The cephalosporin antibiotics in pediatric therapy.

The cephalosporins have been available for clinical use for nearly 20 years and a large number is presently marketed, including drugs with a wide range of different pharmacokinetic and microbiologic properties. While some of these agents have certain specific uses in which they excel, the cephalosporins have not replaced older antibiotics but do provide the physician with a broader range of choices for the treatment of many infections, allowing greater individualization of therapy.

Permeability of Pseudomonas aeruginosa outer membrane to hydrophilic solutes.

Pseudomonas aeruginosa is usually resistant to a wide variety of antibacterial agents, and it has been inferred, on the basis of indirect evidence, that this was due to the low permeability of its outer membrane. We determined the permeability of P. aeruginosa outer membrane directly, by measuring the rates of hydrolysis of cephacetrile, cephaloridine, and various phosphate esters by hydrolytic enzymes located in the periplasm. The permeability to these compounds was about 100-fold lower than in the outer membrane of Escherichia coli K-12. Also, we found that the apparent Km values for active transport of various carbon and energy source compounds were typically higher than 20 microM in P. aeruginosa, in contrast to E. coli in which the values are usually lower than 5 microM. These results also are consistent with the notion that the P. aeruginosa outer membrane indeed has a low permeability to most hydrophilic compounds and that this membrane acts as a rate limiting step in active transport processes with high Vmax values.

In vitro evaluation of pyridine-2-azo-p-dimethylaniline cephalosporin, a new diagnostic chromogenic reagent, and comparison with nitrocefin, cephacetrile, and other beta-lactam compounds.

Pyridine-2-azo-p-dimethylanaline cephalosporin (PADAC), a chromogenic reagent which is purple and changes to yellow upon cleavage of its beta-lactam ring, was evaluated in comparison with other chromogenic cephalosporins. PADAC exhibited little antimicrobial activity against gram-negative bacteria, but did have good activity (minimum inhibitory concentration, 0.12 to 0.5 microgram/ml) against Staphylococcus aureus, a quality comparable to nitrocefin. Nitrocefin, however, demonstrated an unexpected and uniquely potent activity against Streptococcus faecalis (minimum inhibitory concentration, less than or equal to 0.06 to 0.12 microgram/ml) The relative hydrolysis rate of PADAC when subjected to six different beta-lactamases was substantially greater than that of cephacetrile, but less than that of nitrocefin. The relative hydrolysis rates of PADAC and nitrocefin were comparable with type IIIa beta lactamase and the derived from Bacillus cereus. The inhibition of beta-lactamase hydrolysis of the chromogenic cephalosporin substrates by six enzyme-stable inhibitors was generally greater with PADAC than with nitrocefin. Unlike nitrocefin, PADAC mixed with 50% human serum or various broth culture media showed no evidence of color change or degradation over several hours. The subsequent enzyme hydrolysis rates of such mixtures were the same as in phosphate buffer. Beta-lactamase-containing bacterial suspensions and clinical specimens containing such bacteria produced positive visual and spectrophotometric color changes when mixed with PADAC or nitrocefin. Although color changes occurred more slowly with PADAC than with nitrocefin, PADAC was not adversely influenced (non-enzyme-related color change) by the protein content of specimens. PADAC appears to be a promising alternative for beta-lactamase diagnostic testing in the clinical and research microbiology laboratory.

Pharmacokinetics of cephacetrile in patients undergoing haemodialysis.

The pharmacokinetics of cephacetrile were studied after its administration as a single i.v. bolus injection of 15 mg/kg body weight to 11 patients with terminal renal inpairment undergoing haemodialysis for 6 h. A two-compartment kinetic model was used to describe the biphasic decrease in plasma concentration. The quantities of antibiotic in the central and peripheral compartments, and the amounts eliminated, were calculated for different times. During haemodialysis sessions, the average pharmacokinetic parameters of cephacetrile determined at the dialyser input were: a = 5.03 h-1, beta = 0.458 h-1, K12 = 2.337 h-1, K21 = 1.996 h-1 K13 = 1.154 h-1, Vc = 5.5081, Vp = 6.4481, Vdss = 11.9561. As a function of the pharmacokinetic parameters of cephacetrile, a regimen of multiple doses was established for patients with terminal renal impairment, which will guarantee safe and effective concentrations of the antibiotic.

On the pharmacokinetics of cephalosporin antibiotics.

A review is given on the pharmacokinetic characteristics of some cephalosporin antibiotics. The use of the pharmacokinetic parameters serum concentration, serum protein binding, serum half life, and apparent volume of distribution as a basis for the selection of the clinically most effective cephalosporin derivative is discussed. It is concluded that these parameters must be used in conjunction with data on tissue distribution to specialized sites, and with information on antibacterial activity and toxicity.

[Fundamental studies on combination of antibiotics; especially on pharmacokinetics. I. Combination of gentamicin with sulbenicillin or cephacetrile (author's transl)].

1. When gentamicin (GM) and sulbenicillin (SBPC) or cephacetrile (CEC), in combination with pre- or post-treatment, were injected intravenously to the rat, their pharmacokinetics were investigated. 2. The antibiotics in the samples were separated by paper electrophoretic technique and their concentrations were determined by cup thin layer plate method using Bacillus subtilis as the test organism. 3. The biological half-life of SBPC in the serum was shortened in pretreatment with GM and prolonged in posttreatment with GM, while that of GM did not vary in pre- or post-treatment with SBPC. 4. The half-life of CEC was prolonged in treatment with GM, while that of GM did not vary. 5. These phenomena may be considered to be produced as the results of a concentration ratio of SBPC and GM or of CEC and GM, and protein binding of these antibiotics, as far as plasma initial levels, tissue distribution, urinary excretion and protein binding of these antibiotics are concerned.

Antibiotics and chemotherapeutics in renal lymph. An experimental study in dogs.

Renal lymph concentrations of ampicillin, carbenicillin, cephacetrile, cephaloridine, and nitrofurantoin were determined in a total of 28 dogs during constant infusion of the drugs together with [125I]iothalamate and [131I]o-iodohippurate for simultaneous determination of glomerular filtration rate and effective renal plasma flow. The lymph concentrations of the radiolabeled clearance substances, serving as a standard were compared to those of the antimicrobial agents. The lymph concentrations of the four antibiotics were all significantly lower than the respective simultaneous arterial plasma concentrations. The nitrofurantoin lymph concentrations were equal to the simultaneous plasma concentrations. It is concluded that the renal lymph concentrations of antibiotics and chemotherapeutics do not exceed the simultaneous plasma concentrations unless the urine flow is obstructed.

[The liver concentration of cephradin and cephacetril and their elimination in the bile]. / Die Lebergewebekonzentration von Cephradin und Cephacetril sowie deren Gallenausscheidung

Liver biopsies and serum samples were collected after intravenous application of 2 g cephradin (n = 13) or 2 g cephacetril (n = 11) during surgery. There was no difference in the serum levels of cephradin and cephacetril. 30 min. after i.v. application of cephradin the liver tissue concentration was 72.62 mcg/g. 30 min. after i.v. cephacetril the liver tissue concentration was 5.83 mcg/g. The quotient of liver tissue concentration to serum concentration for cephradin was between 0.36 and 0.83, and for cephacetril between 0.02 and 0.16. The excretion of cephradin and cephacetril in human bile was studied by collecting bile samples from the common bile duct via T-tube drainage (n = 17). Cholecystomized patients were given 2 g of antibiotics intravenously. Serum levels of cephradin were 263 mcg/ml 5 min after application, and 22 mcg/ml after 240 min. Serum levels of cephradin were 263 mcg/ml 5 min after application, and 22 mcg/ml after 240 min. Serum levels of cephacetril were 193 mcg/ml 5 min after application, and 27 mcg/ml after 240 min. The highest levels of cephradin in the bile were found 75 min after injection at a concentration of 86.4 mcg/ml; the highest level for cephacetril was 21.8 mcg/ml at 15 min. In patients with hyperbilirubinaemia cephradin reached a mean maximum concentration of 29.6 mcg/ml in bile samples, in comparison to 117.4 mcg/ml in normal patients, while no difference was seen with cephacetril. After intravenous administration of 2 g cephradin biliary concentration are achieved which may be sufficiently high to be effective not only against the very sensitive gram-positive organisms, but also against most strains of E. coli, Klebsiella and indol-negative Proteus. Cephradin is effective in the treatment of cholangitis and intrahepatic abscesses, as was observed in 18 patients. A free bile-flow is essential.

Metabolic fate of cephacetrile after parenteral administration in rats and rabbits.

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.