Daptomycin may attenuate experimental tobramycin nephrotoxicity by electrostatic complexation to tobramycin

Abstract

). In an attempt to explain these results, the in vivo and in vitro interactions between daptomycin and tobramycin were studied. Tobramycin alone and preincubated with negatively charged phospholipid bilayers (liposomes) was dialyzed against increasing concentrations of daptomycin in buffer at pH 5.4. A significant drop in the concentration of tobramycin was observed when daptomycin was added to the opposite half cells. Furthermore, daptomycin induced a concentration-dependent release of lipid-bound tobramycin. Gold labeling experiments showed that daptomycin could be incorporated into phospholipid layers. Female Sprague-Dawley rats were treated with daptomycin alone, with tobramycin alone, or with the combination over 2 to 10 days. Levels of daptomycin and tobramycin in serum were similar in all groups. The levels of tobramycin in the renal cortex increased significantly with time and, on day 10, reached values of 654 ± 122 and 844 ± 298 ,ug/g of tissue (mean ± standard deviation; not significant) in animals treated with tobramycin and the combination of daptomycin-tobramycin, respectively. No significant difference was observed in the levels of tobramycin in the kidneys between animals treated with tobramycin or the daptomycin-tobramycin combination at any time. By contrast, daptomycin levels were significantly 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 immunogold labeling studies, animals were killed 4 h after a single injection of daptomycin alone or daptomycin in combination with tobramycin. Daptomycin was found throughout the matrixes of the lysosomes of proximal tubular cells of animals treated with daptomycin alone. In animals treated with the combination of daptomycin and tobramycin, daptomycin was associated with intralysosomal myeloid bodies. Our results suggest that daptomycin might attenuate experimental aminoglycoside nephrotoxicity by interacting with the aminoglycoside, perhaps electrostatically, and thereby protecting intracellular targets of toxicity.

Multicenter Evaluation of the Clinical Outcomes of Daptomycin with and without Concomitant β-Lactams in Patients with Staphylococcus aureus Bacteremia and Mild to Moderate Renal Impairment

“…Daptomycin has shown no evidence of nephrotoxicity in humans or animals. In fact, data from rats suggest that it may provide protection against aminoglycoside nephrotoxicity (25)(26)(27). In clinical trials (17,28), daptomycin did not appear to pose risks of nephrotoxicity among patients with preserved renal function, and in fact, daptomycin has been used as a treatment option for patients with S. aureus infections who developed nephrotoxicity on vancomycin (29).…”

Attenuation by daptomycin of gentamicin-induced experimental nephrotoxicity

“…The association of daptomycin with intralysosomal phospholipid in aminoglycoside-treated rats is consistent with these results and is probably responsible for the longer retention of daptomycin in the lysosomes of animals treated with the combinations daptomycin-tobramycin (10) and daptomycingentamicin (as observed in the present study) than in the lysosomes of animals given daptomycin alone. Other studies done in our laboratory show that daptomycin may attenuate tobramycin nephrotoxicity by electrostatic complexation to tobramycin (10). All these data suggest that the protection is most likely due to a neutralization of the toxicity rather than to a redistribution of these drugs within the cell.…”

“…After 10 days of treatment, daptomycin was still seen at the same subcellular site (2). In animals given daptomycin in combination with an aminoglycoside, daptomycin was seen over myeloid bodies inside the lysosomes of proximal tubular cells in the renal cortices of animals treated during 10 days with the combination daptomycin-tobramycin (2) and in the renal cortices of animals treated during 10 days with the combination daptomycin-gentamicin and killed 4 days after the end of therapy (Fig. 6D to F).…”

“…The absorption of the antibodies with an excess of the opposite antigen did not modify the labeling. Moreover (10) showed that daptomycin levels on days 6, 8, and 10 after the beginning of therapy were significantly higher in the renal cortices of animals treated with daptomycin-tobramycin than in the renal cortices of animals treated with daptomycin alone. Data from our study also suggest that daptomycin does not accumulate in the renal cortical tissue of animals given daptomycin alone, but significantly higher levels of daptomycin were measured in the renal cortices of animals treated with the combination daptomycin-gentamicin 4 days after the end of therapy.…”

“…This dilution was found to yield optimal results, with high labeling and low background levels. Figure 1 shows the influence of daptomycin on the intracortical accumulation of gentamicin in animals treated during 10 days with gentamicin alone or in combination with daptomycin.…”