Although many new antibiotics preclude the need for the administration of ototoxic aminoglycosides for many infections, aminoglycosides are still in common clinical use to treat serious Gram-negative aerobic bacterial infections when other antibiotics are ineffective or the patient is allergic to them (Yorgason et al. 2006). Although aminoglycosides are broad spectrum antibiotics (Schacht et al. 2012), they are not typically used to treat Gram-positive infections because alternate antibiotics with less toxic side effects are available for treating these infections in the United States. However, aminoglycosides are used routinely in the United States and globally for the management of acute infections common in cystic fibrosis patients (Prayle and Smyth 2010) as well as patients with multi-drug resistant tuberculosis (MDR-TB). In the United States, aminoglycosides are used as the last line of defense against some infectious diseases because they are stable against resistance when compared to other classes of antibiotics (Bassetti and Righi 2013). However, use is more widespread in developing countries.

The largest use of aminoglycosides occurs in developing countries because of their low cost (Chen et al. 2007), widespread availability, and effectiveness in the treatment of MDR-TB (Duggal and Sarkar 2007). With the World Health Organization (WHO) reporting that one-third of the world’s population is presently infected with the TB bacterium, global aminoglycoside use has become extensive and the numbers of those infected are expected to steadily increase over time (WHO 2009, 2010). Therefore, the incidence of aminoglycoside ototoxicity is also expected to increase among those treated for MDR-TB worldwide. In the absence of ototoxicity monitoring programs in most of these countries, incidence data are currently unavailable for many sites. However, Seddon et al. (2013) reviewed results from 35 studies of ototoxicity for MDR-TB worldwide and reported varying incidences ranging from 2.1 to 61.5 % depending on treatment regimen and definition of ototoxic change. In South Africa, where high-dose aminoglycosides are routinely used for MDR-TB, Harris et al. (2012) reported a 58 % incidence of ototoxic hearing loss with the majority being severe to profound. DIHL from aminoglycoside treatment is also considered to be a significant factor contributing to treatment noncompliance in these developing countries (Duggal and Sarkar 2007).

Cisplatin (CDDP), the original platinum-based chemotherapeutic, has been effective in treating soft tissue neoplasms since first approved by the FDA (Platinol^®, Bristol–Myers Squibb) for cancer treatment in the late 1970s (Blakley et al. 2002). The cancer types most often treated with cisplatin include ovarian, testicular, cervical, head and neck, lung and bladder (Rybak et al. 2007) in adults and osteosarcoma, neuroblastoma, hepatoblastoma, and germ-cell tumors in children (Langer et al. 2013). Although cisplatin typically provides powerful antitumor efficacy it also has been found to induce serious side effects such as sensorineural hearing loss, nephrotoxicity, neurotoxicity, and tinnitus (Adams et al. 1989; Blakley et al. 2002; Barabas et al. 2008). While researchers have found ways to circumvent the nephrotoxic side effects of cisplatin (Muraki et al. 2012), to date, no proven treatment has been found to prevent cisplatin-induced neurotoxicity and ototoxicity.

The incidence of cisplatin-induced hearing loss (CIHL) has been reported to highly vary in both adults and children receiving cisplatin therapy. The wide range of CIHL incidence variability for adults is largely due to differences in cumulative dosage, duration of treatment, types of assessments used to measure ototoxicity, and the scales used to rate the severity of ototoxicity. For children, an additional contributing factor to the high variability is the difficulty in assessing hearing thresholds in pediatric cancers that affect very young children (Brock et al. 1992). The median age of patients with neuroblastoma and hepatoblastoma is less than 18 months (Brock et al. 1992), an age range that can be challenging to obtain accurate hearing threshold assessments even among healthy children. The incidence of tinnitus is less well documented in adults receiving cisplatin therapy and is very difficult to assess in young children. Overall, the side effect of CIHL is of great concern in both the adult and pediatric populations undergoing cisplatin treatment. However, the pediatric population is at greater risk for CIHL as Li et al. (2004) have reported that children younger than 5 years of age were 21 times more likely to develop significant hearing impairment when compared to older children (15–20 years).

d-methionine, the optical isomer of l-methionine, has been found to be protective against the ototoxic effects of antineoplastics (cisplatin and carboplatin) (Campbell et al. 1996, 1999, 2007; Lockwood et al. 2000) as well as aminoglycosides (Sha and Schacht 2000; Campbell et al. 2007) in animals. Protection against cisplatin-induced hearing loss has also been described in humans (Campbell et al. 2009). Data from animal models indicate that d-methionine does not interfere with either the antitumor effect of cisplatin (Cloven et al. 2000) or the antimicrobial action of aminoglycosides (Sha and Schacht 2000).

d-methionine has been effective when administered by intraperitoneal injection, as a pulmonary inhalant, applied directly to the round window, or consumed as an oral suspension (Campbell et al. 1996, 1999, 2007; Korver et al. 2002; Grondin et al. 2013). Having multiple options for different delivery methods can be advantageous in that round window membrane administration may avoid any possible interference with the ototoxic drug’s therapeutic effect but precludes any systemic protection from other side effects (e.g., cisplatin-induced peripheral neuropathy). However round window membrane administration may not be practical on a daily basis such as for NIHL or for patients with infectious disease being treated with aminoglycosides who are more likely to have otitis media. Oral administration is generally less expensive, easier, may allow for self-administration and provides the potential of systemic protections. d-methionine is currently in Phase 3 clinical trials (NCT01345474) with the US Department of Defense to prevent permanent NIHL. One Phase 2 clinical trial to prevent cisplatin-induced hearing loss has been completed and further Phase 2 studies for both cisplatin-induced and aminoglycoside-induced hearing loss are planned. Currently oral d-methionine administration is planned for all our clinical trials.

A Phase 1 safety study was completed (Lynch and Kil 2009), and now Ebselen is currently in Phase 2 clinical trials to assess potential prevention temporary noise-induced threshold shift (NCT01444846). Several preclinical studies have demonstrated ebselen protection from cisplatin-induced ototoxicity as a single agent (Rybak et al. 2000) or in combination with allopurinol (Lynch and Kil 2005) although not all studies have shown significant ebselen protection from cisplatin-induced ototoxicity (Lorito et al. 2011). Baldew et al. (1990) reported that ebselen did not interfere with cisplatin’s antitumor action against MPC 11 plasmacytoma or Prima breast tumor in BALB/c mice. Clinical trials for prevention of cisplatin-induced hearing loss are posted on www.​clinicaltrials.​gov (see Table 12.2).

Takumida et al. (1999) reported that ebselen also reduced gentamicin-induced ototoxicity in guinea pigs but reportedly no clinical trials for prevention of aminoglycoside-induced hearing loss have been registered on clinicaltrials.gov. Like d-methionine, ebselen can be administered by injection (Rybak et al. 2000) or orally (Lynch and Kil 2005). Currently, all planned clinical trials are for oral administration.

N-Acetylcysteine has been studied in clinical trials to prevent NIHL but without significant otoprotection (Kramer et al. 2006; Toppila et al. 2002). Lin et al. 2010 reported some protection from temporary threshold shift depending on genetic profile of the workers.

In an early preclinical study, N-acetylcysteine was reported to exacerbate aminoglycoside-induced ototoxicity in the guinea pig (Bock et al. 1983). However, in two human studies, N-acetylcysteine has been reported to reduce aminoglycoside-induced ototoxicity (Feldman et al. 2007; Tokgoz et al. 2011). Clinical trials for prevention of aminoglycoside-induced ototoxicity are ongoing (see Table 12.2).

Transtympanic injections of N-acetylcysteine to prevent cisplatin-induced hearing loss yielded variable results in two clinical trials (Riga et al. 2013; Yoo et al. 2014). Riga et al. (2013) reported statistically significant N-acetylcysteine otoprotection for the frequency of 8,000 Hz using the patient’s contralateral ear as a control. Yoo et al. (2014) reported that 2 out of 11 patients demonstrated N-acetylcysteine protection from cisplatin-induced ototoxicity but group results did not reach statistical significance.

Although N-acetylcysteine can be administered either orally (Feldman et al. 2007) or transtympanically (Riga et al. 2013; Yoo et al. 2014) the transtympanic route may be used to avoid any possible interference with the therapeutic action of the ototoxic drug, e.g., cisplatin. Further clinical trials are listed on clinicaltrials.gov (Table 12.2) for both cisplatin and aminoglycoside otoprotection.

Sodium thiosulfate has been studied for decades as a potential otoprotective agent for cisplatin- and carboplatin-induced ototoxicity (Otto et al. 1988; Neuwelt et al. 1996); also see Table 12.2. Clinical trials for otoprotection from platinum-based chemotherapy are ongoing as listed in www.​clinicaltrials.​gov. Sodium thiosulfate has not been found to prevent NIHL (Pouyatos et al. 2007) or gentamicin-induced hearing loss (Hochman et al. 2006) in preclinical studies, thus sodium thiosulfate clinical trials for otoprotection are currently focusing on chemotherapy otoprotection.

One consideration for sodium thiosulfate as an otoprotective agent is its action as a cisplatin neutralizer when given simultaneously with platinum-based chemotherapeutics (Church et al. 1995; Jones et al. 1991). Consequently, sodium thiosulfate otoprotection protocols have been designed using delay of the sodium thiosulfate administration by several hours after cisplatin administration to provide otoprotection without antitumor interference (Muldoon et al. 2000; Harned et al. 2008). Sodium thiosulfate cisplatin otoprotection has been reported by parenteral administration including injection, intravenous or intra-arterial administration. An oral formulation is available and has been used for other purposes (AlBugami et al. 2013). Several clinical trials for sodium thiosulfate are listed on www.​clinicaltrials.​org.

Clinical trials with amifostine have not demonstrated significant efficacy in preventing or reducing cisplatin-induced hearing loss, according to a meta-analysis across multiple clinical trials (Duval and Daniel 2012). Currently, it is not recommended for either otoprotection or neuroprotection by the American Society of Clinical Oncology 2008 Clinical Practice Guideline Update Use of Chemotherapy and Radiation Therapy Protectants American Society of Clinical Oncology 2008 clinical practice guideline update: use of chemotherapy and radiation therapy protectants (Hensley et al. 2009). However, it is included in one clinical trial as a secondary end point on clinicaltrials.gov.

Formal audiological monitoring during known ototoxic drug administration is vital to detect drug-induced cochlear or vestibular changes clinically. Early detection of ototoxic changes provides the opportunity to consider possibly modifying the course of treatment to reduce these side effects or their progression.

Ototoxicity monitoring is also essential in clinical trials with new drugs that have ototoxic potential and in assessing new otoprotective agents to prevent or treat drug-induced hearing loss. Because ototoxic drugs can first cause subtle hearing changes, patient self-report or informal testing (e.g., tuning forks, watch tick, finger rub) are not sufficient for detecting drug-induced ototoxicity or for pharmacologic protection from drug-induced ototoxicity.

Because intersubject variability for DIHL is high, a priori decisions will need to be clear in the clinical trial design regarding when and if hearing loss changes will result in a subject being discontinued from the clinical trial. Although, no separate formal approved guidelines exist for ototoxicity monitoring with new drugs in clinical trials, the FDA makes recommendations for appropriate ototoxicity monitoring based upon ototoxic potential on a case-by-case basis for each clinical trial. These recommendations include modifications in the protocol if adverse events involving cochlear or vestibular changes occur. Ototoxicity monitoring is also the best means to determine the outcome of clinical trials for new pharmaceutical agents specifically targeted to treat or prevent DIHL.

A successful monitoring program requires the coordination/collaboration/cooperation among the treating physicians, nurses, and the diagnostic audiologists (AAA 2009). Identifying appropriate audiologic support and standardizing the audiologic equipment, personnel, and test procedures across multiple clinical sites, particularly if multiple countries are involved, can be challenging. Hearing healthcare professional organizations, such as the American Speech Language Association (ASHA 1994) and the American Academy of Audiology (AAA 2009), have created guidelines for ototoxicity monitoring. However, no universally accepted standardized protocols currently exist to detect or measure drug-induced ototoxicity as a whole, still less for individual drug classes. At present, each medical facility that actively administers aminoglycoside or antineoplastic therapy is responsible for developing and maintaining their own ototoxicity monitoring program (ASHA 1994). The guidelines developed by the American Speech Language Hearing Association (ASHA 1994) designate the team audiologist with the responsibility for the design and implementation of a comprehensive ototoxicity monitoring program. However, in the case of an FDA-approved clinical trial, all of the clinical trial procedures must be standardized and are part of the overall IND and Institutional Review Board (IRB) documents and procedures cannot be left to individuals at each site. Many clinical audiologists will need to be trained regarding FDA data collection and reporting procedures.

A major consideration in designing clinical trials to test the efficacy of a pharmacologic agent to prevent DIHL is selection of the patient population. First, a patient population with unavoidable drug-induced ototoxicity of an incidence and degree of hearing loss to test for protection must be identified. These data bases are sometimes not readily available. Other considerations will include accessibility to the subject pool, other clinical trials they are being recruited to, and whether or not they are able to fully understand and provide written informed consent. In some cases, the patient populations’ projected longevity and attrition during a clinical trial may be a factor. The testing time points for audiologic measures will need to be coordinated possibly with patient travel to the clinical area, patient travel costs, and complicated scheduling for other appointments. The clinical trial coordinators will need to work closely with the medical treatment, audiology, and clinical trial team to ensure timely and productive communication between the treating physicians, nurses, and the audiologist. Formal ototoxicity monitoring is presently recommended for patients undergoing treatment with either of the two classes of drugs known to cause severe and permanent hearing loss, the platinum-based antineoplastics (cisplatin and carboplatin) and aminoglycosides (ASHA 1994). Therefore, for pharmacologic protective agents for those two drug classes, it may be possible to coordinate audiologic testing for a protective agent with their usual and customary audiologic care. Currently, monitoring every patient exposed to a potential or low-risk ototoxic agent is neither feasible nor cost-effective clinically, and therefore audiologic testing is not generally a part of their usual and customary clinical care. However, in clinical trials that may include testing to determine if a new drug has even a low incidence of ototoxicity that determination is made on a case-by-case basis for each clinical trial.

The team audiologist(s) should take into consideration the logistics of monitoring hearing thresholds for both adults and children receiving treatment for life-threatening diseases in different environments when designing an ototoxicity monitoring program. For example, in clinical practice, sometimes “bedside” audiologic testing is requested for very ill patients. Studies have shown good test–retest reliability of EHF “bedside” behavioral audiometric threshold responses in hospital wards if appropriate earphones are utilized (Gordon et al. 2005). However, for clinical trials, standardized audiologic test methods including use of a sound treated booth with a patient that can provide reliable data will be needed.

In addition, the audiologist should also develop a comprehensive counseling and rehabilitation program for a patient when ototoxic changes occur. Although the purpose of the clinical trial will be to determine protection from DIHL, even if the protective agent is fully effective, in the placebo group some patients may be expected to develop ototoxic hearing loss during the clinical trial and the patients will require full management of their hearing loss. Until the clinical trial is unblinded, the investigators will not know which subjects are in which arm of the study, but that fact will not alter the need for management of patient hearing loss during the course of the study. The rehabilitation program should include proper education, appropriate fitting of amplification, selection of FM devices or other rehabilitative equipment as needed, or cochlear implantation if necessary. Pre- and post-treatment counseling is an essential part of an ototoxicity monitoring/rehabilitation program as the psychological impact of the combination of a life-threatening disease with the possibility of severe permanent hearing loss can be a devastating situation for a patient and their families.