Aminoglycoside-induced Hearing Loss Research Articles

Genedrive kit for detecting single nucleotide polymorphism m.1555A>G in neonates and their mothers: a systematic review and cost-effectiveness analysis.

Neonates with suspected sepsis are commonly treated with gentamicin, an aminoglycoside. These antibiotics are associated with high risk of ototoxicity, including profound bilateral deafness, in people with the m.1555A>G mitochondrial genetic variant. This early value assessment summarised and critically assessed the clinical effectiveness and cost-effectiveness of the Genedrive MT-RNR1 ID Kit for identifying the gene m.1555A>G variant in neonates and mothers of neonates needing antibiotics or anticipated to need antibiotics. Following feedback from the scoping workshop and specialist assessment subgroup meeting, we also considered the Genedrive MT-RNR1 ID Kit for identifying the m.1555A>G variant in mothers prior to giving birth. For clinical effectiveness, we searched three major databases in October 2022: MEDLINE, EMBASE and CINAHL (Cumulative Index to Nursing and Allied Health Literature). For cost-effectiveness, in addition to the three mentioned databases we searched Cochrane and RePEc-IDEAS. Study selection and risk-of-bias assessment were conducted by two independent reviewers (Ryan PW Kenny and Akvile Stoniute for clinical effectiveness and Hosein Shabaninejad and Tomos Robinson for cost-effectiveness). Any differences were resolved through discussion, or by a third reviewer (Nick Meader). Risk of bias was assessed using Quality Assessment of Diagnostic Accuracy Studies-2. One study (n = 751 neonates recruited) was included in the clinical effectiveness review and no studies were included in the cost-effectiveness review. All except one outcome (test failure rate: low risk of bias) were rated as being at moderate risk of bias. The study reported accuracy of the test (sensitivity 100%, 95% confidence interval 29.2% to 100%; specificity 99.2%, 95% confidence interval 98% to 99.7%), number of neonates successfully tested (n = 424/526 admissions), test failure rate (17.1%, although this was reduced to 5.7%), impact on antibiotic use (all those with a m.1555A>G genotype avoided aminoglycosides), time taken to obtain a sample (6 minutes), time to genotyping (26 minutes), time to antibiotic treatment (55.18 minutes) and the number of neonates with m.1555A>G (n = 3). The economic component of this work identified key evidence gaps for which further data are required before a robust economic evaluation can be conducted. These include the sensitivity of the Genedrive MT-RNR1 ID Kit for identifying the gene m.1555A>G variant in neonates, the magnitude of risk for aminoglycoside-induced hearing loss in neonates with m.1555A>G, and the prevalence of the m.1555A>G variant. Other potentially important gaps include how data regarding maternal inheritance may potentially be used in the clinical pathway. This early value assessment suggests that the Genedrive MT-RNR1 ID Kit has the potential to identify the m.1555A>G variant and to be cost-effective. The Genedrive MT-RNR1 ID Kit dominates the current standard of care over the lifetime, as it is less costly and more effective. For a 50-year time horizon, the Genedrive MT-RNR1 ID Kit was also the dominant strategy. For a 10-year time horizon, the incremental cost-effectiveness ratio was estimated to be £103 per quality-adjusted life-year gained. Nevertheless, as anticipated, there is insufficient evidence to conduct a full diagnostic assessment of the clinical effectiveness and cost-effectiveness of the Genedrive MT-RNR1 ID Kit in neonates directly or in their mothers. This report includes a list of research priorities to reduce the uncertainty around this early value assessment and to provide the additional data needed to inform a full diagnostic assessment, including cost-effectiveness modelling. This study is registered as PROSPERO (CRD42022364770). This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: NIHR135636) and is published in full in Health Technology Assessment; Vol. 28, No. 75. See the NIHR Funding and Awards website for further award information.

Assessment of Aminoglycoside-Induced Hearing Loss Risk in the Perinatal Period.

This study aimed to determine the prevalence and heteroplasmy level(s) of MT-RNR1 variants m.1555A > G and m.1494C > T, which are associated with aminoglycoside-induced hearing loss, in a general perinatal population. This study also aimed to characterize the association of these variants and their heteroplasmy levels with hearing loss outcomes with and without aminoglycoside exposure. Droplet digital polymerase chain reaction was performed on 479 maternal DNA samples from a general perinatal biobank at our institution to detect the presence and heteroplasmy levels of MT-RNR1 variants m.1555A > G and m.1494C > T. Testing of paired neonatal specimen(s) was planned for positive maternal tests. A retrospective chart review was performed to characterize the population, identify aminoglycoside exposures, and determine hearing outcomes. All maternal samples tested negative for MT-RNR1 variants m.1555A > G and m.1494C > T. Maternal and neonatal subjects had high rates of aminoglycoside exposure (15.9 and 13.9%, respectively). No subjects with sensorineural or mixed hearing loss had documented aminoglycoside exposure. This study demonstrated that a larger sample size is needed to establish the prevalence of these variants as no subjects tested positive. Determination of variant prevalence in the neonatal population, association of variant heteroplasmy levels with hearing outcomes, and reliability of maternal testing as a surrogate for neonatal testing are important next steps toward universal prenatal or newborn screening. · MT-RNR1 variants are associated with aminoglycoside-induced hearing loss.. · Prevalence of MT-RNR1 variants is uncertain.. · Universal screening for MT-RNR1 variants may be indicated..

P250 An information leaflet about MT-RNR1 testing to reduce the risk of aminoglycoside-induced hearing loss in people with cystic fibrosis

P250 An information leaflet about MT-RNR1 testing to reduce the risk of aminoglycoside-induced hearing loss in people with cystic fibrosis

Mechanisms and otoprotective strategies of programmed cell death on aminoglycoside-induced ototoxicity.

Aminoglycosides are commonly used for the treatment of life-threatening bacterial infections, however, aminoglycosides may cause irreversible hearing loss with a long-term clinical therapy. The mechanism and prevention of the ototoxicity of aminoglycosides are still limited although amounts of studies explored widely. Specifically, advancements in programmed cell death (PCD) provide more new perspectives. This review summarizes the general signal pathways in programmed cell death, including apoptosis, autophagy, and ferroptosis, as well as the mechanisms of aminoglycoside-induced ototoxicity. Additionally, novel interventions, especially gene therapy strategies, are also investigated for the prevention or treatment of aminoglycoside-induced hearing loss with prospective clinical applications.

MT-RNR1 Genotype Should Not Affect Childhood Vaccination—Unintended Consequences of Guidelines

This Viewpoint discusses whether routine vaccination is safe for children with MT-RNR1 gene variants that predispose to aminoglycoside-induced hearing loss.

The Mitochondrial tRNASer(UCN) Gene: A Novel m.7484A>G Mutation Associated with Mitochondrial Encephalomyopathy and Literature Review

Mitochondrial tRNASer(UCN) is considered a hot-spot for non-syndromic and aminoglycoside-induced hearing loss. However, many patients have been described with more extensive neurological diseases, mainly including epilepsy, myoclonus, ataxia, and myopathy. We describe a novel homoplasmic m.7484A>G mutation in the tRNASer(UCN) gene affecting the third base of the anticodon triplet in a girl with profound intellectual disability, spastic tetraplegia, sensorineural hearing loss, a clinical history of epilepsia partialis continua and vomiting, typical of MELAS syndrome, leading to a myoclonic epilepticus status, and myopathy with severe COX deficiency at muscle biopsy. The mutation was also found in the homoplasmic condition in the mother who presented with mild cognitive deficit, cerebellar ataxia, myoclonic epilepsy, sensorineural hearing loss and myopathy with COX deficient ragged-red fibers consistent with MERRF syndrome. This is the first anticodon mutation in the tRNASer(UCN) and the second homoplasmic mutation in the anticodon triplet reported to date.

Влияние индивидуальных генетических особенностей организма на успешность применения антибактериальных препаратов

To date, numerous studies have reported significant associations of adverse drug reactions with genetic factors. In particular, the connection between drug-induced liver injury and carriage of certain MNS haplotypes when using amoxicillin and flucloxacillin has been demonstrated. The influence of polymorphisms of the PTPN22, ERAP2, PXR, ST6GAL1 genes was also observed. The pharmacokinetics of cephalosporins is affected by polymorphisms of drug transporter genes such as SLCO1A2, SLC22A8, ABCC2, ABCG2, ABCB1, which, however, requires further clarification. The pharmacokinetics of macrolides, according to some reports, may be related to the CYP3A4, SLCO1B1, ABCC2, and ABCB1 genes. The association of mutations in the mitochondrial DNA 12S rRNA genes in the development of non-syndromic and aminoglycoside-induced hearing loss has been well studied. The most important are the substitutions m.1095C>T, m.1494C>T and m.1555A>G. Risk factors for the development of neurological adverse reactions during the use of fluoroquinolones may be the carriage of alleles of blood-brain barrier transporters: ABCB1, ABCG2, SLCO1A2. Cutaneous adverse reactions with vancomycin may be associated with carrying MNS haplotypes, and urinary tract adverse reactions with the rs2789047 polymorphism. Daptomycin rarely contributes to the development of myopathy, which is presumably influenced by both renal functional status and the ABCB1 gene polymorphism. Key words: pharmacogenetics, genetic polymorphism, single nucleotide polymorphisms, antibiotics, adverse reactions

Detecting mitochondrial mutations associated with aminoglycoside ototoxicity by noninvasive prenatal testing.

Numerous diseases and disorders are associated with mitochondrial DNA (mtDNA) mutations, among which m.1555A > G and m.1494C > T mutations in the 12 S ribosomal RNA gene contribute to aminoglycoside-induced and nonsyndromic hearing loss worldwide. A total of 76,842 qualified non-invasive prenatal (NIPT) samples were subjected to mtDNA mutation and haplogroup analysis. We detected 181 m.1555A > G and m.1494C > T mutations, 151 of which were subsequently sequenced for full-length mitochondrial genome verification. The positive predictive values for the m.1555A > G and m.1494C > T mutations were 90.78% and 90.00%, respectively, a performance comparable to that attained with newborn hearing screening. Furthermore, mitochondrial haplogroup analysis revealed that the 12 S rRNA 1555A > G mutation was enriched in sub-haplotype D5[p=0, OR=4.6706(2.81-7.78)]. Our findings indicate that the non-invasive prenatal testing of cell-free DNA obtained from maternal plasma can successfully detect m.1555A > G and m.1494C > T mutations.

Aminoglycoside induced ototoxicity risk in the cystic fibrosis population: The utility of large-scale screening.

MT-RNR1 variants are a well-known cause of aminoglycoside-induced hearing loss (AIHL). Individuals with cystic fibrosis (CF) routinely receive aminoglycosides and are at high risk of AIHL. However, genetic testing before treatment is not routinely performed due to perceived rarity of risk, and cost ineffectiveness with traditional technologies. Assess the utility of large-scale screening for AIHL risk in the CF population, usingdigital droplet polymerase chain reaction (ddPCR), a novel and scalable low-cost molecular technique. Using a clinically validated ddPCR assay, we performed retrospective testing on 122 and prospective testing on 32 individuals with CF for the two most common pathogenic variants associated with AIHL, MT-RNR1 m.1555 A > G and m.1494 C > T. Our study screened the largest known cohort of pediatric cases of CF (94/154) for these specific alterations. We identified two individuals positive for MT-RNR1 m.1555 A > G and no positives for m.1494 C > T. Of 32 prospective cases, 17 had aminoglycoside exposure. The positive case in our prospective group recently began inhaled tobramycin and denied hearing issues. The clinician adjusted to care for both the patient and sibling with CF (not included in cohort) who is presumed positive for m.1555 A > G due to the nature of mitochondrial inheritance. Our findings demonstrate the utility of pretreatment screening in the cystic fibrosis population for AIHL risk using ddPCR, a scalable and robust testing methodology at a fraction of the cost as compared to other sequencing-based methods. Therefore, the use of large-scale screening for AIHL risk in the cystic fibrosis community should be re-visited.

Using a bedside test to detect genetic susceptibility to aminoglycoside-induced hearing loss: Has the future arrived?

Aminoglycosides are among the most commonly prescribed antibiotics in hospitalised Australian adults and children. A proportion of individuals with an underlying genetic predisposition to aminoglycoside-induced hearing loss (AIHL) can develop bilateral sensorineural hearing loss that is immediate and profound after just a single standard dose of an aminoglycoside. A recent publication described the use of a rapid point-of-care test (POCT) in a neonatal nursery in the United Kingdom for real-time detection of infants at risk of AIHL, in whom exposure to aminoglycosides could then be avoided. This proof of concept study should provide a catalyst for further development of similar assays that would be suitable for Australia's genetically diverse population. The barriers to mitigating the impact of AIHL on Australian children are not primarily technical, but involve a lack of data on the prevalence of the MT-RNR1 mutations in our current neonatal and paediatric populations and intensive care nurseries.

Mitochondrial tRNAGln 4394C>T Mutation May Contribute to the Clinical Expression of 1555A>G-Induced Deafness

The mitochondrial 1555A>G mutation plays a critical role in aminoglycoside-induced and non-syndromic hearing loss (AINSHL). Previous studies have suggested that mitochondrial secondary variants may modulate the clinical expression of m.1555A>G-induced deafness, but the molecular mechanism has remained largely undetermined. In this study, we investigated the contribution of a deafness-associated tRNAGln 4394C>T mutation to the clinical expression of the m.1555A>G mutation. Interestingly, a three-generation family with both the m.1555A>G and m.4394C>T mutations exhibited a higher penetrance of hearing loss than another family harboring only the m.1555A>G mutation. At the molecular level, the m.4394C>T mutation resides within a very conserved nucleotide of tRNAGln, which forms a new base-pairing (7T-66A) and may affect tRNA structure and function. Using trans-mitochondrial cybrid cells derived from three subjects with both the m.1555A>G and m.4394C>T mutations, three patients with only the m.1555A>G mutation and three control subjects without these primary mutations, we observed that cells with both the m.1555A>G and m.4394C>T mutations exhibited more severely impaired mitochondrial functions than those with only the m.1555A>G mutation. Furthermore, a marked decrease in mitochondrial RNA transcripts and respiratory chain enzymes was observed in cells harboring both the m.1555A>G and m.4394C>T mutations. Thus, our data suggest that the m.4394C>T mutation may play a synergistic role in the m.1555A>G mutation, enhancing mitochondrial dysfunctions and contributing to a high penetrance of hearing loss in families with both mtDNA pathogenic mutations.

RIPOR2-mediated autophagy dysfunction is critical for aminoglycoside-induced hearing loss.

Aminoglycosides (AGs) are potent antibiotics that are capable of treating a wide variety of life-threatening infections; however, they are ototoxic and cause irreversible damage to cochlear hair cells. Despite substantial progress, little is known about the molecular pathways critical for hair cell function and survival that are affected by AG exposure. We demonstrate here that gentamicin, a representative AG antibiotic, binds to and within minutes triggers translocation of RIPOR2 in murine hair cells from stereocilia to the pericuticular area. Then, by interacting with a central autophagy component, GABARAP, RIPOR2 affects autophagy activation. Reducing the expression of RIPOR2 or GABARAP completely prevents AG-induced hair cell death and subsequent hearing loss in mice. Additionally, abolishing the expression of PINK1 or Parkin, two key mitochondrial autophagy proteins, prevents hair cell death and subsequent hearing loss caused by AG. In summary, our study demonstrates that RIPOR2-mediated autophagic dysfunction is essential for AG-induced hearing loss.

Pitavastatin protects against neomycin-induced ototoxicity through inhibition of endoplasmic reticulum stress.

Irreversible injury to inner ear hair cells induced by aminoglycoside antibiotics contributes to the formation of sensorineural hearing loss. Pitavastatin (PTV), a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, has been reported to exert neuroprotective effects. However, its role in aminoglycoside-induced hearing loss remains unknown. The objectives of this study were to investigate the beneficial effects, as well as the mechanism of action of PTV against neomycin-induced ototoxicity. We found that PTV remarkably reduced hair cell loss in mouse cochlear explants and promoted auditory HEI-OC1 cells survival after neomycin stimulation. We also observed that the auditory brainstem response threshold that was increased by neomycin was significantly reduced by pretreatment with PTV in mice. Furthermore, neomycin-induced endoplasmic reticulum stress in hair cells was attenuated by PTV treatment through inhibition of PERK/eIF2α/ATF4 signaling. Additionally, we found that PTV suppressed the RhoA/ROCK/JNK signal pathway, which was activated by neomycin stimulation in HEI-OC1 cells. Collectively, our results showed that PTV might serve as a promising therapeutic agent against aminoglycoside-induced ototoxicity.

Oridonin alleviates kanamycin-related hearing loss by inhibiting NLRP3/caspase-1/gasdermin D-induced inflammasome activation and hair cell pyroptosis

Aminoglycoside antibiotic drugs induce hearing loss in children and adults every year; however, the pathological mechanisms remain unknown. Previous studies have shown that the accumulation of reactive oxygen species (ROS) and inflammation in the inner ear may be responsible for kanamycin (KM)-induced hair cell death and hearing loss. Nucleotide-binding oligomerization domain-, leucine-rich repeat-, and pyrin domain-containing protein 3 (NLRP3) is a specific ROS sensor that initiates inflammasome assembly as well as activates caspase-1 and downstream inflammatory factors. Therefore, this study aimed to determine whether NLRP3 inflammasomes are involved in KM-related hearing loss in mice. Compared with the control (saline) group, increased levels of activated caspase-1, interleukin (IL)-1β, IL-18, N-terminal fragment of gasdermin D (GSDMD-N), and NLRP3 were detected by immunofluorescence, western blot, and enzyme-linked immunosorbent assay (ELISA) in the KM-plus-furosemide (LASIX)-treated group. Moreover, we also found that the NLRP3 inhibitor oridonin (Ori) could significantly rescue KM-related hearing loss by inhibiting NLRP3-inflammasome activation and caspase-1/GSDMD-related hair cell pyroptosis. These findings demonstrate that apoptosis, as well as pyroptosis, may be involved in KM-related hearing loss and that the NLRP3/caspase-1/GSDMD pathway may be a new target for treating aminoglycoside-induced hearing loss.

RNA targeting using CasRx can prevent aminoglycoside-induced hearing loss

RNA targeting using CasRx can prevent aminoglycoside-induced hearing loss

Increased mitophagy protects cochlear hair cells from aminoglycoside-induced damage

ABSTRACT Aminoglycosides exhibit ototoxicity by damaging mitochondria, which in turn generate reactive oxygen species that induce hair cell death and subsequent hearing loss. It is well known that damaged mitochondria are degraded by mitophagy, an important mitochondrial quality control system that maintains mitochondrial homeostasis and ensures cell survival. However, it is unclear whether dysregulation of mitophagy contributes to aminoglycoside-induced hair cell injury. In the current study, we found that PINK1-PRKN-mediated mitophagy was impaired in neomycin-treated hair cells. Our data suggested that mitochondrial recruitment of PRKN and phagophore recognition of damaged mitochondria during mitophagy were blocked following neomycin treatment. In addition, the degradation of damaged mitochondria by lysosomes was significantly decreased as indicated by the mitophagic flux reporter mt-mKeima. Moreover, we demonstrated that neomycin disrupted mitophagy through transcriptional inhibition of Pink1 expression, the key initiator of mitophagy. Moreover, we found that neomycin impaired mitophagy by inducing ATF3 expression. Importantly, treatment with a mitophagy activator could rescue neomycin-treated hair cells by increasing mitophagy, indicating that genetic modulation or drug intervention in mitophagy may have therapeutic potential for aminoglycoside-induced hearing loss. Abbreviations: AAV: adeno-associated virus; ABR: auditory brainstem response; ATF3: activating transcription factor 3; ATOH1/MATH1: atonal bHLH transcription factor 1; BafA1: bafilomycin A1; CCCP: carbonyl cyanide m-chlorophenyl hydrazone; COX4I1/COXIV: cytochrome c oxidase subunit 4I1; CTBP2/RIBEYE: C-terminal binding protein 2; DFP: deferiprone; EGFP: enhanced green fluorescent protein; FOXO3: forkhead box O3; GRIA2/GLUR2: glutamate receptor, ionotropic, AMPA2 (alpha 2); HC: hair cell; HSPD1/HSP60: heat shock protein 1 (chaperonin); IHC: inner hair cell; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MYO7A: myosin VIIA; OPTN: optineurin; OMM: outer mitochondrial membrane; PRKN: parkin RBR E3 ubiquitin protein ligase; PINK1: PTEN induced putative kinase 1; RT-qPCR: real-time quantitative polymerase chain reaction; TOMM20/TOM20: translocase of outer mitochondrial membrane 20; TUNEL: Terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling; USP30: ubiquitin specific peptidase 30; XBP1: X-box binding protein 1.

ASK1 is a novel molecular target for preventing aminoglycoside-induced hair cell death

Aminoglycoside antibiotics are lifesaving medicines, crucial for the treatment of chronic or drug resistant infections. However, aminoglycosides are toxic to the sensory hair cells in the inner ear. As a result, aminoglycoside-treated individuals can develop permanent hearing loss and vestibular impairment. There is considerable evidence that reactive oxygen species (ROS) production and the subsequent phosphorylation of c-Jun N-terminal kinase (JNK) and P38 mitogen-activated protein kinase (P38) drives apoptosis in aminoglycoside-treated hair cells. However, treatment strategies that directly inhibit ROS, JNK, or P38 are limited by the importance of these molecules for normal cellular function. Alternatively, the upstream regulator apoptosis signal-regulating kinase 1 (ASK1/MAP3K5) is a key mediator of ROS-induced JNK and P38 activation under pathologic but not homeostatic conditions. We investigated ASK1 as a mediator of drug-induced hair cell death using cochlear explants from Ask1 knockout mice, demonstrating that Ask1 deficiency attenuates neomycin-induced hair cell death. We then evaluated pharmacological inhibition of ASK1 with GS-444217 as a potential otoprotective therapy. GS-444217 significantly attenuated hair cell death in neomycin-treated explants but did not impact aminoglycoside efficacy against P. aeruginosa in the broth dilution test. Overall, we provide significant pre-clinical evidence that ASK1 inhibition represents a novel strategy for preventing aminoglycoside ototoxicity.Key messagesASK1 is an upstream, redox-sensitive regulator of P38 and JNK, which are known mediators of hair cell death.Ask1 knockout does not affect hair cell development in vivo, but significantly reduces aminoglycoside-induced hair cell death in vitro.A small-molecule inhibitor of ASK1 attenuates neomycin-induced hair cell death, and does not impact antibiotic efficacy in vitro.ASK1 may be a novel molecular target for preventing aminoglycoside-induced hearing loss.

Apigenin alleviates neomycin-induced oxidative damage via the Nrf2 signaling pathway in cochlear hair cells.

Oxidative stress plays an important role in the pathogenesis of aminoglycoside-induced hearing loss and represents a promising target for treatment. We tested the potential effect of apigenin, a natural flavonoid with anticancer, anti-inflammatory, and antioxidant activities, on neomycin-induced ototoxicity in cochlear hair cells in vitro. Results showed that apigenin significantly ameliorated the loss of hair cells and the accumulation of reactive oxygen species upon neomycin injury. Further evidence suggested that the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway was activated by apigenin treatment. Disruption of the Nrf2 axis abolished the effects of apigenin on the alleviation of oxidative stress and subsequent apoptosis of hair cells. This study provided evidence of the protective effect of apigenin on cochlear hair cells and its underlying mechanism.

Systemic toll-like receptor 9 agonist CpG oligodeoxynucleotides exacerbates aminoglycoside ototoxicity

The Toll-like receptor (TLR) signaling pathway is the key regulator of the innate immune system in response to systemic infection. Several studies have reported that the systemic TLR4 agonist lipopolysaccharide exacerbates aminoglycoside ototoxicity, but the influence of virus-associated TLR7 and TLR9 signaling cascades on the cochlea is unclear. The present study aimed to investigate the auditory effects of systemic TLR7 and TLR9 agonists during chronic kanamycin treatment. CBA/CaJ mice received the TLR7 agonist gardiquimod or TLR9 agonist CpG oligodeoxynucleotides (ODN) one day before kanamycin injection and on the 5th and 10th days during a 14-day course of kanamycin treatment. We observed that systemic gardiquimod or CpG ODN alone did not affect the baseline auditory brainstem response (ABR) threshold. Three weeks after kanamycin treatment, gardiquimod did not significantly change ABR threshold shifts, whereas CpG ODN significantly increased kanamycin-induced ABR threshold shifts. Furthermore, outer hair cell (OHC) evaluation revealed that CpG ODN reduced distortion product otoacoustic emission amplitudes and increased kanamycin-induced OHC loss. CpG ODN significantly elevated cochlear Irf-7, Tnf-α, Il-1, and Il-6 transcript levels. In addition, an increased number of Iba-1+ cells, which represented activated macrophages, was observed in the cochlea treated with CpG ODN. Our results indicated that systemic CpG ODN exacerbated kanamycin-induced ototoxicity and increased cochlear inflammation. This study implies that patients with underlying virus infection may experience more severe aminoglycoside-induced hearing loss if it occurs.

Clinical Pharmacogenetics Implementation Consortium Guideline for the Use of Aminoglycosides Based on MT-RNR1 Genotype.

Aminoglycosides are widely used antibiotics with notable side effects, such as nephrotoxicity, vestibulotoxicity, and sensorineural hearing loss (cochleotoxicity). MT-RNR1 is a gene that encodes the 12s rRNA subunit and is the mitochondrial homologue of the prokaryotic 16s rRNA. Some MT-RNR1 variants (i.e., m.1095T>C; m.1494C>T; m.1555A>G) more closely resemble the bacterial 16s rRNA subunit and result in increased risk of aminoglycoside-induced hearing loss. Use of aminoglycosides should be avoided in individuals with an MT-RNR1 variant associated with an increased risk of aminoglycoside-induced hearing loss unless the high risk of permanent hearing loss is outweighed by the severity of infection and safe or effective alternative therapies are not available. We summarize evidence from the literature supporting this association and provide therapeutic recommendations for the use of aminoglycosides based on MT-RNR1 genotype (updates at https://cpicpgx.org/guidelines/ and www.pharmgkb.org).