Pipemidic acid (PPA) was orally administered to 21 cases of various urinary tract infections at daily doses of 750-3, 000 mg for days and the following results were obtained.
1) The efficacy rates of PPA were 100% (excellent ; 7 cases, effective ; 1 case) in acute simple cystitis, 100% (excellent ; 2 cases, effective ; 2 cases) in chronic simple urinary tract infections, and 55.6% (effective ; 5 cases, ineffective ; 4 cases) in chronic complicated urinary tract infections.
The total efficacy rate was 80.9% (excellent ; 9 cases, effective ; 8 cases, ineffective ; 4 cases) in 21 cases treated.
2) Efficacy of PPA was excellent in the infections due to E. coli as well as Klebsiella sp.
3) The MICs of PPA were determined in 78 strains isolated from patients suffering from urinary tract infections. Most strains (89.4%) ofE. coliwere inhibited by 1.56-4.25 μg of PPA per ml, and most strains of Proteus mirabilis and Klebsiella sp. by 1.56-12.5 μg of the drug per ml. More than half of the strains of Pseudomonas aeruginosa were inhibited by 3.13-6.25 μg/ml, and the rest by 25 μg/ml.
4) Mild nausea was observed in 2 cases as side effect.
5) It is concluded from these results that PPA is an excellent chemotherapeutic for urinary tract infections especially due to gram-negative bacilli.

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Pipemidic acid was administered to 29 in-and out-patients suffering from urinary tract infections at daily doses of 500-2, 000 mg. Clinical results were excellent in 15 cases, good in 7 cases and poor in 7 cases, the efficacy rate being about 76%. Temporary mild nausea and stomach discomfort were observed in 1 case as side effects.

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1) The antibacterial activity of pipemidic acid trihydrate (PPA) was determined and was found to be slightly stronger than that of nalidixic acid againstE. coil isolated from clinical materials.
2) Blood levels of PPA were 10.3-13.4 and 11.5-13.5 μg/ml at 2 hours in human adults given a single oral dose of 1.5 and 3.0 g respectively.
3) Urinary recoveries of PPA during 8 hours after administration were ranged 48.5-77.7 % of the dose (1.5 g) and 19.8-57.1 % of the dose (3.0 g).
4) Excellent and good responses were seen in 18 of 23 cases with acute simple urinary tract infections, while poor in 2 cases of chronic complicated urinary tract infections.
5) Side effects were observed in 2 of 25 cases; anorexia and abdominal pain. No abnormalities were observed in hematological and blood biochemical analyses.

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Pipemidic acid was administered to 34 cases of acute simple urinary tract infections and was effective in 28 cases. The efficacy rate was 82.4 %.
Mild side effects (stomach-ache, nausea, rash) were observed in 3 cases, which disappeared after discontinuation of medication.
Pipemidic acid seems to be comparable to available antibiotics.

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Clinical and laboratory studies on pipemidic acid were conducted, and the results obtained are described below.
1. Pipemidic acid was administered orally at a dose of 125 mg in 7 healthy adults to determine the blood levels. Blood levels of the drug attained to a peak of 1.08 μg/ml on an average after 1 hour. And the urinary recovery was 102.95 % (90. 74-115. 9 %) on an average for 6 hours.
2. A total of 25 patients with acute simple cystitis was treated with pipemidic acid. Excellent results were obtained in 15 cases, and good results in 10, the rate of effectiveness being 100 %.
3. There were no abnormal signs due to the drug except for exanthema in one patient.

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The following results were obtained in urinary tract infections treated with pipemidic acid.
1. Clinical effects were excellent in 20 and good in 5 of 25 cases of acute urinary tract infections. The rate of effectiveness was 100%.
2. In 18 cases of chronic urinary tract infections having underlying diseases, 5 were excellent, 6 good, 4 moderate and 3 ineffective. The rate of effectiveness was 61. 1%.
3. Among 37 strains isolated from these urinary tract infections, Escherichia coil, Proteus mirabilis and Klebsiella sp. were inhibited by 0. 786. 25 μg of pipemidic acid per ml, and Enterobacter and Pseudomonas sp. by 6. 25-100 μg of the drug per ml. Compared to piromidic acid, nalidixic acid, ampicillin, cephalexin and gentamicin, pipemidic acid followed gentamicin in antibacterial potency.
4. No subjective side effects such as gastro-intestinal disturbances and rash were observed. GOT, GPT, BUN and creatinine levels in plasma did not rise in all cases, but decreases in the number of leucocytes were seen in 2 cases.

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Die pipemidische Säure wurde benutzt für die urogenitale Infektionen. Die Wirkung für E. coli und Cystitis acuta war sehr gut. Die Nebenwirkung in 15 % als Magenbeschwerden gefunden.

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Pipemidic acid (PPA) is a new oral chemotherapeutic agent developed recently in Japan. It is active principally against gram-negative organisms. The in vitro activity of PPA against isolates of E. coli, Klebsiella, Proteus mirabilis and Pseudomonas was more potent than those of nalidixic acid (NA) and piromidic acid (PA) used in this study for comparison.
When PPA was given to healthy adult volunteers at a single oral dose of 500 mg, a peak serum level of 3.46 μg/ml was attained 2 hours after administration and gradually declined thereafter. The urinary level reached a peak of about 1, 800 μg/ml and the recovery within 6 hours was about 52 %.
Prostatic fluid levels reached a concentration of 6.55 μg/ml 1 hour after dosing of 500 mg of the drug.
PPA was used in 68 cases of genito-urinary tract infections (19 of pyelonephritis, 32 of cystitis, 12 of bacterial prostatitis and 5 cases of non-gonococcal urethritis) at doses of 25 to 2, 000 mg/day for 3 to 28 days. The rates of effectiveness were 92.5% in acute cystitis, 60.0% in chronic cystitis, 100% in acute pyelonephritis, 63.6% in chronic pyelonephritis, 41.7% in bacterial prostatitis and 80.0% of non-gonococcal urethritis evidently indicating that the rates were high in acute uncomplicated infections. The side effects of PPA were the disturbances of gastrointestinal tract such as stomatitis, stomach distress, nausea, etc., which were seen in 7.4%. No abnormal effects on BUN, creatinine, S-GOT and peripheral hematology were observed.
Conclusion :
1. PPA was superior to other relative compounds, NA and PA, in antibacterial activity, principally against gram-negative bacteria. Against E. coli strains, the activity was 2 times as high as that of NA, and 4 times as high as that of PA.
2. The urinary excretion of PPA was much higher than that of NA and PA.
3. For the genito-urinary tract infections due to gram-negative bacteria, especially caused by E. coli, PPA was an excellent chemotherapeutic agent of oral use.

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In vitro antibacterial effect and clinical response of chemotherapeutics were studied in the view point of body fluid levels. In this study, a new oral antimicrobial agent, pipemidic acid (PPA), was applied.
The in vitro activity of PPA against most gram negative bacilli was superior to that of piromidic acid and nalidixic acid, especially against P. aeruginosa.
Thin layer chromatography (TLC) and bioautography of urine excreted after PPA administration revealed that antimicrobial substance in urine was PPA alone.
A peak blood level was achieved about one hour after 500 mg dosing of PPA following meals, and the concentration was 3.5 μg/ml. This blood level exceeded the average MIC of PPA against most clinically isolated E. coli for a while.
According to biophotometric assay, however, even 1/2 MIC of PPA showed the bacteriostatic or bactericidal activity against E. coli (NIHJ JC-2) (MIC 3.12 μg/ml).
The fact suggests that even if the serum level hardly exceeded the MIC for bacteria, effective therapeutic response would be expected. On the other hand, in the case that PPA acted on P. aeruginosa in logarithmic phase, bactericidal action was observed with 1/2 MIC of PPA, nevertheless 4 MIC of PPA could not kill all of them.
A peak urine level was 2, 000 μg/ml 2 hours after 500 mg dosing of PPA following meals and 51.7% was recovered within 6 hours. Those urine seemed to have sufficient bactericidal activity against P. aeruginosa not only E. coli and others.
On account of those results, PPA was expected to have sufficient therapeutic effect by oral administration. PPA was administered as a dose of 1.0 g per day to 32 cases with urinary tract infections for 3 or 4 days, and excellent or good responses were observed in 16 out of 17 acute cases and 8 out of 15 chronic cases.
As for the side effects, subjective symptoms were checked without noticing any serious side effects.

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In order to evaluate the efficacy and safety of a new antimicrobial agent, pipemidic acid (PPA), in complicated urinary tract infections, a controlled study with ampicillin (ABPC) as the reference standard was carried out by the double-blind method. From the results obtained, the following conclusions were drawn.
1. The background characteristics of the two groups were statistically analyzed in terms of sex, age, site of infection, underlying disease, catheter, type of infection, severity of pyuria, organisms isolated from urine, MIC distribution and frequency of appearance of each symptom.
There was no serious bias between both groups, indicating that they had essentially a sufficient homogeneity for the present study.
2. The dose for both PPA and ABPC was 2g each. All treatments were given for 7 days and clinical effects were evaluated in a total of 160 cases comprizing 77 PPA cases and 83 ABPC cases.
The overall therapeutic efficacy was found to be 22. 1% with PPA and 14. 5% with ABPC in terms of excellent response and to be 54. 5% with PPA and 41.0% with ABPC in terms of both excellent and good response, showing no significant difference between the two drugs.
The efficacy on pyuria or bacteriuria was also found to have no significant difference between them.
3. When the stratification was made according to the site of infection, we found that the rate of efficacy of PPA on the prostatic bed infection was significantly higher than that of ABPC.
PPA was also significantly higher than ABPC in the rate of disappearance of causative GNB isolated from urine. PPA tended to be more effective than ABPC in the rate of disappearance of strains such as Pseudomonas, Proteus and Klebsiella although there was no significant difference between both the drugs.
4. The incidence of side effect was 13. 7% and 6. 3% in PPA and ABPC respectively. No significant difference of incidence of side effect was found between PPA and ABPC.

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As a clinical investigation related to the recurrence of complicated urinary tract infections, a doubleblind controlled study of pipemidic acid (PPA) was carried out in comparison with a placebo.
The results were summarized as follows :
1. In 27 cases, the rate of the recurrence was 66.7% in 2 weeks and 61.1% of the recurrence was due to reinfections. The organisms isolated from them were very common and similar to those usually isolated from patients with complicated urinary tract infections in species and frequency. The recurrence was observed within 1 week in most cases.
2. When given one gram of PPA, the rate of recurrence was 31.2% showing that PPA was significantly more effective than the placebo.
3. Eighty percent of the recurrence in PPA treated cases was due to reinfections. The MICs of PPA against the organisms isolated were more than 25 μg/ml.
4. The suppressive effect of PPA on the recurrence was more marked in bladder infections than in renal infections.
5. The suppressive effect of PPA on the recurrence was better in cases previously treated with a different drug than in those follow by PPA treatment.

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Twenty two cases of urinary tract infections were treated with PPA. Excellent effects were observed during 3 to 7 days after administration of the drug.
Improvement of urinary findings, disappearance of subjective symptoms, and elimination of pathogens were obtained in 20 of 22 cases. No serious side effects were observed. Significant hematological and biochemical changes were not seen after administration of the drug. PPA was thought to be a recommendable therapeutics for urinary tract infection.

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Fundamental and clinical studies were carried out on a new synthetic antibacterial drug, pipemidic acid (PPA). The results obtained were as follows.
1. In the sensitivity distribution of various organisms isolated from urinary tract infections, the peak MIC values were 1. 56 μg/ml in E. coli, 3. 13-25 μg/ml in Klebsiella, 3. 13 μg/ml in Proteus, 25 μg/ml in Pseudomonas and 25 μg/ml in Staphylococcus. PPA was 2 to 4 times more potent than nalidixic acid (NA) and 8 to 16 times more potent than piromidic acid (PA) against E. coli, Klebsiella and Proteus. The MIC distribution of PPA was similar to that of NA and aminodeoxykanamycin in Serratia strains which were relatively sensitive to gentamicin.
2. When PPA was given to 2 healthy human male adults at a single oral dose of 1 g, the average peak plasma level was 5. 5 μg/ml 2 hours after dosing and the average peak urine level was 3, 250μg/ml in 1-2 hour urine. The urinary recovery for 12 hours was 55.6% on th average.
When 250 mg of PPA was orally given to 5 healthy male adults, the peak concentration in plasma was 1. 9 μg/ml on the average 1 hour after dosing. The highest average concentration of 620 μg/ml was observed in 0-2 hour urine and the average urinary recovery was 80%.
In a patient with renal insufficiency receiving PPA at a single oral dose of 500 mg, the plasma level attained a peak of 43. 5 μg/ml 1 hour after dosing and was 27. 5 μg/ml even 8 hours later. The urinary recovery for 8 hours was 2.6%.
3. PPA was used for 157 cases of urinary tract infections with the results of 92 excellent, 51 good, 13 ineffective and 1 unknown cases. The rate of effectiveness was 91.7%.
In 92 cases of simple urinary tract infections, 62 cases were excellent, 26 cases good and 4 cases ineffective, the rate of effectiveness being 95. 7%. In 65 cases of complicated urinary tract infections, 30 cases were excellent, 25 cases good and 9 cases ineffective, the rate of effectiveness being 85.9%. When classified according to causative organisms, the rate of effectiveness ranged between 85.7 and 100% in the infections due to E. coli, Klebsiella, Proteus and Pseudomonas. PPA was clinically effective against organisms resistant to NA, ampicillin and cephalexin as expected from its in vitro result that there is no cross-resistance between PPA and NA or antibiotics.
4. Nausea was observed in 3 (1.9%) of 157 cases treated with PPA. Medication was discontinued in 1 case due to the side effect, but the other 2 cases ceased complaining in spite of continued medication of PPA. No abnormalities were observed with respect to blood analysis, liver and kidney function tests in 10 cases examined before and after medication.

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1) Minimal inhibitory concentrations of pipemidic acid were determined in 94 strains isolated from urinary tract infections by the plate dilution method. Many strains of E. coli and Proteus mirabilis were inhibited at the concentration of 6.25 μg/ml or lower. Some strains of Proteus vulgaris and Pseudomonas aeruginosa were inhibited at the concentration of 25 μg/ml or lower. Most strains of Staphylococcus aureus were resistant to 100 μg/ml of pipemidic acid.
2) Twenty-three cases with urinary tract infections were treated with pipemidic acid at oral doses of 750-2, 000 mg per day. Excellent or good results were obtained in 18 cases.
3) Anorexia was observed in 1 case and temporary elevation of GOT and GPT in 3 cases on laboratory findings.

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Ten patients suffering from complicated urinary tract infections following operation and catheterization were treated with pipemidic acid (PPA) at a dose of 1 or 2 g/day for 7 days, and following results were obtained.
1. Most clinical isolates were sensitive to PPA.
2. Clinical effects were good in all cases. The effects were usually more favorable in the patients given 2 g of PPA than in those given 1 g.
3. No side effects were observed subjectively in all cases. Hepatic and renal functions, and blood pictures did not change significantly in all cases.

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Forty-two patients suffering from acute and chronic cystitis were treated with pipemidic acid (PPA).
PPA was administered orally at the dosage of 375-1, 000 mg for 7 days. Of 10 patients with acute simple cystitis, clinical responses were satisfactory in all patients. Of 17 patients with chronic simple cystitis, good responses were seen in 15 patients, poor in 2, and of 15 patients with chronic complicated cystitis, good in 10 patients and poor in 5.
The overall efficacy rate was 83. 3 %. Out of 42 strains, 33 strains (78.6 %) were disappeared, 2 strains (4.8 %) were decreased, 6 strains (14.3 %) were unchanged and only one was substituted.
As for side effects, nausea was observed in 4 patients and exanthema in 2 patients.

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Pipemidic acid was administered to 20 in- and out-patients suffering from urinary tract infections. Its daily doses were 0.5, 0.75 and 1.5 g for acute simple cystitis, and 1. 5 g for complicated urinary tract infections. Medication was made for 3 to 7 days. The results obtained were excellent in 8, good in 4, and ineffective in 8 of total 20 cases tested, the rate of effectiveness being 60%. When the cases were divided into acute simple cystitis and complicated urinary tract infections, all were treated successfully (6 excellent and 2 good cases) in the former disease with the efficacy rate of 100%, while the latter consisted of 2 excellent, 2 good and 8 ineffective cases with the efficacy rate of 33%. Infecting organisms disappeared after the treatment of this drug in 10 cases (50% efficacy rate from the bacteriological point of view), 9 of which were caused by Escherichia coli. Nausea was observed in 3 cases as side effect of the drug.

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Pipemidic acid was administered orally at daily doses of 500-1, 000mg for 2-8 days to 17 cases of acute cystitis and 5 cases of complicated urinary tract infections.
1) Of 22 cases treated, excellent results were obtained in 18 (81.8%), especially in acute cystitis usually at a daily dose of 500 mg.
2) No side effects were observed except for 1 case complaining of anorexia.

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Pipemidic acid was administered to 21 cases of complicated and simple urinary tract infections. Clinical results were excellent in 8 cases, good in 4 cases and poor in 9 cases with the rate of efficacy of 57.1 %.
Subjective symptoms observed as side effects were exanthema in 1 case and gastrointestinal disturbance in 1 case. No significant adverse reaction was observed in clinical laboratory findings of hemogram, and the tests on renal and hepatic functions.

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Pipemidic acid (PPA) is a new synthetic antibacterial agent, whose chemical structure is similar to piromidic acid and nalidixic acid, and has been developed by Dainippon Pharmaceutical Co., Ltd. in Japan.
Some advantages of PPA has been known compared with the latter two chemotherapeutic agents, one of them being antibacterial activity against Pseudomonas aeruginosa.
Fundamental and clinical studies on PPA were carried out with following results.
1) Minimum inhibitory concentrations of PPA against 53 strains of Pseudomonas aeruginosa isolated from urinary tract infections ranged between 3. 12 μg/ml and 100 μg/ml except for 2 resistant strains.
Eight out of 11 strains of E. coli were inhibited at the concentration of 25 μg/ml or lower.
2) Serum and urine levels after oral administration of PPA (500 mg) in fasting and non-fasting conditions were measured in 3 healthy adults respectively.
The serum and urine levels in the non-fasting group were higher than those in the fasting one. Peak serum levels were obtained one hour after administration in the both groups, which were3. 9 μg/ml in the non-fasting group and 2. 0 μg/ml in the fasting one.
The total recovery rates from urine up to 6 hours were 41.5% in the fasting group and 52.8% in the non-fasting one.
3) PPA was administered at doses of 0. 75 to 2.0 g/day in 28 cases of urinary tract infections, consisting of 16 cases of acute simple cystitis, 6 cases of chronic complicated cystitis and 6 cases of chronic pyelonephritis.
Excellent or good clinical results were obtained in 14 of 16 cases of acute simple cystitis (87. 5%), 1 of 6 cases of chronic cystitis, (16. 7%) and 3 of 6 cases of chronic pyelonephritis (50%).
4) No particular side effect was observed in all patients.
No significant change was found in liver and renal function tests performed before and after administration.

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