Literature Reading OTOTOXIC ANTIBIOTIC

1Literature ReadingMechanism Of Aminoglycoside and Salycilate in Ototoxicity

Inda Rizkia Oktaviani

Pembimbing utama:dr.Yussy Afriani Dewi,Mkes,SpTHT-KL (K)

Department of Otorhinolaryngology-Head & Neck SurgeryFaculty of Medicine Padjadjaran UniversityHasan Sadikin General HospitalBandung2014

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INTRODUCTION2Inner ear damage caused by the drug, often overlooked

Physicians should recognize drugs ototoxic

Ototoxic drugs: drugs that have the potential to cause toxic reactions in the structures of the inner ear such as kokhlea, vestibule, semicircular canals and the otolith.

Ototoxicity: kokhlea and damage to structures in the ear or vestibular due to exposure to chemicals.

Symptoms: hearing loss, tinnitus and balance disorders.

INTRODUCTION3Ototoxicity 1944 Streptomycin (TBC)Cochlea disfunction and irreversible vestibular pathology.Other ototoxic drugs :AminoglikosidMakrolidChemotherapySalicylateQuinineLoop Diuretic

4Ototoxicity : American Speech-Language-Hearing Association (ASHA) and The National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) :Decrease by 20 dB or more in pure tone audiometry at frequenciesDecrease of 10dB or more at the two adjacent frequenciesNo response on the OAE or BERA examinations on repeated examination 3 times where previously no response.

Grade of Ototoxicity5 CTAE: 1st Grade : Hearing threshold 15-25dB down from the previous examination (1 year), averaged at 2 or more consecutive frequencies. 2nd Grade: The hearing threshold of 25-90dB down from the previous examination (1 year), averaged at 2 or more consecutive frequencies. 3rd Grade : Hearing loss requiring hearing aid intervention (> 20 dB at a frequency of bilateral conversations,> 30dB at frequencies unilateral conversation) 4th Grade: Hearing loss requiring hearing aid intervention and implant cochlea.

Brocks6Grade 0: Less than 40dB hearing threshold at all frequencies Grade 1: Hearing threshold> 40dB at a frequency of 8.000Hz Grade 2: Hearing threshold> 40dB at a frequency of 4.000-8.000Hz Grade 3: Hearing threshold> 40dB at a frequency of 2.000-8.000Hz Grade 4: Hearing threshold> 40dB at frequency 1.000-8.000Hz

GENETIC FACTORS OF OTOTOXICITY7Aminoglikosid ototoxic, even in low doses

Found in a family case many are experiencing ototoxicity due aminoglikosid

Certain individuals have a genetic predisposition more susceptible to the effects of ototoxicity against aminoglokosid.

Recent findings: mutations in mitochondrial DNA

8Early 1990 mutation at position 1555 on the mitochondrial 12S ribosomal RNA nucleotides:

aminoglikosid ototoxicity caused in some families of Chinese descentnonsindromik deafness cases in patients with no therapy aminoglikosid.

Further research: mutation at nucleotide of mitochondrial DNA identical

9Mutations result: there is specific receptors bind to aminoglikosid thus increasing sensitivity to ototoxic effects of aminoglikosid.

Similar studies carried out more and more additional information expected to be developed molecular methods of examination before therapy prevent ototoxic effects

OTOTOXICITY OF TOPICAL ANTIBIOTICS FOR EARS10Preparation: powder, cream or drops

Powder: stick to the surface of the moist, last longer in CAE, middle ear cavity or mastoid cavity (last s / d 1 month)

Powder preparation:outer ear: chloramfenikol, sulfanamide, hidrokortisonemastoid cavity: ciprofloxacin, clotrimazole or deksametasone.

Research in mice: provision of ciprofloxacin ear drops-dexametasone intratimpani for 21 days did not cause ototoxic effects

11Cream preparation: the outer ear antibiotics and anti-fungal

Antibiotic cream: neosporin or tobramycin

Most preparations: Ear Drops Grouped:presence or absence of antibioticscontained antibioticspHconsistencysingle agent or combination

12Topical antibiotic ear advantages:

Higher concentrations in the area of infectionNo effect of systemicCan fix things around the area of infectionUsually the price is cheaper when compared to systemic drug delivery

Disadvantages:Achieving effectiveness drops to the area of infection is quite difficultCan cause toxic effects locally in the middle ear and the inner earCan cause local sensitivity reaction

13If antibiotic ear drops did not reach the area of infection ineffective

Caused by:-Hatching improper education-Covered wax extraction - Purulent secretions hydrogen peroxide- Granulation tissue curettage

OTOTOXICITY OF SYSTEMIC DRUGS14Antibiotik AminoglikosidStreptomisinGentamisinNeomisinKanamisinAmikasinTobramisin

Other Antibiotik EritromisinAzitromisin & ClindamisinVankomisin Diuretik Antineoplastik Salisilat Kuinin

Aminoglycoside 151944 - present: streptomycin, dihidrostreptomisisn, kanamycin, gentamicin, neomycin, tobramycin, and amikacin netilmisin.

Bactericidal antibioticsbound to the 30S ribosome and inhibit bacterial protein synthesis process.

Widely used: septicemia, urinary tract infections, respiratory tract infections, intra-abdominal infections and osteomyelitis caused by aerobic bacteria gram negative rods.

Ototoxic effects: Cokhleotoksik and or vestibulotoksik.

PATOFISIOLOGY16Toxic to: renal system and kokhleovestibuler

Kokhlea toxicity impaired hearing at high frequencies

Irreversible damage to the outer hair cells in the organ korti, especially in the basal kokhlea.

Aminoglikosid levels in the inner ear fluid last longer than levels in serum

Ototoxic effects of latent

Monitoring the effects of ototoxic and vestibulotoksik until 6 months

17Mechanism:

Disruption of protein synthesis process in mitochondriaformation of free radicalsAt the cellular level:outer hair cell damage kokhlea

Aminoglikosid free radicals in the inner ear (activates nitric oxide synthetase) increased concentration of nitric oxidereaction between nitric oxide + oxygen radical peroxynitrite radical

radical peroxynitrite: destructive, stimulates cell death directly

18Apoptosis: the major mechanism of cell death, mediated by intrinsic cascade mediated by mitochondria.

The end result: permanent damage hair cells outside kokhlea permanent hearing loss

19Aminoglikosid ototoxicity: a multifactorial

Further research is needed

Still researched how to prevent ototoxic effects by providing:iron chelatorsantioxidantsgene therapy

Now: amplification and implant kokhlea,

Prevention is very important

Epidemiology20Hearing disorders: 66% in developing countries

Audiogram changes 33% in adult patients receiving therapy aminoglikosid

Vestibular toxicity: 4% in adult patients

Toxicity kokhlea: 2% in patients with neonatal

21Risk Factors

Therapy with high-doseHigh serum concentrationsTherapy in a long timelongevityImpaired renal functionPrevious history of hearing disordersFamily history of ototoxicityCurrently receiving diuretic treatment at the same time

22Signs and Symptoms

Toxicity kokhlea: tinnitus.

Decrease in hearing threshold at high frequencies (> 4.000Hz)

may increasingly become heavy when therapy was continued and permanent

When therapy is stopped immediately prevent further damage

Vestibular toxicity: impaired balance (dark) and symptoms of visual disturbances (oskilopsia)

23Prevention

Research on animals:- antioxidants, vitamin E, alpha lipoic acid, ebselen, ginkgo biloba- Further research is still needed

Monitor serum drug levels and renal function

Hearing inspection before, during and after therapy

Identification of patients with risk factorsUse of alternative medicine

Education: avoid noisy environment s / d 6 months

24Aminoglikosid removed from the body by the kidneys

Impaired renal function in serum prolong increased concentrations of ototoxic risk >>>

Monitor renal function in patients with:and normal serum creatinine levels:Therapy s / d 14 days: check creatinine levels 2 x / week.Therapy> 14 days: check creatinine levels 3 x / weekserum creatinine levels were increased but stable:check creatinine levels 2 days.serum creatinine levels were not stable:Check creatinine levels every day.

25Streptomycin

The first Aminoglikosid

The effect was mainly on gram-negative bacteria

Vestibulotoksik more dominant effect

26Gentamicin

Vestibulotoksik more dominant effect

Serum levels: 10-12mcg/mL safe

The dose should be adjusted with caution when used in patients with renal impairment

27Neomycin

Most kokhleotoksik

Systemic use is not recommended

Very slowly disappeared from perilymph

Toxicity often occurs later (1-2 weeks after cessation of therapy)

Neomycin ear drops are effective

Alternatives that are equally effective but safer widely available.

28Kanamycin

Lower toxic effects than neomycin

Can cause severe damage to hair cells kokhlea and severe hearing loss at high frequencies

Now rarely used

Should not be administered intravenously

29Amikacin:

Kanamycin derivative

Vestibulotoksik effects are very minimal compared to gentamicin

indications:severe infectionsaccording to the results of culture and resistanceAdjust the patient's response.

30Tobramycin

Ototoxic effects similar to amikacin

Occurred less high frequency hearing.

Tobramycin is often used as preparations ototopikal

Generally regarded as safe

Salycilate31Acetyl salicylic acid = aspirin Inhibitor of platelet aggregation Anti-inflammatory, anti-pyretic and analgesic Usage: history of stroke, angina or myocardial infarction. Acetyl salicylic acid is absorbed rapidly liver hydrolysis in the active form of salicylic acid Therapeutic levels: 25-50mcg/mL as an analgesic and antipyretic 150-300 mcg / mL in the treatment of rheumatic fever Serum levels 200mcg/mL tinnitus

Patofisiologi32The mechanism is multifactorial and multi-location Salicylic acid rapid entry into kokhlea levels in perilymph ~ levels in serum Increased levels of tinnitus and SNHL while, (audiogram: flat) Minimal morphological abnormalities have been reported OAE results: the outer hair cell abnormalities kokhlea Decreased blood flow is also thought to have a role kokhlea Biochemical changes, and the permeability of the outer hair cells that are not normal can also affect

33Epidemiology approximately 1%

Risk factors High dose Longevity Dehydration

34Signs and Symptoms

Tinnitus, impaired hearing, nausea, vomiting, headache.

Mild-moderate hearing disorders bilaterally symmetrical Recovery in 24-72 hours tinnitus: Once thought to be an early sign of ototoxicity Now should not be used as markers in the serum levels of salicylate

Ototoxic effects can occur despite low levels of serum salicylate

35Therapy

Monitoring electrolyte levels Fluid administration Giving oxygen and mechanical ventilation may be required in severe cases

Important Things To Ototoxicity36Early Detection of OtotoxicityBefore, during and after therapyPatients with complications :Level of consciousnessAgeParticular profession: adjusting tones of musical instruments (piano, guitar, etc.), singer, pilot Patient history, family history, examination of the ear otoskopiPure tone audiometry 0.25-8kHzOAE and ABR

37Information on the patient's risk of ototoxic

Immediately report symptoms: tinnitus, hearing loss, or impaired balance oskilopsia

Check the hearing (audiometric) with a fixed time interval

Symptoms of ototoxicity + stop drug

Standard vestibular examination: caloric tests Romberg test

38Therapy

Prevention

Maintain communication skills

Hearing disorders + prevent communication impairment, social and educational hearing aids

CONCLUSION39Ototoxic drugs: potential toxic reactions in the inner ear (kokhlea / vestibular)

Ototoxicity: damage kokhlea / vestibular due to exposure to chemicals

Symptoms: hearing loss, tinnitus and balance disorders

40Ototoxicity: ASHA and (CTCAE):

Decrease by 20 dB or more in pure tone audiometry at frequencies

Decrease of 10dB or more at the two adjacent frequencies

No response on the OAE or BERA examinations on repeated examination 3 times where previously no response.

41If the forced used ototoxic drugs inform risk to patients and their families

Primary therapy: prevention

Goal: Maintain communication skills

hearing disorder hearing aids

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