In vitro and in vivo antibacterial activity of cefoperazone (CPZ, T-1551) were compared with those of cefazolin (CEZ) and cefotiam (CTM) against gram-positive and gram-negative bacteria which were isolated from clinical materials in Japan.
CPZ has a broad spectrum of antibacterial activity against gram-positive and gramnegative bacteria. CPZ is more effective than CEZ against gram-negative bacilli, that is, Escherichia coli, Klebsiella pneumoniae, Proteus species, Pseudomonas aeruginosa, Citrobacter freundii, Enterobacter cloacae and Serratia marcescens. It is noteworthy that CPZ has high antibacterial activity particularly against P. aeruginosa and inhibited the growth of more than 80% of the total number of P. aeruginosa strains tested at a concentration of 6.25μg/ml.
CPZ acts.bactericidally on bacteria at a minimum inhibitory concentration (MIC) or a little higher concentration.
A remarkable influence of inoculum size on the antibacterial activities of CPZ is observed as shown in the other β-lactam antibiotics.
It is another remarkable characteristic that CPZ is rather stable to β-lactamase produced by gram-negative bacteria. Relative rates of hydrolysis of CPZ by cephalosporinases (CSases) are 7.0 to 0.01, taking the absolute rate of cephaloridine (GER) hydrolysis as 100. CPZ is more stable to various type of penicillinase (PCase) than penicillin G (PCG) and CER.
No great difference is observed in the MIC values of CPZ when human serum is added to the medium.
In vivo antibacterial activities of CPZ, CEZ and carbenicillin (CBPC) were compared using the systemic infections of mice with P. aeruginosa, K. pneumoniae and E. coli. The ED₅₀ values (mg/kg) were consistently less than those of CEZ and CBPC.

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Antibacterial activity of cefoperazone (CPZ, T-1551) was tested against a total of 993 clinically isolated bacterial strains such as Streptococcus, Staphylococcus, Haemophilus, Salmonella, Escherichia, Klebsiella, Enterobacter, Citrobacter, Serratia, Proteus, Pseudomonas, Flavobacterium and Achromobacter in comparison with that of other cephalosporins. The results of the tests are as follows:
1) CPZ showed an antibacterial activity similar to CEZ against Streptococcus but inferior to CEZ against Staphylococcus.
2) CPZ showed a markedly potent antibacterial activity against H. influenzae compared with other cephalosporins.
3) CPZ showed a potent antibacterial activity against the bacterial strains Salmonella, E. coli, C. diversus and P. mirabilis of the Enterobacteriaceae family though several strains showed a resistance to the drug.
4) CPZ showed a markedly potent antibacterial activity against P. aeruginosa, P. putrefaciens and A. xylosoxidans compared with other cephalosporins.

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Cefoperazone (CPZ, T-1551), a new semisynthetic cephalosporin, was studied on the in vitro and in vivo antibacterial activities and the following results were obtained.
1) CPZ showed a broad antibacterial spectrum against gram-positive and gramnegative bacteria. Antibacterial activities of CPZ were especially more active than those of CEZ, CXM, CMD and CMZ against the main species of gram-negative rods, but were less active than other cephalosporins against gram-positive cocci.
2) Moreover, CPZ showed potent antibacterial activities against Enterobacter cloacae, Serratia marcescens, Pseudomonas aeruginosa and the other non-fermentative gramnegative rods which had almost resistance to other cephalosporins.
3) CPZ was very stable to various type of cephalosporinase, but not so stable to penicillinase.
4) In vivo antibacterial activity of CPZ was effective in experimental infection of mice caused by cefazolin-resistant E. coli. In experimental infection caused by P. aeruginosa, CPZ therapy was also effective.

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Bacteriological evaluation of a new cephalosporin for injection, cefoperazone (CPZ, T-1551), was conducted in comparison with cefazolin and cefmetazole.
CPZ exhibited a broad antibacterial spectrum covering gram-positive and gramnegative bacteria similar to that of cefazolin and cefmetazole.
CPZ showed superior antibacterial activity against gram-negative bacteria including Neisseria gonorrhoeae, β-lactamase induced bacteria and Pseudomonas aeruginosa than cefazolin and cefmetazole.
CPZ showed a dose-response bactericidal activity against Escherichia coli, Klebsiella pneumoniae and Serratia marcescens, and showed an almost similar activity against Pseudomonas aeruginosa as carbenicillin.
CPZ had an excellent therapeutic effect against mice experimentally infected with susceptible and resistant bacteria to cefazolin, i.e., CPZ's activity against Escherichia coli and Klebsiella pneumoniae was superior to cefazolin and cefmetazole, and also superior to carbenicillin against Pseudomonas aeruginosa, which means that the effectiveness of CPZ was confirmed in vivo as well as in vitro.
CPZ had a therapeutic effect against experimental infections with Proteus inorganii and Serratia marcescens similar to cefmetazole and superior to cefazolin, but against Proteus vulgaris inferior to cefmetazole.

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The antibacterial activity of a new cephalosporin antibiotics, cefoperazone (CPZ, T-1551) against Pseudomonas aeruginosa E-2 was examined from the viewpoint of morphological alteration in comparison with carbenicillin.
Scanning electromicroscopy revealed that when CPZ was activated even at the moment of onset of bactericidal effect, the shape of the bacteria was altered into a filament cells, i.e., no spheroplast-like structural change which was found at the time of carbenicillin activation was observed.
Possible influence on the ability to form spheroplast was studied using stabilizers.
CPZ exhibited little influence on spheroplast formation which differs from carbenicillin.

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General pharmacology of a new cephalosporin antibiotic, cefoperazone (CPZ, T-1551), whcih has the identical side chain to that of piperacillin, was investigated.
1) When CPZ was injected to mice in a dose of 2, 000 mg/kg intraperitoneally, no effect on ether anesthesia, pentobarbital sleep, pentetrazol convulsions, analgesic action and muscle-relaxing action, was observed.
2) Effects of CPZ on autonomic nervous system were investigated in situ and in vitro. No effect on respiration and ECG was observed, but slight elevation of blood pressure was observed in doses more than 100 mg/kg. This effect was not influenced by pretreatment of α-and β-blockers.
It stimulated intestine and inhibited trachea and uterus in vitro in concentrations more than 200 μg/ml.
3) When CPZ was injected to rats, it did not influence excretion of urine and of its electrolytes.

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Pharmacokinetics (blood and organ levels, excretion in urine, transfer to rat fetuses and binding to proteins) of cefoperazone (CPZ, T-1551), which has the identical side chain to that of piperacillin was investigated when mice, rats and rabbits were injected CPZ intravenously or intramuscularly.
When CPZ in a dose of 50 mg/kg was injected to rabbits (intravenously), rats (intramuscularly) or mice (intramuscularly), biological half-lives of CPZ were 46.51 min., 47.5 min. or 32.47 min., respectively. The biological half-lives of CPZ in the injected site of muscle were 30.39 min.(in the rats) and 18.05 min.(in the mice).
CPZ penetrated into the organs. Its concentration in liver was especially high and bile excretion was high. Blood and organ levels were proportionately elevated with doses when mice were injected CPZ in doses of 50, 100 and 200 mg/kg intramuscularly.
Excretion rates in urine were 23.5% of a total dose injected in rabbits (6hr. urine) and 15.74% in rats (24hr. urine).
A fetal level was 23.2% of a maternal blood level.
A binding rate of CPZ to human serum protein was 82.11% and binding coefficient (1/n) to bovine albumin was 1.9702. Partition coefficient to rat lipid in pH 7.0 was 0.0516.
Therefore, CPZ is rapidly absorbed, penetrates into organs and is excreted into urine and bile. It highly binds to serum protein.

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The antigenicity of cefoperazone (CPZ, T-1551), its cross reactivity with cephalothin (CET), cefazolin (CEZ) and aminobenzylpenicillin (ABPC) and Coombs test were studied in order to clarify the immunological characteristics of CPZ.
The results obtained were as follow.
1) Antibody production against CPZ was not observed in rabbits immunized withsingle administration of CPZ or with the emulsion of CPZ and Freund complete adjuvant (FCA).
2) Hapten-specific antibody production against CPZ was demonstrated by indirect hemagglutination test, hemagglutination inhibition test, 3 hr PCA and 3 hr PCA inhibition tests of guinea pigs in the rabbit serum hyperimmunized with BSA-conjugated CPZ and FCA.
3) IgE antibody production in mice immunized with the emulsion of CPZ. BSA and alminium hydroxide gel was not observed at all.
4) Anaphylactic syndrome was not observed in guinea pigs sensitized actively with CPZ or passively with rabbit anti CPZ serum.
5) Ability of CPZ to give a positive reaction in Coombs test was rather weak in comparison with CET or CER.

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Evaluation of the effect of cefoperazone (CPZ, T-1551) on the spiral and vestibular organ of the inner ear was performed in young rats of Wistar strain and the effect of CPZ was compared with that of kanamycin (KM). Fifty Wistar rats were divided into 5 groups. One of them was served as control and treated with physiological saline solution at dose of 10ml/kg/day for 4 weeks intravenously. CPZ was administered to 2 groups at dose of 1000mg/kg/day and 2000 mg/kg/day intravenously for 4 weeks, respectively. KM was given to 2 groups at dose of 200mg/kg/day and 400mg/kg/day intramuscularly for 4 weeks, respectively. The ototoxic effect was evaluated by differential frequency pinna reflex test in frequency ranging from 200 Hz to 20000 Hz before, during and after the administration of these drugs, and then investigated histopathologically on serial celloidin sections of the bilateral temporal bones. At the same time, the effect of these drugs on kidney and liver were investigated histopathologically.
The results obtained in present study were as follows;
1) In 20 rats receiving CPZ at both dose levels, there were no impairment in pinna reflex in the frequencies tested and histopathologically no remarkable change both in the cochlea and in the vestibulum. There was no remarkable change in kidney and liver.
2) In 10 rats receiving KM at 200 mg/kg/day, there was no impairment in pinna reflex, but histopathologically the loss of outer hair cells alone in the lower 1/4 of the first turn was observed in 80%. Inner hair cells were present. In the vestibular organs, scattered loss of hair cells was noted in 70%. There were slight pathologic changes in kidney and liver.
3) In 9 rats receiving KM at 400mg/kg/day, two rats showed the loss of pinna reflex. These two rats histologically, indicated extensive loss of outer hair cells and less extensive loss of inner hair cells. On the other hand, in the remaining rats without impaired pinna reflex, the loss of outer hair cells was rather extensive, but the missing of inner hair cells was unilaterally or confined to basal end of the first turn. In the vestibular organ, scattered loss of hair cells were noted in 100%. In kidney, scattered degeneration and necrosis combined with regeneration of the tubular epithelia and interstitial cell infiltration occurred frequently.
4) The present study indicates that as to ototoxicity, CPZ can be tolerated much better than KM.

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In vitro and in vivo antibacterial activity of cefoperazone (CPZ, T-1551) have been carried out, and the following results were obtained:
1) CPZ showed broad antibacterial spectrum against gram-positive and gramnegative bacteria.
2) The in vitro antibacterial activity of CPZ against clinical isolates of Serratia sp., indole (+) Proteus, Enterobacter sp. and Pseudomonas sp. was found to have more effective than cefazolin (CEZ) and cephalothin (CET).
3) Bactericidal activity of CPZ was studied, minimum bactericidal concentration (MBC) was almost the same as its minimum inhibitory concentration (MIC).
4) Antibacterial activity of CPZ was not affected by the change of pH and media, and addition of human serum to culture media.
5) Stability to β-lactamase extracted from penicillin and cephalosporin resistant clinical isolated bacteria was demonstrated. CPZ was very stable than CEZ and CET against cephalosporinase, and was similar to CEZ and CET against penicillinase.
6) On the protecting effects for systemic infections of various bacteria in mice, CPZ was more active than CEZ.

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The therapeutic effects of cefoperazone (CPZ, T-1551) on systemic infections in mice, subcutaneous abscess in mice and pyelonephritis in rats were studied in comparison with other antibiotics.
On systemic infections with Pseudomonas aeruginosa S-68 and Klebsiella pneumoniae Y-3 in mice, single administration of CPZ was less effective than frequent administration at intervals of one or two hours. CPZ was strongly remarkable over carbenicillin (CBPC) and cefazolin (CEZ).
With regard to the therapeutic effects on subcutaneous abscess in mice, CPZ was inferior to CEZ and cephalothin (CET) at low doses, but the same to both drugs at high doses in the infection with S. aureus F-142. But CPZ was superior to piperacillin (PIPC), CBPC and sulbenicillin (SBPC) in the infection with P. aeruginosa S-262.
On the therapeutic effects on pyelonephritis in rats, CPZ was superior to CEZ and CET in the infection with E. coli GN 3435, almost the same to CEZ and superior to CET in the infection with E. coli NIHJ JC-2. Moreover with regard to the infection with P. aeruginosa S-68, CEZ and PIPC were less effective than CPZ.

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The in vitro and in vivo synergistic activities of cefoperazone (CPZ, T-1551) and aminoglycosides, macrolides, or tetracycline against, clinical isolates of Serratia marcescens and Pseudomonas aeruginosa were studied.
The combinations of CPZ and aminoglycosides (gentamicin, amikacin, tobramycin, dibekacin) showed markedly synergistic activity in both in vitro antibacterial activity against S. marcescens and P. aeruginosa and protective effects on experimental infection in mice. And the combined actions were bactericidal.
On the other hand, in vitro combinations of CPZ and macrolides (kitasamycin, lincomycin, erythromycin) or tetracycline showed rather weak synergism.

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A microbiological method for the quantitative determination of cefoperazone (CPZ, T-1551) in body fluids is described. Determination of CPZ in serum and urine was made most suitably by a thin layer disc method using Micrococcus luteus ATCC 9341 for the test organism in a custom prepared medium containing polypeptone 6 g, beef extract 1.5g, yeast extract 3g, glucose 1g, agar 15g, distilled water 1 liter (pH 6.5-6.6). The inhibition zones of CPZ in human serum, Monitrol-I and Consera were narrower than that in M/15 phosphate buffer (pH 7.0). Human serum levels of CPZ obtained by the bioassay method using human serum as the diluent were in good agreement with results by high pressure liquid chromatography (HPLC). The limit of detection by the bioassay method was 0.39μg/ml in M/15 phosphate buffer (pH 6.0) and 1.56μg/ml in human serum. CPZ was stable at-20°C in human serum and urine.

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The absorption, excretion and tissue distribution of cefoperazone (CPZ, T-1551) were studied in various animals and human in comparison with cefazolin (CEZ), and the following results were obtained.
1) When CPZ was administered subcutaneously and intramuscularly to various animals at a dose of 20 mg/kg, the order of the peak serum levels of CPZ was shown as follows; monkey>rabbit>dog>rat>mouse. In monkey and rabbit, the serum levels of CPZ showed high and prolonged as compared with CEZ in cross over test.
2) In the biliary and urinary excretion of CPZ, a specific difference among various animals was found. CPZ was excreted mainly into bile in rat, while was excreted into urine in monkey, dog and rabbit.
3) When CPZ was administered intramuscularly to volunteers at a dose of 1000 mg, the mean peak serum level showed 78μg/ml after 1 hour, and its biological half life was about 120 minutes. The urinary excretion of CPZ was about 35% within 10. hours.
4) In mouse and rat, the tissue concentration of CPZ was lower than that of CEZ, but the ratios (tissue conc./serum conc.) of CPZ were higher than CEZ.
5) The excretion of CPZ to goat's milk was 0.0056% within 6 hours.
6) There is a remarkable species variation in the serum protein binding of CPZ, and it showed over 80% in monkey, rabbit and human serum.

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The serum protein binding rate of cefoperazone (CPZ, T-1551) was as high as that of cefazolin (CEZ) in human. Therefore, CPZ was investigated on the binding to serum and tissue proteins in detail, and the result was as follows.
The binding of CPZ to human serum protein was reversible similarly to CEZ. Moreover, it was found that the binding constant (K) and maximum binding number (n) for CPZ to human serum albumin were 2.63×10⁴ and 0.79, which were very similar to that for CEZ (K=2.56×10⁴, n=0.73).
The binding rate of CPZ to human serum albumin was influenced by the drug and albumin concentrations, but it was little influenced by the pH or temperature.
The affinity of CPZ to rat tissue pastes was determined by extraction of its free form by phosphate bufer. The result showed that most of CPZ was recovered by four extractions. The specificity of affinity of CPZ to each tissue was not found. The affinity of CPZ to liver and kidney pastes was little different from that of CEZ.

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Cefoperazone (CPZ, T-1551) is a newly developed cephalosporin antibiotic which, has been demonstrated to be bactericidal against gram-negative bacteria, especially Pseudomonas and Enterobacter. The present study was carried out to evaluate the acute toxicity of CPZ administered to mice, rats and beagle dogs.
The following results were obtained.
1) LD_5O values of CPZ were about 4 g/kg in mice and rats, and over 4 g/kg in dogs by intravenous injection, and over 15 g/kg, over 13 g/kg or about 9 g/kg in mice by oral, subcutaneous or intraperitoneal administration, respectively, and over 12 g/kg in rats by oral, subcutaneous or intraperitoneal administration.
2) In new born rats of 4 to 5 days old, LD₅₀ value of CPZ was about 5 g/kg by subcutaneous or intraperitoneal injection.
3) In mice and rats treated with CPZ at the higher dose levels, writhing, ascites and hyperemia of peritoneum were observed by intraperitoneal injection, and severe inflammation of injection area was seen by subcutaneous injection. By intravenous injection, significant pulmonary edema was noted, and the cause of death was the obstruction of the trachea based on pulmonary edema.
4) In beagle dogs received 6 g/kg of CPZ intravenously, all animals showed vomiting, soft stools, diarrhea, salivation and lacrimation during administration, and died 2 to 15 hours after injection with a large amount of hemorrhage in the intestinal canal. In dogs received 4 g/kg intravenously, vomiting, soft stools, diarrhea and salivation were seen during administration, and slightly temporary elevations in serum GOT, GPT, ALP, LDH and cholesterol with the peak at one hour after injection were observed, thereafter, no significant toxic signs were recognized.

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Cefoperazone (CPZ, T-1551) is a newly developed cephalosporin antibiotic which has been demonstrated to be bactericidal not only against gram-positive bacteria but also against gram-negative bacteria, especially Pseudomonas and Enterobacter. The present study was conducted to evaluate the subacute and chronic toxicities of CPZ administered to rats daily by intraperitoneal injection. Rats (72 males, 72 females) divided into four CPZ groups at dose levels of 4000, 2000, 1000 and 500 mg/kg/day, a cephalothin (CET) group at dose level of 2000 mg/kg/day and a saline control group were injected intraperitoneally once a day, 7 day a week, for a month in the subacute toxicity. Rats (100 males, 100 females) divided into four CPZ groops at the above dose levels and a saline control group were injected 6 days a week, for six months in the chronic toxicity.
The results obtained are as follows:
1) Temporary writhing was observed immediately after injection in rats receiving the higher doses of CPZ and CET. Soft stool and diarrhea appeared sporadically in the same groups.
2) The body weight gain was depressed in rats at 4000 mg/kg/day of CPZ for a month, and was also depressed in rats at 4000, 2000, 1000 and 500 mg/kg/day of CPZ for six months.
3) Increase in urine volume and excretion of Na into urine were found at the termination of the dosing period in male and female rats receiving 4000mg/kg/day of CPZ for six months.
4) Dose-related enlargement of the lumen of the cecum was observed in male and female rats treated with CPZ or CET. In addition rats receiving the higher doses of CPZ or CET had the symptom of peritonitis, such as hyperemia of the peritoneum, ascites, perihepatitis, perisplenitis, peripancreatitis and so on in both subacute and chronic toxicities.
5) Hyaline droplet degeneration in the proximal tubular epithelium was observed in rats receiving up to 1000 mg/kg/day of CPZ. This change was tended to be recovered in rats of recovery test.
6) Thus, the no effect intraperitoneal dose level of CPZ in rats was thought to be 500 mg/kg/day from the present experiment.

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In the previous papers, the acute toxicity test of cefoperazone (CPZ, T-1551) in mice, rats and dogs, and the subacute and chronic toxicity tests of CPZ in rats with intraperitoneal administration have been already reported. The present study was conducted to evaluate the toxicity of CPZ administered to beagle dogs daily by intravenous injection for 35 days.
Thirty-five beagle dogs (20 males, 15 females) divided into four CPZ groups at dose levels of 4000, 2000, 1000 and 500 mg/kg/day and a saline control group were injected iv once a day, 7 days a week, for 35 days. Six to eight dogs were used in each group.
The results obtained are as follows:
1) Dose-related vomiting, soft stools, diarrhea, sa, livation and lacrimation were observed throughout the duration of the study in groups receiving up to 1000 mg/kg/day. Three out of six dogs receiving the highest dose level of 4000 mg/kg/day suddenly began to have severe convulsions in response to stimulation by sound, light and touch at the latter half of the study. The three dogs were sacrificed on day 28 and 30 due to their moribund condition.
2) Slight decrease in RBC, hemoglobin and hematocrit, and slight elevations in serum GOT and GPT were observed in one out of seven dogs at 1000 mg/kg/day, one to two out of eight dogs at 2000 mg/kg/day and one to two out of three sacrificed moribund at 4000 mg/kg/day.
3) Most dogs in the highest dose group of 4000 mg/kg/day and a few dogs receiving 2000 and 1000 mg/kg/day had slight increase in the relative weights of liver, kidney and spleen. Histologically, drug-related renal lesions consisted of hyaline droplet degeneration of the epithelial cells of the proximal tubules and associated electronmicroscopic changes in dogs receiving the higher doses of 2000 and 4000 mg/kg/day of CPZ. There were no other significant findings in this study.
4) Thus, the maximum safety dose of CPZ in dog=is thought to be 1000 mg/kg/day from the present study.

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The subacute toxicity test of cefoperazone (CPZ, T-1551), a new cephalosporin antibiotic, was carried out in 16 crab-eating monkeys. CPZ was given im to each group (2 male and 2 female monkeys) at dose level of 100mg/kg/day, 200mg/kg/day and 400mg/kg/day, respectively for one month. As a control, physiological saline was given im to 2 male and 2 female monkeys for one month. The following results were obtained.
1) Signs of pain were observed immediately after injection of CPZ during all the experimental period in all of monkeys given CPZ at 400mg/kg/day and in a part of monkeys given CPZ at 200mg/kg/day. In addition, induration of injection site was recognized during the period from the 2nd week to the final week in monkeys of the same groups.
2) In monkeys received high doses of CPZ, hemorrhage, necrosis and inflammatory changes of the muscle of injection site were observed with the dose-relation, and in the same monkeys, number of leukocyte increased in association with the above changes. In monkeys given CPZ at 100mg/kg/day, changes of the muscle of injection site were the same degree as those of control, macroscopically and histologically.
3) In growth curves, urinary test, hematological examination, histological observation and electromnicroscopic observation of the liver and the kidney, there were no significant changes except the changes of the muscle of injection site.
4) Based on the fact that no significant changes of the muscle of injection site were found in monkeys given CPZ at 100mg/kg/day, the maximum safety dose of CPZ was thought to be 100mg/kg/day.

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This report is concerned with the reproduction study of rats given cefoperazone (CPZ, T-1551).
1) Fertility study
CPZ was administered subcutaneously to male rats at the dose of 125, 250 and 500mg/kg/day for 60 days from 6 weeks after birth prior to mating and then was continued to administer till the performance of copulation after mating and was also administered to female rats at the same doses from 2 weeks before mating to 7 days after pregnancy.
In male rats, dose-related inhibition of body weight and increase of water intake in group administered 500mg/kg of CPZ were observed. In female rats before pregnancy, inhibition of body weight was observed in all groups administered CPZ. Any abnormality of reproductive function was not observed in male and female in all groups. In the observation of external, internal and skeletal abnormalities of fetuses, there was no signiflcant difference between administered animals and the control.
2) Teratological study
Rats, 14 weeks old were used. CPZ was administered intravenously at the dose of 250, 500 and 1000 mg/kg/day to pregnant rats from the 7th to the 17th day of gestation. In dams, decrease of body weight in groups administered 250 mg/kg and 1000 mg/kg of CPZ was observed. In all groups administered CPZ, inhibition of food consumption and increase of water intake were observed. In female fetuses administered 1000 mg/kg of CPZ, inhibition of body weight was observed. External and internal malformation and skeletal variation were similar to those of the control. The delivering rates, the weaning rates and the survival rates of all treated groups had no significant difference from those of the control. Growth of offsprings of the treated groups had no significant difference from the control except inhibition of body weight of female offsprings in group administered 250 mg/kg of CPZ. There was no adverse effect on behavior, emotion, learning ability and fertility of offsprings.
3) Perinatal and postnatal study
Rats, 12 weeks old were used. CPZ was administered subcutaneously at the dose of 125, 250 and 500 mg/kg/day from the 17th day of gestation to the 21st day after delivery. In the pregnant period, any significant differences of body weight, food consumption and water intake were not recognized among each group, but after delivery, body weight and water intake of dam were significantly increased in all groups administered CPZ. The delivering rates, the weaning rates and the survival rates of all treated groups had no significant difference from those of the control. External malformation, growth, postnatal differentiation, behavior, emotion, learning ability and fertility of offsprings were normal in all groups.

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The present study was carried out to evaluate an influence of cefoperazone (CPZ, T-1551), cephalothin (CET) and cefazolin (CEZ) in combination with glycerolfurosemide on rat renal function and morphology. Since a mild degree of renal impairment is known to be induced with glycerol (4ml/kg) in rats, CPZ, CET or CEZ was given intravenously to rats at dose levels of 250mg/kg and 1000mg/kg, respectively, in combination with furosemide (50mg/kg) plus glycerol (4ml/kg) simultaneously. In addition, each antibiotic, mentioned above, was given alone to rats at 1000mg/kg, intravenously.
The following results were obtained.
1) In rats receiving CPZ, CET or CEZ at dose levels of 250mg/kg and 1000mg/kg in combination with glycerol+furosemide, increase in amount of urinary lysozyme (LZM) of 5-24 hr following their administration, BUN and serum creatinine at 24 hr after their administration was observed, and degenerative changes and focal necrosis of the renal proximal tubular epithelium were noted. These changes except LZM in rats given CPZ+G+F revealed the dose-response.
2) The renal functional damages, particularly reflected by value of urinary LZM, were milder in rats given CPZ+G+F than either in rats given CET+G+F or in rats given CEZ+G+F at both doses of 250mg/kg and 1000mg/kg. In rats given CET+G+F and in rats given CEZ+G+F, the damage was almost the same degree at each dose level of 250mg/kg and 1000mg/kg, respectively.
3) Histologically, the renal tubular damages were virtually the same in rats given 250mg/kg of CPZ+G+F, that of CET+G+F and that of CEZ+G+F respectively, and at dose level of 1000mg/kg, the damage was slightly milder in rats given CPZ+G+F than either in rats given CET+G+F or in rats given CEZ+G+F.
4) In rats given CPZ, CET or CEZ alone at 1000mg/kg, no significant changes were observed.

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Basic and clinical studies on cefoperazone (CPZ, T-1551), a new broad spectrum cephalosporin derivative with 2, 3-dioxopiperazine, were carried out and the following results were obtained.
1) The MIC value distribution of CPZ was examined by plate dilution method against 200 clinical isolates of Pseudomonas aeruginosa. The peaks of susceptibility distribution of CPZ at inoculum size of 10⁸ CFU/ml and 10⁶CFU/ml were 12.5μg/ml and 6.25μg/ml, respectively. These results were similar to those of piperacillin.
2) The serum level and half-life of CPZ were measured following drip intravenous infusion of 1 and 2g doses for 1 hour. The mean peak level at the end of administration was 130μg/ml, ranged from 95μg/ml to 200μg/ml and the serum level after 2g administration was twice as high as those of 1g. The mean serum half-life was 2.36 hour and the mean urinary recovery within 6 hour was 20.5±1.9%, respectively. In 2 patients with obstructive jaundice due to pancreatic cancer, the biliary levels of CPZ following intravenous administration of 1 g were studied. The biliary level after 6 hour obtained was 106 μg/ml in 1 case, however, in other case was below assay limit.
3) Nineteen patients with various infections (6 respiratory, 4 biliary and 7 urinary tract infections and 2 other infections) were treated with CPZ in daily doses of 2 to 4g for 7 to 16 days. The majority of them were in advanced age and 10 patients had underlying diseases such as diabetes. GNR were mainly isolated 23 out of 29 strains, which were composed of each 4 of E. coli, Klebsiella and Pseudomonas and others. Clinical responses were excellent in 9 cases, good in 8 and fair in 2. The effective rate was 89.5%.
As to the side effect, a rash was observed in 1 case. The elevations of ALP and transaminase were observed in 2 cases. One case accompanied with rash was thought to be due to the drug administration, however, another case seems to have no direct correlation with the drug. Also, a slight decrease in RBC, Ht and Hb in 2 cases was thought to he not associated with the drug administration. It is concluded that CPZ was useful to the treatment of various infections due to GNR.

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The minimal inhibitory concentrations (MIC) of cefoperazone (CPZ, T-1551) was measured against S. aureus, E. coli, K. pneumoniae, Proteus, S. marcescens and P. aeruginosa isolated from clinical materials. CPZ was administered to 23 cases of respiratory tract infections and 1 case of cholecystitis and 2 cases of urinary tract infections (UTI).
1) The MIC values of CPZ against over each 50% of strains of S. aureus, E. coli and K. pneumoniae were less than 1.56μg/ml, 50% of strains of Proteus was less than 3.13μg/ml, while about each 30% of strains of S. marcescens and P. aeruginosa were less than 6.25μg/ml.
2) Excellent clinical response was obtained in 2 cases of pneumonia. Good response was obtained in 16 cases of pneumonia, in 1 case of lung abscess, in 2 cases of acute bronchitis, in 1 case of cholecystitis and in 1 case of UTI. Fair response was obtained in 1 case of lung abscess. Poor response was obtained in 1 case of chronic bronchitis and in 1 case of UTI.
3) As side effect, rash was seen in 2 cases and elevation of transaminase was seen in 3 cases.

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Laboratory and clinical investigations of cefoperazone (CPZ, T-1551) were performed and results obtained were as follows.
1) Susceptibility of clinically isolated strains to CPZ was tested by the agar plate dilution method and compared with susceptibility to several antibiotics. The minimum inhibitory concentrations of CPZ for H. influenzae, Klebsiella, E. coli, Serratia, P. aeruginosa and Enterobacter were 0.2, 0.41, 0.68, 2.3, 7.1 and 0.28 μg/ml, respectively. Thus, CPZ has extremely wide antimicrobial activities among the antibiotics as far as tested.
2) Among 17 patients treated with CPZ for respiratory tract (in 15 cases) and other infections, clinical results were effective in 14 cases. No side effect clearly due to this drug was observed.

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From the results of in vitro tests a new semi-synthctic cephalosporin derivative, cefoperazone (CPZ, T-1551), was shown to be especially active against patient strains of gram-negative species, such as Pseudomonas aeruginosa, Klebsiella pneumoniae, E. coli and Enterobacter sp.
Twenty two patients of respiratory tract infections were treated by intravenous drip infusion of one to two grams of CPZ twice a day and in most of them a positive response was obtained.
No undesirable symptom was observed in them, except for drug fever in a patient and diarrhea in the other. A slight degree elevation of serum transaminascs and alkaline phosphatase was seen in a few cases during the course of the treatment with the drug but the deteriorations in laboratory findings were transient and the values returned to normal levels after with drawal of the agent.

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Cefoperazone (CPZ, T-1551) has been studied in clinic, and the following results were obtained.
1) CPZ was injected intravenously at a dose of 1, 000 mg into the 5 patients with various renal functions, and its concentrations in the blood and urine were determined. The CPZ concentration in the blood was 90 μg/ml 1 hour later in uremic cases. In contrast, 3 cases with Ccr. above 32.9 ml/min showed lower concentrations which had no appreciable deviations. Regardless of the degree of renal dysfunction, however, there was little difference between the CPZ concentrations in the blood in all cases between 4 and 6 hours after the injection. The serum concentrations of CPZ slowly declined to an undetectable level after 24 hours.
The urinary excretions were 2.0% and 0.37% in uremic cases and were below 30% in the other cases by 6 hours later.
2) CPZ was administered to 42 patients: 19 respiratory tract infection, 2 pyothorax, 11 biliary tract infection, 4 urinary tract infection, 1 myositis purulenta, 2 sepsis, and 3 fever of unknown origin.
Clinical results were excellent in 4, good in 21, fair in 2, poor in 7, and undetermined in 8.
Each patient sufferer from one of the following adverse reaction: drug fever, pain and diarrhea. The elevation of GOT was observed in 3 patients, the elevation of GPT in 4, the elevation of the bilirubin in 1, the decrease on Ht in 3, leucopenia in 2 and eosinophilia in 4, but no severe side effects caused by CPZ were observed.

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Clinical application of cefoperazone (CPZ, T-1551) was attempted in 10 patients with various infections.
A patient with biliary tract infection due to Klebsiella showed good response of CPZ therapy by ivd infusion of 3 g every 8 hours, though failed to respond to ivd administration of 1 g and 2 g of CPZ every 8 hours. In one patient with peritonitis clinical effect was good. In three patients with respiratory tract infection (two were pneumonia, one with secondary respiratory tract infection due to P. aeruginosa complicating lung cancer), therapeutic effects were good in one, poor in one, fair in one respectively. In five patients with urinary tract infection caused by 1 strain of Klebsiella, 1 of E. coli and 3 of various type of Proteus species, therapeutic effects of CPZ were good in four patients and poor in one, as replaced to P. aeruginosa from P. vulgaris.
Concentrations of CPZ in the sera were assayed by HPLC method and agar diffusion method with M. luteus ATCC 9341 in two patients in the therapeutic course of CPZ. The values of each serum concentration assayed by both methods were nearly coincident. In one patient aged 68 years with Ccr of 69.2 ml/min., serum concentrations of CPZ ranged from about 20 to 60 μg/ml and serum half life was about 4.5 hours after the 49th im injection of 1 g of CPZ every 8 hours. In another patient with Ccr of 5.2 ml/min., serum half life was about 6.5 hours.

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On cefoperazone (CPZ, T-1551), a new cephalosporin derivative developed, in vitro antibacterial activities against gram-negative bacteria were compared with a variety of cephalosporins and cephamycins using clinical isolated bacteria including E. coli, E. cloacae, E. aero genes, K. pneumoniae, K. oxytoca, K. ozaenae, P. mirabilis, P. vulgaris, Serratia, P. aeruginosa and H. influenzae. CPZ was found to be more effective than CEZ, particularly against P. vulgaris, Serratia and P. aeruginosa.
CPZ was tested to the following infectious diseases and the following results were obtained. It was effective to 2 out of 3 cases of acute bronchitis, to 6 out of 7 cases of chronic bronchitis, to 13 cases of bacterial pneumonia, to 1 case of bronchiectasis, to 4 cases of pyothorax, to 3 out of 4 cases of acute pyelonephritis, to 5 out of 6 cases of chronic pyelonephritis, to 1 case of U.T.I., to 2 cases of acute cholecystitis and none of 2 cases of F.U.O. It was effective to 37 out of 43 cases in total and effective rate was 86.0%.
Classifying on the strains of causative organisms, it was effective to 1 case of S. aureus, to 9 of 11 cases of Pseudomonas, to 1 out of 2 cases of Klebsiella, to 5 out of 6 cases of E. coli, to 1 case of Citrobacter and to 1 case of Acinetobacter.
Side effects were noticed in total 4 cases consisting of 3 drug fever (1 with rash) and 1 case of elevation in serum transaminase and ALP (with eosinophilia). These values returned to normal immediately after the cessation of CPZ therapy.

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The antibacterial activity, absorption, excretion and clinical effects on cefoperazone (CPZ, T-1551) were investigated and the following results were obtained.
1) Antibacterial activity
The antibacterial activities of CPZ against the following clinically isolates of E. coli, K. pneumoniae, S. marcescens and E. cloacae were evaluated. The activity of CPZ against E. coli and K. pneumoniae was inferior to that of cefotiam. Against the other bacteria tested, CPZ showed the same activity or more than 2 tubes superior to that of cefotiam and cefmetazole, more than 2 to 3 tubes superior to that of cefazolin and more than 4 to 5 tubes superior to that of cephalothin, cephaloridine or cephalexin. The activity against clinically isolates of P. aeruginosa was slightly inferior to that of cefsulodin or gentamicin, and almost same as that of piperacillin and 4 to 5 tubes superior to that of carbenicillin.
2) Absorption and excretion
The mean blood concentration after 5 minutes of intravenous injection of 1.0g of. CPZ was 110.53 μg/ml, and the mean half life was 0.15 hours in α-phase and 2.15 hours in β-phase. The mean urinary excretion after 1 hour of injection was 2553.3 μg/ml and the mean urinary recovery rate was 40.04% by 12 hours after intravenous injection.
3) Clinical effects
CPZ was administered to a total of 41 patients with respiratory tract infection, urinary tract infection, biliary tract infection, septicemia, peritonitis and retropharyngeal abscess.
Except for 2 unknown cases, among the 39 cases, CPZ was found to be excellent in 6 cases, good in 24 cases, fair in 6 cases and poor in 3 cases.
The side effects were rash in 1 case, serum transaminase elevation in 2 cases and cosinophilia in 1 case, but all were reversible and no other severe side effects were observed.

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On a new cephalosporin derivative, cefoperazone (CPZ, T-1551), several experiments were performed. Antibacterial activity of CPZ against clinical isolates of gram-negative bacilli was excellent regardless of difference of species. The correlation of MICs between CPZ and CEZ or CTX showed that activity of CPZ exceeded the former but was somewhat inferior to the latter.
The serum, biliary and urinary levels of CPZ injected to rats treated with CC14 to cause acute and chronic liver injuries were determined comparing with normal rats. In CC1, treated rats, biliary excretion reduced in proportion to the increasing of urinary excretion. Only the serum level of chronically injured rats was higher than the other two groups.
Clinically CPZ was given to four cases. Bacteriuria due to Pseudomonas aeruginosa in a patient with indwelling catheter responded well. As a result, one case of postoperative cholangitis was good, and two patients with pyrexia of unknown origin who had been suspected of sepsis were fair. In one case eruption appeared after the eighth day of treatment. After the cessation of administration, it subsided gradually. The abnormal finding was not observed on the clinical laboratory tests.

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Fundamental and clinical studies on cefoperazonc (CPZ, T-1551), a new cephalosporin, were performed and the following results were obtained.
The antibacterial activity of CPZ against E. coli, Klebsiella, Enterobacter, S. marcescens and P. aeruginosa was recognized to be superior to that of cefazolin (CEZ). Especially, with an inoculum of 10⁶ cells per ml, its activity was prominent. However, against S. epidermidis, CPZ was somewhat inferior to that of CEZ.
Serum level and urinary excretion were investigated in three healthy adults. At 30min, 1, 2, 4 and 6 hour after 1g intravenous injection of CPZ, mean serum levels wcre 89.0±11.1, 54.4±7.2, 31.1±4.6, 11.8±3.3 and 5.8±13μg/ml, respectively and the mean 6 hour urinary recoveries of about 23% were observed. When subjects were predosed with probenecid, serum level and urinary excretion of CPZ were not greatly influenced with probenecid.
The clinical effect of CPZ was evaluated in 2 cases of chronic pyelonephritis and 1 case of acute pyelonephritis, using 1 to 2g per day, and found to be effective in all these cases. No side effects were observed.

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Cefoperazone (CPZ, T-1551) has an excellent antibacterial activity against gramnegative bacilli, with a broad antibacterial spectrum. It shows an antibacterial activity similar to PIPC against P. aeruginosa and an activity far superior to ABPC against H. influenzae.
The blood concentration and the urinary excretion rate after 1g intravenous injection of CPZ were examined by cross-over method with CEZ. The blood concentration of CPZ was found to be slightly higher than that of CEZ and has a longer half life than that of CEZ. The excretion rate of CEZ was approximately 100% by 24 hours, while that of CPZ was approximately 35%.
The concentration in bile after 1g intravenous injection of CPZ was measured in two cases with biliary tract infection. The peak level was approximately 1000μg/ml in both cases.
Clinical evaluation was carried out in 13 cases of RTI, 7 cases of BTI, 2 cases of UTI and a total of 22 cases. Among the 13 cases of RTI, CPZ was effective in 8 cases and non-effective in 5 cases. Out of the 5 non-effective cases, CPZ was not indicated for four of them. CPZ was effective in 2 cases of serious infection. Therefore, CPZ might be effective for RTI.
Five of 7 BTI cases that showed clinical symptoms responded well to CPZ and bacteria in bile disappeared in 2 of 3 cases. CPZ was effective in 2 cases complicated urinary tract infection.
As side effects, 2 cases of eruption were observed among 22 cases. Changes of GOT, GPT and ALP were found in 4 cases of BTI before and after administration but these change were thought not to be related to CPZ.
From the results above, CPZ can be considered a new antibiotic which can be used effectively against RTI, BTI and UTI.

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Cefoperazone (CPZ, T-1551) is a new cephalosporin against a broad spectrum of gram-positive and gram-negative microorganisms.
Results of clinical evaluation in 8 cases of respiratory tract infections (5 cases of pneumonia, 2 of bronchiectasis, one of diffuse panbronchiolitis) administered 2-4g per day were remarkably effective in 4 cases (excellent), effective in 3 cases (good) and slightly effective in one case (fair).
As side effect, elevation of transaminase (S-GOT 33→100 u, S-GPT 23→58u) caused by CPZ administration was observed in only one patient and any other abnormality was not observed in hematological or urine examination.
It is considered that CPZ is a useful antibiotic for respiratory tract infections.

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Clinical study was made on cefoperazone (CPZ, T-1551), a new cephalosporin derivative, and the following results were obtained.
1) CPZ was found effective in 60% of 14 patients with intractable respiratory tract infections to whom other drugs had not responded well.
2) CPZ was found markedly effective in all of 5 patients with diffuse panbronchiolitis and pulmonary emphysema caused by H. influenzae. CPZ was slightly effective in 2 of 7 patients with diffuse panbronchiolitis caused by P. aeruginosa and gram-negative bacillus.
3) CPZ caused fever and diarrhea in one patient and eosinophilia in one patient, but these symptoms were reversible after cessation of drug.

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Serum concentration was determined in three aged patients after intramuscular injection of 1g of cefoperazone (CPZ, T-1551). Serum concentration ranged from 61 to 87.5μg/ml at a peak level, and decreased slowly to 24.5-37μg/ml at 6 hours after injection.
Clinical evaluation was performed on 2 patients with septicemia, 4 patients with UTI, 2 patients with pneumonia, 1 patient with decubital infection and 9 patients with hepatobiliary infection. Satisfactory response was obtained 1 patient with septicemia, 4 with UTI, 1 with pneumonia, 1 with decubital ulcer and 8 with hepatobiliary infection. CPZ revealed revolutional clinical effect on patients with ascending hepatobiliary infections, who had been undertaken hepatojejunostomy for carcinoma of bile duct.
Prothronbin prolongation and hemorrhage were observed in one patient with obstructive jaundice during the course of CPZ therapy.

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The clinical effects of cefoperazone (CPZ, T-1551), a new cephalosporin antibiotic, were observed in 24 cases of relapsed chronic bronchitis and 6 cases of pneumonia with underlying disease.
The background factors of these patients were mostly middle-aged or elderly in 40's and over. Two grams of CPZ were administered twice a day for 14 days on an average, intravenously. Efficacy rate of this drug was 83.3% in chronic bronchitis group and also 83.3% in pneumonia group.
No serious side effects were found on clinico-laboratory findings, although there were 2 cases with eruption and 1 with eosinophilia.
From the above results, the drug can be considered to be useful against the advanced chronic respiratory tract infections, such as relapsed chronic bronchitis, pneumonia with underlying disease.

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A new antibiotic, cefoperazone (CPZ, T-1551), was administered by intravenous drip infusion for 5-46 days at daily doses of 2-4 g to 18 patients, including 13 cases of pneumonia, 1 of lung abscess, 3 of acute pyelophritis and 1 of cholecystitis.
The results obtained showed to be effective in 9 cases out of 13 patients with pneumonia except one drop out (efficacy rate 75%), effective in one case with lung abscess and all of 3 cases with acute pyelonephritis, but ineffective in one case with cholecystitis.
Skin rash was noted in one case and elevation of serum transaminase was noted in on case. The value of transaminase returned to normal after discontinuation of CPZ.

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Cefoperazone (CPZ, T-1551) was evaluated in trials and the following results were obtained.
1) The MIC of CPZ was superior three to four steps or more to that of CEZ against E. coil, Klebsiella, Serratia, Enterobacter, P. aeruginosa and P. cepacia.
2) CPZ was administered to 17 patients with severe underlying disease in the field of internal medicine. As the result, CPZ showed good response in 11 and the efficacy rate was 64.7%.
3) No side effects were seen and abnormal values in liver and renal functions were thought to be due to underlying disease.
4) CPZ will be a useful antibiotic if propei choice will be taken into consideration.

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Laboratory and clinical investigation have been carried out on cefoperazone (CPZ, T-1551) and following results were obtained.
1) Minimum inhibitory concentration (MIC) of CPZ was determined in 178 clinical isolates compared with those of cefazolin (CEZ), cephalothin (CET) and cephaloridine (CER) by using the plate dilution method and antibacterial activity of CPZ was found superior to that of CEZ, CET and CER against E. coli, Citrobacter, Klebsiella, Enterobacter, Serratia, Proteus and P. aeruginosa.
2) Concentrations of CPZ in serum, sputum and spinal fluid were carried out in several patients receiving drip infusion at dose of 1 g or 2 g of CPZ for 2 hrs. Mean serum level exhibited a peak concentration after 2 hrs. started of drip infusion, on the other hand peak concentration of CPZ in sputum showed 4.6-9.8μg/ml by 1g and 36.5μg/ml by 2g with ethanol treatment. Spinal fluid concentration of CPZ was measured in a meningitis and 2.81μg/ml at 5 hrs. and 3.1μg/ml at 8 hrs. after the start of drip infusion 2 g of CPZ.
3) CPZ was administrated by intravenous drip infusion to 15 patients with respiratory tract infection (RTI), 2 patients with biliary tract infection (BTI), 2 patients with septicemia (one patient combinated meningitis) and 8 patients with urinary tract infection (UTI). Response was excellent in 2 patients and good in 10 out of 15 RTI, excellent in 2 BTI, excellent in 1 and good in 1 out of 2 septicemia, and excellent in 3 good in 3 out of 8 UTI.
4) Except for eosinophilia observed in 2 cases, no other adverse reaction or side effect were noted.

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Laboratory and clinical studies on cefoperazone (CPZ, T-1551) were performed and the following results were obtained.
1) Tissue concentrations in rats reached peak values at 30 minutes after subcutaneous administration and they were the following order of kidney, liver, serum and lung. Afterwards they decreased rapidly, and 4 hours later CPZ was not detectable in all organs except kidney.
2) In a patient with chronic renal insufficiency (under hemodialysis), serum concentration of CPZ, 24 hours after intravenous administration of 1g, showed high value (27μg/ml).
3) Clinical trial of CPZ were performed in 16 patients, 10 with moderate and serious respiratory tract infections, 3 with biliary tract infections and 3 with urinary tract infections. The treatment was markedly effective in 2, moderately effective in 10, ineffective in 2 and unevaluable in 2. Except for skin eruption observed in one case, no other adverse or side effects were noticed.

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Cefoperazone (CPZ, T-1551), a new cephalosporin, was applied to the treatment of 14 patients with respiratory tract infections.
The drug was administered intravenously, 4 g/day, divided into two doses, for the period of 7-14 days mainly.
The results were as follows, excellent in two cases, good in five cases, slightly good two cases and ineffective in one case. Remaining three cases were excluded due to unsuitability for CPZ therapy (tuberculosis, sarcoidosis, aspergillosis). Effectiveness rate was 70%.
Drug eruption and fever were observed in one patient, and elevation of GOT, GPT was observed in another patient.

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Cefoperazone (CPZ, T-1551), a new cephalosporin with antipseudomonal activity stability of β-lactamase, were carried out and the results obtained were as follows.
1) The antibacterial activity of CPZ against S. aureus, E. coli, Klebsiella, P. mirabilis, P.vulgaris and P. aeruginosa isolated from clinical specimens was compared with that cefazolin. Peaks of MIC distribution of CPZ against such various clinical isolates were 1.56, 0.2-3.13, 0.39, 1.56, 0.78 and 3.13 μg/ml at a lower inoculum size, respectively.
The antibacterial activity of CPZ against Klebsiella, P. mirabilis, P. vulgaris isolated from clinical specimens was more excellent than that of cefazolin, and against S. aureusit was inferior to that of cefazolin. Against E. coli, CPZ showed generally stronger activity than cefazolin, but in part there were a few nonsensitive strains to CPZ.
The antibacterial activity of CPZ was influenced by the inoculum size and the antibacterial activity decreased with the increase of inoculum size, especially against E. coli and P. aeruginosa.
2) CPZ was administered to one case with sepsis, two cases with infected lung cancer, one case with liver abscess, one case with pyelonephritis and one case with miliary tuberculosis, totally six cases, at a daily dose of 2-6 g for 4-29 days by intravenous drip infusion.
The clinical effects obtained were excellent in one case, good in two cases and poor in two cases with infected lung cancer, and one case with miliary tuberculosis was excluded by reason of unsuitability for CPZ therapy.
Side effects noted were fever in one case and rash with eosinophilia in one case.

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Cefoperazone (CPZ, T-1551), a cephalosporin derivative, was examined on its in vitro anti-bacterial activity against bacteria isolated from human infection foci, as well as on its distribution in the body. Some clinical trials were also carried out. The results obtained were as follows:
1) In vitro antibacterial activity: As to Staphylococcus aurcus strains, CPZ was found to be superior to carbenicillin and piperacillin, but inferior to other cephalosporins examined (cefazolin, cephalothin, and cefmetazole). CPZ was found to have a great advantage of the activity against most of GNB, i.e. E. coli, Klebsiella pneumoniae, as well as Serratia and Pseudomonas aeruginosa. In addition, the drug has an distinctive feature: Hundred-fold dilution of the bacterial inoculum caused remarkable descent of MIC, thus rendering even resistant bacilli to quite sensitive. That is to say, the superiority of CPZ was magnified by the dilution of the inoculum.
2) Distribution in the body: A preliminary experiment revealed that the assay method using Micrococcus luteus ATCC 9341 as the test organism and the nutrient agar as the culture medium was appropriate for measurement of the drug concentration in body fluids. Rats administered with CPZ (20mg/kg or 100mg/kg im) showed highest concentration in the liver, followed by the blood, kidney and lung. Such a distribution pattern has never been seen hitherto in our studies on cephalosporins. One of the patients receiving drip infusion of CPZ (2g in 1.5 h.) showed serum concentration of 195μg/ml at the end of the infusion, and 14μg/ml 7.5 h. thereafter, the urinary excretion rate being 86% in 7.5 h.
3) Clinical trials: Thirteen patients (E. coli sepsis 1; R.T.I. 5; B.T.I. 5; U.T.I. 2) were treated with CPZ (2-4g/day, mostly by iv drip infusion) Those patients, excepting one, had some underlying disease. Eleven of them responded to the therapy, at least fairly. Neither clinical side effects nor changes in laboratory data attributable to the drug were observed, except for slight elevation of serum transaminases in one case.
These results obtained suggest that CPZ can be expected as an excellent new antibiotic for treatment of GNB infections.

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Laboratory and clinical investigation on cefoperazone (CPZ, T-1551) were performed and the results were obtained as follows.
1) Sensitivity of clinically isolated strains to CPZ was tested by agar plate dilution method and compared with that of CEZ and CER. The antibacterial activity of CPZ against most of clinical isolates was found to be superior to that of CEZ.
2) CPZ was administered to 9 cases with respiratory tract infection and 1 case with sepsis. The results were evaluated as 7 cases good, 1 case fair, 1 case poor and 1 case unknown.
No side effect was observed in all patients.

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Cefoperazone (CPZ, T-1551) was used in the treatment of respiratory tract infection: 4 cases of pneumonia, 2 cases of lung abscess, 7 cases of chronic bronchitis and 7 cases of bronchiectasis. The drug was administered by intravenous drip infusion at a daily dose of 2g to 4g.
Nine out of 20 cases, the causative bacteria were isolated from sputum: Haemophilus influenzae 8 cases, Streptococcus pneumoniae 1 case and Pseudomonas aeruginosa 1 case.
We estimated the effectiveness of the drug from the improvements in subjective symptom, laboratory data, radiological findings and bacteriological effect. The effect was excellent in 9 cases, good in 9 cases, fair in 1 case and poor in 1 case. The rate of effectiveness was 90%.
Side effects were found in three cases: fever in 1 case, fever and eruption in 1 case and elevation of GOT, GPT in 1 case. But they were not so severe that they improved without treatment.

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Laboratory and clinical studies on cefoperazone (CPZ, T-1551), a newly developed broad-spectrum cephalosporin antibiotic were carried out with following results.
The in vitro antibacterial activity of CPZ was determined against 20 standard strains and 1, 013 routine clinical isolates including Enterobacteriaceae, non-fermentative gram-negative bacilli and Haemophilus species in comparison with those of antibiotics (cefazolin, cephalothin, cefamandole, cefotiam, cefmetazole, cefuroxime, aminobenzylpenicillin, ticarcillin and sulbenicillin).
CPZ was not so active against Staphylococcus aurcus compared with CEZ, CET, CMD, CTM, CMZ and CXM. On the contrary, CPZ was the most active against Enterobacter cloacae, E. aerogenes, Citrobacter freundii, C. diversus, Proteus morganii, P. rettgeri, P. inconstans, Serratia marcescens, Pseudomonas aeruginosa, P. maltophilia, Aeromonas hydrophila, Vibrio parahaemolyticus, Haemophilus influenzae, H. parainfluenzae and H. parahaemolyticus.
CPZ was administered to three patients with pulmonary infections at a dose of one gram by intravenous drip infusion for one hour. The peak serum levels were 235-250μg/ml at the termination of infusion and CPZ was still detectable at 6 hours after infusion. Two patients were given at a dose of two grams, the peak levels obtained at the end of infusion were 250-267μg/ml and 17μg/ml of CPZ was measurable at 6 hours after injection. Urinary recovery rates of CPZ after intravenous drip administration of one and two grams were 43.2-57.8% and 29.7%, respectively.
CPZ was administered to a patient with chronic bronchitis at a dose of one gram by intravenous drip infu/sion, the peak sputum level of 1.2μg/ml was assayed at 3 hours, Streptococcus pneumoniae in sputum began to decrease in number from 10⁷ to 10⁴/ml during the 11-hour study. This organism was eliminated from the sputum from the second day. Twenty-one patients with respiratory infections and 3 with urinary infections were treated with CPZ by intravenous drip infusion. Eighteen out of 23 evaluable respo nded effectively to the treatment and efficacy rate was 78.3%.
Six strains of Streptococcus pneumoniae, one of S. aureus, 2 of H.influenzae, 2 of E. coli and 2 of K. aerogenes were eliminated and bacteriological efficacy rate was 86.7%
Total 5 patients showed the following adverse reactions;eosinophlia in 2, an elevation of BUN in I and that of alkaline-phosphatase in 1.

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Cefoperazone (CPZ, T-1551) is a new semisynthetic cephalosporin antibiotics, which possesses much the same moiety, or 2, 3-dioxopiperazine ring, as piperacillin has. Clinical and laboratory study has been performed on CPZ in order to evaluate its usefulness mainly in respiratory tract infections.
Antibacterial activity of CPZ was superior to the other broad-spectrum cephalosporins against respiratory pathogenic Streptococcus pneumoniae, Haemophilus influenzae, Pseudomonas aeruginosa, and Klebsiella pneumoniae. Stability to β-lactamase was established, utilizing β-lactamase-producing ampicillin-resistant Haemophilus influenzae (4 strains) and Haemophilus parainfluenzae (1 strain). This cephalosporin antibiotic combined with netilmicin, a new aminoglycoside, was synergistic against 17 strains of Pseudomonas aeruginosa isolated from a patient with the serious respiratory tract infection caused by Pseudomonas aeruginosa, by the method of checkerboard dilution.
The concentration of CPZ in serum, sputum, and other specimens was determined by either a cup or an agar-well method, using Proteus mirabilis ATCC 21100 as the test organism. The minimum measurable concentration of the cup method was as low as 0.01μg/ml, and that of the agar-well method was 0.5μg/ml. Concentration of tissues in rats after intramuscular injection of 100mg/kg or 20mg/kg was in order: Serum>Kidney>Liver>Lung.
The serum half-life of CPZ in a patient was approximately two hours. Ratios of maximum sputum level to peak serum concentration ranged from 0.196% to 1.36% in five patients with chronic respiratory tract infections, while ratio of maximum intrabronchiolar level to peak serum concentration was as high as 12.4% in a patient with chronic bronchiolitis.
An experiment on experimental Kiebsiella pneumoniae B-54 pneumonia in mice demonstrated expected superiority over cefotiam as well as cefazolin.
Thirty-three respiratory tract infections and four urinary tract infections were subjected to clinical evaluation of CPZ, indicating favorable clinical response, that is, the rates of clinical therapeutic efficacy were 81.8% and 100%, respectively. Two of them showed reversible slight elevation of transaminases with or without that of alkaline phosphatase. The safety of the antibiotic was good.
From the above results, CPZ is a useful cephalosporin antibiotics, in terms of high activity against respiratory pathogenic organisms including Pseudomonas aeruginosa, stability to β-lactamase, favorable clinical effectiveness, and good safety.

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Cefoperazone (CPZ, T-1551), a new cephalosporin antibiotic, was studied fundamentally and clinically, and the following results were obtained.
CPZ was compared with cefazolin and piperacillin in antibacterial activity against gram-negative bacilli and gram-positive cocci isolated from clinical materials. Against gram-negative bacilli CPZ was the most active than cefazolin. Against Pseudomonas and S. marcescens CPZ showed equal activity to piperacillin.
As the result of CPZ treatment, CPZ was effective in all 11 cases (8 with respiratory tract infection, 1 with biliary tract infection and 2 with urinary tract infection).
No side effects were observed with CPZ in hemogram, liver function, kidney functinn and others.

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A new cephalosporin, cefoperazone (CPZ, T-1551), was evaluated in regard to MICs to 131 strains of various clinical isolates and passage into the CSF in experimental staphylococcal meningitis in rabbits, and the following results were obtained.
1) MICs of CPZ to 15 strains of Staphylococcus aureus were higher than those of cefazolin by fourfold, and those to gram-negative rods were superior to those of cefazolin. However, CPZ was much affected by the inoculum size. Peak concentrations of MIC distribution at the inoculum size of 10⁶/ml of the following isolates were as follows; E. coli (32 strains), 0.1-0.8μml: Salmonella typhi (3), 0.4μg/ml: Salmonella Group B (1), 0.8μg/ml: Klebsiella pneumoniae (5), 0.4μg/ml: Klebsiella oxytoca (43), 0.8-1.6μg/ml: Proteus mirabilis (8), 0.8-3.1μg/ml: Proteus vulgaris (1), 6.3μg/ml: Proteus morganii (2), 0.8-1.6μg/ml: Proteus rettgeri (1), 25μg/ml: Enterobacter (3), 0.8-50μg/ml: Citrobacter (2), 1.6-3.1μg/ml: Serratia marcescens (5), 0.8-3.1μg/ml: and Pseudomonas aeruginosa (10), 3.1μg/ml.
2) Blood and CSF concentrations of the drug were determined at 30-min interval following a single one shot intravenous injection of 100mg/kg in 6 rabbits with experimental staphylococcal meningitis. Peak concentration in CSF was obtained 60-min after the injection, i.e., 6.7±1.39μg/ml, with a CSF/serum ratio of 6.4%.
3) Other 5 rabbits with experimental meningitis were given the same dose similarly, and blood and CSF concentrations were determined at 15-min interval for 8 times and twice at 30-min interval, 10 times in total. Pharmacokinetics of CPZ were evaluated on the basis of the above results. Two out of 5 rabbits gave very high CSF concentrations. An average of CSF concentrations of other 3 rabbits was maximal at 45 min, i.e., 6.57±0.66μg/ml; the area under the curve (AUC) up to 3 hrs, 666.68 min·μg/ml: percentage of CSF/serum ratio of the AUC, 13.7%: T1/2 of CSF concentration, 54.2 min, i.e., 1.31 times higher than that of blood. These results were better than those reported with penicillin G, methicillin and cephalothin, and almost comparable to those of ampicillin and cefazolin.
4) Protein binding rate of the drug in human subjects and rabbits was about 86% and was the second highest among cephalosporins next to cefazolin. Combined results of the previous and present studies suggested that the extent of passage of the cephalosporins into the CSF was not always correlated with the protein binding rate and demonstrated that there was no relationship between the disappearance rate from the CSF of a cephalosporin and its protein binding rate.
5) The above results appeared to indicate that CPZ is a potent new antibiotic in the treatment of bacterial meningitis in human subjects. The drug should first be tried clinically in ampicillin-resistant Haemophilus influenzae meningitis.

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Clinical effect and excretion into peritoneal exudate of a new cephalosporin, cefoperazone (CPZ, T-1551), were studied.
Two grams of CPZ was administered intravenously twice a day and total dosage was ranged between 32g and 96g.
CPZ was given in 10 cases of surgical infections; 5 cases of acute purulent peritonitis in which a case with septicemia was involved, and each one case of subphrenic abscess, acute cholecystitis, aspiration pneumonia, empyema and acute pleuritis. Clinically favorable results were observed in 4 cases (40%), poor effect in 1 case and fair in the other 5 cases.
Out of 14 cases including 4 cases of prophylactic use, no subjective, nor objective adverse effects were noticed. On laboratory examination elevation of s-GOT and s-GPT which was possibly due to the drug was revealed in one case.
Excretion of CPZ into peritoneal exudate collected through the catheter left in the left subphrenic space at the end of operation were observed in 5 patients.
In 4 postoperative cases of gastric carcinoma daily amount of exudate was maximum in the first 24 hours, then decreased gradually. In contrast, in the postoperative case of acute peritonitis the amount was much larger and had a peak on the second day.
The concentration of the antibiotic increased day by day up to 30μg/ml in 4 cases which was considered to be a character of CPZ as well as the high serum protein binding capacity.

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