From the laboratory and clinical studies on Cefazolin, the following results were obtained.
1. The sensitivity to Cefazolin of 32 strains, isolated from pathological materials in our clinic, was measured by the agar plate dilution method. The sensitivity distribution was from 0. 19mcg/ml to 6. 25mcg/ml in Staphylococci and other Gram positive cocci tested, and was from 3.12mcg/ml to 12.5mcg/ml in E. coli and Klebsiella pneumoniae. Pseudomonas aeruginosa and Proteus vulgaris were highly resistant to this antibiotic.
2. A single intramuscular dose of 500 mg produced the peak serum levels of 13.5 mcg/ml at 1 hour on an average in 3 healthy adults.
3. Levels of Cefazolin in tonsils and mucous membrane of maxillary sinuses were measured in 3 patients respectively. An average tissue level was 7.6mcg/g in tonsils and 3.5mcg/g in mucous membrane of maxillary sinuses at 1 hour after the intramuscular administration of 500mg.
4. Cefazolin was clinically effective in 28 of the 32 patients with ear, nose and throat infections (effectiveness rate 81.3%).

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Cefazolin, 7- [1- (1H) -tetrazolylacetamido] -3- [2- (5-methy1-1, 3, 4-thiadiazolyl) -thiomethyl] -Δ³-cephem -4-carboxylic acid, is a new antibiotic derived from 7-aminocephalosporanic acid. Cefazolin is a broad-spectrum antibiotic active against penicillinase-producing Staphylococcus aureus also. Cefazolin was apparently bactericidal in vitro at or above the minimal inhibitory concentration. In mice, Cefazolin provided an excellent effect against experimental infections caused by various strains of Staph. aureus (penicillin-susceptible and penicillin-resistant), Diplococcus pneumoniae, Escherichia coli, and Proteus mirabilis. In volunteers, satisfactory concentrations of Cefazolin in serum and urine were obtained after single intramuscular doses. The maximal concentration in serum at dosing of 500 mg was 44. 6 mcg/ml, which was about twice as high as that of Cephaloridine (17. 2 mcg/ml). The recovery rate of Cefazolin in the 24 hour urine was at 95.9% dosing of 250 mg and 82.4% at 500 mg which w ere also higher than that of Cephaloridine (70.2% at 500 mg). Therapeutically effective concentrat ions of Cefazolin in serum and urine were maintained as long as 10 hours after administration. Biliary excretion of Cefazolin in dogs revealed that 3.3% of the intramuscularly administered dose (20 mg/kg) was recovered in the 24 hour bile. This rate was similar to that of ampicillin, and was markedly higher than that of Cephaloridine or Cephalothin. In rats, Cefazolin was well distributed in the kidneys, liver, heart, spleen, and lungs when given in a dose of 20 mg/kg intramuscularly.

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The antigenicity of Cefazolin and its cross reactivity with Benzylpenicillin, Ampicillin and Cephaloridine were studied and the following results were obtained. Cefazolin showed a sensitizing activity, as evidenced by the elicitation of specific precipitin antibodies and of hemagglutinating antibodies in experimental animals immunized with protein conjugates of this antibiotic, as do conjugates of Penicillins and Cephalosporins. Cefazolin gave a minimal cross reactivity, not only with Benzylpenicillin but also with Ampicillin and Cephaloridine. Quantitative hapten inhibition of precipitation, against anti-Benzylpenicillin antibodies, by haptens of 7-aminocephalosporanic acid and 6-aminopenicillanic acid was only minimal. This finding suggests the possibility that the cross reaction between Cephalosporin derivatives and related Penicillins against Benzylpenicillin is mediated mainly by the acyl side chain of the molecules.
Cefazolin was tested for its reactivity in direct antiglobulin test in vitro in comparison to other related antibiotics. The positive antiglobulin reaction occured in order of descending powers of Cephalothin, Benzylpencillin, Cephaloridine, and Cefazolin.

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It has been observed by MOLTHAN et al. that the direct Coombs test is positive in patients receiving Cephalothin (CET).This is considered to be caused by plasma protein binding to the erythrocyte to which CET has adhered.
We carried out in vitro experiments with CET, Cephaloridine (CER), Cephaloglycin (CEG), Cephalexin (CEX), and Cefazolin (CEZ) to determine the concentrati on of each antibiotic at which the direct Coombs test was positive.
Four Cephalosporins except CEZ showed similar values, but these values were somewhat different according to the kind of antiglobulin serum. When Ortho's antiglobulin serum was used for these four Cephalosporins, we had a positive direct Coombs test at similar concentrations ranging from 1.67 to 7.5mg/ml. However, when Green Cross's antiglobulin serum was used, four Cephalosporins showed the values ranging from 0.167 to 0.666 mg/ml.
CEZ showed a rather high value than other Cephalosporins, ranging from 0.666 to 16.7mg/ml.

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1) The MIC values of Cefazolin were a little lower for newly isolated E. coli (45 strains), and a little higher for Staph. aureus (9 strains) than those of other Cephalosporin C derivatives, such as Cephalothin, Cephaloridine and Cephalexin.
2) The bacteriolytic action of Cefazolin was observed in the automatically recorded growth curve of Staph. aureus 209 P strain and E. coli NIH-J strain, using Biophotometer Jouan. The same action against the above two strains was also observed in sera after an intramuscular injection of Cefazolin 500 mg. In the course of experiments the so-called normal bacteriolysin against E. coli was clearly observed in the sera of patients before treatment.

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The inactivating enzyme of Cefazolin, a new derivative of Cephalosporin, was investigated in comparison with that of other Cephalosporins and Penicillin G. The results are as follows :
1) Two-hundred and sixty-seven strains of Escherichia, Citrobacter, Klebsiella, Enterobacter A and B, Morganella, Rettgerella, Providencia, Serratia, Pseudomonas, Salmonella, Shigella and Staphylococcus were examined for their sensitivity to Cefazolin and their ability of inactivating the drug by the bioassay procedure. Cefazolin inactivation was exhibited in most of the broth cultures of gramnegative bacteria, except Pseudomonas and Morganella, against which the MIC of Cefazolin ranged from 3. 12 to 6. 25 mcg/ml. No inactivation was observed in ones against which the MIC was less than 3. 12 mcg/ml.
Cefazolin inactivation was exhibited in the broth cultures of Staphylococcus against which the MIC was 0.39 mcg/ml or more, and no inactivation was observed in ones against which the MIC was less than 0.39 mcg/ml.
Thus, a close correlation between the resistance to and inactivation of Cefazolin was recognized.
2) The inactivating ability of the broth cultures of 123 strains of Staphylococci was tested with Cefazolin, Cephaloridine and Penicillin G. As a result, 43 strains of Staphylococci inactivated all three antibiotics; 51 strains, Cephaloridine and Penicillin G; 11 strains, Penicillin G only; and 18 strains, none of the three drugs. Therefore, Cefazolin is seemed to be relatively stable to the enzymes.
3) By the mixed culture of Shigella sonnei N-30 and Escherichia coli K-12 (S), the Cefazolin and Penicillin G resistance of Sh. sonnei N-30 was transferred to E. coli K-12 (5). Simultaneously, the recipient obtained the inactivating ability of the drugs. So, the presense of the transferring R-f actor on Cefazolin was also observed.
4) Cefazolin-inactivating enzymes isolated from naturally resistant Staphylococcus aureus 56 and transferred resistant Escherichia coli K-12 R were investigated. The enzyme activity was optimal at 42°C, lost by heating for 30 minutes at 60°C, and did not require the co-factors.
The infrared absorption spectra of decomposition products of the antibiotic by both bacteria showed disappearance of the absorption peculiar to β-lactam ring and appearance of that to carboxy group, and the enzymes were established to be β-lactamases.
Partially purified β-lactamase preparations from their broth filtrates and cell bodies were obtained by the column chromatography, but the β-lactamases were not specific to Penicillin G or cephalosporins.
5) Cefazolin, Cephaloridine and Penicillin G had the ability to induce the formation of β-lactamase in Staph. aureus 56 and E coli K-12 R.
6) By the treatment with Panfuran S (Furan derivative) for elimination of drug-resistance factor, loss of the resistance and the ability of inactivation of Cefazolin and Penicillin G was observed in the frequency of 0.31 % in Staph. aureus 56 and of 0.48 % in E. coli K-12 R. From these results, Cefazolin resistance also appears to be related with penicillinase-plasmid.

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Cefazolin is a new synthetic cephalosporin derivative developed at Central Research Laboratories of Fujisawa Pharmaceutical Co. in 1969.
Presented in this report are the results of our study where this new antibiotic was compared with two known antibiotics of the cephalosporin family, Cephalothin and Cephaloridine, as to in vitro antimicrobial activity including antimicrobial spectrum, sensitivity of clinically isolated strains of Staphylococci, E. coli, etc., the effect of culture pH on the antimicrobial activity, stability against beta-lactamase, bactericidal activity, and development of resistance and in vivo therapeutical effect in experimentally induced infections in mice with Staphylococcus aureus, Diplococcus pneumoniae, E. coli and Klebsiella pneumoniae.
Results :
1. Cefazolin is virtually the same antimicrobial spectrum as that of Cephalothin and Cephaloridine. In the antimicrobial activity, Cephaloridine was found superior to the other two, these latter two being virtually equal, when tested with Gram-positive organisms, while the three were comparable to each other when tested with Gram-negative ones.
2. Clinically isolated staphylococcal strains were sensitive in the range of 6.25-0.05mcg/ml to Cephaloridine, in the range of 6.25-0.2mcg/ml to Cefazolin, and in the range of 0.78-4.2 mcg/ml to Cephalothin. Clinically isolated E. coli strains, on the other hand, were sensitive in the range of 50-3.12mcg/ml to Cephaloridine, in the range of 25-0.78mcg/ml to Cefazolin, and in the range of 100-0.78mcg/ml to Cephalothin.
3. The antimicrobial activity tended to increase when the pH of culture increased in relative acidity.
4. As was the case with Cephalothin and Cephaloridine, Cefazolin was found stable against betalactamase produced by Staphylococci.
5. In therapeutical effect on infections in mice induced by Gram-positive organisms such as Staphylococci and Diplococcus pneumoniae, Cephaloridine was found best, followed by Cefazolin, then by Cephalothin. The same order of effectiveness resulted when cephalosporins were tested on the infections induced by Gram-negative organisms including E. coli and Klebsiella pneumoniae.

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CEZはラットに皮下投与した場合には2000mg/kgで体温下降, 250 mg/kg以上で尿量増加を, 犬に静脈内投与では, 1000 mg/kgでアドレナリンおよびノルアドレナリン昇圧ならびにアセチルコリン降圧の軽度の増強, 64 mg/kg以上で後肢血流量の軽度増加, 250 mg/kg以上で冠血流量の軽度増加を, 猫に静脈投与では, 64mg/kg以上で軽度の血圧上昇と心搏数増加, 1000 mg/kgで交感神経節の遮断をきたした。しかしこれらの量は臨床1回常用量 (500mg/人, すなわち約10 mg/kg) よりかなり大量であり, したがつて, このものは臨床常用量では特に不都合な副作用を示すものではないと思われる。

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The toxicity and teratogenicity of Cefazolin sodium were examined in experimental animals. In acute toxicity test, Cefazolin showed low toxicity and no specific symptoms. The renal toxicity of Cefazolin in rabbits seemed to be lower than that of Cephaloridine. The significant findings observed in three-month and six-month subcutaneous toxicity tests in rats and dogs were hemorrhage at the site of injection due to the hypertonicity of Cefazolin solution administered.
As a result of the hemorrhage, were noted anemia, loss of albumin and hypererythropoieses in the spleen and bone marrow. However, no toxic signs of the antibiotic were found after one-month intravenous administration in dogs.
No teratogenic effects were observed in mice, rats and rabbits in subcutaneous and/or intravenous tests.

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The results of some studies on Cefazolin were summarized as follows :
1. The MICs of Cefazolin against clinical isolates were tested by plate dilution method. Of 47 Staph. aureus strains, 41 were inhibited at concentrations ranging from 0.4 to 3.1 mcg/ml; 8 of the 14 E. coli at less than 6.3 mcg/ml; and 4 of Pseudomonas were resistant.
2. In dogs receiving an intravenous dose of 20 mg per kg, the half life of the serum level was 0.5 hour; Cs, Cr and Cb were 457.3, 32.1 and 1.87 ml/min, and Ks, Kr and Kb were 1.29, 0.75 and 0.045, respectively. The biliary excretion of Cefazolin was better than that of Cephalexin and Cephaloridine.
3. In rats receiving an intramuscular dose of 20 mg per kg, the concentration in kidney and liver was higher than that in plasma.
4. In patients given intramuscular doses of 250 and 500 mg, the peak blood level was 8.3 and 15. 5 mcg/ml and the urinary recovery rate for the first 6 hours was 77.4 and 43.3 % of the dose administrated, respectively.
5. Protein binding ratio of Cefazolin to human serum was more than 60 % both by the cellophane bag dialysis and ultracentrifugation method.
6. In hapten inhibition test, Cefazolin showed very low titer to Benzylpenicillin antibody.
7. Of 29 patients, with various infections treated with Cefazolin, 23 responded well. No patient. had any side effects.

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Cefazolin, a new Cephalosporin derivative, was studied experimentally and clinically. The results were as follows.
1) Sensitivity
Sensitivity of clinically isolated or laboratory strains to Cefazolin (CEZ) was tested and compared with that to Cephaloridine (CER), Cephalothin (CET) and Cephalexin (CEX). The sensitivity distribution of 46 Staph. aureus strains had the peak at 0.78 mcg/ml for CEZ, at less than 0.2 mcg/ml for CER and at 6.25 mcg/ml for CEX.
The distribution of 10 E. coli strains for CEZ was similar to that for CER, and cross resistance was observed between the 2 antibiotics on this species of bacteria.
The distribution of 20 Hemophilus strains also was similar to that for CER, having the peak at as high as 25 mcg/ml. CEZ was not so active as CER, CET and CEX.
2) Tissue distribution in rats
CEZ levels attained the peak in any organs at 30 minutes following an intramuscular dose of 20 mg/kg, viz, 90 mcg/ml in kidneys, 30 mcg/ml in blood, 27. 5 mcg/ml in lungs and 18 mcg/ml in liver, which suggests CEZ is mainly excreted by kidney and liver, the half life being 1 to 2 hours in any organs.
3) Levels in serum and sputum
The average level in 3 patients (renal function : normal) following intravenous drip for 3 hours of CEZ 3g in 500 ml of 5% glucose solution was 60 mcg/ml in serum and 1 to 1. 8 mcg/ml in sputum.
4) Clinical examination
CEZ was administered to 41 patients with respiratory, urinary-tract and biliary-tract infections in daily doses of 0.75 to 3.0 g by the intramuscular route or by drip infusion.
CEZ was remarkably or moderately effective in 25 of the 34 patients with respiratory infection and in all patients with urinary-tract and biliary-tract infections. However, suspected recurrence due to L-form bacteria was observed in one patient with urinary-tract infection.
5) Side effect
Renal and hepatic function test and blood examination were carefully done in 32 patients before and after CEZ administration. There was no abnormalities except for a slight degree of eosinophilia in 2 patients.
Clinically, skin eruption was observed in one patient. Two patients sensitive to Penicillin-G received CEZ without any adverse reaction.

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Several experiments were performed on a new cephalosporin C derivartive of Cefazolin (CEZ) with the following results obtained.
1. At the sensitivity test using two-fold tube dilution method, the antibacterial activity of CEZ was a little bit inferior in the 37 strains of clinically isolated Staph. aureus, but superior in two to four tubes in the respective 21 and 24 strains of E. coli and Kl. pneumoniae to that of Cephaloridine.
2. Indicator organisms and assay procedures were studied for determining CEZ levels in human serum and urine. The following organisms and assays proved to be available.
Indicator organism Assay
B. subtilis
Staph. aureus 209P} Cup method
Strept. hemolyticus S-8
Strept. hemolyticus Cook} Superposition assay method
3. The serum levels of CEZ determined by the standard curve obtained with serum dilution were different from those with phosphate buffer, possibly due to the high binding of CEZ to serum protein. The serum levels of CEZ were also affected by the kinds of serum for dilution, and accordingly the standard curve with human serum is desirable for measuring serum levels of CEZ in human.
The serum levels were examined by superposition and cup method in 2 healthy volunteers after a single intramuscular dose o f 500 mg. The serum levels determined by the standard curve with phosphate buffer reached the peak of 7.8-9.0 mcg/ml at 1 hour, decreasing to 4.5-7.0 mcg/ml at 3 hours and 1.6-2.2 mcg/ml at 5 hours; and those with human serum of 19 26 mcg/ml at 1 hour, decreasing to 13. 4 18 mcg/ml at 3 hours and 5.2-5.5 mcg/ml at 5 hours.
4. CEZ was administered to 3 patients with chronic pyelonephritis and one patient with acute pneumonia and was effective in the 2 patients.
No side effects were observed in any patients.

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This study comprised of a basic and clinical evaluation of Cefazolin, a new Cephalosporin derivative, with the following results.
(1) Antimicrobial activity
The antimicrobial activity of Cefazolin against gram-positive cocci was found nearly equal to that of other Cephalosporins and its effects were very potent against gram-negative rod.
(2) Absorption, excretion and organ concentration of CEZ
a) Serum concentration
In healthy adults the peak concentration of the drug in serum was about 13 mcg/ml (at pH 7.2 buffer) following the IM injection of Cefazolin in a dose of 0. 5 gm, which exceeded the values of Cephalothin and Cephaloridine given in the same dose. The half life of Cefazolin was 2.3 hours which apparently was longer than that of the other Cephalosporins.
b) Organ concentration
The organ concentration of Cefazolin in rats was found to be the highest in kidneys, liver, followed by lungs and spleen. The results were comparable to that of Ampicillin.
(3) Mechanism of renal excretion
Mechanism of renal excretion of this drug appeared to be the combination of the glomerular filtration and tubular excretion.
(4) Renal toxicity
In rats the effects of Cefazolin on kidneys were evaluated and its toxicity was very mild, and was nearly comparable to that of Cephalothin and lower than that of Caphaloridine.
(5) Clinical data
Of the 20 patients with respiratory and urinary tract infections in the field of internal medicine, 17 responded well by the administration ot Cefazolin in doses of 2 to 3 gm per day.
Cefazolin was most effective for bacterial pneumonia and acute pyelonephritis which suggests specific distributions to lungs and kidneys of this drug. No appreciable side effects were noted except for some pains and redness at the site of injection.

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On a new Cephalosporin derivative produced in Japan, Cefazolin (abbreviated as CEZ), several basic and clinical investigations were carried out and the following results were obtained.
1. The MIC values of CEZ against Staphylococcus aureus were between those of CER and CET in general. However, in cases of E. coll. and Klebsiella, CEZ showed the most excellent activity in comparison with CER and CET.
2. Peak serum level following intravenous injection of CEZ to rabbits in a dose of 75 mg/kg reached 32 to 52 mcg/ml at 15 minutes. Half-life was calculated to be 0.3 hour on an average.
3. The bile level in dog elevated to ten times or more of serum level after CEZ intramuscular injection in a dose of 50 mg/kg. Moreover the urine level reached 30 times or more of serum level in the same experiment.
4. When CEZ was injected to mice intramuscularly in a dose of 20 mg/kg, peak values in each organ ranked in order of the kidneys, lungs, liver and spleen. The kidney level exceeded that of serum, but CEZ could not be detected in the brain. Oral administration of CEZ to mice in a dose of 100 mg/kg resulted in a very high level of caecum contents. In the liver, kidneys and spleen, CEZ was slightly found in bioassay, though the levels were somewhat lower than that of serum.
The reduction of CEZ activity by mixing with homogenates of mice organs was relatively great only in the liver, and almost null in other organs.
5. CEZ was administered to two cases. One case of acute pneumonia showed no good result, and the other case of bronchopneumonia responded well at first, but did not respond at relapsing time. The number of cases is too small so far, further investigation will be needed for its clinical evaluation.

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1) The sensitivity of 67 strains of Staph. aureus, 10 strains of Kl. pneumoniae and 10 strains of E. coli to Cefazolin was determined by the plate dilution method. Seven strains were inhibited at concentrations of less than 0.2 mcg of Cefazolin per ml and thirty-four strains at the same concentration of Cephaloridine. The antimicrobial activity of Cephaloridine against many strains of Staph. aureus was two times superior to that of Cefazolin. However, the antimicrobial activity of Cefazolin against Kl. pneumoniae and E. coli was superior to that of Cephaloridine.
3) The binding rate to human albumin was studied by the equilibrium dialysis method. The rate was 58.2% in Cefazolin and 6.3% in Cephaloridine respectively.
2) One patient with pyelitis and three patients with pneumonia were treated with a daily dose of 1 g or 2 g of Cefazolin. The therapeutic results were fairly effective in 2patients, slightly effective in 1, and no side effect was observed.

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Cefazolin (CEZ), a new cephalosporin antibiotic, was tested for its minimum inhibitory concentration against 50 strains of coagulase-positive Staphylococci. The results showed CEZ to be higher than Cephalexin (CEX) and lower than Cephaloridine (CER) in the in vitro antimicrobial activity.
The minimum inhibitory concentrations of CEZ were also measured against 50 strains of E. coli, with antimicrobial activity of CEZ higher than that of CER, CEX and Cephalothin (CET). But the differences of antimicrobial activity in these cephalosporin antibiotics were not so great.
Intramuscular administration of CEZ 500 mg produced relatively high serum concentrations (standard; human serum); the peak ranged from 22.0 mcg/ml to 42.3 mcg/ml (average 32.9 mcg/ml in 6 volunteers) and 3. 14 mcg/ml in average value was sustained even after 8 hours. These values were higher than those of CER. Urinary excretion of CEZ at the intramuscular injection of CEZ 500 mg was also higher than that of CER.
CEZ was administered intramuscularly to 13 patients with various bacterial infections in doses of 500 mg twice daily, of whom 11 well responded to this drug. No side effects were seen in any of the patients treated.

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The results obtained are as follows :
I. Basic study
Cefazolin was given intramuscularly in a dose of 500 mg to 5 healthy adults. The blood level reached an average maximum of 7.2 mcg/ml at 30 minutes, and was found to be 1.3 mcg/ml at 6 hours, after administration.
II. Clinical study
Cefazolin was administered to 18 patients of various infections, with satisfactory results obtained in 13 (72.2%).
The drug was proved to be effective against SBE in 1 out of the 2 patients after 6weeks' administration in a daily dose of 6. 0 g. It was proved to be effective in one of sepsis due to E. coli and 2 of biliary infection.
In respiratory infection, 4 out of the 6 patients were treated with success. Cefazolin was effective in 5 of the 7 patients with urinary tract infection.
III. Side effects
Serious side reactions were not observed in any of the patients including one who received massive doses of 6g daily for 28 days.

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1. In vitro antibacterial activity of Cefazolin (CEZ) was examined against Staph. aureus, E. coli and Kl. pneumoniae. The M. I. C. of CEZ against Staph. aureus was 0. 2-1. 6 mcg/ml for 40 strains out of the total 47 strains, and was higher than that of CER, lower than that of CEX and about the same as that of CET. Against E. coli and Kl. pneumoniae, the M. I. C. of CEZ was more excellent than that of CER and CET.
2. Following a single intramuscular administration of 500 mg of CEZ, the average serum level reached the maximum of 46.0 mcg/ml (when the standard was made by dilution of human serum) and 13. 7 mcg/ml (the standard was made by dilution of buffer) at 30 minutes after injection, decreasing to 3. 3 mcg/ml (human serum) and 0.97 mcg/ml (buffer) at 8 hours.
3. Urinary excretion of CEZ was higher than that of CER, and the average urinary recovery rate was 76.2% within 8 hours.
4. The binding of CEZ to human serum was as high as 72-82%.
5. Clinically, CEZ was effective in 24 of the 31 patients, showing the effectiveness rate of about 77%.
6. No marked side effects were encountered, except local pain after intramuscular administration in 4 cases.

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Fundamental and clinical tests of Cefazolin were performed in this study.
1. Minimal inhibitory concentrations of Cefazolin against 32 strains of clinically isolated Staphylococcus aureus, including 26 of penicillin-G resistant strains, ranged from 0. 1 to 6. 25 mcg/ml except for one strain grown at the concentration of 12. 5 mcg/ml.
2. The influence of inoculation size on minimal inhibitory concentrations of Cefazolin and penicillin-G against penicillin-G resistant strains was studied, and these residual potencies were determined by the incubation with overnight cultured bouillon of penicillin-G resistant strains for 15 to 60 minutes at 37°C, Cefazolin was more resistant to β-lactamase produced by Staphylococcus aureus than penicillin-G.
3. Serum concentrations of Cefazolin were kept at a significantly high level and urinary recovery rate decreased in patients with severely impaired renal function. The average serum half-life of Cefazolin after a single intravenous administration of 500 mg was 1. 60 hours in three patients with normal renal function, 2. 67 hours in three with moderately impaired renal function, 14. 91 hours in three with severely impaired renal function and 2. 67 hours in three under hemodialysis with Kiil type artificial kidney. The average urinary recovery rate of Cefazolin and renal clearance were 84% and 49. 13 ml/min. in the group with normal renal function, 33% and 12. 10 ml/min. in the moderately impaired group, and 10% and 1. 45 ml/min. in the severely impaired group.
A modified dosage schedule of Cefazolin was designed according to the degree of impaired renal function. It would be adequate to inject 500 mg of Cefazolin by the intramuscular or intravenous route at intervals of 6 hours in the patients with normal or mildly impaired renal function (Ccr : >60 ml/min.), of 8 hours in the moderately impaired group (Ccr : 60-30 ml/min.), of 12-24 hours in the severely impaired group (Ccr : <30 ml/min.) and 36-48 hours in the anuric patients (Ccr : <10ml /min.). No additional injection of Cefazolin would be necessary on the day, of hemodialysis.
4. Cefazolin was used in 16 patients with respiratory infection and 3 patients of other infections. The results were excellent or good in 12 patients, fair in 4 and poor in 3. No side effects and disorders were observed in the liver and kidney function of any patients.

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Antibacterial activity of Cefazolin, a new derivative of Cephalosporin C, was somewhat superior to or similar to that of Cephaloridine against various laboratory strains and clinical isolates. It was notable that Cefazolin showed much higher activity than Cephaloridine or Cephalothin against 20 strains of clinical isolates of Klebsiella.
After a single intramuscular administration of 500mg to 4 healthy adults, the serum level reached its maximum of 18.75mcg/ml on an average at 30 minutes, and the urinary recovery rate for the first 6 hours averaged 76.1%.
Cefazolin was clinically applied to 17 patients with infections caused by Staph. aureus, E. coli and Klebsiella with good results in 15.
A slight local pain at the site of the injection was observed in only one patient.

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Cefazolin, a new cephalosporin C derivative, was evaluated in respect to its antibacterial activity, serum level, urinary recovery, binding rate to serum protein, and clinical effectiveness.
The results obtained were as follows.
1. The MIC values of Cefazolin against Staphylococcus aureus were a little higher than those of Cephaloridine and the values against Escherichia coli, Proteus mirabilis, and Klebsiella species were a little lower than those of Cephaloridine and Cephalexin.
2. The blood level and the urinary excretion by an intramuscular administration of each 500 mg of Cefazolin and Cephaloridine, and by an oral administration of 500 mg of Cephalexin were studied in 3 male adults by cross over method. The mean blood level of Cefazolin reached the maximum of 24 mcg/ml at 1 hour. The urinary excretion of Cefazolin was higher than that of Cephaloridine and Cephalexin. The mean urinary recovery rate was 78. 7% for 6 hours and 90. 3% for 24 hours.
3. Binding rate of Cefazolin to human serum protein was 68% by dialysis method, which was higher than that of Cephaloridine and Cephalexin.
4. Of the 20 patients with infections in internal medicine, including respiratory, biliary, and uncomplicated and complicated urinary tract infections, treated with Cefazolin, 55% showed clinical response. Side effects were skin rash in 1 patient, leukopenia in 1, eosinophilia in 1, azotemia in 1, exacerbation of SLE in 1 and weakly positive direct Coombs test in 4 patients.

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Studies were made on the characteristics of “Cefazolin” a new derivative of cephalosporin-C, with special reference to the comparison with the other cephalosporin-C derivatives.
1) In vitro sensitivity of micro-organisms isolates from patients : Cephalosporin derivatives such as Cefazolin (CEZ), Cephaloridine (CER), Cephalothin (CET) and Cephalexin (CEX) showed definite differences in their antimicrobial potency from each other, though a considerable correlation was observed.
CER against Staphylococci was the strongest in activity, followed by CET, CEZ and CEX in order. However, CEZ against E. coli and Klebsiella was the strongest, followed by CER, CEX and CET against the former, and by CEX, CER and CET against the latter.
2) Blood levels : Five healthy adult volunteers were examined for their blood levels after a single intramuscular injection of CEZ 500mg. A preliminary experiment revealed that the inhibition zone in band culture method produced by CEZ became smaller when the drug was dissolved in the human serum than when dissolved in buffer solution. The average blood levels which were determined with the human serum standard curve were as follows; 21.1mcg/ml at 1/2 hr, 29. 7 at 1 hr, 22.4 at 2 hr, 18.5 at 3 hr, 8.3 at 4 hr, 3.9 at 6 hr, 1.4 at 8 hr, 0.2 at 10 hr. When standard curve with buffer solution was used, each of the above figures was reduced to 11.9 mcg/ml, 16. 8, 13.0, 10.6, 4.7, 2.3, 0.8 and 0.12 respectively. Nevertheless, crossover tests revealed that the blood levels of CEZ were significantly higher than those of CER after the same dosage.
3) Urinary excretion : 65.7-97. 5% (avg. 85. 8%) of the administered CEZ was recovered in urine within 16 hours; while the recovery of CER was 56.3-77.8% (avg. 66.9%). The greater part of the excretion took place within 6 hours.
4) Distribution in the body : Concentrations of CEZ in rat organs were estimated at 30 minutes, 1 and 2 hours after an intramuscular administration of 100 mg/kg. The values were corrected by the in vitro recovery rates from organ emulsions. The highest concentration was obtained in kidneys and liver, followed by lungs and blood. In muscle, spleen and brain low concentrations were detected. High concentrations in liver and lung were characteristic of CEZ as compared with CER or CET.
5) Biliary excretion : Concentration of CEZ in the bile of rabbits taken from choledochus by canule was estimated at 10 min. intervals after an intravenous injection of 50mg/kg. These concentrations were markedly higher than those of the sera. The total biliary recovery reached 0.9-2.7% of the dose, while that of CER was 0.16-0.4%.
6) Clinical experiences : 14 patients including pyelonephritis (3), chronic bronchitis (1), lung abscess (1), suspected sepsis (1), phlegmon (2), upper respiratory tract inflammation (2), perithy-phlitis (1), otitis media with uremia (1), osteomyelitis with diabetes (1) and decubitus after being hospitalized with CO poisoning (1) were treated with CEZ. Daily doses from 0.5 to 2.0 g were injected intramuscularly. The treatment was markedly effective in 7 out of the 12 (the remaining two could not be followed up). One patient showed itching rash on the third day of the treatment. No untoward reactions were found in the other patients.
Conclusion : CEZ was found to be a new antibiotic which has several characteristics compared with conventional cephalosporin-C derivatives : 1) a potent antimicrobial activity especially against E. coli and Klebsiella, 2) high blood levels, 3) a high biliary excretion rate, and 4) concentrating distribution in liver and in lung. These data of fundamental studies as well as our preliminary clinical experiences encourage us for further clinical application of this antibiotic.

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Following results were obtained in our fundamental and clinical studies of Cefazolin which was newly synthesized in Japan.
1. Sensitivity of 146 strains (Staphylococci 71, E. coli 50 and Kl. pneumoniae 25) clinically isolated to Cefazolin was examined and compared with that of Cephaloridine, Cephalothin, Cephalexin a a Ampicillin.
Cefazolin inhibited 59 out of the 71 strains of Staphylococci at less than 0. 39 mcg/ml and 71 at less than 3. 12. Antimicrobial activity of Cefazolin against Staphylococci was more potent than that of Cephalexin, similar to that of Cephalothin and somewhat less than that of Cephaloridine.
The sensitivity distribution of 50 strains of E. coli to Cefazolin indicated its peak at 1. 56mcg/ml. Out of the 50 strains, 46 were inhibited their growth at less than 12.5mcg/ml.
The sensitivity distribution of 25 strains of KZ. pneumoniae to Cefazolin showed its reak at 1. 56 to 3. 12mcg/ml. Out of the 25 strains, 20 were inhibited their growth at less than 25mcg/ml. Cefazolin was more active against E. coli and Kl. pneumoniae than Cephaloridine, Cephalothin, Cephalexin and Ampicillin.
2. In vitro resistance development in B. H. I. broth of Staph. aureus and E. coli to Cefazolin was stepwise, which showed the same tendency as with Cephaloridine and Cephalothin.
3. With a single intramuscular administration of 1 g of Cefazolin to 2 healthy adults, serum levels reached a peak of 48. 5 mcg/ml at 1 hour, decreasing to 3. 75 mcg/ml at 6 hours. The urinary recovery rate was 88. 8% for the first 6 hours. One patient with renal impairment showed the serum concentration about twice as high as that in the healthy adults and the urinary excretion was one half of that in the healthy adults.
4. Tissue levels in rats following an intramuscular dose of 50 mg/kg, were the highest in muscle, decreasing in the kidneys, serum, liver, lungs, heart, spleen and brain in order at 1 hour, and almost undetectable at 4 hours except the kidneys, muscle, serum and spleen.
5. Cefazolin was given to 7 patients with respiratory tract infection, 1 with urinary tract infection, 1 with sepsis and 1 with subacute bacterial endocarditis at an intramuscular dose of 2 to 4 g daily. The effect was markedly effective in 6 patients, good in 1 and no response was obtained in 3.
No side effects were encountered except one case of exanthema.

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Cefazolin, a new derivative of Cephalosporin C series, was newly synthesized by the Central Research Laboratories of Fujisawa Pharmaceutical Co., Ltd.
The antimicrobial activity of Cefazolin was somewhat inferior against Staph. aureus, but superior against E. coli and Klebsiella to Cephaloridine.
The serum level of Cefazolin and Cephaloridine administered at an intramuscular dose of 500 mg was determined in three patients using cross over technique. In this test, higher serum levels were obtained with Cefazolin than with Cephaloridine.
However, scarcely any significant differences were observed in the growth inhibiting activity against Staphylococci between Cefazolin and Cephaloridine in the above serum.
Cefazolin was administered to 10 patients with infections in daily doses of 500-1000 mg for 3 to 10 days. It was effective in all except 2 patients with E. coli infections in whom the MIC was 3 mcg/ml.
No side effects were observed in any patients.

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From basic and clinical studies with Cefazolin (CEZ), the following results were obtained.
1) Antimicrobial activity of Cefazolin was examined against clinical isolates of coagulase positive Staphylococcus aureus, E. coli and Kl. pneumoniae, and proved to be excellent except for a few of resistant bacteria, in which cross resistance was observed between this antibiotic and Cephaloridine. Bactericidal activity of Cefazolin was comparable against E. coli to that of Cephaloridine but a little bit less potent against Penicillin G-resistant Staphylococcus aureus, which is to be considered in clinical application of the antibiotic.
2) Absorption into serum and excretion into urine of Cefazolin by the intramuscular route were good enough for clinical application.
3) Cefazolin was tried in various infections of children, and could be appraised as a drug of choice.
4) From our experiences, daily recommended dose in children was intramuscularly 50mg/kg divided into 3 to 4 portions for mild to moderate infections, and might be increased up to 100 mg/kg for serious ones.
In one patient given Cefazolin, an increase of GOT value was observed, the cause of which is not clear to date.

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nd clinical studies of Cefazolin, a newly developed Cephalosporin derivative in our country, was made on antimicrobial activity, absorption and excretion into body and clinical effect with the following results.
1) Antimicrobial activity of Cefazolin was tested with fresh isolates of Staph. aureus (42 strains), Str. hemolyticus (36 strains) and E. coli (30 strains). MIC distribution of Cefazolin against Staph. aureus and Str. hetnolyticus was nearly the same as that of Cephaloridine. Against E. coli Cefazolin showed a little bit lower MIC values than that of Cephaloridine.
2) Cefazolin showed high blood levels when given intramuscularly. In neonatal 20 mg/kg i. m. injection of Cefazolin produced the peak blood level of 32.6 mcg/ml after one hour and 7.3 mcg/ml even after 7 hours. Blood level of the antibiotic reached higher at peak and maintained longer in neonatal than in children. Urinary excretion of the antibiotic was also excellent.
3) High blood levels could be maintained longer when Cefazolin was given by drip infusion.
4) Cefazolin was given to 70 patients with acute infection mainly by intramuscular route, and effective in 66 patients with the effectiveness rate of 94%.
It was impressive above all, Cefazolin showed demonstrable effect against the refractory pneumonia possibly caused by Staph. aureus in a new born baby, suppurative diseases of the lung and septicemia.
5) No local or systemic side effects were encountered through the course of treatment.

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Several experiments on Cefazolin, a new Cephalosporin derivative, were performed bacteriologically and clinically with the following results.
Sensitivity of clinically isolated Staphylococci to Cefazolin was examined in a total of 56 strains. The M. I. C. s were 0.75 mcg/ml or less against 38 strains, 0. 75 to 1. 5 mcg/ml against 13 and 1. 5 to 3. 12 mcg/ml against the remaining 5.
Cefazolin was intramuscularly administered in a daily dose of 50 mg/kg to 38 children with various infections for 5 to 18 days. The therapeutic results were remarkable in 7 patients, fair in 27 and no response in 4. The effectiveness rate was 89. 5%. No noticeable side effects were observed except for a slight ecchymosis at the site of injection in one patient.

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Cefazolin was given to the following 38 patients; 4 with urinary tract infections, 10 with pneumonia or pyothorax, 20 with bronchitis and 4 with other upper respiratory infections. This antibiotic was intramuscularly given in doses of 50-400 mg/kg/day. Remarkable or fair clinical effect was obtained in 29 of the 38 patients, the effectiveness rate being 76.3%. No serious side effects were observed, except for local pain at the site of injection and induration in one each. Careful observations showed no functional abnormality of liver, kidney and blood picture, except for an increase of GOT and GPT in one patient, which remains unknown.

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The authors have carried out the laboratory and clinical studies of Cefazolin. The results were as follows;
The sensitivity was measured by the plate dilution method with 59 strains of Staph. aureus, 30 strains of E. coli and 13 strains of Klebsiella isolated from patients. The growth of 54 strains of Staph. aureus was inhibited at concentrations of less than 1.56 mcg/ml. The growth of 20 strains of E. coli was inhibited at concentrations of less than 12. 5 mcg/ml, and 8 strains of Klebsiella, at less than 6. 25 mcg/ml.
Cefazolin was given in a single intramuscular dose of 10 and 20 mg per kg. b. w. to two children, respectively. The maximum blood level was reached at 1 hour after administration. The levels were 16.0 mcg/ml and 40.0 mcg/ml, respectively.
The excretion rate of Cefazolin in the urine after a single intramuscular dose of 20 mg per kg. b. w. was 89.35 % up to 8 hours of period.
Cefazolin was administered intramuscularly or intravenousely at a daily dose of 25-75 mg per kg. b. w. to 17 children with bacterial infections.
Cefazolin was effective in 12 cases of them.
As a side effect, induration was observed in one case.

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Cefazolin, a new semisynthetic cephalosporin antibiotic, was studied experimentally with the following results obtained.
1) Serum levels of Cefazolin were studied in 4 children aged 6 to 8 years after an intramuscular dose of 250 mg. The maximum level of 30. 5 mcg/ml was reached at one hour, followed by 16.1 mcg/ml at two hours, 4. 1 mcg/ml at four hours, and 1.2 mcg/ml at eight hours when measured by the standard curve obtained by diluting Cefazolin with human serum. Due to high serum protein binding : of the antibiotic, serum level of Cefazolin was 19. 1 mcg/ml at a peak when measured by the standard curve obtained by phosphate buffer. In both assay methods, the serum level of Cefazolin was higher than that of Cephaloridine. The urinary recovery rate was 76. 7 per cent during six hours after the administration.
2) Marked or good clinical effect was obtained in 20 (87%) of the 23 patients treated.
3) The examinations were made on urine, peripheral blood, liver-and kidney-function before, . during and after this therapy. These results showed no abnormalities.

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Cefazolin, a new semi-synthetic Cephalosporin derivative was tested for its antimicrobial activity against clinical isolates of Staph. aureus, E. coli and Proteus, and also for its transfer into body fluids of man, and into tissue of rats. Clinical response to Cefazolin was also studied in 29 patients with surgical infections.
1) The serum level following an intramuscular administration of 500 mg Cefazolin to three healthy volunteers attained the peak of 34. 1mcg/ml on an average at one hour and still 6.2mcg/ml at six hours.
2) The urinary level in the above three volunteers reached the peak of 4, 000 mcg/ml on an average also at one hour after the administration, and the recovery rate averaged 62.6% for the first six hours.
3) Level in spinal fluid following an intravenous dose of 10 mg/kg was determined in 4 patients and was 0.4mcg/ml at 0. 5, 1, 2 and 4 hours after the administration in each patients.
4) Tissue level following an intramuscular dose of 200mg/kg to rats was the highest in kidneys, decreasing in serum, liver, heart, lungs and spleen in order, at 30 minutes after the administration, when the highest level was obtained in every organs. However, CEZ was slightly detectable in brain only at one hour.
5) Sensitivity for CEZ of 71 strains of clinically isolated Staph. aureus was ranged 0. 4 to 6.25 mcg/ml, That of 51 strains of E. coli was ranged mostly from 1. 56 to 6.25 mcg/ml, having its peak at 3. 12 mcg/ml, but a few strains were distributed at 12. 5 mcg/ml to more than 100 mcg/ml.
Of the 19 strains of Proteus group, 9 strains were distributed at less than 6.25 mcg/ml, but 8 were at more than 100mcg/ml.
6) CEZ was administered to 29 patients with surgical infections, and markedly effective in 3 patients, and moderately in 22 patients.
However, no response was obtained in the rest 4 patients.
No clinical side effect and disorder in liver and kidney were encountered in any patients.

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The average peak blood level of Cefazolin in 3 healthy adults was 3.8 and 22.0 mcg/ml respectively at 1/2 and 1 hour after intramuscular doses of 500 mg and 1, 000 mg, and there was detected 0.40 and 1.07 mcg/ml even after 6 hours. The average urinary excretion rate in the above 3 adults was 18. 5%and 14.8%respectively for the first 6 hours.
The MICS of Cefazolin against 56 strains of Staphylococcus aureus, Staphylococcus epidermidis mostly ranged from 3. 12 to 0.045 mcg/ml. Cefazolin was studied in 13 patients, mostly with surgical infections, including furuncle, paronychia, phlegmon and abscess at intramuscular doses of 0.25 to 2.0 g daily for 4 to 9 days, and was found clinically effective in 11.

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Following results were obtained in our fundamental and clinical studies of Cefazolin which was lately developed in Japan.
1. Sensitivity
Sensitivity of various clinically isolated organisms to Cefazolin was examined by tube dilution method and compared with that to Cephaloridine and Cephalothin. The MIC of Cefazolin was shown to be 0. 39 mcg/ml in 31 of the 48 strains of Staph. aureus and 12. 5 mcg/ml or more in only 3. In highly sensitive Staph. aureus, the antimicrobial activity of Cefazolin was less potent in one or two tubes than that of Cephaloridine and Cephalothin. In 16 strains of E. co : i Cefazolin inhibited their growth below 3. 13 mcg/ml in as many as 75 per cent of them, showing antimicrobial activity more potent in two or three tubes than that of Cephaloridine, Cephalothin, Cephalexin and Ampicillin. Antimicrobial activity against Klebsiella pneumoniae was very characteristic of this agent. Namely in 16 strains isolated, the MIC of Cefazolin ranged as sharp as from 3. 13 to 6. 25 mcg/ml in 50 per cent, having its peak at 3. 13 mcg/ml. While, that of Cephaloridine, Cephalothin and Cephalexin showed a peak between 12. 5 and 25 mcg/ml and that of Ampicillin a peak at 100 mcg/ml. Six strains of Pseudomonas aeruginosa were not sensitive to Cefazolin and to other Cephalosporin derivatives. In Protenstested 34 per cent of them were inhibited at concentrations less than 12. 5mcg/ml.
Inhibition rate of test antibiotics below 6. 25 mcg/ml against clinically isolated anaerobic bacteria was 72% with Cefazolin, 54% with Cephaloridine, 63% with Cephalothin, 54% with Cephalexin and45% with Ampicillin respectively.
2. Absorption and excretion
It is demonstrated that Cefazolin is highly bound to human serum protein. Assay results of serum level of the antibiotic, therefore, considerably differ according to whether the standard curve is obtained with human serum or phosphate buffer. In the volunteers after a single intramuscular dose of 500 mg, the serum level attained the peak of 32. 5 mcg/ml on an average at 1 hour, decreasing to 24. 0 mcg/ml at 3 hours, 7. 3 mcg/ml at 6 hours and 3. 5 mcg/ml at 9 hours, when assayed with serum standard curve. Cross over study with Cefazolin and Cephaloridine in other 2 healthy volunteers showed that serum levels of Cefazolin were 1. 5 to 3 times as high as those of Cephaloridine.
Urinary excretion was simultaneously examined in the above volunteers. The recovery rare was as excellent as 86. 1% on an average.
3. Clinical experiences
Cefazolin was administered to 34 patients with infections and remarkably effective in 4 patients, moderately effective in 27, non-effective in 2 and unknown in one, the effectiveness rate being as good as 91%.
Diagnosis of the patients comprised chiefly of appendicitis, peritonitis and hepatic or biliary-tract infection. Virtually, Cefazolin was given to 10 patients with acute appendicitis or perforans peritonitis due to appendicitis, the causative organism of which was E. coli in most of them, and brought a rapid cure relatively in a short term of period, simultaneously with remarkable amelioration of clinical symptoms.
Cefazolin gave successful results in all the patients with hepatic or biliary-tract infections, especially with serious biliary-tract infection complicated after operation, which suggests favorable transfer of the antibiotic into liver and/or biliary-tract.
This antibiotic was remarkably effective in a very short period of administration by drip infusion in a patient with abscess of the liver, in which remittent fever had continued for about 4 months despite of treatment with Cephalothin. Cefazolin, however, was not effective in 2 patients with burn infection caused by Pseudomonas aeruginosa and with post operative cystitis by Proteus.
Hepatic and renal functions and hematologicol findings were carefully studied before and after Cefazolin administration. No

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Cefazolin is a newly developed semi-synthetic cephalosporin derivative in Japan, which has abroad spectrum antimicrobial activity against both gram-positive and gram-ne gative bacteria including penicillinase-producing Staphylococcus aureus.
The present authors made studies on its sensitivity, absorption and excretion and clinical effectiveness. The results obtained were as follows.
1. Sensitivity of 4 species from clinical sources
i) Staph. aureus
Nos. of tested strain : 50
Average minimal inhibitory concentration (MIC) : 0.46 mcg/ml [Standard deviation (SD) : 0. 79]
Concentration at peak of sensitivity distribution : 0. 39 mcg/ml
Cross resistance coefficient of Cefazolin with Cephaloridine : 0. 7229
Those data indicate there were scarcely any strains resistant to Cefazolin.
Cefazlin was also very active against those strains of Staph. aureus with lytic pattern by phage 80/81.
ii) E. coli
Nos. of tested strain : 79
Average MIC : 6. 4 mcg/ml (SD : 2. 56)
Concentration at peak of sensitivity distribution : 1. 56 mcg/ml
Cross resistance coefficient of Cefazolin with Cephaloridine and with Cephalothin : 0. 6172 and 0. 6143 respectively.
The strains tested were sensitive to Cefazolin at the rate of 73. 45 %.
III) Klebsiella pneumoniae
Nos. of tested strain : 27
Average MIC : 7.45 mcg/ml (SD : 2.05)
Concentration at peak of sensitivity distribution : 6. 25 mcg/ml
Corss resistance coefficient of Cefazolin with Cephaloridine and with Cephalothin : 0. 7860 and 0.8740 respectively
The strains tested were sensitive to Cefazolin at the rate of 85 %.
iv) Proteus mirabilis
Cefazolin was also active against the clinically isolated 31 strains of Proteus mirabilis, the sensitivity distribution of which having its peak at 3. 13 mcg/ml.
However, the sensitivity was very low in the 12 strains of Proteus vulgaris tested. The cross resistance coefficient of Cefazolin with Cephaloridine and Cephalothin was 0. 8832 and 0. 8411 respectively.
2. Absorption and Excretion
It is demonstrated that Cefazolin is highly bound to human serum. Assay results of serum level of the antibiotic, therefore, differ considerably according to whether the standard curve is made with human serum or the other. Two standard curves were adopted in our study, which were obtained with human serum, or phosphate buffer added to human serum at the ratio of 1 : 1.
The serum level was examined in 3 healthy volunteers after a single intramuscular dose of 500 mg. The serum level reached the average peak of 19.5 mcg/ml at 1 hour, when assayed with serum standard curve and of 31.7 mcg/ml at 30 minutes, when assayed with phosphate buffer added to serum.
The average urinary excretion rate in the above volunteers was as favourable as 54.2 % in the first 3 hours and 90 % in 24 hours after the administration.
Bile level was also examined in 2 patients inserted external biliary fistula after drip infusion for one hour in a dose of Cefazolin 500 mg. The bile level attained the peak of 60 mcg/ml immediately after completion of the administration to one patient, and of 68 mcg/ml at one hour in the other, which suggests this antibiotic is promising in biliary-tract infections.
3. Clinical examination
Cefazolin was given to the 17 patients with surgical infections.
The therapeutic effect was remarkable in 5 patients, fair in 7, slight in 4 and no response was obtained in 1. The effectiveness rate was 70. 6 %. Cefazolin was especially effective in the patients with biliary tract infection due to E. coli.
No noteceable side-effects were encountered throughout the course of treatment.

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Cefazolin, a new derivative of 7-ACA, has been evaluated at our laboratory on clinical isolates and clinically on urinary tract infections. Cefazolin has bactericidal effect on most E. coli strains. It is also active against some other coliform bacilli an i some Proteus strains even when they are highly resistant to all synthetic penicillins due to penicillinase production. However, most indole positive Proteus and Pseudomonas species are resistant to this drug as in the cases of other cephalosporin C antibiotics. Clinically, Cefazolin has been proved effective in more than 90% of acute urinary tract infections due to E. coli strains. However, in many complicated urinary tract infections, superinfection due to resistant Pseudomonas and Proteus strains has made Cefazolin treatment ineffective. No severe untoward effect has been found except for mild to moderate pain at the injection site.

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Nine patients with various urinary tract infections were treated with Cefazolin by the intramuscular route. The effect was remarkable in 3 patients (33.4%), fair in 2 (22.2%), slight in 2 (22.2%), and no response was obtained in 2 (22.2%). No noticeable side-reactions were observed. Local pain at the site of injection was noticed in two patients. Careful observation showed no functional abnormalities in liver and kidneys.

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1) Minimal inhibitory concentration of Cefazolin (CEZ) was determined on 118 strains isolated from urinary tract infections by plate dilution method. Most strains of Staphylococci, E. coli and Proteus mirabilis tested were inhibited at concentrations below 6. 25 mcg/ml, but Pseudomonas and almost all of Proteus vulgaris tested were resistant to the antibiotic.

2) With an intramuscular injection of CEZ 500 mg, the blood level reached the maximum level (19.5-23.5mcg/ml) in 1/2-1hour after administration, decreasing rapidly thereafter.
3) The urinary recovery rate was 97.5% during 24 hours after injection in normal 3 subjects.
4) Fourteen cases with urinary tract infections were treated with CEZ, and good results were obtained in 9.
5) No side effect was observed throughout the course of treatment.

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Cefazolin, a new cephalosporin derivative synthesized in Japan, was tested for its antimicrobial activity against various fresh isolates from patients, and for its absorption and excretion in man an clinical effectiveness in patients with urinary tract infections. The results obtained were as follows.
1. Cefazolin was given to the 32 patients with urinary tract infections either intramuscularly, intravenously or by drip infusion. The effectiveness was remarkable in 16, moderate in 9, and no response obtained in 7 (effectiveness rate of 78. 1 per cent).
2. The serum level following a single intramuscular dose of 500 mg in 3 healthy adults reached the maximum at 30 minutes and clinically effective serum level was maintaine 1 for 6 hours.
3. The urinary excretion rate following a single intramuscular dose of 500 mg in 3 healthy adults was more than 60 % for the first 6 hours after the administration.
4. The antimicrobial activity of Cefazolin was more favourable against clinically isolates of E. coli than the other cephalosporins.
5. No side effects were observed in any of the patients.

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Cefazolin was administered intravenously at a daily dose of 2 g to 23 patients with urinary tract infections mostly associated with various urogenital diseases. As a result of bacteriological test with urine, E. coli was found in 15, Ps. aeruginosa in 7, Pr. mirabilis in 7, Pr. vulgaris in 2, Klebsiella in 4, Citrobactor in 2 and, Morganella in one. Mixed infections were observed in 7 out of the 23 patients.
The therapeutic results were remarkable in 5 patients, fair in 6, slight in 4, and no response was obatined in 8, with the effectiveness rate of 47. 8 per cent. No side effects were found in any of the patients except morbilliform eruption in two. No influences of Cefazolin were noted in the liver and kidney functions.

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Laboratory and clinical studies on Cefazolin, a new Cephalosporin antibiotic, were made and the results were summarized as follows.
1. The distribution of the sensitivity was mostly 0.39 to 3.12 mcg/ml against Staph. aureus and 1. 56 to 6. 25 mcg/ml against E. coli.
2. The MIC values of Cefazolin against Staph. aureus were a little higher than those of Cephalo-ridine and Cephalothin but were almost the same or a little lower than those of Cephaloridine and Cephalothin against E. coli.
3. Serum levels of Cefazolin after a single intramuscular administration of 500 mg were at the maximum of 11.3 to 16. 0 mcg/ml at 30 minutes and became undetectable at 10 hours.Cefazolin was excreted in the urine at the rate of 65. 6% during 10 hours.
4. The level of Cefazolin in cord blood of 3 cases was about 1/5 to 1/3 that of maternal blood and was about 2 mcg/ml in amniotic fluid.
5. Tissue levels of Cefazolin in normal and pathogenic sexual organs (uterus, ovarium and endometrium) after intramuscular injection to patient were about 1/2 to 1/3 of the blood level.
6. Thirteen cases of genital infection and 18 cases of urinary tract infection were treated with Cefazolin a nda good result was observed excluding urinary tract infections associated with carcinoma uteri.
7. As to side effects, schock-like syndroms were observed in one patient 40 minutes after the first intramuscular injection, but disappeared in a few hours.
8. No significant changes attributable to the antibiotic were observed in clinical laboratory test of S-GOT, S-GPT, Alkaliphosphatase and BUN.

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Clinical studies on Cefazolin were made in the field of obstetrics and gynecology, and the following results were obtained :
1. Minimum inhibitory concentrations of Cefazolin against pathogenic organisms of 20 strains of Staphylococcus aureus, 16 strains of E. coli, 2 strains of Klebsiella and 2 strains of Proteus were estimated by agar plate method. The minimum inhibitory concentration was 0.78 mcg/ml against Staphylococci, 1.56mcg/ml against E. coli and Klebsiella, and 6.25mcg/ml against Proteus in most cases.
2. The average serum concentration of Cefazolin in 2 lying-in women reached its peak of 35.5 mcg/ml at 1 hour, and was 5.8 mcg/ml at 12 hours respectively after an intramuscular injection of 500 mg, the half-life being 4.2 hours.
3. The urinary excretion rate in 24 hours after an intramuscular injection of 500 mg was 70.44% in an adult with normal kidney function.
4. The concentration of Cefazolin transferred into mother's milk was very low.
5. The transfer rate into the cord blood 15 to 70 minutes after an intramuscular dose of 500 mg in 6 pregnant women was about 36 to 44% of the blood level.
6. The average of serum Cefazolin concentration in 9 newborn reached its peak of 64. 68 mcg/ml at 1 hour, and was 10. 66mcg/ml at 12 hours respectively after an intramuscular injection of 25 mg/kg.
7. The urinary excretion rate in 8 newborns averaged 41. 18% after an intramuscular injection of 25 mg/kg.
8. Eighteen patients with gynecological infection were treated with Cefazolin at a daily dose of 1.0 g for 4 to 13 days and good results were obtained in 88%. No side effect was observed in any of patients.

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合成Cephalosporin C系抗生物質として, Cephalothin, Cephaloridineにつづき, わが国ではじめて開発されたCefazolin (以下CEZと略記) は, 臨床上有用な新製剤と推定されるので, その基礎的・臨床的検討を行なつた。CEZは, 1967年, 藤沢薬品中央研究所で合成された新しい誘導体であつて, 7-aminocephalosporanic acidの7位にtetrazolacetyl基を, 3位のmethyl基につくacetoxy基を2- (5-methyl-1, 3, 4-thiadiazolyl) -thio基で置換した安定な新規化合物である。

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Cefazolin, a newly developed Cephalosporin C derivative, was given to patients with various gynecological and obstetrical infections.
In the present study, the blood level of 20. 2 mcg/ml was obtained at one hour and the total urinary excretion rate of 97 per cent, in 24 hours, after 500 mg intramuscular injection.
In the clinical trial of this drug, 22 out of the 25 patients showed a good therapeutic response. The patients were 4 of adnexitis, 9 of cystitis, 4 of pyelonephritis, 1 of post-operative bronchitis, 1 of peritonitis, 2 of mastitis, 2 of uteral infection and 2 of genital infection. Isolated pathogens were 8 strains of E. coli, 10 of Staphylococcus, 2 of Proteus and 1 of Klebsiella.
No significant side effects were observed.

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Eighteen 'patients, mainly of staphylococcal skin infection, were treated with Cefazolin. Cefazolin revealed to be very effective against the staphylococcal skin infection. It was evaluated to be effective in 78 % of the patients treated. The minimal inhibitory concentration of Cefazolin for staphylococcal strains obtained from the clinical lesions treated, ranged from O. 2 to 1. 56 mcg/ml. The strains of St. aureus and St. epidermidis were revealed in general to be sensitive to Cefazolin. The sensitivity to Cefazolin seems to be somewhat superior to that for Cephalexin and somewhat inferior to that for Cephaloridine. Concerning the dosage, no difference in the effectiveness was found between the cases treated with 500 mg/day and those with 1000 mg/day. Minor untoward effects of Cefazolin were encountered in 2 out of the 18 cases.

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Clinical observation on Cefazolin, a new antibiotic developed in Japan, were performed in our clinic. Twenty-four cases of pyogenic skin disorders were treated with Cefazolin, which was given to the patients at a daily dose of 1 g. intramuscularly for two to six days. The therapeutic effects were as follows :
Eleven cases showed a satisfactory response, 4 cases a good, 6 cases, a fair and 3 cases a poor response. Thirteen strains of Staph. aureus, 3 strains of Staph. epidermidis, and each one strain of Proteus mirabilis and Klebsiella were isolated from the patients. The patients with the latter bacilli showed a poor response. No remarkable side effects were seen.

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Cefazolin (CEZ) was studied experimentally and clinically and the following data were obtained. 1) In vitro antibiotic activity :
The sensitivity to CEZ of 31 strains of coagulase positive Staph. aureus obtained chiefly from deeper pyodermas was studied using plate dilution method. The MIC was 6.3 mcg/ml against I strain, 3. 1 against 2, 1. 6 against 3, 0. 8 against 12 and 0. 4 against 13 strains. CEZ was slightly inferior to Cephaloridine (CER) in the sensitivity against Staph. aureus.
2) Serum level :
The serum levels were measured after an intramuscular injection of 500 mg of CEZ to 3 persons. The mean value at 30 minutes, 1, 2, 3, 6 and 9 hours was 35. 8, 36. 9, 33. 7, 26. 0, 14. 2 and 4. 5 mcg/ml respectively.
3) Clinical evaluation :
CEZ was given to 3 patients with skin infection. Two of them showed beneticiai results.

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Bacteriological and clinical experiments on ophthalmic use of Cefazolin (CEZ) were performed, and the results were as follows.
1) The MICs of CEZ against 34 strains of 8 species of bacteria causing ocular infections were 25-50 mcg/ml for KOCH-WEEKS bacilli, 0. 01-0. 05 mcg/ml for MoRAX-AXENFELD diplobacilli, 0. 05-1. 56 mcg/ml for Pneumococci, 0. 2-0. 39 mcg/ml for C. diphtheriae, 0. 025 mcg/ml for Gonococci, 0. 025-0. 05 mcg/ml for Strept. hemolyticus, 12. 5-50 mcg/ml for Strept. viridans, 0. 1-0. 78 mcg/ml for Staphylococci and 100 mcg/ml for Ps. aeruginosa.
2) Sensitivity for 100 strains of Staph. aureus ranged between 0.2 and 1. 56 mcg/ml, being 0. 39 mcg/ml in most of the strains (63%). Resistant strains to other antibiotics were also sensitive to CEZ.
3) The maximum serum level (36. 3 mcg/ml) of CEZ was reached 1 hour after a single intramuscular injection of 500 mg. The serum level decreased relatively slowly, and was 5. 5 mcg/ml 6 hours after administration.
4) After an intramuscular injection of 50 mg/kg to rabbits, the aqueous humour levels were recognized from 1/2 to 4 hours, and the peak level (8.0 mcg/ml) was obtained 1 hour later. Aqueous humour-serum ratio was 4. 3%-14. 3%. CEZ concentrations in the ocular tissues of rabbits 1 hour after intramuscular injection of 50 mg/kg were high in conjunctiva, eyelid, iris and ciliary body, extra ocular muscles, sclera, retina and chorioid, and were low in cornea, vitreous body and lens. Assayable concentrations of CEZ in the ocular tissue were found 4 hours after administration.
In comparison with those after an intramuscular injection of 50 mg/kg Cephaloridine (CER), the levels of CEZ were remarkably higher than those of CER in almost all parts of the ocular tissue.
5) An intramuscular injection of 1 g CEZ, once or twice daily revealed good effects in 17 of the 22 patients with ocular infection, such as hordeolum, dacryocystitis, corneal ulcer, panophthalmitis, orbital phlegmone, and perforating injury, and in 9 of the 10 patients treated for prevention of postoperative infection of ocular surgery.
6) Systemic rash developed in one of the 32 patients treated, but otherwise no severe side effects were noticed.

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Cefazolin (CEZ) is a new semi-synthetic cephalosporin derivative with a broad antibacterial spectrum and its potoncy is high. We have recently obtained the following results through the fundamental and clinical studies of CEZ.
1) In vitro antibacterial activity : Sensitivity of CEZ against coagulase-positive Staphylococci isolated from patients was distributed below 6. 25 mcg per ml in MIC in almost all strains, showing its peak at 0. 39 mcg per ml.
Growth of clinically isolated Streptococcus hemolyticus and Diplococcus pneumoniae was inhibited in concentrations of less than 0.78 mcg per ml, and the antibiotic also demonstrated antibacterial effect against Proteus vulgaris and E. coli isolated from clinical materials. Thus, CEZ demonstrated a broad spectrum of antimicrobial activity.
2) Serum concentration : Peak serum levels of 13. 5 mcg per ml were reached at one hour after an intramuscular injection of 500 mg to 5 healthy adults. Even at 8 hours after injection, clinically effective serum CEZ concentration of 0.4 mcg per ml was still demonstrable.
3) Excretion into urine : In 5 healthy adults receiving 500 mg of CEZ the intramuscular route, excretion of the antibiotic in the urine showed an average recovery rate of 73. 6 per cent for the first 8 hours.
4) Concentration in tissues : CEZ activity was demonstrable in concentrations of 7. 1 and 3. 3 mcg per gram on an average in 8 human palatine tonsilla and 3 maxillary sinus specimen respectively at one hour after an intramuscular injection of 500 mg, and serum levels of CEZ were 13. 3 and 11.7 mcg per ml respectively.
5) Side effect : Liver functions, serum electrolytes and audiotory acuity were tested on subjects receiving CEZ 1, 000 or 2, 000 mg a day for 5 to 12 days, with any significant adverse findings.
6) Clinical evaluation : In the clinical tests in otorhinolaryngological infection, it was found that CEZ showed good to excellent response in as many as 26 of the 36 patients by the intramuscular route or loal aplication of 20 mg per ml solution (effectiveness rate of 72 per cent).
No side effects were observed.

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Cefazolin was applied in the treatment of otorhinolaryngological infections, and the following results were obtained.
1. The sensitivity of 23 strains of clinically isolated Staphylococci to this antibiotic was determined by the agar plate dilution method. The MIC of Cefazolin for them ranged from 0.39 mcg/ml to 1. 56 mcg/ml, and showed a peak at 0.39 mcg/ml (70%). These values were slightly higher than those of Cephaloridine. On the other hand, gram negative bacteria, i. e., Proteus, Pseudomonas, and Providencia isolated clinically were resistant to Cefazolin in concentrations of more than 100 mcg/ml.
2. The therapeutic effect in 40 patients with otorhinolaryngological infections was marked in 22 patients (55%) and good in 7 (17. 5%), the total effectiveness rate being 72.5 per cent. When the nine patients, 2 with Proteus, 3 with Pseudomonas, 3 with Providencia and one with gram negative bacteria were excluded, the effectiveness rate was 96 per cent.
3. No side effect was observed.

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From the laboratory and clinical studies on Cefazolin, a new semi-synthetic antibiotic, the following results were obtained.
1. The MIC values of CEZ were a little higher against newly isolated Staph. aureus (9 strains), and a little lower against E. coli (45 strains), than those of other Cephalosporin C derivatives, such as Cephalothin, Cephaloridine and Cephalixin.
2. The bacteriolytic action of Cefazolin was observed from the automatically recorded growth curve of Staph. aureus 209 P strain, using Biophotometer Jouan. The same activity against the above strain was observed in the sera of patients receiving an intramuscular dose of CEZ 250 or 500 mg.
3. Cefazolin was clinically applied to 43 paients of ear, nose and throat infections and the results were as follows : remarkable in 32 patients (74. 4%), moderate in 7 (16. 3%) and ineffective in 3 (7%). The effectiveness ratio was 90. 7%.
4. As for the side effect, eruption was encountered in one out of the 43 patients.

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