A clinical investigation was made on the concurrent use of amikacin (AMK) and cefoxitin (CFX) against complicated infections with hematological disorders. The results obtained were summarized as follows:
1. Eleven patients were treated with AMK and CFX. Clinical responses were excellent in 2 (18%), good in 4 (36%), fair in 1 (9%), and poor in 4 (36%), with an efficacy rate of 64%.
2. No significant side effects requiring cessation of the treatment were observed.

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1. Subjects were in-patients with bacterial urinary tract infections, ranging in age 4 months to 11 years 4 months. As a rule, daily dose was either four 125 mg (in potency) suppositories or four 125 mg (in potency) oral form given at 6-hour intervals over a period of 5 days.
2. The number of children subjected to this study was 105. These children were divided into 2 groups (suppository 54; oral form 51) with matched pretreatment background factors.
3. Therapeutic effectiveness rates were 70.4% for the suppository and 66.7% for the oral form, and no significant difference was observed between the 2 groups. Rates of efficacy by severity, presence or absence of underlying and/or complication diseases, daily dose and causative microorganisms did not differ significantly between the 2 groups.
4. There was no significant difference in time-courses of improvement of clinical signs and symptoms between the 2 groups.
5. Eradication rates for causative microorganisms were 65.9% for the suppository and 62.5% for the oral form.
Most frequently isolated causative microorganisms were Escherichia coli and Proteus mirabilis.
6. No significant differences were recognized in the therapeutic effect and usefulness evaluated by physicians in charge.
7. The frequency of side effects did not differ significantly between the suppository group (6 with diarrhea and 1 with anal pain: 12.1%) and the oral form group (5 with diarrhea, 1 with displeasure and 1 with vomiting: 12.7%).
Abnormal laboratory findings appeared in 6 cases (2 with eosinophilia, 2 with increased GOT and 2 with increased GPT) in the suppository group and 7 cases (2 with eosinophilia, 2 with thrombocytosis, 2 with increased GOT and 1 with increased GPT) in the oral form group.

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Tissue distribution of rokitamycin (TMS-19-Q) was studied after oral administration of 50 mg/kg to fasted Beagle dogs.
Tissue concentrations of TMS-19-Q reached their peaks at 1-2 hours after the administration.
The order of tissue concentrations of TMS-19-Q was liver > kidney > spleen >lung > mesenteric lymph node >heart >tonsil> serum > prostate gland > uterus > skin.
At the peak time, drug concentrations in tonsil and lung were about 1.1 and 1.4 times higher, respectively, than that in serum.

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Blood concentrations of ¹⁴C-rokitamycin (¹⁴C-TMS-19-Q) reached their peaks at 1 hour after a single oral (200 mg/kg) administration to male and female rats, and they were 28.0±0.8 and 24.9±2.0 μg/ml, respectively. No significant differences were observed between male and female in AUC values or maximum blood concentrations.
The distribution of TMS-19-Q was good, and concentrations of ¹⁴C were high in liver, kidney, spleen, pancreas, adrenal, pituitary gland, thyroid, trachea, exorbital lacrimal gland, submaxillary gland and bone marrow.
During the 72 hours period after a single oral (200 mg/kg) administration of ¹⁴C-TMS-19-Q to male rats, 8.0 and 89.6% of the dose were excreted in urine and feces, respectively and a total recovery rate was 97.5% of the dose.
During the 48 hours period after a single intraduodenal (200 mg/kg) administrationof ¹⁴CTMS-19-Q in male rats, 6.9 and 36.2% of the dose were excreted in urine and bile, respectively.
Reabsorption of ¹⁴C excreted from the bile was negligible.
Absorptions of TMS-19-Q from the duodenum, jejunum, ileum and colon were good, but absorption from the stomach was negligible.
Major metabolic reactions of TMS-19-Q were deacylation and hydroxylation, and the major metabolites in rats of TMS-19-Q found in the plasma, urine and bile after oral and intraduodenal administration were 10-OH-TMS-19-Q, leucomycin AT, leucomycin V and 14-OH-leucomycin V.

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After a consecutive oral administration of 200 mg/kg/day of ¹⁴C-rokitamycin (TMS-19-Q) daily for 28 days to male rats, the accumulation of radioactivity in tissues and its disappearance after the cessation of the administration was studied.
Blood concentrations at peak times and 24 hours after each administration were determined daily. Both values increased gradually until the 14th day and thereafter remained roughly constant.
The extent of elimination of radioactivity from the blood was practically not affected by the consecutive administration.
Affinities of radioactivity to the liver, kidney, spleen, adrenal, pituitary gland, preputial gland, thyroid, intraorbital lacrimal gland and bone marrow were comparatively higher than those to other tissues. Tissue concentrations in the above mentioned tissues at the 1st day after the completion of consecutive administrations for 14 and 28 days were 2.6-6.1 and 3.2 6.8 times higher, respectively, than those at the 1st day after a single administration.
The elimination of radioactivity from the tissue after the consecutive administration for 28 days was slightly slower than that after a single administration.
In the consecutive daily administration for 28 days, the metabolic fate of radioactivity reached a steady state after 14 days of consecutive daily administration.
Hence, the accumulation of the radioactivity did not particularly occurred.
During the consecutive administration, recoveries of radioactivity in the urine and feces werealmost at a constant rates, with 8.0 and 93.8% of the total radioactivity given excreted in the urine and feces, respectively, within 10 days after the last administration.

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Transmigration of ¹⁴C-radioactivity to fetus or milk were studied in 17-18 day-pregnant rats and mother rats on the ¹⁴th day after parturition after a single oral administration of ¹⁴C-rokitamycin (TMS-19-Q) at a dose of 200 mg/kg.
The blood concentration of the drug in the mother reached a maximum level of 22.8 μg/ml at 2 hours after administration.
Maximum concentrations of TMS-19-Q in placenta, ovary and uterus were attained in 2 hours, and were 28.9, 26.0 and 26.2 μg/g, respectively.
The distribution to these tissues were considered good.
The maximum concentration of TMS-19-Q in the amniotic fluid was attained in 2 hours, at a level of 5.4 μg/ml.
The transmigration to the amniotic fluid was considered poor.
The maximum concentration of the drug in the fetus was achieved in 2 hours at a level of 13.7 μg/g.
Maximum concentrations of the drug in fetal liver and brain were attained in 4 hours, and were 32.8 and 11.4 μg/g, respectively.
Whole body autoradiography was done when the radioactivity in maternal blood reached peak concentration. It was found that radioactivities in placenta and fetal membrane were similar to the radioactivity in maternal blood, while the radioactivity in fetal brain was considerably lower than that in maternal blood.
Maximum concentrations were found at 1 hour in the blood and at 4 hours in the milk, and were 14.8 and 21.5 μg/ml, respectively.
Transmigration to the milk was good.

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Absorption, metabolism and excretion of rokitamycin (TMS-19-Q), were studied after oral (50 mg/kg), intraduodenal (50 mg/kg) and intravenous (10 mg/kg) administrations of ¹⁴C-TMS-19-Q to male dogs.
Maximum blood and plasma concentrations of the drug reached at 2 hours after oral administration, and they were 11.1 and ¹⁴.3 μg/ml, respectively.
Maximum blood and plasma concentrations reached at 30 minutes after intraduodenal administration, and they were 10.7 and 12.0 μg/ml, respectively.
Blood and plasma concentrations at 3 minutes after intravenous administration were 8.4 and 11.1 μg/ml, respectively. At 24 hours, they were 0.6 and 0.7 μg/ml, respectively.
During the first 72 hours period after oral administration, 12.8 and 82.6% of the dose were excreted in the urine and feces, respectively. A total recovery rate was 95.4% of the dose.
During the first 72 hours period after intravenous administration, 19.4 and 75.3% of the dose were excreted in the urine and feces, respectively. A total recovery rate was 94.7% of the dose.
During the first 24 hours period after intraduodenal administration, 18.0 and 48.3% of the dose were excreted in the urine and bile, respectively. A total recovery rate was 66.3% of the dose.
Major metabolic reactions on TMS-19-Q were deacylation and hydroxylation, and the major metabolites of TMS-19-Q found in the plasma urine and bile after intraduodenal administration to dogs were 10-OH-TMS-19-Q, LM A7, LM V and 14-OH-LM V.

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Three different bioassay methods for rokitamycin (TMS-19-Q) were compared to each otherin vitro and in vivo.
Method I was a paper disc method using Micrococcus luteus ATCC 9341 as the test organism in nutrient agar (pH 8.0), method II was a paper disc method using Streptococcus pyogenes COOK in brain heart infusion agar (pH 7.4) and method III was an agar well method using M. luteus ATCC 9341 in the agar medium provided in the Minimum Requirements for Antibiotic Products of Japan (pH 6.5).
Ratios of relative potency of TMS-19-Q and its metabolites calculated from standard curves in human plasma using these bioassay methods, were 1.00: 1. 13: 3. 34: 0. 96 (TMS-19-Q: 10-OHTMS-19-Q: LM A₇: LM V) in method I, 1.00: 1.58: 0.40 (TMS-19-Q: LM A₇: LM V) in method II and 1.00: 0. 51: 0.86: 0.114 (TMS-19-Q: 10-OH-TMS-19-Q: LM A₇: LM V) in method III.
The relative potency obtained from method I, generally used for macrolide antibiotics, greatly contradicted MIC values of TMS-19-Q and its metabolites against clinically isolated 190 strains of Staphylococcus aureus. On the other hand, the relative potency obtained from method III reflected closely MIC values of TMS-19-Q and its metabolites. Therefore, method III should be the most suitable bioassay method to measure the plasma concentration of TMS-19-Q.
Plasma concentrations measured by these 3 different methods were compared to each otherin vivo, after oral administration of TMS-19-Q at a dose of 1,200 mg to each of fasted healthy volunteers. Values obtained from method I were about 4.3 times higher than those method III.
The difference in plasma concentrations among these 3 bioassay methods was found due to differences in relative potencies of metabolites to TMS-19-Q.

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Six-month oral chronic toxicity study and two-month recovery tests on rokitamycin (TMS-19-Q) were performed in Beagle dogs at daily doses of 90, 180 and 360 mg/kg.
The results were summarized as follows:
1. No death occurred to any animals in these experiments.
2. In higher dosage groups (180 and 360 mg/kg), vomiting, salivation and reduction of body weight gain with decrease in food intake were observed.
3. Body temperature and pulse rate were normal, and ECG, sperm and vaginal smear tests, urinalysis, blood and biochemical examinations also revealed normal values.
4. No marked changes in organ weights, necropsy, histopathological and electron microscopic observations were detected.

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A comparative toxicity study on macrolide antibiotics, rokitamycin (TMS-19-Q) and josamycin, was performed in male rats. These drugs were given orally for 1 month at daily doses of 250,500, 1000, and 2,000 mg/kg.
No animals died in the study. No abnormal symptoms or changes in body weights and food consumption were observed.
Results of urinalysis, hematological analysis and biochemical analysis of serum and organ weights were normal except that a dose-dependent hypertrophy of caecum was observed in all dosage groups.
Necropsy revealed no notable drug related abnormalities except in caecum of all test groups.
Pathological examination found no significant drug-related abnormalities in the test groups.
No toxicological signs were detected in the group administered with 2,000 mg/kg of either drug and no difference was found between the 2 drugs.

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A teratological study was performed on rokitamycin (TMS-19-Q), a new macrolide antibiotic, using rabbits. TMS-19-Q, at dose levels of 100,300 and 600mg/kg, was orally administered from the day 6 to the day 18 of gestation to dams.
Diarrhea and decrease in body weight gain and food consumption were observed in dams at or above 300mg/kg.
Decrease in numbers of live fetuses was observed at dose levels of 300 and 600mg/kg but there was no teratogenicity at any dose levels.
The maximum non-toxic dose level for TMS-19-Q in this study was 100mg/kg.

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The antigenicity of rokitamycin (TMS-19-Q, TMS) was studied. Rabbits and mice were repeatedly challenged with TMS emulsified with adjuvant to be strongly immunized. Neither IgG nor IgE antibodies were, however, detected in serum from these animals when assayed by PCA and PHA reactions. Furthermore, guinea pigs immunized with TMS together with FREUND'S complete adjuvant did not exhibit any systemic anaphylactic reactions when elicited with TMS alone.
In contrast, specific antibody production against TMS was confirmed in animals immunized with chemically introduced antigen of TMS-carrier protein conjugate, where TMS had antigenic nature as hapten.

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Cefuzonam (L-105, CZON) was studied in pediatric infections. A summary of the results is as follows:
1. For recently isolated Staphylococcus aureus strains, Peak MICs of CZON were distributed. between 0.39 and 0.78μg/ml showing a greater susceptibility of S. aureus to CZON than to cefoperazone (CPZ), latamoxef (LMOX), and cefmenoxime (CMX).
2. Peak MICs of CZON for Escherichia coli were 0.10-0.20 μg/ml, similar to those of CPZ, LMOX, and CMX. Ampicillin (ABPC)-resistant strains were also susceptible to CZON. MICs for Salmonella were similar to those for E. coli.
3. Peak MICs of CZON for Vibrio parahaemolyticus were 0.20-0.39μg/ml. The susceptibility of the bacteria to CZON was far greater than to ABPC, and was similar to CPZ, LMOX, and CMX.
4. With 20 mg/kg drip infusion, serum concentrations reached their peaks at the end of administration with values of 20.6-68.7 μg/ml, which decreased to 0.43-1.70 μg/ml after 2 hours. Half-lives of CZON in serum were 0.68-1.2 hours. With 50 mg/kg drip infusion, serum concentrations reached their peaks at the end of administration with levels of 69.0-82.0μg/ml, and at after 2 hours 1.85-3.45 μg/ml. Thus, an apparent dose response was observed. Half-lives of CZON in serum were 0.63-0.99hours.
5. Urinary recovery rates in 6 hours were 39.9-80.5%.
6. A total of 44 cases of 10 different types of acute pediatric infections was treated by CZON intravenous drip infusion as the main therapeutic procedure. The efficacy rate was 93.2%, and the compound was effective on purulent infections, acute urinary tract infection, etc. with pathogens such as ABPC-resistant S.aureus, E. coli, and Enterococcus faecalis. Dosage levels per day were 50 to 80 mg/kg in most cases.
7. In infections with S.aureus (8 strains), Streptococcus pneumoniae (3 strains), E. faecalis (1strain), Haemophilus parahaemolyticus (1 strain), Haemophilus parainfluenzae (2 strains), Haemophilus influenzae (11 strains), Bordetella pertussis (1 strain), E. coli (3 strains), a total of 30 strains, bacterial elimination was noted with an exception of 1 strain of S.aureus.
8. The compound was used for 4 to 15 days, but side effects observed clinically were only 1 case of diarrhea and 1 case of thrombocytosis.

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A new parenteral cephalosporin antibiotic, cefuzonam (L-105, CZON), was evaluated for its safety, efficacy and pharmacokinetics in children. Twenty-two cases of bacterial infections including pneumonia, lung abscess, sepsis, urinary tract infection and soft tissue infections were treated with CZON. Clinical effective rate was 95%.
Serum half-lives of CZON were 1.04-1.33 hours in children with normal renal and hepatic functions. Significant depressions of the normal fecal flora were observed and diarrhea or loose stool was encountered in 7 of the 22 treated cases (32%).

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Pharmacokinetic and clinical studies were conducted to evaluate cefuzonam (L-105, CZON), a new cephem type antibiotic, in the pediatric field.
1. A total of 9 pediatric patients (2-14 years) was treated with intravenous injection of CZON: 4 cases with one shot of 20 mg/kg, 2 cases with one shot of 40 mg/kg and 3 cases with drip infusion over 1 hour of 40 mg/kg. CZON concentrations in serum and the excretion in urine were determined.
Mean serum concentrations of CZON after one shot intravenous injection of 20 mg/kg were 49.0, 22.7, 9.03, 2.13, 0.37, and 0.09 μg/ml at 15, 30 minutes, 1, 2, 4 and 6 hours, respectively. With 40 mg/kg one shot intravenous injections, mean serum concentrations were 117.5, 68.0, 26.2, 8.80, 0.63 and 0.19 μg/ml at 15, 30 minutes, 1, 2, 4 and 6 hours, respectively. With 40 mg/kg intravenous drip infusions over 1 hour, mean concentrations were 57.1, 78.8, 12.9, 1.12 and 0.23 μg/ml at 30 minutes, 1, 2, 4 and 6 hours, respectively. Mean half-lives were 0.69 hour for 20 mg/kg one shot injections, 0.44 hour for 40 mg/kg one shot injections, and 0.58 hour for 40 mg/kg 1 hour drip infusions.
Urinary recovery rates in 6 hour after administration were 70.8% (mean) for the 20 mg/kg one shot injection, 44.1% (1 case) for the 40 mg/kg one shot injection, and 60.0% (mean) for the 40 mg/kg 1 hour drip infusion.
2. CZON was administered in 26 cases of pediatric infections, and the clinical efficacy, antibacterial activity, and side effects were evaluated.
Of the 26 cases 2 were excluded for the reason of not having bacterial infection, and the remaining 24 cases were assessed. Included in the 24 cases were 16 cases of acute pneumonia, 2 cases of acute purulent lymphadenitis, and 1 case each of acute bronchitis, acute purulent otitis media, acute apical periodontitis, staphylococcal scalded skin syndorome (SSSS), acute pyelonephritis, and acute enteritis. Clinical efficacy evaluation showed 19 excellent cases and 5 good cases, with an efficacy rate of 100%. Bacteriologically, Staphylococcus aureus 1 strain, Streptococcus pneumoniae 1 strain, β-Streptococcus 1 strain, Haemophilus influenzae 10 strains, Haemophilus parainfluenzae 1 strain, Proteus mirabilis 1 strain, and Campylobacter jejuni 1 strain were determined or assumed as pathogens, but all of them were eradicated.
Side effects were not observed clinically. Abnormality in laboratory test values included 2 cases of GOT elevation and 1 case of eosinophilia, but posttreatment examination showed no abnormality at all.
From these results CZON was considered to be a highly effective and safe antibiotic for the pediatric field.

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Studies were carried out on the penetration of cefuzonam (L-105, CZON), a new synthetic cephalosporin antibiotic, into cerebrospinal fluid, and on the clinical efficacy against bacterial infections. The results are summarized as follows:
1. Concentrations of CZON in cerebrospinal fluid at 1 hour after intravenous administration of 100 mg/kg in cases of furunculosis of the external canal, encephalitis and mumps meningitis were 0.56 μg/ml, 1.44 μg/ml and 0.33 μg/ml, respectively. Concentrations of CZON in cerebrospinal fluid at 1 hour after intravenous administration of 100 mg/kg in 3 cases of purulent meningitis were 2.80-6.40 μg/ml at the acute stage and 0.56-1.45 μg/ml even at the recovering stage.
2. Sensitivities of clinically isolated strains to CZON were determined and expressed as MIC. MICs of CZON on Haemophilus influenzae, Escherichia coli, Proteus mirabilis and Klebsiella pneumoniae were similar to MIC's of cefmenoxime (CMX), and lower than those of cefoperazone (CPZ), cefmetazole (CMZ), cefatiam (CTM) and Cefazolin (CEZ). The MIC of CZON on Staphylococcus aureus was similar to those of CEZ, CMZ and CTM, and lower than those of CMX and CPZ.
3. Clinical responses of CZON were good in 2 cases of purulent meningitis, good in 2 cases of pyothorax, excellent in 1 case of septicemia, excellent in 3 cases of urinary tract infections, excellent in 7 cases and good in 3 cases out of 10 cases of pneumonia. Clinical responses of other diseases were excellent in 4 cases of bronchitis, good in 1 case of furunculosis of the external canal, excellent in 1 case of tonsillitis.
4. No side effects nor abnormal laboratory findings were observed except 2 cases of mild diarrhea out of 24 cases.

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Cefuzonam (L-105, CZON) was given intravenously to 20 pediatric patients with the following acute bacterial infections: 13 of bronchopneumonia and 1 each of tonsillitis, purulent cervical lymphadenitis and acute tonsillitis, laryngitis, bronchitis, pyothorax, purulent meningitis complicated with septic arthritis, and urinary tract infection. Good clinical responses were obtained in all of the 20 patients and bacterial eradication of all 16 strains. No side effect was observedexcept 3 cases of slight elevation of transaminase, and 1 case each of soft stool and eosinophilia.
From the above clinical results, it appears that CZON is a useful antibiotic for the treatment of pediatric patients with various kinds of bacterial infections.

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A new cephem antibiotic, cefuzonam (L-105, CZON) was studied for its concentrations in serum and clinical efficacy in the field of pediatrics.
1. To examine the concentration of CZON in serum, 20 mg/kg of CZON was administered by intravenous drip infusion to a male patient of 6 years and 7 months. The half-life of the drug in serum was 0.97 hour after administration.
2. CZON was administered to 7 cases of pediatric infections, and clinical result were “excel-lent” in 4, “good” in 1, “poor” in 2: the efficacy rate was 71.4% or 5 cases out of 7. As an adverse reaction, eruption was observed in 1 patient

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