Effects of daptomycin and vancomycin on tobramycin nephrotoxicity in rats

Beauchamp, Denis; Pellerin, M; Gourde, Pierrette; Pettigrew, M; Bergeron, Michel G.

doi:10.1128/aac.34.1.139

Cited by 53 publications

(42 citation statements)

References 33 publications

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“…Since no concomitant histopathological alteration toward subcellular structure in proximal tubular cells or other cortical cells was observed (5), it can be inferred that the protection is due to neutralization of the toxicity of these drugs rather than to their tissue or cellular redistribution. One cannot exclude a complexation between daptomycin and tobramycin in serum, in urine, or inside the lysosomes that would prevent an inhibitory effect of these drugs toward phospholipid catabolism.…”

Section: Discussionmentioning

confidence: 99%

“…This biosynthetic antibiotic is active against gram-positive bacteria and inhibits cell growth by interfering with lipoteichoic acid synthesis. It has been demonstrated that daptomycin protects proximal tubular cells from tobramycin-induced nephrotoxicity without reducing aminoglycoside levels in the renal cortex (5,29). Similarly, coadministration of poly-L-aspartic acid with aminoglycosides was also shown to protect against gentamicin and tobramycin nephrotoxicity in vivo (3,4,12,23,27,28 (iii) Tobramycin assays.…”

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Daptomycin may attenuate experimental tobramycin nephrotoxicity by electrostatic complexation to tobramycin

Couture

Simard

Gourde

et al. 1994

Antimicrob Agents Chemother

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). 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.

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Section: Discussionmentioning

confidence: 99%

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Daptomycin may attenuate experimental tobramycin nephrotoxicity by electrostatic complexation to tobramycin

Couture

Simard

Gourde

et al. 1994

Antimicrob Agents Chemother

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“…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 of toxicity is still unknown.…”

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Attenuation by daptomycin of gentamicin-induced experimental nephrotoxicity

Thibault

Grenier

Simard

et al. 1994

Antimicrob Agents Chemother

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). 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...

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“…In fact, drugs such as cisplatinum 4) and vancomycin 5) increase the nephrotoxicity of aminoglycosides, while recent studies showed that poly-L-aspartic acid, 6) daptomycin, 7,8) carbenicillin, 9) ticarcillin 10) and ceftriaxone 11) protected the kidney against aminoglycoside-induced nephrotoxicity.Fleroxacin is a synthetic broad-spectrum antibiotic belonging to the class of fluoroquinolones.12) It shows good antibacterial activity against many gram-negative bacteria, and less activity against gram-positive bacteria. 13,14) A recent investigation showed that fleroxacin (intraperitoneally) protected against gentamicin-induced nephrotoxicity in rats when both drugs were administered in combination.…”

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Protective Effect of Fleroxacin against the Nephrotoxicity of Isepamicin in Rats

Yazaki¹,

Yoshiyama²,

Wong³

et al. 2002

Biological & Pharmaceutical Bulletin

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Its advantages included having low nephrotoxicity and effectiveness with only once daily dosing in the treatment of numerous infections.2,3) Since fleroxacin is often combined with isepamicin, and this combination has been shown to be very effective as a first-line antibiotic combination in the treatment of severe infections, the potential of additive nephrotoxicity in the fleroxacin isepamicin combination regimen is of great clinical importance.Different compounds or drugs used concomitantly with aminoglycosides may either increase or decrease aminoglycoside toxicity. In fact, drugs such as cisplatinum 4) and vancomycin 5) increase the nephrotoxicity of aminoglycosides, while recent studies showed that poly-L-aspartic acid, 6) daptomycin, 7,8) carbenicillin, 9) ticarcillin 10) and ceftriaxone 11) protected the kidney against aminoglycoside-induced nephrotoxicity.Fleroxacin is a synthetic broad-spectrum antibiotic belonging to the class of fluoroquinolones.12) It shows good antibacterial activity against many gram-negative bacteria, and less activity against gram-positive bacteria. 13,14) A recent investigation showed that fleroxacin (intraperitoneally) protected against gentamicin-induced nephrotoxicity in rats when both drugs were administered in combination. 15) In Japan, fleroxacin is given orally. In rats, fleroxacin reaches peak serum levels within 1 h after oral administration, with a half-life of 2.3 h. 16) In contrast with several other quinolones, fleroxacin is not metabolized and is mainly excreted unchanged in the urine.14,17,18) Fleroxacin reaches peak kidney concentrations within 0.5-1 h. In fact, high concentrations of fleroxacin have been measured in the kidney of rabbits 19) and in the human kidneys. 20) Moreover, the accumulation of fleroxacin was higher in the kidneys of patients with symptomatic complicated urinary tract infections. 21)To our knowledge, there are no data on the effects of fleroxacin (orally) on the nephrotoxicity of administered isepamicin. In view of the particular distribution of fleroxacin within the kidney, we have evaluated the nephrotoxic potential of the fleroxacin (orally) isepamicin combination regimen. MATERIALS AND METHODSAdult male Wistar rats weighing between 130-150 g were used. The animals were housed in a light-controlled room (lights on from 0800 to 2000 h) at a room temperature of 24Ϯ1°C and humidity of 60Ϯ10% for 1 week. They were acclimated for one week, and they had free access to food and water throughout the experiment.Isepamicin was dissolved in saline (0.9% NaCl). Fleroxacin was suspended in 0.3% sodium carboxymethyl cellulose (CMC-Na).For 14 d, animals were given one of the 4 regimens: a single injection of either saline (intraperitoneally) and CMC-Na (orally), saline (intraperitoneally) and fleroxacin 100 mg/kg (orally), isepamicin 300 mg/kg (intraperitoneally) and CMCNa (orally) or isepamicin (intraperitoneally) with fleroxacin (orally) at the same dose as when used alone. Animals were injected at 1300 h. This dosing schedule was determined from ...

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Effects of daptomycin and vancomycin on tobramycin nephrotoxicity in rats

Cited by 53 publications

References 33 publications

Daptomycin may attenuate experimental tobramycin nephrotoxicity by electrostatic complexation to tobramycin

Daptomycin may attenuate experimental tobramycin nephrotoxicity by electrostatic complexation to tobramycin

Attenuation by daptomycin of gentamicin-induced experimental nephrotoxicity

Protective Effect of Fleroxacin against the Nephrotoxicity of Isepamicin in Rats

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