Ototoxic drugs and the detection of ototoxicity.
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Drug-Related Side Effects and Adverse Reactions↗
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Ototoxic drugs and the detection of ototoxicity.
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Drug-Related Side Effects and Adverse Reactions↗
Ototoxic drugs and the detection of ototoxicity.
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Drug-Related Side Effects and Adverse Reactions↗
[Ototoxicity of the aminoglycoside antibiotics (author's transl)].
A report is given on advances in our knowledge of the ototoxicity of aminoglycoside antibiotics. The pharmacokinetics of gentamicin, tobramycin, sisomicin and amikacin in the inner ear, cerebrospinal fluid, compartments of the eye and serum were determined by means of pharmacokinetical investigations. The influence of long-term treatment, and the effects of otitis media and uremia were also studied. Furthermore, the influence of therapeutic methods on ototoxic damage was investigated, and the ototoxicity of these antibiotics was compared. The experiments were performed in guinea pigs, concentrations of the antibiotics being measured by a microbiological method and confirmed by investigations with C14 labeled gentamicin. The hair cell degeneration pattern after administration of the new aminoglycosides was determined using surface preparations. The prophylactic effect upon ototoxicity of the administration of dimercaptopropanol or of dividing up the daily dosage was examined. Studies were made of ototoxicity in children, and in patients with otitis media or renal impairment, and the effect of simultaneous ethacrynic acid or noise was assessed. The problem of delayed and progressive ototoxicity, and the reversibility of ototoxic damage caused by these antibiotics was examined histologically, and the ototoxicity of gentamacin, tobramycin, sisomicin and amikacin was compared. The influence of the new aminoglycoside antibiotics upon the amount of acidic and alkaline phosphatase and unspecific esterases in the inner ear was studied. The clinical importance of the latest experimental findings is emphasised. The clinical picture of ototoxic damage after administration of the new aminoglycoside antibiotics shows no special characteristics. The ototoxicity of these antibiotics after topical use is mentioned. Attention is drawn to guidelines for the prevention of ototoxic damage by aminoglycosides.
Acid Phosphatase↗
Ototoxicity of tobramycin: a clinical overview.
In a survey of data on 3,506 patients treated with tobramycin, the 21 cases of drug-related ototoxicity are reported and reviewed. In seven patients the effects were auditory only, in nine vestibular only, and in five both auditory and vestibular. Effects subsided in 14 of the 18 patients who were available for monitoring after therapy. High-frequency audiometric losses persisted in three patients, and a hearing decrease persisted in one. In only one of the three patients did audiometric losses exceed 40 decibels. The patients with drug-related ototoxicity were compared to a group of 49 patients for whom both audiometric testing (before and after therapy) and clinical observation showed that no ototoxic reactions had occurred. Preexisting renal impairment, prior and/or concomitant therapy with other possibly ototoxic drugs, and therapy for 10 days or more with a dose of greater than 3 mg/kg per day were found to be associated with ototoxicity.
Adult↗
[Pharmacokinetical, histological, and histochemical investigation on the ototoxicity of gentamicin, tobramycin, and amikacin (author's transl)].
The pharmacokinetics of gentamicin, tobramycin, and amikacin in the inner ear fluids and serum of the guinea pig were studied. The concentrations of these antibiotics were determined by a microbiological method and could be confirmed by the use of 14C-labeled gentamicin. Retention was clearly demonstrated in perilymph and endolymph, whereas there was no retention in the cerebrospinal fluid and the compartments of the eye. A linear relation between concentrations in the perilymph and dosage of gentamicin was ascertained. There was no difference between the concentration of drug in endolymph and that in perilymph. The concentrations of these antibiotics in the perilymph were symmetrical and many times higher than those in the brain. Long-term treatment did not influence the pharmacokinetics of the three antibiotics in the inner ear. However, increased levels of drug in the inner ears in animals with uremia and in some animals with otitis media explained the increased ototoxicity that was observed in histological investigations of these two conditions. Cisternal puncture and diuretics did not change the concentrations of aminoglycoside antibiotics in the inner ear. In large experimental series the hair cell degeneration pattern of the new aminoglycoside antibiotics was determined by the surface preparation technique as well as the influence of the different factors upon this pattern. A prophylactic effect on the ototoxicity of the aminoglycoside antibiotics could not be found in the 2,3-dimercaptopropanol, but by dividing the daily dosage administered. Young guinea pigs were generally not very sensitive to gentamicin, in some cases however much more. Late ototoxicity could not be found after administration of gentamicin. The pharmacokinetical and especially the histological investigations allowed an evaluation of the ototoxicity of the new aminoglycoside antibiotics. By histochemical investigations no influence of the new aminoglycoside antibiotics upon the amount of unspecific esterases and alkaline phosphatase in the inner ear could be detected, but an increase of the amount of acid phosphatase in slightly damaged outer hair cells.
Amikacin↗
Ultrastructural cochlear changes following acoustic hyperstimulation and ototoxicity.
Using guinea pigs and chinchillas as experimental animals, modes and patterns of sensory cell damage by acoustic hyperstimulation and kanamycin intoxication were compared. In general, outer hair cells were more vulnerable to both acoustic trauma and ototoxicity (particularly in the basal turn) than inner hair cells. However, in kanamycin ototoxicity, the inner hair cells were more vulnerable in the apical coil. Nerve endings and nerve fibers generally were resistant to both acoustic trauma and kanamycin intoxication, and their degeneration appears to be secondary to the sensory cell degeneration. A large number of unmyelinated nerve fibers were seen in both the organ of Corti and the osseous spiral lamina even three months after the organ of Corti had been completely degenerated by ototoxicity. The total number of unmyelinated and myelinated nerve fibers in the osseous spiral lamina far exceeded the scanty surviving ganglion cells in Rosenthal's canal, indicating the possibility of regeneration of these fibers following kanamycin intoxication. The remaining few ganglion cells were mainly type II or type III cells, and a majority of the type I ganglion cells appeared to be degenerated. Signs of strial damage were observed in both acoustic trauma and ototoxicity, but their pattern did not correlate well with that of sensory cell degeneration.
Animals↗
The relationship between kanamycin ototoxicity and glucose transport.
The clinical utility of the aminoglycoside antibiotics is hampered by their well-known capacity to cause labyrinthine and renal damage. The mechanism by which these damages are produced is unknown. Attention was focused on the aminosugar moiety of these antibiotics by the finding of Owada (1962) which demonstrated that 3-aminoglucose is as ototoxic as its parent antibiotic, kanamycin. It is known that aminosugars compete with glucose for transport and that the sensory cells of the cochlea depend on glucose as a primary energy source. The hypothesis that grew out of these considerations was that kanamycin might be causing its ototoxicity by inhibiting glucose transport at one of several sites in the inner ear. To test this hypothesis the ototoxicity of kanamycin was determined in hyperglycemic animals. Hyperglycemia clearly and dramatically protects animals against ototoxicity as evidenced both by electrocochleographical and histological examination.
Animals↗
Delayed elimination of the ototoxic compound atoxyl from the inner ear.
Whether an active accumulation of ototoxic substances or their metabolites occurs in the cochlea, or whether there exists a delayed elimination of these products from the endo-and perilymphatic fluids, following a passive equilibrium between the blood and the body tissues, is still a subject for discussion. To investigate the cochlear distribution of an ototoxic substance and its elimination rate, compared to other organs in the body, atoxyl, with known ototoxic effects (Anniko and Wersäll, 1975a, b; Anniko, 1976a, b) was used as a test substance. The neutron activation analysis technique was used to measure the atoxyl concentration in various parts of the body (cochlea, blood, muscle, kidney and cortical femoral bone) after various lengths of time following a subcutaneous injection of 100 mg/kg b.w. of atoxyl. Atoxyl was retained in the cochlea for a long period and a delayed elimination occurred from the inner ear. The excretion of atoxyl was likely to appear via the kidneys.
Animals↗
The influence of pigmentation of rats and guinea-pigs on the ototoxicity of kanamycin and neomycin.
Following the finding that melanin pigment played a role in the accumulation of ototoxic drugs in the inner ear, an investigation was made of the possible influence of the pigmentation of animals on their susceptibility to the ototoxic effects of drugs. Hearing acuity was assessed by measurement of acoustic startle reaction. Preliminary experiments suggested that pigmented animals might be more likely to suffer hearing impairment following ototoxic drug administration. However, in a controlled study using rats treated with kanamycin, it was not possible to confirm this and albino animals appeared no less vulnerable than pigmented animals to kanamycin-induced deafness.
Acoustic Stimulation↗
Detection of tobramycin- and netilmicin-induced ototoxicity in guinea pigs with evoked action potentials.
To evaluate the action potentials evoked in the cochlea in aminoglycoside-induced ototoxicity, 80 guinea pigs were given 25, 50, 75, or 100 mg of tobramycin or netilmicin/kg per day for 14 or 28 days. Ten other guinea pigs (controls) were given 200 mg of ampicillin/kg per day for 14 or 28 days. Cochlear evoked action potentials (CEAP) before and after treatment were measured, and the cochlea was examined microscopically after treatment. Comparison of initial and final values showed that the threshold of the main negative (N1) wave rose (p less than 0.00001 for dose and duration factors), the amplitude decreased (P less than 0.00001 for dose factors at sound intensities of 120 and 90 dB, P less than 0.001 at 70 dB), and the latency lengthened (P less than 0.0001 for dose factors at 120 and 90 dB). The CEAP method appeared to be more sensitive than microscopic examination of the cochlea for detection of ototoxicity induced by the lower dosages of the aminoglycosides. No significant differences were observed between the effects of tobramycin and netilmicin. In conclusion, the CEAP method appears to be a promising tool for detection of aminoglycoside-induced ototoxicity.
Acoustic Stimulation↗
Neomycin ototoxicity.
A case of oral neomycin ototoxicity is presented, followed by a summary of known cases in the English literature. While it is known that neomycin is concentrated in the inner ear fluids, at the present time the biochemical basis of its ototoxic effect has not been definitively elucidated. High frequency audiometry can aid in the early detection of the onset of neomycin-induced deafness. Dialysis has a limited but useful role in preventing neomycin ototoxicity.
Deafness↗
A prospective study of gentamicin ototoxicity.
Twenty patients were included in a prospective otoneurological study performed to assess the ototoxicity in gentamicin therapy. Gentamicin was administered intravenously, and the serum level was currently determined. Audiographic and electronystagmographic studies were carried out at the institution and discontinuation of the treatment and again a few weeks later. Ten patients exhibited ototoxic actions, predominantly cochlear, 4 of the cases being fully reversible. Two patients developed severe hearing loss, associated in one with bilateral extinction of vestibular function. Low serum levels of gentamicin did not rule out the possiblity of ototoxicity. These results urge the continuing of prospective studies and indicate that gentamicin should be used only as a link in the primary treatment of severe infection or in cases in which other, less toxic agents have failed.
Adolescent↗
[Evaluation of ototoxicity of amikacin (BB-K8) by animal test (author's transl)].
Seventy Hartley strain guinea pigs (350 g body weight at start of the experiment) were used. BB-K8, gentamicin (GM) and kanamycin (KM) were given to the animals intramuscularly for 28 days at following various doses: (see article) These guinea pigs underwent a differential frequency pinna reflex test in wide frequency range from 20KHz to 0.5 KHz before the administration, during the injection and after the last one. For histopathological examination of the inner ears the guinea pigs were subjected to intravital fixation with Wittmaack's fixative under nembutal general anesthesia. Blocks including the bilateral temporal bones were removed from the skulls and then fixed in the same fixative for 1 similar to 2 weeks. After routine procedure for decalcification, dehydration and celloidin embedding, horizontal serial sections of the inner ears were made and stained with hematoxylin-eosin. The differential frequency pinna relfex test in the 70 guinea pigs indicated positive pinna reflex in 90% at 20KHz and in 100% at 15, 12, 10, 8, 6, 4, 3, 2, 1 and 0.5 KHz before start of the administration. Administration of the antibiotics for 28 days occasionally resulted in the pinna reflex loss which always involved the highest frequency, 20 KHz and then was followed in relatively regular succession by 15, 12, 10, 8, 6, 4, 3, 2, 1 and 0.5 KHz (Tables 1 similar to 8). On the other hand, histopathological examination of the inner ears disclosed that the loss of the outer hair cells in the spiral organ which are the most sensitive to the ototoxic antibiotics, occurred always at the basal end of the spiral organ and then spread from there to upper portion of the spiral organ (Tables 9 similar to 16). Based on the differential frequency pinna reflex test in the wide frequency range and extensive histopathological examination of the inner ears, ototoxicity of BB-K8 is considered to be more mild than GM. However, there was not so remarkable difference in ototoxicity between BB-K8 and KM in the present experiment. The result or examination of the guinea pigs received BB-K8 at 40 mg/kg and 100 mg/kg respectively for 28 days suggests that BB-K8 at expecting clinical dose, 500 mg per day (for 28 days) may be safe from ototoxicosis in the inner ears. In the vestibular organs of the animals received BB-K8 there was no decrease in number of the hair cells.
Amikacin↗
[Comparative ototoxicity of aminoglycoside antibiotics in a guinea pig model (author's transl)].
Tobramycin, gentamicin, sisomicin and amikacin are aminoglycoside antibiotics that are used clinically. A significant side effect of aminoglycoside antibiotics is the production of hearing loss. Our study was done to determine the relative ototoxic liability of these 4 drugs. All drugs were given in daily doses of 0, 50,100 or 150 mg/kg to guinea pigs subcutaneously for 4 weeks. In addition, 200 mg/kg was was given to the animals receiving amikacin and sisomicin. There were 10 animals in each dosage group. Seven animals were used for auditory study and 3 were used for pharmacokinetic study. Auditory damage was assessed by determining the Preyer pinna reflex, the ability of the cochlea to generate the AC cochlear potential, and the number of sensory hair cells missing from the organ of Corti. The concentration of aminoglycoside antibiotics is determined in the cochlear perilymph and plasma by a radioenzymatic assay. On a equal dose basis the ototoxic liability of gentamicin and sisomicin were very similar and tobramycin and amikacin being less ototoxic than the gentamicin and sisomicin. The pharmacokinetics of single 150 mg/gk doses of the drugs were similar. The exception was that tobramycin reached lower peak levels in plasma and perilymph and its time to peak level in perilymph was delayed relative to the other drugs. Analysis of plasma and perilymph following chronic administration revealed higher concentration of gentamicin and sisomicin than of tobramycin and amikacin.
Amikacin↗
[Risk of inner ear damage from ototoxic eardrops (author's transl)].
Antibiotic eardrops with ototoxic properties are widely used in the treatment of discharging ears and have also been used in cases with perforated tympanic membranes. There has thus far been no information available on the incidence of ototoxic inner ear damage caused by such treatments. An inquiry among the members of the Swiss Otolaryngological Society uncovered 15 such cases with inner ear damages: 8 patients with total loss of hearing and 7 patients with profound deafness. The risk of such ototoxic injury is approximately 1 case in 1--3000 treatments. The present study indicates that topical treatment in cases with perforated tympanic membranes should not be given longer than 10 days, or it should be interrupted as soon as mucosal swelling subsides.
Administration, Topical↗
MT-RNR1 genotype testing for preventing aminoglycoside-mediated ototoxicity: A guideline developed by the UK Centre of Excellence in Regulatory Science and Innovation in Pharmacogenomics (CERSI-PGx).
Aminoglycosides are broad-spectrum antibiotics used in the management of severe infections. Aminoglycosides are associated with nephrotoxicity and ototoxicity. Although dosing strategies such as once-daily administration and therapeutic drug monitoring have reduced the incidence of nephrotoxicity, ototoxicity remains unpredictable and may occur at therapeutic concentrations. A strong association between specific mitochondrial DNA variants in MT-RNR1 (m.1555A > G, m.1494C > T and m.1095 T > C) and aminoglycoside-induced hearing loss exists. These variants (frequency ~1 in 330 individuals across populations) predispose to irreversible, sensorineural hearing loss following aminoglycoside exposure, sometimes after a single dose. Avoidance of aminoglycosides is recommended at any detectable variant level. In England, laboratory-based MT-RNR1 testing is nationally commissioned, whereas point-of-care testing in time-critical settings like neonatal sepsis is delivered in some centres. Approximately 20% of aminoglycoside use is predictable providing opportunities for pre-emptive pharmacogenetic testing. Where MT-RNR1 testing results are unavailable and clinical urgency is high, aminoglycoside treatment should not be delayed. Early health economic evidence suggests that point-of-care testing in neonates may be cost-saving by preventing lifelong hearing loss. Regulatory and Health Technology Assessment bodies support targeted implementation of testing alongside further evidence generation. Overall, integration of MT-RNR1 pharmacogenetic testing offers a feasible and proportionate strategy to reduce harm while preserving access to life-saving antibiotic therapy. This guideline is grounded in the latest evidence in this field but cannot account for all individual factors relevant to patient care. Therefore, prescribers must conduct a thorough assessment of each patient's risk-benefit profile, ensuring that therapy is optimized to maximize benefits while minimizing potential harms.
Humans↗
Comparative ototoxic liability of netilmicin and gentamicin.
Netilmicin sulfate is a new aminoglycoside antibiotic currently undergoing clinical investigation. All of the aminoglycoside antibiotics now in clinical use are ototoxic. This study was done to determine the ototoxic liability of netilmicin when it is compared directly with gentamicin sulfate. Groups of ten guinea pigs each were given doses of 0, 50, 100, or 150 mg/kg of either gentamicin or netilmicin daily for four weeks. After a two-week stabilization period, the Preyer pinna reflex, the cochlea's ability to generate the ac cochlear potential, and the missing hair cells from the cochleas were determined. Additionally, the pharmacokinetics of both drugs in the plasma and perilymph were determined. Little or no cochlear damage was detected with netilmicin, even at the highest dose, while even the smallest dose of gentamicin produced measurable changes in cochlear function.
Acoustic Stimulation↗