DAPTOMYCIN MAY ATTENUATE EXPERIMENTAL TOBRAMYCIN NEPHROTOXICITY BY ELECTROSTATIC COMPLEXATION TO TOBRAMYCIN

The lipopeptidic antibiotic daptomycin is reported to reduce experimen tal tobramycin nephrotoxicity (D. Beauchamp, M. Pellerin, P. Gourde, M . Pettigrew and M. G. Bergeron, Antimicrob. Agents Chemother. 34:139-1 47,1990; C. A. Wood, H. C. Finkbeiner, S. J. Kohlhepp, P. W. Kohnen, a nd D. C. Gilbert, Antimicrob. Agents Chemother. 33:1280-1285, 1989). I n an attempt to explain these results, the in vivo and in vitro intera ctions between daptomycin and tobramycin were studied. Tobramycin alon e and preincubated with negatively charged phospholipid bilayers (lipo somes) was dialyzed against increasing concentrations of daptomycin in buffer at pH 5.4. A significant drop in the concentration of tobramyc in was observed when daptomycin was added to the opposite half cells. Furthermore, daptomycin induced a concentration-dependent release of l ipid-bound tobramycin. Gold labeling experiments showed that daptomyci n could be incorporated into phospholipid layers. Female Sprague-Dawle y rats were treated with daptomycin alone, with tobramycin alone, or w ith the combination over 2 to 10 days. Levels of daptomycin and tobram ycin in serum were similar in all groups. The levels of tobramycin in the renal cortex increased significantly with time and, on day 10, rea ched values of 654 +/- 122 and 844 +/- 298 mug/g of tissue (mean +/- s tandard deviation; not significant) in animals treated with tobramycin and the combination of daptomycin-tobramycin, respectively. No signif icant difference was observed in the levels of tobramycin in the kidne ys between animals treated with tobramycin or the daptomycin-tobramyci n combination at any time. By contrast, daptomycin levels were signifi cantly higher in the renal cortexes of animals treated with daptomycin -tobramycin in comparison with those in the renal cortexes of animals treated with daptomycin alone on days 6, 8, and 10 (P < 0.01). For imm unogold labeling studies, animals were killed 4 h after a single injec tion of daptomycin alone or daptomycin in combination with tobramycin. Daptomycin was found throughout the matrixes of the lysosomes of prox imal tubular cells of animals treated with daptomycin alone. In animal s treated with the combination of daptomycin and tobramycin, daptomyci n was associated with intralysosomal myeloid bodies. Our results sugge st that daptomycin might attenuate experimental aminoglycoside nephrot oxicity by interacting with the aminoglycoside, perhaps electrostatica lly, and thereby protecting intracellular targets of toxicity.