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Daptomycin may attenuate experimental tobramycin nephrotoxicity by electrostatic complexation to tobramycin
M Couture1, M Simard, P Gourde
1Laboratoire et Service d'Infectiologie, Université Laval, Ste-Foy, Québec, Canada.
Antimicrobial Agents and Chemotherapy
|April 1, 1994
Summary
Daptomycin may reduce tobramycin kidney toxicity by binding to it, altering its cellular uptake and accumulation. This interaction protects against experimental aminoglycoside nephrotoxicity.
Area of Science:
- Pharmacology
- Nephrology
- Microbiology
Background:
- Aminoglycosides like tobramycin are essential antibiotics but can cause kidney damage (nephrotoxicity).
- Daptomycin, a lipopeptidic antibiotic, has shown potential in reducing experimental tobramycin-induced nephrotoxicity.
Purpose of the Study:
- To investigate the in vitro and in vivo interactions between daptomycin and tobramycin.
- To elucidate the mechanism by which daptomycin may attenuate tobramycin nephrotoxicity.
Main Methods:
- In vitro dialysis experiments to assess tobramycin-daptomycin interaction in the presence of liposomes.
- In vivo studies in Sprague-Dawley rats treated with daptomycin, tobramycin, or combination therapy.
- Measurement of drug levels in serum and renal cortex.
- Immunogold labeling to localize daptomycin within kidney cells.
Main Results:
- Daptomycin significantly reduced tobramycin concentration in vitro and released lipid-bound tobramycin.
- In vivo, co-administration did not alter serum levels of either drug but increased daptomycin levels in the renal cortex.
- Daptomycin localized to intralysosomal myeloid bodies in combination-treated rats, differing from its distribution in daptomycin-alone treated rats.
Conclusions:
- Daptomycin interacts with tobramycin, potentially via electrostatic mechanisms.
- This interaction may alter tobramycin's cellular disposition, leading to reduced accumulation in renal proximal tubular cells.
- Daptomycin's protective effect against experimental aminoglycoside nephrotoxicity is likely mediated by altering the interaction of tobramycin with intracellular targets.