Influence of daptomycin on staphylococcal abscesses and experimental tobramycin nephrotoxicity.

The antibacterial efficacies of daptomycin and vancomycin were compared in male Fischer rats with subcutaneous abscesses caused by either methicillin-susceptible Staphylococcus aureus (MSSA) or methicillin-resistant S. aureus (MRSA). The influence of daptomycin on tobramycin nephrotoxicity was also assessed. MSSA or MRSA abscesses were treated with subcutaneous daptomycin (10 mg/kg every 12 h), vancomycin (125 mg/kg every 12 h), or diluent (every 12 h) for 5 to 10 days. Rats in both antibiotic treatment groups had lower abscess bacterial counts than did controls at days 5 and 10 (P less than 0.0025). The daptomycin treatment groups had lower abscess bacterial counts than did the vancomycin treatment groups for MSSA at day 5 (P less than 0.0025) and day 10 (P less than 0.025) and for MRSA at day 10 (P less than 0.0025). Nephrotoxicity treatment groups included animals treated for 3, 7, 10, 14, and 17 days with subcutaneous diluent (every 12 h), daptomycin (20 mg/kg every 12 h), tobramycin (40 mg/kg every 12 h), and the combination of daptomycin and tobramycin. Compared with controls, animals treated with daptomycin alone exhibited no detectable nephrotoxicity. Rats given tobramycin alone developed functional and histopathologic abnormalities from days 7 through 17. Animals treated with daptomycin and tobramycin for 14 days had a lower mean concentration of creatinine in serum (P less than 0.005), higher mean creatinine clearance values (P less than 0.05), and less cortical tubular cell regeneration (P less than 0.05) than did rats treated with tobramycin alone. In rats with staphylococcal subcutaneous abscesses, daptomycin was superior to vancomycin in treating both MSSA and MRSA. Daptomycin alone caused no detectable renal injury, and in rats given daptomycin combined with tombramycin, there was less histologic and functional renal injury than in animals given tobramycin alone.     

Effects of daptomycin and vancomycin on tobramycin nephrotoxicity in rats

Daptomycin is a new biosynthetic antibiotic which belongs to a new class of drugs known as lipopeptides. The objective of this study was to evaluate the effects of daptomycin and vancomycin on tobramycin-induced nephrotoxicity. Female Sprague-Dawley rats were treated during 4 and 10 days with either saline (NaCl, 0.9%) or tobramycin at doses of 4 and 40 mg/kg per day (given every 12 h [q12h] intraperitoneally). Each treatment was combined with saline, daptomycin at a dose of 20 mg/kg per day (given q12h subcutaneously), and ancomycin at a dose of 50 mg/kg per day (given q12h subcutaneously). Daptomycin and vancomycin had no effect on the intracortical accumulation of tobramycin. Daptomycin did not accumulate in renal tissue even after 10 days of treatment. Tobramycin given at a dose of 40 mg/kg per day during 10 days induced a significant inhibition of sphingomyelinase activity in the renal cortex (P less than 0.01) and increased cellular regeneration (P less than 0.01), as measured by the incorporation of [3H]thymidine into DNA of the renal cortex. These changes were minimal when daptomycin was combined with tobramycin. Histologically, signs of tobramycin toxicity were also less severe in the presence of daptomycin. The intracortical accumulation of vancomycin was not modified by tobramycin. The sphingomyelinase activity was significantly more inhibited (P less than 0.01) when vancomycin was associated with tobramycin (4 and 40 mg/kg) without affecting the rate of [3H]thymidine incorporation into DNA. Histologically, signs of tobramycin toxicity were not affected by vancomuycin, but the cellular vacuolizations which were also observed in vancomycin-treated animals were still present in the proximal tubular cells of animals that were treated with the combination vancomycin-tobramycin. This study strongly suggests that daptomycin protects animals from tobramycin-induced nephrotoxicity but that vancomycin may enhance the effect of tobramycin. We conclude that daptomycin is safe and protects kidney cells from tobramycin-induced nephrotoxicity.     

Subcellular localization of tobramycin and vancomycin given alone and in combination in proximal tubular cells, determined by immunogold labeling.

The subcellular localization of tobramycin and vancomycin in the renal cortices of rats was determined with ultrathin sections by immunogold labeling. Four groups of four rats each were treated for 10 days with saline (NaCl, 0.9%), tobramycin at dosages of 20 mg/kg of body weight per 12 h intraperitoneally, vancomycin at dosages of 25 mg/kg/12 h subcutaneously, or the combination tobramycin-vancomycin. On day 11, the animals were killed, and cubes of renal cortex were fixed overnight in phosphate-buffered glutaraldehyde (0.5%), dehydrated in ethanol, and embedded in Araldite 502 resin. Ultrathin sections were made and incubated with sheep antitobramycin antibody followed by protein A-gold (15-nm diameter) complex or rabbit antivancomycin antibody followed by gold (30-nm diameter)-labeled goat anti-rabbit antibody. For the double labeling, incubations were made on opposite sides of the grid. Tobramycin was detected over the lysosomes of proximal tubular cells, but the labeling was concentrated into small areas in the matrix of the lysosomes. Vancomycin was seen over the lysosomes of proximal tubular cells and was distributed uniformly throughout the matrix of the lysosomes. In rats treated with tobramycin-vancomycin, both drugs were still detected in lysosomes of proximal tubular cells. It is concluded that tobramycin and vancomycin accumulate in lysosomes of proximal tubular cells throughout 10 days of treatment and that vancomycin has no effect on the subcellular distribution of tobramycin.     

Comparative Nephrotoxicity of Gentamicin and Tobramycin in Rats

A rat model was utilized to compare the nephrotoxic potential of gentamicin and tobramycin. Gentamicin, 40 mg/kg per day, predictably produced renal failure and morphological evidence of proximal tubular necrosis over 14 days of treatment. An identical dosage of tobramycin was associated with only minimal morphological changes and normal concentrations of serum creatinine and blood urea nitrogen. Similar results were obtained even after the tobramycin dosage was tripled to 120 mg/kg per day. A decrease in urine osmolality, mechanism unknown, was observed in all aminoglycoside-treated rats, but the lowest osmolalities were found in the gentamicin-treated rats. According to both histological criteria and renal function measurements, gentamicin was more nephrotoxic than tobramycin in this animal model.     

Attenuation of experimental tobramycin nephrotoxicity by ticarcillin.

It is well known that in vitro the combination of carbenicillin, ticarcillin, or other antipseudomonal penicillins with gentamicin, tobramycin, or other aminoglycoside antibiotics results in the inactivation of the antibacterial activity of the aminoglycoside. To assess the influence of the in vivo interaction of tobramycin and ticarcillin on experimental nephrotoxicity, male Fischer 344 rats were given either tobramycin alone (120 mg/kg per day), tobramycin (120 mg/kg per day) and ticarcillin (250 mg/kg per day) concomitantly, or the combination of these drugs at the same doses that had been preincubated for 24 h and at the time of delivery contained but 63 and 25%, respectively, of the initial concentrations of tobramycin and ticarcillin as measured by conventional analytical procedures. Initial experiments were conducted to determine the concentrations of the antibiotics in serum achieved after administration of each test solution. After a single dose of the test solution, ticarcillin concentrations in serum were higher and more prolonged in rats given tobramycin plus ticarcillin than in rats given ticarcillin alone. After 7 days of exposure to the test solutions, inulin clearance in animals given tobramycin alone was 0.15 +/- 0.1 (mean +/- 2 standard errors) ml/min per 100 g of body weight as compared with 0.53 +/- 0.1 in rats given tobramycin and ticarcillin concomitantly, 0.59 +/- 0.1 in animals given the partially inactivated tobramycin-ticarcillin mixture, and 0.79 +/- 0.1 in control rats. Although there was some improvement in inulin clearance in the group containing tobramycin alone, the three treatment groups maintained the same rank relationship in inulin clearance through 14 days of treatment. Real histology confirmed the attenuation of tubular injury in animals given tobramycin and ticarcillin concomitantly. There was no evidence of toxicity from the presumed inactivation complexes of tobramycin-ticarcillin. These results document an in vivo protective effect of ticarcillin on experimental tobramycin nephrotoxicity.     

Ceftriaxone protects against tobramycin nephrotoxicity.

The effect of ceftriaxone on tobramycin-induced nephrotoxicity was investigated. Female Sprague-Dawley rats were treated during 4 and 10 days with saline (NaCl, 0.9%), ceftriaxone at a dose of 100 mg/kg of body weight/12 h subcutaneously, tobramycin at doses of 40 and 60 mg/kg/12 h intraperitoneally, or the combination ceftriaxone-tobramycin. Creatinine levels in serum were significantly higher in animals treated with tobramycin alone given at 60 mg/kg/12 h during 10 days, compared with control animals (P < 0.01) or animals receiving the combination tobramycin-ceftriaxone (P < 0.01). After 10 days of treatment, ceftriaxone did not accumulate in renal tissue but did reduce the renal intracortical accumulation of tobramycin (P < 0.05). Tobramycin given alone at either 40 or 60 mg/kg/12 h induced a significant inhibition of sphingomyelinase activity compared with control animals (P < 0.05). However, this enzyme activity was significantly less inhibited when tobramycin was injected in combination with ceftriaxone (P < 0.05). Ceftriaxone alone had no effect on the activity of this enzyme. The [3H]thymidine incorporation into the DNA of renal cortex was also significantly lower in animals treated with tobramycin-ceftriaxone compared with animals receiving tobramycin alone (P < 0.05). The 24-h urinary excretion of beta-galactosidase was significantly reduced in animals treated with the combination tobramycin-ceftriaxone compared with the administration of tobramycin alone at 40 and 60 mg/kg/12 h after 5 and 10 days (P < 0.05). Histologically, ceftriazone induced very few cellular alterations and reduced considerably the presence of typical signs of tobramycin nephrotoxicity. This investigation demonstrated that ceftriaxone protects animals against tobramycin-induced nephrotoxicity.     

Cisplatin nephrotoxicity and protection by milk thistle extract in rats

The protective effect of methanolic extract of milk thistle seeds and silymarin against cisplatin-induced renal toxicity in male rats after a single intraperitoneal injection of 3 mg kg cisplatin were studied. Over 5 days, cisplatin-treated rats showed tubular necrosis and elevation in blood urea nitrogen (BUN) and serum creatinine (Scr). Pretreatment of animals with silymarin (50 mg kg) or extract (0.6 g kg) 2 h before cisplatin prevented the tubular damage. Rats treated with silymarin or extract 2 h after cisplatin had BUN and Scr significantly lower than those receiving cisplatin, but mild to moderate necrosis was observed. These results suggested that milk thistle may protect against cisplatin-induced renal toxicity and might serve as a novel combination agent with cisplatin to limit renal injury.     

Attenuation of gentamicin-induced nephrotoxicity in rats by fleroxacin.

The effect of fleroxacin on gentamicin-induced nephrotoxicity was evaluated with female Sprague-Dawley rats. Animals were injected during 4 or 10 days with saline (NaCl; 0.9%), gentamicin alone at doses of 10 and 40 mg/kg of body weight/12 h (subcutaneously), fleroxacin alone at a dose of 25 mg/kg/12 h (intraperitoneally), or the combination gentamicin-fleroxacin in the same regimen. Gentamicin induced a dose- and time-dependent renal toxicity as evaluated by gentamicin cortical levels, sphingomyelinase activity in the renal cortex, histopathologic and morphometric analysis, blood urea nitrogen and serum creatinine levels, and cellular regeneration ([3H]thymidine incorporation into DNA of cortical cells). The extent of these changes was significantly reduced when gentamicin was given in combination with fleroxacin. Although the mechanisms by which fleroxacin reduces the nephrotoxic potential of gentamicin are unknown, we propose that the fleroxacin-gentamicin combination enhances exocytosis activity in proximal tubular cells, as suggested by the higher excretion of urinary enzymes and lower cortical levels of gentamicin observed in animals treated with the combination fleroxacin-gentamicin compared with those treated with gentamicin alone. The protective effect of fleroxacin on gentamicin nephrotoxicity should be investigated further.     

Attenuation by daptomycin of gentamicin-induced experimental nephrotoxicity.

Previously, daptomycin was shown to reduce tobramycin nephrotoxicity in vivo (D. Beauchamp, M. Pellerin, P. Gourde, M. Pettigrew, and M. G. Bergeron, Antimicrob. Agents Chemother. 34:139-147, 1990; C. A. Wood, H. C. Finkbeiner, S. J. Kohlhepp, P. W. Kohnen, and D. C. Gilbert, Antimicrob. Agents Chemother. 33:1280-1285, 1989). 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 ([3H]thymidine 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.     

Experimental studies on the nephrotoxicity of amphotericin B in rats.

The renal effects of amphotericin B alone and in combination with cyclosporin A, tobramycin, fosfomycin, D-glucaro-1,5-lactam and verapamil were studied in rats. The parameters for nephrotoxicity were urinary loss of tubular cells and malate dehydrogenase, as well as creatinine clearance. Repeated intraperitoneal injections of amphotericin B led to an increase of urinary tubular cell elimination and malate-dehydrogenase. After co-administration of amphotericin B and cyclosporin A, the urinary loss of tubular cells increased and creatinine clearance was reduced. A combination of amphotericin B and tobramycin reduced tubular cell elimination but the creatinine clearance improved. When verapamil was combined with amphotericin B, endogenous creatinine clearance increased, though the loss of tubular cells was elevated. Furthermore, fosfomycin reduced the loss of tubular cells and improved renal functional parameters in combination with amphotericin B. In addition, D-glucaro-1,5-lactam was found to reduce the urinary loss of tubular cells induced by amphotericin B.     

Daptomycin may attenuate experimental tobramycin nephrotoxicity by electrostatic complexation to tobramycin.

The lipopeptidic antibiotic daptomycin is reported to reduce experimental tobramycin nephrotoxicity (D. Beauchamp, M. Pellerin, P. Gourde, M. Pettigrew and M. G. Bergeron, Antimicrob. Agents Chemother. 34:139-147, 1990; C. A. Wood, H. C. Finkbeiner, S. J. Kohlhepp, P. W. Kohnen, and D. C. Gilbert, Antimicrob. Agents Chemother. 33:1280-1285, 1989). 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 micrograms/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.     

Relationship between rat renal accumulation of gentamicin, tobramycin, and netilmicin and their nephrotoxicities.

Gentamicin, tobramycin, and netilmicin were given to rats in daily doses of either 5 or 20 mg/kg for 30 days to determine the renal accumulation kinetics of the compounds and to correlate steady-state renal parenchymal concentrations with nephrotoxicity. Four rats from each group were sacrificed daily and renal parenchymal tissue concentrations were determined microbiologically. Nephrotoxicity was assessed by changes in creatinine values in serum, renal creatinine clearances, and pathological scores. There was no indication of aminoglycoside-induced nephrotoxicity in any tests performed. The following steady-state levels resulted: 36, 148, and 176 micrograms/g after 5 mg/kg per day and 148, 260, and 510 micrograms/g after 20 mg/kg per day for tobramycin, gentamicin, and netilmicin, respectively. We conclude that aminoglycoside parenchymal accumulation in rats follows this order: tobramycin less than gentamicin less than netilmicin. Therefore, differences in the relative toxicities of gentamicin, tobramycin, and netilmicin do not correlate with the renal parenchymal accumulation of these agents and may be more dependent on intrinsic toxicity to the renal proximal tubule than to the concentration of the aminoglycoside in the kidney.     

Temporal changes of pharmacokinetics, nephrotoxicity, and subcellular distribution of tobramycin in rats.

The present study was designed to determine the temporal changes in tobramycin nephrotoxicity during the dark and the light periods of the day and to look for the mechanisms of such changes. Female Sprague-Dawley rats (9 to 11 weeks old) were housed in a 14-h-light-10-h-dark cycle (lights on 0600 to 2000 h). A bolus of tobramycin (60 mg/kg of body weight) was intravenously injected into a first group of 15 rats, at either 1400 or 0200 h. Six blood samples were taken from each rat, 30 to 210 min after the bolus injection. The total clearance of the drug was reduced during the rest period (1400 h) of rats compared with the activity period (0200 h) (P = 0.0007). Another group of 99 rats was given intraperitoneally a single dose of tobramycin (40 mg/kg), and renal cortices were collected 2 to 222 h after injection. The cortical drug levels were always higher in animals injected at 1400 h than in those injected at 0200 h. A last group of 32 rats was used in the studies of tobramycin (30 mg/kg/day, once daily for 10 days, intraperitoneally) nephrotoxicity and subcellular distribution. Weight gain in the rats receiving tobramycin (both 1400 and 0200 h) was significantly (P = 0.028) less than that in the controls. Nephrotoxicity, indicated by the incorporation of [3H]thymidine into cortical DNA and urinary excretion of N-acetyl-beta-D-glucosaminidase, was significantly higher in animals treated at 1400 h than in those treated at 0200 h. No difference in the subcellular distribution of tobramycin was observed. The data indicate that the reduction in the clearance of tobramycin during the rest period is in part responsible for the higher nephrotoxicity in rats.     

Renal function in rats with essential fatty acid deficiency

1. Renal function was studied in 50-, 70-, 90- and 200-day-old rats with essential fatty acid deficiency. The pharmacokinetics of tobramycin was investigated in 90-day-old essential fatty acid-deficient rats. 2. A higher glomerular filtration rate and a higher serum concentration of urea were seen in 50-day-old essential fatty acid-deficient rats compared with age-matched controls. Later, the glomerular filtration rate progressively deteriorated in parallel with a decline in effective renal plasma flow and with a concomittant rise in serum levels of urea and creatinine. The serum concentration of protein was lower in the rats with essential fatty acid deficiency and that of sodium was higher than in the control rats. The non-renal clearance of tobramycin was increased in the rats with essential fatty acid deficiency. 3. The early hyperfiltration in essential fatty acid-deficient rats with the subsequent fall in glomerular filtration rate, which was paralleled by a rise in serum levels of urea and creatinine, as well as the increased non-renal clearance of tobramycin, are in accordance with the clinical manifestations of cystic fibrosis. Rats with essential fatty acid deficiency might be a useful model with which to study the pathophysiological renal changes in cystic fibrosis related to the progressive essential fatty acid deficiency in this disease.     

Chronic tubulointerstitial nephritis and renal insufficiency associated with long-term "subtherapeutic" gentamicin

To determine whether long-term "subtherapeutic" concentrations of aminoglycoside produce chronic tubulointerstitial nephropathy, Fisher rats were given gentamicin, 20 mg/kg/day, for up to 6 months via indwelling osmotic infusion pumps. Studies included renal histology, autoradiographic quantitation of renal cell tritiated thymidine uptake, renal function and renal cortical gentamicin assay. Acute proximal tubular injury, without tubular necrosis, followed by recovery, occurred during the first month. Subsequently only mild, nonprogressive tubulointerstitial changes and a twofold increase in tubular cell turnover were observed. Inulin clearance fell more than 50% during the 6 months of treatment compared with 10% in age-matched controls. Serum creatinine and creatinine clearance overestimated glomerular filtration rate during treatment and did not distinguish treated animals from controls. During the month after 6 months of gentamicin, tubular microcystic changes and active tubulointerstitial nephritis developed, with a continued fall in inulin clearance. In summary, gentamicin, in "subtherapeutic" doses, produces mild chronic tubulointerstitial nephritis with progressive renal failure. Cessation of treatment is associated with microcystic and inflammatory changes, suggesting that the renal response to tubular injury can be dissociated from the amount of toxin in the renal cortex. Keeping serum aminoglycoside levels below accepted therapeutic range for 6 months did not preclude nephrotoxicity.     

Nephrotoxicity due to combination antibiotic therapy with vancomycin and aminoglycosides in septic critically ill patients

The aim of this prospective observational study was to evaluate the incidence of nephrotoxicity due to combination therapy with vancomycin and aminoglycosides in septic critically ill patients admitted to the intensive care unit. METHODS: Thirty consecutive critically ill patients were treated with vancomycin concurrent with aminoglycosides for sepsis. Inclusion criteria were: the need for mechanical ventilation and the presence of severe infection due to bacteria susceptible to vancomycin and aminoglycosides. Exclusion criteria were: age <18 years, impaired renal function (24-hour creatinine clearance <90 ml/min) or previous adverse reaction to either drug. Serum creatinine and urea concentrations, creatinine clearance, 24-hour urinary excretion of proteins, beta2-microglobulin and enzymes were measured immediately before starting therapy and at different times thereafter. RESULTS: Eleven of the 30 patients had a transient and modest increase in serum urea, 15 patients presented with urinary excretion of beta2-microglobulin and tubular enzymes, and 14 patients had urinary proteins.In the only patient with severe acute renal failure (serum creatinine 8.2 mg/dl), the clinical course was complicated by prolonged hypotension. CONCLUSION: Concurrent administration of vancomycin and aminoglycosides to critically ill septic patients with normal renal function at baseline induced mainly slight and transient toxic tubular effects. The only clinically significant nephrotoxic event occurred in a patient with septic shock.     

Protective effect of piperacillin against the nephrotoxicity of cisplatin in rats.

The protective effect of piperacillin against the nephrotoxicity of cisplatin was compared with that of fosfomycin in Fischer 344 rats. Blood urea nitrogen, serum creatinine, and morphological changes were evaluated as the renal toxicological parameters. Rats receiving 2 mg of cisplatin per kg of body weight for 5 days showed significant (P less than 0.01 by multiple-comparison test) elevation of blood urea nitrogen and serum creatinine concentrations compared with rats receiving saline alone and also exhibited development of cell lesions in the pars recta of the tubules in the outer stripe of the outer medulla. However, piperacillin (250 and 1,000 mg/kg) significantly (P less than 0.01 by multiple-comparison test) reduced these toxicological parameters in comparison with results for cisplatin alone. The protective effect of piperacillin was superior to that of fosfomycin, although platinum levels in the kidney were higher with the combination of cisplatin and piperacillin than with cisplatin plus fosfomycin. Although the nephrotoxicity of cisplatin was also reduced when cisplatin was administered concomitantly with sodium chloride in mole-equivalents to 250 and 1,000 mg of piperacillin per kg, its protective effect was less than that of the corresponding piperacillin dose. These results suggest that piperacillin may have a role as a protective agent against the nephrotoxicity of cisplatin.     

Investigating the protective effects of aged garlic extract on cyclosporin-induced nephrotoxicity in rats

Cyclosporin A (CsA) nephrotoxicity has been described in solid organ recipients and in the patients who were treated for autoimmune diseases. Reactive oxygen species-induced oxidative stress and lipid peroxidations are implicated in the pathophysiology of CsA-induced renal injury. Aged garlic extract (AGE) has been reported to exhibit potent antioxidative and free radical scavenging abilities in various disease conditions. The present study was designed to investigate whether AGE could possibly have a protective effect against nephrotoxicity induced by CsA. Male Wistar rats were treated orally with CsA (50 mg/kg/day), CsA + AGE (0.25, 0.5, 1, and 2 g/kg/day started 3 days before the first dose of CsA), or the vehicle of CsA for a period of 10 days. Blood urea nitrogen, serum creatinine, creatinine clearance, and renal histopathological changes were evaluated after 24 h of the last treatment. CsA caused an increase in blood urea nitrogen and serum creatinine by 117 and 100%, respectively, whereas it decreased creatinine clearance by 78% compared with the vehicle-treated rats (all P < 0.001). AGE treatment (0.5, 1 and 2 g/kg) significantly protected animals against CsA-induced biochemical changes, albeit blood urea nitrogen and creatinine clearance in the 0.5 g/kg AGE treated-animals were only partially restored. Kidney sections taken from CsA-treated rats showed severe vacuolations and tubular necrosis. These histopathological changes were markedly improved by pretreatment of rats with AGE at the dose of 0.5--2 g/kg. The results indicate that AGE ameliorates renal dysfunction and morphological changes induced by CsA, and imply that it could be a beneficial remedy for attenuating the CsA nephrotoxicity.     

Nephrotoxicity of vancomycin, alone and with an aminoglycoside

The incidence of nephrotoxicity in patients receiving vancomycin alone or in combination with an aminoglycoside was prospectively evaluated. A total of 231 courses of antibiotic therapy in 224 patients were consecutively monitored over 28-month period. One hundred and sixty-eight patients received vancomycin alone, 63 patients received vancomycin with an aminoglycoside, and 103 patients received gentamicin. Nephrotoxicity was defined as an increase in serum creatinine of 0.5 mg/dl or a 50% increase above baseline, whichever was greater. Eight patients (5%) receiving vancomycin alone, 14 patients (22%) receiving vancomycin with an aminoglycoside, and 11 patients (11%) receiving gentamicin alone were found to have nephrotoxicity. Factors found to be associated with increased risk of nephrotoxicity in patients receiving vancomycin were concurrent therapy with an aminoglycoside, length of treatment with vancomycin (greater than 21 days), and vancomycin trough serum concentration (greater than 10 mg/l). Although the incidence of vancomycin nephrotoxicity is low, patients receiving vancomycin therapy with the above risk factors should be closely monitored.     

The renin-angiotensin system in aminoglycoside-induced acute renal failure

To examine the role of the renin-angiotensin system in aminoglycoside-induced acute renal failure, we gave rats gentamicin (80 mg/kg/day), gentamicin + captopril (an angiotensin-converting enzyme inhibitor), captopril alone or saline sham injections, for 10 days. Blood pressure, sodium excretion, urine osmolality and creatinine clearance were measured four times during treatment. Plasma renin activity, angiotensin I-converting enzyme and renal histology were determined at sacrifice. Although angiotensin I-converting enzyme activity was markedly suppressed by captopril treatment, the addition of captopril failed to consistently influence blood pressure or urine osmolality. In addition, it did not promote natriuresis in the face of gentamicin toxicity. Creatinine clearance decreased progressively in groups receiving gentamicin and was lowest (P less than .05) in the groups receiving gentamicin + captopril. Captopril did not prevent the development of tubular epithelial nor glomerular endothelial changes associated with gentamicin toxicity. In a separate experiment rats received captopril for 3 days prior, before receiving the gentamicin + captopril regimen for 10 days. Captopril pretreatment did not influence the results. This study does not support a pivotal role for the renin-angiotensin system in the production of the decreased glomerular filtration rate observed in nephrotoxic acute renal failure induced by gentamicin in rats.