Sensitivity of various clinical isolates to pipemidic acid, a new synthetic antibacterial agent developed at Research Laboratories, Dainippon Pharmaceutical Co., Ltd., was examined in vitro with the following results.
1. Pipemidic acid showed potent antibacterial activity primarily against gram-negative bacteria.
2. The MIC values of pipemidic acid for Pseudomonas aeruginosa ranged around 12.5 μg/ml, and those for nalidixic acid-resistant bacteria around 25 μg/ml.
3. Most of the strains of Escherichia coli and Klebsiella sp. were inhibited by 3.13 μg of pipemidic acid per ml or lower, but a few Klebsiella strains required 25 μg of the drug per ml to be inhibited.

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In vitro and in vivo antibacterial activity of pipemidic acid (PPA) was examined with the following results.
1. PPA showed potent antibacterial activity mainly against gram-negative bacilli and it was more potent against most enteric bacteria and Pseudomonas aeruginosa than piromidic acid and nalidixic acid. There were some organisms insusceptible to PPA among gram-negative bacilli which did not ferment glucose.
2. PPA showed good therapeutic effect by the oral route in mouse experimental infections due to Pseudomonas aeruginosa isolated from clinical materials.
Its ED₅₀ values were higher than those of anti-Pseudomonas aminoglycosides and lower than of anti-Pseudomonas penicillins.

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Pipemidic acid is a new synthetic antibacterial agent structurally related to nalidixic acid. Pipemidic acid was inherently similar to nalidixic acid in antibacterial spectrum, though the former was generally more potent than the latter in in vitro antibacterial activity.
Nalidixic acid-resistant bacteria and Pseudomonas aeruginosa were also inhibited by pipemidic acid. Pipemidic acid was stable when dissolved in water and kept at 37°C for 1 month. Its antibacterial activity tended to become higher when medium pH was alkaline, but serum addition and high inocula caused a descent in the activity of pipemidic acid as well as nalidixic acid. Pipemidic acid was generally bactericidal above its minimal inhibitory concentrations. Frequencies of mutants resistant to pipemidic acid were lower than those of mutants resistant to nalidixic acid, streptomycin and rifampicin.
Scanning and transmission electron microscopy revealed that pipemidic acid caused damage to the cell surface of Pseudomonas aeruginosa.
In the experimental infections with various bacteria in mice, pipemidic acid was always more effective than nalidixic acid. The infection due to Pseudomonas aeruginosa or nalidixic acid-resistant organism was also succesfully treated with pipemidic acid by the oral route.

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Pipemidic acid, 8-ethyl-5, 8-dihydro-5-oxo-2- (1-piperazinyl) -pyrido [2, 3-d] pyrimidine-6-carboxylic acid, is a new derivative of piromidic acid. It was active against gram-negative bacteria including Pseudomonas aeruginosa as well as some gram-positive bacteria. Its potency against gram-negative bacteria was generally greater than that of piromidic acid, nalidixic acid and cephalexin. Crossresistance was not observed between pipemidic acid and various antibiotics, and most of bacteria resistant to piromidic acid and nalidixic acid were moderately susceptible to pipemidic acid.
The activity of pipemidic acid was scarcely affected by the addition of serum, sodium cholate or change of medium pH, but was subject to the influence of inoculum size. Its action was bactericidal above minimal inhibitory concentrations. Additive effect was observed when pipemidic acid was used in combination with carbenicillin or gentamicin. Pipemidic acid was effective by the oral route on various experimental infections in mice. Its in vivo efficacy against gram-negative bacteria was generally better than that of piromidic acid, nalidixic acid, cephalexin, ampicillin and carbenicillin. The infection with bacteria resistant to piromidic acid and nalidixic acid was successfully treated with pipemidic acid.
In Pseudomonas aeruginosa infections, orally administered pipemidic acid was more effective than subcutaneously injected carbenicillin.

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The MICs of pipemidic acid (PPA) were 100 μg/ml or more against most anaerobic bacteria, but were 50 μg/ml against C. perfringens. Strains of P. acnes stocked in our laboratory showed 100 μg/ml or more, but those isolated from clinical materials showed 25 pg/ml to 50 μg/ml in 8 of 11strains.
Antimicrobial activity of PPA against anaerobic bacteria was a little better than that of PA in gram-positive cocci, but was similar to that of PA in gram-negative rods and positive rods. It seemed that PPA was generally better than NA in antimicrobial activity against anaerobic bacteria.

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Pharmacological properties of pipemidic acid (PPA), a new antibacterial agent, were investigated with the following results.
(1) By oral administration, PPA did not show significant pharmacological effects except for a few experimental items such as antagonism to methamphetamine-induced hyperactivity in mice and hypotension in spontaneously hypertensive rats.
(2) By intravenously administration, PPA caused hypotension and an increase in heart rate in anesthetized cats, but only minor changes were observed in blood pressure and heart rate of dogs and rabbits.
(3), EEG pattern in cats was slightly affected by intravenous administration of PPA, but no appreciable changes were observed in respiration, ECG pattern, tone of nictitating membrane and contraction of skeletal muscle.
(4) In the experiments with isolated organs, PPA did not show appreciable effects except for a slight increase in tone of guinea-pig ileum and was deferens.
From these results, it could be considered that pharmacological properties of PPA closely resembles those of piromidic acid (PA).

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¹⁴C-Pipemidic acid was administered to male dd mice weighing about 20 g at a single oral dose of 0.5 mg (5.5 μCi) per body, and its distribution was examined by periodic macro-autoradiography followed by a so-called tissue scanning method, in which optical densities of macro-autoradiograms were scanned with a computerized auto-scanning microscope photometer. The results obtained were as follows.
1. ¹⁴C-Pipemidic acid administered orally showed good distribution to various tissues except for the central nervous system such as cerebrum, cerebellum and spinal cord, and its concentrations were extremely high in kidneys (medulla>cortex) and liver followed by parotid, myocardium, skin, skeletal muscle, etc. The concentrations in lung and spleen were as high as those in blood.
2. The concentrations of ¹⁴C-pipemidic acid in the foetuse were as high as those in placenta, i. e. maternal blood.
3. ¹⁴C-Pipemidic acid was rapidly distributed in high concentrations to an acute inflammatory area with cell infiltration in the experimental pyelonephritic mouse kidney, and remained there evidently 4 hours later. However, its distribution to a necrotic area of the kidney was found to be low.
4. In macro-autoradiograms prepared later than 4 hours after administration of ¹⁴C-pipemidic acid, darkend areas were found restrictedly in the peritoneal cavity, especially in liver and the inside of intestinal tracts, suggesting the presence of the enteric-hepatic circulation of the drug. Remains of ¹⁴C-pipemidic acid in mucous membranes corresponding to glandular stomach were also observed 24 hours after administration.
5. ¹⁴C-Pipemidic acid showed an affinity for bones and cartilages, and remained there at high concentrations even 6 hours later. However, it disappeared almost completely from those osteochondral tissues in macro-autoradiograms prepared 24 hours after single oral administration.

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Disposition and biotransformation of pipemidic acid (PPA) were studied in rats and mice orally given a single or multiple doses of 50 mg ¹⁴C-PPA/kg/day with the following results.
1) After a single dosing to rats and mice, ¹⁴C-PPA was absorbed rapidly to give maximum blood levels (5.0 μg Eq/ml in rats and 7. 7 ug Eq/ml in mice) within 1 hour post administration, followed by gradual decreases.
2) In both species, the levels in most of organs and tissues examined changed in parallel with the blood levels. The highest tissue levels were found in liver, gastrointestinal tracts, kidneys and urinary bladder, whereas lower levels as compared with blood levels were found in brain, eye balls, fat and testes. Other tissue levels were found to be higher than blood levels.
3) Twenty-four hours post dosing, tissue levels in both species were so decreased that the recoveries of radioactivity from liver, an organ showing the highest level, were about 0. 1 % of the dose administered.
4) Twenty-four hours, after a single dose, about 40% of the administered dose was recovered from rat urine, about 50% from rat feces, about 10% from rat bile, about 25% from mouse urine and about 60% from mouse feces.
5) When administered to rats once a day for 7 days, the blood level at 1 hour after dosing was gradually elevated to attain a twice higher level on the 7th dosing as that on the 1st dosing.
6) Tissue distribution of ¹⁴C-PPA in rats after 8 consecutive doses was found to be similar to that after a single dose, suggesting no appreciable tissue accumulation of the drug. Daily excretions into urine and feces were also found to be virtually unchanged.
7) Whole-body autoradiographic studies of rats given a single or multiple doses showed tissue distributions being in good agreement with those obtained by radiometric assay.
8) Whole-body autoradiograms of pregnant mice given a single dose showed that fetal tissue levels were similar to maternal blood levels, and elimination rates of the label from fetal tissues were also similar to those of maternal tissues.
9) Both in rats and mice, 90% of either 24-hour urinary or fecal radioactivity was associated with unchanged PPA and the remainder with its glucuronide and an unidentified metabolite.
10) TLC of 6-hour rat bile showed three major peaks together with a minor peak. Major peaks were found to be unchanged PPA, its glucuronide and an unidentified metabolite, respectively.

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The subcommittee on pipemidic acid determination examined various factors which might affect bioassay data of pipemidic acid, and following conclusions were obtained.
1. Pipemidic acid tablets were found to be good in their content, stability, disintegration and dissolution.
2. Pipemidic acid in plasma and urine was stable at both 4°C and-20°C.
3. The thin-layer cup-plate method using Escherichia coli Kp as an indicator organism was a simple and accurate method of pipemidic acid determination with high sensitivity provided that important factors were controlled properly.
4. The data determined by the thin-layer cup-plate method recommended by the subcommittee were consistent with those determined by the fluorometry.

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1) Pipemidic acid showed good antibacterial activity against gram-negative bacilli such as E. coli, Klebsiella, Serratia, Pseudomonas and Acinetobacter, which was superior to that of piromidic acid and nalidixic acid.
2) Pipemidic acid administered orally was well absorbed from digestive organs and excreted mainly into urine. The average peak serum level of pipemidic acid was 7.2 pencil at a single oral dose of 2 g, being higher than 6.7 μg/ml, the average peak serum level of nalidixic acid at the same dose. The average urinary recovery of pipemidic acid for 6 hours was about 40 % which was much higher than 9.4 %, the average urinary recovery of nalidixic acid.

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Pipemidic acid (PPA) was well absorbed by the oral route. When administered to mice, rats, dogs, monkeys and men at a single oral dose of about 50 mg/kg, average plasma levels reached peaks ranging between 4.7 and 11.9 μg/ml. About 20% of PPA was bound to proteins in dog plasma and about 30% in human serum. PPA was widely distributed to various organs and tissues at concentrations comparable to or higher than the plasma level. Peak urine levels of PPA were around 1, 000 μg/ml in animals and men, and 24 to 88% of administered doses was recovered from urine for 24 hours. An average recovery from feces was about 25% in men receiving a single oral dose of 1 g. A main active principle in plasma and urine was unchanged PPA itself.

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The renal excretion mechanism of pipemidic acid (PPA) was examined in anesthetized dogs. The renal clearance method and the stop-flow method were applied to study for estimation of renal excretion rate, tubular excretion site and proximal excretory mechanism of PPA.
The following results were obtained.
1) About 45 to 68% of urinary excretion of PPA was excreted by glomerular filtration and the rest by tubular excretion.
2) PPA was excreted at proximal tubule by probenecid-sensitive excretory mechanism, and was scarcely reabsorbed at distal tubule.

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The acute toxicity of pipemidic acid (PPA) was examined in mice, rats, dogs, monkeys and neonatal rats with following results.
animal route sex LD₅₀ (mg/kg)
mouse i. v. male 610
female 649
s. c. male 1, 274
female 1, 516
p. o. male >5, 000
female >5, 000
animal route sex LD₅₀ (mg/kg)
rat i. v. male 575
female 584
s. c. male 1, 635
female 1, 799
p. o. male >5, 000
female >5, 000
animal route sex LD₅₀ (mg/kg)
dog p. o. male >2, 000
female >2, 000
monkey p. o. male >2, 000
female >2, 000
neonatal p. o. male 1, 597
rat female 2, 156
Intravenous administration of PPA near the mean lethal doses caused tonic convulsion, mydriasis, ataxia, muscle relaxation, a decrease in spontaneous locomotion and interrupted respiration.
Subcutaneous administration of PPA near the mean lethal doses also induced sedation, ataxia, ptosis, a decrease in spontaneous locomotion, a drop in body temperature, paralysis of respiration, etc. On the other hand, oral administration of PPA did not cause any toxic signs even at high doses in all the animals examined except for a slight decrease in the body weight gain of neonatal rats.
It seems that there is no significant difference between animal species or sexes in the acute toxicity of PPA.

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Subacute and chronic toxicity studies on pipemidic acid (PPA) were performed in male and female rats.
In rats given PPA at daily oral doses of 100, 300, 1, 000, 3, 000 and 5, 000 (male only) mg/kg/day for 30 days, no abnormalities were observed except for a slight decrease in weights of heart, liver and thymus, and the dilatation of cecum at high doses. The decrease in organ weight was not accompanied by histopathological abnormalities, and the dilatation of cecum was similar to that commonly observed after long-term administration of antibiotics.
In rats given PPA at daily oral doses of 50, 200, 800 and 3, 200 mg/kg/day for 6 months, no abnormalities were observed except for a slight variation in body weight gain and the dilatation of cecum. These results indicate that the oral toxicity of PPA is low in rats.

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In the subacute toxicity test, mild ataxia, a decrease in body weight and a drop in the plasma albumin level were observed in the group of 800 mg/kg/day early in dosing term, but no abnormalities in the group of 400 mg/kg/day. The toxic signs observed in the group of 800 mg/kg/day disappeared in 3 weeks in spite of continuous drug administration. A slight dilatation of uriniferous tubules was detected by the histopathological examination in 2 of 4 dogs of the group of 800 mg/ kg/day, though abnormalities were not observed in urinalysis and blood analysis.
In the chronic toxicity test, no abnormalities were detected in various checked items except for a mild and focal dilatation of uriniferous tubules observed in 1 or 2 dogs of the all dosages groups, and a slight elevation in the plasma glutamic pyruvic transaminase level observed in 1 dog of the 400 mg/kg/day group.
From these results, it may be suggested that the oral toxicity of PPA is mild in beagles at relatively high doses.

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Pipemidic acid (PPA) was orally administered to male and female monkeys twice a day at doses of 100, 400 and 1, 600 mg/kg/day for 1 month.
Abnormalities possibly due to PPA were not observed with regard to body weight gain, appearance, hematological analyses and biochemical analyses of plasma and urine, except for a slight increase in liver weight and a slight descent in the plasma total cholesterol level in the group of 1, 600 mg/kg/ day. The increase in liver weight was not dose-related nor was it accompanied by abnormalities in plasma glutamic oxaloacetic transaminase and glutamic pyruvic transaminase levels, and histopathologic changes of liver.
PPA seems to have little toxic effect upon monkeys by the oral route.

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The MICs of pipemidic acid against 12 strains of Escherichia coli and 8 strains of Pseudomonas aeruginosa isolated from patients were lower than those of nalidixic acid and piromidic acid as determined by the plate dilution method.
Concentrations of the drug were determined in serum and urine of 3 normal volunteers after oral administration of 1g. The mean peak concentration in serum was 5. 8μg/ml after 2 hours and the mean urinary recovery rate was 52. 6% in 6 hours.
Twenty five courses of the therapy in 22 patients with infectious diseases (8 of acute cystitis, 6 of acute pyelonephritis, 4 of acute cholecystitis, etc.) were treated with 1.0 to 2.0g of the drug per day for 5 to 14 days.
These diseases were found to be caused by E. coli in 14 cases, by Klebsiella in 5, by Citrobacter in 3 and so on. Therapy with the drug resulted in cure in 15 of 25 courses, whereas infection was persistent in 6 courses.
Superinfection occurred in 2 courses and relapse in 2 courses.
As to the side effect of the drug, epigastric discomfort and fullness feeling were observed in 1 patient.

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The laboratory and clinical studies on pipemidic acid (PPA), a new derivative of piromidic acid, were performed with following results.
1) The antibacterial activity of PPA against clinically isolated pathogenic bacteria, E. coli 8 strains, Klebsiella pneumoniae 5 strains and Pseudomonas aeruginosa 14 strains, was better than that of nalidixic acid, piromidic acid and carbenicillin.
2) The tissue levels of PPA following oral administration of 100 mg/kg to rats were in order of kidney, liver, lung and serum.
3) H. W. (male, 48 yr., 57 kg, chronic cystitis, carcinoma of rectum and chronic hepatitis) was administered 2.0 g of PPA daily (0.5g, 0.5 g, 1.0 g). The serum levels were 1.7 μg/ml 1 hour after oral administration of 0.5 g, 2.8 μ/ml 3.5 hours after oral administration of 1.0 g. Urinary concentrations of PPA were ranged from 113 to 270 μ/ml.

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Pipemidic acid was orally given at daily doses of 1.0-2.0 g for 7-69 days to 16 patients with various infectious diseases (bronchitis 4, cystitis 1, pyelonephritis 8, cholecystitis 1, susp. bacillary dysentery 1, infected decubitus 1).
1. The clinical results were excellent in 4, good in 6, fair in 4 and poor in 2 patients.
2. Pipemidic acid was effective in all cases infected with nalidixic acid sensitive organisms but ineffective in 2 cases infected with organisms less sensitive to nalidixic acid.
3. Side effects were observed in only one patient (anorexia and nausea).
4. Serum concentrations of pipemidic acid were examined in 3 patients at 1, 2, 4 and 6 hours following oral administration of 250 mg before meal. Mean levels were 2. 3, 1.8, 1.4 and below 1.0 μg/ml, respectively.

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Laboratory and clinical studies on a new synthetic chemotherapeutic agent, pipemidic acid, were performed with the results which summarized as follows :
1) In a study by the agar plate dilution method on a total of 89 strains of 9 species, E. coli (23 of 24 strains), Klebsiella (11 of 11 strains), E. aerogenes (7 of 7 strains), E. cloacae (2 of 2 strains), Proteus group (6 of 6 strains) were found to be sensitive to the agent with the MICs of 25 pg/ml or less. Staphylococcus aureus strains were less sensitive with the MICs more than 50 μg/ml. MICs to Pseudomonas aeruginosa were distributed from 100 μg/ml to 3.12 μg/ml, then 13 of 18 strains were fairly sensitive with the MICs of 25 μg/ml or less.
2) All of 40 strains of Yersinia enterocolitica and 19 strains of Yersinia pseudotuberculosis including isolates from men or domestic animals and reference strains were found to be sensitive with the MICs of 6.25 μg/ml or less.
3) By the thin-layer cylinder-plate method using Sh. flexneri 3a 5184, as the test organism, active concentration in body fluids was assayable to the lower limit of 0.1 μg/ml.
Following a single oral administration of 500 mg pipemidic acid, the blood peak levels of 2.8-4.4 μg/ml were observed at 1-4 hours. On these occasions, urinary peak levels were 520-540 μg/ml and urinary recoveries were 40.0-40.9%
4) Pipemidic acid was administered in 2 cases of urinary tract infection and was effective clinically and bacteriologically in both cases. And no side effect was noted.

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Studies on pipemidic acid (PPA) were carried out with respect to its antibacterial activity, absorption, excretion and clinical efficacy, and the following results were obtained.
1) Antibacterial activity
PPA was about 8 times more potent than nalidixic acid (NA) in antibacterial activity against E. coil and Klebsiella sp. Strains of E. coli resistant to 400 μg of NA or higher were susceptible to 25 or 100 μg of PPA per ml.
The MIC of PPA for Pseudomonas sp. resistant to carbenicillin (CBPC) ranged from one half to one sixteenth of those of CBPC.
2) Absorption and excretion
Peak serum concentration of PPA in healthy adults were 1.56 to 3.61 μg/ml and 2.46 to 6.29 μg /ml about 1 to 2 hours after a single oral dose of 0.5 and 1.0 g respectively. The half life of PPA in serum was found to be 2.81 to 4.81 hours. A dose response was obtained with increasing dosage of PPA.
Serum level of PPA maintained longer in patients with renal insufficiency whereas its elimination tended to be shortened by hemodialysis. Urinary recoveries of PPA for 6 hours after the oral administration ranged 30 to 55%.
3) Clinical efficacy
PPA was tried in 30 cases of urinary tract infections in doses of 1.0 to 3.0 g per day for the period of 3 to 18 days. The results of trial were excellent or effective in 23 cases, ineffective in 6 cases and undetermined in 1 case. In view of the efficacy as to the causative organisms, the rate of efficacy were 80 % in those with urinary tract infections due to E. coli and 60 % in those due to Pseudomonas sp.
As to the untoward reactions of PPA, gastro-intesinal troubles were observed in 3 cases, turbid urine in 2 cases, skin eruption in 1 case and convulsive seizure in 1 case. No other serious adverse reactions were noted in the present series.
It is concluded from above results that PPA is to be placed as a first choice of chemotherapeutics for uncomplicated urinary tract infections especially those due to E. coli.

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On a new chemotherapeutic agent, pipemidic acid, some studies were carried out and the following results were obtained.
1. The organ levels following oral administration of pipemidic acid to mice ranked in order of their height, kidneys, liver, lungs and serum.
2. The protein binding rate of pipemidic acid using dialysis against horse serum was the smallest comparing with nalidixic acid and piromidic acid.
3. The serum levels during the consecutive dosings of pipemidic acid to healthy volunteers were maintained regularly. The daily peak level reached about 8 μg/ml in 1 g dosings every 8 hours and 16 μg/ml in 2 g dosings in the same manner.
After one week, transient proteinuria, abdominal fullness and pain, borborygmus and diarrhea were complained in some cases, but all volunteers tolerated well through one week administration.
4. Clinically pipemidic acid was administered to 10 patients with urinary tract infections. The results were as follows : 1 excellent, 5 good, 3 fair and 1 poor. The poor one was chronically affected by Pseudomonas aeruginosa. Besides, one case of cholecystitis was treated and responded well. Side effects were experienced in one case who showed transient diarrhea.

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On 8 cases of respiratory tract infections due to Pseudomonas aeruginosa, 1 case of acute bronchiolpneumonia was markedly improved by administration of pipemidic acid (PPA) and 1 case of chronic bronchitis was significantly improved. The other 6 cases did not respond to this drug. As the case of acute bronchiolpneumonia successfully treated with PPA had previously failed to respond to sulbenicillin, gentamicin and colistin, PPA seemed to have a clinical meaning to be appreciated.
PPA administration was discontinued in 1 case due to such side effect as fever and headache but no abnormality was observed in biochemical tests.
It is considered that PPA is a useful drug for respiratory tract infections due to Pseudomonas aeruginosa though its application seems to be limited to diseases other than diffuse panbronchiolitis.

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Pipemidic acid is a new chemotherapeutic drug, developed in Japan. The minimal inhibitory concentration of pipemidic acid for 47 of the 50 strains of E. coli clinically isolated ranged 0.78-4. 56 μg/ml.
The minimal inhibitory concentration of this drug for 42 of the 50 strains of Klebsiella clinically isolated ranged 1.56-3.13 μg/ml.
The minimal inhibitory concentration for 34 of the 50 strains of Pseudomonas aeruginosa was 12. 5μg/ml.
The serum concentrations and the urinary excretions of pipemidic acid after oral administration were examined in 3 healthy volunteers in the fasting state. The peak of serum concentrations given 500 mg of pipemidic acid was 3. 5 to 4. 5 μg/mi at 1 hour after the administration, and the serum concentrations at 6 hours after the administration were undetectable.
The peak of serum concentrations given 1, 000 mg of pipemidic acid was 4. 1 to 5.7μg/ml at 1 or 2 hours after administration, and the serum concentrations at 6 hours after administration were undetectable.
The average urinary recoveries within 6 hours after the administration of 500 mg and 1, 000 mg of pipemidic acid were 54.7% and 46.7% respectively.
On the therapeutic efficacy of this drug to 8 cases of bacterial infections, clinical responses were good in 4 of 5 cases of urinary tract infections and in 1 of 3 cases of biliary infections.
There were no side effects of this drug clinically and in clinical laboratory tests.

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Pipemidic acid (PPA) was clinically applied to various infections with the following results.
1) PPA was effective in 29 (76%) of 38 cases (3 cases were omitted from 41 cases treated because of discontinuation of medication due to side effects). The rates of effectiveness were 82% in urinary tract infections, 67% in respiratory tract infections, 100% in pharyngitis, 100% in acute colitis and 0% in cholecystitis.
The organisms successfully responded to PPA were Escherichia coli (90%) and the other gram negative bacteria such as Pseudomonas, Klebsiella, Enterobacter, Vibrio, etc.
2) As side effects, exanthema was observed in 4, GOT elevation in 2, and decrease in thrombocytes in 1 out of 41 cases treated. The frequency of side effects was 17%.
It is our impression that PPA is effective on the infections due to gram negative bacteria, especially on urinary tract infections.

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Fundamental and clinical studies on pipemidic acid were made with the following results.
1. Pipemidic acid was more potent than piromidic acid and nalidixic acid in in vitro activity against Escherichia coli, Klebsiella and Pseudomonas aeruginosa, and as potent as carbenicillin against Pseudomonas aeruginosa.
2. Some of nalidixic acid-resistant Escherichia coli was found to be sensitive to pipemidic acid.
3. Five of 9 cases were successfully treated with pipemidic acid, the efficacy rate being 55. 5%.
4. Except for 1 case complaining stomachache, no side effect was observed. No abnormality was found as to liver and kidney functions.
Pipemidic acid having more potent antibacterial activity than nalidixic acid is considered to be a promising drug especially for urinary tract infections.

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Fundamental and clinical studies on pipemidic acid (PPA) were carried out with the following results.
1. In the activity against standard and clinical strains of Staphylococci, PPA was equal or slightly superior to nalidixic acid (NA) and fairly inferior to piromidic acid (PA).In the activity against gram-negative bacilli such as E. coli, Klebsiella pneumoniae, Proteus sp. and Pseudomonas aeruginosa, PPA was evidently superior to both PA and NA. Superiority of PPA over PA and NA was remarkable especially in Pseudomonas aeruginosa.
2. When administered to healthy adults at a single oral dose of 500 mg, the peak PPA levels in serum were 1. 4 μg/ml 2 hours after administration and those in urine were about 400-600 times higher than them. The urinary recovery for 6 hours was 23. 6% on the average.
3. The average rate of PPA excretion into bile for 3 hours was 4.4% in perfused liver of rats.
4. In 11 cases of urinary tract infections treated with PPA, 2 were excellent, 7 effective and 2 ineffective.
No notable side effect was observed in all cases.

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Fundamental and clinical studies on pipemidic acid (PPA) were carried out with the following results.
1. Seven of 31 clinical isolates of Staphylococcus aureus were resistant to PPA and the other 24 isolates had MIC values of 50-100 μg/ml. Twenty-one of 22 strains of E. coli were inhibited by 1. 56, -3. 12 ug of PPA per ml, 6 of 13 strains of Klebsiella sp. by 1. 56-12. 5 μg/ml, 20 of 21 strains ofProteus sp. by 3. 12-6. 25 μg/ml, and 14 of 15 strains of Pseudomonas sp. by 12. 5-50 μg/ml.
The antibacterial activity of PPA against gram-negative bacteria was more potent than that of piromidic acid.
2. When PPA was orally given once to fasting healthy adults, its peak serum levels were 3. 6-5.6μg/ml at a dose of 1 g and 5. 2-5. 6 μg/ml at a dose of 2 g. Urinary recoveries for 6 hours were 18. 1-42. 3 % at a dose of 1 g and 16. 2-49. 4 % at a dose of 2 g.
3. PPA was administered to 13 clinical cases comprising 3 cases of respiratory tract infections, 1 case of biliary tract infection, 1 case of intestinal tract infection, 7 cases of urinary tract infections, and 1 case of sepsis. In respiratory tract infections, results were good in 1, ineffective in 1, and unknown in 1 case. The drug was ineffective in 1 case of biliary tract infection, but showed excellent effect in 1 case of intestinal tract infection and 1 case of sepsis. Its effect was excellent in 4 cases of urinary tract infections and good in 3 cases. Disturbance of digestive tracts was observed in 2 cases and rash was observed in 1 case as its side effects.

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Pipemidic acid (PPA), a newly synthesized piromidic acid derivative, was examined on its antibacterial activity and absorption after oral administration. Some clinical trials were also carried out.
1) Tests on the sensitivity of clinical isolates revealed that the sensitivity of E. coli strains to PPA was higher than that to NA and PA, and the sensitivity of Klebsiella and Proteus strains to PPA mostly resembled that to NA.
2) Blood levels of PPA in human adults administered 1 g PPA per os showed a peak (7.2-7.5μg/ml) at 1 hour after administration.
3) The rate of urinary recovery was 23. 6-43. 8% within 6 hours.
4) PPA was used in 8 cases with respiratory-or urinary-tract infections. Favourable results were obtained in 5 of the cases.
5) No side effects were observed in all patients treated with the drug except one who complained nausea after administration, but it was obscure if the nausea of this patient was attributable to the drug or not, because drugs for hypertention were simultaneously given.

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Fundamental and clinical studies were performed on pipemidic acid (PPA), a new oral antibacterial agent, with the following results.
1) The MICs of PPA were compared to those of nalidixic acid (NA) in 22 standard strains reserved in our laboratory and 435 strains (Staphylococcus aureus 64, Salmonella 16, Shigella 16, Escherichia coli 64, Klebsiella aerogenes 64, Enterobacter aerogenes 32, Proteus vulgaris 20, Proteus mirabilis 32, Serratia marcescens 63 and Pseudomonas aeruginosa 64) isolated from clinical materials. PPA usually showed 2 to 4 times more potent activity than NA.
2) The plasma levels of PPA attained a peak of 5. 4-6. 6 μg/ml in 3 healthy adults receiving a single oral dose of 1, 000 mg 1 hour after a meal, and they descended to 1.8 μg/ml on the average 6 hours later. The average urinary recovery for 6 hours was 29.2%.
3) PPA was administered to 7 cases of chronic respiratory tract infections (bronchiectasis 3, chronic bronchitis 2, panbronchiolitis 2) at a daily dose of 1, 500-3, 000 mg divided into 3 times. Clinical effectiveness was fair in one and poor in the rest. An active substance was not detected in sputum of the patient suffering from bronchiectasis given 1, 000 mg of PPA.
4) No abnormalities were observed in all cases with respect to subjective and objective symptoms, hematological analysis, biochemical test, and urinalysis.

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Pipemidic acid (PPA), a derivative of piromidic acid (Panacid^®), was studied basically and clinically, and the following results were obtained.
The antibacterial activity of PPA was lower against Pseudomonas aeruginosa and Klebsiella than E. coli and Proteus.
The MIC values of the latter two organisms were usually below 6.25 μg/ml.
Concentrations in serum after single oral administration of 500 mg PPA attained a peak ranging 2.5 to 4.1 μg/ml in 2 to 4 hours.
PPA was clinically used in 18 cases of respiratory infections and the efficacy rate was 47.1 %.As for side effects, five cases complained of gastro-intestinal disturbance, though the symptoms ceased after stopping administration.

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A series of fundamental and clinical studies on pipemidic acid, a new synthetic antibacterial agent, was made in the field of pediatrics, and the following results were obtained.
1. The MIC values of pipemidic acid were 1. 56 μg/ml or lower for all of the Shigella strains isolated recently, some of which were resistant to streptomycin, tetracycline, chloramphenicol and ampicillin. Ninety-eight % of Salmonella sp. was inhibited by 3. 13 μg or lower of pipemidic acid per ml and 84 % of Pseudomonas aeruginosa by 6. 25-25 μg of the drug per ml. The MIC values of pipemidic acid were lower than those of piromidic acid.
2. After oral administration of pipemidic acid, it was detected in plasma, urine and feces at high concentrations as an antimicrobially active state.
3. When pipemidic acid was orally given at doses of about 40-50 mg/kg/day for 5-7 days to the cases of bacillary dysentery, some of which were caused by the strains resistant to chloramphenicol and ampicillin, satisfactory results were obtained clinically and bacteriologically in most cases.
4. Acute colitis was successfully treated by a similar dosing regimen of pipemidic acid.
5. No abnormalities were observed in liver and kidney functions when pipemidic acid was orally administered at doses of about 30-100 mg/kg/day for 5-7 days.

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Laboratory and clinical studies were made on pipemidic acid and the following results were obtained.
1. Peak blood levels were 9.5-20μg/ml 1 hour after oral administration of pipemidic acid at doses of 10 and 25 mg/kg.
2. Pipemidic acid was administered at a daily dose of about 50 mg/kg to 17 cases of urinary tract infections, 1 case of cholecystitis after operation of congenital bile duct atresia and 2 cases of lymphadenitis colli purulenta bearing skin abscess. Clinical results were excellent or good in 14 of 17 cases of urinary tract infections, good in 1 case of cholecystitis and good in 1 of 2 cases of lymphadenitis colli purulenta bearing skin abscess.
The rate of clinical effectiveness was 80% in a total of 20 cases treated. Causative organisms disappeared in 13 cases but were maintained in 3 cases except for 4 unknown cases.
In all cases, there were no untoward side effects regarding symptoms, hematological analysis and renal and hepatic functional tests.

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The authors have carried out the laboratory and clinical studies of pipemidic acid. The results were as follows;
The sensitivity was measured by the plate dilution method with 30 strains of Staphylococcus aureus, 27 strains of Pseudomonas aeruginosa, 15 strains of E. coli and 14 strains of Proteus isolated from patients.
The peak in the distribution of Staphylococci susceptible to pipemidic acid was MIC of 50 μg/ml and the growth of 93. 3% of these was inhibited in concentration of less than 50 μg/ml. The growth of 33. 3% of Pseudomonas aeruginosa and E. coli was inhibited in concentration of less than 12. 5 μg/ml.
Pipemidic acid was given at a single oral dose of 500 mg to 4 children.
The maximum blood level reached at 1 hour after administration was 4.0 μg/ml and the blood level at 6 hours was 0. 68 μg/ml.
The excretion rates of pipemidic acid in the urine for 6 hours after a single oral dosing were 21.89, 53.38, 88.74 and 58. 55% respectively in 4 children.
Pipemidic acid was effective in 7 of 8 cases with the enteric and urinary tract infections. No side effects were observed.

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Pipemidic acid was administered to 60 cases of bacillary dysentery, 4 cases of colitis due to Salmonella, 8 cases of colitis due to Vibrio parahaemolyticus and 22 cases of acute colitis where causative organisms could not be detected. Clinical symptoms were improved by this drug in almost all cases. The rate of effectiveness as determined by the elimination of infecting organisms was 86.7% in bacillary dysentery. No adverse effect was observed in all cases.

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Antibacterial activity of pipemidic acid (PPA) was examined in 70 clinical isolates of Shigella sp. All isolates were inhibited by 1.56 μg of the drug per ml except for one resistant strain. Compared to nalidixic acid (NA) and piromidic acid (PA), PPA was 2 to 4 times more potent than NA and 8 to 16 times more potent than PA. PPA was not completely cross-resistant with the other two drugs.
Clinical results, when PPA was administered mostly at 1 to 2g for 5 days, were effective in 18 of 20 cases of bacillary dysentery, ineffective in 1 and unknown in 1, the efficacy rate being 94. 7 %. Causative bacteria were eliminated in 17 of 19 cases, the elimination rate being 89. 5 %. Of 13 carriers of dysentery bacilli, effectiveness was observed except for one showing re-appearance of the infecting organism. Among the other dysentery-like diseases, PPA showed excellent effect in 3 cases of food poisoning due to Vibrio parahaemolyticus, but failed to eliminate the infecting organism in 1 carrier of Salmonella sp. at a daily dose of 1. 5 g for 15 days. In 13 cases where causative organisms were not able to be detected, 12 were effective and 1 ineffective. It was found that the sensitivity of the infecting organisms to PPA and NA became lower when they re-appeared after treatment with the former drug in 2 cases of bacillary dysentery.
Side effects were not observed subjectively and objectively in all cases. In 2 cases showing high S-GOT and S-GPT levels, these levels were normalized after medication in one and remained

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Basic studies on pipemidic acid (PPA) were performed with the following results.
1) Antibacterial spectrum
PPA showed excellent antibacterial activity mainly against gram-negative bacteria such as Escherichia coli, Klebsiella pneumoniae, Proteus sp., Pseudomonas aeruginosa and Shigella sp. Its activity was 2 to 4 times higher than that of piromidic acid and nalidixic acid.
2) Sensitivity of organisms isolated from infected sites
PPA showed excellent antibacterial activity against strains of Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa, its MICs for most strains of Pseudomonas aeruginosa ranging from 25 to 50μg/ml. Considering its good distribution to bile and urine, PPA seems to be applied to biliary and urinary tract infections caused by these organisms.
3) Serum and urine levels
By the cup-plate method using a standard calibration curve of Moni-trol, average peak serum levels of PPA in men were 3.0μg/ml 30 minutes after 500 mg dosing, 5.1μg/ml 1 hour after 1, 000 mg dosing and 5.4μg/ml 2 hours after 2, 000 mg dosing. Dose-response was not clear with this results. The urine levels of PPA in men attained a peak of 420, 1, 160 and 1, 697μg/ml 1 hour after dosing of 500, 1, 000 and 2, 000 mg, and the urinary recoveries for 6 hours were 30. 4, 15.3 and 19.6% respectively.
4) Tissue levels
Tissue levels were determined in groups of 3 SD rats given 50 mg of 14C-PPA per kg. PPA concentrations were high in the order of kidneys, serum, liver, heart, muscle, spleen and lung by radioassay, and in the order of kidneys, serum, liver by bioassay. PPA was not detectable by bioassay in the other tissues.
5) Metabolism
Urine of men given PPA and rats given ¹⁴C-PPA was developed by thin-layer chromatography followed by bioautography, radioautography or radiochromatogram scanning.
There were two bio-active spots at the Rf value of 0.45 (corresponding to PPA) and the Rf value of 0.82 (possibly methabolites) in human urine, and similar spots (Rf 0.45 and 0.75) were detected in rat urine.
6) Clinical results
PPA was used for 25 cases of infections in the surgical field and the results were effective in 20 cases, ineffective in 3 cases and unknown in 2 cases. The efficacy rate was 87%. As side effects, anorexia was observed in 1 case, anorexia and nausea in 1 case, and a epigastric pain in 1 case, the frequency being 12.0%. Medication was discontinued in 1 case but not in 2 cases.

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Fundamental and clinical studies on pipemidic acid were investigated, and the following results were obtained.
(1) Antibacterial activity
The sensitivity of PPA and NA was examined in Staphylococcus aureus and gram-negative bacteria. In comparison with NA it was effective to gram-negative bacteria, whilst it was slightly ineffective to Staphylococcus aureus.
(2) Absorption and excretion
PPA (1g) was administered once at fasting in 3 healthy adults, and blood level and urinary excretion were examined. Peak blood level on average was 6.5μg/ml at 1 hour and recovery from urine within 8 hours was 33.7%.
Biliary excretion was measured in 3 clinical cases. PPA was excreted well in bile in spite of the presence of abnormality in hepatic function.
(3) PPA was administered to 2 patients with surgical infections and no particular side effects were observed.

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Pipemidic acid (PPA), derived from piromidic acid (PA), has been reported to be more effective on gram-negative bacilli than ampicillin, cephalexin, and carbenicillin.
The authors investigated on its clinical effectiveness and untoward side effects.
Pipemidic acid was administered to 19 patients with infections in the field of surgery, and the results were excellent in 1 case, good in 5, fair in 6 and poor in 7, the effectiveness rate being 63.2 %.
Among untoward side effects, there were redness around the orifice of the urethra in 1 case, anorexia in 1 case and liver disfunction in 2 cases receiving blood transfusion.

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Ten patients with inflammatory biliary diseases (group A) and 6 patients with other surgical infections (group B) were treated orally with pipemidic acid at doses ranging from 1. 0 to 2.0 g per day for periods from 3 to 14 days. Group A consisted of 3 cases with cholecystolithiasis, 3 cholecystocholedocholithiasis, 1 choledocholithiasis, 1 cholangitis after choledochoduodenostomy, 1 cholangitis after pancreatoduodenectomy for carcinoma of papilla duodeni and 1 carcinoma of gallbladder. Group B consisted of 2 cases with post-surgical wound infection, 1 traumatic wound infection, 2 panaritium and 1 acute cystitis.
The therapeutic results of the drug in group A were evaluated clinically as good in 6, fair in 1 and poor in 3, and so an over-all efficacy was 60%. Those in group B were as good in 5 and fair in 1, its efficacy being 83%. No adverse side effects were observed in either clinical signs or laboratory data.
The biliary excretion following single oral administration of 1. 0 g of the drug was determined in 3 patients with external biliary drainage. The peak of biliary levels of the drug in each patient was 8.8 μg/ml at 5 hours after administration, 9.7 μg/ml at 3 hours and 20.6 μg/ml at 4 hours.The biliary level of the drug was found to be maintained over 5 μg/ml even at 7 hours in 2 patients.

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Studies on pipemidic acid (PPA) were carried out in our clinic.
The results were as follows ;
1. The serum level of PPA, following the oral administration of 500 mg of PPA, was determined by the cup-plate method, using E. coli Kp as a test organism. The serum level was 1.7 μg/ml at 30 minutes, 3.3 μg/ml at 1 hour and 1.3 μg/ml at 6 hours after the administration.
2. Urinary excretion of PPA was also determined by the same method, and 27 % of the administered dose was recovered in urine within 12 hours after a single dose of 500 mg per os.
3. The transfer of PPA from mother to fetus was examined in 6 cases of normal pregnant women. The levels of PPA in umbilical cord blood and in amniotic fluid were extremely low.
4. PPA was effective in 29 of 35 cases in our clinic, including urinary tract and pelvic infections.
5. In one case, drug eruption appeared. One complained of epigastralgia and the other had diarrhea. No other side effects nor adverse reactions were found in other cases.

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Fundamental and clinical studies of pipemidic acid (PPA) were made with the following results.
1. In vitro antibacterial activity of PPA was compared with that of piromidic acid (PA), β-hydroxypiromidic acid (β-OHPA) and nalidixic acid (NA) using 242 strains isolated from various infections in the field of obstetrics and gynecology. Most of gram-negative bacteria were inhibited by 6.25 μg of PPA per ml which were generally more active than PA, β-OHPA and NA. About 50 % of pseudomonads was inhibited by 50 μg of PPA per ml, whereas more than 90% was resistant to 100 pg of PA, β-OHPA or NA per ml.
2. Concentrations of PPA in various tissues and body fluids were determined after a single oral administration of 250 mg. Its peak levels were about 2-3 μg/ml in maternal serum 2-4 hours after administration, about 2-μg/ml in amniotic fluid 3 hours, and about 2.7 μg/ml in maternal milk 2 hours. PPA was not detected in fetal tissues.
3. PPA was administered to 11 cases of infections at daily doses of 750-1, 000 mg for 5-45 days with favorable results in 7 cases (efficacy rate : 63.6%).
4. Side effects were not observed at all.

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Fundamental and clinical investigation with a new pyridopyrimidine derivative, pipemidic acid, was performed with the results which may lead to the following conclusion.
1. In vitro antibacterial activity : The minimal inhibitory concentration (MIC) of pipemidic acid was measured by the agar plate dilution method using heart infusion agar (Eiken). Pipemidic acid revealed an excellent antibacterial activity against 29 standard strains of various bacterial species. Pipemidic acid had the same antibacterial spectrum as those of piromidic acid and nalidixic acid. The MICs of pipemidic acid against 80 strains of coagulase-positive Staphylococcus aureus isolated from otorrhoea ranged from 12.5 to ≥100 μg/ml, with a peak at ≥100 μg/ml. Clinical isolates of Escherichia coli, Proteus mirabilis, and Klebsiella pneumoniae were inhibited by 0.78 to 12.5 μg/ml of pipemidic acid. Pipemidic acid showed the MICs of 6.25-≥100μg/ml against 60 strains of pathogenic Pseudomonas aeruginosa.
2. Concentration in serum : The serum level of pipemidic acid in healthy adults given 1, 000 mg reached a maximum of 5.7 pg/ml 2 hours after administration. Even at 6 hours after administration, clinically effective serum pipemidic acid concentration, 1.1 pg/ml, was still demonstrable.
3. Concentration in tissues : Activity of pipemidic acid was demonstrable at the concentration of 1.1 μg/g in human palatine tonsilla and 0.6 μg/g in mucous membrane of maxillary sinus 2 hours after administration of 1, 000 mg, when the serum concentration of pipemidic acid was 5.96 and 6.0 μg/ml respectively.
4. Results of clinical treatment : When pipemidic acid was orally administered to 30 cases of representative infections in the otorhinolaryngologic field, clinical results were excellent in 6 cases, good in 18 cases and fair in 6 cases. When the excellent and good cases were considered together, clinical responses were obtained in 24 cases, 80 percent.
5. Side effect : No side effect was shown with oral administration of pipemidic acid. The comparative examination of hepatic functions, electrolytes and auditory acuity before and after administration showed no significant anomaly.

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Clinical evaluation of pipemidic acid (PPA) was made in the field of otorhinolaryngology.
1. A peak of the MICs of pipemidic acid was 25 μg/ml against 51 strains of Pseudomonas aeruginosa isolated from the site of infections.
2. The average peak level of PPA in serum was 3.4μg/ml 1 hour after single oral dosing of 500 mg and 7. 5 μg/ml 2 hour after single oral dosing of 1, 000 mg. The levels of PPA in faucial tonsil, concha inferior and mucous membrane of maxillary sinus were low compared to the serum levels.
3. PPA was orally applied to 20 cases of infections due to gram-negative bacteria including Pseudomonas aeruginosa, and the results were excellent in 6 cases and effective in 10 cases.
4. No side effects were observed in blood analysis, liver and kidney functions except for one case complaining nausea.
It is noted that PPA is clinically more effective than it is expected from its antibacterial activity and its tissue levels.

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Pipemidic acid was administered to 14 cases of chronic suppurative otitis media at a daily dose of 1.5 or 2 g for 6 to 10 days. Clinical results were effective in 7 cases, slightly effective in 3 cases and ineffective in 4 cases. The efficacy rate was 50 %. It was interesting that some cases due to gram-negative bacilli, especially 3 cases due to Pseudomonas aeruginosa, were favorably treated with this drug because such cases were usually difficult to be cured. No side effects were observed in all cases treated.

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Results of basic and clinical studies for ophthalmic use of pipemidic acid (PPA) are summarized as follows.
1) PPA has an antibacterial activity against gram-negative bacteria including Pseudomonas aeruginosa.
2) The sensitivity of 20 strains of Pseudomonas aeruginosa was distributed in the MIC range of 12. 5->100μg/ml, and 12 strains of them (60%) were inhibited by 25μg/ml or lower.
3) The blood concentrations of PPA in healthy adults by single oral administration of 1.0 g and 2.0 g reached the highest levels of 4.9μg/ml and 14. 25μg/ml respectively 2 hours after administration, and were high enough to be measured even at 6 hours.
4) When PPA was orally given to rabbits at a single dose of 500 mg, the aqueous humor levels were below 1.25μg/ml throughout 1-6 hours. However the aqueous humor levels were detected to be 3.8μg/ml after 2.5 hours and 4.3μg/ml after 4 hours, and the ocular tissue concentrations were recognized to be relatively high in both of outer and inner parts of the eye when 500 mg PPA was administered twice every 4 hours.
5) The oral administration of PPA at a dose of 1 g, 4 times a day, combined with the local application of 5% PPA ointment, showed satisfactory effects on 4 cases of corneal ulcer and 1 case of acute dacryocystitis caused by Pseudomonas aeruginosa.
6) No side effects were noted in any of the cases.

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Basic studies on pipemidic acid (PPA) were made in ophthalmology, and the results obtained are summarized below.
1. The sensitivity of Staphylococci isolated from clinical materials to PPA ranged between 25->100 μg/ml of MIC.
2. The PPA concentration in serum attained a peak of 6. 0 μg/ml 30 minutes after single oral administration of 200 mg/kg to albino rabbits, and descended to a level of 1.4 μg/ml after 5 hours.
PPA was not detected in the aqueous humor.
3. The average of PPA concentration in human serum was 1.6 μg/ml 1 hour after single oral administration of 500 mg, and 1.1 μg/ml 5 hours after administration.

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Simple and complicated urinary tract infections were treated with pipemidic acid at daily doses of 750 mg to 1, 500 mg for 6 to 14 days.
Three cases of simple urinary tract infections were all treated successfully with this drug. In 13 cases of complicated urinary tract infections with underlying diseases, which were considered to be difficult to be cured, the efficacy rate of pipemidic acid was about 40 %.
There was no problematic side effect possibly due to this drug.

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Pipemidic acid (PPA) was administered to 11 cases of acute simple urinary tract infections at a daily dose of 750 mg for 7 days and its effect was excellent in all cases. When the drug was administered to 9 cases of chronic complicated urinary tract infections at a daily dose of 750 mg or 1, 000 mg for 14 days, the results were excellent in 1 case, effective in 2 and ineffective in 6.
The sensitivity of organisms isolated from urine to PPA was closely correlated with the clinical effect of the drug in acute urinary tract infections, while it was not in chronic urinary tract infections possibly due to host factors interrupting a cure.
No side effects were observed in subjective symptoms and blood biochemical analysis in 20 cases treated with PPA.

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Clinical and bacteriological studies were made on pipemidic acid (PPA) in 17 patients suffering from urinary tract infections.
The results were as follows.
1) MICs of PPA against 30 strains of Pseudomonas aeruginosa were distributed in the range of 12.5μg/ml to 100μg/ml, and the peak of MIC was 25μg/ml.
2) Against E. coli, MICs of PPA were distributed in the range of 3.13μg/ml to more than 200μg/ml and the peak was 3.13μg/ml.
3) The antibacterial activity of PPA against Pseudomonas aeruginosa was found to be approximately comparable to or higher than that of P-CBPC and I-CBPC.
4) No remarkable side effects to be mentioned were observed.

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