Role of sodium in protection by extended-spectrum penicillins against tobramycin-induced nephrotoxicity

Abstract

Salt depletion is known to potentiate aminoglycoside nephrotoxicity, while salt replacement attenuates it. Recent studies have shown that ticarcillin protects against tobramycin and gentamicin nephrotoxicity. It has been suggested that this protection is due to an interaction between ticarcillin and the aminoglycoside. However, it can also be explained by the salt load associated with ticarcillin administration. This study was conducted to examine this question. Tobramycin was administered to eight groups of rats at 100 mg/kg per day intraperitoneally for 10 days. Group 1 rats were salt depleted, while group 2 rats were on a normal salt diet. Rats in groups 3 through 8 were also salt depleted but received, in addition, the following interventions intraperitoneally: group 3, ticarcillin, 300 mg/kg per day (0.37 to 0.39 meq of Na supplement per day); group 4, ticarcillin, 300 mg per day (1.56 meq of Na supplement per day); group 5, ticarcillin, 300 mg/kg per day, and NaCl supplement (1.17 to 1.19 meq/day), resulting in a total load of 1.56 meq/day; group 6, piperacillin, 400 mg/day (0.76 meq of Na supplement per day and equimolar to the ticarcillin dose [300 mg/day] in group 4 rats); group 7, piperacillin, 400 mg/day, and NaCl supplement (0.8 meq/day) for a total Na load of 1.56 meq/day; and group 8, 1.56 meq of Na per day as NaCl. Rats in groups 2, 4, 5, 7, and 8, which received a normal salt diet or its equivalent Na supplement, had no significant change in creatinine clearance (CLCR) over the 10-day period. The remaining groups sustained significant reductions in CLCR, as follows: group 1, -53.0% (P < 0.05); group 3, -66.2% (P < 0.05); group 6, -79.8% (P < 0.05). A positive correlation was found between the concentration of tobramycin in the kidneys and the percent change in CLCR at the end of the study. Concentrations of drugs in plasma were highest in group 1 rats, lowest in the rats in groups in which protection was observed, and moderately elevated in the remaining groups of rats. The results of this study suggest the following: (i) that the protective effect of ticarcillin against tobramycin nephrotoxicity is secondary to the obligatory sodium load associated with it, (ii) pharmacokinetic and pharmacodynamic interactions between salt and tobramycin are proposed to explain this effect, (iii) the nephrotoxicity of tobramycin is probably related to the degree of accumulation of the drug in the kidney, and (iv) an in vivo interaction between tobramycin and ticarcillin does not contribute to the protective effect of the penicillin but may influence concentrations in plasma, especially under conditions of severe renal impairment.