Toxicology of Vancomycin in Laboratory Animals

The influence of vancomycn on tobramycin nephrotoxicity was assessed in male Fischer rats. Treatment groups included controls receiving diluent and groups receiving vancomycin alone at a dosage of 200 mg/kg (body weight) per day, tobramycin alone at a dosage of 80 mg/kg per day, and a combination of vancomycin and tobramycin at the above dosages. All regimens were injected on a twice-a-day schedule. The animals were sacrificed on days 1, 3, 10, 14, 17, and 21. When compared with controls, animals receiving vancomycin alone exhibited no detectable renal toxicity. Compared with the case with controls, tobramycin alone was toxic, as manifested by lower mean animal weights, increased blood urea nitrogen concentrations on days 14 and 17 (P < 0.005), increased serum creatinine concentrations on days 17 and 21 (P < 0.005), and the presence of renal cortical tubular necrosis and regeneration. When compared with tobramycin alone, the combination of vancomycin and tobramycin caused earlier and more severe toxicity. By day 10, the magnitude of weight loss, the rise in blood urea nitrogen, and the increase in serum creatinine concentration were all greater in the rats given the combination of vancomycin plus tobramycin than in the animals given tobramycin alone (P < 0.005). In addition, there was more proximal tubular necrosis and regeneration in rats given vancomycin plus tobramycin compared with those given tobramycin alone. In this animal model, vancomycin alone caused no detectable renal injury, tobramycin alone produced minimal proximal tubular damage, and the combination of vancomycin and tobramycin resulted in a greater degree of kidney injury than observed with tobramycin alone.In recent years, clinical indications for combination antimicrobic therapy with vancomycin and an aminoglycoside have increased. Selected examples are prosthetic valve endocarditis caused by Staphylococcus epidermidis (9), serious infections caused by methicillin-resistant Staphylococcus aureus (10), and endocarditis caused by group D streptococci in patients allergic to penicillin (8,15).The dose-dependent nephrotoxic potential of the aminoglycosides is well known. The nephrotoxic potential of vancomycin is uncertain. Early clinical studies with vancomycin described patients who developed granular casts, increases in blood urea nitrogen (BUN), and severe anemia and even died from acute renal failure. Subsequently, impurities present in the initial vancomycin preparations were removed (7, 17). More recent clinical studies describe a very low incidence of renal injury in patients given only vancomycin (1,3,4,13,14). However, it has been suggested that vancomycin given concomitantly with an aminoglycoside may increase the frequency of aminoglycoside nephrotoxicity (3). Farber and Moellering described, retrospectively, more nephrotoxicity in patients given the combination of vancomycin and an aminoglycoside than in patients administered only vancomycin (3). Unfortunately, the latter study did not include a control group of patients given only an...

Section: Discussionsupporting

confidence: 90%

Vancomycin enhancement of experimental tobramycin nephrotoxicity

Wood¹,

Kohlhepp²,

Kohnen³

et al. 1986

“…The elimination the cortex and were detected only at high doses (2). Daily ts were similar between control and endotoxininjections of 150 mg/kg given during 4 days induced renal in the renal cortex and medulla but were higher failure (1,33), and very large doses infused intravenously a of animals injected with endotoxin compared were needed to induce renal failure and death in dogs (32). (19) reted in the urine of endotoxin-treated rats than have observed that while the level of vancomycin in serum rmal rats (219.6 ± 45.1 versus 937.8 ± 321.7 pLg, decreases rapidly, the concentrations in the kidneys remain P < 0.01).…”

Section: Methodsmentioning

confidence: 74%

Intrarenal distribution of vancomycin in endotoxemic rats

Ngeleka

Auclair

Tardif

et al. 1989

We previously observed that the intrarenal distribution of aminoglycosides was modified by Escherichia coli endotoxin in the absence of any major renal physiological disturbance or histological changes. In the present study, we evaluated the role of E. coli endotoxin on the intrarenal distribution of vancomycin. At the beginning of the experiment, female Sprague-Dawley rats were infused intravenously with saline (control) or endotoxin (0.25 mg/kg) during 15 min. Thereafter, saline was constantly infused for the following 4 h. Two hours after the beginning of the infusion, animals were injected intravenously with a single dose of vancomycin (20 mg/kg).The drug levels in serum; renal cortex, medulla, and papilla; and urine were evaluated from 0.08 to 24 h after injection. Analysis of the area under the curve of the drug concentration in the different kidney components versus time showed a higher accumulation of vancomycin in the renal cortex and medulla in the endotoxininfused rats than in the normal rats (P < 0.01). Endotoxin was associated with an increase in the half-life in serum (P < 0.01) and a lower elimination rate constant. The total clearance of vancomycin from plasma was significantly decreased in endotoxin-treated rats (P < 0.01). These results demonstrate that endotoxin modifies the renal handling of vancomycin.Vancomycin is a glycopeptide antibiotic with potent activity against gram-positive bacteria which may increase the nephrotoxic potential of aminoglycosides. The early preparation introduced in the 1950s had many impurities (14). During that period, although the nephrotoxic potential was not clearly established, up to 25% of patient were reported to have increased azotemia (29). When less toxic antistaphylococcal antibiotics, including the semisynthetic penicillins and cephalosporins, appeared, vancomycin use drastically diminished; but the emergence of methicillin-resistant staphylococci has prompted the resurgence of its use (27). The currently available compound has been purified and is believed to be less toxic than the parent compound. The incidence of nephrotoxicity with the new vancomycin has been less than 8% (11,23,27). In animals, large doses of antibiotics are needed to induce renal damage, and the mechanism of renal toxicity has not been determined. It seems that vancomycin accumulates within the renal parenchyma and induces an interstitial nephritis and proximal tubular necrosis.Endotoxin, an important constituent of the cell wall of gram-negative bacteria, has been classified as a major offender that is responsible for many complications associated with severe infections, including septic shock and renal failure. Endotoxin, which is liberated in infected patients and released in excess during antibiotic therapy (25), is able to modify the hemodynamic status of the host (13), to activate the immunological and inflammatory processes (6), to induce vasoconstriction (28), and to act directly on target cells and organelles to induce cell injuries (15,18).Previous experimental studies fr...

“…Wold and Turnipseed demonstrated that the combination of vancomycin and an aminoglycoside resulted in a higher incidence of nephrotoxicity in the rat model than either agent alone (28). In a more recent study, Wood et al determined histologically that rats treated with the combination of vancomycin and tobramycin showed a greater degree of proximal tubular necrosis than rats treated with either agent alone (29).…”

Section: Discussionmentioning

confidence: 99%

“…In a more recent study, Wood et al determined histologically that rats treated with the combination of vancomycin and tobramycin showed a greater degree of proximal tubular necrosis than rats treated with either agent alone (29). In addition, information regarding the combination of vancomycin with aminoglycosides in patients thus far indicates a higher risk of nephrotoxicity with the combination than with either agent alone (7,20,25,28,29).…”

Section: Discussionmentioning

confidence: 99%

“…While the mechanism of aminoglycoside-induced tubular toxicity has been described and shown to correlate with increased 12M and AAP urinary elimination, the vancomycin mechanism of action for nephrotoxicity has yet to be determined (1,16,17). In animal studies, kidney damage secondary to treatment with both aminoglycosides and vancomycin has been reported and the mechanisms of the drugs have been postulated as similar (1,15,16,28,29). To determine the significance of this potentiation of nephrotoxicity, we examined the elimination of AAP and P2M from patients receiving vancomycin alone, gentamicin alone, or concomitant vancomycin and gentamicin.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Alanine aminopeptidase and beta 2-microglobulin excretion in patients receiving vancomycin and gentamicin

Rybak

Frankowski

Edwards

et al. 1987

The effects of vancomycin, gentamicin, and combination vancomycin-gentamicin treatments on alanine aminopeptidase (AAP) and 02-microglobulin (02M) elimination in 30 hospitalized patients were assessed and compared with elimination in a control group. Twenty-four-hour urine excretion values for AAP and j2M were determined on treatment day 1 and day 5 for patients receiving the three treatment regimens and for the control group. AAP excretion values for the vancomycin-treated group were not found to be statistically different from those of the control group. Both the gentamicin and the vancomycin-gentamicin groups had statistically higher AAP excretion values on treatment day 1 as well as on treatment day 5 when compared with the vancomycin and control groups. AAP excretion on day 5 of treatment was highest for the vancomycin-gentamicin group.Overall, ,2M elimination was variable in all treatment groups. Although the ,2M values were elevated as early as day 1 in all treatment groups, they were significantly elevated only in the vancomycin-gentamicin group on day 1 and only in the gentamicin group on day 5 compared with the vancomycin and the control groups. AAP appears to be a sensitive indicator of renal tubular damage. The combination of vancomycin and gentamicin results in greater AAP excretion than does either agent alone.