[in Japanese]

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Cefpiramide (CPM) shows antibacterial activity against Staphylococci, Enterococci, Pseudomonas aeruginosa and anaerobic Bacteroides spp. CPM is a cephalosporin antibiotic which also exhibits antibacterial activity against Klebsiella and intestinal bacteria including Escherichia coli. Concentrations in blood of CPM which has antibacterial activity against main bacterial species detected during gastrointestinal surgeries and concentration transferred to the large intestinal tissue were measured in patients with cancer of the large intestine. Eighteen patients who were hospitalized and underwent large intestinal surgery from December, 1985 to March, 1987 wereexamined as subjects. CPM was administered at a dose 1 g each of 11 cases and 2 g to each of 7 cases. Concentrations in blood after administration of 1 g of CPM were in a range of 81. 56-212. 6 μ g/ml between 25 minutes and 2 hours 20 minutes after administration, and concentrations in the large intestinal tissue were in a 14. 17-66. 95 μ g/g range. Ratios of the tissue to the blood concentrations were 0. 08-0. 49, averaging 0. 24± 0. 05. Concentrations in blood after ad-ministration of 2 g of CPM were 128. 4-253. 5 μ g/ml between 1 hour 10 minutes and 3 hours 50 minutes after administration. Tissue concentrations were 48. 33-416. 5 μ g/g between 1 hour 10 minutes and 5 hours 15 minutes after administration. Ratios of the tissue to the blood concentrations were 0. 21-0. 55, averaging 0. 42± 0. 05 between 1 hour 10 minutes and 3 hours 5 minutes. Tissue transfer at a dose of 2 g was more than twice as high as that 1 g. When 2 g of CPM was administered, reported MIC₈₀ values of clinical isolates of most of the above mentioned bacteria were exceeded at any time of measurement. Therefore, concentrations of CPM in the blood and concentration transferred to tissues were high enough suggesting that CPM is effective in the prophylaxis of postoperative infections and a dose level of 2 g is useful.

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Reliability of the cefamandole (CMD) disc susceptivility test in estimating approximate values of MICs was studied using various clinical isolates totaling 246 strains with Showa discs (8 mm diameter containing 30μ g of CMD). Clinical significance of a 4 category system for the interpretation of the CMD disc tests, which is normally used in Japan, was also evaluated to determine whether this system would be suitable or not for the evaluation of a proper dose of administration.
The results obtained with the disc method were compared with MICs determined using the agar dilution method at an inoculum level of 10⁸ CFU/ml. The results of the CMD disc susceptibility test were well correlated with MICs, showing the reliability of the disc method to estimate approximate values of MICs. Break points in MIC values proposed for the classification ofbacteria into 4 categories of susceptibility are (+++) MIC ≤ 3μ g/ml,(++) MIC > 3-15μ g/ml, MIC > 15-60 μ g/ml,(-) MIC > 60 μ g/ml. Only 4 (1.6%) out of the 246 strains tested showed false positive results and 11 (4.5%) showed false negative results, showing the excellent reliability of this test.
In this study, approximately 90% of strains of Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis isolated from clinical materials randomely were inhibited by CMD at concentrations less than 3. 13 μ g/ml. Proteus vulgaris and Enterobacter aerogenes were sensitive to CMD at 67 and 69% of strains, respectively, at concentrations below 6. 25 μ g/ml. CMD was not active against Pseudomonas aeruginosa, Serratia marcescens and Enterococcus faecalis. About 90% of Staphylococcus aureus were inhibited at dose levels smaller than 6. 25 μ g/ml and 70% of the strains at levels less than 3. 13 μ g/ml.
Susceptibilities to 15 μ g/ml CMD of highly methicillin-resistant strains (MIC > 30 μ g/ml)of S. aureus were examined. Ten of 12 strains examined were found susceptible to CMD, but only 6 of the 12 to cefmetazole. Imipenem/cilastatin was effective to 5 of the 12 strains at levels lower than 3 μ g/ml and to one at a level less than 15 μ g/ml. Minocycline was effective against 11 strains at concentrations below 2 μ g/ml.
Based on the antimicrobial activity and pharmacokinetic data of the recommended dosage schedule of CMD (less than 4 g a day) MIC break points of < 3 μ g/ml and < 15 μ g/ml in a 4 category system appear to be more useful than those of < μ g/ml and < 32 μ g/ml utilized in a 3 category system for evaluation of a proper administrative dose.

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Ceftriaxone (CTRX), a newly developed cephalosporin antibiotic, was administered to patients with various bacterial infections in the field of obstetrics and gynecology, and the following results were obtained.
1. Two grams of CTRX was administered once daily by drip infusion for a total dosage of 6g to 20g to each of 3 cases of intrauterine infection, 1 case of adnexitis, 1 case of intrapelvicinfection and 2 cases of infection of the external genitalia.
2. Clinical efficacy of CTRX was good in all cases. No laboratory abnormalities were observed nor subjective or objective adverse reactions occurred during the treatment.
The administration of CTRX at a dose of 2g once daily is a clinically convenient treatment regimen, and it results in satisfactory clinical efficacy.

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In a study of rokitamycin (RKM) dry syrup for its usefulness in pediatric infections, the following results were obtained:
1. Frequencies of RKM-resistant strains among fresh isolates from sick children were very low, and 4. 4% of 68 isolates of Staphylococcus aureus, 4. 2% of 48 isolates of Streptococcus pneumoniae, and none of 96 isolates of Streptococcus pyogenes were found to be RKM-resistant.
2. Hypo-to achlorhydria was found in 2 (3.77%) of 53 children.
3. When children were administered once orally with 5, 10 and 15 mg/kg of RKM dry syrup at fasting, mean peak values of plasma concentration were 0. 25, 0. 55 and 0. 74 μ g/ml witha T 1/2 (β) of 2.18, 1.97 and 2. 00 hours, respectively.
Urinary recovery rates during the first 0-6 hours were quite low, and values were 1. 21, 1. 38 and 2. 23%, respectively.
4. The clinical efficacy of RKM dry syrup was studied on children chiefly with acute pneumonia, mycoplasmal pneumonia and tonsillitis. Among 379 children from whom pathogens had been determined, responses to the treatment were excellent in 186, good in 144, fair in 24, poor in 20 and unknown in 5 patients, the overall efficacy rate being 88.2%. Among all 598 treated patients, including those with undetermined pathogens, responses were excellent in 247, good in 269, fair in 42, poor in 35 and unknown in 5 patients, the efficacy rate being 87.0%.
5. The clinical efficacy of the drug in treating Chlamydia infection in 12 patients including aChlamydia carrier and the clinical efficacy in treating Campylobacter enteritis in 36 patients were studied. All the cases showed “good” responses. Among 66 patients with mycoplasmal pneumonia, responses were excellent in 33 and good in 27 patients, with an efficacy rate of 90.9%.
6. The optimal dose of RKM dry syrup seemed to be in the range between 20 and 40 mg/kg. It appeared, however, that a dose of about 40 mg/kg would be required to eradicate the pathogen from the pharynx in S. pyogenes infection.
7. Adverse reactions to RKM dry syrup were found in 9 (1.45%) of 622 patients. The reactions were gastrointestinal symptoms except eruption occurred in 1 patient, but they were all mild. Laboratory examinations revealed eosinophillia in 19 and abnormal hepatic enzyme activities in 8 of 455 patients studied, but such abnormalities were all transient and mild.

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Twenty five children were treated with rokitamycin (RKM) and its clinical efficacy and side effects were evaluated. Ages of the patients ranged from 13 days to 10 years. Doses of RKM ranged 17. 1-39. 3 mg/kg/day for 2. 3 to 17. 7 days. Twenty four patients including 8 Mycoplasma pneumonia, 5 bronchopneumonia, 6 brochitis, 2 streptococcosis, 1 otitis media, 1 tonsillitis and 1 Chlamydia conjunctivitis were evaluated for clinical efficacy. Results were excellent in 7, good in 12, fair in 4, and poor in 1 patient. One patient was excluded from the evaluation, because the patient was treated with erythromycin before entering this study. Out of the 25 patients, 3 cases showed eosinophilia, 2 cases showed elevated GOT and GPT but no adverse clinical signs due to RKM were observed.
The pharmacokinetics of RKM was studied in 5 patients whose ages ranged from 8 to 12 years. Plasma peak concentrations of RKM in 2 patients were 0. 14 and 0. 16 μ g/ml at 30 minutes after doses of 5 mg/kg. Peak concentrations in 3 patients ranged from 0. 32 to 1. 02 μ g/ml after doses of 10 mg/kg. Portions of the drug excreted into urine within 6 hours were 0. 49 and 1. 03% in 2 patients each of whom was given doses of 5 mg/kg, and ranged from 1. 16 to1. 30% in 3 patients, each given 10 mg/kg. Metabolic products in urine within 4 hours after doses of 5 to 10 mg/kg were studied in 4 patients. Leucomycin AT and leucomycin V accounted for almost 90% of all the related compounds excreted.

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Clinical efficacies of a new macrolide antibiotic, rokitamycin (RKM, TMS-19-Q), were studied in acute pediatric infections.
Responses to the RKM administration were evaluable in 62 out of 68 patients consisted of 7 patients with pharyngitis (efficacy rate of 85. 7%, 6/7 patients), 4 with bronchitis (25. 0%, 1/4), 9 with tonsillitis (100%, 9/9), 13 with mycoplasmal pneumonia (100%, 13/13), 13 with hemolytic streptococcal infections (92. 3%, 12/13), 14 with pneumonia (57. 1%, 8/14), one with pertussis (100%, 1/1) and another with Chlamydia pneumonia (100%, 1/1) thus an overall efficacy rate of 82. 3% was achieved.
Urticaria was observed in one of the patients as an adverse reaction to the drug, while abnormal laboratory test results were noted in 3 patients, but none of such changes were severe.
The drug, even when administered in combination with a theophylline preparation, exerted no effects on the serum concentration of the latter.

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Rokitamycin dry syrup (RKM), a new macrolide antibiotic preparation, was evaluated for its safety, efficacy and pharmacokinetics in 19 children. RKM was effective in mycoplasmal pneumonia, Chlamydia trachomatis pneumonitis and Campylobacter gastroenteritis. Efficacies of RKM in streptococcal pharyngitis and Haemophilus influenzae pneumonia, however, were insufficient.
Pharmacokinetic observations seemed to indicate that RKM achieved higher blood concentrations than older macrolides, but a large individual variation was observed.
Diarrhea which was the only type of side effect observed in our cases, was encountered in 2 of 17 evaluable cases.
From these data, RKM seems to have a place in the treatment of pediatric infectious diseases.

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Rokitamycin (RKM) dry syrup was administered to a group of pediatric patients. The results obtained are summarized as follows.
1. Of the recent isolates of Streptococcus pyogenes, fewer strains were highly resistant to RKM than to josamycin (JM), midecamycin (MDM), erythromycin and lincomycin. Also, macrolides (MLs)-resistant strains proved to be susceptible to RKM.
2. Recent isolates of Staphylococcus aureus, Streptococcus agalactiae, group G Streptococci, S. pyogenes, Streptococcus pneumoniae and Haemophilus influenzae were more susceptible to RKM than to midecamycin acetate and JM. Oral administrations of 10-15 mg/kg of the drug were followed by its peak concentrations of 0. 07-0. 77 μ g/ml in the blood at 30 minutes in many patients, and by an undetectable level at 6 hours also in many of them. T 1/2 values were 1. 2-2. 6 hours, and first 6-hour urinary excretion rates were 1. 26-4. 74%.
3. Fifty-two patients with acute upper and lower respiratory tract infections, Campylobacter enteritis, etc. were treated with RKM at about 20-40 mg/kg daily for 4-44 days, with an overall efficacy rate of 88. 5%.
4. An eradication rate of 81. 4% was achieved for 43 strains of 7 species isolated from the patients.
5. No abnormal laboratory test values were observed after treatment with drug for 4-14 days. A side effect, stomach discomfort, was observed in 1 patient.

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The usefulness of a new macrolide antibiotic rokitamycin (RKM, TMS-19-Q) was evaluated in the field of pediatrics.
1. Twenty seven patients were enrolled in the study. One patient was excluded from the study because the illness was due to a viral infection. They included 14 boys and 13 girls with ages 7 months to 9 years 11 months.
2. The patients were treated with RKM at daily doses ranging 19.2-41.1 mg/kg, divided into 3 equal portions. The administration was done orally at fasting, lasting 2-15 days, with total doses of 22.2-500.0 mg/kg.
3. The patients were diagnostically classified into the following categories: 9 with acute pharyngitis, 15 with acute bronchitis, and one each with pneumonia, purulent lymphadenitis and Campylobacter enteritis.
4. The clinical response to the treatment was good or excellent in 22 of the patients with an overall efficacy rate of 81.5%. An efficacy rate of 88.9% was achieved for the patients with acute pharyngitis, 80.0% for those with acute bronchitis, and 100% for the patient with purulent lymphadenitis and the patient with Campylobacter enteritis. From the patient with pneumonia whose response was evaluated “fair” was Haemophilus influenzae isolated by culturing pharyngeal material. This organism was found resistant to RKM by the disk method.
5. Bacteriological responses were as follows; of 26 isolates presumed to be pathogens, 9 were eradicated, 5 decreased, 7 unchanged and 5 unknown, with an eradication rate of 42.9%.
6. Neither adverse reactions nor abnormal changes in laboratory findings were observed with the medication in any patients during and after the end of the treatment. None of the patients refused the medication. RKM was found very effective and safe in treating pediatric infections: it is a useful drug in the field of pediatrics.

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Bacteriological, pharmacokinetic and clinical studies were done on the effect of rokitamycin (RKM, TMS-19-Q) in the field of pediatrics. The results are summarized below.
1. Antibacterial activities
Antibacterial activities of RKM against Staphylococcus aureus (including 50 methicillin-sensitive and 50 methicillin-resistant strains), 18 strains of Haemophilus influenzae and 50 strains of Campylobacter jejuni were studied comparatively with activities of josamycin (JM), midecamycin (MDM), erythromycin (EM) and cefaclor (CCL) or ampicillin.
Minimum inhibitory concentrations (MICs) of the 5 antibiotics against methicillin-sensitive S. aureus showed a wide variation but RKM was somewhat superior among them. MIC₈₀ of those antibiotics tested against methicillin-sensitive S. aureus were as follows; RKM 1.56, JM 12.5, MDM 12.5, EM 6.25, and CCL 3.13 μg/ml. Among methicillin-resistant S. aureus (MRSA), ratios of strains highly resistant to these antibiotics (MIC≥100 μg/ml) to total number of strains tested were: 18% to RKM, and 26%, 34% and 48% to JM, MDM and EM, respectively, again showing the superiority of RKM and the proliferation of resistant organisms to EM.
MICs of RKM against H. influenzae were distributed in a range between 0.78 and 12.5 μg/ml, which were similar to MIC range of CCL, and approximately twice as high as that of EM, but 4 folds lower than those of JM and MDM.
Against C. jejuni, the MIC range of RKM was quite broad, 0.10-12.5 μg/ml, with a peak value of 0.20 μg/ml. The cumulative number of strains vs. MIC curve was similar to that of EM, and RKM was approximately 4 to 8 folds more effective than the other 3 antibiotics.
2. Absorption and excretion
The absorption and the excretion of RKM were studied with its dry syrup preparations. Dose levels examined were 5 mg/kg in 2 cases, 10 mg/kg in 7 cases, 15 mg/kg in 2 cases and 20 mg/kg in 1 case. Peak concentrations of RKM in blood were not dose-dependent and were 0.16-0.23, 0.29-0.91, 0.35-0.46 μg/ml and 0.53 μg/ml, respectively, for the 4 dose levels. Most of drug levels dropped below the detection limit in 4 hours after the administration when dose levels up to 10 mg/kg were used, and when dose levels were at or above 15 mg/kg, 0.07-0.09 μg/ml of RKM was detected in blood at 6 hours after the administration. Urinary recovery rates in 6 hours were between 0.19 and 3.31%.
3. Clinical study
Clinical efficacies were examined in a total of 53 cases including 17 cases of mycoplasmal pneumonia, 7 cases of bacterial pneumonia, 3 cases of bronchitis (including 1 concurrent case tonsillitis), 13 cases of tonsillitis/pharyngitis, 9 cases of scarlet fever/streptococcal infections, and 1 case each of pertussis, chlamydial infection, colitis (due to Klebsiella), and campylobacterial colitis. Clinical efficacies were excellent in 37 cases, good in 11 cases, fair in 1 case, and poor in 4 cases, hence the efficacy rate was 90.6%. A dose level between 27.3 and 40.0 mg/kg was used in each case, and 3 daily doses were administered in all cases but one. Bacteria were cultured from 19 cases, and they were eradicated from 16 of these cases.
No noticeable abnormalities were found as side effects but 1 case of watery stool. No abnormal laboratory test values were observed.

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Pharmacokinetic and clinical evaluations of rokitamycin (RKM, TMS-19-Q), a new macrolide antibiotic, were carried out.
RKM was administered orally to 14 patients with congenital heart diseases before cardiocatheterization and angiography. Peak plasma levels of RKM were observed at 30 minutes after the administration at dosages of 5, 10, 15 mg/kg. Although the reason is not clear, there were great variations among plasma levels. Peak plasma levels of patients with relatively good absorption were high enough against bacteria such as β-hemolytic Streptococcus, Mycoplasma pneumoniae and Chlamydia trachomatis.
Clinical responses were evaluated in 5 children comprising 2 cases of mycoplasmal pneumonia, 2 cases of Chlamydia infection and 1 case of β-hemolytic streptococcal tonsillitis. All of these cases had excellent or good responses without any side effect. Furthermore, no child refused to take RKM dry syrup.

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A total of 29 patients with pediatric infections was treated orally with 21.4-44.4 mg/kg/day of rokitamycin (RKM) dry syrup. The obtained results are summarized as follows.
1. Clinical responses to RKM in 24 evaluable patients were excellent in 2 and good in 3 of 5 patients with tonsillitis and laryngitis; excellent in 3 and good in 5 of 8 patients with bronchitis; excellent in 3, good in 2 and fair in one of 6 patients with bronchopneumonia; excellent in 2 and good in the other of 3 patients with psittacosis; and excellent in 2 of 2 patients with Campylobacter colitis. The overall efficacy rate was 95.8%.
2. Bacteriological responses to the drug were: reduction in 1 and no change in the other of 2 strains of Streptococcus pyogenes; eradication of a strain of Streptococcus pneumoniae and 2 strains of Staphylococcus aureus; eradication of 2 and no change in 3 of 5 strains of Haemophilus influenzae; and eradication of 2 out of 2 strains of Campylobacter spp.
3. Diarrhea was complained of as an adverse reaction to the RKM medication by 1 patient, abdominal pain was reported by another, and anorexia by another of the 27 patients treated. Laboratory examination was performed on some patients, but no abnormal test values were found except in 1 case showing an increase in platelet count from 27.6 to 78.2×10⁴/mm³.
The results suggested that RKM dry syrup might be a very useful and safe drug for the treatment of pediatric infections.

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