Fundamental and clinical studies on PC-904, a new semisynthetic penicillin developed by Sumitomo Chemical Company Limited, were performed in 46 institutions in Japan and the results were presented at the 25th Congress of Chemotherapy (the annual meeting of Japan Society of Chemotherapy), New Drug Symposium, Gifu, 1977. The results are summarized as follows.
1) In vitro activity of PC-904 against Pseudomonas and other gram-negative bacteria was more potent than the other broad-spectrum penicillins.
2) When 2g of PC-904 were administered by drip infusion, the peak serum level was more than 100μg/ml and its urinary recovery within 6 hours was more than 30%. It was characteristic that 50-60% of administered dose was excreted in bile.
3) Clinical effects of PC-904 against various infections were analyzed by the results of 613 cases out of total 650 cases treated with PC-904. The effective rate in 335 cases of the field of internal medicine was 63. 6% and the effective rate in 275 cases in the field of surgery, urology, obstetrics and gynecology, otorhinolaryngology and ophthalmology was 72.4%, and the effective rate in total of 613 cases was 67.5%.
4) No severe side effects were observed while incidence of allergic reactions was comparatively high. Abnormalities in laboratory findings were observed in some cases, but they turned to normal immediately after discontinuing the drug.

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The antimicrobial and bactericidal activity of PC-904, a new semisynthetic penicillin synthesized in the laboratory of Sumitomo Chemical Co. Ltd., were examined using various species of clinical isolates. The results are summarized as follows.
(1) PC-904 was active against almost all of gram-negative bacilli as well as gram-positive organisms, superior to ABPC or CBPC. This agent showed potent activity especially against Pseudomonas aeruginosa, Ps.cepacia, Escherichia coli and Proteus species.
(2) PC-904 was active against ABPC-resistant Enterobacteriaceae and CBPC-resistant Ps.aeruginosa. It showed no cross-resistance with GM.
(3) The antibacterial and bactericidal activities were, in some cases, influenced by the inoculum size. The inoculum size effect showed good correlationship with the specific activity of beta-lactamase produced. PC-904 acted bactericidally in low inoculum.
(4) PC-904 was resistant to hydrolysis by cephalosporinase as well as ABPC. But, it was hydrolyzed by penicillinase and its relative rate of hydrolysis was similiar to that of ABPC, except for a part of type IV penicillinase, against which PC-904 was relatively resistant.
(5) PC-904 was more effective than CBPC against infections with E.coli, K.pneumoniae and Ps.aeruginosa in mice.

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The antibacterial activities of PC-904 on 428 strains of bacteria such as S.faecalis, H.influenzae, Salmonella, Serratia, P.vulgaris, P.inconstans, P.aeruginosa, P.maltophilia, A.calcoaceticus and Bacteroides, which were isolated in Juntendo University Hospital from 1976 to 1977, were compared with those of carbenicillin, sulbenicillin, ampicillin and gentamicin. These results were obtained.
1) Against P.aeruginosa, PC-904 was more active than carbenicillin and sulbenicillin but less than gentamicin. PC-904 had an inhibitory activity on GM-highly resistant strains.
2) Against H.influenzae, PC-904 and ampicillin had equal activity, and these antibiotics were more active than carbenicillin and sulbenicillin.
3) Against A.calcoaceticus, PC-904 was less active than gentamicin but more active than other penicillin antibiotics.
4) Against Salmonella, PC-904 had the activity equal to or a little less than that of ampicillin and rather many strains were highly resistant to PC-904.
5) Against S.faecalis, PC-904 was more active than carbenicillin and sulbenicillin but less than ampicillin.
6) Minimum inhibitory concentrations of PC-904 on P.vulgaris, P.inconstans, P.maltophilia and Bacteroides were distributed in wide ranges and the inhibitory activity on Serratia was weak.
7) Increase of inoculum size of bacteria tended to increase MIC values of PC-904 and especially this tendency was remarkable in PC-904 less susceptible strains.

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In vitro and in vivo antibacterial activity of PC-904, broad spectrum, semisynthesized penicillin, were examined, and it was revealed that the drug has a strong activity against various strains of gram-negative bacilli.
1) The effect of therapy with PC-904 was better than with either SBPC or T-1220 against P.aeruginosa when in vivo experiments with challenge by a large inoculum or small inoculum were applied.
2) It was revealed that PC-904 had marked antibacterial activity in vitro or in vivo even on gentamicin-resistant Pseudomonas aeruginosa.
3) Against Serratia, PC-904 was ineffective, though other conventional drugs were susceptible.
4) PC-904 was revealed to be effective in vitro on glucose non-fermentation gram-negative bacilli which were resistant to conventional antibiotics.

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Strains (134) of anaerobic bacteria were tested for susceptibility to PC-904 using agar dilution technique. Many strains of gram-positive anaerobic bacteria were susceptible to this drug.
Antibacterial activity of this drug was little affected by various factors (medium pH, inoculum size and medium).
Population of natural resistant mutant and developement of resistance to this drug were studied. Fusobacterium varium (10¹⁰/ml viable cell) was streaked on GAM agar plate containing 62.5μg/ml PC-904 and natural resistant mutants were obtained. After 4 serial cultures in GAM semi-solid media containing this drug, the minimal inhibitory concentration against Fusobacterium varium increased from 6.25μg/ml to 100μg/ml or more. Developement of resistance against Peptostreptococcus anaerobius advanced slowly.
Chemotherapeutic effect of PC-904 on subcutaneous abscess of mouse (dd-N) due to Fusobacterium necrophorum (S-45) was investigated. Injection of 40 mg/kg/day of this drug to mouse was effective. Subcutaneous abscess was treated completely.

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The in vitro and in vivo antibacterial activity of PC-904 was compared with that of Ampicillin (ABPC), Carbenicillin (CBPC), Sulbenicillin (SBPC) and Gentamicin (GM). The following results were obtained.
1) PC-904 showed broad antibacterial spectrum against gram-positive and gram-negative bacteria.
2) PC-904 was more active than ABPC, CBPC and SBPC against gram-negative bacteria such as Escherichia coli, Klebsiella pneumoniae, Proteus vulgaris and Pseudomonas aeruginosa which were isolated from clinical specimens.
Most striking was the inhibitory effect of PC-904 against Ps.aeruginosa. PC-904 was at least 30 times more active than CBPC against Ps.aeruginosa. The susceptibility of PC-904 against Ps.aeruginosa was located at 3.13μg/ml, which was comparable to that of GM.
3) Influence of medium pH and horse serum protein on in vitro antibacterial activity of PC-904 showed the same tendency to CBPC. The antibacterial activity of PC-904 decreased as inoculum size became heavier.
4) Stability of PC-904 to β-lactamase extracted from penicillin and cephalosporin resistant E.coli was generally similar to that of ABPC and CBPC.
5) PC-904 was bactericidal against most sensitive organisms at concentrations generally equal to or only two fold higher than the minimum inhibitory concentration. Bactericidal action of PC-904 has turned out to be bacteriostatic as inoculum size became heavier.
6) It was confirmed that PC-904 had a very potent in vivo antibacterial activity against grampositive and gram-negative bacteria. Against systemic infection with E.coli No.29, K.pneumoniae and Ps.aeruginosa E-2 in mice, PC-904 is several times more active than CBPC.
The therapeutic efficacy of PC-904 on multiple administrations was more effective than that of CBPC.
7) The filamentous cells of Ps.aeruginosa E-2 exposed to PC-904 and CBPC were actively ingested by phagocytes of guinea pig, but the intact cells were not.

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The effects of PC-904 and carbenicillin on the morphology of Pseudomonas aeruginosa E-2 were examined with the phase contrast microscope and scanning electron microscope. The following results were obtained.
1. With a phase contrast microscope, exposure to PC-904 resulted in the fomation of marked filamentous cells. However, the spheroplast-like structures could not be observed by the treatment with PC-904. Exposure to carbenicillin resulted in the formation of spheroplast-like structures.
2. With a scanning electron microscope, typical spheroplast-like structures could not be observed when PC-904 was allowed to act on Ps.aeruginosa E-2 cells.
3. Possible influence on the ability to form spheroplasts was studied using stabilizers. As a result, it was found that spheroplasts were not formed wheri, PC-904 was allowed to act on Ps.aeruginosa E-2 cells.
The morphological alterations of Pseudomonas aeruginosa E-2 treated with carbenicillin observed in this study were similar to those noted by PERKINS and PRIOR

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PC-904, sodium 6-[D (-)-α-(4-hydroxy-1, 5-naphthyridine-3-carboxamido) phenylacetamido] penicillanate, is a broad-spectrum semisynthetic penicillin with marked antipseudomnal activity, derived from ampicillin. Following results concerning its in vitro and in vivo antibacterial activities were obtained.
1. Its antibacterial activities against gram-positive bacteria were comparable or superior to carbenicillin. In particular, PC-904 exhibited more potent activity than carbenicillin against Streptococci. This agent possessed a characteristic to be active on Streptococcus faecalis insensitive to carbenicillin and gentamicin to a considerable extent.
2. As far as gram-negative bacteria concerns, PC-904 was generally much more active than carbenicillin. Particularly, on Ps.aeruginosa, it exhibited about 30 to 100 times more potent activity than carbenicillin.
3. PC-904 also possessed potent antibacterial activities on carbenicillin-resistant Ps. aeruginosa or E.coli, and on carbenicillin-insensitive K.pneumoniae, indole-positive Proteus, Serratia and gentamicininsensitive anaerobes etc.
4. Its antibacterial activities were only little influenced with test media and pH. Its activity was weakened to only about 1/2 to 1/4 by serum addition.
5. Antibacterial activities of PC-904 were influenced with heavy inoculum size.
6. This agent acted bactericidally in light inoculum size, but in heavy inoculum size majority of bacteria were killed and only a portion of bacteria survived and regrew after a latent period.
7. In vivo effect of PC-904 in experimental systemic infection in mice was also confirmed in both subcutaneous and intravenous injection.
On Ps.aeruginosa its efficacy was several to 10 times more potent than carbenicillin and on E.coil and Pr.mirabilis comparable to carbenicillin.
8. When dividedly dosed, the effect of PC-904 was potentiated. The ED₅₀ values in divided dosing were more markedly lowered than carbenicillin compared with those in single dose.

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The pharmacological actions of PC-904, a new type of semisynthetic penicillin, were investigated.
Summary of pharmacological actions and minimal effective doses (MED) were as follows; fall of blood pressure of the rabbit (50mg/kg), bradycardia from the findings of rabbit ECG (50mg/kg), inhibition of isolated guinea pig atrium (2×10^-3g/ml), inhibition of isolated frog heart (10^-3g/ml), constriction of isolated rabbit ear vessels (5×10^-8g/ml), stimulation of permeability of rabbit skin vessels (100μg), stimulation of isolated rabbit and guinea pig intestine (10^-3g/ml and 2×10^-3g/ml, respectively), and inhibition of isolated non-pregnant rat uterus (2×10^-8g/ml). No effect on respiration of the rabbit and isolated guinea pig trachea (2×10^-1g/ml) and isolated pregnant rat uterus (2×10^-3g/ml) was observed. No specific action of histamine release by PC-904 from rat peritoneal mast cells was also observed.
MED of PC-904 were much largeer than minimal inhibitory concentrations and maximal blood levels in clinical uses, and were similar to those of ABPC. MED of AB-1405 were smaller than those of PC-904, and MED of A₁ were larger than those of PC-904.
When the rat was injected PC-904 once a day for 7 days at doses from 25 to 100mg/kg, urinary excretion of potassium and urinary findings were similar to normal values and those of the control group. Tendency of decreased urinary excretion of sodium was observed.

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Fates of PC-904 (half life, distribution, urinary and fecal excretion, transfer to the fetus, binding to protein and partition coefficient), a new semisynthetic penicillin which is effective against severe infections by gram-negative bacilli, were investigated in the rats using-¹⁴C-PC-904.
When rats were intravenously or intramuscularly injected PC-904 and ¹⁴C-PC-904 in a dose of 50mg/kg, biological half lives were 10.56 and 25.48min. respectively by measuring biological activities, or were 13.34 and 23.10min. respectively using radioisotope. The biological half life of PC-904 in the injected site of muscle was 25.96 (biological activities) or 22.14min.(radioisotope). The organ levels attained to maximum within 15min. after administration, and the duodenum and kidney levels were higher than the serum level. The total amount excreted in 24hr. urine of the rat which was injected PC-904 was approximately 11% of the injected amount. Most of this penicillin was excreted within the first 4hr. after administration. The evaluations between biological and radiological activities were not of significant difference. The maximal intestine level of PC-904 moved to lower intestine with course of time. Biologically active PC-904 in the feces was 2.06% and total amount excreted in feces (radioisotope) was 46. 17%. Only PC-904 existed in the urine, and most of a metabolite of PC-904 was existed in the feces.
Therefore, PC-904 is rapidly transfered to the organs from blood, and excreted in the urine and bile. PC-904 is transformed by cleavage its lactam ring in the lower intestine, and excreted in the feces.
The cord blood level of PC-904 was approximately 10% of maternal serum level in the pregnant rats.
A binding rate of PC-904 to human plasma was 93.14%, and approximately half of binding PC-904 had again biological activity by dissociation from protein.

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The absorption, distribution and excretion of PC-904 were studied mainly by the intravenous administration in animals such as mice, rats, dogs and rhesus monkeys. The results were as follows:
1. The serum levels of PC-904 following an intravenous injection or drip infusion in animals decreased exponentially. The serum half lives had a tendency to become longer in bigger animal species and at higher doses. The dose response of calculated initial concentrations in sera was obvious. No accumulation was observed after a consecutive administration of daily 100 or 300mg/kg for 2 weeks in rhesus monkeys.
2. PC-904 was distributed in the tissues in the order of liver>kidney>serum>lung>testis, spleen and muscle, when administered intavenously in mice and rats. The distribution and the disappearance were rapid.
3. The urinary recovery rates of PC-904 at a dose of 50 mg/kg were about 11% in rats and less than 10% in dogs. However, the recovery rates in dogs were up to 20% at doses more than 100 mg/kg. Those in rhesus monkey were about 20 to 34% when 100 or 300 mg/kg of PC-904 was administered.
4. The bile level of PC-904 in mice was much higher than that in urine, and the biliary recovery rate in rats was about 65%. It was concluded that the major excretory route of PC-904 in mice and rats was liver-bile duct system.
5. Urinary active metabolites of PC-904 were studied by thin-layer chromatography and bioautography. The only active compound detected in human and animal urine was PC-904 itself. The major metabolite (penicilloic acid of PC-904) and the 4-hydroxy-1, 5-naphthyridine-3-carboxylic acid of the side chain had no antibacterial activity.
6. The stability of PC-904 in biological materials was studied. PC-904 was stable at least for 7 days in fresh human serum and urine at 4°C and-20°C. It was unstable in rat feces at 25°C and in rat liver homogenate at 37°C.

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The biological disposition and metabolic fate of PC-904, sodium (2 S, 5 R, 6 R)-6-[(R)-2-(4-hydroxy-1, 5-naphthyridine-3-carboxamido)-2-phenylacetamido]-3, 3-dimethy1-7-oxo-4-thia-l-azabicyclo [3. 2. 0] heptane-2-carboxylate, were studied in rats after intravenous injection of ¹⁴C-PC-904.
1) Plasma levels of ¹⁴C rapidly decreased with a biological half life of about 20 minutes until 3 hours after injection (50 mg/kg), then gradually decreased.
2) The liver, kidneys and blood showed the highest ¹⁴C levels, while the brain and the spinal cord showed the lowest levels.
3) A dose response in the tissue levels of ¹⁴C was observed 1 hour after injection when the dose was raised (12. 5, 50 and 200 mg/kg).
4) Both male and female rats excreted about 80% and 20% of the ¹⁴C dose in the feces and urine, respectively, in 72 hours after injection (50 mg/kg).
5) Biliary excretion of ¹⁴C decreased (72 to 38%) when the dose was raised (50 to 800 mg/kg), while the urinary excretion increased 22 to 55% of the ¹⁴C dose, the total ¹⁴C excretion being unchanged. About 83% of the dose was excreted in the urine in bile-duct ligated rats within 24 hours after injection of ¹⁴C-PC-904 (50 mg/kg).
6) Tissue distribution of ¹⁴C in pregnant rats showed much lower levels of ¹⁴C in fetuses than that in the dams that showed a similar pattern of ¹⁴C distribution to male rats.
7) Analyses by HLC revealed that most of the ¹⁴C in the urine and bile was unchanged PC-904.

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1. Binding rates of PC-904 with serum pr Otein of rat, dog, bovine and human determined by the centrifugal ultrafiltration method were generally high (95-98%), except for 82% in mouse serum.
2. Those results were confirmed by the ultracentrifugation method, but the binding rate obtained by the equilibrium dialysis method was relatively low (81%).
3. The serum protein binding of PC-904 was not so firm, but comparatively loose. It was confirmed by the determination of the binding constant.
Binding data obtained using 4% human serum albumin were as follows: PC-904: K=1.03 × 10⁴ M^-1, N=1.13 cefazolin: K=1.18×10⁴ M^-1, N=1.00 dicloxacillin: K=3.95 × 10⁴ M^-1, N=1. 95
The binding constant of PC-904 was very similar to that of cefazolin and lower than dicloxacillin.
4. It was further confirmed by the dilution technique that its binding was reversible.
5. The binding rates (about 80%) of PC-904 with rat liver or kidney homogenates were lower than that with serum protein. Its binding was reversible.

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Studies on the bioassay method of PC-904 concentration in body fluids were performed and the following results using Micrococcus luteus ATCC 9341 as an assay organism in heart infusion agar (p H 7.2) were obtained.
1) Detectable sensitivity limit of this method for PC-904 was 0.1-0.2 μ g/ml by thin layer cup method or 0.2-0.39 μ g./ml by paper disc method.
2) Standard curve of PC-904 using M/15 phosphate buffer (p H 7.0) as diluent of PC-904 as slightly different from that of fresh human serum or Moni-Trol I.

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The serum levels and urinary excretion of PC-904 of 25 healthy adult volunteers were studied.
The results obtained were as follows:
1) The serum levels of intramuscular injections of 500 mg of PC-904, administered twice a day for 3 days, were examined.
The maximum serum levels were achieved 1 hour after the injections, and showed 28 to 37 μ g/ml. The urine collected for the first 2 hours after the injection showed maximum levels of 175 to 328 μ g/ ml. The total urinary recovery rates were 23 to 26%, and almost all of them were achieved within 6 hours.
2) The serum levels of 2 hour drip infusion of 1 g of PC-904, administered twice a day for 3 days, and 2g and 3g administered twice a day for 1 day respectively, were examined. The maximum serum levels were achieved when the last of the infusion was administered, and showed 47 to 58, 138 to 146 and 183 to 191 μ g/ml, respectively. The urine collected for the first 2 hours showed the maximum levels of 228 to 697, 608 to 1, 273 and 764 to 819 μ g/ml, respectively. The total urinary recovery rates were about 21 to 32%, and almost all of them were achieved within 6 hours.
3) No side effects or adverse reactions in the clinical findings of this drug were observed.

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Pharmacokinetic and pharmacological investigations on PC-904, a new semisynthetic penicillin, were done in 10 healthy adult volunteers.
The results obtained were as follows:
1) Serum concentration: The peak concentrations of 14-17μ g/ml were attained 1/2-1 hour after an intramuscular administration of 350 mg. Its half life in serum was 1.3-1.4 hours.
2) Urinary excretion: PC-904 was recovered in urine at recovery rate of about 20% durine24 hours after injection, and almost all of them were achieved within 6 hours.
3) Clinical reactions: The moderate pain and redness at the site of injection which lasted for 4-5 hours were observed following an injection. However, no other clinical reactions, local or systemic, were observed.
4) Clinical examinations: Renal and liver function test and blood examination were done in all volunteers before and 4 days after injection. There were no abnormalities except elevation of amylase activity in serum of 2 volunteers after the injection. But the relation between the abnormality of amylase activity and PC-904 was not revealed.

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For the purpose of investigating reactions of toxicity of PC-, 904 when it was one-shot injected intravenously (iv), 500mg or 1000 mg of the drug were infused iv with 2 or 4 min. respectively into healthy adult men.
Clinical signs were observed by checking blood pressure, electrocardiogram, peripheral blood analysis, blood chemistry and urine tests before and after the administration.
As the results, no abnormal changes were noted in blood pressure, heart rate and electrocardiogram., Other laboratory findings also did not reveal any abnormalities.
From these data, it is believed that PC-904 does not affect any detectable toxicity on various kinds of organs' functions including circulatory system, when the drug is administered by iv one-shot with the above mentioned dosage and infusion speed.
The abstract of this paper was presented at the 25 th Congress of Chemotherapy (Japan Society of Chemotherapy), New Drug Symposium, Gifu, June 1977.

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Basic and clinical studies on PC-904, a new broad spectrum penicillin derivative with strong antipseudomonadal activity were carried out as follows.
1) In absorption and excretion study on 6 patients without serious renal or hepatic impairment, 28.7 μ g/ml of mean peak blood level were found at the end of 1 g drip infusion.
Calculated serum half-life of the drug was about 2 hr and the total urinary recovery in 6 hr. 12.2% respectively.
2) In TLC analysis of the urine of 2 patients with poor urinary excretion, biologically active metabolites were not found.
3) The activity of the drug dissolved in Moni-Trol 1 was reduced to one-half of theoretical concentration and recovered completely by serial dilution. These results seem to show reversible binding of the drug to serum protein.
4) In clinical evaluation of PC-904 in 21 patients with various kinds of infections including 6 respiratory, 4 biliary and 11 urinary tract infection, 10 responded favourably, 6 showed fair, and 4 poor results.
Most patients were in advanced age and have bad underlying diseases such as diabetes mellitus. Bacterial findings were 8 E. coli, 5 Klebsiella, and others. Bacterial replacement or recurrence has occurred in 4 patients with chronic infections after treatment. A slight decrease in RBC, Hb, Ht and Platelet counts was observed in one female patient. Others showed no abnormal fluctuation of laboratory values before and after the treatment.

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Nine cases of serious lung infectious diseases were treated with PC-904 which was used intravenously by one shot or/and drip infusion; 2g each injection, 1 or 2 times a day, during 4 to 14 days long, in total dosage 14 g in 3 cases, 16 g in 1, 28 g in 3, 56g in 2 cases. All but 1 case, 84 years old man, suffered from acute pneumonia by Enterobacter at the severe condition of bladder cancer, were observed effective clinical results, on the points of views, such as subjective and objective findings, chest X-ray findings and bacteriological changes in sputums. No side effects were observed and no abnormalities were affected on liver, kidney and blood organ functions by using PC-904.
During the past 6 months, we could often observe some patients of lung diseases, showed high titers over 32 times of cold hemoagglutination (CHA) and mycoplasma-CF (MP-CF), and their clinical appearances might be probably modified by clinically unclear infection of mycoplasma pneumoniae among 62 in-patients, 27 (43.6%) in CHA, 16 (25.8%) in MP-CF, and among 41 out-patients, 24 (58.5%) in CHA, 14 (34.2%) in MP-CF.
Then these showed the presence of mycoplasma infection, and it will be necessary to give in combination with the sensitive drugs against the incidental infection at the treatment of serious lung diseases.

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Antimicrobial activities and therapeutic effects of PC-904, a new penicillin derivative, were studied and the following results were obtained.
The minimum inhibitory concentrations of PC-904 against 17 clinical isolates of Klebsiella pneumoniae ranged from 25μg/ml to 1600μg/ml, but it was shown that PC-904 was more active against those strains than CBPC and SBPC in a degree of 3 or 4 fold dilutions. The susceptibilitis of those strains to CEZ were nearly equal to those to PC-904.
The growth of the clinically isolated strains of Pseudomonas aeruginosa was inhibited at 4 to 8 fold lower concentration of PC-904 than those of CBPC and SBPC
Nineteen cases with respiratory tract infection, a case with biliary and 3 cases with urinary tract infections were treated with PC-904. 1g or 2g of the drug was administered by drip infusion twice a day for a period of 1 to 3 weeks.
An excellent response was obtained in 6 cases, a good or moderate therapeutic effect was observed in 8 and 5 cases respectively, out of total 19 cases with respiratory tract infections.
In all 4 cases with biliary or urinary tract infections, the response was excellent.
Adverse effects were observed in 6 cases out of total 23 cases treated with PC-904, including a case with eruption, a case with drug fever showing transient leukopenia, 2 cases with symptoms such as fever and myalgia etc. probably due to hypersensitivity to the drug, and 2 cases with slightly elevated values of transaminases or BUN.
In all of these cases, symptoms and signs of adverse effects subsided and deteriorated laboratory findings became normal shortly after the withdrawal of the drug.

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The following results were obtained in the clinical and experimental studies on PC-904.
1) Antibacterial activity
The MIC of PC-904 against E. coli, Klebsiella and Psudomonas aeruginosa were measured, then it was revealed that the drug had excellent susceptibility on Pseudomonas aeruginosa.
2) Absorption and excretion
The dose response relationship was obtained between the serum levels and the dosage (250mg and 1000mg) of the given drug intravenously. When 1000mg were administered, the serum levels were 60μg/ml at 30min., 22.5μg/ml at 1 hour, 7.1μg/ml at 2 hours, 1.8μg/ml at 4 hours and 0.5μg/ml at 6 hours after administration. Cumulative urinary recovery rate for 6 hours was around 18%.
3) Clinical results PC-904 was administered at 2g per day to 8 patients respectively, 4 cases of cholecystitis, 2 of pneumonia, 2 of urinary tract infection, and the effect was considered excellent in 5 cases. As far as adverse effects were concerned, skin rashes, fever and elevation of GOT and GPT were observed in 1 case and elevation of GOT was observed in 1 case.

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PC-904 was given to 24 patients, 10 with urinary tract infections, 10 with respiratory infections and others.
1) Efficacy rate counted 50 percent in UTI, and 70 percent in respiratory infections. The drug was effective in one case of two with acute enteritis, good in one case of cholecystitis caused by E. coil, while α-Streptococcus SBE was resistant even when large doses was given.
The overall efficacy rate was 64 percent.
2) As classified by causative bacteria, 4 were eliminated out of 5 strains of E. coli, 2 out of 5 strains of Klebsiella, and 1 out of 2 strains of Proteus.
3) Skin rash was seen in two cases. Slight transient elevation of transaminasis was noted in one case. Other side effects, such as elevation of BUN or amylase level, change of peripheral blood, were not noted.

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On a new semisynthetic penicillin, PC-904, some clinical studies were performed and the following results were obtained.
1. The sensitivity tests of clinical isolates of gram-negative bacilli were performed. Comparing with the MIC values obtained using original overnight broth culture, as inoculum, the MIC values in 100-fold diluted culture were markedly small, showing good antibacterial activity of PC-904. The superiority was clearly demonstrated in the correlation of MICs between carbenicillin or ticarciLtin in inoculum size of 100-fold diluted culture.
2. In CCl₄-pretreated rats, biliary level was far lower, but serum level was somewhat higher than that of controls respectively.
3. To one patient from whose sputum and urine P. aeruginosa and Klebsiella had been found simultaneously, PC-904 was administered in drip infusion. Klebsiella disappeared from urine, but P. aeruginosa remained in sputum.
Another patient of bronchiectasia infected with P. aeruginosa did not respond well. After 11 daydosing of PC-904, urticaria-like eruption appeared. Recovery followed promptly the cessation of therapy.

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Antibacterial activity, absorption, excretion and clinical effects of PC-904 were studied, and the following results were obtained.
1) Antibacterial activities
MIC of PC-904 against E. coli was more susceptible by 1 to 2 stages than ABPC and CBPC, and against Klebsiella pneumoniae, it was more susceptible by 2 to 5 stages than CBPC. It was noteworthy that PC-904 showed far strong antibacterial activity against Pseudomonas aeruginosa compared with conventional penicillins while it was 1 to 2 stages less than gentamicin.
2) Absorption and excretion
(1) Serum level When 250mg and 500mg of PC-904 were intramuscularly administered to healthy volunteers, serum peak levels were 8.9-10.1μg/ml and 20.3-22.1μg/ml respectively at 60 minutes after administration. PC-904 showed similar decrease pattern of serum levels at both dosage and when 500mg of PC-904 were intramuscularly administered, its serum level was 1.8-2.5μg/ml at 6 hours after. Dose response relationship was apparently observed.
(2) Urinary excretion Average excretion rates of PC-904 in urine after intramuscular injections of 250mg and 500mg within 6 hours were 24.9% and 23. 3%, respectively. The low urinary excretion rate of drug was suggested.
3) Distribution
When 20mg/kg of PC-904 was intramuscularly administered to rats, the concentration of PC-904 was the highest in the liver, then the kidneys, serum and lungs in this order. The peak distribution of PC-904 to experimental pouch transudation was as low as 0.54μg/ml after 1 hour of intramuscular injection. We think that low peak level was caused by its high protein binding ratio of more than 90%.
4) Clinical effects
PC-904 was adminstered to 6 cases of respiratory tract infections, 1 case of cervical lymphadenitis, 2 cases of biliary tract infections, 12 cases of urinary tract infections and 3 cases of septicemia, totally 25 cases, at the dosage of 1.0-9.0g/day for 1-13 days. Effectiveness were shown good in 14 (efficacy ratio: 60.9%), fair in 3, poor in 6 and unknown in 2 cases.

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PC-904, a new synthetic penicillin, was evaluated in eleven elderly patients (one patient with septicemia, 7 patients with pneumonia, 1 patient with bronchiectasis, and 2 patients with UTI). Ten out of these 11 patients had some compromised defense mechanisms.
Seven patients responded satisfactorily and 4 patients failed to respond.
In regard to Pseudomonas infection, the patients with septicemia favorably responded with a drip infusion of 1 gram of PC-904 for 2 hours twice a day for 14 days. Another patient with bronchiectasis, Pseudomonas persisted in sputum during the course of 0.5 g PC-904 therapy, given intramuscularly twice a day for 5 days.
No significant adverse effect was noted in this series.

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Fundamental and clinical examinations of PC-904 were performed, and the following results were obtained.
1) Antibacterial activity
PC-904 had better susceptibility than CBPC against Ps. aeruginosa, E. coli and Klebsiella pneumoniae.
2) Absorption and excretion
When 1g of PC-904 dissolved in 500ml of saline was infused for 2 hours into 3 patients, mean serum levels of the drug were 42.5μg/ml, 53.25μg/ml and 9.7μg/ml at 1, 2 and 6 hours after initiation of the infusion, respectively.
Cumulative urinary excretion rates in 2 cases were 30.4% and 23.4% for 6 hours, respectively.
Excretion of the drug into bile was measured in 2 patients with external biliary fistula while i. v. drip infusion of 1g was performed. Bile levels of the drug were 130μg/mi at 30 minutes after the initiation of infusion in one case and 352μg/ml at several hours after in other case. Amount of 4.32% was excreted into bile for 6 hours in the latter case.
3) Clinical results
PC-904 was administered in 14 infections, and majority of them were induced by gram-negative bacilli accompanied with basic diseases. The effect of the drug was considered excellent in 1, good in 4, fair in 4, poor in 4 and not determined in 1 case.

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1) PC-904 was administered into 8 respiratory tract. infections caused by either K. aerogenes or D. pneumoniae or Ps. aeruginosa or A. xylosoxidans, and clinical improvements were observed in 5 of them. It is noteworthy that PC-904 was effective excellently against K. aerogenes-induced pneumonia.
2) The best method of administration and dosage of PC-904 was i. v. drip-infusion of 2g twice a day, but usually 1 g twice a day was enough for common acute pneumonia.
3) As far as the side effects were concerned, 1 pyrexia, 1 dyspnea attack, 3 elevations of serum GOT and 2 elevations of BUN were observed, but all these symptoms were improved after the withdrawal of the drug.

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The clinical effects of newly synthesized penicillin, PC-904 were examined, and effectiveness rate was 60% against relapse in chronic bronchitis and 80% against acute pneumonia. Background analysis of the above mentioned cases revealed that majority cases of the former were not effective to the conventional antibiotics, and many of the latter were accompanied with chronic respiratory diseases.
Severe side effects were not observed, though 4 cases (8. 8%) of abnormal liver function tests and 1 case of thrombocytopenia were indicated.
From these data, PC-904 seems to be useful for various kinds of infections such as relapse of chronic infections or acute ones in respiratory tracts. This drug is considered to he worthwhile for serious respiratory infectious diseases, because it shows antibacterial effect on therapy-resistant gram-negativtbacilli, such as Pseudomonas aeruginosa.

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PC-904 is a new antibiotic agent with a broad spectrum against gram-positive and gram-negative microorganisms.
PC-904, daily dose 2 g, was administered intravenously to 4 cases of pulmonary infectious deseases.
The results were as follows: remarkable effectiveness in 1 case and unknown effectiveness in 3 cases.
Side effects were noted in 2 cases: generalized skin eruptions with elevation of S-GOT and eosinophilia in a suspected pneumonia, and eosinophilia in another one. There disappeared, however, soon after cessation of the administration.

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PC-904 (sodium (2S, 5R, 6R)-6-[(R)-2-(4-hydroxy-1, 5-naphthyridine-3-carboxamido)-2-phenylacetamido]-3, 3-dimethy1-7-oxo-4-thia-1-azabicyclo [3. 2. 0.] heptane-2-carboxylate) is a new semisynthetic penicillin. We studied its antibacterial activity against some clinically isolated bacteria and its clinical effectiveness.
The results obtained were as follows.
1) MIC values of PC-904 against 7 strains E. coli out of 10 were distributed 0.9 to 12.5 μg/mI. Those against Ps. aeruginosa 10 strains and Prot. mirabilis 6 strains were all less than 3.12 μg/ml. Three of the 5 strains of Kleb. pneumoniae and all of the 3 strains of Serratia marcescens were resistant to PC-904.
2) The antibacterial activities of PC-904 against Ps. aeruginosa and Prot. mirabilis were superior to CBPC and GM. Those against E. coli were superior to CBPC but inferior to GM:
3) PC-904 was administered intravenously to 9 patients (urinary infection 6 cases and pulmonary infection 3 cases) at daily dose 2.0-4.0 g, and good responses were obtained in 7 cases.
4) As a side effect, the transient falling of arterior blood pressure after intravenous injection was observed in 1 patient.

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Clinical application of the semi-synthesized penicillin, PC-904, led to the following results.
1) MICs of PC-904 were lower than those of CBPC or SBPC against E. coil, Klebsiella and Pseudo-monas aeruginosa.
2) The effect of PC-904 on 21 infectious diseases in the field of internal medicine was considered excellent or good in 13 cases (61.9%).
3) The bacteriological effects revealed that 11 (68.8%) of 16 strains were converted negatively or decreased.
4) As far as side effects were concerned, skin rash or anorexia were observed in 5 cases, though these symptoms were eliminated by the withdrawal of, drug in all cases.
5) Because PC-904 has powerful antibacterial effects and is characterized by the excellent transdiffusion into liver and bile, this drug seems to be a useful antibiotic if application is selected prudently.

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On PC-904, fundamental experiment and clinical evaluation were performed.
1. The degree of binding of PC-904 to human serum protein was more than that of other penicillins: 99% of PC-904, 96% of penicillin G, 48% of sulbenicillin, 38% of ampicillin and 28% of carbellicillin.
2. PC-904 was incubated individually with each of the following aminoglycoside antibiotics: gentamicin, dibekacin, tobramycin, KW-1062, lividomycin and amikacin. The residual activity of each aminoglycoside in this mixture was measured by bioassay. Amikacin and lividomycin remained almost active, but other aminoglycosides were inactivated by the mixture of PC-904.
3. Serum levels of PC-904 were measured in 2 realthy adults and 2 patients with moderately impaired renal function (Creatinine clearance 55.4 and 41. 5 ml/min) after 500 mg of PC-904 were administered by drip infusion for 2 hours. Serum half-lives were 0.52 and 0.73 hours in the healthy adults. On the other hand, these times were 0.42 and 1.15 hours in the patients with impaired renal function. Urinary recoveries were 20 and 15.9% in the healthy adults, but in the patients with impaired renal funtion were decreased to 10.6 and 11.6%.
4. No active metabolite was demonstrated in urine from healthy adult after the dministration of PC-904.
5. The clinical evaluation of PC-904 was performed in 10 patients: 4 patients with lower respiratory tract infections, 3 patients with lower urinary tract infections, each one with cholecystitis, bacterial endocarditis and meningitis. The treatment with PC-904 enabled a complete clinical success to be achieved in 5 cases, a partial success being obtained in a further 2 cases. For the side effect of PC-904, there were rash and fever in a patient, and eosinophilia in another patient.

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1) The concentration in blood of a new synthetic penicillin PC-904 was measured in patients with impaired renal function. The results indicated that the blood level of the penicillin was lowered more quickly in cases of renal failure than in those with mild impairment of renal function.
2) PC-904 was administered alone to a total of 22 hospitalized patients (with 6 of them having renal failure) comprising 8 with respiratory infection, 8 with abdominal or biliary tract infection and 6 with urinary tract infection. The clinical effect of this antibiotic therapy was rated as excellent or good in 13 cases, as fair in 3 cases and as none or failure in 6 cases. It seems that the drug, when given at a daily dose of less than 1 g, may not be anticipated to prove of therapeutic benefit irrespective of the degree of integrity of renal function.
3) Side effects were encountered 12 times in 10 of the entire 22 cases treated. While a fever and skin eruptions, seen in 5 instances, appeared to be rather high in incidence, eosinophilia, seen in 4 instances, does not seem to be a significant problem.

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Laboratory and clinical investigations have been carried out on PC-904, a new semisynthetic penicillin, and following results were obtained.
1) PC-904 exhibited a growth inhibitory action widely against Gram-positive cocci and Gram-negative bacilli, and stronger antibacterial activity than ABPC and CER against Enterococcus, Klebsiella, Serratia and P. aeruginosa.
2) PC-904 was ialected intravenously by drip infusion singly as chemotherapeutic drug for the respiratory tracy infections, gallbladder infections and urinary tract infections, then favorable results were obtained in 11 cases (91.6%) out of 12 respiratory tract infections and 1 gallbladder intection, while remarkable effects were obtained in 3 cases (609) out of 5 urinary tract infections.
3) No hematological abnormality was noted but rash was observed in 2 cases.

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PC-904, a new semisynthetic penicillin, was administered to 30 episodes of the infections in 21 patients of acute leukemia. Fourteen episodes (46. 7%) responded to this antibiotic and response rate was TIM dependent on the number of circulating polymorphonuclear neutrophils. PC-904 was most effective against Pseudomonas infections, including 2 cases of Pseudomonas septicemia with dramatic response after having failed to respond to either Carbenicillin or Sulbenicillin, or both. No significant side effect was observed with PC-904.

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Laboratory and clinical studies have been carried out on a new antibiotic PC-904, and the following results were obtained.
1. In the activity against clinical strains of Gram-negative bacilli such as Proteus sp. and Pseu-domonas aeruginosa, PC-904 was effective.
2. PC-904 was administered intramuscularly in rats to determine levels in blood and various organs. The peak concentration in serum and tissue was attained in 30 minutes after administration, and decreased immediately.
3. Transference of PC-904 in extra biliary drainage and perfusing isolated liver of rat was higher and biliary excretion was the highest in perfusing isolated liver of rat compared with other penicillins.
4. Clinical effects of PC-904 in 11 patients with various kinds of respiratory infections were excellent in 4 cases, good in 5 and unknown in 2. Side effect was observed in 1 case of slight elevation of s-GOT.

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PC-904, a new antibiotic of ampicillin analogue, was applied to the treatment of 17 patients with respiratory infections and one patient with chronic cystitis.
The drug was administered intravenously by drip infusion, 1g-6g/day, divided into 2-3 doses, for the period of 5 to 21 days.
The results obtained were excellent in 3 cases, good in 8 cases, slightly good in 5 cases and failed in 2 cases.
No marked side effects were observed, except urticaria in 1 case and itching in 1 case.

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PC-904, a newly synthesized penicillin derivative (Sumitomo Chem, Lab.) was examined on its activity against bacteria isolated from human infection foci, serum levels and urinary excretion rates in humans after its administration, tissue concentrations in rats, as well as its effectiveness in clinical cases. The results obtained were as follows:
1) Antibacterial activity in vitro: Staphylococcus aureus, E. coli as well as Proteus mirabilis sho-wed similar sensitivity pattern against PC-904 to those against sulbenicillin or carbenicillin, although the number of the strains sensitive to the former was larger than those to the latters. Klebsiella strains were mostly resistant to PC-904, but, when the inoculum conc. was reduced to 10⁶/ml, their MIC came down to 1.6-6.2μg/ml. The most remarkable advantage of PC-904 was found in its activity against Pseudomonas aeruginosa, i. e. the peak of MIC was located at 6.2μg/ml (inocul. conc. 10⁶/ml) or 1.6-3.1μg/ml (10⁶/ml).
2) Blood level and urinary excretion rates in humans: The peak levels of PC-904 in the plasma of three adult volunteers after single i. m. administration of 250 mg were found to be 36.5-37.1μg/ml, the urinary excretion rates being 30-40% in six hours after administration. Intravenous one shot injection of PC-904 to two adult volunteers yielded average blood levels as follows: 15 min. 233; 1/2 hr. 54.2; 1 hr. 40.2; 2 hr. 11.4; 3 hr. 9.3; 4 hr. 3.2μg/ml.
3) Tissue concentrations in rats: The organ levels of PC-904 30 min. after i. m. administration ranked in order of liver, kidneys, serum and lungs, being detectable from spleen and muscles.
4) Clinical trials: Two patients, one with U. T. I. complicated with S. L. E. and the other with pneumonia complicated with reticulosis, responded with good results to PC-904 therapy. Although no severe side effects were observed in those patients, the S. L. E. case yielded suspected drug fever in course of the therapy.

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Studies on PC-904, a new broad-spectrum semisynthetic penicillin developed in Japan, were carried out, and the following results were obtained.
1) Peaks of MIC distribution of PC-904 against various clinical isolates were; 3.12μg/ml against Staph. aureus, 3.12 μg/ml and more than 100μg/ml against E. coli, 50μg/ml against Klebsiella, 1.56 μg/ml against Proteus sp. and 3.12μg/ml against Ps. aeruginosa. At a lower inoculum size, they were; 1.56μg/ml against Staph. aureus, 1.56μg/ml and 50μg/ml against E. coli, 3.12μg/ml against Klebsiella, 0.78μg/ml against Proteus sp. and 1.56μg/ml against Ps. aeruginosa.
PC-904 was almost as potent as carbenicillin against Staph. aureus and Proteus sp., it was about 4 times as potent as carbenicillin against E. coli and it was 30-50 times as potent as carbenicillin against Klebsiella and Ps. aeruginosa. PC-904 showed antibacterial activity also against gentamicin-resistant Ps. aeruginosa and Ps. cepacia.
2) Peak serum levels of PC-904 were 34 μg/ml when 250 mg of PC-904 was administered by intramuscular injection and 170μg/ml when 2g of PC-904 was administered by drip infusion for 2 hours. Urinary excretion rate of PC-904 was about 35% within 6 hours.
3) Binding ratio of PC-904 with rabbit serum proteins was higher than 80%. However, it was suggested that the binding was reversible.
4) Daily 0.5-4.0g of PC-904 was administered mainly by drip infusion to 10 cases of respiratory tract infections, 1 case of urinary tract infections, 1 case of respiratory and urinary tract infections, 2 cases of hepatic and biliary tract infections, 1 case of septicemia and 1 case of fever of unknown origin, totally 16 cases. The results were excellent in 1 case, good in 6 cases, fair in 4 cases, poor in 2 cases and unassessable in 3 cases. As to side effects, allergic reactions such as rash, fever and eosinophilia were observed in 4 cases.

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A new antibiotic PC-904 which has been developed in Japan, was given by drip infusion at daily dosage of 1 g × 2 with 300 ml of 5% glucose solution for 7 to 21 days to 10 cases with various infectious diseases.
These cases included 7 cases of respiratory tract infection, 1 case of sepsis, pyelonephritis, and pulmonary infiltration with eosinophilia (PIE syndrome).
The remarkable effect was obtained in 3 cases, good effect in 3 ones and clinical findings were not improved in 2 cases. One case was avoided for the clinical evaluation because diagnosed as PIE syndrome after 7 days treatment.
As a side effect, rash was observed in 2 cases and rapidly disappeared within 2 to 7 days after treatment.

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Laboratory and clinical studies on PC-904 were performed, and the results were obtained as follows;
1) Sensitivity of clinically isolated strains to PC-904 was compared with that to T-1220, ABPC, CBPC, GM, and TOB. The antibacterial activity of PC-904 against most clinical isolates, especially Pseudomonas aeruginosa was found to be superior to that of other synthesized penicillins.
2) Serum concentrations of PC-904 after 1 g of intravenous infusion for 1 or 2 hours reached peakat the nd of infusion and the levels ranged from 36 to 64 μg/ml. The peak levels after 2g of intr-avenous infusion for 1 or 2 hours ranged from 125 to 160 μg/ml at the end of infusion. In the caseof 1g of one shot intravenous administration for 5 minutes, the peak serum levels were 110 to 150 μg/ml. The concentrations of PC-904 in sputum were examined and from the results 2g drip infusion, was considered to be necessary for the therapy of respiratory tract infections. The concentrations of PC-904 in pleural fluid were 2. 3 to 29 μg/ml.
3) PC-904 was applied clinically to 23 cases with respiratory tract infections. Excellent clinicalresponses were obtained in 16 out of 22 cases which were capable to be evaluated, slightly good werein 3, and poor were in 3. As the side effects, nausea in 1 case, diarrhea in 1, and skin rash in 2were noticed. No abnormalities of laboratory findings were observed except elevation of s-GOT ands-GPT in 2 cases.

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PC-904 was administered intravenously at a dose of 2g daily to the patients with various bacterialinfections and clinical effect was estimated. Clinical effect was noted in 9 of 13 patients and not in 4 patients with malignant underlying disease. When liver functions and kidney functions were measuredafter PC-904 administration, one patient had a slight elevation of transaminase (s-GOT), but afterthe administration, the enzyme level became normal. Another patient had depression of blood pressuresoon after injection without any adverse signs of shock. The third patient felt hot during the PC-904injection. No side effect was noticed on other patients.

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Fundamental and clinical examinations on PC-904, a new semisynthetic penicillin, were carried outand the following results were obtained.
1) Out of 115 strains isolated from various clinical materials (Staphylococcus aureus 21, Streptococ-cus 4, E. coli 23, Klebsiella 19, Enterobacter 21, Serratia 6, and Pseudomonas 21), sensitive strainsagainst PC-904 of which MIC were less than 12.5μg/ml were Staphylococcus aureus 7 (33%), Streptococ-cus faecalis 2 (50%), Enterobacter 1 (5%), and Pseudomonas 11 (52%). Especially against Pseudomonas, the antibacterial activity of PC-904 was more powerful compared with ABPC, CBPC and SBPC.
2) When 1g of PC-904 was administered by drip infusion or one shot intravenous infusion, thepeak serum concentration was 113.6μg/ml; and 242μg/ml at the end of infusion. Each half life ofserum concentration were 40 minutes and 30 minutes, and serum concentration was 4.3μg/ml and 7.0μg/ml at 6 hours after infusion, respectively.
3) When 1g of PC-904 was administered by drip infusion or one shot intravenous infusion, urin-ary excretion rates for 6 hours after infusion was 13.7% and 13.0%, respectively.
4) The clinical effects of PC-904 on 5 respiratory tract infections, 3 urinary tract infections and 3 other infections at the dosage of 1.0-3.0g per day for 2-38 days, was considered good in 7, fair in 2 and poor in 2. It is noteworthy that PC-904 was effective against infections caused by Pseudomonas and Strept. pneumoniae. No side effects were noted.

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Fundamental and clinical examinations were carried out on newly developed antibiotic, PC-904, and the following results were obtained;
1) Antibacterial effect
Against 976 strains isolated recently from various clinical materials (Staphylococcus aureus 81, Sal-monella 33, Shigella 47, Citrobacter freundii 63, E. coli 81, Erwinia herbicola 11, Klebsiella aerogenes 81, Enterobacter aerogenes 43, Enterobacter cloacae 42, Serratia marcescens 161, Proteus vulgaris 26, Proteus mirabilis 51, Proteus rettgeri 22, Proteus inconstans 17, Proteus morganii 42, Aeromonashydrophila 23, Vibrio parahaemolyticus 24, Pseudomonas aeruginosa 128) and 23 standard strainswhich were kept in our department, each MIC when PC-904 or Sulbenicillin (SBPC) were applied wasdetermined, then these MICs were compared each other.
In general, the antibacterial effect of PC-904 was as same as or a few times as powerful as that of SBPC.
2) Drug concentration in organs of rats
The drug concentration in organs of male rats (Wistar) after the intramuscular injection of 20 mg/kg of PC-904 was the highest in the liver, then in the kidneys, lungs and serum in order.
3) Serum concentration
2g of PC-904 diluted in 500ml of 5% glucose solution were drip infused for 2 hours into 3 chronic bronchitis patients whose renal functions were normal, then serum concentrations of PC-904 were measured. The peak levels were from 59 to 126 μg/ml at the end of infusion and it was from 15 to 30 μg/ml at 2 hours after and from 4.2 to 9.0μg/ml at 6 hours after the completion of infusion.
The half life of serum concentration revealed to be from 0.5 to 0.8 hours.
4) Diffusion of PC-904 into sputum and its concentration
When 2g of PC-904 were i. v. drip infused for 2 hours into 2 chronic bronchitis patients characte-rized by purulent sputa, the peak drug concentrations in sputa were from 0.06 to 0.62μg/ml, whichwas from 0.05 to 1.05% of the maximal serum levels.
5) Clinical application
The effects of PC-904 (from 2 to 4g per day) on 15 respiratory tract infections (9bronchopneumonia, 4 chronic bronchitis, 1 chronic panbronchiolitis, 1 pyothorax), 2 urinary tract infections and 1 cholecy-stitis were considered excellent in 5, good in 7, fair in 5 and poor in 1 case.
Among them, skin rashes were noted in 2 cases, but they were recovered quickly after withdrawalof the drug in one case and in the other one drug administration was continued without additionaltroubles.

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Laboratory and clinical studies on PC-904 were performed with the following results.
1) MIC values of PC-904 against respiratory pathogenic organisms were measured. 86.4% of MICs of PC-904 against 59 strains of Streptococcus pneumoniae was 0.006 to 0.025 μg/ml. Only one strain ofthe organism revealed MIC value of 1.56 μg/ml and it was resistant to PC-904. 88.8% of MICs of PC-904 against 80 strains of Hemophilus infiuenzae was 0.2 to 0.78 μg/ml.
The distribution of MICs against 34 strains of Pseudomonas aeruginosa was divided into 2 groups. They were the susceptible group (20 strains) with MIC values of 0.78-6.25 μg/ml and the resistantgroup (14 strains) with MIC values more than 25 μg/ml.
The distribution of MICs against 8 strains of Klebsiella pneumoniae was divided into 2 groups. They were the susceptible group (6 strains) with MIC values of 3.13-6.25 μg/mi and resistant group (2 strains) with MIC values of more than 100 μg/ml.
The antibacterial activity of PC-904 for susceptible group of Pseudomonas aeruginosa was the highestamong the antibacterial activities of CBPC, SBPC, ticarcillin and piperacillin.
In this studies on Pseudomonas aeruginosa, E. coli and Kleb. pneumoniae, PC-904 showed crossresistance with CBPC and SBPC, but not completely.
2) The in vitro synergetic effect of PC-904 and sisomicin against Pseudomonas aeruginosa wasdefined by using bio-photorecorder.
3) After intramuscular administration of PC-904 100 mg/kg in rats, serum concentration reachedpeak in 15 min. and the concentrations in other tissues reached peak in 30 min. The peak levels intissues were high in serum, kidney, liver and lung in order of concentration. PC-904 was not detectedin 3 hours after the administration and 4 hours after the administration in other tissues.
4) In the study on 5 patients with chronic respiratory infection, serum concentrations were in therange from 30 to 63 μg/ml by administering PC-904 1-3g intravenously over 2 hours period and ave-rage of the half lives was about 1 hour. In these patients the ratio of the sputum peak levels to theserum peak levels were in the range from 0.2 to 2.0%.
We already reported that the antibiotic levels in the bronchiolar secretions were obviously higherthan those in sputa in the case of chronic respiratory infection. In 1 patient with chronic brochiolitisamong 5, the levels of PC-904 in bronchiolar secretion were found to be higher than those in sputa. In this patient the levels in bronchiolar secretions were higher than MICs against Pseudomonas aeru-ginosaisolated from corresponding bronchiolar secretions. The treatment was performed according tothe levels in the bronchiolar secretions with good response.
5) PC-904, 0.5 to 6 g/day, mainly by instillation, was administered against 20 episodes in 18 pati-entsand following results were obtained.
In the case of acute respiratory infections (2 cases of acute bronchitis and 1 case of pneumonia), PC-904 was evaluated to be “excellent” in 2 cases and “good” in 1 case. On the other hand, this, anti-biotic was excellently effective in 5 episodes of chronic respiratory infections due to Hemophilusinfluenzae, and in 7 episodes of those due to Pseudomonas asruginosa the antibiotic was evaluated tobe “excellent” in 1 case and “good” in 2 cases. The effectiveness of the combined administration of PC-904 and sisomicin was evaluated to be good against 1 case of Psoudomonas asruginosa infection, in which the administration of PC-904 only was ineffective. As side effects 1 case of eoeinophllla and 1 case of increased GOT value were observed but these side effects disappeared by discontinuation ofthe antibiotic.

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1. Fundamental and clinical examinations on PC-904, a new semi-synthesized penicillin, withbroad-spectrum, were carried out.
2. Antibacterial spectrum of PC-904 was similar to that of CBPC and SBPC, but PC-904 hadobvious antibacterial activity even against Klebsiella pneumoniae.
3. Among the pathogenic germs which were isolated from surgical foci, against Staphylococcusaureus, PC-904 showed almost the same degree of antibacterial activity as CBPC and SBPC, but atthe same time much more resistant strains of PC-904 were recognized of which MICs were more than 100 μg/ml. Against E. coli or Proteus mirabilis, antibacterial activity of PC-904 was revealed to beseveral stages as powerful as CBPC or SBPC. Against Klebsiella pneumoniae, when CBPC or SBPC was applied, resistant strains of which MICs were more than 100 μg/ml were recognized in all casesstudied. On the contrary, many moderately susceptible strains were noticed with PC-904. PC-904showed antibacterial activity against Pseudomonas aeruginosa 6 to 8 fold as powerful as CBPC or SBPC.
4. As for the serum concentration of the drug was concerned, maximal level of 7.6 μg/ml wasrecorded at 15 minutes after intravenous injection of 250 mg. Serum concentration then gradually decre-ased.
Cumulative urinary recovery rate was only 13. 6% for 6 hours and this result led us to speculate that PC-904 was excreted considerably into bile.
5. The concentrations of PC-904 in organs of SD strain rats were examined. That was the highestin liver, then kidneys, lungs, spleen, serum, heart, brain followed in order.
6. Clinical applications of PC-904 were done in 8 surgical infections cases. Firstly PC-904 500 mgdiluted in 500ml of 5% glucose were iv drip infused. But they were not effective in all cases. When 1, 000 mg of PC-904 were used, some cases responded effectively. When iv one shot injections of 500mg or 1, 000mg of PC-904 in 20ml of 20% glucose were performed in 3 cases, excellent responses wereobtained in all cases. Side effects were not noted and especially PC-904 did not influence at all uponcirculatory system.
It would be worthy to mention that iv one shot should be performed as slow as possible.

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Fundamental and clinical studies of PC-904 were investigated and the following results wereobtained.
(1) Antibacterial activity
The sensitivity of PC-904 and CBPC was examined in Pseudomonas aeruginosa. PC-904 was moreeffective than CBPC to Pseudomonas aeruginosa.
2) Absorption and excretion
A single intramuscular dose (20 mg/kg) in rabbit (n=3) gave a peak blood level of 10 μg/ml (themean value of 3 cases) 30 minutes after its administration. The biliary recovery rate was 51.6%within 6 hours.
In two patients (with hepato-biliary disorder) with a single intramuscular dose of 250 mg, a peakblood level was 32.9 μg/ml and a peak bile level was 34.5 μg/ml (the mean value of 2 cases). Thebiliary recovery rate was 0.66% within 6 hours.
(3) Clinical effectiveness
PC-904 was administered to 14 patients with surgical infections and the results were good in 10 cases, fair in 2 cases and poor in 2 cases. Among untoward side effects, eruption was observed in onecase and an elevation of s-GOT and s-GPT in 2 cases. However, these levels returned to normalimmediately following discontinuation of the administration.

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PC-904, a new semisynthetic penicillin, was investigated on its serum level, bile level, clinicaleffectiveness and side effects.
1) Following drip infusion either 1 or 1. 5g PC-904 in 4 patients, the serum level showed a peakat one hour and continued high level at 6 hours after the intravenous drip infusion, but the bileshowed no definite distribution of the drug.
2) PC-904 was given to 30 patients with various infections in the field of surgery. Clinical responsesevaluated in 6 patients with biliary tract infections were excellent and good in each 3 cases, excel-lent in 4 cases, good in 4 cases and fair in 1 case among 9 ones with peritonitis, excellent in 4 cases, good in 3 cases and poor in 1 case among 8 ones with periproctal infections (efficacy rate 87.5%), and excellent in 2 cases, good in 3 cases, fair in 1 case and poor in 1 case among 7 ones withthe other infections (efficacy rate 85. 7%). Totally efficacy rate was 93.3%.
No side effects were noted. Abnormal elevations in serum and urine amylase unit were noted inone case, though these were reversible.

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Fundamental and clinical examinations on PC-904, a new semi-synthesized penicillin, were carried out and the following results were obtained.
1) Antibacterial activity of PC-904
The antibacterial activity of PC-904 against the various strains isolated from clinical specimens (10 strains of Staph. aureus, 23 strains of E. coli, 6 strains of Klebsiella, 6 strains of Proteus mirabilis, 11 strains of Pseud. aeruginosa) was in general similar or a few tubes superior to that of ABPC and CBPC.,
2) Absorption and excretion of PC-904
The peak serum levels of PC-904 in 2 healthy volunteers after 1 hour drip infusion of 1g showed 42μg/ml on the average at the end of infusion, and in the case of 30minutes drip infusion of 0.5g in 1 healthy volunteer, the peak level was achieved at the end of infusion and showed 27μg/ml.
Urinary excretion rates were about 35% in these cases.
Biliary excretion of PC-904 after 1g drip infusion was examined in 2 patients. The peak levels were 735 and 315 μg/ml at 2-3 hours after administration and at 5-6 hours 320 and 220 μg/ml were detected respectively. These levels seemed to be so high that PC-904 was expected to be clinically effective against infectious diseases in bile duct.
3) Results of clinical application
PC-904 was administered to 6 infectious cases, and the effects of the drug were considered to be good in 3, fair in 2 and poor in 1.
Among them, no side effects and abnormalities of laboratory findings were noted.

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Some laboratory and clinical studies in the surgical infection have been carried out on a new antibiotic agent, PC-904.
PC-904 was administered intramuscularly, intravenously and by drip infusion in 21 patients.
Results were obtained as follows;
1) Absorption and excretion
The peak values of serum concentration of PC-904 following an i. m. administration of 125 mg and 250 mg were 7. 5 and 18.6μg/ml respectively.
The peak value of biliary concentration of PC-904 following an i. m. administration of 250mg was 1680μg/ml.
The urinary excretion was obtained mostly within 6 hours after i. m. administration.
2) Results of clinical application
PC-904 was mainly applied to the treatment of biliary tract infections and infected wounds after the operation.
The therapeutic results of 21 cases were excellent in 6 cases, good in 13 cases and poor in 2 cases.
There were no serious side effects except transient elevations of GOT or GPT values in two cases of biliary infection with gallstone.

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