EAR TREATMENT AN UPDATE ON OTOTOXICITY

Transcription

1 EAR TREATMENT AN UPDATE ON OTOTOXICITY

2 OTOTOXICITY IS DEFINED AS TOXIC EFFECTS TO THE INNER EAR OF DRUGS, CHEMICAL AGENTS OR TOXINS THE DAMAGE CAN BE TO THE COCHLEA, VESTIBULAR APPARATUS AND THE VESTIBULOCOCHLEA NERVE SOME TOXINS WILL TARGET SPECIFIC PARTS OF THE INNER EAR OTHER SHOW PAN-TOXICITY WITH SOME AGENTS TOXICITY IS REVERSIBLE WITH OTHER IT IS IRREVERSIBLE TOXINS CAN ENTER THE INER EAR THROUGH SYSTEMIC OR TOPICAL ROUTE

3 CLINICAL SIGNS OF OTOTOXICITY WHEN VESTIBULAR APPARATUS IS AFFECTED ANIMALS SHOW SIGNS OF CIRCLING, NYSTAGMUS, ATAXIA, STRABISMUS AND A HEAD TILT. COCHLEA DAMAGE LEADS TO HEARING LOSS

4 IN ORDER TO ASSESS OTOTOXICITY THERE NEEDS TO BE AN ACCURATE WAY TO ASSESS DAMAGE TO BOTH THE VESTIBULAR APPARATUS AND THE COCHLEA VESTIBULAR DAMAGE CAN BE ASSESSED BY CLINICAL EXAMINATION COCHLEA DAMAGE IN THE WAY OF HEARING LOSS CAN BE ASSESS BY BEHAVIOURAL METHODS OR BY BRAIN STEM AUDITORY EVOKED RESPONSES (BAER)

5 BEHAVIOURAL ASSESSMENT OF HEARING Assessment involves making a noise outside the animal s visual field and monitoring its response Animals usually respond by pricking back their ears (Preyer s reflex) or by moving their head towards the sound. Preyer s reflex will identify profound hearing loss in mice, limited value where hearing loss less severe Dogs that are unilaterally deaf still retain their Preyer s reflex in both ears, making assessment of unilateral hearing deficits almost impossible using this behaviour method Jero J, Coling DE, Lalwani AK. The use of Preyer's reflex in evaluation of hearing in mice. Acta Otolaryngol. 2001;121(5):585-9.

6 Use of a hearing loss grading system and an owner-based hearing questionnaire to assess hearing loss in pet dogs with chronic otitis externa or otitis media Mason, C. L. Paterson, S. Cripps, P. J. Vet Derm 24 (5) Owners completed a questionnaire to assess their dog's response to common household noises. (door closing, door bell ringing, clapping hands, whispering etc. ) Brainstem auditory-evoked response measurements were performed on each dog and the two results compared.

7 The minimal hearing threshold (MHT) in db NHL recorded. Categorized using WHO grading (human grading system based on NHL) Grade 0 </=25 db NHL, grade db NHL, grade db NHL, grade db NHL, grade 4 >/=81 db NHL. Owners were able to identify NHL grade 0 Owners were unable to identify unilateral or grade 1 bilateral hearing loss Owners able to identify bilateral hearing loss >/= grade 2. Questionnaire sensitivity was 83%

8 BAER TO ASSESS HEARING 1) BAER testing non-invasive method to record activity in the peripheral and brainstem auditory structures in response to the sound stimulus, usually a series of clicks. 2) Measurements made via scalp electrodes, inserted into the skin on head of a gently restrained or sedated patient 3) BAER records series of peaks (I V) at 1ms intervals, starting 2ms after clicks start. Each peak corresponds to part of the auditory pathway from the auditory nerve (cranial nerve VIII) (peak I) to the mid or upper pons in the brain (peak IV and V)

9 WAVE FORMS OF THE BAER Activity in : Wave 1 Vestibular cochlear nerve in segment closest to cochlear Wave 2 Extramedullary intracranial segment of cranial nerve VIII Wave 3 Dorsal nucleus of trapezoid body Wave 4 Rostral pons Wave 5 Caudal colliculus

10 Studies on the ototoxicity of drugs in dogs and cats should therefore be interpreted on the basis of 1) Have they been performed in dogs and cat 2) Have studies have been performed in normal animal or those with otitis media; 3) How has ototoxicity been assessed 4) If BAER is used what are the range of stimulus intensities of normal hearing that are assessed has lowest threshold of hearing been identified 5) Type and concentration of the drug used

11 OTOTOXICITY TO EAR CLEANERS IN CATS AND DOGS

12 HOW SAFE ARE THESE CERUMINOLYTIC AGENTS? SQUALENE CARBAMIDE PEROXIDE SODIUM DOCUSSATE (DOSS)

13 The effects of four commercial ceruminolytics on the middle ear Mansfield PD et al (1997) JAAHA 33, Each product instilled into middle ear via myringotomy of dogs and g. pigs on a single occasion. Neurological and BAER assessed weekly for 4 weeks Squalene Dioctyl sodium succinate Carbamide peroxide Triethanolamine Animals sacrificed & 2 nd ear used for comparison in each case. Only squalene flushed ear failed to show neurological or morphological damage

14 OUR EXPERIENCE Squalene is very safe. We use 22% squalene to flush middle ears without any adverse effects Carbamide hydroxide is ototoxic We have seen several cases where it has been used in dogs and cats with damage to the ear drum and it has caused deafness No experience with DOSS

15 HOW SAFE ARE THESE FLUSHING AGENTS? EDTA TRIS CHLORHEXIDINE LACTIC ACID

16 Igarashi Y et al (1985) Cochlear ototoxicity of Chlorhexidine gluconate in cats Arch Otorhinolaryn 242 (2) Igarashi Y et al (1988) Vestibular ototoxicity following intratympanic application of chlorhexidine gluconate in the cat Arch Otorhinolaryn 245 (4) Igarashi Y et al (1988) Mucosal injury following intratympanic application of chlorhexidine gluconate in Cats Arch Otorhinolaryn 245 (5) Series of studies in cats suggesting marked ototoxicity for vestibular and cochlear function at 2% Less at 0.05% but still vestibular damage recorded. Also damage to mucociliary clearance mechanism in tympanic bulla Chlorhexidine has been shown to be vestibulotoxic and cochleotoxic in cats even at concentrations as low as 0.05%

17 Merchant SR et al (1995) Ototoxicity of a chlorhexidine otic preparation in dogs Progress in Veterinary Neurology % chlorhexidine instilled into ears canine ears before and after experimental myringotomy. No significant abnormalities were detected. Study was performed on sedated dogs and threshold values for normal hearing were not performed i.e. hearing was not taken down to the lowest possible level. Despite this no evidence of cochleotoxicty was recorded In normal dogs the round windows would be likely to be more vulnerable to ototoxic effects so this should suggest chlorhexidine is safe

18 Ototoxicity and tolerance assessment of a TrisEDTA and polyhexamethylene biguanide ear flush formulation in dogs Mill PC et al J Vet Pharmacol Ther 28(4), healthy mixed breed dogs used to determine if a Tris (tromethamine)- buffered test solution, containing disodium ethylenediamine tetraacetic acid (EDTA; 1.21 g/l) and polyhexamethylene biguanide (PHMB; 0.22 g/l) caused ototoxicity or vestibular dysfunction. Control group were treated with saline flush or test solution both before (7 days) and after (14 days) a bilateral myringotomy Throughout the study, dogs were examined for clinical health, and underwent otoscopic, vestibular and auditory examinations (BAER). No dog showed any ototoxic effect suggesting the test solution is very safe even if the ear drum is damaged

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20 OUR EXPERIENCE Chlorhexidine 0.15% and EDTA are very safe. We routinely flush middle ears with proprietary ear cleaners containing this combination Lactic acid appears to be ototoxic. We have seen several cases where it has been used in dogs and cats with damage to the ear drum and it has caused deafness

21 OTOTOXICITY OF DIFFERENT ANTIBIOTICS IN DOGS AND CATS

22 AMINOGLYCOSIDES CATS Aminoglycoside antibiotics have been shown to cause signs of ototoxicity when administered both topically and systemically in cats Streptomycin Gentamicin Neomycin Kanamycin Amikacin

23 AMINOGLYCOSIDES CATS Ototoxicity of topical gentamicin in the cat. Webster JC et al. J Infect Dis. 1971;124 Suppl:S Ototoxicity of gentamicin. Histopathologic and functional results in the cat. Webster et al Trans Am Acad Ophthalmol Otolaryngol. 1970;74(6): Comparative ototoxicity of amikacin and gentamicin in cats. Christensen E. et al. Antimicrob Agents Chemother. 1977;12(2): Cochlear pathology of long term neomycin induced deafness in cats. Leake, PA et al. Hear Res. 1988;33(1):11-33.

24 AMINOGLYCOSIDES CATS A review of antibiotic-induced ototoxicity Puteikis K et al. Neurologijos seminarai. 2016;20(69): The ototoxicity of dihydrostreptomycin and neomycin in the cat Hawkins, J. E., Jr Ann Otol Rhinol Laryngol (4), Profound hearing loss in the cat following the single co-administration of kanamycin and ethacrynic acid Xu, SA Hear Res 70 (2) Cat appear to be more sensitive than the dog. Is it related to round window structure or fact dogs often have or have had disease and thus have a thickened RW.

25 AMINOGLYCOSIDES DOGS Aminoglycoside antibiotics have been shown to cause signs of ototoxicity when administered both topically and systemically in dogs Neomycin Kanamycin Tobramycin

26 AMINOGLYCOSIDES DOGS Effects of neomycin on the waveform of auditory-evoked brain stem potentials in dogs Morgan J.L et al Am J Vet Res 1980, 41 (7)

27 TOPICAL GENTIMICIN DOGS Strain GM, Merchant SR, Neer TM, Tedford BL. Ototoxicity assessment of a gentamicin sulfate otic preparation in dogs. Am J Vet Res. 1995;56(4): Paterson S. Brainstem auditory evoked responses in 37 dogs with otitis media before and after topical therapy. J Small Anim Pract. July 2017.

28 Strain GM, Merchant SR, Neer TM, Tedford BL. Ototoxicity assessment of a gentamicin sulfate otic preparation in dogs. Am J Vet Res. 1995;56(4): Healthy retired greyhounds were treated with 7 drops (0.35ml) of 3mg/ml gentamicin in a buffered aqueous vehicle twice daily for three weeks, both before and after myringotomy. No hearing loss was observed. Despite the absence of adverse effects, this study was not performed in anaesthetised animals, so threshold determinations were not performed to evaluate absolute safety for this drug. However lack of adverse effects in normal ears is an encouraging result

29 Paterson S. Brainstem auditory evoked responses in 37 dogs with otitis media before and after topical therapy. J Small Anim Pract. July Dogs with chronic Pseudomonas spp. otitis media were treated twice daily with 0.5ml of a 0.27% (2.7mg/ml) solution of aqueous gentamicin in aqueous EDTA tris. All dogs were assessed by a neurological examination and then by BAER under general anaesthetic before and after the completion of treatment (up to six weeks in some cases). No dog showed any signs of ototoxicity No adverse effects, baselines were measured. Concentration of gentimicin lower than Strain report. Dogs had chronic disease likely there was thickening of RWM

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31 Paterson S. Brainstem auditory evoked responses in 37 dogs with otitis media before and after topical therapy. J Small Anim Pract. July Dogs with chronic Pseudomonas spp. otitis media were treated with a 0.85% marbofloxacin solution in EDTA tris; Dogs treated with the marbofloxacin solution showed no evidence of ototoxicity which is in line with findings in man, where multiple studies have shown that topical fluoroquinolones are not ototoxic.

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33 Paterson S. Brainstem auditory evoked responses in 37 dogs with otitis media before and after topical therapy. J Small Anim Pract. July Dogs with chronic Pseudomonas spp. otitis media were treated 1% tobramycin in EDTA tris and 2.5% ticarcillin solution in sterile water. Dogs treated topically with ticarcillin and tobramycin in the study showed marked reduction in BAER tests suggesting these drugs, at the treatment concentrations are cochleotoxic This is particularly important as these were dogs with chronic disease suggesting they had thickened RWM suggesting these drugs are potentially highly ototoxic

34 BAER trace before and after administration of aqueous TICARCILLIN Time between traces 6 weeks. Marked reduction in BAER

35 BAER trace before and after administration of aqueous TOBRAMYCIN. Time between traces 8 weeks. Marked reduction in BAER

36 Ototoxicity of topical ticarcillin and clavulanic acid in the chinchilla Jakob T et al. Arch Otolaryngol Head Neck Surg 121 (1) Twenty chinchillas in 2 groups. 10 were given a single middle ear application of ticarcillin; the remaining 10 animals received ticarcillin disodium plus clavulanate potassium (Timentin). 5 animals from each of the two groups were killed after 1 week to assess short-term effects and the other five animals in each group were kept for 4 weeks before their temporal bones were removed for histologic study. Significant toxic effects, involving both the middle and inner ear, were seen in both groups. Changes in middle ear at 1 week included inflammation, hemorrhage, and effusions. Middle ear cholesteatomas were observed at 4 weeks. Inner ear changes seen at 1 and 4 weeks included hair cell loss, supporting cell degeneration, and strial damage.

37 STRATEGIES TO PREVENT OTOTOXICITY Mechanisms of ototoxicity differ between drugs and chemicals thus no one drug that can be used to reduce or prevent ototoxic effects. There are no guidelines for protective co-treatments for dogs and cats receiving potentially ototoxic medication. The co-administration of antioxidants or similar scavengers of ROS can help prevent cochlear damage induced by aminoglycosides. Drugs with potential benefit include deferoxamine, dihydroxybenzoic acid, glutathione, D methionine and N acetylcysteine

38 STRATEGIES TO PREVENT OTOTOXICITY Popa R, Anniko M, Takumida M. Otoprotectant minimizes hearing defects caused by Pseudomonas aeruginosa exotoxin A. Acta Otolaryngol. 2000;120(3): The mechanism of cochleotoxicity of Pseudomonas exotoxin may be mediated through nitric oxide production. A study to look at the ototoprotective effects of N(G)-nitro-L-arginine methyl ester (L-NAME), a known inhibitor of nitric oxide synthesis against Pseudomonas exotoxin showed amelioration of hearing loss in rats