Fourteen pediatric patients with infections (21 episodes) were treated with intravenous vancomycin (VCM) and the clinical efficacy and side effects were evaluated. The ages of the patients ranged from 1 month to 13 years and their body weights from 1.9 to 49kg. The drug was administered by intravenous drip infusion for 60 minutes. Doses given were 10 (except one with 20) mg/kg every 6 (8 or 12 in patients with renal dysfunction) hours for 5 to 27 days. A leukemic patient was given the drug for 3.5 months.
Those episodes which responded well to the VCM treatment included 10 episodes in 8 children with methicillin-resistant Staphylococcus aureus infections, 4 in 2 children with methicillin-resistant Staphylococcus epidermidis (MRSE) infections and 2 in 2 children with methicillin-susceptible S. aureus infections. Those infections included sepsis, empyema, bronchitis, subcutaneous abscess, cellulitis and lymphadenitis. Clinical effects were fair in 1 patient with gingival abscess due to MRSE, and undetermined in 4 patients with infections of which etiologies were unknown. The drug was well tolerated, although rash, which disappeared after more prolonged infusion, was noted in 2 episodes and elevated serum concentrations of transaminases occurred in 4 episodes (both side effects occurred in 1 patient given 20mg/kg every 6 hours).
The minimal inhibitory concentrations of VCM against isolated staphylococci were 0.5-1μg/ml.
Monitoring for serum concentrations of drug was performed in 10 patients. The peak concentrations of VCM (at the end of 60 minutes infusion) were 28.3±12.8μg/ml on the 6-20th day of treatment in 4 patients and trough levels were 6.9±1.9μg/ml on 2-20 th day of treatment in 9 patients with normal renal function receiving 10mg/kg of the drug every 6 hours. Those serum levels were much higher in 2 patients with minor renal dysfunction receiving 10mg/kg every 6 or 8 hours hence the administration schedule was changed to every 12 hours.
Intravenous VCM treatment would be well tolerated in children and it would be useful in patients with serious infections due to methicillin-resistant staphylococci.

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The pharmacokinetics of flomoxef (FMOX), an oxacephem antibiotic, were investigated in pediatric patients undergoing chronic hemodialysis. The results are summarized as follows.
1. FMOX was given intravenously in a single dose of 10mg/kg to 5 pediatric patients (ranging from 7 to 15 years of age) undergoing chronic hemodialysis. It was also given in a dose of 5mg/kg to 2 of these patients. Its concentrations in serum and urine were determined using bioassay. Pharmacokinetic analyses were performed using a two compartment open model.
2. The serum concentrations of FMOX, administered in doses of 10mg/kg or 5mg/kg on non-hemodialysis days, were 33.3±4.09μg/ml(mean±standard deviation) and 17.6μg/ml (mean) at 30 minutes after injection, 29.6±3.51μg/ml and 15.9μg/ml at 1 hour, 27.2±2.14μg/ml and 15.1μg/ml at 2 hours, 23.5±1.90μg/ml and 13.0μg/ml at 4 hours, 20.8±2.44μg/ml and 12.2μg/ml at 6 hours, 18.9±1.86μg/ml and 11.0μg/ml at 8 hours, and 9.64±1.43μg/ml and 6.16μg/ml at 24 hours, respectively.
3. The urinary concentrations of FMOX, administered in a dose of 10mg/kg, were 42.4-123μg/ml between 0-6 hours after injection, 14.1-52.5μg/ml between 6-24 hours, and 2.86-23.7μg/ml between 24-48 hours. The urinary excretion rate in the first 48 hours after injection ranged from 9.1 to 10.5%.
4. Pharmacokinetic analyses showed that k₁₀ was 0.070±0.007hr^-1, an extremely low value, T 1/2α was 0.51±0.46 hour, moderately prolonged, T1/2/3 was 15.03±1.34 hours, very prolonged, Vc was 0.23±0.03L/kg, a moderately low value, and AUC was 616.5±90.9μg·hr/ml, an extremely high value, in patients undergoing chronic hemodialysis as compared to those values in a child with normal renal function.
5. These findings suggest that FMOX should be administered intravenously once a day at a dose of 10mg/kg to pediatric patients undergoing chronic hemodialysis and that the dose may be lowered to 5mg/kg in some bacterial infections.

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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 (T 1/2) 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 10mg/kg. i. v., mean C₃₀(30 minutes concentration) values were 21.2, 21.8 and 21.3μg/ml, respectively, in the different groups mentioned above, and the mean T 1/2 values were 3.37, 1.85 and 1.63 hours. At 20mg/kg i. v., mean C₁₅(15 minutes concentration) values were 54.4, 51.4 and 50.7μg/ml, and mean T 1/2's were 2.99, 2.32 and 1.79 hours, respectively. At a dose of 40mg/kg i. v., mean C₁₅ values were 104.0, 95.9 and 99.2μg/ml, and the mean T 1/2's were 3.40, 1.20 and 1.80 hours, respectively.
(2) Plasma concentrations and T 1/2 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 40mg/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, 106.0μg/ml, and T 1/2'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 T 1/2 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 40mg/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 20mg/kg in the neonate groups (or the premature infant groups) as follows: Mean C₅₀ values were 31.0, 32.7 and 23.4μg/ml, and T 1/2 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 indentified in 71 cases (A group) and not indentified in 128 cases (B group).
Diseases among the A group were sepsis in 13 cases, purulent meningitis in 1, pneumonia in 18, other respiratory tract infections (RTI) in 3, urinary tract infection (UTI) in 13, skin and soft-tissue infection (SSTI) in 20, intrauterine infection in 2 and other infection in 1.
The clinical efficacies in the A group was excellent in 40 cases, good in 27, fair in 1 and poor in 3. The over-all efficacy rate was 94.4%.
Diseases in the B group included suspected sepsis in 24 cases, purulent meningitis in 1, pneumonia in 42, bronchitis in 2, other RTI in 2, UTI in 2, SSTI in 7, intrauterine infection in 44 and other infections in 4.
The clinical efficacies in the B group were excellent in 54 cases, good in 69 and fair in 2. The over-all efficacy rate was 96.1%.
FMOX was administered to 104 patients for prophylaxis with satisfactory results were obtained in all cases.
3. Bacteriological studies
Seventy three strains of pathogens were isolated from 71 cases. Bacteriological effects of FMOX were as follows, eradicated; 62 strains, decreased; 1, unchanged; 2, unknown; 7 and 1 strain was replaced. The bacteriological eradication rate was 95.5%.
4. Side effects and abnormal laboratory test results were found at rates of 1.3% and 8.5%, respectively. However, all of these cases were transient and no severe incidents were observed.

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Clinical studies on flomoxef (FMOX) were performed in neonates and the results obtained are summarized as follows.
Treatment with FMOX was made in 4 cases of neonatal bacterial infections; 2 cases of sepsis (suspected) and 1 case each of infection of umbilicus and staphylococcal scalded skin syndrome. Results obtained were excellent in 1 case, good in 3 cases.
No significant side effects due to the drug were observed in any cases.

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Flomoxef (FMOX), an oxacephem antibiotic of β-lactam antibiotic family, was administered to 16 infants including 6 neonates and 10 premature infants at a dose of 20 or 40mg/kg via intravenous injection, and plasma and urinary concentrations and the urinary recovery were determined. In addition, FMOX was administered via intravenous injection at daily doses averaging 85.5mg/kg divided into 2 to 4 times for durations averaging 9 days to 96 infants from 0-to 90-day old (mainly neonates and premature infants). In 44 of the 96 infants with bacterial infections, clinical and bacteriological efficacies were evaluated, and prophylactic effects of FMOX were determined in the remaining 52 infants. Adverse reaction and laboratory tests abnormalities were evaluated also. The obtained results are summarized as follows.
1. Upon administration of FMOX at 20 or 40mg/kg to neonates and premature infants via intravenous injection, plasma concentrations, half-lives and AUC were determined. In 3 neonates of 5, 7 and 16 days of ages administered with 20mg/kg of FMOX, peak plasma concentrations of 62.5 to 99.7μg/ml were achieved in 5 or 15 minutes after injection. Half-lives of FMOX in these neonates were 1.48 to 1.78 hours and AUC's were 112 to 161μg·hr/ml. The same dose (20mg/kg) of FMOX was administered to 3 premature infants of 5-16-and 19-day of ages and initial blood samples were obtained at 5 minutes after injection from the 5-day old subject and at 15 minutes after injection from the 16-and 19-day old subjects. Peak plasma concentrations of 63.6 to 79.9μg/ml were observed in the samples. Half-lives were 1.69 to 2.20 hours and AUC's were 174 to 201μg·hr/ml. When 3 neonates (one 17-day old and two 24-day old subjects) were administered with 40mg/kg of FMOX, peak plasma concentrations obtained at 5 minutes after injection were 99.7 to 122.0μg/ml. Half-lives were 1.28 to 1.92 hours and AUC's were 170 to 357μg·r/ml. In 6 premature infants (one 3-day old, one 5-day old and four between 16 and 24 days of ages) administered the same dose, the peak plasma concentrations achieved at 5 minutes after injection were as follows: 113.0μg/ml in the 3-day old, 108.0μg/ml in the 5-day old and between 112.0 and 148.0μg/ml in the other 4 cases, half-lives were 3.85, 2.86 and between 1.70 and 2.25 hours, respectively, and AUC's were 493, 407 and between 310 and 361μg·hr/ml, respectively, for the 3 groups of subjects.
2. Urinary concentrations and urinary recovery rates were also determined for 14 subjects of the 15 subjects for whom plasma concentrations were determined as mentioned above. It was not possible to collect urinary samples in the remaining 1 case (a neonate administered with FMOX at 20mg/kg). In addition to the 15 cases, a premature infant was administered with FMOX at a dose of 20mg/kg and urinary recovery concentrations and recovery rates were determined though plasma concentrations were not. In the 2 neonates of 5-and 7-day of age who were administered with 20mg/kg, peak urinary concentrations were reached between 0 and 2 hours after administration at 1,770 and 2,300μg/ml, respectively. Urinary recovery rates in the first 6 hours after injection were 89.3 and 82.0%, respectively. In the 4 premature infants of 5-, 16-, 17-and 19-day of ages who received 20mg/kg, peak urinary concentrations were between 417 and 2,260μg/ml observed urine samples collected between 0 and 2 hours or 2 and 4 hours after administration. Urinary recovery rates in the first 6 hours after administrations were between 40.4 and 78.0%. In the 3 neonates who received 40mg/kg (one 17-day and two 24-day olds) peak urinary concentrations were observed either in samples collected between 0 and 2 hours or 2 and 4 hours after administration, with peak concentrations between 1,800 and 4,170μg/ml. Urinary recovery rates in the first 6 hours after administration were between 66.6% and 77.8%.

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Pharmacokinetic and clinical studies on flomoxef (FMOX) in the perinatal period were carried out and following results were obtained
1. The pharmacokinetic parameter T 1/2's of FMOX in maternal serum, umbilical cord serum and amniotic fluid in mothers after single intravenous injection of 1g (n=46) and 2g(n=34) were 1.11, 9.24, 9.24 hours and 2.54, 12.49, 12.49 hours, respectively. Cmax's and Tmax's ofumbilical cord serum and amniotic fluid were 12.71, 11.77 μg/ml and 0.57, 3.35 hours upon single dose of 1 g i. v., and 35.17, 12.37 μg/ml and 0.32, 3.42 hours upon single dose of 2g i. v., respectively.
2. Clinical usefulness were evaluated in 93 cases including were various infections in pregnancy and puerperal period. In pregnancy cases, clinical efficacy rate was 95.5% (21/22), and 100% in puerperal period.
Bacteriological response rate was 84.6% (eradicated: 29, decreased: 4, unchanged: 2, replaced: 4 and unknown: 8 cases).
No severe side effects nor clinical laboratory test results were observed in any cases.
From above basic and clinical results, we conclude that FMOX is a useful and safe agent for various infections in pregnancy and puerperal period.

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The clinical efficacy of cefditoren pivoxil (CDTR-PI, ME 1207) was evaluated in 45 patients with various infections. CDTR-PI was administered after meals at a dose of 3mg/kg t. i. d. to most patients. The clinical efficacy rate was 95.3%. As side effects, diarrhea occurred in 2 patients. Cefditoren showed excellent antibacterial activities against Haemophilus influenzae, Streptococcus pyogenes and Streptococcus pneumoniae, and was more effective against Staphylococcus aureus than other cephems.

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Pharmacokinetic, bacteriological and clinical studies on cefditoren pivoxil (CDTR-PI, ME 1207) were performed in children.
The results were as follows:
1. A total of 18 patients (19 infections) were treated with CDTR-PI. The doses ranged 2.1-3.2mg/kg, and it was orally administered 3 times daily, for 4-10 days. Clinical efficacies of CDTR-PI in 18 patients with 19 bacterial infections (3 with tonsillitis, 1 with bronchitis, 7 with pneumonia, 1 with acute maxiller sinusitis, 4 with otitis media, 1 with urinary tract infection, 2 with skin and soft tissue infection) were evaluated as excellent in 13 infections and as good in 6 infections with an efficacy rate of 100%.
Twelve causative strains of 5 species were found in 11 patients.
Streptococcus pneumoniae in 2 cases out of 3, Haemophilus influenzae in 4/4, Staphylococcus aureus in 2/2, Haemophilus parainfluenzae in 2/2 and Escherichia coli in 1/1 were eradicated.
Two patients had mild diarrhea but did not need spesific treatment. Severe adverse reaction was not observed in any of the 18 patients.
2. MICs of CDTR were examined against 4 clinically isolated S. pneumoniae strains. Two strains of S. pneumoniae were relatively resistant to penicillins.
3. Pharmacokinetic studies
Peak serum CDTR concentrations in 3 patients were 2.38μg/ml, 0.72μg/ml and 2.25μg/ml at a dose of CDTR-PI 3mg/kg orally administered at 30-minute after meal.
Based on the above results and the broad spectrum of antibacterial activities of CDTR, it is considered that CDTR-PI is a promising antibiotic which is usable as a single agent for the primary therapy of respiratory tract infections in children.
Because antibacterial activity against S. aureus is relatively weak, however, a use of relatively high dose of CDTR-PI in patients with skin and soft tissue infections may give favorable result.

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Clinical evaluations of cefditoren pivoxil (CDTR-PI, ME 1207) in granules were carried out. The obtained results are summarized as follows.
1. Thirty-nine patients with pediatric infections were treated with CDTR-PI. Clinical responses of 36 assessable cases were excellent in 25, good in 9 and fair in 2. The overallefficacy rate was 94%.
2. Bacteriologically, 30 of the 31 identified bacteria presumed to be pathogens were eradicated and the eradication rate was 97%.
3. Side effects observed were diarrhea in 3 of 39 patients. The incidence was 7.7%. Abnormal laboratory test results were not observed.
The results suggested that CDTR-PI might be a very useful and safe drug for the treatment of pediatric infections.

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Bacteriological, pharmacokinetic and clinical studies on cefditoren pivoxil (CDTR-PI, ME 1207) in granules, a new oral cephalosporin, were performed in the field of pediatrics. The results are summarized below.
1. Antibacterial activities:
Antibacterial activities of CDTR were studied against Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Haemophilus influenzae, Haemophilusparainfluenzae and Branhamella catarrhalis in comparison with those of cefteram (CFTM), cefixime (CFIX), cefaclor (CCL), cefpodoxime (CPDX) and cefotiam (CTM). MIC₈₀'s of CDTR against S. aureus,S. pneumoniae, S. pyogenes, H. influenzae, H.parainfluenzae and B. catarrhalis were 1.56, 0.39,≤0.025,≤0.025, 0.05 and 0.20μg/ml, respectively. These results showed that CDTR has high antibacterial activities against these organisms.
2. Absorption and excretion:
Serum concentrations and urinary recovery rates of CDTR-PI (administered in granules) were determined.
Upon single oral doses of 3mg/kg and 6mg/kg, the peak serum concentrations were 0.5-2.45μg/ml at 2 to 4 hours and 1.79-4.05μg/ml at 1 to 4 hours, respectively, and T 1/2 was 1.07-9.67 hours and 0.99-3.00 hours, respectively. At 8 hours after dosing, serum concentrations were 0-0.87μg/ml with a dose of 3mg/kg and 0.27-0.73μg/ml with 6mg/kg. These values indicated that the drug has a dose-dependent pharmacokinetic behavior. Urinary recovery rates in the first 8 hours were 12.9-34.2% with a dose of 3mg/kg and 11.8-26.9% with 6mg/kg.
3. Clinical study:
Clinical efficacies were examined in a total of 81 cases consisting of 20 cases of acute bronchitis, 13 of acute pneumonia, 21 of tonsillitis, 5 of pharyngitis, 7 of scarlet fever, 2 each of impetigo, otitis media and purulent cervical lymphadenitis, 1 of pertussis and 8 of UTI. The clinical efficacy rate was 97.5% (79/81), and bacteriological eradication rate was 100% (76/76). As for side effects, 2 cases of watery stools and 1 case of minor elevation of GPT were observed.

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We have carried out clinical studies on cefditoren pivoxil (CDTR-PI, ME1207) in granules. The results are summarized as follows.
Treatment with CDTR-PI was made for 14 cases of pediatric bacterial infections: 4 cases of tonsillitis, 2 cases of pneumonia, 3 cases of scarlet fever, 3 cases of impetigo, 1 case of subcutaneous abscess and 1 case of urinary tract infection.
Results obtained were excellent in 12 cases, good in 1 case and poor in 1 case. No significant side effects due to the drug were observed.

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