cases : 1 gi, m. b. d.
one case : 0.5 gi. m. b. d.
one case : 1 gi. m. o. d.
The results were described as markedly effective in one, effective in 6, and ineffective in 9 cases. Four of these 9 cases had resistant Pseudomonas infections.
c) No severe adverse reactions were observed but pain at the injection site was remarked upon by 4 patients.

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Studies with Cephacetrile in the treatment of patients with various infections, the majority of gynaecological origin, were carried out and the following results obtained :
1. Cephacetrile was administered intramuscularly to 37 patients, 27 with urinary tract infections, 3 with acute tonsillitis and 5 with acute pelvicperitonitis. The clinical results obtained were classified as excellent in 7 cases, good in 14 cases, fair in 9 cases, and poor in 7 cases. The percentage efficacy obtained was 56.8% (21/37 cases).
2. In one case a skin eruption was observed and the treatment was discontinued. In a further case the pretreatment subcutaneous test gave a positive reaction against this compound and Cephacetrile was therefore not given.
3. General hematologic, hepatic and renal function tests were performed before and after the medication, and no abnormal data were obtained.

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Antibacterial activity and clinical effectiveness have been studied on Cephacetrile (CEC), a new cephalosporin derivative, and the following results were obtained.
1. The peak blood level of 14.6μg/ml was obtained 30 minutes after intramuscular administration of CEC 1.0g to healthy women, and presence of CEC in blood was detected even after 6 hours from administration.
Intravenous administration of CEC 1.0g achieved the peak of 47.0μg/ml 15 minutes after administration, and the concentration was observed after 4 hours.
By drip infusion the results were about the middle of two forms of administrations.
CEC was excreted in urine more than 60%.
2. The transfer of this compound into fetus was considered to be relatively better than those of other cephalosporin antibiotics.
3. The distributions of sensitivity to clinical isolates were examined and 78% of Staph. aureus were inhibited by CEC at 0. 78-1.56μg/ml, 68% of E. coli at 6.25-25μg/ml.
MICs of CEC against Klebsiella sp., Proteus sp. were distributed in a wide range, and some strains of Proteus sp. resistant to indole (-) were inhibited by 6.25-12.5μg/ml of CEC.
4. Against Staph. aureus CEC demonstrated a similar antibacterial activity to that of CET, but against E. coli CEC showed a sharper sensitivity distribution than that of CET.
However, there observed closer corelation of sensitivity distribution between the two.
MICs of cephalosporins against Staph. aureus in the order of peak values were CER<CEZ<CEC=CET< CEX, and against E. coli, CEZ<CER<CEC<CET<CEX.
5. Clinical results in the treatment of gyneco-obstetric infections.
CEC was administered to 13 patients including 2 cases of pelvic peritonitis at dose 2-10 g/day for 3 to 10 days intravenously and chemotherapeutic levels were achieved in 9 patients. One patient had a skin eruption but no adverse reaction was observed. Laboratory findings showed no abnormality.

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Cephacetrile (CEC) was studied for its antibacterial action, its penetration from maternal serum into umbilical cord serum and amniotic fluid and assessed for its clinical efficacy. The following results were obtaiend :
1) Peak MIC values of CEC for clinical isolates were 0.78 μg/ml for tested strains of Staph. aureus, 6.25u g/ml for the tested E. coli and Klebsiella and 12.5-25μg/ml for Proteus mirabilis. CEC was slightly inferior to CET in respect to MIC value with these particular organisms tested.
2) Peak levels in maternal and umbilical cord serum were obtained at 13.0μg/ml and 8.2μg/ml respectively, 2 hours after administration of 1 g of CEC i. m. The level in umbilical cord serum is approximately 63% that of the maternal serum value.
The peak level obtained in amniotic fluid was 2.4μg/ml at 2.5 hours after intramuscular administration.
Following intravenous administration of lg of CEC, the maternal serum and umbilical cord serum reached peak levels of 12.5μg/ml and 6.2μg/ml respectively. The latter value being about 50% to that of maternal serum. Amniotic fluid level attained to a peak level of 1.7, μg/ml at 4 hours after intravenous administration.
3) CEC at a dose of lg was administered to mothers either intramuscularly or intravenously, and various fetal organ levels were measured at 2 hours following intramuscular administration and 8 hours after intravenous administration. At 2 hours from intramuscular dosing concentrations in the liver and kidney of the fetuses were 0.2μg/g and 0.28μg/g and below trace levels in other organs. At 8 hours from intravenous administration concentrations in fetal organs were below traceable levels.
4) CEC at a dose between 1 to 4g/day was administered to 13 patients, consisting each one case of rupture of the bag, abscess of mammary gland, mastitis and intrauterine infection, 3 cases of pelvicperitonitis and 6 cases of pyelonephritis with an effectiveness rate of 84.6%, having remarkable effectiveness in one case, effectiveness in 10 cases and failure in two cases.
5) Hepatic and renal function symptoms were examined on those 13 patients without any abnormal data attributable to the drug.
No side effects were observed.
6) From laboratory data and clinical findings we consider this antibiotic is useful in the field of obstetrics and gynecology, particularly in respect of its passing the placental barrier effectively and its low toxicity despite the antibacterial activity of this drug being equal, or with some organisms slightly inferior, to that of CET.

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Cephacetrile (CEC) at a dose of 1 g was administered intravenously to patients with the following results.
1. Concentration of CEC in blood :
Healthy volunteers were given CEC and CET, each at a daily dose of 1 g intravenously using a cross over method and the blood levels were measured by the thin layer cup method. In the case of CEC, a higher level in the blood was evident 30 min. to 5 hr. after administration.
2. Sensitivity of Staphylococcus, a pathogen of pyodermia to CEC :
Forty two strains were examined regarding sensitivity to various cephalosporine C derivatives and no organism produced a high resistance to CEC. When CEC and CET were compared as to antibacterial action, CEC was observed to be slightly less effective than CET.
3. Clinical results :
CEC at a dose of 1 g daily i. v. was given to 14 patients with deep pyodermia and to one patient with sepsis. A combined treatment was not carried out, however, cold packs and an application of ointment were administered. Oral antibiotics were not given nor was any surgical incision involved.
In the one patient with sepsis (Table 2) the fever was reduced in 2 days and the temperature returned to normal in 5days. The pustule disappeared leaving a slight pigment deposition in 10days. Thus the agent proved to be remarkably effective. Out of the 14 patients with deep pyodermia, marked improvement was seen in 4, effectiveness seen in 4 and slight improvement seen in 3. In no case was the agent ineffective. Thus the rate of effectiveness, inclusive of marked effect was calculated to be 72.7%.
4. Side effects :
Significant side effects were nil. Some patients experienced nausea when the agent was injected rapidly. Such being the case, the agent should be injected slowly and a 1-2 min. infusion rate should be followed. In light of these clinical findings, CEC appears to be a potent antibiotic agent with an effective clinical application.

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1. Minimum inhibitory concentrations of CEC against 32 strains of Staphylococcus aureus isolated from skin infections were studied. MICs were 0.4μg/ml against 1 strain, 0.8μg/ml against 19 strains, 1.56μg/ml against 11 strains and 3.13μg/ml against 1 strain.
2. Serum and skin levels of CEC were followed after intramuscular injection of the drug at the dosis of 20mg/kg in rats. Skin levels paralleled serum levels and the peak was seen at 30 minutes. Skin level was 1/3 of serum level at 30 minutes and 1/2 at 1 hour.

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1. The peak MIC of Cephacetrile (CEC) against Staphylococcus aureus was observed at 1.56μg/ml.
2. The serum (diluted 10 fold) obtained at 30 minutes, one and two hours from intramuscular injection of 1g of CEC inhibited the growth of 209 P strain of Staphylococcus aureus.
3. Blood level concentrations.
The peak blood level following intramuscular injection of 1g of CEC was 19.3 μg/ml one hour after the injection and even after 6 hours the level was 2.1 μg/ml.
4. Tissue concentrations.
The concentration of CEC in the palatine tonsil one hour from intramuscular administration of 1 g of CEC was 4.3 μg/g in the palatine tonsil, 1.7 μg/g in the mucous membrane of sinus maxillaris and 1.7 μg/g in the membrane of the inferior turbinate. The concentration of mucous membrane one hour after the intramuscular injection of 2g of CEC was 3.7 μg/g.
5. CEC was administered to 27 patients with otorhinolaryngological infections. There was excellent in 20 (74.1%), good in 5 (18.5%) and no offect in one patient. Administration was discontinued in one patient who developed a eruption on the skin.
6. Side effects.
As this agent induces pain at the injection site, a dilution with lidocaine was utilized. One pediatric patient with tonsillitis had a eruption following an intramuscular administration, however there were no thoer adverse effects having a clinical significance.

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From the laboratory and clinical studies on Cephacetrile (CEC), the following results were obtained.
1) Activity of CEC was measured by the plate dilution method on 117 strains isolated from pathological materials in our clinic. The peaks of MIC were 0.78μg/ml with Staphylococcus aureus (55st.), Pseudomonas species were highly resistant to this antibiotic similarly to other cephalosporin antibiotics.
2) Tissue (tonsil and sinus membrane) and blood concentrations of CEC were determined 30 minutes after i. m. injection, 17.7μg/ml in blood, 0.58μg/g in tonsil (mean values of 15 cases) and 1.74μg/g in sinus membrane (mean values of 2 cases).
3) CEC was used clinically in 22 cases of ear nose and throat infections, and effective rate was 85%.
4) Adverse reaction was observed in one case : eruption appeared after 4 th day i. v. drip-infusion.

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Basic and clinical experiments were performed on Cephacetrile (CEC) in ophthalmological field, and the results obtained were as follows.
1. Antimicrobial activity of CEC against various organisms were 12.5μg/ml for KOCH-WEEKS bacillus, 0.08-0.39μg/ml for MORAX-AXENFELD bacillus, 0.39μg/ml for Pneumococcus, 0.39-0.78μg/ml for Coryne.diphtheriae, 0.39 μg/ml for Neisseria gonorrhoeae, 0.39 μg/ml for Strept. haemolyticus, 25μg/ml for Strept. viridans, 0.39-0.78μg/ml for Staph. aureus and>100μg/ml for Pseud. aeruginosa.
2. The distribution of the sensitivity for 100 strains of Staph. aureus was in the range of 0.39-6.25μg/ ml, and most of them (60 strains, 60%) were in 0.78μg/ml.
3. The peak of serum level (10.7μg/ml) was attained 1 hour after intramuscular injection of 1.0g CEC, then decreased gradually up to 6 hours (3.1μg/ml). After drip infusion of 4.0g CEC, the peak level (192μg/ ml) was obtained at 30 minutes and decreased quickly to 4 hours (13. 4μg/ml).
4. Ocular penetration in rabbit eye :
1) Aqueous humor concentration
The peak level of aqueous humor (3.5μg/ml) was obtained at 1 hour after intramuscular injection of 50 mg/ kg CEC. Aqueous/serum ratio was 12.7%. After intravenous injection of 50mg/kg CEC, the peak of aqueous level revealled at 30 minutes, 3.53μg/ml, and A./S. ratio was 10.7%.
2) Ocular tissue concentration
The ocular tissue concentration after intramuscular or intravenous injection of 50mg/kg CEC were high in the outer parts of the eye, such as in bulbar conjunctivitis, extraocular muscle, sclera, and low in the inner parts of the eye, iris and ciliary body, retina and chorioid.
5. Clinical results
Intramuscular or intravenous injection of 1.0g CEC one or two times daily revealled excellent or good effects on 15 of 20 cases, such as hordeolum, conjunctivitis, dacryocystitis, corneal ulcer, orbital phlegmone and endophthalmitis.
6. Side effects :
No severe side effects like allergic reactions were observed, and no abnormal findings in hepatic and renal tests were observed.

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