Attenuation by daptomycin of gentamicin-induced experimental nephrotoxicity

Abstract

). Female Sprague-Dawley rats were treated with saline (NaCl, 0.9%), daptomycin (10 mg/kg of body weight every 12 h, subcutaneously), gentamicin (30 mg/kg/12 h, intraperitoneally) or with a combination of daptomycin plus gentamicin over a 10-day period. Animals were killed 4, 10, and 20 days after the end of treatment. Four days after the end of drug administration, gentamicin and daptomycin levels in the renal cortices of animals treated with the combination of daptomycin and gentamicin were significantly higher than in those of rats given gentamicin or daptomycin alone (P < 0.01). Despite the higher cortical concentrations of gentamicin, rats given the combination of gentamicin and daptomycin had less reduction in renal cortex sphingomyelinase activity, less evidence of regeneration of cellular cortical cells ([3HJthymidine incorporation into cortex DNA), lower creatinine concentration in serum, and less histopathologic evidence of injury than rats given gentamicin alone. By immunogold technique, both daptomycin and gentamicin were localized to the lysosomes of proximal tubular cells, regardless of whether animals received the drugs alone or in combination. Interestingly, myeloid body formation occurred in both those animals given gentamicin alone and those given daptomycin plus gentamicin. No significant changes were observed for all groups between 10 and 20 days after the end of therapy, suggesting that the toxicity of gentamicin was not delayed by the concomitant injection of daptomycin. The results confirm that daptomycin can attenuate experimental gentamicin nephrotoxicity.Aminoglycoside antibiotics are widely used in the control of severe gram-negative infections. Their use is, however, associated with oto-and nephrotoxicity. Aminoglycosides are not metabolized in the body but are essentially eliminated by glomerular filtration and partially reabsorbed by proximal tubular cells. Lysosomes have been shown to be the unique site of accumulation of aminoglycosides into proximal tubular cells (1,3,9,20). They induce a lysosomal phospholipidosis (15) which is accompanied by cellular necrosis and postnecrotic cell regeneration (13,16,17).The reduction of the toxicity of these drugs remains a concern among clinicians, and efforts have been made toward a better assessment of potential risk factors. An alternative strategy is the pre-or coadministration of inhibitors, but the clinical use of these is still questionable. Poly-L-aspartic acid has recently been shown to protect against aminoglycoside nephrotoxicity without reducing the cortical accumulation of aminoglycosides (4,5,12). Recent studies have also shown that daptomycin, a lipopeptide antibiotic active against methicillinresistant staphylococci and other clinically important aerobic, facultative, and anaerobic gram-positive bacteria, protected proximal tubular cells against tobramycin-induced renal toxicity in the presence of a similar (6) or even an increased (26) accumulation of the aminoglycosides in the renal cortex. The mechanism of this inhibition o...

Daptomycin: a novel agent for Gram-positive infections

“…Daptomycin appears to have a protective effect on aminoglycoside-induced nephrotoxicity. With one exception [64], rat models suggest that daptomycin reduced functional and histological renal changes associated with gentamicin or tobramycin administration [65][66][67][68]. Patients treated with daptomycin at up to 3 mg/kg q12 h in combination with aminoglycosides showed no evidence of nephrotoxicity.…”

In Vitro Activities of Daptomycin, Arbekacin, Vancomycin, and Gentamicin Alone and/or in Combination against Glycopeptide Intermediate-Resistant Staphylococcus aureus in an Infection Model

“…In an evaluation of staphylococcal abscesses in rats, it was determined that there was less of an increase in serum creatinine and less cortical necrosis when daptomycin plus tobramycin was used than with tobramycin alone (21). Another animal study evaluating the protective effect of daptomycin on gentamicin-induced nephrotoxicity in rats found that daptomycin was detected within the lysosomes of the proximal tubular cells as early as 1 h after a single infusion (17). This combination resulted in less nephrotoxic effects (i.e., lower serum creatinine levels and less histopathologic change) for up to 20 days postinfusion of the drugs.…”

G418-mediated ribosomal read-through of a nonsense mutation causing autosomal recessive proximal renal tubular acidosis

“…The origin of this toxicity is multifactorial, including but not limited to interactions with phospholipids, inhibition of phospholipases, formation of free radicals, and binding to both the eukaryotic ribosomal A-site and mitochondrial 12S rRNA A-site. To limit the toxicity, various approaches are being attempted including 1) the use of antioxidants to reduce free radical levels (31,51); 2) the use of poly-L-aspartate (4, 13) and daptomycin (55,56) to reduce the ability of aminoglycosides to interact with phospholipids; 3) the administration of agonists that compete for aminoglycoside binding to megalin (61); and 4) structural modifications that limit toxicity without altering the efficacy of PSC read-through (45) and the isolation of a nonnephrotoxic aminoglycoside (gentamicin) congener (49). Whether any of these approaches will turn out in the long run to be accepted is currently unknown.…”