SYSTEMIC GENTAMICIN OTOTOXICITY: DOSING REGIMENS, RISK FACTORS AND MEDICO-LEGAL CONCERNS Prepageran Narayanan FRCS, Vitaly Kisilevsky MD, A.R. Scott FRCS John A Rutka MD, FRCSC

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SYSTEMIC GENTAMICIN OTOTOXICITY DOSING
REGIMENS, RISK FACTORS AND MEDICO-LEGAL
CONCERNSPrepageran Narayanan FRCS, Vitaly
Kisilevsky MD, A.R. Scott FRCS John A Rutka MD,
FRCSC
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IntroductionAminoglycosides

• commonly used gram negative infections,some
  gram positive
• wide spectrum, low resistance,
• Unique mode of action-ribosomal binding

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Aminoglycosides

• reservations over prolonged use
• potential nephrotoxic and ototoxic

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Dosage regimes

• Single daily dose(SDD) vs multiple daily doses
  regimens(MDD)
• animal studies SDD consistently less toxic
  (mainly nephrotoxicity)
• Human studies
• SDD greater efficacy, less toxicity?
• SDD vs MDD no significant difference?

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CONCERN?

• failure to appreciate the ototoxic potential of
  SDD regimen?
• false sense of security for SDD? Outpatient
  therapy, need for monitoring?

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OBJECTIVE

• To compare and contrast the ototoxicity effects
  due to single daily dose (SDD) Gentamicin
  (aminoglycoside) therapy from those induced by
  multiple daily dosage(MDD) regimens.

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METHODS AND MATERIAL

• retrospective review of patients with documented
  ototoxicity
• Systemic Aminoglycosides
• 1992 till present

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REVIEW

• indications duration of treatment
• pre-existing co-morbidity
• ototoxicity clinical presentation,investigations
• serum level monitoring
• therapeutic induced renal impairment

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RESULTS

• 29 patients confirmed aminoglycoside induced
  ototoxicity by ENG and rotational chair studies.
• female 13 , male 16
• age 34-78 years

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Results

• SDD 9 patients (31)
• MDD20 patients (69)

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Indications
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Clinical manifestations
SDD MDD Total
unsteadiness 2 6 8
severe ataxia 3 4 7
imbalance 1 9 10
oscillopsia 2 1 3
vertigo 1 1
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ANTIBIOTICSSINGLE OR COMBINATION
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Serum monitoring

• 14 had documented serum gentamycin monitoring
• 10(71.4) adequately monitored
• 4(29.6) inadequately monitored

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Serum monitoring

• Normal 9/14 (64.3)
• Elevated5/14 (35.7)

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concomitant nephrotoxicity

• 21 pts had sufficient documentation
• 8/21(38.1) developed nephrotoxicity

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onset of nephrotoxicity vs ototoxicity

• 2 prior to ototoxicity
• 3 at the same time
• 2 after ototoxicity
• 1 could not be determined

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Discussion

• Aminoglycosides ototoxicity, irreversible damage
  end organ sensory hair cells in cochlea
  vestibular labyrinth
• Incidence 2-3,
• gentamicin 8 cochlear toxicity , 14 vestibular
  
• higher incidence with objective testing.
• 50 permanent threshold shift with ultrahigh
  frequency audiogram
• Most cochlear toxicity 9 to 15kHz, not routinely
  tested
  

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Otoxicity

• Cochlear toxicity organ of corti
• Starts at basal turn, progressive
• Outer hair cells, inner row of outer hair cells
  most sensitive
• Similar microscopic findings to noise induced
  hearing loss
• Vestibulotoxicity crista ampularis more
  sensitive
• Type I hair cell more sensitive
• Exact mechanism unknown ?gentamicin-iron complex

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SDD Vs MDD

• Studies conflicting results? Reasons?
• Inherent bias of criteria,difference in study
  groups and doses of antibiotics
• Discrepancy in diagnosis, measuring outcome, use
  of laboratory tools

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SDD Vs MDD

• Ototoxicity occurs in both SDD MDD
• SDD toxicity appears earlier 77 less than 3
  weeks.
• Accumulation of aminoglycosides in labyrinth
  related to prolonged exposure/ cumulative doses,
  not dosing regimes
• related to transient elevated serum levels(peak)
  in SDD?
• Animal studies ototoxicity related to total
  daily dosing not frequency

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Serum Monitoring

• Serum monitoring doesnt prevent ototoxicty
  64.3 had normal levels.
• Levels not adequately monitored in some instances
• May be important from medicolegal point of view
• No safe gentamicin level or dose, genetic
  susceptibilty

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the way ahead?

• Awareness of clinical features of
  vestibulotoxicity
• Imbalance, unsteadiness not vertigo
• Gait ataxia, Rhomberg, oscillopsia and post head
  shake nystagmus
• 5 out of 29 cases(16.3) have medicolegal suits
  ongoing

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Conclusion

• SDD can result in ototoxicity, earlier than MDD
• Toxicity depends on cumulative dose and duration
  not frequency.
• High index of suspicion important