A semisynthetic penicillin, TA-058, is a derivative of amoxicillin. In vitro and in vivo antibacterial activities of TA-058 against gram-positive and gram-negative bacteria were compared with mainly ampicillin and piperacillin. The results are summarized as follows.
1) TA-058 possesses a broad spectrum of in vitro antibacterial activity against gram-positive and gram-negative bacteria.
2) In vitro antibacterial activites against gram-positive and gram-negative bacteria were compared using 1412 clinical isolates of 21 species of bacteria. TA-058 was as active as piperacillin against P. mirabilis and H. infiuenzae, but not against other bacteria.
3) Greater bactericidal activity toward the three strains, i. e., S. aureus, E. coli and P. aeruginosa, was demonstrated with TA-058 than with ampicillin and piperacillin.
4) TA-058, like penicillin G, was hydrolyzed by penicillinase. TA-058, ampicillin and piperacillin were more stable against cefuroximase and cephalosporinase than against penicillinase.
5) In vivo antibacterial activities of TA-058, ampicillin and piperacillin were compared, using systemic infections of mice with S. aureus, E. coli, K. pneumoniae, S. marcescens, P. aeruginosa and P. mirabilis. The 50 % effective doses of TA-058 were lower than those of piperacillin against E. coli and P. mirabilis.

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The antibiotic activities of TA-058 were examined against 1, 119 strains isolated clinically from the year 1981 to 1982 including two species of Streptococci, two Staphylococci, five Enterobacteriaceae, six Pseudomonas, two Acinetobacter, one Achromobacter, Flavobacterium and B. fragilis in comparison with other penicillins. Antimicrobial activities against B. fragilis were compared with cephems.
TA-058 showed more active antimicrobial activities or at least similar activities to SBPC in most of the strains tested. But antimicrobial activities of TA-058 were inferior to those of PIPC and MZPC against many of the strains tested. Resistant strains which show more than 100μg/ml of minimum inhibitory concentrations were observed in all strains except for S. agalactiae and P. putrefaciens.

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The in vitro antibacterial activities of TA-058, a new amoxicillin derivative with aspartic acid residue, were found to be broad against both gram positive and negative bacteria, especially effective against S. Pyogenes, S. pneumoniae and P. mirabilis. Its activities against S. aureus, S. faecalis, E. coli and B. fragilis were sufficient as PIPC, whereas less active against K pneumoniae, P. inconstans and P. aeruginosa. The minimum inhibitory concentrations of most of the strains of P. vulgaris and S. marcescens were distributed in over 100μg/ml.
TA-058 was stable in cepharosporinase but labile in penicillinase as those other broad spectrum penicillins.
Therapeutic effects of TA-058 in the experimentally infected mice either with E. coli C-11 or K. pneumoniae No10 or P. aeruginosa PI-21 were similar to those of PIPC and thus, superior to CBPC, SBPC, ABPC and AMPC but inferior to APPC. Therapeutic effects on cyclophosphamidetreated mice infected either with E. coli C-11 or P. aeruginosa PI-21 were superior to CBPC, PIPC, ABPC or CEZ.

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Bacteriological evaluation to anaerobic bacteria was made on TA-058, a new penicillin, and the following results were obtained.
TA-058 had a broad antibacterial spectrum against anaerobic bacteria and at 1.56μg/ml inhibited the growth of many test species except B. fragilis, B. thetaiotaomicron, B. disiens, B. bivius, E. lentum and C. difficile. The antibacterial activity of TA-058 against these bacteria was more potent than that of SBPC, CBPC, and TIPC but was less potent than that of ABPC.
TA-058 was as effective as CFX against experimental mice infection by a beta-lactamase producing strain of B. fragilis (GAI 0558), for which MICs of TA-058 and CFX were 400 and 12.5μg/ml respectively.
TA-058, unlike ABPC, SBPC and CBPC, supressed the abnomal growth of C. difficile in caecum contens of mice.

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In vitro and in vivo antibacterial activities of TA-058, a new semisynthetic penicillin, were compared with those of Carbenicillin (CBPC), Piperacillin (PIPC) and Apalcillin (APPC). The following results were obtained.
1. TA-058 showed a broad antibacterial spectrum against gram-positive and gram-negative bacteria which were maintained in Kyoto College of Pharmacy. The potency of TA-058 was similar to that of CBPC, but it was less than that of PIPC and APPC.
2. TA-058 exhibited stronger activity than PIPC and APPC against clinically isolated E. coil, H. influenzae and P. mirabilis, while it was slightly less active than CBPC against clinical isolates of P. aeruginosa.
3. TA-058 showed high bactericidal activities against E. coli and P. aeruginosa. The activities against E. coli at the higher concentrations over MIC of TA-058 were stronger than those of reference penicillins until 2 hours after the addition of drugs. The activities against E. coli were markedly higher than those of PIPC and APPC, especially when a large inoculum size (about 10⁸ cells/ml) was used. Against P. aeruginosa, the activity of TA-058 at a small inoculum size was similar to those of reference drugs, while at a large inoculum size, the activity was more potent than PLPC, equally to APPC and less than CBPC.
4. TA-058 excelled CBPC, PIPC and APPC in its therapeutic efficacy in experimental mice infections caused by E. coli, K. pneumoniae and P. aeruginosa. The excellence on the therapeutic effect was noted especially when a large challenge dose was used for the experiments.
5. When the drugs were administered to the mice with the infections, TA-058 gave higher serum and peritoneal fluid concentrations than those of PIPC.

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The therapeutic effects of TA-058 against local experimental infections in mice were compared with those of piperacillin (PIPC) and carbenicillin (CBPC). The following results were obtained.
1. TA-058 was more effective than PIPC and CBPC against experimental urinary tract infections induced by E. coli KC-14 in mice.
2. Against experimental pneumonic infection induced by inhalation of K. pneumontae DT-S in mice, TA-058 excelled PIPC and CBPC in the therapeutic efficacy.
3. With subcutaneous treatment of infected mice, TA-058 decreased viable bacterial cells in the infectious lungs more rapidly than PIPC and CBPC.
4. In subcutaneously administered mice, TA-058 gave higher drug concentrations in the blood, kidney and lung than PIPC and CBPC. These higher concentrations of TA-058 maintained longer than those of PIPC and CBPC.

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A new penicillin, TA-058, was evaluated in regard to MICs to 220 strains of various clinical isolates and passage into the cerebrospinal fluid (CSF) in experimental stapylococcal meningitis in rabbits, and the following results were obtained.
1) Antibacterial activity of the drug was slightly more active than ABPC against E. coli, Salmonella and P. mirabilis, however it showed cross-resistance against about 50% of E. coli isolates, those MICs were>100μg/ml and TA-058 was less active than ABPC against S. aureus. Both TA-058 and ABPC were scarcely active against Klebsiella and indole (+) Proteus, whereas few strains of Enterobacter, Citrobacter and S. marcescens was susceptible to ≤6. 25μg/ml of TA-058 only and also in P. aeruginosa few strains were susceptible to 25-100μg/ml of the drug.
2) With experimental staphylococcal meningitis in rabbits, concentration of TA-058 in the CSF was more higher than ABPC, since TA-058 maintained well absorbed in serum.
But a CSF/serum ratio of maximum concentration and AUC up to 2 hours was 4.84 % and 10.1%, respectively, then these values were lower than those of ABPC which had already been reported. However, TA-058 was recorded highest value in both T1/2 of CSF concentration and CSF/serum ratio compared with all other penicillins.
Based on-above results, it was suggested that TA-058 is a novel antibiotic in pharmacokinetically.

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In vitro antibacterial activity of a new semisynthetic penicillin, TA-058, was tested and the following results were obtained:
1) Like ABPC, TA-058 showed a broad spectrum activity against gram-positive and gramnegative bacteria and it was as active as SBPC against P. aeruginosa.
2) Antibacterial activity of TA-058 against clinical isolates of E. coli, P. mirabilis and H. influenzae was superior to those of reference penicillins.
3) Examination of the effect of various factors on antibacterial activity of TA-058 revealed that the activity was almost not affected by the factors except for the inoculum size of P. aeruginosa.
4) TA-058 had a similar strong bactericidal activity to ABPC and SBPC. Lytic form of the bacterial cells (E. coli NIHJ JC-2) were observed by microscopic examination at concentrations more than 12.5μg/ml of TA-058.
5) TA-058 was hydrolyzed by penicillinases of gram-negative rod bacteria.

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In vivo efficacy of TA-058, a new parenteral semisynthetic penicillin, was examined in comparison with ampicillin (ABPC), amoxicillin (AMPC), carbenicillin (CBPC), sulbenicillin (SBPC) and piperacillin (PIPC) to see if its broad antibacterial spectrum in vitro is reflected in its antibacterial effects against experimental infections in mice. TA-058 was more effective than the reference drugs against intraperitoneal infections by various gram-negative bacterial species. However, TA-058 was inferior to ABPC and AMPC against infections by gram-positive bacteria.
Furthermore, on the abscess caused by subcutaneous infection with S. aureus or S. hemolyticus, TA-058 exhibited greater suppressive effects than ABPC. TA-058 showed more potent therapeutic effects than PIPC and CBPC against experimental pneumonic infections induced by inhalation of K. pneumoniae B-54 and against ascending urinary tract infections by P. mirabilis or E. coli in mice.

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The concentrations of TA-058 in the body fluids were determined by the cylinder-plate assay, the disc-plate assay and the agar well assay methods using E. coli ATCC 27166, M. luteus ATCC 9341 and B. subtilis ATCC 6633. The most suitable method may be chosen depending on the sample concentration and volume. The clear and large inhibitory zones were obtained by adjusting the pH of assay medium to 6.0. The cylinder-plate method was most sensitive, which was followed by the agar well and the disc-plate methods in the sensitivity.
The inhibitory zone diameters of TA-058 in human or various animal serum and bile were found to be smaller than those of in M/15 phosphate buffer. However, when the specimens were diluted over 5-fold with the phosphate buffer, the potency of TA-058 was completely recovered. Thus, the concentrations of TA-058 could be determined by using standard curves which were prepared with the same body fluids or the phosphate buffer as a diluent. Since the potency of TA-058 in the serum and bile decreased by the preservation in a refrigerator (5°C) for one day, the potency in these specimens desire to determine rapidly. The potency of TA-058 in the body fluid was, however, stable at-20°C for 7 days. TA-058 was also stable in human urine and did not affect the inhibitory zone diameter.

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The High-Performance Liquid Chromatographic (HPLC) assay method for the quantitative determination of TA-058 in body fluids and the stability in human bile were described.
The chromatographic separation of TA-058 and body fluids blank was good. The recovery rates of added TA-058 from those body fluids were 96-103%.
The concentration of TA-058 in human serum, urine and bile detected by HPLC methods were in good agreement with those obtained by the Microbiological method.
TA-058 was stable in human bile during 7 days when it was kept in frozen state at-20°C.

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In experimental animals, distribution and excretion of TA-058 to the body fluids and various tissues were compared with those of reference penicillins. TA-058 was intravenously or intramuscularly admistered to mice, rats, rabbits and dogs in single doses ranging 20 to 100mg/kg.
The serum levels of TA-058 were higher than those of carbenicillin, ampicillin and piperacillin and persisted much longer than the reference penicillins in the above experimental animals. The biological half lives of TA-058 were 0.59, 0.96 and 0.99 hr for rats (i.v.), dogs (i.v.) and dogs (d.i.), respectively, at doses of 20mg/kg. In mice, TA-058 was distributed in high concentrations to various tissues in the descending order of the liver, kidney and lung. In rats, the following order was observed; kidney>liver>lung.
TA-058 was excreted mainly in the urine of rat, rabbit and dog within 5 to 24 hrs. after the administration. The biliary excretions of TA-058 were 18.8 and 13.6% within 24 hrs for rats and rabbits, respectively. These rates were lower than those of piperacillin.
TA-058 was stable in the body fluids and tissues in a cold or in a frozen state and no active metabolite except TA-058 was observed in these biological samples.

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The disposition and metabolism of TA-058, a new semisynthetic penicillin, were studied in mice and rats.
1) The plasma half-lives of radioactivity in mice and rats after intramuscular injection of ³H-TA-058 (20mg/kg) were 17 and 18 minutes
The tissue levels in both animals were highest at about 15 minutes after the injection. The kidney, liver, lung and plasma showed high concentrations of radioactivity while the brain had the lowest level.
2) When ¹⁴C-TA-058 (20mg/kg) was injected intravenously, the tissue levels in rats were similar to those obtained after intramuscular injection of ³H-or ¹⁴C-TA-058.
3) In the whole body autoradiograms of mice and rats after intravenous injection of ¹⁴C-TA-058 (20mg/kg), considerable radioactivities were observed in the kidney, liver, lung, subcutaneous connective tissue and oral and nasal mucosa.
4) The urinary excretion rates of radioactivity in mice and rats were about 83% and about 72% of the dose, respectively, within 72 hours after intramuscular injection of ³H-TA-058 (20 mg/kg and 100mg/kg) and the fecal excretion of radioactivity was about 15% in mice and about 24% in rats in the same period. Most of the urinary radioactivity was excreted within 4 hours after administration.
The urinary excretion rates obtained by radioassay and bioassay were nearly equal in both animals, but no antibacterial activity was found in the feces of both animals.
5) After intravenous and intramuscular injection of ¹⁴C-TA-058 (20mg/kg) to rats, the radioactivity excreted within 72 hours was about 70% of the dose in the urine and about 28% in the feces, and there was no sex difference in either urinary or fecal excretion.
When ¹⁴C-TA-058 (20mg/kg) was injected intramuscularly to rats, the radioactivity excreted into the bile and that expired as ¹⁴CO₂ were 30% and 0.05% of the dose, respectively.
6) Within 6 hours after intramuscular injection of ¹⁴C-TA-058 to rats, most of the radioactivity excreted in the urine and bile was intact TA-058, and the rest consisted mainly of penicilloic acid and a dimer of TA-058.
7) When ¹⁴C-TA-058 (20mg/kg) was injected intramuscularly to pregnant rats at the late stage of gestation, the radioactivity in the fetus was 0.083% of the dose at 60 minutes and it became undetectable at 8 hours.
No or very low radioactivity was found in the tissues of suckling rats when the dam rats were intramuscularly injected with ¹⁴C-TA-058.
8) When ¹⁴C-TA-058 (50 mg/kg) was injected intramuscularly to rats once daily for 6 days, the radioactivity in each tissue at 24 hours after the last administration was only 1.1-2.0 times higher than that after single administration and no tendency of tissue accumulation of the radioactivty was recognized.

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The combination effects of TA-058 and several aminoglycoside antibiotics (AGs) were examined and the results obtained are summarized as follows:
1. S. aureus 209-P JC-1 and E. coli. NIHJ JC-2 were both sensitive to TA-058 and AGs tested alone but combinations of TA-058 with each AGs produced only an additive or a weak synergistic effect (Fig. 1).
2. S. marcescens, P. vulgaris, P. rettgeri and P. aeruginosa were not always sensitive to TA-058 or AGs, however, combinations of the two drugs gave a moderate or a marked synergistic effect (Fig 1).
3. The combinations of TA-058 and AGs were synergistic for 16 strains (80%) of 20 clinical isolates of P. aeruginosa (Table 1).
4. The synergistic effect against clinically isolated P. aeruginosa was most potent with combination of TA-058/gentamicin (GM) and followed by TA-058/tobramycin (TOB), TA-058/dibekacin (DKB) and TA-058/amikacin (AMK)(Table 1).
5. The combination of TA-058/AMK also exhibited a marked in vivo synergistic effect in an experimental infection of mice with P. aeruginosa (Table 2).

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The autobacteriograms of mice infected intraperitoneally with E. coli KC-14 RFPr showed that the bacterial cells rapidly increased first in the peritoneal cavity and then in the blood. Fourteen hrs. after infection the cells were distributed in the whole body. On the contrary, in the mice infected intraperitoneally with P. aeruginosa No.12 a lag time of 8 hrs. elapsed before the bacterial cells started to increase in the peritoneal cavity. The cells were not distributed in the whole body even immediately before death. The bacterial number in the blood remained less than 10⁴cells/ml throughout.
The in vivo antibacterial effects of TA-058 and some reference drugs were compared in terms of bacterial growth on the autobacteriograms of mice infected with bacteria and treated with drug 1 hr. after infection. All the animals were sacrificed for autobacteriography 20-44 hrs. after infection shortly before the death of non-medicated, infected controls. The bacterial distribution and density in these mice were dependent on the administered dose of the antibiotics and their efficacy well reflected their ED₅₀. The excellent in vivo antibacterial effect of TA-058 was well substantiated in this autobacteriographical study.

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The changes of microflora in rats feces were studied in the course of subacute toxicity tests for TA-058 (5 week and 3 month periods). The changes were also examined in rats given the drug daily for 10 days.
In all of dosage groups tested, administration of TA-058 decreased the numbers of the drug sensitive species, Streptococcus faecalis group and Staphylococci, in microflora. However, the numbers of Enterobacteriaceae and Bacteroides almost remained unchanged or moderately increased. Pseudomonas aeruginosa was not detected in all feces. Among Enterobacteriaceae, Klebsiella sp. was found to be most dominant species, but Escherichia coli was rarely detectable one. Almost of all Proteus sp. isolated fromTA-058 administered rats were identified as indole-positive species.
In rats given the drug daily for 10 days, the numbers of Escherichia coli decreased 1 to 3 days after the drug administration and began to increase imediately after the withdrawal of the drug. On the other hand, the numbers of Klebsiella sp. increased for 4 to 7 days after the administration and gradually decreased.
he changes of fecal flora caused by the administration of TA-058 (5 weeks) were almost recovered to normal flora levels 4 weeks after the discontinuation of the drug administration.

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General pharmacological activities of TA-058 were studied.
TA-058 did not show any of the following activities pertaining to the central nervous system in mice or rats at an intravenous dose of 1, 000 mg/kg: muscle-relaxant, hypnotic-potentiating, anticonvulsive, sedative, anti-apomorphine, anti-methamphetamine, anti-physostigmine, anti-depressive, analgesic, hypothermic and antipyretic activities. No drug-related changes were observed on the spontaneous EEG in rabbits and in the spinal reflex potentials in cats (300 mg/kg, i.v.).
For the cardiovascular system, TA-058 only slightly increased the mean arterial blood pressure and heart rate in anesthetised rats, but only less than 20 % at 1, 000 mg/kg, i.v. In anesthetised dogs, no changes were observed in the mean arterial blood pressure, heart rate and renal blood flow at 300mg/kg, i. v. The respiratory rate and femoral (at 100mg/kg, i. v.) and commoncarotid blood flow (at 300mg/kg, i.v.) increased rapidly but transiently. Since similar changes in the cardiovascular parameters were produced by intravenous injection of an iso-osmotic solution of mannitol (ca. 1, 500 mOsm), it may be concluded that these changes were mainly due to the hyperosmolarity of the TA-058 solution.
In conscious rats, Na- and Cl-excretion in 5 hr.-urine were decreased slightly but significantly after single subcutaneous administration of 1, 000mg/kg or daily administration of 300 mg/kg/day for 8 consecutive days. In the latter experiment, a slight decrease in urinary volume was also observed. The growth curve was not affected by the daily administration. Since any signs of severe renal toxicity have not been reported in the subacute and chronic toxicity tests of TA-058, this antibiotic probably causes no serious side effects on the renal function.
TA-058 exerted no effects on the gastrointestinal system at 1, 000mg/kg (i.v. or s.c.) except for a slight decrease in gastric juice volume and free HCl concentration in rats.
TA-058 neither contracted nor relaxed isolated smooth muscle preparations such as guinea pig ileum and was deferens and rat uterus even at a concentration as high as 10^-3g/ml: anti-Ach, anti-histamine (H₁ and H₂), ganglion blocking, adrenergic alpha-blocking, anti-oxytocin and papaverine-like activities were not observed
TA-058 did not have any anti-inflammatory and local anesthetic activities.
These results indicate that TA-058 is a pharmacologically inert substance.

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TA-058, a new parenteral penicillin, has been investigated to give following results.
1) Antibacterial activities
MICs of TA-058 against 220 strains of S. aureus, E. coli, P. aeruginosa and Proteus spp. isolated clinically was determined using plate dilution method inoculum size in 10⁶ cells/ml. The peak of the minimum inhibitory concentration was 12.5μg/ml for S. aureus, 3.13 for E. coli, 0.78 forP. mirabilis, 3.13 for P. morganii, and 1.56 for P. aeruginosa.
2) Pharmacokinetics
Serum levels and urinary excretion of TA-058 after single intravenous injection of 2.0 g of the drug were measured in 6 healthy male volunteers.
The mean peak serum level of the drug, five minutes after injection was 263.3μg/ml, and 4.4μg/ml in serum was detected after 6 hours. The mean value of biological half life in serum was calculated 1.62 hours in β phase.
The mean urinary excretion rate was 76.1% within 6 hours. Although clinical laboratory tests were examined, no abnormal finding due to the drug was observed.
TA-058 was thought to be a good tolerable drug from this study.
3) Clinical results
Twenty four patients with various infectious diseases including sepsis, respiratory tract infections, bilary tract infections and urinary tract infections were treated with 2-4g daily dose of TA-058 for 5-15 days. Clinical effect was excellent in 11 cases, good in 7 cases, fair in 3 cases and poor in 3 cases. It was 75.0% of the efficacy rate of the drug.
As to the side effect, diarrhoea was occured in one patient, and no abnormal laboratory findings were noted.

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To evaluate the clinical efficacy of TA-058, the treatment was made with the drug in 17 patients including 5 with bacterial pneumonia, 2 with primary atypical pneumonia, 2 with mycoplasma pneumonia, 3 with acute bronchitis, 1 with chronic brochitis, 1 with acute cystitis, 1 with acute pyelonephritis, and 1 with chronic pyelonephritis. Response was excellent in 2 patients, good in 13 and poor in 2.
Side effect observed was warm feeling during the infusion in 1 patient. Laboratory abnormalities were observed as slight eosinophilia in 1 and slight elevations of GOT and GPT in 1 patient.

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(1) TA-058, a new parenteral penicillin antibiotic, was prescribed to 9 patients with bacterial pneumonia and one with bacterial meningitis. TA-058 was administered 1 to 4 gram twice a day by intravenous drip-infusion from 2 to 18 days respectively. Causative organisms isolated before administration of TA-058 were S. pneumoniae in 2 cases, S. aureus, S. viridans and K. pneumoniae in each one case and unknown in 4 cases with bacterial pneumonia and in one case with meningitis.
Clinical efficacies of TA-058 were excellent in 2 cases, good in 4 cases including one case with meningitis, fair in 2 cases and poor in 2 cases.
And the case of adverse effects due to TA-058 were not observed but transient elevations of serum transaminase or serum alkaline-phosphatase were noticed in three cases during TA-058 therapy.
(2) The pharmacodynamic effect of TA-058 on plasma glucose was studied.
Two gram of TA-058 with 20 ml of saline was administrated intravenously within 5 minutes to four diabetic patients who were controlled with diet only before breakfast, and serum or plasma levels of TA-058, glucose, insulin, glucagon and cortisol were measured before and after 15, 30, 60, 90 and 120 minutes TA-058 administration.
Serum concentrations of TA-058 were 181.9μg/ml after 15 minutes TA-058 administration and 49.3μg/ml after 120 minutes. No remarkable changes were observed before and after TA-058 administration on the concentration of glucose, insulin, glucagon and cortisol.
These results were suggested that TA-058 was considered to be a useful penicillin antibiotic in the treatment of infectious disease.

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Clinical investigation on TA-058, a new derivative of amoxicillin, was performed and the results obtained were as follows:
Among 6 patients treated with TA-058 via drip infusion twice daily (2-4g) for their respiratory tract infections due to Haemophilus influenzae including a β-lactamase producing strain, 4 cases resulted in bacteriologically eradicated. In the case with β-lactamase producing strain (MIC; 25 μg/ml) the causative organism decreased from 10⁸ cfu/ml to 10⁸ cfu/ml. The remaining case (MIC;0.1μg/ml) showed the change to Pseudomonas aeruginosa as causative agent. The clinical results were effective in 5 cases. No adverse effect clearly due to this drug was observed except one case in which GOT and GPT elevated transiently during the administration.
From the above results, it was suggested that TA-058 is useful for respiratory tract infections caused by Haemophilus influenzae.

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In vitro antimicrobial activity of TA-058, a new derivative of ampicillin, was examined by a broth dilution method with Dynatech MIC 2, 000 system. Also, therapeutic efficacy of TA-058 in the treatment of patients with respiratory tract infections was evaluated.
The minimum inhibitory concentrations (MICs) of TA-058 were compared with those of piperacillin (PIPC) and sulbenicillin (SBPC) against following 20 strains each of clinical isolates, S. aureus, E. coli, K. pneumoniae, S. marcescens, P. aeruginosa. Although, TA-058 was more weakly active against these five species than piperacillin, TA-058 was more highly active against gram-negative rods, such as E. coli, K. pneumoniae, S. marcescens than sulbenicillin. TA-058 was almost as active as sulbenicillin against S. aureus.TA-058 was given to a total of nine patients by an intravenous drip infusion. The subjects examined consisted of four patients of acute pneumonia, one patient with infection associated with bronchial asthma, one patient with diffuse panbronchiolitis, one patient with infection associated with pulmonary emphysema and two patients with infection associated with lung cancer. A daily dose of TA-058 given was 2 grams to four patients, 4 grams to four patients and 6 grams to one patient. Clinical response to the treatment with TA-058 was excellent in three patients, good in four patients and poor in two patients. Following six potential pathogens were recovered from the sputum of these patients at the start of the treatment with TA-058; three strains of H. influenzae, one strain each of S. aureus, S. pneumoniae and K. pneumoniae. All of them but one strain of K. pneumoniae were eradicated during the treatment with the drug. In two patients among these nine patients, transient elevation of serum transaminase was observed but returned to normal after cessation of the drug.

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Clinical investigations were performed on TA-058, a newly synthetic penicillin.
TA-058 was administered to 10 cases of respiratory tract infections, at daily dose 2.0g for 5-14 days.
Clinical effectiveness of TA-058 was excellent in two cases and good in 8 cases (efficiency 100%).
Bacteriological effectiveness was good (87.5%) including 4 cases of Klebsiella sp.
Side effect with TA-058 was not observed.

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TA-058, a new synthetic penicillin, was used in 10 cases with respiratory tract infections and the following results were obtained.
TA-058 was administered to 6 cases of pneumonia, and each one case of pulmonary suppuration, chronic bronchitis, bronchiectasia and diffuse panbronchiolitis, on the dose of 2g twice a day by intravenous drip-infusion dissolved in 100ml of 5% glucose.
The therapeutic responses were good in 9 cases and poor in 1 case.
As for the side-effect, wheeze and dyspnea, probably provoked by TA-058, was found in one case appeared after 11 days of administration. An elevation of transaminase was observed in two cases.

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TA-058 has been studied clinically, and the following results were obtained.
1. TA-058 was administered to 10 patients; 9 respiratory tract infections, and 1 urinary tract infection.
2. TA-058 was given intravenously at a daily dose of 1 to 4 g to these patients.
3. Clinical response was excellent in 3 patients, effective in 5 and fair in 2.
3. Clinical response was excellent in 3 patients, effective in 5 and fair in 2.
4. Laboratory examinations revealed eosinophilia in 1 patient. No side effects were observed.

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A new antibiotic TA-058 was studied in the clinic, and the following results were obtained.
TA-058 was administered to 14 patients: 12 respiratory tract infections, 2 urinary tract infections.
TA-058 was given intravenously in all cases at a daily dose 2.0g or 4.0 g to the patients.
Clinical response was good in 10 patients, and poor in 4.
Diarrhea occured in one patient, but it was able to continue the administration of TA-058 with the antidiarrheal agents. Although laboratory tests revealed the elevation of Al-P in one patient, this finding alleviated rapidly following cessation of the therapy. No severe side effects caused by the drug were observed.

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A clinical administration of TA-058 was conducted with five patients who were suffering from various infections.
To one patient who had infective endocarditis which was caused by S. faecals associated mitral insufficiency, drip injections of 1g of TA-058 for 1.5 hrs. three times a day were given for ten days. This treatment eradicated the causative organism, but did not normalize her body temperature. Abatement of fever and normalization of laboratory data were gained by drip injection of 2g of TA-058 three times a day. The maximum serum level of 2g of TA-058 was 123 μg/ml, and the minimum level before the next drip injection was 13.2μg/ml.
In other four patients TA-058 was used 1 g twice a day. Therapeutic effects of TA-058 were fair in one patient with pneumonia, and good in one with acute exacerbation of chronic bronchitis caused by S. pneumoniae.
In two patients with acute exacerbation of chronic pyelonephritis, effects of TA-058 were good in one caused by S. faecalis, and fair in one caused by E. coli. No side effects and abnormalities of laboratory data were found in any one case.

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TA-058 is a new semisynthetic penicillin for parenteral use and possesses the advantage of broader antibacterial spectrum, higher and longer-lasting concentration in the serum than those of other existing penicillins. Hence, it is expected that TA-058 has a potent antibacterial activity in vivo.
The clinical effectiveness of TA-058 was evaluated in 23 patients which included 10 pneumonia, 1 pulmonary abscess, 3 pyelonephritis, 5 cystitis, 2 cholecystitis, 1 anorectal abscess and 1 lymphadenitis. The drug was administered by intravenous drip infusion at a dose of 2-4g/day.
The effectiveness rate was calculated as 80% in pneumonia, 100% in lung abscess and in pyelonephritis, 80% in cystitis, 100% in cholecystitis, anorectal abscess and lymphadenitis. No adverse reaction was observed.
Therefore, TA-058 was thought to be safe and very useful for clinical use against infectious diseases.

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The antimicrobial activity, absorption, excretion and clinical effects on TA-058 were investigated and the following results were obtained.
1) Antimicrobial activity
The antimicrobial activities of TA-058 against the following clinically isolated organisms, i. e. E. coil, K. pneumoniae, Enterobacter sp., C. freundii, indole-positive Proteus sp., P.mirabilis and P aeruginosa, were 1-2 steps higher than ampicillin, carbenicillin and ticarcillin to E. coil, K. pneumoniae, Enterobacter sp., C. freundii, P. mirabilis and P. aeruginosa, while 2 steps lower than piperacillin to those organisms.
2) Serum levels
The serum levels of TA-058 in healthy adult volunteers after intravenous injection in a single dose of 1, 000 mg attained to 94μg/ml within 5 min. and 20 μg/ml within 1 hr. after the injection. When TA-058 was administered in combination with probenecid to the same volunteers, serum levels were almost similar to those when TA-058 was administered alone.
3) Urinary excretion
The maximum urinary concentration of TA-058 reached to 1, 900-4, 600μg/ml, and within 8 hours after TA-058 injection, 74.3 % of the drug was recovered in average from the urine.
4) Clinical results
TA-058 was administered in 3 cases of urinary tract infections who had chronic renal diseases. The results were 2 good and 1 poor. No side effect was observed.

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ntimicrobial activity of TA-058 was examined against gram negative rods from clinical materials in comparison with ABPC and PIPC. Minimum inhibitory concentrations of TA-058 against 41 strains of E. coli and 20 strains of K. pneumoniae were distributed from 0.8 to >200μg/ml and from 1.6 to >200 μg/ml respectively, showing similar activity to those of ABPC and inferior to those of PIPC. Minimum inhibitory concentrations against 21 strains of P. aeruginosa were distributed from 0.2 to 100μg/ml, showing superior activity to ABPC but inferior to PIPC.
Serum concentrations of TA-058, which resulted from the experiment with four healthy male adult volunteers who were administered 1g by drip infusion, reached their maxima immediately after the completion of infusion. Maximum serum concentration was 53.9μg/ml in average, half life in β-phase was 1.5 hrs., and AUC was 90.0 μg/ml·hr. On the other hand those parameters of ABPC, which was administered to the same subjects in crossed over design with TA-058, were 43.5μg/ml, 1.1 hrs. and 51.6μg/ml·hr., respectively. Urinary recovery of TA-058 up to 8 hours after the administration was 65.5% whereas that of ABPC was 67.6%. No abnormal change in blood sugar level was observed after the administration of either TA-058 or ABPC.
For the examination of clinical efficacy, TA-058 was administered to a case of biliary tract infection by drip infusion of 1g twice a day for 10 days. Improvement was observed both in subjective and objective observations thus impressed as fairly effective. No adverse clinical reaction was found, nor any abnormal laboratory findings in that case.

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TA-058, a new semisynthetic penicillin derivative developed by Tanabe Seiyaku Co. Ltd., has a wide spectrum of activity against gram-positive and gram-negative bacteria.
TA-058 was used in the treatment of 7 cases of respiratory infectious disease: 3 cases of bronchiectasis, 3 cases of respiratory infectious tract infection with bronchial asthma and pulmonary emphysema and one case of pneumonia. TA-058 was administered by intravenous drip infusion at a dose of 1.0 g twice daily for 5 to 14 days except in one case who had an adverse effect.
Response was excellent in 5 cases, good in one case and not determined in one case because of adverse reaction.
Adverse reaction noted was eruption and eosinophilia in one patient but in the other 6 cases, no side effects were observed during the course of the administration.
From the results of the investigation it is concluded thact TA-058 is as effective as ampicillin treating respiratory infectious disease.

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Four grams of TA-058 were administered to 6 cases including acute pyeloncphritis, bronchiolitis, bronchopneumonia, meningitis, suppurative spondyhtis and acute cholecystitis. The clinical results were as follows, exccellent in 1, good in 4 and fair in 1 cases.
No side effects were found including laboratory data of urine, peripheral blood, renal and hepatic function.

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A new antibacterial agent, TA-058, was administered to 6 patients including 2 cases of pneumonia, one case of acute bronchitis, 2 cases of acute cholecystitis and one case of chronic pyelonephritis. TA-058 was given by I. V. D. infusion at a daily dose of 2-4 g for 3. 5-10 days. Clinical efficacy was excellent in one (acute cholecystitis), good in one (acute cholecystitis), fair in 2 (pneumonia, chronic pyelonephritis), poor in one (acute bronchitis) and undetermined in one (pneumonia). No side effects were observed.

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1. MICs of TA-058 against 25 strains clinically isolated each of S. aureus, E. coli, K. Pneurnoniae, E. cloacae, P. mirabilis, and P. vulgalis were compared with those of AMPC and PIPC. Antibacterial activity of TA-058 was about similar to those of AMPC and inferior to those of PIPC.
2. Clinical effects of TA-058 in 4 cases of respiratory tract infection were evaluated as follows: excellent in 1, good in 1, fair in 1, and poor in 1 case.
Though we had only a few cases, it seemed that the clinical effects depended on a dosage of TA-058 from the above results.
3. Neither clinical side effects nor abnormal clinical laboratory findings were observed.

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Pharmacokinetic study of TA-058 in 4 aged patients with normal serum creatinine levels was performed. Serum concentration of TA-058 by bolus intravenous injection of 1 g at 1/12, 1/2, 1, 2, 4, 6 and 8 hours after injection were 112, 63.4, 43.6, 31.7, 17.6, 9.0 and 5.4μg/ml respectively. Serum half life of β phase was 2.4 hours. Area under the curve was 209.9 hr·μg/ml. Urinary recovery rate during first 8 hours was 52.3 %.
TA-058 was given in 7 aged patients (4 with pneumonia, 1 with acute bronchitis, 1 with erysipelas and 1 with U. T. I.). Satisfactory response was obtained in 5 patients by administration of TA-058 of 0.5 to 1 g on every 12 hours. Non adverse effect was noted in every patients.

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Clinical efficacy and adverse effects of TA-058, a new penicillin antibiotic, were studied in 14 patients with the respiratory tract infections receiving 1.0 to 2.0g b. i. d. by drip infusion.
Among them, 8 cases were lower respiratory tract infection, 5 cases were pneumonia and 1 case was pulmonary empyema.
The obtained results were excellent in 2, good in 10 and fair in 2 cases, thus producing moderate to marked clinical improvement in 85.7% of cases studied.
As for abnormal laboratory findings, slight elevations of GPT and Al-P were seen in 1 case. These findings improved shortly after cessation of the drug.

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TA-058, a new synthetic penicillin, was studied in respiratory tract infections and following results were obtained.
TA-058 was administered in 6 cases, 3 cases of pneumonia and 3 of chronic bronchitis, which were performed by drip infusion or intravenous injection of 1g, twice a day. Underlying diseases of these cases were chronic bronchitis and lung cancer.
The clinical efficacy was good in 4 cases and poor in 2 cases, and there were no side effects observed, nor any abnormal findings in the laboratory examinations.
Though we expected TA-058 to be effective in lower respiratory tract infection, it is necessary to use more dosis, according to these results in clinical efficacy and safety.

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TA-058, a new parenteral penicillin, has been investigated to give following results.
Eleven patients with various infectious diseases including pneumonia, tonsillitis, acute pyelonephritis and septicaemia were treated with 2-3 g daily dose of TA-058 for 3 to 14 days. It was 63% of the efficacy rate.
Neither adverse effect, nor abnormal laboratory findings were noted except for the elevation of GOT and GPT in only one case with chronic hepatitis.

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TA-058 was clinically evaluated. The results obtained were summarized as follows;
1) Antibacterial activity of TA-058 against clinical isolates of E. coli, S. marcescens and P. aeruginosa was superior to that of ABPC and AMPC.
2) Susceptibility of K. pneumoniae to TA-058 was poor.
3) Treatment with TA-058 was effective in 3 patients of 5 patients.
4) Neither adverse effect nor abnormal laboratory findings were observed.

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TA-058 was administered to 20 patients with respiratory tract infection. The drug was administered by D. I. injection twice a day with the dosis of 1 to 2g and total dosis ranged from 3 to 80g.
The following results were obtained.
1) Clinical response to therapy was excellent in 2 cases, good in 12 cases, fair in 1 case, poor in 4 cases and unevaluable in 1 case. Effective rate was 73.7%.
2) As for side effects, the elevation of GPT and Al-P was found in 1 case, but it was transient.

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Laboratory and clinical studies on TA-058 were performed and the following results were obtained.
1) Minimum inhibitory concentration (MIC) of TA-058 was determined in 136 clinical isolates compared with those of PIPC. TA-058 showed an antibacterial activity similar or inferior to PIPC against E. coll. K. pneurnoniae, Serratia, P. aeruginosa and Proteus genus.
2) Clinical trial of TA-058 was performed in 23 patients, 18 with respiratory tract infections, 3 with biliary tract infections, 1 with urinary tract infection and 1 with fever unknown origin. Responses were excellent in 2, good in 14, fair in 3, poor in 3 and unknown in 1. Effective rate was 72.7%. Two patients showed the following adverse reactions, nausea and elevation of GOT, ALP in one patient, elevation of GOT, GPT and leukopenia in another one.

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The authors report on the results of their clinical investigations of TA-058, a new semisynthetic penicillin antibiotic.
The antibacterial activity of TA-058 was compared to that of ampicillin (ABPC) and piperacillin (PIPC) in a total of 150 clinically isolated strains of S. aureus, E. coli, Citrobacter, Klebsiella, Enterobacter, Serratia, Psudomanas and Proteus.
TA-058 exhibited greater antibacterial activity against P. mirabilis than did ABPC and PIPC, and it was proved to be almost the same or slightly weak as PIPC against other strains.
TA-058 was then administered to a total of 17 patients, among whom there were 13 cases of respiratory tract infections (R. T. I.), one case of septicemia and 3 cases of urinary tract infections (U. T. I.).
Results obtained were good in 10 (77.0%) out of 13 R. T. I., good in the sole case of septicemia and U. T. I. also showed good in all cases.
No side effect nor adverse reaction of the drug observed in all cases.

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TA-058 was administered to 17 patients with respiratory tract infection. The clinical effectiveness was excellent in 4 patients, good in 9, fair in 3 and poor in 1. The clinical effective rate was 76.5%.
As side effects, one case showed a decrease in leucocyte counts from 3, 100/mm³ to 1, 400/mm³ four days' administration of TA-058, one case showed eosinophilia and one case showed slight elevations of GOT and GPT in serum.
The causative organisms were able to isolate in 14 cases: H. influenzae; 7 cases, S. pneumoniae; cases, H influenzae and S. Pneumoniae; 5 cases.
These organisms didn't yield after administration of TA-058 except one case isolated β-lactamase produced H. influenzae.

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The new penicillin antibiotic TA-058 was applied to 10 cases with varieus infections. Excellent or good results were obtained in 3 of 4 cases with pulmonary infections, all 3 cases with urinary tract infections, one case with cholecystitis and a leukemic patient with fever, and a case with severe tonsillitis, bronchitis and cystitis. No side effect was observed.
It is expected that this antibiotic may constitute an advance in the antibiotic treatment of gram-positive and gram-negative infections.

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TA-058, a new derivative of amoxicillin recently developed by Tanabe Seiyaku Co., Ltd. was examined on its blood levels and urinary excretion rates in humans administered with the drug.
Some clinical trials were as follows;
1) In vitro antibacterial activity against bacteria isolated from human infection foci: MIC of the drug against S. aureus strains distributed from 0.4 to > 100μg/ml; while those resistant to apalcillin or piperacillin showed somewhat better sensitivity against TA-058.
Against E. coli, TA-058 showed similar activity to piperacillin, the MIC peak being located at O.8-6.2μg/ml. TA-058 was less active against P. aeruginosa and K. pneumoniae than piperacillin or apalcillin.
2) Blood levels and urinary excretion rates in human: The blood level of TA-058 in plasma after intravenous drip infusion of 500mg in 15 min. was 60μg/ml.
The urinary excretion rate of the antibiotic during six hours after administration was 78.8%.
3) Clinical trials: All of thirteen patients with various infections (pneumonia 7, acute bronchitis diffuse panbronchitis 1, and acute exacerbation of chronic bronchitis 3) responded at least fairly the treatment with TA-058 (2-4g/day, intravenous drip infusion, 6-11 days), excepting a case Candida in sputum and a case of diffuse panbronchitis by H. influenzae.
As to the side effects or abnormal laboratory findings attributable to the drug, only one out of the thirteen cases showed a transient elevation of S-GOT and S-GPT.

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From fundamental and clinical studies on TA-058, a new semisynthetic penicillin, the following results were obtained.
1) Peak minimum inhibitory concentrations of TA-058 against clinical isolates, S. aureus, E. coli, K. pneumoniae, P. mirabilis, P. vulgaris, P. aeruginosa were 1.56-6.25, 3.13, 100, 0.2, > 100, 50μg/ml respectively in the low inoculum size.
But in the high inoculum size, antibacterial activities of TA-058 were decreased.
2) TA-058 was administered to 2 cases with respiratory tract infections at a daily dose of 2-4g.
Good effect was observed in the case with chronic bronchitis but poor effect in the case with infected bronchiectasis. No adverse reaction was recognized.

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TA-058, new semisynthetic penicillin, was administered to 8 severe infections cases suffering from malignant neoplasms of the hematopoietic organs.
Daily doses of TA-058 was 4 to 8 grams, and clinical efficacy was excellent in 1 case, good in 1 case, poor in 5 cases and undecided in 1 case.
No serious side effects were observed.

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Clinical effectiveness of TA-058, a new semisynthetic penicillin, was studied in 9 adult cases of infectious diseases. These cases consisted of 8 cases of acute and chronic upper or lower respiratory tract infections and 1 case of urinary tract infection TA-058 was given to the patients with dosage of 1-2 g/day intravenously. Clinical effectiveness was determined about 7 days later. Clinical and bacteriological effectiveness were obtained in 5 out of 7 cases (71.4 %). Excellent efficacy was obtained in 4 cases, good in one case and poor in two cases respectively. There were no serious adverse reactions.
It was concluded that TA-058 was supposed to be active and useful antibiotic against respiratory infections by gram-negative bacteria without major side effects.

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Fundamental and clinical studies on TA-058, a new injectable penicillin, were carried out.
1) Sensitivity of clinically isolated strains to TA-058 was tested by agar plate dilution method and compared with that of ABPC, CBPC and PIPC.
The antibacterial activity of TA-058 against most of clinical ioslates was found to be inferior to that of PIPC and similar to CBPC.
The peak MIC to H.influenzae was 0.1μg/ml, but sensitivities of β-lactamse producing strains were inferior to that of ABPC.
2) The maximum serum concentrations of TA-058 after 2.0g drip infusion in one hour were 66-112.5μg/ml (mean value 89.3μg/ml) and the mean values after 2, 4 and 6 hours from the start of infusion were 26.0, 14.3, 6.9μg/ml respectively. The peak level of TA-058 in pleural effusion from patient with lung cancer, after 2.0g drip infusion was 37.5μg/ml.
3) TA-058 was administered to 6 patients with daily doses of 2.0-6.0g for 3-41 days and clnical and side effect were investigated.
The drug efficacy was excellent in 1, good in 1, fair in 1 and poor in 3 patients and the effective rate was 33.3%.
No side effect was observed in all patients.

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The clinical effects of TA-058 were evaluated in patients with respiratory tract infections including four cases of chronic bronchitis, two cases of bronchopneumonia and one case of bronchiectasis.
TA-058 was administered intravenously for 7-10 days at a daily dose of 1-2g. The results in this series were excellent in one case, good in three cases, fair in one case, poor in two cases. No adverse reaction due to TA-058 was clinically observed in all cases.
This results indicate usefullness of TA-058 in the treatment of respiratory tract infections.

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