1. Antibacterial spectrum of carfecillin is the same as that of CBPC and I-CBPC, and its antibacterial activity is almost similar to that of CBPC, while it is a little weaker than that of I-CBPC especially against Gram-positive bacteria.
2. Sensitivity distribution of carfecillin to clinically isolated Staphylococcus, Escherichia, Proteus and Pseudomonas is almost the same to that of CBPC, and no correlation was noticed between two drugs.
3. Carfecillin was inactivated by β-lactamase extracted from penicillin resistant Escherichia isolated clinically.
4. Bactericidal action of carfecillin appears more rapidly to Staphylococcus than CBPC, and the action was recognized even at 1/4 MIC. To Escherichia, however, CBPC began bactericidal action more rapidly than carfecillin.
5. As to the treatment effect by oral administration of carfecillin in experimental infection of mice, I-CBPC exhibited most superior effect both in Escherichia and Pseudomonas. Though the treatment effect of carfecillin was a little inferior to I-CBPC, it was better than that of CBPC. As to the treatment time, immediately after the infection gave the best effect as well as 2 hours after.
6. As to the blood level and organs level in mice, the value of carfecillin was a little higher than that of CBPC, though it was lower than that of I-CBPC.

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Carfecillin (P-CBPC) はCBPCのphenylesterで, CBPCと類似した抗菌スペクトラムをもつ。患者分離のStaph.aureus, Str.faecalisに対してはCBPCより強い抗菌活性を示す。しかしP-CBPCは37℃で, 中性ないしアルカリ溶液, 常用培地中では比較的速やかに加水分解をうけ, CBPCを遊離するので, P-CBPCの示す抗菌活性が, ester体固有のものかどうか不明である。各種の菌培養液中におけるP-CBPCの水解率は一定でなく, 菌種によってCBPCの生成率は異なる。また血清のP-CBPCの水解活性には, 動物種差があり, マウス, ラットは最も活性が強く, ついでヒト, ウサギ, イヌの順となる。つぎにラット組織のP-CBPC水解活性を血清と比較したが, 血清の活性が最も強く, 肝, 腎がこれにつぎ, 肺, 小腸, 大腸の順となった。また, これらの活性はP-CBPCの大量連続投与によって変化しない。
マウスの実験的感染に対するP-CBPCの経口投与による防御効果は, 菌種により一定しないが, CBPCの皮下投与と遜色のない効果が得られた。

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1. ラットに100mg/kg, 経口投与時の最高血清中濃度は, 4週令ラットで11.9μg/ml (30分), 6週令ラットでは8.8μg/ml, 8週令ラットで5.6μg/mlと幼若ラットほど高い血清中濃度が得られた。
2. ラットに100mg/kg, 経口投与時の組織内濃度では, 肝内濃度はラットの週令によって, かなりの相違が認められる。すなわち6週令ラットでは64.2μg/g, 8週令ラットの53.4μg/gに対し, 4週令ラットでは40.3μg/gであった。しかし, 腎内濃度は6週令ラット (46.4μg/g) と8週令ラット (43.9μg/g) との間では近似値を示したが, 4週令ラットでは72.0μg/gと幼若ラットにおいて明らかに高い値を示した。また, 肺内濃度は一般に低濃度ではあるが, 幼若ラットほど高い傾向を示した.
3. ラットでの尿中排泄は, 8週令ラット17.5%, 6週令ラット22.3%, 4週令ラット38.2%と, 血清中濃度と同様に幼若ラットほど排泄率は高かった。
4. ラットでの胆汁中排泄は, 8週令ラットで6.7%, 6週令ラットで11.3%, 4週令ラットで14.0%と, 幼若ラットほど排泄率は高かった。
5. ラットの消化管を胃, 小腸上部, 中部および下部と等分に結紮して, 各部位にP-CBPCを20 mg/kg注入し, CBPCの血清中濃度と各部位からのP-CBPCの減少率を求めた。血清中のCBPC濃度は小腸上部に注入した時が, 他の部位に注入したのに比べ最も高かった。いっぽう, CBPCを同一濃度注入しても, 血清中濃度はきわめて低い値を示した。結紮部位からのP-CBPCの減少率も, 小腸上部が最も高率 (35.2%) で, 他の3部位は11.7-13.1%であった。他方, CBPCの注入部位での減少率は10.7-17.2%の範囲で, 特異的吸収を裏づける部位は認められなかった。
6. P-CBPCの消化管内分布をみると, 経口投与3時間後では大部分のP-CBPCはCBPCに変化し, 小腸上部または下部に存在するが, 少量の未変化のP-CBPCは胃および小腸に残存している。6時間後では大部分がCBPCとして小腸下部, 大腸, 盲腸, 便に集中する。さらに24時間後では胃, 小腸上部, 下部にはCBPCおよびP-CBPCの残存はほとんどなく, CBPCとしてすべて大腸, 盲腸, 便に移行している。
7. イヌに100mg/kg経口投与すると, 末梢血中にはCBPCとして10.6-10.3μg/ml (1-2時間) が得られた。また, 門脈血中にはCBPCとして11.5-11.2, ug/ml (2-3時間) が検出されたが, 未変化のP-CBPC濃度は3.3ug/ml (3時間) であった。さらに大腿静脈血中のCBPC濃度, 9.1-9.7, ug/ml (2-3時間) に対し, 未変化のP-CBPC濃度は0.3ug/ml (30分) ときわめて低濃度が検出された。
8. 同時に尿中排泄を求めると, CBPCの24時間総回収率は7.2%と低率であった。
9. ヒトにP-CBPCを1g経口投与した場合の血中CBPC濃度は14.5μg/ml (60分) がピーク値である。また, この時の血清中にはP-CBPCの存在は認められなかった。10. 同時にヒトの尿中回収率をみると, 6時間までに34.2%のCBPCが回収された。さらにこの尿中にはP-CBPCはまったく検出されなかった。

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1) P-CBPCはウサギに50mg/kg, 30日間, 隔日に経口投与しても, 抗体の産生が認められない。
2) P-CBPCは非経口的に投与すると血球凝集抗体, 沈降抗体およびPCA抗体の産生が認められた。
3) P-CBPCとCBPCとの間には, 強い交差性が認められた。
4) P-CBPC, CBPCはPCGと, いくらか弱い交差性が認められた。

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The pharmacological actions of carfecillin (P-CBPC) which is phenyl ester of carbenicillin and those of phenol which is one of the hydrolyzed metabolites of P-CBPC were investigated.
Outline of pharmacological actions and minimal effective doses (MED) of P-CBPC was as follows : fall on blood pressure of the rabbit (5mg/kg), bradycardia on ECG of the nonanesthetic rabbit (20mg/kg), inhibition on excised guinea pig atrium and toad heart (10^-3g/ml), dilation on excised rabbit ear vessels (10^-2g/ml) and contraction (5 x 10-2g/ml), stimulation on permeability of rabbit abdominal skin vessels (1, 000 ug), stimulation on excised rabbit intestine (10^-4g/ml) and inhibition (10^-3g/ml) and inhibition on excised rat uterus (5x10^-4 g/ml for nonpregnant uterus and 2 x 10^-5g/ml for pregnant uterus). No effect on respiration of the rabbit, excised guinea pig intestine and tracheal muscle was observed at doses up to 80 mg/kg, 10^-3g/ml and 2 x 10^-3g/ml, respectively.
Outline of pharmacological actions and MED of phenol was as follows : fall on blood pressure of the rabbit (O. 5 mg/kg), inhibition on respiration of the rabbit (5 mg/kg), bradycardia on ECG of the nonanesthetic rabbit (5 mg/kg), arrhythmia on ECG of the pentobarbital anesthetized rabbit (5 mg/kg), stimulation followed by inhibition on excised the guinea pig atrium (10^-4g/ml), contraction on excised rabbit ear vessels (10^-2 g/ ml), stimulation on excised rabbit intestine (10^-5g/ml), inhibition on excised guinea pig tracheal muscle (2 x 10^-4g/ml) and inhibition on excised rat nonpregnant and pregnant uterus (2×10^-5g/ml). No effect on excised guinea pig intestine was observed at doses up to 10-3g/ml.
The pharmacological actions of phenol were partly identical to those of P-CBPC, and MED of phenol was much less than that of P-CBPC. All MED of P-CBPC except that on excised rat pregnant uterus were much higher than minimum inhibitory concentrations and Maximum blood levels in clinical uses.
The increase in body weight, urinary volume, urinary excretion of electrolytes and urinary findings in the rat applied P-CBPC (from 25 to 100 mg/kg) or phenol (20 mg/kg) orally once a day for 7 days were similar to normal values and those of control group, except decrease in urinary excretion of Na in the rat applied 100 mg/kg of P-CBPC.
Therefore, it is concluded that P-CBPC is one of the antibiotics with much less pharmacological actions, when it is applied orally.

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The MIC's of carfecillin, using plate dilution method, against Staphylococcus aureus, E. coli, Ps. aeruginosa and Klebsiella were found to be almost similar to those of carbenicillin.
Concentrations of carbenicillin were determined in serum and urine of 4 patients with normal renal function after administration of single 500 mg oral dose of carfecillin. The average peak level in serum was 3. 45μg/ ml after one hour and the average recovery rate was 27.3% in 6 hours.
Cross-over studies in 6 healthy volunteers revealed that the administration of single 1 g oral dose of carfecillin after food intake brought higher serum concentration and urinary recovery of carbenicillin than those in the fasting state.
Twenty-five courses of therapy in 23 patients with urinary tract infections were treated with 2.0, 3.0 or 4.0 g of carfecillin per day for 3 to 14 days. In this group, therapy with the drug resulted in cure on bacteriuria in 16 of the 18 courses with E. coli and in 2 of the 4 courses with Enterobacter. Infection was persistent in 2 courses. Superinfection was occurred in 2 courses and relapse in one course. The rate of clinical good responses was 80% in this group.
As to the side effect of carfecillin, nausea, anorexia, vomiting and diarrhea were occurred in 6 patients.

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On a new esterified carbenicillin (CBPC), carfecillin, some studies were carried out and the following results were obtained.
1. The serum levels after oral dosing of carfecillin to volunteers by cross over method comparing with that of indanyl-CBPC were the approximately same values each other.
2. The organ levels 1 hour after oral administration of carfecillin to mice ranked in order of the liver, kidneys, serum and lungs.
3. Carfecillin was converted to CBPC completely on the bioautogram, being incubated in broth at 37°C overnight. Carfecillin was rapidly hydrolyzed in the mixture with organ homogenates. The speed of hydrolysis of carfecillin was the same as or slightly faster than that of indanyl-CBPC, depending upon each organ tested. There found also the difference among animal species in the speed of carfecillin hydrolysis by organ homogenates.
4. Clinically 8 patients with urinary tract infection were treated with carfecillin. The response of five cases was good, one was fair and two was poor. In two cases abdominal discomfort and diarrhea were complained respectively.

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A series of investigation has been carried out on carfecillin, the a-phenyl ester of carbenicillin. The results obtained were as follows.
1. Absorption and excretion Carfecillin was administered orally as single 500 mg- and 1 g- dose to 5 fasting healthy adults under the cross-over method. The peak serum levels of carbenicillin were approximately twice as high in the volunteers given 1 g (10.54 μg/ml) as those of a 500 mg dose (5.80, μg/ml). In both groups, about 40 % of carbenicillin was recovered in the urine during the first 6 hours.
2. Organ levels in animals Organ levels after oral administration of carfecillin at dose of 50, 100 or 200 mg/kg to rats were the highest in liver, lowering in order in kidney, serum and lung.
3. Clinical results Carfecillin was administered orally at a daily dose of 2 to 3 g to 13 patients with urinary tract infection. The results obtained were excellent in 2 cases, good in 10 and poor in 1. Any remarkable side effect was not observed except loss of appetite in 1 case.

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Carfecillin is carbenicillin phenyl ester which is rapidly hydrolyzed to carbenicillin in the body. This report describes the studies of the absorption and urinary excretion as well as the clinical trial with this drug.
The average serum concentrations in six healthy volunteers were 6. 0, 5. 2, 3. 4, 0.7 and 0 μg/ml at 1/2, 1, 2, 4 and 6 hours after oral administration of 1, 000 mg of carfecillin. The average urinary recovery within 6 hours was 50.8%. In the comparative studies of the absorption and urinary recovery after oral administration of carfecillin at fasting and non-fasting, no difinite difference was seen between these two conditions.
Ten cases with urinary-tract infections and 2 cases with respiratory infections were treated with 1. 5-4. 0 g of carfecillin, divided into 3-4 times daily, for 8-30 days. In ten cases of urinary-tract infections, the half of them was acute simple cases, and other half was chronic complicated cases. The causative organisms of them were E. coli except one case with Enterobacter cloacae. Clinical and bacteriological effects were good in all acute cases and one chronic case, the rest 4 cases of chronic ones showed no responses.
In two cases of respiratory infections with Pseudomonas aeruguinosa, clinical and roentgenologic improvement were seen in one case, but no response was seen in another case. As side effects, gastro-intestinal symptoms were seen in one case, although the administration was able to continue for 30 days. Abnormal laboratory findings were not seen in all cases before and after the administration of this drug.

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Carfecillin was administrated orally to 16 patients including 13 cases of acute pyelonephritis and 3 cases of chronic pyelonephritis. The results obtained were as follows;
Among 13 cases of acute pyelonephritis, carfecillin was effective in 9 cases and ineffective in 4 cases.
Among 3 cases of chronic pyelonephritis, the drug was effective in 1 case and ineffective in 2 cases. It was noted that the causative organism of this effective case was Pseudomonas and Enterobacter.
As side effects with carfecillin, 1 patient complained of a pain in epigastric region after the administration, though the drug interruption was not necessary.
In laboratory findings, 1 case was noticed the decrease of white blood cells count in blood examination, and another case was noticed the slight increase of S-GPT value which was suspected due to liver function damage by acute pancreatitis. Nevertheless, no serious side effect was encountered with the treatment.

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P-CBPC and I-CBPC, CBPCs for oral use, were administered orally by cross over method to 6 volunteersof healthy adults, and their absorption and excretion were compared to obtain following results.
1. After 1g and 0.5 g of P-CBPC were cross overed in 2 cases, average maximum blood level was 10.25 μg/ml and 7.2μg/ml, and average half-life of blood level was 1.40 hours and 1.56 hours. Cumulative urinaryrecovery ratio was 42.4% and 53.5%.
2. After each 1g of P-CBPC and I-CBPC was cross overed in 4 cases, average maximum blood level was 10.15μg/ml with P-CBPC and 8.25μg/ml with I-CBPC, and average half-life of blood level was 1.32 hours and 1.58 hours respectively. Cumulative urinary recovery ratio was 34.7% and 41.5%.
3. One g of P-CBPC was administered orally to a case of renal insufficiency with creatinine clearance of 2.4 ml/min., and maximum blood level was 22.0 μg/ml and half-life of blood level was 29.26 hours. Cumulative urinary recovery ratio was 2.8% within 6 hours, and 7.4% within 24 hours.

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Serum concentration of carbenicillin was determined after carfecillin was administered orally once at a dose of 1g in 4 patients of severe renal dysfunction (on or off hemodyalysis) and 2 patients of pyelonephritis.
As to the former patients, peak concentration in serum was 8.3μg/ml on an average in patients on hemodyalysis and 12.4 μg/ml on an average in patients off hemodyalysis respectively 4 hours after administration, and level decreased gradually to 1.8 and 2.7 μg/ml respectively after 24 hours. Urinary recovery rate in those patients was only less than 0.8 % at maximum within 24 hours.
As to the latter patients, serum concentration reached a peak of 7.9 and 4.4μg/ml respectively at 1 hour in patients of subchronic and chronic pyelonephritis in whom GFR was 154 and 97 ml/min. Urinary concentration showed 290 and 260μg/ml, and recovery rate was 7 and 9 % respectively within 6 hours.
In clinical trial of 11 cases with urinary tract infection, carfecillin treatment with a daily dose of 2-4 g resulted in remarkable effect in 2 cases, good in 7 cases and poor in 2 cases.
As for side effect, renal function, liver function and blood chemistry were examined, setting apart 2 patients with renal insufficiency in whom tests on renal function were omitted, as their values would have been fluctuated by hemodyalysis. Eosinophil count was elevated slightly in 4 cases, and yet no skin rash nor liver dysfunction were noticed there. Other side effects, such as gastro-intestinal disorder and skin rash, were not observed throughout the clinical studies.

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Carfecillin (phenyl-carbenicillin) was examined on its serum levels and urinary excretion, as well as its effectiveness in clinical cases. The results obtained were as follows :
1) Peak serum levels of the antibiotic (estimated as CBPC) as high as 6.1-12.5 μg/ml were obtained in five adult volunteers after single oral dosage of 500 mg carfecillin in 12 hours fasting; while, when the drug was given them 30 minutes after meal, the peak levels were much lower (0. 9-1. 8 μg/ml). The average urinary excretion rate was 50. 6 % in fasting, and 28. 7% after meal. These findings proved that the drug can be easily absorbed from human intestine, especially in fasting.
2) Seven clinical cases (three with respiratory tract infections, four with urinary tract infections) were treated with oral administration of carfecillin 3 g daily, which seemed to be effective in four of them. Although one of the cases complained of diarrhoea, others showed no side effects.

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Investigation has been made on carfecillin, phenyl ester of carbenicillin (abbr. CBPC), and following results were obtained.
1) Antimicrobial activity of carfecillin against clinically isolated Staph. aureus, E. coli, Klebsiella, Proteus and Pseudomonas was compared with that of CBPC. As a result, antimicrobial activity of carfecillin against Staph. aureus was 2-4 times stronger than that of CBPC, while no large difference was observed between antimicrobial activity of carfecillin against Gram-negative bacteria and that of CBPC.
2) Carfecillin was administered orally to healthy adults at a dose of 1 g before or after meal. Peak of CBPC level in serum was noticed in both groups 1 hour after the administration, average value being 16.6μg/ml in 2 cases of before-meal group, and 11.2 μg/ml in 3 cases of after-meal group. Values from 2 hoursafter the administration showed no difference between those of before-meal group and those of after-meal group, being around 7.5 μg/ml in 2 hours, around 1.0 μg/ml in 4 hours, and undetected in 6 hours. Average urinary recovery ratio within 6 hours was around 53% in both groups, and more than one half was excreted in urine within 2 hours after the administration. Inside of 2 hours after the administration, both urinary level and urinary recovery were higher in before-meal group than in after-meal group.
3) Carfecillin was administered orally at a daily dose of 2-4 g for 8-24 days to 4 cases of urinary tract infection and 2 cases of respiratory tract infection. Clinical effect obtained was excellent in 1 case, good in 3 cases and failure in 2 cases, while bacteriological effect was noticed only in 1 case. No side effect was observed, except a temporary elevation of BUN in 1 case.

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Carfecillin was administered to 14 cases of urinary tract infection, and its clinical and bacteriological effects were investigated.
1. Among 14 cases treated by the drug, the results obtained were excellent in 8 cases, good in 2 cases, failure in 3 cases, and interruption in 1 case. Effectiveness was noticed thus in 10 cases out of 13 cases (76.9%), setting apart 1 case of interruption.
2. Being classified by disease, effectiveness was observed in 4 out of 5 cases of acute cystitis, in 3 out of 3 cases of chronic cystitis, and in 3 out of 5 cases of chronic pyelotis.
3. Being classified by isolate, effectiveness was recognized in 7 out of 9 strains (77.8%) of E. coli, in 1 out of 3 strains (33.3%) of Klebsiella, in 1 out of 2 strains (50%) of Staphylococcus epidermidis and in 1 out of 1 strain (100%) of Pseudomonas.
4. As to side effect, nausea was noticed in 2 cases out of 14 cases treated, and yet no abnormal variation was exhibited in hypersensitive reaction, blood biochemistry and renal function.

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1) Carfecillin sodium, a new carbenicillin derivative for oral administration was studied on its blood level and excretory rate into urine by using 20 volunteers after 1, 000 mg oral administration. Blood level showed the peak at 1 hour (13.98 μg/ml), and half life was relatively short (1 hr. 18 min.). Excretory rate into urine was 30.7% during 4 hours.
2) Carfecillin was administered orally to 58 patients with urinary tract infections (acute cystitis : 15 cases, chronic cystitis : 21 cases, acute pyelonephritis : 11 cases, chronic pyelonephritis : 7 cases and prostatitis : 4 cases) at mean daily dose of 2.4 g. Carfecillin was remarkably or moderately effective in 39 cases out of 57 (67.2%).
3) Side effects were noticed in 11 cases out of 58. Most of them were mild gastro-intestinal disturbances, which were relieved by symptomatic treatment, without discontinuance of the drug.
On hepatic function tests and blood examinations, transaminase slightly elevated in only 1 patient with cholelithiasis, and no abnormality was detected in the other patients.

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A series of investigations were carried out with BRL 3475 (carfecillin), carbenicillin for oral administra tion, in the field of pediatrics, and the following rmsults were obtained.
1) The peak blood concentration of carbenicillin appeared from 1-3 hours after oral administration ofcarfecillin, and notably decreased 6 hours after administration.
2) Active carbenicillin was excreted in urine at the ratio of 12-16% within 6 hours after administration of carfecillin.
3) For infections of the upper and lower respiratory tracts, dosages of 30-50 mg/kg/day for 4-7 days were clinically effective in most cases.
4) For acute cystitis due to E.coli or Staphylococcecs, carfecillin was effective in dosages of 50 mg/kg/day.
5) The clinical effective ratio obtained in 30 cases with 7 kinds of pediatric diseases was approximately 93.3%.
6) Nausea and vomiting occurred in 3 of 32 cases, but no hepatic and renal dysfunction due to continued administration was found.

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Laboratory and clinical investigations have been carried out on carbenicillin phenyl sodium (P-CBPC), and following conclusions were obtained.
1) Antibacterial spectrum
Antibacterial activity of P-CBPC was almost the same as that of CBPC.
2) Susceptibility of bacteria isolated from surgical fields
Although the agent has antibacterial activity against Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Proteus group and Pseudomonas aeruginosa, it is necessary to understand, besides influence on intestinal florae, susceptibility distribution of CBPC, as P-CBPC is hydrolysed to CBPC in vivo.
3) Serum level and urinary concentration
Group administered 500 mg : A dose of 500 mg of P-CBPC was administered at fasting to determine serum level by cup method using Moni-trol serum as standard curve, and a peak serum level of 6. 1 μg/ml was obtained on an average 1 hour after administration.As to urinary concentration determined similarly, a peak of 1, 033μg/ml was exhibited after 1 hour. Recovery ratio in urine was 24. 1% within 6 hours.
Group administered 1, 000 mg : Peak of serum level obtained was 8.6μg/ml on an average 1 hour after administration. Peak of urinary concentration was 1, 187-4, 200μg/ml 1-2 hours after administration. Urinary recovery ratio was 42.0% within 6 hours.
Group administered 2, 000 mg : Average peak of serum level was 18. 1 μg/ml 1 hour after administration.
Urinary concentration attained a peak of 3, 920-3, 940μg/ml 1-2 hours after administration. Urinary recovery ratio was 25.3% within 6 hours.
4) Tissue concentration
Groups of 3 SD rats received 50 mg/kg or 75 mg/kg of P-CBPC, and the levels ranged as kidney, liver and serum in descending order, while a group administered 100 mg/kg exhibited a high level in order of liver, kidney and serum. No transfer to other organs was noticed in all groups.
5) Metabolism in vivo
Metabolism of P-CBPC in vivo was investigated on human urine. It was proven that P-CBPC was hydrolysed to CBPC in vivo, by preparing bioautogram using thin layer chromatography.
6) Result of clinical application
P-CBPC was applied to 20 cases of surgical infections, and the results obtained were effective in 15 cases and ineffective in 5 cases. As side effect of the drug, 1 case out of 20 cases complained of epigastric pain though the treatment was continued without interrupting the administration. No other side effect was noticed to be noteworthy.

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The fundamental investigation on carfecillin was performed, and the following results were obtained.
The organ levels in rats after oral administration of carfecillin ranked in order of the liver, kidney, serum, lung and spleen with peak concentrations obtained one hour after administration.
The serum levels after a single oral administration of 500 mg of carfecillin in 5 healthy adults at fasting were investigated. Peak concentrations were obtained 40 minutes after administration in 3 cases, 60 minutes in one case and 90 minutes in one case. Average concentrations were 0.9μg/ml after 20 minutes, 2.9 μg/ml after 40 minutes, 2.7 μg/ml after 60 minutes, 2.1 μg/ml after 90 minutes and 1.2 μg/ml after 120 minutes.
Average urinary recoveries of the 5 subjects were 79.96 mg as carbenicillin in the first 2 hours, 30.3 mg in the next 2-4 hours and 9.74 mg in 4-6 hours with total recovery rate of 30.2% as carbenicillin within 6 hours after administration.

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Minimal inhibitory concentration of carfecillin was determined on 35 strains of Pseudomonas aeruginosa isolated from urinary tract infections by the plate dilution method. Twenty-six of 35 strains (74.3%) were inhibited at the concentration of 100μg/ml or less.
Twenty-one cases with urinary tract infections were treated with a new antibiotic, carfecillin (carbenicillin phenyl sodium) at a daily dose between 1.0 and 2.0g. Of 10 cases with acute urinary infection (cystitis : 8 cases, urethritis : 2 cases), excellent response was seen in 9 cases and poor response in 1 case. Of the chronic urinary tract infections (cystitis : 2 cases, pyelonephritis : 3 cases, prostatitis : 1 case and urethritis : 5 cases), good response was seen in 3 cases, fair in 4 cases and poor response in 4 cases.
Side effects observed included nausea and loss of appetite in one of the 21 cases and loss of appetite in another one case.
Total dose of carfecillin amounted to 308 g in one case, and yet any side effect was not encountered throughout the experience one case.

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Laboratory and clinical investigations on carfecillin, a new semisynthetic penicillin, were studied. The results were as follows;
1) The MIC was measured on CBPC and ABPC, and no difference was observed between both.
2) Carfecillin was administered orally to determine the serum concentration, and urinary excretion of CBPC. The peak serum level was 16.9μg/ml at the 1st hour and excretion rate was 40.4% within 6 hours on the average.
3) Carfecillin was applied to the urinary tract infection, as a result, excellent effect was obtained especially for acute cystitis.
4) No proportional relationship was noticed between dosage and effect in view of the treatment effects classified by disease and bacteria, and yet a satisfactory effect was obtained with a dosage of 1, 000 mg.
5) No severe side-effect occurred in this treatment, confirming the safety of this drug. Blood was taken before and after treatment from some patients to examine the blood, hepatic and renal disorders. The result proved that this drug has no influence which may be due to the drug.

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1) The sensitivity distribution of E. coli isolated clinically was 6.25-100 μg/ml for carfecillin.
2) Thirteen cases of acute simple, 2 cases of complicated and 5 cases of chronic complicated urinary tract infections were treated with carfecillin.
3) Acute urinary tract infections were treated with daily administration of 1-3 g of carfecillin f or 3-7 days. Chronic urinary tract infections were treated with daily administration of 1-3 g of carfecillin for 7-14 days.
4) Of 15 cases with acute urinary tract infections, excellent response was seen in 10 cases, and of 5 cases with chronic urinary tract infections, satisfactory bacteriological response was seen in 4 cases.
5) No side effects were observed except one case in which diarrhea was noticed.
6) No abnormal findings were revealed in peripheral blood, kidney (BUN) and liver function test.

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Some laboratory and clinical investigations have been performed on carfecillin, synthetic penicillin preparation for oral use, and following results were obtained.
1. One g of carfecillin was administered to 6 cases of renal infection before nephrectomy, and levels in renal tissue were determined to obtain the values of 4.8-57.9μg/g. These values were about 2 fold in comparison with those of blood levels measured simultaneously.
2. Carfecillin was administered at a daily dose of 1-2 g to 26 cases of urinary tract infection to investigate its treatment effect. In 16 cases of acute infection, the result was excellent in 8 cases, effective in 6 cases and ineffective in 2 cases, effective ratio being 87.5%. In 10 cases of chronic infection, the result was effective in 3 cases and ineffective in 7 cases, effective ratio being 30%.
3. After 11 cases of chronic urinary tract infection turned bacteria to negative by injection of CBPC or GM, carfecillin was tried as a maintaining treatment, and the effect was obtained in 9 cases out of 11 cases (81.8%). Classifying by bacteria, no relapse was noticed with Pseudomonas and Proteus, while relapse was observed in 1 case out of 2 cases with E. coli, and in 1 case out of 1 case with Enterobacter.
4. Side effect of carfecillin was investigated on 39 cases. No gastrointestinal disturbance nor allergic symptom was observed at all, and further no abnormal value was noticed on clinical tests which could be performed on 14 cases.

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An orally administrated phenyl ester of carbenicillin “carfecillin” was evaluated in 16 courses of 15 patients with difficult urinary tract infections as therapeutic and suppressive agents. The patients were initially treated with gentamicin or carbenicillin parenterally and then 4 g of carfecillin per day were administrated for 2 weeks. This drug was very effective to the Pseudomonas infections, including 100% of therapeutic and 100% of suppressive excellent results. However, to the E. coli, Proteus rettgeri and Citrobacter infections, the results were poor. The superinfections were noted in 6 out of 16 courses, including E. coli, Klebsiella and Citrobacter.
Carfecillin is useful for therapy and suppression of Pseudomonas and Proteus infections, but a possibility of superinfection or relapse with resistant organism should be kept in mind.

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Thirty-six cases with urinary tract infections were treated with carfecillin (BRL 3475) at daily dose between 2.0 and 3. 0 g.
Of 15 cases with acute urinary tract infections (cystitis 13 cases, pyelonephritis 1 case and epididymitis with cystitis 1 case), excellent response was seen in 8 cases, good response in 5 cases, fair response in 1 case and poor response in 1 case.
Of 21 cases with chronic urinary tract infections (pyelonephritis 11 cases and cystitis 10 cases), excellent response was seen in 4 cases, good response in 6 cases, fair response in 5 cases and poor response in 6 cases.
As a result of bacteriological test with urine of chronic urinary tract infection cases, E. coli was found in 5, Pseudomonas in 2, Prot. mirabilis in 2, Morganella in 2 and other strains in 9. Clinical effects were found in all cases of E. coli, 1 out of 2 in Pseudomonas, 0 out of 2 in Prot. mirabilis, and all cases of Morganella.
As side effect with carfecillin, nausea was noticed in 2 cases and stomatitis in 1 case.

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Carfecillin (phenyl-carbenicillin) has been evaluated in the treatment of urinary tract infections. Blood and urinary level studies employing healthy volunteers showed that absorption and excretion of phenyl carbenicillin were comparable to those of ampicillin. Maximal blood level was obtained one hour after oral intake in each of 500 mg and 1, 000 mg doses. Urinary recovery was more than 30% in 6 hours following intake. Clinical studies were done in 36 urinary tract infections. Of them 12 were simple acute infections and 24 were chronic complicated ones. In acute cases satisfactory responses were noticed excluding a non-gonococcal urethritis (Mycoplasma was the suspected pathogen) and a prostatitis case. However, in complicated infections excellent results were noticed only in 3 cases of post-TUR infections and a prostatitis case with BPH. Super-infection and cross-infection were noticed during the medication course in 5 cases. Phenyl carbenicillin was ineffective in established chronic infections with severe complications in which Pseudomonas strains were predominant.
Conclusively, phenyl carbenicillin can be indicated in 1) chronic urinary infections accompanied with mild predisposing factors such as post-TUR prostatocystitis, pyelonephritis with vesicoureteral reflux or low grade chronic hydronephrosis etc. 2) long-term management of urinary infections following parenteral short-term treatment.

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The recurrence suppression effect of carfecillin was examined in twenty patients suffering from complicated chronic urinary tract infection.
Carfecillin was administered at daily dose of 3 or 4 g for two weeks after the effective treatment of carbenicillin. Urinary organisms isolated from the patients were 7 Proteus mirabilis, 3 Proteus vulgaris, 3 Pseudomonas, 3 E. coli, 1 Citrobacter, 1 Staph. epidermidis and 2 Strept. faecalis.
Good effect was observed in 12 patients, moderate effect in 5 patients and poor effect in 3 patients.
MIC of CBPC for the organisms in the effective cases were mostly below 1. 58 μg/ml.
MIC of organisms increased during carfecillin treatment in 2 cases of E. coli and 1 case of Proteus vulgaris, decreased in 1 case of Proteus vulgaris and unchanged in 1 case of E. coli.
No serious side effect of carfecillin was observed in this series.

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Carfecillin (Carbenicillin phenyl ester) is an oral derivative of carbenicillin (CBPC) with broad spectrum especially against Ps. aeruginosa and Proteus species.
After an oral administration of carfecillin, it was absorbed from the gastrointestinal tract and at the same time hydrolyzed to CBPC by esterase.
1. Susceptibilities to carbenicillin against 191 strains causing acute simple cystitis were almost the same as those to ampicillin.
2. Urinary excretion of carfecillin was compared in two healthy adults with that of ampicillin by a cross over method. Both higher concentrations of carfecillin and ampicillin were obtained more rapidly in urine.
After an oral administration of 500 mg after meal, total urinary excretion of carbenicillin was 30 % of the dose in 6 hours, greater than 18 % of ampicillin.
3. Antibacterial activities of urine obtained after an oral administration of 500 mg of carfecillin were compared with those of ampicillin. All excretion products were able to eliminate E. coli (IX-3) within at least 24 hours. Antibacterial activities of carfecillin were stronger than those of ampicillin.
4. Carfecillin was administered to 28 patients with urinary tract infections. Acute infections : Excellent results were observed in 8 cases and poor in 2 cases. Effective rate was 80 %.
Chronic infections : Excellent results were observed in 3 cases, good in one, poor in 10, and 6 cases were dropped out. Effective rate was 33 %.
5. Four cases of the 8 strains of E. coli in poor cases were recured during 7 days by administration of carfecillin.
6. As to side effects, one case with slight stomach pain was noticed. GOT, GPT, Al-Pase were investigated with regared to the hepatic functions. In all cases, no abnormal values were observed.

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1. Antibacterial activity
MICs of carfecillin to 32 strains of Serratia m. isolated from urinary tract infection, were distributed between 12.5-≥100μg/ml, MICs of CBPC 3.13-≥100μg/ml, peak being 25-50μg/ml and ≥100μg/ml, and strains of ≥100μg/ml were observed in more than 70% with both drugs.
2. Clinical result
Carfecillin was applied to 39 cases of urinary tract infection, and the results obtained were excellent in 18 cases, effective in 5 cases, and ineffective in 16 cases, effective ratio being 59.0%. Stating the items, 23 cases of simple urinary tract infection resulted in effective ratio of 82.6%, and 16 cases of complicated urinary tract infection effective ratio of 25%.
3. Side effect
GOT and GPT rose temporarily in 1 case out of 39 cases. A case was obliged to interrupt drug admini-stration due to nausea and vomiting. No special abnormality was observed besides.

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1) In one case with normal renal function, the serum level of CBPC reached to the maximum (5.9μg/ ml) at one hour after oral administration of carfecillin 1.0 g at fasting time. In the same case, the urinary recovery of CBPC was 272.7 mg during 6 hours after administration of carfecillin 1.0g and its urinary recovery rate was 34.3% as CBPC.
2) Twenty cases with chronic urinary tract infections were treated with carfecillin 2.0-4.0g per day, and excellent or good results were obtained in 15 of 20 cases.
3) Side effects were observed in 3 of 20 cases (2 slight gastro-intestinal disorder, 1 elevation of S-GOT and S-GPT).

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Single and multiple dose studies of carfecillin orally administered were carried out on 5 volunteers with normal renal function and 6 older patients with various renal insufficiency, and the following results were obtained.
1. For volunteers with normal renal function, mean concentration of CBPC in serum after 1 g single dose of carfecillin was 9. 4 μg/ml at 90 min. after dosing and decreased rapidly to 1. 6 μg/ml at 4 hrs. after, respectively and that after multiple dose of carfecillin were 12. 1 μg/ml at 60 min. on 3 rd day and 7. 4 μg/ml on 7 th day, and the level at 6 hrs. after the final dosing was 1. 6 μg/ml. The average urinary concentration obtained within 2 hrs. in cases receiving single dose was found to be 783 μg/ml and that in cases receiving multiple dose were 1, 584 μg/ml on 3 rd day and 931 μg/ml on 7 th day, respectively exceeding the level obtained in single dose study. Mean recovery within 6 hrs. for single dose study was 23. 1 per cent of administered drug and that for multiple dose study exceeded to that of single dose study.
As the serum and urinary levels reached to their peak in different time from case to case, mean of each peak level was determined. The mean of peak serum level after single dose was 12. 3 μg/ml and that after multiple dose was 12.7 μg/ml on 3 rd day and 9. 3 μg/ml on 7 th day.
The mean of peak urinary level after single dose was 932 μg/ml and that after multiple dose was 1, 634 μg/ ml on 3 rd day and 1, 064 μg/ml on 7 th day.
2. For single dose study in older patients with renal insufficiency, mean level in serum obtained at 60 min. after dosing was 6. 3 μg/ml and decreased slowly compared to healthy volunteers, i. e. 4. 6 μg/ml at 6 hrs. The urinary concentration of 382 μg/ml was obtained within 2 to 4 hrs. after dosing and mean recovery was 15.6 per cent of administered drug within 6 hrs. and 27.1 per cent within 24 hrs., respectively. For multiple dose study, mean serum concentration of 8.4 μg/ml was obtained at 4 hrs. after the final dosing, and decreased gradually to 4. 0 μg/ml at 6 hrs. after, respectively. The mean recovery from urine of patients with renal insufficiency had delayed with lower urinary concentration of 349 μg/ml within 2 to 4 hrs. after the final dosing.
The mean of peak serum level after single dose was 8.8 μg/ml and that after multiple dose was 9.9 μg/ml.
The mean of peak urinary level after single dose was 493 μg/ml and that after multiple dose was 360 μg/ ml.
The patients with renal insufficiency had delayed excretion of CBPC with lower urinary concentration than that with healthy men, but patients with moderate renal insufficiency who have the level of endogenous creatinine clearance more than 30 ml/min. would excrete sufficient CBPC, following single oral administration of carfecillin to treat satisfactory lower urinary tract infections due to most strains of urinary pathogens and even with multiple dose study it would be well tolerated and not encountered the abnormal signs caused by oral administration of carfecillin.

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Carfecillin, penicillin preparation for oral use of phenyl ester of carbenicillin, has been applied in clinical practice, and following results were obtained.
As a dosage, the drug was administered at a dose of 2.0 g divided into 4 for 7 days in a group of urinary tract infection, while the same dose for 14 days in a group of prostatitis.
As to a treatment effect of urinary tract infection, an effective ratio of 75.0% was obtained in 12 cases of simple acute urinary tract infection, 50. 0% in 6 cases of chronic and recurrent urinary tract infection, and 75. 0% in 4 cases of complicated urinary tract infection.
As to a treatment effect of prostatitis, the result was excellent in 1 case and effective in 2 cases out of each 6 cases, effective ratio being 50%.
As a side effect of the drug, no influence was observed on peripheral blood picture and blood biochemical value, setting apart eruption in 1 case and gastrointestinal disturbance in 2 cases.

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CBPC was administered by intravenous drip at a daily dose of 4-8g for 5 days to the patients of complicated urinary tract infection under catheterization, and bacteria count in urine became less than 103/ml in 12 cases, to whom carfecillin was administered succesively at a daily dose of 2-4g divided into 4 for 7 days, and following results were obtained.
1) Clinical treatment effect was excellent in 8 cases, effective in 4 cases, and ineffective in none.
2) On first week after carfecillin administration end, recurrence of leucocyte count in urine and that of bacteria count in urine were observed in each case.
3) As side effect of carfecillin, no influence was noticed on peripheral blood picture and blood biochemical value, setting apart a case complained of diarrhea.

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1) Carfecillin was administered to 20 cases which were diagnosed as urinary tract infection among in- and out-patients of Department of Urology, Kyushu University.
2) Results obtained were excellent in 8 cases, good in 5 cases and failure in 7 cases, effective ratio being 65%.
3) All of 8 cases of simple urinary tract infection were excellent. Twelve cases of complicated urinary tract infection resulted in good in 5 cases and failure in 7 cases, effective ratio being 42%.
4) Bacteria disappeared in 11 strains out of 20 strains, bacteriologically effective ratio being 55%.
5) No side-effect was observed, except 1 case complained of nausea.

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Combined therapy of aminoglycoside antibiotics and nalidixic acid or colistin is well known as a treatment of the infections due to Pseudomonas and Proteus which have been increased recently. Aminoglycoside antibiotics are used now widely in clinical practice as both in vitro effect and clinical effect are favorable there.
Aminoglycoside antibiotics are hesitated to be used with ease, however, because their route is limited only to intramuscular injection and their side effect is hazardous to be exhibited in kidney or the eighth nerve.
Development of an oral agent against Pseudomonas and Proteus group has been awaited thus. The present authors have applied carfecillin, penicillin family preparation for oral use, developed by Beecham, England. Considerations were made on urinary tract infection, especially complicated one, and following results were obtained.
1) Effective ratio obtained was 41% (7 out of 17 cases) for urinary tract infection.
Especially simple infection showed an effective ratio of 67% (2 out of 3 cases), while complicated one that of 36% (5 out of 14 cases).
2) Effects by causative organism were 57% to E. coli, 17% to Pseudomonas, 33% to Cloaca and 100% to Proteus.
3) Carfecillin was administered orally after CBPC was administered intravenously, and both suppression effect and relapse prevention effect were observed in urinary tract infection. It may be recommended as a method to suppress the infection that carfecillin is administered orally successively in the cases which proved an effectiveness by massive administration of CBPC.
4) No noteworthy side effect was observed both subjective and objective one throughout 21 cases treated except 1 case of rash.

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Fourteen cases with complicated urinary tract infections were treated by oral administration of carfecillin at a daily dose of 3.0 g for 4 to 14 days.
Excellent results were obtained in 5 cases, good in 5, poor in 4. No appreciable side effects were observed throughout this series.
Laboratory examinations were took before and after carfecillin treatment in all patients showing no abnormal findings.
Considering the data described above, carfecillin is thought to be promising for treating urinary tract infections.

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Carfecillin, carbenicillin phenyl ester, has been compared with ampicillin (ABPC) on the clinical effect and side effect by means of a double blind test on the cases of acute simple cystitis.
Carfecillin (one tablet containing 250 mg) and ABPC (one tablet containing 250 mg) were administered at a dose of 2 tablets 4 times a day for 3 days respectively. The transition of subjective and objective symptoms were studied on 3 rd or 4 th day after the initiation of administration, and the recurrence was examined on the 7 th day after the discontinuance of administration.
The criteria of judgement of clinical effect are shown in Fig. 1. One hundred and eighty-one cases (carfecillin 88 cases, ABPC 93 cases) were discussed about clinical effects. The constitutions of cases and the clinical results of two drugs were compared statistically by means of X2 test, MANN-WHITNEY U test, FISHER's exact probability test and Sign test.
No significant difference was observed between two drug groups on the constitution of cases, i. e., age, body weight, days after onset of symptoms, grade of pyuria, frequency of appearance of each symptoms, infecting organisms and their MIC of carbenicillin or ABPC.
As for the clinical results, the excellent effective cases were 40. 9% with carfecillin and 46. 2% with ABPC, and the good effective cases were 52. 3% with carfecillin and 50.6% with ABPC. The statistical examination was tried between two drugs, and no significant difference was observed.
Concerning the effect on symptom, pyuria and bacteriuria, the statistical examinations were also tried between two drugs, and no significant differences were observed in the effect on symptom and bacteriuria. But concerning the effect on pyuria, “persisted” rate was 12.5% with carfecillin and 3.2% with ABPC, and the difference between two drugs was statistically significant at the level of 5%. The patients discussed about recurrence were 114 cases (carfecillin 52 cases, ABPC 62 cases). Ratio of recurrence was 13.5% in carfecillin group and 19.4% in ABPC. No significant difference was observed between two drug groups.
The side effects were followed in 213 cases (carfecillin 106 cases, ABPC 107 cases) and the appearance ratio was 2.8% (3 cases) in carfecillin group and 5.6% (6 cases) in ABPC group, showing no significant difference between two drugs. The kind of the side effects was gastro-intestinal disorder in carfecillin group, but was mainly eruption in ABPC group.
In short, a quite similar result was obtained both with carfecillin and ABPC on the clinical effect, recurrence and side effect in the treatment of acute simple cystitis.

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1) The usefulness of carfecillin, a new carbenicillin-derived antibiotic intended for oral use, was compared with that of CEX in 134 women with acute simple cystitis by a double blind method.
Of the 134 patients, those subjected to the final evaluation were 116 consisting of 56 receiving carfecillin and 60 receiving CEX.
2) The 4 th or 5th day's judgment showed that carfecillin does not differ significantly from CEX except for the global judgment, eradication of all the causative organisms including E. coli, clarification of urinary turbidity, and restoration of urinary WBC.
The 8 th day's judgment showed that there was no significant difference between the two antibiotics, with respect to relapse of infection, side effects, and any other items.
3) Four patients showed no improvement with carfecillin in the 4 th or 5 th day's global judgment. The causative organism was identified as E. coli (3 patients; MIC of CBPC 400, μg/ml or larger) and Ps. aeruginosa (1 patient; MIC of CBPC : 12. 5 μ/ml).
4) The effect of carfecillin in patients infected with CBPC-sensitive organisms (MIC 50μg/ml or less) was compared with that of CEX in patients infected with CEX-sensitive organisms (MIC : 50 μg/ml or less). The results showed that carfecillin did not differ significantly from CEX in therapeutic effectiveness in any of the items studied.

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Clinical pharmacology and evaluation were made on carfecillin, a new semisynthetic penicillin, in the fieldof obstetrics and gynecology.
Carfecillin was well absorbed and produced peak serum concentration over 10 μg/ml after oral administration of 1, 000 mg.
The rate of urinary excretion was 30-40%, and urinary concentration obtained was sufficient to treat urinary tract infection.
Clinical response was 84.8% in acute cystitis at daily dose of 2.0 g.
Side effects were recognized in 4 cases.
Carfecillin was judged clinically significant in urinary tract infection from antibacterial spectrum, activity, and distribution.

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With the purpose of clarifying clinical significance of carfecillin, phenyl ester of carbenicillin (CBPC), its antibacterial action, transfer in body, and clinical result were investigated, and following findings were obtained.
1. Distribution of carfecillin susceptibility was examined on 139 strains of various bacteria clinically isolated recently, and its distribution was closely similar to that of CBPC, though MIC of the former was a little higher than that of CBPC to Streptococcus pyogenes, Indole (-) Proteus sp., and Morganella, while it tended to be contrary to Pseudomonas aeruginosa.
2. After 1g of carfecillin was administered orally to healthy humans, its blood level attained a peak of 8. 7 pg/ml after 1 hour, remaining some level until 4-6 hours. Recovery ratio in urine was then 34. 4%.
3. Carfecillin transferred into human umbilical cord blood, 3-hour value being 1/4 of that in mother's blood. As to the transfer into fetus in pregnant rat, its value in blood, liver and kidney was 1/5, 1/3 and1/4 of that of mother's body respectively.
4. Carfecillin was administered orally 2-4 g daily for 2-10 days to 10 cases of acute and chronic urinary Tract infections, and the results obtained were effective in 6 cases, ineffective in 3 cases and unknown in 1 case. Some patients complained of slight gastrointestinal disturbance during carfecillin administration.

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