In vitro antibacterial activity of Cefsulodin (SCE-129, CFS), a new cephalosporin antibiotic, was studied on various pathogenic strains.
CFS was confirmed to have a specifically potent activity against Pseudomonas aeruginosa. Peak distribution of MICs of CFS existed at 1.56-3.12μg/ml against P. aeruginosa with an inoculum of 10⁶ cells/ml, and the activity was almost equivalent to that of gentamicin. The activity against other gram-negative organisms, however, was weak. CFS was active also against gentamicin-resistant strains of P. aeruginosa in vitro and in vivo, and the activity was better than that of sulbenicillin.
The antibacterial activity of CFS against the gram-positive bacteria, Staphylococcus, was weaker than those of carbenicillin and sulbenicillin.

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Cefsulodin [3-(4-carbamoyl-1-pyridiniomethyl)-7β-(D-α-sulfophenylacetamido)-ceph-3-em-4-carboxylate monosodium salt](SCE-129, CFS), a new antipseudoinonal cephalosporin, shows potent antibacterial activity against Pseudomonas aeruginosa and some gram-positive bacteria, whereas it shows low activity against many gram-negative rods. Against clinical isolates of P.aeruginosa, cefsulodin was about 10 times more active than sulbenicillin and carbenicillin, and had a similar activity to gentamicin and dibekacin. Gentamicin-resistant strains of P.aeruginosa were sensitive to cefsulodin, but not to dibekacin. Sulbenicillin-(carbenicillin-) resistant strains of p.aeruginosa were moderately resistant to cefsulodin. Against the strains of Staphylococcus aureus, cefsulodin had similar activity to sulbenicillin. Variations in pH, addition of horse serum, and type of growth medium had no significant effect on the activity of cefsulodin however, the inoculum size had some effect on the activity. Cefsulodin is an effective bactericidal agents against P.aeruginosa and S. aureus. The protective effect of cefsulodin on P.aeruginosa infection in mice varied according to the dosage schedule and the challenge dose. In a multiple dose schedule, a smoller amount of cefsulodin was necessary that in a single dose schedule. The effect of cefsulodin after subcutaneous or intraperitoneal administration were more potent than those by intraveneous administration. No protective effect was observed by oral administration. In mice infected with sulbenicillin-(carbenicillin-) and gentamicin-susceptible strains, cefsulodin was about 12 to 60 times more active than sulbenicillin and carbenicillin, and had similar activity to gentamicin. In mice, the activity of cefsulodin was independent whether the strains are resistant to gentamicin or not, but was considerably affected by the strains resistant to sulbenicillin anocarbenicillin. The protective effects of cefsulodin in mice infected with S. aureus was more potent than carbenicillin.

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Bacteriological evaluation on Cefsulodin (SCE-129, CFS), a new semisynthetic cephalosporin, was made and the following results were obtained.
1. MICs of CFS against Pseudomonas aeruginosa were 0.78-6.25μg/ml, which were 8-16 times superior to those of Sulbenicillin (SBPC) and similar to those of Gentamicin (GM), whereas they were rather high against other bacteria, which are highly susceptible to ordinary β-lactam antibiotics.
2. CFS showed a potent antibacterial activity to SBPC and GM-resistant strains of the clinical isolates of Pseudomonas aeruginosa.
3. Antibacterial activity of CFS was slightly influenced by inoculum size, medium pH and addition of horse serum.
4. The mode of the in vitro antibacterial action of CFS was quite similar to that of CEZ against Staphylococcus aureus and E. coli and to that of SBPC against Pseudomonas aeruginosa.
5. CFS was very stable to β-lactamases derived from a variety of gram-negative bacteria. It was especially noteworthy that CFS was stable not only to Pseudomonas aeruginosa specific cephalosporinase, but also to penicillinases derived from clinically isolated Carbenicillin (CBPC)-or SBPC-resistant strains of Pseudomonas aeruginosa.
6. CFS showed relatively good protecting effects in mice intraperitoneally infected with both SBPC-and GM-sensitive strains and SBPC-and GM-resistant strains of Pseudomonas aeruginosa.
The protecting effect of CFS by multiple dosing was better than that of single dosing, and it was superior to that of GM.

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Antibacterial activities of Cefsulodin (SCE-129, CFS) were examined against P. maltophilia, P. putida, P. stutzeri, P. fluorescens, Flavobacterium, Alcaligenes, Achromobacter, Klebsiella, Proteus and Bacteroides, isolated from various clinical materials at Clinical laboratories of Juntendo University Hospital in 1975 to 1977.
CFS showed a potent antibacterial activity against P. aeruginosa, extent of which was superior to those of Sulbenicillin and Carbenicillin, similar to that of Amikacin and a little inferior to those of Gentamicin (GM) and Dibekacin (DKB).
Twelve percent of the strains tested of P. aeruginosa was resistant to CFS, GM and DKB.

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Resistance of Cefsulodin (SCE-129, CFS) to hydrolysis by β-lactamases was examined in relation to the antibacterial activity mainly against Pseudomonas aeruginosa.
1) CFS was strongly active as Gentamicin against most strains of P. aeruginosa including strains which were highly resistant to antipseudomonal penicillins such as Sulbenicillin (SBPC) and Carbenicillin (CBPC).
2) All strains of P. aeruginosa tested produced cephalosporin β-lactamase (cephalosporinase), and Sulbenicillin-resistant strains, which were isolated in the frequency of several percents in clinical specimen, produced either of type I (RTEM) type II (Cloxacillin hydrolysing) or type IV (Carbenicillin hydrolysing) penicillin β-lactamase (penicillinase) in addition to cephalosporinase.
3) CFS was hardly hydrolysed by cephalosporinase of P. aeruginosa. It was also resistant to hydrolysis by three types of penicillinase. The affinity of these penicillinases for CFS was remarkably lower than for other cephalosporins and penicillins tested.
4) The MICs of SBPC and CBPC to P. aeruginosa were affected largely by the presence of penicillinase. Whereas, the differences in the MIC levels of CFS to the most strains with or without penicillinase were much less than those of SBPC and CBPC.
5) Although CFS was also remarkably resistant to hydrolysis by β-lactamases from various bacteria as well as those from P.aeruginosa, it was weakly active against bacteria except Staphylococcus aureus and P. aeruginosa.

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Antibacterial activity of Cefsulodin (SCE-129, CFS), a new cephalosporin-derivative, was tested in vitro. The minimum inhibitory concentrations of the new agent against clinically isolated strains of Staphylococcus, Pseudomonas, Klebsiella, Escherichia coli and Enterobacter, were measured and compared to those of CTM (another new cephalosporin-derivative), Sulbenicillin (SBPC) and aminoglycosides.
At the concentration less than 25μg per ml of CFS, the growth of 32 out of 39 strains of Pseudomonas tested was inhibited while only 2 strains out of them were inhibited at the same concentration of SBPC. The concentration over 200μg per ml of CTM was needed to inhibit the growth of the same strains of Pseudomonas aeruginosa. Except for Kanamycin, the minimum inhibitory concentrations of aminoglycosides (Dibekacin, Tobramycin, Gentamicin and Amikacin) against Pseudomonas were slightly lower than those of CFS.
Among the strains of Pseudomonas tested no cross resistance was observed between CFS and aminoglycosides.
Substantially, CFS did not show any antibacterial activity against clinical isolates of Klebsiella and Enterobacter. The minimum inhibitory concentrations against the patient strains of Staphylococcus aureus and Escherichia coli were over 6.25 and 25μg per ml respectively.
In conclusion, CFS is the first cephalosporin derivative having a potential antibacterial activity against Pseudomonas and its activity seemed exclusively restricted against this species among gram-negative bacilli. Clinical utilization of such a narrow spectrum but potential antibiotic may provide a therapeutic benefit for treatment of Pseudomonas infections.

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Cefsulodin (SCE-129, CFS), a new semisynthetic cephalosporin, has a characteristic antibacterial spectrum. It is more effective than Sulbenicillin (SBPC) and Penicillin G (PCG) against Pseudomonas aeruginosa. Antibacterial mechanisms of CFS were investigated and compared with those against Escherichia coli, which is poorly sensitive to CFS.
Peptidoglycan synthesis catalyzed by membrane enzyme system from P. aeruginosa was inhibited by low concentration of CFS as SBPC and PCG. On the other hand, CFS inhibited the synthesis catalyzed from E. coli for about 10 times less than that from P. aeruginosa. Moreover, CFS showed a higher permeability than SBPC and PCG in both organisms.
These properties may reflect the characteristic antibacterial spectrum of CFS.

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In vitro and in vivo antibacterial activities of Cefsulodin (SCE-129, CFS), a new semisynthetic cephalosporin developed as a drug for use in Pseudomonas aeruginosa infections, were studied in comparison with Gentamicin (GM) and the following results were obtained.
1. In vitro minimal effective concentrations of both the drugs against Pseudomonas aeruginosa E-2 were about the same (0.78-1.56μg/ml). The mode of the onset of the bactericidal action of CFS, however, was much different from that of GM. CFS was only bacteriostatic for an hour to one and half hours but showed a remarkable bactericidal action thereafter. Elevation of the CFS concentrations up to as high as 100μg/ml resulted in almost no change in time of the onset of the bactericidal action and potency of the antibiotic. While, GM showed a faster and more potent bactericidal activity as the concentration was elevated. The organism exposed to CFS and GM began to proliferate an hour after drug elimination in a manner similar to that of the normal oraganism.
2. In in vivo experiments, the protective effect of CFS in mice intraperitoneally infected with Pseudomonas aeruginosa improved as the frequency of injections increased. Total ED₅₀ as well as ED₅₀ per injection of CFS were markedly smaller with repeated doses. In the case of GM, however, ED₅₀ per injection was smaller with repeated doses, but toal ED₅₀ remained almost unchanged. Thus, ED₅₀ of CFS was slightly inferior to that of GM in single dosing, but in multiple dosing the total ED5o as well as ED₅₀ per injection of CFS were superior to those of GM.
3. From the time-course change of the drug concentration in the peritoneal fluid it was presumed that an important factor which gave influence to the protective effect was the total duration of the time for which the effective concentration was maintained in the case of CFS, and it was the total amount absorbed in the case of GM. It was also presumed that the mininal effective concentration of CFS by the peritoneal fluid of the mouse was 0.5-1.0μg/ml, which were almost the same as those observed in the in vitro experiment, whereas that of GM was about 5μg/ml.
4. The bactericidal potency of CFS received little influence even when its concentration in the peritoneal fluid of the mouse was much higher than the minimal effective level, but that of GM became higher as the dose was increased. Both the drugs showed a growth-inhibitory effect for a period longer than expected from their time-course change of the concentration in the peritoneal fluid. The regrowth inhibition period of CFS, which is the time when the infectious organism exposed to a drug begins to proliferate again after the drug is eliminated, was thought to be related to the time for which the organism was exposed to the effective concentrations, whereas that of GM to the total amount of the drug absoibed by the ogranism.

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Pharmacodynamic effects of Cefaulodin (SCE-129, CFS) were investigated with experimental animals. An intramuscular dose of 1, 000 mg/kg in mice did not affect any of the behavior, electroshock or pentylenet. etrazol seizure, coordination of skeletal muscles, methylhexabital sleeping time or phenylquinone writhing. The same dose in rats also did not affect the body temperature of normal and pyretic rats or carrageenin edema. An intravenous dose of 400 mg/kg in cats did not affect the behavior or mono-and polysynaptic reflexes, and an intramuscular dose of 200 mg/kg in dogs did not inhibit the apomorphine-emesis. A higher intravenous dose of 1, 000 mg/kg in cats produced muscular tremor and salivation in 2 of 3 animals, ernesis in 1 of the 3 and respiratory stimulation in all the animals. Intravenous infusion of CFS at a rate of 20 mg/kg per min in d-tubocurarine-immobilized cats produced seizure discharges in the spontaneous EEGs at a total dose of 667±120 mg/kg (±S.E.M., n=3). An intravenous bolus dose of 200 mg/kg did not affect the spontaneous EEGs or behaviors in unanesthetized cats with chronically indwelled electrodes but a higher dose of 500 mg/kg produced seizure discharges in 1 of 2 cats studied. In chloralose-urethane anesthetized cats, an intravenous injection of 200 mg/kg of CFS hardly affected the blood pressure, heart rate, respiration or ECG and a higher intravenous dose of 400 mg/kg produced a slight hypotension, bradycardia with respiratory stimulation. An intramuscular dose of 500 mg/kg of CFS did not affect the intestinal transport of charcoal in mice or urine and electrolyte excretions in rats. The isolated atria, ileum, and trachea of guinea pigs as well as isolated uterus of rats were not influenced by 100μg/ml of CFS.

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Cefsulodin (SCE-129, CFS), a new cephalosporin antibiotic effective against Pseudomonas aeruginosa, was examined for its subacute and chronic toxicity in rats (two strains), rabbits, dogs and monkeys. The results were summarized as follows.
1.In a 1-month intramuscular toxicity study in JCL: Fischer rats, CFS was somewhat hepatotoxic at high doses ; slightly at 300 mg/kg/day and moderately at 1, 000 mg/kg/day. In Ta Wistar rats, however, it was slightly nephrotoxic but only minimally hepatotoxic even at 1, 000 mg/kg/day by intramuscular or intraperitoneal injection for 1 month.
2. In JW-NIBS rabbits, a slight nephrotoxicity was observed at 1, 000 mg/kg/day after 1-month intramuscular treatment.
3. In beagle dogs, even though a minimal nephrotoxicity was suspected in 1 female and a slight enlargment of thyroid follicles in 2 other animals treated intravenously with 1, 000 mg/kg/day for 1 month, CFS showed no organ-toxicity in 3-month intramuscular injections at doses up to 600 mg/kg/day nor in 6-month similar dosings at up to 300 mg/kg/day.
4. In cynomolgus monkeys, CFS showed no remarkable toxicity after 1-month intramuscular dosings at up to 1, 000 mg/kg/day, except a slight to moderate local lesion at the injection site.
5. In summary, it was concluded that the toxicity of CFS in these experimental animals was comparable to that of other cephalosporins such as cephalothin and cefazolin in one respect or another and that its maxi mum non-toxic dose in the experiments was at least 100 mg/kg/day.

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A microbiological method for the quantitative determination of Cefsulodin (SCE-129, CFS) in biological specimens is described. This method is essentially a cylinder-plate technique using Pseudomonas aeruginosa NCTC 10490 as the test organism grown in the DST agar medium supplemented with 0.1% sodium acetate. As low as 0.2 to 0.4μg/ml of CFS in human serum specimens can be measured. A method for the detection of the active metabolites of CFS is also presented. The procedure involves a reversed-phase thin-layer chromatography on silica gel plate combined with a bioautography using Staphylococcus aureus HS-9 as the test organism grown in the Sulbenicillin assay medium supplemented with 0.1% N-acetyl-D-glucosamine.

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A single dose of 20 mg/kg of Cefsulodin [3-(4-carbamoyl-1-pyridiniomethyl)-7 β-(D-α-sulfophenylacetamido)-ceph-3-em-4-carboxylate monosodium salt](SCE-129, CFS) was administered subcutaneously to mice, intramuscularly to rats and intramusculary or intravenously to dogs. The plasma and tissue levels reached the peak 15 to 30 min after administration. CFS distributed at high concentrations in the diminishing order to kidney, plasma, lung, liver and spleen. The CFS levels in the lung of rats and dogs were relatively high. In the plasma and tissues of mice and rats, the levels of CFS declined rapidly, and in dogs, the levels declined gradually. The biological half-lives were 0.85 to 0.99 h for intravenous administration and 0.73 to 0.89 for intramuscular administration. CFS was mainly excreted into the urine and the excretion into the bile was very slight.

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Normal adult male volunteers received single intramuscular doses of 125 mg to 500 mg or 500 mg twice a day for 1-2 days or 250 mg twice a day for 5 days, to study the safety and pharmacokinetics of Cefsulodin (SCE-129, CFS). Each dose of CFS as an aqueous solution in 2 ml of 0.5% mepivacaine hydrochloride, was injected into the semilunar region of the gluteal muscle. The following results were obtained.
1) Either of the test doses of CFS was proved to be safe, exerting no effects on the various functions of the body. It exerted only a slight local irritant effect. It may therefore be judged reasonable to initiate the clinical investigations on the patients within the dosage range given in this trial; its blood and urinary levels also supporting this judgement. However, white blood cells in the urinary sediment were slightly increased in some of the subjects.
The relation of this observation with CFS may be deniable but is not yet clarified; hence, it appears necessary to proceed with further studies on this antibiotic with ample attention to this fact.
2) CFS, when administered intramuscularly, was rapidly absorbed, with the serum peak level reached in 0.5 to one hour. Its biological half-life was found to be 1.4 hours on the average. The maximum serum level (about 17μg/ml after a single dose of 500 mg) and AUC increased mostly in proportion to the dose. The mean 24-hour urinary excretion rate was about 70% of the administered dose, with the major portion of the output excreted within several hours after its administration: thus, high urinary levels were attainded. Even when either 250 mg or 500 mg was administered repeatedly, at a six-hour interval, the antibiotic would not be accumulated in the blood.
3) Active metabolites were not detected in the urine.
4) The elimination of CFS did not appear to be influenced by concurrent administration of probenecid. Therefore, renal excretion of CFS is considered to be largely the result of glomerular filtration.

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The safety, serum level and urinary excretion of Cefsulodin (SCE 129 CFS), a new cephalosporin, were studied following intravenous administration in ten normal male volunteers who participated in the studies after giving informed consents.
Six subjects received a single dose of 500 mg, 1, 000 mg or 2000, mg of the antibiotic by the intravenous drip infusion (i.v.d.) over 1 hour. Another two subjects were given two i.v.d. doses of 500 mg with an interval of six hours. A single dose of 1, 000 mg was injected as a bolus to the remaining two subjects. Each subject was checked by physical examinations, hematology, blood chemistry and urinalysis serially before and after the administration of CFS.
The intravenous administration of CFS at these doses levels showed no adverse effects, and it is suggested to be clinically applicable. However, the intravenous injection of CFS as a bolus was followed by a transient decrease in white blood cells (WBC) four to six hours after the injection. As this group consisted of only two subjects, and also because the reversed variation were achieved in the subjects given by intravenous drip infusion, it is inconclusive that the decrease of WBC is accounted for the administration of CFS; this finding indicates the necessity of exercising ample care regarding the behavior of WBC following intravenous administration, especially, intravenous injection as a bolus.
The serum levels of CFS at the end of the intraNenous drip infusion and the area under the serum leveltime curve were mostly proportionate to the doses administered. The serum level after the intravenous injection as a bolus remained higher than the level achieved by the one-hour intravenous drip infusion of the same dose, for the first 30 minutes, and then rapidly decreased. The mean 24-hour urinary excretion rate in all subjects was about 80% of the administered dose, and the major portion was excreted within several hours after the administration.

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Cefsulodin (SCE-129, CFS), a new antipseudomonal cephalosporin preparation has been investigated to give following results.
1) Insusceptibility test of 315 strains of P. aeruginosa isolated from clinical specimens using plate dilution method, 71.4% of strains were inhibited by 25μg/ml of the drug. Sensitivity distribution curve of these strains showed 2 peaks.
Correlation coefficients between MICs of the drug and Apalcillin (APPC) and Piperacillin (PIPC) were 0.568 and 0.515 respectively, suggesting no strong cross-resistances between these drugs.
2) Absorption and excretion study following 250 mg i. m. administration was carried out on patients in advanced age. In 5 cases without serious renal or hepatic impairment, mean peak level of 3.86±0.46μg/ml and mean urinary recovery of 52.0±3.8% were obtained and worked out mean half life was about 3.0 hour, whereas in a case with moderate ienal failure, prolonged serum concentration and poor urinary excretion were obtained.
3) In clinical evaluation in 11 patients with Pseudomonas infections including 4 respiratory and 7 urinary tract infection, 4 responded favourably, 4 showed fair, and 3 poor results. Most patients were in advanced age and had underlying diseases. Bacterial replacements or relapse have occurred in 5 cases. There were no abnormal fluctuation of laboratory values except in one case with renal impairment with increase in BUN and S-Cr values after the treatment.

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On a new cephalospori n antibiotic, Cefsulodin (SCE-129, CFS), clinical investigations were performed and the following results were obtained.
1. In the sensitivity test of a variety of gram-negative bacilli isolates from clinical specimens, only Pseudomonas aeruginosa had specific sensitivity against CFS, while others were relatively resistant to it.
2. Two patients suffering from chronic respiratory infection were treated with CFS. One responde4 well. but another failed. No side effects were observed.

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Cefsulodin (SCE-129, CFS) a new semisynthetic cephalosporin antibiotic for parenteral administration, was evaluated on its antibacterial activity, pharmacokinetic behavior and clinical effectiveness.
The antibacterial activity of CFS against Pseudomonas aeruginosa was found to be markedly influenced with inoculum sizes. MICs of this antibiotic with an inoculum of 100-fold dilution against P. aeruginosa were lower by 5 to 6 grades than those of Carbenicillin and they were almost compared to those of Gentamicin. Against Escherichia coli and Klebsiella pneumoniae, MICs of CFS were higher by 4 to 5 grades than those of Cephaloridine, Cephalothin, Cefazolin and Cephalexin.
Peak concentrations of CFS occurred in serum after 30 min. following intramuscular injection of single 250mg doses in two healthy adult volunteers exhibiting concentrations of 5.3 and 7.5μg/ml, which declined to 0.27 and 0.35μg/ml after 6 hrs, respectively. A cross-over study with probenecid showed that peak concentrations of 5.6 and 8.8μg/ml, respectively, occureed in serum after 30 min, following same doses, and these declined to 0.52 and 0.94μg/ml after 6 hrs.
Urinary recovery of CFS in 0-6 hr urine samples following intramuscular injection of single 250mg doses in same volunteers reached 52.48% and 63.74% without probenecid and 24.59% and 39.88% with probenecid, respectively.
CFS was given to 14 patients with respiratory-tract infections (3) infection associated with tracheoesophageal fistula (1) and urinary-tract infections (10) which were all due to P. aeruginosa in daily doses of 250 to 1, 500 mg for 3 to 56 days. The results were good in 8 patients (61.5%), fair in 1, poor in 4 and inevaluable in 1. Bacteriologically, P. aeruginosa was eradicated in 7 patients (but, relapse in one case) and persisted in 7, the rate of eradication being 46.5% excluding the case of relapse. In the 3 cases of urinarytract infections due to plural pathogens including P. aeruginosa, eradication or diminution of P. aeruginosa count was noted, but the bacterial count of the other coexisting gram-negative rods increased.
No side effects nor abnormalities of laboratory tests associated with CFS treatment occurred.

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Cefsulodin (SCE-129, CFS) was administered to 10 cases with Pseudomonas infection comprising of 6 cases with urinary tract infection, 1 case with acute pneumonia, 1 case with bronchiectasis, 1 case with skin burn and 1 case with infected decubitus. It was effective in 7 out of 10 cases with the efficacy rate of 70% No.side effect was observed in all cases.

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Laboratory and clinical studies on Cefsulodin (SCE-129, CFS), a new antipseudomonal cephalosporin antibiotic, were performed and the following results were obtained.
1. Antibacterial activity of CFS against Pseudomonas aeruginosa was compared with that of Gentamicin (GM). It was inferior to that of GM in the inoculum size of 108cells/ml but was superior to that of GM in the inoculum size of 10⁶ cells/ml.
2. Absorption and excretion of CFS were studied in a patient with chronic bronchitis who was received 1g by two-hour-intravenous drip infusion. Blood levels were 32μg/ml at 30 minutes, 19μg/ml at one hour, 12.5μg/ml at 2 hours and 3.0μg/ml at 6 hours after the end of the drip infusion. Urinary recovery in 0-6 hours was 63.1%. Mean concentration in sputa (2.1ml) in 0-6 hours was 1.1μg/ml.
3. CFS was given to 7 patients with respiratory tract infections and to four patients with urinary tract infections, in a daily dose of 500mg-2g bid, intramuscularly, intravenously or by intravenous drip infusion. Clinical effects were good in 6 patients, fair in 2 patients and poor in 3 patients. Bacteriologically, Pseudomonas aeruginosa was eliminated in all patients but in 5 patients Pseudomonas aeruginosa was replaced by new bacteria other than Pseudomonas aeruginosa.
4. There was seen allergic fever in one patient as a side effect. No abnormal laboratory finding were seen.
5. CFS is an unique cephalosporin antibiotic whose antibacterial activities were potent against Pseudomonas aeruginosa and weak against other gram negative bacteria. It should therefore be recommended to use concomitantly with other broad spectrum antibiotics.

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Clinical evaluation on Cefsulodin (SCE-129, CFS), a new cephalosporin antibiotic, was made to obtain the following results.
1. CFS was given to 3 patients with severe Pseudomonas aeruginosa infections comprising of 2 cases of septicemia and 1 case of phlegmon, with a daily dose of 1-2g, divided into 4 times every 6 hours or twice every 12 hours by intravenousdrip infusion for a period of 6-40 days.
2. CFS gave excellent therapeutic effects to the patients. However, to mixed infections including P. aeruginosa the concomitant therapy with other broad spectrum antibiotics should be recommended.
No adverse reactions and abnormal laboratory findings attributed to CFS were observed.
3. CFS showed a excellent antibacterial activity against P. aeruginosa isolated from the patients.
Minimal inhibitory concentrations of CFS to the isolates were 1.56-6.25μg/ml in the inoculum size of 10⁶cells/ml and 1.56-3.12μg/ml in 10⁶ cells/ml.

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1. After 0.5g of Cefsulodin (SCE-129, CFS) was injected intravenously into the patients with renal failure, serum concentrations were measured.
The decrease of CFS levels in the serum slightly delayed in cases with moderate renal damage.
2. In uremic patients, the average of CFS levels was 73μg/ml at the peak, and was 25.5μg/ml 24 hours after the administration.
When these patients received a hemodialysis for 5 hours after the CFS administration, the CFS level dropped to 6.8μg/ml in 24 hours although its peak was same as above.
3. Total 6 CFS treatments were performed for 5 patients with P. aeruginosa infection.
Based on the judgement of individual treatments, clinical results were excellent in 1, good in 2, and fair in 3. No side-effects were recognized.

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Cefsulodin (SCE-129, CFS), a new cephalosporin derivative developed by Takeda Chemical Industries LTD., was examined as to its in vitro activity against clinically isolated bacteria, its serum level and urinary excre tion rate in humans after intramuscular injection, tissue concentrations in rats as well as its effectiveness in clinical cases.
The results obtained were as follows:
1) Antibacterial activity: MIC of CFS against 50 strains of Pseudoinonas aeruginosa were 0.8 to 3.1μg/ml similar to those of Dibekacin and Gentamicin.
2) Serum levels in adult men: The drug showed a serum peak level as high as 13-23μg/ml one hour after 0.5g i.m. injection, being still detectable (1, 7-4.0 μg/ml) 6 hours after the administration.
3) Distribution in rat organs: The highest tissue concentration of CFS in rat organs aftei i.m. administration (10mg/kg) was found in kidneys, followed by blood, lung, spleen, liver and muscles.
4) Clinical trials: Six clinical cases with Pseudornonas infections (chr. bronchitis 1 UTI 3, and decubitus 2; all having underlying diseases) were treated with CFS 250-1, 000 mg/day i.m. Although the Pseudomonas infections of the five cases, except for one bronchitis case, well responded to the therapy, substitution of the pathogen by other organisms were commonly observed after the treatment. No adverse effects or abnormal laboratory findings caused by CFS were observed.

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Laboratory and clinical studies on Cefsulodin (SCE-129, CFS) were performed and the following results were obtained.
1. Serum levels
Mean serum level of CFS was 15.2μg/ml at 15 minutes after a single intravenous injection of 500mg.
In intravenous drip infusion, peak serum levels were observed just after the end of the drip infusion in every dose and period of the injection.
The peak sei um levels weie 26.4μg/ml in 750mg, 42.6μg/ml in 1, 000mg with the one-hour-drip infusion and 14.0μg/m; in 250mg, 21.4μg/ml in 500mg and 30.5 μg/ml in 750mg with the two-hour-drip infusion.
CFS was rapidly excreted from the blood after injection and was detected a little amount (0.9, -3.3μg/ml) in serum in 5-6 hours after the end of injection.
CFS gave the biological half-life of ca. 1.4 hours in every dose and dosing period.
2. Urinary excretion
CFS was excreted in urine well and gave a urinary recovery of 60-80% in hours after the end of injections.
3. Clinical application
CFS was given intravenously or by intravenous drip infusion, a daily dose of 750 or 1, 000mg, for 3-23 days to four patients in a remission stage of acute myelocytic leukemia with such infections as septicemia, urinary tract infections, liver abscess and pnuemonia.
Chemotherapeutic results were excellent in 3 patients and poor in one patient with pneumoina due to CFS-resistant strain of P. aeruginosa.
No adverse effect was seen in every patient.

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Cefsulodin (SCE-129, CFS), a newly developed anti-pseudomonal cephalosporin was studied basically and clinically. Following results were obtained.
1) Antimicrobial activity:
Minimum inhibitory concentrations (MICs) of CFS against 22 standard strains subcultured in our department and 856 clinical isolates (Pseudomonas aeruginosa 106, Staphylococcus aureus 54, Salmonella 36, Citrobacter freundii 38, C. diversus 30, C. amalonatica 10, E. coli 53, Shigella 45, Klebsiella pneumoniae 53, Enterobacter aerogenes 54, E. cloacae 54, Serratia marcescens 54, Proteus vulgaris 12, P. mirabilis 41, P. rettgeri 22, P. inconstans 16, P. morga Following results were obtained.
1) Antimicrobial activity:
Minimum inhibitory concentrations (MICs) of CFS against 22 standard strains subcultured in our department and 856 clinical isolates (Pseudomonas aeruginosa 106, Staphylococcus aureus 54, Salmonella 36, Citrobacter freundii 38, C. diversus 30, C. amalonatica 10, E. coli 53, Shigella 45, Klebsiella pneumoniae 53, Enterobacter aerogenes 54, E. cloacae 54, Serratia marcescens 54, Proteus vulgaris 12, P. mirabilis 41, P. rettgeri 22, P. inconstans 16, P. morganii 43, P. putida 31, P. maltophilia 33, P. putrefaciens 14, Flavobacterium spp. 50 and Acinetobacter anitratus 7) were determined by agar plate method.
MICs of CFS against 106 Pseudomonas aeruginosa were compaied with those of Sulbenicillin (SBPC) and Piperaciliin (PIPC). MICs of CFS against 86 out of 106 P. aeruginosa were determined in combination with Gentamicin (GM). MICs of CFS against 22 standard strains and clinical isolates excluding P. aeruginosa were compared with those of Cefazolin (CEZ).
CFS had 1-4 tubes higher activities against P. aeruginosa than SBPC and PIPC and it was more than 4 tubes stronger than CEZ.
On the contrary, MICs of CFS against 84 P. aeruginosa were around one tube weaker than those of GM.
MICs of CFS against standard strains and clinical isolates excluding P. aeruginosa were almost the same as those of CEZ or higher.
2) Serum levels in man:
A 46 year-old 53 kg male patient with chronic diffuse panbronchiolitis and a 68 year-old 49kg female patient with chronic bronchitis were given 1, 000mg of CFS by intravenous drip infusion with 300ml solution foi two hours. Peak serum levels were 18μg/ml and 38μg/ml at the end of injection in both cases. Six hours after injection 1-2μml of the drug was measurable.
3) Urinary excretion and trends of bacteria in urine:
Urinary recovery rates of CFS in the above mentioned male patient were 65% at 2 hours and 87% at 8 hours after the end of injection respectively.
A 37 year-old 40 kg female patient with chronic cystitis and viral meningitis was treated with 1, 000mg intravenous drip infusion of CFS a day.
CFS was excreted in urine at the concentration of 340μg/ml 2 hours after injection, and numbers of P. aeruginosa and E. coli which were cultured more than 105 ml and 10 mlin number respectively at the beginning started to decrease around 3 hours. Both bacteria were less than 10²/ml at 8 hours after injection and were eliminated from the urine from the second day.
MICs of CFS against each P. aeruginosa strain isolated hourly were constant.

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The effects of Cefsulodin (SCE-129, CFS) on chronic respiratory infections caused by Pseudomonas ginosa have been studied with special reference to the possibility of retrograde superinfection, i.e. the change of pathogens from Pseudomonas aeruginosa to Haemophilus influenzae.
Antibacterial activities of CFS against 141 strains of respiratory pathogens isolated more than 10⁷/ml from sputum were measured as the MIC values. And it was revealed that CFS was very active against Pseudomonas aeruginosa (MICs:≤0.2-12.5μg/ml;≤1.56μg/ml against the majority) and almost equal to tobramycin, and that CFS was less active than other cephalosporins against Streptococcus pneumoniae (MICs: 1.56-12.5μg/ml), Haemophilus influenzae (3.13->100μg/ml). E. coli (12.5->100μg/ml) and Klebsiella pneumoniae (50-400μg/ml). On the one hand, pharmacokinetic studies in rats and patients with chronic bronchiolitis showed that the maximum sputum level of CFS in patients with chronic respiratory infections after the administrations of 0.25 to 1.0g dose is about 1μg/ml at the best. Therefore, CFS may suppress only Pseudomonas aeruginosa and cause superinfections.
And then, 5 patients (chronic bronchitis; 2, chronic bronchiolitis; 2, bronchiectasis; 1) infected with Pseudomonas aeruginosa and one patient with acute pneumonia due to Haemophilus influenzae complicated to chronic bronchiolitis due to Pseudomonas aeruginosa were treated with CFS 0.25g to 1.0g b.i.d. for 4 to 20 days. In 4 of 6 patients, Pseudomonas aeruginosa was eradicated from respiratory tract. And after that, Haemophilus influenzae appeared in one patient, and Streptococcus pneumoniae in another patient. CFS was not effective to Haemophilus influenzae pneumonia. Clinical effectiveness of CFS against pseudomonal chronic respiratory infections was good for 2 cases, fair for 2, and poor for 1. Side effects were not recognized at all.
Before, we made it clear that the most cases of pseudomonal chronic respiratory infections were brought about by the repeated superinfections after antibiotic treatment for Haemophilus influenzae infections using ampicillin, amoxicillin, etc., and that to let them turn back to the state of Haemophilus influenzae infection is favorable to the treatment of those patients. Under this recognition, the possibility of retrograde superinfection caused by CFS was discussed.
On the basis of these results, it is concluded that CFS has a unique and good effect for pseudomonal chronic respiratory infections.

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Evaluation of Cefsulodin (SCE-129, CFS) was done by basic and clinical studies and the following results were obtained:
1) Gram-positive and gram-negative bacteria other than S. faecalis, K. pneumoniae, Bacillus species and P. morganii were susceptible to 50μg/ml or less of CFS. The antibacterial activity of CFS was less potent than those of Amikacin (AMK) and Gentamicin (GM) but the activity against P. aeruginosa was more potent than those of AMK and GM.
2) CFS was antibacterial against clinically isolated strains of P. aeruginosa, E. coli, Klebsiella, P. mirabilis etc. The antibacterial pattern of CFS against strains of P. aeruginosa was similar to those of AMK and KW-1062. MICs of CFS against E. coli and Klebsiella were most frequently distributed at 100μg/ml, while those of other cephalosporins were at lower concentration. MICs of CFS were mostly 100μg/ml or higher against P. mirabilis.
3) The blood and urinary CFS levels following an intramuscular dose of 500mg were determined by the cylinder-plate mothod using P. aeruginosa NCTC 10490. The blood CFS level reached maximum (mean: 15.7μg/ml) 30 minutes after administration. The concentration in the urine was the highest (mean: 2623μg/ml) an hour after administration. Mean recovery of the antibiotic in the 0-6 hour urine was 49.9%.
4) Examination of the pharmacokinetic parameters by the single compartment open model showed ka (hr-1) of 6.8, kel (hr^-1) of 0.536, T_1/2 of 1.29 hr., Cmax of 15.1μg/ml, t-max of 0.54 hr., Vd (L) of 26.6, CR (ml/min.) of 238 and AUC (μg/ml) hr of 35.1.
5) Tissue distribution of CFS was examined in a group of three SD rats given an intramuscular dose of 20mg/kg. The concentration of CFS was higher in the order of muscle of the injection site, kidney, serum, lung, liver, muscle of the non-injection site, heart and spleen. CFS was not detected in the brain at any time.
6) Metabolism in man was examined on the urine obtained after CFS administration. Bioautograms prepared by use of TLC indicated that CFS was excreted in the urine without being metabolized.
7) Four patients with surgical infections (complicated UTI, burn, acute pyelonephritis and chronic cystitis) were treated with CFS to give one excellent response, two good responses and one poor response. No side effects, subjective and objective, and no abnormal laboratory findings were noted.

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Fundamental and clinical studies with Cefsulodin (SCE-129, CFS) were performed in the surgical field and following results were obtained.
1) Antibacterial activity
Antibacterial activity of CFS to P. aeruginosa isolated from surgical field was examined. As the result, the activity of CFS was almost the same as that of Amikacin.
2) Serum level and biliary excretion
After a single intramuscular injection of 250 mg of CFS to two patients with gallstone disease, serum and bile levels were determined. The serum levels reached to the peak after 1 hour (14.3μg/ml and 16.8μg/ml) and the bile levels reached to the peak after 1 to 2 hour (3.4μg/ml and 4.8μg/ml). Therefore, biliary excretion of CFS was not so good.
3) Clinical effectiveness
CFS was administered to 6 patients with surgical infections caused by P. aeruginosa and the results were good in 4 cases, fair in 1 and poor in 1. And no side effects were found.

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Cefaulodin (SCE-129, CFS) was administered to 14 patients with Pseudomonas infection in the field of surgery, resulting in excellent and good responses in 6 cases and fair in 4, there was no serious side effect in the present series.
The serum levels and urinary excretion were investigated on adult volunteers, using a bioassay procedure. Following the intramuscular injections of 250mg and 500 mg of CFS, the average serum levels reached their peaks of 31.0μg/ml. in 1 hour and 40.5μg/ml. in 30 minutes respectively, and the average serum levels in 8 hours after the administration were 0.31μg/ml and 3.78μg/ml respectively. The average urinary excretion within 8 hours after injections of 250mg and 500mg were 226.7mg (90.7%) and 362.3mg (72.4%) respectively.
The biliary distribution was also studied on the bile collected through a PTCD catheter indwelt in 2 postoperative patients. Following intramuscular injections of 500 mg of CFS, the average bile concentration reached its peak of 3.6μg/ml in 2 to 3 hours and continued the detectable level for 6 hours.

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Laboratory and clinical evaluation on Cefsulodin (SCE-129, CFS) was made and the following results were obtained.
1) Absorption and excretion
CFS was given 250mg intramuscularily to hepatic insufficient patients with choledocho-drainage after operation of cholelithiasis to measure blood, urinary and biliary concentrations.
Blood level reached to a peak (10.0μg/ml at one hour after injection and decreased gradually to 0.5μg/ml at 6 hours and was not detected at 24 hours after dosing.
Biliary concentration reached to a peak (31.1μg/ml) in 3, -4 hours after injection and then decreased rapidly to undetectable range (0.4μg/ml) in 6-24 hours after dosing. Urinary concentration was a high level of 1, 264-1, 488μg/ml in one to two hours after dosing. Urinary recovery of 024 hours was 75.4%.
2) Clinical application
CFS was given to 7 patients with Pseudomonas aeruginosa infections after operation of such underlying diseases as duodenal cancer, rectal cancer, acute appendicitis and cholelithiasis in a daily dose of 500 to 4, 000mg by intravenous drip infusion or intravenous injection as a bolus for 5-10 days.
Therapeutic effect in patients with such Pseudomonas infections as locallized peritonitis, wound infection, periproctal and intraabdominal abscesses was good in 6 patients and poor in one patient with metastasis of gastric cancer to liver. Clinical effective rate was 85.7%.
Bacteriologically Pseudomonas aeruginosa was eradicated in 3 patients out of 7. In mixed infections with P. aeruginosa and E. coli, replacement to Enterobacter and Bacteroides was found.
No side effect was seen except transient elevations of GOT and GPT in one patient with peritonitis after operation of cholelithiasis.

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Cefsulodin (SCE-129, CFS), a new antimicrobial agent, had a activity against Pseudomonas aeruginosa. Antimicrobial activity, concentration in blood and urinary excretion were studied on this agent, and results were as follows:
The values of minimal inhibitory concentrations obtained with CFS against clinically isolated Pseudomonas aeruginosa, 88 strains had three peaks at 3.13μg/ml, 25μg/ml and >1, 600μg/ml when inoculum size was 10⁸ cells/ml, and at 3.13μg/ml and 12.5μg/ml when 10⁶ cells/ml.
Intramuscular administration of 500 mg of CFS produced serum concentrations of 10.1-11.0μg/ml after one hour. Half lives were between 2.7 and 2.1 hours. Following the intramuscular administration of 500mg of this agent, urinary levels were 1, 800-2, 300μg/ml in the 0 to 2 hour specimen, and urinary recovery rate in the 0 to 6 hour specimens were 46.0 to 50.6%.
Sixteen patients with complicated urinary tract infections due to Pseudomonas aeruginosa received CFS.
Clinical response was found to be excellent in five cases, good in three and poor in eight. Efficacy rate was 33.3 percent in the group received 500mg daily, while 53.8 percent received 1, 000mg of this agent daily.
Bacteriological response in the group received 1, 000 mg daily was superior to that in the group received 500mg daily.
Two patients experienced adverse reactions as result of administration of CFS in the present study. One was eosinophilia, and the other was elevation of GOT and GPT.

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Laboratory and clinical studies on Cefsulodin (SCE-129, CFS) have been carried out to obtain the following results.
1. Antibacterial activity of CFS against clinical isolates of Pseudomonas aeruginosa was 4 times potent than that of Sulbenicillin (SBPC).
2. Maximum mean serum level of CFS was 24.5μg/ml in 3 patients at one hour after a single dosing of 500mg by one-hour intravenous drip infusion and 13.7μg/ml in 3 patients with 250mg by intramuscular injection.
Mean urinary excretion of CFS was 60% in patients with 250mg by intramuscular injection and 39% in patients with 500mg by intravenous drip infusion in hours after dosing.
3. Clinical iesponse of CFS in 7 patients with chronic complicated UTI was examined to result in overall clinical effectiveness of 57.0%, in which 0% was in patients with catheter and 80% was in patients without catheter.
4. No adverse effect such as allergic reaction and gastric discomfort was found. There found slight pain on injection site in one patient with intramuscular dose of CFS but the pain did not affect succesive dosing.

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Laboratory and clinical studies on Cefsulodin (SCE-129, CFS) were performed and the following results were obtained.
1. CFS showed a peak MIC of 3.13μg/ml on susceptibility against 27 strains of clinically isolated P. aeruginosa.
2. CFS was given to six patients with chronic complicated urinary tract infections. The therapeutic effects were excellent in one patient, good in 2 patients and poor in 3 patients.
3. No side effect was seen except slight elevations of GOT and GPT in a patient with the complications of bilateral hydronephrosis and invasion of prostatic cancer to vesical wall.

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Clinical evaluation of Cefsulodin (SCE-129, CFS), a new antipseudomonal cephalosporin, was made and the following results were obtained.
1) CFS was given to 13 patients with chronic, complicated urinary tract infections due to Pseudomonas aeruginosa by mainly intramuscular dose of 600-1, 000mg per day.
Good therapeutic effects were obtained in 6 patients out of 13 or 46.2%.
2) No adverse effect was seen except abnormal changes in laboratory findings in 3 pateints. One is a slight elevation of GOT or GPT in 2 patients and these laboratory findings became normal after discontinuation of the treatment. The other abnormal changes were elevation of BUN and s-Cr in one patient. It is impossible to claim that the abnormal changes in renal function were completely induced by CFS because of pre. and posttreatment of the other antibiotics. The abnormality return to normal by taking two weeks, so CFS should be given with cation to patients with potential renal insufficiency.
3) CFS is an unique cephalosporin antibiotic which shows good therapeutic effet, similar to aminoglycosides or antipseudomonal penicillins, against Pseudomonas aeruginosa infections.

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Cefsulodin (SCE-129, CFS), a new semisynthetic cephalosporin, was evaluated bacteriologically and clinically and following results were obtained.
1) The in vitro activity of CFS against 93 clinical isolates of P. aeruginosa was compared with Sulbenicillin (SBPC). Generally, CFS appeared to be a more effective agent than SBPC. 52%(48/93) of these strains of which the inoculum size was adjusted to 10⁸ CFU/ml were inhibited by concentration of 12.5μg/ml or less.
2) The in vitro activity of CFS was tested against various anaerobic bacteria. When the inoculum size was adjusted to 10⁸ CFU/ml, almost anaerobic cocci and anaerobic gram-positive rods were inhibited at a level of 12.5μg/ml. But, anaerobic gram-negative rods were required for MICs equivalent to 25μg/ml or greater. Additionally, when the inoculum size of Genus Bacteroides were increased to 10⁸ CFU/ml, the significant increases of MICs of them were observed.
3) CFS was administered to 9 patients with complicated urinary tract infections caused by P. aeruginosa only 2 patients responded favorably.
Bacteriological examination showed that 2 strains of P. aeruginosa disappeared, 5 persisted and 2 were replaced with another organisms.
4) After administration of 125 mg and 500 mg of CFS, blood and urine concentration were assayed in 2 patients. Considering MIC of this drug against P. aeruginosa and levels of blood and/or urine, we came to a conclusion that our dosage were generally little to improve this type of infections.
5) Throughout this study, there were no side effects and no abnormalities of laboratory findings.

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Cefsulodin (SCE-129, CFS), a new cephalosporin antibiotic, was given to 7 patients with chronic complicated urinary tract infections due to Pseudomonas aeruginosa. Five out of 7 patients were catheterized. In those patients four patients have 250mg×2 intramuscularly, 2 patients 500mg×2 intramuscularly and one patient 500mg×2 by intravenous drip infusion for 5 days. Clinical response was excellent in one case, good in 3 cases and poor in 3 cases. Overall clinical effectiveness rate was 57.1%.

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Cefsulodin (SCE-129, CFS), a new cephalosporin derivative synthesized in Japan, was evaluated experimentally and clinically. The results obtained were as follows:
1) Minimal inhibitory concentrations of CFS, sulbenicillin (SBPC) and gentamicin (GM) were determined against 18 clinical isolates of Pseudomonas aeruginosa. CFS was more active than SBPC or GM.
2) CFS was administered intramuscularly at a single dose of 250 mg to 2 male healthy volunteers and 6 patients with normal or impaired renal function. The serum and urinary concentrations were assayed by cup method during 6 hours after administration. The serum concentrations showed peak at 1 hour after injection in all cases. The half-life of CFS was calculated for 1.3 hours in the volunteers, and became prolonged as the renal function fell.
Seventy-six per cent of administered dose was excreted in the urine during the first 6 hours of administration.
3) Twelve patients with Pseudomonas infection of urinary tract were given CFS intramuscularly in daily dose of 500 mg twice a day for 7 days. The clinical results obtained were excellent in 2 cases (16 7%), good in 1 case (8.3%) and poor in 9 cases (75.0%).
4) No marked side effects were observed.

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Cefsulodin (SCE-129, CFS) was administered to 8 cases of urinary tract infection with Pseudomonas aeruginosa. It was effective in 5 out of 8 cases with the efficacy rate of 62.5%.
There was no difference in the incidence of pain at the site of intramuscular injection between CFS alone and combined with lidocaine hydrochloride.

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Effects of Cefsulodin (SCE-129, CFS) administered 250 mg intramuscularly two times at day for 5 to 7 days were evaluated on 20 patients with complicated urinary tract infection. The results were as follows.
1) From the view point of both improvements on bacteriuria and pyuria, excellent effectiveness was observed in 2 out 20 cases (10%), moderate effectiveness in 11 (55%) and no effectiveness in 7 (35%), resulting in the total effective rate of 65%.
2) From the view point of both improvements on bacteriuria only by Pseudomonas and pyuria, excellent effectiveness was observed in 2 out of 20 cases (10%), moderate effectiveness in 15 (75%) and no effectiveness in 3 (15%), resulting in the total effectiverate of 85%.
3) Neither bone marrow depression nor liver and renal dysfunction was observed in any case of this study.
4) The administration of CFS in combination with other broad-spectrum antibiotics might be advisable for complicated urinary tract infection.

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Antibacterial activity of Cefsulodin (SCE-129, CFS) was tested in vitro. In the minimum inhibitory concentration against clinically isolated Pseudomonas, aeruginosa, 62 strains had biphasic peaks at 3.12μg/ml and <100μg/ml when inoculum size was 10⁸ CFU/ml, and a peak at 1.56μg/ml when 10⁶ CFU/ml. In maximum allowing concentration, 62 strains had a peak at 0.78μg/ml when inoculum size was 10⁸ CFU/ml and 0.39μg/ml when10⁶ CFU/ml.
CFS was administered to 4 cases of urinary tract infection with Pseudomonas aeruginosa.
The efficacy rate was 100%.
No side effect was observed

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1. Antibacterial activity.
Cefsulodin (SCE-129, CFS) showed more potent activity by 5-7 stage against Pseudomonas aeruginosa in comparison with Sulbenicillin, but had the same activity as Gentamicin.
2. Serum concentration.
a) When 250 mg of CFS was injected i.m. in healthy male volunteers, the peak of serum concentration was 13.5μg/ml at 30 min. after the initiation, then the concentration gradually decreased to 10.3μg/ml at lhr. after, 5.3μg/ml at 2hrs. after, 1.9μg/ml at 4hrs. and the trace amount at 6hrs.
b) When 125 mg of CFS was injected i.m. in healthy male volunteers, the peak of serum concentration was 5.6μg/ml at 30 min. after the initiation, then the concentration gradually decreased to the trace amount at 6hrs. after.
c) When 125 mg of CFS was injected i.m. in renal insufficient patient (Ccr=32ml/min.), the peak of serum concentration was 8.3μg/ml at 4hrs. after the initiation, then the concentration gradually and slowly decreased to 0.8μg/ml at 24hrs. after.
3. Urinary excretion.
a) When 250 mg of CFS was injected i.'m. to healthy male volunteers, the mean urinary recovery rate was 59.5% within 6hrs. after the administration.
b) When 125 mg of CFS was injected i.m. to healthy male volunteers, the mean urinary recovery rate was 67.5% within 6hrs. after the administration.
c) When 125mg of CFS was injected i. m. to the renal insufficient patient, the urinary recovery rate was 47.5% within 24hrs. after the administration.
4. Clinical effects.
CFS was applied into 22 cases with complicated urinary tract infections. Clinical effects were evaluated excellent in 10, good in 7, and poor in 5 cases and overall clinical effectiveness was 77.3%.
5. Side effects.
There were no side effects and no abnormalities of laboratory findings.

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1) Minimal inhibitory concentration of Cefsulodin (SCE-129, CFS) were determined by plate dilution method on 136 strains isolated from urinary tract infections. At 10⁸ cells/ml inoculum size, 6 strains of Staphylococcus aureus were inhibited at concentrations between 3.12 and 6.25μg/ml. Sixteen of 23 strains of Pseudomonas aeruginosa were inhibited at concentrations between 1.56-12.5μg/ml, and other 7 strains were resistant to 50μg/ml or more. Most strains of E. coli, Proteus mirabilis, Proteus vulgaris, Klebsiella and Serratia were resistant to 25μg/ml or more.
2) In cross sensitivity with inoculum size of 10⁸ cells/ml, CFS was effective against some strains of Pseudomonas aeruginosa which were resistant to Gentamicin and Dibekacin. There were no strains which were resistant to Ainikacin and sensitive to CFS.
3) The peak serum level in a normal adult to whom 500 mg of CFS was given by intravenous drip infusion for one hour, was 12.0μg/ml at one hour, and the urinary recovery rate was 87.8% within 6 hours. The serum level in the other normal adult reached to the maximum (3.3μg/ml) at 30 minutes after intramuscular administration of CFS 125 mg, and the urinary recovery rate was 62.5% within 6 hours.
4) CFS levels in prostatic tissues were determined with extirpated prostatic tissues of 4 prostatic hypertrophy patients and one prostatic cancer patient, administered 500 mg of CFS intravenously at the time of operation. Serum levels of CFS in these patients were also determined at the same time. The mean CFS level in prostatic tissues was 6.8μg/ml which was equal to 58.2% of the serum level at 30 minutes, and 5.6μg/ml, 40.2% of the serum level at 50 minutes after administration of CFS.
5) Seventeen cases with chronic complicated urinary tract infections were treated with 500 mg or 1, 000 mg of CFS per day for 5 to 9 days. Excellent or good effect was obtained in 10 out of 14 cases. Three cases dropped out. There were 10 cases whose isolated organism was Pseudomonas only. The clinical results of these cases were consistent of excellent in 2 cases, good in 7 and poor in 1. The number of Pseudomonas isolated before administration of CFS were 12, and 9 of them were eradicated.
6) Side effects were not observed in this series.

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Clinical investigation has been performed on Cefsulodin (SCE-129, CFS), and the following results were obtained.
1) CFS was administered in 14 cases with complicated urinary tract infections.
2) CFS was injected intramuscularly 500 mg per day for 7 days and intravenously by drip infusion 1, 000 mg per day for 5 days.
3) Clinical results were excellent in 4 cases, good in 3, fair in 4, poor in 3. The effective rate was 50.0%.
4) Bacteriologically Pseudomonas aeruginosa were eradicated in 10 (71.4%), decreased in 1 and unchanged in 3 out of 14 strains.
5) No side effects were observed in this investigation.

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1) Antibacteriological effect
The MIC of Cefsulodin (SCE-129, CFS) against P. aeruginosa showed the peak of susceptibility at 6.25μg/ml with 10⁸/ml of inoculated bacteria and at 3.12μg/ml with 10⁶/ml. It has a higher superiority when compared with Carbenicillin or Ticarcillin and similar to that of GM.
2) Absorption and excretion
This was compared in patients between normal and abnormal kidney function. In the patients with normal kidney function, blood concentration revealed the peak at 16μg/ml within 30 minutes after intraveneous injection with t1/2 of 11/2 hour. Urinary concentration showed 1, 000μg/ml within one hour and excretion rate was 67.6% after six hours. In the patients with abnormal kidney function, to whom 500 mg was administered, blood concentration was higher than normal patients with slower curve in excretion. T1/2 was also prolonged and urinary concentration was more than 1, 000μg/ml within an hour. Its recovery rate in urine was 56.7%. In the same group of patients to whom 250 mg was administered, the highest blood concentration was observed between 30 minutes and 4 hours with its peak between 15 and 7.9μg/ml. Urinary concentration was low with mean value of 500μg/ml. Recovery rate in urine was also delayed with a value of less than 40%. No cumulative tendency was observed in multiple dose study for the patients with abnormal kidney function.
3) Clinical results
General clinical effect revealed no case of markedly effective, 2 cases of effective, and 9 cases of noneffective. Bacteriological effect revealed one strain of vanishment, 5 strains of replacement by newly substitute and 5 strains of persistence among 11 strains of P. aeruginosa.
4) The correlation among MIC of CFS against causative bacteria, urinary concentration and bacteriological effect
There were 8 out of 10 strains which showed higher value than MIC of CFS in urinary concentration. Among these 8 strains, 5 showed vanishment of P. aeruginosa. The disapperance rate of P. aeruginosa was 62.5% in cases which showed higher value than MIC of CFS in urinary concentration. However, in the patients with abnormal kidney function, there was no case of urinary concentration enough to secure a bacteriological effect with 250 mg of administration.
5) Side effect
Three cases (27.2%) showed elevated GOT and GPT.

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1. Cefsulodin (SCE-129, CFS) was administered to the cases of complicated urinary tract infection caused by Pseudomonas aeruginosa for the hospitalized patients in the departments of urology at Kyushu University, Kyushu Kosei Nenkin Hospital and Miyazaki Prefectural Hospital.
2. CFS was administered to 15 cases, however, Pseudomonas aeruginosa was disappeared in 2 cases prior to medication.
3. The period of administration was 5 days except for 1 case of 7 days and 2 cases of 10 days. The route of administration was intravenous drip in 12 cases with 500 mg twice per day and 2 cases with 1, 000 mg twice per day except for another case of intramuscular injection of 250 mg twice per day.
4. The efficacy rate was 47% with markedly effective in 2 cases, effective in 5 cases and non effective in 8 cases.
5. Pseudomonas aeruginosa was isolated in 13 cases of which 2 cases were markedly effective, 4 cases effective and 7 cases non effective, and efficacy rate was 46%.
6. Bacteriologically, disappearance rate of Pseudomonas aeruginosa was 54%(7 out of 13 strains) with 4 strains of vanishment, 6 strains of persistence, and 3 strains of cross over. The cross over bacteria were consisted of Serratia 1 strain, Enterobacter 1 strain and Enterobacter cloacae 1 strain.
7. Adverse reaction was not observed in any case.
8. The efficiacy of CFS against Pseudomonas aeruginosa in the patients with complicated urinary tract infection was confirmed, however, the appearance of micbisme selectionne et substitue should be carefully obseved.

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Clinical evaluation on Cefsulodin (SCE-129, CFS) was made to obtain the following results.
1) CFS was given to 13 patients with urinary tract infections due to P. aeruginosa in the Kurume University and its related institutes.
2) Clinical efficacy was 38.5%; excellent in 4 patients, good in one patient and poor in 9 patients.
3) Clinical efficacy with daily dose was 30% in 500 mg group and 66.7% in a 1, 000 mg group.
4) No side effect was observed except transient elevations of GOT and GPT in one patient.

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1) Clinical efficacy of Cefsulodin (SCE-129, CFS) was evaluated among 12 patients with complicated urinary tract infections (7 cases of chronic cystitis and 5 cases of chronic pyelonephritis). Five hunched to 1, 000 mg of CFS was given intramuscularly or intravenously every day for 5 days.
2) Clinical responses to therapy were excellent in 1 case, good in 6. As side effect, blood picture, kidney function and transaminase showed no abnormalities associated with CFS.

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Cefsulodin (SCE-129, CFS) is a unique cephalosporin-group antibiotic which possesses strong and narrow antibacterial activity to Pseudomonas aeruginosa and gram positive cocci.
A peak of MIC of CFS against 83 strains of Pseudomonas aeruginosa isolated from patients with urinary tract infection was at 3.12μg/ml with inoculum size of 10⁶/ml. Sensitivity distribution of the drug against Pseudomonas aeruginosa seemed to be as same as that of Gentamicin.
CFS was also thought to be more than 3 times sensitive than Sulbenicillin against Pseudomonas aeruginosa. Two hundred and fifty mg of the drug with a dose from 3.13 to 4.72mg/kg was given to three healthy adults through intramuscular route.
Peak of the drug in the serum reached 7.2±1.6μg/ml within 30 minutes after the administration. Urinary recovery rate up to 6 hours was measured as 49.5% with a peak urinary level of 750μg/ml within 2 hours after the injection.
CFS was given to 17 cases of chronic complicated urinary tract infection caused by Pseudomonas aeruginosa. intramuscularly in 2 cases and intravenously in others. Clinical response was evaluated according to a criterion for clinical evaluation of antimicrobial agent on chronic complicated UTI proposed by UTI committee in Japan.
Overall clinical effectiveness was proved excellent or good in 9 cases out of all (52.9%).
Pseudomonas aeruginosa was eradicated in 10 cases (58.8%).
No adverse side effect was noticed except for a case who complained of local pain after intramuscular administration. Abnormal laboratory data due to the treatment were shown in a case with elevated GOT and GPT immediately after and persisted for a month after the administration of CFS.

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Cefsulodin (SCE-129, CFS), a new cephalosporin antibiotic, was evaluated as to its therapeutic efficacy, safety and clinical usefulness in patients with chronic, complicated urinary-tract infections due to Pseudomonas aeruginosa by a double-blind technique using sulbenicillin (SBPC) as control drug.
1. Of a total of 186 patients who received medication, 29 were excluded because of inadequacy for the study and 1 were drop-outs. All of the remaining 156 patients were included in the analyses. Eighty-one of them received CFS and 75 SBPC.
2. No variance existed in the demographic characteristics and diagnosis of the patients in both treatment groups except for age and sex, in which variance was judged to have no influence to the clinical evaluation.
3. Clinical evaluation was done prior to and after treatment with daily dosages of 1g of CFS and 10g of SBPC for 5 days. Overall clinical efficacy in all the patients was “excellent” in 11% after CFS and in 3% after SBPC. It was “excellent” and “good” in 44% after CFS and in 37% after SBPC, respectively. The difference was not statistically significant. In the patients infected with Pseudomonas aeruginosa, overall clinical efficacy was “excellent” in 15% after CFS and in 5% after SBPC, of which difference was not significant. The “excellen” and “good” responses in these patients, however, were obtained in 81% after CFS and in 56% after SBPC and the difference was significant.
4. Pyuria was cleared in 20% after CFS and in 7% after SBPC. The difference was statistically significant, but there was no significant difference between the two treatment groups when compared as to the cases in which pyuria was cleared and decreased (37% after CFS and 36% after SBPC).
5. No difference was noted between the two treatment groups as to the efficacy on bacteruria (eliminated in 27% after CFS and in 25% after SBPC and eliminated or suppressed in 34% after CFS and 34% after SBPC). New organisms appeared in 36% after CFS treatment and in 16% after SBPC treatment, and the degree of bacteruria remained unchanged in 30% after CFS and in 49% after SBPC, showing a significant superiority of CFS over SBPC.
6. CFS was significantly superior to SBPC in the efficacy on pyocyanic bacteruria (eliminated in 65% after CFS and in 48% after SBPC, and eliminated or suppressed in 81%after CFS and in 56% after SBPC).
7. Stratified analyses of overall clinical efficacy significantly favored CFS over SBPC in the patients with single infections and in those with indwell catheter. Especially when limited to Pseudomonas aeruginosa the results were satisfactory with CFS in more than 60% in every diagnostic subtype of single and mixed infections.
8. Bacteriological responses showed that CFS was significantly superior to SBPC. Pseudomonas aeruginosa was eradicated in 65.4% after CFS and in 48.0% after SBPC. Gram-negative bacilli including Pseudomonas aeruginosa were eliminated in 68.5% after CFS and in 52.0% after SBPC.
9. Global judgements by doctors in charge significantly favored CFS over SBPC, which was seemed to be due to the significant superiority of CFS treatment over SBPC treatment in single infections. Clinical usefulness was also evaluated in favor of CFS over SBPC in single infections with a significant difference.
10. Side effects occurred in 4% of the CFS-treated patients and in 8% of the SBPC-treated patients. The difference was not significant, but suggested a higher safety of CFS treatment.
11. The overall results of this study indicate that CFS is a useful drug for therapy of chronic, complicated urinarytract infections due to Pseudomonas aeruginosa.

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Fundamental and clinical evaluation on Cefsulodin (SCE-129, CFS), a new antipseudomonal cephalosporin, was made and the following results were obtained.
1) CFS, like Gentamicin, has a potent antibacterial activity against P. aeruginosa isolated from gynecoobstetric materials.
2) CFS given to four patients with urinary tract infections and wound infections afforded therapeutic effect of 75.0%.
3) No adverse effects and abnormalities in labaratory findings were observed.

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The clinical study on Cefsulodin (SCE-129, CFS), a new derivative of semisynthetic cephalosporin, was made in the field of obstetrics and gynecology, and following results were obtained.
The absorption of the drug was rapid and the peak level reached to 10.7μg/ml after intramuscular injection of 250 mg in women, and reached to 21.9μg/ml after intravenous injection of 250 mg.
The transference of the drug into umbilical cord blood and amniotic fluid was rapid and good.
CFS was administered at daily dose of 1, 000 mg intramusculary to gynecological post operative infection with P. aeruginosa, and clinical response was good.
No side effect was noted with administration of CFS.

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