Pharmacokinetic and clinical studies on amikacin in neonates

Pharmacokinetic and clinical studies on amikacin (AMK) were performed in neonates and the results obtained are summarized as follows. 1. After intramuscular injection of single doses of AMK at 3 mg/kg, peak serum levels were 6.8 micrograms/ml in a 2-day-old neonate and 7.0 micrograms/ml in a 20-day-old neonate. Serum levels of AMK in the above 2 neonates at 8 hours after injection were 1.5 micrograms/ml and 1.4 micrograms/ml, respectively, and the half-life of AMK was 3.3 hours. After intramuscular injection of single doses of 4 mg/kg of AMK, the mean peak serum level was 8.1 +/- 1.1 micrograms/ml, and half-lives of AMK were 6.1 hours in a 1-day-old neonate and 4.0 hours in a 3-day-old neonate. The mean peak serum level of AMK reached at 1 hour after intramuscular administrations at single dose of 6 mg/kg was 10.5 +/- 0.5 micrograms/ml in a 3-day and a 4-day-old neonates. Serum levels at 8 hours after administrations were 3.1 micrograms/ml and 2.8 micrograms/ml, in the 3-day and the 4-day-old neonates, respectively. Half-lives of AMK in sera were 3.9 hours in the 3-day-old neonate and 3.5 hours in the 4-day-old neonate. 2. In three 2-day-old neonates, the mean peak serum level of AMK after an intravenous drip infusion for 30 minutes at single dose of 3 mg/kg was 10.0 +/- 1.1 micrograms/ml at the end of infusion and serum levels decreased to 2.3 +/- 0.6 micrograms/ml at 6.5 hours after infusion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Investigation on the use of amikacin in the newborn

The use of amikacin (AMK) in newborns was investigated and the results obtained are summarized as follows. 1. AMK was administered to 3 rabbits at an intramuscular dose of 6 mg/kg. Mean blood levels determined according to methods of bioassay (BIO) and fluorescent immunoassay (FIA) were 28.6 and 22.2 micrograms/ml, respectively, at 30 minutes after dosing. Then, the blood levels declined rapidly. Mean T 1/2 values obtained with the above 2 assay methods were 0.76 and 0.63 hours, respectively. 2. When AMK was administered at a dose of 5.7 mg/kg to a 64 day-old newborn by drip intravenous infusion for 30 minutes, a peak blood level was attained at the end of drip intravenous infusion, which was 20.0 micrograms/ml according to BIO and was 15.5 micrograms/ml according to FIA. The blood levels declined gradually thereafter with a T 1/2 value of 2.33 hours (BIO) or 2.03 hours (FIA). When the drug was administered at 5.3 mg/kg to a 26 day-old newborn using the same infusion method, the peak blood level obtained at the end of drip intravenous infusion was 18.0 micrograms/ml according to BIO and was 14.8 micrograms/ml according to FIA, and T 1/2 values were 4.76 and 3.68 hours, respectively. 3. As there was a close correlation between the values obtained with BIO and with FIA in both rabbits and clinical cases, with a coefficient of 0.990, and also the BIO values could be estimated using a formula of FIA value X 1.2 + 2.2, it would be possible to monitor AMK levels in the blood of patients at bedside using the FIA.(ABSTRACT TRUNCATED AT 250 WORDS)     

A pharmacokinetic study in (mature and premature) neonates treated with amikacin through intravenous drip infusion

A pharmacokinetic study was conducted in neonates (mature, premature) to which amikacin (AMK) was administered through intravenous drip infusion. The results of the study are summarized below. 1. Changes in blood concentrations of AMK obtained after intravenous drip infusion over a period of 30 or 60 minutes were comparable to those after intramuscular injection. 2. When AMK was administered to neonates (mature, premature) at a single intravenous (30 or 60 minutes) dose of 6 mg/kg, peak levels of 15.5 to 26.3 micrograms/ml were attained. These values were within the range of 15 to 30 micrograms/ml which are considered to be safe and effective peak levels. 3. In 0 day-neonates, half-lives of blood AMK levels rather long and widely varied (3 to 8 hours) but, in about 7 day-neonates, half-lives were 3 to 4 hours. 4. It is considered from the above results that the safe and effective blood concentrations of AMK in 0 to 7 day-old neonates can be obtained from intravenous administrations at each dose of 6 mg/kg repeated with intervals of 12 or 24 hours and, in 8 days or older neonates, from intravenous drip infusions over 30 or 60 minutes at each dose of 6 mg/kg repeated with intervals of 12 hours. 5. For neonates with very low birth weights, individual doses and intervals should be separately investigated.     

Laboratory and clinical studies of sulbactam/ampicillin in pediatric field

We have carried out laboratory and clinical studies on sulbactam/ampicillin (SBT/ABPC). The results are summarized as follows. SBT/ABPC was given by 30-minute drip infusion to 1 child at a single dose of 15 mg/kg and to 2 children at a single dose of 30 mg/kg. After the 30-minute drip infusion, peak serum levels of ABPC(SBT) obtained for the 2 dose levels were 18.0 micrograms/ml (12.4 micrograms/ml) for the former dose level and 81.0 micrograms/ml (53.7 micrograms/ml) and 300 micrograms/ml (200 micrograms/ml) for the latter at the end of injection, and half-lives were 0.84 hour (0.82 hour) for the former and 0.96 hour (1.44 hours) and 0.93 hour (1.19 hours) for the latter. In another trial, SBT/ABPC was given to 1 child at a single dose of 60 mg/kg. After the 30-minute drip infusion, peak serum level of ABPC (SBT) was 82.3 micrograms/ml (45.9 micrograms/ml), and half-life was 1.20 hours (1.36 hours). The urinary excretion rates of ABPC (SBT) were 51.3% (49.5%), 55.8 +/- 10.4% (65.3 +/- 9.1%), 74.0% (76.1%) up to 6 hours after the 30-minute drip infusion of 15 mg/kg, 30 mg/kg and 60 mg/kg, respectively. Treatment with SBT/ABPC was made in 21 cases of pediatric bacterial infections: 8 cases of tonsillitis, 4 cases of bronchitis, 3 cases of pneumonia and 1 case each of pharyngitis, peritonsillar abscess, lymphadenitis, impetigo, abscess and urinary tract infection. Results obtained were excellent in 14 cases, good in 7 cases. No significant side effect due to the drug was observed in any cases except 1 case of fever and rash.     

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.     

Experimental and clinical evaluation of cefsulodin in the pediatric field

Antimicrobial, pharmacokinetic and clinical evaluation of cefsulodin (CFS) was made and the following results were obtained. 1. Antimicrobial activity of CFS against P. aeruginosa was similar to a little lower than that of GM. Antimicrobial activity of CFS against S. aureus was similar to that of SBPC and against E. coli CFS showed lower antimicrobial activity. 2. Twenty or 50 mg/kg CFS was administered by 1 hour intravenous drip infusion. Average serum levels at the completion of the infusion were 35.1 +/- 8.0, 114.5 +/- 36.1 micrograms/ml and 1.6 +/- 0.7, 4.5 +/- 3.2 micrograms/ml at 6 hours afterward with the half life times of 1.50, 1.29 hours respectively. In case of 12.1 mg/kg 1 hour intravenous drip infusion, peak serum level was 13.4 micrograms/ml at the completion of infusion, and the concentration in the sputum was 1.0 micrograms/ml at 5 hours after completion of infusion. Average serum levels of CFS by one shot infusion of 20 mg/kg were 58.4 +/- 6.8 micrograms/ml, 2.7 +/- 2.5 micrograms/ml at 15 minutes and 6 hours after injection respectively. Half-life time was 1.54 hours. Average urinary excretion rates of CFS were 64.4%, 64.2% and 48.9% up to 6 hours after 1 hour intravenous drip infusion of 20 mg/kg, 50 mg/kg CFS and one shot intravenous of 20 mg/kg CFS respectively. 3. CFS was administered to 2 pneumonia cases caused by P. aeruginosa, i.e. one was 15 years and 11 months old male accompanying bronchial asthma and the another 4 years old male with LENNOX syndrome. Neither bacteriological nor clinical efficacy was, however, observed. Side effect as well as bacterial superinfection were not observed.     

Laboratory and clinical studies of flomoxef in the pediatric field

We have carried out laboratory and clinical studies on flomoxef (FMOX, 6315-S). The results were summarized as follows. FMOX was given by 5-minute intravenous administration to 3 children at a single dose of 20 mg/kg. After the intravenous administration, mean serum levels of FMOX were 110.1 +/- 30.95 micrograms/ml at the end of injection, 44.4 +/- 10.55 micrograms/ml at 15 minutes, 11.0 +/- 1.72 micrograms/ml at 1 hour and 0.42 +/- 0.17 microgram/ml at 6 hours. The mean half-life was 1.14 +/- 0.30 hours. The mean urinary excretion rate was 68.8 +/- 17.4% up to 6 hours after the intravenous administration. FMOX was given by 30-minute drip infusion to 2 children at a single dose of 20 mg/kg and to 3 children at a single dose of 40 mg/kg. After the 30-minute drip infusion, mean peak serum levels of FMOX obtained for the 2 dose levels were 45.5 +/- 0.45 micrograms/ml and 87.4 +/- 18.35 micrograms/ml at the end of injection, respectively, and mean half-lives were 0.63 +/- 0.23 hours and 0.70 +/- 0.27 hours, respectively. The mean urinary excretion rate was 53.4 +/- 6.1% up to 6 hours after the 30-minute drip infusion of 40 mg/kg FMOX. Treatment with FMOX was made in 24 cases of pediatric bacterial infections; 5 cases of purulent tonsillitis, 2 cases of bronchopneumonia, 12 cases of pneumonia, and 1 case each of lymphadenitis, pyothorax, purulent meningitis, cellulitis, and abscess. Results obtained were excellent in 15 cases and good in 9 cases. No significant side effect due to the drug was observed in any cases.     

Fundamental study of amikacin in the newborn

Amikacin (AMK) is one of the aminoglycoside antibiotics, derived from kanamycin A. It has a broad spectrum against Gram-negative rods but its usefulness is mainly in the efficacy against Gram-negative rods which do not respond to commonly used kanamycin and gentamicin. The efficacy and the safety of AMK have been confirmed in children and mature babies. In the trial reported here, we evaluated AMK in newborn. 1. AMK was administered to 13 mature and 8 premature babies via intramuscular injection or intravenous drip infusion for 30 minutes or 1 hour and its blood concentrations were determined. These administrations resulted in blood concentrations 4.47-9.67 mcg/ml with dosage levels 2.3 mg/kg (mean 6.92 +/- 1.66 mcg/ml), 5.86-26.1 mcg/ml with 5-6 mg/kg (mean 15.4 +/- 4.63 mcg/ml) and 27.5-37.7 mcg/ml with 7.5 mg/kg (mean 31.0 +/- 4.76 mcg/ml). Blood half-lives were 1.88 to 9.66 hours, showing longer half-lives in younger subjects. 2. Exchange transfusion (150-180 ml/kg) was performed in 5 mature babies and the variation of blood concentrations of AMK was studied. The study showed that blood concentrations of AMK after the exchange transfusion were 25.6-41.5% (mean 32.3 +/- 5.4%) of the levels detected before the transfusion.     

Laboratory and clinical studies of cefodizime in pediatric field

We have carried our laboratory and clinical studies on cefodizime (CDZM, THR-221). The results were summarized as follows. CDZM was given by 30-minute drip infusion to 2 children at a single dose of 10 mg/kg and to 2 children at a single dose of 20 mg/kg and to 3 children at a single dose of 40 mg/kg. After the 30-minute drip infusion, mean serum levels of CDZM obtained for the 3 dose levels were 76.16 +/- 5.52 micrograms/ml, 170.49 +/- 16.70 micrograms/ml, 270.01 +/- 50.44 micrograms/ml at the end of injection, respectively, and serum half-lives were 2.03 +/- 0.78 hours, 2.03 +/- 0.38 hours, 2.28 +/- 0.30 hours, respectively. The mean urinary excretion rate of CDZM were 83.3 +/- 22.3%, 73.1 +/- 13.9%, 51.1 +/- 8.5% in the first 8 hours after the 30-minute drip infusion of 10 mg/kg, 20 mg/kg, 40 mg/kg, 40 mg/kg, respectively. Treatment with CDZM was made in 28 cases of pediatric bacterial infections; 5 cases of tonsillitis, 2 cases of bronchitis, 10 cases of pneumonia, 6 cases of enteritis, 3 cases of urinary tract infection and 1 case each of maxillary sinusitis and laryngitis. Results obtained were excellent in 13 cases, good in 7 cases, fair in 2 cases, poor in 6 cases. No significant side effect due to the drug was observed except one case of thrombocytosis and 2 cases each of elevated GOT and elevated GOT and GPT.     

A study of the absorption and excretion of fosfomycin sodium in children

Fosfomycin sodium (FOM-Na, Forocyle-S) was administered at 25 mg/kg or 50 mg/kg to 15 children between the ages of 3 and 15 through intravenous injection or through 1 hour intravenous drip infusion, and concentrations in blood serum and excretion through urine were examined and a pharmacokinetic analysis was carried out using the one-compartment model. 1. Average concentrations in the blood serum after injections with 25 mg/kg and 50 mg/kg were 55.3 +/- 6.3 micrograms/ml and 118.8 +/- 31.1 micrograms/kg 30 minutes after injection, respectively, and their half-lives were 1.04 +/- 0.15 hours and 0.98 +/- 0.17 hours, respectively. Six hours after injection, the levels were 2.7 +/- 1.6 micrograms/kg and 6.2 +/- 5.5 micrograms/kg, respectively. With 1 hour intravenous drip infusion of 25 mg/kg and 50 mg/kg, average concentrations the blood serum were 34.2 +/- 14.9 micrograms/ml and 89.7 +/- 6.7 micrograms/ml, respectively, and their half-lives were 0.87 +/- 0.24 hour and 0.69 +/- 0.10 hour, respectively. Six hours after the administration, the levels were 2.7 +/- 1.8 micrograms/ml and 6.7 +/- 0.8 micrograms/ml. There was a clear dose response in the concentration levels in the blood in those given the drug at 25 mg/kg and 50 mg/kg in either method of administration. 2. Average levels in urine after injection of 25 mg/kg and 50 mg/kg were 5,778 +/- 2,257 micrograms/ml and 6,268 +/- 3,329 micrograms/ml 0-2 hours after administration, respectively, and average levels at 4-6 hours were 701 +/- 765 micrograms/ml and 1,588 +/- 1,324 micrograms/ml, respectively. Average excretion, rates into the urine were 72.8 +/- 11.0 and 73.9 +/- 11.1%, respectively. In case of 1 hour drips infusion of 25 mg/kg and 50 mg/kg, average concentrations in the urine 0-2 hours after administration were 3,570 +/- 1,540 micrograms/ml and 11,800 micrograms/ml, respectively, and averages for 4-6 hours were 211 +/- 124 micrograms/ml and 1,300 micrograms/ml. Average rates of excretion into the urine for the first group was 57.9 +/- 16.3% and the second group was 78.4%. Clear dose response was observed in changes of drug concentration levels in the urine with 25 mg/kg and 50 mg/kg doses through either administration method, and in terms of excretion into the urine, no noticeable differences were observed between the different amounts administered or different administration methods.(ABSTRACT TRUNCATED AT 400 WORDS)     

Pharmacokinetic and clinical studies on cefodizime in the pediatric field. Pediatric Study Group of Cefodizime

A multi-center open study was conducted to investigate cefodizime (CDZM), a newly developed cephem antibiotic, from pharmacokinetic, bacteriological and clinical aspects, in the pediatric field with the participation of 17 institutions and their related facilities. The results are summarized as follows: 1. Serum concentrations and urinary excretion: The pharmacokinetics in pediatric patients was investigated with a dose of 20 mg/kg, via a bolus intravenous injection or intravenous drip infusion over 30 or 60 minutes. The results were nearly the same as those in adult patients. Mean serum concentrations 5 minutes after a bolus intravenous injections were: 105.5, 264.0 and 461.7 micrograms/ml with 10, 20 and 40 mg/kg, respectively, and T 1/2 (beta)'s for the 3 dosages were 1.75, 1.92 and 1.88 hours, respectively. With 30-minute intravenous drip infusion, mean serum concentrations at the end of infusion were: 90.5 micrograms/ml with a dose level of 10 mg/kg, 178.3 micrograms/ml with 20 mg/kg, and 322.8 micrograms/ml with 40 mg/kg, and T 1/2 (beta)'s for these dosages were 1.90, 2.15 and 1.93 hours, respectively. With 60-minute intravenous drip infusion, mean serum concentrations at the end of infusion were: 66.3 micrograms/ml with a dose level of 10 mg/kg, 136.0 micrograms/ml with 20 mg/kg and 259.2 micrograms/ml with 40 mg/kg, and T 1/2 (beta)'s for these dosages were 1.43, 2.05 and 1.46 hours, respectively. In 8 hours after administration of CDZM, urinary excretion rates were 82.1, 77.7 and 76.5% for bolus intravenous injections of 10 mg/kg, 20 mg/kg and 40 mg/kg, respectively, and 83.3, 71.3 and 68.1% for 30-minute intravenous drip infusions of 10 mg/kg, 20 mg/kg and 40 mg/kg, and 84.4 and 84.3% for 60-minute intravenous drip infusions of 20 mg/kg and 40 mg/kg, respectively. 2. Concentrations in cerebrospinal fluid: Penetrations into cerebrospinal fluid in patients with purulent meningitis reached levels of 1.96-9.48 micrograms/ml with administration of CDZM at 50 mg/kg in acute cases within 6 days after onset. The penetration rates of CDZM were about a median range among injectable beta-lactam agents. 3. Clinical results: Of 457 cases treated with CDZM, 53 cases were excluded from the clinical evaluation. Clinical efficacies were evaluated as "excellent" in 126 and "good" in 78 out of 221 case from which causative agents were isolated, with an efficacy rate of 92.3%. Efficacies were "excellent" in 97 and "good" in 69 out of 183 cases from which pathogens were not isolated giving an efficacy rate of 90.7%.(ABSTRACT TRUNCATED AT 400 WORDS)     

Pharmacokinetic and clinical studies of cefotiam in mature neonates

Pharmacokinetic and clinical studies on cefotiam (CTM) in mature neonates were carried out. The results were summarized as follows: The serum peak level of CTM after intravenous bolus injection at a single dose of 10 mg/kg was found at 15 minutes after the injection. The serum peak level was 32.9 micrograms/ml in a 1 day-old neonate and it was 17.7 micrograms/ml in a 4 day-old neonate. Serum levels at 6 hours after injection were 4.5 micrograms/ml and 0.7 microgram/ml for the 1 day-old and the 4 day-old, respectively. Half-lives were 2.1 and 1.2 hours in the 1 and 4 day-old neonates, respectively. Serum peak levels of CTM at 15 minutes after intravenous bolus injection at a single dose of 20 mg/kg were 40.9 micrograms/ml in a 1 day-old neonate and 36.5 micrograms/ml in a 5 day-old neonate. Serum levels of CTM at 6 hours were 8.0 micrograms/ml in the 1 day-old neonate and 2.3 micrograms/ml in the 5 day-old neonate. Half-lives were 2.5 and 1.5 hours in the 1 and 5 day-old neonates, respectively. With each dosage, the younger showed extended half-lives. A dose-response relationship was observed. In 2 cases of 2 day-old neonates given CTM 20 mg/kg by 30-minute intravenous drip infusion, the mean peak concentration at the termination of the infusion was 25.1 micrograms/ml. Even after 6 hours the concentration was found at 8.7 micrograms/ml. Half-lives were 2.9 and 3.7 hours. Urinary excretion rates of CTM in 1 to 5 day-old neonates were as low as about 20% in any of cases subjected to a 10 mg/kg intravenous bolus injection, a 20 mg/kg intravenous bolus injection a 20 mg/kg 30-minute intravenous drip infusion. It was possible to evaluate the efficacy of CTM in only 1 case of pneumonia. CTM was clinically and bacteriologically effective in this case. No abnormal clinical symptoms and findings were observed in all of the 5 cases.     

Fundamental and clinical studies with imipenem/cilastatin sodium, a new carbapenem antibiotic, in the field of pediatrics

Fundamental and clinical evaluations of imipenem/cilastatin sodium (MK-0787/MK-0791) were carried out in pediatric patients. The following results were obtained: After intravenous drip infusion of single doses of 10 mg/10 mg/kg to 20 mg/20 mg/kg of MK-0787/MK-0791 in children, peak plasma levels of MK-0787 ranged from 32.0 to 82.0 micrograms/ml at the end of the infusion. The half-life was 49.9 to 64.0 minutes. The cumulative urinary recovery at 6 to 7 hours after the 1 hour drip infusion ranged from 65.5 to 88.9%. Fecal levels of MK-0787 were 4.2 and 23.1 micrograms/g at 6 hours after a 30-minute intravenous drip infusion of 200 mg/200 mg of MK-0787/MK-0791. MK-0787/MK-0791 was administered by intravenous drip infusion to patients with purulent meningitis. Penetration into the cerebrospinal fluid was satisfactory, as were the clinical responses. MK-0787/MK-0791 was administered clinically in doses of 30 mg/30 mg/kg/day to 200 mg/200 mg/kg/day by intravenous drip infusion 3 or 4 times a day for 3 to 22 days to 26 patients with acute pediatric infections. The clinical response was excellent in 18 patients and good in 8 patients. Eradication occurred with 16 isolates; only two strains of Salmonella-B were not eradicated. Anorexia in 1 patient was the only clinical adverse effect reported, and the only adverse effects found in laboratory tests were eosinophilia and thrombocytosis in 1 patient, respectively, and elevation of the S-GOT and S-GPT in 1 patient.     

Clinical studies on the effect of imipenem/cilastatin sodium on infections in obstetrics and gynecology. Tissue concentrations and clinical effects

Tissue transfer and clinical effects of imipenem/cilastatin sodium (MK-0787/MK-0791), a new carbapenem antibiotic, were studied and the following results were obtained. Penetrations of MK-0787 into uterine arterial blood and into pelvic dead space exudate were good. When MK-0787/MK-0791 was administered at a dose of 500 mg/500 mg by a 30-minute intravenous drip infusion, the peak level of MK-0787 in uterine arterial blood was 22.2 micrograms/ml, 30 minutes after the completion of the drip infusion. The peak level of MK-0787 in pelvic dead space exudate was 12.9 micrograms/ml at 2 hours and it dropped to 2.6 micrograms/ml at 6 hours. MK-0791 levels were similar to those of MK-0787. Penetrations of MK-0787 into tissues were also good. When MK-0787/MK-0791 was administered at a dose of 500 mg/500 mg by a 30-minute intravenous drip infusion, the level of MK-0787 was 2.2 +/- 1.1 micrograms/g in the oviduct, 2.7 +/- 2.1 micrograms/g in the ovary, 2.5 +/- 1.2 micrograms/g in the endometrium, 3.0 +/- 1.6 micrograms/g in the myometrium, 3.1 +/- 1.9 micrograms/g in the cervix uteri and 3.8 +/- 2.0 micrograms/g in the portio vaginalis at 1 hour after administration. These levels were reduced to halves, respectively, in approximately 2 hours. Four patients with intrauterine infections and 2 with vaginal stump infections were treated with MK-0787/MK-0791 at a daily dose of 1 g/1 g (500 mg/500 mg X 2). Good clinical and bacteriological responses were observed in 5 patients and causative organisms were eradicated in 2 patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Studies of meropenem in pediatric infections]

Pharmacokinetic and clinical evaluations of meropenem (SM-7338, MEPM) were carried out in pediatric patients. The following results were obtained. 1. After 30-minute intravenous drip infusion at a dose of 20 mg/kg, plasma concentrations of MEPM reached their peaks at the end of drip infusion with an average value of 48.8 +/- 3.64 micrograms/ml, and the average plasma half-life was 0.93 +/- 0.21 hour in the beta-phase. After 30-minute intravenous drip infusion at a dose of 10 mg/kg, the average peak plasma concentration was 27.7 +/- 4.33 micrograms/ml and the average plasma half-life was 0.78 +/- 0.20 hour. 2. Urinary excretion rates of MEPM after 30-minute intravenous drip infusion at doses of 20 and 10 mg/kg were 44.8 +/- 4.54% and 40.9 +/- 1.78%, respectively. 3. MEPM was administered to 13 cases (upper and lower respiratory infections, pneumonia and lymphadenitis) at daily doses between 60-90 mg/kg/day divided into 3 dosages using 30-minute intravenous drip infusion. Clinical responses were "excellent" in 12 patients, "good" in 1, hence an efficacy rate of 100% was obtained. 4. Bacteria identified in various disease cases included 12 strains of 5 species, and the eradication rate was 100%. 5. No side effects were observed in any children. Laboratory test results showed abnormalities in 2 cases with elevations of GOT and GPT. These results suggest that MEPM may be a very useful and safe drug for the treatment of pediatric infections.     

Studies on panipenem/betamipron in the pediatric field]

Pharmacokinetic and clinical evaluations of panipenem/betamipron (PAPM/BP) were carried out in pediatric patients. The following results were obtained: 1. Upon 30-minute intravenous drip infusion at a dose of 20 mg/kg, plasma concentrations of PAPM/BP reached their peaks at the end of drip infusion with average values of 62.94/47.32 micrograms/ml, and their plasma half-lives were 1.00/0.51 hour in the beta-phase. Upon 30-minute intravenous drip infusion at a dose of 10 mg/kg, peak plasma concentrations were 32.10/23.76 micrograms/ml and plasma half-lives were 0.93/0.59 hour. 2. The urinary excretion rates of PAPM/BP after 30-minute intravenous infusion at doses of 20 and 10 mg/kg were 25.09/81.04% and 32.14/84.66%, respectively. 3. PAPM/BP was administered to 18 cases (upper and lower respiratory tract infections, pneumonia and urinary tract infections) at daily doses of 30-88.9 mg/kg/day divided into 3 dosages using 30-minute intravenous drip infusion. Clinical responses were "excellent" in 12 patients, "good" in 5, and "poor" in 1, hence an efficacy rate of 94.4% was obtained. 4. Bacteria identified from various diseases involved 11 strains of 6 species, and the eradication rate was 90.9%. 5. No side effect was recognized in any patient. Laboratory test results showed abnormalities in including 1 case with leukopenia, and in 2 cases with elevation of GOT and GPT.     

Pharmacokinetic and clinical studies on imipenem/cilastatin sodium in neonates and premature infants

Imipenem/cilastatin sodium (IPM/CS) was administered in a dose of 10 mg/10 mg/kg or 20 mg/20 mg/kg by a 1-hour intravenous drip infusion to 19 mature and premature neonates with ages from 1 to 12 days with various bacterial infections, and plasma concentrations and urinary recovery rates in these subjects were measured. Because of the small number of patients recruited, neonates were not divided into mature and premature groups, but into 3 groups based on their day-ages: 0-3 days, 4-7 days and 8 days or older. A clinical evaluation of IPM/CS was carried out in 10 male and 3 female neonates with ages 0-28 days. These patients included 6 with pneumonia, 4 with urinary tract infection and 1 each with septicemia, suspected septicemia and maxillary sinusitis. 1. Plasma concentrations and urinary recovery rates (1) The 1-hour intravenous drip infusion at 10 mg/10 mg/kg of IPM/CS IPM: Its peak plasma concentrations were obtained at the end of drip infusion of the test drug in all 3 groups, their values ranged from 18.18 to 19.90 micrograms/ml with no statistically significant variations. The plasma concentrations rapidly decreased to 0.32-0.98 microgram/ml at 8 hours after administration of IPM/CS. The half-lives tended to be shorter in older neonates, with mean half-lives being 1.87, 1.55 and 1.40 hours, respectively. CS: Its peak plasma concentrations were obtained for all 3 groups at the end of drip infusion and were ranging from 28.23 to 30.00 micrograms/ml with no significant variations. Plasma concentrations in the 0-3 day-age group and the 4-7 day-age group slowly decreased to 6.30 micrograms/ml and 4.58 micrograms/ml at 8 hours after administration of IPM/CS, respectively. Half-lives were 4.10 hours and 3.08 hours, respectively. On the other hand, those of the 8-day or older group rapidly decreased to below the detection limit in 8 hours after administration with a half-life of 1.6 hours. (2) The 1-hour intravenous drip infusion at 20 mg/20 mg/kg of IPM/CS IPM: Peak plasma concentrations were obtained in all 3 groups at the end of drip infusion and were ranging from 31.1 to 38.24 micrograms/ml. Plasma concentrations rapidly decreased, and were 0.95-2.08 micrograms/ml at 8 hours after administration with half-lives of 1.5-1.88 hours. CS: Peak plasma concentrations were obtained in all 3 groups at the end of drip infusion and were ranging from 47.0 to 55.82 micrograms/ml.(ABSTRACT TRUNCATED AT 400 WORDS)     

Studies on panipenem/betamipron in the field of pediatrics]

Pharmacokinetic and clinical studies in pediatrics were performed on panipenem/betamipron (PAPM/BP), a combined drug of a carbapenem antibiotic (panipenem) and organic ion inhibitor (betamipron) at a weight ratio of 1:1. 1. Plasma levels and urinary excretion were studied when PAPM/BP, at 10 mg/10 mg/kg (4 cases) or 20 mg/20 mg/kg (5 cases), was administered using intravenous drip infusion in 30 minutes to 9 children (4-14 years old). The plasma PAPM level at the end of drip infusion was 30.75 +/- 4.98 micrograms/ml in the cases administered with 10 mg/10 mg/kg and 68.72 +/- 5.73 micrograms/ml in the cases administered with 20 mg/20 mg/kg. Drug concentrations then gradually decreased with half-lives of 1.08 +/- 0.09 hours and 0.98 +/- 0.02 hour, and reached 0.39 +/- 0.14 micrograms/ml and 0.62 +/- 0.06 micrograms/ml, respectively, after 5.5 hours. Plasma BP levels at the end of drip infusion was 18.93 +/- 3.75 micrograms/ml in the cases administered 10 mg/10 mg/kg and 37.09 +/- 2.68 micrograms/ml in the cases administered 20 mg/kg, and half-lives were 0.55 +/- 0.07 hour and 0.61 +/- 0.03 hour, respectively; the plasma BP level could not be determined in any cases after 5.5 hours. Mean urinary recovery rates of PAPM in the first 6 hours after the start of intravenous drip infusion were 33.0 +/- 6.1% in the cases administered 10 mg/10 mg/kg and 21.8 +/- 2.3% in the cases administered 20 mg/20 mg/kg and those of BP were 77.0 +/- 2.4% and 76.6 +/- 7.3%, respectively. 2. When PAPM/BP, was administered at 31.3 mg/31.3 mg/kg thought by intravenous drip infusion in 30 minutes to 1 case of purulent meningitis, PAPM levels were 0.76 micrograms/ml at the end of drip infusion but varied between 0.80 to 1.97 micrograms/ml 30 minutes after the end of drip infusion during 8 days of treatment. 3. PAPM/BP was administered to 43 cases, 47 diseases of bacterial infections in the domain of pediatrics to study its clinical efficacy, bacteriological efficacy and adverse reactions. Single doses were 5.2mg/5.2mg to 31.3 mg/31.3 mg/kg; frequencies of administration were 3 to 4 times a day, and durations of administration were 3 1/3 to 11 days; and total dosages ranged between 1.125 g/1.125 g and 11.0 g/11.0 g.(ABSTRACT TRUNCATED AT 400 WORDS)     

Clinical and pharmacokinetic evaluation of imipenem/cilastatin sodium in children

Nineteen episodes of infection in 17 children (one had 3 episodes) were treated with imipenem/cilastatin sodium (MK-0787/MK-0791), and the clinical efficacy and side effects were evaluated. The ages of patients ranged from 1 month to 8 years 1 month and their body weights ranged from 3.9 to 25.2 kg. The MK-0787/MK-0791 was administered intravenously by a 30-60 minutes infusion, in doses ranging from 8-42 mg/8-42 mg/kg every 6 to 12 hours for 3 to 40.5 days. Among 18 episodes in 16 patients (one patient proved to have rubella meningoencephalitis and was excluded from evaluation of the clinical efficacy) with bacterial infections including sepsis, pneumonia, acute suppurative thyroiditis and urinary tract infections, the results were excellent in 10, good in 5, fair in 2, and poor in 1 episode. Some side effects were noted; among all 19 episodes in the 17 patients diarrhea was noted in 3, rash in 1, slightly elevated serum transaminases in 1 and thrombocytosis in 1 episode. Pharmacokinetic studies were done in 7 patients whose ages ranged from 3 years 2 months to 13 years 1 month. Plasma concentrations of MK-0787 in 2 children were 19.6 and 20.0 micrograms/ml at 15 minutes and 5.6 and 2.1 micrograms/ml at 2 hours after a 10 mg/10 mg/kg intravenous 30-minute drip infusion of MK-0787/MK-0791. Plasma half-lives of MK-0787 were 1.52 and 0.74 hour, and total urinary recoveries were 54.6 and 71.4% during 0-6 hours. After a 20 mg/20 mg/kg intravenous 30-minute drip infusion into 2 other children, plasma concentrations of MK-0787 were 46.8 and 44.0 micrograms/ml at 15 minutes and 7.8 and 7.4 micrograms/ml at 2 hours. Plasma half-lives were 0.82 and 0.83 hour, and total urinary recoveries were 110.2 and 80.5% during 0-6 hours. Plasma concentrations of MK-0787 were less than 0.2, 0.2 and 1.2 micrograms/ml just before the next doses in 3 patients given 11-20 mg/11-20 mg/kg of MK-0787/MK-0791 every 6-8 hours. The time course of the plasma levels and urinary excretion in these patients were similar to those noted in the previous 4 patients following a single dose. Plasma concentrations of MK-0787 in a girl were 0.3 micrograms/ml just before the next dose and 8.2 micrograms/ml at 2 hours after multiple doses of 14 mg/14 mg/kg every 6 hours for 3 days and then 28 mg/28 mg/kg every 6 hours for 35 days.(ABSTRACT TRUNCATED AT 400 WORDS)     

Evaluation of antibiotics by the method of initial bactericidal activity

Minimum inhibitory concentration (MIC) has been generally used to evaluate the activity of antimicrobial agents. However, there is some discrepancy between clinical efficacy and the MIC value. We studied the relationship between initial bactericidal activity of imipenem (IPM), panipenem (PAPM), meropenem (MEPM), ceftazidime (CAZ) and amikacin (AMK) and the respective MIC values against Pseudomonas aeruginosa PAO1. Initial bactericidal activity was defined as percent reduction of initial bacterial cell concentration (10(6) cells/ml) after 1 hour incubation following addition of antibiotic. The concentration of antibiotic used in this experiment was the blood level of each antibiotic at 3 hours after administration by drip infusion of the usual dose (IPM, PAPM and CAZ were 1 g for 1 hour drip infusion, MEPM was 1 g for 0.5 hours drip infusion and AMK was 200 mg for 1 hour drip infusion, respectively). The antibiotic concentration of IPM, PAPM, MEPM, CAZ and AMK were 8.77 micrograms/ml, 6.37 micrograms/ml, 4.12 micrograms/ml, 12.0 micrograms/ml and 5.18 micrograms/ml, respectively. MICs of IPM, PAPM, MEPM, CAZ and AMK were 2 micrograms/ml, 64 micrograms/ml, 1 microgram/ml, 1 microgram/ml and 2 micrograms/ml, respectively. Initial bactericidal activity of IPM, PAPM, MEPM, and CAZ against P. aeruginosa PAO1 was 98.2%, 86.1%, 48.1%, and 43.4% reduction in bacterial concentration, respectively. AMK shows the strongest initial bactericidal activity with more than 99.9%. The killing speed of IPM was obviously the most rapid among the three carbapenems. The MIC of PAPM was significantly higher than the other antibiotics, and the initial bactericidal activity of PAPM was second to IPM. We can classify antibiotics into two groups based on initial bactericidal activity against P. aeruginosa; one class is antibiotics having rapid initial killing such as AMK, IPM and PAPM, the other is CAZ, MEPM showing slow initial killing.