The results of experimental and clinical studies on a cephalosporin derivative for oral use, cefatrizine, performed by 72 institutions in this country were summarized in this paper. The conclusion obtained is as follows.
1. Bacteriological results
The antibacterial spectrum of cefatrizine was about the same as those of other cephalosporin derivatives, but cefatrizine was superior to cephalexin in the sensitivity distribution of clinical isolates.
2. Absorption, excretion and metabolism
The serum concentration and urinary excretion of cefatrizine were lower as compared with those of cephalexin by means of cross-over method. Cefatrizine was not metabolized in the human body.
3. Clinical results
A total of 1, 074 cases with infections in the field of internal medicine or surgery were treated with cefatrizine. Response was good in more than 80% of the cases with infections in the field of internal medicine and in the 70% level of those with surgical infection. Cefatrizine was active against infections due to Strept. pneumoniae, β-hemolytic Strept., Staph. aureus, E. coli, Proteus mirabilis and Klebsiella. Cefatrizine was given at a single oral dose of 1, 000 to 3, 000 mg 2 to 4 times a day, as an adults dose. As side effects, eruption and gastrointestinal symptoms were mainly observed, and its frequency was 4.7% in the cases with infections in the field of internal medicine and 5.5% in those with surgical infection. No severe side effects were observed in the present series.

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Antibacterial activity of cefatrizine (CFT), a new oral cephalosporin antibiotic, was examined in comparison with cephalexin (CEX), and the former was found superior in antibacterial activity both in vitro and in vivo.
With regard to the in vitro antibacterial activity, CFT was stronger than CEX, either in minimum inhibitory concentration (MIC) or in bactericidal action.
As for the antibacterial activity in vivo, CFT protected more strongly against mice infection with E. coli, Klebsiella and P. mirabilis, and ED₅₀ of CFT was less than one twentieth that of CEX.
CFT showed nearly the same maximum serum concentration with CEX, which was attained at about 30 minutes after the administration, not markedly different between the two. CFT was later than CEX in excretion, thus maintaining the longer effective serum concentration.

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Antibacterial activities of cefatrizine against 882 strains complied with Staphylococcus aureus, hemolytic Streptococci, Enterococci, Streptococcus pneumoniae, Haemophilus, Escherichia coli, Klebsiella, Citrobacter, Serratia, Proteus and some anaerobic bacteria isolated from clinical materials for two years from 1974 to 1975 were compared with cephalexin, cephalothin and cefazolin by plain agar diluted method.
Cefatrizine demonstrated stronger antibacterial activities against almost all the strains than those of cephalexin, and in not a few cases antibacterial activities of cefatrizine were 2 to 4 times or more when compared with cephalexin.
In comparison with cephalothin or cefazolin antibacterial activities of cefatrizine were slightly superior in some organisms but mostly same or slightly inferior.

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Cefatrizine (CFT), a new oral cephalosporin antibiotic, was evaluated in vitro against gram-negative and gram-positive bacteria.
The results are summarized as follows :
1. The antibacterial spectrum was similar to that of previously reported cephalosporin analogues.
2. The antibacterial activity against the clinical isolates of E. coli, Salmonella, Klebsiella, Staphylococci and Streptococci was demonstrated to be good.
3. Pseudomonas strains or the most of Proteus strains were resistant to cefatrizine.
4. Cefatrizine was relatively stable against β-lactamases extracted from E. coli, E. freundii, Proteus, Pseudomonas or Staphylococcus.
5. ICR strain mice were infected intraperitoneally with 3 × 10⁶ cells (2. 4 MLD) of E. coli and administered per os with CEX or CFT 60 minutes after infection. Survival rates were determined 7 days after infection and ED50 of each antibiotic was calculated by the method of WEITZ, J. A.
The results indicate that CFT is significantly effective against infection with E. coli as compared with CEX.

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Cefatrizine, a new derivative of cephalosporin, was investigated in comparison with cephalexin, cephaloridine, cephalothin, cephapirin, cefazolin, ampicillin and penicillin G on the action of β-lactamases produced by Escherichia coli, Klebsiella pneumoniae, Hafnia alvei, Serratia marcescens, Enterobacter aerogenes, Yersinia enterocolitica and Streptomyces sp.
Results indicated that cefatrizine and cephalexin displayed a similar pattern of susceptibility to hydrolysis by the β-lactamases. Both were very stable to the β-lactamases of penicillinase type and were less susceptible than other cephalosporins to that of cephalosporinase and intermediate type.

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A new cephalosporin derivative, cefatrizine (CFT) was evaluated bacteriologically in comparison with cephalexin (CEX) as a control drug. The result obtained was that CFT has broad spectrum of antibacterial activity against both Gram-positive and Gram-negative organisms as CEX does, and that CFT's antibacterial activity (MIC) was 2 to 8 times and 4 to 8 times stronger in Gram-positive and Gram-negative organisms respectively when compared with CEX.
We examined the sensitivity distribution of CFT against clinically isolated E. coli and Proteus sp.and sensitivity correlation. Sensitivity distribution of CFT was approximately 6. 25 μg/mi in E. coil and moved to 1. 56 μg/ml in 10^-2 diluted solution of E. coli, therefore, it indicates that sensitivity distribution was influenced by the inoculum size. Sensitivity distribution of CFT against Proteus sp. was about 1. 56 μg/ml. The antibacterial activity of CFT was 2 to 8 times stronger against both organisms when compared with CEX. In the evaluation of sensitivity correlation between CFT and CEX there observed almost no correlation in E. coli except some organisms, and in Proteus sp. almost no correlation was noted except resistant strains more than 100 μg/ml.
In influence of various factors on in vitro antibacterial activity, the antibacterial activity was enhanced when the pH of culture media ranged in acid and the inoculum size decreased. Addition of horse serum showed almost no influence on the antibacterial activity.
According to our new findings, in evaluating bactericidal activity of CFT by disk diffusion method, turbidimetry and method for viable cell count CFT had strong bactericidal activity during a shorter time when compared with CEX, and it was certified morphologically, too.
Lastly, curative effect of CFT was investigated using experimentally infected mice. CFT was more effective on the infections induced by both Gram-positive and Gram-negative organisms than CEX was.
Treatment time and frequency of the administration were also studied. As the result, the commencement of the treatment was most effective during the time two hours before and after the infection. Concerning the frequency of the administration the most favourable effect was observed in one administration of CFT while CEX showed best effect in two administrations.

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Since cefatrizine is unstable in vitro, a fixed method to determine its tissue distribution was deviced. Although considerably accurate result will be obtained by this method, experimental conditions or dealings of the specimens may produce some difference. Therefore, two determination curves will be recommended to be used to obtain the values as accurate as possible. From the characterisitc of this agent, authors endeavored to minimize the lowering of antibacterial activity of cefatrizine in vitro.

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1. Antibacterial activities of cefatrizine (CFT) and cephalexin (CEX) against 20 strains of Staphylococcus aureus, 23 of Escherichia coli and 7 of Klebsiella isolated from patients were examined using the plate dilution method. The MICs of CFT against Staphylococcus aureus and Escherichia coli were found to be 2 to 4 times lower than those of CEX. Similar results were obtained with Klebsiella. Probable cross resistance was found between these 2 cephalosporins.
2. Absorption and excretion of the drug were examined in 4 patients without renal and hepatic impairment following 250mg single oral administration 1 hour after breakfast. Mean peak level of 3. 6μg/ml was obtained 4 hours after dosing. Cumulative urinary excretion in these subjects was variable (28-65%), and in one case no activity was found in urine. Urinary pH of the patient was over 8, and she has had bacteriuria.
3. Forty patients with various infections including 11 with tonsillitis, 13 with bronchitis, 14 with urinary tract infection and others were treated with the drug orally. Thirty-three patients responded favourably to the treatment, 2 failed and 5 were unassessable. No gastrointestinal disorder nor allergic reactions had been shown. There were 2 female patients showing decrease of RBC and hemoglobin content after the treatment, but no significant relation to the drug administration was found.

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Fundamental and clinical studies on a new compound of cephalosporins, cefatrizine, were carried out and the following results were obtained.
1. Serum levels and urinary excretion after the oral administration of 1.0g of cefatrizine to 3 healthy adults and 3 patients with impaired renal functions showed as follows : Serum peak levels and half life times of cefatrizine were 6.6-15. 2μg/ml and 0.76-1.20 hours, respectively, in 3 healthy adults and 2 out of the 3 patients whose creatinine clearance had 61. 6 and 51. 6ml/min., respectively, indicating no significant difference among these 5 cases. In one patient (creatinine clearance 23. 1 ml/min.), however, the serum peak level was 30.4μg/ml, and the half life time revealed 2.04 hours which may suggest a retention of cefatrizine in blood.
Urine levels at intervals of 2 hours for 6 hours after cefatrizine administration were 420-5, 000μg /ml in the group of healthy adults and 250-6, 900μg/ml in the group of the patients. The urinary recovery during 6 hours from healthy adults and the patients showed 23.9-74. 1% and 11.3-59.4%, respectively.
2. To detect metabolites in serum and urine after oral administration of cefatrizine, bioautographies used with thin layer chromatographies did not show any active substances except cefatrizine itself.
3. Cefatrizine administered to 21 patients with respiratory or urinary infections was effective clinically in 19 cases (90%), while no effects were seen in 2 cases.
4. The following side effects were observed : epigastralgia and diarrhea in each one case and a slight elevation of transaminase in 2 cases.

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Cefatrizine was applied in 22 cases of which 19 were pulmonary, 2 were intestinal tract, and L was urinary tract infection.
The daily doses were from 750 mg to 2, 000 mg, and the results obtained were excellent in 5, good in 10, slightly good in 7.
No side-effect was noticed clinically and in renal, liver and bone-marrow functions.

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Antibacterial activities of cefatrizine (CFT) were examined. The growth of all 5 clinical isolates of Staphylococcus aureus was inhibited by the drug. About a half of 16 patient strains of Klebsiellapneumoniae were inhibited, but the remaining strains were not. None of 7 clinically isolated strains of Pseudomonas aeruginosa was sensitive to the drug.
Clinical evaluation of cefatrizine was made on 8 patients with respiratory infectious diseases. In a patient with primary lung abscess, an excellent therapeutic effect was obtained by the oral administration of 2g daily dose of the drug. In 2 out of 4 patients with primary pneumonia, the therapeutic effect was good, but in the other two the responses were not satisfactory. Of 3 patients with secondary bacterial infections to underlying respiratory diseases, only a patient showed a good clinical and bacteriological response.
The values of laboratory tests on kidney and liver functions remained in normal ranges after the administration of the drug, except for a patient in whom a moderately elevated S-GPT value was observed, probably because of co-existence of biliary tract infection.

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Cefatrizine, a new oral cephalosporin, was applied to 20 patients with respiratory infection. The drug was administrated orally for 16-61 days at a daily dose of 1. 5-2. 0 g. Total dosage was ranged 32-122 g.
1) The results obtained were excellent in 2 cases, good in 14 cases, fair in 2 cases and poor in 2 cases out of 20 cases, showing effectiveness in 18 cases (90%).
2) Out of 15 cases of pneumonia, excellent in 2 cases, good in 11 cases, fair in 1 case and poor in 1 case. CFT was good to pulmonary suppuration, chronic bronchitis complicated with pneumonia, bronchiectasis with pneumonia, but poor was noted in bronchiectasis with pulmonary suppuration. Fair was ohserved on infections accompanied by pulmonary tuberculosis.
3) No abnormality was revealed by the clinical examinations in either the blood picture or the hepatic and renal functions, except fever and drug eruption in 1 case.

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Antibacterial activity, absorption and excretion as well as clinical efficacy of cefatrizine were studied, and following results were obtained :
Antibacterial activity of cefatrizine against clinically isolated E. coli and Klebsiella pneumoniae was 2 to 3 times superior to cephalothin, cephaloridine and cephalexin, and was very similar to cefazolin.
The peak blood level of 12.5-19.8 μg/ml was obtained 2 hours after 1.0g single oral administration of cefatrizine. Cefatrizine disappeared from the blood with 2.9 hour half life, and its blood. level became 2.4-2.6μg/ml 6 hours after dosing.
When cefatrizine was given concomitantly with probenecid, higher blood concentration than that of cefatrizine alone was observed, and the prolonged half life until 4 hours was noted.
Urinary recoveries in healthy patients for 6 hours after 1.0 g administration were 33-42%.
Twenty patients with bacterial pneumonia (1 case), chronic bronchitis (1 case), cholecystitis (1 case) and urinary tract infections (17 cases) were treated with cefatrizine at daily doses of 1.0-2.0g and 19 of them showed marked effectiveness.
As to the side effects, no unfavourable reaction has been noted so far.

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The investigations on a new antibiotic, cefatrizine, were performed, and the following results were obtained.
1. The drawing of standard curve for bioassay of cefatrizine and the method of treatment of clinical specimen to be tested were examined.
2. From our bioautogram, there found no bioactive metabolite in human urine collected dividedly after cefatrizine administration.
3. Clinically cefatrizine was administered to three cases of respiratory tract infection and two of urinary tract infection, all of them being evaluated as effective.No side effects were observed.

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Cefatrizine (CFT) is a new cephalosporin developed by Bristol Laboratories (U. S. A.). This report describes the studies of antibacterial activities and the absorption and urinary excretion as well as the clinical trial with this drug.
CFT was more active than CEX against Staphylococcus aureus, E. coli and Klebsiella clinically isolated.
In the peak of absorption and the rate of urinary excretion, CEX was higher than CFT. The serum concentrations were 2.86 and 4.4μg/ml at 1 and 2 hours after oral administration of 500mg of CFT, although those were 6.6 and 4.88μg/ml at 1 and 2 hours after oral administration of 500mg of CEX.
The serum level of CFT at pH 6.0 was somewhat higher than that at pH 7.0. Clinical results of CFT in 11 cases of respiratory infections were good in 5 cases, fair in 3 cases, and poor in 3 cases.
No abnormal clinical and laboratory findings were seen in all cases.

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1) The MICs of cefatrizine, using plate dilution method, against Staphylococcus, E.coli, Klebsiella, Indol (+) Klebsiella and Enterobacter, Cloacae were found to be more active than those of cephalexin.
2) Concentrations of cefatrizine were determined in serum and urine of 3 normal cases. The concentrations of serum were 1.8μg/ml at 1 hour, 3.95μg/ml at 2 hours, 3.60μg/ml at 4 hours and 1.31 μg/ml at 6 hours after 500mg oral administration. Average urinary recoveries in these volunteers were about 31% during 6 hours.
3) Cefatrizine was administrated to a total of 8 cases, 2 cases of pneumonia and 6 cases of urinary tract infection. Clinical response of cefatrizine obtained in those cases was good in 7 cases. Administration was discontinued in 1 case of eruption. No side effects were experienced except this 1 case of eruption.

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Investigation has been made on cefatrizine and the following results were obtained.
1) The susceptibilities of the clinical isolates to cefatrizine were shown with a peak of distribution at an MIC of 1.56 μg/ml, 6.25 μg/ml, 1.56 μg/ml and 3.12 μg/ml in Staph. aureus, E. coli, Klebsiella and Proteus, respectively. The in vitro antibacterial activity of cefatrizine was 4 to 8 times more potent than that of CEX. All the strains of Pseudomonas were resistant to more than 100 μg/ml of cefatrizine.
2) The peak of serum concentration level in fasting healthy adults was obtained 2 hours after the oral administration of cefatrizine at a single dose of 500mg, its value being 4.2-7.1μg/ml.A serum concentration of 1.6μg/ml was given as average 6 hours after dosing. The urinary recovery within 6 hours was 27.2-46.9%, its average being 40.7%.
3) Cefatrizine at a daily dose of 1 to 3g was administered to 13 patients consisting of 8 with respiratory tract infection, 1 with biliary tract infection and 4 with urinary tract infection. The results were good in 8, ineffective in 4 and unkown in 1. Slight elevation of GOT·GPT in one, nausea·vomiting in one and soft feces in one were observed, as its side effects.

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Cefatrizine, a new semi-synthetic cephalosporin antibiotic, was examined on its in vitro activity against clinically isolated bacteria, its serum level and urinary excretion in human after oral administration as well as on its effectiveness in clinical cases. The results obtained were as follows :
1) Antibacterial activity : The M. I. C. of cefatrizine against 34 strains of Staphylococcus aureus isolated from human infection foci were distributed between 0.4 and 50μg /m1 and those against E. coli were between 0.8 and 50 μg/ml.
2) Serum level and urinary excretion in human : The drug showed a serum concentration curve with gentle slope in normal adults, reaching in 2 hours to the peak of 7. 1 μg/m1 on average and disappearing in 6 hours after single oral dosage of 500 mg. The average urinary recovery of the drug in 6 hours was 41. 4% of the dose.
3) Clinical trials : Eleven patients (R. T. I. 9 and U. T. I. 2) were treated with the oral administration of cefatrizine 1. 0 or 1. 5 g daily, and the result was more or less effective in all of the cases. No side effects were found by clinical and laboratory observations except for one of the patients showed exanthema during the therapy.

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Cefatrizine (CFT) was administered orally at the dose of 1 g daily to the patients with respiratory infections, and clinical effect was observed. Clinical effect was noted in 11 of 17 patients and 5 complicated patients of 17 were not effective. One patient had elevation of transaminase (GOT, GPT), but, after administration, the enzyme level returned to normal.
Antimicrobial activity of CFT was estimated on 173 strains of bacteria which were isolated from the clinical specimens.
Good antimicrobial activity against strains of E. coli, Klebsiella sp., Proteus mirabilis, Staphylococci and Streptococci was demonstrated.

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1) Minimum inhibitory concentrations (MICs) of cefatrizine (CFT) against clinical isolates were determined. Growth was inhibited at 87.5% of 16 strains of Staphylococcus aureus, 34% of 35 strains of Escherichia coli and 51.8% of 27 strains of Klebsiella respectively at an MIC of 12. 5 μg/m1 or less, while all the strains of Enterobacter and Pseudomonas aeruginosa were resistant to CFT. A correlation between the MICs of cephalexin (CEX) and CFT showed that CFT was 1 to 3 times superior in concentration to CEX.
2) The peak serum concentration of CFT administered at an oral dose of 250 mg was observed 2 to 3 hours after dosing, its level being 3. 9 fig/mi. The concentration of 0.9 μg/m1 was maintained even after 6 hours of dosing.
3) CFT was administered at a daily dose of 1 to 2g to 15 patients with respiratory tract infections, 2 with parodontitis, 4 with biliary tract infections, 8 with urinary tract infections and 3 with other infections. Response was excellent in 7, effective in 11, slightly effective in 7, ineffective in 3 and undecided in 4.
4) As far as side-effects were concerned, there were observed increase of serum transaminases in 5, digestive symptoms in 2, eruption in 1 and feeling of swinging in 1. Direct COOMBS' tests revealed negative reactions within a range of the tests.

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Cefatrizine (CFT), a new developed cephalosporin derivative, was examined basically and administered to the patients suffering from respiratory infections. The results obtained were as follows :
1) Antibacterial activities : Minimal inhibitory concentrations of CFT against total 517 strains complied with 21 standard strains and 496 clinically isolated strains stored in our laboratory (Staphylococcusaureus 64, β-hemolytic streptococcus 32, Salmonella 16, Shigella 15, Escherichia coli 64, Klebsiella aerogenes 64, Enterobacter aerogenes 32, Enterobacter cloacae 32, Serratia marcescens 64, Proteus vulgaris 20, Proteus mirabilis 29, Pseudomonas aeruginosa 64) were determined by the standard method of Japan Society of Chemotherapy, and compared with those of cephalexin (CEX).
In most cases CFT demonstrated the same antibacterial activities or 1 to 3 tubes stronger when compared with CEX.
2) Application to respiratory infections : Total 8 patients complied with 4 patients with bronchopneumonia, one with lung abscess and 3 with bronchiectasis were given CFT 1, 500mg daily divided into 3 times, and marked effect was obtained in one patient with bronchopneumonia and one with lung abscess.
Adverse reaction was noted in one patient showing slight elevation of SGPT and increase in eosinocyte, but recovered to normal immediately after the discontinuation of dosing.

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Laboratory and clinical studies on cefatrizine were performed with following results.
1) MIC values of cefatrizine against 65 strains of respiratory pathogenicHaemophilus influenzae ranged from 1. 56 to 25 μg/ml, and those values were four times lower than those of cephalexin.
2) After oral administration of cefatrizine 100 mg/kg in rats, tissue concentrations reached peak values in 1 hour. Tissue levels in order of concentration were kidney, serum, liver, and lung, and each value was 112, 100, 28. 0, 11. 2μg/ml. Half life of cefatrizine in tissues was between 1 hour to 2 hours.
After oral administration of cephalexin 100 mg/kg in rats, tissue concentrations reached peak values in 30 minutes. Tissue levels in order of concentration were kidney, serum, liver, and lung, and each value was 204, 148, 44.0, 12.4 μg/ml. Half life of cephalexin in tissues was between 30 minutes to 1 hour.
3) After oral administration of cefatrizine 200 mg/kg in mice, tissue concentrations reached peak values in 30 minutes. Tissue levels in order of concentration were serum, liver, kidney, and lung, and each value was 100, . 62. 9, 35.0, 12.0μg/ml.
After oral administration of cefatrizine 200 mg/kg in BCG-infected mice, tissue concentrations reached peak values in 30 minutes. Tissue levels in order of concentration were serum, liver, kidney, and lung, and each value was 130, 83.0, 37.0, 18.0 μg/ml.
4) Cefatrizine was administered orally to 23 patients. Respiratory infections were 15 patients (pneumonia 1 case, chronic bronchitis 8 cases, bronchiectasis 3 cases, chronic bronchiolitis 1 case, pulmonary fibrosis 2 cases), and cefatrizine was administered at a daily dose of 2.0g. Three cases responded well, 4 cases fair, and 8 cases poor.
Urinary infections were 7 patients (acute cystitis 6 cases, chronic cystitis 1 case), and cefatrizine was administered at a daily dose of 1.0g-2.0g. All cases were well responded.
Biliary infection was 1 case (acute cholecystitis), and cefatrizine was administered at a daily dose of 2.0g. Cefatrizine was effective in this case.
5) One case with respiratory infection had minimal hyperazotemia, and after administration of cefatrizine hyperazotemia was increased slightly. The others had no adverse reactions.

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Nineteen cases of bacillary dysentery, diarrhea caused by enteropathogenicEscherichia coli and scarlet fever were treated with cefatrizine (S-640P) to assess clinical value as well as to measure antibacterial activity of the drug against clinical isolates.
1) Among 8 cases of intestinal infections, only one case responded to the therapy, whereas the remaining 7 cases continued to eliminate the pathogenic organism during the therapy. Ten cases of scarlet fever rapidly responded to treatment, exculusive of the case complicated osteomyelitis.
2) Thein vitro activities of cefatrizine against clinical isolates were determined by agar dilution method.
All strains ofSalmonella, Shigella and enteropathogenic E. coli were sensitive to concentration of 0.39-1.56μg/ml of the drug. A groupStreptococci were more sensitive to the drug, with the minimum inhibitory concentration (MIC) ranging from 0.05-0.78μg/ml.
3) In 2 of the 19 cases treated, maculopapular skin eruption appeared.

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Dry syrup and capsules of cefatrizine, a cephalosporin derivative for oral use, were administered to the patients in the field of pediatrics, and the following results were obtained.
1) This drug was well absorbed in oral forms. Active blood concentration was high during the time of 1 to 3 hours, and 47. 6 to 78. 8% of the drug administered were excreted into the urine in active state.
2) Forty-seven patients suffering from 6 kinds of infantile acute infections were given capsules of cefatrizine, and satisfactory result was obtained in most of the patients treated. The daily doses were 20 to 30 mg/kg in slight or moderate infections, and 30 to 40 mg/kg in pneumonia and others.
3) Thirty-threec patients with infantile acute infections who suffered from almost same infections as the patients given capsules, were administered dry syrup. Except one patient to whom continuous medication was difficult due to the dislike of drugs, favourable clinical results were obtained in all the patients, and the dosage was similar to capsules. Dry syrup was well accepted to the infant patients.
4) The patients with lower respiratory infections confirmed a lot of resistant strains ofStaphylococcus aureusin pharyngeal mucus and phlegm showed favourable responses to this drug.
5) No unfavourable influence to liver and renal functions was observed within 10 days medication of about 30 to 50 mg/kg/day.

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The authors have carried out the laboratory and clinical studies of cefatrizine. The results were obtained as follows
The sensitivity was determined by the plate dilution method with 22 strains ofStaph. aureus, 13 strains ofE. coliand 6 strains ofKlebsiella pneumoniae. The growth of 81. 8% ofStaph. aureuswas inhibited at a concentration of less than 1. 56 fig/ml. The growth of 69. 2% of E. coli was inhibited at a concentration of less than 12. 5 μg/ml.
The peak of sensitivity distribution ofKlebsiella pneumoniaeto cefatrizine was in the area of 3. 13μg/ml.
Cefatrizine was given a single oral dose of 500 mg to two children.
The maximum blood level of 14. 0 μg/ml was reached at one hour after administration. And the blood level at 6 hours after administration was 0. 6 μg/ml. The excretion rate of cefatrizine in the urine after a single oral administration was 30. 1-49. 2% up to 6 hours of period.
Cefatrizine was effective in 8 of 10 cases of bacterial infections. No side effects were observed except eruption in one case of cystitis.

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Absorption and clinical effects of cefatrizine dry syrup were studied, and the following results were obtained.
1. Blood concentration of cefatrizine dry syrup and cephalexin dry syrup was compared in rabbits after an oral administration of a single dose of 100 mg/kg of each antibiotic (cross over test). The peak blood concentration of cefatrizine dry syrup appeared 30 minutes after that of cephalexin and was approximately half that of the latter.
2. Blood concentration of cefatrizine dry syrup was followed in rabbits after an oral administration of a single dose of 50, 100 and 200 mg/kg of cefatrizine dry syrup (cross over test). A definite dose response was recognized between 50 mg/kg and 100 mg/kg but was not between 100 mg/kg and 200 mg/kg. It was noted that the increase of absorption of this antibiotic after an oral administration of its massive dose was not proportional to the given amount.
3. Twenty-four children were given 30 to 76.2 mg/kg/day of cefatrizine dry syrup for 3 to 17 days for the following acute bacterial infections ; 20 cases of tonsillitis, 1 case of suppurative lymphadenitis and 3 cases of urinary tract infection. The results were excellent in 17 and good in 7, with no failure at all.
4. In regard to the adverse reactions, diarrhea was noted in one patient and a mild eosinophilia in another.
5. Based on the above results, it was concluded that cefatrizine dry syrup is a potent oral cephalosporin which is superior to cephalexin.

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Basic and clinical investigation; on cefatrizine (CFT) was made and following results were obtained :
1) Antibacterial spectrum
Excellent antibacterial activity of CFT against Gram-positive and Gram-negative organisms exceptingStreptococcus, B. cereus, Proteus morganiiandPs. aeruginosawas observed.
2) Sensitivity against clinically isolated organisms
Excellent antibacterial activity againstStaphylococcus aureus, Escherichia coliandKlebsiella pneumoniaewas noted, especially, againstKlebsiella pneumoniaeCFT demonstrated equal result obtained with CEZ and CTZ.
3) Serum and urinary concentrations
The results obtained by paper disc showed the peak concentration at 2 hours after 500 mg oral administration with an average of 3. 73, μg/ml. Peak urinary concentration was observed 1 hour after dosing with an average of 1. 412 μg/ml, and the average recovery from the urine during the time of 6 hours was 31. 3%.
4) Tissue concentrations
Tissue concentrations when orally administered 20 mg/kg of¹⁴C-labeled CFT to SD strain rats (a group of 3 rats) were high, both by bioassay and radioassay, in serum, liver, lungs, spleen, heart and muscles in order.
5) Metabolism
Metabolism in human plasma and urine after CFT administration as well as metabolism in rat urine given¹⁴C-labeled CFT were investigated. The results obtained by bioautogram and radioscanning with TLC demonstrated that there was no bio-active metabolite in the human plasma and urine. However, in rat urine the metabolites with antibacterial activity were produced with the lapse of time.
6) Clinical results
Thirty-four infectious patients in surgical fields were treated with CFT, all the patients suffering from soft tissue infection. The clinical result was effective in 28, ineffective in 5 and impossible to evaluate in 1 out of 34 patients and the effectiveness rate of 82. 3%. No markable adverse reaction was noted, excepting that one patient who complained of anorexia.

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Blood levels of cefatrizine after 500 mg oral administration in adults showed the maximum at 2 hours as high as 9. 7 μg/ml and detected at 6 hours as 3. 2 μg/ml.
The relative electrophoretic mobility to albumin of cefatrizine was-0.136 in human serum.
Out of 14 cases of soft tissue surgical infections treated with oral cefatrizine of 250 mg x 4/day, 5cases were good in clinical results and 6 and 3 cases were evaluated as fair and poor respectively. There were no side effects such as allergic reaction, GI tract symptoms, and hematological studies on 4 cases did not show any remarkable change after oral cefatrizine administration for 6 to 8 days.

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This study was designed to evaluate the in vitro efficacy of CFT and to get further informations on its clinical utilization in surgery.
Brief summaries were given as follows :
1) Serum levels of CFT in the case of 1) and 2) were shown in Table 4 and Fig. 3. Peak drug concentration of 6. 4 μg/ml was achieved in Case No. 2.
2) MICs of 20 strains of E. coli were ranged between 0.78, -3.12 μg/ml of the drug. Ninety % of the strains were inhibited the growth by the concentration of 1. 56 μg/ml.
For 21 strains ofStaph. aureus, 955 of the strains was inhibited the growth by the concentration lower than 1. 56, μg/ml.
3) Twenty-four patients were treated with CFT. A summary of clinical results is shown in Tables 6 and 7.

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Some laboratory experiments have been made on a new antibiotic cefatrizine, and this drug has been applied clinically in an oral preparation in surgical infections. The following conclusions were obtained.
1) Antibacterial activity
Antibacterial activity of cefatrizine and cephalexin againstStaphylococcus aureusand gram negative bacilli isolated from surgical lesions, demonstrated stronger activity of cefatrizine againstStaphylococci, E. coli, KlebsiellaandProteusthan that of cephalexin in this study.
2) Absorption and excretion
Cefatrizine was administered once at fasting in 6 healthy adults, and blood levels and urinary excretion were examined. Average concentrations were 2.2μg/ml after 30 minutes, 4.1μg/ml after 1 hour, 6.1μg/ml after 2 hours, 2.9μg/ml after 4 hours and 1.4μg/m1 after 6 hours. Average urinary recovery within 6 hours after administration was 45. 8%. Biliary excretions were measured in rabbits and in clinical cases. Cefatrizine was excreted well in bile.
3) Result of clinical application
Cefatrizine was applied in acute suppurative infections of soft tissues in surgical field. Out of 12 cases treated, the results obtained were good in 8 cases, fair in 1 case and poor in 3 cases. No side effect was observed.

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Cefatrizine (CFT) was given for acute cases of infections mainly in soft tissues, and effective responses were seen on 42 of all 49 patients. In addition the serum level and urinary excretion were investigated using a bioassay procedure.
Cefatrizine is a promising antibiotic highly effective for acute infections in the field of surgery without any untoward side effect.

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A new semisynthetic cephalosporin antibiotic, cefatrizine (S-640 P) was used for 28 patients with acute cystitis. Cefatrizine was administered orally for 3 days at a daily dose of 500 mg. The therapeutic results were as follows, 24 cases were excellent, 3 cases good. In one case, nausea and vomiting were observed. Most strains of E. coli were inhibited by cefatrizine at a concentration of 3.13 μg/ml.

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Comparative double blind trial of cefatrizine (CFT) and cephalexin (CEX) was performed with 335 patients of simple acute cystitis. Patients were treated at a daily dose of 0.5g or 1g of CFT or 1 g of CEX for 3 days.
The results obtained were summarized as follow;
The background characterisitics of the three groups were statistically analyzed and no significant difference was found.
The clinical efficacy was evaluated on 89 cases of 0.5g CFT, in 95 cases of 1g CFT and in 92 cases of 1g CEX. The ratio of excellent response was 77.5% with 0.5g CFT, 75.8% with 1g CFT and 72.8% with 1g CEX, showing no significant difference.
Side effects were observed in 3.6% of 110 cases with 0.5g CFT, 2.7% of 111 cases with 1g CFT and 3.8% of 106 cases with 1g CEX, showing no significant difference.
Recurrence within one week after completion of the treatment was observed in 18.2% of 67 cases with 0.5g CFT, in 7.7% of 67 cases with 1g CFT and in 7.4% of 68 cases with 1g CEX, showing no significant difference.
And these results demonstrate that the treatment either at a daily dose of 0.5g or 1g of CFT is very effective in the field of the urinary tract infection.

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1) Cefatrizine zu 17 urologische Patienten benützt. Für 15 Patienten, effektiv und für 2 nicht effektiv, als Ergebniss.
2) Die Nebenwirkung war in zwei Fälle befunden. Die waren leichte Appetitlosigkeit und Diarrhoe.
3) Cefatrizine wirkt für E. coli in geringer MHK als CEX.

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A new antibiotic, cefatrizine (CFT), was studied both bacteriologically and clinically in the urological field, and following conclusions were obtained.
1) MIC of CFT for 18-standard strains, 105-urinary E. coli, 43-urinary Klebsiella, and 60-urinary P. mirabilis were superior to those of CEX.
Especially, P. mirabilis strains were inhibited by concentration of 6. 25 μg/ml or less except one.
2) Ability of growth inhibition of CFT against E. coli EC-437, which produces a large quantity of β-lactamase, was better than that of CEX or CET.
3) CFT had superior synergetic ability to ABPC than CEX against E. coli NIHJ JC-2.
4) Urinary concentration of CFT reached the peak at 2-3 hours after oral administration and urinary recovery rate for 6 hours was about 60%.
But this data was changed by the pH of diluent buffer.
5) By the result of various studies, there were no antibacterial substances in urine except CFT after oral administration.
6) All of 14 patients with acute urinary tract infections exhibited excellent or good response to CFT treatment, and 75% of 20 patients with chronic UTI did same effect.
7) General uriticaria was observed in 1 out of 53 cases who were administrated CFT in this trial, and transient increase of S-GOT, S-GPT and S-GOT was noted in 2 out of 8 cases.
8) All of 5 patients, who were treated UTI with any antibiotic, could exhibit suppressive effect to recurrence by CFT 375 mg/day.

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Fundamental and clinical studies were carried out on a new semisynthetic cephalosporin antibiotic, cefatrizine. The results obtained were as follows.
1) Serum level
Cefatrizine was administered orally once at dose of 500 mg. in 4 healthy human male adults and the peak of serum concentration was attained 2 hours after dosing, value being 5.6μg/ml on an average. The value of 1.2μg/ml was noticed even after 6 hours.
2) Urinary recovery rate
Five hundreds mg of cefatrizine were administered to the same healthy adults who were measured the serum level, and urinary recovery rate obtained within 6 hours was 46.9% on an average.
3) Antibacterial activity
The MIC distribution of cefatrizine was 4 to 8 times more potent than CEX against E. coli, Proteus mirabilis and Klebsiella. Serratia marcescens was resistant to cefatrizine and CEX and their MIC was not less than 100μg/ml.
4) Clinical results
Cefatrizine was applied clinically in 50 cases of urinary tract infections, and the results obtained were excellent in 33 cases, good in 7 cases and poor in 10 cases, effective ratio being 80%. Thirty cases of simple urinary tract infections resulted in effective ratio of 96.7 %, 20 cases of complicated urinary tract infections in effective ratio of 55. 0%.
5) Side effect
Cefatrizine was administered to 50 patients, but no noteworthy side effect was noted subjectively in any of the cases.

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1) Minimal inhibitory concentration of cefatrizine was determined by the plate dilution method on 73 strains isolated from urinary tract infections. A half of strains of E. coli and Proteus mirablis were inhibited at the concentration of 6.25μg/ml or less. All strains of Proteus vulgaris and Pseudomonas were resistant to 100μg/ml of cefatrizine. All strains of Staphylococcus aureus were inhibited at the concentration of 1.56μg/ml or less.
2) In a case with normal renal function, the blood level reached at the maximum level of 5.1μg/ml. The urinary recovery rate was 54. 2% during 6 hours after administration of cefatrizine 250mg per os at fasting time.
3) Twenty-one cases with urinary tract infections were treated with cefatrizine. Excellent and good results were obtained in 18 cases.
4) In this series, exanthema was observed in one of 21 cases as side effect.

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Cefatrizine was used for treatment of 26 cases of acute gonococcal urethritis at doses of 1.5 to 1.0 g/day for 5 to 10 days.
The results were excellent in 15, good in 9 and recurrence in 2.
The good and excellent rate was 92.3% in total cases. No side effect was observed in all cases.

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1) Cefatrizine was administered to 45 patients with urinary tract infections and acute gonorrhea consisting of out- and in-patients of Department of Urology, Kyushu University and Sanshinkai Hara Hospital. Since 8 patients were dropouted, 37 were subject to the evaluation.
2) Three of 7 patients with simple urinary tract infections were administered 500 mg daily, and other patients with urinary tract infections were given 1, 000 mg daily. Out of the patients with acute gonorrhea, 3 patients were administered 1, 000 mg daily, 11 were given 1, 500 mg daily and 3 were given 2, 000 mg daily.
3) Seven patients with simple urinary tract infections resulted in 2 excellent and 5 good with effectiveness rate of 100%. Thirteen patients with complicated urinary tract infections resulted in 2 excellent, 4 good and 7 poor with effectiveness rate of 46%. In acute gonorrhea 10 patients were excellent and 7 were good.
4) Nausea was noted in 7 patients out of whom one patient was discontinued the medication, although the nausea disappeared after the discontinuation.
5) Although the resistant strains would appear in future, cefatrizine may be considered as a useful drug for the treatment of urinary tract infections and acute gonorrhea.

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1. Minimal inhibitory concentration of cefatrizine (CFT) against the strains clinically isolated from the patients suffering from various infections in the obstetric and gynecological fields was studied in comparison with cephalexin (CEX) CFT's MIC against Staphylococcus aureus, Escherichia coli and Klebsiella was one tube stronger and its MIC against Proteus mirabilis was 2 to 3 tubes stronger when compared with CEX. MIC against Proteus vulgaris and Pseudomonas aeruginosa was more than 100 μg/ml in CFT and CEX.
2. Blood level in umbilical code and amniotic fluid level when 500 mg of CFT was given orally to mothers was studied. The serum level of umbilical code was not less than one-third when compared with mothers serum level. Therefore, CFT seems to pass well into umbilical code. On the other hand, the level of CFT in amniotic fluid was as low as that of other antibiotics.
3. Eighteen patients with infectious diseases in the obstetric and gynecological field were orally given CFT at daily doses of 1 to 2 g for 4 to 10 days. The result obtained was marked effective in 4 patients, effective in 11 and ineffective in 3.
4. Three out of 18 patients complained of loss of appetite, but it was slight and did not obstruct the continuation of dosing. BUN, GOT, GPT, Al-phosphatase and WBC were checked, and no abnormal findings were noted.

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In order to evaluate cefatrizine, a new oral cephalosporin C, antibacterial activities, tissue distribution and clinical effect were examined, and following results were obtained.
1. Minimal inhibitory concentration of cefatrizine against 125 strains recently isolated from patients ranged mostly 0.39 to 0.78 μg/m1 in Staphylococcus aureus and 0.78 to 6.25, μg/m1 in E. coli, and in most cases cefatrizine demonstrated more marked sensitivity distribution when compared with cephalexin.
2. The peak blood level in human umbilical code was about 4 μg/m1 4 hours after dosing. Organ distribution in fetuses when administered to pregnant rats showed high in urine, kidneys, plasma, liver, heart, lungs, spleen, pancreas, muscle, uterus and brain in order.
3. Eleven patients with obstetric and gynecologic infections were given cefatrizine 1 to 2g daily for 3 to 10 days, and favourable effect was obtained in 7 patients. Adverse reaction was noted in one patient showing soft feces.

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Laboratory and clinical studies on cefatrizine (CFT), a new cephalosporin antibiotic, were performed to obtain the following results;
1) Antibacterial activities of CFT against clinically isolated strains of Staphylococcus, E. coli, Klebsiella and Proteus sp. were 0.78 to 6.25 μg/ml, 1.56 to 100 μg/ml, 1.56 to 6.25 μg/ml and 1.56 to 25μg/ml respectiveiy.
2) Antibacterial activity of CFT against clinically isolated gram positive and negative rods was more active than that of CEX.
3) After an oral administration of CFT 500 mg, peak serum levels of 6.51 to 7.49μg/ml were obtained at 1 hour to 2 hours, and urinary recoveries during 6 hours were 44.2 to 57.2% respectively.
4) Twenty-five cases of urinary tract infections and 10 cases of genital organ infections were treated with CFT, and clinical effect was excellent in 5 cases, good 22 cases and failure 8 cases.
5) Clinical effectiveness of CFT was 77. 1%.
6) No side effect or adverse reaction on clinical laboratory findings was observed.

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1. Peak of MIC distribution of cefatrizine (CFT) against Staphylococcus aureus isolated from the focus was noted at 1. 56 μg/ml and it was stronger than that of cephalexin (CEX).
2. Antibacterial activity of CFT against Streptococcus hemolyticus (β type) was observed at the range from 0.025 to 1. 56 μg/ml.
3. Antibacterial activity of CFT against Staphylococcus aureus (209P-strain) in serum (10^-1diluted) after oral administration was examined by biophotometer. Proliferation of the organism was completely inhibited 1 and 2 hours after 250 mg oral administration of CFT, and the curve showing complete inhibition of the organism proliferation was observed 1, 2, 3 and 4 hours after 500 mg oral administration.
4. The peak serum concentration of CFT in adults was noted 2 hours after 125 and 250 mg oral administration. And even 6 hours later CFT was observed, therefore CFT is considered to show prolonged serum concentration.
5. The concentration in maxillary sinus membrane and tonsillar tissues was noted at 0.8-1.0μg/ ml 2 hours after 250 mg oral administration.
6. Fifty-nine patients of oto-rhino-laryngological infections were medicated by CFT and the result obtained was markedly effective in 33 (55.9%) and good effective in 17 (28. 8%), with the total effectiveness rate of 84. 7%.
7. As to the adverse reactions during the treatment, 2 patients complained of exanthema and diarrhea, for which the medication was discontinued.

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From the laboratory and clinical investigations on CFT, the following results were obtained.
1) Antibacterial activity of CFT was measured by the plate dilution method on 121 strains isolated from pathological materials in our clinic. The peak of MIC was 1. 56 μg/ml with Staphylococcus aureus (55 strains). Pseudomonas species were highly resistant to this antibiotic similarly to other cephalosporin antibiotics.
2) Tissue (tonsil) and blood concentrations of CFT were determined about 2 3 hours after oral administration, 0. 65μg/g in tonsil and 0. 50 μg/ml in its corresponding blood concentration (mean of 10 cases).
3) CFT was prescribed clinically in 34 cases of ear, nose and throat infections, and effective rate was 67.6%.
4) Adverse reaction was observed in 2 cases, one was diarrhea appeared after 4 th day of administration, and the other was eruption appeared after 10 th day of administration.

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Laboratory and clinical experiments were performed on cefatrizine (CFT) in ophthalmological field, and the results obtained were as follows.
1. Antimicrobial activity of CFT against various organisms was 25 μg/ml for KOCH-WEEKS bacillus, 0.39 μg/ml for MORAX-AXENFELD diplobacillus, 0.39-3.13 μg/ml for D. pneumoniae, 0.78 μg/ml for Coryne. diphtheriae, 0.2 μg/ml for N. gonorrhoeae, 0.39 μg/ml for Strept. hemolyticus, 12.5-25 μg/ ml for Strept. viridans, 0.78-1.56μg/ml for Staph. aureus and > 100 μg/ml for Ps. aeruginosa.
2. The distribution of the sensitivity for 20 strains of Staph. aureus was in the range of 0.78-1.56 μg/ml, and most of them (14 strains, 70.0%) were in 0.78 μg/ml.
3. The peak of serum level was attained 2 hours (4.25 μg/ml) after oral administration of 250 mg CFT. then decreased gradually until 6 hours (0.68 μg/ml).
4. After oral application of 50 mg/kg in rabbit, the peak level of aqueous humor was obtained at 2 hours (0.92 μg/ml). Aqueous/serum ratio was 8.76%.
The ocular tissue concentrations at 2 and 4 hours after oral appiication or 50 mg/kg were high in both outer and inner parts of the eye.
5. Clinical results
Oral administration of 0.5, 1.0 or 2.0 g daily revealed good effects in 29 of 34 cases, such as external hordeolum, internal hordeolum, acute chalazion, acute conjunctivitis, acute dacryocystitis, chronic dacryocystitis, corneal infiltration, corneal ulcer, orbital phlegmon and iridocyclitis purulenta.
6. Side effects
Two cases of anorexia and a case of eruption were experienced, but no other severe side effects, such as allergic reaction and abnormality of hepatorenal function, were noticed.

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Laboratory and clinical studies on a new antibiotic, cefatrizine, were made with the results as follows :
1. Minimum inhibitory concentration against coagulase positive Staphylococci (21 strains) isolated from ocular suppurative lesions was in a range of 0.39-3.12μg/ml.
2. Penetration of the drug into rabbits aqueous humor was measured simultaneously with the measurement of serum concentration. Aqueous humor concentration of cefatrizine reached maximum (0.5μg/ml) 2 hours after an oral administration of 50 mg/kg, and the maximum serum concentration (16.8μg/ml) was obtained 1 hour after the injection.
3. Single oral administration of cefatrizine (500 mg to adults) produced serum concentration of 6. 1μg/ml after 2 hours in volunteer.
4. Twenty-six patients with ocular suppurative disease were succesfully treated by cefatrizine at a daily dose of 750mg-1, 500mg.

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To investigate the possibility of the application of cefatrizine (CFT) in the field of ophthalmology, some basic and clinical studies were carried out, and following results were obtained :
1) When 100 mg/kg of CFT were given orally to the mature white rabbits, the peak serum level of 11.5μg/ml was observed 2 hours after dosing, while the peak aqueous humor level of 1.0μg/ml was noted 4 hours after the administration. When given 50 mg/kg of CFT, each peak level was 8.7μg/ml 2 hours after dosing, and 0.6μg/ml2 or 3 hours after the administration.
2) In the healthy adults, the changes of the drug concentration in serum were examined. The average peak level of 3.3μg/ml and 1.2μg/ml was noted 2 hours after dosing when administered 250 mg and 125 mg of CFT, respectively.
3) Eleven patients with cataract were given orally 250 mg of CFT, and aqueous humor was taken just before the operation. The aqueous humor level was 0.1-0.2μg/ml, 0.1-0.5μg/ml and 0.1-0.4 μg/ml, 1, 2 and 3 hours after the oral administration, and 0.4μg/ml was observed in 2 patients 4 hours after dosing.
4) As to the clinical effect, the patients with external ophthalmic infections were treated by CFT at daily oral doses of mainly 750-1, 000mg. The evaluation on the 3 rd day after dosing resulted in 27 (75%) effective, 6 (17%) slightly effective and 3 (8%) ineffective out of 36 patients. The side effect of diarrhea was noted in one patient, though it was slight.

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Thirty-five infants were underwent with cefatrizine syrup treatment for their pyodermas. The results revealed 3 cases of excellent, 22 cases of good, 8 cases of fair and 2 cases of no effects. It was concluded that more doses are required for the treatment of furuncle and hydroadenitis than for the treatment of impetigo. The least dose for the treatment of impetigo was 150mg a day for 6 year infant. No side effect was noted other than one case of diarrhoea.

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1) Distribution of MICs was examined on 32 strains of Staphylococcus aureus isolated from the lesions of skin infection. The result was as follows : 0.8μg/ml in 23 strains, 1.6μg/ml in 8 strains and 3.2 μg/ml in a strain. No resistant strain was found. Cefatrizine was found to be 2 to 8 times more active than cephalexin against Staphylococcus.
2) Serum and skin levels of this antibiotic were studied in rats after the oral administration through a catheter at the dosis of 50 mg/kg. The mean values were as follows : serum levels were 86.0μg/ml at 1 hr., 85. 0 at 2 hrs. and 10. 5 at 4 hrs., and skin levels were 15.5μg/g (wet) at 1 hr., 14.5 at 2hrs. and 2. 8 at 4 hrs.
3) The drug was used clinically in 13 cases of skin infection. The result was excellent in 4 cases, good in 5 cases and fair in 4 cases.

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