Genetic susceptibility to aminoglycoside ototoxicity

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Abstract

Introduction

Aminoglycosides are a well-known clinically relevant antibiotic family used to treat bacterial infections in humans and animals and can produce toxic side effects. Aminoglycoside-induced hearing loss (HL) has been shown to have a genetic susceptibility. Mitochondrial DNA mutations have been implicated in inherited and acquired hearing impairment.

Objective

Literature review of genetic mutations associated with aminoglycoside-induced ototoxicity.

Methods

PubMed was accessed from 1993 to 2017 using the search terms “aminoglycoside, genetic, ototoxicity, hearing loss”. Exclusion criteria consisted of a literature in a language other than English, uncompleted or ongoing studies, literature with non-hearing related diseases, literature on ototoxicity due to cisplatin/carboplatin based chemotherapy, literature on ototoxicity from loop diuretics, animal studies, literature studying oto-protective agents, and literature without documented aminoglycoside exposure.

Results

108 articles were originally identified, and 25 articles were included in our review. Mitochondrial 12S rRNA mutations were identified in all 25 studies in a total of 220 patients. Eight studies identified A1555G mutation as primary genetic factor underlying HL in cases of aminoglycoside-induced ototoxicity. The next most common mutation identified was C1494T.

Discussion

Mitochondrial 12s rRNA mutation A1555G was present in American, Chinese, Arab-Israeli, Spanish and Mongolian ethnicities. All mutations leading to aminoglycoside ototoxicity were mitochondrial mutations.

Conclusions

Consideration of preexisting genetic defects may be valuable in treatments involving aminoglycosides. In particular populations such as those of Chinese origin, clinicians should continue to consider the increased susceptibility to aminoglycosides.

Introduction

Patients who are treated with aminoglycosides are mostly premature or critically ill neonates. Studies have reported adverse auditory effects with the use of the aminoglycosides [1,2]. At least one article has investigated familial inheritance of aminoglycoside-induced ototoxicity, suggesting mitochondrial involvement [3]. Aminoglycosides act by directly binding to 16S ribosomal RNA in the 30S subunit of the bacterial ribosome, disrupting or prematurely terminating protein synthesis. Research established a genetic basis for aminoglycoside-induced hearing loss (HL) through sequence analysis of the mitochondrial genome, which resulted in the characterization of mutations in the human 12S rRNA that are correlated with aminoglycoside induced ototoxicity [4].

Section snippets

Objectives

Our study sought to review specific mutations in cases with reported sensorineural hearing loss (SNHL) due to aminoglycosides.

Methods

We performed a systematic review of the literature published from July 16, 1993 through April 14, 2017, for patients who had genetic mutations associated with aminoglycoside-induced ototoxicity. Searches of the PubMed database used the terms “aminoglycoside, genetic, ototoxicity, hearing loss”. Studies were included if they were peer reviewed studies, in English, specifically addressed ototoxic genetic mutations and included human subjects. Exclusion criteria consisted of a literature in a

Results

The initial search resulted in 108 articles. We reviewed 25 articles for the study. A PRISMA flow diagram to reflect the selection of these articles is shown in the Fig. 1.

Mitochondrial 12S rRNA mutations were identified in all 25 studies in a total of 220 patients. The mutations are summarized in the table. Of the studies that mentioned gender, the A1555G mutation was identified in 36 females and 61 males. The table lists studies that included the number of subjects with known aminoglycoside

Discussion

Neonatal infections can account for approximately 580,000 newborn deaths globally per annum. Low income and middle income countries have the greatest number of fatalities [5]. Cases of neonatal possible serious bacterial infection were estimated to about 6.9 million neonates over 32 weeks gestation age in South Asia, sub-Saharan Africa, Latin America and the Carribean [6]. Current World Health Organization's (WHO) guidelines recommend gentamicin with ampicillin or penicillin as the first line

Limitations

The population of USA is largely heterogenous (73.3% Caucasian, 12.6% African or African-American, 0.8% American Indian and Alaska Native, 5.2% Asian, 0.2% Native Hawaiian and other Pacific Islander, 4.8% Other, based on the 2015 US census data) [39]. Majority of the ethnicities with the mitochondrial mutations are of Asian ethnicity, so until the prevalence of the mutations in the US population are better defined, the role of genetic testing remain undefined.

Conclusions

Aminoglycosides remain a commonly utilized treatment worldwide due to efficiency in treating severe infections. Consideration of preexisting genetic defects may be valuable in treatments involving aminoglycosides. In particular populations such as those of Chinese origin, clinicians should continue to consider the increased susceptibility that arises from the combination of aminoglycosides and genetic defect. In the interim, infants who received aminoglycosides should have their hearing

Conflicts of interest

No Conflict of Interest.

Financial disclosures

No Financial Disclosures.

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    Work was done at Virginia Tech-Carilion School of Medicine and Akron Children's Hospital.

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