1) T-1982 had a broad spectrum of in vitro antibacterial activity against gram-negative bacteria except P. aeruginosa. It was more active than other cephyamycin derivatives, that is, CFX, CMZ and CTT, particularly against S. marcescens, E. cloacae and C. freundii.
2) But antibacterial activity of T-1982 against gram-positive bacteria, that is, S. aureus and S. epi dermidis and against anaerobic bacteria, B. fragilis was slightly less potent than that against gram-negative bacteria.
3) T-1982 was stable against various types of β-lactamases.
4) Its antibacterial activity was not influenced by type or pH of medium, addition of human serum or inoculum size.
5) T-1982 showed high bactericidal activity at low concentrations. It was characteristic that bacterial regrowth did not take place even at 24 hours after incubation due to complete bactericidal activity.
6) The therapeutic effect of T-1982 against experimental infections of mice was much higher than that of CFX, CMZ, CTT and LMOX.

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To clarify the prominentin vivo effect of T-1982, a new parenteral cephem antibiotic, studies were carried out on the synergetic bactericidal and phagocytic effect of the drug with serum complement and cultured mouse macrophages. Other investigations were also performed to see whether or not the drug possesses a direct immuno-potentiating effect to host animals.
10⁵ cells of Escherichia coli NIHJ JC-2 were completely killed within several hours in the presence of T-1982 at the concentration of 50% growth inhibition (ID₅₀) plus 20% human serum and 2% guinea pig complement, each of which showed incomplete bactericidal activity. This effect was found to be most prominent in T-1982 among known cephem antibiotics.
Since T-1982 binds the PBP 3, lb and Ia, cells ofE. coli are converted into filamentous bodies with bulges in the presence of subMIC of the drug. When live cells of E. coil NIHJ JC-2 were added to the mouse cultured macrophages with 1 to 1/2 MIC of T-1982, the filamentous bacterial cells were well phagocytized and digested within 4 hours. Whereas, normal bacterial cells added to the macrophages in the absence of the drug multiplied in the animal cells and destroyed them at 4 hours after incubation.
No immunostimulating effects were confirmed when mice were pretreated with T-1982 and then challenged with Candida parapsilosis or C. albicans. It was suggested that the prominence of in vivo effect of T-1982 depends upon the conversion of bacterial surface as to be easily killed by host defence mechanisms.

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Antibacterial activity of T-1982 was studied in comparison with that of other cephems against a total of 1, 019 strains of Staphylococcus, Streptococcus, Escherichia, Klebsiella, Citrobacter, Enterobacter, Serratia, Proteus, Pseudomonas, Flavobacterium, Acinetobacter, Achromobacter, Alcaligenes, Peptococcus, Clostridium and Bacteroides isolated from various clinical specimens during the years of 1980 and 1981. The following results were obtained.
1) Antibacterial activity of T-1982 against gram-positive cocci was weak and inferior to that of most other cephems.
2) T-1982 was highly active against E. coli and Klebsiella strains, and those resistant to CEZ and CPZ were susceptible to the drug. It exhibited low MIC values against not a few strains of C. freundii, E. cloacae and Serratia which were resistant to most cephems of 1st and 2nd generations. Antibacterial activity of T-1982 against 5 species of Proteus was inferior to that of CZX, but superior to that of CEZ and equal or superior to that of CPZ.
3) Antibacterial activity of T-1982 was relatively weak against glucose-non-fermentative species.
4) Among anaerobes tested, T-1982 was highly active against Peptococcus and C. perfringens and fairly active against B. melaninogenicus. Against B. fragilis and other Bacteroides, T-1982 exerted relatively potent activity comparable to that of CZX.

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The in vitro antibacterial activity of T-1982, a new cephamycin antibiotic, was studied.
T-1982 proved to possess a broad antibacterial spectrum against various strains of gram-positive and gram-negative bacteria. The drug was active particularly against Streptococcus pyogenes, Streptococcus prieu. moniae, Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Proteus species (Proteus mirabilis, Proteus vulgaris, Proteus rettgeri, Proteus inconstans) and Enterobacter cloacae. The activity was less potent against Staphylocbccus aureus, Staphylococcus epiderrnidis, Proteus morganii, Serratia marcescens, Citrobaxter freundii, Pseudomonas cepaia, Flavobacterium meningosepti cum, Acinetobacter calcoaceticus, Achromobacter xylosoxidans and Bacteroides fragilis but superior to that of other existing cephamycin antibiotics. T-1982 was not active against Pseudomonas aeruginosa and Pseudomonas maltophilia like other cephamycins.
The drug was highly stable against all types of β-lactamase as classified by Richmond comparably to other cephamycins (cefoxitin, cefmetazole and cefotetan).
In protecting effect against experimental infections in mice due to Escherichia coli C-11, Klebsiella pneumoniae 3K-25, Serratia marcescens No.2 and Citrobacter freundii GN 346, T-1982 was superior to cefoxitin, cefmetazole, cefazolin and cefoperazone, equal to cefotetan, but slightly inferior to latamoxef.

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The MICs of T-1982 were studied in comparison with those of CPZ, CFX, CTM, CEZ, PIPC, CBPC, AMK and MINO against 226 strains of glucose non-fermentative gram negative rods (GNFGNR) isolated from clinical specimens. The results obtained were as follow
The overall outcomes were good for PIPC, CPZ, AMK and MINO. T-1982 was relatively active against P. putrefaciens and A. faecalis. Other species demonstrated low sensitivity to T -1982 although some variations by species and strains were found.
Consequently, T-1982 is not much expected in the treatment of infections caused by GNF-GNR., However, T-1982 exhibited the Mies of below 12.5μg/ml against some strains of certain species. T-1982 may be useful for the treatment of properly selected infectious diseases.

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The antibacterial activity of T-1982, a new cephamycin antibiotic, was studied.
The following results were obtained.
1) The antibacterial spectrum of T-1982 against anaerobes was almost conformable to that of cefmetazole and cefotetan. Its antibacterial activity against B. fragilis was slightly more potent than that of cefmetazole and cefotetan, with the MIC of 1.56-6.25μg/ml. Against anaerobic cocci, T-1982 was less active than cefazolin, cefotaxime and cefoperazone but comparable to cefmetazole and cefotetan. The activity was weak against B. thetaiotaomicron, E. lentum, C.difficile and C. rarnosum.
2) Like cefmetazole and cefotetan, T-1982 was very stable to β-lactamase produced byB. fragilis.
3) In the bouillon containing T-1982 (at the MIC), B. fragilis was almost completely lyzed and filamentation was scarcely observed.
4) In the broth containing T-1, 982, resistance of B. fragilis was gradually increased with the passage of culture.
5) Following s.c. administration of T-1982 at a dose of 2 mg for 7 days in mice, abnormal growth rate of (C. difficile was 80% in the, cecum, although the number of organisms detected was extremely small. 6) T-1982 exhibited potent in vivo antibacterial activity against B. fragilis intraperitoneally inoculated in mice.

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The bacteriological evaluation of T-1982, a new cephamycin antibiotic, was studied in comparison with that of cefmetazole and cefotetan. The following results were obtained.
T-1982 showed a broad antibacterial spectrum against gram-positive and gram-negative bacteria as well as cefmetazole and cefotetan, and its antibacterial activity was almost the same as cefotetan in the sensitivity distribution to various clinical isolates.
Moreover, T-1982 was active against Bacteroidxs fragilis, but was not active against Pseudonumas aeruginosa.
T-1982 showed a dose-response bactericidal activity against Escherichia coli, Klebsiella przeumoniae and Serratia marcescens.
The correlation between MICs and MLCs of T-1982 against Escherichia coli and Serratia marcescens was similar to that of cefmetazole and cefotetan.
Therapeutic effect of T-1982 on experimental infection in mice with Escherichia coli, Klebsiella pneumoniae and Serratia marcescens was somewhat superior to that of cefotetan, but inferior to that of cefmetazole on infection with Proteus morganii.
The morphological change in Escherichia coil K-12 was observed by a phase contrast microscope. At concentrations of 0.05 and 0.5μg/ml, T-1982 made the bacteria elongated.
A study on the binding of T-1982 to the penicilin-binding proteins in Escherichia coli K-12 and Pseudomonas aeruginosa E-2 revealed that T-1982 had the highest affinity for PBP 3.

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Antibacterial activities of T-1982 and cefmetazole (CMZ) in the urine against each strain of E. coil, K. pneumoniae, E. cloacae and S. marcescens isolated from patients with urinary tract infections were measured.
Urine samples were collected in 12 hours after intravenous injection of 1g of the drug to 6 healthy male volunteers. Urine samples collected at intervals of 2 hours were diluted 2-fold with synthesized urine, Inoculum size of the bacteria was 10⁵/ml. Bacteriostatic and bactericidal dilutions were measured after 20 hours incubation at 37°C.
So-called urinary MIC and MBC values were calculated by dividing drug levels in the fractional urine samples by dilutions to obtain bacteriostatic and bactericidal state.
Urinary MIC values of T-1982 were smaller than those measured by agar dilution method against all bacterial strains tested, while urinary MICs of CMZ were larger than those values except S. marcescens. Differences between urinary MIC and MBC were also recognized.
Thus, the prospect of in vivo effect of antimicrobials in the urine may be possible by measuring antibacterial activities in the urine samples obtained after giving the drugs, because the results totally reflect urinary concentrations, inactivation of the drugs by bacteria and antibacterial activities of the drug.

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Antibacterial activity and passage into CSF of T-1982, a new cephamycin antibiotic, was evaluated.
MICs of the drug against 205 strains of clinical isolates were compared with those of latamoxef and were found to be equal against E. coli, S. typhi, Klebsiella and S. marcescens. However, latamoxef was some-what superior against Salmonella group B, Enterobacter sp., Citrobacter sp. and S. aureus and remarkably ftsuperior against Proteus. T-1982 showed no demonstrable activity against P. aeruginosa.
CSF concentrations of T-1982 were determined in experimental staphylococcal meningitis in 4 rabbits after intravenous injection of 100mg/kg of the drug and the average maximal concentration of 6.49±2.41μg/ml was obtained at 1 hour with its CSF/serum ratio of 3.9%. CSF/serum ratio of AUC up to 12 hours was 9.21% with a CSF/serum ratio of T1/2 being 3.50. Among cephamycin antibiotics, these values were closely comparable to those of cefoxitin and cefmetazole and were remarkably higher than those of cefotetan.
The above results indicate that T-1982 may be a potentially effective antibiotic in the treatment of oacterial meningitis, although with some limitations, and is worth being clinically evaluated.

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Thein vitro and in vivo antibacterial activities of T-1982 were compared with those of cefmetazole (CMZ), latamoxef (LMOX), cefoxitin (CFX) and cefazolin (CEZ). The following results were obtained.
1) T-1982 had a broad spectrum with a high degree of activity against gram-positive and gain.negative bacteria, including those which are resistant to the other cephalosporins. Especially, T-1982 showed potent activity against Escherichia coli, Klebsietlepneumoniae, Serratia marcescens and Proteus sp. and iso against Bacteroides fragilis.
2) The antibacterial activity of T-1982 was bactericidal at the MIC, and was hardly changed by pH of medium, inoculum size of cells and addition of human serum into the medium.
3) T-1982 had the same stability as CMZ, CFX and LMOX against penicillinase and cephalosporinase.
4) Competition of T-1982 with benzylpenicillin for penicillin-binding proteins of E. coli was strong in relative order of PBP-3>lA>1Bs
5) The therapeutic effects of T-1982 on intraperitoneal infections in mice with various gainnegative bacteria, including resistant strains to CEZ, were superior to those of CMZ, CFX, LMOX and CEZ.

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The in vitro and in vivo combined actions of T-1982 and aminoglycosides, macrolide, or tetracycline against Serratia marcescens were studied.
The combinations of T-1982 and aminoglycosides (gentamicin, dibekacin) showed markedly synergistic activity in bothin vitro antibacterial activity and therapeutic effect on experimental infection in mice, and the combined actions were bactericidal.
On the other hand, in vitro combinations of macrolide (erythromycin) or tetracycline with T-1982 showed rather weak synergism.

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The therapeutic effects of T-1982 on various experimental infections in mice or in rats were studied in comparison with other cephem antibiotics.
1) The therapeutic effect of T-1982 was equal to that of cefoperazone (CPZ), latamoxef (LMOX) and cefotetan (CTT) and was superior to that of cefmetazole (CMZ), cefoxitin (CFX) and cefazolin (CEZ) in severely infected mice with Escherichia coli TK-16 and Serratia marcescens IID 620.
2) T-1982 decreased remarkably the number of viable bacteria in peritoneal cavity of mice infected intraperitoneally with E. coli TK-16 and S.marcens IID 620.
3) The therapeutic effect of T-1982 was superior to that of LMOX, CFX and CMZ on intraperitoneal infections withE. coli TK-16 and Klebsiella pneumoniae Y-41 in mice pretreated with immunosuppressive cyclophosphamide.
4) Judging from the number of viable bacteria in foot pad of mice which was infected with E. coli TK-16, the therapeutic effect was good in relative order of T-1982, CPZ>CMZ>CEZ.
5) On pyelonephritis withE. coli TK-39, E. coli TK-117 and P. mirabilis KU-1 in rats, the therapeutic effect was good in relative order of T-1982, LMOX> CPZ, CFX CMZ, CEZ as judged by counting of viable bacteria in infected kidney.
6) T-1982 was more effective than CMZ on intrauterine infections with E. coli TK-143 and K. pneumoniae Y-41 in rats.
7) Judging from the tendency of viable bacteria in exudate of rat's granuloma pouch which was infected with E. coli TK-16, good therapeutic effects were obtained in relative order of T-1982, CPZ>CMZ, CEZ at both high dose and low dose of the drugs.

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A microbiological assay method for the quantitative determination of T-1982 in body fluids was established. The suitable conditions for assay was double layer paper disc method using Klebsiella pneumoniae ATCC 10031 as the test organism in the originally prepared medium (KA medium) which was composed of polypeptone 6g, beef extract 1.5g, yeast extract 3g, glucose 1g, agar 15g and distilled water 1 liter at pH 6.5-6.6.
It was possible to detect T-1982 concentration ranging from 0.39μg/ml to 100μg/ml.
For the quantitative determination of T-1982 in human serum, pooled human serum and Consera were suitable for the use as the diluent of the standard solution of T-1982, but Moni-Trol I was unsuitable.
When T-1982 was administered to the volunteer, the concentrations of T-1982 in the serum obtained by the bioassay method were in agreement with those by the high pressure liquid chromatography.
For the quantitative determination of T-1982 in urine, bile and the other tissue fluid, 1/15 M phosphate buffer (pH 6.0) was suitable for the use as the diluent of the standard solution of T-1982.
T-1982 in body fluids was stable at -20°C for at least 1 month.

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T-1982, a new parenteral cephem derivative antibiotic, was administered to experimental animals (mice, rats, rabbits, dogs, monkeys and goat) at a single dose ranging from 20mg/kg to 100mg/kg. The following results were obtained.
1) When T-1982 was administered intravenously to various animals at 20mg/kg, the serum level was high in the order of monkeys>dogs>rabbits>rats>mice. In rabbits and monkeys, the serum levels of T-1982 were higher and persisted longer than those of cefmetazole (CMZ).
2) T-1982 was rapidly distributed into various tissues of rats and mice and the concentrations in the liver and kidney were higher than in other tissues.
3) T-1982 was mainly excreted into bile in rats, while it was excreted into urine in rabbits, dogs and monkeys.
4) Though serum levels of T-1982 in bile duct-ligated rats or renal artery and vein-ligated rats were higher and eliminated later than those of control rats, T-1982 was recovered completely in the urine or bile respectively.
5) The transference rate of T-1982 into goat's milk was 0.0077% of the given dose within 24 hours.
6) The concentration of T-1982 in the cerebrospinal fluid of meningitis rabbits, which were infected with Haemophilus influenzae, was extremely higher than that of control rabbits.
7) One g of T-1982 was administered intravenously to healthy volunteers. Seurm level of T-1982 showed 118μg/ml after 15 minutes, and then gradually decreased with half-life of about 95 minutes. Urinary recovery rate was 76.8% within 9 hours.
8) In urine of various animals and healthy volunteers, T-1982 A and T-1982 B were found slightly.
9) There was a specific difference among various animals in the serum protein binding of T-1982. The binding rate to human serum protein was 54.9% using the centrifugal ultrafiltration method.

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The effect of probenecid on both serum level and urinary excretion of T-1982 was investigated using various experimental animals.
When T-1982 was administered to rats, rabbits and dogs, significant difference between with and without probenecid was not observed in serum level and urinary excretion. The renal excretion of T-1982 took place mainly through glomerular filtration.
On the other hand, when T-1982 was administered to monkeys with probenecid, serum level of T-1982 was higher, and urinary excretion of T-1982 was lower than that of T-1982 alone. Those results suggested that renal excretion of T-1982 was related to not only glomerular filtration but also tubular secretion.

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Pharmacokinetics of T-1982 and its decomposition products were studied in 3 patients with renal failure.
T-1982 was administered by drip infusion to patients. As the impairment of renal function was more serious, plasma concentration of T-1982 became higher and persisted later. In the urine and the plasma, T-1982 A and T-1982 B which were decomposition products of T-1982, were detected in a small amount.
As the results of the pharmacokinetic analysis using a compartment model in the patient, the formation rate constants of T-1982 A and T-1982 B from T-1982 were estimated to be very small, and 0.0147 hr^-1 and 0.0297 hr^-1, respectively. And the excretion rate constants of T-1982 A and T-1982 B were larger than that of T-1982.
From these results, we concluded that probably T-1982 A and T-1982 B did not produce accumulation in the body tissues.

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For the purpose of basic study on T-1982 in the field of obstetrics and gynecology, the concentrations of T-1982 in the serum and various tissues of the uterus after intravenous injection of 1g were measured by bioassay. And a pharmacokinetic analysis was studied in 30 patients.
1) The serum levels were calculated by two compartment model and various tissue levels were calculated by three compartment model, and these simulation curves were obtained.
2) T-1982 was rapidly distributed to these tissues, and these tissue levels werecorrelated with the serum levels. And sufficient tissue levels were maintained for an adequate period.

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T-1982, a new cephamycin antibiotic, was studied for its biliary excretion and stability in human bile, and the following results were obtained.
1) Biliary levels and excretion rates of T-1982 were measured at 20-30 minutes intervals for 6 hours after intravenous administration of 1g in 6 patients with balloon occludable T tube. Among the 4 cases with almost normal liver function, 3 received 1g of CMZ and 1 received 1g of CFX by crossover method. The highest biliary levels of T-1982 were 3300μg/ml, 2270μg/ml, 2200μg/ml and 1700μg/ml and 10-20 times as high as those of CMZ and CFX. The biliary recovery rates in 4 cases were 16.0%, 5.3%, 13.1% and 4.6% during 6 hours as compared with 1.34%, 0.25% and 2.2% for CMZ and 0.17% for CFX. In the 2 cases with slight liver dysfunction, the biliary levels of T-1982 were about one tenth but as high as 192 eagirril and 240 tcg/ml at 1.5 hours after administration.
2) Biliary excretion and its rates were studied at different doses. The maximum excretion during 30 minutes after administration of 250mg, 500mg and 1000mg were remarkably dose-dependent and 5.78mg, 12.55mg and 20.61mg, respectively. The recovery rates during 6 hours were similar and 12.4%, 12.0% and 10.5%, respectively.
3) Metabolite A (T-1982A) and metabolite B (T-1982B) were investigated by HPLC for their biliary excretion in humans and generation during storage. Bile was taken at 1.5 hours after intravenous administration of 500mg and measured for levels of T-1982 and its metabolites. T-1982A and T-1982B increased remarkably after standing at room temperature for 6 hours. It was also noted that T-1982A and T-1982B were generated at 25-30% in the bile stored at -20°C. However, the generation of the metabolites was only several percent when the bile was stored at -80°C or stored after diluted with 1/10 M phosphate buffer. The levels of both T-1982A and T-1982B were almost same when measured immediately after sampling at 1.5 hours and 6 hours following intravenous administration of 500mg.
4) Since minimal amounts of T-1982A and T-1982B were detected by HPLC in the bile taken directly from the intrahepatic duct, it was confirmed that the generation of the metabolites was not merely due to the pH changes.

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The extent of the binding of T-1982 to human serum albumin was examined with the equilibrium dialysis and the centrifugal ultrafiltration method.
T-1982 bound reversibly to human serum albumin.
The binding rate of T-1982 as well as latamoxef (LMOX) and cefmetazole (CMZ) was influenced by the concentration of the drug and human serum albumin. That is, the binding rate of T-1982 became higher as the concentration of human seum albumin became higher. Further that of T-1982 became lower as the concentration of T-1982 became higher.
From the result of scatchard plot, it became clear that T-1982 had 1 binding site on albumin, and LMOX and CMZ had 2 sites. The maximum binding number and the association constant of T-1982 to human serum albumin were 0.58 and 3.60×10³ respectively. Addition of T-1982 didn't influence on the binding of bilirubin to human serum albumin.
T-1982 showed the good transference activity to exudate fluid of experimental animals with granuloma pouch.
Although there was the specific difference of the serum protein binding ratio between rats and rabbits, no appreciable difference was observed in the tansference of T-1982.

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Influence of T-1982 and cefrnetazole (CMZ) on the human intestinal bacterial flora was studied. The drugs were intravenously administered to 4 healthy volunteers alternately at an interval of 7 days.
Both drugs demonstrated a tendency to reduce obligative and facultative anaerobes and aerobes when given as the first drug. When given 8 days later as the second drug, however, neither drugs demonstrated uniform reductions of the bacteria due to the influence of the first drug. Such reductions by T-1982 were less evident than those by CMZ, and influence of T-1982 on the flora was deemed to be comparatively moderate.

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The antigenicity or immunological characteristics of T-1982 was studied employing rabbits, guinea pigs and mice.
The results obtained were as follows:
1) Antibody production against T-1982 was not observed in rabbits immunized with single administration of T-1982 or with the emulsion of T-1982 and complete Freund's adjuvant (CFA).
2) Hapten-specific antibody production against T-1982 was demonstrated by indirect hemagglutination test, hemagglutination inhibition test and 3 hr PCA of guinea pigs, employing rabbit anti T-1982 serum hyperimmunized with the emulsion of T-1982 coupled to human serum albumin and CFA.
3) IgE antibody production in mice immunized with the mixture of T-1982 and silica gel was not observed at all.
4) Anaphylactic syndrome was not observed in guinea pigs actively sensitized with T-1982 or passively sensitized with rabbit anti T-1982 serum.
5) The ability of T-1982 to give a positive reaction in Coombs' test was rather weaker than that of CET or PCG.

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General pharmacology of a new cephamycin antibiotic, T-1982, was investigated.
1) When T-1982 was injected to mice at a dose of 1000mg/kg i.v., no effect on ether anesthesia, pentobarbital sleep, pentetrazole convulsions, hot plate method and sedative-ataxic score was observed. A slight decrease in number of writhing by acetic acid method and no change of rabbit rectal temperature was observed at a dose of 1000mg/kg.
2) T-1982 given intravenously at a dose of 500mg/kg caused a transient slight fall of blood pressure in dog. No effect on the isolated guinea pig atria and rabbit ear vessels was observed at a concentration of 10^-3g/ml of T-1982.
3) T-1982 at a concentration of 10^-3g/ml did not influence any kind of smooth muscles which were investigated in our laboratory.
4) In isolated phrenic nerve-diaphragm preparations of rats, T-1982 produced no inhibition of end-plate and muscle contractions at a concentration of 10^-3g/ml.
5) A study on the urinary excretion of electrolytes in the rat revealed a marked decrease in Na⁺ excretion and a moderate decrease in K⁺ excretion at doses of more than 500mg/kg for 7 days.

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Pharmacokinetics (blood levels, distributions, excretion in bile and urine, and binding to proteins) of T-1982 was investigated in rabbits, rats and mice.
1) When T-1982 was given to rabbits, rats and mice at a dose of 20mg/kg, biological half-lives of T-1982 in plasma were 37.06 min. in rabbits (i.v.), 11.92 min. in rats (i.v.), 15.94 min. in rats (i.m.) and 12.97 min. in mice (i.m.). When T-1982 was given i.m., half-lives in injected muscle were 11.63 min. in rats and 10.31 min. in mice.
2) Estimation of distributions of T-1982 in rats revealed that blood levels were highest. Its distributions were in descending order; kidney, liver, lung, heart, spleen, muscle and testis. In mice, concentrations in kidney, liver and duodenum were higher than blood levels.
3) Excretion rates (0-6 hr.) in urine were 30.07-39.45% of total amount given in rats and 35.33-39.66% in rabbits, approximately half of which was excreted within 1 hour.
4) Excretion rates (0-6 hr.) in bile were 7.51-11.57% and its levels were 1.3 to 6.0 fold of blood levels in rabbits.
5) Species difference was observed in binding to proteins. The binding rate to human plasma was 62.8%, approximately half of which was of reversible type. The binding coefficient (1/n) was 0.9194.

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T-1982, a new cephamycin antibiotic, possesses remarkable antibacterial activity against β-lactamase-producing organisms and gram-positive or gram-negative bacteria. This study was carried out to evaluate the acute toxicity of T-1982 in mice, rats and beagle dogs.
The following results were obtained.
1) LD₅₀ values of T-1982 were as follows: in mice, over 10g/kg by oral, subcutaneous, intraperitoneal or intravenous administration; in rats over 10g/kg by oral, subcutaneous or intraperitoneal administration and 9.55 10.19g/kg by intavenous injection; in infant rats (5-6 days aged), about 10g/kg by subcutaneous injection; in beagle dogs, over 8g/kg by intravenous injection.
2) In mice and rats, intensive inflammation was obseved at the area of subcutaneous injection, and writhing was seen by intraperitoneal injection. By intravenous injection, significant pulmonary edema and congestion were noted, which caused respiratory arrest and death. Toxic symptoms and pathological findings in infant rats by subcutaneous injection were similar to those in 6 weeks aged rats.
3) In beagle dogs, slight elevation of serum GOT, GPT, LDH and blood glucose levels were temporarily observed by 8g/kg or 6g/kg administration of T-1982.
Fast-moving albumin components were observed on serum electrophoresis in all the beagle dogs administered T-1982.

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One hundred and fifty rats (75 males, 75 females) divided into 4 T-1982 groups at dose levels of 2000, 1000, 500, and 250 mg/kg/day and a saline control group were received daily subcutaneous injection for 3 months. Ten rats (5 males, 5 females) of each group were used for the recovery study after the termination of treatment.
The following results were obtained.
1) Vocalization was observed during injection of T-1982 in higher dose groups, and in a part of rats of these groups, hemorrhage and induration of the infection site were also recognized. The dose-related changes such as hemorrhage, edema and inflammatory cell infiltration were seen in T-1982 injected groups in macroscopic and histological observations. These changes may be based on the injection of high concentrated solution.
2) There was no mortality in all groups.
3) There was no abnormality based on T-1982 dosing in growth curves, food intakes, urinalysis and hematological examinations.
4) In serum electrophoresis, fast albumin component with the faster mobility to plus pole was observed in rats given T-1982 at 2000 mg/kg/day or 1000 mg/kg/day, respectively. However, the above fast albumin component diminished in the recovery study. There was no other significant change in biochemical examinations.
5) Dose-related enlargement at the lumen of cecum was observed in male and female rats treated with T-1982, however, no histological change of the mucous membrane of the cecum was seen. In the recovery study, enlargement of the lumen of the cecum disappeared.
6) Based upon the above results, the maximum safety dose of T-1982 was estimated to be 500mg/kg/day in this experiment.

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Thirty-five beagle dogs (18 males, 17 females) distributed into three T-1982 groups at dose levels of 400, 200 and 100mg/kg/day and a saline control group received daily intravenous injection for 3 months. Two (1 male, 1 female) control dogs and 2 (1 male, 1 female) dogs at 400 mg/kg were maintained for 1 month for a recovery study after the termination of 3 months administration.
The following results were obtained.
1) There were no mortality, toxic signs or significant toxic effects on body weight gain, urinalysis, ECG, organ weight and microscopic findings attributable to the injection of T-1982.
2) Four of 8 dogs receiving the high dose of 400 mg/kg/day showed the slight decrease of red blood cells, hemoglobin and hematocrit and slight increase of reticulocytes in the 2nd month. However, these hematological changes were not distinctly observed in the 3rd month. No related microscopic abnormality of the bone marrow was observed.
3) Dose-related total cholesterol elevatioin was observed in the 1st and 2nd month examinations. However, all dogs in each group showed values within normal range in the 3rd month. This phenomenon was clearer in the female dogs than in the male dogs.
4) In serum electrophoresis, fast albumin component with the faster mobility to plus pole was observed in T-1982 dosing dogs with the dose-dependence. However, the above fast albumin component diminished distinctly in the recovery study.
5) In this subacute toxicity study, the maximum safety dose of T-1982 was estimated to be 200mg/kg/day

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Twenty crab-eating monkeys (10 males, 10 females) divided into three T-1982 groups at dose levels of 400, 200 and 100mg/kg/day and a saline control group were injected intramuscularly once a day, 7 days a week, for 3 months. Recovery study was performed in a T-1982 group at a dose level of 400mg/kg/day and a control group (in each group, 1 male and 1 female monkeys) for 1 month after the termination of T-1982 treatment.
The following results were obtained.
1) There were no mortality and significantly toxic changes in growth curves, urinalysis, hematology and clinical chemistry.
2) Soft stool, which was dose-related, was observed intermittently in all monkeys receiving T-1982 throughout the entire 3 months period.
3) In cellulose acetate electrophoresis of serum, fast-moving albumin component was observed in all monkeys receiving T-1982. This change was dose-related and reversible in the recovery period.
4) In histological observation, there was no significant change except the muscular damage of injected site. This damage indicated the inflammatory reactions (necrosis, hemorrhage, edema, cell infiltration and fibrosis) and especially in monkeys receiving 400mg/kg/day of T-1982, the severest injury was recognized.
5) Based upon the above results, the maximum safety dose level of T-1982 in monkeys was estimated to be 200mg/kg/day.

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This report is concerned with the reproduction of rats given T-1982.
1) Fertility study
T-1982, given subcutaneously at dose levels of 0 (control), 500, 1000 and 2000mg/kg/day to male rats for 63 days and to female rats for 14 days prior to and during mating, and to pregnant female up to day 7 of gestation, had no effect on fertility and fetal development. There was no evidence of maternal toxicity in T-1982 treated groups, except for increase in maternal water intake and soft stools.
The number of corpora lutea, implantations, live fetuses and body weight were comparable to control in 500 and 1000mg/kg groups. In 2000mg/kg group, the number of implantations and live fetuses were slightly decreased and fetal body weight was significantly increased to those of the control.
External malformations were found in each group; an omphalocele presented in control group, an acrania (absence of skull) presented in 500mg/kg group, a reduction deformity of the forelimb with the heterotopic digits (absence of ulna) presented in 1000mg/kg and a kinky tail presented in 2000mg/kg.
Each one case of skeletal malformation was observed in 500mg/kg and in 1000mg/kg groups. The incidence of the skeletal variations and internal malformations in the treated groups were not significantly different from the control.
2) Teratological study
Pregnant rats were administered T-1982 intravenously at dose levels of 0, 500, 1000 and 2000mg/kg/day from day 7 to day 17 of gestation.
No toxic signs were observed in treated groups, except for decrease in food intake during initial stage of drug administration, increase in water intake from day 7 post partum and soft stools during the administration period.
No external malformations were observed in fetuses. Skeletal malformations were confined to two cases; a nodulated ribs presented in control group and absence of unilateral 13th rib presented in 1000mg/kg. The incidence of internal malformations and skeletal variations were comparable to control.
3) Perinatal and postnatal study
Pregnant rats were administered T-1982 subcutaneously at dose levels of 0, 500, 1000 and 2000 mg/kg/day from day 17 of gestation to day 21 of lactation.
On maternal toxicity in T-1982 treated groups, decrease in food intake during initial stage of drug administration, increase in food intake from day 4 post partum throughout the lactation period, increase in water intake and soft stools during administration period were observed.
In 2000mg/kg group, the number of live ftuses increased and in all treated groups inhibition of body weight of pups were observed, but 6 weeks after birth, no significant difference from the control was observed. The duration of gestation, perinatal mortality, the delivering rates, the weaning rates and the survival rates of all treated groups had no significant difference from those of the control. There was no adverse effect on behavior, open field test, water maze test and fertility of offsprings.

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T-1982, a newly developed cephamycin antibiotic, was injected intravenously at dose levels of 250mg/kg and 1000mg/kg to rats which were pretreated by glycerol (4 ml/kg, s. c.) and furosemide (50mg/kg, s. c.). At 24 hrs after treatment, the influcence of T-1982 on the kidney was examined in comparison with CET and CEZ by the urinalysis, the plasma urea nitrogen and creatinine and the renal morphological observations. In addition, T-1982 at 1000mg/kg was given alone or in combination with furosemide (s. c.) to rats intravenously.
The following results were obtained.
1) Renal damage was seen neither in rats given T-1982 at 1000mg/kg alone nor in rats given T-1982 at 1000mg/kg+F.
2) Renal damage was severer in rats given T-1982 at 250 or 1000mg/kg in combination with G+ F. This tendency was clearer at the high dose level.
3) Toxic signs of the above renal damage was shown by the following observations; proteinuria, elevation of the plasma urea nitrogen and creatinine, necrosis of the renal tubular epithelium in micro scopic findings and degenerative or necrotic changes of the proximal tubular epithelial cells in electronmicroscopy.
4) Similar stretched renal damage was revealed by an additional injection of CET or CEZ to G+F pretreated rats.
5) In this experiment, the influence on die kidney appeared to be CET≅CEZ≥T-1982.

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Basic and clinical evaluation of T-1982, a new ureido-type cephamycin, was carried out to give the following results.
1) MICs of T-1982, cefmetazole and cefazolin to clinical isolates of gram negative bacilli were determined by the modified standard method of the Japanese Society of Chemotherapy with an inoculum size of 10⁶/ml.
Antibacterial activities of the drug against each 27 strains of E. col, Klebsiellai and Serratia and 20 strains of Proteus morganii were superior to those of cefmetazole and cefazolin, but inferior to those of cefmetazole against Proteus mirabilis.
Most strains of E. coli and Klebsiella were inhibited by 0.2μg/ml of the drug.
2) Blood concentration and urinary excretion of the drug crossed over with cefotiam were bioassayed following one shot i.v. administration of 1g in 6 normal subjects.
Blood levels of T-1982 were 61μg/ml at 1 hour, 14.2μg/ml at 4 hour and 2.8μg/ml at 8 hour and 2-3 times higher than those of cefotiam.
Pharmacokineftic parameters worked out were as follows: serum half-lives 95 min. and 62 min., AUC 14.06 mg-min/ml and 6.40mg min/ml, respectively. The rate of urinary excretion (72.8%) was somewhat higher than that of cefotiam (65.5%).
Calculated renal clearance of the former was 52.3ml/min and smaller than that of the latter (102.6ml/min).
These values seem to indicate the lower metabolic rate of T-1982 than that of cefotiam.
Investigation of blood level and urinary excretion following i. v. or 1 hour drip infusion in 6 patients showed similar results to healthy subjects, although in patients with renal impairment, prolongation of half-lives and decrease of excretion rates were observed in proportion to the decrease of renal function.
3) Clinical effects on 24 cases of various infections including 10 cases of RTI, 11 cases of UTI and 2 cases of BTI and 1 case of meningitis were evaluated. Most patients were treated with daily 2 times i. v. drip infusion of the drug.
Clinical responses were effective in 18 cases, fair in 3 cases, poor in 1 case, and undetermined in 2 cases, with the efficacy rate of 81.8%.
All of the 19 cases, where significant bacteria were found, responded bacteriologically.
Two patients showed allergic side effects, and the fluctuations of laboratory values (the increase s of transaminases and the slight decreases of RBC and Hb content in each 2 cases) were observed.

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The clinical efficacy of T-1982, a new cephamycin antibiotic, was studied in patients with respiratory tract infections. Twenty patients (14 males and 6 females) comprising 14 with acute pneumonia and 6 with chronic or acute bronchial infections, were intravenously administered daily 2-4g for 3-15 days, the total amounts being 12-60g. The diseases were graded as mild in 3 cases, moderate in 16 cases and severe in 1 case, and underlying diseases were also recognized in 12 cases.
The clinical efficacy was 92.9%, 80% and 89.5% respectively for acute pneumonia, bronchial infections and both diagnosis. Pathogens in sputum disappeared in 70% of the patients. In laboratory findings, slight elevations of GOT and GPT in 3 cases and eosinophilia in 1 case were observed, but no case required discontinuation of the drug.

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To evaluate the clinical efficacy of T-1982, the treatment was made with the drug in 32 patients, including 9 with acute pneumonia, 3 with acute bronchitis, 1 with acute pneumonia with pyothorax, 1 with lung abscess, 4 with acute pyelonephritis, 2 with chronic pyelonephritis, 3 with acute cystitis, 7 with chronic cystitis and 2 with acute cholecystitis. Responses were excellent in 4 patients, good in 23 and poor in 5. Of the 38 patients, 5 patients showed the following abnormal laboratory findings after the treatment; temporal elevation of S-GOT, or S-GOT and S-GPT in each 1 case, temporal elevation of eosinophile in 2 cases and temporal leukopenia in 1 case.

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Antibacterial activity and clinical effectiveness of T-1982, a new cephamycin antibiotic, were investigated and the following results were obtained:
1) In vitro antibacterial activity
MICs of T-1982 against 77 strains of clinically isolated H. influenzae were examined. Forty-six strains (60%) were inhibited by 1.56μg/ml or less of T-1982. ABPC-resistant (β-lactamase positive) 18 strains of H. influenzae were sensitive to T-1982 (MICs ranged between 0.39 and 6.25μg/ml). This result showed the usefulness of T-1982 to ABPC-resistant strains of H. influenzae.
2) Clinical evaluation
T-1982 was administered intravenously at a daily dose of 2g to 5 cases of respiratory tract infection (2 cases of chronic bronchitis, 1 case of CPE with acute exacerbation, 2 cases of pneumonia). Clinical responses of T-1982 were excellent in 1 case, good in 2 cases and fair in 2 cases.
No adverse reaction was observed in any 5 cases.

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In vitro antimicrobial activity of T-1982, a new cephamycin, was examined by a broth dilution method with Dynatech MIC 2000 system. Also, therapeutic efficacy of T-1982 in the treatment of patients with respiratory and urinary tract infections was evaluated.
The minimum inhibitory concentrations (MICs) of T-1982 were compared with those of cefazolin (CEZ), cefotiam (CTM), cefoxitin (CFX) and cefmetazole (CMZ) against following 20 strains each of clinical isolates; Staphylococcus aureus, Escherichia coli, Kkbste.lla pneumoniae, Enterobacter cloacae, Serratia marcescens, Pseudomonas aeruginosa. It was revealed that T-1982 was more highly active against gramnegative rods, such as Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae and Serratia marcescens except Pseudomonas aeruginosa and more weakly active against Staphylococcus aureus than cefazolin, cefotiam, cefoxitin and cefmetazole. Especially, reductions in the MICs of T-1982 were marked for β-lactamase producing strains of Escherichia coli, Enterobacter cloacae and Serratia marcescens.
A daily dose of 2 grams of T-1982 was given by an intravenous drip infusion to a total of 4 patients with respiratory tract infections, such as 2 patients with acute pneumonia, 1 patient with infection associated with bronchiectasis and 1 patient with infection associated with lung cancer, and 1 gram of the drug to 1 patient with acute pyelonephritis. Clinical response to the treatment with T-1982 was excellent in 2 patients and good in 3 patients. Each 2 strains of Haemophilus influenzae and Escherichia coli were recovered from the specimen of these patients at the start of the treatment with T-1982. All of them were eradicated during the treatment with the drug. In 1 patient of these 5 patients, transient elevation of slight degree of serum transaminase was observed but returned to normal after cessation of the drug.
From the above results, it was concluded that T-1982 is one of the most effective and useful antibiotics against gram-negative bacterial infections in compromised hosts

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T-1982, a new cephamycin antibiotic, was studied for its clinical efficacy and safety in 7 patients with respiratory tract infections.
All the cases treated were with bacterial pneumonia, and the clinical responses were excellent in 4 cases, good in 2 cases and poor in 1 case to make an efficacy rate of 85.7%.
Bacteriologically, 3 pathogenic strains isolated were all eliminated.
In laboratory findings, a slight elevation in GOT and a moderate decrease in leukocyte count, both of which were not critical, were noted respectively in 1 case.

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Clinical application of T-1982 was attempted in 8 patients with urinary tract infection, 22 patients with respiratory tract infection and one patient with peritonitis. The drug was administered at a daily dose of 1.0-4.0g intravenously for 5 to 44 days. The good responses were demonstrated in all patients with urinary tract infection, 20 patients with respiratory tract infection and one patient with peritonitis.
No side effect was observed except for 2 patients, who experienced mild diarrhea. Elevation of eosinophil was observed in 2 patients and slight elevation of transaminase in 3 patients.

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A clinical administration of T-1982 was conducted with nine patients who were suffering from various infections. The results of the administration were as follows:
1) To one patient who had bacterial endocarditis which was caused by Klebsiella, originating from the urinary tract and associated with mitral insufficincy, a daily drip injection of two g of cefotiam was given for eight days. This injection did not eradicate the causative organism which was highly sensitive to cefotiam by sensitivity disc method. Excellent clinical and bacterial responses, however, were obtained by an intravenous drip injection of T-1982 (one g every eight hours).
2) In five cases (four patients with pneumonia and one with secondary respiratory tract infection complicated by interstitial pneumonitis), the therapeutic effects of T-1982 were all good.
3) The clinical effects were poor in one case with post-ERCP cholangitis complicated by cholangiocarcinoma.
4) In two patients with urinary tract infections, the therapeutic effects of T-1982 were good in one patient (infection caused by E. coli) and fair in one patient.
5) No side effects and abnormalities of laboratory data were found in any cases.

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The following results were obtained in the experimental and clinical studies on T-1982.
1. Antibacterial activity
The MICs of T-1982 against S. marcescens, E. coli, E. cloacae and C. freundii were measured, then it was revealed that the drug had much stronger antibacterial activity than CMZ and CEZ, and nearly equal to LMOX and CMX.
2. Clinical results
T-1982 was given to 19 patients, 8 with respiratory tract infections, 9 with urinary tract infections and others.
1) Efficacy rate was 86% in respiratory tract infections and 100% in urinary tract infections. The drug was effective in 1 case of adnexitis and furunculosis. The overall efficacy rate was 94 %.
2) As for bacteriological response, 6 strains of E. coli, each 1 strain of Proteus, S. marcescens and Enterococcus and 2 strains of Klbsiella were all eliminated. One strain of Klebsiella was replaced by P. maltophilia.
3) Skin rash was seen in 1 case. No other side effects were noted.

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Antibacterial activity of T-1982 was superior against E. coli, K. pneumoniae, E. cloacae, C. freundii and S. marcescens to that of cefoxitin, cefmetazole and cefotetan and equal or inferior by about one step against P. mirabilis and indole positive Proteus sp. to that of cefotetan.
Serum levels of T-1982 at 5 minutes after intravenous injection of 1000 mg in healthy adults were 166.5±16.4 μg/ml and half lives were 0.132±0.015 hr (α-phase) and 1.344+0.074 hr (β-phase). The levels were higher and more sustained than those of cefmetazole.
Urinary recovery rate of T-1982 was 72.1±6.5%(8 hr) and lower than that of cefmetazole (82.1±3.5%).
When probenecid was administered at a dose of 1000 mg 30 minutes before intravenous injection of T-1982, serum half lives were significantly more prolonged than those of T-1982 alone, suggesting that tubular secretion is involved in the renal excretion mechanism of T-1982.
Eight patients with urinary tract infections were treated with T-1982. Therapeutic results in 6 cases excluding 2 inevaluable cases were excellent in 1 case, good in 3 cases and poor in 2 cases. Causative organisms were eradicated, in 2 cases of 5 evaluable cases.
As for side effects and abnormal laboratory findings, nausea and vomiting, flush and fever and slightly elevated S-GOT and S-GPT were noted respectively in 1 case. These findings improved shortly after cessation of the drug.

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Antibacterial activity of T-1982, a new antibiotic of cephamycin group developed in Japan, was tested against clinical isolates of a variety of gram-negative bacilli comparing with cefoperazone, cefmetazole and cefazolin. T-1982 showed the best activity among them except for glucose nonfermenters.
The serum level and urinary recovery were measured in cross-over method using 0.5 g of T-1982 and 1 g of CMZ by one-shot intravenous injection to 4 healthy volunteers. T-1982 showd longer sustained serum level, while CMZ recovered more into urine.
Clinically, 5 cases were treated with T-1982 mainly in drip infusion. Good result was obtained in 4 cases, but 1 case was poor perhaps due to severe underlying fatal disease. No adverse reaction was observed.

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T-1982, a newly developed cephamycin antibiotic, was studied for its clinical efficacy
T-1982 was given to 8 patients with urinary tract infection comprising 2 with chronic pyelonephritis, 4 with chronic cystitis and 2 with acute pyelonephritis.
Therapeutic response was good in 5, fair in 1 and poor in 1. One case was not evaluated because of side effects.
As pathogens, E. coli, Klebsiella, Serratia, Enterobacter, P. mirabilis and P. aeruginosa were detected. All the strains except P. aeruginosa were eradicated. S. faecalis appeared in 4 cases after therapy.
As for side effects, eruption and fever were observed in 1 case. No abnormal laboratory findings were noted.

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T-1982, a new cephamycin antibiotic stable against β-lactamase, was administered by intravenous drip infusion (one case by one shot intravenous injection) to 10 patients with respiratory tract infections.
The clinical effects were excellent in 3 cases, good in 4 cases and fair in 1 case. Two cases were excluded by reason of unsuitability for T-1982 therapy.
As side effect, slight elevation of transaminase (s-GOT, 19-49) caused by T-1982 administration was observed in 1 case but any other abnormality was not observed in hematological or urine examination.
It is considered that T-1982 is a useful antibiotic for respiratory tract infections.

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T-1982, a new cephamycin antibiotic developed in our country, exhibits a broad spectrum antibacterial activity. The antibiotic is active particularly against gram-negative rod bacteria, but scarcely active against P. aeruginosa.
When intravenously given at a dose of 500 mg or 1000 mg, the serum concentrations of T-1982 were respectively 51.8 μg/ml and 92.5 μg/ml at 30 minutes, and respectively 1.2 μg/ml and 3.2 μg/ml even at 8 hours. The intravenous drip infusion of the same doses attained the highest levels of 53.3 μg/ml and 105 μg/ml respectively at the end of infusion (1 hour after start), and even at 8 hours the levels were 2.0 μg/ml and 4.0 μg/ml, respectively. Thus, the serum levels were well sustained by both routes of administration, the half lives being around 90 minutes for intravenous injection and 100 minutes for intravenous drip infusion.
About 80% of the doses by both routes were excreted into urine within 12 hours after administration.
A total of 11 subjects comprising 6 with pneumonia, 2 with pulmonary abscess, 1 with FUO and 2 with pyelonephritis were treated with T-1982. Patients except 2 cases were given daily 2000 mg of T-1982 for 4-22 days.
The therapeutic results were more than good in 5 cases, fair in 2 cases and poor in 1 case out of 8 RTI cases, excellent in 1 case of FUO, and good and fair respectively in 1 case of pyelonephritis.
Clinical side effects were not observed in any cases. In laboratory findings, slight elevations of GOT and GPT were noted in 1 case.
From the above results, it is concluded that T-1982 is a useful antibiotic in the treatment of RTI and UTI.

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T-1982, a new cephamycin antibiotic developed in our country, exhibits a broad spectrum antibacterial activity. The antibiotic is active particularly against gram-negative rod bacteria, but scarcely active against P. aeruginosa.
When intravenously given at a dose of 500 mg or 1000 mg, the serum concentrations of T-1982 were respectively 51.8 μg/ml and 92.5 /kg/ml at 30 minutes, and respectively 1.2 μg/ml and 3.2 μg/ml even at 8 hours. The intravenous drip infusion of the same doses attained the highest levels of 53.3 μg/ml and 105 μg/ml respectively at the end of infusion (1 hour after start), and even at 8 hours the levels were 2.0 μg/ml and 4.0 μg/ml, respectively. Thus, the serum levels were well sustained by both routes of administration, the half lives being around 90 minutes for intravenous injection and 100 minutes for intravenous drip infusion.
About 80% of the doses by both routes were excreted into urine within 12 hours after administration.
A total of 11 subjects comprising 6 with pneumonia, 2 with pulmonary abscess, 1 with FUO and 2 with pyelonephritis were treated with T-1982. Patients except 2 cases were given daily 2000 mg of T-1982 for 4-22 days.
The therapeutic results were more than good in 5 cases, fair in 2 cases and poor in 1 case out of 8 RTI cases, excellent in 1 case of FUO, and good and fair respectively in 1 case of pyelonephritis.
Clinical side effects were not observed in any cases. In laboratory findings, slight elevations of GOT and GPT were noted in 1 case.
From the above results, it is concluded that T-1982 is a useful antibiotic in the treatment of RTI and UTI.

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T-1982, a new cephamycin antibiotic, was clinically investigated for its efficacy in 4 RTI, 2 BTI and 2 UTI patients. The patients were administered daily 2 g of T-1982 b. i.d. by intravenous drip infusion.
The therapeutic responses were excellent in 1 case, good in 2 cases and unknown in 1 case of the RTI group, excellent and unknown respectively in 1 case of the BTI group and good in both cases of the UTI group. Slight elevations of GOT and GPT were observed in 1 case but returned to normal after the therapy.

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A new cephamycin antibiotic (T-1982) was administered by intravenous drip infusion or intramuscularly for 6-28 days at daily doses of 1-4 g to 9 patients, including 3 cases of pneumonia, 1 of bronchitis and 5 of acute pyelonephritis, to evaluate the clinical efficacy.
Response was good in 8 cases and fair in 1 case of pneumonia due to Staphylococcus aureus.
No side effects such as hepatic, renal and hematologic impairments were observed during this trial

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Blood levels and urinary excretion were determined in 3 aged patients (mean age; 77 years old, mean serum creatinine; 0.7mg/dl, mean creatinine clearance; 40.8ml/min.) after bolus intravenous infusion of 1g of T-1982. The mean concentration at 5 minutes after infusion was 224.8μg/ml and declined to 4.8μg/ml at 12 hours after infusion. The serum half life of β-phase was estimated to be 2.5 hours. Urinary recovery rate during first 6 hours was 50.8%.
Five patients with pneumonia, 2 patients with chronic cystitis and 1 patient with liver abscess were evaluated for daily 2 or 3 doses of 0.25 to 1.0g of T-1982. Six patients responded satisfactorily.
One patient with liver abscess responded partially. One patient was excluded from evaluation, because miliary tuberculosis was found later. On the course of this therapy, skin eruption and drug fever were seen in 1 patient.

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Clinical effectiveness and adverse effects of T-1982, a new cephamycin antibiotic, were studied in 11 patients with the respiratory tract infections receiving 0.5 to 2 g b.i.d. by drip infusion. Among them, 8 cases were lower respiratory tract infection, 2 cases were pneumonia and 1 case was lung abscess.
The treatment was excellent in 5, good in 4, fair in 1 and poor in 1, thus producing moderate to marked clinical improvement in 82 % of the cases studied.
The T-1982 therapy was effective in 5 cases of respiratory tract infection with H. influenzae.
None developed any serious adverse effects.
The results indicate usefulness of T-1982 in the treatment of respiratory tract infection.

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A new cephamycin antibiotic, T-1982, was given to total 8 patients with infectious diseases (2 cases with bronchopneumonia associated with lung cancer, 3 cases with bacterial pneumonia, 2 cases with acute pyelonephritis and 1 case with chronic pyelonephritis), and the following results were obtained.
The drug was intravenously (in one shot or drip infusion) administered in a dose of 1.0 g b. i.d. for 3 to 14.5 days.
1) Clinical effectiveness: Fair responses were obtained in 2 cases with acute bronchopneumonia associated with lung cancer. Good responses were obtained in 2 cases out of 3 cases of pneumonia. Excellent and good responses were obtained in 2 cases with acute pyelonephritis, and good response was obtained in 1 case with chronic pyelonephritis. Overall efficacy rate in entire 8 cases was 62.5 %.
2) Bacterial effectiveness: S. epidermidis was isolated from sputa in 1 case with acute bronchopneumonia associated with lung cancer. K. pneumoniae was isolated from urine in 2 cases with acute pyelonephritis, and E. colt and Enterobacter were isolated from urine in 1 case of chronic pyelonephritis. All these strains were eliminated by this drug.
3) Side effects: No adverse reaction due to this drug was observed. All the patients were monitored by hematological and biochemical examinations before and after the administration, and no abnormal fi ndings on urine, peripheral blood, liver function or renal function due to this drug were observed.

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T-1982 was clinically evaluated. The results obtained were summarized as follows.
1) Antibacterial activity of T-1982 against clinical isolates of E. coli, K. pneumoniae and S. marcescens was superior to that of CEZ, CFX and CTM.
2) Susceptibility of glucose-non-fermentative bacteria to T-1982 was poor.
3) Treatment with T-1982 was effective in 6 of 9 patients treated.
4) Transient elevations of GOT and AlP were noted in 1 case. No other abnormal laboratory fi ndings nor side effects due to the drug were observed.
5) T-1982 was effective in 5 of 7 cases resistant to other drugs.
6) T-1982 appears to be a useful antibiotic, if an adequate selection of patients is considered.

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