1. Mecillinam, which is the active form of pivmecillinam, showed remarkably potent antibacterial activity against E. coli. Proteus, Klebsiella and Enterobacter were also susceptible to the drug.
2. Antibacterial activity and bactericidal action of mecillinam were influenced by inoculum sizes.
3. Morphological study revealed that E. coli did not make filament-shaped cells but swollen round-shaped cells in the presence of mecillinam.
4. In vitro synergistic effects of mecillinam with other penicillins and cephalosporins were demonstrated.
5. Pivmecillinam was clinically effective in patients infected by ampicillinor amoxicillin-resistant E. coli.
6. Main indications of pivmecillinam may be urinary-tract infections. The drug was satisfactorily effective at daily doses of 150-200 mg for simple urinary-tract infections, but it was sometimes necessary to increase doses up to 300-400 mg per day for complicated urinary-tract infections. Thus, the drug has its merit in good efficacy with lower doses than conventional oral penicillins.
7. The drug was well tolerated in clinical use, and caused comparatively few adverse reactions though GOT and GPT elevation and RBC decrease were reported.

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In vitro and in vivo antimicrobial activities of mecillinam, a new semisynthetic penicillin were studied using various species of bacteria which were isolated from clinical specimens. The results obtained are summarized as follows.
(1) Mecillinam was found to be effective against Escherichia coli and Klebsiella pneumoniae, but ineffective against Pseudomonas aeruginosa. MBC (minimum bactericidal concentration) test has disclosed that the antibacterial action of the drug is bacteriostatic.
(2) Mecillinam was hydrolyzed by both Type I penicillinase and Type II penicillinase. But mecillinam was not hydrolyzed by penicillinase produced by both Pseudomonas aeruginosa and Staphylococcus aureus, but was ineffective against these strains.
(3) In vivo effect of mecillinam was examined by mice infected with E. coli. Mecillinam exhibited to be more effective than ampicillin, but dose response of this drug was weaker than that of ampicillin.

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We tested the antibacterial activity of mecillinam against various pathogens isolated from clinical materials in Clinical Laboratories of Juntendo University Hospital during 1975. Pathogens we used are E. coli, Klebsiella, Enterobacter, Proteus, Acinetobacter, Haemophilus influenzae and Streptococcus faecalis. We also compared the antibacterial activity of this drug with ampicillin and amoxicillin.
The minimum inhibitory concentration of mecillinam is much influenced by inoculum size, so we used 10⁶/ml bacterial suspension for inoculation. This inoculum size is about 1/100 of routinely used size.
Mecillinam showed strong antibacterial activity against E. coli, Klebsiella, Enterobacter and Proteus and correlations of activity were not observed between this drug and ampicillin or amoxicillin.
The antibacterial activity of mecillinam against Acinetobacter, Haemophilus influenzae or Streptococcus faecalis was rather weak.

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In the bacteriological evaluation of mecillinam and pivmecillinam, newly developed penicillins, with ampicillin (ABPC) as a reference drug, the following results were obtained.
1) Mecillinam showed, unlike ABPC, more potent antibacterial activities against gram-negative bacilli than against gram-positive bacteria.
2) When the inoculum size was 10⁶ cells/ml, clinically isolated Escherichia coli showed higher susceptibility to mecillinam than to ABPC. Such strains as were found resistant to mecillinam with 10⁸ cells/mlinoculation turned sensitive to mecillinam with 10⁶/m1 inoculation. The same phenomenon was observed with Klebsiella pneumoniae, but was less remarkable than with E. coli.
3) Influence of inoculum size upon MIC was studied with E. coli. Mecillinam received more influence than ABPC.
4) Influence of inoculum size upon growth curve was also studied. With Staphylococcus, dose-related bactericidal effect was found. While, with E. coli, inoculum size was highly influential and only bacteriostatic effect was shown even with high concentration of mecillinam when the size was large.
5) In vitro study on development of resistance to mecillinam was performed by use of E. coli, Klebsiella pneumoniae and Proteus as test organisms. The resistance development varied with species and strains. Virulence of such resistant strains in mice was less potent than that of the original strains.
6) Studies on synergistic effect of mecillinam and dicloxacillin were conducted with E. coli and Klebsiella pneumoniae and a remarkable synergism was observed.
7) Spherical cells of E. coli which was formed by the action of mecillinam were a little more easily phagocytized by PMN of neutrophil of man and guinea-pigs than normal cells. Such spherical cells as well as normal cells were killed when treated with human serum.
8) In the mouse experimental infections with E. coli, pivmecillinam showed more potent therapeutic effect (lower ED₅₀ value) than ABPC. In addition, pivmecillinam was effective against ABPC-resistant strains. However, mecillinam received more influence of inoculum size than ABPC as in vitro study. Pivmecillinam showed the highest survival rate when administered immediately after challenge.

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A morphologic study was made of the antimicrobial activity of mecillinam on Escherichia coli NIH by the use of phase contrast microscope, scanning and transmission electron microscopes.
1) The observation with the phase contrast microscope disclosed that when 0.001 μg/ml of mecillinam was allowed to act on the test organism, the organism grew in a similar manner to the control, and thatwhen 0.01, 0.1, 1.0, 10 and 100 μg/ml of the antibiotic were allowed to act on the organism, they eventually produced spherical cells, but there was a dose-dependent difference in the number of cell division to the formation of spherical cells.
2) The observation with the scanning electron microscope showed that the surface structure of normal cells assumed a smooth, rod shape, and that the cells exposed to mecillinam were sterically caught hold of as rounded cells, that is, four hours after the addition of 1 μg/ml of mecillinam, the cells were abnormally swollen or abnormal cell division was taking place in them.
3) The observation with the transmission electron microscope showed that one hour after the addition of 1μg/ml of the antibiotic, the cells of the test organism presented bleb-like structures in their outer layer, and plasmolysis was also observed in them. As the antimicrobial activity of the antibiotic further abvanced, the cells assumed a round shape, to convert themselves into a spherical form.
These cells had the cell wall and contained vacuolar structures in their cytoplasm. Such an abnormal cell division that a septum was formed from one directoin of the cell wall was observed, too.

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The in vitro antibacterial activity of mecillinam and pivmecillinam was investigated and the following results were obtained.
1. Antibacterial activity of mecillinam against gram-positive bacteria was inferior to that of ampicillin (ABPC) and amoxicillin (AMPC), while it was superior to that of ABPC and AMPC against a wide range of gram-negative bacteria except Pseudomonas aeruginosa.
2. Mecillinam was active against clinical isolates of E. coli, Klebsiella pneumoniae, Serratia marcescens and Proteus spp.
It was demonstrated that the number of sensitive strains increased at small inoculum size and this was remarkable in Proteus spp. Mecillinam was also active against ampicillin-resistant strains of E. coli and Klebsiella pneumoniae.
3. The kind of medium influenced the antibacterial activity of mecillinam and it was mainly due to the concentration of NaCl in the medium. Furthermore, the antibacterial activity of mecillinam against several bacterial species and strains was influenced by inoculum size.
As the cause of this phenomenon, mutation rate, time which requires to exhibit the bactericidal activityafter the addition of the drug, or productivity of β-lactamase of the organism are complexly concerned.The degree of concern of these causes differs from one test organism to another.
4. Mecillinam acted bactericidally against E. coli and Klebsiella pneumoniae, but not so distinctly against Serratia marcescens and its action against Proteus vulgaris and Proteus mirabilis was bacteriostatic.
The bactericidal activity of mecillinam was influenced by inoculum size, time of drug addition, culture condition of the organism and addition of NaCl.
5. The organism, which had been exposed to mecillinam once or continuously in vitro, gained resistance to the antibiotic.
The resulting resistant strains became sensitive after transfers in the medium free from the antibiotic, and its process differed among the test organisms. The strains which became resistant to mecillinam grew more slowly than the parent strains and the growth speed of them still fell in the medium containing the antibiotic. The lactose-ferment bacteria in the feces of mice, which had been administered pivmecillinam or ampicillin orally, gained resistance to each antibiotic in a similar way.

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Protective effects of pivmecillinam in mice infected intraperitoneally with E. coli, Klebsiella pneumoniae, Proteus vulgaris and Proteus mirabilis were compared with that of ampicillin and cephalexin. Pivmecillinam showed considerablly higher protective effect than ampicillin in mice infected with E. coli and Klebsiella pneumoniae. Comparable activity of pivmecillinam and ampicillin was observed in mice infected with Proteus vulgaris and Proteus mirabilis, whereas pivmecillinam was less active than ampicillin against infection with Staph. aureus. Pivmecillinam was found to be more active than cephalexin against infections with the highly ampicillin-resistant strains of E. coli, Klebsiella pneumoniae and Proteus vulgaris. Protective effect of pivmecillinam decreased with increasing the challenge dose as in the case of ampicillin and cephalexin.

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Resistance of mecillinam to hydrolysis by β-lactamase from Escherichia coli was examined in relation to the antibacterial activity against 88clinical isolates of E.coli.
1) Mecillinam exhibited apProximately 32times stronger antibacterial activity against ampicillin sensitive strains and approximately 512times stronger activity against ampicillin resistant strains than ampicillin.
2) All strains of E.coli resistant to ampicillin produced β-lactamase. The MIC of mecillinam against those strains was 4-500 times higher than that againstβ-lactamase non-producing strains. While, the MIC of ampicillin against β-lactamase producing strains was 100-2, 000 times higher than that against β-lactamase non-producing strains.
3) There was correlation between the amount of β-lactamase produced by ampicillin resistant strains and the susceptibility of the strains to mecillinam and ampicillin.
4) Three different types of β-lactamase produced by ampicillin resistant strains of E.coli showed extremely lower affinity to mecillinam than to ampicillin, and then mecillinam was more resistant to hydrolysis by these enzymes than ampicillin.
5) Although the MIC of mecillinam was not significantly influenced by the inoculum size in ampicillin sensitive strains of E.coli, in ampicillin resistant strains it was strongly influenced proportionally to the amount of the β-lactamase produced.

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Immunological cross-reactivity of mecillinam in comparison with penicillin-G, ampicillin, carbenicillin, sulbenicillin and cephalothin was examined. Like several penicillins, anti-mecillinam-HSA (human serum albumin) antibody was obtained in the rabbits sensitized with the mixture of mecillinam-HSA conjugate and FREUND'S complete adjuvant. From the quantitative precipitintest, hapten inhibition test and agar-gel precipitation test, immunologically specific reaction was observed between anti-mecillinam-HSA serum and mecillinam-BGG (bovine gamma globulin) conjugate, although weak cross-reaction was observed among all test penicillins. While immunological specificity of mecillinam with penicillins was not clear in passive cutaneous anaphylaxis (PCA) test. No cross-reaction of mecillinam with cephalothin was observed in all methods tested.

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For the determination of mecillinam concentration in body fluids, a thin-layer cylinder-plate method, using Escherichia coli NIHJ as the test organism, was established. Sensitivity of this method for mecillinam wasabout 0.02μg/ml. A thin-layer chromatography-bioautography system was used for differentiation of pivmecillinam and mecillinam.

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Plasma levels, tissue distribution and urinary and biliary excretion of mecillinam after oral administration of pivmecillinam were studied in mice, rats, rabbits given a dose of 100 mg/kg and in dogs given a dose of 20 mg/kg.
1) The absorption of pivmecillinam was so rapid that antibiotic levels in blood and tissues as mecillinam were found to reach the peak 0.5 or 1 hour after administration.
2) Antibiotic activity which was measured as mecillinam distributed widely in visceral organs and relatively high distribution was noted in the liver and kidney.
3) Within 8 hours after pivmecillinam administration, approximately 25, 10, 20 and 19% of the given dose as mecillinam were excreted via urine in mice, rats, rabbits and dogs, respectively.
4) Biliary excretion of mecillinam in rats was 0.25% of the given dose as mecillinam within 8 hours after pivmecillinam administration.

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The metabolism of a delivative of penicillin, pivaloyloxymethyl-6β- [(hexahydro-1 H-azepin-1-yl) -methylene amino] -penicillanate hydrochloride (pivmecillinam), in rats was studied using ¹⁴C-pivmecillinam synthesized by labelling the methylene amino portion with _l4C. The urine (0-8hr.), bile (0-8hr.) and plasma at peak time (30 min.) were taken from rats to which ¹⁴C-pivmecillinam was administered orally and the radioactive metabolites in these samples were analysed by HLC and TLC. The results are summalized as follows.
1. The urine contained at least 8 radioactive metabolites which consists of 3 major metabolites, 6-β- [(he-xahydro-1 H-azepin-1-yl) -methyleneamino] -penicillanic acid (mecillinam), disodium 5, 5-dimethyl-2- (1'-fo-rmamidomethyl) -thiazolidine-1', 4-dicarboxylate (BB-517) and 6-β- [(hexahydro-1 H-azepin-1-yl) -methylene amino] -penicilloic acid (BB-511), each distribution ratio of which was 28.2, 23.2 and 19.9% of the total radioactivity in the sample, and 5 minor metabolites, 5, 5-dimethyl-2-β- (N-formamidomethyl) -thiazolidine-4-carboxylic acid (FL 1114), (8.4%), 2- [1'-carboxy-1'- (hexahydro-1 H-azepin-1-yl) -methyleneaminomethyl] -5, 5-dimethyl thiazolidine-4-carboxylic acid (FL 1115), (7.3%), sodium-6-formamido-penicillanate (FL 1115) and 2 unknown compounds.
2. In the bile, the major metabolites identified were mecillinam (18.4%) and BB 511 (29.9%) and the minor metabolites identified were BB-517 and FL 1114.
3. The major metabolite in the plasma collected at peak time was mecillinam (50.9%) and the minor metabolites were BB-511, FL 1114, BB-517 and FL 1115.
4. Pivmecillinam was not detected in any sample.

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Pivmecillinam metabolites and their excretion rate in human urine were studied in the two volunteers. After administration of tablets of pivmecillinam containing 500 mg as mecillinam to man, the urine up to 6 hours were collected for every 2 hours and analysed by liquid chromatography, gas chromatography and TLC-fluorodensitometry. The following resultsl were obtained.
The principal metabolite in the human urine was mecillinam, and minor quantities of BB-511, BB-517 and HIS-1201 were also detected as the metabolites from the penicilline structure. Total recoveries of administered dose for the two volunteers were approximately 60 and 40%, respectively, and found relatively lower excretion rate of the minor metabolites to mecillinam than that in the case of rat.
As for the metabolites from the side chains, hexamethylenimine and pivalic acid were detected.

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Pivmecillinam, an ester of mecillinam, which is a new β-lactam antibiotic, has been investigated to give the following results.
MIC's of meciliinam for 18 strains of Escherichia coli were in the range of 0.1 to 100 μg/ml with inoculum size of 10⁸/ml using plate dilotion methed. Lower MIC's of the drug in the range of 0.1to 1.6 μg/ml was found with inoculum size of 10⁶/ml.
The peak concentration in serum after pivmecillinam (equimolar to 200 mg of mecillinam) given orally in 5fasting healthy volunteers averaged 2.6 μg/ml at one hour, as compared with 1.71 μg/ml when administered with food to the same volunteers. Forty-four per cent of the administered dose was excreted in the urine over the 6-hour collection period in the fasting state and 30 per cent of when given with food.
Administration of pivmecillinam in pre-prandial or post-prandial state did not influence the concentrations in serum and urinary recovery of the drug in the study of two repeated doses.
Thirty-four cases, including 29 of urinary tract infections, and 5 of biliary infections, were treated with pivmecillinam for 7 days orally. One of 29 patients with urinary tract infections showed excellent, response 22good, 5 moderate and one no response. Four of 5 patients of biliary infections failed to respond. As to the side effect of the drug, anorexia and diarrhea were observed in 2 patients. An increase in GOT was observed in 3 patients.

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1) Pivmeciilinam converts in vivo into mecillinam. Mecillinam showed, with 10⁶ cells/ml inoculum size, potent in vitro antibacterial activities against E. coli and Klebsiella, but was less potent against Serratia and Acinetobacter.
2) After oral administration of pivmecillinam at a dose of 100 or 200 mg, peak plasma mecillinam level reached about 1 μg/ml.When it is given after meal, the plasma level was comparatively low. Urinary recovery during 6 hours after administration was about 30-40%.

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On a new β-lactam antibiotic, pivmecillinam, some studies were performed and the following results were obtained.
1. The susceptibility of various species of gram-negative bacilli isolated from clinical specimens was tested against mecillinam comparing with those of ampicillin. It was observed that the MIC values were apt to be influenced by inoculum size and sometimes colonies were found on the plates containing with higher concentration of drug, skipping one or more plates in the graded series of two fold dilution. The susceptibilities of some strains of Klebsiella and E. coli using inoculum size of 100 fold dilution of overnight culture were considerably excellent comparing with that obtained by original culture.
2. The conversion of pivmecillinam to mecillinam in broth and pH 7.0 phosphate buffer solution was confirmed using bioautography. The mixing of pivmecillinam with organs' homogenates of various animal species led to the production of mecillinam at different speeds. Especially the speed was the slowest in case of dog intestine.
3. Clinically pivmecillinam was administered to a total of 11 cases, that is, 3 of pneumonia, 3 of tonsillitis and 5 of urinary tract infection. The results were judged as effective in 6 cases, fair in 3 and poor in 2. Though urticaria-like eruption was observed transiently in one case, it subsided during the continuation of administration without the confirmation of causative agent. Various laboratory findings obtained before and after the medication revealed no abnormal values in any item of examination.

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Pivmecillinam was clinically studied to give the following results.
1. Antibacterial activities
In vitro antibacterial activities of mecillinam which is produced by hydrolysis of pivmecillinam were influenced by inoculum sizes. With inoculum size of 10⁸ cells/ml, a peak MIC distribution of E. coli was at 12.5 μg/ml, and that of Klebsiella and Proteus mirabilis was at 100 μg/ml. While, with inoculum size of 10⁶ cells/ml, mecillinam showed MIC of 0.39-0.78 μg/ml against these organisms.
2. Absorption and excretion
Three fasting healthy adults were given pivmecillinam in a 50mg oral dose. Peak serum Mecillinam level (1.15-1.56 μg/ml.) appeared one hour after administration. The level rapidly decreased with half-life of about 1 hour. Mean 6-hour urinary recovery was 49.1%. While, in a patient with chronic renal insufficiency (creatinine clearance : 14.0ml/min), high serum mecillinam level was maintained for a comparatively long time (hal-lfife in serum : 2.26 hours) and 6-hour urinary recovery was only 12.5%.
3. Clinical responses
One case with cystitis, 1 case with acute cystitis, 1 case with chronic cystitis and 2 cases with acute pyelonephritis were given pivmecillinam at daily doses of 400mg for 10-31 days. Of them, the responses were good in 4 cases and poor in 1 case. Against the Klebsiella pneumoniae which was a causative organism of the poor clinical response, mecillinam showed MIC of 6.25 μg/ml at the beginning of treatment. However, after 10-day treatment with daily doses of 400mg, 100 μg/ml of mecillinam did not inhibit the Klebsiella isolated from the patient. No side effects were observed.

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1. In vitro antibacterial activities of mecillinam varied with inoculum size. Its antibacterial activities with 10⁶ cells/ml inoculum size were more potent than with 10⁸ cells/ml. Staphylococcus aureus and Serratia marcescens were less susceptible to mecillinam than to ampicillin with 10⁶ cells/ml. E. coli showed, with 10⁸ cells/ml, slightly higher susceptibility to mecillinam than to ampicillin and, with 10⁶ cells/ml, exceedingly higher susceptibility to mecillinam than to ampicillin. Klebsiella showed, with 10⁶ cells/ml, considerably higher susceptibility to mecillinam than to ampicillin, but was less susceptible with 10⁸ cells/ml to mecillinam as well as to ampicillin.
2. Peak serum mecillinam level appeared one hour after oral administration of pivmecillinam. The peak level was 0.78 μg/ml following a 50mg dose, 1.71 μg/ml following a 100mg dose and 2.95 μg/ml following a 200 mg dose. Six-hour urinary recovery was 56.8% after a 50 mgdose, 51.5% after a 100mg dose and 51.7% after a 200mg dose. Bile mecillinam concentration increased with time until 3 hours after administration but was lower than the serum level.
3. Three cases with biliary infections and 9 cases with urinary-tract infections were given pivmecillinam. Of 3 cases suffered from cholecystitis with gallstone, the response was clinically good in 2 cases and bacte-riologically good in 1 case. Of 2 cases with acute pyelonephritis and 3 with acute cystitis, 4 cases responded to the therapy clinically and bacteriologically. Of 4 cases with chronic cystitis with indwelling catheter, the response was clinically good in 2 cases and bacteriologically good in 1.
4. No note worthy side effects were observed except gastric disterbances noted in 2 cases who were given doses of 600 and 800 mg per day. Chemical analysis of blood demonstrated no abnomal findings.

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Pivmecillinam as well as mecillinam, the real active form of pivmecillinam in the body, were examined on their antibacterial activity, and some clinical trials were also carried out. The results obtained were as follows :
1) MIC of bacteria isolated from human infection foci :
Method : Standard method recommended by Jap. Soc. Chemoth., inoculum conc. of bacteria was 10⁸/ml. Most E.coli strains showed lower MIC of mecillinam or pivmecillinam than those of ampicillin. The major part of ampicillin resistant strains, too, were found to be more or less sensitive to this drug. On the other hand, mecillinam was less effective to Staphlococcus aureus than ampicillin or penicillin G.
2) Influence of pH and serum on the antibacterial activity :
Method : Band culture method (Okubo, H. et al.), Comparing the length of inhibition zones produced by the drug dissolved in 100% human serum with those in phosphate buffer (pH 7.2 or 8.0), the activity of the drug, being more potent in pH 7.2 buffer than in pH 8.0 one, seemed not to be impaired byserum protein.
3) Clinical trials :
Sixteen patients with infections, mostly of urinary or respiratory tract, were treated with the drug 200 mg/day. The results were as follows : Favorable both bacteriologically and clinically…8, Favorable only clinically, as the pathogens could not be identified…5, No effectiveness…2, Undetermined…1.
Although no severe side effects were observed in those patients, some of them showed decrease of red blood cell count and of hemoglobin content, which might be attributed to infection, but, in one of the patients, aggravation of the existing anemia by the drug administration could not be ruled out. In this respect, it would be better to pay attentions in further clinical use of the drug.

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1) Antibacterial activities
For 22 standard strains preserved in our department and 513 strains of clinical isolates (Escherichia coli, 81 strains; Klebsiella aerogenes, 81 strains; Serratia marcescens, 212 strains; Proteus vulgaris, 22 strains; Proteus mirabilis, 50 strains; Proteus rettgerii, 14 strains; Proteus inconstans, 11 strains and Proteus morganii, 42 strains), MICs of pivmecillinam, mecillinam and ampicillin were determined by the standard method of Japan Society of Chemotherapy. Mecillinam showed more potent antibacterial activities than ampicillin against E. coli, Klebsiella aerogenes, Proteus vulgaris and Proteus mirabilis, but was less potent than ampicillin against gram-positive cocci. MIC of mecillinam varied with inoculum sizes and MIC with 108 cells/ml inoculum size was considerably lower than with 10⁸ cells/ml.
2) Absorption and excretion
Three healthy adults were orally given 100 mg (as mecillinam) ofpivmecillinam. Peak plasma mecillinam level reached 0.54-0.95 μg/ml one to two hours after administration. No mecillinam was detected in the plasma 6 hours after administration. The mean 6-hour urinary recovery was 38.7%.
3) Clinical results
Six cases with acute cystitis, 2 cases with chronic cystitis and 2 cases with chronic pyelonephritis were given pivmecillinam in doses of 300-400 mg per day for 7-21 days. The response was excellent in 7 cases, good in 1, poor in 2. No abnomal findings were demonstrated with hematological examination, blood chemistry test and urine analysis except slight increase of total serum bilirubine (1.0 mg/dl→1.3 mg/dl) in one case, which was rapidly normalized.

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In the basic and clinical studies on pivmecillinam, a new synthetic oral penicillin, the following results were obtained.
Four patients were orally given a 200mg dose of pivmecillinam and mecillinam level in plasma and bile were determined. The plasma level was 2.8μg/ml as peak at one hour after administration and 1.4, 0.8, 0.4μg/ml at 2, 4, 6 hours after dosage respectively. Mecillinam level in choledochus bile was 1.1μg/ml at one and half hours after administration. Mecillinam level in gallbladder bile was 10 times as high as that in choledochus bile when the cystic duct was patent.
The relative electrophoretic mobility of mecillinam in serum to albumine was-0.63 and was different from that of ampicillin (+0.61).
Twenty-nine cases with soft tissue infections were treated with pivmecillinam in oral doses of 400-4, 800 mg per day. Of them, 19 cases (66%) responded to therapy. No side effects were observed.

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1) MIC (overnight culture) of mecillinam against clinically isolated organisms was determined. None of 54 isolates of Staph. aureus were susceptible to less than 25 μg/ml of mecillinam and, of them, 49 strains were not susceptible to 100 μg/ml or less. However, E. coli showed much higher susceptibility to mecillinam than to ampicillin. Of 54 isolates of E. coli, 39 (72%) were susceptible to 1.56 μg/ml, or lower of mecillinam. Number of resistant strains which were not susceptible to less than 100 μg/ml was 8 with mecillinam and 18 with ampicillin. The antibacterial activities of mecillinam against susceptible strains of E. coli were comparable to gentamicin. None of Proteus mirabilis and Pseudomonas aeruginosa were susceptible to 100 μg/ml or less of mecillinam. Of 27 isolates of Klebsiella, mecillinam showed MIC of 0.4 μg/ml for one, but more than 100 μg/ml for the other 26.
2) Three fasting healthy adults were orally given 200 mg of pivmecillinam and serum mecillinam level was determined : 3.13 μg/ml 30 minutes after administration, 5.28 μg/ml at one hour as peak level and 0.58 μg/ml at 4 hours. The antibiotic was rapidly well absorbed. Six-hour urinary recovery was 74.9%. Bile mecillinam level in man was 7.0 μg/ml one hour after a 300 mg oral dose which was three times as high as the serum level.
3) Tissue level
Mecillinam level in various organs in rats was determined after a 20 mg/kg oral dose of pivmecillinam. The antibiotic rapidly transfered into organs and the peak level appeared 0.5-1 hour after administration. Mecillinam in organs was rapidly eliminated and no accumulation was observed. Mecillinam level was high in the order of liver, kidney, serum, lung, spleen and heart. No mecillinam was detected in brain.
4) Metabolism
Bioautogram of the urine sample from healthy adults orally given 200 mg of pivmecillinam showed no metabolites with antibacterial activities except mecillinam.
5) Clinical responses
Of 2 patients with periproctal abscess, 1 responded to therapy. One patient with infected atheroma showed good response to therapy. No side effects were observed.

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The biliary excretion of pivmecillinam and amoxicillin was studied in 5 patients with common bile duct drainage for cholelithiasis by a cross-over method. After single oral administration of 100mg of pivmecillinam, an average peak serum level was 0.90±0.46μg/ml at 2 hours after administration, and this of 250 mg of amoxicillin was 2.79±0.49μg/ml at 2 hours after administration.
An average peak biliary level was 4.03±0.79μg/ml at one hour after administration of pivmecillinam, and this of amoxicillin was 1.87±2.08μg/ml at 2 hours after administration. The peak biliary level of pivmecillinam was 4.4 times higher than the peak serum level of this drug.
Urinary recovery in the first 8-hour urine sample was 28.37±8.44% for pivmecillinam and 37.30±28.29% for amoxicillin.

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Pivmecillinam, a new derivative from 6-aminopenicillanic acid, was investigated on its serum level, bile level, urinary excretion, clinical effectiveness and side effects.
1. Following an oral administration of either 50 or 100mg pivmecillinam in 4 healthy adult volunteers, the mean serum level showed a peak of 0.66μg/ml 30mins. after the former dose and 1.31μg/ml 1 hourafter the latter one, while urinary excretion of the agent accounted for 52.7 and 43.3 per cent respectively within 8 hours.
2. Oral pivmecillinam showed no definite distribution of the active agent in bile, which had been collected through a T-shaped catheter indwelt in the common bile duct after a biliary tract surgery.
3. Oral pivmecillinam was given to 49 patients with various infections in the field of surgery, and its effectiveness was documented in 41 ones (83.7%). Clinical response evaluated in 12 patients with biliary tract infections was excellent on 2 cases, good 5, fair 3 and poor 2, efficacy rate accounting for 83.3 per cent, in 10 ones with urinary tract infections excellent on 1 case, good 3, fair 3 and poor 3 (efficacy rate 70.0%) and in 17 ones with miscellaneous infection excellent 2, good 9, fair 3 and poor 3 (efficacy rate 82.4%).
4. A few reversible side effects following oral dose of pivmecillinam were seen, i.e. epigastric discomfort on 1, nausea 2, shingles 1, and elevated serum GOT 1, while none dropped out the trial because of toxicity induced by the agent.

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Laboratory and clinical studies on pivmecillinam, a new 6β-amidinopenicillanic acid, were carried out and the following results were obtained.
1) Antimicrobial activity (Minimum Inhibitory Concentration) : Excellent antibacterial activity was revealed against E. coli at 10⁶ cells/ml inoculum size, but poor against Klebsiella pneumonia, Proteus and Pseudomonas aeruginosa.
2) In cross over method, average peak blood level of 3 fasting healthy adults was 2.1μg/ml 1 hour after 200mg dosing with half life of 1.5 hour, and 4.4μg/ml 1 hour after 400mg dosing with half life of 1.7 hour.
Urinary excretion were 50.4% for 6 hours in the former and 50.5% for 12 hours in the Iatter situation.
In the patient with mildly impaired renal function, peak blood level was 0.8μg/ml 1 hour after 100mg dosing with half life of 3.5 hours. Urinary excretion was 27% for 12 hours.
3) In clinical use seven of 8 simple acute urinary tract infection (simple acute cystitis) and one of 2 simple chronic urinary tract infection responded satisfactorily to pivmecillinam. And Four of 8 complicated chronic urinary tract infection responded satifactorily.
These results suggest that about 200mg daily will be sufficient for simple acute cystitis., but for complicated chronic urinary tract infection around 1, 000mg will be required.

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1) In the studies of antibacterial activities of mecillinam against clinically isolated organisms, mecillinam showed comparatively low MIC against E. coli but showed high MIC against Proteus mirabilis and Staph. epidermidis.
2) Thirty-two patients suffering from urinary tract infections were orally given pivmecillinam at the daily dose of 200 mg. The drug showed a remarkable efficacy against simple acute cystitis but was less effective against urethritis.
3) Administration of pivmecillinam for 3 days or longer resulted in positive therapeutic response in 90.6%.The patients of simple acute cystitis given the drug for 3-4 day sresponded to therapyin 92.6%.
4) As classified by causative bacteria, the drug was clinically effective against infections due to Staph. epidermidis and E. coli.
5) The side effects noted were slight gastro-intestinal disturbances in 3 of 32 cases.
6) When 7 patients of simple acute cystitis were given 200 mg at a single dose, therapeutic response was recognized only in 3 of them.

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The in vitro activity of mecillinam against bacteria isolated from infected urines, compared with that of ampicillin, is low against Staphylococcus epidermidis (MIC, more than 50 μg/ml), but remarkably high against E. coli strains (MIC, ≤=0.2-3.12μg/ml), even against those of ampicillin resistance, the MIC varies from 0.39 to 6.25 μg/ml.
Pivmecillinam was applied for the treatment of 85 cases of urinary tract infections. The cases were 72 of acute simple cystitis, 2 of prostato-cystitis, 6 of acute or chronic uncomplicated pyelonephritis and 5 of chronic complicated lower urinary tract infections. Fourty-two cases of acute simple cystitis and prostatocystitis were treated in a dose of 0.3-10mg divided two times a day, for the purpose of investigations on small dose therapy. The bacteriological response was gained 77.5% in these cases. In 32 cases of acute cystitis at a dose of 100mg to 600mg a day, the rate of effectiveness was 90.6%, even in the cases caused by penicillin-resistant strains, the cure rate was as high as 86.7%. In 6 cases of pyelonephritis, the rate was 50% in acute or chronic. Five complicated lower urinary tract infections were treated at a dose of 100-750mg a day for 2 weeks. Five of 3 were gained bacteriological response.
The side effects of pivmecillinam were the disturbances of gastrointestinal tract such as stomach distress, loss of appetite, loose stool, which were seen in 4.7%. No abnormal effects on BUN, creatinine, S-GOT and peripheral hematology were observed.
Conclusion
Mecillnam is suprior to other broad-spectrum penicillin derivatives such as ampicillin, amoxicillin, etc., principally against gram-negative bacteria, even against penicillin-resistant strains producing penicillinase.
Against the urinary tract infections due to gram-negative bacteria, especially caused by E. coli, including penicillin-resistant strains, pivmecillinam is an excellent chemotherapeutic agent of oral use.

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A new antibiotic, pivmecillinam, was studied both bacteriologically and clinically in the urological field and following conclusion were obtained.
1) MIC of pivmecillinam against 106-urinary E. coli, 60-urinary Klebsiella, and 59-urinary Proteus mirabilis were equal to or inferior to those of ampicillin. MIC of this antibiotic is altered by inoculum size of the organisms, especially for E. coli strains. Pivmecillinam has an extremly high level of antimicrobial activity at a concentration of 10⁶ of organism against E. coli.
2) Mecillinam had superior synergenic ability to cefalexin than ampicillin against E. coli NIHJ JC-2.
3) Pivmecillinam may have an exellent antimicrobial activity to so called highly resistant strains against ampicillin. But these strains have not always been in high frequency.
4) The organism contacted with mecillinam is likely to gain resistance more easily than those done with ampicillin.
5) Urinary concentration of mecillinam reached its peak at 0.5-1 hours after oral administration of 150 mg of pivmecillinam and urinary recovery rate for 6 hours was about35%. By the result, of bioautogram, there were no antibacterial substances in urine except mecillinam.
6) The therapeutic efficacy of the drug evaluated in 35 patients with UTI. 14/15 patients with acute UTI exhibited excellent or good response to pivmecillinam treatment, but efficiency rate of chronic UTI was not so good; 35%.
7) Side effects were noted in 4 out of 35 cases, three were gastrointestinal symptoms and other one showed pruritus at the external genitalia.

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1. In vitro antibacterial activities
A peak of distribution of 50 clinical isolates of E. coli was at 0.2μg/ml, when seen from MIC of mecillinam with inoculum size of 10⁸ cells/ml, and its peak was at 0.1μg/ml or lower with inoculum size of 10⁶ cells/ml. None of 20 clinical isolates of Klebsiella were susceptible to 12.5μg/ml and lower of mecillinam with inoculum size of 10⁸ cells/ml and most of them showed MIC of mecillinam of>100μg/ml. However, a peak distribution of the isolates was as 0.39μg/ml as MIC with inoculum size of 10⁶ cells/ml. Twenty isolates of Serratia were not susceptible to 400μg/ml of mecillinam with inoculum size of 10⁸ cells/ml. Some Serratia, however, were susceptible to 12.5μg/ml or lower with inoculum size of 10⁶ cells/ml. MIC of mecillinam varied with inoculum sizes, but was lower than that of ampicillin against above gram-negative bacilli.
2. Serum level
Healthy adults were orally given pivmecillinam at a dose of 50 mg or 100mg or 200mg (as mecillinam). Peak serum mecillinam level of 1.09μg/ml appeared one hour after a 50mg dose and the peak level was 1.6μg/ml after a 100mg dose. When 200mg of the antibiotic were administered before meal, the peak level was 1.95μg/ml and it was 2.47μg/ml when given after meal. No influence of meal upon serum level was found.
3. Urinary recovery
Eight-hour urinary recovery was 61.9-46.1% following a 50mg or 100mg or 200mg dose.
4. Clinical results
Of 51 cases with urinary-tract infections, the response was excellent in 32 cases, good in 11, poor in 8. Thus, 84.3% of the patients responded to therapy. Thirty-seven cases with simple urinary-tract infections responded to therapy in 100%, and an optimum dose in the simple infections was considered 150-200mg per day.
5. Side effects
Side effects noted were pyrosis in one case and dry mouth and fatigue in one (3.9%). No abnormal findings were demonstrated with laboratory tests.

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1) Minimal inhibitory concentration of mecillinam were determined in 94 strains isolated from urinary tract infections by the plate dilution method. In 10⁸ inoculum size, 10 strains of E. coli (30 strains) were inhibited at 12.5μg/ml or less. Most strains of other species were resistant to 100μg/ml of mecillinam.In 10⁶ ineculum size, 24 strains of E. coli were inhibited at 0.39μg/ml or less. Antibacterial activities of mecillinam against clinically isolated E. coli were rather stronger than ampicillin. Those against clinically isolated Proteus mirabilis and Staphylococcus aureus were rather weak than ampicillin.
2) In one case with normal renal function, the blood level reached to the maximum (1.7μ9/ml) at 1 hour after oral administration of pivmecillinam 200mg, decreased rapidly thereafter, and the urinary recovery rate was 35.1% within 6 hours.
3) Sixty-eight cases with urinary tract infections were treated with pivmecillinam at oral doses of 150-400mg per day. Excellent or good results were obtained in 59 cases.
4) Gastrointestinal symptom was observed in 3 cases and slight elevation of GPT on laboratory findings in 1 case throughout this series.

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On ten volunteers with reduced kidney function, 146.2mg pivmecillinam (equimolar to 100 mg mecillinam) was administered orally for the single dose study and given orally in a dose of 146.2mg q. i. d. for 7 days for the multiple dose study. The patients were divided into three groups according to their kidney functions. The level of mecillinam in serum or urine after dosing of pivmecillinam was compared between the three groups or the studies, and the following results were obtained.
1) In the patients with severe renal insufficiency, who had the level of creatinine clearance less than 30 ml/min, higher mecillinam blood level of greater duration than that of the patients in the other two groups was recognized.
2) The average of urinary concentration and of recovery from urine decreased in company with thelowering of their kidney functions, but the difference between the groups or the studies was statisticallynot significant.
3) In the patients with mild and moderate renal insufficiency, urinary concentration more than the level, necessary to heal urinary tract infections, was expected.

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Thirty-one patients with complicated urinary-tract infections were given pivmecillinam, a new β-lactam antibiotic, in daily doses of 200mg or 400mg for 7 days, and the following results were obtained.
1) With judgement 7 days after terminating treatment, of the patients given 200mg per day, the responsewas excellent in 3 cases, good in 4 cases, fair in 5 cases and poor in 2 cases. Of the patients given 400mgper day, the response was excellent in 7 cases, good in 1 case and fair in 9 cases. In total, 48.4% of thepatients responded to therapy.
2) As classified by causative organisms, the antibiotic is effective against E. coli, Enterobacter, Proteus vulgaris, and Proteus morganii, but was less potent against gram-positive bacteria.
3) Although MIC of mecillinam against most causative organisms except E. coli was more than 100μg/ ml, E. coli showed high susceptibility to the drug.
4) Side effects noted were nausea and gastralgia in one case. No abnomal findings were demonstrated with hematological examination and blood chemistry test.

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Thirty-nine in-and out-patients suffering from urinary tract infections were treated with pivmecillinam.
Pivmecillinam was administered orally at the dosage of 300 mg or900 mg for 7 days.
Of 26 patients with simple acute and chronic cystitis, clinical responses were excellent in 20, good in 3 and poor in 3.
Of 13 patients with complicated chronic cystitis, excellent in 5, good in one, fair in 3 and poor in 4.
Efficacy rates were 74.4% of patients with cystitis, 88.5% of 26 patients with simple cystitis and 46.2% of 13 patients with complicated cystitis.
Out of 39 strains, 30 strains (76.9%) were disappeared, 7 strains (18.0%) were unchanged and 2 strain (5.1%) were substituted.
As for side effect, anorexia was observed in 3 patients (7.7%).
Value of S-GOT and S-GPT were in normal range after treatment inall cases.

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1) Pivmecillinam was administered in 30 cases of various urinary infections diagnozed by Urological Department of Kyushu University. As 4 cases dropped out, examinations were possible in 26 cases.
2) The results obtained were excellent in 14 cases, good in 2 cases and poor in 10 cases out of 26 cases, effective ratio being 62%.
3) Among 12 cases of simple acute cystitis, all cases were excellent. Among 14 cases of complicated urinary infection, the results obtained were excellent in 2 cases, good in 2 cases and poor in 10 cases, effective ratio being 29%.
4) The bacteriological effect obtained were disappearance in 18 strains out of 29 strains, bacteriological effective ratio being 62%. Especially, among 17 strains of E. coli, 14 strains disappeared, bacteriological effective ratio being 82%.
5) The side effect obseved was nausea in 3 cases. No other untoward effects were observed.

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1) Thirty-four patients with urinary-tract infections were given Pivmecillinam.
2) Of the 34 cases, the response was excellent in 16 cases (47.1%), good in 6 cases (17.6%), fair in 3 cases (8.8%) and poor in 9 cases (26.5%). Thus, 64.7% of the patients showed good to excellent response. Patients with simple urinary-tract infections responded to the therapy in 100%, while, those with complicated urinary-tract infections responded in 40%.
3) Efficacy classified by causative organisms was as follows : E. coli, 75.0%; Staph. aureus, 83.3%; Staph. albus, 100%; Cloaca, 71.4%; Pseudomonas, 0%; Proteus mirabilis, 50.0% and Proteus vulgaris, 0%.
4) Pivmecillinam was found effective with small doses and may be recommended as drug of first choice for simple acute urinary-tract infections.
5) No side effects were observed both subjectively and objectively.

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Pivmecillinam is a unique antibiotic of which metabolic derivative, mecillinam, is highly sensitive to gram negative bacteria such as E. coli and Klebsiella. Sensitivity distribution of pivmecillinam and mecillinam to 65 strains of E. coli isolated from UTI patients showed sensitivity peak at 1.56 μg/ml. and 0.39 μg/ ml. Peak serum level reached to 1.04 μg/ml 2 hours after oral administration of pivmecillinam 100 mg in2 healthy adults under non-fasting condition. The urinary recovery rate up to 8 hours was 47.1% and urinary concentration higher than 100 μg/ml continued for 6 hours after the administration.
Pivmecillinam 200 mg q.i.d was given to 30 cases of acute simple cystitis for 3 to 7 days. Bacterial and clinical response were obtained at 90% and 96.7% respectively. Pivmecillinam 600 mg t.i.d was given to 8 cases of chronic complicated cystitis. of 8, eradication of bacteria in a case and decrease of bacterial counts in the urine in 2 cases were observed No unfavourable side effect was noticed.

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In order to make clear the usefulness of pivmecillinam (if pivmecillinam is a valuable addition to the existing chemotherepeutic agents), a double-blind controlled study was carried out in acute simple cystitis on pivmecillinam and amoxicillin. The results of this comparative study were as follows :
1. Although the dosage of pivmecillinam was 1/5 that of amoxicillin, the global judgement and the judgement by the urologist in charge significantly favored pivmecillinam over amoxicillin. Especially, a greater number of excellent responses were obtained with pivmecillinam.
2. In judgement of usefulness, pivmecillinam was significantly superior to amoxicillin.
3. When judgen by symptoms, pivmecillinam was significantly superior to amoxicillin in improvement ofbacterial count and urinary frequency.
4. Pivmecillinam was effective for the infection due to amoxicillin-resistant E. coli.
5. Determination of MICs of the causative organisms before and after treatment revealed less development of resistance with pivmecillinam than amoxicillin.
6. Adverse reactions noted were less frequent with pivmecillinam than amoxicillin and no eruption was recognized with pivmecillinam.
The results indicate that pivmecillinam is more useful for therapy of acute simple cystitis than amoxicillin.

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Basic and clinical studies on pivmecillinam were performed in the field of obstetrics and gynecology to give the following results.
1. Antibacterial activities of mecillinam against clinically isolated E. coli and Klebsiella were determined in comparison with ampicillin. With inoculum size of 10⁸ cells/ml, mecillinam showed as potent antibacterial activities as ampicillin did. While, with inoculum size of 10⁶ cells/ml, mecillinam was more potent than ampicillin.
2. Healthy adults and pregnant women were orally given pivmecillinam. Peak plasma mecillinam level in healthy adults appeared one hour after a 100 mg dose. Mecillinam was proved to transfer into umbilicalcord blood. The antibiotic was detected also in amniotic fluid when given continually.
3. Forty-eight patients with urinary-tract infections or intra-pelvis infections were given pivmecillinam and 81.2% of the patients responded to therapy. No noteworthy side effects were observed except slight gastrointestinal disturbances in 2 cases.

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In vitro antibacterial activities of mecillinam against 108 clinical isolates, and absorption, distribution and excretion as well as therapeutic effects of pivmecillinam in pregnant women were studied to give the following results :
1. Mecillinam showed more potent activities than ampicillin against E.coli
2. Patients in late period of pregnancy suffered from gestational toxicosis showed slower increase and elimination of blood mecillinam level and lower urinary recovery than nomal women. Mecillinam level in umbilical-cord blood was 1/3-1/4 times as high as that in maternal blood. From 2 hours after administration, mecillinam was detected in amniotic fluid. Mecillinam was not detected in milk.
3. Six patients were treated with pivmecillinam in oral doses of 400 mg per day for 5-12 days. The antibiotic showed good therapeutic effect in urinary-tract infections. No side effects were observed.

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Antibacterial activity of pivmecillinam was compared with those of ampicillin and amoxicillin against clinical isolated organisms. Pivmecillinam was more active than ampicillin and amoxicillin to E. coli and Klebsiella pneumoniae.
Pivmecillinam was administered orally at a dose of 50 mg or 100 mg, and various levels were examined in the field of obstetrics and gynecology. The placental passing of pivmecillinam was similar to that of other antibiotics. The amniotic fluid level was higher than other oral antibiotics. The milk level was not recognized in the least.
Pivmecillinam was applied clinically in 9 cases of urinary tract infection and results obtained were good in 6 cases and poor in 3 cases. Among 9 cases, anorexia was obtained in one case and pyrosis in one.They were not severe enough to withdraw the medication.

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