Preclinical toxicology studies with tobramycin

Welles, John S.; Emmerson, John L.; Gibson, W. P. R.; Nickander, R; Owen, N.V.; Anderson, Robert C.

doi:10.1016/0041-008x(73)90313-x

Cited by 40 publications

(12 citation statements)

References 5 publications

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“…The production of such an intermediate grade of nephrotoxicity facilitates the development of a dose response and permits a more accurate microscopic comparison than do larger, more destructive doses (13). The light microscopic changes were confined to the proximal tubules and were consistent with those ascribed to aminoglycosides in rats and humans (10,13,24,29). Some acute focal tubular epithelial degeneration and necrosis were evident, particularly at the higher doses of all aminoglycosides (Fig.…”

supporting

confidence: 53%

“…Unfortunately, there is no satisfactory marker to predict impending nephrotoxicity in clinics (6). Microscopic examination of kidney sections is an accurate and sensitive method of assessing subclinical nephrotoxicity in animals, particularly if there is only slight to moderate focal renal damage (13,14,26,29,33). Comprehensive prospective, double-blind clinical studies comparing various aminoglycosides would be highly desirable, especially if more sensitive renal function tests and estimates of glomerular filtration more reliable than creatinine were included, but "until such data in man are available, reliance must be placed on animal studies" (16).…”

Section: Discussionmentioning

confidence: 99%

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

Hottendorf¹,

Gordon²

1980

Antimicrob Agents Chemother

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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...

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supporting

confidence: 53%

Section: Discussionmentioning

confidence: 99%

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

Hottendorf¹,

Gordon²

1980

Antimicrob Agents Chemother

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“…The renal pathology of rats receiving tobramycin alone or in combination with cefamandole nafate was similar to the effects of tobramycin reported previously (20). Histopathological evaluation ofkidney tissue indicated a doserelated increase in severity of renal tubular reparative nephrosis and necrosis in rats receiving tobramycin ( mg/kg in acute experiments and 500 mg/kg per day in subacute experiments) produced no significant toxicity when given alone in these experiments or in more extensive studies (J. S. Wold, J. S. Welles, N. V. Owen, W. R. Gibson, and D. M. Morton, J. Infect.…”

Section: Resultssupporting

confidence: 63%

“…Tobramycin (Nebcin, Eli Lilly & Co.) is a recently introduced aminoglycoside with an antibiotic spectrum and profile of toxicity in laboratory animals that compares favorably with those of gentamicin (17,20). Cefamandole nafate (Mandol, Eli Lilly & Co.) is a new cephalosporin antibiotic with an expanded antibacterial spectrum compared with cephalothin (21).…”

mentioning

confidence: 99%

Effect of Cefamandole Nafate on the Toxicity of Tobramycin

Wold

Turnipseed

Broddle

et al. 1977

Antimicrob Agents Chemother

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Because of the potential for an interaction betwen cephalosporins and aminoglycosides leading to renal injury, an evaluation of the effect of a new cephalosporin, cefamandole nafate, on the toxicity of the aminoglycoside tobramycin was performed in laboratory animals. High doses of cefamandole nafate did not increase the acute toxicity (lethality) of tobramycin in rats or mice. In a subacute experiment in rats, dose-related tobramycin nephrotoxicity, as evidenced by blood urea nitrogen changes, increased kidney weights, and histologically determined tubular nephrosis and necrosis, was observed. Concomitant treatment with cefamandole nafate, 500 mg/kg, did not increase tobramycin nephrotoxicity, but protected against the aminoglycoside-induced renal injury. Determination of tissue radioactivity after administration of ['4C]tobramycin indicated that cefamandole nafate treatment resulted in uniformly lower tobramycin tissue concentrations compared with the control, suggesting that the protective effect was produced by enhanced excretion of tobramycin after cefamandole nafate treatment.The concomitant use of an aminoglycoside and a cephalosporin represents a frequently used approach to the initial therapy of lifethreatening infections.There are a number of case reports attributing renal injury to the simultaneous use of the aminoglycoside gentamicin (Garamycin, Schering Laboratories, Bloomfield, N.J.) and the cephalosporin cephalothin (Keflin, Eli Lilly & Co., Indianapolis, Ind.) in seriously ill patients (3,4,8,12,15,16 The combined use of cefamandole nafate and tobramycin represents a potentially useful therapy for serious infections. Because of the controversy surrounding the potential for nephrotoxicity resulting from the concomitant use of aminoglycosides and cephalosporins, an evaluation of the interaction between cefamandole nafate and tobramycin in laboratory animals was undertaken as a part of the toxicological evaluation of this new cephalosporin antibiotic.MATERIALS AND METHODS Animals. In acute toxicity experiments, female Wistar rats weighing 110 to 135 g or female ICR mice weighing 16 to 18 g (Harlan Industries, Cumberland, Ind.) were used. In the subacute experiments, male and female Wistar rats, specific pathogen-free and cesarean derived, weighing 104 to 146 g (Harlan Industries) were caged individually with free access to water and food.Antibiotic administration. Cefamandole nafate was dissolved in 1.67% aqueous sodium carbonate (3.3 ml/g) to make a 25% solution comparable to that obtained after reconstitution of the formulated product (11). Tobramycin was administered as tobramycin sulfate in the commercially available formulation containing 4% tobramycin. This solution was diluted with saline for administration of lower doses, and a 10% solution was prepared for the administration of high doses in the acute toxicity experiments.In acute toxicity experiments, mice (10 per dose) received intravenous doses of saline, 8 ml/kg, or cefamandole nafate, 2,000 mg/kg, followed after 1 min by intravenous do...

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“…Aminoglycoside antibiotics are used for serious life-threatening infections be cause of the potent bactericidal activity against a wide range of Gram-positive and -negative bacteria, including Pseudomo nas aeruginosa [22,23,27]. However, nephrotoxicity and ototoxicity as main adverse reactions were found for these an tibiotics [3,8,24].…”

Section: Introductionmentioning

confidence: 99%

Comparative Ototoxicity of Ribostamycin, Dactimicin, Dibekacin, Kanamycin, Amikacin, Tobramycin, Gentamicin, Sisomicin and Netilmicin in the Inner Ear of Guinea Pigs

Kitasato

Yokota²,

Inouye³

et al. 1990

Chemotherapy

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Nine aminoglycoside antibiotics, ribostamycin (RSM), dactimicin (DAC), dibekacin (DKB), kanamycin (KM), amikacin (AMK), netilmicin (NTL), tobramycin (TOB), gentamicin (GM) and sisomicin (SISO) were administered intramuscularly to guinea pigs for 4 weeks, and ototoxicity and drug concentration in the inner ear fluid were determined. RSM and DAC showed the weakest ototoxicity against the cochlea and vestibular organs. AMK and KM were more toxic to cochlea than vestibular organs. DKB, TOM, GM and SISO were equally toxic to vestibular organs and cochlea. NTL was more toxic to vestibular organs than cochlea. As judged from the pinna reflex response and hair cell damage in the cochlea, the order of auditory toxicity was the following: SISO > GM > TOB > AMK > DKB > KM > NTL, DAC RSM, whereas the vestibular toxicity was in the following order: SISO > GM > DKB > TOB > NTL > AMK > KM > DAC, RSM. RSM, causing the weakest ototoxicity, showed a low drug concentration in the inner ear fluid, while GM, causing severe ototoxicity, showed the highest drug level under the same conditions.

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Preclinical toxicology studies with tobramycin

Cited by 40 publications

References 5 publications

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

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

Effect of Cefamandole Nafate on the Toxicity of Tobramycin

Comparative Ototoxicity of Ribostamycin, Dactimicin, Dibekacin, Kanamycin, Amikacin, Tobramycin, Gentamicin, Sisomicin and Netilmicin in the Inner Ear of Guinea Pigs

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