Ototoxicity

By Marcello Cherchi, MD PhD

For patients

In simple terms, the word “ototoxicity” broadly refers to the damaging (toxic) effects that various chemical agents (such as therapeutic drugs or industrial compounds) can have on hearing and balance.

While there is substantial literature on this topic, there is also substantial controversy. Some drugs are better documented to have toxic effects on balance and/or hearing. For other drugs the connection is less clear.

The most important first step is to identify whether there are measurable deficits in balance and/or hearing. Your doctor may try to figure this out from a variety of auditory tests and vestibular tests.

The vast majority of cases of ototoxicity are irreversible. Nevertheless, if objective evidence of auditory and/or vestibular deficits are found in a patient in whom there is reasonable suspicion that potentially ototoxic agents may be contributory, then if medically feasible it is reasonable to stop the offending medication, and avoid its use in the future.

In some life-threatening diseases, current treatments have known ototoxicity, but withholding the treatment may not be a realistic option, so patients and their practitioners treat in full awareness of this risk. The diseases in question are usually certain kinds of infections (that require treatment with aminoglycoside antibiotics) and certain forms of cancer (that require treatment with platinum-based chemotherapeutic agents).

For clinicians

Overview

Ototoxicity refers to damage of otologically-mediated auditory and/or vestibular function by a chemical compound.  Drug-related ototoxicity is nearly always undesirable (with the main exception being purposeful ablation of labyrinthine function by transtympanic gentamicin injection).  An extraordinarily broad range of chemical compounds have been documented to have potential ototoxicity, including various anti-microbial agents, anti-arrhythmic agents, immunosuppressants, anti-neoplastic agents, diuretics and others.  Various attempts at monitoring cochlear and vestibular ototoxicity, protecting against ototoxicity, and treating ototoxicity have been attempted, without clear success.

Definition

For purposes of this discussion we define ototoxicity as damage of otologically-mediated auditory and/or vestibular function by a chemical compound.

We use the phrase “otologically-mediated” to delimit the topic to damage of the labyrinth and/or vestibulocochlear nerve. We specifically exclude damage of other anatomical structures. Thus, for example, chronic alcoholism can damage the cerebellum; one may say that a chemical (ethanol) has led to imbalance, the main structure affected by the chemical is the cerebellum, not the labyrinth or vestibular nerve.

We use the phrase “chemical compound” to include prescribed medications (drugs), as well as illegal substances (e.g., marijuana (Qian & Alyono, 2020)) or misused chemicals (e.g., inhaled toluene). We also use this phrase to excluded non-chemical otologic damage, such as radiation toxicity.

Is ototoxicity always bad?

In short, ototoxicity is nearly always a bad thing, with very few exceptions. The main exception in otoneurology is when gentamicin is intentionally administered transtympanically for chemical ablation of the labyrinth as treatment for Ménière’s disease.

Agents implicated

Hundreds of drugs and other chemicals have been implicated as ototoxic. It is impractical to review these all, but a sense of the breadth can be conveyed by the following diagram (Watts, 2019).

The main regulated ototoxic medications encountered in clinical practice include aminoglycoside antibiotics (usually gentamicin) and platinum-based chemotherapeutic agents (usually cisplatin), but there are many other agents for which ototoxicity has been implicated though less well substantiated. PubMed search with the term “ototoxicity” returns >6000 hits.

Anti-microbial agents: Aminoglycoside antibiotics

Aminoglycoside antibiotics are well-documented to be ototoxic (Henley & Schacht, 1988; Huth, Ricci, & Cheng, 2011; Rizzi & Hirose, 2007; Ruhl et al., 2019; Warchol, 2010), such as amikacin (Aksoy et al., 2015; Beaubien et al., 1989, 1990; Beaubien et al., 1991; Endo et al., 2022), gentamicin (Chatterton et al., 2022; Smyth et al., 2019), kanamycin (Brummett, Bendrick, & Himes, 1981; Ghafari et al., 2020; Mantefardo & Sisay, 2021; Voogt & Schoeman, 1996), neomycin (Kavanagh & McCabe, 1983; Ward & Rounthwaite, 1978) and streptomycin (Adeyemo, Oluwatosin, & Omotade, 2016; Md Daud, Mohamadl, Haron, & Rahman, 2014; Voogt & Schoeman, 1996; Wanamaker, Slepecky, Cefaratti, & Ogata, 1999).

Anti-microbial agents: Other anti-bacterial drugs

Beyond aminoglycosides (Buziashvili et al., 2019; Owusu, Amartey, Afutu, & Boafo, 2022; Stevenson, Biagio-de Jager, Graham, & Swanepoel, 2021), other agents used in the treatment of tuberculosis may also exhibit ototoxicity, such as isoniazid (Altiparmak, Pamuk, Pamuk, Ataman, & Serdengecti, 2002).

Some anti-bacterial agents from other classes also have documented ototoxicity, including the macrolide antibiotics erythromycin (Agusti, Ferran, Gea, & Picado, 1991; Bizjak, Haug, Schilz, Sarodia, & Dresing, 1999; Brummett, 1993; Levin & Behrenth, 1986; McGhan & Merchant, 2003; Moral et al., 1994; Sacristan et al., 1993; Schweitzer & Olson, 1984; Swanson et al., 1992; Thompson, Wood, & Bergstrom, 1980; van Marion, van der Meer, Kalff, & Schicht, 1978) and azithromycin (Haydon, Thelin, & Davis, 1984; Mamikoglu & Mamikoglu, 2001; Wallace, Miller, Nguyen, & Shields, 1994), and the glycopeptide antibiotic vancomycin (Gendeh, Gibb, Aziz, Kong, & Zahir, 1998; Gomceli, Vangala, Zeana, Kelly, & Singh, 2018; Humphrey, Veve, Walker, & Shorman, 2019; Kavanagh & McCabe, 1983; Lestner, Hill, Heath, & Sharland, 2016; Marissen et al., 2020; Mellor, Kingdom, Cafferkey, & Keane, 1984; Traber & Levine, 1981).

Anti-microbial agents: Anti-fungal drugs

Some anti-fungal agents, such as amphotericin (Ramu et al., 2021; Singh & Sharma, 2019), have documented ototoxicity.

Anti-microbial agents: Anti-parasitic drugs

Several anti-malarial medications have documented ototoxicity (Dillard, Fullerton, & McMahon, 2021; Jozefowicz-Korczynska, Pajor, & Lucas Grzelczyk, 2021).

Quinine and its derivatives

Quinine-based drugs are used as anti-malarial agents (Dillard et al., 2021; Jozefowicz-Korczynska et al., 2021) and against certain autoimmune diseases such as rheumatoid arthritis; some of these medications have documented ototoxicity. These include quinine itself (Nielsen-Abbring, Perenboom, & van der Hulst, 1990; Semedo, Dias-Silva, Migueis, & Pita, 2021; Tange, Dreschler, Claessen, & Perenboom, 1997), chloroquine (Bortoli & Santiago, 2007; Fernandes, Vernier, Dallegrave, & Machado, 2022) and hydroxychloroquine (Fernandes et al., 2022).

Anti-arrhythmic agents

Some anti-arrhythmic agents, such as amiodarone (Gurkov, 2018; Gurkov et al., 2017), have been reported to exhibit ototoxic properties.

Immunosuppressants

Several medications and medication classes that influence the immune system have documented ototoxicity. These include a variety of immunosuppressants (Franz et al., 2022) such as cyclosporine (Waissbluth, 2020).

Anti-neoplastic agents: Platinum derivatives

Platinum based anti-neoplastic agents have well-documented ototoxicity.  The oldest of these medications, cisplatin, is perhaps the most ototoxic of these (Brock 2022; Hodge et al. 2021; Low et al. 2010; Nitz et al. 2013; Paken et al. 2016, 2019; Rybak et al. 2007; Sanchez et al. 2023; Santucci et al. 2021; Sriyapai et al. 2022; Tserga et al. 2019; Yildirim et al. 2022).  Newer platinum-based agents are less so, but still ototoxic, including carboplatin (Batra et al. 2015; Bhagat et al. 2010; Cavaletti et al. 1998; Chevreau et al. 2005; Geurtsen et al. 2017; Kennedy et al. 1990; Musial-Bright et al. 2011; Nitz et al. 2013; Parsons et al. 1998; Qaddoumi et al. 2012; Waissbluth et al. 2018; Waissbluth et al. 2017) and oxaliplatin (Guvenc et al. 2016; Hijri et al. 2014; Malhotra et al. 2010; Oh et al. 2013; Vietor and George 2012).

Anti-neoplastic agents: Others

Other anti-neoplastic agents also have documented ototoxicity, including the taxane-derived anti-mitotic agent docetaxel (Xuan et al. 2020).

More recent anti-neoplastic agents, such as immune checkpoint inhibitors, have documented ototoxicity (Hu et al. 2020b; Lemasson et al. 2019; Sturmer et al. 2021).

Loop diuretics

Several loop diuretics have documented ototoxicity, including furosemide (Ahmed et al. 2012; Bates et al. 2002; Brummett et al. 1981; Halmagyi and Curthoys 2018; Kaka et al. 1984; Rybak 1985; Rybak and Whitworth 1986; Tuzel 1981) and bumetanide (Brummett et al. 1981; Tuzel 1981)

Other medications

Unregulated ototoxic medications (not requiring a prescription) include salicylates (Boettcher and Salvi 1991; Brien 1993; Day et al. 1989; Kim et al. 2013; Peleg et al. 2007; Stypulkowski 1990), the most common of which is acetylsalicylic acid (aspirin), which often is combined with other medications (such as in Excedrin Migraine).

Iron chelating agents have also documented ototoxicity (Derin et al. 2017).

Non-medical compounds

Various industrial volatile aromatic solvents (Fife et al. 2018; Gagnaire and Langlais 2005) have documented ototoxicity, such as styrene (Hoet and Lison 2008; Karasawa and Steyger 2015; Lawton et al. 2006; Makitie et al. 2003; Sass-Kortsak et al. 1995) and toluene (Hoet and Lison 2008; Juarez-Perez et al. 2014; Schaper et al. 2003; Schaper et al. 2008).

Various heavy metals have been implicated as ototoxic, including arsenic (Ishii et al. 2019; Kesici 2016; Kesici et al. 2016; Shokoohi et al. 2021) and mercury (Hoshino et al. 2012).

Marijuana may be ototoxic insofar as it can provoke tinnitus in some patients (Qian and Alyono 2020).

Natural history of ototoxicity

Generally ototoxicity is dose-dependent, so the larger the dose administered, and the more frequently the drug is administered, the more likely it is that ototoxic effects will occur, and the more pronounced those effects will be.

In contrast to the usual dose-dependent pattern are occasional case reports of dramatic toxicity from a single dose of medication (Garinis et al. 2021a; Gooi et al. 2008; Halmagyi and Curthoys 2018; Harruff et al. 2021; Yildirim et al. 2022).

Ototoxicity can be enhanced or potentiated by concomitant issues, such as renal insufficiency (which may impede excretion of the offending drug), co-administration with other agents (Aksoy et al. 2015; Bates et al. 2002; Brummett et al. 1981; Driessen et al. 2019; Kaka et al. 1984), specific genetic mutations(Clemens et al. 2020; Gao et al. 2017; McDermott et al. 2022; Nguyen and Jeyakumar 2019; Steyger 2021; Tserga et al. 2019; Turan et al. 2019), co-administration with radiation therapy (Cohen-Cutler et al. 2021; Driessen et al. 2019; Low et al. 2010; Low et al. 2020), ischemia (Lin et al. 2011) and noise exposure(Bhattacharyya and Dayal 1984; Brown et al. 1981; Castellanos and Fuente 2016; Garinis et al. 2021b; Li and Steyger 2009; Makitie et al. 2003; Steyger 2009).  Whether these additional factors have a synergistic or merely additive effect is unclear.

Surprisingly, for some ototoxins there additionally appears to be a diurnal pattern of vulnerability (Blunston et al. 2015; Tserga et al. 2020).

Some longitudinal studies suggest that long-term hearing loss from cisplatin ototoxicity “dovetails” with age-related hearing loss (Skalleberg et al. 2021; Skalleberg et al. 2020).

Some studies describe some spontaneous improvement from vestibular ototoxicity in some vestibular testing parameters but not others (Black et al. 2001).

Can cochlear ototoxicity be monitored?

Since one of the most common ototoxic clinical manifestations is hearing loss, it is logical to look to assessment of hearing as a method for detecting and monitoring ototoxicity (Campbell and Durrant 1993; Le Prell et al. 2022; Simpson et al. 1992).

In ototoxicity from aminoglycoside antibiotics and platinum-based chemotherapeutic agents, usually cochleotoxicity initially affects high frequencies, and later affects low frequencies (Clemens et al. 2020; Gao et al. 2017; McDermott et al. 2022; Nguyen and Jeyakumar 2019; Steyger 2021; Tserga et al. 2019; Turan et al. 2019).  Because of this pattern, methods for testing frequencies above those of a standard audiogram have been explored, including high-frequency audiometry (Caumo et al. 2017; Fausti et al. 1992, 1993; Fausti et al. 2003; Jacob et al. 2006; Singh Chauhan et al. 2011; van der Hulst et al. 1991) and otoacoustic emissions (Jacob et al. 2006).

Given the possibility of ototoxic agents directly affecting the cochlear nerve, some studies have explored the utility of using brainstem auditory evoked responses as a detection/monitoring technique (Bernard 1985; Chen et al. 2021; De Lauretis et al. 1999; Fausti et al. 1992, 1993; Ishii et al. 2019).

Beyond the idea of testing hearing, some studies have explored whether hearing tests can be performed with insert earphones (Gordon et al. 2005), whether they can be performed at home (Jacobs et al. 2012; Konrad-Martin et al. 2021) or even by a pharmacist (McKinzie et al. 2022) or by telehealth (Robler et al. 2022).

It has even been suggested that imaging the labyrinth by MRI (Veiga et al. 2021) or monitoring putative serum biomarkers (Generotti et al. 2022) might play a role in detecting/monitoring ototoxicity.

Despite various proposed monitoring recommendations (Bass and Bhagat 2014; Le Prell et al. 2022), no specific protocol has been widely adopted.

The clinical assessment of ototoxicity, and the broader scientific study of this subject, is sometimes complicated by medico-legal dimensions.  An example of this is the legal practice (https://ksdlaw.com) of Keith S. Douglass (https://www.linkedin.com/in/keith-s-douglass-assoc-llp/) which focuses on medical malpractice claims related to aminoglycoside antibiotics.

Can vestibular ototoxicity be monitored?

The vast majority of ototoxicity literature pertains to cochleotoxicity.

Regrettably, the literature regarding vestibular ototoxicity is much more limited (Baguley and Prayuenyong 2020; Black et al. 2004; Black and Pesznecker 1993; Chatterton et al. 2022; Fife et al. 2018; Hsu et al. 2015; Jiang et al. 2021; Mount et al. 1995; Rutka 2019; Sedo-Cabezon et al. 2014; Smyth et al. 2019; Tsuji et al. 2000).

Can ototoxicity be prevented?

In many instances the use of an ototoxic medication is unavoidable, such in the chronic management of cystic fibrosis (Caumo et al. 2017; Dong et al. 2021; Elson et al. 2021; Garinis et al. 2021a; Harruff et al. 2021), or when a severe infection is only susceptible to an aminoglycoside antibiotic, or when an aggressive malignancy only responds to a platinum-based anti-neoplastic agent.  Faced with likely ototoxicity in such circumstances, investigators have explored whether there are any mechanisms to attenuate ototoxicity (Barbara et al. 2022; Jiang et al. 2021; Laurell 2019; Pham et al. 2020; Rybak and Kelly 2003; Wu et al. 2021; Yurtsever et al. 2020; Zhang and Yu 2019; Zheng et al. 2020b).

Much of this research has been directed at aminoglycoside antibiotics (Kawamoto et al. 2004; Kitcher et al. 2019; Lopez-Gonzalez et al. 2000b; Momiyama et al. 2006; Pavlidis et al. 2014; Perletti et al. 2008; Zong et al. 2021), specifically at gentamicin (Kucharava et al. 2019; Niu et al. 2021; Wen et al. 2022), amikacin (Zadrozniak et al. 2019) and neomycin (Zheng et al. 2020a).

Considerable research has also explored otoprotective strategies against cisplatin ototoxicity (Bhatta et al. 2019; Drogemoller et al. 2019; Fang and Xiao 2014; Fernandez et al. 2021; Freyer et al. 2019; Freyer et al. 2020; Fritzsche et al. 2022; Guan et al. 2020; Hu et al. 2020a; Karasawa and Steyger 2015; Kitcher et al. 2019; Lee et al. 2020; Liang et al. 2021; Liu et al. 2021; Lopez-Gonzalez et al. 2000a; Navarro-Ruiz 2020; Paciello et al. 2020; Ruhl et al. 2019; Rybak et al. 2007; Santos et al. 2020; Simsek et al. 2019; Tan et al. 2022; Tas et al. 2021; Terzi et al. 2021; Wang et al. 2022; Wen et al. 2021; Yurtsever et al. 2020; Zhang et al. 2020; Zhang et al. 2022).

Relatively little research has been directed against ototoxicity from furosemide (Zadrozniak et al. 2019) and other agents.

Can ototoxicity be treated?

The short answer is that there is not yet any known direct therapy for any form of ototoxicity.

Hearing loss is usually treated with amplification by hearing aids, or (in severe cases) with cochlear implantation.

Imbalance is usually treated with vestibular rehabilitation therapy.

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