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[in Japanese]

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¹⁴C-Rokitamycin (RKM) at the dose of 200 mg/kg was administered orally to fasted infant rats to study the absorption, distribution, metabolism and excretion in infant animals.
The mean blood level of ¹⁴C-RKM reached its peak of 20.25 μg/ml in 30 minutes. The mean area under the curve was 93.23 μg·hr/ml.
In vivo plasma protein binding rates of ¹⁴C-RKM were about 30% in both infant and adult rats.
¹⁴C-RKM was distributed at high concentrations into liver, kidney, lung, spleen, pancreas, bone marrow, submaxillary gland and some other tissues.
Major metabolites detected in plasma, urine and bile were 10-OH-RKM, leucomycin A₇, leucomycin V and 14-OH-leucomycin V.
In excretion studies, about 97% of the administered radioactivity was recovered in urine and feces within 144 hours. After intraduodenal administration to rats with cannulated bile ducts, 7.42% and 25.66% of the radioactivity were excreted within 24 hours in the urine and bile, respectively.

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Absorption and excretion of rokitamycin (RKM) were studied after oral administration of 50 mg/kg to fasted infant and adult Beagle dogs.
In infant Beagle dogs, the mean plasma level of RKM reached its peak of 6.53 μg/ml in 15 minutes after administration. The area under the curve (AUC) value was 11.04 μg·hr/ml.
In adult Beagle dogs, the mean plasma level of RKM reached its peak of 8.62 μg/ml in 30 minutes after administration. The AUC value was 18.25 μg·hr/ml.
Ratios of C_max and AUC value in infant Beagle dogs to those in adults were about 75% and 60%, respectively.
In infant Beagle dogs, urinary excretion of RKM was 2.55% of the dose within 24 hours.
In adult Beagle dogs, urinary excretion of RKM was 3.03% of the dose within the same period.
The excretion ratio of RKM in infant Beagle dogs was about 85% of the adults' value.

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The absorption and excretion of rokitamycin (RKM) in dry syrup form for children were studied following oral administration to fasted healthy volunteers with high gastric acidity as a suitable model to estimate bioavailability of RKM in children.
In a comparative study on tablet and dry syrup forms, peak plasma concentrations of RKM and areas under plasma concentration-time curve (AUC) values were calculated using the trapezoidal rule. RKM dry syrup gave about 84 and 86% of these values for RKM tablet.
Urinary recovery of RKM in 8 hours with the administration of dry syrup was also about 80% of the value obtained with tablet.
Judging from these results, the bioavailability of RKM administered as dry syrup, was fairly close to that obtained with RKM tablet.
The AUC values were dose dependent when examined with dose levels of 300, 500 and 800mg administered as RKM dry syrup.
The AUC value and urinary recovery of RKM administered as dry syrup were 3-4 times higher than these values for midecamycin acetate administered also as dry syrup.

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In order to determine whether rokitamycin (RKM), one of the macrolide antibiotics, has any side effects on the gastrointestinal tract, the effect of intraduodenal administration of RKM (1.0, 3.0 and 9.0mg/kg) on gastrointestinal contractile activity was studied by means of force transducers implanted chronically on the gastric body, gastric antrum, duodenum and upper jejunum in conscious dogs. Erythromycin (EM 0.3, 1.0 and 3.0mg/kg) and kitasamycin (LM 1.0, 3.0 and 9.0mg/kg), both macrolide antibiotics, were used as control drugs. RKM, when given at 3.0mg/kg and 9.0mg/kg doses, induced segmentation contractions only in the duodenum where it was administered. The duration of the RKM-induced contractions was 7.5±2.5 minutes for 3.0mg/kg and 15.8±3.0 minutes for 9.0mg/kg, and the contractile force of the contractions was 43 to 82% of the maximum contractile force of the interdigestive contractions in the duodenum. EM, at 0.3mg/kg, evoked a series of strong contractions quite different from those induced by RKM but similar to the natural interdigestive contractions, and with large doses, dose-dependent long-lasting interdigestive contractions were induced. On the other hand, LM did not stimulate notable gastrointestinal contractile activity even at a 9.0mg/kg dose. In order to eliminate the possibilities of the contraction being caused by the effect of RKM on the duodenum through the general circulation upon absorption, 3.0mg/kg RKM was given intravenously. It was found that intravenous injection of RKM did not evoke any contractions attributable to the direct action of RKM in the circulation. It has therefore been concluded that RKM does not induce contractions similar to those induced by EM when it is introduced into the duodenum and it has therefore been considered that RKM does not evoke side-effects on the gastrointestinal tract in therapeutic doses.

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MICs of a new macrolide antibiotic, rokitamycin (RKM), for Chlamydia psittaci and Chlamydia trachomatis were determined. Meanwhile, the organisms were observed under the electron microscope for morphologic changes with the addition of RKM.
1. MICs of RKM for C. psittaci MP and 3 strains of C. psittaci isolated from budgerigars kept by patients ranged from 0.05 to 0.10 μg/ml, and those for 3 strains of C. trachomatis B, E and L₂ ranged from 0.20 to 0.39 μg/ml. These MICs were higher than MICs of minocycline (MINO), doxycycline and rifampicin, but lower than MICs of erythromycin and midecamycin against these organisms.
2. The addition of MINO or RKM to C. psittaci IZAWA and C. trachomatis L₂ at concentrations twice as high as MICs resulted in no formation of elementary body or intermediatry form inside the inclusion body, and abnormal enlargement of reticulate body containing irregularly distributed cytoplasmic components.

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The ability of antibiotics to enter cells, especially phagocytic cells, may be an important factor affecting therapy for infections caused by organisms which survive and proliferate intracellularly. It is well known that macrolides and clindamycin have high intracellular penetration ability1-4). We studied the uptake of rokitamycin (RKM), a new oral macrolide, using rabbit alveolar macrophages and 2 other macrolides for comparison. Intracellular concentrations of erythromycin and josamycin were, respectively, approximately 20 and 40 times higher than extracellular concentrations when they were incubated at an initial extracellular concentration of 5 μg/ml (I/E=20.1±2.6, 40.8±7.4). In comparison to these 2 macrolides, the uptake of RKM was massive and very rapid. The cellular concentration of RKM was approximately 120 times higher than the extracellular concentration. Uptake of the 3 macrolides by rabbit alveolar macrophages at 4° was approximately 10% of that at 37°. This study demonstrated that RKM was rapidly and massively accumulated by alveolar macrophages, and that the drug accumulation depends on temperature. These observations suggest that RKM therapy may be very effective for the treatment of some infectious diseases.

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Twelve oral antimicrobial agents were tested for their antimicrobial activities against causative organisms isolated from pediatric infections. Activities of these antimicrobial agents against Streptococcus pyogenes were also examined in relation to T-antigen typing of the species. The results of the investigation are summarized as follows.
1. Against Staphylococcus aureus, rokitamycin (RKM), josamycin, ofloxacin, minocycline exhibited strong antimicrobial activities, and few strains of S. aureus showed resistance to these antimicrobial agents. More strains exhibited resistance to erythromycin (EM) than to other macrolide antibiotics (MLs) examined. Amoxicillin (AMPC)-resistance was often observed also.
2. Against S. pyogenes, β-lactam antibiotics (β-lactams) and RKM had MIC₈₀ of 0.20 μg/ml or below, and no resistant strains of this organism were observed against these antibiotics. Only 2 resistant strains (2.0%) of S. pyogenes to MLs were detected, but resistance to tetracyclines (TCs) was observed at a high frequency, with 71.4% or more strains among T-4, T-6, T-12 and T-28 antigen types exhibited resistance to TCs. Among the 21 strains of T-12 antigen type examined, only one strain (4.8%) was found resistant to MLs. These observations suggested that the reduction in the frequency of ML-resistant strains was not due to the reduction in the number of T-12 antigen type strains but due to losses of resistance factors against MLs of plasmids.
3. Antibacterial activities of β-lactams and MLs against Streptococcus pneumoniae strains were good, similarly to activities against S. pyogenes. But many strains of S. pneumoniae were resistant to TCs.
4. New quinolone antimicrobial agents (quinolones) showed excellent activities against Branhamella catarrhalis strains with EM and RKM showing the next best activities. The number of resistant strains against quinolones, however, seemed to be on an increase.
5. Quinolones had strong antimicrobial activities against Haemophilus influenzae, few strains of which showed resistance to quinolones. AMPC had the next best activity, but approximately 10% of H. influenzae exhibited resistance to this antibiotic.
6. Against Campylobacter spp., quinolones and MLs showed the best activities with MIC₈₀ values at or below 0.25 μg/ml, and no resistant strains of the species against these antimicrobial agents were observed. Fosfomycin and TCs showed somewhat inferior activities to quinolones and MLs, with β-lactams showing still lower activities.
7. Only few strains of Mycoplasma pneumoniae and Chlamydia trachomatis were examined, but MLs and TCs appeared to be effective against these organisms.
As described above, vast differences in antimicrobial activities exist among these drugs against different bacteria. It is, therefore, important to take identities of causative organisms into consideration when antimicrobial agents are selected for the treatment of pediatric infections.

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A clinical study on rokitamycin (RKM) dry syrup was carried out and the results obtained are summarized as follows:
1. Good clinical responses were achieved with 30-40mg/kg/day dose of RKM dry syrup.
2. Diagnostically, acute bronchitis and bronchial pneumonia responded better than other diseases examined.
3. The efficacy rate was low in the group of patients complicated by bronchial asthma.

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1. A total of 15 patients with pediatric respiratory tract infections were medicated with rokitamycin (RKM) dry syrup, and its clinical effects were excellent in 2, good in 10, fair in 1 and poor in 1.
2. The efficacy rate in Streptococcus pneumoniae pneumonia and mycoplasmal pneumonia was 100%.
3. Clinical effects on 7 patients with Haemophilus influenzae were excellent in 1, good in 4, fair in 1 and poor in 1.
4. No adverse reaction was observed, and the taste and odor of RKM was well accepted by the children.
5. RKM is useful and one of the first choice antibiotics on respiratory tract infections in pediatric field.

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A total of 22 patients with acute pediatric infections was treated with rokitamycin (TMS-19-Q, RKM) dry syrup, a new macrolide antibiotic developed by Toyo Jozo Co., Ltd., Ohhito, Japan, to investigate its clinical efficacy.
1. A girl of an age 4 years 2 months (weighing 16.5kg) was administered orally 10mg/kg of RKM, and a boy of an age 8 years 7 months (weighing 24.5kg), 15mg/kg, and blood concentrations of RKM in these subjects were measured to investigate its absorption and excretion. Blood concentrations of the drug reached a peak of 0.84 μg/ml in an hour after the administration in the girl, 0.72 μg/ml in 30 minutes in the boy, with T 1/2 of 0.86 and 1.82 hours, respectively. Their 6-hour cumulative urinary recovery rates were 2.79 and 2.13%, respectively.
2. A total of 20 patients was treated with RKM dry syrup. These patients included 3 with acute pharyngitis, one with acute tonsillitis, 4 with hemolytic streptococcal infections, 7 with acute bronchitis, 2 with pneumonia, another 2 with pertussis, and one with Campylobacter enteritis. The treatment was effective in 18 of them with a clinical efficacy of 90.0%.
3. Bacteriological responses to RKM dry syrup were as follows: eradication of pathogens in 5, pathogens decreased in 3, and no changes were observed in 3 of 12 patients from whom pathogens had been isolated prior to the treatment, thus the eradication rate was 45.5% with the exception of 1 patient whose bacteriological response was unknown.
4. There were no symptoms that indicated the occurrence of side effects of the RKM treatment in any of the 22 patients examined. With regard to laboratory test values, a slight elevation of GPT was found in 1 patient only.

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Rokitamycin (RKM, TMS-19-Q) was used for the treatment of infections in patients with underlying diseases. Many antibiotics are tended to be used on these patients with underlying diseases mainly for prophylactic purposes and, as a consequence, microbes resistant to antibiotics frequently become pathogens in these cases. Responses of our patients to RKM, however, were generally excellent but one who had EB virus infection.

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Laboratory and clinical studies on rokitamycin (RKM) dry syrup, a new macrolide antibiotic, were carried out in the field of pediatrics. The results are summarized as follows.
1. Plasma concentrations and urinary recovery rates after oral administration on fasting of RKM dry syrup at doses of 10mg/kg and 20mg/kg to 2 and 1 cases, respectively, were determined. Peak plasma levels were obtained in 30 minutes after administration of both dosages with half-lives of 1.5 to 2.2 hours. A clear-cut dose response was observed. Urinary recovery rates in the first 6 hours after administration ranged from 1.75 to 2.26%.
2. The MICs of RKM against 80 clinical isolates (Streptococcus pyogenes 9, Streptococcus pneumoniae 14, Branhamella catarrhalis 4, Haemophilus influenzae 27, Haemophilus parainfluenzae 9, Haemophilus haemolyticus 2, Haemophilus parahaemolyticus 14 and Campylobacter jejuni 1) were compared with MICs of midecamycin acetate (MOM), josamycin (JM) and erythromycin (EM). The antibacterial activity of RKM was superior to those of MOM and JM and slightly inferior to that of EM.
3. Twenty-eight pediatric patients with acute infectious diseases (acute tonsillitis 4, streptococcal infection 4, acute bronchitis 9, pneumonia 4, mycoplasmal pneumonia 2 and Campylobacter enteritis 5) were treated with RKM dry syrup at a daily dose of 12-42.9mg/kg t. i. d. as a rule. Efficacy rates were 92.9% clinically and 58.6% bacteriologically.
4. No adverse reactions were observed. Abnomal laboratory findings were mild; thrombocytosis in 2 and eosinophilia in 1.
5. The taste and the odor of RKM dry syrup preparation were sufficiently tolerable for the pediatric patients to accept it.

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Pharmacokinetic, bacteriological and clinical studies on a new macrolide antibiotic, rokitamycin (RKM) dry syrup for pediatric use, were done, and results as summarized below were observed:
1. Five children with ages between 6 and 10 years were administered orally with RKM at a dose level of 10mg/kg either at 30 minutes before or 30 minutes after meal on a crossover design, and plasma concentrations and urinary excretion rates of the drug were measured. Plasma concentrations of RKM following the administration before meal were 0.50μg/ml at 1/2 hour, 0.43μg/ml at 1 hour, 0.15μg/ml at 2 hours, 0.03μg/ml at 4 hours, and not detectable at 6 hours. Plasma concentrations following the administration after meal were 0.11μg/ml at 1/2 hour, 0.15μg/ml at 1 hour, 0.09μg/ml at 2 hours, 0.03μg/ml at 4 hours, and not detectable at 6 hours. The 0-6 hour urinary recovery rates were 1.41% following the administration before meal, and 0.93% following the administration after meal.
These results suggested that the drug might be absorbed more rapidly, giving a higher plasma concentration, when administered before meal than when administered after meal. Changes in plasma concentrations of RKM following the administration of 10mg/kg before meal were similar to those of two 100mg RKM tablets (TMS-19-Q·GC tablets) to adult patients. Therefore, it seemed optimal to administer 10mg/kg 3 times daily at fasting to children as a rule.
2. A total of 39 patients with ages between 1 month and 11 years with pediatric infections were medicated with RKM dry syrup, and investigated for clinical response, bacteriological response and side effects to the drug. Clinical responses to the drug were evaluated in 2 patients with acute pharyngitis, 12 with acute purulent tonsillitis, 1 with acute bronchitis, 9 with acute pneumonia (including 3 with mycoplasmal pneumonia), 1 with acute purulent lymphadenitis, 2 with acute purulent otitis media, 1 with pertussis and 2 with acute enteritis: responses were excellent in 17, good in 11 and fair in 2 of them, hence the efficacy rate was 93.3%. Four strains of Streptococcus pyogenes and 3 of Haemophilus influenzae were isolated as pathogens from 7 cases, and bacteriological responses were that 1 of S. pyogenes was eradicated, but the other 6 remained, thus the eradication rate was 14.3%. Neither side effects nor abnormal laboratory test values were found in any patients. Also, none of the patients refused or complained of difficulty in the oral administration of the drug.
The results suggested that RKM dry syrup would be clinically very effective in treating various pediatric infections, including the infections for which other macrolides had been taken as primary treatment, and be associated with no safety problems, although some difficulties were encountered for the eradication of some strains.

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We have carried out laboratory and clinical studies on rokitamycin (RKM, TMS-19-Q). The results are summarized as follows.
Serum and urinary concentrations of RKM were determined in 6 children with ages between 6 and 12 years given single oral doses of 5, 10 and 15mg/kg. Mean serum concentrations peaked at 30 minutes after administration of 5, 10 and 15mg/kg, and respective peak values were 0.30μg/ml, 0.79μg/ml and 1.32μg/ml. Biological half-lives for 5, 10 and 15mg/kg were 2.0 hours, 1.65 hours and 1.36 hours. The 6-hour urinary recovery ranged from 1.11% to 2.58% after administration of 5mg/kg, and the mean 6-hour urinary recoveries were 1.35% after administration of 10mg/kg and 2.28% after administration of 15mg/kg.
Therapeutic responses were recorded as excellent or good in 22 (73.3%) of the children, comprising 6 with tonsillitis, 2 with pharyngitis, 4 with bronchitis, 1 with bronchopneumonia, 1 with Mycoplasma pneumonia, 2 with whooping cough, 5 with streptococcal infections, 5 with Campylobacter enteritis, 3 with impetigo and 1 with SSSS.
The microbiological effectiveness of RKM on identified pathogens comprising 4 strains of Staphylococcus aureus, 1 strain of Streptococcus pneumoniae, 6 strains of Streptococcus pyogenes, 4 strains of Haemophilus influenzae and 5 strains of Campylobacter spp. was not so satisfactory as evidenced by a eradication rate of 50.0%.
No significant side effect due to the drug was observed in any cases.
In conclusion, RKM was found to be efficacious and safe for the treatment of bacterial infections in children.

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We studied the absorption and excretion as well as the clinical effect of rokitamycin (RKM, TMS-19-Q) dry syrup. The results we found are summarized as follows:
1. When 3 pediatric patients were medicated orally with a single dose of 10mg/kg of the drug, its peak concentrations of 0.75 and 0.51μg/ml appeared in the blood in 30 minutes after administration in 2 patients, and of 0.21μg/ml in 1 hour in the other patient. At 4 hours after administration, its concentration in the blood was 0.07-0.08μg/ml in all of the patient, and at 6 hours, it was undetectable. T 1/2 values were 1.05-2.08 hours. First 6-hour urinary recovery rates of the drug in the first 2 patients were 1.52 and 1.11%, respectively.
2. Twenty-four patients with 25 diseases were medicated with 7.14-12.5mg/kg of the drug 3-4 times daily for 4-10 days.
The patients consisted of 12 with tonsillitis, 7 with bronchitis, 3 with colitis, one each with Haemophilus influenzae pneumonia, mycoplasmal pneumonia, and pertussis. Clinical responses to the treatment were excellent in 7, good in 13, and poor in 5, with an efficacy rate of 80.0%. Bacteriologically, of 17 isolates whose changes were followed, 8 were eradicated, 1 decreased, and 8 remained unchanged, with an eradication rate of 47.1%.
3. No adverse reactions to the drug were observed in any of these patients, while abnormal laboratory test values observed were slight eosinophilia and also slight elevations of S-GOT and S-GPT in one of the patients.
4. One of the patients disliked the drug, but no patient refused to take it. The taste and odor of the drug appeared rather acceptable to children.
5. These results suggest that the drug may be a useful, new antibiotic preparation for use in the pediatric field.

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Rokitamycin (RKM), a newly developed macrolide antibiotic with a 16-membered ring, dissolves well under acidic conditions. It has been improved over other macrolides to minimize individual variations in its absorbability.
We measured, using the GA-test, variations in gastric acidities of 43 children with ages between 1 to 14 years, and investigated the relationship between gastric acidities and pharmacokinetic values. Also activities (expressed in MICs) of antimicrobial agents were studied against clinically isolated 229 bacterial strains using an inoculum size of 10⁶cells/ml. Tested organisms included Streptococcus pyogenes (77 strains), Streptococcus agalactiae (29), Streptococcus pneumoniae (2), as Gram-positive cocci, and Haemophilus influenzae (1), Haemophilus parainfluenzae (1), Bordetella pertussis (12), Salmonella sp.(4) and Campylobacter jejuni (103) as Gram-negative bacilli. Against stock strains of bacteria, MICs of 10 drugs (RKM, erythromycin (EM), josamycin (JM), midecamycin (MDM), midecamycin acetate (MOM), clindamycin (CLDM), amoxicillin (AMPC), cefaclor (CCL), minocycline, ofloxacin (OFLX)) were determined. Against isolates from patients who underwent treatment with RKM, MICs of only 4 drugs (RKM, EM, JM, MOM) were determined.
Measurements were made on plasma and urinary concentrations of RKM and its urinary recovery rates after patients including 6 boys with ages between 5 years 1 month and 11 years 6 months were administered with RKM (dry syrup). Two groups of 6 boys were administered between meals with RKM at dose levels of 5 and 10mg/kg, respectively.
Clinical and bacteriological effects of RKM were evaluated for 175 patients including 5 cases of pharyngitis, 3 tonsillitis, 32 pneumonia, 17 mycoplasmal pneumonia, 34 atypical pneumonia, 28 streptococcal infections, 29 Campylobacter enteritis, 4 Salmonella gastroenteritis, and 23 enteritis due to unknown organisms. Five drop-out cases were excluded from the evaluations. In the evaluable cases, an average dose level used was 31.8mg/kg/day, with a daily dose divided into 3 to 4 administrations and with an average treatment duration of 9 days. Adverse reactions of RKM and its effects on laboratory test values were investigated in these patients including the drop out cases. Obtained results of these studies are summarized below.
1. The GA-test produced pH values indicating that amounts of gastric acid were mostly either normal or high in 42 of the 43 subjects tested (97.7%), and only one low acid case (2.3%) was observed.
2. Against 52 stock strains of S. pyogenes, MIC₉₀ of RKM was less than 0.05μg/ml, thus RKM showed the next best activities to AMPC, and its activities were better than activities of the other 8 antibiotics. MIC₉₀ of RKM against 25 isolates from patients treated with this drug was 0.39μg/ml, which was the next lowest to MIC₉₀ of EM, similar to that of JM and lower than that of MOM. MIC₉₀ of RKM against 29 stock strains of S. agalactiae was 0.20μg/ml, thus the activity of RKM was the next highest to AMPC, and higher than those of the other 8 antibiotics. MIC's of RKM against 2 isolates of S. pneumoniae obtained from RKM-treated patients were 0.10 and 0.20μg/ml, thus activities of RKM were lower than those of EM, similar to JM, but higher than MOM. MIC's of RKM against one each strain of H. infiuenzae and H. parainfluenzae isolated from patients treated with RKM were higher than those of EM, but lower than those of JM and MOM. Against 12 stock strains of B. pertussis, RKM showed an MIC₉₀ of 0.10μg/ml, which was similar to those of JM, MDM, MOM and OFLX, was higher than that of EM, MINO, but lower than those of CLDM, AMPC and CCL.

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