Aspects of the Pharmacology and Toxicology of Tobramycin in Animals and Humans

The pharmacokinetics of netilmicin, gentamicin, and tobramycin in plasma and in perilymph of guinea pigs were studied after a single intravenous Ototoxicity on both the vestibular and cochlear portions of the inner ear is a recognized side effect of aminoglycoside antibiotic therapy. It has been reported that the aminoglycoside antibiotics that are widely used in clinical practice, such as gentamicin, tobramycin, and amikacin, show similar perilymph drug concentrations (5) and provoke substantially overlapping ototoxic reactions (1, 3, 5, 9). Studies on neomycin, streptomycin, dihydrostreptomycin, and kanamycin (8, 11) also have shown that the relative ability of each aminoglycoside antibiotic to reach greater perilymph concentration was directly related to the extent of their ototoxic damage in guinea pigs. These data suggest a possible relationship between the drug concentration achieved in the inner ear and the ototoxicity of aminoglycoside antibiotics.Netilmicin, a new semisynthetic aminoglycoside antibiotic and a 1-N-ethyl derivative of sisomicin, has been demonstrated in animals to be several times less ototoxic (1, 2, 4, 12) than gentamicin, tobramycin, sisomicin, amikacin, and kanamycin. Since the available information on the pharmacokinetics of aminoglycoside antibiotics in guinea pigs is limited, the present study was conducted to obtain detailed pharmacokinetics of gentamicin, netilmicin, and tobramycin in the perilymph as well as in the plasma of guinea pigs. A possible relationship between the pharmacokinetic properties of the aminoglycoside antibiotics and their comparative ototoxicities was also examined. MATERIALS AND METHODSStudy procedure. A total of 157 guinea pigs weighing between 300 and 350 g and with normal Preyer's reflex were used in this study.For the pharmacokinetic study in plasma, 15 of the experimental animals were randomly divided into three drug treatment groups of 5 animals each. Each animal was anesthetized with tribromoethanol (200 mg/kg, intraperitoneal injection), and both the left jugular vein and right carotid artery were cannulated. The animals were then placed in restricted cages. After complete recovery from anesthesia, the assigned drug (gentamicin, netilmicin, or tobramycin) was administered intravenously into the jugular vein at a dose of 40

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Comparative pharmacokinetics of aminoglycoside antibiotics in guinea pigs

Chung¹,

Parravicini²,

Assael³

et al. 1982

“…In vivo animal studies of antibacterial activity again show similar degrees of activity, except that tobramycin is more active against P. aeruginosa infections (5,30). The pharmacokinetics of the two drugs in humans are felt to be virtually identical (9,12,22,28). Comparative toxicity studies of the effects of these two drugs in humans have not been reported.…”

mentioning

confidence: 89%

“…Tobramycin was found to be less ototoxic than gentamicin in guinea pigs (2). Tobramycin was considered less nephrotoxic than gentamicin in rats on the basis of subtle but consistent histological changes and differences in drug-induced urinary lysosomal enzymes (12,21). Since a clear difference in nephrotoxic potential would have clinical importance, studies were designed to more precisely detect any abnormalities in renal structure or function.…”

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confidence: 99%

Comparative Nephrotoxicity of Gentamicin and Tobramycin in Rats

Gilbert

Plamp

Starr

et al. 1978

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. This study was undertaken as a result of our interest in determining whether there were any important differences between the aminoglycoside antibiotics gentamicin and tobramycin. A review of the literature indicated only minor differences in in vitro antibacterial activity (1,6,8,14,20,31). Gentamicin is slightly more active against Serratia species, and tobramycin is slightly more active against isolates of Pseudomonas aeruginosa. In vivo animal studies of antibacterial activity again show similar degrees of activity, except that tobramycin is more active against P. aeruginosa infections (5,30). The pharmacokinetics of the two drugs in humans are felt to be virtually identical (9,12,22,28). Comparative toxicity studies of the effects of these two drugs in humans have not been reported.In a rat model, tobramycin was found to have a lower lethal dose than gentamicin (5). Tobramycin was found to have a lower lethal dose than gentamicin (5). Tobramycin was found to be less ototoxic than gentamicin in guinea pigs (2). Tobramycin was considered less nephrotoxic than gentamicin in rats on the basis of subtle but consistent histological changes and differences in drug-induced urinary lysosomal enzymes (12, 21). Since a clear difference in nephrotoxic potential would have clinical importance, studies were designed to more precisely detect any abnormalities in renal structure or function.Initially, a prospective randomized doubleblind study in humans was considered. A recent report describes such a study comparing gentamicin and amikacin (26). However, it appears virtually impossible to determine the incidence of aminoglycoside-induced nephrotoxicity in humans. There is no way for the investigator to separate disease-induced toxicity from drug-induced toxicity. Also, preillness measurements of renal structure and function are rarely available. Because of these concerns, we chose to use a rat model of aminoglycoside nephrotoxicity. Nephrotoxicity was quantitated by histological changes and alterations in renal fimction. The results demonstrate that, in this model, tobramycin is less nephrotoxic than gentamicin.MATERIALS AND METHODS Animals. Adult male Fischer 344 rats, weighing 175 to 275 g, were used. The rats were kept sing...

“…Different patterns of antimicrobial activity have been shown for these different drugs, which are more or less sensitive to bacterial enzyme degradation (9,11,15,19,23,25,28). All these agents have similar pharmacokinetic properties in humans (7,14,16,20,21). Some discrepancies between these antibiotics as to their toxicity have been outlined (2,24,27).…”

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confidence: 99%

Comparative distribution of gentamicin, tobramycin, sisomicin, netilmicin, and amikacin in interstitial fluid in rabbits

Carbon¹,

Contrepois²,

Lamotte-Barrillon³

1978

We compared the penetration of five aminoglycosides into interstitial fluid (IF). IF was obtained in rabbits from Silastic tissue cages. Intramuscular injections were made: 1.5 mg/kg per dose for gentamicin (G), tobramycin (T), sisomicin (S), and netilmicin (N) and 7.5 mg/kg per dose for amikacin (A). Serum levels and IF concentrations were studied for 12 h after a single injection. IF levels were also compared in a six-injection study (one injection every 8 h). Peak serum levels were significantly higher with A than with G, T, S, and N, which gave similar concentrations. In IF, G gave the highest levels 1 h after the first injection. At 4 and 8 h, the concentrations achieved with G and A were similar but significantly greater than those achieved with T, S, and N. Twelve hours after a single injection, N gave higher IF levels than the other drugs except A. In the six-injection study, the IF levels of G and A reached 4.6 +/- 1.5 and 5.27 +/- 1.1 microgram/ml, respectively, at 48 h. S and N gave identical concentrations (2.07 +/- 0.25 and 2.42 +/- 0.42 microgram/ml, respectively). T induced the lowest levels (1.17 +/- 0.30 microgram/ml). Thus, in this rabbit model, the IF concentrations achieved with G and A were above the minimal inhibitory concentrations for most susceptible strains. Possible relations between IF aminoglycoside concentrations and therapeutic efficiency or toxicity are pointed out but deserve further studies.