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[in Japanese]

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1. Therapeutic effects of cefmetazole (cefmetazon, CMZ) were examined in 22 cases of bronchopneumonia.
2. Among the 22 cases, 17 cases (77%) showed better response than ‘effective’. However, 10 cases (91%) showed better response than ‘effective’ if a daily of 4 g (11 cases) was taken into consideration.
3. No particular symptomatic side effect of CMZ was shown. Abnormality in such laboratory tests as transaminase (1 case of GOT, and 2 cases of GPT) and 1 case of alkaline phosphatase were observed, and the abnormality was ascribable to CMZ administration.

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1. Medium to large amount of CMZ (100-270 mg/kg/day) was administered to 4 cases of neonatal infants having severe infections due to pathogenic E. coli and sepsis due to E. coli. CMZ was remarkably effective in all cases, and the causative bacteria disappeared in 100%.
2. Among 10 cases which administered CMZ, 5 cases showed side effect. Eruption, diarrhea and increase of GOT, GPT and LDH activities were observed but no case suggested interruption of administration.
3. Blood level of CMZ was determined in 4 cases of 0-1 day old, premature infants. The half life of CMZ was 8.55-15.3 hours, prolonged considerably, and 12 hours after one shot (20 mg/kg) of intravenous CMZ administration, 20.2μg/ml of blood level was maintained.
4. Intraspinal CMZ level was determined in aseptic meningitis. When one shot 50 mg/kg CMZ was given intravenously, intraspinal CMZ levels after 30 minutes and 1 hour were 20.3μg/ml and 34.5 g/ml, respectively, and distribution of CMZ in the cerebrospinal fluid was shown to be excellent.
5. Exchange blood infusion (amount of exchange, 170 ml/kg) was performed in a small premature newborn baby, and blood transformation of CMZ was examined. It was found as the result that the blood level of CMZ was decreased to 53% of the pretreated level.
6. MIC of CMZ was examined in 3 strains of E. coli isolated from blood and cerebrospinal fluid. MICs were 0.39-0.78μg/ml when 10⁶/ml was inoculated and 0.78-1.56 when 10⁸/ml was inoculated.

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1. Cefmetazole was administered to mature and immature neonates for the purpose of treatment and prophylaxis of infections, and the blood level was examined. The mean blood level (monitrol Istandard) of cefmetazole after a single administration, 20mg/kg intravenously, were 63.9mcg/ml in 0 to 3 days old neonates and 57.4mcg/ml in 4 to 7 days old neonates after 30 minutes, and 24.2mcg/ml and 12.4mcg/ml, respectively, after 6 hours.
2. The mean half-life of the blood level was 5.42 hours in 0 to 3 days old neonates and 2.55 hours in 4 to 7 days old neonates.
3. The urinary excretion was varied, but approximately 80% of the administered dose seemed to be excreted during 0 to 12 hours.
4. Cefmetazole is seemed to be clinically effective by a single dose of 20 mg/kg giving twice daily in every 12 hours in 0 to 3 days old neonates, a dose of 20mg/kg giving three times daily in every 8 hours in 4 to 7 days old infants, and a single dose of 20mg/kg giving 3 to 4 times in every 6 to 8 hours in older than 8 days old neonates.

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The authors studied the antibacterial activity, absorption and excretion, and clinical use of cefmetazole in neonatal period, and obtained the following results.
1. The minimal inhibitory concentrations (MICs) of cefmetazole (CMZ) were measured, to compare with those of cefazolin (CEZ), for clinical isolates of S. aureus (31 strains), E. coil (29 strains) and K. pneumoniae (30 strains).
On a cumulative percentage basis, 77% of S. aureus, 76% of E. coli and 90% of K. pneumoniae were inhibited by ≤3.13μg/ml of CMZ with a higher inoculum size. When compared with CEZ, MICs of CMZ were found to be superior or equal against E. coil, K.pneumoniae and some of S. aureus, but to be inferior against most of S. aureus.
Most of strains which were resistant to CEZ were more sensitive to CMZ.
These results suggested that CMZ is highly active against Gram-negative bacteria and is stable to fi-lactamase.
2. The serum concentration was measured in 7 neonates (5-25 day-old) and 5 infants (1-3 monthold) after a single intravenous administration of 20-25 mg/kg of CMZ.
The mean concentration in neonates was 58.3μg/ml at 1/2 hour postinjection, 57.0μg/ml at 1 hour, 35.4μg/ml at 2 hours, 18.1μug/ml at 4 hours and 9.5, ug/ml at 6 hours. The mean half-life was 2, 04 hours. Theμeak concentration of each neonate seemed to be related more to individual variation than to the days after birth.
The mean concentration in infants was 60.7μg/ml at 1/2 hour, 42.8μg/ml at 1 hour, 22.2μg/ml at 2 hours, 9.2μg/ml at 4 hours and 3.2μg/ml at 6 hours. The mean half-life was 1.31 hours.
There was little difference in the mean peak concentration between neonates and infants, but the mean concentration after that were higher in neonates than infants.
It was apparent that the half-life tends to be shortened in proportion to advanced age in days and months.
3. CMZ was administered clinically in 3 cases of acute bronchopneumonia. Its clinical effect was excellent or good in all of the cases.
No adverse reaction or abnormal laboratory values were found.

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CMZ is a derivative of cephamycin antibiotics having a potent resistance to β-lactamase, so that itexerts strong effect on β-lactamase producing resistant strain, and it is an antibiotic agent having wide antibacterial spectra.
Highly effective and safe properties were proved and identified in children (Presented at 11th I.C.C.), so that a study group was organized to examine the usefulness of CMZ for the various infections of the newborn and immature infants. Blood level and urinary excretion: A half life (T 1/2) of the intravenously administered CMZ (20 mg/kg) in blood was 4.18, 2.39 and 1.78 hours in 3 days, 4 to 7 days and ≥8 days old newborn infants, respectively. Immature infants reveals longer T 1/2 by ≤3 days after birth but normalizes fairly soon. Urinary excretion of CMZ was examined in 10 infants up to 7 days old. The relation between the urinary volume and urinary recovery were well correlated. Clinical effect: CMZ was administered to respiratory infections, septicemia, meningitis, uriary tract infections, and other infections in 51 cases of newborn and immature infants.
A daily dose, 60 to 100 mg/kg, was divided in 2 to 4 times, and administered intravenously. The causative organisms were E. coli, Klebsiella, Serratia and Staph. aureus and 97% of eradication rate was obtained. CMZ was clinically effective in 100% for respiratory infections (17 cases), septicemia (7 cases) and purulent meningitis (4 cases), and in 91.7% for UTI. The overall effective rate was 94.1%.
No notable adverse effect was found. Cefmetazole is a safe and effective antibiotics in treating severe infections in newborn and immature infants.

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This is studies concerning the absorption and excretion of cefmetazole in neonates and the excretion into the bile of infants with congenital biliary atresia.
1. The concentration of cefmetazole was measured in the serum and urine of 2 neonates at the postoperative period.
2. The concentration measured in the serum showed a level similar to those of cases in pediatrics at other institutes regardless of the operation.
3. The recovery value of cefmetazole in the urine of the neonate is not different from those of other institutes even if it is a postoperative case, provided that the urine quantity is maintained.
4. Excretion of cefmetazole into the urine and bile was measured in 2 cases of congenital biliary atresia after the biliary diversion.
5. The concentration of cefmetazole in the bile of infants with congenital biliary atresia is lower than those of adults. It follows that the recovery percentage in the bile is low but the converse was true in the urine recovery. This seemed to be due to liver dysfunction that are characteristic in congenital biliary atresia. However, the concentration of cefmetazole in the bile was sufficient to obtain effective therapeutic level.

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Cefmetazole has a high safety rating when used in perinatal stage chemotherapy and thus it is a very useful antibiotic. However, cefmetazole is not an antibiotic to be administered primarily as a preventive. It should be used mainly in treating other agents resistant Gram-negative bacilli infections. In doing so, cefmetazole will become highly useful.
1. The safe dose of cefmetazole (CMZ) to the mother in the perinatal period is 1-2 g/day. The administration of 4 g/day in a severe case is not contraindicated.
2. The fetus showed no signs of distress or side effects from cefmetazole (CMZ) crossing the mother's placental barrier. The transition of cefmetazole (CMZ) into the mother's milk is insignificant quantitatively but remains unknown qualitatively.

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The fundamental study of cefmetazole treatment in a clinical situation during the perinatal period were made, and the following results were obtained.
Absorption of CMZ in pregnant women is rapid; and the intravenous injection, intravenous drip infusion and intramuscular injection of CMZ all reached their peak serum levels in a short time with a half-life of approximately 1 hour or so.
The transference of CMZ to the fetus through the placenta is good. It is so good that a single dose of 0.5-1.0 g by intravenous injection, intravenous drip infusion or intramuscular injection can obtain desired concentration levels covering MIC of main causative pathogenic organisms in the cord blood, amniotic fluid and blood in the fetus. Therefore, the administration of CMZ with this dose and method of administration once or twice daily can prevent or treat intrauterine infection.
The transition of CMZ to mother's milk is a small quantity and the transition of CMZ through mother's milk to a neonate is considered to be a very small amount.
The absorption of CMZ in a neonate is rapid. It reaches a peak serum concentration 15 minutes after the intravenous injection. The half-life varies depending on the number of days after birth.
With the administration of 20mg/kg, the half-life at 0 day after birth is 6.32-6.78 hours, 3.79 hours at 1st day after birth and 2.27-2.72 hours at 5th-6th day after birth. Excretion into the urine is slow on 0 day after birth and becomes rapid on the 6 th day after birth, coinciding with the maintained level of CMZ in the blood.
Positive results were obtained from the overview of CMZ administration in the prophylaxis or treatment of intrauterine infection during the perinatal period. No abnormalities were noted from the examinations performed on a neonate delivered from a mother who had received CMZ during perinatal period.
Judging from the various results mentioned above, 20mg/kg of CMZ administered to a neonate twice a day at 12 hour intervals would be sufficient to attain therapeutic efficacy.

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Clinical efficacy was studied with cefadroxil powder for syrup in 35 pediatric patients including 20 acute tonsillitis and pharyngitis, 6 scarlet fever, 2 cervical lymphadenitis and 7 urinary tract infections. The results indicated a 97% effectiveness when ‘excellent’ and ‘good’ ratings were combined. A mild skin rash was observed in 1 patient.

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The clinical effects of cefoperazone (CPZ) treatment for 10 patients with bile duct infection were investigated and the following results were obtained.
1. Absorption and excretion of CPZ: CPZ of 500mg was administered with intravenous one shot injection to 2 patients of which one was malignant tumor case and the remaining was non tumor case. A peak of CPZ level in serum was 63.0mcg/ml and 54.7mcg/ml respectively. CPZ level in bile was maximum at 81.5mcg/ml and 292.5mcg/ml respectively.
2. Clinical effectiveness: Of 10 patients treated with CPZ, the results were excellent in 2 cases, good in 5 cases and poor in 3 cases.
3. Side effects of CPZ: No significant side effects were observed in these patients except for one case in which rash appeared in whole body.

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Compound R-75-1 is a very potent rifamycin derivative prepared from rifamycin SV at the Sichuan Institute of Antibiotics Industry, China in 1975. This compound showed a strongactivity against Mycobacterium tuberculosis and Gram-positive organisms.
Here we describe the assignment of the H NMR spectrum of this novel compound.

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The oral administration of 300mg of clindamycin was undertaken on 23 patients, of 500mg of cefadroxil on 11 patients and of 250mg of talampicillin on 12 patients, and then tooth extraction was performed under local anesthesia. Blood samples were taken from the extraction wound and the peripheral vein at the same time and assayed by the bioassay method.
The blood levels of clindamycin and cefadroxil indicated a similar pattern between the extraction wound and the peripheral vein, but the blood level of talampicillin reached peek level rapider than clindamycin and cefadroxil. The blood levels of the extraction wound were 60-80% as compared with the venous blood levels with each antimicrobial agent.

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The bacteriological and pharmacokinetic properties of cefotaxime, including antibacterial spectrum and activity and CSF penetration in animals, suggested that this compound may beclinically effective in the treatment of purulent meningitis in children. The safety and effectiveness of cefotaxime were therefore evaluated in a multicenter clinical trial carried out by the Pediatrics Research Group (Chairman: Prof. RYOCHI FUJII).
Seventeen children with purulent meningitis were treated with cefotaxime. Four patients were aged less than 3 months, 5 from 3 to 12 months, and 8 from 1 to 3 years. The causative organisms were S. epidermidis, α-Streptococcus, S. pneumoniae and H. parainfluenzae in 1 patient each, H. influenzae in 5 patients, E. coli in 2 patients, and unknown in 6 patients.
Cefotaxime was administered in a dose of about 50 mg/kg 4 to 6 times daily in 14 patients. The route of administration was intravenous bolus injection or 30-minute to 1-hour intravenous drip infus on in the majority of patients. The duration of treatment ranged from 7 to 35 days with a mean of 17 days.
The therapeutic efficacy of cefotaxime was evaluated to be excellent in 10 patients, good in 5 patients, and failure in 2 patients for a responder rate of 88.2%. The 2 failures suffered from S. epidermidis and α-Streptococcus meningitis in association with a CSF shunt. Among the 15 cefotaxime responders, sequelae consisted of subdural effusion in 2 patients and cerebral palsy in 1 patient. The clinical condition of all 3 of these patients was severe and the initiation of treatment delayed. Sequelae were not noted in the other 12 patients. Eight laboratory abnormalities attributed to cefotaxime, consisting of 2 instances of eosinophilia, 4 elevations of GOT, and 2 elevations of GPT, were seen in 5 patients. All abnormalities were transient and not severe enough to warrant withdrawal of the drug.
CSF concentrations of cefotaxime, determined 26 times after a 50 mg/kg intravenous bolus injection or 30-minute intravenous drip infusion in 5 patients ranged from a minimum of 1.0μg/ml to a maximum of 13.2μg/ml. Penetration to the CSF tended to decrease as the patient showed signs of recovery from meningitis, but concentrations of ≥4μg/ml, sufficiently above the MICs of causative organisms, were seen in most patients during the first week of treatment. CSF con-centrations of ampicillin were determined in 2 patients after a single 77 mg/kg intravenous bolus injection. In both patients ampicillin levels were lower than those seen after a 50 mg/kg intravenous dose of cefotaxime.
Considering that cefotaxime is at least comparable to or superior to ampicillin in terms of antibacterial activity against group B Streptococcus and E. coli, and H. influenzae and S. pneumoniae, the major pathogens during neonatal and subsequent stages respectively, including ampicillin-resistant strains, the above results strongly suggest that cefotaxime should be the drug of choice for the treatment of purulent meningitis in neonates, infants, and older children.

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An antibiotic drug of aminoglycoside group, dibekacin (DKB) for parenteral use was used in 48 patients hospitalized due to acute or subacute infection of abdominal organs: 36 appendicitis, 9 cholecystitis and 3 others. DKB in a dose of 100 mg was given intramusculary in 38 cases, and in 10 cases was given intravenously by single or drip infusion before the operation. The materials of A-bile, B-bile, wall of gallbladder, the appendix wall, ascites with pus and serum were taken during the operation. DKB concentration was measured by bioassay method with Bacillus subtilis ATCC 6633 strain. With a few marked exceptions, DKB concentration in B-bile were higher than those in A-bile. DKB concentrations in gallbladder wall and appendix wall were directly proportional to the degree of pathological changes of inflammation. DKB concentrations in infected tissues after intravenous drip infusion, they were higher relatively than those after intramuscular administration. DKB concentrations in serum after intravenous drip infusion reached to peak immediately the end of infusion, and in the infected tissue they reached to peak at the same time and stayed for a relatively long time, then they were declined slowly.
For the therapeutic purpose, DKB was given to the 6 patients with acute peritonitis of the above cases. DKB in a dose of 100 mg were administered by intravenous drip infusion for 2 hours, twice in a day for 3-10 days. Clinical response was excellent in 2 cases, good in 3 cases, fair in 1 case and poor in none. No adverse effect was observed.
Therefore, it was supposed that DKB could be used safety by intravenous drip infusion.

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Clinical trial of cefotiam was made in children and the following results were obtained.
1. Pharmacodynamic studies of the drug in CSF of experimental staphylococcal meningitis in rabbits showed a CSF/serum ratio of T 1/2 of 3.52, which was relatively high, but a percentage of CSF/serum ratio of AUC of only 3.42% up to 3 hours, suggesting a low efficiency of passage of the drug into CSF.
2. Blood concentrations of the drug were determined in children after an intravenous bolus in-jection of 20mg/kg and were 46mcg/ml (15 min.) and 26mcg/ml (30 min.), T 1/2 being 40.8 min. Urinary recovery rate was 91.3% up to 4 hours in one patient and 61.9% up to 6 hours in another, respectively.
3. Thirteen patients with the following 14 episodes of infections were treated with cefotiam; urinary tract infection (5 cases), pneumonia (5), empyema (1), tonsillitis (1) and suspected sepsis (2). An overall efficacy rate was 100%, i.e., excellent in 12, good in 2 and no failure. No adverse reactions were clinically discernible and only laboratory abnormalities were transient or slight elevations of trans-aminase levels in 2 patients.
4. Based on the above results, it was concluded that cefotiam is a potent new antibiotic in the treatment of bacterial infections. Spectrum and antibacterial activity of the drug suggest that the drug particularly indicated for pneumonia.

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Studies on the antibacterial activity, absorption and excretion and also clinical investigation in the field of pediatricg have been carried out with cefotiam (SCE-963, CTM), a new cephalosporin antibiotic.
1) The MICs of CTM against the following clinical isolates were measured and compared with those of CEZ: S. aureus (81 strains), E. coli (27) and K. pneumoniae (27), with CTM being inferior by 1 tube in S. aureus, being superior by 2 to 3 tubes in E. coli and by about 2-3 tubes in K. pneumoniaev.
2) Absorption and excretion
After intravenous one shot injection at dose levels of 10 mg/kg and 20 mg/kg, the peak in the serum concentration was shown in the 15-minute value with 18.1 and 36.6 mcg/ml for 10 mg/kg and 20 mg/kg, respectively. The half-life in the serum was 1.14 and 0.61 hours, respectively. In the case of 1-hour intravenous drip infusion at a dose level of 10 mg/kg, it was 14.3 mcg/ml, with 0.98-hour half-life in the serum. The recovery rates from the urine within 0 to 6 hours were 50.6% and 66.2% in the case of intravenous one shot injection at dose levels of 10mg/kg and 20 mg/kg, respectively, with 71.1% in the case of the 1-hour intravenous drip infusion.
3) Two to 3 hours after intravenous one shot injection of CTM in H. influenzae-meningitis every 4 hours at a dose level of 62.5 mg/kg at one time, the cerebrospinal fluid concentration of CTM was only 2.12 to 10.0 mcg/ml, and this fact suggests that CTM is a useful cephalosporin for treating purulent meningitis.
4) CTM was administered in 19 clinical cases, with the results being: excellent in 4 out of 4 cases of bronchitis; excellent in 5 and good in 1 out of 6 cases of pneumonia; excellent in 3 cases of pyelitis; good in purulent parotitis, purulent meningitis and bacterial pericarditis; and excellent in peritonsillar abscess, purulent osteomyelitis and staphylococcal scalded skin syndrome (S.S.S.S.). No side effects have been observed in all cases. As for abnormal laboratory findings, 3 cases of eosinophilia were seen.

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Our investigation of cefotiam in pediatric infection produced the following results:
1. Cefotiam was administered intravenously by one shot or drip infusion in 20 patients with infectious diseases. These diseases consisted of 13 pneumonia, 3 upper respiratory tract infections, 3 pyelonephritis, 2 other urinary tract infections and one purulent meningitis. Cefotiam was effective in all cases.
2. Transient elevation in serum GOT, OPT, AI-P and LDH was observed in 3 cases. But other side effect was not noted in any cases.

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The basic and clinical studies of cefotiam (CTM) in pediatric infections were carried out, and the following results were obtained:
1. The antibacterial activity of CTM against S. aureus was equal or slightly less than that of cefazolin (CEZ). Those of CTM against E. coli and K. pneumoniae were eight times more active than those of CEZ.
2. CTM 20mg/kg was administered either by 30 minutes or 1 hour intravenous drip infusion. The peak serum levels were obtained at the end of each drip infusion, with the mean peak levels being 44.8 and 41.4mcg/ml respectively. The serum levels at 1.5 and 2 hours after drip infusion were 2.8 and 2.2mcg/ml respectively, and at 3.5 and 4 hours after drip infusion were 0.3 and 0.7mcg/ml respectively. The half lives were 0.62 and 1.15 hours, respectively. The mean urinary excretion over 6 hours were 52.8% in the 30 minutes drip infusion group and 42.6% in the 1 hour drip infusion group.
3. Clinical efficacy was evaluated in sixteen cases suffering from tonsillitis (4 cases), pneumonia (4), bronchitis (2), cervical lymphadenitis (2), purulent meningitis (2), suppurative arthritis (1) and suspected sepsis (1). Good and excellent responses were obtained in 15 of 16 cases (93.8%). Bacteriologicalresponse in the form of eradication was noted in 4 of 6 cases. Side effect observed was rash in 1 case, and laboratory abnormalities were elevation of BUN in 1 case and elevation of GPT in 2 cases.

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