Effect of ursodeoxycholate on the biliary excretion of cefotiam and sulbenicillin in patients with percutaneous transhepatic biliary drainage.
(9/31)
The effects of ursodeoxycholate administration on the biliary excretion of the antibiotics cefotiam and sulbenicillin were studied in five patients with stable hepatic function receiving percutaneous transhepatic biliary drainage for obstructive jaundice. Cefotiam (I g) and sulbenicillin (2 g) were administered intravenously before and after ursodeoxycholate administration, and the maximum concentrations of the antibiotics in the bile and total amounts excreted in the bile during the 4 h after administration were determined. After ursodeoxycholate administration, both the maximum concentration of cefotiam in the bile and the amount excreted increased significantly. Ursodeoxycholate also increased the peak concentration and total excretion of sulbenicillin. For both cefotiam and sulbenicillin, the amount of antibiotic excreted in the bile during the 4 h after administration showed a significant correlation with the amount of bile acids excreted in the bile. This strongly suggests a common mechanism for the biliary excretion of these antibiotics and bile acids. Ursodeoxycholate administration is a benign way to increase both the concentration and the total amount of antibiotic excreted in the bile. Therefore, it may be useful in the treatment of serious biliary tract infections, especially in patients receiving biliary drainage. (+info)
Comparative efficacy of cefotiam, cefmenoxime, and ceftriaxone in experimental endocarditis and correlation with pharmacokinetics and in vitro efficacy.
(10/31)
To determine the influence of in vitro activity, pharmacokinetic properties, and therapeutic regimen on the antibacterial effect in vivo, we compared three cephalosporins, cefotiam, cefmenoxime, and ceftriaxone, in a rabbit model of experimental Escherichia coli endocarditis after 4 days of treatment. The MBCs of cefotiam, cefmenoxime, and ceftriaxone for the E. coli strain were 0.5, 0.125, and 0.06 microgram/ml, respectively. Killing curves at 10 times the MBC were similar for the three cephalosporins. In serum, the elimination half-life of ceftriaxone was twice as much as the elimination half-life of cefotiam or cefmenoxime (2.8 +/- 0.45 versus 1.4 +/- 0.25 or 1.3 +/- 0.4 h, respectively). Ceftriaxone was much more effective than cefotiam. The bacterial titer in the vegetations (log10 CFU per gram of vegetation) was 7.56 +/- 1 with cefotiam and 2.41 +/- 2.6 with ceftriaxone, as their concentrations were 18 and 466 times higher, respectively, than their MBCs. Although ceftriaxone and cefmenoxime exhibited a similar rate of killing and percentage of protein binding, ceftriaxone was more effective than cefmenoxime at the same regimen of 15 mg/kg twice a day (3.08 +/- 1.1 versus 4.82 +/- 3.2 log10 CFU/g of vegetation). When antibiotic was given as a single daily injection of 30 mg/kg, the antibacterial effect persisted for ceftriaxone, but not for cefmenoxime. The longer elimination half-life and the higher local concentration/MBC ratio of ceftriaxone explained these results. The bacterial titer measured 24 h after the fourth injection of 30 mg of ceftriaxone per kg confirmed that this regimen prevented regrowth of bacteria. These results suggest that the local antibiotic level/MBC ratio roughly correlated with the antibacterial effect and could represent an adequate basis to explain the differences observed between the drugs in vivo. They also demonstrate that, provided that the dose is sufficient, a long-acting broad-spectrum cephalosporin may be effective in severe gram-negative infections, even when given at relatively long dosing intervals, in contrast with a rapidly cleared drug with the same intrinsic activity. (+info)
Preparation of 1-acyloxyethyl esters of 7-[2-(2-aminothiazol-4-yl)acetamido]-3-[[[1-(2-dimethylaminoe thy l)-1H-tetrazol-5-yl]thio]-methyl]ceph-3-em-4-carboxylic acid (cefotiam) and their oral absorption in mice.
(11/31)
In a separate study on the orally active acyloxymethyl esters (1) of 7-[2-(2-aminothiazol-4-yl)acetamido]-3-[[[1-(2-dimethylaminoethyl) - 1H-tetrazol-5-yl]thio]methyl]ceph-3-em-4-carboxylic acid (cefotiam, CTM), we have shown, by quantitative structure-oral bioavailability (BA) relation analysis, that the R2 group in the acyl group R2CO must have both an adequate lipophilicity (Hansch's lipophilic parameter, pi) and steric hindrance (Taft's Es value). However, to satisfy these requirements, a complex alkyl group R2 must be employed, the ester of which is difficult to synthesize and has unique metabolic fate. In this study, we selected and prepared the 1-acyloxyethyl esters (2) of CTM instead of 1 to avoid R2 groups that are too complicated. We found that the esters (2) gave improved oral BAs over 1: the 1-(3-methyl-valeryloxy)ethyl ester (2h) showed the highest peak plasma CTM level (Cmax) comparable to that obtained after subcutaneous injection of CTM. The 1-(cyclohexylacetoxy)ethyl ester (2t), the 1-(2-ethylbutyryloxy)ethyl ester (2j), and 2h showed BAs near 100%. For these esters (2), good correlations were also observed among the pi, the Es values of R2, and the log Cmax and log BA in the analysis of the quantitative structure-oral bioavailability relation: an ester having an alkyl group as R2 with a pi value of 3.07 or 3.08 and a Es value of -1.04 or -1.29 gave the highest Cmax or BA, respectively. As expected, the optimal pi values are almost the same as those obtained with 1 but the optimal Es values are larger (Es = -2.07). Thus, it has been confirmed by preparing 1-acyloxyethyl esters (2) of CTM that the oral bioavailability of CTM can further be improved without preparing acyloxymethyl esters (1) with a complicated acyl group. (+info)
Orally active 1-(cyclohexyloxycarbonyloxy)alkyl ester prodrugs of cefotiam.
(12/31)
Orally active 1-(alkyl substituted cyclohexyloxycarbonyloxy)alkyl ester prodrugs (9b-h) of 7 beta-[2-(2-aminothiazol-4-yl)acetamido]-3- [[[1-(2-dimethylaminoethyl)-1H-tetrazol-5-yl]thio]-methyl]ceph+ ++-3- em-4-carboxylic acid (cefotiam, CTM) have been studied as well as the thia (9i) and aza (9j) analogs. These represent derivatives of the 1-(cyclohexylacetoxy)ethyl ester (2) of CTM. The syntheses and oral bioavailability (BA) in mice are described. Among them, the 1-(cyclohexyloxycarbonyloxy)butyl ester (9h) gave the highest BA, 93.5%; the esters having a cyclohexyloxy group in the ester moiety gave BAs of more than 75%, although the BA of the 1-(ethoxycarbonyloxy)ethyl ester (9a) was only 23.9%. The thia analog showed a moderate BA, 46%, but the aza analog, 9j, did not show a BA of CTM. These results indicate that the 1-(substituted cyclohexyloxycarbonyloxy)alkyl group was the suitable promoiety to improve the oral BA of CTM. Chiral 1-(alkoxycarbonyloxy)alkyl groups used as the ester moiety, gave an almost 1: 1 mixture of diastereoisomeric esters. These were tested as such. However, an experiment in which the separated isomers of the 1-(cyclohexyloxycarbonyloxy)ethyl ester (9d) were administered orally confirmed that both diastereoisomers gave identical BAs. (+info)
Pharmacokinetics of cefotiam in humans.
(13/31)
After intravenous bolus injections of 0.5, 1, and 2 g of cefotiam to three healthy volunteers, the mean (+/- standard deviation) total plasma clearances measured for each dose were, respectively, 26.8 +/- 2.7, 22.8 +/- 0.8, and 17.8 +/- 0.9 liters/h; the terminal elimination half-lives were 54.0 +/- 0.1, 68 +/- 15, and 98 +/- 36 min; and the renal clearances were 16.0 +/- 2.9, 13.3 +/- 1.4, and 11.3 +/- 2.6 liters/h. The 24-h urinary recovery was independent of the dose and averaged 53% of the dose. After intramuscular administration of 1 g of cefotiam to three healthy volunteers, a mean (+/- standard deviation) peak concentration of 16.6 +/- 5.1 micrograms/ml was reached at 0.75 to 1 h post dosing. The concurrent intramuscular administration of lidocaine and cefotiam did not modify the kinetics of cefotiam. During a constant-rate infusion, the steady-state plasma clearance decreased slightly when the infusion rate was increased. There was no trend towards accumulation of cefotiam in plasma during chronic treatment with 1 g intravenously every 12 h for 10 days. (+info)
Cefotiam susceptibility testing criteria.
(14/31)
Interpretive zone size breakpoints for diffusion tests with 30-micrograms cefotiam disks are diameters of greater than or equal to 18 mm for susceptible and less than or equal to 14 mm for resistant strains. The standard control strains Escherichia coli ATCC 25922 and Staphylococcus aureus ATCC 25923 should both give zones 27 to 33 mm in diameter. Tests with 579 clinical isolates yielded an unacceptably high rate of very major discrepancies between disk tests and microdilution tests; such discrepancies were especially common among Enterobacter spp. Additional studies support the concept that standard microdilution tests and standard disk diffusion tests may fail to detect a potential for resistance among some microorganisms. (+info)
Cefotiam therapy of lower respiratory tract infections.
(15/31)
Cefotiam, a new cephalosporin, was evaluated in the treatment of lower respiratory tract infections in 29 patients. The bacteria isolated from the sputum of these patients included Streptococcus pneumoniae (31%), Klebsiella pneumoniae (31%), and Haemophilus influenzae (28%). Satisfactory response was observed in 90% of the patients. There were three treatment failures, two superinfections, and four colonizations with gram-negative organisms resistant to the drug. Superficial phlebitis was noted in two patients. The results of this study suggest that cefotiam is an effective and well-tolerated antibiotic for the treatment of lower respiratory tract infections due to susceptible organisms. (+info)
Pharmacokinetics of cefotiam and cefsulodin after simultaneous administration to patients with impaired renal function.
(16/31)
The possible influence of the concomitant administration of cefotiam and cefsulodin on their respective pharmacokinetics was studied in 15 patients with renal insufficiency and 10 anuric patients. Linear relations were found between the clearance of creatinine and the total clearance, as well as the renal clearance, of each drug. These relations for each cephalosporin were not significantly different from previous results obtained after separate administration. In hemodialyzed patients, the two cephalosporins were readily eliminated from the blood after simultaneous administration: ca. 35% of the dose of cefotiam and 30% of the dose of cefsulodin was recovered in the dialysate over 5 h. These results suggest that the pharmacokinetics of the two drugs are not modified by their simultaneous administration and that the dosing schedule previously proposed for administration of the two cephalosporins alone in the presence of renal insufficiency can be applied without modification when they are given together. Patients on hemodialysis should receive a loading dose after each dialysis period, and then reduced doses according to recommendations for anuric patients. (+info)