Cefmetazole was investigated on stability to β-lactamases produced by Bacteroides fragilis and on therapeutic effects in mice infected with B.fragilis.
1.Cefmetazole, like other cephamycins, was found extremely stable to β-lactamases obtained from B.fragilis.
2.Cefmetazole showed good antimicrobial activities to 50 strains of B.fragilis and extremely high stability to their β-lactamases.
3.Cefmetazole showed an excellent protecting effect to infections due to β-lactamase producing B.fragilis.
4.Cefmetazole exhibited an excellent chemotherapeutic effect against polymicrobial infections in mice due to E.coli (β-lactamase-) and B.fragilis (β-lactamase+).

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The 868 strains of S.aureus were isolated at the Department of Pediatrics, Third Hospital and Aoto Hospital, The Jikei University, School of Medicine and at the Kanagawa Prefectural Nursing and Hygienic School Hospital during 6 months from May to October in 1981.
From them 66 strains not sensitive to CEZ were selected by a 3-concentration disk method. A total number of 54 strains except for 12 isolated from the same infant patient was examined for their MIC's for 6 drugs, CMZ, CEZ, CTM, CXM, MCIPC and GM. Moreover, phage typing and β-lactamase activity determination were carried out in them.
1. Antibacterial activity
Sixty-six (7.6%) of 868 strains were not sensitive to CEZ. The MIC's of CMZ against these resistant strains were between 1.56 and 50, ug/ml with a peak between 3.13 and 6.25 μg/ml when the 10⁸ cells/ml bacterial suspension were inoculated. CMZ was superior in antibacterial activity to CEZ and CXM by about 4 degrees and to CTM by about 3 degrees. MCIPC and GM had higher antibacterial activity against a few strains than CMZ. However, the number of strains with MIC higher than or equal to 50 μg/ml was 17 for MCIPC and 40 for GM, but only 2 for CMZ. Thus, the former 2 drugs were far inferior to the latter one.
2. Phage type
(1) Nineteen strains (35.2%) had MIC's for CEZ≤50 μg/ml and CMZ≤6.25 μg/ml. Seventeen of them belonged to the nontypable.
(2) Fourteen (25.9%) had MIC's for CEZ≥100 μg/ml and CMZ≥12.5 μg/ml. Of them 9 were allocated to the group III, 3 to the mixed (I+II+III, I+III) group and 2 to the nontypable.
(3) Of 20 strains (37.0%) which had MIC's for CEZ≥100 μg/ml and CMZ≤6.25 μg/ml 5 belonged to the group I, 3 to the group III and 12 to the nontypable.
(4) Five strains classified into the group III were all isolated at the Kanagawa Prefectural Nursing and Hygienic School Hospital.
(5) Eleven of 15 strains belonging to the group III were isolated at the Third Hospital, The Jikei University, School of Medicine.
(6) Seventeen of 21 strains isolated at the Aoto Hospital, The Jikei University, School of Medicine belonged to the nontypable.
(7) Phage type was considered to be influenced by difference in areas, infection within hospitals, etc,.
3. β-Lactamase activity
β-Lactamase activity was demonstrated at levels between 0.07 and 3.26, umol/min/mg in all 54 strains. There was no correlation between MIC for CEZ or CEZ and A-lactamase activity. It was suggested that β-lactamase might not contribute to mechanism of resistance of S. aureus to each drug examined.

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A total number of 13 administrations of cefmetazole (CMZ) was done against severe infections in 11 patients with blood diseases which consisted of 7 with acute leukemia, 1 with chronic myelogenous leukemia (changed to acute type), 1 with malignant lymphoma (changed to leukemia), and 2 with hypoaplastic anemia. CMZ was evaluated to be moderately to markedly effective in about 70% of patients. No serious side effects were found. CMZ was considered as a desirable antibiotic in treatment of severe infections accompanied by blood diseases.

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The time course of the concentration of cefmetazole (CMZ) in the serum and in skin and intestinal tissues was determined after a single intravenous injection of 2 g of the drug. CMZ moved into them well.
Furthermore, 41 patients with postoperative wound infection (superficial in 29 and deep in 12) were treated with CMZ 2 4 g daily. Bacteriological examination of the lesions with simultaneously carried out. As a result, 101 strains of bacteria were isolated and identified. Mixed infection was found in 27 cases (65.9%). Fifteen strains (14.9%) of E. coli, 15 (14.9%) of B. fragilis, 7 (6.9%) of Klebsiella sp. and 7 (6.9%) of Proteus sp., were the main bacteria isolated. Eight cases (19.5%) had mixed infection of E. coli and B. fragilis.
The committee (3 members) evaluated CMZ to be effective in 75.6% (31 of 41 cases) and bacteria disappeared in 60.5% (23 of 38 cases). The side effects observed were pyrosis and feeling of gastric malaise in 1 case.
The results suggest that CMZ is useful, which exerts an excellent effect on postoperative wound infections.

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Preparation of highly purified cephamycin C (CM-C) is described in this report. The purification of CM-C was carried out by Sephadex LH-20 chromatography of the N-BOC-CM-C developed with Me0H followed by removal of the protecting group. Partially purified CM-C was further refined by Sephadex LH-20 chromatography developed with Me0H and Diaion HP-20 SS chromatography developed with H₂O.
CM-C thus obtained showed the UV absorption at 265 nm [E^1%_1cm 184.4 (H₂O) 1] which is the strongest absorption ever appeared in the literatures.

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The various effects have been examined against the anaerobes by administering tinidazole when the operations of gynecology and obstetrics and the following results were obtained.
1. The serum concentrations after the single administration of 1,000 mg of TDZ showed 56.6 μg/ml of thepeak value (3 hours) and 27.7μg/ml of 24 hours value, and the antibacterial potency was maintained for a long duration. The concentration in the vaginal secretions was 21.8 μg/tampon within 24 hours.
2. The detections of anaerobes were made in 74 cases, before the administration, with the results of 1 case alone and 73 cases mixed with aerobes, 10 species and 133 strains being detected, which comprise 33 cases with 1 species, 27 cases with 2 species mixed, 10 cases with 3 species mixed and 4 cases with 4 species mixed. The main species detected were Bacteroides fragilis in 46 strains (34.6%), Peptostreptococcus spp. in 31 strains (23.3%) andPeptococcus spp. in 26 strains (19.5%).
3. The MIC values of the detected bacteria to the TDZ centered upon 0.78μg/ml for Bacteroides fragilis, 3.13 itg/ml for Peptococcus spp. and 0.78 μg/ml for Peptostreptococcus spp. and those of the others were low, a lot of those being of sensitive strains.
4. The bacteriological effects on the anaerobes were, after the medication, observed to be 71.4% and found significantly more effective than 33.3% of natural eradication and decrease observed in the not administered group.
5. Clinically, no anaerobic infections were observed often operation and the therapeutical effects were observed. A little side effect was observed.
6. According to the above-mentioned results, it was observed possible to prevent from the anaerobic infections after operation in gynecology and obstetrics by administration of TDZ.

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Twelve strains out of 75 Gram negative rods, which were isolated at the clinical laboratory in the hospital, were highly resistant to cephaloridine (CER) and relatively sensitive to gentamicin (GM).Nine strains out of the 12 strains revealed synergistic effect when small doses of GM were used together with CER.A mechanism of synergistic effect on Enterobacter cloacae, 1 strain of the 9 strains, was studied through change of P-lactamase activities.The levels of viable cell count decreased when small doses of GM were added compared with the ones obtained without the addition of GM.
Similarly the levels of protein concentration and β-lactamase activities in the sonicated component of sediment decreased, so did the level of β-lactamase activities per cell.
On the contrary, however, the 3-lactamase activities in the supernatant fluid showed no difference irrespective of the existence of GM. Based upon the above mentioned findings, it is suggested that synergistic effect of CER and GM might be due to inhibition of protein synthesis as well as due to subsequent inhibition of β-lactamase synthesis. This is compared with the author's previous study, 1) in which the mechanism of synergistic effect of CER and chloramphenicol (CP) was partly due to inhibition of protein synthesis, but mostly due to inhibition of β-lactamase synthesis.

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The concentration of sulbenicillin in the serum and myocardial tissue of 13 patients were determined at cardiac surgery.About 100 mg/kg of sulbenicillin were administered intravenously for 60 minutes.Right auricle resected at the vena caval cannuration was examined for myocardial tissue.
The serum concentration was also examined every 30 minutes after injection, 30 minutes, 60 minutes, 90 minutes, 120 minutes and 150 minutes.Mean values of serum concentration were 213.6, μg/ml, 432.5μg/ml, 181.6μg/ml, 236.3μg/ml and 101 μg/ml, respectively.
The values determined in myocardial tissue were 146.5 jug/g (60 minutes), 39.2μg/g (90 minutes), 66.0μg/g (120 minutes) and 23.5μg/g (150 minutes).
The mean value of concentration ratio of sulbenicillin in myocardial tissue was 0.23 of serum concentration.
The high myocardial tissue levels of sulbenicillin suggests that its use at cardiovascular surgery would protect the myocardial tissue from the bacterial infections.

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Susceptibilities of 189 strains of 28 bacterial species to cephradine were determined by the 2-fold agar dilution method in parallel with the diameter of inhibition zone by the single-disc method, under the experimental condition established by KANAZAWA.
The experiments demonstrated significant correlation between MIC by the dilution method and diameter of inhibition zone in each of conventional assay of the over-night (about 16 hours) incubation, delayed assay (about 24 hours incubation), and rapid assay (after 3 ti 4 or 5 N 6 hours incubation), thus confirming applicability of the single-disc assay for cephradine
Analysis of the data obtained by using cephradine disc containing 30 μg revealed the primary regression equation to be: D (diameter, mm) = 28.5-11.2 log MIC (μg/ml) in conventional assay, D = 35.1-14.6 log MIC (μg/ml) in delayed assay, D=18.0-5.41 log MIC (μg/ml) in 3 4 hours rapid assay and D =23.2-8.33 log MIC (μg/ml) in 5-6 hours rapid assay, respectively.
The range of variations in MICs estimated from the diameter of inhibition zone by the disc test was then calculated in comparison with that in MIC determined by the 2-fold agar dilution assays, as reference for the experimental errors which may be involved in the estimation of MIC of cephradine by the single-disc assay.

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Susceptibilities of 101 strains of 29 bacterial species to cefotaxime were determined by the 2-fold agar dilution method in parallel with the diameter of inhibition zone by the single-disc method, under the experimental condition established by KANAZAWA.
The experiments demonstrated significant correlation between MIC by the dilution method and diameter of inhibition zone in each of conventional assay of the over-night (about 16 hours) incubation, deayed assay (about 24 hours incubation), and rapid assay (after 3-4 or 5-6 hours incubation), thus confirming applicability of the single-disc assay for cefotaxime.
Analysis of the data obtained by using cefotaxime disc containing 30μg revealed the primary regression equation to be: D (diameter, mm)=26.5-9.4 log MIC (μg/ml) in conventional assay, D=33.1-11.7 log MIC (μg/ml) in delayed assay, D=16.8-4.6 log MIC (μg/ml) in 3 4 hours rapid assay and D=21.4-6.6 log MIC (μg/ml) in 5-6 hours rapid assay, respectively.
The range of variations in MICs estimated from the diameter of inhibition zone by the disc test was then calculated in comparison with that in MIC determined by the 2-fold agar dilution assays, as reference for the experimental errors which may be involved in the estimation of MIC of cefotaxime by the single-disc assay.

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Fundamental and clinical investigations of cefotaxime were carried out in neonates. The following results were obtained.
1. Seven neonates with serious infections caused by identifiable pathogens, including Group B streptococcal meningitis and Group A streptococcal sepsis, were treated by intravenous bolus injection of 20-200mg/kg of cefotaxime 2 or 3 times daily (60-400mg/kg/day). The clinical efficacy of cefotaxime was assessed to be good in 6 patients and fair in 1 patient. Bacteriological efficacy was evaluable in 4 patients, all of whom displayed complete eradication of pathogens.
2. Among 22 neonates administered cefotaxime, adverse reactions appeared in 3 patients. Adverse reactions consisted of a transient skin rash in 1 patientand elevation of GOT in 2 patients.
3. Serum concentrations of cefotaxime and desacetyl cefotaxime were investigated in 8 mature infants and 5 immature infants on days 0-7postpartum.A single intravenous injection of 20 mg/kg produced peak serum concentrations of 31.8-49.7mcg/ml, associated with a half-life of 1.38-4.47 hours, in mature infants and peak serum concentrations of 35.5-55.0 mcg/ml, associated with a half-life of 3.22-6.43 hours, in immature infants. On days 0-2postpartum the half-life was longer than on subsequent days. This tendency was particularly remarkable in immature infants.Serum concentrations of desacetyl cefotaxime displayed high individual variations; no consistent trends were noted.
4. Cefotaxime and desacetyl cefotaxime serum concentrations were studied in 3 neonates undergoing exchanged transfusion (exchanged volume 177 ti 180ml/kg) on 1-4 days postpartum.Serum concentrations of cefotaxime after exchanged transfusion were equivalent to 32.6-63.9% of the pretransfusion level, while those of desacetyl cefotaxime were 75.2-106% of the pretransfusion level.
5. Minimal inhibitory concentration (MICs) and minimal bactericidal concentration (MBCs) of cefotaxime were determined against clinical isolates.MICs for inoculum sizes of 10⁸/ml and 10⁶/ml were respectively 3.13-25mcg/ml and 3.13-25mcg/ml against S.aureus, 0.024mcg/ml and 0.012mcg/ml against Group A Streptococcus, 0.05 mcg/ml and 0.05mcg/ml against Group B Streptococcus and 0.39mcg/ml and 0.1mcg/ml against E. coli.MBCs for an inoculum size of 10⁸/ml were 3.13-100mcg/ml or over against S. aureus, 0.012mcg/ml against GroupA Streptococcus, 0.39mcg/ml against Group B Streptococcus and 1.56mcg/ml against E. coli.

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Cefotaxime (CTX) was used in the treatment and prophylaxis of infections in neonates and immature infants. The following results were obtained.
1. Mean serum concentrations (bioassay) 30 minutes after a single intravenous injection of about 20mg/kg of CTX were 44.5 mcg/ml in neonates and 47.2mcg/ml in immature infants aged 0-3 days, 45.8mcg/ml in neonates and 56.4mcg/ml in an immature infant aged 4-7 days and 40.6mcg/ml in neonates and 38.1mcg/ml in immature infants aged 8 or more days. Sixhour values were respectively 10.9mcg/ml, 17.0mcg/ml, 4.6 mcg/ml, 13.4mcg/ml, 3.8mcg/ml and 2.7mcg/ml.
2. Mean serum concentration half-lives were 3.0 hours in neonates and3.2hours in immature infants aged 0-3days, 1.8 hours in neonates and3.2hours in an immature infant aged4-7 days, and 1.5 hours in neonates and 1. 6hours in immature infants aged 8 or more days.
3. Urinary recovery rates were 0.8-78.0% for 0-6 hours after treatment.
4. Adequate clinical efficacy can be expected by the intravenous injection of CTX in doses of 20mg/kg 2 times daily, every 12 hours, in neonates and immature infants aged 0-3days, 20mg/kg 3 times daily, every 8 hours, in neonates and immature infants aged 4-7 days, and 20mg/kg 3 to 4 times daily, every 6-8 hours, in neonates and immature infants aged 8 or more days.
5. The clinical efficacy of CTX was good in all 4 cases of sepsis (including suspected case), excellent in 1 case of urinary tract infection, and good in all 4 cases of fever of unknown origin for a cure rate of 100%.
6. Adverse reactions were not noted in any cases.

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It has been proven that, when cephem group antibiotics are administered intravenously to neonates, the peak serum level of the drug is higher, and the half-life is longer, compared with the values attained in suckling infants. The same pattern is seen even with cefmetazole. That is, the Post-and Perinatal Period Research Group recently reported that, when 20 mg/kg of cefmetazole was administered intravenously, the mean serum half-life of the drug was 4.18 hours in infants up to 3 days after birth, while by about the age of 2 weeks there was no longer a difference with suckling infants.
In the present study, cefotaxime was administered at a dosage level of 20 mg/kg by intravenous drip infusion over a 30-minute period. The administered subjects were a 16-day-old neonate and a 45-day-old suckling infant, and the serum level of cefotaxime was monitored. The peak concentration was found to be higher in the younger subject, and the half-life in the serum was longer, i.e., 2.52 hours compared with 1.5 hours in the suckling infant.
In addition, 4 cases of newborn infection were treated with cefotaxime at 120-504 mg/day (approximately 35-300 mg/kg/day), given intravenously for a period of 6 to 21 days. Clear clinical efficacy and bacteriological efficacy were achieved in relation to 1 case of staphylococcal pneumonia, 1 case of septicemia compounded by purulent meningitis caused by Enterobacter aerogenes and 1 case of fever of undetermined origin.
The following summarizes the results of the present study.
1) There was no adverse effect exerted on the hepatic or renal functions.
2) Cefotaxime was efficacious in the treatment of neonates suffering from infections caused by staphylococci and a Gram-negative rod.

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Cefotaxime was administered to a total of 28 infant patients. These infants consisted of 12 mature babies who ranged from 0 to 11 days, and 16 premature babies who showed an age range of 1 to 27 days. Cefotaxime was administered at dosage levels of 20 mg/kg, either as a single intravenous injection or as a 30-minute intravenous drip infusion, and 10 mg/kg as a one-shot intravenous injection. Following these administrations, the change in the concentration of cefotaxime in the serum was monitored with the passage of time. Both the mature babies and the premature babies in the 20 mg/kg administration group were divided into 3 subgroups as a function of the number of days since birth, i.e., 0-3 days, 4-7 days and 8-28 days, and the results were compared.
A clinical investigation of the efficacy of cefotaxime therapy was performed in 9 neonates aged between 0 and 27 days, consisting of 4 males and 5 females. A breakdown of their diseases reveals 4 cases of purulent meningitis, 1 case of suspected purulent meningitis, 1 case of bronchopneumonia, 1 case of septicemia, 1 case of phlegmonouscellulitis and 1 case of staphylococcal scalded skin syndrome.
The following results were obtained.
1. 20 mg/kg, one-shot intravenous injection: In the 3 subgroups of mature babies the peak serum con centrations of cefotaxime were found to range from 42.5 to 61.5, μg/ml. Although there was no significant difference, the half-life of the drug became shorter as the age of the neonates increased.
2. 20 mg/kg, 30-minute intravenous drip infusion: This administration regimen was used for both mature babies and premature babies. As above, both of these types of neonates were divided into 3 subgroups on the basis of the number of days since birth, and then compared for dose-dependent patterns. The peak cefotaxime concentration in the serum was the level existing at the time of completion of the intravenous drip infusion, and this showed a range of 32.0 to 44.9 μg/ml. As the age of the neonates increased, the half-life of cefotaxime in the serum tended to become shorter.
3. 10 mg/kg, one-shot intravenous injection: Again, this cefotaxime administration regimen was used for both mature and premature babies. For both of these neonates, all 3 subgroups showed a peak serum concentration between 15 and 30 minutes after the injection. The actual peak concentrations were spread over a fairly wide range, i.e., 12.5-32.1 μg/ml. There were no significant differences seen in the patterns of maintenance of the cefotaxime serum concentration in these subjects which could be attributed to their age. However, there was a tendency for the drug half-life to be shorter in the more mature subjects.
4. The 9 patients who were clinically treated with cefotaxime were intravenously administered a daily dose of 61.5-198.7 mg/kg, given in 3-4 divided doses. Evaluation of the clinical response of these patients revealed that this cefotaxime therapy was efficacious (good or excellent) in all 5 of the purulent meningitis cases (including the 1 suspected case), both of the cases of dermal soft tissue infection, and the 1 case of bronchopneumonia. The therapy was ineffective only in the 1 case of septicemia. The overall efficacy rate in these 9 patients was thus 88.9%.The causative organism had been identified in 6 of these patients (E. coil in 4 cases and S. aureus in 2 cases).Cefotaxime was found to be bacteriologically efficacious in 5 of 6 cases since the bacteria disappeared from the culture specimens during the course of the therapy and 1 case had been unknown.
5. Consideration was also given to the proper dosage and administration schedule for use in these mature and premature babise. When cefotaxime was administered at 20 mg/kg, almost all of the subjects maintained 5 μg/ml or higher serum concentrations of the antibiotic for up to 6 hours after the administration.

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A study was made of the use of cefotaxime, a new cephem antibiotic, in the treatment of neonates. The following results were obtained.
1. Cefotaxime was administered to 7 neonates 3 to 28 days after birth (these patients consisted of 4 premature and 3 mature neonates) as a single intravenous injection at a dosage level of 20 mg/kg. The mean serum concentration of cefotaxime in these patients was 31.9 μg/ml at 15 minutes after the injection, 26.0 μg/ml at 30 minutes, 20.7 tig/ml at 1 hour, 12.5 μg/ml at 2 hours, 6.1 μg/ml at 4 hours and 3.1 μg/ml at 6 hours. The mean half-life of cefotaxime in the serum was 1.78 hours. In addition, during the 6-hour period following the administration, the mean urinary concentration of cefotaxime was determined to be 543 μg/ml, and the urinary recovery rate was 47.4%.
2. The findings were compared for the premature and mature neonates. For the first hour after the intravenous injection, the serum concentration of cefotaxime in the premature neonates was lower. Thereafter, however, the premature neonates were found to have a higher serum concentration than the mature neonates. In addition, the urinary recovery of cefotaxime was somewhat lower in the premature neonates.
3. Comparison was also made of the results when both the premature and the mature neonates were divided into 2 groups: those under 10 days of age (i.e., since birth) and those 10 days or older. It was found that the peak serum concentration of cefotaxime increased in the following order: 10-days-or-older mature neonates < under-10-days-old mature neonates < under-10-days-old premature neonates <10-days-or-older premature neonates. The rate of disappearance of the antibiotic from the serum increased in the following order: 10-days-or-older mature neonates < under-10-days-old mature neonates < 10-days-or-older premature neonates <under-10-days-old premature neonates. It was thought that these differences are due to differences between premature and full-term neonates in terms of the volume of extracellular fluid relative to the body weight, and the urinary excretion capacity.
4. It was concluded that, for the treatment of neonates with cefotaxime, the administration level should generally be 20 mg/kg per dose. Furthermore, it was concluded that the suitable dosage schedule for full-term neonates is 2 to 4 of the above doses per day, while for premature neonates it should be 2 to 3 doses a day, with consideration given to the number of days since birth in each of these cases.
5. Cefotaxime was administered to 6 clinical cases: 3 cases of acute bronchopneumonia, 1 case of pyothorax, 1 case of pyelonephritis and 1 case of purulent meningitis. The clinical efficacy, bacteriological efficacy and the side effects were then investigated in these treated patients. The clinical efficacy was evaluated in 4 of the patients, and was rated excellent in each. One strain each of E. coil and K. pneumoniae were suspected of being the causative organisms in 2 of the patients, and both of these microbes disappeared as a result of the cefotaxime therapy. As side effects, diarrhea was seen as a clinical symptom in 1 patient, and eosinophilia was detected as an abnormal laboratory finding in 1 patient. Both of these conditions returned to normal following discontinuation of the drug administration upon completion of the therapy.

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The pharmacokinetics of cefotaxime was investigated in neonates.The following results were obtained.
1.The peak serum concentration of cefotaxime, seen 15-minutes after a single intravenous of 20 mg/kg, was 51.6±9.3mcg/ml by bioassay.After 6 hours the mean serum concentration decreased to 5.6±3.1 mcg/ml.Concentrations obtained by HPLC paralleled those determined by bioassay.The peak serum concentration of the desacetyl metabolite was attained 30 minutes to 2 hours after injection.The mean serum desacetyl metabolite concentration was about 1/2.5 times higher than the cefotaxime concentration.The half-life of cefotaxime was 4.15 hours in a neonate 1 day postpartum.The half-life was inversely related to the age of the neonate, decreasing to 1.64 hours on day 11 postpartum.
2.Serum concentrations determined by bioassay and HPLC after administering a dose of 10 mg/kg of cefotaxime by 30-minute intravenous drip infusion were comparable.The peak serum concentration at the completion of intravenous drip infusion was 21.0mcg/ml by bioassay.The half-life of cefotaxime was 2.85 hours.The peak serum concentration of the desacetyl metabolite, seen at the completion of intravenous drip infusion, was about 1/2 times that of the peak cefotaxime concentration.
3.The peak serum concentration at the completion of a 30-minute intravenous drip infusion of 20 mg/kg displayed a mean value of 33.5±10.3mcg/ml by bioassay.After 6 hours the mean serum concentration was 4.0±1.0mcg/ml.The peak serum concentration of the desacetyl metabolite, seen at the completion of infusion to 2 hours thereafter, was equivalent to about 1/2.2 the peak cefotaxime concentration.
4.The mean urinary excretion rate of cefotaxime in 2-day-old neonates was 23.4% by bioassay 6 hours after a 30-minute intravenous drip infusion of 10mg/kg.The mean urinary excretion rate of the desacetyl metabolite was 8.7%.Mean 6-hour excretion rates in 2-day-old and 4-day-old neonates administered 20 mg/kg of cefotaxime by 30-minute intravenous drip infusion were 6.2% and mean 37.7%, respectively.The corresponding values for the desacetyl metabolite were 2.4% and 12.4%, respectively.

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One full-term newborn infant and 2 premature ones were treated with cefotaxime for the treatment of suspected sepsis and umbilical suppurative inflammation. Pathogenic organisms could not be identified in all cases.
A good result was obtained with the case of suspected sepsis.But the other 2 cases were not evaluable because underlying diseases such as massive pulmonary atelectasis or respiratory distress syndrome masked the effects of this agent.
Serum levels of cefotaxime in 3 of the 4 cases were determined with bioassay.Time courses of the serum levels in 2 of them resulted in peculiar biphasic disappearance curves.
This fact implies the possibility that desacetylation of cefroxime proceeds also in newborns as in adults and that desacetyl metabolite accumulates in the body owing to the premature function of the neonatal kidney.

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Plasma and urinary concentrations and urinary recovery of cefotaxime (CTX) up to 6 hour after a single intravenous dose of 20mg/kg were determined in 27 newborn and immature infants 2-27 days postpartum by bioassay and HPLC.In 3 infants with purulent meningitis cerebrospinal fluid and plasma concentrations of CTX were measured after a single intravenous dose of 37.5-59.5mg/kg.Drug sensitivity tests were done for 7 strains of group B Streptococcus (S.agalactiae) to CTX, cefmetazole (CMZ) and cefazolin (CEZ).Sixteen new born and immature infants, aged 0-21 days, and 3 nursing infants, aged 1, 2 and 3 months with bacterial infections were intravenously administered CTX in a mean daily dose of 118.5mg/kg, in 2-6 divided doses, for a mean period of 20 days.Clinical and bacteriological effects were evaluated.Adverse reactions were investigated in a total of 56 patients, including 37 dropouts.The following results were obtained.
1.Plasma concentrations after a single intravenous injection of CTX were determined in 27 newborn and immature infants divided into age groups of 0-3, 4-7, 8-14, 15-21, and 22 or more days.Peak concentrations were seen at 15 minutes after injection in all groups, but the peak level was slightly lower in infants aged 7 days or less than in those aged 8 days or more.Plasma concentrations were lower and the mean half-life was longer than in general pediatric cases, particularly in infants aged 7 days or less.
2.Plasma concentrations were determined in the same cases by HPLC.Except for the peak mean CTX concentration being seen at 30 minutes in infants aged 4-7 days, peak concentrations occurred at 15 minutes similar to bioassay.If desacetyl cefotaxime (D-CTX) concentrations are included, concentrations determined by HPLC were comparable to those measured by bioassay.Unlike general pediatric cases, D-CTX concentrations were dispersed over a wide range and no consistent tendency was noted.
3.Urinary concentrations determined by bioassay attained peak values in all age groups in 0-2 hours. Urinary concentrations and recovery rates were lower than in general pediatric cases, but the recovery rate increased as the infant grew older.
4.Urinary concentrations determined by HPLC attained peak values in 2-4 hours in the group aged 8-14 days, unlike the results obtained by bioassay.However, peak concentrations were seen in 0-2 hours in all other groups.If D-CTX concentrations are included, the results were comparable those obtained by bioassay.A similar tendency was also seen for urinary recovery.D-CTX concentrations showed large intersubject fluctuations. The mean urinary recovery rate of D-CTX tended to increase as the infant grew older, but was lower than in general pediatric cases.
5.Cerebrospinal fluid concentrations in 3 patients were favorable in consideration of the day of disease on which samples were taken.
6.The MIC of CTX against all 7 strains of S.agalactiae was 0.05mcg/ml for inoculum sizes of 10⁶ and 10⁸cells/ml.The antibacterial activity of CTX was superior to that of CMZ and CEZ.
7.The clinical and bacteriological success rates in 19 patients with various bacterial infections were 84.2% and 100%, respectively.These were very good results.
8.As an adverse reaction, diarrhea occurred in 1 patient (1.8%).Laboratory abnormalities conslsted of eosinophilia in 2 patients (3.6%).Other examinations did not reveal any abnormalities.

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The therapeutic efficiency of a new cephalosporin derivative, cefotaxime, which is stable against beta-lactamase hydrolysis, has been studied in cases involving perinatal infection.
The following results have been obtained.
1.In the treatment of 7 cases of infection, the preparation showed excellent efficacy in 1 case and good efficacy in 5 cases except 1 unknown case.
2.This drug has demonstrated its efficacy in the treatment of 5 cases of infections refractory to ABPC, out of which 1 had excellent and 3 had good results.
3.No side effects were observed in any of our patients.
In conclusion, this drug shows excellent efficacy and high safety in the treatment of cases involving infection

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The transplacental passage of a single intravenous dose of cefotaxime (CTX), 1,000mg, was examined in 11 pregnant women undergoing delivery at term by cesarean section.The results were as follows.
1.Measurements by HPLC: After a single 1,000mg intravenous dose, the maternal blood level of CTX took the following course: 40.1±3.4mcg/ml (mean±S.E.) at 15 minutes, 22.5±1.9mcg/ml at 30 minutes, 10.8± 0.9mcg/ml at 60 minutes and 3.2±0.4mcg/ml at 120 minutes.Slightly high maternal blood levels of 0.7 and 1.1 mcg/ml were obtained at child deliveries made at 200 minutes, but only a trace amount was found at a child delivery at 356 minutes.The CTX level in the umbilical cord blood was comparatively high until the measurement at 222 minutes, and then declined.In the amniotic fluid, peak levels were observed at 222 to 252 minutes, thereafter decreasing slowly.Desacetyl-CTX, a metabolite of CTX, showed maternal blood levels of 5.8±0.5mcg/ml at 15 minutes, 6.3±0.6mcg/ml at 30 minutes, 6.8±0.7mcg/ml at 60 minutes and 4.9±0.7mcg/ml at 120 minutes.Thus, the maternal blood level of desacetyl-CTX showed an increasing tendency until 60 minutes after intravenous administration, and decreased rapidly from 120 minutes onwards.No consistent tendency was noted in desacetyl-CTX levels in the umbilical cord blood and the amniotic fluid.
2.Measurements by bioassay: Maternal blood levels of CTX determined by bioassay were 45.2±3.3mcg/ml at 15 minutes, 25.8±2.2mcg/ml at 30 minutes, 12.4±1.0mcg/ml at 60 minutes and 4.0±0.5mcg/ml at 120 minutes.At the time of child delivery, maternal blood levels of CTX were 1.1 and 2.6mcg/ml at 200 minutes, and then decreased slowly.Trace levels were noted at 336 minutes and CTX was undetectable at 356 minutes.
3.The HPLC study demonstrated that the level of CTX remained comparatively high in the umbilical cord blood and the aminiotic fluid even 6 hours after administration (0.3-0.4mcg/ml and 4.0 mcg/ml, respectively). This result suggests, in consideration of CTX's MIC values for causative organisms, that CTX will produce a sufficient clinical effect in perinatal infections.
No side effects were observed in the mothers or their babies.

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Pharmacokinetic studies of cefotaxime (CTX) were carried out in perinatal mothers and infants.
CTX was promptly absorbed after intravenous injection, intravenous drip infusion and intramuscular injection in pregnant women, producing dose-related peak blood levels.
Placental passage to the fetus was favorable. After intravenous injection, intravenous drip infusion and intramuscular injection of 500-1,000mg of CTX, drug concentrations of the cord blood, amniotic fluid and fetal blood exceeded MICs of the main pathogenic organisms.By administration of this dose 1 to 2 times daily it is possible to successfully prevent or treat uterine infections.
Passage of CTX into the milk of lactating mothers was minimal, suggesting that only minute quantities can possibly be transferred from the milk to newborn infants.
Absorption of CTX in neonatal infants was prompt.The peak blood levels of 47.9μg/ml were attained 15-30 minutes after intravenous injection of 20 mg/kg.The half-life ranged from 2.4-5.56 hours, depending on the number of days postpartus.
CTX was effective in the prophylaxis or therapy of perinatal uterine infections.Moreover, newborn infants delivered from mothers receiving CTX treatment did not exhibit any laboratory test abnormalities.
The above results demonstrated that CTX is a clinically useful antibiotic for the prophylaxis and therapy of perinatal infections.

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Fundamental and clinical studies on the perinatal use of cefotaxime (CTX, HR-756), a new cephalosporin antibiotic, were done, with the following results.
1.Following intravenous administration of 2 g of CTX, transport of CTX from maternal serum toumbilical cord serum and to amniotic fluid was found to be good.CTX was not transferred into mother's milk.
2.In clinical use, CTX was given to 16 pregnant patients with premature rupture of the membrane.It showed excellent efficacy in preventing perinatal infection. Five patients with perinatal infections were administered CTX, and in 4 patients CTX had good efficacy.
No side effects were noted in any cases.

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Fundamental and clinical studies of cefotaxime (CTX) were carried out in pregnant women.The following results were obtained.
CTX was more rapidly eliminated from the serum of pregnant women than that of adult males.Urinary excretion of CTX in pregnant women was comparable to that in nonpregnant women and adult males.
Passage of CTX to the embryo, fetus and fetal appendages was minimal.
Peak amniotic fluid concentration (9.8mcg/ml) was attained at 3.5 hours after administration of CTX and gradually declined thereafter.This amniotic fluid concentration was sufficiently higher than reported MIC₉₀ of CTX against E.coli strains.
CTX was used in the treatment of 6 pregnant patients with acute pyelonephritis and 2 with puerperal infections. The bacteriological and clinical responses were both 100%.
Since passage of CTX into the amniotic fluid is favorable, CTX can be expected to be effective for the prophylaxis of intrauterine amniotic infection associated with early rupture of the membrane.
CTX was used in the treatment of a neonate with purulent meningitis. The clinical response was effective.
CTX did not cause any noteworthy adverse reactions or laboratory data abnormalities in our patients or neonates.

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The passage of cefotaxime into umbilical cord serum and amniotic fluid was favorable, respectively attaining levels equivalent to about 25% and 15% of maternal serum concentrations.Passage of cefotaxime into the milk was not detected.There were no abnormalities, including laboratory findings of total bilirubin, in neonates.The safe dose range of cefotaxime in perinatal mothers was estimated to be1-2g/day, with the maximum safe dose being4g/day.

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