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Effects of daptomycin and vancomycin on tobramycin nephrotoxicity in rats
D Beauchamp1, M Pellerin, P Gourde
1Service d'Infectiologie, Hospitalier de l'Université Laval, Sainte-Foy, Quebec, Canada.
Abstract:
Daptomycin is a new biosynthetic antibiotic which belongs to a new class of drugs known as lipopeptides. The objective of this study was to evaluate the effects of daptomycin and vancomycin on tobramycin-induced nephrotoxicity. Female Sprague-Dawley rats were treated during 4 and 10 days with either saline (NaCl, 0.9%) or tobramycin at doses of 4 and 40 mg/kg per day (given every 12 h [q12h] intraperitoneally). Each treatment was combined with saline, daptomycin at a dose of 20 mg/kg per day (given q12h subcutaneously), and ancomycin at a dose of 50 mg/kg per day (given q12h subcutaneously). Daptomycin and vancomycin had no effect on the intracortical accumulation of tobramycin. Daptomycin did not accumulate in renal tissue even after 10 days of treatment. Tobramycin given at a dose of 40 mg/kg per day during 10 days induced a significant inhibition of sphingomyelinase activity in the renal cortex (P less than 0.01) and increased cellular regeneration (P less than 0.01), as measured by the incorporation of [3H]thymidine into DNA of the renal cortex. These changes were minimal when daptomycin was combined with tobramycin. Histologically, signs of tobramycin toxicity were also less severe in the presence of daptomycin. The intracortical accumulation of vancomycin was not modified by tobramycin. The sphingomyelinase activity was significantly more inhibited (P less than 0.01) when vancomycin was associated with tobramycin (4 and 40 mg/kg) without affecting the rate of [3H]thymidine incorporation into DNA. Histologically, signs of tobramycin toxicity were not affected by vancomuycin, but the cellular vacuolizations which were also observed in vancomycin-treated animals were still present in the proximal tubular cells of animals that were treated with the combination vancomycin-tobramycin. This study strongly suggests that daptomycin protects animals from tobramycin-induced nephrotoxicity but that vancomycin may enhance the effect of tobramycin. We conclude that daptomycin is safe and protects kidney cells from tobramycin-induced nephrotoxicity.
Insights
Daptomycin protects against tobramycin-induced kidney damage, unlike vancomycin which may worsen it. This study shows daptomycin is safe and beneficial for kidney health when used with tobramycin.
Area of Science:
- Pharmacology
- Nephrology
- Toxicology
Background:
- Tobramycin is an aminoglycoside antibiotic known to cause nephrotoxicity.
- Daptomycin is a lipopeptide antibiotic, and vancomycin is a glycopeptide antibiotic.
- Understanding drug interactions is crucial for patient safety and effective treatment.
Purpose of the Study:
- To evaluate the impact of daptomycin and vancomycin on tobramycin-induced nephrotoxicity in a rat model.
- To assess the potential protective or detrimental effects of co-administered daptomycin or vancomycin with tobramycin on kidney function and histology.
Main Methods:
- Female Sprague-Dawley rats were treated with tobramycin (4 and 40 mg/kg/day) alone or in combination with daptomycin (20 mg/kg/day) or vancomycin (50 mg/kg/day) for 4 and 10 days.
- Evaluated intracortical drug accumulation, sphingomyelinase activity, cellular regeneration (using [3H]thymidine incorporation), and histological changes in renal tissue.
- Compared the effects of tobramycin alone versus tobramycin in combination with daptomycin or vancomycin.
Main Results:
- Daptomycin and vancomycin did not affect tobramycin accumulation in the kidney.
- Daptomycin mitigated tobramycin-induced inhibition of sphingomyelinase activity and reduced cellular regeneration and histological signs of toxicity.
- Vancomycin did not improve tobramycin-induced nephrotoxicity and was associated with persistent cellular vacuolizations.
Conclusions:
- Daptomycin demonstrates a protective effect against tobramycin-induced nephrotoxicity in rats.
- Vancomycin may exacerbate the nephrotoxic effects of tobramycin.
- Daptomycin is safe and offers renal protection when co-administered with tobramycin.