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

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

Aminoglycosides reservations over prolonged use reservations over prolonged use potential nephrotoxic and ototoxic potential nephrotoxic and ototoxic

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

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

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. 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.

METHODS AND MATERIAL retrospective review of patients with documented ototoxicity retrospective review of patients with documented ototoxicity Systemic Aminoglycosides Systemic Aminoglycosides 1992 till present 1992 till present

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

RESULTS 29 patients: confirmed aminoglycoside induced ototoxicity by ENG and rotational chair studies. 29 patients: confirmed aminoglycoside induced ototoxicity by ENG and rotational chair studies. female : 13, male : 16 female : 13, male : 16 age: years age: years

Results SDD :9 patients (31%) SDD :9 patients (31%) MDD:20 patients (69%) MDD:20 patients (69%)

Indications

Clinical manifestations SDDMDDTotal unsteadiness268 severe ataxia 347 imbalance1910 oscillopsia213 vertigo11

ANTIBIOTICS:SINGLE OR COMBINATION

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

Serum monitoring Normal : 9/14 (64.3%) Normal : 9/14 (64.3%) Elevated:5/14 (35.7%) Elevated:5/14 (35.7%)

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

onset of nephrotoxicity vs ototoxicity 2 prior to ototoxicity 2 prior to ototoxicity 3 at the same time 3 at the same time 2 after ototoxicity 2 after ototoxicity 1 could not be determined 1 could not be determined

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

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

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

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

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

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

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