[Influence of dexamethasone on the clinical course of bacterial meningitis in children. Especially on secondary fever. Experiences in 27 institutions].

Of pediatric patients with purulent meningitis seen at the institutions listed in the title page of this paper between 1986 and 1994, 93 patients treated with antibiotics and dexamethasone (DXM) were compared with 91 patients treated with antibiotics alone. The patients receiving antibiotics with dexamethasone achieved overall improvement in inflammatory symptoms and signs and cerebrospinal fluid findings and became afebrile significantly earlier than those receiving antibiotics alone. However, some of the patients became febrile again. The secondary fever rate for the DXM group was much higher than that for the antibiotic alone group (p < 0.0001). In most of the rebounded cases, the body temperature rose above 38 degrees C and remained elevated for 2-4 days. Cerebrospinal fluid (CSF) was cultured daily in 54 and 32 patients receiving antibiotics with and without DXM, respectively. Although this study was not a controlled study in a strict sense, these patients compared. In both groups, the CSF became mostly culture-negative within 48 hours. In a few patients receiving DXM, however, it became culture-negative after 72 hours or longer. DXM caused an adverse effect in a patient with meningitis caused by Streptococcus pneumoniae. The adverse effect was mild gastrointestinal bleeding, which recovered spontaneously. From the findings described above, the use of DXM combined with antibiotic therapy was considered to accelerate the relief from fever and improvement of inflammatory symptoms and signs and CSF findings. The body temperature rose again in more than half of the patients receiving DXM, but fell to normal spontaneously without treatment. The elevation doubtlessly could not be distinguished from recurrence of the meningitis itself or complications. It seems to be likely that no treatment but careful observation is required even if the fever recurs as far as the CSF findings showed favorable progress with excelluent general conditions. When DXM is given, it is essential that CSF tests and culture are repeated during the early stages and the progress is monitored carefully.

Beta-2-microglobulin and ferritin in cerebrospinal fluid for evaluation of patients with meningitis of different etiologies.

To determine whether or not the beta-2-microglobulin (beta2-m) and/or ferritin levels in cerebrospinal fluid (CSF) can be used as markers for the differential diagnosis of meningitis and determination of the response to treatment, 122 subjects with etiologically well-characterized diagnoses were classified into three groups: bacterial meningitis (n = 5; mean age +/- SD. 1.0+/-1.0 year), viral meningitis (n = 39; 5.9+/-3.8 years), and a non-meningitis group (n = 78; 5.2+/-4.9 years). The levels of beta2-m and ferritin in CSF were determined by means of a latex photometric immunoassay. The statistical significance of the data was analyzed with the Mann Whitney U-test. A receiver operating characteristic curve was used to evaluate the diagnostic accuracy of each prediction marker. This study indicated that (1) the levels of beta2-m and ferritin in CSF were related with age in the non-meningitis group: subjects of up to 5 months of age exhibited higher concentrations of these proteins than ones of above 6 months of age (beta2-m, 1.89+/-1.13 vs. 0.84+/-0.65 mg/l. P < 0.01; ferritin, 2.97+/-2.04 vs. 1.81+/-1.34 microg/l, P = 0.09); (2) the beta2-m level was significantly higher in the CSF of patients with viral meningitis than in ones without meningitis (2.41+/-1.23 vs. 0.84+/-0.65 mg/l, P < 0.01): the best cut-off value was 1.2 mg/l (3) the ferritin level was significantly higher in the CSF of patients with bacterial meningitis than in ones with viral meningitis (43.24+/-39.49 vs. 6.81+/-7.41 microg/l, P < (.01): the best cut-off value was 7.5 microg/l; and (4) sequential measurement of the CSF ferritin level was of value for determination of the response to antibiotic treatment for bacterial meningitis. These results only apply to patients of greater than 6 months of age. beta2-m and ferritin in the CSF can be used as an ancillary tool for diagnostic guidance in the acute phase of meningitis and determination of the response to treatment for bacterial meningitis.

[Trend of bacterial meningitis in children over a 14 year period (1981 through 1994) in Japan--an analysis based on studies in 27 institutions].

We observed 266 children with purulent meningitis in 27 institutions in Japan during the 14 years from 1981 on dividing these years into 3 periods, 1981-1985, 1986-1990 and 1991-1994, and studied the trend of causative organisms identified in 254 among the 266 patients. Their ages were less than 3 months after birth in 50 children and 3 months or older in 216: there were 141 boys and 125 girls. The causative organisms were H. influenzae in 134 patients and S. pneumoniae in 50, most of them being aged 3 months or older. Next to the above bacteria ranked S. agalactiae in 29 and E. coli in 12, many of the patients were aged less than 3 months. Staphylococcus spp. was found in 7 patients and about 70% of them were aged 3 months or older. L. monocytogenes was found in 4 patients and N. meningitidis in 3 and they were aged 3 months or older in both patient groups. S. pyogenes, Enterococcus spp., Peptostreptococcus spp., P. Mirabilis and Enterobacter spp. were detected each in 1 patient. The causative organism was unknown in 21 patients and there was no double infection. H. influenzae were detected in 18 patients in 1981-1985 period (36.7%), in 56 in 1986-1990 (54.9%) and in 60 in 1991-1994 (63.8%) showing an increasing tendency, but S. pneumoniae exhibited neither an increasing nor decreasing tendency. There was a decreasing tendency with S. agalactiae and E. coli, but the details were not clear because there were few patients aged less than 3 months. Although the period of coexistence of 4 main bacterial species was not made clear in this study. Listeria is considered to develop mainly in the early childhood, and we believe that the conventional way of using a cephem preparation and ampicillin combined for patients under 6 years need not be altered. However, panipenem (phonetic) is likely to be effective for insensible S. pneumoniae for the time being.

[Pharmacokinetic, bacteriological and clinical studies on cefozopran in neonates and premature infants. A study of cefozopran in the perinatal co-research group].

The following results were obtained in pharmacokinetic, bacteriological and clinical investigations of a cephem antibiotic for injection, cefozopran (SCE-2787, CZOP), administered to neonates and premature infants. 1. Pharmacokinetics (1) Half-lives (T 1/2's) of CZOP in 0-day-old (less than 24 hours after birth) neonates and premature infants were longer than those in 1-day-old or older infants. When half-lives were compared between 0-day-old neonates and 0-day-old premature infants, longer half-lives were observed in premature infants. (2) When CZOP was intravenously administered to 1-day-old or older neonates and premature infants at a dose of 20 mg/kg, no differences were noted in blood concentrations between neonates and premature infants from 30 minutes to 6 hours after administration as well as T 1/2's. (3) Blood concentration of CZOP administered at doses of 10, 20 and 40 mg/kg were dose-dependent. (4) Urine excretion rates of CZOP administered to 1-day-old or older neonates and premature infants were approximately 30 to 60% in the first 6 hours after administration. Urine excretion rates in 0-day-old neonates and premature infants were low. 2. Clinical results (1) Of a total of 136 cases to which CZOP was administered, clinical efficacy evaluation was possible in 96 cases, and safety evaluation in 132 cases. (2) The clinical efficacy rates were 78.6% (22/28) in 28 cases in which causative organisms were detected (Group A), and 97.1% (66/68) in 68 cases in which no such organisms were detected (Group B), with the total efficacy rate (Groups A and B) of as high as 91.7% (88/96). (3) Bacteriological evaluations were made with 33 strains isolated from the 28 cases of Group A. Elimination rates for Gram-positive and Gram-negative bacteria were 88.2% (15/17) and 92.3% (12/13), respectively, with the total elimination rate of 90.0% (27/30). No microbial substitution was noted. (4) As an adverse reaction, diarrhea was noted in one case (0.8%). Abnormal laboratory test values were noted in 15 cases (12.3%) including eosinophilia, elevated GPT, and elevated gamma-GTP. All of these abnormalities were transitory, and none of them critical. As a result of above pharmacokinetic and clinical investigations, CZOP is considered to be highly useful in the treatment of indicated infections in neonates and premature infants. It appears that 20 mg/kg of CZOP can be administered by intravenous injection or intravenous drip infusion to neonates and premature infants aged 0-day (less than 24 hours after birth) once or twice daily, to those aged 1 (24 or more hours after birth) to 7 days twice or three times daily, and to those aged 8 or more days three to four times daily, and that the dose can be increased up to 40 mg/kg in cases of critical or intractable infections.

Alobar holoprosencephaly with diabetes insipidus and neuronal migration disorder.

A 2-year-old girl with alobar holoprosencephaly associated with facial abnormalities, central diabetes insipidus, and a neuronal migration disorder is reported. The diagnosis of diabetes insipidus was based on low urine osmolality and low plasma ADH concentration during a water deprivation test, and clinical and biochemical improvement after desmopressin acetate administration. Because the posterior portion of the pituitary was located in the sella turcica and the hypothalamo-pituitary stalk was intact, the diabetes insipidus was presumed to have been caused by hypothalamic osmoreceptor dysfunction. MRI findings were compatible with alobar holoprosencephaly. In addition, heterotopic gray matter was recognized as a continuous band over a single ventricle. Defective cleavage of the prosencephalon associated with a neuronal migration disorder is characteristic of alobar holoprosencephaly.

[Comprehensive evaluation of pharmacokinetic and clinical studies on tazobactam/piperacillin in pediatric field].

To evaluate the pharmacokinetic and clinical effects of the newly developed combination antibiotic tazobactam/piperacillin (TAZ/PIPC, YP-14) on various infections in pediatric field, a study group was organized, and a joint research by 17 institutions and their related hospitals was conducted. Informed consents of subjects were obtained prior to the study. The results obtained in this study are as follows: 1. Blood concentration and urinary excretion Pharmacokinetics of TAZ/PIPC was studied in children at doses of 25 and 50 mg/kg through intravenous injection or intravenous drip infusion. With intravenous injection, maximum blood concentrations (Cmax's) of TAZ and PIPC were achieved 5 minutes after the administration. Cmax's of TAZ were 26.9 micrograms/ml with 25 mg/kg and 45.1 micrograms/ml with 50 mg/kg, and those of PIPC were 131.0 and 199.6 micrograms/ml, respectively. Values of the total area under the blood concentration curve (AUC's) of TAZ were 14.2 micrograms.hr/ml with 25 mg/kg and 26.1 micrograms.hr/ml with 50 mg/kg, and those of PIPC were 64.0 and 112.8 micrograms.hr/ml, respectively; thus dose dependency was observed with both TAZ and PIPC. The Cmax's of desethyl piperacillin (DEt-PIPC), the active metabolite of PIPC, achieved at 60 minutes after administration, were 1.2 and 2.0 micrograms/ml, respectively. The AUC's of DEt-PIPC were 2.6 and 4.2 micrograms.hr/ml, respectively. The half-lives (T 1/2's) of TAZ were 0.60 and 0.54 hour, respectively, and those of PIPC were 0.62 and 0.65 hour, respectively. In the first 6 hours after the initiation of administration, the cumulative recovery rates of TAZ in the urine were 46.7 and 56.0% respectively, those of PIPC were 46.1 and 57.2%, respectively, and those of DEt-PIPC were 5.9 and 3.0%, respectively. With intravenous drip infusion, the Cmax's of both TAZ and PIPC were achieved at the completion of drip; the Cmax's of TAZ were 12.1 micrograms/ml with 25 mg/kg and 28.9 micrograms/ml with 50 mg/kg, and those of PIPC were 54.6 and 137.9 micrograms/ml, respectively. The AUC's of TAZ were 11.6 micrograms.hr/ml with 25 mg/kg and 25.6 micrograms.hr/ml with 50 mg/kg, and those of PIPC were 49.0 and 117.2 micrograms.hr/ml, respectively; thus dose dependency was observed with both TAZ and PIPC. Cmax's of DEt-PIPC, achieved at 60 minutes after completion of drip, were 0.9 and 1.7 micrograms/ml, respectively. The AUC's of DEt-PIPC were 2.0 and 3.8 micrograms.hr/ml, respectively. The half-lives (T 1/2's) of TAZ were 0.59 and 0.62 hour, respectively, and those of PIPC were 0.58 and 0.57 hour, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)

[Clinical evaluation of biapenem (L-627) in children].

Twenty-four children were treated with biapenem (L-627) and the clinical efficacy and side effects were evaluated. The ages of the patients ranged from two months to 11.5 years and their body weights from 5.9 to 43.5 kg. Doses given were 5.5-12.4 mg/kg every 8 hours for 2.67 to 11.33 days. Those patients who responded well to L-627 treatment included 11 children with pneumonia, 1 with scarlet fever, 1 with cervical lymphadenitis, 2 with cellulitis, 6 with urinary tract infection. Among 21 children, the results were excellent in 13 and good in 8. The drug was well tolerated, although slightly elevated serum concentrations of transaminases occurred in 2 patients among the 24 patients.

[Pharmacokinetic and clinical studies with L-627 (biapenem) in the pediatric field. Pediatric study group of L-627].

To conduct pharmacokinetic and clinical studies on newly developed L-627 (biapenem) against various infections in pediatrics, a study group was organized and a joint research by 15 institutions and their related hospitals was undertaken. Informed consents of subjects were obtained prior to the study. The obtained results are as follows. 1. Plasma concentrations and urinary excretion Pharmacokinetics of L-627 in children was studied in 29 subjects using 30 minutes intravenous drip infusion of 6 mg/kg and 12 mg/kg. Maximum plasma levels of L-627 was observed at the completion of drip infusion and were 25.1 micrograms/ml with administration of 6 mg/kg and 39.2 micrograms/ml with administration of 12 mg/kg on average. Dose dependency was noted in Cmax and AUC with these doses. Maximum blood levels in all of the 5 participated sucklings under the age of one year were similar to the average. As for urinary excretion, L-627 was excreted 66.0% with administration of 5 mg/kg and 62.3% with 12 mg/kg. 2. Cerebrospinal fluid concentrations Cerebrospinal fluid concentrations ranged from 0.76 to 8.54 micrograms/ml in 30-240 minutes after the completion of drip infusion with dose of 20-40 mg/kg in 9 subjects with purulent meningitis, when they were measured within 3 days after the initiation of the treatment with L-627. 3. Clinical results Thirty-three cases of exclusion and drop-out were deducted from a total of 330 cases, hence 297 cases were evaluated as the subjects in the study for analysis of clinical effects. As for clinical effects in group A where pathogenic bacteria were detected, 166 out of 173 were rated as effective or above, hence the efficacy rate of 96.0% was obtained. In group B where pathogenic bacteria were not detected, 114 out of 124 cases were rated as effective or above, thus the efficacy rate was 91.9%, which is similar to that of the group A. The overall efficacy rate was 94.3% in the entire 297 cases. The rates of "excellent" responses out of the cases rated as effective or above were 62.7% (104/166) in the group A and 55.3% (63/114) in the group B, thus the rate was markedly high in the former group. Efficacy rate for each pathogenic strain was also high, and that in subjects infected by a single pathogenic strain was 96.7% (145/150) and that in subjects infected by two or more pathogenic strains was 91.3% (21/23).(ABSTRACT TRUNCATED AT 400 WORDS)

[Pharmacokinetics and clinical studies on flomoxef in neonates and premature infants. A study of flomoxef in the perinatal collaboration research group].

We investigated pharmacokinetics and clinical effects of flomoxef sodium (6315-S, FMOX) in neonates and premature infants. These results are summarized as follows: 1. Pharmacokinetics (1) Plasma concentration (Ct) and half-lives (T1/2) were determined upon after intravenous one-shot injection (i.v.) of FMOX to neonates of different day-age groups (0-3 (n = 25), 4-7 (n = 18), 8-28 (n = 32) days of birth). At a dose of 10 mg/kg. i.v., mean C30 (30 minutes concentration) values were 21.2, 21.8 and 21.3 micrograms/ml, respectively, in the different groups mentioned above, and the mean T1/2 values were 3.37, 1.85 and 1.63 hours. At 20 mg/kg i.v., mean C15 (15 minutes concentration) values were 54.4, 51.4 and 50.7 micrograms/ml, and mean T1/2's were 2.99, 2.32 and 1.79 hours, respectively. At a dose of 40 mg/kg i.v., mean C15 values were 104.0, 95.9 and 99.2 micrograms/ml, and the mean T1/2's were 3.40, 1.20 and 1.80 hours, respectively. (2) Plasma concentrations and T1/2 after intravenous one-shot injection of FMOX in premature infants in group (0-3 (n = 14), 4-7 (n = 10), 8-28 (n = 13) days of birth). Mean C15's at doses of 10, 20 and 40 mg/kg in the different groups of infants were 24.0, 28.6, 21.7 and 54.0, 54.6, 55.5 and 98.2, 93.0, 106.0 micrograms/ml, and T1/2's were 4.10, 2.53, 2.57 and 4.28, 2.27, 3.02 and 4.66, 2.86, 2.09 hours, respectively. Mean Cmax values were clearly dose dependent, and mean T1/2 values tended to be longer in premature infants compared to neonates. (3) Urinary recovery rate of FMOX after intravenous injection in neonates and premature infants. Mean urinary recovery rates of FMOX in the first 6 hours after i.v. (one-shot) at doses of 10, 20 and 40 mg/kg to neonates and premature infants were 38.9-62.8% in the neonates and 30.7-61.5% in the premature infants. (4) Plasma concentrations and urinary recovery rates upon 1 hour drip infusion of 20 mg/kg in the neonate groups (or the premature infant groups) as follows: Mean C50 values were 31.0, 32.7 and 23.4 micrograms/ml, and T1/2 were 2.94, 3.68 and 2.25 hours, respectively. The recovery rates were 35.2-52.9% in the first 6 hours after administration. 2. Clinical studies The number of clinically evaluable cases in the FMOX treatment of premature infants was 199, in which the causative pathogens were identified in 71 cases (A group) and not identified in 128 cases (B group).(ABSTRACT TRUNCATED AT 400 WORDS)

Acquisition of nonmaternal Enterobacteriaceae by infants delivered in hospitals.

To determine whether Escherichia coli strains that colonize the intestinal tract of newborn infants in hospitals are of maternal origin or come from the environment, plasmid profiles of E. coli strains isolated from the stools of infants were compared with those from the stools of their mothers. Twenty-nine mother-infant pairs were studied in three different hospitals. In only 4 of 29 pairs, plasmid profiles of E. coli or other Enterobacteriaceae were shared by infant and mother; vertical transmission seemed to be uncommon, unlike findings in previous reports. In one hospital, 8 of 10 infant fecal E. coli strains shared a single plasmid profile, strongly suggesting nosocomial acquisition. In another, 7 of 9 neonate strains also shared a unique profile, and additionally carried K1 capsular antigen, a known virulence factor. Two other infants from the latter nursery acquired a urinary tract infection with E. coli K1 carrying the same plasmid profile. This study indicates that nosocomial acquisition of hospital strains of E. coli by neonates may be common in some hospitals and that the clinical implications are potentially serious.

[Athyreotic congenital hypothyroidism in two sisters].

Two sisters with athyreotic congenital hypothyroidism are described. This is the fifth report on athyreotic congenital hypothyroidism in siblings. The elder sister is 14 years old and the younger one is 12. The parents have no consanguinity or family history of thyroid disease. Both of the patients were born before the start of neonatal screening tests for congenital hypothyroidism. After birth, they had jaundice, abdominal distention and constipation, which are typical symptoms of congenital hypothyroidism. Serum T4 levels were decreased, and the serum TSH levels were markedly increased. Therefore we diagnosed them as having congenital hypothyroidism. They have received replacement therapy with thyroxine since diagnosis and have shown normal development physically and psychologically. They were tested for thyroid scintigram when the elder sister was 9 years old and the younger one was 7. 123I thyroid uptakes were 0.69% and 0.64%, respectively. The thyroid scans demonstrated no focus of accumulation of 123I. They do not have trapping defect of iodine, because 123I ratio of saliva and serum were 41.3 and 46.3, respectively. From these results, we diagnosed them as having athyreotic congenital hypothyroidism. They and their mother do not have any antithyroid antibodies. We suppose that some genetic factor is responsible for the athyreotic congenital hypothyroidism.

[Characteristics of group A streptococci isolated from children with non-suppurative complication or severe infection].

We determined the characteristics of group A streptococci isolated from 29 sporadic cases with non-suppurative complication or severe infection during a 15-year period from 1977 to 1991. The clinical diagnoses of children included 4 patients with rheumatic fever, 2 with reactive arthritis, 2 with central nervous system complication, 5 with glomerulonephritis, 11 with Honoch-Schölein purpura, 4 with sepsis and 1 with empyema. Twenty-four strains were isolated from throat swabs, 4 from blood specimens and one from pleural fluid. M/T-serotypes and the number of isolates were as follows; 1/1:10, 3/3:1, 3.3R/3:3, 4/4:7, 5/NT:1, 12/12:3, 18/18:2, 62/12:1, NT/13:1. All 29 isolates had productivity for at least one of streptococcal pyrogenic exotoxins (SPEs) A, B and C. Two strains were positive for A, 2 for A and B, 3 for A, B and C, 9 for B and 13 for B and C. Of 11 isolates from patients with Henoch-Schönlein purpura, 7 and 2 strains were serotyped in M1 and M4, respectively, but none was in M12. Ten of 11 isolates were positive for SPE B or SPEs B and C.

[Pharmacokinetic and clinical studies with meropenem in the pediatric field. Pediatric Study Group of Meropenem].

Pharmacokinetic and clinical evaluations in pediatrics were made on meropenem (SM-7338, MEPM), a new parenteral dehydropeptidase-1 stable carbapenem used without any inhibitors, at 33 medical institutions. The results are summarized as follows. 1. Pharmacokinetic studies. MEPM at a dose of 10, 20, or 40 mg/kg was administered to 53 children by 30-minute drip infusion. Peak plasma concentrations (Cmax's) and plasma half-lives (T1/2's) of these doses were 28.5, 47.2 and 130.0 micrograms/ml, and 0.80, 0.93 and 0.94 hours, respectively. A clear dose response was observed in Cmax's and T1/2 values were quite similar to those observed in adults. In the first 6 hours after administration, 54.4 to 68.1% of the administered drug was recovered in urine. The cerebrospinal fluid (CSF) levels of MEPM in patients with purulent meningitis were 0.13 microgram/ml at a dose of 6 mg/kg, and 0.64 to 4.22 micrograms/ml at a dose of 29 to 44 mg/kg within day 4 of onset. The penetration rate of MEPM showed an intermediate value among those for other cephalosporin antibiotics. 2. Clinical study. Clinical efficacies of MEPM were evaluated in 389 cases. The most common doses used were 10 to 20 mg/kg/once, 2 to 3 times a day. The maximum dose was 173 mg/kg/day q.i.d. MEPM gave "excellent" or "good" responses in 242 (97.6%) out of 248 cases in which causative organisms were documented and in 134 (95.0%) out of 141 cases in which causative organisms were not identified. Clinical efficacy rates were 100% in 11 patients with purulent meningitis, 85.7% in 7 with septicemia, 98.8% in 173 with pneumonia, and 100% in 65 with UTI. Bacteriologically, 260 strains (96.7%) out of 269 strains were eradicated by MEPM treatment. Eradication rates were 89.2% for Staphylococcus aureus (37 strains) and 100% for Streptococcus pneumoniae (35 strains). The overall eradication rate for Gram-positive bacteria was 94.6%. Among Gram-negative bacteria, 98.3% out of 172 strains were eradicated. The eradication rate of Haemophilus influenzae (73 strains) was 98.6% and Pseudomonas aeruginosa (11 strains) was 90.9%, and all of Branhamella catarrhalis (15 strains), Escherichia coli (42 strains), and Klebsiella pneumoniae (6 strains) were eradicated. Out of 84 cases for which previous antibiotic therapies of 3 days or longer were not successful, MEPM gave "excellent" or "good" responses in 77 cases (91.7%) and excellent bacteriological responses (95.7%).(ABSTRACT TRUNCATED AT 400 WORDS)

[Clinical and pharmacokinetic evaluation of meropenem and its effect on fecal flora in children].

Forty-five children were treated with meropenem (MEPM) and the clinical efficacy and side effects were evaluated. The ages of the patients ranged from 1 month to 9 years and their body weights from 5.2 to 25 kg. Doses given were 17.2-45.5 mg/kg every 6 to 8 hours for 2 to 24.5 days. Those patients who responded to the MEPM treatment included 15 children with pneumonia, 7 with pharyngitis, 3 with cervical lymphadenitis, 3 with cellulitis, 10 with urinary tract infections and 4 with other infections. Among 42 children, the results were excellent in 29, good in 12 and fair in 1. The drug was well tolerated, although slightly elevated serum concentrations of transaminases occurred in 5 patients, eosinophilia in 2 patients, and neutropenia in 1 patient among 45 patients examined. The pharmacokinetic studies on MEPM were done in 6 patients. Their ages ranged from 2 to 9 years and body weights from 14.5 to 23.2 kg. In 4 patients, plasma concentrations at the end of 30 minutes drip infusion of 20 mg/kg were 29.28 +/- 10.29 micrograms/ml and those 3 hours later were 0.49 +/- 0.26 micrograms/ml. Serum elimination half-lives of the drug were 0.66 +/- 0.12 hours in these patients. Excretion rates of this drug into urine in the first 6 hours after initiation of drug administration were 53 and 40% in 2 of these patients. In 2 patients with 35 and 44 mg/kg of drug administration, plasma concentrations were higher than those given 20 mg/kg of the drug.(ABSTRACT TRUNCATED AT 250 WORDS)

[Flomoxef in neonates and young infants; clinical efficacy, pharmacokinetic evaluation and effect on the intestinal bacterial flora].

Forty-three newborn and young infants including 13 low-birth-weight (LBW) infants were treated with flomoxef (FMOX) and the clinical efficacy and side effect were evaluated. The ages of the patients ranged from 0 to 99 days, and their body weights from 797 to 9,000 g. Dose levels were 10.5 to 48.5 mg/kg every 6 to 8 hours for 3 to 12 days. Those patients who responded to the FMOX treatment included 8 infants with sepsis, 14 with suspected sepsis, 6 with intrauterine infection, 2 with meningitis, 7 with pneumonia, 1 with staphylococcal scalded skin syndrome, 1 with epididymitis and 4 with urinary tract infections. The results were excellent in 17 and good in 22 patients. The drug was well tolerated, although diarrhea occurred in 2, slightly elevated serum concentrations of transaminases in 2, and eosinophilia and thrombocytosis in 1 patient each. Pharmacokinetic studies on FMOX with 20 mg/kg dose were done in 19 patients including 8 LBW infants. Serum concentrations at 15 minutes after intravenous bolus injection in five 1- to 6-day-old LBW, five 1- to 6-day-old and four 8- to 19-day-old mature infants were 52.6, 52.7 and 58.0 micrograms/ml, respectively, and those at 4 hours were 22.1, 13.3 and 5.2 micrograms/ml, respectively. Serum half-lives of the drug were 3.93, 2.29 and 1.62 hours, respectively, and excretion rates of this drug into urine in the first 6 hours after administration were 30.4, 45.1 and 58.7%, respectively. Mean serum concentrations just after intravenous 1-hour drip infusion in three 8- to 54-day-old LBW and two 8- and 10-day-old mature infants, were 31.5 and 18.9 micrograms/ml, respectively, and those at 4 hours were 15.3 and 4.3 micrograms/ml, respectively. Serum half-lives of the drug were 2.88 and 1.75 hours, respectively, and excretion rates of the drug into urine in the first 6 hours were 22.6 and 47.5%, respectively. The cerebrospinal fluid level at 3 hours after a dose was 7.09 micrograms/ml on the second day of treatment in a patient with Staphylococcus aureus meningitis receiving 50 mg/kg of the drug every 6 hours per day. Its level at 1 hour after a dose was 3.52 micrograms/ml on the 8th day of treatment in the same patient. The influence of FMOX on the fecal flora was studied in 7 patients. The characteristic pattern observed during the drug administration was the disappearance of Bifidobacterium, the decrease or disappearance of Enterobacteriaceae and the preservation of Streptococcus.(ABSTRACT TRUNCATED AT 250 WORDS)

[Pharmacokinetic and clinical evaluation of imipenem/cilastatin sodium in neonates and premature infants. A study of imipenem/cilastatin sodium by a perinatal co-research group].

Pharmacokinetics and clinical studies of imipenem/cilastatin sodium (IPM/CS), a combined preparation of a new carbapenem antibiotic and a dehydropeptidase-I inhibitor, respectively, were carried out in neonates and premature infants in a joint study by a co-research group. 1. Peak blood levels of IPM/CS when administered at 10 mg/10 mg/kg or 20 mg/20 mg/kg by 30- or 60-minute intravenous drip infusion were achieved at the end of infusion. A dose response was clearly observed between the doses and the peak levels achieved. 2. The areas under the blood concentration time curve (AUC) of CS were greater than those of IPM in most patients. Blood half-lives of IPM and CS tended to be longer in younger neonates and premature infants than in older subjects. The blood half-life of CS tended to be longer than that of IPM. 3. Cumulative urinary recovery rates of CS were greater than those of IPM, cumulative urinary recovery rates tended to be greater in older neonates and premature infants than younger subjects. 4. One hundred and thirteen patients were treated for bacterial infections with IPM/CS and 32 patients were treated prophylactically. Daily doses of IPM/CS ranged from 9 mg/9 mg/kg to 150 mg/150 mg/kg. 5. Clinical efficacies of IPM/CS were evaluated in a total of 56 patients with identified etiologic pathogens. The efficacy rate was 98.2% with 33 patients rated as excellent, 22 patients as good and 1 patient as fairly good. (Diagnoses were sepsis in 10 patients and meningitis in 2 patients, etc.) Fifty-seven patients with no identified etiologic pathogens were rated as excellent for 22 patients, good for 34 patients and fairly good for 1. The efficacy rate in these patients was 98.2%. Thirty-two patients were treated prophylactically and the results obtained were satisfactory. 6. Bacteriologically, the eradication rate was 94.5% in 56 patients; i.e., 52 were eradicated, 2 were decreased, 1 persisted and 1 was unknown. 7. Adverse effects were observed in 7 (4.4%) of 160 patients, i.e., 2 patients had diarrhea and 2 patients had rash, etc. Abnormal laboratory data considered related to the therapy occurred in 28 (17.6%) of 159 patients, with 10 patients with eosinophilia (6.3%) and elevation of GOT and/or GPT, etc. All these were non serious, and all values returned to normal after discontinuance of therapy. An abnormal prothrombin (PIVKA II) was observed in 1 of 10 patients tested.(ABSTRACT TRUNCATED AT 400 WORDS)

[Pharmacokinetics and clinical evaluation of ceftriaxone in neonates].

A parenteral cephem antibiotic ceftriaxone (CTRX) was studied for its pharmacokinetic features and clinical efficacy and safety in various infections in neonates including premature infants at 11 institutions associated with Japan Perinatal Infection Research Group. The following results obtained are summarized as follows. 1. Following single intravenous bolus injections with 10 and 20 mg/kg of CTRX, serum levels of the drug at 30 minutes post-dose 36-42 micrograms/ml and 46-76 micrograms/ml, respectively, and those at 12 hours post-dose were 10-14 micrograms/ml and 13-21 micrograms/ml, respectively, in a total of 105 neonates. Serum levels detected were on very gentle descending curves. 2. Half-lives (T 1/2) of the drug in serum were significantly prolonged in 0-3 day age groups of both mature and premature infants: it was especially long in premature infants with age of 0-3 days; i.e., 17.1 hours. There was no difference in T 1/2 between the 4-7 day and 8-28 day age groups. 3. Urinary excretion rates were 20-30% in the first 6 hours post-dose and 30-40% in 12 hours post-dose, in 80 neonates examined. 4. Clinical efficacy: Clinical efficacies were evaluated in 112 of 168 enrolled excluding infants with 90 days of age or older, who were treated for prophylaxis and unevaluable cases. The safety was evaluated in 161 of the 168. (1) Demographic background of the 112 cases: The 112 cases were composed of 89 neonates with ages of 28 days or younger, 21 premature infants, 57 males and 55 females. The drug was given to 102 of the cases by intravenous bolus injection, with 81 cases administered twice a day and 97 cases receiving 10-50 mg/kg a day. (2) Efficacy rate in the 112 cases: In 60 cases for whom causative pathogens were identified the efficacy rate was 90.0% in total (excellent: 31/60; good: 23/60); efficacy rates of 87.5% were obtained in 8 cases with purulent meningitis and 90.9% in 11 with septicemia. In 52 with causative pathogen not identified, the efficacy rate was 96.2% in total (excellent: 21/52; good: 29/52). (3) Adverse reaction: Adverse reactions were noted in 14 of the 161 cases where the safety was evaluated (8.7%). These reactions included diarrhea in 11, vomiting in 2 and exanthema in 1. Abnormalities in laboratory test values were observed in 25 of the 152 cases (16.4%). They included eosinophilia in 14, elevated GOT in 4 and thrombocytosis in 3 etc.(ABSTRACT TRUNCATED AT 250 WORDS)

[Ceftriaxone in neonates and young infants; clinical efficacy, pharmacokinetic evaluation and effect on intestinal bacterial flora].

Twenty-two newborn and young infants, including 13 premature infants, were treated with ceftriaxone (CTRX) and the clinical efficacy and side effects were evaluated. Ages of the patients ranged from 0 to 106 days, and their body weights from 1.19 to 3.92 kg. Dose levels were 15 to 23 mg/kg every 12 to 24 hours for 2 to 13.5 days. Eighteen infants with sepsis and 1 infant with purulent coxitis were considered to have responded to the CTRX treatment. The results were excellent in 13 and good in 6 patients. The drug was well tolerated, although diarrhea occurred in 2 patients, eosinophilia in 6 patients, slightly elevated serum concentrations of transaminases in 2 patients and thrombocytosis in 1 among the 22 patients. The pharmacokinetic studies on CTRX were done in 8 patients including 3 premature infants. The ages ranged from 3 to 50 days, and body weight from 2.20 to 3.94 kg. Plasma concentrations 30 minutes after single 10 mg/kg intravenous bolus injection in two 4- to 5-day-old premature neonates were 48.4 and 50.0 micrograms/ml and those at 6 hours were 22.7 and 23.4 micrograms/ml, respectively. In 2 mature neonates, plasma levels were 42.2 and 39.1 micrograms/ml at 30 minutes and 23.4 and 26.6 micrograms/ml at 6 hours after single 20 mg/kg doses. In four 12- to 50-day-old patients, plasma concentrations ranged from 35.9 to 175.0 micrograms/ml at 30 minutes and from 21.9 to 32.8 micrograms/ml at 6 hours after multiple doses of 20 mg/kg intravenous bolus injection. The plasma half-lives of the drug ranged from 6.6 to 16.8 hours in these 8 patients. Excretion rates of this drug into urine within 12 hours were 21.4 to 63.4% in 7 patients. Urine concentrations of the drug in 34 samples collected at various times from the 7 patients ranged from 28.3 to 469.0 micrograms/ml. The cerebrospinal fluid level at 2 hours after a dose was 3.33 micrograms/ml on the 5th day of treatment in 1 patient with sepsis receiving 18 mg/kg of the drug every 12 hours. Its level at 3 hours after a dose was 6.07 micrograms/ml on the 6th day of treatment in another patient with aseptic meningitis receiving 20 mg/kg every 12 hours. The influence of CTRX on the fecal flora was studied in 3 patients receiving 20 mg/kg X 2/day. The characteristic pattern observed during the drug administration was the disappearance of Bifidobacterium and Enterobacteriaceae, the preservation of Streptococcus and Staphylococcus, and the increase in Candida.(ABSTRACT TRUNCATED AT 400 WORDS)

Pharmacokinetics of methimazole in children and adolescents with Graves' disease. Studies on plasma and intrathyroidal concentrations.

Methimazole concentrations in plasma and in the thyroid glands were measured by means of high-performance liquid chromatography. Pharmacokinetics of methimazole were studied after a single oral dose (175 mumol/m2) in nine children and adolescent who were in the thyrotoxic state. Plasma levels of methimazole showed peak concentrations of 4.4 to 12.6 (median 9.2) mumol/l at 0.5 to 4 h after drug administration. Plasma half-life, area under the curve, and distribution volume ranged from 2.73 to 6.04 h, 32.8 to 77.9 mumol X l-1 X h-1, and 0.516 to 0.913 l/kg, respectively. These pharmacokinetic parameters showed a wide variation among the patients, but were quite reproducible in the same subject. Intrathyroidal concentrations of methimazole were measured in another nine subjects including four adolescents and five adults who underwent thyroidectomy. The drug concentrations in the thyroid glands ranged between 3.5 and 23.8 mumol/kg tissue and were far higher than those in the plasma obtained at the time of surgery. In this series of experiments, the dose of the drug varied from 76 to 319 mumol/m2, time after the last dose to surgery from 5 to 24 h, and the mode of drug administration from a single to three divided doses. Among these variable factors, only the daily dose of methimazole corrected by body surface area showed significant correlation with the intrathyroidal concentration, whereas the time after the last dose of the drug and the mode of drug administration did not.(ABSTRACT TRUNCATED AT 250 WORDS)

[Clinical and pharmacokinetic evaluation of ceftazidime in neonates and young infants].

Seventeen newborn and young infants including 6 premature infants were treated with ceftazidime (CAZ) and the clinical efficacy and side effects were evaluated. Ages of the patients ranged from zero to 55 days, and their body weights ranged from 1.35 to 3.87 kg. Doses of CAZ ranged 10-50 mg/kg every 6 to 12 hours for 3 to 14 days. Twelve infants with infections including meningitis, sepsis, pneumonia and urinary tract infections, were considered to have responded to the CAZ treatment. Among them, results were excellent in 2, good in 9 and fair in 1 patient. The drug was well tolerated, but 1 had diarrhea and 3 patients had eosinophilia among the 17 patients. The pharmacokinetics of CAZ was studied in 22 patients including 11 premature infants. Their ages ranged from 1 to 60 days, and body weights ranged from 0.85 to 3.96 kg. Serum concentrations in 7 patients ranged from 24.2-38.5 micrograms/ml at 30 minutes after single doses of 10 mg/kg intravenous bolus injections and 4.36-12.4 micrograms/ml at 6 hours. Mean elimination half-lives of the drug were 3.20 hours in 2 patients under 7 days of age and 2.31 hours in 5 patients from 7 days of age or older. In 8 patients, serum concentrations ranged 32.6-57.9 micrograms/ml at 30 minutes and 8.10-20.7 micrograms/ml at 6 hours after single doses of 20 mg/kg. Elimination half-lives were 3.53 hours in 4 patients under 7 days of age and 2.79 hours in 4 patients from 7 days of age or older.(ABSTRACT TRUNCATED AT 250 WORDS)