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The renal excretory mechanism of cefmenoxime in rabbits was compared with that of 6 other cephalosporins (cefotaxime, deacetylcefotaxime, cefotiam, cefazolin, cephaloridine, and cefsulodin). The clearance ratios (Cf-Drug/CInulin=CRf) of cefmenoxime (337) and cefazolin (73) were considerably higher than those of the 5 other cephalosporins (0.9-20). When p-amino-hippurate (PAH) was administered concurrently with each of the cephalosporins, the CRf values of the cephalosporins except for cefsulodin were significantly decreased. These findings indicate that cefmenoxime and the 5 other cephalosporins except cefsulodin are actively incorporated in the proximal tubular cells and secreted into the tubular lumen. In the case of cefotiam and cefsulodin, glomerular filtration tended to exceed urinary excretion with highest dose of PAH (40 mg/kg/minute), suggesting the possibility of tubular reabsorption of these drugs. On the other hand, glomerular filtration of cefmenoxime and the 4 other cephalosporins did not exceed urinary excretion. The drug concentration ratio of the cortex to medulla indicated that the tubular cell level of cefmenoxime was lower than, higher than, and similar to those of cephaloridine, cefotaxime, and the remaining cephalosporins, respectively. These results demonstrate that the renal excretory mechanisms of cefmenoxime is similar to that of cefazolin but not to that of the remaining cephalosporins.

The therapeutic effects of seven antipseudomonal beta-lactam antibiotics on experimental urinary tract infection caused by Pseudomonas aeruginosa P 9 in mice were compared, and the results were analyzed in relation to their in vitro antibacterial activities and pharmacokinetic properties. The CD50 values were (mg/kg): cefsulodin, 6.19; cefoperazone, 162; sulbenicillin, 167; ticarcillin, 184; azlocillin, 121; mezlocillin, 390; and piperacillin, 227. Cefsulodin was more active than the other antibiotics not only in therapeutic effects but also in in vitro antibacterial effects evaluated according to growth inhibitory, bactericidal, and bacteriolytic activities. It also penetrated and persisted well in the kidney of mice. The therapeutic effects of cefoperazone, azlocillin, and piperacillin were much less than expected from their in vitro antibacterial activities; the CD50 values were more than 18-fold as large as that of cefsulodin, whereas the differences of their MIC values were less than four-fold.

Distributions of cefsulodin (CFS) and cefotiam (CTM), new parenteral cephalosporins, to human aqueous humor and cornea were studied in comparison with those of sulbenicillin (SBPC) and cefazolin (CEZ), and pharmacokinetic analysis was made by theory of compartment model, to obtain the following results. 1. Maximum aqueous humor levels of CFS and CTM were noticed at 2.5 hours after the start of 1 g CFS or CTM administration by 30 minute intravenous drip infusion, with the levels of 3.6 micrograms/ml and 4.2 micrograms/ml respectively. On the other hand, in case of 5 g SBPC or 2 g CEZ administration maximum aqueous humor levels were 12.5 micrograms/ml and 5.2 micrograms/ml respectively. 2. The ratios of maximum aqueous humor level to plasma level of the same time in CFS, CTM, SBPC and CEZ were 15.0, 16.8, 6.4% and 5.5%. Distribution of CFS or CTM was 2 to 3 times better than that of SBPC or CEZ. 3. From the result of pharmacokinetic analysis, ratios of aqueous humor to plasma levels in area under curves (AUC) of CFS, CTM, SBPC and CEZ were 25.6, 29.9, 16.4% and 7.9% respectively. Maximum aqueous humor levels of CFS, CTM, SBPC and CEZ were 2.9, 3.6, 11.4 micrograms/ml and 4.3 micrograms/ml and biological half life of gamma-phase were 2.57, 2.31, 2.77 hours and 2.24 hours respectively. 4. Cornea levels of CFS or CTM at one hour after the start of 1 g CFS or CTM administration by 30 minutes intravenous drip infusion were 2.9 micrograms/g and 5.2 micrograms/g, and their ratios to plasma level were 7.5% or 14.3% respectively. In case of 5 g SBPC or 2 g CEZ administration, the cornea levels were 26.7 micrograms/g and 5.0 micrograms/g, and the ratios were 9.4% and 3.4% respectively. 5. From the above, the distribution of CFS or CTM to human aqueous humor and cornea is better than that of SBPC or CEZ, and it is considered that clinical usefulness of both CFS and CTM by parenteral administration is expected in intraocular infections.

The renal excretory mechanism of cefmenoxime was compared with those of 6 other cephalosporins (cefotaxime, deacetylcefotaxime, cefotiam, cefazolin, cephaloridine and cefsulodin) in rats and rabbits. In rats, renal clearance (Cf-Drug: corrected for serum protein binding) of cefmenoxime (4.06 ml/minute) was lower than that of cefazolin, similar to that of cefotiam, and higher than those of cefotaxime, deacetylcefotaxime, cephaloridine, and cefsulodin. In rabbits, the value for cefmenoxime (2,519 ml/minute) was markedly higher than those for the other drugs. If the clearance ratio (Cf-Drug/CInulin = CRf) is more than unity, tubular secretion of a drug is indicated. In rats, the tubular secretion of cefmenoxime equalled the glomerular filtration (CRf = 2.17). The tubular secretion of cefmenoxime was lower than that of cefazolin but similar to that of cefotiam. None of the other cephalosporins seemed to be secreted significantly. In rabbits, a large amount of cefmenoxime was secreted (CRf = 208). The tubular secretion was larger than those of the other cephalosporins. All the drugs except cefsulodin showed significant tubular secretion. A species difference was observed in the CRf of the cephalosporins: the values were generally higher in rabbits than in rats.

The levels of cefmenoxime (SCE-1365) [7 beta-[2-(2-aminothiazol-4-yl)-[Z]-2-methoxyiminoacetamido]-3-[(1-methyl-1H-tetr azol-5-yl)thiomethyl]ceph-3-em-4-carboxylic acid] and cefotaxime [7 beta-[2-(2-aminothiazol-4-yl)-[Z]-2-methoxyiminoacetamido]-3-acetoxymethyl-ceph -3-em-4-carboxylic acid] in plasma and tissues, and the excretion in urine and bile of experimental animals were compared. A single dose of 20 mg/kg of cephalosporins was administered subcutaneously to mice and intramuscularly to rats, rabbits and dogs. The cefmenoxime and cefotaxime levels in plasma and tissues reached a peak in 15 approximately 30 minutes after administration. The cefmenoxime levels in plasma were slightly higher than that of cefmenoxime in rats and slightly lower in mice, rabbits and dogs. The tissue levels of cefmenoxime, however, were much higher than those of cefotaxime. In mice and rats, cefmenoxime was distributed in high concentration to various tissues in the descending order of the kidney, plasma, liver, lung, spleen and brain; in rabbits, kidney, plasma, lung, liver, spleen and brain; and in dogs, kidney, liver, plasma, lung, spleen and brain. The plasma and tissue levels of cefmenoxime persisted much longer than those of cefotaxime. Both cephalosporins were excreted principally in the urine. A high biliary excretion of cefmenoxime was observed in rats and dogs. In the specimens from animals given cefotaxime, deacetylcefotaxime was found in various amounts.

A single dose of 20 mg/kg of SCE-963 [7beta-]2-(aminothiazol-4-yl)acetamido]-3-[[[1-(2-dimethylaminoethyl)-1H-tetrazol-5-yl]thio]methyl]ceph-3-em-4-carboxylic acid] was administered subcutaneously to mice, intramuscularly to rats, rabbits and dogs. Plasma and tissue levels of SCE-963 reached a peak in 15 approximately 30 minutes after administration. In mice, rats and dogs, SCE-963 was distributed at high concentration in the descending order in the kidney, liver, plasma, lung and spleen, and in rabbits, in the kidney, plasma, lung, liver and spleen. The SCE-963 levels in the liver of mice, rats and dogs were higher than those of cefazolin, cephaloridine and cephalothin. The plasma and tissue levels of SCE-963 in mice and rats diminished rapidly, but those in rabbits and dogs declined gradually. SCE-963 was mainly excreted in the urine. The rate of excretion of SCE-963 in the bile was two to three times higher than that of cefazolin.

Cefotiam dihydrochloride (CTM) in a dose of 2 g was given by intravenous bolus injection to 15 patients operated upon for acute or subacute abdominal organs. They were included to 5 cases of acute localized peritonitis due to perforative appendicitis, 3 of diffuse peritonitis due to perforative duodenal ulcer, 1 of diffuse peritonitis with intestinal obstruction, 1 of perforative sigmoid colon cancer, 2 of gastric cancer or polyp with cholelithiasis, and 3 of cholangitis with cholecyst-choledocholithiasis. The materials of exudate from drain were taken at intervals by sterilized paper disc and determined by paper disc bioassay method with Proteus rettgeri ATCC 9250 or Proteus mirabilis ATCC 21100 as the test organisms to CTM concentrations. CTM concentrations in purulent exudate from drain of patients with acute peritonitis, they were increased quickly after intravenous bolus injection, and reached higher levels at early time after injection in cases 2 or 3 days after operation. CTM concentration in purulent exudate from drain was tended to increase in proportion to the severity of the inflammation. The CTM levels in infected exudate were higher than the MICs against clinically isolated organisms for a long time after administration. Therefore, CTM was very useful drug when used for chemotherapy of postoperative peritonitis.

Concentrations of cefotiam (CTM) in the exudate after abdominal operation were studied. The exudates were collected by 6 mm paper discs and the antibiotic concentrations were determined by the paper disc method using Proteus rettgeri ATCC 9250 as test organism. Comparison between agar well and paper disc assay for CTM in ascites specimens showed good correlation. Two grams of CTM was intravenously given to the patients after abdominal operations. The concentration of CTM in the exudate for 6 hours after injection was 0.4--14.2 micrograms/ml and this value exceeded the antibacterial level of CTM. It is, therefore, concluded that CTM will be effective for the postoperative prophylaxis.

Cefotiam (CTM) in a dose of 2 g was given by intravenous bolus injection to 16 patients with breast cancer operated upon radical mastectomy with suction drainage. The materials of exudate from drain were taken at intervals by sterilized paper disc and determined by the paper disc method with Proteus mirabilis ATCC 21100 as the test organism to CTM concentrations. CTM concentrations in exudate from suction drain of patients increased quickly after intravenous injection, and reached to peak early time on 2 to 3 days after operation. While on 6 days after operation, the CTM concentrations were comparatively lower and reached to peak at 2 approximately 3 hours after injection. The CTM concentrations in exudate exceed the antibacterial levels of CTM and are thought to be sufficient to produce prophylactic effects in the operation.

A single dose of 20 mg/kg of cefsulodin [3-(4-carbamoyl-1-pyridiniomethyl)-7 beta-(D-alpha-sulfophenylacetamido)-ceph-3-em-4-carboxylate monosodium salt] was administered subcutaneously to mice, and intramuscularly to rats and dogs. The plasma and tissue levels reached the peak 15 approximately 30 minutes after administration. In mice and rats, no plasma levels were measurable 2 and 4 hours after administration. In dogs, the plasma levels were measurable 6 hours after administration. The level in the kidney of mice was slightly lower than the plasma level, while in rats and dogs, the level in the kidney was higher than the plasma level. The cefsulodin levels in the lung of rats and dogs were relatively high, and the level in mice was relatively low. The hepatic levels were very low in all test animal species. Cefsulodin was mainly excreted into the urine, and the excretion of cefsulodin into the bile was very slight.

Synthesis and in vitro activity of a number of cephalosporins having alpha-sulfoacyl- or other acyl groups, e.g., alpha-carboxyacyl- and alpha-sulfoaminoacyl- at the 7-position and bearing a variety of heterocyclic thioether or pyridinium moieties at the 3-position are described.

1. The metabolic fate of 14C-cephacetrile was studied in rats and rabbits. The plasma level of intravenously injected cephacetrile decreased with half-lives of 17 and 22 minutes in rats and rabbits respectively, this decline being associated with a rapid appearance of the active metabolite, desacetylcephacetrile. Intramuscularly injected cephacetrile was rapidly absorbed by rats with a maximum plasma level at 20 minutes and a half-life of 16 minutes. Cephacetrile and desacetylcephacetrile did not enter erythrocytes. Cephacetrile was weakly bound to the plasma protein in the rat, rabbit and man. 2. Both in rats and rabbits, almost all of the injected radioactivity was excreted in the urine within 72 hours as the intact antibiotic and desacetylcephacetrile, only small amounts appearing in feces via bile. Neither the gamma-lactone of desacetyl-7-cyanacetamidocephalosporanic acid nor the violet-reddish pigment (CGP-695) produced from cephacetrile were detectable in the plasma or urine of the animals. 3. In rats given the labeled antibiotic intravenously, the radioactivity was widely distributed with concentrations being high in the kidney, plasma and liver, and lowest in the brain. The radioactivity crossed the rat placenta and appeared in the fetus. Radioactivity in these tissues disappeared as the plasma level declined. 4. During daily intramuscular injection of 14C-cephacetrile to rat, no significant changes were observed in the peak level of the plasma radioactivity or in the half-lives. In addition, dosing of the labeled antibiotic for 7 days caused no increase in tissue levels of radioactivity.