Ototoxicity of tobramycin, gentamicin, amikacin and sisomicin in the guinea pig

Brummett, Robert E.; Fox, Kaye E.; Bendrick, Thomas W.; Himes, Donna

doi:10.1093/jac/4.suppl_a.73

Cited by 66 publications

(26 citation statements)

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“…Many investigators believe that the inner ear damage is related to the concentration of AG in the perilymph (1,3,5,8,12,14). Although the rates of entry of AG into perilymph are much slower than those of AG into plasma, these drugs seem to accumulate in the perilymph after repetitive dosing because of their slow elimination rates from this body fluid.…”

mentioning

confidence: 99%

“…In the perilymph fluid, however, the concentration of amikacin was not modified by pentobarbital, indicating that factors other than concentration in blood can affect the entry of amikacin into the inner ear. Because the ototoxic potential of aminoglycosides is thought to be related to the drug concentration in the perilymph fluid (1,12,14), a better understanding of factors affecting their transfer from blood to perilymph would help in predicting conditions likely to increase or decrease the ototoxicity of AG.…”

mentioning

confidence: 99%

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Effect of pentobarbital anesthesia on amikacin concentrations in plasma and perilymph and evaluation of multiple sampling in perilymph of guinea pigs

Desjardins-Giasson¹,

Beaubien²,

Cauchy³

1985

Antimicrob Agents Chemother

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The purpose of this study was to determine whether a multiple-sampling procedure could be used in guinea pigs to study the kinetics of amikacin in perilymph. Amikacin was infused intravenously for 6 h into conscious anesthetized guinea pigs, and the concentrations of the drug in plasma and perilymph were measured. From each anesthetized guinea pig, five to six perilymph samples were collected from one ear, and one sample was collected from the other ear at 6 h. The concentrations of amikacin in perilymph were dose proportional and increased slowly during the 6-h infusion. However, after 6 h of intravenous infusion, the concentrations of amikacin in perilymph of the multiply sampled ears were significantly higher than those of the singly sampled ears, indicating that the multiple-sampling procedure should not be used as is to study the kinetics of amikacin in perilymph. Amikacin concentrations in perilymph were linearly related to amikacin concentrations in plasma in pentobarbital-anesthetized animals, as had previously been observed for conscious guinea pigs. However, the slope of the regression line was only 0.09 for anesthetized animals compared with 0.24 for conscious animals. Drug concentrations in plasma were found to be threefold higher in anesthetized animals, whereas drug levels in perilymph were the same in both groups at similar dosing rates. These results indicate that the amikacin concentration in perilymph is not solely dependent upon its concentration in plasma and that other factor(s) can affect the entry of amikacin into the inner ear.Ototoxicity is a well-known adverse effect of aminoglycoside antibiotics (AG). Many investigators believe that the inner ear damage is related to the concentration of AG in the perilymph (1,3,5,8,12,14). Although the rates of entry of AG into perilymph are much slower than those of AG into plasma, these drugs seem to accumulate in the perilymph after repetitive dosing because of their slow elimination rates from this body fluid.Investigators in our laboratory are presently trying to determine the relationship between ototoxicity and the concentrations of amikacin in the perilymph and plasma of guinea pigs. While trying to determine the kinetics of amikacin in perilymph, we wanted to reduce the number of animals required to establish the various rate constants. Since the perilymph compartment is both small and poorly accessible, generally only a single data point can be obtained from each animal (3, 15). We recently modified a radioimmunoassay technique so that only 1 ,ul of perilymph sample is required (4). This small size made multiple sampling of the perilymph feasible in an anesthetized animal. 350 g were used. Food and water were provided ad libitum. Room temperature (21 to 22°C), humidity (50 to 55%), and light cycle (12 h on, 12 h off) were kept constant throughout the experiment.The control group consisted of 19 conscious guinea pigs which had undergone jugular cannulation 48 h previously. Each animal received one of the following i.v. doses of amikacin for 6...

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confidence: 99%

mentioning

confidence: 99%

Effect of pentobarbital anesthesia on amikacin concentrations in plasma and perilymph and evaluation of multiple sampling in perilymph of guinea pigs

Desjardins-Giasson¹,

Beaubien²,

Cauchy³

1985

Antimicrob Agents Chemother

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“…28 In animal models gentamicin is thought to be more ototoxic than tobramycin and amikacin. 29 The use of genta-micin in our patient population may have increased the risk of ototoxicity.…”

Section: Discussionmentioning

confidence: 96%

Toxicity of single daily dose gentamicin in stem cell transplantation

Warkentin

Ippoliti

Bruton

et al. 1999

Bone Marrow Transplant

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Summary:To determine the safety of single daily dose (SDD) gentamicin in recipients of stem cell transplantation (SCT), we evaluated all adult patients at MD Anderson Cancer Center who received SDD gentamicin for treatment of febrile neutropenia. Thirty-three patients received gentamicin 5 mg/kg i.v. every 24 h. Mean duration of therapy was 7 days (range 3-32 days). All patients received vancomycin and 17 received cisplatinum. All patients had normal renal function prior to therapy. Serum gentamicin levels were monitored only when renal function deteriorated. The incidence of nephrotoxicity and clinically significant ototoxicity was 3% and 12%, respectively. All four patients who developed ototoxicity had normal renal function before and during therapy. The mean duration of gentamicin therapy was significantly longer in patients who developed ototoxicity, 20 days vs 9 days (P = 0.001). Patients treated with SDD gentamicin for Ͼ10 days were more likely to develop ototoxicity (P = 0.045). Single daily dosing of gentamicin was associated with clinically significant ototoxicity in 12% of our patients. A larger randomized EORTC trial evaluating SDD vs MDD amikacin failed to detect a difference in ototoxicity. However, the median duration of therapy was only 8 days. The increased incidence of ototoxicity in our study may be due to prolonged therapy, type of aminoglycoside used, concomitant ototoxic agents, small sample size, or a combination of the above.

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“…Aminoglycoside-induced loss of auditory function is characterized by the gradual destruction of sensory hair cells in the cochlea, starting in the basal turns and ascending to the apex. 37,38 Aminoglycosides have been reported to affect DNA, RNA and protein synthesis, and have an effect on metabolism. It has been hypothesized that aminoglycosides may form cochleotoxic metabolites, because saturating concentrations of aminoglycosides are present in the inner ear within hours after parenteral administration, although loss of auditory function develops gradually.…”

Section: Discussionmentioning

confidence: 99%

Are GJB2 mutations an aggravating factor in the phenotypic expression of mitochondrial non-syndromic deafness?

et al. 2010

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Hearing impairment is a frequent condition, and genes have an important role in its etiology. The majority of hearing loss occurs in non-syndromic form, with deafness being the only clinically recognizable feature. More than 60 nuclear genes or loci have been shown to be involved in non-syndromic hearing loss, but mutations in mitochondrial DNA also cause hearing impairment. Mitochondrial DNA mutations usually lead to progressive hearing loss with an age of onset varying from childhood to early adulthood. It is interesting to note that there is a great variability among phenotypes between individuals harboring the same mitochondrial mutation, even within the same family, and the phenotype may range from profound deafness to completely normal hearing. In the past years, the debate on mitochondrial mutations has been about the penetrance, the tissue specificity and the mechanisms of modifier genes that can modulate the severity of the phenotypic expression of the deafness-associated mitochondrial DNA mutations. Here we summarize evidence regarding modifying genes, and we discuss the effect of the coexistence of mitochondrial and GJB2 mutations in families reported to date.

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Ototoxicity of tobramycin, gentamicin, amikacin and sisomicin in the guinea pig

Cited by 66 publications

References 0 publications

Effect of pentobarbital anesthesia on amikacin concentrations in plasma and perilymph and evaluation of multiple sampling in perilymph of guinea pigs

Effect of pentobarbital anesthesia on amikacin concentrations in plasma and perilymph and evaluation of multiple sampling in perilymph of guinea pigs

Toxicity of single daily dose gentamicin in stem cell transplantation

Are GJB2 mutations an aggravating factor in the phenotypic expression of mitochondrial non-syndromic deafness?

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