Comparative low-dose nephrotoxicities of gentamicin, tobramycin, and amikacin

Abstract

Most investigations of the comparative nephrotoxicities of aminoglycosides in animals have utilized large multiples of the human dose. Furthermore, many of these assessments have used only one or two dose levels and have not described a dose-response comparison among antibiotics. Because of this lack of comparative dose-response data over a range of low multiples of the human dose, the nephrotoxicities of gentamicin, tobramycin, and amikacin were investigated in 180 rats, utilizing doses ranging from one to seven times the equivalent human clinical doses. Histopathological evaluations of both kidneys from each rat were scored without knowledge of the treatment, and statistical analyses of the results indicated that a linear and parallel dose-response relationship existed for each drug, the relative nephrotoxicity over the range of doses analyzed was gentamicin > tobramycin > amikacin (P = 0.0001), and, unlike amikacin, the human dose equivalents (milligrams per kilogram) of gentamicin and tobramycin were significantly nephrotoxic in rats (P < 0.05).The prevalent utilization of doses many times greater than those used in human antibacterial therapy when comparing the nephrotoxicities of aminoglycosides in animals has been questioned (1, 31). Additionally, many of these studies have employed only one or two dose levels and have not defined relative dose-response relationships. Relative toxicity is classically defined by comparing dose-response relationships which are linear and paralel over a range of responses of a similar magnitude (11,15). Based on results of a previous limited comparison (13), the relative dose-response nephrotoxicities of gentamicin, tobramycin, and amikacin were explored in rats by utilizing a range of low doses anticipated to produce similar magnitudes of nephrotoxic responses.MATERIALS AND METHODS Animals. A total of 180 adult male Sprague-Dawley rats (Charles River Breeding Laboratories, Inc.), weighing between 105 and 140 g upon arrival, were conditioned for 14 days before initiation of the study. The rats were housed individually in cages of appropriate type and size in an environmentally controlled room, given Purina Laboratory Chow and fresh drinking water ad libitum, ranked by body weight, and then randomly divided into groups of 10 after being individually identified by a tag number attached to an ear.Aminoglycoside administration. The 18 groups of 10 rats each were dosed for 28 days as shown in Table 1. Doses were selected with regard to antibiotic activity, split, and administered twice a day at approximately 9 a.m. and 3 p.m. by subcutaneous injection through a 27-gauge needle. The five gentamicin doses (4 to 20 mg/kg per day), six tobramycin doses (4 to 40.5 mg/kg per day), and six amikacin doses (15 to 98 mg/kg per day) were each geometrically spaced, except for the lowest doses of tobramycin and amikacin. The human therapeutic doses recommended in the package inserts are as follows: gentamicin and tobramycin, 3 to 5 mg/kg per day (we used 4 mg/kg per day); amikacin, 15 mg/kg p...

Correlation between renal membrane binding and nephrotoxicity of aminoglycosides

“…These inhibitory potencies reflect the relative affinity of these aminoglycosides for the renal membranebinding site. The relative affinities are in good agreement with the in vivo nephrotoxic potentials of these aminoglycosides (14)(15)(16)30). Neomycin is consistently the most nephrotoxic aminoglycoside, whereas streptomycin is essentially nonnephrotoxic.…”

Increased renal DNA synthesis in vivo after administration of low doses of gentamicin to rats

“…A similar pattern of reaction is seen after mercuric chloride intoxication (5). Moreover, long-term exposure to gentamicin induces marked interstitial infiltration, leading to fibrosis and focal inflammatory peritubular reaction (11).…”

“…Tubular regeneration is also observed after treatment at low doses, but becomes unambiguously detectable by conventional histology only after prolonged treatment (28 days or more) (4,11).…”

Comparative Study of Erythrocyte Sedimentation Rate after Aminoglycoside and Aminocyclitol Treatment in Goats (Capra hircus)

“…The analysis of amikacin and gentamicin survey data indicates that in kidney damage along with important biochemical indicators (such as elevation of urea and creatinine concentration), ESR is also increased (Dhar et al, 2013;Mumtaz et al, 2014;Sayarifard et al, 2015). The slight variations of ESR values after amikacin administration can be explained by the low nephrotoxic potential of this aminoglycoside, less than the same for gentamicin and tobramycin (Hottendorf and Gordon, 1980). Spectinomycin leads to significant increase of ESR, followed by a trend to recovery of the baseline values.…”

“…Given the effectiveness of these drugs is concentration-dependent and count on rapid achievement of high serum concentrations, the first dose can be injected intravenously, and the next ones -intramuscularly (Lacy et al, 1998). Well known are the nephrotoxic changes caused by these antibiotics in high doses (Hottendorf and Gordon 1980;Schentag et al, 1981) and in this respect there are comparative trials (Brion et al, 1984;Hottendorf and Gordon, 1980;Rankin et al, 1980;Schentag et al, 1981). However, there are experiments on the impact of low therapeutic doses of these antibiotics on biochemical and hematological parameters (Dinev et al, 2005;Yazar et al, 2003).…”