Ticarcillin, a new semi-synthetic penicillin, was investigated in 79 research facilities in Japan, and the results were published in the 25th General Meeting of Japan Society of Chemotherapy.
Conclusions obtained with ticarcillin are described as below.
1. Bacteriological results
Ticarcillin has a broad antibacterial spectrum against various organisms including Pseudomonas and Proteus similarly to CBPC and SBPC, and its action is bactericidal. Ticarcillin exhibited stronger antibacterial activity than CBPC and SBPC in sensitivity distribution of clinically isolated Pseudomonas. Its treatment efficacy was superior to the above two drugs in the infection preventive experiments.
2. Absorption, distribution metabolism and ercretion
Ticarcillin gave high levels in serum rapidly after its intramuscular or intravenous injection, and 70-80% of the drug was excreted in urine within 6 hours after the administration.
Comparison with SBPC by cross over method, serum level and urinary excretion of ticarcillin tended to be similar or slightly higher.
3. Clinical results
Clincal evaluations of ticarcillin were investigated on 733 cases in the fields of internal medicine, pediatrics, surgery, obstetrics and gynecology, and urology.
This drug was administered mostly at a daily dose of 2-4 g divided into 2-3 times, and the efficacy rate obtained was 60 -80% in each field.
Side effects of the drug were observed at 4. 4%, and these consisisted chiefly of eruption, pain at injected site and digestive symptom.
No severe side effect was reported up to now.

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The in vitro and in vivo antibacterial activity of ticarcillin (TIPC) was compared with that of carbenicillin (CBPC) and sulbenicillin (SBPC). The following results were obtained.
1) The antibacterial spectrum of TIPC was similar to that of CBPC and SBPC.
2) The in vitro antibacterial activity of TIPC against clinical isolates of Staphylococcus aureus, E. coli, Proteus species, Klebsiella pneumoniae, Serratia marcescens and Pseudomonas aeruginosa was similar to that of CBPC and SBPC.
3) Influence of medium pH, horse serum protein and inoculum size on in vitro antibacterial activity of TIPC showed the same tendency to CBPC and SBPC.
4) Pattern of development of resistance on TIPC in vitro was similar to that of CBPC and SBPC.
5) Bactericidal action of TIPC against E. coli and Pseudomonas aeruginosa appears more rapidly than CBPC.
6) Stability of TIPC to β-lactamase extracted from penicillin resistant E. coli was generally similar to that of CBPC.
7) On the protecting effects for systemic infections in mice, the effect of TIPC was similar to that of CBPC for E. coli and was superior to CBPC for Pseudomonas aeruginosa. The therapeutic efficacy of multiple administration of TIPC was more effective than that of CBPC.

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The most effective administration of a semisynthetic penicillin, ticarcillin (TIPC), has been studied in the experimental mice infection with Pseudomonas aeruginosa.
1) Pseudomonas aeruginosa damaged by TIPC or carbenicillin (CBPC), when the drug was free, immediately began to regrow in vitro.
2) The therapeutic efficacy of TIPC on multiple administrations was more effective than that of CBPC.
3) An important factor to decide the therapeutic efficacy of TIPC and CBPC was the total duration of the effective concentration rather than the total dosing amounts of the drug.

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新しくビーチャム社で開発されたTicarcillinの Pseudomonas aeruginosa E-2に対する抗菌像について, 比較薬剤としてCarbenicillinを用い, 位相差顕微鏡, 走査電子顕微鏡により検討をおこなった。
1. 位相差顕微鏡による観察では, Ticarcillin やCarbenicillinを作用させた場合, 菌体の付ament 化やspheroplast様構造を観察することができた。
2. 走査電子顕微鏡による観察でも同様で, TicarcillinやCarbenicillinの作用により典型的な spheroplast様構造を観察することができた。
3. Stabihzerを用いた spheroplast 形成能におよぼす影響では, Ticarcillin は Carbcniciillnと同様にspheroplast が形成されることが判った。

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TIPCはCBPCおよびSBPCと類似した広域抗生物質で, CBPCおよびSBPCより強いin vitro抗Pseudomonas活性を示す。Indole陽性および陰性のProteus groupに対する抗菌活性はABPCより著明に強い。グラム陰性菌のうち, ABPC高度耐性E. coliにTIPCは抗菌活性を示さないが, ABPC感受性のE. coliにはCBPCおよびSBPCより活性はやや強い。Ps.aeruginosaによるマウスの全身感染およびラットの尿路感染に対し, TIPCは概してCBPCおよびSBPCより強い治療効果を示した。またin vitroにおけるウサギ多形核好中球によるPs. aeruginosaその他の細菌の貪食殺菌をTIPCが増強することを認めた。

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実験動物 (ラット, ウサギおよびイヌ) にTIPCを20 mg/kg筋注し, 血清中濃度, 尿中排泄, 胆汁中排泄および組織内濃度を検討した。
TIPCの血清中濃度と半減期は動物種により異なる。イヌにおいて20～80 mg/kgのTIPCを筋注した際, 投与量と血清中濃度の間に明瞭なdose responseが認められた。その他, TIPCの尿および胆汁中排泄, 組織内濃度はCBPCと大差のない結果を得た。
健康志願者6名にTIPC 1gを3～5分で静注し, 血清中濃度および尿中排泄を検討した。最高血清中濃度は平均91.8 μg/ml, 投与後8時間までのTIPCの尿中回収率は平均79.7%であった。尿中代謝物として, TIPCのpenicilloate が認められ, 投与8時間までに14.8%が回収された。
健康成人で得られたTIPCの血清中濃度をtwo compartment model式に回帰して得られた定数から点滴注入時の各種投与条件におけるTIPCの血清中濃度を算出予測し, 投与条件と血清中濃度との関係を比較した。

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Ticarcillin, a new semisynthetic penicillin, was investigated on the antibacterial activity chiefly against gram-negative bacilli as Ps. aeruginosa derived from blood, and on the combination effect with aminoglycoside antibiotics to compare carbenicillin and sulbenicillin. Results obtained were as follows.
1. Ticarcillin showed stronger antibacterial activity than carbenicillin and sulbenicillin against all species of Ps. aeruginosa, Enterobacter and Serratia.
2. Ticarcillin and gentamicin or dibekacin were found to be synergistically bacteriostatic against all strains of Ps. aeruginosa, the effect being 8-16 times stronger compared with a single administration. Compared with sulbenicillin, ticarcillin was shown to inhibit the growth of Ps. aeruginosa equally to sulbenicillin with 1/2 concentration of sulbenicillin, if concentration of gentamicin was fixed.

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1. Ticarcillinとcarrier proteinとの共有結合物でウサギを免疫すると, 他のペニシリンと同様特異赤血球凝集抗体, 沈降抗体およびPCA抗体の産生が認められた。
2. Ticarcillinとcarrier proteinとの共有結合物でマウスを免疫すると, 他のペニシリンと同様, 特異IgE型抗体の産生が認められた。
3. Ticarcillinは, 生理条件下でヒト血清アルブミンと反応させると, 他のペニシリンと同程度のpenicilloylprotein結合物を形成する。
4. TicarcillinはCarbenicillinおよびBenzylpenicillinとの間に比較的強い免疫学的交差性を示す。
5. Ticarcillinのin vitroクームス陽性化能は, Sulbenicillin, CarbenicillinおよびBenzylpenicillinにくらべ若干弱い。

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Pharmacological effects of ticarcillin (TIPC) on the cardiovascular system, central nervous system, smooth muscles and urinary excretion were investigated in whole animals and isolated organs.
TIPC had essentially no effect on the systemic blood pressure, heart rate, respiration and electrocardiographic pattern in the anesthetized dog. In isolated guinea-pig atrium, the drug was virtually without effect on positively or negatively inotropic and chronotropic activities.
At a large subcutaneous dose of 3, 200 mg/kg, TIPC produced a slight decrease in the body temperature, but the change was within a normal range. At subcutaneous doses more than 1, 000 mg/kg of TIPC, the locomotor activity in mice revealed a slight tendency toward reduction to a statistically insignificant extent.
Although a slight and transient inhibition of spontaneous contraction of the pyloric antrum in the morphine-urethne anesthetized dog was observed after an intravenous administration of 1, 000 mg/kg of TIPC, the compound was entirely devoid of effect on contraction of the isolated rabbit ileum and rat uterus.
Intravenous injection of 320 and 1, 000 mg/kg of TIPC produced an increase of urinary volume. The change was most remarkable immediately after the administration and then gradually decreased. An increase in urinary excretion on Na⁺ was almost comparable to an increase in urine volume. On the other hand, increase of K⁺ excretion was slight in degree and not lasting.

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Ticarcillin, a new broad spectrum penicillin preparation, has been investigated to give following results.
1. To measure the M. I. C.s of ticarcillin against 215 strains of Pseudomonas aeruginosa isolated from patients, using plate dilution method, 173 strains of those organisms were in the range 25 to 100 μg/ml. Antimicrobial activity of ticarcillin against Pseudomonas aeruginosa was higher than that of carbenicillin.
2. The mean peak blood level in 4 female patients was 153. 8 μg/ml in 15 minutes following administration of 2 g intravenously. The mean of half life in the blood was found to be 1. 44 hours and the urinary recovery rate was 57. 5% in 6 hours.
3. Thirty one patients with various infections were treated with ticarcillin receiving 2 to 6 g per day intravenously. Five of 31 patients were excellent (cured) and 18 were good. Four patients with chronic infections were poor response. As to the side effect of the drug, rash and pain at chest, belly and back in injection was occurred in one patient and eosinophilia and pyrexia in other patient.

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Seven cases of severe, hardly treated pulmonary infectious diseases, including three cases of diffuse panbronchiolitis, were treated with TIPC, which was used intravenously by one shot or/and drip infusion, at total dosage of 42-132 g, for 7-22 days. All but one case, of severe lung abscess at the end stage of lung cancer, exhibited the effective clinical results, from the points of view as subjective and objective findings, chest X-ray findings and bacteriological changes in sputa.
None was observed side effects and was affected on liver and kidney functions and blood pictures by using TIPC.

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Ticarcillin was administered at a daily dose of 12g to 11 cases of severe infections complicated with acute leukemia, malignant lymphoma, aplastic anemia etc., and a good efficacy was obtained in 7 cases. Especially by combinating with aminoglycoside antibiotics, satisfactory results were obtained.
As to side effect, eruption was observed in only one case, which disappeared after interruption of administration.

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A new antibiotic, ticarcillin (TIPC) was studied on its antibacterial activity and clinical effects, and the following results were obtained.
1) Sensitivity of microorganisms to TIPC which were isolated from sputa of patients with chronic respiratory diseases was tested by agar plate dilution method, and compared with that of aminobenzylpenicillin (ABPC) and sulfobenzylpenicillin (SBPC).
The minimum inhibitory concentrations of TIPC against 47 strains of H. influenzae, 25 strains of Klebsiella, 26 strains of E. coli, 16 strains of Enterobacter and 50 strains of Ps. aeruginosa were 0.2 or less to 25 μg/ml, 50 to 200 μg/ml or over, 1.56 to 100 μg/ml or over, 1.56 to 100 μg/ml or over, 0.39 or less to 800μ g/ml or over respectively. The antibacterial activity of TIPC was the same to that of ABPC, SBPC against H. influenzae and superior to that of SBPC against Ps. aeruginosa.
2) In 8 cases of Ps. aeruginosa infections, bacteriological elimination was obtained in 3 cases of chronic bronchiolitis, and clinical improvements of symptoms were observed in 7 cases.
3) No side effects were found.

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The susceptibility of gram-negative bacteria to TIPC (Ticarcillin) and its clinical effects on 10 patients with gram-negative pulmonary infection were evaluated and the following results were obtained.
1) The MIC value of TIPC against 21 strains of Pseudomonas aeruginosa isolated from the case of respiratory infections ranged from 12.5 μg/ml to 800 μg/ml. About 40 percent of the strains was inhibited by TIPC at a concentration of 50 μg/ml, whereas only 20% was inhibited by the same concentration of CBPC and SBPC.
2) The effects of ABPC exceeded somewhat those of TIPC against 15 clinical isolates of Klebsiella pneumoniae.
3) Half of the isolates of E. coli had an MIC of 1, 600 μg/ml or more.
4) No cross resistance was observed between TIPC and other semisynthetic penicillins on Ps. aeruginosa.
5) The clinical effects were evaluated principally on the basis of bacterial response in sputum. In 4 of the 10 cases Pseudomonas aeruginosa and Klebsiella pneumoniae disappeared. In another 4 cases the gram-negative bacilli temporarily disappeared during the administration and/or the bacterial counts markedly diminished.
6) Only 2 cases showed no bacterial response to TIPC therapy.
7) Heavy headedness was observed in 2 cases, and chill and fever in another case.
8) The hepatic and renal function tests, and the examination of the peripheral blood showed no abnormalities.

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On a new semisynthetic penicillin, ticarcillin, some basic and clinical investigations were performed, and the following results were obtained.
1. The sensitivity of various gram-negative bacilli of clinical isolates against ticarcillin exceeded that of carbenicillin in a majority of strains. However, there found cross resistance between the sensitivity of ticarcillin and carbenicillin.
2. The serum levels and urinary excretion were measured following ticarcillin 3g administration by drip infusion to six healthy volunteers. The serum levels and urinary excretion following intravenous administration of 1g of ticarcillin and sulbenicillin to six healthy volunteers by cross over method were compared. The both values of ticarcillin somewhat exceeded those of sulbenicillin.
3. The serum, biliary and urinary levels of ticarcillin following intramuscular injection to CCl⁴-treated rats were compared with those of controls. There was no fixed tendency in serum and biliary levels, but the difference was found among urinary excretions.
4. Clinically, a total of five cases with a total of nine infection sites was treated with ticarcillin. As a result, three were effective, one was fair, and five were poor. No side effect was found.

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Ticarcillin was studied on its antibacterial activity, absorption, excretion and clinical effects, and the following results were obtained.
1. Antibacterial activity
The antibacterial activities of ticarcillin against E. coli and Pr. mirabilis were 2 to 8 times stronger than those of ampicillin and carbenicillin.
With an inoculum size of 10⁶ cells/ml, ticarcillin was at least two fold more active against Ps. aeruginosa than sulbenicillin and carbenicillin, 76% of isolates being inhibited by 50 pag/ml or less.
2. Absorption and excretion
After a single intramuscular dose of 0.5 and 1.0 g to 6 healthy adults, the mean peak concentrations of ticarcillin in serum were 14. 8 and 28.8 μg/ml respectively at 30 minutes. The biological half life of ticarcillin ranged 0.87 to 1. 18 hours. Ninety-four to 75% of the dose was excreted in the urine during the first 6 hours after injection.
A dose response was obtained with increasing dosage of ticarcillin.
The serum levels of ticarcillin maintained longer in patients with renal insufficiency.
3. Clinical results
Ticarcillin was clinically applied to 20 patients with bacterial infection, including 9 cases of respiratory tract infection, 5 cases of biliary tract infection and 6 cases of urinary tract infection, and the results obtained were good in 15 cases, fair in 1 case, and poor in 4 cases.
No marked side effects were observed.

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Clinical studies on ticarcillin, a new semisynthetic penicillin, were performed in the severe infections complicated with hemopathy. The results obtained were as follows.
1. Ticarcillin was administered successfully at a daily dose of 6 to 16g in combination mainly with aminoglycoside antibiotics to 4 cases of suspected septicemia with underlying disease of acute myelogenous leukopenia (AML).
2. Ticarcillin was administered successfully at a daily dose of 16 g in combination with CEZ and GM to 1 case of pneumonia due toEnterobacter andKlebsiella with AML.
3. No noteworthy side effect of ticarcillin was observed, except eruption in 2 cases out of 10 cases in 7 patients treated.

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Ticarcillin is a new semi-synthetic penicillin with structure similar to that of CBPC.
1) The antibacterial spectrum of ticarcillin is almost the same with that of CBPC and its antibacterial activity is stronger than that.
2) The absorption and excretion of ticarcillin is also almost the same with that of SBPC. The serum concentration in 2 patients with bronchiectasia following 3. 0 g drip infusion was around 100 μg/ml at the end of D. I. and the sputum level was respectively 6. 8 and 14. 0 μg/ml at 2 hours in D. I..
3) Ticarcillin was administered to 6 patients with respiratory tract infection and one patient with urinary tract infection at a daily dose of 6.0 g during 6-15 days. As the result, overall clinical response was good in 4 cases and bacteriological effect was good in 3 cases. These clinical results may be as well from the antibacterial activity, absorption and excretion of ticarcillin.
From above, ticarcillin has stronger antibacterial activity than CBPC and it may have an availability in the infection due to Ps. aeruginosa with low toxicity and mass medication.

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Ticarcillin is a new semisynthetic penicillin with a similar chemical structure to carbenicillin.
In order to study the effectiveness and side effect of this agent, ticarcillin was administered to 11 patients (8 men and 3 women), consisting of 10 cases of respiratory tract infection and 1 case of urinary tract infection.
Clincal response of ticarcillin was good in 8 cases treated. It is noteworthy that this agent was effective in 3 out of 4 cases ofPseudomonas infections.
As to the side effects, slight elevation of transaminase (S-GOT, S-GPT) was noted in 1 case, though normal values were recovered immediately after the discontinuation of dosing.

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1) Ticarcillin was administered to 10 patients suffering from respiratory infections caused byPs. aeruginosa, E. coliand glucose non-fermenting G. N. R. As the result, five cases were improved clinically, and six cases bacteriologically.
2) Relationship between MICs of infecting organism and effects of ticarcillin are encountered in the pulmonary parenchymal infections, but it was difficult in the other respiratory tract infections due to the severity of the underlying diseases or the sites of foci.
3) None of the cases treated with ticarcillin experienced any side effects; therefore, ticarcillin can be considered to be an effective drug with good clinical responses.

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(1) Antimicrobial activity of ticarcillin (TIPC) against clinically isolatedPs. aeruginosa, E. coli, Kleb.pneumoniaeandStaph. aureus was compared with that of sulbenicillin (SBPC), carbenicillin (CBPC) and ampicillin (ABPC). As the result, TIPC showed better antimicrobial activity againstPs. aeruginosathan SBPC and CBPC.
(2) Intravenous drip infusion of 2 grams of TIPC was done in 2 cases (the one has slight renal impairment, the other has none). Maximal serum concentration of TIPC at the end of drip infusion were 74 μg/ml, 110 μg/ml and urinary excretion rates in 6 hours were 27. 1%, 47. 3% respectively. T112 (half-life time) was around 1 hour.
(3) Two grams of TIPC were administered twice a day to 8 cases including pneumonia (4 cases), pyelonephritis (2 cases), gangrene (1 case) and enteritis (1 case). The clinical results were as follows : excellent in 1, good in 5, fair in 1 and undetermined in 1 case.
(4) No side effect was found including laboratory findings of urine, peripheral blood, renal and hepatic functions.

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Ticarcillin (TIPC) was evaluated in clinical trials and the following results were obtained.
1. The MICs of ticarcillin were superior 1 to 2 steps to that of CBPC againstPs. aeruginosa, Proteus spp., Klebsiella andE. coli.
2. Ticarcillin was administered to 11 patients with severe underlying disease in the department of internal medicine. As the result, ticarcillin showed good response in 4, fair in 4 and poor in 3 cases.
3.Ps. aeruginosa was eradicated in 5 of 6 strains and as a whole, the bacteriological effect was seen in 10 strains of 13 isolated organisms.
4. No side effects were seen and abnormal values in liver and renal functions were thought to be due to underlying disease.
5. Recurrent cases were often seen. So, ticarcillin will be a useful antibiotic if dosage, medication and combined therapy with other antibiotics will be taken into consideration.

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Ticarcillin was intravenous infused continuously for 2 hours at a dose of 3 g to 4 volunteers of healthy adult, and the drug transfers were investigated in serum and urine. Results obtained were as follows.
1. Maximum serum levels at infusion completion were 75-96 μg/ml, 87 ±9. 2 (S. D.), μg/ml on the average, and Half-life after infusion completion were 0. 82-0. 91, 0. 88 ± 0. 04 hours on the average, levels lowered almost straight on hemilogarithmic graph, and these were 3, -4, μg/ml after 6 hours.
2. Urinary recoveries were 1. 222, -1. 764, 1. 41 ± 0. 249 g on the average, within infusion completion, that is, 47% of infused dose was recovered on the average. Recovery volume within 6 hours was 1. 981-2. 135 g, 2. 066±0. 064 g on the average, and a mean recovery rate was 68. 9%.

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1) Clinical pharmacological studies of ticarcillin were conducted in patients with impaired renal function.The ticarcillin concentrations in the serum of patients 1, 2, 4, 6, 24 hours after an intravenous injection of 1 g are shown in Table 1 and Fig. 1. Serum half-lives of ticarcillin are about 2 hours (Ccr. 74 ml/min.), 4. 5 hours (Ccr. 26 ml/min.), 13 hours (Ccr. less than 5 ml/min.) and 4-7 hours (Ccr. less than 5 ml/min., during hemodialysis),
2) Ticarcillin was used in 12 cases. Results are shown in Table 2 and 3. Two cases (Case 3, 5) were proven not to be infectious disease, and they were excluded from the effect evaluation. Clinical effects were good in 7 cases, fair in 1 case and poor in 2 cases. No distinct side effects were observed.

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Eight infectious episodes in the patients with acute leukemia were treated with ticarcillin (12-16g/day) combined with dibekacin or gentamicin. Three cases responded to the combination antibiotics therapy, while 5 failed. Mild elevation of serum GPT and alkaline phosphatase was noted after all 3 administrations in one patient.

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Ticarcillin was administered to the 10 cases of the infections of respiratory organs consisting of 4 cases of pneumonia, 4 cases of acute exacerbation of bronchiectasis, 1 case of bronchitis and 1 case of pyothorax, and the clinical effect of the drug was investigated. A dose of 2-5 g was used twice daily for 3-16 days.
As the result, excellent effect was obtained in 5 cases, good effect in 3 cases, and fair effect in 2 cases, effective ratio being 80%. Isolated organisms consisted ofPs. aeruginosa8 cases, Proteus1 case, and unknown 1 case. As for the transition of organisms, 8 strains ofPs. aeruginosaand 1 strain of Proteus disappeared all, and yet 3 strains ofKl. pneumoniaeand 1 strain of GNR appeared as substituted microbes.
Other antibiotics were ineffective before in 6 cases out of 10 cases investigated, and yet excellent effect was obtained in 4 cases and good effect in 2 case.
As to the side effect, values of GOT and GPT were elevated in 1 case, but these returned to normal on 22nd day after the interruption of administration. Another 1 case complained of eruption, and this disappeared spontaneously by stopping the administration.
The present investigation was performed on the infections due toPs. aeruginosaor the infections which did not respond before to other antibiotics. These infections are difficult to be treated, as local preventive function lowers as well as general resisting power. Considering this, the results obtained may be fairly satisfactory.

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Ticarcillin was administered at a daily dose of 2-12 g for 8-38 days to 15 cases of acute exacerbation of chronic bronchitis complicated with chronic panbronchiolitis.
As to the global effects classified by causative organism, 12 cases of Ps. aerugionosa resulted in excellent effect in 3 cases, good effect in 3 cases, and no effect in 6 cases, and 2 cases of Klebsiella and 1 case of Enterobacter excellent effect. As to the effects classified by dose, cases ofPs. aeruginosa (majority of the cases) resulted in no effect in all 3 cases at a daily dose of 2-3 g, while no effect in 1 case out of 9 cases at a dose of more than 4 g. Ticarcillin should be administered thus at a daily dose of more than 4 g, more than 10 g if possible, to chronic bronchitis complicated with chronic panbronchiolitis due to Pseudomonas.
As for the side effect of the antibiotic, no finding was found by ticarcillin administration except that a transient eosinophilia was noticed in 1 case.

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Ticarcillin was applied to eight leukemic patients with severe gram-negative infections. Six of 8 cases could be evaluated on the effect of ticarcillin in this trial. Five of 6 cases with Pseudomonas pneumonia or with pneumonia caused by Pseudomonas and other gram-negative organisms were cured or improved. One case with Pseudomonas pneumonia was failed to respond. No remarkable side effect was observed except one erythematous skin rash, and one phlebitis patient. It is expected that ticarcillin may constitute an advance in the antibiotic treatment against Pseudomonas infection in patients of leukemia.

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1) Sensitivity of Pseudomonas aeruginosa to ticarcillin (TIPC) :
The MIC of TIPC against 50 strains of Pseudomonas aeruginosa isolated from human infections was 25-50 μg/ml, similarly to CBPC or SBPC.
2) Tissue concentrations of TIPC in rats :
Studies on the distribution of TIPC in rats organs after intramuscular injection revealed the highest concentration in liver, followed by kidney.
3) Blood levels and urinary excretion in a patient :
Following a single intravenous administration (drip infusion for one hour) of 1. 0 g TIPC, the maximum serum level was 320 μg/ml after one hour. The urinary recovery rate was 31. 3% in eight hours.
4) Clinical trials :
Four of the six patients responded favorably to the treatment with TIPC.
No side effects (clinically and laboratory findings) were found.

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Laboratory and clinical studies were performed on ticarcillin, a new semi-synthetic penicillin with broad antibacterial spectrum, and the following results were obtained.
1) As to the distribution of ticarcillin sensitivity in clinical isolates, a peak was 6.25 pg/ml for Staph. aureus, 6.25 μg/ml and more than 100 μg/ml for E. coli, more than 100 μg/ml for Klebsiella, 0.78 μ/ml for Proteus sp., and 50 μg/ml for Pseudomonas aeruginosa. When the inoculum size was decreased, a peak of sensitivity moved to 3. 12 μg/ml for Staph. aureus, 3. 12 μg/ml and more than 100 μg/ml for E. coli, and 25μg/ml for Pseudomonas aeruginosa.
Compared these antibacterial activities of ticarcillin with those of CBPC, no wide difference was observed for Staph. aureus, Klebsiella and Proteus sp., while the antibacterial activity of ticarcillin was 2 times stronger than that of CBPC for sensitive E. coli and Pseudomonas aeruginosa.
2) Ticarcillin was adminstered intravenously by drip infusion of a daily dose of 2-10g to 5 cases of respiratory tract infection and 2 cases of urinary tract infection each due to Pseudomonas aeruginosa, 7 cases in total. The clinical effects obtained were good in 4 cases and failure in 3 cases. As to the bacteriological effect, Pseudomonas aeruginosa was eradicated in 5 cases out of 7 cases. As to the side effects, epigastric malaise, and phlebitis at injected site were observed each in 1 case.

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A new semi-synthetic penicillin, ticarcillin (TIPC) was investigated in laboratory and clinical field and the followings were obtained.
1) Antibacterial activity
Minimal inhibitory concentration of TIPC was compared with that of carbenicilln (CBPC). As the result, the antibacterial activity of TIPC was parallel with that of CBPC. But, in Ps. aeruginosa, E. coli, Salmonella and Enterobacter aerogenes strains TIPC showed better antibacterial activity than CBPC.
2) Concentration in serum and sputum
The peak of serum concentration was 140.0 and 250. 0 μ/ml respectively following 3.0 g and 6. 0 g drip infusion of TIPC. The half life was 0. 72-0. 78 hour. The peak of the concentration in sputum was 0.7 μg/ml following 6. 0 g drip infusion. And the ratio of serum concentration to sputum one was 0.003.
3) Clinical evaluation in respiratory infections
TIPC was administered to 5 chronic pulmonary infections caused by Ps. aeruginosa and one bronchopneumonia. The daily dose was 3. 0 to 6. 0 g and duration 4 to 22 days. As the results, clinical response was excellent in one, good in 2, fair in one and poor in 2 cases. Ps. aeruginosa in sputum was disappeared in one case. No side effects nor abnormal laboratory findings were observed.

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Laboratory and clinical studies on ticarcillin were performed with following results.
1. Antibacterial activity of ticarcillin against respiratory pathogenic bacteria isolated from sputum was measured.
1) MIC values against 80 strains of Haemophilus influenzae ranged from 0.1 to 0.78 μg/ml. Ticarcillin was active as much as ampicillin, and slightly superior to amoxycillin, carbenicillin and sulbenicillin. There was no resistant strain against ticarcillin.
2) Against sensitive group of 34 strains of Pseudomonas aeruginosa, the activity of ticarcillin was 2 times superior to sulbenicillin and 4 times superior to carbenicillin. But against resistant strains, MICs of ticarcillin were same as those of sulbenicillin and carbenicillin.
2. After intramuscular administration of ticarcillin 100 mg/kg in rats, the concentrations of organs reached peak levels at 15 minutes and they were the following order of kidney, liver, serum and lung. Two to 4 hours later, ticarcillin was not detectable in all organs.
3. Nine patients with chronic respiratory tract infections were administered ticarcillin by intravenous drip infusion, and the concentrations in serum, saliva, sputum and intrabronchial secretions were measured. Serum levels of ticarcillin showed dose response according to administration dose volume and instillation time. The half life in serum was between 40 to 60 minutes. Probenecid prolonged the half-life of ticarcillin in all 4patients, and elevated the sputum level, too.
4. Ten patients with chronic respiratory infections (chronic bronchitis; 3, bronchiectasis; 3, chronic bronchiolitis; 4) were treated with intravenous drip infusion of ticarcillin 3 to 20 g a day for 5 to 14 days. Treatment succeeded in all of 8 patients infected with Haemophilus influenzae, and in one of 5 patients infected with Pseudomonas aeruginosa. Effects of ticarcillin for bacterial respiratory infections depended on transported concentration into infected bronchus and susceptibility of causative agents to ticarcillin.
5. There was no adverse reaction.

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Ticarcillin (TIPC) was intravenously administrated to the 27 pediatric patients and the follwing basic and clinical results were obtained.
1. TIPC was administrated about 30. 0-50. 0 mg/kg (body weight) intravenously. The serum concentration peak of TIPC was at the end of administration (one shot and drip infusion), and its high concentration was kept over 1 hour and higher than that of sulbenicillin.
2. Urinary excretion rate was about 85% in active state within 6 hours.
3. On two whooping cough cases TIPC was administrated at a dose of 160 mg/kg/day for 7-10 days, on 3 acute bronchitis, 3 measles pneumonia, 9 bronchopneumonia and 3 other cases 60-140 mg/ kg / day for 3-8 days. Excluding 1 mumps, 1 meningitis and 3 mycoplasmal pneumonia cases, good clinical response was obtained.
4. On purulent tympanitis case isolated Ps. aeruginosa, TIPC was administrated at a dose of 200mg/ kg / day for 8 days and clinical effectiveness was obtained.
Also, on sepsis isolated Klebsiella accompanied leukemia, TIPC was administrated at a dose of 400 mg /kg / day with GM. As a result, the patient was cured.
5. No abnormal finding was observed in renal and liver function after administration of TIPC.
6. Clinical good response was observed in 23 cases excluding 4 cases.

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The authors have carried out the laboratory and clinical studies of ticarcillin.
The results were as follows;
The sensitivity was measured by the cup plate dilution method with 31 strains of Ps. aeruginosa, 14 strains of E. coli, 15 strains of Klebsiella pneumoniae and 32 strains of Staph. aureus. The growth of 48.2% of Ps. aeruginosa was inhibited in concentration of less than 25 μg/ml. The antimicrobial activity of ticarcillin was 2 times the activity of carbenicillin. The growth of 57. 1% of E. coli and of 40. 6% of Staph. aureus was inhibited in concentration of less than 12. 5 μg/ml and 3. 13 μg/ml, respectively. But Klebsiella pneumoniae was not sensitive to ticarcillin.
Ticarcillin was given a single intravenous dose of 50 mg per kg b. w. to two children. The maximum blood level was reached at one hour after drip infusion (for 1 hour). And these levels were 90 μg/ml and 138 μg/ml, respectively.
And the levels at 4 hours after injection were 2. 7 μg/ml and 5. 2 μg/ml, respectively. The excretion rate of ticarcillin in urine after injection was 83. 2-90. 7% up to 6 hours of period.
Ticarcillin was clinically applied to 2 cases of pneumonia and 2 cases of urinary tract infection. Good response was obtained in 3 cases.
Eosinophilia occurred in one patient.

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Ticarcillin (TIPC) was administered to 22 cases of urinary tract infection, septicemia and its suspected, and acute pneumonia which were hospitalized in the Department of Pediatrics, Kurume University School of Medicine. Clinical effects and side effects were investigated with the treatment, as well as sensitivity of isolates to the drug was compared with CBPC, SBPC and ABPC.
The antibiotic was one shot administered intravenously at a dose of 28-369 mg/kg (189 mg/kg on the average). As the result, global effects were excellent in 4 cases, good in 9 cases, none in 5 cases and unknown in 4 cases, effective ratio being 72.2%.
As to the drug sensitivity of E. coli, antibacterial activity was the strongest for CBPC, followed by TIPC at inoculum size of 10⁸/ml, while it was the strongest for TIPC at 10⁶/ml. TIPC showed the strongest activity against Kl. pneumoniae and Pr. mirabilis. Against Ps. aeruginosa, TIPC exhibited 50-≥100 μg/ml at 10⁸/ml, and some strains showed less than 1/2 MIC compared with SBPC and CBPC, as well as MIC of TIPC ranged 3. 12-100 μg/ml at 10⁶/ml, proving thus this antibiotic is the most superior among 4 drugs.
As for the side effect of one shot intravenous administration, 7 cases complained of pain at blood vessel, and 1 case transient eruption. As to the laboratory finding, LDH value worsened in 1 case of which value had been higher before the drug administration, and BUN value rose slightly in 1 case. Other abnormalities would have been rather due to the underlying disease.

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Fundamental experiments and clinical studies on ticarcillin were performed, and the following results were obtained.
1) The concentrations of ticarcillin in the skin and serum of rabbits were determined.
(i) Intravenous administration of ticarcillin 100 mg/kg in one shot :
The peak of concentration in serum was 217 μg/ml (mean value) 30 minutes after injection. On the other hand, the peak in skin was 138.1 μg/g (mean value) after 30 minutes. The ratio of concentration in the skin to the serum showed 64%.
(ii) Drip infusion of ticarcillin 100 mg/kg in 1 hour :
The peak of concentration was observed immediately after the administration, both in serum and skin. The ratio of the skin to the serum was 40%.
2) Ticarcillin, 750 mg to 6 g per day, was admininstered to the 12 cases (burned ulcer : 8, ulcer due to traffic accident : 1, post-operative ulcer : 1, decubitus : 1, post-operative pneumonia : 1). Ticarcillin was observed to be effective in 10 cases of 12.
In a few cases, elevation of S-GOT, S-GPT and Al-P were observed, but it was not sure as a result of side effect or not.
3) Minimum inhibitory concentration of ticarcillin against Ps. aeruginosa isolated from the infective ulcers was examined.
Ticarcillin was more effective than carbenicillin, 2-4 times. While in comparison to sulbenicillin, ticarcillin was same or twice in effectiveness.

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Laboratory and clinical investigations have been carried out on ticarcillin (TIPC) and following conclusions were obtained.
1) Antibacterial spectrum
Antibacterial spectrum of TIPC was almost the same as that of carbenicillin (CBPC).
2) Susceptibility to bacteria isolated from surgical field
TIPC has antibacterial activity against Staphylococccus aureus, Escherichia coli, Pseudomonas aeruginosa. Especially, TIPC was one step superior to CBPC against E. coli and Ps. aeruginosa. But, against Klebsiella pneumoniae the agent has no antibacterial activity.
3) Serum level and urinary excretion
A dose of 2.0 g of TIPC was administered by intravenous injection to determine serum level by cup method and a peak serum level of 342.4 μg/ml on an average at five minutes after administration. As to urinary concentration determined, a peak of 18. 26 mg/ml on an average was exhibited after one hour. Recovery ratio was 90.5% within six hours. TIPC was shown the highest values at 15 minutes in the serum concentration compared with SBPC and CBPC. And TIPC next to SBPC was exhibited a high ratio in the urinary recovery rate within six hours.
4) Tissue concentratiin in rats Group of SD rats received 200 mg/kg of TIPC by intramuscular injection and the levels ranged as muscle in injected site, liver, kidney, serum and spleen tissue in descending order, while muscle in the contrary site, heart, lung and brain was exhibited in a level in order.
5) Results of clinical application
TIPC was applied to two cases of intra-peritoneal abscess and the results were effective in one case and ineffective in the other. As to side effect of the drug, an increase of GOT and GPT values was noticed at third day after administraion, but GOT values returned within normal values after the end of administration.

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1) The peak of serum and biliary level of ticarcillin following 3.0 g drip infusion were 166.0 and 100.0μg /ml respectively and the urinary excretion rate was 46.7% during 6 hours.
2) Ticarcillin was applied to 9 infections and 4 cases for the purpose of protection of post operative infections in the surgical field. Some of cases were combined therapy with GM, DKB and CLDM. The effective rate was 84.6% (11/13).
3) The daily dose was 6.0 g in 12 cases and 9.0-12.0 g in one case. The maximum total dose and duration were 186.0 g and 31 days respectively. No side effects were observed except a slight liver dysfunction after administration of ticarcillin was noticed in 1 case.

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Ticarcillin (TIPC) was administered to 14 cases of skin infections including mostly secondary infection of burned ulcer, and the following results were obtained.
1. Among 12 cases of secondary infection of burned ulcer, efficacy was good in 6 cases, fair in 5 cases, and none in 1 case, efficacy rate being 50%. As a whole, efficacy was noticed in 7 cases out of 14 cases, and efficacy rate was 50%.
2. Among 7 cases of single or mixed infection due to Ps. aeruginosa, efficacy was good in 2 cases, while6 cases of infection due to Staph. aureus exhibited good efficacy in 4 cases.
3. No abnomality was observed in any case on subjective side effects and laboratory test values.
4. In conclusion, TIPC exhibits a certain effect in the treatment of secondary infection of burned ulcer, and yet a combination use would be recommended with local administration of antibiotic.

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The following conclusions were obtained on a new semisynthetic penicillin, ticarcillin (TIPC).
1) Antibacteria activity
The minimum inhibitory concentraion (MIC, μg / ml) of TIPC and carbenicillin (CBPC) was examined against Ps. aeruginosa, E. coli and Klebsiella pneumoniae isolated from surgical lesions. The results demonstrated stronger activity of TIPC against Ps. aeruginosa and E. coli than that of CBPC, same as Kleb. pneumoniae.
2) Absorption and excretion
Biliary excretions and serum levels were measured in rabbits and clinical cases. Bile levels oi TIPC in rabbits were 34.7 μg / ml after 0-1 hours, and that was higher than serum level. In two human clinical cases, bile levels were 15-30, μg / ml after 1-3 hours.
3) Results of clinical applications
TIPC was administered in 9 patients, and the clinical results obtained were excellent in 3, good in 3, fair in 1, poor in 1 and unknown in 1 case, then clinical effective rate was 75%. Bacterial eradicated rate was 85%.
4) No side effect was obtained.

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1) Antimicrobiological activity of ticarcillin was compaired with sulbenicillin and carbenicillin on clinical isolated ps. aeruginosa, E. coli and Proteus spp.
Ticarcillin was more active than carbenicillin on Ps. aeruginosa and same as sulbenicillin.
2) Ticarcillin was administrated to 12 infection cases of post operation, and the results were excellent in 4 cases, good in 5 cases, fair in 1 case and poor in 2 cases.
Clinical effective rate was 75%.
3) No side effects were found.

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1) Ticarcillin was administered to the 16 patients with urinary tract infection at a daily dose of 0.5-3.0 g for 4-12 days.
2) The clinical response was 100% effective in acute uncomplicated urinary tract infection and 70.0% in complicated U. T. I.
3) In the patients infected with E. coli, Pr. vulgaris and Pr. mirabilis, clinical response was well correlated with sensitivity test using carbenicillin disc. In 3 cases of Pseudomonas infection, good clinical response was observed, despite lack of carbenicillin sensitivity in disc test.
4) No abnormal finding of blood and blood chemistry was noticed after ticarcillin administration.
5) Side effects were seen in one case. It was a transient dizziness which did not necessitate the discontinuance of administration.

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Ticarcillin was administered to 14 chronic complicated urinary tract infections, studied in clinical trials and the followings were observed.
1. The clinical evaluation rate was 57. 1% (excellent; 1, good; 7, poor; 6 cases in 14 cases).
2. Bacterial response on isolated organisms was eliminated in 7, suppressed in 1, unchanged in 4 and replaced in 2. Bacterial effective rate was 66. 7% (excluded 2 cases of replaced).
3. No side effects and laboratory findings were noticed before and after administration of ticarcillin.

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Ticarcillin was administered clinically to 18 cases of chronic complicated urinary tract infection, and the following results were obtained.
1. Clinical efficacy was obtained in 12 cases out of 18 cases, efficacy rate being 66.7%. Classified by dose, no difference was observed on the effects, as both 2 g group and 4 g group showed an efficacy in 6 cases out of 9 cases, efficacy rate being 66. 7%. Classified by catheterization, efficacy rate was lower in catheterization group, as catheterization group showed an efficacy in 5 cases (55.6%) out of 9 cases, while non-catheterization group in 7 cases (77.8%) out of 9 cases.
2. As to the bacteriological effects classified by bacterial species, Ps. aeruginosa disappeared in 8 strains out of 11 strains, disappearance rate being 72.7%, moreover even 7 CBPC resistant strains resulted in disappearance in 6 strains. In the cases of E. coli, all 4 strains disappeared, and 3 strains of them were ABPC resistant.
3. As to the side effect of the drug, S-GOT was elevated in 2 cases, though a causal relation with the drug was unknown. No other side effect a symptom was observed, nor abnormality on laboratory tests.

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TIPC was administrated to urinary tract infections (U. T. I.) caused by Ps. aeruginosa and Proteus spp. and the followings were obtained.
(1) The contents of 10 U. T. I. were one acute U. T. 1., 2 chronic U. T. I., one acute cystitis, 3 chronic cystitis and 3 chronic prostatitis. The clinical effective rate was 50% and bacteriological effect 70%.
(2) Six of 9 cases caused by Ps. aeruginosa showed good response.
(3) In the comparison of MICs between TIPC and CBPC, TIPC was two steps superior to CBPC.
(4) An increase over normal limits in GOT values was observed, and no side effect observed in other cases.

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1. Minimal inhibitory concentrations of ticarcillin, carbenicillin (CBPC) and sulbenicillin (SBPC) were determined by the plate dilution method against 48 strains of Ps. aeruginosa isolated from infected urine.
In vitro antibacterial activities of ticarcillin varied with inoculum size. Its activities with 10⁶ cells/ml inoculum size were more potent than 10⁸ cells/ml. With 10⁶ cells/ml of inoculum size, ticarcillin was 2 to 4 times more active than CBPC or SBPC against Ps. aeruginosa, 28 out of 48 strains (58.3%) being inhibited by concentration of 50 μg/ml or less.
2. Ticarcillin was administered parenterally at a dose of 1 g twice a day for 7 days to 10 patients with chronic urinary tract infection.
Results obtained were good in 5 cases, fair in 1 case and poor in 4 cases. The medication was well tolerated with no side effects.

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1. The serum levels of ticarcillin after administration of 3 g to 5 healthy volunteers by the intravenous route were almost comparable of sulbenicillin. to those Most of the ticarcillin was excreted within 6 hours.
2. The transference of ticarcillin to prepuce after 1.0 g was given intramusculary, was 8-44 μg/ g while it was not so good into the testis.
3. Of five patients treated with ticarcillin the results were judged to be clinically “good” in three cases and “poor” in two cases. Good results were obtained in two out of three cases where Ps. aeruginosa was the causative organism.
4. In total 16 patients, to whom ticarcillin was administered, no side effects were seen.

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1. Antibacterial spectrum of ticarcillin is almost similar with that of CBPC and SBPC against gram negative rod. But, ticarcillin showed 2-4 times superior results as to Pseudomonas in antibacterial activity.
2. Absorption and excretion were compared in healthy volunteers and in renal normal patients and in renal impaired ones. The peak of serum concentration following intravenous injection was just after administration, thereafter, fell rapidly and disappeared after 4-6 hours. The urinary recovery rate was approximately 70-90% till 6 8 hours, The renal impaired patients showed slow excretion, high serum concentration, slow fall and low urinary recovery rate.
3. Ticarcillin was administered to 22 patients with urinary tract infection. Two acute uncomplicated urinary tract infections showed an excellent result within 4 days of therapy. The effective rate was 60% (9/15) in 15 chronic complicated U. T. I. excluding 5 superinfections. In 12 cases caused by Pseudomonas, the effective rate was 85. 7% (6/7) excluding 5 superinfections (excellent; 5, good; 1, poor; 1, superinfection; 5) on causative organisms. Four cases caused by Klebsiella showed poor response. The daily dose was 4. 0 g-6.0 g excluding one case with bacteremia.
4. Bacteremia caused by Pseudomonas was cured by daily dose of 12. 0 g of ticarcillin and that of 200 mg of DKB.
5. Four increased values of GOT and one of GPT were noticed in liver function in 20 cases. But, these increased values were all slight and returned to normal values within 2 weeks after discontinuance of administration. No abnormal findings were seen in renal function and blood chemistry.
6. Ticarcillin showed good response in U. T. I. caused by Pseudomonas and Proteus spp. So, ticarcillin can be expected the same or more response at a half dose compared with CBPC and SBPC in these infections.

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Twenty cases with urinary tract infections were treated with ticarcillin at daily dose between 1.0 and 4.0g.
Of 18 cases with chronic pyelonephritis, excellent response was seen in 8 cases, good response in 6 cases, and poor response in 4 cases. Excellent results were obtained in 1 case with chronic cystitis and in 1 case with acute prostatitis.
As the results of bacteriological test with urine of urinary tract infection cases, Ps. aeruginosa was found in 10 cases, E. coli in 9, Pr, vulgaris in 2, and Serratia in 2. Clinical effects were found in 8 out of 10 of Ps. aeruginosa, 7 out of 9 of E. coli, all cases of Pr. vulgaris, and 1 out of 2 of Serratia.
As side effects with ticarcillin, dizziness was noted in 1 case of gastric ulcer.

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The therapeutic efficacy of ticarcillin has been evaluated in 28 cases (33 strains) with complicated chronic urinary tract infection.
Ticarcillin was administrated by intramuscular injection for 2 to 10 days at a daily dose of 2 to 4 g.
Some effects were obtained in 21 cases, of which 11 cases showed remarkable effect.
Organisms isolated from patients were first Pseudomonas aeruginosa (15 strains), followed by 4 Citrobacter, 4 Klebsiella, 3 Proteus mirabilis, 2 E. coli and 4 other groups.
In spite of high MIC against Pseudomonas, clinical effect of ticarcillin was especially good : Some effect was observed in 14 strains among 15 strains, and remarkable effect in 6 cases of them.
As the side effect, one patient had severe pain at injected site and one had exanthema respectively after intramuscular administration of ticarcillin.

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