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Pharmacokinetic and clinical studies on cefozopran (CZOP, SCE-2787), a new cephalosporin antibiotic, were carried out in the field of pediatrics. The results obtained are summarized below. 1. Serum concentrations and urinary excretion rates were determined after intravenous bolus injection of CZOP at a dose of 20 mg/kg for 5 minutes in 3 cases. The mean serum concentration of CZOP was 45.9 micrograms/ml at 30 minutes with the serum half-life of 1.77 hours. The mean cumulative urinary excretion rate in the first 8 hours after administration was 71.4%. 2. Fourteen patients with bacterial infections (pneumonia 9 cases, urinary tract infection 4 cases and lymphadenitis 1 case) were treated with CZOP at a daily dose of 55.8-65.7 mg/kg. The overall clinical efficacy and bacteriological eradication rates were both 100%. 3. No adverse reactions were observed. Abnormal laboratory test results were mild, slight elevation of GOT and GOT, GPT & LDH in 1 each and eosinophilia and thrombocytosis in 2 cases each.

A new oral cephem antibiotic, S-1108, was evaluated for its clinical efficacy and safety in children. S-1108 was effective in 95% of the 59 examined cases of respiratory, middle ear, skin and urinary tract infections. S-1108 was highly effective in infections of Streptococcus pyogenes, Haemophilus influenzae and Escherichia coli, but was less effective in penicillin-resistant Streptococcus pneumoniae and Staphylococcus aureus infections. The serum half-life was 1.26 +/- 0.36 hours upon after meal administration of 4 mg/kg. No severe adverse reaction was encountered. From these data, S-1108 appears to be safe and effective in children with susceptible bacterial infections.

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)

Flomoxef (FMOX), an oxacephem antibiotic of beta-lactam antibiotic family, was administered to 16 infants including 6 neonates and 10 premature infants at a dose of 20 or 40 mg/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 85.5 mg/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 40 mg/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 20 mg/kg of FMOX, peak plasma concentrations of 62.5 to 99.7 micrograms/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 161 micrograms.hr/ml. The same dose (20 mg/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 79.9 micrograms/ml were observed in the samples. Half-lives were 1.69 to 2.20 hours and AUC's were 174 to 201 micrograms.hr/ml. When 3 neonates (one 17-day old and two 24-day old subjects) were administered with 40 mg/kg of FMOX, peak plasma concentrations obtained at 5 minutes after injection were 99.7 to 122.0 micrograms/ml. Half-lives were 1.28 to 1.92 hours and AUC's were 170 to 357 micrograms.hr/ml.(ABSTRACT TRUNCATED AT 400 WORDS)

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 3 mg/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.

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, Haemophilus parainfluenzae 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, < or = 0.025, < or = 0.025, 0.05 and 0.20 micrograms/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 3 mg/kg and 6 mg/kg, the peak serum concentrations were 0.5-2.45 micrograms/ml at 2 to 4 hours and 1.79-4.05 micrograms/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 0-0.87 micrograms/ml with a dose of 3 mg/kg and 0.27-0.73 micrograms/ml with 6 mg/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 3 mg/kg and 11.8-26.9% with 6 mg/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.

Cefprozil (CFPZ, BMY-28100) is a new oral cephem antibiotic without an ester linkage. Pharmacokinetic and clinical studies using CFPZ 10% fine granules were performed in pediatric patients. 1. Pharmacokinetic investigation Peak serum concentrations of CFPZ after dose of 7.5 mg/kg and 10 mg/kg were, respectively, 3.65 +/- 0.24 micrograms/ml and 6.38 +/- 3.23 micrograms/ml at 1-2 hours. The average half-life with 7.5 mg/kg administration was 0.90 +/- 0.16 hours and that with 10 mg/kg was 1.29 +/- 0.50 hours. The urinary excretion of CFPZ was about 45% (35.3-50.0%) in 6 hours. 2. Clinical investigation Enrolled in the study were 22 patients including 4 with pharyngitis, 3 with tonsillitis, 3 with bronchitis, 5 with pneumonia, 4 with urinary tract infection, and 1 each with pertussis, purulent lymphadenitis and otitis media. Responses were excellent in 14 patients, good in 5 patients and fair in 1 patient. In the assessment of the bacteriological efficacy, 8 out of 17 strains of organism identified previous to the treatment were eradicated, 5 strains were found replaced by other bacteria and 4 strains persisted, hence the eradication rate was 76.5%. 3. No adverse reactions attributable to the drug were observed. From the above results, it has been concluded that CFPZ is a highly effective and safe agent for moderate respiratory and urinary tract infections in children.

Cefdinir (CFDN), a newly developed oral cephalosporin in 5% fine granular form, was administered to 10 boys at 1 hour before meal (in the fasting state) and concentrations of the drug in plasma and urine and its urinary recovery rates were determined. The subjects were divided into 2 groups of 5 boys each; one group received 3 mg/kg of CFDN, and the other, 6 mg/kg. To 6 of the 10 children the drug was administered in the two different dose levels using the cross-over method. To study clinical and bacteriological effects of this drug, a mean dose of 4.6 mg/kg t.i.d. was administered for 8 days on the average to 40 children with various infections; pharyngitis (4 cases), tonsillitis (2), acute bronchitis (2), pneumonia (8), scarlet fever (6), acute purulent otitis media (1), urinary tract infection (12), impetigo (2), phlegmon (1), lymphadenitis (1) and subcutaneous abscess (1). MICs were determined for 6 drugs including CFDN, cefaclor, cefixime (CFIX), methicillin, cloxacillin (MCIPC), amoxicillin (AMPC) against 13 strains of 6 species freshly isolated from children receiving CFDN. An inoculum size of 10(6) cfu/ml was used in the MIC-determinations. Adverse reactions and abnormal laboratory findings attributable to this drug were also examined in these patients. The results obtained are summarized as follows. 1. Mean plasma peak levels of CFDN were observed at 3 hours after administration in both the 3 mg/kg and 6 mg/kg groups with mean peak values of 0.68 and 1.35 micrograms/ml, respectively. Mean half-lives were 2.06 hours in the 3 mg/kg group and 1.61 hours in the 6 mg/kg group, and mean AUCs were 3.5 in the former and 6.5 micrograms.hr/ml in the latter. Thus, dose-response between the 2 doses was observed in plasma levels and AUCs. 2. To 3 patients, CFDN was given in the two different doses using the cross-over method. Mean plasma peak levels of CFDN were 0.71 and 1.31 micrograms/ml in the doses of 3 mg/kg and 6 mg/kg, respectively. Half-lives were 1.39-2.90 hours in the 3 mg/kg group and 1.21-1.48 hours in the 6 mg/kg group, with AUCs of 3.4-3.7 and 4.1-7.5 micrograms.hr/ml, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)

To assess the usefulness of single dose treatment with isepamicin (ISP) against chronic complicated urinary tract infection (CC-UTI), laboratory and clinical studies were carried out. The results are summarised as follows. 1. Serum concentrations. Serum concentrations of the drug were assayed for patients after the administration of ISP at a dose of 400 mg by intravenous drip infusion for 30 or 60 minutes. Patients tested consisted of 3 groups with different degrees of renal functions (Ccr: ml/min); 1) normal, 130.8, 2) slightly impaired, 70.8, 3) moderately impaired, 45.9. When the peak/trough concentrations in the 3 groups were compared on 1st-2nd day/5th-6th day of the administration, no significantly different values were recognized among the 3 groups in the peak/trough concentrations. 2. Clinical efficacy Twenty three patients including 18 (78%) patients over 61 years of age were treated at a dose of 400 mg once a day for 4-10 days. Of 21 evaluable cases, 15 (71%) were evaluated as excellent or moderate according to the Japanese UTI criteria. Against the clinical isolates, 21 (68%) out of 31 strains were eradicated after the treatment. 3. Safety Neither subjective side reactions nor clinical abnormal values were encountered throughout the treatment. 4. Conclusions The clinical effectiveness of daily single dose treatment with ISP (400 mg once a day, i.v.d.) was considered to be almost comparable to the treatment with 200 mg twice a day. Furthermore, since no problems on safety were noted even in treating aged patients with slight to moderate renal impairments, the drug appears to be evaluated as highly useful.

Thirty children were treated with cefdinir (CFDN) for the evaluation of its clinical efficacy and side effects. Their ages ranged from 1 to 9 years. The dosage of CFDN ranged from 8.1 to 15.9 mg/kg/day with the treatment continued for 2 to 10 days. Twenty-eight of the 30 patients were evaluated for clinical efficacy; 10 patients with tonsillitis, 3 with scarlet fever, 4 with lower respiratory infections, 2 with otitis media, 2 with cervical lymphadenitis, 3 with urinary tract infections and 4 with skin and soft tissue infections. The remaining 2 patients who had viral diseases were included in the evaluation for side effects. Clinical responses were excellent in 14 patients, good in 12, fair in 1 and poor in 1 with an efficacy rate of 92.9%. Diarrhea was noted in one of the 30 patients. A pharmacokinetic study on CFDN was performed in 8 fasting patients whose ages ranged from 3 to 7 years. Serum concentrations of CFDN peaked at 0.59 to 1.76 micrograms/ml (mean 1.13 microgram/ml) at 2 hours after dosing of 3 mg/kg in 4 patients, and 0.89 to 2.49 micrograms/ml (mean 1.49 micrograms/ml) 2 or 3 hours after dosing of 6 mg/kg in the other 4 patients. The 8-hour urinary excretion rates were 16.0% to 21.3% (mean 17.4%) in 4 patients given a dose of 3 mg/kg and 10.9 to 21.1% (mean 15.5%) in 4 patients given a dose of 6 mg/kg.

Norfloxacin (NFLX, AM-715), a new quinolone antibiotic agent, was evaluated clinically and bacteriologically for its efficacy and safety in pediatrics by a study group organized with pediatricians from all over the country. A summary of the results of the evaluation is as follows. 1. Incidence of NFLX-resistant strains (MIC over 12.5 micrograms/ml) isolated from children with various infections was 1.6% (8/512). One resistant strain was observed among 45 isolates of Staphylococcus aureus, and none among 30 isolates of Pseudomonas aeruginosa. 2. After single oral administration of 1.5-2.9, 3.0-4.8 and 5.1-6.1 mg/kg NFLX in tablet form at fasting, mean peak values of serum concentration of 0.37, 0.56, 0.92 micrograms/ml, T1/2 of 2.5, 2.6, 2.6 hours and urinary recovery rates in 8 hours at 25.3, 25.3, 27.1% were observed, respectively. 3. Clinical effects were studied chiefly in intestinal and urinary tract infections. Among 317 patients from whom pathogens had been isolated, responses to the treatment were excellent in 187, good in 79, fair in 9, poor in 7, and unknown in 35 cases. The overall efficacy rate was 94.3% (266/282) and the efficacy rate for excellent responses was 70.3% (187/266). Among all the 406 patients treated, including those with undetermined pathogens, responses were excellent in 233, good in 106, fair in 11, poor in 11, and unknown in 45 cases. The overall efficacy rate was 93.9% (339/361). 4. Clinical effects of NFLX classified by diseases with identified pathogens were 81.8% (9/11) for acute pneumonia, 80.8% (21/26) for other respiratory infections, 95.8% (23/24) for bacillary dysentery, 98.6% (70/71) for Campylobacter enteritis, 100% (24/24) for Salmonella enteritis, 100% (6/6) for other acute enteritis and 98.1% (104/106) for urinary tract infections. Including other infections as high as 94.3% (266/282) of efficacy rate was obtained in total. There was no significant difference in NFLX efficacies between unidentified and identified pathogens. Thus, the total clinical efficacy rate was 93.9% (339/361). 5. The total eradication rate of 325 pathogens evaluable was 84.3%, with identical eradication rates for Gram-positive cocci (GPC) (43/51) and for Gram-negative rods (GNR) (231/274). 6. The optimal daily dose of NFLX seemed to be in a range between 6.0 and 12.0 mg/kg, and the optimal duration of treatment to be 7 days for children over 5 years old. 7. The clinical efficacy in treating P. aeruginosa infections in 12 patients was 100% (11/11) and the eradication rate was 83.3% (10/12).(ABSTRACT TRUNCATED AT 400 WORDS)

Studies were carried out on the in vivo kinetics and clinical efficacy of latamoxef (LMOX) in neonates and premature infants. The results are summarized below. Serum concentration and T1/2 following intravenous injection of LMOX to neonates LMOX was intravenously administered to neonates as one shot doses of 10 mg/kg and 20 mg/kg. The serum concentration of LMOX showed a dose-response to the 10 and 20 mg/kg doses in each of the 0--3 day-old group, 4--7 day-old group and 8--28 day-old group. The T 1/2 values were as follows; for the 10 mg/kg dose, 5.17 hours in the 0--3 day-old group, 3.28 hours in the 4--7 day-old group and 2.79 hours in the 8--28 day-old group; for the 20 mg/kg dose, 5.58 hours in the 0--3 day-old group, 3.46 hours in the 4--7 day-old group and 3.14 hours in the 8--28 day-old group. Thus, it is seen that the half-life of both dosages decreased as the infants became older. Serum concentration and T 1/2 following intravenous injection of LMOX to premature infants Similar to the case of neonates described above, the concentration of LMOX in the serum of the premature infants showed a dose-response to the 10 mg/kg and 20 mg/kg dosages. The T 1/2 values for the 0--3, 4--7 day-old and 8--28 day-old groups were 7.54, 3.93 hours and 6.25 hours, respectively, for the 10 mg/kg dose, and 10.8, 4.05 hours and 3.23 hours, respectively, for the 20 mg/kg dose. Again, it is seen that the half-life of both dosages decreased as the age of the prematurely-born infants increased. Serum concentration and T1/2 following 1-hour intravenous drip infusion of LMOX to neonates LMOX was administered to neonates in doses of 10 mg/kg and 20 mg/kg, by i.v. drip infusion over a 1-hour period. With both dosages, the peak serum concentration of LMOX occurred at the time of completion of the infusion. The T1/2 values for the 0--3, 4--7 day-old and 8--28 day-old groups were 5.41, 3.68 hours and 1.92 hours, respectively, for the 10 mg/kg dose, and 5.31, 2.67 hours and 4.86 hours, respectively, for the 20 mg/kg dose. Urinary excretion of LMOX in neonates and premature infants. The percentage of the administered LMOX dose contained in the urine excreted during the 6-hour period following intravenous administration of LMOX to neonates and premature infants was determined.(ABSTRACT TRUNCATED AT 400 WORDS)

Cefpodoxime proxetil (CPDX-PR, CS-807) is a new oral cephem derivative drug in which carboxylic acid was esterified to the 4-position of CPDX (oxime type cephem antibiotic). CPDX-PR is hydrolyzed mainly with esterase in intestinal wall and CPDX exists as an active form in body fluid. While there are numerous study reports using CPDX-PR in tablet forms in Japan, the dry syrup formula for pediatric use was newly developed. The dry syrup of CPDX-PR was orally administered 20 minutes after meal to the 6 boys of ages from 8 years and 1 month to 10 years and 10 months, with doses of 3 and 6 mg/kg, respectively, for 3 cases each. Serum concentrations and urinary concentrations and recovery rate of the drug were investigated. In addition to the above, the clinical and bacteriological studies were performed in a total of 105 cases consisting of children with ages ranging from 2 months to 11 years and 8 months, upon administering an average dose of 3.4 mg/kg, 3 to 4 times per day (96 cases of 3 times and 9 cases of 4 times). The 105 cases included 13 cases of pharyngitis, 21 cases of tonsillitis, 4 cases of acute bronchitis, 6 cases of pneumonia, 1 case of pleurisy, 13 cases of scarlet fever, 41 cases of urinary tract infection, 3 cases of posthitis and 3 cases of bacillary dysentery. Drug sensitivity test was performed for the following strains: (i) Strains retained by our department; 52 strains of Streptococcus pyogenes, 18 strains of Streptococcus agalactiae, and 11 strains of Bordetella pertussis, and (ii) strains isolated from cases to which CPDX-PR was administered; 2 strains of Staphylococcus aureus, 8 strains of S. pyogenes, 2 strains of Haemophilus influenzae, 10 strains of Escherichia coli, and 1 strain of Proteus mirabilis. Drug sensitivities of the strains retained by our department were tested with the inoculum sizes of 10(8) and 10(6) cfu/ml for R-3746 (Na-salt of CPDX), cefaclor (CCL), cephalexin (CEX), amoxicillin (AMPC), and methicillin (DMPPC), and those against strains separated from the cases to which CPDX-PR was administered were tested with the same inoculum sizes for R-3746, CCL, CEX, cefadroxil, ampicillin (ABPC), DMPPC and cloxacillin (MCIPC). Adverse reactions and abnormal clinical laboratory test results were also examined.(ABSTRACT TRUNCATED AT 400 WORDS)

Pharmacokinetic, bacteriological, and clinical studies in pediatrics on cefpodoxime proxetil (CPDX-PR, CS-807) (pediatric dry syrup) were performed. 1. Serum concentrations and urinary excretions of CPDX after administration of CPDX-PR to children (ages between 6 and 14) were investigated. Four cases were administered with CPDX-PR at a dose level of 3 mg/kg 30 minutes before or after meal. Effects of timings of administration were investigated using a crossover study. Average serum concentrations in the group administered with the drug before meal reached their peaks at 1 hour after administration with an average level of 2.34 +/- 0.16 micrograms/ml and diminished with a half-life of 1.94 +/- 0.08 hours to 0.29 +/- 0.04 microgram/ml at 8 hours after administration. In the group administered with the drug after meal, average serum concentrations attained their peaks at 4 hours after administration at an average level of 1.93 +/- 0.09 micrograms/ml, and decreased with a half-life of 2.08 +/- 0.19 hours to 0.58 +/- 0.16 microgram/ml at 8 hours. Urinary recovery rates of CPDX in the first 8 hours after administration of CPDX-PR in the before-meal and the after-meal groups averaged 34.4 +/- 6.3% and 38.5 +/- 7.0%, respectively. In a separate experiment, 7 cases were administered with CPDX-PR, 30 minutes after meal, at a dose level of either 3 or 6 mg/kg. Effects of the 2 different dose levels were investigated also using a crossover study. Average serum concentrations at their peaks attained at a 4 hours after administration for the 2 dosage groups (3 and 6 mg/kg) were 1.76 +/- 0.11 and 3.08 +/- 0.41 micrograms/ml, respectively. Average half-life values for the 2 groups were 2.40 +/- 0.14 and 2.25 +/- 0.07 hours, respectively, with average 8 hour values of 0.64 +/- 0.10 and 1.30 +/- 0.21 micrograms/ml, respectively. Urinary recovery rates in the first 8 hours after administration averaged 40.4 +/- 3.2% and 46.3 +/- 6.5%, respectively. From these results, it appeared that the absorption of the drug was affected by the timing of administration (before or after meal), and the presence of ingested foods in the digestive system delayed the absorption. The overall quantity absorbed, however, did not seem to be affected by the timing of administration. These data also showed that serum and urinary concentrations of the drug depended on dose levels.(ABSTRACT TRUNCATED AT 400 WORDS)

Pharmacokinetic, bacteriological and clinical studies on cefpodoxime proxetil (CPDX-PR, CS-807), a newly developed oral cephem, were carried out in the treatment of infectious diseases in the field of pediatrics. 1. Since CPDX demonstrates very powerful antimicrobial actions against such Gram-negative bacilli as Escherichia coli, Salmonella sp., Klebsiella pneumoniae and Serratia sp., such Gram-positive cocci as Streptococcus pyogenes and Streptococcus pneumoniae, and beta-lactamase producing Branhamella catarrhalis and Haemophilus influenzae, this drug was thought to be useful for the treatment of pediatric infectious diseases when main causative bacteria in the field of pediatrics were taken into account. 2. When changes in blood and urine concentrations of CPDX following the administration of this drug at 3.7 mg/kg before meal were determined, Cmax and T1/2 were found to be 2.98 micrograms/ml at 2-hour and 1.73 hours, respectively; an urinary excretion rate in the first 6 hours and a maximum urine concentration were 32.5% and 52 micrograms/ml, respectively. 3. Clinically, 8 of 8 patients with the upper respiratory tract infections (100%), 28 of 29 patients with bronchitis and/or pneumonia (96.6%), 3 of 4 patients with otitis media (75%), 2 of 2 patients with sinusitis (100%), 3 of 3 patients with the skin soft tissue infections (100%), 1 of 1 patient with bacterial enteritis (100%) and 11 of 14 patients with urinary tract infections (78.6%) responded well to the treatment with CPDX-PR, showing a 91.8% efficacy rate in all the patients treated. 4. Bacteriologically, Staphylococcus aureus, Staphylococcus epidermidis, S. pyogenes, S. pneumoniae, E. faecalis, B. catarrhalis, H. influenzae, E. coli and Salmonella typhimurium were all eradicated from 5, 1, 4, 6, 1, 5, 5, 11 and 1 patient, respectively. An eradication rate in all the patients examined was 97.5% (39/40). 5. Gastrointestinal symptoms appeared as side effects in 2 of 71 patients (vomiting in 1 and diarrhea in 1), hence, an incidence of side effects was 2.8% (2/71). As for abnormal laboratory findings, eosinophilia, thrombocytosis and increases in GOT and GPT were observed in 3 of 39 patients examined (7.7%), 1 of 39 patients (2.6%) and 2 of 34 patients (5.9%), respectively. In addition, we also examined the effect of the drug on the hemostatic system, but found no changes upon the treatment. Based on these results, it appeared that CPDX-PR was a useful and safe drug in treatment of infectious diseases in the field of pediatrics when administered 2-3 times a day at a dose of 3-6 mg/kg.

Pharmacokinetic, bacteriological and clinical studies of ceftizoxime (CZX) were performed in neonates. 1. Serum concentrations and urinary excretion of CZX were investigated in 12 neonates ranging ages from 1 to 27 days (gestational age, 35-41 weeks; birth weight, 2,150-4,030 g) and 2 infants ranging ages from 55 to 57 days (gestational age, 39-40 weeks; birth weight, 2,320-2,650 g). Each of the subjects was given a single intravenous dose of 20 mg/kg by one shot. Serum concentrations of CZX in the neonates were 24.9-53.7 micrograms/ml at 1/4 hour after intravenous injection, with an average of 40.6 +/- 7.6 micrograms/ml. Serum half-lives of CZX were 1.32-4.75 hours and averaged 2.60 +/- 1.06 hours. Serum concentrations ranged from 2.01 to 14.6 micrograms/ml at 6 hours after injection with an average of 7.70 +/- 3.89 micrograms/ml. In the 2 infants, serum concentrations were 42.0 and 46.2 micrograms/ml at 1/4 hour (average: 44.1 +/- 3.0 micrograms/ml), and 2.91 and 5.04 micrograms/ml at 6 hours after injection (average: 3.98 +/- 1.51 micrograms/ml). Half-lives were 1.54 hours in 1 infant and 1.93 hours in the other (average: 1.74 +/- 0.28 hours). Furthermore, 6-hour urinary recovery rates were 28.5-71.7% (average: 49.3 +/- 12.8%) in the neonates and 42.1-55.5% (average: 48.8 +/- 9.5%) in the infants. The above results suggest that the following 3 points are accepted; 1) peak serum concentrations (at 1/4 hour) in neonates were similar to those in infants and older children irrespective of age (days after birth). 2) Serum half-lives of CZX in neonates shortly after birth were 4 or 5 times longer than those in older children, but decreased rapidly with the advance of day-ages. The half-life in neonates of 2 weeks of age or so became shorter to about twice the normal value in infants. Furthermore, half-lives of the drug in those at an age of the first half of infancy were similar to those in older children. 3) The urinary excretion rates tended to be somewhat low with neonates soon after birth, but became very similar to those in infants and older children at a relatively early stage.(ABSTRACT TRUNCATED AT 400 WORDS)

Laboratory and clinical studies were performed on a new semisynthetic cephalosporin, cefamandole (CMD), and following results were obtained. (1) Serum concentrations and urinary recovery rates of CMD were determined after an intravenous administration of CMD 30 mg/kg in 13 children with normal renal function. In 5 of 13 children, mean serum levels after a one shot intravenous injection were 112.5 micrograms/ml at 15 minutes, 52.2 micrograms/ml at 30 minutes, 23.3 micrograms/ml at 1 hour, 4.9 micrograms/ml at 2 hours and trace at 4 hours. In other 5 children, mean serum levels after drip infusion for 1 hour were 78 micrograms/ml at 30 minutes, 59 micrograms/ml at 1 hour, 9.8 micrograms/ml at 2 hours and trace at 4 hours, after the onset of drip infusion. In the remaining 3 children who received CMD by drip infusion for 2 hours, mean serum levels were 24.3 micrograms/ml at 30 minutes, 35.3 micrograms/ml at 1 hour, 30.2 micrograms/ml at 2 hours, 5.3 micrograms/ml at 3 hours and 1.5 micrograms/ml at 4 hours after the onset of drip infusion. Urinary recovery rates in 5 children were 154.7%, 98.3%, 93.2%, 111.8% and 66.9%, respectively, during 8 hours. (2) CMD was administered to 40 patients with various infections (acute U.T.I. 8, acute angina lacunaris; 2, acute bronchitis; 5, cervical purulent lymphadenitis; 2, post-measles bronchopneumonia; 3, acute bronchopneumonia; 18, pyothorax; 2, S.S.S. syndrome; 1) by one-shot intravenous injection at a dose of 40-120 mg/kg per day. The clinical efficacy rate was 92.5% and bacteriological efficacy rate was 79.2%. (3) As the side effect of CMD, eosinophilia was observed in 1 case, rash and elevation of GOT and GPT in 1 case, and proteinuria in 1 case.

Plasma and urine concentrations of sulbactam (SBT) and ampicillin (ABPC) were determined following bolus administration of injectable SBT/ABPC combined in a fixed ratio of 1:2 to 6 pediatric patients, 3 at a dose of 30 mg/kg and the other 3 at 60 mg/kg. Clinical and bacteriological efficacies of SBT/ABPC were evaluated in a total of 65 patients composed of 45 cases with pneumonia, 3 cases each with bronchitis, urinary tract infections, staphylococcal scalded skin syndrome, purulent lymphadenitis, 2 cases each with tonsillitis, pleuropneumonia, phlegmon and 1 case each with pyothorax, submaxillitis. The dosage used was 101.2 mg/kg daily given in 3 or 4 divided doses (t.i.d. in 24 patients and q.i.d. in 41 patients) by bolus intravenous injection for 7 days on an average. Side effects and effects on clinical laboratory parameters were monitored in the 65 patients. The results of these evaluations are summarized as follows. 1. Mean serum concentrations of SBT and ABPC in 3 children each given an intravenous bolus injection of 30 mg/kg and other 3 each given 60 mg/kg reached peak levels at 5 minutes after administration with values of 49.8 and 90.3 micrograms/ml, respectively, for SBT and 99.8 and 189.7 micrograms/ml, respectively, for ABPC. The latter values were about twice as high as SBT, and both were dose-related. Mean half-lives were 0.889 hour for SBT and 0.857 hour for ABPC in the 30 mg/kg group and 0.882 hour for SBT and 0.834 hour of ABPC in the 60 mg/kg group, showing similarities between the 2 dosage groups as well as between SBT and ABPC. 2. Mean urine concentrations in the 2 groups mentioned above were the highest for both SBT and ABPC during the first 2 hours after administration, with values of 1,677 micrograms/ml for SBT and 2,730 micrograms/ml for ABPC in the 30 mg/kg group and 2,693 micrograms/ml and 3,623 micrograms/ml, respectively, in the 60 mg/kg group. Mean recovery rates in urine in the first 6 hours were 72.4% for SBT and 56.8% for ABPC in the low dosage group and 72.7% and 52.0%, respectively, in the high dosage group. In the 2 groups, the amounts of ABPC recovered were less than those of SBT. 3. Clinical efficacies of SBT/ABPC in 65 patients with various bacterial infections were excellent or good in 62 (95.4%) patients. 4. The bacteriological efficacy was evaluable with 10 patients. The pathogenic bacteria were eradicated in 9 patients and the efficacy rate was 90%.(ABSTRACT TRUNCATED AT 400 WORDS)

Cefotiam (CTM) was given to 25 mature and premature infants, ranging in age from 0 to 24 days, who have various nearly-healed bacterial infections. CTM was administered at the dose of 10 mg/kg by intravenous injections or by 1-hour intravenous drip infusions, or at the dose of 20 mg/kg by intravenous injections. Only a small number of subjects being examined, they were divided by their aged day into 3 groups; 0-3 days old, 4-7 days old and 8-24 days old. We compared the time courses of changes in serum and urine levels of CTM in these groups. The clinical study was done with 8 male and 4 female infants ranging in age from 3 days to 4 months. One had septicemia, 4 had bronchopneumonia, 3 had urinary tract infection, 1 had colitis, 2 had abscess, and 1 had maxillary sinusitis. Changes in serum and urinary levels of CTM Changes in serum levels after 10 mg/kg intravenous injection. Peak serum CTM levels of all 3 groups were achieved at 30 minutes after administration; the levels were between 11.7 and 23.6 micrograms/ml; and differences were not significant. Serum levels then gradually decreased in all the groups to 0.5-7.0 micrograms/ml at 6 hours after administration. Half-lives of serum CTM levels tended to be shorter in older infants; means were 2.7, 2.2 and 1.3 hours for the 0-3 day-old, the 4-7 day-old and the 8-24 day-old respectively. Changes in serum levels of CTM after 10 mg/kg 1-hour intravenous drip infusion. The 0-3 day-old and the 4-7 day-old had peak serum CTM levels, ranging from 16.3 to 35.8 micrograms/ml, at the end of drip infusion. Half-lives of serum CTM levels tended to be shorter in older infants, with 3.2 hours for the 0-3 day-old and 2.0 hours for the 4-7 day-old groups. Changes in serum levels after 20 mg/kg intravenous injection. The 0-3 day-old and the 4-7 day-old had peak serum levels, ranging from 30.6 to 42.1 micrograms/ml, at 30 minutes after administration, then serum levels of CTM in either group showed a gradual decrease to 2.5-11.4 micrograms/ml at 6 hours after injection.(ABSTRACT TRUNCATED AT 400 WORDS)

Single doses of cefotiam (CTM) by bolus injection of 20 mg/kg of CTM were given to 17 neonates and premature babies (11 prematures) and plasma and urine CTM levels as well as urinary recovery rates of CTM were determined. The CTM was also evaluated clinically with regard to therapeutic and protective effects, bacteriological efficacy as well as safety. A mean daily dose of 56.6 mg/kg of CTM was given intravenously in 2 to 4 divided doses for an average of 8 days to 11 neonates and prematures consisting of 1 case with pneumonia, 2 suspected septicemia, 3 urinary tract infections and 5 for prophylaxis against infections. (In the 6 babies evaluated for clinical effects, a mean dose of 59.8 mg/kg/day of CTM was given for an average 9 days). The findings of these studies are summarized below: The mean peak plasma level of 2 cases of 4-7 day-old neonates was 32.3 mcg/ml 5 minutes after injection. The mean AUC was 96.6 mcg X hr/ml, and the mean half-life was 2.12 hours. In 3 of the 4 neonates of 8-14 day-old group, the mean peak plasma level of 55.6 mcg/ml was obtained after 5 minutes. The mean AUC was 63.0 mcg X hr/ml and the mean half-life was 0.82 hour. Compared to the 4-7 day-old group, AUC was smaller and half-life was shorter in this group. In premature infants, plasma CTM levels were determined in 2, 1, 1, 5 and 2 cases of the 0-3, 4-7, 8-14, 15-21 and 22-28 day-old infants, respectively. In the 8-14 day-old group and one of 15-21 day-old group, peak plasma levels were obtained after 15 minutes. Peak plasma levels in the remaining groups, were attained after 5 minutes. Peak plasma levels in the 5 groups were 40.7, 48.4, 33.9, 38.1 and 45.3 mcg/ml, respectively. Mean or individual AUC's obtained after excluding markedly varying values from the respective groups were 122.0, 96.2, 65.2, 72.8 and 60.4 mcg X hr/ml, respectively. With the increasing age, the AUC tended to decrease. Mean or individual half-lives were 2.31, 1.47, 1.28, 1.41 and 0.96 hours, respectively, showing a tendency to decrease with increasing age. In 6 neonates, high urinary levels continued up to 6 hours after administration. Mean 6-hour urine recoveries in the 4-7 and 8-14 day-old groups were 16.6% and 43.0%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Seven neonates and young infants were treated with cefotiam (CTM) in doses ranging from 8-25.6 mg/kg every 6 to 24 hours for 1 to 14 days, and the clinical efficacy and side effects were evaluated. Among 5 infants with bacterial infections including bacteremia, perianal abscess, pneumonia, urinary tract infection and probable sepsis and meningitis, clinical responses were excellent in 1 and good in 4 patients. In the 7 patients, no side effect attributable to CTM was observed. Serum concentrations of CTM were measured in 5 patients administered with 10 to 20 mg/kg of CTM by bolus intravenous injection. Peak serum concentrations of 21.9 to 38.0 micrograms/ml were noted in samples taken at 15 minutes after injection. Serum half-lives of the drug were 2.35 hours in 2 day-old neonate, 0.72 to 0.85 hours in 3 infants of 25 to 37 days, and 8.46 hours in an 18 day-old neonate with renal insufficiency.

Twenty nine children were treated with cefpodoxime proxetil (CPDX-PR, CS-807) and the clinical efficacy and side effects were evaluated. Ages of the patients ranged from 2 months to 10 years. Dose levels of CPDX-PR ranged from 7.5 to 12.0 mg/kg/day for 5 to 12.7 days. The 29 patients included 9 tonsillitis, 2 otitis media, 5 scarlet fever, 3 bronchopneumonia, 1 lymphadenitis, 8 urinary tract infections and 1 staphylococcal scalded skin syndrome, and they were evaluated for the clinical efficacy of CPDX-PR. Results were excellent in 21 and good in 8 patients. Out of the 29 patients, 3 cases showed diarrhea and 2 cases showed elevated GOT and GPT. The pharmacokinetics of CPDX-PR was studied in 9 patients whose ages ranged from 1 to 9 years. The serum peak concentrations of CPDX in 5 patients were between 1.37 and 4.10 micrograms/ml (mean: 2.53 micrograms/ml) at 1 to 6 hours after dosing 3 mg/kg before meals. Those of 4 patients ranged 3.29 to 4.88 micrograms/ml (mean: 4.36 micrograms/ml) at 2 hours after administering 6 mg/kg before meals. Portions of CPDX excreted into urine within 6 hours ranged from 20.3 to 34.3% (mean 27.1%) in 5 patients who were given 3 mg/kg, and ranged from 24.1 to 65.7% (mean 41.1%) in 4 patients given 6 mg/kg.

Laboratory and clinical studies on cefodizime (CDZM, THR-221), a newly developed cephem antibiotic, were done. The results obtained are summarized as follows: 1. Absorption and elimination were examined in a total of 5 cases including a case of 10 mg/kg intravenous drip infusion for 30 minutes, 2 cases of 20 mg/kg rapid intravenous injection and 2 cases of 40 mg/kg drip infusion for 30 minutes. Maximum serum levels were attained immediately after drip infusion or rapid injection. Cmax's were 119.2 micrograms/ml for 10 mg/kg, 374.9 micrograms/ml or 255.7 micrograms/ml for 20 mg/kg, and 321.3 micrograms/ml or 431.8 micrograms/ml for 40 mg/kg. These values were determined using an high performance liquid chromatography (HPLC) method. In general, values using the bioassay were higher than those with the HPLC method. T 1/2 (beta)'s were between 1.74 and 1.93 hours using HPLC, and between 1.77 and 2.24 hours using bioassay. Urinary recovery rates were examined in 3 out of 5 cases. Cumulative urinary recovery rates were 57.9-90.6% with HPLC method and 50.4-88.0% with bioassay in a period of 0-8 hours after administration. 2. Clinical efficacy was evaluated in a total of 22 cases including 14 cases of respiratory tract infections, 5 cases of urinary tract infections and 3 cases of cellulitis. Clinical efficacy rate was 95.2%. Bacteriologically, pathogenic organisms were eradicated in 90.0%. As adverse reactions, 1 angular stomatitis, 1 diarrhea and 1 loose stool were noted. Abnormal laboratory test values detected were 1 case of increased GPT and 1 case of increased GOT and GPT.

Bacteriological, pharmacokinetic and clinical studies on cefpodoxime proxetil (CPDX-PR, CS-807), a new oral cephem antibiotic, were carried out in the field of pediatrics. The results obtained are summarized as follows. 1. Antibacterial activities of R-3746 (Na-salt of cefpodoxime (CPDX] against clinically isolated strains of Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus, Enterococcus faecalis, Branhamella catarrhalis, Escherichia coli, Proteus mirabilis and Haemophilus influenzae were compared with those of cefaclor, cephalexin and cefadroxil. R-3746 is superior to other antibiotics against S. pneumoniae, S. pyogenes, B. catarrhalis and Gram-negative rods. 2. Serum concentrations of CPDX after administration of CPDX-PR at doses of 3 mg/kg (fasting), 6 mg/kg (non-fasting) and 6 mg/kg (fasting) were determined. Mean AUC (area under curve)'s of CPDX obtained were 9.60, 31.35 and 17.89 micrograms.hr/ml, respectively for the 3 dosages. The mean half-lives of CPDX were 3.35, 1.88 and 1.76 hours, respectively. The mean urinary recovery rate within 8 hours after administration of CPDX-PR at a dose of 3 mg/kg (fasting) was 39.2%. 3. CPDX-PR was administered to 37 pediatric patients with various bacterial infections (pyelonephritis 9, cystitis 4, pneumonia 7, acute bronchitis 3, otitis media 2, tonsillitis 10, subcutaneous abscess 1 and purulent lymphadenitis 1). The overall clinical efficacy rate was 91.9% and the overall bacteriological eradication rate was also 91.9%. 4. No adverse reactions were observed. Abnormal laboratory findings were moderate, eosinophilia in 2 and slight elevation of GOT and GPT in 1. The taste and the odor of the CPDX-PR preparation was sufficiently tolerable. From the above results we have concluded that CPDX-PR is a useful oral antibiotic in the treatment of bacterial infections in children.

Cefpodoxime proxetil (CPDX-PR, CS-807) was evaluated for its efficacy, safety and pharmacokinetics in children. CPDX-PR was effective in 93.6% of 47 cases with respiratory tract, middle ear, skin or urinary tract infections. Twice or 3 times daily administration of 3 mg/kg each was sufficient to treat streptococcal pharyngitis and Haemophilus influenzae infections. No severe adverse reaction was encountered in 52 cases treated with CPDX-PR. The serum half-life was approximately 2.17 +/- 0.24 hours after oral administration.

In vitro enzymatic degradation rate of ampicillin (AB-PC) in urine of patients with complicated urinary tract infection and its protective effect of dicloxacillin (MDI-PC) was studied using a specific fluorometric assay for aminobenzylpenicilloic acid (AB-PA), which is converted from AB-PC by bacterial beta-lactamase. The results showed that average degradation rate of AB-PC in the urine of 10 patients were 12.2%, 21.5%, 34.3% and 48.2% at 15, 30, 60 and 120 minutes, respectively. While MDI-PC prevented the enzymatic transformation of AB-PC in such urinary samples and the average degradation rates at 15, 30, 60 and 120 minutes were considerably reduced to 7.7%, 12.2%, 21.6% and 32.8%, respectively. In vivo urinary excretion rate of AB-PA was compared between a total of 5 patients and 4 healthy volunteers after oral administration of 250 mg AB-PC. It was found that the patients excreted 9.1%, 10.7% and 12.7% of total dose at 0 approximately to 2 hours, 2 approximately to 4 hours, 4 approximately to 6 hours, respectively, while the average excretion rates in healthy volunteers were 1.54%, 2.88% and 7.94%, respectively. In 4 patients cross-over administration study, the combined dose of AB-PC and MDI-PC has been proved to clearly decrease the urinary excretion rate of AB-PA in 2 cases, but there was no significant difference in the average rate between the single and the combined dose.