Studies on T-1220, a broad-spectrum penicillin derivative, were presented at The 23rd East Section Congress of Chemotherapy (Japan Society of Chemotherapy), New Drug Simposium, Tokyo, 1976.
The results of the fundamental and clinical studies in 106 research laboratories in Japan are summarized as follows.
1) T-1220 had broad antibacterial spectrum against gram-positive and gram-negative bacteria.
2) It was more active than the other broad-spectrum penicillins against gramnegative bacilli, especially Pseudomonas aeruginosa, Klebsiella pneumoniae, Proteus sp. and Serratia marcescens.
3) Therapeutic effect of T-1220 against experimental infections of mice was more effective than that of CBPC and SBPC.
4) The serum levels showed dose response relationship and the half life was approximately 0.6 hr.
5) It was mainly excreted from kidney and most of them were excreted as unchanged form and the transfer to bile was also favorable.
6) It was rapidly absorbed after subcutaneous, intramuscular or intravenous injection, indicating especially higher transfer to kidney, liver and then in order, serum, lung, spleen and muscle.
7) The binding rate of the drug with serum protein was 20-30%.
8) The effective rate in 426 cases of the fields of internal medicine, pediatrics and dermatology was 72.5% and the effective rate in 788 cases of the fields of surgery, orthopedics, urology, obstetrics and gynecology, otorhinolaryngology, ophthalmology and oral surgery was 73.6% and the effective rate in total of 1, 214 cases was 73.2%.
Considering the fact that a number of severe infections were included, the clinical result of the drug was considered to be favorable as broad-spectrum synthetic penicillins.
9) Side effects were observed in 47 cases of 1, 266 cases (3.71%) but severe side effect was not observed. Side effects were mainly eruption, nausea, vomiting and diarrhea. Elevation of GOT and GPT, leukopenia, eosinophilia and pyrexia were observed in some cases.

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A synthetic penicillin, T-1220, is a derivative of aminobenzylpenicillin. In vitro and in vivo antibacterial activities of T-1220, ampicillin (ABPC) and carbenicillin (CBPC) were compared against gram-positive and gram-negative bacteria which were isolated from clinical specimens. The results were summarized as follows :
1) T-1220, ABPC and CBPC exhibited almost similar effectiveness against grampositive bacteria.
2) In vitro antibacterial activities against gram-negative bacteria were compared using about 100-300 clinical isolates of each species of bacteria including E. coli, K. pneumoniae, Proteus group, S. marcescence, E. cloacae and P. aeruginosa. T-1220 was found to be more effective than ABPC and CBPC, particularly against P. aeruginosa, K. pneumoniae, Proteus group and S. marcescence.
3) Antibacterial activity of T-1220 was not affected by the changes of pH and media. Addition of human serum to culture media did not show any big effect on the antibacterial activity of T-1220.
4) Greater bactericidal activity was demonstrated with T-1220; minimum bactericidal concentration (MBC) toward various strains of gram-negative rod bacteria was almost the same as their minimum inhibitory concentration (MIC) values and was less than the MBCs of ABPC and CBPC.
5) The 50 percent inhibition dose (ID₅₀) of T-1220 was found to be much less than that of CBPC.
6) T-1220 as well as penicillin G was hydrolyzed by penicillinase (PCase). But T-1220 was very stable than CBPC against PCase derived from P. aeruginosa. Cephalosporinase (CSase) did not hydrolize T-1220, CBPC and ABPC.
7) In vivo antibacterial activities of T-1220, ABPC and CBPC were compared using the systemic infections of mice with P. aeruginosa, K. pneumoniae and E. coli. The ED₅₀ values (mg/kg) of T-1220 were consistently less than those of ABPC and CBPC.

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We studied on the antibacterial activity of T-1220 against 788 strains of various pathogens such as Streptococcus pneumoniae, Streptococcus faecalis, Neisseria, Haemophilus, E. coli, Klebsiella, Enterobacter, Serratia, Proteus, Pseudomonas aeruginosa and Bacteroides and compared the activity with that of sulbenicillin (SBPC), carbenicillin (CBPC), ampicillin (ABPC), cephalothin (CET) and cefazolin (CEZ).
Against the gram-negative bacilli T-1220 is most active among four penicillins, especially against Haemophilus influenzae and Pseudomonas aeruginosa. T-1220 has very strong antibacterial activity against Streptococcus pneumoniae almost same as ampicillin, but the activity of T-1220 against Streptococcus faecalis is weaker than ampicillin. Three strains of Neisseria gonorrhoeae and one strain of Neisseria meningitidis were very susceptible to six antibiotics tested.

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A study of the bactericidal effect of broad-spectrum Penicillin T-1220 in vitro and in vivo showed a wide bactericidal spectrum and an in vitro bactericidal effect for bacteria strains resistant to conventional penicillin.
The in vivo results showed that a challenge with a small inoculum was more effective than CBPC and SBPC against Serratia and equally effective against P. aeruginosa and E. coli. The therapeutic effect of a challenge with a large inoculum, however, was not as marked as that of a challenge with a small inoculum.

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The bacteriological evaluation on T-1220 was performed in comparison with other antibiotics, Carbenicillin (CBPC), Sulbenicillin (SBPC), Ampicillin (ABPC) and Gentamicin (GM), as control.
The following results were obtained.
1) T-1220 showed broad antibacterial spectrum against Gram-positive and Gram-negative bacteria.
2) T-1220 showed stronger antibacterial activity against Gram-negative bacteria which were isolated from clinical specimens than that of CBPC, SBPC and ABPC. Especially the susceptibility of T-1220 against Pseudomonas aeruginosa was similar to that of GM.
3) The MIC value of T-1220 was affected by inoculum size, because the MIC value by the inoculum size of 10⁸ cells per milliliter of T-1220 was far from that of 10⁶ cells per milliliter.
4) The therapeutic efficacy of T-1220 on multiple injection was more effective than that of CBPC.

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Studies on the appropriate administration method of T-1220 against infectious diseases by Pseudomonas as the object, were carried out employing CBPC as the control drug.
1) Pseudomonas injured by T-1220 and CBPC disunited and reproduced in vitro and in vivo immediately, if the drug were removed.
2) It was demonstrated that total amount of administration of T-1220 was smaller than that of CBPC when T-1220 were administered by the method of multiple injection than by single administration.
3) The minimal effective concentrations of both drugs in vivo seemed to be almost essentially same to that in vitro.
4) The factors influencing the effect of treatment of both drugs were found to be total maintaining hours of the effective concentration in vivo.
5) When the duration of treatment were set to certain days, the more the times of administration increase the total administration dose required to the treatment decreased.

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The effects of T-1220 and carbenicillin on the morphology of Pseudomonas aeruginosa E-2 were examined with the phase contrast microscope and scanning electron microscope.
Exposure to T-1220 resulted in the formation of marked filamentous cells. However, the spheroplast-like structure was not observed by the treatment with T-1220. Exposure to carbenicillin resulted in the formation of spheroplast-like structures. The morphological alterations of Pseudomonas aeruginosa E-2 treated with carbenicillin observed in this study are similar to those noted by PERKINS and PRIOR.

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Antibacterial activities of T-1220 against clinically isolated bacteria, 107 strains of Escherichia coli, 28 strains of Klebsiella pneumoniae, 11 strains of Proteus and 87 strains of Pseudomonas aeruginosa, were examined by the twofold agar-dilution method, using Difco Heart Infusion Agar. Minimal inhibitory concentrations (MIC) of this drug were mainly distributed from 0.39 μg/ml to 6.25 μg/ml. Further, the sensitivities of these strains were compared with T-1220 and other penicillins, aminobenzylpenicillin (ABPC), carbenicillin (CBPC) and cephalexin (CEX). Almost of these isolated strains of E. coli were sensitive to these drugs. However, MIC of T-1220 was the lowest among these drugs. All of the strains of Pseud. aeruginosa were resistant to ABPC, C13PC and CEX, but 82% of these strains were highly sensitive to T-1220.

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The pharmacological actions of T-1220, which is a new type of semisynthetic penicillin and is effective against severe infections by gram-negative bacilli, were investigated.
Summary of pharmacological actions and minimal effective doses (MED) were as follows : fall. of blood pressure of the rabbit (200 mg/kg), inhibition of isolated frog heart (10^-3 g/ml), dilation of isolated rabbit ear vessels (5×10^-2 g/ml), inhibition of isolated guinea pig intestine (10^-3 g/ml), and no effect on respiration of the rabbit (upto 500 mg/kg), on rabbit ECG (upto 100 mg/kg), on isolated guinea pig heart (upto 5×10^-3 g/ml), on permeability of rabbit skin vessels (upto 1, 000 μg), on isolated rabbit intestine (upto 2×10^-3 g/ml), on isolated guinea pig trachea (upto 5×10^-3 g/ml), on isolated rat uterus (upto 2×10^-3 g/ml) and on isolated uterus of the pregnant rat (5 ×10^-3 g/ml).
MED of T-1220 were much larger than minimal inhibitory concentrations and maximal blood levels in clinical uses.
MED of T-1220 were much smaller than those of ampicillin and similar to those of carbenicillin.
The pharmacological actions and MED of P-32 were similar to those of T-1220, except stimulating effect on isolated intestine.
The increase in body weight, volume of urine, urinary excretion of potassium and urinary findings in the rat applied T-1220 in doses from 100 to 500 mg/kg subcutaneously once a day for 7 days were similar to normal values and those of control group. Decreased urinary excretion of sodium was observed in proportion to the doses applied.

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Distribution, fate and excretion of T-1220, which is effective against severe infections by gram-negative bacilli, were investigated.
Rats were intravenously or intramuscularly injected T-1220 in a dose of 20 mg/kg. Biological half lives of T-1220 in rat serum were 5.72 min and 7.54 min, respectively. Biological half life of T-1220 in the injected site of muscle was 4.11 min. The levels in kidney and liver were higher than the serum level. The high level in duodenum was also observed. The total amount excreted in 24 hr urine of the rat was 22% of the injected amount. The cord blood levels were 32.46 to 76.19% of maternal serum levels in the pregnant rats. The fetal liver level was higher than other organ levels. The amniotic level was low. Approximately 30% of T-1220 was bound to serum proteins.

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In vitro and in vivo studies on the antimicrobial activity of T-1220 have been carried out, and the results are summarized as follows :
1) The in vitro activity of T-1220 against clinical isolates of Staphylococcus aureus was not so effective as that of Ampicillin (ABPC), but T-1220 was more active than ABPC and Carbenicillin (CBPC) against various gram-negative clinical isolates. Especially, the sensitivity of T-1220 against Pseudomonas aeruginosa was 8 times as high as that of CBPC.
2) Antibacterial activity of T-1220 was affected with the inoculum size of S. aureus and Klebsiella pneumoniae, but as for other strains, it was not affected with.
3) T-1220 acted bactericidally against S. aureus, Escherichia coli and P. aeruginosa.
4) T-1220 was much more stable than ABPC and CBPC against the penicillinase (PCase) derived from P. aeruginosa, but T-1220 as well as ABPC was hydrolized by other PCase. However, the cephalosporinase derived from Serratia marcescens slightly caused hydrolysis of T-1220 to the same extent as Penicillin G and ABPC.
5) T-1220 was stable in Brain heart infusion broth and Heart infusion broth at 37°C for 20 hours, while it was less stable in Nutrient broth and Trypto-soy broth, and showed 70% of initial activity at 37°C after 20 hours. When T-1220 was kept at 5°C for 10 days in human alkaline bile, it showed 50% of initial activity.
6) Protecting effects of T-1220 against experimental infections of mice caused by S. aureus and E. coli were nearly equal to those of CBPC. But T-1220 was more effective than CBPC in mice infected with P. aeruginosa and K. pneumoniae.

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The combination of T-1220 and Gentamicin enhanced the antibacterial activity in vitro against clinically isolated strains of Pseudomonas aeruginosa and Serratia marcescens. Bactericidal activity against P. aeruginosa S-68 was enhanced by combining the two antibiotics.
Synergistic activity of the two antibiotics was also observed in protective effect against experimental infection in mice by P. aeruginosa S-68.

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Absorption, excretion and tissue distribution of T-1220 were studied in various animals in comparison with carbenicillin and the following results were obtained.
1) When T-1220 (20 mg/kg) was administered intramuscularly or subcutaneously to various animals, the serum levels of T-1220 were higher in order as follows; dog> monkey> rabbit> rat> mouse. In dog, serum level of T-1220 was similar to that of CBPC in cross over test.
2) Total amounts of T-1220 excreted in urine of rat, rabbit and dog administered intramuscularly were 25.2%, 52.8% and 60.2% respectively, while in bile, 54.3%, 27.3% and 10.5% respectively.
3) The distributions of T-1220 in the kidney and liver of mouse and rat were higher than those in other tissues and serum.
4) When T-1220 was intramuscularly administered to healthy adult men at doses of 250, 500 and 1, 000 mg, serum levels attained to maximum at 30 minutes after administration and those levels were 5.0 μg/ml, 12.8 μg/ml and 33.4 μg/ml respectively. Excretion rates of T-1220 in urine were 64.6-66.6% within 6 hours.
5) Excretion rate of T-1220 in goat's milk was 0.015% within 24 hours, which was one sixth of that of CBPC.
6) When T-1220 was administered intrathecally to dogs, cerebrospinal fluid level of T-1220 decreased rapidly.
7) Serum level and excretion in urine and bile of T-1220 in rats pretreated with CCl4 were not remarkably different from those in normal rats.

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T-1220の血清蛋白結合率を超遠心, 遠心限外炉過および平衡透析法を用いて測定した。T-1220は動物種差による結合能に大きな差はなく, ヒト, イヌ, ウサギおよびラットでそれぞれ21.2%, 24.0%, 27.5%および248%であった。またその結合は, 可逆的であり強固なものではなかった。さらに実験炎症モデルを用いて, 炎症巣への移行性を他の薬剤と比較した結果, 蛋白結合率の低いT-1220は, 結合率の高いMPIPCより炎症巣への移行性は良好であった。

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It has been demonstrated that T-1220, a derivative of aminobenzylpenicillin, had a broad antibacterial spectrum against gram positive and negative microorganisms and was especially effective against Pseudomonas aeruginosa.
The acute toxicity test of T-1220, therefore, was carried out in mice, rats, dogs and monkeys in this experiment. The results are as follows.
1) The acute intravenous LD₅₀ was 5 g/kg in mice, 2.7 g/kg in rats, more than 6 g/kg in beagle dogs and more than 4 g/kg in monkeys. These values indicated that intravenous LD₅₀ varied depending upon the species, and T-1220 was more toxic to rats than the others.
2) When the possible maximum dose, 10 g/kg, was administered orally and subcutaneously to mice and rats, they only showed the transient depression of spontaneous movement. Mice and rats died following the administration revealed a large amount of bloody exudate in the abdominal and thoracic cavities in intraperitoneal administration and massive hemorrhage of the lung in intravenous administration. Such changes were thought to be the cause s of death.
3) In beagle dogs treated intravenously with T-1220 at 6 g/kg, the toxic signs of vomiting, diarrhea, salivation, watery eye, blepharoptosis and borgorygmus were observed during and immediately after the administration. GOT and GPT increased moderately on a day after the administration. Any abnormalities, however, were not seen in autopsy and histological examination. In beagle dogs treated intravenously with T-1220 at 2 and 4 g/kg respectively, values of GOT, GPT, LDH and ALP did not change, while in 1 out of 3 and all 3 dogs treated intravenously with ABPC and CBPC at 2 g/kg respectively, levels of GOT, GPT and LDH increased.
The LD₅₀ value of T-1220 in dogs administered into the cisterna magna was about 10 mg/kg, and the maximum nontoxic dose was 1 mg/kg.
4) In monkeys treated intravenously with T-1220 at 4 g/kg, any abnormalities were not observed, except for the slight and moderate increases of GOT, GPT and LDH values.

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The subacute and chronic toxicities of T-1220 were examined in rats using the intraperitoneal administration route, and compared with those of aminobenzvlpenicillin (ABPC). Male and female rats of age 6-7 weeks were applied. In the subacute toxicity, rats were administered in daily intraperitoneal doses of T-1220 for a month at 1, 000, 2, 000 and 4, 000 mg/kg, and in the chronic toxicity, administered for 6 months at 500, 1, 000 and 2, 000 mg/kg. ABPC was used at 2, 000 mg/kg in both toxicities. Control rats were treated with physiological saline.
The results are as follows.
1) The body weight gain was depressed in male rats treated with T-1220 at 4, 000 mg/kg for a month, and at the final administration its body weight was significantly different from that of control (p<0.05). The writhing syndrom was observed immediately after the administration in proportion to dose levels of T-1220 and ABPC.
2) In hematological and blood biochemical examinations, there were no abnormalities produced by the administration.
3) The enlargement of the unilateral renal pelvis, which had the localized ishemic change, and localized cecitis were sporadically observed in autopsy, but the dose-relation was not clear. Any abnormalities were not seen in the other organs.
4) The urinary volume, BUN and kidney weight increased remarkably in female rats treated with ABPC at 2, 000 mg/kg. The enlargement of the renal tubular lumina, degeneration of the renal tubular epithelium and cellular infiltration and fibrosis of the interstitium were, histologically, observed in both sexes of ABPC.
5) The maximum safety dose of the intraperitoneal injection of T-1220 was estimated to be 2, 000 mg/kg in these experiments.

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The subacute toxicity of T-1220 was examined in rats, using the intravenous administration route, and compared with that of aminobenzylpenicillin (ABPC). Male and female rats of age 6 weeks were applied. T-1220 was administered to the rats in daily doses of 500, 1, 000 and 2, 000 mg/kg for a month and ABPC was used at 2, 000 mg/kg. Control rats were treated with physiological saline.
The results are as follows.
1) 5 out of 15 males and 7 out of 15 females given T-1220 at 2, 000 mg/kg were died because of massive hemorrhage of the lung.
2) The body weight gain was slightly depressed in rats of both sexes treated with T-1220 at 2, 000 mg/kg.
3) There were no dose-related changes of urinary examination, biochemical examinations and hematological findings in all the groups of T-1220.
4) Any abnormalities caused by the administration of T-1220 were not found in the organ weight, autopsy and histological observation.
5) The appreciable increase of urine volume and slight increase of BUN were observed in females treated with ABPC at 2, 000 mg/kg. The tubular lumina of the renal cortex was slightly dilated and the tubular epithelium had the hydropic change in the same females. There was, however, no significantly histological change in the kidneys of rats treated with T-1220.
6) The maximum safety dose of intravenous administration of T-1220 to rats seemed to be 1, 000 mg/kg.

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The subacute toxicity of T-1220 was tested using female beagle dogs treated with the daily intramuscular administration for a month, and compared with that of aminobenzylpenicillin (ABPC). T-1220 was injected to the dogs with daily doses of 250 and 1, 000 mg/kg, and ABPC was with daily dose of 1, 000 mg/kg. Control dogs were treated with physiological saline.
The results are as follows.
1) The signs showing severe pain were observed immediately after the administration in groups of T-1220 and ABPC, respectively, at 1, 000 mg/kg.
2) The bacterial flora of the bowel of the beagle dogs treated with T-1220 for a month was examined. The administration of T-1220 produced a slight decrease in total number of organisms that was mainly due to the disappearance of Bifidobacteria and Clostridia.
3) The GOT, GPT and LDH increased slightly in groups of T-1220 and ABPC at 1, 000 mg/kg. The histological examination, however, showed only hydropic changes of the hepatic cells and did not any inflammatory changes throughout the livers in both groups.
4) The group of T-1220 at 250 mg/kg had no abnormalities produced by the administration.

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The chronic toxicity of T-1220 was tested in beagle dogs using the intravenous ad-ministration, and compared with that of aminobenzylpenicillin (ABPC). Dogs were administered in daily intravenous doses of T-1220 for 6 months at 500, 1, 000 and 2, 000 mg/kg. ABPC was used at 2, 000 mg/kg. Control dogs were treated with physiological saline.
The results are as follows.
1) 1 (male) out of 5 dogs of T-1220 at 1, 000 mg/kg and 2 (male) out of 7 dogs of ABPC died or were killed because of debility during the experimental period.
2) The significant change of body weight was not seen in all dogs alive.
3) In 1 (male) out of 7 dogs of T-1220 at 2, 000 mg/kg, decreases of RBC, hemoglobin and hematocrit values, increase of LDH value and slight increases of kidney and liver weights were observed.
4) The megakaryocyte of spleen increased, histologically, in dogs treated with T-1220 at 2, 000 mg/kg.
5) The injury of injection site of T-1220 was milder than that of ABPC.
6) The maximum safety dose of intravenous administration of T-1220 to dogs estimated to be 500 mg/kg in male and 1, 000 mg/kg in female.

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T-1220, a new penicillin analogic antibiotics has the broad antibacterial spectrum against gram positive and negative bacteria, and is especially effective against Pseudomonas aeruginosa and Klebsiella pneumoniae.
This report is concerned with the reproduction study of mice given T-1220.
1) Fertility study
T-1220 was administered subcutaneously to male mice at the doses of 500, 1, 000 and 2, 000 mg/kg/day for 60 days from 6 weeks after birth prior to mating and then was continued to administer till the performance of copulation after mating, and was also injected to female mice at the same doses from 2 weeks before mating to 6 days after pregnancy.
Any abnormality of reproductive function was not observed in male and female. External, internal and skeletal abnormalities were almost similar in all treated groups and control group.
2) Teratological study
Mice, 14 weeks old were employed. T-1220 was administered intravenously at the doses of 500, 1, 000 and 2, 000 mg/kg/day to pregnant mice from the 6th to the 15th day of gestation. Number of implants, fetal mortality, external, skeletal and visceral malformations, body weight and sex of each fetus by cesarean section were examined on the 18th day of gestation.
External and visceral malformations were not seen in all treated groups and control group, except that the 14th rib formation was observed in group of 1, 000 mg/kg/day. Growth and behaviour of newborns of the treated group had no significant difference from control in the period from birth to the 6th week after birth. F¹ mice, 12 weeks old had the normal reproductive function.
3) Perinatal and postnatal study
Mice, 14weeks old were also employed for mating. T-1220 was administered subcutaneously at the doses of 500, 1, 000 and 2, 000 mg/kg/day from the 15th day of gestation to the 21st day after delivery. In the pregnant period, any significant differences of body weight were not recognized among each group, but after delivery, its remarkable increases were observed in the treated groups. Pregnant period was normal in all groups.
The delivering rates, the weaning rates and the survival rates of all treated groups had no significant difference from those of the control, respectively. External malformation, behavior, differentiation after birth and growth of newborn were also normal in all groups. In addition, no abnormality of reproduction of F1 mice was observed.

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12-14 weeks old rats of Wistar strain were employed. T-1220 was administered subcutaneously at the doses of 250, 500 and 1, 000 mg/kg/day to pregnant rats from 7th to 17th day gestation. On the 21st day of gestation, 2/3 of the pregnant rats were examined for the number of implants, fetal mortality external malformations, skeletal malformations, visceral malformations, body weight and sex of each fetus by cesarean section. Growth and behavior of newborns delivered spontaneously from the remaining 1/3 of the pregnant rats were observed.
As the result, in the observation of external malformations, skeletal and visceral malformations, there were no significant difference between administered animals and the control. The delivering rates, the weaning rates and the survival rates of all treated groups had no significant difference from those of the control, respectively. External malformation, behavior, differentiation after birth and growth of newborns were also normal in all groups. In addition, no abnormality of reproductive function of F1 rats was observed.

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The local irritation effect of T-1220 was investigated as compared with that of ABPC or CBPC. The results obtained are as follows.
1) 25 and 50% solution of T-1220 and 50% solutions of ABPC or CBPC were dropped in the lower eyelid of rabbits. Appreciable inflammation of the cornea and conjunctiva was not caused by the solutions.
2) 25, 35 and 50% solutions of T-1220, ABPC or CBPC were administered intracutaneously to the abdominal skin of rats, and thereafter Evans blue was injected intravenously to the same rats. In the region administered with test sample, the area of dye spot and the amount of Evans blue were measured, and the results indicated that the local irritation effect of T-1220 was almost equal to that of ABPC or CBPC.
3) 25 and 35% solutions of T-1220 or CBPC were administered intramusculary to adult and juvenile rabbits. Judging from the examinations, muscle weight, gross local reaction and the histological observation, the local irritation of T-1220 was a little milder than that of CBPC. The inflammatory reactions on the drugs were almost similar in adult and juvenile.
4) In the ear of rabbits, 20% solutions of T-1220, ABPC and CBPC were allowed to remain in the sealed section of the vein. The frequency of thrombogenesis, length of thrombus, area of inflaming region and histological observation were examined. The results showed that local irritation effect of T-1220 was a little milder or equal to that of ABPC or CBPC.

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The antigenicity of T-1220, its cross reactivity with Penicillin G (PCG) and Aminobenzylpenicillin (ABPC) and Coombs test were studied in order to know the immunological characteristics of T-1220.
The results were as follows.
1) Antibody production against T-1220 was not shown in beagle dogs injected intravenously for 6 months and in rabbits injected intramuscularly for 15 days.
2) Cross reactivity of T-1220 with ABPC and PCG was observed in hapten inhibition of hemagglutination, hapten inhibition of quantitative precipitation and PCA reaction, but the reactivity was slight.
3) Ability of T-1220 to give a positive reaction in Coombs test and its direct hemolytic activity were both weak.

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Studies on T-1220, a new broad antibacterial spectrum penicillin, were carried out and the following results were obtained.
1) The average blood levels in 4 clinical cases administered 2 g with drip infusion for 2 hr were 56 μg/ml at the initiation of drip infusion, 17.8 μg/ml at 1 hr, 4.5 μg/ml at 2, hr and the calculated half-life in blood was 0.6 hr. The average excretion amount in urine from the initiation of drip infusion to 4 hr after the termination of drip infusion was 1131.6 mg (recovery rate was 56.6%), showing the maintenance of high concentration in urine.
2) Clinical evaluation against 33 cases with various kinds of infectious diseases was carried out. Most of the cases were advanced ages, having underlying diseases. The microorganisms detected were 19 cases of E. coli and 10 cases of the other GNB. However, most of them were the cases administered intravenously at the daily dose of 2-4 g. The effective cases were 3 out of 5 in respiratory tract infections, 5 out of 7 in the biliary tract infections and 16 out of 19 in the urinary tract infections.. It was also effective to 2 out of 3 against the cases detected Pseudomonas.
3) The change of the values in clinical laboratory examination in the above cases before and after the administration of the drug was investigated. In 3 cases abnormal values were observed, but any direct correlation with the administration of this drug was not observed. The shock-like symptom was observed in one case having drug allergy (aminopyrine) as the past history.

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The effect of antibacterial activity of T-1220 was measured by MIC (Standard Method of Japanese Society of Chemotherapy) against many kinds of strains isolated from clinical materials. T-1220 was administered intravenously or intramuscularly at daily dose of 1-6 g for 5-60 days to 22 cases of respiratory tract infections. The results obtained were as follows.
1) The MIC values in most of the bacterial strains were in very low concentration of T-1220.
2) The MIC values in most of the each 20 bacterial strains of Staphylococcus aureus, Serratia marcescens and Pseudomonas aeruginosa were in the range of 3.12-12.5 μg/ml, 3.12-12.5 μg/ml and 1.56-25 μg/ml.
3) Excellent clinical responses were obtained in 3 cases of lacunar tonsillitis, 1 case of bronchopneumonia, 6 cases of pneumonia and 1 case of pyothorax. Good responses were obtained in 1 case of lacunar tonsillitis, 1 case of bronchopneumonia, 7 cases of pneumonia. Slightly good response was obtained 1 case of lung abscess. Poor response obtained in 1 case of primary atypical pneumonia.
4) No side effect was seen in all these 22 cases.

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Laboratory and clinical investigations on T-1220 were performed and the results were obtained as follows.
1). Susceptibility of clinically isolated strains to T-1220 was tested by agar plate dilution method and compared with that to SBPC, ABPC, Cephalosporin antibiotics and others. The minimum inhibitory concentrations of T-1220 against 47 strains of Hemophilus influenzae, 25 strains of Klebsiella pneumoniae and 50 strains of Pseudomonas aeruginosa were less than 0.2 μg/ml, 0.39 to more than 200 μg/ml and 0.39 to 100 μg/ml respectively. 21 out of 25 strains of Klebsiella pneumoniae and 32 out of 50 strains of Pseudomonas aeruginosa were inhibited at the range of 0.39 to 6.25 4μg/ml of T-1220.
2) 7 cases out of 10 patients with respiratory tract infections treated with T-1220, showed effective clinical results. No side effect was observed in all patients clearly due to the drug.

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Antimicrobial activity of T-1220, a new penicillin derivative, was studied. The drug showed lower levels of MICs than those of Sulbenicillin against clinical isolates of Klebsiella pneumoniae and Pseudomonas aeruginosa.
Clinical evaluation of the drug was made by intravenous administration to a total 7 cases with secondary respiratory tract infections with gram negative bacilli. In 2 cases the drug was withdrawn because of the onset of chill and fever during the drip infusion in a case and of eruption in the other.
Of 5 cases treated with daily doses of 4 to 8 grams of T-1220 a day for the periods of 10 to 15 days, a case of infected lung cancer with Pseudomonas showed an excellent therapeutic response. A fairly good clinical response was seen in a case of infected lung cancer, but no positive response was obtained in the remaining 3 cases.
No significant deterioration was observed in laboratory findings after the administration of T-1220.

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Fundamental and clinical studies were carried out on T-1220, a new penicillin antibiotic.
1) In order to observe the interaction between T-1220 and aminoglycoside antibiotics the mixture of these drugs was incubated at 37°C for up to 48 hours in pH 7.8 phosphate buffer solution and the residual activity of each aminoglycoside was assayed biologically by thin layer cup method.
T-1220 inactivated GM, DKB, KW-1062 and TOB in particular. On the other hand, it did not inactivate Amikacin and LVDM remarkably.
2) T-1220 administered to 4 patients with pulmonary infections was effective in 3 cases and ineffective in 1 case. No side effects were observed.

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On a new semisynthetic penicillin derivative, T-1220, some laboratory and clinical studies were performed.
The results obtained were summarized as follows :
1) By the thin-layer cylinder-plate method using B. subtilis ATCC 6633 as a test organism, T-1220 levels in body fluids were assayable to the lower limit of 0.05, μg/ml.
2) Following an intravenous drip infusion of 3 g. T-1220 for 3 hours, blood level was 16.8, g/ml at 10 minutes after injection and the agent was excreted in urine with a peak of concentration up to 3, 100, μg/ml and urinary recovery rate was 913% within 9 hours.
3) Active levels were also obtained in sputum and pleural effusion following T-1220 administration.
4) T-1220 was effective in two cases of pulmonary abscess. No any side effect caused by this drug was ascertained in these two cases except a slight suspicion of drug fever in one case.

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Clinical and experimental studies on T-1220, semisynthetic penicillin, were carried out and the following results were obtained.
1) Antibacterial activity of T-1220 was more active than CBPC against Pseudomonas aeruginosa.
2) Concentrations of T-1220 and SBPC were determined in serum and urine of 2 normal volunteers. The serum concentrations of T-1220 was similar to that of SBPC, though urinary recovery of T-1220 was a little lower than SBPC. The average urinary recovery of T-1220 was about 47% during 6 hours, while the recovery of SBPC was 77%.
3) T-1220 was applied clinically in 2 cases of pneumonia and 1 case of acute pyelonephritis. Clinical results obtained were good in all the cases treated. No side effect was noted in any of the cases.

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Laboratory and clinical investigations on T-1220, a new semisynthetic. penicillin derivative, were performed, and the following results were obtained.
1) Minimum inhibitory concentrations of T-1220 against the bacilli isolated from the clinical specimens were examined. Seventy three per cent of E. coli, 86% of Klebsiella, 46% of Enterobacter, 80% of Proteus sp., 21% of gentamicin-resistant Providencia, 92% of GM-sensitive and 61% GM-resistant Pseudomonas aeruginosa were, respectively, inhibited at concentration of 12.5, u, g/ml of T-1220.
2) Twelve adult patients affecting from severe infections with underlying diseases were treated with T-1220 at daily dose of 2 to 8 g, and duration ranging from 3 to 63 days period. Excellent effects were obtained in 6 cases and good effects in 3 cases, but no effects were observed in the 3 cases who had ultimately fatal underlying diseases. As side effects, it was observed that development of S-GOT and S-GPT and skin rash that were reversible after discontinuation of the therapy in a case, respectively.

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T-1220 was tested to the following infectious diseases and the following result was obtained.
It was effective to a case of acute bronchitis, to 8 out of 11 cases of bacterial pneumonia, to a case of acute cystitis, to 7 out of 9 cases of acute pyelonephritis, to 5 out of 7 cases of chronic pyelonephritis, to 3 cases of cholecystitis and to a case of purulent peritonitis. It was effective to 26 out of 33 cases in total and the effective rate was 78.8%.
Dividing from the group of the diseases depending on the strains of causative organisms, it was effective to 11 out of 14 cases of E. coli, to 2 cases of Enterobacter, to 2 cases of Citrobacter, to 4 out of 6 cases of Pseudomonas, to 1 out of 2 cases of Klebsiella and to a case of Proteus vulgaris. It was effective to 21 out of 27 cases in total and the effective rate was 77.8%.
As side effect, drug fever caused by T-1220 administration was observed in only one patient and any other abnormality was not observed in hematological examination or urine examination.

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The antibacterial activity, absorption, excretion and clinical effects on T-1220 were investigated and the following results were obtained.
1) Stability in the culture media
T-1220 was slightly instable than carbenicillin, but it was distinctively more stable than ampicillin and penicillin G.
2) Antibacterial activity
The antibacterial activities of T-1220 against the following clinically isolated strains : i.e. E. coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa and Serratia, were 1-3 steps higher than ampicillin and carbenicillin to E. coli, remarkably higher than ampicillin and carbenicillin to Klebsiella pneumoniae and almost equivalent to carbenicillin to Klebsiella pneumoniae and almost equivalent to carbenicillin against Proteus mirabilis.
It was about 4 steps higher than that of carbenicillin against Pseudomonas aeruginosa and also was effective to some strains of Serratia.
3) Blood levels
The peak concentration of T-1220 in healthy adult volunteers after intravenous injection in a dose of 1 g attained to 130μg/ml within 5 min after the injection. In the cases whom T-1220 was administered in combination with probenecid blood levels 2-3 times higher than those without combination were observed.
From the studies on the dialysability of this drug, the blood levels during hemodialysis were 1/2 to 2/3 of those without dialysis.
4) Urinary concentrations
Within 4 hours after intravenous injection 78.5% of the drug was recovered in average from the urine and the urinary concentration reached to 2, 200-2, 800 μg/ml.
5) Tissue concentrations
In the studies of rats renal and hepatic concentrations of the drug were significantly high followed by the serum and the lung in order.
6) Clinical results
The drug was administered in total of 36 cases consisting of 13 cases of respiratory tract infections, 3 cases of hepato-biliary tract infections, 17 cases of urinary tract infections, 2 cases of sepsis and 1 case of thrombophlebitis. The results were 5 excellent, 17 good, 5 fair, 8 poor and 1 unknown. The overall effective rate was 77.1%.
As side effects in total 6 of cases consisting of 4 leukopenia (2 with eosinophilia), 4 elevation in serum transaminase, 2 of drug fever and 1 nausea were observed. These turned to normal by discontinueing the drug.

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On a new penicillin derivative, T-1220, some experimental and clinical trials were performed and the following results were obtained.
1) The sensitivity of gram negative bacilli of clinical isolates was clearly superior to that of carbenicillin or ticarcillin. There were marked differences between MICs measured with inoculum sizes of original ov1ernight broth culture and its 100-fold dilution.
2) In the rats with liver impairment by CCl₄, biliary and urinary excretions of T-1220 were less than that of normal controls.
3) Two patients with pneumonia were treated with T-1220 and the effect was evaluated as good in both cases. No side effect was observed.

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The bacteriostatic activities of T-1220 against E. coli, Klebsiella, Pseudomonas aeruginosa, Enterobacter isolated from blood in the period between 1972 and 1976, and Enterobacter isolated from other clinical materials in 1975 at Keio University Hospital were evaluated by the agar plate two fold dilution method. The inoculum was a 10-2 dilution of heart infusion broth overnight culture.
T-1220 were more active than ampicillin but less active than cefazolin against E. coli and Klebsiella. The antibacterial activities of T-1220 against E. coli, Enterobacter and P. aeruginosa were similar or more than that of carbenicillin or sulbenicillin.
Out of 4 patients treated with T-1220 of 2 g to 16 g a day, each patients with urinary tract infection and angina lacunaris were successfully treated with 2 g to 6 g a day of T-1220. No side effect was detected.

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T-1220 is a new antibiotic agent against a broad spectrum of gram-positive and gramnegative microorganisms.
10 patients with respiratory infections from whom Pseudomonas aeruginosa was isolated were treated with T-1220 at the dose of 2-8 gms per day by i.m. or i.v. injection or i.d. infusion, 2 patients had acute pneumonia, 6 patients had diffuse panbronchiolitis, 1 patient had chronic bronchitis and 1 patient had pyothorax.
Clinical response of T-1220 was good in 4 cases, fair in 3 cases and poor in 3 cases.
Side effects were observed in 2 cases; 1 case had icterus on the 5th day after the administration and the other had fever on the 2nd day after the administration. It is advisable not to use this drug for the patients with liver disorders.
It is considered that T-1220 is a useful drug for respiratory infections caused by Pseudomonas aeruginosa though its effect seems to be limited in case of diffuse panbronchiolitis.

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T-1220 was administered clinically to 10 cases of infection complicated with hematological disorders. Daily dose of T-1220 was 3 to 12 g and it was administered intravenously at 3 times a day. The results were obtained as follows : excellent in 4 cases, good in 2 cases.
In only one case, transient liver damage was found during administration.

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On T-1220, a new semisynthetic penicillin, sehsitivity distribution of clinically isolated absorption, excretion and clinical efFect were investigated.
1) The sensitivity of T-1220 against E. coli, Klebsiella and Serratia isolated from clinical specimens was more excellent than that of ABPC and CBPC. Especially the effect was more remarkable.in the cases that 10⁶ cells/ml were used as inoculum size in comparison with the cases when 10⁸ cells/ml were used as inoculum size. Similar result was obtained against Pseudomonas aeruginosa, showing that the activity of T-1220 was 4-8 times higher sensitivity than that of CBPC under the inocululn size of 10⁶ cells/ml.
2) The average serum levels were 63.96, 39.12 arid 3.14μg/ml at 1/2, 1 and 4 hours after intravenous administration of 2 g of T-1220 in 5 cases, and 1.6μg/ml at 6 hours after administration in one of these case& The serum levels were higher than those of CBPC and duration of detectable serum levels was longer than that of CBPC. The average urinary excretion within 6 hours Was 59.3%.
3) Serum levels in 3 patients administered 2 g of T-1220 with drip infusion for 2 hr were about 100μg/ml at 30-60 min after administration and 1.03-21.4μg/ml at 6 hr after the onset of drip infusion. The urinary excretion within 6 hours was 67.7% in 1 case. Serum levels administered 5 g of T-1220 with drip infusion for 2 hr were 423 μg/ml at 2 hr after administration and 12.8μg/ml at 6 hr.
4) Clinical cases treated with this drug were total ll cases including 7 cascs of acute pneumonia, each l case of bronchiectasis, pulmonary fibrosis, secondary infectious case of old tuberculosis and acute pyelonephritis
Clinical response obtained in these cases was “excellent” in l case, “cgood” in 8 cases “poor” and “unknown” in 1 case respectively. The dose of administration per day was 2-10g and to most of the cases 2-4gwas administered every day. As the method of administration, intravenous injection and drip infusion were used in most of the cases.
As side effect 2 out of ll cases drug fever was observed. No dysfuction was shown in haematological examination, liver function and renal function.

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T-1220 was evaluated on 10 patients : 4 patients with septicemia, 1 patient with fever after pacemaker implantation, 1 patient with purulent peritonitis, 3 patients with respiratory infection and 1 patient with pyelonephritis.
The clinical responses were considered to be satisfactory except 1 patients with Pseudomonas septicemia and lung cancer. Two patients experienced skin rash in the course of the treatment. A patient who received 291 gram of T-1220 of total dose experienced anemia in moderate degree.

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Fundamental and clinical investigations of T-1220, a synthetic penicillin widespread antibacterial spectrum were carried out and the following results were obtained.
1) The minimal inhibitory concentrations (MIC) of this drug against 67 strains recently isolated in our hospital were measured. MIC against 10 out of 15 strains of Staphylococcus aureus were within the range of 0.78-1.56 μg/ml and the titers were not different from that of ABPC and SBPC. MIC of T-1220, ABPC and SBPC against 3 strains of Streptococcus haemolyticus were all less than 0.2 μg/ml. Specific distribution of MIC against Serratia marcescens was observed, showing that MIC against strains was 1.56 μg/ml. MIC against the other 13 strains were ≥100 μg/ml. But all 15 strains were resistant to ABPC and SBPC and MIC were over ≥ 100 μg/ml. MIC against 12 out of 15 strains of Pseudomonas aeruginosa were 0.78-6.25 μg/ml and it was superior to that of ABPC and SBPC. MIC against 12 strains of Klebsielia pneumoniae were 3.13-12.5 μg/ml and it was superior to that of ABPC and SBPC. Among 7 strains of E. coli tested MIC against 5 strains were 1.56 μg/ml and the antibacterial activity was 2-4 times superior to that of ABPC and SBPC.
2) Clinical evaluation was studied in the clinics of our hospital and the total number of cases were 59 cases.
As the administration dose and method, intravenous drip infusion of 1-4 g per day for adult and 100 mg/kg for infant was employed as a rule.The efficacy of the treatment was judged in each clinic following each standard.
The results show that among 59 cases remarkably effective cases (Good) was 38, effective cases (Fair) 9, ineffective cases 12 and the effective rate was 64%. As side effect in 1 case treated in Department of Pediatrics exanthema was observed and in 4 cases treated in Department of Internal Medicine, Surgery and Orthopedics, rise of GOT and GPT was observed. However, the symptom of side effect was not so severe.

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Laboratory and clinical investigation have been carried out on T-1220, a new ampicillin derivative antibiotic, and following results were obtained.
1) Antimicrobial activity of T-1220 against clinically isolated E. coli, Klebsiella pneumoniae, .Proteus and Pseudomonas aeruginosa was more active than that of conventional penicillin derivatives CBPC and SBPC.
2) Clinically, T-1220 was applied to 8 patients with infectious diseases, and 5 out of 8 patients were improved, the efficacy rate being 75.0 percent.
3) T-1220 was found to have neither adverse effect on renal and liver function, nor on the peripheral blood.
4) T-1220 having potent antibacterial activity against Pseudomonas sp. and Klebsiella pneumoniae is considered to be a promising drug especially for urinary and respiratory tract infections.

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Laboratory and clinical investigations have been carried out on a new penicillin T-1220 and following results were obtained.
1) T-1220 exhibited an antibacterial activity widely against Gram-positive and Gram-negative bacteria, and a stronger antibacterial activity than ABPC and CER against Serratia, Proteus and Pseudomonas aeruginosa. There included ABPC, and CER-resistant strains among the above Proteus and Pseudomonas aeruginosa, nevertheless T-1220 exhibited a strong antibacterial activity even against those bacteria.
2) Serum concentrations of T-1220 were determined to 10 volunteers, comparison with CBPC. Average serum levels exhibited a peak concentration of 59.1 μg/ml to 1 g, 130 μg/ml to 2 g of T-1220 at 15 minutes after a single intravenous administration. Comparison with T-1220 and CBPC, the serum concentration of CBPC always maintained higher level than that of T-1220.
3) Average urinary recoveries of T-1220 in these volunteers were about 65% during 6 hours.
4) T-1220 was mainly injected intravenously by drip infusion singly as chemotherapeutic drug for the severe or middle respiratory infection and urinary tract infection, then favorable result was obtained in 14 cases (82.3%) out of 17 respiratory infections, while remarkable effect was obtained in 4 cases (100%) of urinary tract infections.
5) No noteworthy side effect was observed with T-1220, except one case to whom injection was given i.m. repeatedly showed local redness and slight swelling.

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Studies on T-1220 were carried out and the following results were obtained.
1) The antibacterial activity of T-1220 against E. coli, Klebsiella, Proteus and Pseudomonas isolated from clinical specimens was more excellent than that of CBPC, and especially in the activity against Klebsiella and Pseudomonas remarkable difference was observed. However, the antibacterial activity of T-1220 was influenced by the inoculum size and the antibacterial activity decreased with the increase of inoculum size. The antibacterial activity of T-1220 against Staphylococcus aureus was inferior to that of CBPC.
2) T-1220 was administered to 4 cases with pneumonia and one case with secondary infection of pulmonary cancer. The results were evaluated as one case “excellent”, 2 cases “ineffective” and 2 cases “unknown”. As side effect exanthema was observed in one case.

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Basic and clinical studies were made on T-1220 (Toyama Chemical Co.), a new ampicillin derivative. The results obtained were as follows :
1) T-1220 was found in vitro to be more potent against gram-negative bacilli (E. coli, Klebsiella, Proteus mirabilis and Pseudomonas aeruginosa) compared with Carbenicillin, Sulbenicillin or Ampicillin; while less potent than Gentamicin, excepting Proteus mirabilis strains which were almost similarly sensitive to both antibiotics.
The MIC of those bacilli were markedly influenced by their inoculum sizes.
2) Intramuscular injection of 2 g T-1220 yielded a peak blood level up to 50μg/ml in 1/2 hour, the urinary recovery being 60% of the dosage in 6 hours.
3) Out of 13 patients with various infections (pulmonary infections 7, UTI 4, SBE 1, sepsis 1 and cholecystitis 1) treated with T-1220 2-10 g per day, 10 responded favourably to the treatment.
No side effects were observed in those clinical trials, excepting 1 patient of SBE, who showed an allergic agranulocytosis in course of T-1220 administration longer than 20 days, recovering rapidly after cessation of the drug administration.
T-1220 seemed to be an antibiotic useful in the clinic, although reasonable attentions should be paid to the allergic reactions to the drug, similarly, to other penicillin derivatives.

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Laboratory and clinical investigations were performed on T-1220 and the results were obtained as follows;
1) Sensitivityof clinically isolated strains to T4220 was tested by agar plate dilution method and compared with that to ABPC, CBPC and GM. The antibacterial activityof T-1220 against most of clinical isolates, especially Pseudomonas cepacia was found to be superior to that of CBPC.
2) Serum concentrations of T-1220 1 hour after the 2.0g of intravenous infusion reached peak and the Ievels ranged from 50 to 82μg/ml with mean concentration of 62μg/ml. But the concentrations of T-1220 in sputum were iower with the range of 0.5 to 2.0μg/ml.
3) Five of eight patients with respiratory tract infections treated with T-1220 showed effective clinical result. No side effect was observed in all patients.

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Fundamental studies on a new penicillin antibiotic, T-1220 and clinical evaluation of the treatment of this drug against respiratory infections were carried out and the following results were obtained.
1) Antibacterial activity
Minimum inhibitory concentrations of T-1220 against total 999 strains consisting of 976 strains isolated from various clinical specimens (81 strains of Staphylococcus aureus, 33 strains of Salmonella, 47 strains of Shigella, 63 strains of Citrobacter freundii, 81 strains of Escherichia coli, 11 strains of Erwinia herbicola, 81 strains of Klebsiella pneumoniae, 43 strains of Enterobacter cloacae, 161 strains of Serratia marcescens, 26 strains of Proteus vulgaris, 51 strains of Proteus mirabilis, 22 strains of Proteus rettgerii, 17 strains of Proteus inconstans, 42 strains of Proteus morganii, 23 strains of Aeromonas hydrophila, 24 strains of Vibrio parahaemolyticus and 128 strains of Pseudomonas aeruginosa) and 23 standard strains subcultured in our department, were compared with those of Sulbenicillin (SBPC).
The antibacterial activity of T-1220 was stronger than that of SBPC in general; in the minimum inhibitory concentrations usually 2-3 tubes' difference was observed.
2) Concentrations in the organs of the rat
The concentrations in the organs of the Wistar strains of rat administered intramuscularly at 40 mg/kg were in order, liver, kidney, serum and lung.
3) Blood level in man
Blood levels in 3 patients of respiratory diseases administered 4 g of T-1220 dissolved in 500 ml of 5% glucose by intravenous drip infusion at the speed for 2 hours were 110-130 μg/ml at the end of drip infusion, 27-48 μg/ml at 2nd hour after the end of the injection and it decreased to less than 10 μg/ml at 4-6th hour after the end of injection.
4) Concentrations in sputa
The concentration in the purulent sputa of the patients with chronic bronchitis administered 4 g by intravenous drip infusion for 2 hours was 2.4 μg/ml and in the case of one shot intravenous injection (for 5 min.) it was 3.8 μg/ml at peak level.
5) Application to respiratory infections
Results of clinical evaluation in 12 cases of respiratory infections (6 cases of pneumonia and bronchopneumonia, 2 of lung abscess, 4 of chronic bronchitis) administered 2-6 g per day was remarkably effective in 2 cases (excellent), effective in 4 cases (good), slightly effective in 1 case (fair) and ineffective in 5 cases (poor). Side effect was not observed in any case.

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The laboratory and clinical studies on T-1220, a new derivative of penicillin, were performed with following results.
1) MIC values against 19 strains of respiratory pathogenic Haemophilus influenzae ranged from 0.05 μ/ml to 0.39 μg/ml, and were several times lower than those of ampicillin. In vitro antibacterial activity of T-1220 against Haemophilus influenzae was the best in 15 tested antibiotics.
2) MICs against 34 strains of respiratory pathogenic Pseudomonas aeruginosa were devided two almost equal groups, whose peak values were 3.13 μg/ml and 100, μg/ml.
3) 6 of 8 strains of respiratory pathogenic Klebsiella pneumoniae were sensitive to T-1220.
4) Klebsiella ozaenae 1 strain and Serratia marcescens 3 strains were all sensitive to T-1220.
5) After intramuscular administration of T-1220 100 mg/kg in rats, tissue concentrations reached peak values in 15 to 30 minutes. Tissue levels in order of concentrations were serum, liver, kidney and lung, and disappeared within 2 to 4 hours.
6) In 5 patients, the concentration of T-1220 were measured after intravenous instillation. Serum levels showed dose response, and increased and prolonged by probenecid. Sputum levels were almost the same as those of other penicillins. In cne patient with bronchiectasis, whose sputum levels of T-1220 were extremely low, blood flow of pulmonary artery was remarkably low in focus, and this fact was thought to be the cause of low sputum levels. In a patient with subacute bacterial endocarditis, the serum bacterial test just after i.v. administrations of T-1220 5 g was 512, and 8 hours later it was 4.
7) 11 patients with respiratory infections, 6 patients with urinary tract infections and one patient with subacute bacterial endocarditis were administered T-1220 mainly by i.v. instillation. T-1220 was remarkably or moderately effective in 3 patients with respiratory infections caused by Streptococcus pneumoniae or Haemophilus influenzae. In the patients with chronic respiratory infections caused by Pseudomonas aeruginosa, T-1220 was effective as long as the pathogenic organisms were sensitive, except one patient with bronchiectasis whose pulmonary blood flow was remarkably low in focus. In 6 patients with urinary tract infections, T-1220 was effective except 3 patients with hemiplegia or indwelling catheter. In one patient with severe subacute bacterial endocarditis, T-1220 was effective.
8) Eruption was observed in one patient, and disappeared soon after cessation of administration. In one patient administered with probenecid, transient granulacytopenia and mild elevation of GOT were observed.

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1) Antibacterial activity
The antibacterial activity against Staphylococcus aureus of this drug seems to be slightly weak than that of ABPC and CBPC, but the antibacterial activity against gram negative bacilli, especially Klebsiella pneumoniae, Escherichia coil, Proteus, Pseudomonas aeruginosa and Serratia was more powerful than that of ABPC and CBPC.
2) Concentrations in blood and sputum
The peaks of the drug were observed at 30 min after intramuscular or intravenous administration of 1 g and at 2 hr after drip infusion and the levels were 27, 50 and 130μg/ml, respectively.
The concentrations in sputum were very different individually and dose response following the dosis of administration was not found and usually it was less than 2 μg/ml.
3) Clinical results
This drug was used for 20 cases of acute and chronic respiratory infectious diseases and 2 remarkably effective cases, 12 effective cases, 1 fairly effective case, 3 ineffective cases and 2 unknown cases of effectiveness were observed.
Especially any side effect was not observed, except that one case complaining of itching sensation accompanying with rash during instillation was observed and the administration had to stop.

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In 18 cases of infants and children with acute infection, T-1220, a new derivative of Ampicillin, was administrated intravenously and the efficacy was examined clinically. The dosage of this antibiotics was 53 to 220 mg/kg/day, divided 2 to 4 times daily respectively. The result obtained that efficacy was excellent in 6 cases, good in 8 cases, fair in 2 cases, poor in 1 case and unknown in 1 case, effective rate being 82%. The drip-infusion method in intravenous administration revealed more effective response, compared with the one-shot method. No serious side effect was recognized. T-1220 may be considered to be a satisfactory antibiotic agent for infectious disease in childhood.

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T-1220, a new semisynthetic penicillin, has been shown to have higher in vitro activities against Hemophilus infiuenzae, Pseudomonas aeruginosa etc. than ABPC, CBPC, or SBPC.
Clinical studies on T-1220 were performed, including the determination of serum, urine, cerebrospinal fluid (CSF), and pleural fluid concentrations. Results were as follows :
1) Intradermal skin test for T-1220 was negative in 16 and positive in 1 of 17 cases.
2) Serum levels of T-1220 in 5 patients (2 pneumonias, 1 purulent meningitis, 1 septicemia, and 1 suspected sepsis) with normal renal functions on 4th to 18th day of administration reached peak at the end of the intravenous drip infusion (d.i.) and decreased rapidly, and were not detectable 6 hours after the starting of d.i., T-1220 was administered 24.0 to 76.9 mg/kg d.i. over 1 hour every 6 hours. Peak levels varied from 44.0 to 155 μg/ml, and serum half-lives calculated by the least squares method ranged from 0.51 to 0.55 hour.
3) Urinary concentration and excretion were measured in 2 patients with normal. renal functions. Urinary excretions within 6 hours in a patient of pneumonia on 4th, 5th, and 6th day of administration of 24.0 mg/kg d.i, over 1 hour every 6 hours ranged from 27.9 to 44.7% (average 35.1%). Urinary excretion within 6 hours in a patient of septicemia on 4th day of administration of 37.2 mg/kg d.i. over 1 hour every 6 hours was 103.3%.
4) Simultaneous CSF and serum T-1220 levels were determined in 2 patients with acute bacterial meningitis and one with no evidence of meningeal disease. In a patient of pneumococcal meningitis, 11/2 to 41/2 hours after 69.0 or 103.4 mg/kg d.i. over 1 hour every 6 hours on 2nd to 17th day of administration, CSF levels varied from 3.27 to 24.5 μg/ml and CSF/serum ratios ranged from 0.36 to 3.65 (average 1.92). In a patient of Hemophilus influenzae, type e, meningitis, 2/2 to 6 hours after 74.3 mg/kg d.i. over 1 hour every 6 hours on 2nd to 22nd day of administration, CSF levels varied from 1.0 to 6.65 μg/ml and CSF/serum ratios ranged from 0.25 to 1.9 (average 0.92). In a patient with AML in remission and without evidence of meningitis, CSF level 5/6 hour after intramuscular injection of 50.3 mg/kg was not detectable, though serum level rose to 43.0 μg/ml.
5) In a patient of empyema due to β-lactamase-producing Staphylococcus aureus, pleural fluid levels 6 hours after 51.1 mg/kg d.i. over 1 hour every 6 hours on 2nd and 3rd day of administration were 3.6 μg/ml and 8.7 pg/ml, respectively.
6) The dose of T-1220 was 94.5 to 104.1 mg/kg/day (average 100.0 mg/kg/day) in 8 cases of pneumonia, and 148.8 to 412.7 mg/kg/day in 7 cases other than pneumonia. One of 4 divided daily dose was administered every 6 hours by d.i. over 1 hour. Clinical effects were as follows :
In 8 cases of pneumonia, excellent response in 4, good in 3, and poor in 1 : In 2 cases of empyema, poor in Staph. aureus and good in H. influenzae, nontypable + Staph. aureus (combined with MCIPC) : In 2 cases of purulent meningitis, good in both Str. pneumoniae and H. influenzae, type e : In a case of septicemia due to Staph. aureus, poor : In a case of suspected sepsis, good : In a case of infraorbital abscess due to Staph. aureus, good : In total, excellent in 4, good in 8, and poor in 3 of 15 pediatric infections.
7) Side effects were noticed in 2 of 15 cases. In a patient of pneumonia, generalized skin eruptions with the elevation of S-GOT appeared transiently. In another patient of pneumonia on Down's syndrome with ECD, transient thrombocytopenia and elevation of S-GOT and LDH were noticed.

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