Cefotetan (CTT, YM09330) is a new cephamycin-type antibiotic with a broad spectrum of antibacterial activities. The antibacterial activity of cefotetan against gram-positive and gram-negative organisms was compared with cefmetazole, cefoxitin and cefazolin. The results are summarized as follows.
1) Cefotetan was more effective than cefmetazole, cefoxitin and cefazolin against gram-negative bacteria including indole-positive Proteus, S. marcescens, E. cloacae, C. freunclii and B. fragilis. Its activity against grampositive bacteria was slightly less than that of cefoxitin. The concentrations of cefotetan which required to inhibit 70% of clinical isolates of E.coli, K.pneumoniae, P. mirabilis and P. vulgaris were between 0.20 and 0.40μg/ml.
2) Bactericidal activity of cefotetan against E.coli, K.pneumoniae and S. marcescens was confirmed by counting viable cells and determining the minimum bactericidal concentration (MBC).
3) Cefotetan was resistant to hydrolysis by various bacterial β-lactamases as well as cefmetazole and cefoxitin. Moreover, cefotetan was found to possess not only antibacterial activity against β-lactamase-producing organisms, but also inhibitory activity against a number of types of β-lactamases.
4) Cefotetan showed a high affinity for almost all PBPs, with a stronger affinity for PBP 3, with a strong affinity for PBPs 1A, 1Bs, 4 and 5/6 and with little affinity for PBP 2.
5) Cefotetan showed much higher antibacterial activity than cefoxitin and cefazolin against systemic infections of mice with E. coli, K. pneumoniae and S. marcescens.

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Antibacterial activities of cefotetan (CTT, YM09330) were examined in comparison with those of other cephem antibiotics against clinically isolated bacteria during 1980 and 1981 consisting of each 27 strains of S. aureus, S. epidermidis, Klebsiella, E. cloacae, C. freundii and Serratia, 200 strains of S. agalactiae, 134 strains of H. influenzae, 234 strains of E. coli and 81 strains of P. aeruginosa and the results were as follows:
1. Cefotetan showed relatively weak antibacterial activities against gram positive cocci.
2. Cefotetan showed potent antibacterial activities against E. coli and Klebsiella among gram negative bacilli.
3. Cefotetan showed broad MIC distribution including some potent antibacterial activities against E. cloacae, C. freundii and Serratia as well as those of cefotaxime, cefoperazone and ceftizoxime.
4. Cefotetan showed similar antibacterial activity to those of cefotiam and cefuroxime but was less active than cefotaxime, cefoperazone and ceftizoxime against H. influenzae.
5. Cefotetan showed comparatively weak antibacterial activity against P. aeruginosa.

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The in vitro and in vivo antibacterial activity of cefotetan (CTT, YM09330), a new cephamycin antibiotic, against both gram-positive and gram-negative bacteria were studied.
Cefotetan showed a particularly greater antibacterial activity than other cephamycins against indole positive Proteus (P. vulgaris, P. morganii, P. rettgeri, P. inconstans), C. freundii, E. cloacae, S. marcescens and showed also greater antibacterial activity against E.coli, K. pneumoniae, P.mirabilis, P.cepacia, but was inactive against P. aeruginosa as other cephamycins.
Cefotetan was as stable as other cephamycins to inactivation by enzyme (penicillinase, cephalosporinase) elaborated by 15 strains of 10 species under class of the RICHMOND classification.
In vivo experiment demonstrated that the therapeutic effect of cefotetan was superior to cefazolin and cefmetazole in the infections due to P. mirabilis and C. freundii, while it was inferior to latamoxef.

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Bacteriological evaluation to anaerobic bacteria was made on cefotetan (CTT, YM09330), a new cephamycin antibiotic, and the following results were obtained.
1) Cefotetan showed potent antibacterial activities against Genus Peptococcus, Eubacterium, Propionibacterium, Clostridium, Fusobacterium and Veillonella. It was more active than cefazolin and cefmetazole against Bacteroides, but not more active than latamoxef.
2) Cefotetan was as stable as latamoxef to β-lactamase of B.fragilis.
3) Cefotetan showed bactericidal action against anaerobes at level of MIC or higher concentration thereof.
4) Cefotetan showed therapeutic effect against experimental subcutaneous abscess in mice caused by E.coli and β-lactamase producing B. fragilis.
5) C. difficile didn't appear in caecum contents of the mice given cefotetan.

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Antibacterial activities of cefotetan (CTT, YM09330), a new cephamycin antibiotic, were studied as compared with cefmetazole, latamoxef and cefazolin.
Cefotetan showed broad antibacterial spectram against both gram positive and negative bacteria, and it was more active than cefmetazole and cefazolin and equally to latamoxef against gram negative bacteria.
Cefotetan showed remarkably potent bactericidal activities against E. coli and K. pneumoniae at 10⁵, 10⁶ and 10⁷ cells/ml.
In experimental infections of mice caused by E.coli, K.pneumoniae, P.vulgaris and S. marcescens, cefotetan showed remarkably potent therapeutic effect than cefmetazole and cefazolin and more or equally potent effect to latamoxef.

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The protective effects of cefotetan (CTT, YM09330), a new cephamycin-type antibiotic on an experimental urinary or respiratory tract infection in mice were compared with those of cefmetazole, latamoxef and cefazolin, and the following results were obtained.
1) Cefotetan showed a more potent protective effect on the experimental urinary tract infection with E. coli and K. pneumoniae than cefmetazole and cefazolin, and was as effective as latamoxef or more.
2) The protective effect of cefotetan on the experimental respiratory tract infection with K. pneumoniae was superior to those of cefmetazole and cefazolin, and was almost the same as that of latamoxef.

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The antibacterial action of cefotetan (CTT, YM09330), a new developed cephamycin, was investigated against E. coli K12, P. aeruginosa KM338 and S. marcescens IFO12648, and was compared with that of cefazolin.
The minimum inhibitory concentrations (MICs) of cefotetan for these organisms were 0.39, 800, and 0.05μg/ml, respectively. The addition of subinhibitory concentration (1/2 MIC) of ethylenediaminetetraacetic acid (EDTA), which damages permeability barrier of the outer membrane, caused little changes in the MICs of cefotetan for E.coli K12 and S. marcescens IFO 12648, whereas marked reduction in the MIC of P.aeruginosa KM338 was observed in the presence of EDTA. Cefotetan was stable to β-lactamase activities from these organisms whereas cefazolin was hydrolyzed rapidly by the enzymes. The cross-linking reaction of peptidoglycan synthesis catalyzed by the ether-treated cells from these organisms was inhibited by markedly lower concentration of cefotetan than that of cefazolin.
The excellent antibacterial activity of cefotetan to E.coli K12 and S.marcescens IFO 12648 was concluded to be due to the high permeability of the outer membrane, the stability against hydrolysis by β-lactamase and/or high affinity to the target enzymes (transpeptidases) of both organisms. In contrast, the relative resistance to cefotetan in P. aeruginosa KM338 was revealed to be due to the permeability barrier of the outer membrane.

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Fundamental studies were made on cefotetan (CTT, YM09330), a new cephamycin antibiotic, in order to evaluate its clinical efficacy in the treatment of bacterial infections in children.
Antimicrobial activity of the drug against gram-positive cocci was slightly inferior to that of cefoxitin but was far superior against gram-negative rods, particularly with the inoculum size of 10⁶/ml, with the exception of P. mirabilis, against which both drugs were equally effective. Against S. faecalis and P. aeruginosa, however, they exhibited no appreciable antimicrobial activity.
Passage of the drug in CSF was evaluated in experimental staphylococcal meningitis in rabbits. The results indicated a large individual variation and a slow passage rate.
Although we have not had occasions to examine, cefotetan is reported to have better antimicrobial activity against H. influenzae than cefmetazole and cefoxitin. Taking into consideration of the above findings that antimicrobial activity of the drug is superior against gram-negative rods than those of other cephamycin antibiotics, cefotetan should be indicated in the treatment of respiratory and urinary tract infections when its efficacy is to be evaluated in children. A promising outcome will be expected from its clinical trial.

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The microbiological assay methods for antibiotic concentration in body fluids after treatment of cefotetan (CTT, YM09330), a new semisynthetic cephamycin antibiotic, were discribed.
The suitable conditions for the assay of the concentration resulted from using of E.coli NIHJ as the test organism and sensitivity test agar as the medium, in which 1% of over-night precultured Trypticase soy broth inoculated with the test organism was added. For the determination of the antibiotic concentration in biological specimens, three assay methods, thin-layer cup, thin-layer disc and agar well method, gave the suitable long-range standard curves and revealed good sensitivity. Cefotetan standard curve was not markedly influenced by pH of the medium and of the diluent buffer solution. By the thin-layer disc method, the detectable concentrations of cefotetan were, at the lowest, 0.2μg/ml for 1/10M phosphate buffer pH 7.0, and 0.78μg/ml for human plasma, Consera and Moni-trol I when used as the diluent for the standard solution. The inhibition zone sizes of cefotetan dissolved in human plasma, Consera and Moni-trol I were smaller than those in phosphate buffer solution at pH 7.0. However, the standard curves of cefotetan using human plasma and Consera as the diluent showed almost the same figure. The concentrations of cefotetan in urine and bile detected by the bioassay method were in good agreement with those obtained by HPLC method.
Cefotetan was stable in phosphate buffer solution at pH 7.0, human plasma and human urine at-20°C over a period of 30 days. In rat bile, cefotetan was unstable somewhat at 4°C but was stable during 7 days storage at-20°C.

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Cefotetan (CTT, YM09330) was subcutaneously or intravenously administered to mice, rats, rabbits, dogs and monkeys in single doses of 20, 50 or 100 mg/kg, and the pharmacokinetic profiles of cefotetan were compared with those of cefmetazole and cefazolin.
The plasma levels of cefotetan after a single dose of 20 mg/kg were highest in monkeys, followed by dogs, rabbits, rats and mice in that order, and the plasma half-lives of cefotetan were 75.6, 55.5, 30.5, 15.9 and 13.0 minutes, respectively. Those of cefotetan in mice, rats and rabbits were shorter than those of cefazolin and it was about the same as that of cefazolin in dogs. In comparison with cefmetazole, however, the plasma halflives of cefotetan were longer in all animal species tested.
Cefotetan was rapidly distributed into various tissues of mice, rats and dogs. The concentrations in the tissues of the rat were proportional to doses and were highest in the kidney, followed by the plasma, liver, lung, heart and spleen in that order. The distribution patterns of cefotetan in mice and rats were similar to those of cefazolin. They were different from that of cefmetazole in the concentrations of the drugs in the liver.
Urinary recoveries of cefotetan in mice, rats, dogs and monkeys over a 24-hour period were ranged from 50% to 67% of the administered dose and 74% of the dose was recovered in rabbit urine. Biliary recoveries were about 48% in rats, 5% in rabbits and 17% in dogs. Fecal recoveries of cefotetan of 38% of the dose for rats and 13% for dogs seemed to be comparable to the recoveries in bile of these animal species.
By means of TLC-bioautography, no active metabolite of cefotetan was detected in the urine and bile of animals tested. However, an antibacterial active tautomer of cefotetan was observed in urine of all species. The extent of serum protein binding of cefotetan measured by centrifugal ultrafiltration method were 47% for mice, 30% for rabbits, 39% for dogs, 87% for monkeys and 91% for humans.

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The metabolic fate of cefotetan (CTT, YM09330) was studied after single or repeated parenteral administration of 20 mg/kg of ¹⁴C-cefotetan to SD rats.
1. At 5 minutes after single intravenous administration, the tissue level of radioactivity was highest in kidney (114.2μg/g) followed by plasma (62.2μg/ml), liver (45.5μg/g), skin, lung, small intestine (15 to 30μg/g), heart, testis, spleen, muscle (5 to 15μg), and brain (0.8μg/g). The tissue levels at 30 minutes after administration decreased 1/2 to 1/3 of those at 5 minutes. At 24 hours after administration, low radioactivity was detected only in renal cortex besides intestinal contents, which were under execretion, in whole body autoradiography.
2. Tissue levels of radioactivity during 15 times-repeated intramuscular administration plateaued within 11 times. Tissue levels at 30 minutes after the last administration were almost as same as those after the first administration except that in kidney in which the level after the last administration was 3.5 times higher than that after the first administration. Tissue levels at 24 hours after the last administration were 2 or 7 times higher than those after the first administration.
3. About 44% of dosed radioactivity was excreted in urine within 3 hours, which amounted to about 47% within 72 hours. The rest of dosed radioactivity was excreted in feces via bile. Total recovery in urine and feces within 72 hours was about 97% of the dose. The ratios of urinary to fecal excretion during repeated administration were similar to those after single administration. Total of urinary and fecal excretion within 48 hours after the last administration was about 97%.
4. Unchanged cefotetan alone was detected in ultrafiltrate of plasma. The ratios of tautomer to radioactivity exreted in urine, bile and feces were 6%, 12% and 16% respectively. The rest of excreted radioactivity in those biological samples was unchanged cefotetan and no metabolite was detected. The antibiotic activity hardly lost in those biological samples. TLC-radiochromatograms of urine did not change during the repeated administration.
5. Radioactivity in fetus, whose concentration was below 1/70 of that in maternal plasma, was extremely low. However, concentrations in generative organs including placenta were 1/2 to 1/5 of that in maternal plasma.
Radioactivity excreted in milk, whose concentration was 1/6 of that in maternal plasma, was not absorbed from suckling's gastrointestinal tract.
Tissue levels of radioactivity in young rats at 1 to 28 days after birth decreased with their growth.

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Cefotetan (CTT, YM09330) was intravenously administered to experimental animals in a single dose of 20mg/kg. The concentrations of cefotetan as well as its tautomer in urine, bile, plasma and tissues were determined by means of high performance liquid chromatography (HPLC). The equilibrium reaction between cefotetan and the tautomer was also examined in in vitro experiments.
Over a 6-hour period after dosage of 20 mg/kg, urinary excretion of the sum total of cefotetan and its tautomer was 64.3% of the dose for mice, 48.3% for rats, 76.3% for rabbits, 54.1% for dogs and 66.2% for monkeys. At the time, a small amount of the tautomer was observed in mice, rats and dogs, while a large amount in rabbits and monkeys, indicating species differences in the amount of the tautomer in urine. In rats, rabbits and dogs, biliary excretion of 44.8%, 5.31% and 17.2% of the dose, respectively, was obtained in the total within 6-hour of administration. The excretion of the tautomer in bile after intravenous administration was low in all species tested. The total drug concentrations of cefotetan and the tautomer in plasma and tissues of rats which determined by HPLC were in good agreement with the results of bioassay method. In plasma, liver and kidneys, only a very low concentration of the tautomer was observed in a short time after administration of cefotetan to rats. And no detectable concentration of the tautomer was observed at 45 minutes after dosing.
Cefotetan-exists in equilibrium with the tautomer in solution. At neutral and acidic pH, the mixture solution of cefotetan and tautomer reached the equilibrium state of the high concentration of cefotetan and the low of the tautomer. And the equilibrium reaction between cefotetan and the tautomer is very slow at that pH range. Almost no tautomer was detected in the solution when cefotetan as the starting material was added at that condition. On the other hand, the ratio of the tautomer to cefotetan increased along with the rising of pH value of the solution. In addition, it was found that the high concentration of Mg⁺⁺ also affected to the equilibrium reaction in the alkaline pH solution, resulted in the high ratio of the tautomer.

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A new cephamycin derivative, cefotetan (CTT, YM09330) was applied to experimental study. Using SD strain rats, distribution of cefotetan in plasma, kidney, liver and in oral tissues such as submaxillary gland, alveolus, mandible, gingiva and lingua was assayed. Cefotetan was administered intravenously at a dose of 100mg/kg, and the distributions in plasma and tissues were assayed by the means of paper disc plate method.
The concentration of cefotetan was highest in the kidney and followed in plasma and tissues ranking as liver, gingiva, lingua, submaxillary gland, mandible and alveolus. The pattern of cefotetan distribution in oral tissues were similar to the pattern of cefazolin and superior than those of cefmetazole in concentration and continuance.

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Cefotetan (CTT, YM09330), a new parenteral cephamycin antibiotic, was administered to 28 healthy male volunteers to study its safety and pharmacokinetics.
Doses of cefotetan were
I) single intravenous bolus injection (i. v.), of 0.5g
II) 0.5g i.v. twice a day for one day
III) single 1.0 g i. v.
IV) 1.0 g i. v. twice a day for one day
V) single intravenous drip infusion (d. i. v.) of 2.0g
VI) single 3.0 g d. i. v.
VII) 1.0 g i.v. twice a day for 2.5 days
VIII) 1.0 g i.v. twice a day for 5.5 days
IX) single intramuscular injection (i. m.) of 0.5g Results were as follows;
1) No abnormalities attributable to cefotetan were noted in any examined items such as symptoms, blood pressure, heart rate, electrocardiogram, body temperature, hematology, blood chemistry, COOMBS' test and urinalysis.
2) The mean plasma levels of cefotetan 15 min after dosing were 85.2 and 171μ2g/ml for 0.5g i. v. and 1.0g i. v. respectively. And they were slowly declined to 7.6 and 17.4μg/ml at 8 h after dosing. The averaget t_1/2 (β) were calculated to be 3.11 h and 3.40 h for 0.5g i.v. and1.0 g i. v. respectively by the two compartment open model. Plasma levels of cefotetan were not accumulated even when cefotetan was intravenously administered with 11 consecutive doses of I g at intervals of 12 h.
3) Seventy-five-eighty-five% of cefotetan were excreted in 24 h urine after dosing, and approximately 5% of cefotetan were found in the form of the tautomer. No metabolites of cefotetan were detected in urine.

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Pharmacokinetics of cefotetan (CTT, YM09330), a new cephamycin antibiotic, in man were investigated. In 6 normal adult volunteers, intravenous administration of cefotetan in doses of 0.5g or 1.0 g yielded that serum levels after 5 minutes were 130μg/ml at a dose of0.5 g and 230μg/ml at a dose of 1.0 g respectively, after 1 hr, the levels were 48.3 and 110μg/ml and finally after12 hrs, the levels were 4.1 and 9.1μg/ml respectively with bioassay method and similar results were obtained with HPLC method.
The β-phase biological half-lives of the compound in accordance with the above data were estimated to be 3.3 hrs and 3.05 hrs respectively. Dose responses were observed in C₀ and AUC data.
The drug was recovered in urine up to 12 hrs by as much as 79.8 and 80.4% with bioassay method and 81.8 and 78.1% with HPLC method respectively.
The results of HPLC method indicated 6.3 and 11.3% of its tautomer in the urine.
Four slight renal impaired patients were administered cefotetan 0.5g once a day for 4 to 7 days but no cumulative blood levels were found.

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Fundamental study on cefotetan (CTT, YM09330), a new semisynthetic cephamycin antibiotic, was carried out and following results were obtained.
1. Antibacterial activities
Minimal inhibitory concentrations (MIC) of cefotetan against clinically isolated strains were examined.
Range of MIC was 0.05-0.39μg/ml against E. coli, 0.05-0.39μg/ml against K. pneumoniae, 0.1-0.2μg/ml against P. mirabilis, 0.2-6.25μg/ml against indole positive Proteus, 0.1-100μg/ml against E.aerogenes, 0.39-6.25μg/ml against E. cloacae, 0.1-1.56μg/ml against C. freundii, 0.39-100μg/ml against S. marcescens, 50->100μg/ml against P. aeruginosa, 0.39-50μg/ml against S. aureus.
The MICs of cefotetan were compared with those of cefmetazole (CMZ), cefoxitin (CFX), latamoxef (LMOX), cefotiam (CTM) and cefazolin (CEZ), and antibacterial activity of cefotetan was superior to those of CMZ against E. coil, K. pneumoniae, P. mirabilis, indole positive Proteus, E. aerogenes, E. cloacae, C. freundii and S. marcescens.
2. Serum levels and urinary excretion
Cefotetan was given intravenously by cotinuous infusions for 2 hrs at a single dose of 2.0 g in 5 patients with normal renal function, and the average serum level of cefotetan at the end of infusions was 231.4μg/ml and the mean half life in the β-phase was 4.94 hrs.
Cefotetan was given intravenously by continuous infusions at a single dose of 2.0 g per day during from 4 to 7 days in 5 patients with normal renal function and the cumulation of cefotetan in the serum was not observed in all of the patients.
Cefotetan was given by a single intravenous administration at a dose of 0.5g in 3 patients with slight inpairment of renal function, and the average serum level of cefotetan was 63.3μg/ml after 30 minutes, and the mean half life in the β-phase was 4.80 hrs, and the average recovery rate in the urine during the first 8 hrs was 50.6%.

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In cross-over study, serum and urinary levels of cefotetan (CTT, YM09330) and cefazolin were determined by bioassay and HPLC methods in 4 healthy volunteers. Cefotetan was given in single doses of 0.5g/1 hr, 1.0g/1 hr, 0.5g/2 hr constant infusions, 0.5 gi.v. and 0.5 gi. m. injections, and cefazolin was given 1.0 gil hr constant infusion.
The results obtained by two determination methods were in good agreement with 0.98 or more coefficients of correlations.
The mean serum levels of cefotetan after one hour with 0.5g/2 hr, 0.5 g/1 hr and 1.0 g/1 hr constant infusions were 35.4, 74.0 and 133.0μg/ml respectively with the ratio of 1:2.1:3.8, revealing the good dose responses. The mean serum level of cefazolin after one hour with 1.0 g/1 hr constant infusion was 115.5μg/ml. Urinary recoveries up to 8 hours of cefotetan were between 68.1% of 0.5/1 hr constant infusion and 53.7% of 0.5g/2 hr constant infusion while that of cefazolin was 93.8%. HPLC method revealed the existence of 10% or less of cefotetan tautomer in urine.
Pharmacokinetic parameters of cefotetan were almost in agreement each other under i.v. administration based on two compartment open model obtained in different administration routes or determination methods, furthermore they resemble to that of one compartment open model under i.m. administration of cefotetan.
The values of serum half-life of the β-phase of cefotetan by pharmacokinetic analysis using the results obtained with bioassay method were 2.56-2.95 hrs and 1.6 times longer than that of cefazolin (1.73 hrs).
Cefotetan showed body clearance (C113) of 30.3-37.3 ml/min which was about 1/2 of that of cefazolin (59.0 ml/min) and renal clearance (Cl_R) of 21.7-26.8 ml/min which was less than 1/2 of that of cefazolin (56.9 ml/min) and CI_R./CI_B ratio of 70-79% which was lower than that of cefazolin (96%).
Serum levels of 0.5 g and 1.0 g administrations of cefotetan were simulated from the data shown above and the relations with MICs against a variety of clinical isolates were discussed.

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The pharmacokinetics of cefotetan (CTT, YM09330), a new parenteral semi-synthetic cephamycin antibiotic, were studied in 8 healthy volunteers and 41 patients with renal insufficiency after a single 500mg intravenous administration. Serum concentrations of cefotetan were determined by paper disc method using E. coli NIHJ as the test organism, and urinary concentrations of cefotetan by both the bioassay and high pressure liquid chromatography. Pharmacokinetic parameters for cefotetan immediately after administration were approximately 150-180μg/ml in all subjects regardless of their renal functions. However, the serum concentrations during β-phase increased in patients parallel with the degree of renal impairment. The mean serum half-life (β) and the mean serum concentration at 8 hours after dosing were 3.0 hours and 8.3μg/ml in the normal subjects as compaired with 12.6 hours and 43.9μg/ml in the patients with creatinine clearance of<10ml/min. There were significant linear correlations between the creatinine clearance and the elimination rate constant and β-phase rate constant of cefotetan (p<0.0001, respectively). The mean cumulative urinary recovery of the administered dose in the 24-hour urine was 83.3% in the normal subjects. As renal function declined, the urinary excretion decreased. It is suggested that lower doses or longer intervals should be employed according to the creatinine clearance in patients with renal insufficiency.

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Acute toxicity of cefotetan (CTT, YM09330), a new semisynthetic cephem antibiotic with a broad spectrum of antibacterial activity, was studied in ICR mice and SD rats after oral and parenteral administration. The animals were closely observed for mortality and clinical signs for 7 days after administration, and necropsies were performed on all animals. The LD₅₀ values were calculated by the probit method, based on 7 day mortality data.
The LD₅₀ values in male mice and female mice were 6.35g/kg and 4.99g/kg i. v., 8.12g/kg and 8.35g/kg i. p., respectively. The LD₅₀ values in male rats and female rats were 8, 48g/kg and 6.79g/kg i. v., 8.37g/kg and 8.25 g/kg i.p., respectively. Oral and subcutaneous LD₅₀ values were higher than 10.0g/kg in both species.
In most of the animals, clinical signs observed after parenteral administration included decreased locomoter activity, prone, ptosis and bradypnea. Similar toxic signs were observed, but to a lesser extent, in animals given the drug orally. Additionally, jumping, clonic convulsion, opisthotonus and tonic convulsion were seen in animals which were treated with high doses parenterally and died within 24 hours due to respiratory arrest.

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Cefotetan (CTT, YM09330) was administered intraperitoneally to male and female SD rats at daily doses of 0, 100, 300, 1, 000 and 3, 000mg/kg for 5 weeks to estimate its toxic effects.
1) There were no deaths. Both males and females receiving 300mg/kg or more showed writhing immediately after every injection as well as excretion of soft feces throughout the dosing period. Body weight increase of males receiving 1, 000mg/kg or more was suppressed.
2) Slight anemia and increase in reticulocyte count were observed in both sexes at 3, 000mg/kg. In plasma biochemistry, cholesterol decreased in both sexes at 1, 000mg/kg or more and albumin decreased in males at 3, 000mg/kg. In urinalysis, urine volumes decreased at 1, 000mg/kg or more during the early period of the treatment.
3) Distention of the cecum was observed in both sexes receiving 300 mg/kg or more. Relative kidney weights increased at 1, 000mg/kg or more. Histopathological studies, however revealed no treatment-related abnormalities in any organs examined including the kidneys.

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The toxicity of cefotetan (CTT, YM09330) was studied in rhesus monkeys of both sexes. The drug was administered intravenously to four groups of 4 males and 4 females each at a daily dose of 0, 100, 300 and 600 mg/kg, respectively, for 26 weeks.
1) Treatment-related clinical signs included vomiting observed through the treatment period and soft feces or diarrhea observed during the early period. These clinical signs were noted at every dose. There were no treatment-related changes in body weights, electrocardiograms and fecal occult blood tests.
2) Erythrocyte counts, hemoglobin and hematocrit values decreased in some animals receiving 300 or 600mg/kg of the drug. Increase in osmotic fragility of erythrocytes and increase in reticulocyte counts were also observed at these doses. Examination of bone marrow showed no evidence of the suppression of hematopoiesis; M/E ratio of the myelogram even decreased in some of these animals. These findings indicated that the anemia was not due to the toxic effects on hematopoietic system. Reversibility of the anemia was examined in some animals receiving 300 mg/kg. The animals recovered completely after 2 weeks of withdrawal period following 26 weeks of treatment.
3) There were no effects on plasma biochemical or urinalysis parameters.
4) No gross pathological changes were evident at necropsy. Spleen was slightly heavier in animals receiving 600 mg/kg. Histopathological examinations revealed slight increase in hemosiderin deposition in spleen at 300 and 600 mg/kg. No treatment-related changes were observed in other tissues and organs.

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Nephrotoxicity of cefotetan (CTT, YM09330), a new cephem antibiotic, alone or in combination with furosemide, was studied in comparison with cefazolin, cephaloridine and cephalothin in female rats. Each group was dosed subcutaneously with vehicle (saline) or furosemide at a dose of 67 mg/kg. Immediately after subcutaneous injection, the rats were treated intravenously with cephaloridine at doses of 600 or 1, 200 mg/kg, or the other cephem antibiotics at doses of 600, 1, 200 or 2, 400 mg/kg. Urine was collected during 0-6 hours and 6-24 hours after treatment. The rats were deprived of diet and water during urine collection. Each rat was sacrificed at 24 hours and the kidney was submitted for micropathological examination.
Nephrotoxicity was not elicited by the administration of cefotetan, cephalothin and cefazolin except that only one of the six rats treated with cefazolin at a dose of 2, 400 mg/kg developed microfocal proximal tubular necrosis. On the other hand, a single dose of 600 mg/kg of cephaloridine produced proteinuria and various grades of focal proximal tubular necrosis, then mild elevations of BUN and serum creatinine were observed in rats receiving cephaloridine at a dose of 1, 200 mg/kg. The nephrotoxicity of four cephem antibiotics was enhanced by coincidental administration of furosemide. In the case of cephaloridine and cephalothin, BUN and serum creatinine values were increased compared with rats receiving antibiotics alone, and proteinuria was observed in rats administered cephalothin in combination with furosemide whereas the administration of cefazolin or cefotetan in association with furosemide exhibited only proteinuria.
These data demonstrate that the order of nephrotoxic potential of the four cephem antibiotics is cephaloridine>cefazolin-acephalothin-acefotetan.

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Cefotetan (CTT, YM09330), cefazolin and cephalothin were intravenously dosed to female rabbits of the New Zealand White strain to study their nephrotoxicity. The dose levels used were 600mg/kg and 1, 200mg/kg, and each dose was given to 6 animals. Eight animals receiving a physiological saline were used as controls. Following a single treatment, all animals were subjected to clinical laboratory tests, and they were killed on day 3 postdosing, followed by pathological examinations.
Cefotetan: Anorexia occurred at both 600mg/kg and 1, 200mg/kg, but no deaths were found. Plasma urea nitrogen and creatinine were not increased. Although glycosuria was not detected in any animals, proteinuria was found in one animal receiving 1, 200mg/kg. Macroscopic examination of the kidneys disclosed a gray nodule in an animal receiving 1, 200mg/kg and small cysts in another animal receiving the same dose. Small cysts were also found in an animal receiving 600mg/kg. Histological examination of the kidneys showed that the gray nodules seen in the animal receiving 1, 200mg/kg was nephroblastoma. An animal receiving 600mg/kg showed necrosis on the proximal tubular epithelium.
Cefazolin: An animal receiving 1, 200mg/kg died about 6 hours after dosing. Anorexia occurred at both 600mg/kg and 1, 200mg/kg. Plasma urea nitrogen and creatinine were increased at 1, 200mg/kg and glucose and protein were detected in the urine in some animals receiving 600mg/kg and 1, 200mg/kg. Macroscopic examination of the kidneys disclosed colour changes of the organs as well as their enlargement in all animals receiving 1, 200mg/kg. Small cysts were also observed in some animals. In 3 animals receiving 600mg/kg, densely packed gray microspots were found. Histological examination of the kidneys showed that necrosis occurred in the proximal tubular epithelium in a dose dependent fashion.
Cephalothin: Mild anorexia was seen at both 600mg/kg and 1, 200mg/kg. Proteins were detected in the urine in an animal receiving 1, 200mg/kg, but no abnormalities were found in plasma bio-chemical tests. The kidneys were also macroscopically examined. The kidneys were coloured yellow-brown in 2 animals receiving 600mg/kg, and small cysts were present in these animals. However, no drug related abnormalities were detected during histological examination of the kidneys.
Although some histological abnormalities were found in the kidneys of the animals receiving cefotetan, these abnormalities were not dose-related, and thus, in conclusion, the renal toxicity of the drug is comparable to that of cephalothin, and considerably weaker than that of cefazolin in rabbits.

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Cefotetan (CTT, YM09330), a new cephamycin antibiotic, was administered intravenously to pregnant rats from day 7 through day 17 of pregnancy to evaluate possible teratogenicity and effects on the growth and functional development of the offspring. Doses were 100, 500 and 2, 000 mg/kg. Control animals received physiological saline. Of 35 to 39 dams of each group, about two thirds were sacrificed on day 20 of pregnancy and fetuses were examined for external, visceral and skeletal malformations.
The remaining dams were allowed to deliver their young and pups were examined for growth, external differentiation and functional development during the lactation period. A part of the pups were examined for postweaning growth and functional development. In addition, some pups were mated within the same dose group after sexual maturation, and allowed to deliver their young to evaluate their reproductive capacity.
In dams, there was a transient body weight decrease after the start of administration, and a decrease of the food intake and soft feces during administration, but there were no teratogenic effects on the fetuses or adverse effects on the postnatal growth, functional differentiation and the subsequent generation (F₂).
These findings suggest that cefotetan, like other cephem-type drugs, has not any teratogenic potentials and toxic effects on reproduction in rats.

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Local irritation of cefotetan (CTT, YM 09330) was studied by injecting the drug to the M. vastus lateralis of rabbits.
Cefotetan was dissolved in normal saline or lidocaine hydrochloride for injection at a concentration of 250mg/ml, and 1 ml of the solution was used in each injection. Local irritation was weaker than that caused by 0.75% or 6% acetic acid, whether the drug was dissolved in saline or lidocaine hydrochloride, and the irritating effect was virtually the same, whether saline or lidocaine hydrochloride was used to dissolve the drug.
When cefotetan dissolved in lidocaine hydrochloride at 250 mg/ml was dosed at 1 ml once daily for 5 consecutive days, extensive necrosis developed on day 2 post final dosing, but the necrosis was persistent only in some animals on day 14. Regeneration developed strongly, and the animals quickly recovered from the damage.
Cefotetan was dissolved in distilled water for injection, at 250 mg/ml, and 1.5 ml of the solution was injected to animals. The local irritating effect of the treatment was compared with those of other cephalosporins, such as cephalothin, cephaloridine and cefazolin. The severity of local irritation of cefotetan was slightly more severe than those of cephaloridine and cefazolin, and less than that of cephalothin.

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Immunogenicity of an antibiotic, cefotetan (CTT, YM09330), was investigated in inice, guinea pigs and rabbits for its antibody production. Immunological crosn reactivity to other antibiotics was also tested using anti-cefotetan rabbit antisera by heterologous pisiveL tticineous anaphylaxis in guinea pigs and also by Lissive hemagglutination test. The effects of cefotetan on human red blood cells were also investigated using direct COOMBS' test.
The results indicated no immunbgenicity of cefotetan in animals when the drug wan injected with adjuvants. The rabbit antibodies produced by the immunization of cefotetan-RSA conjugates showed an extremely high specificity to cefotetan. No direct effect of cctntetan on human red blood cells suggested front direct COOMBS' test.

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The antibacterial activity of cefotetan (CTT, YM09330), a new cephamycin antibiotic, was tested against strains of S. aureus, E. coli and K. pneumoniae isolated from clinical specimens, and clinical response to the drug was investigated in 31 patients with infections treated in internal medicine clinics.
The antibacterial activity was weak against S. aureus, and the MICs of the drug were 0.8 to 3.2 μg/ml in E. coli with the inoculum of 10⁶ cells/ml, and 0.2 to 3.2 μg/ml in K. pneumoniae.
Cefotetan was administered with intravenous injection or with drip infusion at 0.5 to 1.0 g twice daily for 5 to 39 days in 12 patients with respiratory tract infections, 5 patients with biliary tract infections, 13 patients with urinary tract infections and one patient with other infection.
Excellent results were found in 8 of these patients, good in 19, fair in 2, and poor in 2. The effective rate, therefore, was calculated as 87.1%. Patients with E. coli or K. pneumoniae as the pathogen gave good results.
No significant side effects were found except one eosinophilia in laboratory findings.

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Seven patients were treated by cefotetan (CTT, YM09330), a new antibiotic, including three complicated with lung cancer (68 yrs, 68 yrs and 71 yrs males) one with mesothelioma (74 yrs, male) one bronchiectasis (56 yrs, female) one acute pneumonia (60 yrs, male) one mycoplasmal pneumonia (29 yrs, male). A method of administration was done by drip infusion, 1.0 g bid, except in case 2, 0.5 g per day as an outpatient was given. A period of administration was 7.5 days through 18 days, average 11.8 days, and the total given dose was 6.5 g through 18 g, average 11.5 g.
This drug was bacteriologically effective in the case 2, H. influenzae pneumonia, in the case 5, P. aeruginosa was erradicated for a while but soon reappeared. Decrease of purulent sputum was observed in the case 1 and case 6 (bronchiectasis and lung cancer).
The overall effective rate was 71.4%, excellent in 1, good in 2, fair in 2, unknown in 2. Abnormal laboratory findings and side effects which seemed to be caused by this drug were found in the case 1, in which, GOT, GPT and ALP value slightly rose and the patient complained of right hypochondria! pain. But all abnormalities normalized in a week after the stop of this drug.

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Clinical studies were performed on cefotetan (CTT, YM09330), a new β-lactamase resistant cephem antibiotic, having more potent antibacterial activity against gram negative bacteria than those of CFX and CMZ, and accompanying with high blood concentration and long half life.
Eighteen inpatients, 6 cases of acute pneumonia and 12 cases of chronic respirat ory tract infections with evident symptoms or ineffective to conventional drugs, were given 1 g b. i. d.(2 g/day) for 14 days with drip infusion.
The clinical effects were evaluated according to scoring method. I. The results of 16 cases of 2 g per day administration.
A. Clinical responses: excellent in 6 cases, good in 5 cases, fair in 5 cases and the effective rate was 68.8%.
B. Chest X-ray photographic responses: excellent in 2 cases, good in 7 cases, fair in 6 cases, poor in 1 case and the effective rate was 56.3%.
C. Bacteriological effects: eliminated in 11 cases, reduced in 3 cases, persisted in 1 case, altered in 1 case and the elimination rate was 68.8% and the improved rate including reduction was 87.5%.
D. Overall evaluation: excellent in 6 cases, good in 4 cases, fair in 6 cases, and the effective rate was 62.5%.
Among them, acute pneumonia of 6 cases were all improved in clinical symptoms and chest X-ray photographs, the pathogenic organisms were all eliminated or decreased and effective rate was 100% including excellent in 2 cases and good in 4 cases.II. In cases of 4 g per day administration, lung abscess of the mixed infection with Pseudomonas showed the improvement.
III. Adverse reaction, one case of eruption occured from the 3rd day, thus the administration was terminated.
No abnormal values were observed in other clinical investigations.
IV. Blood concentrations of cefotetan were measured in healthy volunteer with 2 g i.v. injection for 3 days and were 8.6, 3.05 and 3.55μg/ml after 18, 42 and 66 hrs respectively. No accumulation was observed except unpleasant feeling probably due to drinking of alcoholic beverage.
From the results shown above, cefotetan is seemed as an effective antibiotic for respiratory infectious diseases.

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To evaluate the clinical efficacy of cefotetan (CTT, YM09330), the treatment was made with the drug in 62 patients including 32 with pneumonia, 4 with acute bronchitis, 2 with chronic bronchitis, 1 with purulent tonsillitis, 4 with acute pyelonephritis, 1 with chronic pyelonephritis, 7 with acute cystitis, 10 with chronic cystitis and 1 with acute cholecystitis. Response was excellent in 20 patients, good in 36, fair in 1 and poor in 5.
Side effect noted was fever in 1 patient. Laboratory abnormalities were observed as luekopenia in 3 and thrombocytopenia in 2 patients. Slight elevations of GOT and Al-P were observed each 1 patient.
From the above results, the drug can be considered to be useful against respiratory tract infections and urinary tract infections.

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A new derivative of cephamycin antibiotic, cefotetan (CTT, YM09330), was applied to 16 inpatients at a divided dose of 1-4 g twice daily.
Among 13 cases with respiratory tract infectious diseases, cefotetan was excellent in 3 cases, good in 7cases, fair in 2 cases and poor in 1 case, showing the efficacy rate of 92.3%. In 2 cases with subacute infective endocarditis, cefotetan was excellent in 1 case and good in 1 case. In a case of perinephritis, the drug was found to be poor.
In 9 cases for which causal bacteria could be identified, bacteriological study was conducted. As a results, it was determined that H. influenzae was eradicated in 3 cases and decreased in 1 case. K. pneunomiae, S. marcescens, S. viridans and enteric GNR in each one case were all eradicated, while S. aureus persisted in 1 case.
Neither subjective nor objective side effects were observed in any case. As an abnormality in laboratory findings, a slight elevation of s-GOT and s-GPT were found in 2 cases, and also a slight elevation of s-GOT, s-GPT and Al-p was found in one case respectively, but these abnormalities returned normal immediately after discontinuation of medication.
It is suggested, therefore, that cefotetan is a useful drug for infections caused by gram-negative bacteria.

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in vitro antimicrobial activity of cefotetan (CTT, YM09330), a new derivative of cephamycin, was examined by a broth dilution method with Dynatech MIC 2000 system. Also, therapeutic efficacy of cefotetan in the treatment of patients with respiratory tract infections was evaluated.
The minimum inhibitory concentrations (MICs) of cefotetan, cefazolin, cefotiam and cefmetazole against following 328 strains of clinical isolates were compared: 53 strains of S. aureus, 79 strains of E. coli, 100 strains of K. pneumoniae, 55 strains of Enterobacter sp., five strains of Citrobacter sp., seven strains of H.alvei and 29 strains of S. marcescens. It was revealed that cefotetan was more highly active against gramnegative rods, such as E. coli, K. pneumoniae, Enterobacter sp., Citrobacter sp. and S. marcescens, and more weakly active against S. aureus than cefazolin, cefotiam and cefmetazole. Cefotetan was almost as active as cefotiam and cefmetazole against H. alvei. A daily dose of 2 grams of cefotetan was given to a total of 12 patients by an intravenous drip infusion. The subjects examined consisted of one patient with acute bronchitis, two patients with acute pneumonia, one patient with lung abscess associated with diabetes mellitus, two patients with infection associated with bronchiectasis, one patient with chronic bronchitis and five patients with infection associated with lung cancer. Clinical response to the treatment with cefotetan was excellent in three, good in six and fairly good in two patients, and poor in one patient.
Following eight potential pathogens were recovered from the sputum of these patients at the start of the treatment with cefotetan, one strain of S. aureus, three strains of H. influenzae, two strains each of K. pneumoniae and E. cloacae. All of them were eradicated during the treatment with cefotetan.
An elevation of slight degree of serum transaminase was observed in two patients and eosinophilia in one patient. These abnormal findings returned to normal after cessation of cefotetan.
From the above results, it was concluded that cefotetan is one of the most effective and useful antibiotics against gram-negative bacterial infections in compromised hosts.

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Clinical investigations were performed on cefotetan (CTT, YM09330), a new β-lactam antibiotic.
Cefotetan was administered to total 13 cases of respiratory tract infections (11 cases of pneumonia and 2 cases of lung abscess), at a daily dose of 2 g for 11 days (one case), 12 days (one case), 14 days (9 cases), 21 days (one case) and 25 days (one case).
Clinical response of cefotetan was excellent in 8 cases, good in 4 cases and fair in one case.
Side effects with cefotetan were observed in 2 cases consisting of skin eruption, drug induced fever and the elevation of serum transaminase.

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Cefotetan (CTT, YM09330), a new cephamycin antibiotic, was applied to 11 patients including 4 cases of respiratory tract infections, 6 cases of urinary tract infections and one case of orchitis. A daily dose of 0.5 to 2.0g was injected intravenously or drip infused for 5 to 12 days. The clinical results were good in all cases, and there were no side effect which might be directly associated with the drug.
Cefotetan seems to be useful for respiratory and urinary tract infections like other cephamycin derivatives.

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We conducted experimental and clinical studies on cefotetan (CTT, YM09330).
Among the 26 strains of clinically isolated bacteria, cefotetan effectively inhibited 3 out of 5 strains of E. coli at≤0.2μg/ml and 2 strains of K. pneumoniae and 3 strains of P. mirabilis at 0.1μg/ml. It also proved to be several levels superior to other drugs against P. vulgalis.
Clinical results based on a total of 19 cases (11 cases of respiratory tract infections and 8 cases of urinary tract infections) showed that when this drug was administered by drip-infusion twice a day, each time 0.5 to 2g over a period of 4 to 14 days, the effective rate for all cases was 66.7% being 70% for respiratory tract infections and 62.5% for urinary tract infections. No side-effects were observed except for one case in which a transitory elevation in S-GOT and S-GPT was seen.

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Antibacterial activity, absorption, excretion and clinical effects of cefotetan (CTT, YM09330), a new cephamycin derivative, were studied and the following results were obtained.
1. Antibacterial activity
Cefotetan exhibited antibacterial activities superior to CFX and similar to CMZ against E. coli and S. marcescens and 2 to 3 tubes superior to CFX and CMZ against K. pneumoniae, Enterobacter sp., C. freundii and Proteus sp.
2. Absorption and excretion
The mean blood concentration after 5 minutes of intravenous injection of 1.0 g of cefotetan was 252.0 μg/ml, and the mean half life was 0.25 hours in α-phase and 2.82 hours in β-phase.
The mean urinary concentration after 2 hours of injection was 4, 440μg/ml and the mean urinary recovery rate was 61.4% by 8 hours after intravenous injection.
3. Clinical effects Cefotetan was administered to 5 cases of UTI and gave following results; excellent in one case, good in two cases, fair and poor in each one case.
No serious side effects were found.

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We conducted a clinical study in the field of internal medicine on the newly developed cephamycin-type antibiotic cefotetan (CTT, YM09330).
The study was conducted on 5 inpatients; 4 cases of urinary tract infections including chronic pyelonephritis (2 cases) and chronic cystitis (2 cases), and one case of pneumonia. The causative bacteria included P. mirabilis, E. coli, and one mixed infection of Enterobacter and S. epidermidis: The bacteria of pneumonia remained unknown.
The method of administration for all cases was drip infusion twice a day at a daily dosage of between 1 and 4 g over a period of 7 to 10 days.
Clinical results showed that it was good in two cases of urinary tract infection and one case of pneumonia and fair in one case and poor in one case of urinary tract infection.
No side effects were observed except that in one case a rise in the GPT and in one case a rise in the alkalinephosphatase was observed.

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Cefotetan (CTT, YM09330) showed favorable antibacterial activities against clinically isolated E. coli, Klebsiella, Proteus, Serratia and Enterobacter and gave better MICs than those of CEZ.
Cefotetan showed tautomerization under basic condition and in the presence of Mg²⁺ ion, and cefotetan and its tautomer can be separated by HPLC (High Performance Liquid Chromatography) and quantitatively determined.
The concentration of cefotetan in the serum, bile and urine were measured by bioassay and HPLC, and the obtained each results in bile and urine showed good correlation. But on the results in serum, no sufficient correlation could be found.
Cefotetan was administered intramuscularly to normal rat at a dose of 40 mg/kg. The mean blood concentration after one hour was 49.3μg/ml and gradually decreased later. Cefotetan was excreted in bile and urine in high concentrations; the recovery rate in bile up to 4 hours was about 80% and in the other experiment urinary excretion up to 6 hours was about 50% and up to 24 hours was about 67%.
In healthy volunteers, the concentration of the tautomer in the urine up to 2 hours with 1 g i.v. administration were only 3.0-9.9% except one case.
Cefotetan was administered to the case of obstructive jaundice at doses of 0.5 g and 1.0 g intravenously; the peak concentrations in bile reached 13.7 and 30.9μg/ml respectively and in urine were 590 and 1, 721.9 μg/ml. The recovery rate in urine up to 6 hours were 51.2% and 49.4% respectively.
Cefotetan was administered to 5 patients and resulted each one case of excellent and good, two cases of fair and one case of undetermined. In one case the elevations of S-GOT, S-GPT and Al-P were found but it is doubtful whether these findings were caused by the drug or not. Other side effects were not found.

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Cefotetan (CTT, YM09330) is a new cephamycin-type antibiotic with an expanded spectrum and potent activity against gram-negative bacteria includingβ-lactamase producing resistant strains.
Cefotetan was used in the treatment of 11 cases of respiratory infectious disease: 5 cases of pneumonia, 4 cases of respiratory tract infection, 1 case of lung abscess and 1 case of lung tuberculosis. Cefotetan was administered intravenously at a dose of 0.5-1.0g twice daily for 2 to 37 days, and results obtained were excellent in 1 case, good in 6 cases, fair in 1 case, poor in 1 case and not determined in 2 cases, effective rate being thus 78%.
Adverse reaction such as drug eruption and vascular pain were not observed in our study, however slight elevation of GPT in 1 case and elevation of GOT and GPT in 1 case were observed.
From the above clinical experience, cefotetan would be a clinically useful antibiotic against respiratory infectious disease and is worth further studies.

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A new cephamycin derivative, cefotetan (CTT, YM09330) was administered to various infectious diseases, including one case of acute bronchitis, 8 cases of pneumonia, 2 cases of acute cholecystitis, each one case of chronic pyelonephritis, decubital infection and diabetic gangrene. This medication was administered by DIV at a daily dose of 1-4 g divided in two times. Clinical efficacy was excellent in 4 cases, good in 8 cases and undetermined in 2 cases. Bacteriological efficacy was eliminated in 3 cases, suppressed in one case and undetermined in 2 cases. Diarrhea was noticed in one case and slight elevation of GPT was noticed in one case.

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Minimum inhibitory concentration (MIC) of cefotetan (CTT, YM09330) against clinically isolated each 25 strains of S. aureus. E. coli, K. pneumoniae, P. mirabilis, P. morganii and S. marcescens were compared with those of CMZ, LMOX and CPZ.
MICs of cefotetan was most unfavorable against S. aureus at>12.5μg/ml, similar to LMOX and somewhat superior to CMZ against E. coli, K. pneumoniae and P. mirabilis, approximately similar to LMOX and CPZ and superior to CMZ against P. morganii, and similar to LMOX and considerably superior to CPZ and CMZ against S. marcescens.
The blood concentrations of cefotetan were measured in two patients with successive i.v. or drip infusion at doses of 0.5-1.0g and the high blood concentrations were obtained. Even after 12 hrs the blood concentrations of >5.0μg/ml with 0.5g drip infusion and high value of >10μg/ml with 1.0g i.v. were maintained but no accumulation of cefotetan was observed.
Cefotetan were administered to 21 cases at dose of 0.5 or 1.0 g i. v. or drip infusion twice a day. 16 cases were RTI and among them 13 cases were pneumonia and 3 cases were infected bronchiectasis. The effect of cefotetan against 13 cases of pneumoniae were excellent 7, good 4 and fair 2.
Against 3 cases of bronchiectasis, the effect of cefotetan was good, fair and poor in each one case. In 3 cases of BTI, two cases were good and one case was poor. Two cases of UTI were all good.
No significant adverse effect was found clinically. In laboratory findings, two cases showed eosinophilia, one case decreased neutrophil and increased lymphocyte, and one case temporarily increased GOT and GPT.

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Serum concentration of cefotetan (CTT, YM09330) was determined in 8 aged patients by intravenous injection of 500mg of cefotetan.
Serum half life was 7.7 hour and serum concentration at 24 hr after injection was 5.9μg/ml.
Cefotetan was given in 11 aged patients, (3 with urosepsis, 3 with UTI, 4 with pneumonia and one with cholecystitis). Nine was treated with single bolus injection of 500mg of cefotetan and 6 responded satisfactorily. One patient who failed to respond was treated with single injection of 1g of cefotetan thereafterand showed good response. On the basis of these results, single bolus injection of 500mg-1g of cefotetan would be recommended for aged patients.

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Clinical study was made on cefotetan (CTT, YM09330), a new cephamycin derivative, and the following results were obtained.
1) Cefotetan was found effective in 35.3% of 17 patients with respiratory tract infection.
2) Cefotetan was found effective in 16.7% of 12 patients with lower respiratory tract infection.
3) Cefotetan was found effective in 80% of 3 cases of pneumonia and 2 cases of lung abscess.
4) Cefotetan caused fever in two patients, elevation of GOT and GPT in two patients, leukopenia in one patient, and eosinophilia in one patient but these findings were alleviated rapidly following cessation of the drug.

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Cefotetan (CTT, YM09330), a new cephamycin antibiotic, was administered to 22 cases of respiratory tract infections (RTI) at a dose of 1g twice a day by intravenous drip infusion. In the 22 cases, 15 patients were chronic bronchitis and 7 were pneumonia.
In the 15 chronic bronchitis cases including 11 non-responder to pre-treatment with other antibiotics, cefotetan proved effective in 9 cases and poor in the other 6 cases.
In the 7 pneumonia patients, 5 cases effectively, one fairly and the other poorly responded respectively.
No side effects were observed, but slight elevation of serum transaminases were noticed in 3 cases.
It is suggested that cefotetan is one of the useful drugs for the treatment of RTI especially lower respiratory tract infections, and is worthwhile trying further more investigations.

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Cefotetan (CTT, YM09330) was intravenously administered to 10 patients with pneumonia including 4 cases with primary atypical pneumonia, 3 patients with acute pyelonephritis, and 3 patients with cholecystitis at the daily dose of 1-2g for 2-17 days.
The clinical results were good in 6, fair in one, poor in 5 out of 12 cases with bacterial infections.
No side effects were observed in any patient except 2 cases of eruption.
No abnormality in laboratory findings was seen in any patient except low grade elevation of S-GOT and S-GPT in a patient during the medication.

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Cefotetan (CTT, YM09330) was administered to 64 patients with a variety of infectious diseases: 52 cases with respiratory tract infection, 5 with abdominal or biliary tract infection and 7 with urinary tract infection. Two patients were injected intramuscularly, 47 were intravenously by one shot and 15 by drip infusion.
Clinical responses were excellent in 10 patients, good in 25, fair in 8, poor in 6 and undetermined in 15. There was no relationship between the administration method and clinical responses.
Skin rash, fever and both rash and fever occured in one individual case, respectively, as the side effect of this antibiotic. Laboratory tests revealed the elevation of GOT in 1 and of GOT and GPT in 4, leukopenia in, eosinophilia in 2 and the positive reaction of direct Coombs' test in 1, although these abnormalities disppeared rapidly following cessation of the administration.

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The antibacterial activity of cefotetan was compared to those of cefazolin and cephalothin in a total of 178 clinically isolated strains of S. aureus, S. faecalis, E. coli, Citrobacter, Klebsiella, Enterobacter, Serratia, Proteus and P. aeruginosa.
Cefotetan exhibited far greater antibacterial activity against E. coli, Citrobacter, Klebsiella, Enterobacter, Serratia and Proteus than did cefazolin or cephalothin.
Cefotetan was then administered to a total of 22 patients of respiratory tract infections by drip infusion or intravenous injection.
The results obtained were excellent and good in 16 (72.7%) out of 22.
As adverse reactions, abnormal laboratory test results were observed in 3 out of 22 patients, elevated GOT and GPT in 2 and elevated Al-p level in 1. These abnormal data, however, returned to normal within 10 days after the completion of administration.

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Cefotetan (CTT, YM09330) was clinically evaluated in 35 cases of moderate to severe infections including pneumonia (25 cases), acute bronchitis (1), chronic bronchitis (1), biliary tract infection (4), chronic cytitis (3) and septicemia (1), and the results of clinical response were good in 16, fair in 6 and poor in 4. The remaining 7 cases were not evaluable because of mycoplasma pneumonia.
Without mycoplasma pneumonia cases, adverse reactions were obNerved in 7 out of 28 case including fever (1), eosinophilia (1), elevation of GOT and GPT (2) and creatinine, BUN (3) respectively.

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The new cephamycin antibiotic, cefotetan (CTT, YM09330) was applied to eleven patients with various infections. Excellent or good results were obtained in 2 of 3 cases with septicemias, 4 of 7 cases with pulmonary infections, 1 case with severe tonsillitis. No side effect was observed except 1 case with GPT, GOT elevation, and 1 case with exanthema. It is expected that this antibiotic may constitute an advance in the antibiotic treatment of gram-positive and gram-negative infections.

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Basic and clinical studies were made on cefotetan (CTT, YM09330), a new developed cephamycin. The results obtained were as follows:
1) Antibacterial activity in vitro: Cefotetan was found to be more potent than cefoxitin and cefmetazole against gram-negative bacilli, especially against Proteus (both indole positive and negative species), E. coli, Klebsiella, Serratia, Citrobacter and Enterobacter, while being less potent against S. aureus than cefazolin.
2) Distribution and urinary recovery: 1g cefotetan was administered by intravenous drip infusion for 1 hour to a patient recovered from acute cholecystitis without any underlying diseases. The blood level attained a peak of 158μg/ml immediately after the termination of infusion, which fell down to 13.8μg/ml four hours thereafter. Urinary recovery rate was 79.1% during 4 hours in this patient.
100mg/kg cefotetan was administered intramuscularly to rats, and its tissue concentrations were estimated serially. Kidneys showed the highest concentration among the organs, closely followed by blood and liver. Concentrations were lowered in order of lungs, muscle and spleen.
3) Clinical trials: Seven patients of various infections were treated with 1-2g cefotetan per day by drip infusion. Good responses were obtained in 6 out of 7 cases, while the remaining one case of UTI (P. aeruginosa) with ureter stone did not respond to the treatment.
Laboratory examinations revealed a slight elevation of GOT and GPT temporarily after the treatment in one of the patients.

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