Effect of Cefamandole Nafate on the Toxicity of Tobramycin

Abstract

Because of the potential for an interaction betwen cephalosporins and aminoglycosides leading to renal injury, an evaluation of the effect of a new cephalosporin, cefamandole nafate, on the toxicity of the aminoglycoside tobramycin was performed in laboratory animals. High doses of cefamandole nafate did not increase the acute toxicity (lethality) of tobramycin in rats or mice. In a subacute experiment in rats, dose-related tobramycin nephrotoxicity, as evidenced by blood urea nitrogen changes, increased kidney weights, and histologically determined tubular nephrosis and necrosis, was observed. Concomitant treatment with cefamandole nafate, 500 mg/kg, did not increase tobramycin nephrotoxicity, but protected against the aminoglycoside-induced renal injury. Determination of tissue radioactivity after administration of ['4C]tobramycin indicated that cefamandole nafate treatment resulted in uniformly lower tobramycin tissue concentrations compared with the control, suggesting that the protective effect was produced by enhanced excretion of tobramycin after cefamandole nafate treatment.The concomitant use of an aminoglycoside and a cephalosporin represents a frequently used approach to the initial therapy of lifethreatening infections.There are a number of case reports attributing renal injury to the simultaneous use of the aminoglycoside gentamicin (Garamycin, Schering Laboratories, Bloomfield, N.J.) and the cephalosporin cephalothin (Keflin, Eli Lilly & Co., Indianapolis, Ind.) in seriously ill patients (3,4,8,12,15,16 The combined use of cefamandole nafate and tobramycin represents a potentially useful therapy for serious infections. Because of the controversy surrounding the potential for nephrotoxicity resulting from the concomitant use of aminoglycosides and cephalosporins, an evaluation of the interaction between cefamandole nafate and tobramycin in laboratory animals was undertaken as a part of the toxicological evaluation of this new cephalosporin antibiotic.MATERIALS AND METHODS Animals. In acute toxicity experiments, female Wistar rats weighing 110 to 135 g or female ICR mice weighing 16 to 18 g (Harlan Industries, Cumberland, Ind.) were used. In the subacute experiments, male and female Wistar rats, specific pathogen-free and cesarean derived, weighing 104 to 146 g (Harlan Industries) were caged individually with free access to water and food.Antibiotic administration. Cefamandole nafate was dissolved in 1.67% aqueous sodium carbonate (3.3 ml/g) to make a 25% solution comparable to that obtained after reconstitution of the formulated product (11). Tobramycin was administered as tobramycin sulfate in the commercially available formulation containing 4% tobramycin. This solution was diluted with saline for administration of lower doses, and a 10% solution was prepared for the administration of high doses in the acute toxicity experiments.In acute toxicity experiments, mice (10 per dose) received intravenous doses of saline, 8 ml/kg, or cefamandole nafate, 2,000 mg/kg, followed after 1 min by intravenous do...