A new oral macrolide, clarithromycin (TE-031, A-56268), was evaluated for its safety, efficacy and pharmacokinetics in 33 children. TE-031 was effective in all cases of mycoplasmal pneumonia, pneumococcal pneumonia, streptococcal pharyngitis, pertussis and Campylobacter gastroenteritis.
The pharmacokinetic availability of TE-031 granule and tablets was much better than the older macrolides; serum half-lives of TE-031 averaged 3.2±0.25 hours (for the granule preparation).
No clinical adverse reaction was encountered, but cases of transient mild elevation of the serum GPT (2 cases) and eosinophilia (2 cases) were encountered.
From these preliminary data, TE-031 seems to have a place in the treatment of pediatric infectious diseases.

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Clarithromycin (TE-031, A-56268) is a new 14-membered ring macrolide antibiotic developed by Taisho Pharmaceutical Co., Ltd. TE-031 has a methoxy group at position 6 in its structure.
In the present study, we carried out laboratory and clinical investigations on TE-031 in the field of pediatrics. The obtained results are summarized as follows.
The antibacterial activity of TE-031 was investigated against 16 clinically isolated strains of Streptococcus pyogenes, Staphylococcus aureus, Haemophilus influenzae, Bordetella pertussis and Campylobacter jejuni. TE-031 showed antibacterial activity comparable to erythromycin.
The pattern of changes in TE-031 concentrations in the blood after administration was investigated. In subjects administered the granular preparation of TE-031, C_max values were 0.64μg/ml in 1 subject given a 5mg/kg dosage, and 5.94 and 9.02μg/ml in 2 subjects administered with 10mg/kg. The tablet form of TE-031 was administered to 3 subjects at 5mg/kg, and C_max values were 2.09-3.92μg/ml, while T 1/2 values were in a range of 2.9-3.8 hours. When drug concentrations in the urine were investigated, it was found that 6-hour recovery rates were 9.9% (dose: 5mg/kg) and 53.4% (dose: 10mg/kg) in the subjects administered the granular form, whereas recovery rates averaged 36.8% in the tablet-administered subjects.
In the clinical trial, TE-031 was administered in 2-3 doses/day for 2-48 days. In cases given the granular form, dosages were 12-38mg/kg/day, while tablets were administered at 12-29mg/kg/day. The overall clinical efficacy rate was 92.8%, i. e., the drug was effective in 64 of 69 patients. TE-031 was ineffective in 1 case of otitis media, but efficacious in 10 of 10 (100%) cases of upper respiratory infection, 15 of 18 (83.3%) cases of bronchitis and pneumonia, 5 of 6 (83.3%) cases of pertussis, 13 of 13 (100%) cases of mycoplasmal pneumonia, 4 of 4 (100%) cases of Chlamydia psittaci pneumonia, 16 of 16 (100%) cases of gastroenteritis (including 15 cases of Campylobacter gastroenteritis), and 1 (100%) case of impetigo.
In bacteriological studies conducted on the patients, the overall elimination rate was 93.1%, i. e., bacterial elimination was obtained in 27 of 29 cases. TE-031 showed especially good bacteriological efficacy (100%) against C. jejuni and B. pertussis, which were eliminated from all of 15 and 2 cases examined, respectively.
Analysis for side effects was conducted in 82 patients administered with TE-031. Adverse symptoms occurred in 6 of those patients, for an incidence rate of 7.3%. These side effects consisted of digestive tract symptoms in 5 patients (1 case each of abdominal pain, vomiting, and abdominal pain and vomiting, and 2 cases of diarrhea or loose stool) and urticaria in 1 patient. Various laboratory test abnormalities were also detected: eosinophilia in one of 38 (2.6%) patients examined, elevated GOT in 3 of 39 (7.7%) patients, and elevated GOT and GPT in one of 39 (2.6%) patients. In addition, studies were carried out to determine whether or not TE-031 exerts any effect on the hemostatic mechanism, but no change was detected in the blood clotting factors by the TE-031 administration regimen.
On the basis of the basic and clinical study results summarized above, it is surmised that TE-031 will be an effective and safe oral antibiotic for use in the treatment of infections in children when administered 2-3 times per day in a dose of 5-10mg/kg.

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Pharmacokinetic, bacteriological and clinical studies were carried out on clarithromycin (TE-031, A-56268) in the pediatric field and following results were obtained.
1. Peak concentrations of TE-031 in the serum occurred at 1-2 hours after administration of 10mg/kg in granular form and at 2 hours after administration of 20mg/kg in granular form.
Half-lives of the drug in serum were 2.5-3.3 hours in cases of 10mg/kg dosage and 5.5 hour in case of 20mg/kg dosage.
TE-031 tablets were administered in a dosage between 1.7 and 5.0mg/kg and peak concentrations in the serum occurred at 0.5-2 hours. Half-lives were 2.0-4.3 hours.
2. Urinary recovery rates obtained upon administration of TE-031 granule during the first 6 hours after administration were 20.3-62.9%, while they were 11.6-42.4% with TE-031 tablets.
3. Antibacterial activity of TE-031 against Campylobacter jejuni was equal to that of erythromycin and slightly superior to those of josamycin, midecamycin acetate and rokitamycin.
4. Bacteriological efficacy rate of TE-031 on 8 species of bacteria isolated from various samples was 88.4% and clinical efficacy rate on 66 cases (upper/lower respiratory tract infections, mycoplasmal pneumonia, Campylobacter enteritis, et al.) was 100%.
5. TE-031 was administered in dosages of 6.8-42.3mg/kg/day (mostly 20-30mg/kg/day) 3 times a day and lengths of administration ranged from 4 to 15 days.
6. Side effects due to TE-031 were observed in 1 case each of transient symptom and abnormal clinical laboratory test value.
According to the above results, TE-031 was recognized as a useful antibiotic for the treatment of infections in the pediatric field.

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Clarithromycin (TE-031, A-56268) is a new macrolide antibiotic developed by Taisho Pharmaceutical Co., Ltd. Basic and clinical studies in the field of pediatrics were carried out on a granular preparation and 50mg tablets of TE-031 designed for use in children. The following results were obtained.
1. Concentrations of TE-031 in the serum and its excretion in the urine were investigated in children. Six children were orally administered with a TE-031 granular preparation at 10mg/kg in a cross-over study 30 minutes before meal and 30 minutes after meal. When the drug was ingested before meal, the mean peak serum concentration occurred 1 hour later and was 5.32±1.20μg/ml. The mean half-life of TE-031 in the serum was 3.6±1.0 hours, and drug levels decreased to 1.94±0.55μg/ml at 6 hours after dosing. In cases of the postprandial administration, the mean peak serum level was 4.21±1.25μg/ml, occurring 2 hours after ingestion. The mean serum half-life in these cases was 3.5±1.3 hours, and serum levels decreased to 1.66±0.47μg/ml at 6 hours after dosing. Mean urinary recovery rates during the initial 6 hours after ingestion were 30.5±6.4% in the cases of preprandial administration and 34.7±7.3% with postprandial administration.
In addition, 30 minutes before meal, 50mg tablets of TE-031 were orally administered to 3 children in a dose level equivalent to approximately 10mg/kg, followed by monitoring of serum and urinary levels. It was found that the mean serum concentration showed a peak value of 4.10±0.44μg/ml at 2 hours after dosing, the mean serum half-life was 3.5±0.7 hours, and the mean level fell to 1.90±0.55 μg/ml by 6 hours after dosing. The mean 6-hour urinary recovery rate was 32.7±12.1%. On the basis of the above results, it has been surmised that, in comparison to conventional microlide antibiotics, TE-031 is better maintained in the blood at a high concentration and is more efficiently excreted into the urine. In addition, the data show that the bioavailability of TE-031 is slightly superior when the drug is administered on an empty stomach compared with after a meal. And finally, it was found that the granular and 50mg tablet preparations of TE-031 are almost equivalent in terms of the absorption and the excretion of the drug.
2. TE-031 was orally administered to 56 children (age range: 10 month to 12 years) with various infections. The granular preparation was used for 52 patients and the tablet preparation for 4 patients. The employed doses were in a range of 5.2-16.7mg/kg administered three times a day before meals. The durations of this drug therapy were in a range of 2.33-9 days. The clinical efficacy, the bacteriological efficacy and the safety of the drug were investigated. The cases included in the evaluation of the clinical efficacy totaled 51 cases, consisting of 2 cases of acute pharyngitis, 26 cases of acute purulent tonsillitis, 12 cases of acute pneumonia (including 7 cases of mycoplasmal pneumonia), 10 cases of acute enteritis and 1 case of impetigo. The efficacy evaluation results showed 41 excellent cases and 10 good cases, for an overall clinical efficacy rate of 100.0%. In addition, the bacteriological efficacy of the TE-031 therapy was investigated in relation to the following bacterial strains which were isolated from 24 patients and identified as the causative microbes: 1 strain of Staphylococcus aureus, 10 strains of Streptococcus pyogenes, 7 strains of Haemophilus influenzae, 1 strain of Haemophilus parainfluenzae and 5 strains of Campylobacter jejuni. All of these strains were judged to have been eradicated, except for 2 strains of H. influenzae and the 1 strain of H. parainfluenzae, and their counts were decreased. The eradication rate was thus 87.5%.

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Laboratory and clinical studies on clarithromycin (TE-031, A-56268), a new macrolide antibiotic, were carried out in the field of pediatrics. The results obtained are summarized as follows:
1. Serum concentrations, urinary concentrations and urinary recovery rates were determined upon oral administration on fasting of TE-031 at doses of 5mg/kg granules in 1 case and tablets in 2 cases, and 10mg/kg granules in 1 and 15mg/kg granules in 1. Peak serum levels were obtained at 30 minutes in 2 cases, at 1 hour in 2 cases and at 2 hours in 1 case after administration of the drug with a range of 2.29-7.10μg/ml with half-lives of 2.2-7.5 hours. Urinary recovery rates in 6 hours after administration ranged from 7.1-34.5%.
2. MICs of TE-031 against 49 clinical isolates (Streptococcus pyogenes 5 strains, Streptococcus pneumoniae 9, Staphylococcus aureus 3, Branhamella catarrhalis 4, Haemophilus influenzae 14, Haemophilus parainfluenzae 7, and Campylobacter jejuni 7) were compared with those of josamycin (JM), erythromycin (EM), and ampicillin (ABPC). The antibacterial activity of TE-031 was superior to those of JM and equal to those of EM.
3. Fifty-five pediatric patients with acute infectious diseases (scarlet fever 3 cases, pharyngitis and tonsillitis 15, pertussis 2, pneumonia 10, bronchitis 14, Campylobacter enteritis 11) were treated with TE-031 at daily doses of 10-35mg/kg t. i. d. as a rule. The efficacy rates were 96% clinically and 72% bacteriologically.
4. Side effects or abnormal laboratory test values were not observed.
5. None of children refused TE-031.

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Clarithromycin (TE-031, A-56268), a newly synthesized macrolide antibiotic, was administered to children and its efficacy was examined.
The clinical efficacy rate of TE-031 was 88.5% in 26 patients with pediatric infections. This rate was regarded as quite high.
A side effect, transaminase elevation, was observed in 1 out of the 26 patients but it was subsided after a cessation of the antibiotic treatment.
TE-031 was considered to be effective antibiotic for the infectious disease in the pediatric fields because of highly efficacy rate.

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A clinical evaluation of clarithromycin (TE-031, A-56268), a newly synthesized macrolide antibiotic, was made for its efficacy and safety in 30 patients with ages ranging from 8 month-old to 12 year-2 month-old with mycoplasmal and bacterial infections. The obtained results are summarized below.
1. A pharmacokinetic study following oral administration of TE-031 at 10mg/kg (granule) or 5.5mg/kg (tablet) resulted in blood concentrations and urinary recovery rates higher than with other macrolides.
2. TE-031 was administered orally to 5 patients with Mycoplasma pneumonia, 21 patients with pneumonia or bronchopneumonia, 2 patients with pertussis and 2 patients with enterocolitis at daily dosages ranging 11.1-31.6mg/kg divided into 3. Clinical evaluations of these 30 patients were as follows; excellent: 19 patients, good: 11 patients. The efficacy rate was 100%.
3. Neither clinical adverse reaction nor abnormal laboratory data was found in any of these 30 patients.
4. MICs of TE-031 against 10 strains of bacteria isolated from 10 patients with pneumonia or bronchopneumonia were as follows. MICs against 3, 2 and 2 out of 7 strains of Streptococcus pneumoniae were less than 0.025μg/ml, 0.05μg/ml and 0.10μg/ml, respectively. MIC against a strain of Haemophilus influenzae was 3.13μg/ml. MICs of 2 strains of Branhamella catarrhalis were 0.20μg/ml.
5. TE-031 is considered to be a new useful and safe antibiotic in pediatric patient with an excellent bactericidal capacity.

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We have carried out laboratory and clinical studies on clarithromycin (TE-031, A-56268). The results are summarized as follows.
Serum and urinary concentrations of TE-031 were determined in 5 children with ages between 6 and 11 years given single oral doses of 5, 6.7, 10 and 15mg/kg. Serum concentrations peaked at 1 hour after administration of 5, 6.7 and 15 mg/kg, and respective peak values were 1.98μg/ml, 2.21μg/ml and 5.58μg/ml. Biological half-lives for the drug at 5, 6.7 and 15mg/kg dose were 2.99 hours, 2.08 hours and 2.09 hours, respectively. Mean serum concentrations peaked at 2 hours after administration of 10mg/kg, and peak values were 3.91±1.64μg/ml. Biological half-lives were 3.00±0.58 hours. The 6-hour urinary recovery rates ranged from 22.7% to 23.8% after administration of 10mg/kg, and the 6-hour urinary recoveries were 30.1%, 20.5% and 39.1% after administration of 5mg/kg, 6.7mg/kg and 15mg/kg, respectively.
Therapeutic responses were recorded as excellent or good in 35 (89.7%) of the children, comprising 5 with tonsillitis, 3 with pharyngitis, 7 with bronchitis, 5 with pneumonia, 15 with Mycoplasma pneumonia, 1 with whooping cough and 3 with Campylobacter enteritis.
The microbiological effectiveness of TE-031 on identified pathogens comprising 2 strains of Streptococcus pneumoniae, 5 strains of Haemophilus influenzae, 2 strains of Haemophilus parainfluenzae, 5 strains of Mycoplasma pneumoniae and Campylobacter spp. was satisfactory as evidenced by an eradication rate of 82.4%.
No significant side effect due to the drug was observed in any cases. In conclusion, TE-031 was found to be efficacious and safe for the treatment of bacterial infections in children.

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1. Clarithromycin (TE-031, A-56268) was given orally to 46 children with respiratory infections, skin infections and others. A total of 9 patients were excluded; 8 patients refused to take the drug because of it's taste, and 1 patient was later found to have viral pneumonia. Clinical efficacy was therefore evaluated in remaining 37 cases and was good or excellent in 27 cases.
2. Bacteriologically, Haemophilus influenzae strains isolated from 4 patients were eradicated in 1 and decreased in 3, respectively. Haemophilus parainfluenzae and Staphylococcus aureus isolated from 1 patient each were both eradicated.
3. Side effect or abnormal laboratory test values were not observed.
4. Based on the above findings, it appears that TE-031 is a safe and is useful antibiotic for the treatment of mild and moderate respiratory infections. It is necessary, however, to improve the taste of the current granule preparation in order to make the drug more easily palatable to children.

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Clarithromycin (TE-031, A-56268), a new macrolide antibiotic, was administered to a total of 25 child patients (age range: 4 months-12 years) to treat infections; the patients consisted of 23 children who received the drug in the form of granules for children and 2 patients who were given tablets. Daily dosages were 14.3mg/kg (in 2 divided doses) in 1 patient, and 18.3-30.3mg/kg (in 3 divided doses) in the other 24 patients. Lengths of administration ranged from 4 to 13 days with 6-8 days for 18 of the patients. The results obtained are summarized as follows.
1. Clinical efficacy evaluations for various infections were as follows: 1 excellent, 4 good and 2 fair cases in 7 cases of pertussis; 3 excellent, 2 good and 1 fair cases in 6 cases of tonsillitis; 1 good case in tonsillitis with bronchitis; 1 excellent and 3 good cases in 4 cases of bronchitis; 1 excellent and 1 good cases in 2 cases of pneumonia; and 4 excellent and 1 good cases in 5 cases of enteritis. Thus, evaluations of a total of 25 patients showed 10 excellent, 12 good and 3 fair cases, with no poor cases. The overall clinical efficacy rate was, therefore, 88.0%. These results were attributed to good antimicrobial activity and absorption of TE-031.
2. Causative bacteria were isolated from 12 of the patients. Bacteriological efficacies of TE-031 on those strains were investigated with the following results. Of 5 Haemophilus influenzae strains, 3 were eliminated, 1 was reduced, and no change was observed in the other. It was not possible to isolate Campylobacter jejuni in the second culture, hence the outcome of TE-031 activity on C. jejuni was unclear. The remaining 6 strains of bacteria (2 strains each of Staphylococcus aureus and C. jejuni, and 1 strain each of Streptococcus pyogenes and Bordetella pertussis) were all eliminated by the therapy. Therefore, the overall elimination rate for the isolated causative bacteria was 81.8%.
3. There were no instances of side effects or abnormal laboratory test values.
4. On the bases of the above results, it was concluded that TE-031 is a useful new macrolide for the treatment of infections encountered in pediatrics. However, there was a problem regarding the granular form of TE-031 employed in this clinical trial in that 3 of the infant patients were hardly able to ingest the drug due to its coarseness and bitter taste. In addition, in 3 patients the drug was not ingested as often as scheduled. We have become aware, therefore, that it is important for physicians to convince parents of child patients that the granular preparation is the most suitable for their treatment, and that the parents must be given careful directions regarding the proper way of making their children take the drug.

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Clarithromycin (TE-031, A-56268) was orally administered to 20 children with the following acute bacterial infections; 1 case of acute pharyngitis, 3 cases of acute tonsillitis, 11 cases of acute bronchitis, 1 case of exacerbation of chronic bronchitis, 1 case of acute bronchopneumonia, 2 cases of Mycoplasma pneumonia and 1 case of impetigo.
Clinical effectiveness was obtained in 15 out of the 20 cases (75.0%).
No clinical side effects and laboratory abnormalities were observed.
The above results suggest that TE-031 is a useful antibiotics for treating pediatric patients with various bacterial infections.

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Studies were conducted on in vivo pharmacokinetics of clarithromycin (TE-031, A-56268) in children and also on the efficacy and the safety of this macrolide antibiotic in the treatment of bacterial infections in children. The results obtained are summarized as follows:
1. TE-031 granules were orally administered to 5 children in a dosage of 5mg/kg before meal. Maximum drug concentrations (range: 0.29-2.0μg/ml) in the serum occurred during a period from 30 minutes to 1 hour after administration, but there were clear differences in blood concentrations among the individuals.
2. TE-031 granules were orally administered in a average dosage of 20mg/kg/day to a total of 17 patients, consisting of 14 children with respiratory tract infections and 3 children with intestinal infections. The clinicalefficacy evaluation resulted in 10 excellent cases, 6 good cases and 1 fair case, for an efficacy rate of 94.1%.
3. Studies on the bacterial efficacy were carried out for 10 cases. The TE-031 bacteriological efficacy evaluation showed elimination in 7 cases, a decreased bacterial count in 2 cases, and no change in 1 case. The elimination rate was, thus, 70.0%. Elimination rates according to different species of bacteria were 66.7% (2 of 3 strains) for Staphylococcus aureus, 100% for both Streptococcus pneumoniae (3 of 3) and Streptococcus pyogenes (1 of 1), and 42.9% (3 of 7) for Haemophilus influenzae.
4. There were no symptoms which were attributable to side effects of the TE-031 therapy. The only laboratory test abnormality detected was eosinophilia in 1 patient.

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A new macrolide antibiotic, clarithromycin (TE-031, A-56268), was studied for its clinical efficacy in the field of pediatrics. Patients treated were infants and children ranging from 2 months to 11 years old suffering from acute bronchitis in 5 cases, acute tonsillitis in 2 cases, Mycoplasma pneumonia in 2 cases, pertussis in 6 cases, scarlatina in 1 case and acute enteritis in 2 cases, a total of 18 cases. TE-031 was administered 19.7-43.5mg/kg in daily doses and lengths of treatment ranged from 4 to 19 days. As regards to its clinical efficacy, good or excellent results were obtained in all cases: excellent in 11 cases and good in 7 cases. No clinical side effects nor abnormal laboratory test values obviously attributable to TE-031 were observed.

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Clarithromycin (TE-031, A-56268) was given orally to 25 children with acute bacterial infections including 5 with bronchitis, 8 with pneumonia, 4 with Mycoplasma pneumonia, 2 with pertussis and 6 with Campylobacter enteritis. Good to excellent clinical responses were obtained in 22 patients with bacterial eradication of all 10 strains. No side effect was observed.
From the above clinical results, it appears that TE-031 is a useful antibiotic for the treatment of pediatrics with various bacterial infections.

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Clarithromycin (TE-031, A-56268) granules were used to treat various infections in the pediatric field and the results obtained are summarized as follows.
1. TE-031 was administered to a total of 10 patients (5 cases of enteritis, 4 cases of bronchitis and 1 case of tonsillitis). Clinical efficacies were excellent in 6 patients and good in 4 with an efficacy rate of 100%.
2. Neither side effects nor abnormal laboratory test values were observed. There was no rejection of drug disturbing the therapy.

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A newly developed macrolide clarithromycin (TE-031, A-56268), with antibacterial spectrum and antibacterial activity nearly equal to those of erythromycin (EM), shows beneficial characteristics such as a higher blood level, higher recovery rate in urine, and better penetration into each tissue than conventional macrolides (MLs). TE-031 has been studied in adults against various infections and proved to be useful.
The present paper describes the results of a study in children to examine the usefulness of TE-031 granules and tablets with a potency of 50mg.
TE-031 granules were administered to 132 children with ages from 6 months to 13 years and 10 months. Excluded from the evaluation were 12 cases in which clinical effects were deemed unevaluable. The evaluable subjects consisted of 1 case with pharyngitis, 3 with tonsillitis, 9 with acute bronchitis, 19 with pneumonia, 19 with mycoplasmal pneumonia, 2 with scarlet fever, 20 with Campylobacter enteritis, 11 with impetigo, 2 with subcutaneous abscess, 18 with primary atypical pneumonia and 16 with acute enteritis of unidentified pathogens; a total of 120 subjects. An average daily dose of TE-031 was 25.9mg/kg, divided into 3 doses except 1 case with 2 daily doses and lengths of the treatment averaged 7 days. TE-031 tablets each containing 50mg potency, were administered to 49 subjects with ages from 3 years and a month to 14 years consisting of 8 cases with pharyngitis, 1 with tonsillitis, 1 with acute bronchitis, 4 with pneumonia, 14 with mycoplasmal pneumonia, 4 with scarlet fever, 5 with Campylobacter enteritis, 7 with impetigo, 1 with atypical pneumonia, 1 with Salmonella gastroenteritis and 3 with acute enteritis caused by unidentified pathogens, at an average daily dose of 13.5mg/kg divided into 2-4 doses (2 doses/day for 12 cases, 3 doses for 32, 4 doses for 5) for 7 days on the average. In addition to examine the clinical and bacteriological effects of the 2 dosage forms of TE-031, minimum inhibitory concentrations (MICs) were determined for 9 antibiotics consisting of 5 MLs including TE-031, EM, josamycin (JM), midecamycin acetate (MDM acetate), and rokitamycin (RKM), 3 penicillins including ampicillin (ABPC), methicillin, cloxacillin and 1 cephem antibiotic, cefaclor (CCL), against 29 strains consisting of 12 strains of Staphylococcus aureus, 7 of Streptococcus pyogenes, 2 of Streptococcus pneumoniae, 2 of Haemophilus influenzae and 6 of Campylobacter jejuni, out of 71 strains of pathogens or possible pathogens that had been isolated from the cases given TE-031. An inoculum size of 10⁶cfu/ml was used. Against C. jejuni, MICs of kanamycin, fosfomycin and ofloxacin as well as all the above antibiotics were determined. Furthermore, side effects and influences on laboratory test values were examined for cases in which TE-031 was used. The results were as follows.
1. The Clinical effect of TE-031 granule was good or excellent in 109 of 120 of various cases of infections, with an efficacy rate of 90.8%. When cases with atypical pneumonia and with acute enteritis due to unidentified pathogens were excluded, the clinical effects of the granules were good or excellent in 79 of 86 cases, with a very high efficacy rate of 91.9%.
2. In clinical evaluations, TE-031 tablets showed good or excellent effects in 48 cases out of 49, with an efficacy rate of 98.0%. When diseases outside the spectrum of TE-031, i. e. atypical pneumonia, Salmonella gastroenteritis and acute enteritis of unidentified pathogens, were excluded as in cases treated with TE-031 granules, the clinical effects of the tablet were good or excellent in 43 of 44 cases, with an efficacy rate of 97.7%, which was similar to the high efficacy rate for TE-031 granules.

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It has been known that clarithromycin (TE-031, A-56268), a new macrolide antibiotic (ML), achieves higher concentrations in blood, is better excreted into urine and is better distributed into various tissues than conventional MLs. We investigated the pharmacokinetics of TE-031 in children upon oral administration of the drug in the following method. TE-031 granular preparation with a potency of 100mg/g was given to 6 boys (5 years 4 months-44 years 0 month) with dose levels of 5mg/kg and 10mg/kg for each 3 boys. A tablet preparation with each tablet containing 50mg of TE-031 was administered to 4 boys and 2 girls (8 years 5 months-11 years 6 months) with dose level of 2 tablets (i. e., 100mg) and 3 tablets (i. e., 150mg) for each 3 children. All administrations were done at 30 minutes before meal. Then, to conduct a cross-over test, the granule preparation was given orally to the 3 children mentioned above who was given 2 tablets and the 1 of 3 cases that were given 3 tablets at the same dose levels (100mg and 150mg) respectively. A bioassay was used to determine concentrations in blood of active antibiotic compounds and an high performance liquid chromatography (HPLC) was used to determine unchanged TE-031 and its main metabolite, M-5. Urinary concentrations of active antibiotic compounds were also determined by the bioassay and the HPLC was used to determine concentrations and proportions of unchanged TE-031 and its metabolites, M-1, M-4, M-5, M-6 and M-7 to figure out the urinary recovery rate in the first 6 hours. The results of these experiments are summarized as follows.
1. As was mentioned above, TE-031 was administered orally to 2 groups of children at dose levels of 5mg/kg and 10mg/kg, respectively. Mean serum levels of total active antibiotic compounds reached their maximum in 1 and 2 hours for the 5mg/kg and the 10mg/kg dosage groups, respectively, at 1.28 and 3.62μg/ml, respectively. Mean half lives of serum concentrations in the 2 groups were quite similar, with values of at 2.1 and 2.0 hours, respectively.
Mean serum concentrations of unchanged TE-031 determined by the HPLC method reached their peaks in 1 hour after administration in either of the 5 and 10mg/kg dosage groups at peak levels of 0.65μg/ml and 2.67μg/ml, respectively. M-5 also reached its highest levels at the same time at mean levels of 0.88 and 1.62μg/ml, respectively. Thus, dose-response relationships were observed with TE-031 and M-5. Half-lives of TE-031 in the 5 and 10mg/kg groups were similar 1.90 and 1.97 hours, respectively, and those of M-5 were 2.58 and 3.62 hours, respectively, thus the 10mg/kg dosage group showed a longer half-life.
2. Mean serum levels of total active antibiotic compounds, determined by bioassay, in the 2 groups of three children receiving 2 or 3 tablets of TE-031 reached their peaks in 1 hour after administration. Peak serum levels in the groups receiving 2 and 3 tablets were 0.45 and 0.54μg/ml, respectively, when these dose levels corresponded 1mg/kg body weight, and 2.23 and 2.68μg/ml, respectively, when those dose levels corresponded 5mg/kg body weight. Mean half-lives were 2.2 and 2.3 hours, respectively. By HPLC method, serum levels of unchanged TE-031 reached their peaks in both groups 1 hour after administration at peak levels of 0.61 and 1.99μg/ml, respectively. M-5 also reached its highest levels at the same time at mean levels of 0.50 and 1.20μg/ml, respectively. Mean half-lives of unchanged TE-031 in the 2 dosage groups were 1.85 and 1.99 hours, respectively, and those of M-5 were 3.29 and 3.38 hours, thus half-lives of these compounds in the 2 groups were respectively similar to each other.

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Pharmacokinetic and clinical studies on clarithromycin (TE-031, A-56268), a new macrolide antibiotic, were performed in the pediatric field.
1. Pharmacokinetic investigation
We studied serum concentrations and urinary excretions after single oral administration of TE-031 granules and tablets. Doses were 1, 5, 10 and 15mg/kg body weight in case of granules (10% TE-031) and 150mg/kg body weight in case of tablets (50mg TE-031, 3 tablets).
As results, T_max's were 1-2 hours after administration in case of both granules and tablets. C_max's in cases of granules were 0.29±0.15μg/ml in 1mg/kg administration, 2.53±0.71μg/ml in 5mg/kg, 4.11±1.37μg/ml in 10mg/kg, 6.28±1.48μg/ml in 15mg/kg showing a dose dependency.
T 1/2's were 1.8-6.5 hours in cases of 1, 5, 10, 15 mg/kg of granules and tablets. T 1/2's became longer with increased doses. Urinary recoveries were 9.4±2.4% to 31.6±19.0% in 6 hours after administration.
2. Clinical investigation
Clinical study was carried out in 24 patients of respiratory infections. Clinical efficacies were excellent in 11 patients, good in 12 patients and fair in 1 patient. The clinical efficacy rate was 95.8%. No side effects were observed.
The above results suggest that TE-031 is a useful oral antibiotic for treating pediatric respiratory infections, especially those due to Mycoplasma pneumoniae.

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Clarithromycin (TE-031, A-56268), a new macrolide antibiotic agent, was evaluated bacteriologically and clinically 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. Absorption and excretion
Pharmacokinetics of TE-031 was examined by single oral administration of 10% granules and 50mg tablets at doses of 1, 5, 10 and 15mg/kg. There were no significant differences between 10% granules and 50mg tablets, and between administrations before and after meal. Peaks and half-life periods of blood level of TE-031 given once at doses of 5, 10 and 15mg/kg (10% granules) bfore meal were 1.58, 4.37 and 3.79μg/ml, and 2.53, 3.17 and 2.20 hours, respectively, and the urinary excretion in 6 hours after the administration were about 20-30%.
2. Antibacterial effects
TE-031 was proved to have excellent antibacterial effect, i. e., inhibiting growth over 80% of strains of Streptococcus pneumoniae and Streptococcus pyogenes at 0.10μg/ml, Branhamella catarrhalis at 0.39μg/ml, and Campylobacter jejuni at 0.78μg/ml. Against Staphylococcus aureus, TE-031 showed very similar activity spectrum to EM, and EM resistant strains were also resistant to TE-031.
3. Clinical results
A total of 764 cases was studied. Clinical effects of TE-031 were evaluated in 717 cases out of the 764, excluding drop-outs and cases which did not meet specified protocols. Clinically, efficacies of TE-031 were “excellent” in 265 cases and “good” in 161 cases out of 453 cases of Group A in which causal agents were identified, with an efficacy rate of 94.0%, and out of 264 cases of Group B in which pathogens were not detected, clinical effects of TE-031 were “excellent” in 115 cases and “good” in 124 cases, with an efficacy rate of 90.5%. In terms of clinical effects of TE-031 classified by diseases when Group A and B were combined, efficacy rates were 91.6% for upper respiratory tract infection (217/237), 90.0% for bacterial pneumonia (108/120), 97.4% for Mycoplasma pneumonia (111/114), 100% for Chlamydia pneumonia (4/4), 85.0% for pertussis (34/40), 100% for scarlet fever (16/16), 83.9% for skin and soft tissue infection (26/31), and 98.9% for Campylobacter enteritis (87/88).
Bacteriologically, 264 strains out of 309 identified as pathogens (85.4%) were eradicated with TE-031. 91.2% of 113 strains of Gram-positive bacteria were eradicated. Bacterial eradication rates were: S. aureus (41 strains), 85.4%; S. pyogenes (42 strains), 90.5%; S. pneumoniae (28 strains), 100%.
Gram-negative bacteria were eradicated in 80.2% of 177 strains. Bacterial eradication rates were: Haemophilus influenzae (62 strains), 56.5%; C. jejuni and Campylobacter sp.(83 strains), 96.4%.
All of Mycoplasma pneumoniae (19 strains) was eradicated. Out of 130 cases that had experienced ineffective of previous antibiotic therapy for 3 days or longer, clinical effects of TE-031 were “excellent” in 61 cases and “good” in 57, so that the efficacy rate was high, 90.8%. 22 of 29 strains identified in these cases were eradicated by the TE-031 treatment.
4. Side-effects and abnormal laboratory test values.
Side-effects, such symptoms as vomiting, abdominal pain, loose stool, diarrhea, eruption and urticaria appeared in 12 of 737 cases (1.6%). As for laboratory data, elevation of GOT or/and GPT, eosinophilia, elevation in platelet count were found in 31 cases (28 patients), but they were all slight and no abnormal findings were significant.
5. Clinical effects and bacteriological effects by dose
There were no clear dose response in clinical effects and bacteriological effects, partly due to the high efficacy rates.

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