Effect of protein binding on drug penetration into blister fluid.
(9/37)
The effect of protein binding on drug penetration into blister fluid was evaluated by using cefonicid, ceftizoxime, and cefotaxime. Drug concentrations in a chamber with a high surface area/volume ratio (i.e., paper disk) follow changes in serum more closely than do those in a chamber with a low surface area/volume ratio. Both the area under the concentration-time curve ratio and the concentration ratio (by the disk method) for cefonicid were statistically lower than the ratios for ceftizoxime and cefotaxime. The high degree of protein binding of cefonicid results in the availability of less drug for diffusion to blister fluid than with the low-protein-binding ceftizoxime and cefotaxime. (+info)
The role of conventional pathology and toxicology in evaluating the immunotoxic potential of xenobiotics.
(10/37)
Investigating the immunotoxic potential of candidate drugs as part of a preclinical safety evaluation poses several problems. These include the need for practical, validated tests, the difficulty in establishing the toxicologic significance of positive findings, and a poor understanding of the predictive value such findings hold for drug effects in man. A key component of this investigation is the toxicologic profile generated through preclinical toxicity and safety studies. As this "routine" assessment becomes increasingly comprehensive and sophisticated, most toxicologically significant drug-associated effects are revealed. Such findings may serve as "triggers" for investigating possible immune mechanisms. Decisions to test specifically for immunotoxicity may also be influenced by the molecular structure and pharmacologic profile of the compound, as well as the intended use of the drug. Examples of such indications and follow-up studies are discussed in this review. We are presently poorly equipped to effectively screen drugs indiscriminately for an immunotoxic potential. We are better prepared, however, to investigate whether a drug-associated change is due to an adverse effect on the immune system. This problem-oriented approach to immunotoxicology challenges us as diagnosticians and immunopathologists, and requires a close working relationship among the toxicologic pathologist, the basic immunologist, the immunopharmacologist, and the clinician. (+info)
Pharmacokinetics of cefonicid in patients with skin and skin structure infections.
(11/37)
The disposition of cefonicid (2 g intravenously every 24 h) was assessed in 15 patients with skin and skin structure infections. Trough and peak concentrations in serum were measured on two successive days to verify the attainment of steady state; and 1 trough and 12 postdose values of the concentration in serum were collected on the following day. Cefonicid concentrations in serum were determined by high-performance liquid chromatography. The cefonicid serum concentration versus time profile after intravenous infusion was clearly biexponential in all patients. The terminal elimination half-life determined by nonlinear regression analysis was 4.63 +/- 1.49 h (mean +/- standard deviation). The steady-state volume of distribution and total body clearance were 0.12 +/- 0.04 liter/kg and 0.369 +/- 0.110 ml/min per kg, respectively. These results are comparable to parameters derived from previous studies in noninfected normal volunteers. Thus, the disposition of cefonicid is not altered in patients with severe skin and skin structure infections. (+info)
The rate of killing of Escherichia coli by beta-lactam antibiotics is strictly proportional to the rate of bacterial growth.
(12/37)
Nongrowing bacteria evade the bactericidal activity of beta-lactam antibiotics. We sought to determine if slow growth rate also alters bactericidal activity. The bactericidal activity of two beta-lactams on Escherichia coli grown in glucose limited chemostats was compared for generation times ranging from 0.7 to 12 h. The degree of killing varied with drug structure and with E. coli strain. However, all killing rates were a constant function of the bacterial generation time: slowly growing bacteria became progressively more phenotypically tolerant to beta-lactam antibiotics as the generation time was extended. (+info)
Peritoneal transport of cefonicid.
(13/37)
The pharmacokinetic characteristics of cefonicid, a highly protein-bound expanded-spectrum cephalosporin, were examined in six noninfected, clinically stable patients undergoing continuous ambulatory peritoneal dialysis. After a 1.0-g intravenous dose of cefonicid, the mean concentrations in serum were 105 +/- 25 and 35.6 +/- 14.4 micrograms/ml at 3 and 72 h, respectively. Despite a prolonged half-life in serum of 49.7 +/- 18 h, the penetration into peritoneal fluid was low. The average concentration in dialysate over the 72-h study period was 2.7 micrograms/ml. The serum clearance was 2.6 +/- 1.0 ml/min, and the distribution volume was 0.14 +/- 0.02 liter/kg. Dosage recommendations and clinical considerations for cefonicid use in continuous ambulatory peritoneal dialysis patients are discussed. (+info)
Effects of cefonicid and other cephalosporin antibiotics on male sexual development in rats.
(14/37)
The purpose of this study was to determine whether cefonicid, a cephalosporin antibiotic with a modified N-methylthiotetrazole (MTT) side chain, caused testicular toxicity when subcutaneously administered to Sprague-Dawley male rats from days 6 to 36 postpartum at doses of 50 to 1,000 mg/kg per day. Moxalactam (a cephamycin antibiotic which will be referred to as a cephalosporin for convenience throughout), which contains the MTT side chain, was used as a positive control and was administered at 100 to 1,000 mg/kg per day, and cephalothin, which lacks an MTT side chain, was used as the negative control at 1,000 mg/kg per day. Moxalactam caused a significant reduction in testicular and seminal vesicle weights in 37-day-old animals, and histological examination revealed bilateral multifocal atrophy of the seminiferous tubules at all dose levels. Animals reared to reproductive maturity had significant deficits in fertility, and histological examination revealed multifocal or diffuse atrophy of the seminiferous tubules at all doses with a severity greater than that observed in the 37-day-old animals. The histological findings were confirmed by marked reductions in testicular sperm production rates and cauda epididymal sperm numbers. Cephalothin and cefonicid had no treatment-related adverse effects on the sexual maturation of prepubertal, juvenile, or adult males. The absence (in cephalothin) or modification (in cefonicid) of the MTT side chain was not associated with adverse reproductive effects. The relevance of these findings to humans in prenatal and prepubertal stages of life cannot be determined at this time. (+info)
Antistaphylococcal activity of ceforanide and cefonicid in the presence of human serum.
(15/37)
Tests with 52 strains of Staphylococcus aureus compared ceforanide and cefonicid. Addition of 50% human serum to the test system reduced the bacteriostatic and bactericidal activities of cefonicid, but ceforanide was not affected as greatly. (+info)
Multiple-dose pharmacokinetics of cefonicid in patients with impaired renal function.
(16/37)
The pharmacokinetics of multiple-dose administration of cefonicid to patients with normal and impaired renal function were studied by using high-performance liquid chromatography to measure serial serum and urine concentrations. Eighteen patients received an initial dose of 15 mg/kg intravenously over 12 min plus two or three subsequent modified doses at intervals of 24 to 72 h, depending upon the degree of renal impairment. Six patients chronically requiring hemodialysis and 12 nondialysis subjects (creatinine clearance, 10 to 80 ml/min per 1.73 m2) were studied. The concentrations of cefonicid in serum after the initial dose were best described by an open two-compartment model. The elimination half-life of cefonicid ranged between 5.5 and 84.9 h. Mean peak and trough concentrations in serum for all patients were 178.2 +/- 29.3 micrograms/ml (plus or minus standard deviation) and 39.0 +/- 17.5 micrograms/ml, respectively. Trough concentrations were higher in patients requiring hemodialysis than in nondialysis subjects, but the difference was clinically insignificant. The renal clearance/plasma clearance ratio of cefonicid was linearly related to creatinine clearance and decreased with impaired renal function. Therefore, nonrenal mechanisms of elimination become more important as renal function declines. Since cefonicid concentrations were within the therapeutic range for nearly all dosing intervals, we conclude that the guidelines used for dosage reduction and interval prolongation in this study result in therapeutically adequate concentrations in serum and, at the same time, result in no significant drug accumulation. (+info)