In vitro and in vivo studies of the antibacterial actions of CBP Cand I-CBPC, an oral preparation of CBPC, were carried out and the results were compared.
The in vitro antibacterial action of I-CBPC against gram-positive bacteria was superior to that of CBPC but almost the same against gram-negative bacteria.
There was no difference in the therapeutic effects of I-CBPC, given orally, and CBPC, administered subcutaneously, in mice experimentally infected with P. aeruginosa and IS. pyogenes.
Against Streptococcus pyogenes infections, I-CBPC and CBPC, both given orally, showed comparable ED₅₀ levels and similar therapeutic effects. The effectiveness of CBPC given orally was probably due to a small amount absorbed from the intestinal tract in mice, which resulted in a serum concentration of CBPC higher than the MIC of the drug against S. pyogenes.
With oral administration of 20 mg/mouse, the serum concentration of I-CBPC reached a peak level of 58 μg/ml at one hour, whereas the peak concentration of CBPC was only 6 μg/ml, reached at 30 minutes.
The results of these experiments indicate that the effectiveness of orally administered I-CBPC is comparable to that of CBPC.

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A bacteriological evaluation was performed on carbenicillin indanyl sodium (I-CBPC) using carbenicillin (CBPC) as a control and the following results were obtained.
1) The antibacteriological spectrum of I-CBPC was similar to that of CBPC and the antibacteriological activity was slightly more potent than CBPC against Staphylococci and gram-positive cocci while it is almost equal to CBPC against other organisms.
2) The distribution and correlation of sensitivity of clinical isolates of Staphylococci, E. coli, Proteus species and Pseudomonas to I-CBPC was similar to those of CBPC.
3) I-CBPC was inactivated by β-lactamase extracted from penicillin resistant Staphylococci and E. coli. 4) The antibacterial activity of I-CBPC against Staphylococci at a concentration equivalent to one fourth of its MIC was observed to be bactericidal.
5) The activity of I-CBPC against experimental infections in mice caused by a variety of organisms was evaluated. The ED₅₀ values were 8.75 mg/mouse in E. coli, 4. 84 mg/mouse in Proteus species and 10.9 mg/ mouse in Pseudomonas, showing an advantage over CBPC by oral route of administration.

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Toxicity study of carbenicillin indanyl sodium (I-CBPC) was performed in mice, rats, rabbits, cats and dogs.
1. The acute oral LD₅₀ in mice and rats was found to be approximately 4, 500 mg/kg in both sexes. The oral lethal dose in rabbits was about 3, 400 mg/kg. The drug was vomitted in cats at the dose level of 500 mg/kg and in dogs at 1, 500 mg/kg, subsequently the lethal dose in these species could not be estimated. Main symptoms observed in all species examined were common following oral administration; decreased spontaneous movement, depression, muscular relaxation, ataxia and diarrhea.
2. In one month oral toxicity study, rats were orally given I-CBPC at the dose level of 4, 000 2, 000 1, 000, 500, 125 or 0 (control) mg/kg. Six out of 10 males and 2 out of 10 females at 4, 000 mg/kg dose level died within one month. No rats died in other dose levels. Growth inhibition was observed in males in two top dose levels. Decreased spontaneous movement and diarrhea were noted in rats at the dose level of 500 mg/kg or more. Food consumption, urinalysis, hematology, clinical chemistry, organ weight, autopsy and histopathology in all treated animal were comparable to those of the control rats except for the cecum enlargement.
3. Rats were treated orally with I-CBPC at dose level of 3, 000, 1, 500, 800, 400, 100 or 0 (control) mg/kg for 6 months. No animal died throughout the treatment period. Growth inhibition was observed in males given 800 mg/kg or more. Parameters examined such as food consumption, urinalysis, hematology, clinical chemistry, organ weight and histopathology were almost the same as those of the controls.
4. The teratogenecity in mice and rats was studied. Pregnant mice were orally treated with I-CBPC at dose level of 3, 000, 1, 000, 400 or 0 (control) mg/kg daily from day 7 to day 12 of gestation. Pregnant rats were orally treated at 3, 600, 1, 200, 400 or 0 (control) mg/kg from day 9 to day 14 of gestation. No external, skeletal or visceral malformations seemed to be caused by the drug in fetuses and newborns of mice and rats. No adverse effects were found in postnatal growth of offsprings.
Based on these results, the safety of I-CBPC is considered to be high.

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General pharmacological effects of I-CBPC were studied and the following results were obtained.
1. I-CBPC at doses of 1, 000 mg/kg-3, 000 mg/kg (p.o.) had no effects on spontaneous motor activity, motor coordination traction performance, gastrointestinal propulsion, hexobarbital sleeping time and pain response in mice.
2. There were no effects of I-CBPC on EEG in rabbits, cornea reflex in guinea-pigs, isolated rabbit heart preparations and skeletal muscle preparations in rats. I-CBPC at high concentration showed very weak spasmolytic activity in isolated guinea-pig ileum.
3. I-CBPC, given i. v., caused a fall of blood pressure in the anesthetized dogs, but had no effect on nictitating membrane contractions in the anesthetized cats.
4. Urine excretion was reduced, and diarrhea was also noted in rats treated with I-CBPC at high oral dose.

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Carbenicillin indanyl sodium (I-CBPC) was readily absorbed after oral administration to the mouse, rat, dog and man, and its antibacterial activity in the serum reached a maximum within 2 hours. On the other hand, carbenicillin (CBPC) when administered orally to those species did not reach comparable blood concentration to I-CBPC. I-CBPC administered to the rat ligated intestine was also better absorbed than CBPC administered same way. It was noticed that I-CBPC was rapidly hydrolyzed by tissue esterases to yield CBPC and indanol, thereby antibacterial activity foundin vivowas virtually due to CBPC. Carbenicillin activity in the urine was also higher by oral administration of I-CBPC than by that of CBPC in all species examined.
Tissue concentration following oral administration of I-CBPC to the mouse and rat showed higher levels in liver and kidney than in other organs and serum.
Bioautography indicated that CBPC was the only antibacterial substance present in the urine of the rat, dog and man after administration of I-CBPC with the free of benzyl penicillin. The indanyl moiety resulting from the hydrolysis of I-CBPC, was also excreted in the human urine in good yield mostly as glucuronide and some as sulfate conjugates.

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The MIC's of carbenicillin indanyl sodium, using plate dilution method, againstStaphylococcus aureus, Escherichia coli, Klebsiella and Pseudomonas were found to be not similar to those of carbenicillin.Concentrations of drug were determined in serum and urine of two normal volunteers after administration of 500 mg orally. The peak concentration in serum was 2.0 μg/ml after 4 hours and urinary recovery rates of 24.2% and 33.4% in 6 hours respectively.Twenty two courses of therapy in 20 patients with urinary tract infections, included 20 withE. coli bacteriuria, were treated with 2.0 or 4.0 g of the drug per day for 4 to 14 days. In this group, therapy with this drug resulted in cure on bacteriuria in 15 of 22 courses. Infection was persistent in 4 courses. Relapse was occurred in 2 courses and superinfection in 2 courses. As to the side effect of the drug, gastrointestinal disturbance was occurred in one patient, eosinophilia in 2 patients and skin rash (?), in one patient.

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1. The susceptibility to I-CBPC of clinical isolatedPseudomonas andE. coli was almost equal to that to CBPC.
2. Since the result of bioassay of I-CBPC usingPseudomonas aeruginosa NCTC 10490 as test organism was significantly different from that usingBacillus subtilis PCI-219, the former strain should be employed in this case because of the spectrum of antibacterial activity of I-CBPC.
3. Following an oral administration of the drug to rat tissue concentrations in terms of peak level were found to be highest in the liver and then in the kidney and blood. The peak level was found 30 minutes to 1 hour after administration and the half-life was less than 2 hours.
4. When 500 mg of the drug were given to a patient with normal renal function, peak blood level of 3.2 pg/ml was found 1. 5 hour after the administration. Excretion rate in urine was 33.8% as CBPC till 6 hours. On the other hand, when renal function was moderately impaired, the blood concentrations were gradually increased and the tendency of the drug accumulation was observed. Furthermore, excretion rate in urine was only 0.75% as CBPC till 12 hours.
5. Clinical response to I-CBPC therapy of 10 patients with acute urinary tract infection and 7 with chronic one was excellent in 10 cases, good in 4, poor in 2 and unknown in 1.
6. Side effect was observed in 5 cases out of 17. In 1 case, the drug administration had to be discontinueddue to side effect. Gastrointestinal disturbances such as heartburn, nausea and anorexia were most common, while there was no incidence of eruption. In one case of renal failure decrease of RBC, and increase of BUN and creatinine were noted. In another case which is a diabetic patient the elevation of GOT and GPT values was observed. Excluding the above described two cases, t here was no abnormal laboratory findings in any other patients.

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Experimental and clinical studies on carbenicillin indanyl sodium (abbreviated as I-CBPC), a new ester type derivative of carbenicillin (CBPC) were performed and the following results were obtained.
1. The sensitivity test of clinical isolates against I-CBPC resulted in similar pattern to CBPC.
2. As a bioassay method for measurement of body fluid levels after I-CBPC administration, the cup plate method was employed using the strain of Pseudomonas aeruginosa and the standard curve drawn by CBPC.
3. The mean peak serum level of 6.3 μg/ml was recorded 1 hour after 1 g of I-CBPC oral administration to five healthy volunteers at fasting time.
4. At that time the urinary recovery within 6 hours after dosing showed 35.2% of CBPC activity. The mean urinary levels were maintained above 1000 μg/ml till 4 hours after dosing.
5. The biliary levels following I-CBPC oral administration to rats were much higher than those of serum.
6. The organ levels 1 hour after I-CBPC oral administration to rats ranked in order of liver, kidneys and serum, being undetectable from lungs and spleen.
In case of mice, levels ranked in order of kidneys, lungs, liver and serum. From any mice organ I-CBPC was not detected, though by much larger dose administration.
7. The increasing rate of organ level in increasing doses of I-CBPC was clearly demonstrated in kidneys, while in liver and lung the rate tended to lessen.
8. The conversion of I-CBPC to CBPC in broth was observed by TLC and bioautogram.
9. By mixing I-CBPC with rat's organ homogenates, the chronological conversion of I-CBPC to CBPC was confirmed. The reaction with liver or kidney homogenates was rapid, that with intestine followed it, and with lung the speed was the slowest among them.
In comparison with the speed of conversion of pivampicillin to ABPC in the same condition, that of I-CBPC to CBPC was considerably slower than pivampicillin. From the viewpoint of production speed of CBPC or ABPC also similar relation was observed.
10. The mixing of liver homogenates with increasing doses of I-CBPC resulted in the delay of conversion, suggesting the limit of reaction.
11. The homogenates of rat's liver pretreated with carbon tetrachloride tended to slower conversion of I-CBPC than that of normal liver.
12. Clinically to seven patients with urinary tract infection caused by P. aeruginosa in 2, E. coli in 1, Proteus in 1, Klebsiella in 1, and S. faecalis in 1 respectively, daily 2 g of I-CBPC was administered in four divided doses. Six of seven cases responded well, and in one the effect was indefinite. In one case transient dizziness was complained.

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Concentration in the blood, excretion in the urine and clinical effects of carbenicillin indanyl sodium were studied, and the following results were obtained.
1) Peak concentrations in serum of a single dose of 1, 000 mg of carbenicillin indanyl sodium given orally in 4 healthy adults right after rising were obtained 2 hours after administration with the range 4.75-9.45μg/ml. The absorption profile of this drug is similar to that of ampicillin.
2) Serum concentrations of carbenicillin indanyl sodium given after meal were approximately one half of those obtained at fasting. From this result, administration 3 hours after meal is considered to be adequate in terms of timing of administration of this drug.
3) Carbenicillin indanyl sodium was used in 23 patients with urinary tract infection. Since treatment was withdrawn in 2 patients due to side effect, therapeutic effect of the drug was assessed on 21 subjects. Eighteen patients responded markedly or moderately to the drug with the positive results of 86%. Side effects were observed in 4 cases, consisting of diarrhea in 2 cases, anorexia in one case and rash in one case. The side effects reported in the 2 patients whose treatment was discontinued were diarrhea and rash. Pre-and post-treatment laboratory tests were performed on 5 patients and no abnormality in GOT, GPT and Al-P was observed in all of the cases.

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Carbenicillin indany1 sodium is rapidly hydrolyzed to CBPC in the body. This report describes the studies of the serum concentrations and urinary excretion of the antibiotic, given to 8 male volunteers, as well as the clinical trials. The peak concentrations in serum which ranged 1.5-12.0 μg/ml were obtained 2 hours after oral administration of 1 g of this drug in fasting state, and the average concentrations at 1/2, 1, 2, 4 and 6 hours after administration were 2.1, 5.6, 7.0, 3.1 and 0 μg/ml, respectively. The average peak concentrations in serum were 3.6 μg/ml at 2 hours after administration of 1 g with meal.
The average urinary recoveries within 6 hours were 54.7% in fasting state. Twenty four cases of urinary infection and 3 cases of respiratory infection were treated with 1.0-2.0 g of this drug divided into 2-4 doses daily, for 7 to 20 days. Three cases of acute simple and 4 cases of chronic complicated urinary infections responded satisfactorily and 9 cases of the latter failed to respond, giving a rate of 47% for positive effect in chronic cases. All cases of respiratory infections responded poorly. No side effects were seen in 27 cases. No abnormal findings in laboratory tests conducted before and after drug administration were obtained in any case.

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A new penicillin derivative, carbenicillin indanyl sodium (I-CBPC) was used in the treatment of the urinary tract infection and the following results were obtained.
1) The total number of clinical cases was 40 cases, and 31 of urinary tract infection and 9 of the others. Sixteen of 31 cases due to Escherichia coli, six to Enterococcus, six to Klebsiella, two to Pseudomonas as causative organisms and good effect in 22 cases, giving rate of positive effect of 71.0%.
2) The extra urinary infections were 9 cases and 8 of the respiratory infection, one of the cholecystitis. Seven of 8 cases with respiratory infection responded well to the treatment but cholecystitis notwell.
3) As to the side effect of the drug, gastrointestinal disturbance was noticed in 3 patients and all cases admitted high dose (4.0 g/day) of I-CBPC.
4) Among various laboratory tests conducted before and after drug administration, GOT and GPT were found elevated in 2 cases, but no abnormalities were seen in other tests.

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1) Serum and urine levels of carbenicillin following the single and multiple oral administration of carbenicillin indanyl sodium are shown in Table 1, Fig. 1 and Fig. 2.
2) From these results, considering the serum and urine levels of carbenicillin achieved by a usual dosage regimen of carbenicillin indanyl sodium (2-4 g/day), clinical and bacteriological effects for the treatment of urinary tract and extraurinary tract infections caused by carbenicillin sensitive microorganisms are expected as follows :
a) In patients with normal or slightly impaired renal function, good-excellent for urinary tract infections and poor-fair for extraurinary tract infections.
b) In patients with chronic renal failure (Ccr below 10 ml/min.), poor-good for urinary tract infections, fair-good for extraurinary tract infections.
3) High dosage (more than 2-4 g/day), if possible, in patients with normal or slightly impaired renal function may provide more effects for the treatment of urinary and extraurinary tract infections caused by carbenicillin sensitive microorganisms.
4) Considering the serum levels of carbenicillin, safe dosage of carbenicillin indanyl sodium in patients with chronic renal failure is up to 4 g (containing about 3 g carbenicillin) /day. Reduction of dosage is recommended in patients with chronic renal failure and hepatic dysfunction.
5) The kidney is the route of excretion for indanol and its derivatives. Continued oral administration of carbenicillin indanyl sodium in usual dosage (2-4 g/day) to patients with chronic renal failure and in high dosage (more than 2-4 g/day) to patients with normal or slightly impaired renal function may increase the risks of toxicity. We did not experience toxicity in a patient with chronic renal failure during and after oral administration of 1.5 g/day carbenicillin indanyl sodium for 10 consecutive days.

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Carbenicillin indanyl sodium (I-CBPC) was examined on its activity against clinically isolated bacteria, serum levels after its oral administration as well as on its effectiveness in clinical cases. The results obtained were as follows :
1) MIC of clinically isolated bacteria : Staphylococcus aureus strains showed diphasic distribution of MIC similarly to carbenicillin (CBPC). No marked differences were found between the antibacterial activities of I-CBPC and CBPC against other bacteria too.
2) Peak levels of the antibiotic (estimated as CBPC) in the sera of five adult volunteers after single oral administration of 1000 mg I-CBPC were found to be 1.1-5.8 μg/ml, the average urinary excretion rate being 42%. These findings proved the good intestinal absorption of the drug.
3) Ten clinical cases (colitis 4, perityphlitis 2, urinary tract infection 3, colitis with cystitis 1) were treated with oral administration of I-CBPC 1.5-3.0 g daily, which seemed to be effective in nine of the cases. As for the untoward reaction of the patients, two complained of gastrointestinal disorders and one fell into shock 5 minutes after the administration who fortunately recovered by appropriate treatments. This shock case had experienced allergic reactions to other several drugs in his past history, although his former reactivity to penicillin derivatives was obscure.

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Carbenicillin indanyl sodium (I-CBPC) is made stable towards acid and more absorbable from the gastrointestinal tract by esterification of α-carboxylic acid of carbenicillin (CBPC). The basic and clinical studies of I-CBPC were performed and the following results were obtained.
1) The antibacterial activity of I-CBPC was compared with that of CBPC for variety of clinical isolates consisted of 45 strains of Staph. aureus, 50 of E. coli, 22 of Klebsiella, 28 of Proteus and 19 of Pseudomonas. MIC of I-CBPC against Staph. aureus varied from 0.39 μg/ml to 25 μg/ml and its antibacterial activity was 2 to 4 times more potent than that of CBPC. Out of 50 strains of E. coli the growth of 25 strains was inhibited by 6.25-25 μg/ml of I-CBPC and 25 strains of Proteus out of 28 by 0.78-6.25 μg/ml. However, 20 strains of Klebsiella out of 22 were resistant to 100 μg/ml of I-CBPC. Among 19 strains of Pseudomonas bacterial growth was inhibited by 50 μg/ml of I-CBPC in 2 strains and by 100 μg/ml in 7, while remaining 10 strains still showed the growth at 100 μg/ml level. In general, no difference was observed between antibacterial activity of I-CBPC and CBPC against gram-negative rods.
2) The peak of blood level (as CBPC) in healthy volunteers was obtained 2 hours after oral administration of 1 g of I-CBPC and the average peak value of 3 volunteers was 9.65 μg/ml. Following that serum level lowered rapidly and 0.6 μg/ml was given as average 6 hours after the administration. The average urinary level within 6 hours was 1983 μg/ml as CBPC and 36.7% of the antibiotic was recovered in the urine.
3) Two patients with urinary tract infection and a patient with respiratory infection was given orally 2-4 g/day of I-CBPC and the clinical effect was evaluated. Excellent result was obtained in a case of chronic pyelocystitis due to Pseudomonas and good result in a case of acute pyelitis caused by E. coli and a case of bronchiectasis with Hemophilus infection. Gastrointestinal side effects were observed in 2 cases, in one of which the administration had to be discontinued because of the side effects. No other side effect was oberved.

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Indanyl carbenicillin, a new broad-spectrum indanyl ester of carbenicillin for oral use, was studied both in the laboratory and in the treatment of urinary tract infections. The results are summarized as follows.
1) The average peak level of 3.6 μg/ml in serum was achieved one hour after dosing when a single dose of 500 mg of the drug was administered to three healthy volunteers. No drug activity, however, could be detected in serum 4 hours after administration. The urinary excretion of indanyl carbenicillin over 6 hours period was 40.7% of the dose on an average.
2) Of 15 cases of urinary tract infections (2 acute and 13 chronic) treated with an oral dose of 2-3g/day for 7-20 days, 3 cases responded remarkably and 2 moderately, while 8 cases showed no response, and 2 dropped out. Antimicrobial activity of indanyl carbenicillin against clinical isolate is : 2 out of 2 Pseudomonas aeruginosa and 4 out of 6 E. coli disappeared, while 4 Klebsiella and 1 Proteus persisted. Reinfection took place in 3 cases (Klebsiella, E. coli and Rettgerella).
3) There were 2 cases with slight nausea but this side effect disappeared spontaneously without interruption of treatment.

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Carbenicillin indanyl sodium (I-CBPC) was basically and clinically investigated. The results are summarized as follows :
1. Antibacterial spectrum : Antibacterial activity of I-CBPC was 2 to 4 times more susceptible than CBPC in vitro.
2. Susceptibility of clinical isolates : I-CBPC showed antibacterial activity against Staph. aureus, E. coil, Klebsiella pneumoniae, Proteus and Pseudomonas aeruginosa. However, the fact that I-CBPC is hydrolyzed CBPC in vivo, the susceptibility of pathogens to CBPC must be taken into account in clinical use.
3. Concentrations in the blood and urine : Cup plate method was employed for the bioassay of blood specimen using monitrol-serum solution of CBPC as standard. Following an oral administration of 1, 000 mg of I-CBPC at fasting, the peak of blood level was found to be 9.1 μg/ml on an average after 2 hours. When I-CBPC was given immediately after meal, the peak was attained 4 hours after the administration and the average value was 5.3 μg/ml.
The peak urinary concentration was 1608-1725 μg/ml on an average which appeared 2-4 hours after administration at fasting. When examined after meal, the highest level appeared at the same time to that in the case of the administration at fasting and was 241 278 μg/ml. The urinary recovery till 6 hours was 28.4% (37.1% as CBPC) for the former and 6.9% (9.0% as CBPC) for the latter on the average.
4. Metabolism in vivo : Human urine samples were analyzed with thin layer chromatography and for the purpose of studying the metabolism with bioautography. It was confirmed that I-CBPC was hydrolyzed to CBPC in vivo.
5. Tissue concentration : SD strain rats were given 100 mg/kg of I-CBPC orally and the tissue concentrations were measured as average values of 3. animals. The highest tissue level was found in the liver and then the kidney and serum in this declining order. However, in other tissues the drug was undetectable.
6. Clinical results : Fourteen patients with surgical infections were treated with I-CBPC of 12 cases excluding 2 dropouts. Clinical response was found to be good in 10 cases, fair in 1 and poor in 1. As for side effect, the administration of I-CBPC had to be discontinued in only 1 patient out of 14 due to gastrointestinal disturbances. Otherwise, no mentionable side effect was observed.

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The basic investigations on carbenicillin indanyl sodium were performed and the following results were obtained.
Sensitivity against I-CBPC of 20 strains each of Staphylococcus aureus, E. coli, Diplococcus pneumoniae, Proteus species and Pseudomonas aeruginosa isolated from surgical infections was determined. The antibacterial activity of I-CBPC for these strains was found to be similar to or slightly less than that of CBPC (carbenicillin).
The organ levels in rats after oral administration of I-CBPC ranked in order of the kidney, liver, serum, lung and spleen with peak concentrations obtained one hour after administration.
The blood levels after single oral administration of 1 g of I-CBPC in 3 healthy adults at fasting were investigated. Peak concentrations were obtained 2 hours after administration in 2 cases and 4 hours in one case. Average concentrations were 0.8 μg/ml after 30 minutes, 3.7 μg/ml after 1 hour, 8.0 μg/ml after 2 hours, 2.7 μg/ml after 4 hours and 1.0 μg/ml after 6 hours. Average urinary recoveries of the 3 subjects were 60.1 mg as carbenicillin in the first 2 hours, 133. 1 mg in the next 2-4 hours and 40.8 mg in 46 hours with total recovery rate of 30.6% as carbenicillin within 6 hours after administration.

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Carbenicillin, a semi-synthetic penicillin, has a wide spectrum of activity against gram-negative and gram-positive bacteria.
The current formulation of carbenicillin can not be given by the oral route because it is rapidly inactivated by gastric acid.
Recently, an indanyl ester of carbenicillin has been made available which is well absorbed when given by the oral route and essentially the same activity as carbenicillin.
This ester is metabolized into carbenicillin upon absorption into the blood stream and is excreted into the urinary tract as carbenicillin.
Antibacterial activity, concentration in blood and urinary excretion were studied with this drug, and carried out follows ;
1) The Minimal Inhibitory Concentration (MIC) values obtained with carbenicillin indanyl sodium against Pseudomonas clinical isolates distributes between 12.5 and 800, ug/ml, peaked at 100 μg/ml.
Comparing with that of carbenicillin, the MIC of carbenicillin indanyl sodium showed to be lower sensitive against Pseudomonas clinical isolates.
2) In the healthy adults, serum levels exceed 2μg/ml in 3 of 4 cases 1 hour after oral administration of 500 mg of carbenicillin indanyl sodium and in all cases 2 hours after administration. The maximal serum concentration is seen at 1 hour in 1 subject, and at 2 hours in the other 3, and obtains an average of 3.6 μg/ml, varying between 2.3 and 5.0, μg/ml.
When administrated to the 2 patients with moderately impaired renal function, the maximal serum concen-tration is seen at 2 hours in 1 subject and at 4 hours in the other one, and average is 3.5μg/ml, varyingbetween 3.2 to 5.4μg/ml
3) The urinary excretion during the 6 hours following the oral administration of 500 mg of carbenicillin indanyl sodium in the healthy adults varies from subject to subject, and lies between 38 and 199 mg, averaging 111mg.
Following the oral administration of 500 mg of carbenicillin indanyl sodium, the average urinary levels were 400μg/m1 in the 0 to 2 hour specimen, 422μg/ml between 2 and 4 hours and 158μg/ml between 4 and 6 hours.
Carbenicillin indanyl sodium was admimistrated orally in doses of 2 to 4 g daily to 8 patients with chronic urinary tract infection. The infections were caused by Pseudomonas (2) and no-identified gram-negative bacteria (5), except 1, which case was negative in urine culture.
Total dose administrated ranged between 16 and 143 g.
The initial bacteria eliminated during therapy in 4 of the 7 patients, in 4 patients of 5 symptomatic patients resolution of symptoms occurred.
There was only one of side effects during therapy in-the 8 patients in this study. In that case, gastrointestinal distress (nausea, vomiting and diarrhea) occurred and required termination of therapy. No hematologic abnor-malities were noted.
Thus, this new oral compound, carbenicillin indanyl sodium promises to be of great value in the treatmentof out-patients, or in cases where chronic infections necessiates long-term treatment, or as a continuatin of a course of treatment initiated by the parenteral route.

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Thirty outpatients with urinary tract infection were treated and the following results were obtained.
1) Rates of clinical response in terms of causative pathogen were 100% with Enterobacter, 86.6% with E. coli, 60.0% with Proteus, 40.0% with Pseudomonas or 60.0% of super infection is counted for effective, 25.0% with Klebsiella and nil with Serratia.
2) The rate of positive effect by diagnosis was 87.5% in acute infection and 42.8% in chronic infection.
3) Four patients or 13.3% of the patients treated complained of adverse effects of dizziness, eructation, bad taste and nausea.

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An orally absorved indanyl ester of carbenicillin was evaluated in 24 courses of 19 patieuts with difficult urinary-tract infections as therapeutic and suppressive agents. The patients were initially treated with aminoglucosides, colistin or some other antibiotics and then 4 g of I-CBPC per day were administrated for 7 to 55 days. This drug was very effective to the Pseudomonas infections, including 67% of therapeutic and 100% of suppressive excellent results. However, to the E. coli infections, the results were poor with 0% of suppressive effect. Moreover, 7 out of 15 superinfections were of E. coli.
Carbenicillin oral is useful for therapy of Pseudomonas urinary-tract infection but superinfection or relapse with resistant organisms, particularly E. coli may be observed.

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Serum carbenicillin concentration and urinary recovery after oral administration of indanyl-carbenicillin were determined in five healthy volunteers. 500 mg and 1, 000 mg of the drug were taken in three fasted and in two postmeal (2 hours) individuals in cross over fashion. Serum concentration in 500 mg dose study did not exceed 3μg/ml, however, in 1, 000 mg dose peak concentration between 4 and 7μg/ml was observed in four of them and 13μg/ml in one fasted. The cumulative six hour excretion of carbenicillin varied case by case irrespe-ctive of the condition at the intake, averaging 31.8% and 26.9% in 500 and 1, 000 mg doses respectively.
Clinical evaluation was done in three separate groups, i.e. acute simple infections, non-Pseudomonas chronic infections and Pseudomonas infections. In 10 acute infections cure was obtained in 5 cystitis, one gonorrhea and one pyelonephritis. In 3 failures one was due to penicillin resistant strain, and in one epididymitis pathogen was unknown. In five chronic non-Pseudomonas infections only one cure was obtained, however three of them were infected by penicillin-resistant Klebsiella strains. In 23 Pseudomonas infections 14 were upper urinary tract infections and 9 were lower tract infections. In 14 complicated pyelonephritis four satisfactory responses were seen. In other 3 cases temporal and rather poorer response was observed resulting in prompt relapses. Only two satisfactory responses were obtained in the lower urinary tract infections, however in another poorer response case no relapse was seen suggesting favorable post-operative course in these cases.
Viewing the responses in these genitourinary infections this oral carbenicillin is thought to be indicated in (1) Proteus or Pseudomonas infections with or without moderate urinary flow disturbances (2) long-term control of chronic infections following temporal eradication of pathogen by parentral medication.

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Carbenicillin indanyl sodium (I-CBPC) is an oral derivative of carbenicillin (CBPC) with broad spectrumespecially P. aeruginosa and indol-positive Proteus species. After oral administration of I-CBPC, it was absorbed from the gastrointestinal tract and then rapidly hydrolyzed to CBPC by esterase.
Thin layer chromatography (TLC) and bioautography of urine obtained after I-CBPC administrationrevealed that it was hydrolyzed almost to CBPC and partially to PCG.
Peak blood levels two hours following 500 mg and 1, 000 mg dose of I-CBPC after meal were 2.1μg/ml and 4.2μg/ml respectively by cross over method. These serum levels hardly exceed the average MIC of clinically isolated E. coll. According to biophotometric assay, on the other hand, it was observed that even 1/8 CBPC concentration of the MIC of E. coli (JC-2) (MIC : 12.5 μg/ml) have bacteriostatic or bactericidal activities. The fact suggests that even if serum levels hardly exceed the MIC, effective therapeutic response would be expected.
Peak urine level was 660 μg/ml two hours following 500 mg dose of I-CBPC after meal and 17.9% was recovered within six hours. Antimicrobial activities of urine obtained 1, 2, 4 and 6 hours after administration were evaluated by two fold dilution method and biophotometric assay. The results were as follows, those urines were able to kill E. coli (JC-2) within at least 24 hours except for the urine obtained 1 hour after administration.
On account of those results, I-CBPC is expected to have sufficient therapeutic effect by oral administration.
Two g/day (×4) of I-CBPC were administered to 20 cases with urinary tract infections for 3 or 4 days, and excellent or good responses were observed in all 4 acute cases and 9 of 16 chronic cases.
As for the side effects, subjective symptoms and blood chemistries were investigated but no serious sideeffects were noted.

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In a clinical investigation related to recurrence of chronic urinary tract infections and the effect of I-CBPC in suppressing recurrent infection of the urinary tract, the following observations were made.
1. Using the actuarial method, the accumulated recurrence rates in 54 cases of chronic complicated infections of the urinary tract that received no suppresive treatment were 28 per cent in the 1st week, 47 per cent in the 2nd week and 64 per cent in the 3rd week.
The relapse consisted of recrudescence in 34 per cent and reinfection in 66 per cent, the majority showing repeated infection.
2. In 48 cases of chronic complicated infections of the urinary tract, I-CBPC was given to observe its effect in suppressing recurrence of urinary tract infection. No recurrence was observed after 10 to 14 days in 58 per cent of the cases, prophylactic effect was observed in 88 per cent of the cases, and an effective therapeutic rate of 57 per cent was obtained. These results, however, were generally lower than the results obtained after 5 to 7 days.
3. The majority or 67 per cent of the recurrences in this series of cases were due to reinfection by bacterial strains that showed MIC's of over 50 pgjrn1 to I-CBPC. No recurrence due to infection by Pseudomonas or Proteus species was observed.
4. The inhibitory effect of I-CBPC was greater in the group that received 2 g/day than in those that were given 1 g/day. On the basis of the results of in vitro experiments and urinary concentrations of I-CBPC, it appeared that no substantial increase in the inhibitory effect of the drug against recurrence could be expected. Thus, a daily dose of 2 g/day was considered sufficient as well as necessary for the treatment to suppress recurrent infection.
5. In regard to the relationship between chemotherapeutics used for initial treatment and the effect of suppressive treatment and the relationship between recurrence and the site of infection, no definitive conclusion was drawn from the results of this study and these points await further investigation.
6. Long-term suppressive treatment with this drug in those withwhom some possibilities for improvement of condition remain might be of value but, otherwise, its use for an extended period is questionable.
7. For the suppresive treatment of urinary tract infections therefore, I-CBPC appears to be a satisfactory drug and merits use in properly selected cases.

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1. I-CBPC was administered orally at the daily dose of 2 g from 5 days to 10 days to 20 cases of acute cystitis and the results were excellent in 10, good in 9 and ineffective in 1.
2. As for side effects, drug eruption was observed in one case among 33.
3. Among various laboratory tests conducted before and after drug administration in 11 cases, no abnormalities were seen.
4. 1973.5-1974.4, in our department, most of isolated organisms were gram negative rods and E. coli were important causal organisms of acute cystitis.
5. The average serum peak level was obtained 2 hours after administration of I-CBPC 500 mg orally and it was 4.08 μg/ml. That of urine was obtained 2-4 hours after the administration and was 870 μg/ml.

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One gram of I-CBPC was orally administered to two healthy volunteers. Peak concentrations in serum were obtained two hours after administration and the average concentration was 6.1μg/ml, the concentrations after 6 hours administration were scarcely detectable. An average urinary recovery in the same subjects with 6 hours after oral administration of one gram of I-CBPC was 43.6%.
The MIC of 82 strains of Serratia isolated from the patients with urinary tract infection against I-CBPC was in the wide range from 0.39 to >100 μg/ml. Since the antibacterial activity of I-CBPC in the body is due to its conversion to carbenicillin by hydrolysis, the MICs of the same isolated against carbenicillin were also determined. As shown in Table 3, the MIC values ranged from 3.12 to > 100μg/ml. Many strains were inhibited at concentration levels between 25μg/ml and 50μg/m1 but about 70% of strains had values of > 100μg/ml.
A total of 35 patients with urinary tract infection was treated with I-CBPC. Excellent results were obtained in 21 cases, good results in 7 giving a rate of positive effect of 80. 0%. There was no abnormal sign due to the drug observed except for a transient elevation of GOT and GPT in one patient.

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1) Minimal inhibitory concentration of carbenicillin indanyl sodium (I-CBPC) was determined on 88 strains isolated from urinary tract infections by the plate dilution method. Many strains of E. coli and some strains of Proteus mirabilis were inhibited at the concentration of 3.12-12.5 μg/ml. Almost strains of Proteus vulgaris and Pseudomonas were resistant to 100 pg/ml of CBPC.
2) In a case with normal renal function, the blood level reached the maximum (5.4 μg/ml) at 90 minutes after administration of I-CBPC 1.0 g per os at fasting time.
3) The urinary recovery was 125.2 mg during 12 hours after administration of I-CBPC 1.0 g per os.
4) Twentytwo cases with urinary tract infections were treated with I-CBPC 1.0-4.0 g per day per os. Excellent or good results were obtained in 11 cases.
5) Gastro-intestinal symptoms were observed in 5 cases of this series and I-CBPC administration was discontinued in 2 cases of them.

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The authors report on the experience with a new semisynthetic broad-spectrum penicillin, indanyl carbenicillin, at the treatment of 40 cases having various urinary infections.
1. In study with some synthetic penicillin preparations, the antibacterial activity of CBPC against E. coli was found to be approximately comparable to that of CER.
2. As treatment regimen, all cases were administered 500 mg by mouth every six-hour for seven days, overall effective rate was obtained in 78% of the cases, but less effective rate was obtained in cases with chronic urinary infection caused by Ps. aeruginosa and Proteus.
3. Recurrence was seen in 2 cases, 6%.
4. Except of 5 cases showing gastrointestinal troubles, no severe side effect has been encountered.

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On 8 patients with reduced renal function, single dose study that was administered 1 g of indanylcarbenicillin orally and multiple dose study that was administered 4 g daily for 7 days orally were carried out. The patients were divided into 2 groups according to their renal function : group I having endogenous creatinine clearance of 48.3-59.6 ml/min. and group II having 17.0-28.1 ml/min., respectively.
After 1 g oral dose regimen, mean serum peak levels were 12.2 μg/ml in group I and 20.6 μg/ml in group II, respectively. After multiple dose regimen, on the other hand, the drug tended to accumulate in group II, but the level thus obtained would not have reached to more than 200-300 μg/ml that will obtained following intravenous administration.
The mean peak urine level was exceeded to 1, 000μg/ml in group I following 1 g oral dose regimen, but could not continuously maintained the level that will effectively acted on Pseudomonas, Klebsiella and Enterobacter in group II in spite of multiple dose regimen.
After 1 g oral dose, mean cumulative urine concentration for 24 hours were 314.2 mg in group I and 120.1 mg in group II, respectively. Following multiple dose study, there were 278 mg for 24 hours in group I and 127.1 mg in group II, respectively.
Total amount of urinary excretion for 24 hours and serum level obtained at 6 hours after ingestion were well correlated with creatinine clearance and also PSP test.

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Clinical studies were made on I-CBPC in 36 patients suffering from urinary tract infection. I-CBPC was administrated orally at the dosage of 2 and 4 g for 7 days. A child was given 1.5 g per day.
Results were excellent in 21 (58.3%), good in 8 (22.2%), fair in 5 (13.9%) and poor in 2 (5.6%) of the 36 cases.
The response was good to excellent in 80.5% of the cases.
Bacteriological results were disappeared in 29, decreased in 4, noeffected in 2 and disappeared but appeared of other organisms in 6 of the 41 strains.
In nine patients gastro-intestinal disturbances were seen, but the drug was continued.

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Indanyl carbenicillin was administered to a group of 20 in- and out-patients with urinary tract infections at Department of Urology, Kyushu University.
1) The therapeutic results were as follows : excellent 6 cases, good 5 cases, failure 9 cases, effective ratio 55%.
2) Of 6 cases of uncomplicated urinary tract infection, all were responded excellently. Of 14 cases of complicated urinary tract infection, 5 cases were responded good, and 9 cases poor.
3) Bacteriologically, 10 out of 22 strains disappeared and the bacteriological effectiveness was 45%.
4) No serious side effects were observed except nausia in one case.

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1) Serum concentrations after a single oral dose of 1, 000 mg of I-CBPC in 2 healthy adults at fasting reached a peak level 2 hours after administration and rapidly decreased to a detectable level 6 hours after drug administration.
2) Urinary levels in these two subjects after a single oral administration of 1, 000 mg of I-CBPC reached a maximum level from 4 to 6 hours and a total urinary recovery rate up to 24 hours was 44.0% as CBPC.
3) I-CBPC was used in 35 patients with urinary tract infection and a rate of positive effect was 100 % with acute infections and 47.8% with chronic infections. Therapeutic response was obtained in 88.2 % of simple urinary tract infection and in 41.2% of complicated urinary tract infection resulting in an overall rate of positive effect of 64.7%. Antimicrobial effect of I-CBPC was positive against 62.5 % of E. coli and Pseudomonas, 50% of Klebsiella, 100% of Proteus, 50% of Staphylococcus and 100% of N. gonorrhoeae.
4) No abnormalities were observed in the liver, kidney and blood. Side effects observed were gastrointestinal disturbance in 3 cases, dizziness in one case and itching of the external genitalia in one case.

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Carbenicillin indanyl sodium (I-CBPC) is a semisynthetic penicillin developed at Pfizer incorporated. This ester is acid-stable and is hydrolyzed in vivo to produce carbenicillin.
MICs of I-CBPC and CBPC against 49 strains of Pseudomonas aeruginosa isolated from urinary tract infections were measured. MICs of I-CBPC ranged more than 25 μg/ml in 48 of 49 strains, while CBPC ranged more than 25 μg/ml in all strains. Serum levels and urinary excretions were measured by cup method in 4 healthy adult volunteers with administration of 500 mg of I-CBPC p.o.; 2 were on fasting and the other 2 were on non fasting. Peak serum levels were obtained 30 minutes after the administration in fasting group recording 3.2 μg/ml, although peak level of 4.4 μg/ml was marked one hour later in non fasting group.
Total recovery ratio in the urine up to 6 hour reached to 14.1 % in fasting group and 11.5% in non fasting group. The highest urine level was recorded 800 μg/ml in fasting group and 440 μg/ml in non fasting group up to 2 hour after the administration. Two grams of I-CBPC were given to 18 patients of urinary tract infections for 7 days.
Excellent in 3 cases and fair in 4 cases were resulted in 8 cases of acute simple cystitis. Thirty persent of bacterial response was required in 10 cases of chronic complicated urinary infections.
General fatigue, upper abdominal pain and constipation were complained in 3 patients. No pathological finding was found in blood chemistry in all patients.

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In order to critically evaluate carbenicillin indanyl in the treatment of urinary tract infections, a double-blind comparative trial of carbenicillin indanyl (I-CBPC) and cephalexin (CEX) was performed with patients having acute simple cystitis. The results are summarized following.
(1) The background characteristics of the two group population were statistically analyzed in terms of age, duration of illness, frequency of appearance of each symptom, severity of pyuria, distribution of causative organisms and MIC distribution, and no significant difference was found, indicating that the two groups have essentially a sufficient homogeneity for the present clinical study.
(2) Patients were treated with a daily dose of either 2 g I-CBPC or 1 g CEX for 3 days and clinical efficacy was evaluated in a total of 194 cases comprizing 99 I-CBPC cases and 95 CEX. The overall therapeutic efficacy, in terms of excellent response, was found to be 55.6% with I-CBPC and 46.3% with CEX, showing no significant difference between the two drugs. On the other hand, the failure rate was 2.0% obtained with I-CBPC and 8.4% with CEX. This difference in the failure rate is statistically significant at significance level of 5%.
(3) The relapse and reinfection rate within one week after completion of the treatment is 18.8% with I-CBPC and 7.4% with CEX, respectively, showing no statistical significance.
(4) The incidence of side effects experienced during the therapy of 101 patients treated with I-CBPC and 96 CEX is 0.99% and 7.29%, respectively, and the difference was statistically significant at 5% level.
(5) The clinical performance of I-CBPC in the treatment of acute simple cystitis appears to be superior to that of CEX 1g per day when it is used in a daily dose of 2 g, and the side effects of I-CBPC were found to be less than those of CEX. These results demonstrate that I-CBPC is very effective in the field of urinary tract infection.

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The therapeutic effectiveness of carbenicillin indanyl sodium (500 mg/tab.) and cephalexin (250 mg/tab.) in the treatment of acute simple cystitis were compared by a double-blind method. Patients received either one of the drugs, one tablet after each meal and before retiring, 4 tablets a day, for 7 days and differences in the results between the two drug groups were evaluated in terms of overall effectiveness (as determined on day 4 or 5 and 8) recurrence, degree of eradicating causative organisms, subjective symptoms, urinary findings and side effect. There were no statistically significant differences observed between the two treatment groups.

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The antibacterial activity of carbenicillin indanyl sodium (I-CBPC), the indanyl ester of disodium carbenicillin, and its therapeutic effectiveness in the infections of the field of obstetrics and gynecology were investigated and the following results were obtained.
1) From the MIC of I-CBPC for clinical isolates of gram negative bacilli and Staphylococcus aureus, its antibacterial activity was found to be similar to that of CBPC.
2) Peak concentrations in serum after oral administration of a single dose of 1, 000 mg of I-CBPC were obtained 2 hours after administration. While concentrations in umbilical blood and amniotic fluid were high, those in milk was low.
3) I-CBPC was used in 23 patients with urinary tract infection including primarily cystitis and pyelonephritis. Seventeen patients of 21 patients with urinary tract infection have been cured with a rate of positive effect of 80.9%.

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From some basic studies and OUP clinical experience with carbenicillin indanyl sodium (I-CBPC) in the treatment of infections in the field of obstetrics and gynecology, the results are summarized as follows.
1. Concentrations of I-CBPC after a single oral dose of 500 mg in blood, amniotic fluid and milk were determined.
i) The concentration in the mother's blood reached a peak 2 hours after administration with a level of 6.06 μg/ml.
ii) The navel cord blood level was similar to that of other existing antibiotics and its peak level was obtained 3 hours after administration with a level of 1.06 μg/ml, one sixth of the mother's blood level.
iii) The concentration amniotic fluid of I-CBPC was rather high for an oral dosage form and was 2.6μg/ml at a peak level which was obtained 4 hours and 45 minutes after administration and wasstill 0. 5 μg/ml even after 12 hours.
iv) The concentration in mother's milk of I-CBPC was high in contrast with other antibiotics, particularly synthetic penicillins which are usually known to show low concentration in mother's milk.
The peak level obtained 2 hours after an oral administration of 500 mg of I-CBPC showed 1.31 μg/ml and that of 1000 mg was 2.63 μg/ml which was also after 2 hours.
2. I-CBPC was administered orally at a daily dose of 2 g in 15 patients and 4 g in one patient, a total of 16 patients with gynecological infections. Excellent result was obtained in 3 cases, good result in 9 and failure in 4. In the one case of intractable pyelonephritis due to Pseudomonas, which was infected following operation of uterus cancer, I-CBPC in daily dose of 4 g was unsuccessful and this particular case was cured with intravenous infusion of 8 g/day of CBPC given in two divided doses. Here seems to be somewhat limitation in the clinical applicability of the oral form of antibiotic.
3. Side effects were observed in 2 cases, anorexia in one case and gastric discomfort in the other case.

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Carbenicillin indanyl sodium (I-CBPC) was used for the treatment of 480 patients with urinary tract infection at 26 institutions. As for Pseudomonas infection, it would not pertinent to discuss so much on the effective ratio in acute infection because of limited number of cases. However, in 45.5% of complicated chronic infection the causative organism was completely eradicated regardless of the presence or absence of indwelling catheter.
Though the observed therapeutic effectiveness in 44% of cystitis and 46.9% of pyelonephritis seems to be not so remarkable, it is generally accepted that the efficacy rate of around 50% is a sufficient indication of practical usefulness of the drug in case of complicated urinary tract infection due to Pseudomonas.
Furthermore, it is noteworthy that both in bacteriological and clinical aspects I-CBPC has shown similar efficacy rate against Pseudomonas to that against E. coli regarding complicated urinary tract infection.
In general, dosage schedule will be 2 g a day for 7 days for acute and 7-14 days for complicated chronic cases. However, the increase of daily dose to 3 4 g will be recommendable when the causative organism is Pseudomonas in the latter.
Concerning side effects, gastrointestinal disturbances were observed in 11.1 % of the patients and rash in 0.4%. The elevation of either GOT or GPT value was seen in 6 cases. Much attention must be paid to the incidence of anaphylactic shock which occurred in one patient during the therapy.
The application of I-CBPC to the patients with hepatic disorder will not be recommended and caution should be exercised when the patients have renal impairment of moderate to severe degree.

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