Species specificity of 2-aryl carbapenem-induced immune-mediated hemolytic anemia in primates.

L-695,256 is a novel 2-fluorenonyl carbapenem antibiotic with significant antimicrobial activity against strains of methicillin-resistant Staphylococci. This prototype compound was administered intravenously to rhesus monkeys (Macaca mulatta) at does of 50 or 200 mg/kg/day for 2 weeks to assess toxicity and found to induce a hemolytic anemia characterized by extravascular hemolysis and splenomegaly. A subsequent study in this species in which 100 mg/kg/day was administered i.v. for 4 weeks showed that all animals were direct antiglobulin test (Coombs' test) positive for IgG with 20-25% reductions in the erythron. Following 3 weeks of recovery, the erythron had returned to normal, although it took an additional 2 months for the Coombs' test to become negative. Challenge of these same animals with 0.5 million U/kg (300 mg/kg/day) of penicillin intravenously indicated no apparent cross-reactivity. Since attempts to establish a model for this immune-mediated hemolytic anemia with this drug in rats or mice were unsuccessful, a 2-week i.v. study in squirrel monkeys (Saimiri sciureus) was conducted at a dose of 200 mg/kg/day. All animals in this study remained Coombs' test negative with no changes in the erythron, suggesting an increased sensitivity to beta-lactam-induced anemia in rhesus monkeys compared to other species. Further support for this hypothesis was obtained using the cephalosporin antibiotic, cefotetan. This compound induced a high incidence of Coombs' test positive hemolytic anemia at clinically relevant doses in rhesus monkeys, despite a very low incidence of this adverse effect in patients with many years of clinical use. These data suggest that although rhesus monkeys respond in a qualitatively similar manner to humans with regard to high doses of beta-lactam antibiotics, their sensitivity may overestimate the risk of immune-mediated hemolytic anemia for clinical use.

Toxicity and clearance of intravitreal cefotetan.

Direct intravitreal injection of antibiotics plays an important role in the management of bacterial endophthalmitis. In the present study we investigated the toxicity and clearance of intravitreally injected cefotetan in a rabbit model. No toxic ocular side effects could be detected by electroretinography (ERG) or light and electron microscopy up to and including a single intravitreal dose of 1000 micrograms. Intravitreal injection of 2000 micrograms cefotetan resulted in mild degeneration of photoreceptor outer segments and, sporadically, in cataract formation. After intravitreal injection of 4000 micrograms, moderate toxic degeneration of photoreceptors occurred, with displacement and mitochondrial swelling of inner segments. In addition, lysosomal lamellar inclusion bodies could be detected in pigment epithelial cells. After a single intravitreal injection of 1000 micrograms cefotetan, concentrations greater than the minimum necessary for the inhibition of most commonly occurring intraocular pathogens (except Pseudomonas aeruginosa and Staphylococcus epidermidis) were maintained in the vitreous humor for greater than 48 h. Cefotetan may be a potentially important drug for intravitreal injection, especially in cases of gram-negative and suspected anaerobic endophthalmitis.

[Local irritation studies of cefodizime sodium].

Four local irritation studies of cefodizime sodium (THR-221), a new developed cephem-type antibiotics, were carried out with NZW rabbits. 1. In eye irritation test, 25% THR-221 water solution had no irritancy on eye mucosa in rabbits. 2. In single injective intramuscular irritation study, regardless of solvents (water or 0.5% lidocaine), 25% THR-221 solution had irritancy equal to 0.75% acetic acid. But recovery process of the muscle injured with THR-221 was faster and better than with 0.75% acetic acid. 3. In five days injective muscular irritation study, the irritancy of 25% THR-221 water solution on the muscle was milder than that of CTT or CET. Histopathological damage with THR-221, necrosis/degeneration of muscle fibers and edema/hemorrhage in interstitium etc., were well recovered. 4. In vessel irritation study, 10% or more THR-221 water solution had irritancy on ear vessel. THR-221, as same as CTT, caused organized thrombi and inflammation at the surrounding area. The degree of irritation of 20% THR-221 solution was slightly stronger than that of 20% CET, but weaker than that of 20% CTT. 5. In a clinical phase, it is to be desired that THR-221 like as CTT or CET shall be avoided repeated intramuscular or intravenous injections at the same site.

[Five-week subacute intravenous toxicity study of cefodizime sodium in dogs].

A subacute toxicity study of cefodizime sodium (THR-221), a new cephem antibiotics, was carried out using male and female beagle dogs. THR-221 was intravenously administered to the dog at dose levels of 500, 1000 and 2000 mg/kg/day for 5 weeks, followed by 4 weeks recovery period. Cefotetan (CTT) as a reference drug was administered in the same manner at a dose level of 2000 mg/kg/day. The summarized results obtained are as follows: 1. Vomiting and salivation were observed in dogs given 1000 and 2000 mg/kg/day of THR-221. However, it caused no deaths or significant effects on body weight and food consumption in all groups treated with THR-221. 2. No toxicological changes associated with the administration of THR-221 were found in urinary and hematological examinations. 3. In serum biochemical examinations, increase or tendencies of increase of albumin and A/G ratio, probably due to the antibacterial action of THR-221, were detected at all dose levels of THR-221. 4. There were no dose-related changes in hepatic and renal function, fecal occult blood, ophthalmological, electrocardiographic and auditory examinations, absolute and relative organ weights. 5. Histopathological examinations revealed fibrosis or granulation in perivascular area of injection sites, particularly in males given 2000 mg/kg/day of THR-221. 6. After 4 weeks of recovery period, above-mentioned changes were generally disappeared and it was suggested that these were reversible ones. 7. In groups treated with CTT (2000 mg/kg/day), damages were recognized mainly in erythron values, liver and kidney, as compared with the same dose of THR-221. Therefore the toxicity of THR-221 was less than that of CTT. 8. From these results, the non toxic effective dose level and the toxic dose level of THR-221 were estimated to be 500 mg/kg/day and more than 2000 mg/kg/day respectively, for male and female dogs.