-
Journal of Otology Mar 2017Aminoglycosides (AmAn) are widely used for their great efficiency against gram-negative bacterial infections. However, they can also induce ototoxic hearing loss, which... (Review)
Review
Aminoglycosides (AmAn) are widely used for their great efficiency against gram-negative bacterial infections. However, they can also induce ototoxic hearing loss, which has affected millions of people around the world. As previously reported, individuals bearing mitochondrial DNA mutations in the 12S rRNA gene, such as m.1555A>G and m.1494C>T, are more prone to AmAn-induced ototoxicity. These mutations cause human mitochondrial ribosomes to more closely resemble bacterial ribosomes and enable a stronger aminoglycoside interaction. Consequently, exposure to AmAn can induce or worsen hearing loss in these individuals. Furthermore, a wide range of severity and penetrance of hearing loss was observed among families carrying these mutations. Studies have revealed that these mitochondria mutations are the primary molecular mechanism of genetic susceptibility to AmAn ototoxicity, though nuclear modifier genes and mitochondrial haplotypes are known to modulate the phenotypic manifestation.
PubMed: 29937831
DOI: 10.1016/j.joto.2017.02.001 -
Journal of Cystic Fibrosis : Official... Mar 2021Cystic fibrosis patients are often adminstered tobramycin to treat pulmonary infections. Unfortunately, a common side effect is hearing loss, which can fluctuate....
BACKGROUND
Cystic fibrosis patients are often adminstered tobramycin to treat pulmonary infections. Unfortunately, a common side effect is hearing loss, which can fluctuate. Ebselen has known anti-inflammatory properties and could reduce the incidence and severity of tobramycin-induced hearing loss.
METHODS
In vitro: neonatal cochlear cultures were treated with tobramycin or cotreated with tobramycin and ebselen for 3 days. In vivo: adult mice were injected with tobramycin or tobramycin and ebselen for 14 days. ABRs were collected in a repeated measures design until 56 days after treatments. ABR threshold shifts were analyzed and a novel cochleotoxic criteria applied to determine the incidence of ototoxicity. Cochlear immunohistology was analyzed for IHC and OHC loss.
RESULTS
Tobramycin leads to significant IHC and OHC loss in cochlear explant cultures. Ebselen co-treatment at 1:20 concentrations resulted in significant otoprotection. Tobramycin leads to significant ABR threshold shifts that are ameliorated by ebselen co-treatment. Hearing loss did not correlate with significant IHC or OHC loss.
CONCLUSIONS
This mouse model of tobramycin-induced ototoxicity is clinically relevant in that it results in an incidence and severity of hearing loss recently documented in clinic. The in vitro experiments show that tobramycin kills hair cells and that ebselen co-treatment can attenuate this ototoxicity. The in vivo model shows tobramycin-induced hearing loss is ameliorated by ebselen co-treatment, but this is not explained by concomitant hair cell loss. These preclinical data support the testing of ebselen in CF patients receiving tobramycin treatment.
Topics: Animals; Evoked Potentials, Auditory, Brain Stem; Hair Cells, Auditory, Outer; Hearing Loss; Isoindoles; Mice; Organoselenium Compounds; Ototoxicity; Tobramycin
PubMed: 32147183
DOI: 10.1016/j.jcf.2020.02.014 -
Medicine Oct 2022The purpose of this study was to evaluate the effects of once daily (OD) or every 48 hours (every-48-h) administration of amikacin (AMK) on renal function and...
The purpose of this study was to evaluate the effects of once daily (OD) or every 48 hours (every-48-h) administration of amikacin (AMK) on renal function and ototoxicity in neonates. We investigated the frequency of nephrotoxicity and ototoxicity in neonates who received AMK OD or every-48-h from April 2015 to March 2021 and underwent dose evaluation by therapeutic drug monitoring (TDM). In addition, the relationships among birth weight, gestational age, AMK peak and trough values, total duration of AMK administration, and total AMK dose were examined separately for nephrotoxicity and ototoxicity. AMK was administered OD in 38 patients and every-48-h in 62 patients. Nephrotoxicity was observed in 8 patients on OD versus 36 patients on every-48-h administration (P < .001), and ototoxicity was observed in 2 patients on OD versus 12 patients on every-48-h administration (P = .192). For nephrotoxicity, only the trough value was relevant (P = .007). In terms of ototoxicity, there were no influencing factors. The risk of nephrotoxicity was higher with every-48-h AMK administration than with OD AMK administration, with nephrotoxicity depending on the trough value. However, compared with OD, the every-48-h group had lower body weight and possibly poorer original renal function. In addition, ototoxicity did not differ by administration method. Based on these results, every-48-h administration of AMK can be used as safely as OD by performing TDM and preventing high concentrations.
Topics: Infant, Newborn; Humans; Amikacin; Ototoxicity; Anti-Bacterial Agents; Renal Insufficiency; Kidney
PubMed: 36316882
DOI: 10.1097/MD.0000000000031425 -
The Cochrane Database of Systematic... Feb 2021Chronic suppurative otitis media (CSOM) is a chronic inflammation and infection of the middle ear and mastoid cavity, characterised by ear discharge (otorrhoea) through... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Chronic suppurative otitis media (CSOM) is a chronic inflammation and infection of the middle ear and mastoid cavity, characterised by ear discharge (otorrhoea) through a perforated tympanic membrane. The predominant symptoms of CSOM are ear discharge and hearing loss. Systemic antibiotics are a commonly used treatment option for CSOM, which act to kill or inhibit the growth of micro-organisms that may be responsible for the infection. Antibiotics can be used alone or in addition to other treatments for CSOM.
OBJECTIVES
To assess the effects of systemic antibiotics for people with CSOM.
SEARCH METHODS
The Cochrane ENT Information Specialist searched the Cochrane ENT Register; Central Register of Controlled Trials (CENTRAL via the Cochrane Register of Studies); Ovid MEDLINE; Ovid Embase; CINAHL; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 16 March 2020.
SELECTION CRITERIA
We included randomised controlled trials comparing systemic antibiotics (oral, injection) against placebo/no treatment or other systemic antibiotics with at least a one-week follow-up period, involving patients with chronic (at least two weeks) ear discharge of unknown cause or due to CSOM. Other treatments were allowed if both treatment and control arms also received it.
DATA COLLECTION AND ANALYSIS
We used the standard Cochrane methodological procedures. We used GRADE to assess the certainty of the evidence for each outcome. Our primary outcomes were: resolution of ear discharge or 'dry ear' (whether otoscopically confirmed or not, measured at between one week and up to two weeks, two weeks to up to four weeks, and after four weeks); health-related quality of life using a validated instrument; ear pain (otalgia) or discomfort or local irritation. Secondary outcomes included hearing, serious complications and ototoxicity measured in several ways.
MAIN RESULTS
We included 18 studies (2135 participants) with unclear or high risk of bias. 1. Systemic antibiotics versus no treatment/placebo It is very uncertain if there is a difference between systemic (intravenous) antibiotics and placebo in the resolution of ear discharge at between one and two weeks (risk ratio (RR) 8.47, 95% confidence interval (CI) 1.88 to 38.21; 33 participants; 1 study; very low-certainty evidence). The study did not report results for resolution of ear discharge after two weeks. Health-related quality of life was not reported. The evidence is very uncertain for hearing and serious (intracranial) complications. Ear pain and suspected ototoxicity were not reported. 2. Systemic antibiotics versus no treatment/placebo (both study arms received topical antibiotics) Six studies were included of which five presented useable data. There may be little or no difference in the resolution of ear discharge at between one to two weeks for oral ciprofloxacin compared to placebo or no treatment when ciprofloxacin ear drops were used in both intervention arms (RR 1.02, 95% CI 0.93 to 1.12; 390 participants; low-certainty evidence). No results after two weeks were reported. Health-related quality of life was not reported. The evidence is very uncertain for ear pain, serious complications and suspected ototoxicity. 3. Systemic antibiotics versus no treatment/placebo (both study arms received other background treatments) Two studies used topical antibiotics plus steroids as background treatment in both arms. It is very uncertain if there is a difference in resolution of ear discharge between metronidazole and placebo at four weeks (RR 0.91, 95% CI 0.51 to 1.65; 40 participants; 1 study; very low-certainty evidence). This study did not report other outcomes. It is also very uncertain if resolution of ear discharge at six weeks was improved with co-trimoxazole compared to placebo (RR 1.54, 95% CI 1.09 to 2.16; 98 participants; 1 study; very low-certainty evidence). Resolution of ear discharge was not reported at other time points. From the narrative report there was no evidence of a difference between groups for health-related quality of life, hearing or serious complications (very low-certainty evidence). One study (136 participants) used topical antiseptics as background treatment in both arms and found similar resolution of ear discharge between the amoxicillin and no treatment groups at three to four months (RR 1.03, 95% CI 0.75 to 1.41; 136 participants; 1 study; very low-certainty evidence). The narrative report indicated no evidence of differences in hearing or suspected ototoxicity (both very low-certainty evidence). No other outcomes were reported. 4. Different types of systemic antibiotics This is a summary of four comparisons, where different antibiotics were compared to each other. Eight studies compared different types of systemic antibiotics against each other: quinolones against beta-lactams (four studies), lincosamides against nitroimidazoles (one study) and comparisons of different types of beta-lactams (three studies). It was not possible to conclude if there was one class or type of systemic antibiotic that was better in terms of resolution of ear discharge. The studies did not report adverse events well.
AUTHORS' CONCLUSIONS
There was a limited amount of evidence available to examine whether systemic antibiotics are effective in achieving resolution of ear discharge for people with CSOM. When used alone (with or without aural toileting), we are very uncertain if systemic antibiotics are more effective than placebo or no treatment. When added to an effective intervention such as topical antibiotics, there seems to be little or no difference in resolution of ear discharge (low-certainty evidence). Data were only available for certain classes of antibiotics and it is very uncertain whether one class of systemic antibiotic may be more effective than another. Adverse effects of systemic antibiotics were poorly reported in the studies included. As we found very sparse evidence for their efficacy, the possibility of adverse events may detract from their use for CSOM.
Topics: Amoxicillin; Anti-Bacterial Agents; Ciprofloxacin; Humans; Otitis Media, Suppurative; Ototoxicity; Pain; Persistent Infection
PubMed: 35819801
DOI: 10.1002/14651858.CD013052.pub2 -
Journal of Otology Mar 2016High levels of arsenic are found in many parts of the world and more than 100 million people may have been exposed to it. There is growing evidence to indicate that... (Review)
Review
High levels of arsenic are found in many parts of the world and more than 100 million people may have been exposed to it. There is growing evidence to indicate that arsenic has a deleterious effect on the auditory system. This paper provides the general information of arsenic and its ototoxic effects.
PubMed: 29937805
DOI: 10.1016/j.joto.2016.03.001 -
The Journal of International Advanced... Apr 2017In this study, we aimed to detect the incidences of ototoxicity in patients with hemoglobinopathies taking deferoxamine (DFO), deferiprone, and deferasirox using the...
OBJECTIVE
In this study, we aimed to detect the incidences of ototoxicity in patients with hemoglobinopathies taking deferoxamine (DFO), deferiprone, and deferasirox using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) scale to obtain more objective data.
MATERIALS AND METHODS
Fifty-five transfusion-dependent patients were evaluated in this study. The NCI CTCAE scale was used to assess ototoxicity levels. The average ferritin and hemoglobin levels, the type of iron chelator, and the duration of therapy of all the patients were recorded.
RESULTS
Ototoxicity was observed in 15 patients (31.9 %), all of whom were taking DFO. The median age was 19.5 (6-43) in patients without ototoxicity and 29 (16-50) in those with ototoxicity; this difference was statistically significant (p<0.05). The median ferritin and pre-tx Hb levels were 1391 ng/mL and 9.06 mg/dL, respectively, in patients with ototoxicity and 986.7 ng/mL and 9.24 mg/dL, respectively, in those without ototoxicity; these differences were not significant (p>0.05). Ototoxicity was not observed in the eight patients who used only deferasirox and deferiprone.
CONCLUSION
The ototoxicity incidence with DFO at doses below 50 mg/kg/day was 27.3%. Deferiprone and deferasirox were not associated with ototoxic effects in patients taking these drugs.
Topics: Adolescent; Adult; Chelation Therapy; Child; Cross-Sectional Studies; Ear Diseases; Female; Humans; Incidence; Iron Chelating Agents; Male; Middle Aged; Thalassemia; Turkey
PubMed: 27879229
DOI: 10.5152/iao.2016.1852 -
Journal of Toxicology and Environmental... 2018To determine the state of the research on ototoxic properties of Pb, evaluate possible synergistic effects with concurrent noise exposure, and identify opportunities to... (Review)
Review
To determine the state of the research on ototoxic properties of Pb, evaluate possible synergistic effects with concurrent noise exposure, and identify opportunities to improve future research, we performed a review of the peer-reviewed literature to identify studies examining auditory damage due to Pb over the past 50 years. Thirty-eight studies (14 animal and 24 human) were reviewed. Of these, 24 suggested potential ototoxicity due to Pb exposure, while 14 found no evidence of ototoxicity. More animal studies are needed, especially those investigating Pb exposure levels that are occupationally and environmentally relevant to humans. Further investigations into potential interactions of Pb in the auditory system with other hazards and compounds that elicit ototoxicity are also needed in animal models. To better assess the effects of Pb exposure on the human auditory system and the possibility of a synergism with noise, future epidemiological studies need to carefully consider and address four main areas of uncertainty: (1) hearing examination and quantification of hearing loss, (2) Pb exposure evaluation, (3) noise exposure evaluation, and (4) the personal characteristics of those exposed. Two potentially confounding factors, protective factors and mixtures of ototoxicants, also warrant further exploration.
Topics: Animals; Environmental Exposure; Environmental Pollutants; Hearing Loss; Hearing Loss, Noise-Induced; Humans; Lead; Noise; Occupational Exposure
PubMed: 30663930
DOI: 10.1080/10937404.2018.1562391 -
Annual Review of Pharmacology and... Jan 2024Each year over half a million people experience permanent hearing loss caused by treatment with therapeutic drugs with ototoxic side effects. There is a major unmet... (Review)
Review
Each year over half a million people experience permanent hearing loss caused by treatment with therapeutic drugs with ototoxic side effects. There is a major unmet clinical need for therapies that protect against this hearing loss without reducing the therapeutic efficacy of these lifesaving drugs. At least 17 clinical trials evaluating 10 therapeutics are currently underway for therapies aimed at preventing aminoglycoside- and/or cisplatin-induced ototoxicity. This review describes the preclinical and clinical development of each of these approaches, provides updates on the status of ongoing trials, and highlights the importance of appropriate outcome measures in trial design and the value of reporting criteria in the dissemination of results.
Topics: Humans; Hearing Loss; Clinical Trials as Topic
PubMed: 37562496
DOI: 10.1146/annurev-pharmtox-033123-114106 -
The Laryngoscope Jul 2021The purpose of this review is to summarize evidence-based data regarding the ototoxic effects of potential COVID-19 therapeutics to treat patients suffering from... (Review)
Review
OBJECTIVE/HYPOTHESIS
The purpose of this review is to summarize evidence-based data regarding the ototoxic effects of potential COVID-19 therapeutics to treat patients suffering from SARS-CoV-2.
METHODS
Medications under investigation as novel therapeutics to treat COVID-19 were identified using the search term coronavirus therapeutics, COVID therapeutics, and SARS-CoV-2 therapeutics on ClinicalTrials.gov and the PubMed Database. A literature review was performed using the PubMed Database for each proposed COVID-19 therapeutic to identify relevant articles. Search criteria included Medical Subject Headings (MeSH) and key word search terms for ototoxicity, vestibulotoxicity, hearing disorders, and vertigo.
RESULTS
Six proposed COVID-19 therapeutics were identified as possessing ototoxic side effects including chloroquine and hydroxychloroquine, azithromycin, lopinavir-ritonavir, interferon, ribavirin, and ivermectin.
CONCLUSIONS
Available evidence suggests that ototoxic effects may be improved or mitigated by stopping the offending agent. Recognition of hearing loss, tinnitus, or imbalance/vertigo is therefore crucial to facilitate early intervention and prevent long-term damage. Hospitals should consider the inclusion of audiologic monitoring protocols for patients receiving COVID-19 therapeutics with known ototoxicity, especially in high-risk patient groups such as the elderly and hearing impaired. Laryngoscope, 131:1626-1632, 2021.
Topics: COVID-19; Humans; Ototoxicity; COVID-19 Drug Treatment
PubMed: 33491234
DOI: 10.1002/lary.29424 -
International Journal of Biological... 2024As an anti-tumor drug widely used in the clinic, cisplatin is limited by its ototoxic side effects associated with various factors, including inflammatory responses....
As an anti-tumor drug widely used in the clinic, cisplatin is limited by its ototoxic side effects associated with various factors, including inflammatory responses. Receptor for Advanced Glycation Endproducts (RAGE) recognizes damage-associated molecular patterns (DAMPs) and promotes stress and inflammation. This study intended to determine the potential behavior of the HMGB1/RAGE axis after cisplatin injury and whether it has a protective effect after inhibiting this pathway. We used FPS-ZM1, a RAGE inhibitor, to modulate the axis of HMGB1/RAGE in neonatal mouse cochlear explants and C57BL/6 mice . Apoptosis was identified by Annexin V-FITC/PI assay, Cleaved Caspase-3, and TUNEL staining. Reactive oxygen species (ROS) level was assessed by MitoSOX Red and CellROX Green assay. The expression of proteins associated with the HMGB1/RAGE axis and apoptosis was observed by western blotting. The expression of inflammatory cytokines was evaluated by qPCR. The protective effect of HMGB1/RAGE knockdown was also assessed on cisplatin-induced ototoxicity. These results demonstrated that cisplatin could activate the HMGB1/RAGE pathway in cochlear hair cells and release inflammatory factors. Pretreatment with FPS-ZM1 alleviated cisplatin-induced ototoxicity and . Knocking down HMGB1 and RAGE achieved specific protective effects. Altogether, inhibiting HMGB1/RAGE axis can reverse the increase of ROS accumulation, the activation of apoptosis, and the production of inflammatory reactions after cisplatin injury. FPS-ZM1 could resist the ototoxicity of cisplatin by suppressing the HMGB1/RAGE signal pathway, and it may be considered the new otoprotective potential strategy for hearing loss.
Topics: Mice; Animals; Cisplatin; Receptor for Advanced Glycation End Products; Reactive Oxygen Species; HMGB1 Protein; Ototoxicity; Mice, Inbred C57BL; Oxidative Stress; Inflammation
PubMed: 38169643
DOI: 10.7150/ijbs.82003