Some pharmacodynamic and biochemical aspects of cefamandole.

The pharmacodynamic and nephrotoxic effects of cefamandole were investigated. Cefamandole at concentrations of 512 and 1024 micrograms/ml bath caused complete relaxation in isolated guinea pig ileum and rabbit duodenum, respectively. Concentrations of 2048 and 4096 micrograms cefamandole/ml bath caused marked stimulation in force and frequency of rat uterine muscle in all stages of sex cycle. Cefamandole in all tested concentrations did not induce any response on isolated guinea pig tracheal chain or isolated rabbit aortic strip. Cefamandole in concentrations of 256 to 1024 micrograms/ml bath as well as 256 and 512 micrograms/ml cannula produced marked inhibition on isolated guinea pig auricles and rabbit heart, respectively. The effect of graded increased concentrations on isolated frog gastrocnemius muscle, frog rectus abdominis muscle and rat phrenic nerve hemidiaphragm was recorded. Cefamandole in a dose of 53.2 mg/kg b. wt. in anaesthetized dogs caused very marked hypotensive effects and decrease in rate of respiration. Single intramuscular injection of cefamandole in a therapeutic (23.3 mg/kg b. wt.) and double therapeutic (46.6 mg/kg.b. wt.) doses in rabbits had no effect on electrocardiographic parameters among a period of 8 hours after injection. Effects of cefamandole on serum and urine concentrations of creatinine, urea, sodium, potassium, calcium, glucose and protein as well as clearance tests were investigated in rats.

Synergistic effect of a recombinant N-terminal fragment of bactericidal/permeability-increasing protein and cefamandole in treatment of rabbit gram-negative sepsis.

As a consequence of their bactericidal actions, many antibiotics cause the release of endotoxin, a primary mediator of gram-negative sepsis. Bactericidal/permeability-increasing protein (BPI) has bactericidal activity and neutralizes endotoxin in vitro and in vivo. We sought to examine the effect of a recombinant N-terminal fragment of BPI (rBPI21) in conjunction with cefamandole, a cephalosporin antibiotic, in the treatment of Escherichia coli bacteremia and septic shock in rabbits. Cefamandole (100 mg/kg of body weight) was injected intravenously. This was followed by simultaneous 10-min infusions of E. coli O7:K1 (9 x 10(9) CFU/kg) and rBPI21 (10 mg/kg). rBPI21 was continuously infused for an additional 110 min at 10 mg/kg/h. The administration of rBPI21 in conjunction with the administration of cefamandole prevented the cefamandole-induced increase of free endotoxin in plasma, accelerated bacterial clearance, ameliorated cardiopulmonary dysfunction, and thereby, prevented death, whereas neither agent alone was protective in this animal model. The efficacy of the combined treatment with rBPI21 and cefamandole suggests a synergistic interaction between the two agents. The data indicate that rBPI21 may be useful in conjunction with traditional antibiotic therapy.

Effects of cefamandole on spermatogenic development of young CD rats.

The testicular toxicity of cefamandole, a beta-lactam antibiotic with an N-methylthiotetrazole side chain, was evaluated in neonatal rats. Cefamandole caused delayed maturity of the germinal epithelium of neonatal rats when given on Postpartum Days 6 through 36. In rats given daily subcutaneous injections of 1000 mg/kg during this period, the most mature germinal cells were acrosome phase spermatids, whereas control rats had spermatids in the maturation phase. In studies of specific developmental phases, the effect of 1000 mg/kg daily cefamandole was primarily on the initial waves of spermatogonia during the period of rapid development (Postpartum Days 4 through 13). In animals treated from birth to Postpartum Day 8 and evaluated sequentially on Postpartum Days 5 through 9, there were no morphologically discernible effects on the transformation of gonocytes to immature spermatogonia, but there were slight degenerative changes in the first waves of developing spermatogonia. Cefamandole, 1000 mg/kg daily, given Postpartum Days 14 through 18 during the initial phase of spermatocyte development, also caused a slight degenerative change of the initial waves of pachytene spermatocytes. The significance of the findings in neonatal rats is unknown because differences in spermatogenic development between rat and human preclude direct extrapolation of the effects of cefamandole in neonatal rats to effects in humans.

Effect of cephalosporins on fascial healing after celiotomy.

A 7 day course of either cefonicid or cefazolin significantly reduced mean wound breaking weight after midline celiotomy in Sprague-Dawley rats compared with control animals. This detrimental effect was not seen when each drug was administered as a single preoperative dose. Even a 3 day course of cefonicid was associated with a significant reduction in the weight required to disrupt a healing abdominal closure. An increased incidence of incisional hernias was also noted among animals treated for 7 days with cefonicid or cefazolin. Shorter antibiotic regimens were not associated with an increased frequency of incisional herniation.

The hematologic effects of cefonicid and cefazedone in the dog: a potential model of cephalosporin hematotoxicity in man.

Cephalosporin antibiotics cause a variety of hematologic disturbances in man, the pathogeneses and hematopathology of which remain poorly characterized. There is a need for a well-defined animal model in which these blood dyscrasias can be studied. In four subacute toxicity studies, the intravenous administration of cefonicid or cefazedone to beagle dogs caused a dose-dependent incidence of anemia, neutropenia, and thrombocytopenia after 1-3 months of treatment. A nonregenerative anemia was the most compromising of the cytopenias and occurred in approximately 50% of dogs receiving 400-500 mg/kg cefonicid or 540-840 mg/kg cefazedone. All three cytopenias were completely reversible following cessation of treatment; the time required for recovery of the erythron (approximately 1 month) was considerably longer than that of the granulocytes and platelets (hours to a few days). Upon rechallenge with either cephalosporin, the hematologic syndrome was reproduced in most dogs tested; cefonicid (but not cefazedone)-treated dogs showed a substantially reduced induction period (15 +/- 5 days) compared to that of the first exposure to the drug (61 +/- 24 days). This observation, along with the rapid rate of decline in red cell mass parameters of affected dogs, suggests that a hemolytic component complicated the red cell production problem and that multiple toxicologic mechanisms contributed to the cytopenia. We conclude that the administration of high doses of cefonicid or cefazedone to dogs can induce hematotoxicity similar to the cephalosporin-induced blood dyscrasias described in man and thus provides a useful model for studying the mechanisms of these disorders.

The hematopathology of cefonicid- and cefazedone-induced blood dyscrasias in the dog.

Cephalosporin treatment in man has been associated with blood dyscrasias that include a time- and dose-related anemia, neutropenia, and thrombocytopenia, the hematopathology of which remains poorly characterized. A similar hematologic syndrome can be produced in dogs following daily intravenous injections of 540-840 mg/kg cefazedone or 400-500 mg/kg cefonicid for 1-3 months. Using this animal model, histologic and cytologic changes in blood, bone marrow, spleen, and liver were studied over the course of the cephalosporin-induced cytopenias. Peripheral blood cytologic observations included an absence, generally, of erythroid regenerative changes, increased numbers of macroplatelets, spherocytosis, erythroblastemia, and toxic neutrophil morphology. Interim and postmortem cytologic and histologic observations of bone marrow included hypoplastic and toxic changes, primarily in cytopenic dogs receiving high doses of cefonicid, and regenerative changes in hematopoietic tissue of affected cefazedone-treated animals. The latter included variable erythroid hyperplasia, increased megakaryocytes, and decreased marrow fat and was accompanied by evidence of extra-medullary hematopoiesis and increased hemosiderin and hemophagocytosis in liver and splenic tissue. The incidence and severity of these changes were dose-dependent, corresponded with the cytopenias observed peripherally, and, like the cytopenias, were fully reversible. These observations suggest that the hematologic syndrome associated with cephalosporin treatment in the dog has multiple toxicologic mechanisms, which include peripheral cytotoxic effects and bone marrow damage with depressed or ineffective hematopoiesis.

Effects of cefonicid and other cephalosporin antibiotics on male sexual development in rats.

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.

[Cefonicid toxicity. I. Effects on the reactivity of the specific immune system]. / Analisi della tossicita' del cefonicid. I. Effetti sulla reattivita' del sistema immunitario specifico.

The degree of toxicity of the antibiotic Cefonicid on the cellular reactivity of the immune system was evaluated. The effects on some lymphokine (IL-2 and IFN-gamma) production and the degree of proliferation of splenic lymphocytes following mitogen stimulation have been considered. Our results show that Cefonicid does not impair the immune response, except at very high doses (500 micrograms/ml).

The role of conventional pathology and toxicology in evaluating the immunotoxic potential of xenobiotics.

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.

Toxicology of vancomycin in laboratory animals.

The 50% lethal dose (LD50) of vancomycin for rodents was higher than that of tobramycin but much lower than that of cefamandole nafate. The rodents died in clonic convulsions immediately after receiving vancomycin. The LD50 for dogs similar to that for rodents; however, deaths occurred several days after administration of vancomycin and resulted from renal failure. Rapid intravenous administration of vancomycin to dogs produced a significant decrease in blood pressure that was prevented by pretreatment with the antihistamine methapyrilene. Subchronic administration of vancomycin to laboratory animals in doses of 12.5-400 mg/kg caused no systemic toxicity. Concomitant administration of vancomycin and tobramycin to rats resulted in significantly increased nephrotoxicity compared to that caused by either agent alone. The nephrotoxic response of rats receiving vancomycin was only partially reversed by large volumes of water given orally before and after the drug.

Pharmacology, Safety, and efficacy of cefamandole in childhood infections.

We used cefamandole in the initial treatment of 34 children (10 months to 15 years of age) with suspected bone, joint, or soft tissue infections. The minimal inhibitory concentration of organisms encountered ranged between 0.015 and 2 microgram/ml. At 1 h after intravenous infusion of 25 mg/kg, the mean serum level of cefamandole was 26.2 microgram/ml (range, 8.9 to 47.5 microgram/ml), and at 3 h the level was 1.8 microgram/ml (range, 0.6 to 4.4 microgram/ml), which is above the minimal inhibitory concentration for most of the organisms encountered. However, when the drug was given intravenously every 6 h, the mean level after a 37-mg/kg dose was 0.9 microgram/ml (range, less than 0.5 to 1.9 microgram/ml) at 4 h and, by extrapolation, would have fallen below 0.1 microgram/ml at 6 h. The mean serum half-life was 34 min. Cefamandole appeared to diffuse well into synovial fluid, with joint fluid levels between 5 and 40 microgram/ml. The drug was tolerated well. Cefamandole appears to be a reasonable alternative in the initial treatment of skeletal infections in children, but need to be administered every 4 h to maintain suprainhibitory serum levels between doses.

[Experimental studies in animals on the nephrotoxicity of some new cephalosporin antibiotics: cefamandole, EMD 29 645, and 29 946 (author's transl)]. / Tierexperimentelle Untersuchungen zur Nephrotoxizität neuer Cephalosporin-Antibiotika: Cefamandol, EMD 29 645 und EMD 29 946.

The cephalosporins cefamandole, EMD 29 645, and EMD 29 946 were tested for their nephrotoxicity in female albino Wistar rats (n = 120). The antibiotics were administered i.m. over a course of 5 days; dosage interval 12 h, dosages 1000, 2000, 3000, and 5000 mg/kg per day, respectively. For comparative evaluation of nephrotoxicity, the urinary excretion of tubular cells and enzymes (MDH, GOT, LDH) were taken. Additionally serum urea and urine protein (qualitatively) were determined. Furthermore the kidneys were investigated histologically. These experiments revealed the following tubulotoxic threshold doses: cefamandole: 3000 mg/kg per day, EMD 29 645: 2000 mg/kg per day, and EMD 29 946: 5000 mg/kg per day. EMD 29 645 was also found to be glomerulotoxic at higher doses.

Toxicologic evaluation of cefamandole nafate in laboratory animals.

The safety of cefamandole nafate in laboratory animals was evaluated in six species. The acute toxicity of cefamandole after intravenous or subcutaneous administration was similar to that of cephalothin sodium. The subacute and chronic toxicity of cefamandole was studied in rats and dogs for periods of two weeks to six months at doses of 250--1,000 mg/kg per day in rats and 125--1,500 mg/kg per day in dogs. No evidence of significant systemic toxicity was observed in these studies. There were, however, various degrees of local injury at the injection sites that resulted in slight decreases in hemoglobin, hematocrit, and red blood cell counts in the animals in which injury at the injection site was most severe. Studies of reproduction in rats and mice indicated that cefamandole nafate had no teratogenic effects and no adverse effects on fertility, gestation, or growth of offspring. Comparative studies of nephrotoxicity in rabbits demonstrated that the nephrotoxicity of cefamandole nafate was considerably less than that of cefazolin.