Cefotaxime (CTX) was administered to 130 children with various bacterial infections of 41 to 400mg/kg/day for 2 to 21 days.
The clinical effect of CTX was very satisfactory in respiratory tract infection, urinary tract infection and meningitis.
The overall clinical effect was excellent in 59, good in 39, fair in 17 and failure in 8 with effective rate of 79.7%.
During this therapy, side effects were seen in 3 cases, diarrhea in 1 and rash in 2.
Abnormal laboratory findings were seen in 5 cases, elevation of GOT in 1, GOT, GPT and Al-P in 1, GOT, GPT and T. Bil. in 1, elevation of BUN, increase of number of basophiles and albuminuria in 1 and observation of albuminuria in 1.
The above results demonstrate that CTX is a clinically useful antibiotic for the therapy of pediatric infections.

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One percent cefmenoxime (CMX) ototopical solution was administered to 302 patients with purulent otitis media and acute diffuse external otitis in open study fashion, and to 216 patients with purulent otitis media in double blind condition. From among the total of 518 cases various bacteria were detected, except 22 of negative detection after incubation and 3 of impossible determination. The main bacteria detected from the above 493 cases were S. aureus (242 strains=49.1%), P. aeruginosa (105 strains=21.3%), S. epidermidis (67 strains=13.6%), Proteus spp.(indole positive)(31 strains=6.3%) and P. mirabilis (24 strains=4.9%) as well as anaerobic bacteria (26 strains=5.3%).
MIC of CMX against those bacteria detected was evaluated at 10⁸CFU/ml and 10⁸CFU/ml, respectively, up to the concentration of 800μg/ml, with MIC of cefazolin (CEZ), chloramphenicol (CP) and fradiomycin (FRM) as the references.
1. With respect to the antibacterial action of CMX against S. aureus, MIC₅₀ of CMX was inferior to that of CEZ by 4-fold, but its MIC₈₀ and MIC₈₀ are almost equivalent to those of CEZ. These results were obtained because there existed relatively few CMX highly resistant strains, while more than 20% strains are said to resist cephem antibiotics.
2. As far as MIC of CMX against P. aeruginosa was concerned, the MIC reached its peak with 100μg/ml at the concentration of 10⁸CFU/ml and with 25μg/ml at 10⁶CFU/ml, respectively, which indicated the real antibacterial value of CMX against P. aeruginosa. However, the strains which showed higher MIC of >800μg/ml were rather few, that is, only 8 out of 105 (7.6%).
3. Antibacterial action of CMX against Streptococcus (except Enterococcus), GNR from intestinal bacteria and anaerobic bacteria was favorable, and the stable and strong antibacterial action was shown against C. freundii, Enterobacter spp., S. marcescens and Proteus spp.(indole positive) which produce chromosome mediated β-lactamase. On the other hand, the antibacterial action of CMX against GNF-GNR except P. aeruginosa was unfavorable for P. cepacia, P. putida and A. xylosoxidans, but relatively favorable for A. calcoaceticus.
4. As a result of MIC evaluation of reference drugs, S. aureus was resistant to CEZ, and Proteus spp.(indole-positive) was resistant to CP, while FRM was highly resisted by almost all strains of bacteria. However, the resistance rate of S. aureus to CP was relatively low, that is, as low as 16.1%.
5. Since the active concentration of CMX in the tympanum about 1 hour after its administration was estimated to be 2,000-3,000μg/ml, it could be presumed that the bacteria detected from the middle ear secretion which showed MIC≤800μg/ml at the concentration of 10⁸CFU/ml was eradicable and that the MIC value and bacteria eradication effect were more highly correlated at the concentration of 10⁸CFU/ml than 10⁶CFU/ml in case the topical treatment was designed like the present study.
As a result of the above evaluation, CMX, the main ingredient of 1% CMX ototopical solution is quite stable and well balanced at the topically administered concentration, and furthermore, its mode of action or mechanism is selectively toxic to bacteria, while its otic toxicity is considered to be relatively low. From the clinical bacteriological standpoint, therefore, 1% CMX ototopical solution is considered to be a remarkably useful preparation in the clinical field for topical otic use.

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A multicenter cooperative clinical trial was carried out on S6472 (a long-acting preparation of cefaclor (CCL)) to evaluate its effectiveness and safety in the treatment of infectious diseases in the field of otorhinolaryngology.
The results are as follows:
1. The clinical efficacy of the drug could be evaluated in 114 patients. An efficacy rate of 65.8% was obtained. The efficacy rate for each disease was found to be 60.0% for acute suppurative otitis media, 12.5% for chronic suppurative otitis media and 44.4% for acute exacerbation of chronic suppurative otitis media. The overall efficacy rate for all cases of suppurative otitis media was 46.4%. The efficacy rate for acute tonsillitis was found to be 93.1%. In the treatment of acute exacerbation of chronic tonsillitis, the efficacy of the drug was rated as excellent or good in all cases. The overall efficacy rate for all cases of tonsillitis was found to be 93.9%. In the treatment of other infectious diseases, the efficacy was rated as excellent or good in all cases.
When the cases by resistant organisms to CCL were excluded from the evaluation, the overall efficacy rate of the drug was found to be 74.2%.
2. The bacteria could be identified in 106 cases. Regarding the bacteriological efficacy of single infections, its bacterial elimination rate was found to be 81.1% for Gram-positive bacteria including S. aureus, S. epidermidis, etc., while it was 42.9% for Gram-negative bacteria. The overall elimination rate of bacteria in single infections was 73.1%. The bacterial elimination rate for mixed infections was found to be 85.7%, whereas it was 76.8% when the single and mixed infections were combined.
3. Regarding side effects, 1 case each of diarrhea, soft stool and rash, or 3 cases in total (2.4%), were
recorded in a total of 123 patients. However, the severity of each side effect was mild. Regarding abnormal laboratory findings, there were 1 case each of an increase in S-GPT, leukopenia and complication of eosinophilia and thrombocytopenia, or 3 cases in total (7.0%). Each of these adverse reactions was, however, transient in nature, and no serious cases were observed.
On the basis of the above results, it was concluded that S6472 can provide sufficient clinical efficacy when it is administered at daily dosage of 750 mg or 1,500 mg in 2 divided doses after the breakfast and dinner.

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Agents capable of preventing the toxicity of mitomycin C (MMC) were investigated by a cytotoxicity assay utilizing the E. coli strain WP2 uvrA, a strain sensitive to the bactericidal action of MMC. Of various compounds, mixtures, and rat tissue extracts assayed, the solution of liver extracts and yeast extracts and DULBECCO'S modified EAGLE'S medium (DMEM) exhibited potent activity in protecting the cells against the MMC toxicity. A further analysis of the individual components of DMEM revealed that glucose is the active principle responsible for the protection seen with DMEM. A similar protection has been observed with the use of mannose, mannitol, 2-deoxyglucose, D-glucuronic acid, glucosamine, and N-acetylglucosamine of 16 sugar derivatives tested. The protection by glucose was specific to treatment of cells with MMC but not with UV-irradiation, cis-diamminedichloroplatinum (II), 4-nitroquinoline 1-oxide, or furylfuramide. Unlike the bacterial cells, there was no protective response in the mammalian cells in culture and in mice, given a lethal dose of MMC, concurrently with glucose or each derivative. The possible mechanisms involved in this prevention of MMC toxicity by glucose are discussed.

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A new cephamycin antibiotic, cefminox (MT-141, CMNX), was intravenously infused into Beagle dogs at a dose of 40 mg/kg in order to study it's distribution to various tissues. The following results were obtained.
1. The maximum serum concentration of CMNX observed at the end of the infusion period was 102.3 μg/ml, and then the concentration decreased. The biological half-life of CMNX in serum was 37.0 minutes. This half-life was similar to the results of previous studies with Beagle dogs and rabbits.
2. The maximum concentrations in tissues and body fluids were highest in B-bile followed by kidney, urinary bladder, serum, liver, vagina, uterus, pericardiac fluid, trachea, ovary, lung, gallbladder, parotid gland, heart, tonsil, thymus, spleen, pancreas, aqueous humor and cerebrospinal fluid, in that order and not detected in brain. The maximum concentrations in gallbladder, B-bile, pericardiac fluid and cerebrospinal fluid were found at 1-2 hours after administration. In other tissues and body fluids, they were obtained at the end of the infusion period.
3. The area under the tissue concentration curve (AUC) was highest in the urinary bladder followed by the kidney, vagina, liver, uterus, gallbladder, trachea, ovary and lung, in that order. These results suggest that CMNX is useful for various infectious diseases in these tissues.
4. The pharmacokinetic parameter (K₁₁K₂₁) derived from serum and tissue concentrations using the deconvolution method well correlated to maximum tissue concentrations.

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Metabolism of lenampicillin hydrochloride (LAPC), especially ampicillin (ABPC) structure of LAPC, was investigated after oral administration in human, dogs and rats.
The unchanged compound was not detected in blood and urine, furthermore in animal portal vein after oral administration of LAPC in human and 2 animals. Therefore, LAPC seemed to be rapidly hydrolyzed during the process of absorption.
The intestinal absorption of LAPC was satisfactory in view of the urinary excretion of metabolites, accounting for 93% of dose in human, 74% in dogs and 55% in rats, respectively.
It could be judged by the bioautograms and the correlation between bioassay and HPLC determination of ABPC that the active metabolite in blood or urine was only ABPC. The major urinary metabolites were ABPC, α-aminobenzylpenicilloic acid (ABPA) and 5S-penicilloic acid isomer (5S-ABPA) in human and 2 animals, but the differences were observed on the excretion ratio between human, dogs and rats.
LAPC was stable in the intestinal contents, but liable to hydrolyze in the intestinal wall, blood and liver of rats.
From the facts described above, it was concluded that LAPC was the efficient prodrug of ABPC in terms of the enhancement of absorption and decrease of side effects.

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The in vitro and in vivo metabolism of promoiety in lenampicillin hydrochloride (LAPC) were investigated in rats and dogs.
After incubation of LAPC with intestinal or liver preparations and blood of rat, diacetyl, acetoin and 2, 3-butanediol were identified as metabolites of LAPC.
The main metabolite in peripheral plasma was 2, 3-butanediol after oral administration of LAPC in rats and dogs. On the other hand, high levels of acetoin were found out in portal plasma for early period after dosing of LAPC. These results suggested that the biotransformation of promoiety in LAPC to acetoin carried out mainly in intestinal tissues, but acetoin was converted to 2, 3-butanediol in liver.
Acetoin and 2, 3-butanediol were also excreted in urine, but their urinary excretion were very low, and the combined excretion were accounting for about 9% of dose up to 48 hours after dosing in rats and less than 1% in dogs, respectively.
The major metabolic pathways of promoiety in LAPC were postulated as below.

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A double-blind controlled clinical study between lenampicillin (LAPC), a newly developed oral ampicillin (ABPC) prodrug, and amoxicillin (AMPC) was conducted for the treatment of suppurative skin and soft tissue infection as grouped in 6 disease types.
LAPC or AMPC were orally administered at a daily dose of 1,000 mg, in 4 equally divided doses. Each group was treated for 14 days. The results indicated that LAPC was equal to AMPC in evaluations of effectiveness and usefulness, although incidence of severe side effects was slightly lower in LAPC.
The number of cases studied was 235 (115 in the LAPC group, 120 in the AMPC group). Among these, 10 patients (4 in LAPC, 6 in AMPC) were excluded and 12 patients (5 in LAPC, 7 in AMPC) dropped out. Final global improvement rating was evaluated in 213 patients (106 in LAPC, 107 in AMPC). General usefulness rating was evaluated in 215 patients (106 in LAPC, 109 in AMPC), and overall safety rating was evaluated in 231 patients (115 in LAPC, 116 in AMPC).
1. Final global improvement rating of LAPC was, “cured”, 55.7% and “cured” and “remarkably improved”, 79.2%. The rate increased to 88.7% when “improved” was included. On the other hand, in the AMPC group, “cured” was 50.5%, and “cured” and “remarkably improved” was 76.6%. The rate increased to 91.6% when “improved” was included.
No significant difference was found between the 2 drug groups.
2. In overall safety rating of LAPC, “safe” was 93.9%, while in the AMPC group, “safe” was 94.0%.
No significant difference was found between the 2 drug groups.
Side effects were noted in 2 of 115 patients (1.7%) among the LAPC group and in 5 of 116 patients (4.3%) among the AMPC group. Incidence of severe side effects was slightly lower in LAPC (P<0.1).
3. General usefulness rating of LAPC was, “remarkably useful”, 56.6% and the rate increased to 86.8% when “useful” was included. In the AMPC group, “remarkably useful” was 51.4%, and increased to 84.4% when “useful” was included.
No significant difference was found between the 2 drug groups.

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Bactericidal activities of aspoxicillin (ASPC) against E. coli (2 strains) and K. pneumoniae (1 strain) were compared with those of piperacillin (PIPC) using in vitro kinetic models simulating human serum levels.
In the model of intravenous injection, both drugs exhibited bactericidal action against the strains of E. coli. The activity of ASPC was found to superior to PIPC and ASPC could decrease viable cell counts from 10⁷ cells/ml to 10⁸ cells/ml. On the other hand, the bactericidal activity of ASPC against K. pneumoniae was weaker than that of PIPC.
In the model of intravenous drip infusion, ASPC showed a high level of bactericidal activity comparable to that observed in the intravenous model against E. coli. Interestingly, the bactericidal activity of ASPC against K. pneumoniae in this model was similar to that of PIPC, though the MIC value of ASPC was higher than that of PIPC.
In the intravenous model, the effects of ASPC and PIPC on the morphology of E. coli KC-14 were examined with a phase contrast microscope. Exposure to PIPC caused only an elongation of the cells, but the treatment with ASPC resulted in the formation of spheroplast-like structure of the cells, which were finally subjected to bacteriolysis.

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Fundamental and clinical studies were made on the intravenous administration of aspoxicillin (ASPC) in pediatric field and the following results were obtained.
1. The peak serum concentrations of 15.6-84.0μg/ml were seen immediately after a 1-hour drip infusion of 10-30mg/kg, there being seen a clear dose response. The half-life was 0.78-1.67 hours and the measurable concentrations were detected in the serum up to 6 hours after administration. The urinary excretion rate was 44.1-78.6% up to 6 hours after drip infusion.
2. Twenty-four patients with acute respiratory tract infection (21 cases), urinary tract infection (3 cases) were treated with ASPC by drip infusion of 50-107mg/kg/day for 5-15 days and resulted in 100% of good response.
3. S. pyogenes, S. viridans, E. coli, H. influenzae and P. aeruginosa were isolated form the culture of sputum or urine in the patients, and they were all eradicated by treatment with ASPC except P. aeruginosa.
4. No side effects were observed except the elevation of GOT and GPT in 1 case.
From the above results, it is concluded that ASPC is one of useful drug for treatment of infections in pediatric field.

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Aspoxicillin (ASPC) was evaluated for its efficacy and safety in 30 infants and children with acute bacterial infections. The disease categories included acute respiratory tract (22), soft tissue (3), urinary tract (3) infections, sepsis with pyothorax (1) and purulent meningitis (1). ASPC was effective in all but 1 case of pneumonia due to β-lactamase-positive H. influenzae (effective rate; 96.7%).
Adverse reactions and abnormalities of the laboratory tests were not associated with the ASPC therapy in any of the cases. The serum half-life of ASPC after an intravenous bolus injection was 0.883±0.194 hour and excretion into urine was rapid.
From the present results, ASPC is a safe and effective antibiotic when used in patients with susceptible bacterial infections.

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Aspoxicillin (ASPC), a new penicillin for injection, was evaluated for its efficacy and safety in 29 children with bacterial infection (Table 1), and the following results were obtained.
1. MICs of ASPC to 26 strains of isolated organisms are shown in Table 2. MICs to 4 out of 13 strains of H. influenzae were higher than 6.25μg/ml. MICs to 5 strains of S. pneumoniae were lower than 0.78μg/ml and 1 out of 3 strains of S. aureus and 1 strain of E. coli showed higher MICs than 100μg/ml.
2. ASPC was administered in 3 or 4 divided doses at a daily dosage ranging from 21 to 98mg/kg by 30 minutes drip infusion or intravenous injection to 29 patients (16 cases of pneumonia, 8 cases of tonsillitis, 3 cases of bronchitis, 1 case of urinary tract infection, 1 case of impetigo) and the following clinical results were obtained: excellent; 11 cases, good; 11 cases, fair; 3 cases, poor; 1 case. The overall efficacy rate was 85% (Table 3, 4).
3. No clinical side-effects were observed in any of the patients. Leukopenia was noted in 1 case. Slight elevation of GOT and GPT was noted in 2 cases, and minimal elevation of GOT was observed in other 2 cases (Table 5).
4. These data suggest that ASPC is an useful new antibiotic in the treatment of children with susceptible bacterial infection and may be used as the first choice antibiotic for the treatment of respiratory tract infection in children.

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Laboratory and clinical studies were carried out with aspoxicillin (TA-058, ASPC), a new semisynthetic penicillin, in pediatric infectious disease, and following results were obtained.
1. The average serum concentrations of ASPC after intravenous injection were 53.6, 151.2μg/ml at 15 minutes, 28.0, 72.8μg/ml at 30 minutes, 17.6, 43.3μg/ml at 1 hour, 7.0, 19.9μg/ml at 2 hours, 0.3, 1.8μg/ml at 6 hours, when the doses were 20mg/kg and 40mg/kg, respectively.
2. The mean half-lives of ASPC in blood after injection were 0.87 hour and 1.1 hours when the doses were 20mg/kg and 40mg/kg, respectively.
3. The mean recovery rates in the urine during 6 hours after intravenous injection of 20mg/kg and 40mg/kg were 62.0 and 62.8%, respectively.
4. The antibacterial activity of ASPC against clinically isolated organisms was determined. ASPC had good activity against H. influenzae, H. parainfluenzae, S. pneumoniae and S. pyogenes.
5. Thirty-four patients; 26 cases of respiratory tract infections, 6 cases of urinary tract infections, 1 case of bacterial meningitis and 1 case of bacterial lymphadenitis, were treated with 57.0-159mg/kg daily dose of ASPC for 4-19 days. The rate of satisfactory clinical response was 85.3%.
6. As to side effects, loose stool was observed in 3 cases, slight elevation of GOT & GPT and elevation of platelet were noted, in 2 cases, respectively. All were transient and considered to be minor.

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Fundamental and clinical studies of aspoxicillin (ASPC, TA-058), a new penicillin antibiotic, were performed in pediatric field.
1. Antimicrobial activity MIC of ASPC was compared with that of piperacillin (PIPC), ampicillin (ABPC) and carbenicillin (CBPC) for clinical isolates of S. aureus (24 strains), S. pyogenes (22 strains), H. influenzae (18 strains), E. coli (21 strains) and K. pneumoniae (23 strains). MIC of ASPC against S. pyogenes was distributed in less than 0.39μg/ml and this numerical value of MIC was very superior. MIC distributions of ASPC against S. aureus, H. influenzae and E. coli had 2 peaks respectively. It was presumed that the results are due to an existence of β-lactamase producing strains. The sensitive strains in those were distributed in less than 1.56-12.5≤0.10 and 0.78-3.13μg/ml, respectively, and those numerical value of MIC was superior. While against K. pneumoniae, all strains were distributed in more than 12.5μg/ml and the antimicrobial activity of ASPC was very inferior. ASPC was as active as PIPC and ABPC against S. pyogenes, but more active then CBPC, ASPC was less active against S. aureus than PIPC and ABPC, but more active than CBPC. And ASPC was less active against H. influenzae and E. coli than PIPC, but more active than ABPC and CBPC. Against K. pneumoniae, strains that showed somewhat low numerical value of MIC at only PIPC were observed, but antimicrobial activities of ABPC and CBPC, as well as ASPC were very inferior.
2. Absorption and excretion Serum level and urinary excretion of ASPC in 6 pediatric patients of 4 months to 12 years of age after one shot intravenous injection of 20mg/kg were examined. The serum mean levels were 51.7μg/ml at 1/4 hour, 38.2μg/ml at 1/2 hour, 22.9μg/ml at 1 hour, 3.0μg/ml at 4 hours and 1.0μg/ml at 6 hours after injection, respectively. The mean half-life of serum level was 1.03 hours. The mean urinary levels were 4,646μg/ml for 0-2 hours, 1,773μg/ml for 2-4 hours and 299μg/ml for 4-6 hours. The mean urinary recovery rate within 6 hours after injection was 64.7%.
3. Clinical studies In order to evaluate clinical response, bacteriological response and side effects, ASPC was applied to 28 cases, i.e., 5 cases of acute purulent tonsillitis, 2 cases of acute purulent otitis media, 2 cases of acute bronchitis and 19 cases of acute pneumonia. Clinical effects on 24 cases excluded 4 cases of Mycoplasma pneumonia were excellent in 20 cases and good in 4 cases. The rate of clinical response (the percentage of cases showed excellent and good efficacy) was 100%. As for bacteriological response, all strains which were determined or supposed to be causative organisms, i.e., 1 strain of S. pneumoniae, 1 strain of S. pyogenes, 9 strains of H. influenzae and 4 strains of H. parainfluenzae were disappeared except 1 strain of H. influenzae after the treatment. The rate of bacteriological response was 93.3%. No clinical side effects were observed in any case. Abnormalities of laboratory findings were observed in 4 cases, including elevation of GOT and GPT in 2 cases, elevation of GOT alone in 1 case and eosinophilia in 1 case, but 3 cases which could be reexamined after the treatment in them returned to normal.
From above-mentioned fundamental and clinical results of ASPC, it was concluded that ASPC is a useful and safe antibiotic in pediatric field.

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Fundamental and clinical studies were performed with aspoxicillin (ASPC), a new developed injectable broad penicillin, in pediatric infectious diseases, and the following results were obtained.
1. Pharmacokinetics
ASPC was administered to 2 cases at a dose of 20mg/kg by one shot intravenous injection. The mean half-life (T 1/2) was 1.17 hours. The mean urinary excretion rate was 58.4% during 6 hours after ASPC treatment.
In 3 cases of intravenous drip infusion with a period of 1 hour at a dose of 10mg/kg (2 cases) and 20mg/kg (1 case), the half-lives (T 1/2) were 1.7 hours, 3.5 hours and 1.0 hour, respectively.
The urinary recovery rate during 6 hours after administration was 57.7%, 32.6% and 42.7%, respectively. At only one case treated with 10mg/kg intravenous drip infusion, the half-life was prolonged and urinary excretion rate was lower than other 2 cases.
2. Clinical study
ASPC was administered 50-80mg/kg/day for 4-8 days to 22 children comprising 6 tonsillitis, 2 bronchitis, 6 pneumonia and 8 urinary tract infections.
Clinical efficacy was excellent in 13 cases, good in 8 cases and fair in 1 case, the total cure rate was 95%. As for the clinical response classified by diagnosis, the each efficacy rate of tonsillitis, bronchitis and pneumonia was 100%, and that of urinary tract infection was 87.5%.
Clinical side effect and abnormal laboratory findings were not observed in any cases.
From the above results, it was concluded that ASPC was one of the useful secure drug for treatment of infections in pediatric field.

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The authors have carried out the clinical and laboratory evaluation of aspoxicillin (ASPC, TA-058). The results were as follows:
1. Antibacterial activities
The susceptibility to ASPC was estimated by plate dilution method on 26 strains each of S. aureus, E. coli, Salmonella and P. aeruginosa and 19 strains of S. marcescens isolated from clinical specimens. Minimum inhibitory concentration (MIC) of ASPC against E. coil and Salmonella was about twice active to compare with ampicillin (ABPC), but MIC of ASPC against S. aureus was two-fold less active than that of ABPC. Antimicrobial activities of ASPC against S. marcescens were similar to that of ABPC, while against P. aeruginosa its activities were two-fold higher than that of carbenicillin.
2. Serum levels and urinary excretions
When ASPC was administered at 20mg/kg by one shot intravenous injection, serum concentration was 75μg/ml after 15 minutes and half-life (T 1/2β) was 1.65 hours. Urinary excretion within 6 hours after ASPC injection reached to 245.6mg (26.1%). The reason of this law urinary excretion rate was due to the underlying disease (hydronephrosis). In case of 20mg/kg administration of ASPC by intravenous drip infusion, peak serum level reached to 88μg/ml at the end of injection, and half-life (T 1/2β) was 0.77 hour. Since ASPC degradation by β-lactamase was proceeded, urinary excretion of this case was not measured by microbiological method. Penicillonic acid and its epimer were detected by HPLC method. It was found that β-lactamase producing strain was S. marcescens which was isolated by urine culture.
3. Clinical results
Treatment with ASPC was made in 9 cases of pediatric infections; 1 case of bronchitis, 7 cases of pneumonia and 1 case of pyelonephritis. Results obtained were excellent in 5 cases and good in 4 cases. No side effect due to the drug was seen in any case.

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A clinical and laboratory evaluation and a blood level studied on aspoxicillin (ASPC), a new injectable penicillin derivative; the following results were obtained.
1. ASPC was intravenously administered in 3 or 4 divided doses at a daily dosage ranging from 83.3 to 111.9mg/kg to 5 patients (1 case of lacunar tonsillitis caused by H. influenzae, 3 cases of pneumonia caused by H. infiuenzae, 1 case of pneumonia caused by E. coli).
As the results, a global effect were excellent in 3 cases and good in 2 cases. The overall efficacy ratio was 100%.
All isolated organisms were eradicated, excluding the only case of pneumonia due to H. influenzae infection.
2. No side effects were found in any of the 7 patients including 2 patients who were dropped out the efficacy evaluation because of Mycoplasma pneumonia.
Laboratory findings showed a slight elevation of GOT and GPT in 2 cases and temporary eosinophilia in 1 case.
3. Blood level of ASPC in 2 cases after 10mg/kg administration by intravenous injection was 28.5 or 35.5μg/ml at 30 minutes, 14.3 or 20.7μg/ml at 1 hour, 6.1 or 8.8μg/ml at 2 hours, 1.3 or 3.02μg/ml at 4 hours. The half-life was 0.81 or 1.01 hours, respectively.
Judging from the results of this blood level and the MIC of ASPC against clinically isolated organisms, good efficacy will be obtained to pediatric infections by the sensitive strains, if it is given 10mg/kg to mild patients or 20mg/kg to moderate or severe patients in 3 or 4 divided dose at a daily dosage.

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Clinical studies were performed as follows on aspoxicillin (ASPC), a new semisynthetic penicillin.
ASPC was intravenously given to 12 patients in doses of 57.7-129.0mg/kg (77.2mg/kg on average) t. i. d. or q. i. d. for 4-7 days (5.7 days on average): 9 with pneumonia, 1 with tonsillitis, 1 with purulent lymphadenitis and 1 with urinary tract infection.
The overall efficacy rate was 83.3%, i. e. efficacy was excellent in 8 (66.7%), good in 2 (16.7%), fair in 1 (8.3%) and poor in 1 (8.3%). Bacteriological efficacy was excellent, i. e. 6 of the 6 strains disappeared.
No clinical side effects were observed during treatment. Laboratory abnormalities were observed in 3 cases, slight elevation of GOT in 1, slight elevations of GOT and GPT in 1 and mild eosinophilia in 1.
The above results suggest that ASPC is an useful antibiotic for treating pediatric bacterial infections.

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Aspoxicillin (TA-058, ASPC) was given intravenously to 20 children with the following acute bacterial infections; 11 cases of bronchopneumonia, 5 cases of urinary tract infection, 2 cases of acute bronchitis, 1 case of staphylococcal scalded skin syndrome and 1 case of subcutaneous abscess.
Clinical effectiveness was obtained in 14 cases out of 20 cases (70%) and bacteriological eradication in 8 cases out of 10 cases (80%).
With ASPC the following side effects developed; transient diarrhea in 1 case, eruption in 1 case and slight elevation of GOT in 1 case.
From the above clinical results, it is apparent that ASPC is an useful antibiotic for treating pediatric patients with various kinds of bacterial infections.

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Studies on efficacy and safety of aspoxicillin (ASPC) were carried out to 14 cases of pediatric infections, and the following results were obtained.
1. Clinical efficacy of ASPC to 10 respiratory infections, 1 urinary tract infection and 1 otitis media was excellent in 6 cases (50%) and good in 6 cases (50%). The efficacy rate was 100%.
2. Bacteriological effect of ASPC to 6 cases which detected the causative organisms (S. aureus, E. faecalis, H. influenzae and P. mirabilis) was eliminate in 3 cases (50%) and replace in 3 cases (50%). The bacterial eliminated rate was 100%.
3. Side effects of ASPC to 14 administered cases were observed in 2 cases, that were urticaria in 1 case and elevation of GOT in 1 case.
4. From the above results, it was concluded that ASPC was the useful and secure antibiotic drug for treatment of infections in pediatric field.

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Clinical application to ascertain the effects of aspoxicillin (ASPC), a new semisynthetic penicillin antibiotic, upon several infectious diseases of children was performed in 7 cases with pneumonia, 5 cases with acute bronchitis, each case with tonsillitis, enterocolitis, urinary tract infection and suspected sepsis.
ASPC was injected by drip infusion and the dosage was 63-117 mg/kg/day in 3 and 4 times a day.
Clinical efficacy obtained as “excellent” was in 7 cases, “good” in 8 cases and “poor” in 1 case, and efficacy rate was 93.8%.
From the bacteriological point of view, eliminated in each of H. influenzae, H. parainfluenzae, group A beta-Streptococcus and unchanged in a case of E. colt.
There were transient thrombocytopenia in 2 cases and eosinophilia in 3 cases.

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Penetration of aspoxicillin (ASPC), a new semisynthetic penicillin, to cerebrospinal fluid (CSF) and clinical studies against bacterial infections were carried out and the following results were obtained.
1. The concentration of ASPC in CSF was below 1μg/ml at 1 hour after intravenous administration of about 50 mg/kg dose to 2 cases of aseptic meningitis on the acute stage.
The concentration of ASPC in CSF was above 10μg/ml at 1 hour after intravenous administration of about 80 mg/kg dose to 3 cases of purulent meningitis on the acute stage, and was above 2μg/ml even on the recovering stage.
On each stage, its concentration was more than minimum inhibitory concentration of H. influenzae (≤0.05μg/ml; at inoculum size of 10⁶ cells/ml).
2. Clinical efficacy of ASPC was good in all 3 cases of purulent meningitis, excellent in 3 cases, good in 3 cases and poor in 1 case out of 7 cases of septicemia, good in 2 cases and poor in 1 case out of 3 cases of gastroenteritis, respectively.
And clinical efficacy of other diseases were excellent or good, that were 2 cases of tonsillitis, 2 cases of soft tissue abscess, 1 case of purulent lymphadenitis and 1 case of urinary tract infection, respectively.
3. Side effects were mild eosinophilia in only 2 cases out of 22 cases.

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Eighteen infants and children with infectious diseases were treated with aspoxicillin (ASPC), a new semisynthetic penicillin. The result was as follows:
1. The clinical responses to ASPC were excellent in 6 patients and good in 5 patients of 11 children with bacterial infections.
2. The bacteria isolated from the culture of throat swab and urine in 5 patients were Streptococcus pneumoniae, Escherichia colt, and Staphylococcus aureus which were all eradicated by the treatment of ASPC.
3. The mean serum concentration of ASPC reached the peaks of 73.3μg/ml in 5 cases with dose of 20 mg/kg, and 136.3μg/ml in 3 cases with dose of 40 mg/kg 15 minutes after the intravenous administration. The mean half-lives of ASPC in the serum were 1.08 hours for the dose of 20 mg/kg and 1.07 hours for the dose of 40 mg/kg.
4. The mean urinary recoveries of ASPC in 6 hours following the intravenous administration were 73.7% in 3 cases with dose of 20 mg/kg, and 79.6% in 1 case with dose of 40 mg/kg.
5. No clinical side effect of ASPC was observed. An increase of platelet was noticed in a child with infectious mononucleosis in the course of administration of ASPC.

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Aspoxicillin (ASPC), a new semisynthesized penicillin, was administered to 20 children; by one shot intravenous injection in the doses of 10, 20 and 40 mg/kg to each of 3 children, and by intravenous drip infusion in the doses of 20 and 40 mg/kg over a period of 1 hour to 8 and 3 children, respectively, and the serum levels, urinary levels and recovery rates were determined. ASPC was administered to 1 patient with tuberculous pleurisy in the dose of 20 mg/kg by one shot intravenous injection, then the thoracic fluid level and serum level were determined. In addition, ASPC was administered to 3 children with tonsillitis, 3 with bronchitis, 40 with pneumonia, one each for pleuropneumonia, pleurisy, lung abscess, scarlet fever, staphylococcal scalded skin syndrome and purulent lymphadenitis and 2 with UTI (total 54 children), in the mean dose of 81.4 mg/kg/day t.i.d.(12 children) or q.i.d.(42 children) by one shot intravenous injection for 6 days on the average, and clinical effectiveness and bacteriological response were evaluated in these cases, and adverse reactions and abnormal laboratory findings were examined in the 60 cases which included 6 dropout cases.
1. After the administration of ASPC to 9 children; 10, 20 and 40 mg/kg to each of 3 children, by one shot intravenous injection, the mean serum levels reached to the peak of 58.4, 147.0 and 221.0mcg/ml, respectively, in 5 minutes.
The mean half-lives were 1.03, 1.01 and 1.23 hours, and the mean areas under the curve (AUCs) were 44.9, 94.1 and 192.9mcg·hr/ml, respectively. A dose response was seen among the 3 dosage levels.
After the administration of ASPC to 11 children; 20 and 40 mg/kg to 8 and 3 children, respectively, by intravenous drip infusion over a period of 1 hour, the mean serum levels reached to the peak of 58.2 and 114.0mcg/ml, respectively, on completion of the administration. The mean half-lives were 1.22 and 1.09 hours, and the mean AUCs were 109.4 and 181.7mcg·hr/ml, respectively. A dose response was observed between the 2 dosage levels.
2. In the above mentioned each 3 cases receiving one shot intravenous injection in the dose of 10, 20 and 40 mg/kg, the mean urinary levels of ASPC reached to the peak of 1,000.0, 2,300.0 and 4,350.0mcg/ml, respectively, at 0-2 hours after the administration, and the urinary recovery rates during the first 6 hours were 66.1, 66.5 and 56.9%, respectively.
In the 11 cases receiving intravenous drip infusion over a period of 1 hour, in 8 cases administered ASPC at 20 mg/kg, the mean value of peak urinary levels was not determinable for lack of urination on some sampling points, but the mean recovery rate during the first 7 hours was 55.6%.
In the other 3 cases administered ASPC at 40 mg/kg, the peak urinary levels were obtained at 0-1 hour after the end of administration. The mean peak level was 7,945.7mcg/ml, and the mean recovery rate during the first 7 hours was 64.4%.
3. In the case of tuberculous pleurisy, treated with ASPC in the dose of 20 mg/kg by one shot intravenous injection, the thoracic fluid level determined at 63 minutes was 6.4mcg/ml, and the serum level, 18.5mcg/ml at 70 minutes after the administration. There was little difference of the sampling points between the thoracic fluid and the serum, in a mere 7 minutes difference in the sampling points, and the ratio of the thoracic fluid level versus serum level being 34.6%, which was good penetration.
4. As to the clinical effectiveness in 54 cases with various bacterial infection, 50 cases were assessed as excellent or good, which showed high efficacy rate of 92.6%.
5. Bacteriological response could be evaluated only 8 cases, the pathogenic organism or isolated organism assumed to be the causation, was eradicated in 7 cases and unchanged in 1 case.

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Aspoxicillin (ASPC), a new semisynthetic penicillin, was administered to a total of 13 children with respiratory tract and other various infections.
Respiratory tract infections in 7 of 13 children were treated with ASPC intravenously, 64 to 144 mg/kg/day t. d. s. or q. i. d. The other 6 patients with various types of infections were also treated with the combination of ASPC and other antibiotics. Their clinical and laboratory data were evaluated only for adverse reactions. Concentration of ASPC level in serum and urine was determined after 60 minutes intravenous drip infusion of 20 mg/kg/dose of ASPC dissolved with the solution of solita T3 in 3 children. The half-life of ASPC was 0.76 to 2.31 hours and urinary excretion rate was 53.0% in first 6 hours.
The effectiveness rate in respiratory tract infections was 100%.
Clinical side effects were not recognized except loose stool in 1 case. The increase and decrease of platelet counts and the elevation of GPT were encountered 3 of 13 cases.

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A new semisynthetic penicillin aspoxicillin (ASPC, TA-058) has been evaluated in regard to distribution into the genital organs and the dead space fluid and also in regard to antibiotic activity against various strains clinically isolated in the field of gynecology.
The pharmacokinetic studies were made by using two-compartment model on the data of concentration in ovary, oviduct, endometrium, myometrium, cervix uteri and portio vaginalis of the genital organs and in dead space fluid.
The following results were obtained.
1. After one shot intravenous administration of 2.0 g ASPC, no marked difference was observed in concentration pattern between peripheral vein and uterine artery. Half-lives were 1.8 hours and 3.5 hours, respectively.
The concentrations in various tissues of genital organs reached to the maximum at 36.2-73.6μg/g during 0.07-0.44 hour with half-life varied from 0.53 to 1.3 hours.
Area under the curves (AUC) of various tissues were reached to 30-65% of that uterine artery.
2. After 2.0g administration of ASPC drip intravenously (d. i. v.; for 30 or 60 minutes), there are no remarkable difference on simulation curve of concentration between peripheral vein and uterine artery. The peak level of various tissues attained to 22.5-40.3μg/g during 0.53-0.56 hours and AUC of their concentration achieved about 20-40% of that of uterine artery after intravenous drip infusion for 30 minutes. After intravenous drip infusion for 60 minutes, tissue level reached to the maximum during 1.01-1.82 hours with half-life of 0.65-1.4 hours and AUC of tissue concentration achieved about 20-57% of that of uterine artery. The concentration of the drug in dead space fluid was reached to the maximum at 3.1 hours after the administration and its half-life was 5.3 hours.
3. The in vitro activities of ASPC against clinical isolates were examined.
The values of MIC₇₀ and MIC₈₀ were ranged 0.35-5.1μg/ml and 0.39

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