[Studies on the intravenous administration of amikacin to neonates].

Amikacin (AMK) was administered mainly to neonates by either intravenous drip infusion or intramuscular injection and its pharmacokinetic changes were investigated. The results obtained are summarized as follows. 1. Serum half-lives of AMK in neonates at ages 0 to 3 days were longer than those at ages 4 to 10 days. Serum half-lives were prolonged particularly in neonates at an age 0 day. Neonates at ages 11 to 15 days, also showed longer half-lives in comparison to infants. Similar peak serum levels were observed in all the neonates with ages 0-15 days. 2. Similar serum AMK levels were obtained in neonates through intravenous drip infusion and through intramuscular injection at a same dose level. 3. When the drug was administered to neonates at 3.0 to 6.0 mg/kg by intravenous drip infusion, peak serum levels did not reach 30 micrograms/ml which is considered to be the critical level for AMK to be toxic. 4. Urinary excretion rates in neonates 11 day or older were almost the same levels as in infants. 5. AMK, when administered through intravenous drip infusion, was observed to have a higher migration rate to saliva when compared with kanamycin administered through intramuscular injection. 6. Based on the results obtained from the present study, the following doses seem to be optimal for neonates, but further studies are required to be conclusive. For neonates: 2.0 to 5.0 mg/kg daily in 1 to 2 divided doses. (For those at ages of 0 to 3 days: 2.0 to 3.0 mg/kg) For infants: 3.0 to 8.0 mg/kg daily in 1 to 2 divided doses through intravenous drip infusion over a period of 30 minutes to 1 hour.

[Study on intravenous drip infusion therapy of cefotiam in neonates and infants].

Intravenous drip infusion (d.i.) of cefotiam (CTM) in neonates and infants produced the following pharmacokinetic and clinical results: In a 2 and 3 day-old neonates group, blood concentrations at 1 and 5 hours after intravenous drip infusion of 20 mg/kg of CTM were 33.0 micrograms/ml and 12.3 micrograms/ml, respectively. Thus high blood CTM levels were maintained in these cases. In a 4 day-old neonate, blood concentrations after 1 and 6 hours were 20.5 micrograms/ml and 5.8 micrograms/ml. respectively. In a 8-13 day-old neonates group, blood levels after 1 and 6 hours were 12.2-18.5 micrograms/ml and 0.7-2.4 micrograms/ml, respectively. Compared to the corresponding values in the 2 and 3 day-old neonates, the blood CTM levels in this group were low. Half-lives of CTM in the blood were 1.8-2.7 hours, 2.1 hours, 1.1-1.7 hours and 0.7 hour, in 2-3 day-old neonates, 4 day-old neonate, 8-13 day-old neonates and a 45 day-old infant, respectively. Half-lives tended to become shorter with increasing age. The 6-hour urinary recoveries ranged between 20.3 and 62.3%. Transport of the drug into the spinal fluid was also observed. The CTM was very effective in the treatment of 6 patients suffering from suppurative meningitis, septicemia, bronchopneumonia or UTI with ampicillin-resistant E. coli. The daily dose ranged between 41 and 175 mg/kg. The duration of the treatment was 5 to 18 days, with total doses of 0.72 to 16.25 g. In only one case, a transient eosinophilia was noted.(ABSTRACT TRUNCATED AT 250 WORDS)

[Fundamental and clinical evaluations of ceftazidime in neonates].

Ceftazidime (CAZ) intravenous injection was evaluated from fundamental and clinical aspects in neonates, and the results obtained are summarized below. Following a 60-minute intravenous drip infusion of CAZ at 10 mg/kg, the peak serum level was 19.8 micrograms/ml at 30 minutes after the completion of the infusion(half-life: 2.75 hours). Following 30 to 60-minute intravenous drip infusions of CAZ at 20 mg/kg, the mean peak serum levels of CAZ were 33.1-33.0 micrograms/ml. Mean levels at 6 hours were 5.2-6.7 micrograms/ml (half-life: 1.6-4.1 hours). Following 30 to 60-minute intravenous drip infusions of CAZ at 25-30 mg/kg, peak serum levels were 51.7-64.6 micrograms/ml (half-life: 1.6-2.05 hours). Dose response relationship was clearly observed in peak serum levels after intravenous drip infusion, and half-lives of serum CAZ levels in neonates aged 0-10 days tended to be longer than those in infants. Following intravenous administration of CAZ at 20-30 mg/kg, urinary excretion rates during the first 6 hours were 18.7-66.5%, and the rates were low in neonates compared to those in infants and children. Following a 60-minute intravenous drip infusion of CAZ at 28.7 mg/kg, the cerebrospinal fluid level was 5.0 micrograms/ml at 3 hours, the ratio of cerebrospinal fluid level to serum level was 22.5%. Eleven neonates were subjected to the present study. Clinical efficacy of CAZ was excellent in sepsis caused by A. anitratus, which showed higher sensitivity to CAZ compared with other cephem antibiotics of the third generation. In all of the other cases, including those of pertussis and acute urinary tract infections and in the prophylaxis of amniotic infection, clinical efficacy of CAZ was excellent or good. S. epidermidis, E. coli and A. anitratus, identified from cultures of pharynx, urine or blood, were rapidly eliminated during the CAZ treatment. Doses of CAZ used in the present study were 29-133 mg/kg/day, mostly in the range of 40-60 mg/kg/day. Durations of treatment ranged from 3 to 10 days. Neither systemic nor local adverse effect was observed, nor was any abnormality observed in laboratory findings.

[Fundamental and clinical studies of ceftizoxime rectal suppositories in the field of pediatrics].

This paper deals with fundamental and clinical results, in the field of pediatrics, of the newly developed rectal suppository (CZX-S) of a cephem antibiotic ceftizoxime (CZX). CZX-S was well absorbed in children. The mean peak serum concentrations of CZX in the 125 mg-administered group (average: 9.9 mg/kg) and the 250 mg-administered group (average: 13.4 mg/kg) were 5.10-7.71 micrograms/ml at 15-30 minutes after dosing. Serum concentrations of CZX were measurable level in almost all the children at 6 hours after administration with the half-lives were 1.34-1.55 hours. The 6-hour urinary excretion rate accounted for 16.5-22.0%. CZX-S was administered to 30 children with acute upper or lower respiratory tract infections about 20-60 mg/kg/day in 3-4 divided portions. CZX-S provided favorable therapeutic-effect in most of the children 3-5 days after administration. The effectiveness rate was 93%. The causative organisms of H. influenzae (3 cases) and S. aureus (4 cases) isolated clinically from pharyngeal mucous and sputum were eradicated after administration of CZX-S. Anal pain and diarrhea experienced in 5 of the 30 children and CZX-S was withdrawn in 4 (of the 5) children, but exhibited satisfactory therapeutic-effect in 2 of the 4 cases up to withdrawal of the drug. An increase in GOT and GPT was observed in 3 cases. The values returned to the normal range in 1 case after the treatment with CZX-S. The test was not reexamined in the other 2 cases. The present clinical result suggests the usefulness of CZX-S substituted for oral and injectable forms in the treatment of various pediatric infections caused by organisms sensitive to CZX.

[Clinical studies on SM-4300, a new human gammaglobulin preparation for intravenous use in pediatrics].

Six cases of severe infections in pediatrics, which showed no or insufficient responses to treatment with antibiotics, were treated with additional intravenous infusion of SM-4300. Results were as follows. Three cases of bacterial infections with high fever, showing no response to chemotherapy, were treated with SM-4300, (68-135 mg/kg). Administration of SM-4300 resulted in defervescence, decreasing pain and swelling and showing a trend for improvement in CRP values. Administrations of SM-4300 (61-100 mg/kg) against pleurisy caused by Mycoplasma were effective in defervescence and improvement in chest findings. Clinical effects of SM-4300 were excellent in 2 cases, good in 3 and fair in 1. In this study, no clinical side reactions nor abnormal laboratory values in blood, liver or renal functions were observed.

[Study on a new cephamycin preparation cefminox in the field of pediatrics].

Cefminox (CMNX, MT-141) was studied both fundamentally and clinically in the field of pediatrics with following results. The MIC of CMNX for Bordetella pertussis was 0.10 micrograms/ml in inoculum size 10(6) cells/ml. Following administration of 10 and 20 mg/kg of CMNX as drip infusion over 1 hour, the blood levels of the drug were 49.0 +/- 18.1 and 69.1 micrograms/ml at completion of infusion, 28.8 +/- 7.7 and 61.6 micrograms/ml at 1.5 hours, 23.6 +/- 9.3 and 44.1 +/- 3.8 micrograms/ml at 2 hours and 1.4 +/- 1.4 and 4.0 +/- 0.6 micrograms/ml at 7 hours, with T1/2 of 1.03 and 1.41 +/- 0.03 hours, respectively. Within the first 7 hours after administration, 61.4 +/- 8.2 and 55.9 +/- 0.8% of the drug dosed were excreted at active form in urine. In child with encephalitis, drug considered to be good as a cephem antibiotic was achieved in the cerebrospinal fluid (the ratio of the level in the cerebrospinal fluid to that in the serum was 7.3%). In addition, in the pus in empyema also high level was reached (its ratio against blood level was 53%). In the treatment of 31 cases of acute infections of pediatric field including upper and lower airway infections, empyema, whooping cough, acute urinary tract infections and phlegmon, CMNX was administered intravenously either as one shot injection as drip infusion. The clinical results obtained were rated as good or more in 93% of the cases and as fair or more in 100% of the cases. The main dosage of CMNX in these cases was about 60 to 70 mg/kg per day in 2 or 3 divided doses. S. aureus, S. pyogenes, S. pneumoniae, H. influenzae and ABPC resistant strain of E. coli demonstrated in various materials could be eradicated after intravenous injection of CMNX. CMNX was administrated for a period of 2 to 16 days to a total amount of 1.5 to 26.5 g. In none of these cases side effects developed nor any abnormality was revealed by hematological findings or results of renal or liver function.

[Experimental and clinical studies on BRL 25000 (clavulanic acid-amoxicillin) granules in the pediatric field].

Fundamental and clinical studies have been performed on the BRL 25000 granules (combination of amoxicillin (AMPC) and potassium clavulanate (CVA) in 2: 1 ratio) in the pediatric field. In bacteriological studies a potentiated antibacterial activity of BRL 25000 was recognized against AMPC-resistant and beta-lactamase producing clinical isolates. The pharmacokinetics of the BRL 25000 granules were studied at dose levels from 10 to 20 mg/kg. The peak serum concentrations of AMPC and CVA achieved approximately 1 hour after dosing were 4.29-9.55 micrograms/ml and 3.87-4.78 micrograms/ml, respectively. The serum half-life was found to be 0.90-1.31 hours for AMPC and 1.01-1.22 hours for CVA. Six-hour urinary excretion rates were 29.5-62.6% for AMPC and 12.6-37.9% for CVA. In the clinical studies, the BRL 25000 granules were administered to 36 pediatric patients (15 with upper and lower respiratory tract infections, 10 with urinary tract infections and 11 with skin or soft tissue infections, etc.) at dose levels of 30-50 mg/kg/day. Clinical results in all cases were excellent or good. In particular, good bacterial and clinical effects were obtained against infections caused by beta-lactamase producing AMPC-resistant strains except E. cloacae 1 strain. No adverse reactions or abnormal laboratory findings were recognized in any patient.

[Evaluation on ceftriaxone in the pediatric field].

Fundamental and clinical evaluation on ceftriaxone (CTRX, Ro 13-9904) was performed in the pediatric field and the following results were obtained. The MIC of CTRX against the recently isolated 10 strains of B. pertussis was less than or equal to 0.05 microgram/ml at inoculum size of 10(6) CFU/ml. The blood level of CTRX after intravenous drip infusion with 10 to 20 mg/kg for 30 minutes to 1 hour reached a peak ranging from 45.3 to 137 micrograms/ml at the end of infusion. The effective blood level was maintained up to 12 hours to be 3.52 to 26.7 micrograms/ml at that time. The half-life time was over 6 hours in most cases, but the multiple intravenous dosage did not cause any elevation of the blood level. The urine excretion rate till 12 to 24 hours after intravenous drip infusion ranged from 58.2 to 84.2%. The excretion of CTRX into the cerebrospinal fluid was favorable in the acute period when administered by intravenous drip infusion in the child with S. pneumoniae purulent meningitis, which was considered to be satisfactory for treatment against the bacteria susceptible to CTRX. The active CTRX was transferred into the feces by the multiple dosage. CTRX was administered by intravenous drip infusion in 26 cases with acute pediatric infections. The clinical efficacy was observed in all the cases with upper/lower respiratory tract infections including bronchopneumonia and pertussis, and the cases with acute urinary tract infections caused by ABPC-resistant E. coli, administered by intravenous drip infusion twice daily with about 40-50 mg/kg/day. The bactericidal efficacy was seen against all bacteria except Salmonella. CTRX by intravenous drip infusion was effective against S. pneumoniae purulent meningitis; the clinical symptom was rapidly improved while the culture of causative strains from the cerebrospinal fluid turned negative. Although CTRX was clinically effective against Salmonella enteritis and typhoid, bacteriological and symptomatological relapses were observed in some cases. An increase in dose of CTRX is considered to be needed for these diseases. No adverse reaction was found clinically but soft stool in 1 case while eosinophilia and thrombocytosis were observed each in 1 out of 30 cases in laboratory test. The efficacy was good or higher in all the 26 cases (100%) administered by intravenous drip infusion. The above-mentioned results indicate that CTRX is useful in the pediatric field.

[Fundamental and clinical studies of sulbactam/cefoperazone in the field of pediatrics].

Sulbactam/cefoperazone (SBT/CPZ) was evaluated in the treatment of pediatric patients to have the following results: Peak serum concentrations which occurred just after the drip infusion of 20 mg/kg SBT/CPZ were 36.4 micrograms/ml and 8.6 micrograms/ml for CPZ and SBT, respectively. The half-life of CPZ was 1.91 hours, and that of SBT, 0.97 hour. Following the 40 mg/kg drip infusion, the peak serum concentration of CPZ was 79.1 micrograms/ml, and that of SBT, 27.0 micrograms/ml. The half-lives were 1.99 hours for CPZ, and 1.07 hours for SBT, respectively. In 6 hours after drip infusion of 20 mg/kg and 40 mg/kg 21.7, 37.0% of CPZ and 41.6, 85.6% of SBT were excreted in urine. Daily doses of about 50-90 mg/kg SBT/CPZ were administered by intravenous or drip infusion to 26 pediatric patients with acute infections such as lacunar tonsillitis, bronchitis, bronchopneumonia, suppurative diseases caused by Staphylococcus (staphylococcal scalded skin syndrome), purulent parotitis, cervical lymphadenitis, phlegmon and acute UTI related with ABPC/CPZ resistant beta lactamase producing E. coli. SBT/CPZ demonstrated the bacteriological effect on all the causative organisms. The clinical efficacy was also confirmed with the efficacy rate of 88.5%. No side effects were observed in all the cases though transient eosinophilia developed in 2 patients.

[Fundamental and clinical studies of ceftazidime, a new cephem antibiotic in the field of pediatrics].

Fundamental and clinical studies of ceftazidime (CAZ) were performed, and the following results were obtained. MICs of CAZ for E. coli which was recently isolated from patients, were less than 1.56 microgram/ml and that for K. oxytoca were less than 0.39 micrograms/ml, and that for Salmonella were less than 0.39 microgram/ml, and that for B. pertussis were less than 0.20 microgram/ml. The mean serum levels after the drip infusion at the doses of 20 to 36 mg/kg for 30 to 60 minutes were between 11.8 and 66.7 micrograms/ml at 1 hour, and the mean half-lives (T 1/2) were between 58 and 105 minutes, and the excretion rates in urine up to 6 hours were between 86.3 and 96.5%. CAZ was given to 35 pediatric patients (include 2 drop cases) by intravenous injection for 4 to 10 days, and the total dosage was between 2.4 and 14.5 g. Thirty-three patients with acute respiratory tract infections, pertussis and acute urinary tract infections with ABPC-resistant E. coli were treated with CAZ by intravenous injection or drip infusion. The efficacy rate of excellent + good was 90.9% (30 cases/33 cases) and the efficacy rate of excellent + good + fair was 100%. The daily doses of CAZ were 50 to 110 mg/kg, given in 2 or 3 divided doses per day. S. pyogenes, S. aureus, H. influenzae, B. pertussis and ABPC-resistant E. coli were isolated from the culture of sputum or urine in the patients, and they were all eradicated by treatment with CAZ. No side effect was observed except for temporary eosinophilia in 2 cases and temporary platelets increased in 1 case.

[Evaluation of cefpiramide, a new cephem parenteral preparation developed in Japan, in pediatrics].

Fundamental and clinical studies of cefpiramide (CPM), a newly developed cephem antibiotic with a broad spectrum, were performed and the following results were obtained. The serum levels of CPM after the intravenous injection or the drip infusion of CPM at dose of 10.0 approximately 46.7 mg/kg reached the peak of 75.8 approximately 274.0 micrograms/ml at 30 approximately 60 minutes after infusion and were 3.9 approximately 55.1 micrograms/ml at 8 hours after the infusion. Half-life of CPM in the blood was between 2.4 and 7.0 hours. The excretion rates of CPM into urine up to 24 hours after the infusion were 5.7 approximately 20.4%. Twenty-five patients with acute respiratory tract infection (RTI, 15 cases), urinary tract infection (UTI, 8 cases), cellulitis (1 case) and salmonellosis (1 case) were treated with CPM. The treatment by intravenous injection or drip infusion of 22 approximately 55 mg/kg/day (40 approximately 50 mg/kg/day) for mean 6 days resulted in 100% of good response in 15 cases of RTI and in 88% of good response in 8 cases of UTI. S. aureus, H. influenzae, E. coli, Proteus, Klebsiella and Salmonella group B were isolated from the culture of sputum or urine in the patients, and they were all eradicated by the treatment with CPM. No side effects were observed except eosinophilia in 1 case and the elevation of GOT and GPT in 1 case.

[Experimental and clinical studies of an ampicillin suppository (KS-R1) in pediatrics].

Absorption of ampicillin (ABPC) suppository (KS-R1) was good with the peak level of ABPC at 15 minutes and the continuous high level for 1 hour by the administration of about 10 approximately 18 mg/kg. About 40% of active form of administered ABPC was excreted into urine within 6 hours. KS-R1 at the dose of about 20-40 mg/kg/day divided into 3-4 times was very against acute respiratory tract infection by the treatment for 3-5 days. The effective rate was 94% in 35 cases. By the administration of KS-R1, group A Streptococcus, S. pneumoniae and H. influenzae were eradicated. After the insertion of KS-R1, weak diarrhea and the discharge of KS-R1 were observed in 2 cases and 3 cases, respectively. It was concluded that KS-R1 is very useful drug for the treatment of infections by ABPC sensitive organisms in place of the oral form of ABPC.

[Fundamental and clinical studies on T-1982 (cefbuperzone), a new cephamycin antibiotic, in the field of pediatrics].

Studies on T-1982 (cefbuperazone), a new cephamycin antibiotic, were carried out in the field of pediatrics, and the following results were obtained. 1. Peak MIC of T-1982 against S. pyogenes (group A) lately isolated was 0.39 micrograms/ml, and the drug was active even against highly resistant strains of macrolides, lincomycin, tetracycline and chloramphenicol. 2. Peak MICs of T-1982 were 0.78 microgram/ml against B. pertussis, 0.2 microgram/ml against E. coli and less than or equal to 0.05 microgram/ml against K. oxytoca, and the drug was also active against ampicillin-resistant bacteria. 3. Serum levels and urinary excretions of T-1982 were investigated in 6 cases. When given at a dose of 20-28 mg/kg by 1 hour intravenous drip infusion, serum concentrations of T-1982 attained the peak level of 63.5-75.9 micrograms/ml at the end of administration and sustained the level of 0.9-2.6 micrograms/ml at 6 hours, the serum half-life (T 1/2) ranging 70-82 minutes. Approximately 20-72% of the dose were excreted in the active form into urine within 6 hours. 4. Twenty-seven cases of acute pediatric infections were treated with T-1982 mainly by intravenous drip infusion, and satisfactory clinical results were obtained in all the cases of angina lacunaris, bronchitis, bronchopneumonia, pertussis, sepsis caused by Serratia and acute urinary tract infections caused by ampicillin-resistant E. coli. The efficacy rate was 96.3%. In this study the drug was administered chiefly at a daily dose of 50-70 mg/kg 2-3 times a day for 2-12 days. 5. Gram-positive cocci (S. aureus, S. pneumoniae, S. pyogenes) and Gram-negative rods (H. influenzae, H. parainfluenzae P. vulgaris, B. pertussis, S. marcescens, E. coli) were eradicated by the treatment with T-1982. 6. No noticeable side effects were observed, except for temporary increase of eosinophil in 2 cases and slight elevation of GOT in 1 case.

[Evaluation of cefsulodin in the field of pediatrics].

A few studies on cefsulodin (CFS) were performed and the following results were obtained. 1. High blood concentration was obtained with intravenous drip infusion of this drug, but it did not last long. 2. In 6 to 12 hours after the conclusion of the infusion, 52-81% of the dose was excreted in active condition. 3. Pseudomonas aeruginosal abscess was completely cured by intravenous drip infusion of this drug. A decrease in Pseudomonas aeruginosa was noted in urine in the case of acute pyelonephritis and in sputum in the case of pneumonia. The minimum inhibitory concentrations of this drug against P. aeruginosa isolated from various materials were below 12.5 micrograms/ml for all strains. 4. In all the patients including 3-month-old infants to whom 55-200 mg/kg of this drug was intravenously drip infused for 5 days, systemic or topical adverse reactions were not recognized. Nor did this drug give any effect on general blood condition, and liver and kidney functions. We plan to further study the clinical efficacy of this drug by adding more cases affected with P. aeruginosa in children.

[Studies on 9,3"-diacetylmidecamycin dry syrup in pediatric acute respiratory tract infections (author's transl)].

The authors have carried out some studies on MOM dry syrup in the field of pediatrics and the results were as follows. 1. After oral administration of MOM at 20 mg/kg, the serum level peaked at 30 minutes and MOM could still be detected in the serum at up to 4 hours. The half-life was 0.67 hour. The urinary recovery rate of MOM was 1.43% up to 6 hours after this oral administration. 2. The clinical efficacy rates with MOM continuous treatment at a daily dose of 19.4 to 50.0 mg/kg (almost about 30 mg/kg) were 85.7% for upper respiratory tract infections, 66.7% for lower respiratory tract infections and 95.7% for Mycoplasma pneumonia. 3. It was easy to administer MOM orally even to the younger children. Although MOM was administered for 4 to 21 days, no side effects were observed locally or systemically except for transient slight diarrhea. These results confirmed the usefulness of MOM in the treatment of acute respiratory tract infections in children.