Aminoglycoside-induced deafness

Excerpt from the CPIC guidelines for Aminoglycosides and MT-RNR1 variants.

The critical pharmacogenetics recommendation for a person with an MT-RNR1 variant which predisposes to AIHL is that aminoglycoside antibiotics are relatively contraindicated, meaning that aminoglycosides should be avoided unless the increased risk of hearing loss is outweighed by the severity of infection and lack of safe or effective alternative therapies. There is insufficient evidence to suggest that the adverse drug reaction may be more profound with some members of the aminoglycoside class than others. As such, this guidance covers all aminoglycoside antibiotics irrespective of class. We provide a strong recommendation that carriers of MT-RNR1 variants that predispose to AIHL should avoid aminoglycosides unless the increased risk of permanent hearing loss is outweighed by the risk of infection without safe or effective alternative therapies… If no effective alternative to an aminoglycoside is thought to be available, we advise use for the shortest possible time, consultation with an infectious disease expert for alternative approaches, therapeutic drug monitoring and frequent assessment for hearing loss, both during and after therapy, in consultation with an audiovestibular physician.

An individual with no detectable MT-RNR1 variant or carrying MT-RNR1 variants not considered to be predisposing to AIHL (normal risk), including the m.827A>G variant, should still be considered at risk of AIHL. In addition to MT-RNR1, AIHL is often associated with other risk factors such as prematurity, renal impairment, severe inflammatory response syndrome, prolonged therapy regimens, and supratherapeutic plasma concentrations. As such, irrespective of the presence of an MT-RNR1 variant which predisposes to AIHL, precautions such as renal monitoring, therapeutic drug monitoring, and utilizing the lowest effective dose should be applied. Finally, if an individual with an actionable MT-RNR1 variant has previously received aminoglycosides and not developed AIHL, this does not preclude them from developing AIHL with subsequent doses.

Considerations for aminoglycoside use in patients at increased risk of AIHL. For the purposes of this guideline, appropriateness for use of aminoglycoside antibiotics can be considered for three scenarios: First, an equally or more effective agent is available for the condition; second, there is reason to believe that an aminoglycoside might lead to superior outcomes, but evidence is poor, the effect-size is small, or the outcome is not clinically meaningful; and third, there is good evidence for significantly superior efficacy of an aminoglycoside-containing treatment regimen for a clinically meaningful outcome.

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In all cases, an aminoglycoside used in patients at increased risk of AIHL due to the presence of an MT-RNR1 variant should be administered for the shortest possible period, under expert supervision, with therapeutic drug and ototoxicity monitoring, and with clinical audiovestibular assessment performed during and after treatment. Irrespective of whether an individual carries a pathogenic MT-RNR1 variant, all patients who receive aminoglycoside antibiotics, especially those prescribed prolonged courses, should be monitored for ototoxicity in line with existing local and international guidelines.

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Based on the available literature, at present there is not sufficient evidence to define a level of heteroplasmy where aminoglycoside administration becomes safe, especially as the mutational load may differ from tissue to tissue and be dependent upon the genotyping technique utilized. As such, we have not tailored this guideline based on the level of heteroplasmy. Rather, we recommend that if a relevant MT-RNR1 variant is detected, the guidance should be followed as set out for a homoplasmic variant.

Please review the complete CPIC therapeutic recommendations that are located here: (4).

Excerpt from the American College of Medical Genetics and Genomics (ACMG) Guideline for the Clinical Evaluation and Etiologic Diagnosis of Hearing Loss:

For individuals lacking physical findings suggestive of a known syndrome and having medical and birth histories that do not suggest an environmental cause of hearing loss, a tiered diagnostic approach should be implemented.

Pretest genetic counseling should be provided, and, with patient’s informed consent, genetic testing should be ordered.

Single-gene testing may be warranted in cases in which the medical or family history, or presentation of the hearing loss, suggests a specific etiology. For example, testing for mitochondrial DNA mutations associated with aminoglycoside ototoxicity may be considered for individuals with a history of use of aminoglycoside antibiotics.

Please review the complete ACMG therapeutic recommendations that are located here: (6).