Fundamental and clinical studies on cefotetan (CTT),a new cephamycin antibiotic,were carried out under a joint study programme in pediatric field,and the following results were obtained.
1. Pharmacokinetic study
In 20 pediatric patients with normal renal function,weighing 15 to 48 kg, CTT was injected intravenously at 20mg/kg in 3 to 5 minutes.
The mean blood concentration of CTT was 215.6μg/ml at 15 minutes after the end of injection, 90.7μg/ml at 1 hour, 57.2μg/ml at 2 hours, 33.9μg/ml at 4 hours and 10.2μg/ml at 8 hours. The halflife of the drug in the β-phase, computed from the mean blood concentrations up to 8 hours postdosing, was 2.61 hours.
The peak of the mean urinary excretion of cefotetan appeared in 0 to 2 hours after the injection and 36.5% of the dose was recovered in the urine.The mean excretion at 0 to 8 hours was 68.1%.
2. Clinical study
Clinical effects of CTT was evaluated in 285 patients with 287 diseases, since 1 patient had both pneumonia and erysipelas, and another both pneumonia and acute otitis media.Daily dosage of CTT ranged from 15 to 123mg/kg,and 266 patients (93.3%) received the drug either 2 or 3 times daily.
The clinical response was seen in 83.3% of the 6 cases with sepsis,89.3% of the 122 cases with pneumonia with or without pyothorax, 96.2% of the 52 cases with either acute bronchitis or tonsillitis, 92.5% of the 67 cases with urinary tract infection and 92.5% of the 40 cases with other infections.
The causative organisms were detected in 160 patients and the rate of complete disappearance was 80.6%.
Out of 310 patients,side effects were seen in 9 cases, diarrhea in 8 (2.6%) and rash in 1 (0.3%). Abnormal clinical laboratory findings were seen in 24 cases,elevation of serum transaminases in 19 (7.8%),elevation of TTT and LDH in 1 (0.4%) and eosinophilia in 4 (1.6%). None of these cases showed serious side effects or abnormal clinical laboratory findings.
From the above results,it is concluded that CTT is one of the useful drug for treatment of infections in pediatric field.

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Fifteen children with acute bacterial infections,including pneumonia (8), pharyngitis (2),cervical lymphadenitis (1), perforative peritonitis (1), gastroenteritis (1) and urinary tract infection (2), were treated with cefotetan.This drug was effective to all of the patients.In 2 patients the result was excellent and in 9 it was satisfactory.
No adverse reactions were observed in the above cases and 2 other patients, during and after the dosage of 30-60 mg/kg/day for 4-11 days.

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Basic and clinical studies on cefotetan (CTT) were carried out and the results were as follows: 1. Absorption and excretion
Two patients were given 10 mg/kg of CTT by one shot intravenous injection. At 30 minutes after injection, mean serum level was 76.5μg/ml and the half-life time was 2.3 hours. Mean 6-hour urinary recovery in same patients was 57.5%.
2. Clinical evaluation
Forty-two patients were treated with CTT,in doses of 19.2-102.9 mg/kg divided 2-4 times per day for 3-10 days intravenously. Responses were excellent in 14, good in 23, fair in 1, poor in 4, and the overall efficacy rate was 88.1%.
As to adverse reaction,urticaria was observed in 1 patient.Abnormal laboratory data noted were elevation of GOT in 1, GOT and GPT in 2, creatinine in 1, and eosinophilia in 3 patients.

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Twenty-five patients in hospital mainly with lower respiratory tract infections and urinary tract infections were treated with cefotetan (CTT). The drug was given intravenously in a dose of 20mg per kg body weight 1 to 3 times per day.The response to treatment was satisfactory in the 21 patients (84%). There was slight changes in liver function tests in 2 patients and exanthem in 1 patient. CTT appears to be an effective antibiotic for the treatment of children with bacterial infection.

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Preclinical studies were carried out on cefotetan (CTT),together with clinical studies in the field of pediatrics. The following results were obtained.
1. A total of 114 clinical isolates that have been stored in the authors' department was employed to determine the minimum inhibitory concentrations (MICs) of CTT against various bacterial species. Against E. coli, Salmonella, K. pneumoniae and P. mirabilis, the MICs of CTT showed a peak at 0.78μg/ml, and most of the strains were inhibited by a CTT concentration of 6.25μg/ml or less. The MICs for S. marcescens strains showed a peak at 25μg/ml, with 25% of the strains having MICs of 3.13μg/ml or less, and 67% having MICs of 25μg/ml or more. All of the P. aeruginosa strains had MICs of over 100μg/ml. Against all of the tested strains of S. aureus, a Gram-positive bacterium, CTT showed MICs of 12.5μg/ml or more, while all of the strains of S. faecalis were found to have MICs of over 100μg/ml.
2. CTT was administered intravenously to pediatric patients as a bolus injection,and then the concentration of the antibiotic in the serum was determined as a function of time. When the dosage rate was 10mg/kg,the mean serum levels were as follows; 58.2μg/ml at 30 minutes, 45.5μ at 1 hour, 33.6μg/ml at 2 hours, 18.0μg/ml at 4 hours and 11.7μg/ml at 6 hours after the injection. The half-life of CTT in the serum at this dosage was thus 2.40 hours. Similarly,at a dosage rate of 20 mg/kg,the mean values at the various times were; 98.6μg/ml at 30 minutes, 75.6 μg/ml at 1 hour, 57.8μg/ml at 2 hours, 35.5μg/ml at 4 hours and 23.2μg/ml at 6 hours subsequent to the injection. The half-life of CTT in the serum in these cases was 2.73 hours.
3. CTT was drip-infused intravenously over a period of 1 hour,and then the serum concentration of the drug was monitored with the passage of time. Subsequent to the administration of 10mg/kg, the mean serum concentrations were as follows; 48.8μg/ml at 30 minutes,81.5μg/ml at 1 hour, 42.2μg/ml at 2 hours, 23.6μg/ml at 4 hours and 14.8μg/ml at 6 hours subsequent to the injection. The half-life of CTT in the serum after this intravenous drip infusion was thus 2.13 hours. Similarly, when the dosage rate was 20mg/kg, the mean values at the measurement times were 78.8μg/ml at 30 minutes, 138.2μg/ml at 1 hour, 71.1μg/ml at 2 hours, 41.8μg/ml at 4 hours and 31.7μg/ml at 6 hours subsequent to the injection. The half-life of CTT in the serum at this dosage rate was 2.48 hours.
4. CTT was administered to 3 meningitis patients,and then the concentration of the antibiotic in the cerebrospinal fluid was measured with the course of time. A single dose of CTT,ranging from 54 to 83mg/kg, was administered, and the CSF concentration ranged from 1.1 to 4.8μg/ml. The ratio of the concentration in the CSF to the serum concentration ranged from 0.8 to 3.6%.
5. No cumulative effect of CTT was seen.
6. CTT was administered intravenously to 16 cases of bacterial infection. A good clinical effect was seen in 14 of these cases (88%).
7. The bacteriological effect of CTT was investigated in 9 patients. In all cases, the causative bacteria were eliminated, for a 100% bacteriological efficacy rate. The bacterial isolates consisted of 5 strains of E. coli, 2 strains of S.pneumoniae, 1 strain of H.influenzae, and 1 strain of H.parainfluenzae.
8. The following side effects to the CTT therapy were recorded; 4 cases of diarrhea,and elevated values of GOT and GPT in 1 patient. All of these side effect symptoms disappeared rapidly after the drug administration was stopped.

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A series of studies was performed on the use of cefotetan (CTT) in the field of pediatrics. The results that were obtained are described below.
1. The minimum inhibitory concentrations (MICs) of CTT against strains of E. coli and K. oxytocathat were recently isolated from child patients were found to mostly be 0.78μg/ml or less. Even strains that were highly resistant to the action of ABPC were sensitive to CTT.
2. CTT was administered to pediatric patients by intravenous drip infusion or by one shot intravenous injection, and then the concentration of the drug in the serum was monitored. The same procedures and dosages were employed for CFX and CMZ.In comparison with these 2 antibiotics, CTT showed a higher peak concentration in the serum,and it was retained in the blood for a longer time. The half-life of the CTT serum concentration was 2 hours or more in most of the subjects. When CTT was administered in a dosage of 10mg/kg by intravenous drip infusion,the drug could still be detected in the serum as long as 12 hours later in some cases.
3. Repeated intravenous drip infusion administration of CTT was not found to result in any accumulation of this antibiotic in the serum.
4. During the 8-hour period following intravenous injection of CTT, about 50 to 80% of the administered dose was found to be excreted in the urine in its active form.
5. During the acute phase of meningitis,intravenously injected (one shot) CTT was found to be transferred to the cerebrospinal fluid in a concentration that was sufficient to kill those bacteria that were sensitive to the action of this antibiotic.
6. It was proven that, following the intravenous injection of CTT, the concentration of this drug in the feces was sufficient to inhibit the growth of Salmonella, Campylobacter, etc.
7. CTT was administered by intravenous drip infusion as therapy to a total of 37 child patients diagnosed as having acute infections; these infections consisted mainly of upper and lower respiratory tract infections, urinary tract infections, intestinal tract infections and suppurative diseases. The dosage of CTT used in the treatment of these diseases ranged almost from 20 to 40mg/kg/day,given as 2 doses per day (at intervals of 10-42 hours). The efficacy rate of this therapeutic regimen was 97%.
8. As a result of the administration of CTT, it was no longer possible to detect most of the strains of S. aureus, S. pyogenes, H. influenzae, H. parahaemolyticus, E. coli, K. pneumoniae, Salmonella and Campylobacter that had initially been isolated from the clinical materials.In some of the other patient materials, a decrease in the bacterial count was achieved.
9. None of the patients were found to experience systemic or local side effects as a result of the administration of CTT. Concerning the laboratory test results, 2 patients showed eosinophilia, but there were no cases of abnormalities in the liver function or kidney function.
10. Based on the preceding results, it can be concluded that the use of CTT in a dosage of 20-40mg/kg/day, given by intravenous injection in 2 daily doses, can be expected to achieve the desired therapeutic effect in most child patients afflicted with acute infections caused by various bacteria that are susceptible to the action of this antibiotic.

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Pharmacokinetic and clinical studies on cefotetan (CTT),a new cephamycin antibiotic, were carried out and the following results were obtained.
1. Pharmacokinetic study
Two patients, 7 years and 10 months of age(22kg of body weight)and 9 years of age(28kg of body weight), were administered 20mg/kg of CTT by 30 minutes intravenous drip infusion.
Serum levels of CTT were 148μg/ml and 92μg/ml immediately after the end of drip, 118μg/ml and 63μg/ml at 1 hour after the drip infusion, 76μg/ml and 39μg/ml at 2 hours after, 34μg/ml and 18.2μg/ml at 4 hours after and 18μg/ml and 8.2μg/ml at 6 hours after. Serum half-lives calculated were 1.92 hours and 1.78 hours respectively.
2. Clinical study
CTT was administered to a total of 14 patients, 3 with pneumonia, 2 with acute pyelonephritis, 2 with acute enteritis,each one with acute tonsillitis, acute bronchitis, acute bronchiolitis, sepsis, acute lymphadenitis,stomatitis and measles.Because that stomatitis and measles, however, were not indications of CTT, 2 cases with those diseases were excluded. CTT was administered at daily dose of 40 to 73mg/kg in 2 to 4 portions for 3 to 5.5 days by intravenous drip infusion. Marked response was seen in 2 cases,moderate response in 9 and no response in 1,thus effectiveness rate was 91.7%.
Neither side effects nor abnormal clinical labolatory findings were observed.

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Preclinical and clinical studies were carried out on cefotetan (CTT),a new synthetic cephamycin antibacterial agent. The results are described below.
1. Antibacterial activity
The minimum inhibitory concentrations (MICs) of CTT, CEZ, CTM and CMZ were determined against clinical isolates of S. aureus, E. coli, K. pneumoniae and P. mirabilis.To CTT S. aureus, showed its sensitivity peak (in the graphic plot of the MIC distribution) at a concentration range of 3.13-6.25μg/ml when a 100-fold dilution of the pathological specimen was employed as the inoculum. These results were inferior to those with CEZ and CTM by 2-4 concentration tubes. The CTT results were also about 2 tubes inferior to the results with CMZ, which is a cephamycin antibiotic.
On the other hand, CTT was found to show very strong antibacterial activity against Gram-negative rods. For example, the sensitivity peak of E. coli,occurred at an antibiotic concentration of≤0.1-0.2μg/ml, regardless of whether the inoculum was the undiluted pathological specimen or the 100-fold dilution thereof. Similar results were obtained in relation to the K.pneumoniae strains: at a CTT concentration of ≤0.1μg/ml, suppression of growth was achieved in 74% of the strains when the inocula were the undiluted specimens, and 86% when the inocula were the 100-fiold dilutions thereof. In addition, against P. mirabilis, when the inoculum consisted of the undiluted pathological specimen the MIC peak for CTT occurred at a concentration range of 0.39-0.78μg/ml,whereas the peak occurred at 0.2-0.39μg/ml when the bacterial inoculum was the 100-fold dilution of the collected specimen.
In contrast, CTM showed slightly stronger antibacterial activity than CTT in relation to P. mirabilis;that is, its MIC peak occurred at ≤0.1-0.2μg/ml when the inoculum was the undiluted pathological specimen,and at ≤0.1μg/ml when the bacterial inoculum was the 100-fold dilution. Otherwise, against these 3 species of bacteria, CTT yielded results which were clearly superior to those achieved with the other 3 antibiotics.
2. Absorption and excretion
CTT was administered to children at a dosage of 10mg/kg and 20mg/kg as a one-shot intravenous injection or as a 1-hour intravenous drip infusion. Thereafter, the serum concentration of the antibiotic was monitored and it excretion rate in the urine was also determined.
In the case of the one-shot intravenous injection, the peak serum concentration for both the 10mg/kg and the 20mg/kg dosages was found to occur at 30 minutes postinjection; their respective peak values were 55.4μg/ml and 137.2μg/ml. Even at 8 hours after the injection, the serum concentration of CTT was seen to still be maintained at the high levels of 4.9μg/ml and 15.1μg/ml.The half-lives of CTT at these 2 dosage levels showed ranges of 2.49-3.59 hours and 2.61-2.97 hours,which are quite long.
When the 10 mg/kg and 20 mg/kg dosages were administered by 1 hour intravenous drip infusion, the peak serum concentrations occurred at the time of completion of the infusion; 81.6μg/ml and 155.9μg/ml. Five hours after the infusion was completed, the respective serum levels were 16.1μg/ml and 28.3μg/ml. The half-lives in this case showed ranges of 2.44-3.64 hours and 2.11-2.62 hours, which are again long.
The urinary recovery rate was determined for the 8-hour period after the one-shot intravenous injection of CTT,and for the 8-hour period after the intravenous drip infusion of the drug.The dosage levels were 10 mg/kg and 20 mg/kg. In the case of the one-shot injection,the urinary recovery rates were 62.1-75.0% and 62.0-77.0%, while in the case of the drip infusion the urinary recovery rates were 67.5-91.0% and 61.9-70.5%.

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Cefotetan (CTT), a new cephamycin antibiotic having a long serum half-life (2.93±0.78 hours), was evaluated for its safety and efficacy in children. Twenty-four patients were treated with a daily dose of 30 to 100mg/kg of CTT by intravenous administrations mostly in 2 divided doses. The diagnoses of the effective patients were acute bronchitis (5), pneumonia (4), acute urinary tract infections (4), acute enterocolitis (2), presumed septicemia (1), and phlegmon (1);and the effectiveness was 77.3%. The pathogens recovered from these patients were S. pneumoniae (1),H. influenzae (3), S. marcescens(1),E. coli(2),and K. oxytoca (1).CTT was not effective in staphylococcal pneumonia and empyema (each 1 case), in Pseudomonas pneumonia (2), and in a case of brain abscess and mastoiditis of unknown etiology.
Diarrhea (2),and transient elevations of the serum GOT, GPT,and LDH (I) were associated with the CTT therapy, but no severe adverse reaction was encountered. The CSF level of CTT seemed to be lower among several new cephalosporins.
From the present study, CTT appears to be a safe and effective antibiotic when used in children with susceptible bacterial infections.A twice-a-day schedule was recommended from its long serum half-life.

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Cefotetan (CTT), a new cephamycin antibiotic, was administered to 21 pediatric patients, 1 year and 1 month to 9 years of age, with moderate or severe infections. CTT was intravenously administered 3 times a day at daily doses of 26.5 to 120mg/kg for 2 to 14 days, and 0.75 to 31.0g of the drug were totally given. Total of 21 cases, 12 cases of respiratory tract infections (each 1 case of acute pharyngitis, acute tonsillitis and asthmatic bronchitis, 6 cases of acute pneumonia, 1 case of lung fibrosis and 2 cases of primary atypical pneumonia), 2 cases of urinary tract infections, 1 case of acute appendicitis, 1 case of perianal abscess, 2 cases of sepsis, 1 case of MCLS, 1 case of REYE'S syndrome and 1 case of meningoencephalitis, were received CTT. Five cases were excluded for the evaluation of clinical efficacy, and good response were obtained in 11 cases (effective rate of 68.8%), fair in 1 and poor in 4. Out of 3 strains of causative organisms isolated before the reatment, H. influenzae and K. pneumoniae were disappeared after the CTT treatment, S. faecalis which was resistant against CTT persisted. Neither adverse effects nor abnormal laboratory findings were observed except 1 case of eosinophilia.

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Fundamental and clinical studies of cefotetan (CTT) were made in pediatric field and the following results were obtained.
1. Antimicrobial activity
MIC₈₀ values of CTT against clinically isolated S. aureus (32 strains), E. coli (33 strains) and K. pneumoniae (33 strains) were 25,0.1 and 0.1μg/ml respectively. Antimicrobial activities of CTT against E. coli and K. pneumoniae were superior to those of CMZ,though the activity against S.aureus was inferior to that of CMZ.
2. Pharmacokinetics
When 20 mg/kg of CTT was administered to 3 children, who were 3 to 8 years of age, by a intravenous bolus injection, the mean serum concentrations of the drug after 1/2, 1, 2, 4, 6 and 8 hours were 110.7±9.2, 81.7±10.1,50.0±7.5, 25.3±4.6, 14.9±5.5 and 7.7±2.8μg/ml respectively, and the mean half-life (β) was 2.01±0.32 hours.The mean concentrations of the drug in urine after 0-2, 2-4, 4-6 and 6-8 hours were 1,377±787,1,045±689, 1,067±680 and 358±80μg/ml respectively,and the mean recovery rate by 8 hours was 67.3±16.2%.
3. Clinical study
CTT was administered to 42 children of 2 monthes to 14 years of age, and clinical response, bacteriological effect and adverse reaction of the drug were studied. Clinical effects were evaluated in 8 cases of acute purulent tonsillitis,each 1 case of acute otitis media and acute bronchitis, 16 cases of acute bronchopneumonia or acute lobar pneumonia, 9 cases of acute pyelonephritis and 1 case of erysipelas,the results were excellent in 30 cases, good in 3,fair in 2 and poor in 1, and thus 91.7% of efficacy rate was obtained. Out of suspected causative organisms including 12 strains of H. influenzae, 1 strain of H. parainfluenzae, 7 strains of E. coli,2 strains of S. pyogenes, 2 strains of S. pneumoniaeand each 1 strain of S. epidermidis and S. faecalis, all the strains except each 1 strain of H. influenzae and S. faecalis disappeared after the treatment. Thus 92.3% of eradication rate was obtained.
No side effects were recognized.Though abnormal laboratory findings were observed in 3 cases (7.1%), including elevation of GOT and GPT in 2 cases and eosinophilia in 1 case, those findings came to be normal after the treatment.

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Clinical trials were carried out with cefotetan (CTT) in pediatric infections.Results were as follows;
1. The mean serum concentrations of CTT following intravenous injection of 20 mg/kg were 204, 97, 56, 15, 10μg/ml at 15, 60, 120, 360, 480 minutes after injection. The serum half-life was 2.18 hours. 68.3%, was excreted in urine within 8 hours after injection.
2. In vitro, the antimicrobial activity of CTT was more active than CEZ and CMZ against E. coli, H. influenzae and K. pneumoniae.
3. CTT was administered clinically to 22 pediatric patients with various infections; 9 pneumonias, 4 bronchopneumonias, 1 acute tonsillitis and 8 urinary tract infections. Overall efficacy rate was 95%. The favorable clinical response could be gained by the doses of 30 mg/kg with being given every 12 hours.
4. Slight elevation of S-GOT and S-GPT with mild diarrhea was observed in 2 patients and eosinophilia in 1 patient.No other serious side effect was observed.

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The authors have carried out the laboratory and clinical studies of cefotetan (CTT), and obtained the following results.
The antibacterial activities of CTT were measured by the plate dilution method against the clinical isolates of S. aureus, E. coli, K. pneumoniae, S. marcescens and Salmonella sp.
The susceptibility distribution of S. aureus to CTT was at concentration of 6.25-12.5μg/ml and the peak of that was obtained at 6.25μg/ml with an inoculum size of 106cells/ml.
And the peaks of susceptibility distribution of E. coli and K. pneumoniae to CTT were obtained at less than 0.1μg/ml respectively,and that of S. marcescens was obtained at 6.25-12.5μg/ml with an inoculum size of 106cells/ml.The growth of all strains of Salmonella sp.was inhibited at concentration of less than 0.1μg/ml.
As for pharmacokinetic study, CTT was given by intravenous bolus injection and drip infusion for 30minutes at a single dose of 20mg/kg.
After intravenous bolus injection of 20mg/kg of CTT, the mean peak serum level was 175.0±7.0μg/ml at 15minutes after injection, and half-life time was 3.53 hours. After 30 minutes drip infusion of 20mg/kg of CTT, the mean serum concentration was 106.0±6.0μg/ml at end of infusion, half-life time was 2.41 hours.
The mean urinary excretion rates were 49.4% and 64.2% up to 8 hours after drip and bolus injection of 20mg/kg of CTT, respectively.
CTT was given 15 cases with bacterial infection.
Daily doses of CTT were from 15.0 to 107.0mg/kg.Clinical results obtained were excellent and good responses in 12 of 15 cases(80.0%).
No side effects were obtained except for 2 cases with elevation of GOT and GPT, and 1 case with eosinophilia.

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Clinical evaluation was made on cefotetan(CTT),a new cephamycin antibiotic,and the following results were obtained.
1. Following 6 patients were treated with a daily dose of 31.0-47.5mg/kg of CTT, which was given in 3 divided doses by an intravenous injection or a 1 hour drip infusion; 2 patients with cystitis (causative organism: E. coli and P. mirabilis, respectively), 3 with pyelonephritis (E. coliin 3) and 1 patient with Salmonella enteritis(S. typhimurium). CTT showed a remarkable therapeutic effect on cystitis and pyelonephritis but was ineffective against Salmonella enteritis.
2. Neither adverse clinical reactions nor abnormal laboratory findings were noted.
3. Based on the above results,CTT is considered to be an appropriate and useful new antibiotic in the treatment of bacterial infections,particularly urinary tract infections in children.The fact that longer duration of blood concentrations has made is possible to give this antibiotic in 2 divided doses will be of great practical benefit.

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The tissue specimens were taken to evaluate the efficacy of cefotetan(CTT),a new cephamycin antibiotic, for otorhinolaryngological infectious diseases. The concentrations of CTT in palatine tonsils, maxillary sinum mucosa,wall of maxillary sinus cysts,discharge from otitis media and saliva were studied.
1. The serum level determined at 3 hours following intravenous injection of 1g of the drug was 49.2μg/ml(n=4).The serum level at 12 hours following intravenous injection of 2g of the drug was 14.4μg/ml(n=4).
2. 15-25% of the serum levels of CTT were demonstrated in palatine tonsils, 20.7-35.7% in maxillary sinus mucosa.
3. We detected high levels of CTT in the effusion of acute maxillary sinusitis, 24.0μg/ml(2g, i. v., 90min.), 26.3μg/ml(1g, i. v., 120min.). On the other hand,we detected only a few per cent of the serum level of CTT in the effusion of chronic maxillary sinusitis.

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For the purpose of carrying out an objective evaluation of the clinical efficacy and safety of cefotetan (CTT), a new cephamycin-type injectable antibiotic,in the treatment of complicated urinary tract infections, cefmetazole (CMZ) was employed as the control drug in a comparative study performed by the double-blind method.
CTT was administered in a dose of 0.5g or 1g,while CMZ was used in a dose of 1g; both of these drugs were administered by intravenous drip infusion twice a day for 5 days.The total number of treated cases was 393; 105 patients in the CTT 1g group, 97 patients in the CTT 2g group, and 96 patients in the CMZ 2g group. The judgment of the clinical effects of these 3 therapeutic regimens was carried out in accordance with the criteria for evaluation of clinical efficacy of antimicrobial agents on UTI (2nd edition). The results are as follows.
1. With regard to the overall efficacy of the drug treatments, the calculated efficacy rates were 54.3% in the CTT 1g group, 63.9% in the CTT 2g group and 52.1% in the CMZ 2g group. The differences between these efficacy rates were not statistically significant.
2. Regarding the efficacy of the treatments in terms of the bacteriuria,the bacterial cultures were seen to become negative in 40% of the cases in the CTT 1g group, 54.6% of the CTT 2g group and 42.7% of the CMZ 2g group.Again,there were no statistically significant differences between the groups.
3. Concerning the efficacy of the drugs against pyuria,by combining the cases found to be normalized and those seen to show improvement,the improvement rates were calculated to be 41.9% for the CTT 1g group, 37.1% for the CTT 2g group, and 37.5% for the CMZ 2g group.These pyuria improvement rates show no statistically significant differences,respectively.
4. The incidences of occurrence of side effects and laboratory test abnormalities thought to be caused by the drug therapy were as follows;1.5% and 5.3% in the CTT 1g group, 1.5% and 3.1% in the CTT 2g group and 0% and 6.9% in the CMZ 2g group.There were no significant differences between the groups.
Based on the above clinical results,it can be concluded that,in the treatment of complicated urinary tract infections,we can expect CTT to provide the same therapeutic efficacy as CMZ when its dosage is the same or even half thereof.In addition, the safety of CTT is equal to that of CMZ. Therefore, CTT is concluded to be a useful drug.

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Respiratory infections of 10 subjects with underlying respiratory diseases were treated with cefmetazole (CMZ) and its clinical effects were studied. Five subjects of them were respiratory tract infection, 3 subjects were pneumonia and 2 subjects were pneumonia followed by empyema. The underlying diseases were chronic pulmonary emphysema in 4 subjects, diffuse panbronchiolitis in 3,chronic bronchitis in 2 and bronchial asthma in 1.The doses of CMZ were 4 to 8 grams per day and the durations of administration ranged 3 to 39 days.The clinical effects were judged from the changes of fever, cough, amount of sputum, dyspnea, rale, chest X-ray, white blood cell counts, erythrocyte sedimentation rates, sputum culture and PaO₂.The clinical effects of 6 subjects were evaluated as good, those of 3 were fair and that of 1 was poor.In 3 subjects H.influenzae in the sputum was eliminated and in 1 subject both H. aphrophilus and α-Streptococcus found in the pleural effusion were eliminated. In 1 subject Klebsiella in the sputum was eliminated and replaced by Enterobacter. No side effects were observed. We conclude that CMZ is considerably useful in the treatment of respiratory infections of the patients with underlying respiratory diseases.

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Thirty-one strains of Mycoplasma pneumoniae were tested for drug sensitivity to both josamycin (JM) and erythromycin (EM),to evaluate the efficacy of JM for mycoplasmal pneumonia in children. In addition to the sensitivity tests of 31 M. pneumoniae strains against JM and EM, 50 patients, between the ages of 3 years 1 month and 13 years 3 months, suspected of suffering from mycoplasmal pneumonia were treated with 50 or 200 mg JM tablets at an average daily dose of 43.1mg/kg t. i. d. or b. i. d. for an average period of 14 days; an additional 31 patients between the ages of 2 years 9 months and 11 years, suspected of suffering from this disease were treated with tablet or dry syrup of EM, with the exception of EM estolate, t. i. d. or b. i. d.at an average daily dose of 72.5mg/kg for an average period of 15 days. Patients were selected in 37 and 22 mycoplasmal pneumonic patients respectively for JM and EM. Clinical and bacteriological effects, efficacy and side effects of the drugs on this disease were studied and the following resuls were obtained.
1. Drug sensitivity test
Of all 31 strains tested for JM sensitivity the populations which exhibited 0.125mcg/ml were most abundant (18/31,58.1%) and MIC pattern of all strains were distributed from 0.0313 to 0.125mcg/ml. In the EM group, 61.3% (19/31) of the populations were sensitive at 0.015mcg/ml, exhibiting the dominant distribution pattern and MIC range of all organism varied from 0.0078 to 0.0313 mcg/ml. Resistant strains were found to neither JM nor EM.EM was approximately 2 to 10 times more active than JM in MIC evaluation.
2. Clinical effects of JM by daily doses
Clinical effects relative to the daily dose were evaluated in 3, 7, 10 days after administration of drugs. The response was favorable, according to assessments of the attending doctors,in 96.7, 100% and 95.8% of the patient group given JM in a daily dose of 40-49 mg/kg,the group to which the largest number of patients belonged.
Similar favorable results were obtained by the assessments of Evaluation Committee,showing 86.7, 96.7% and 100% of favorable response. Upon comparison, in the same interval, of these results with those of the groups given EM in a daily dose of 50 mg/kg, the group in which the largest number of patients were seen, there was no significant difference in the assessments either of the attending doctors or of the Evaluation Committee.
3. Global effects
The Evaluation Committee assessed the global effects at days 3, 7 and 10 of treatment and obtained high efficacy rates with both JM and EM, namely 96.7% with JM and 86.7% with EM. JM was 10% more effective than EM, but there was no significant difference between the 2 drugs.Efficacy relative to daily dose was 95.8% in the group receiving 40-49 mg/kg JM and 88.9% in that receiving 50 mg or more/kg EM, 7% higher in JM than in EM. However, no significant difference was present. These results suggest that clinical JM, when administered at a daily dose of 40-49 mg/kg, could be as effective as EM.
4. Comparison of efficacy of JM and EM according to the starting date of administration JM and EM were compared in efficacy without regard to dose levels. Apart from the limited number of cases in each group, no significant difference could be determined. According to the global judgement of the Evaluation Committee, there were no noticeable differences at any state of the comparisons.
5. Bacteriological effects
Bacteriological effects were noted in 8 JM-treated patients and in 3 EM-treated ones: JM displayed an eradication of organisms in 3 patients with no effect observed in the other 5, and EM in 1 patient and the other 2 patients respectively.
6. Efficacy judged by the attending doctors
Efficacy was assessed at 86.5% in JM and 86.4% in EM, with an extreme same profile and no significant difference.

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A chronic toxicity of cefpiramide (CPM) was studied in Cynomolgus monkeys. Groups of 4 males and 4 females were given daily doses of 100, 300mg/kg or 600mg/kg by intravenous administration for 26 weeks. Another group of 4 males and 4 females was given physiological saline and served as the control.
1. In CPM groups, diarrhea or soft feces was observed after the commencement of administration at every doses. The frequency of these signs decreased as the study progressed and animals at lower doses returned to normal earlier. There were no treatment-related changes in body weights, fecal occult blood and electrocardiograms.
2. A female in the 600mg/kg group died after 13 weeks of treatment. The cause of death was assumed to be an acute myocardial necrosis resulting from thromboarteritis.It was not considered to be treatment-related.
3. Ophthalmological examination revealed no abnormalities attributable to the treatment.
4. Erythrocyte counts,hemoglobin and hematocrit values decreased in 3 animals receiving 600 mg/kg of the drug.The changes,however,were transient at least in 2 of these animals.
5. There were no effects on plasma biochemical and urinalysis parameters.
6. Small yellow spotes were noted in the renal cortex of 2 monkeys in the 600mg/kg group at necropsy.
7. Liver and kidneys were slightly heavier in animals receiving 600mg/kg.
8. Histopathological examinations revealed focal nonsuppurative interstitial nephritis in 1 animal given 300mg/kg and S animals given 600mg/kg. No treatment-related changes were observed in other organs and tissues.
9. From these results, the maximum non-effective dose level of CPM was considered to be 100mg/kg.

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A subchronic toxicity of cefpiramide (CPM) was studied in rhesus monkeys.The drug was administered intravenously to 4 groups of 2 males and 2 females each at a daily dose of 0, 100,300mg/kg and 1,000mg/kg,respectively,for 6 weeks.
1. Vomiting and diarrhea were observed at every dose of CPM,more frequently at the beginning of the treatment period. In addition, salivation was observed at 300mg/kg or more and a transient subdued mood and inappetence at 1,000mg/kg.A slight decrease of body weight was noted in a female given 1,000mg/kg. There were no treatment-related changes in fecal occult blood test and electrocardiograms.
2. Ophthalmological examinations showed no abnormalities being attributable to the treatment.
3. A transient or slight anemia was observed in 2 monkeys receiving 1,000mg/kg. Examination of bone marrow revealed no abnormalities.
4. There were no effects on plasma biochmical parameters.
5. In urinalysis, a female in the 1,000mg/kg group showed a glycosuria.
6. Kidneys of 3 animals given 1,000mg/kg were pale at necropsy.
7. Liver and kidneys were heavier in some animals at 300mg/kg or more and at 1,000mg/kg, respectively.
8. Histological examination revealed a multifocal degeneration and regeneration of the proximal renal tubular epithelium in all animals receiving 1,000mg/kg.No treatment-related changes were encountered in other organs and tissues.
9. From these results, the maximum non-effective dose level of CPM was considered to be 300mg/kg.

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Cefroxadine (CXD), a new cephalosporin,was orally administered to 22 cases in total;5 with wound infection, 4 with felon, 3 with acute pyelonephritis, 2 with furuncle, 2 with infected atheroma, 2 with phlegmone, 2 with abscess, 1 with acute mastitis, and 1 with lymphadenitis.
The daily dose was 500 to 1,000mg, and maximal total dose and duration was 5g and 5 days, respectively.
Therapeutic results were good in 20 cases(effectiveness rate:91%),fair in 1 and poor in 1.
No side effect was observed in all cases among 22 patients with CXD.

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A clinical study was performed on concentration of cefotiam (CTM)in the gallbladder bile and the gallbladder tissue in benign diseases of the biliary tract. By an hour intravenous infusion the CTM concentration obtained 2 hours after the start of the infusion revealed that the level of the CTM in A bile was atmost same as that in B bile (3.1-46.0μg/ml). The concentration in gallbladder tissue was 5.7-116μg/ml.
In addition, the CTM level was higher enough than the MIC of CTM covering more than 80% of the strains of E. coli and Klebsiella obtained from the focus. From these results, it is concluded that CTM is clinically effective and useful in the case of biliary disease.

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A double-blind clinical comparison of cefadroxil granules (CDX) and a long-acting preparation of cephalexin granules (L-CEX)was conducted in the treatment of impetigo in children.The long-acting cephalexin preparation was composed of 3 parts of granules soluble in the stomach and 7 parts of those soluble in the intestine.
Drugs were administered at 3 different doses depending on the body weight of patients (Group I: less than 10kg, Group II:between 10kg and 20kg, Group III: over 20kg).
1. Overall clinical evaluation by attending doctors: CDX group scored slightly better but not statistically significant results.
2. Evaluation of usefulness:CDX group scored slightly better but not statistically significant results.
3. Partially standardized evaluation:CDX scored statistically significantly higher points in the evaluation of total cases and Group II on Day 5, and Group II on Day 7. Cumulative points through Day 5 and Day 7 were not statistically significant.
4. Follow-up evaluation by attending doctors: CDX group got a better result in total cases and Group II on day 3, and in total cases on days 5 and 7.
Otherwise there was no statisticaly significant difference.
5. Incidence of side effects was not significantly different between the 2 drug groups.
As shown in Fig.1, CDX was administered on rising in the morning, after lunch, and at bed time whereas L-CEX was given on rising and at bed time when the patients were relatively in fasting condition. This may have reduced the expected merit of L-CEX and some reserve is required in the interpretations of the results shown herein.

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Serum and renal levels of cefotaxime (CTX) were studied.Biological half-life time values in serum of rat following 100mg/kg intraperitoneal injection were 27.58 minutes by bioassay and 25.02 minutes by high performance liquid chromatography, and that in kidney was 27.79 minutes by bioassay.
CTX attained high levels in kidney of both human and rat.The concentration was higher in the cortex than that in the medulla. The activity could not be detected in the fraction of brush border, mitochondria and lysosome. This finding was thought to be a favorable characteristic in conjunction with the gradual decrease in the kidney tissue parallel to serum level.

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Concentrations of cefotaxime (CTX) in serum and prostatic tissue were studied in human and rat.
CTX kept high level of 40 to 100μg/g in prostatic tissue at least as long as 2 hours following intraperitoneal injection in a dosis of 100mg/kg of body weight in rat.Patients intravenously injected of 1g of CTX showed the activity of 6.8±4.1g/μg in prostatic tissue.

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In vitro activities of antibacterial agents against E. coli, Klebsiella, Citrobacter and Proteus which were isolated from patients with urinary tract infections at 8 hospitals in Japan, were investigated bydil ution broth method using MIC 2000 (Dynatec) during July to October in 1981.
The summarized results are as follows:
1. Among oral antibacterial agents,MPC and PPA have showed potent antibacterial activities against E. coli and Klebsiella. In vitro activities of oral antibacterial agents against Proteus and Citrobactershowed not so potent.
2. Among the first and second generation's parenteral antibacterial agents, CTM has showed potent antibacterial activities against E. coli and Klebsiella.
3. Among the third generation's parenteral antibacterial agents, CMX, CTX and CZX have showed potent antibacterial activities agaist E. coli, Klebsiella, Proteus and Citrobacter.

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Since 1979 the antibacterial activity of antibiotics against E. coli, Klebsiella, Citrobacter and Proteusisolated from patients with urinary tract infections has been investigated.
The serious transition of susceptibilities of E. coli and Klebsiella could not be recognized inthese antibiotics (MPC, ABPC, NA, PPA, CEX, CEZ, CTM, CMZ and CFX).
However, a few resistant organisms against the third generation's antibiotics (CTX, CMX, CZX, LMOX and CPZ) have already, been appeared, we have to observe these results, continuously.

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Routine susceptibilities testing of microorganisms isolated from patients are of restricted usefulness in the treatment of patients because of the delay in obtaining results.
Thus, the empiric chemotherapy based on the susceptibility of microorganisms isolated from patients is necessary for the majority of patients with simple and complicated urinary tract infections.
In this study the relation between changing susceptibility and background factors such as age, a sex distinction,antibiotics,areas in Japan,simple and complicated UTI and so on, has been investigated.

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A new antibiotic drug of cephalosporin group, with marked resistance to β-lactamase, cefmenoxime (CMX) for parenteral use was tested in 15 patients with acute peritonitis. CMX in a dose of 500mg was given intramusculary before the operation, to 8 cases with appendicitis, and 2 cases with intestinal obstruction. In 3 cases with appendicitis and a case with intestinal perforation,CMX in a dose of 500-1,000mg was given by intravenous injection before or during the operation.And in a case with appendicitis, CMX in a dose of 1g was given by intravenous drip infusion before the operation. Tissue specimens of different sites or body fluids were taken during the operation and from the removed organs. The materials of purulent ascites were subsequently taken at intervals. Determination of CMX concentration was performed according to cup bioassay method with Proteus mirabilisATCC 21100 strain.
The peak of CMX concentration in purulent ascites of patient with panperitonitis for intestinal perforation was 39.5μg/ml at 41 minutes after 1g intravenous administration.Concentration of CMX in pus in the appendix was 52.5μg/ml at 20 minutes after 1g intravenous administration.
In 15 patients with acute peritonitis, 11 patients were given CMX in a dose of 500mg by intramuscular administration twice a day,and the serious 4 patients were given in a dose of 500mg to 1g by intravenous drip infusion twice a day. Clinical responce was excellent in 10 cases,good in 5 cases,fair and poor were none.
On the CMX concentration in patients with peritonitis, the concentration in purulent ascites, pus in the appendix and infected tissues were observed higher than the MIC of CMX against pathological bacilli. Therefore, CMX will be a very useful drug when used for chemotherapy of acute peritonitis.

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Cefoxitin (CFX) was administered to 13 patients who were admitted to the surgical ward of the hospital. The results of the study as follows;
1. Disc susceptibility tests of the 11 strains isolated from the patients to antibiotic were performed and 10 strains showed good susceptibility to CFX.
2. The clinical response was good in all 4 patients with surgical infections. It is noted that 1 patient with mixed infection caused by E. coli, Clostridium sp. and Bacteroides sp.showed good response to CFX.
3. Out of 9 patients treated with CFX for prophylaxis of postoperative infections,8 patients responded effectively to CFX,and clinical efficacy rate was 88.9%.
4. No side effects were noted due to CFX.
It is considered from these results of the study that CFX is a highly effective and safe drug for treatment of infections and for the prevention of postoperative infections in surgery.

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Growth of fertilized mouse eggs treated with acetylspiramycin (ASPM) for 24 hours in their diplophase and octaplophase was observed morphologically.Changes in function of the fertilized cells in growth process were also examined,determining cell counts,mitotic index,and sister chromatid exchange as indices.
These indices were all inhibited after treatment with ASPM. However, it seems that the effect was induced by H₂SO₄ which was used as solvent rather than by ASPM because growth inhibition and functional changes of cells were also caused by H₂SO₄.
Therefore, it is thought that ASPM, at the concentration of 3-10μg/ml,has little effect on the development of fertilized eggs.

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