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Year : 2022  |  Volume : 28  |  Issue : 4  |  Page : 306-309

Evaluation of cochlear ototoxicity with otoacoustic emissions and pure-tone audiogram following treatment for multidrug-resistant tuberculosis in our tertiary care center

Department of Otorhinolaryngology, Government Kilpauk Medical College, Chennai, Tamil Nadu, India

Date of Submission03-Aug-2022
Date of Decision15-Oct-2022
Date of Acceptance30-Oct-2022
Date of Web Publication29-Dec-2022

Correspondence Address:
Dr. P Thamizharasan
Department of Otorhinolaryngology, Government Kilpauk Medical College, Chennai, Tamil Nadu
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/indianjotol.indianjotol_131_22

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Background and Objectives: Hearing is a vital function and can be impaired by drugs causing ototoxicity which is inevitable in situations such as multidrug-resistant tuberculosis (MDR-TB). A longitudinal study was conducted to evaluate cochleotoxicity by otoacoustic emissions (OAEs) and pure-tone audiogram (PTA) in patients following treatment for MDR-TB. Materials and Methods: Sixty-five patients were included in the study after excluding cases as per criteria. Baseline pure-tone audiometry and OAEs were done. If asymptomatic, the patient followed up with PTA and distortion product OAE after 3 months and 6 months of treatment with a selected regimen for MDR-TB. Results: Compared to the pretreatment prevalence of 67% hearing loss, 81% of patients had hearing loss at 3 months and 97% at 6 months. OAEs were abnormal in 32% before treatment, which increased to 86% at 3 months and 97% at 6 months' follow-up. Conclusion: OAEs were able to pick up early the cochlear damage before it became apparent in PTA and well ahead of becoming symptomatic in patient. OAEs should be included in the pre- and post-treatment assessment of hearing with a high-frequency PTA for follow-up in MDR-TB patients or any patient on treatment which may cause ototoxicity.

Keywords: Cochleotoxicity, multidrug-resistant tuberculosis, otoacoustic emission, ototoxicity, pure-tone audiogram

How to cite this article:
Thamizharasan P, Muthuchitra S, Indu S P, Venkatesh S. Evaluation of cochlear ototoxicity with otoacoustic emissions and pure-tone audiogram following treatment for multidrug-resistant tuberculosis in our tertiary care center. Indian J Otol 2022;28:306-9

How to cite this URL:
Thamizharasan P, Muthuchitra S, Indu S P, Venkatesh S. Evaluation of cochlear ototoxicity with otoacoustic emissions and pure-tone audiogram following treatment for multidrug-resistant tuberculosis in our tertiary care center. Indian J Otol [serial online] 2022 [cited 2023 Feb 5];28:306-9. Available from: https://www.indianjotol.org/text.asp?2022/28/4/306/365954

  Introduction Top

Hearing normally is a basic prerequisite for communication. Hearing loss of any degree will affect the quality of life and mental well-being.[1] Delaying in diagnosis can have adverse effects. There are many conditions where the patient remains asymptomatic and diagnosed only in the later stages. Ototoxicity caused by drugs is the most under-diagnosed condition.

Tuberculosis (TB) is a common infectious disease causing 20 lakhs deaths and 1 crore cases annually worldwide according to the World Health Organization (WHO) report in 2019.[2] India has 20 lakhs cases out of 90 lakhs prevailing cases worldwide according to that report.[2] Isoniazid, rifampicin, ethambutol, and pyrazinamide are the first-line drugs for the treatment of TB.[3] Moreover, about 61% of people with bacteriologically confirmed TB were tested as rifampicin resistant.[4]

The drug regimen for multidrug-resistant TB (MDR-TB) according to the WHO guidelines of 2018 includes aminoglycosides such as kanamycin, capreomycin and amikacin and quinolones such as ciprofloxacin and levofloxacin. Ofloxacin, moxifloxacin, and other drugs including ethionamide, terizidone, cycloserine, prothionamide, thioacetazone, para-aminosalicylic acid, and rifabutin.[4] The second-line drugs are given; five drugs with an injectable aminoglycoside for at least 8 months and oral drugs for 12 months according to the WHO guidelines of 2019.[5]

All these are essential and life-saving drugs and had to be taken in spite of their toxicity. There is a delay in diagnosing drug-induced ototoxicity because patients become symptomatic only later.[6] Furthermore, other variables such as age-related hearing loss, comorbid illness, and ignoring auditory symptoms compared to other worse symptoms may lead to a delay in diagnosis and seeking treatment.

We had done a study to evaluate cochlear ototoxicity with pure-tone audiogram (PTA) and otoacoustic emissions (OAEs) following treatment for MDR-TB.

  Materials and Methods Top

Ethical Committee Approval

This study was approved by the Institutional Ethics Committee.

Study design

This was longitudinal study.

Sample Size

Sample size was 70.

Inclusion Criteria

All Patients diagnosed with MDR-TB started on the second-line drugs treatment were included in the study.

Exclusion Criteria

Patients with other external or middle ear diseases, other chronic diseases which can cause hearing loss, history of previous ear surgery, other ototoxic drug intake, family history of deafness, and chronic exposure in a noisy environment were excluded from the study.


Patients with clinical diagnosis of multidrug-resistant TB confirmed by the chest physician's opinion were referred to our ENT department. History collection and detailed examination with the standard questionnaire were done by an ENT surgeon. After explaining the study and obtaining consent, they were enrolled. Pure-tone audiometry and OAE were done by an audiometrician. Recordings were taken. Results were confirmed by repeating the recording by an audiologist. Baseline recordings were documented. The patient started on drug regime, asked to report if there are any audiological symptom or else to follow-up after 3 months and 6 months. PTA and OAE were repeated after 3 months and 6 months. Results obtained in both were analyzed statistically using SPSS software. The pure-tone average of 500, 1000, 2000, and 4000 was taken for both ears separately, and the total hearing loss was calculated using hearing loss percentage calculation advised by as per the Rights of Persons with Disabilities Act 2016 published by the Government of India. They were classified as mild, moderate, severe, profound, and total. DPOAEs s were reported as pass, fail, and refer which were taken in both ears, and the worse ear result was documented.

  Results Top

Of 70 patients, one patient died, four patients lost follow-up. Sixty-five patients were evaluated in the study. We had 50 male and 15 female patients from 16 years to 73 years age group (the mean age was 43 years).

Thirty patients had comorbidities with 24 of them having diabetes or hypertension, 11 had diabetes, five had hypertension, and eight had both. Other comorbidities in patients were two with heart disease, one had pancreatitis, one was positive with HIV, one was alcohol-dependent, and one had carcinoma tongue with MDR-TB. These 30 patients were taking medications for their comorbidities with drugs for MDR-TB.

All patients had rifampicin resistance as predominance 23 high, 19 intermediate, 10 very low, 7 medium, and 6 low extent of resistance as per the gene expert study.

Of 65, 57 patients were given a short-course regimen with injectable aminoglycoside and eight with all long regimens without aminoglycoside. The master chart including all details is enclosed in supplementary material. The concise data of results are shown in [Table 1].
Table 1: Concise data of results

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  Discussion Top

Most of our study participants were male with a male:female ratio of 3:1 signifying the high incidence of drug-resistant TB in males. The WHO report, 2020, also signifies similar results of male preponderance.[2] It also coincides with most of other studies where men significantly contribute to the total MDR-TB burden.

Of 65 patients, eight of these recurrent cases and defaulters were started on all-oral longer regimen, and the rest 57 of them were started on a shorter course regimen containing injectable aminoglycoside, most commonly kanamycin.

Dillard et al. included 18 studies from 10 different countries and noted a pooled prevalence of ototoxic hearing loss.[6] Hong et al. found that HIV coinfection makes 22% higher risk for aminoglycoside-induced hearing loss in MDR-TB patients.[7]

When initial audiological assessment was done in the study population before starting treatment, 22 had normal hearing, 25 people had mild hearing loss, while 13 people had moderate hearing loss, three with severe hearing loss, and 2 having profound hearing loss. The prevalence of hearing loss was 67% already. After 3 months, 13 people had normal hearing, 32 mild, 15 moderate, two severe, and three with profound hearing loss with a prevalence of 81% hearing loss among the study group. After 6 months, only one patient had normal hearing, 38 with mild, 19 with moderate, seven with severe, and five with profound hearing loss with a prevalence of 97% of patients having hearing loss.

Duggal and Sarkar studied the audiologic monitoring of 64 patients on the second-line aminoglycoside treatment for MDR-TB with follow-up of 1 year after the discontinuation of drug and noted threshold shift in the frequencies range of 4K–8KHz (HFL) with 18.75% of persons developing a high-frequency SNHL and 6.25% hearing loss in speech frequencies.[8] Khan et al. studied 104 patients using the second-line drugs, at the end found, 58% had a high-frequency loss and 31.5% had dead ear, with amikacin being the most ototoxic.[9] Sogebi et al. did a study involving MDR-TB patients on the baseline audiogram configurations and associations with 132 patients, 79% of them developed sensorineural hearing loss.[10] Fausti et al. conducted a study in 77 patients undergoing therapy for TB with streptomycin and observed 8K Hz hearing losses preceding other frequencies.[11] Vasconcelos et al. did a descriptive study on 97 males and females undergoing treatment for active pulmonary TB, and abnormal audiometric findings were observed in 69.7%.[12]

In our study, there was a threshold shift in auditory levels following the administration of the short-course regimen at the end of 6 months with a significant P < 0.001. The average of threshold shifts in those who received all-oral regimen without injectable aminoglycoside was found to be 30.18%, whereas the average in those who received a shorter course regimen with an injectable aminoglycoside was found to be 60.3%, which was found to be twice higher.

When OAE was done before initiation, 44 persons had passed in either ear, 21 refer, and no fail, thereby implicating 32% of people with cochlear hair cell damage. At 3 months' follow-up, only nine patients had pass in either ear, 44 persons refer, and 12 failed showing 86% early or complete cochlear hair cell damage. At 6 months' follow-up, only two persons withstood ototoxicity bypass, 41 had refer, and 22 fail implying 97% with signs of hair cell injury.

Md Daud et al. performed a study on streptomycin-treated TB patients. At day 7, distortion product OAE (DPOAE) detected ototoxicity in 47.7% of the cases, whereas PTA detected only 2.3% of patients.[13]

In our study, OAE changes were detected earlier to change of grading of hearing in 34/65 patients, i.e., in about 52.30%. The remaining had either audiological threshold changes more significant than OAE or had pretreatment hearing impairment where OAE was absent initially.

The studies were done by Md Daud et al.[13] and Knight et al.[14] prove that OAEs are very sensitive in detecting early changes in the cochlea secondary to ototoxicity.

The use of OAE in addition to PTA for screening ototoxicity helps in reducing test time and helps in clinical monitoring.

The hearing loss initiated by these second-line injectables is found to be slowly progressive and usually starts at high frequencies. Initially, when only the high frequencies are involved, the hearing loss may be left unnoticed by the patients and it may go undetected. Further continuation of the injectable may lead to further decline in hearing and a permanent hearing loss.

This hearing loss undetected by normal audiometry can be signified much earlier by changes in OAE, which is a simple essential tool. Moreover, the procedure is carried out as a simple outpatient department procedure, where it can detect changes in hair cell damage even before it becomes evident as a detectable hearing loss by PTA.

The PTA average includes only speech frequencies 500, 1000, 2000, and 4000 Hz. Ototoxicity-induced hair cell damage starts in the basal turn of the cochlea responsible for higher frequencies more than 8000 Hz, which can be assessed by OAEs or high-frequency audiogram.

Our study population had 97% hearing loss at the end of 6 months' follow-up; 30% of further impairment in terms of PTA was compared to pretreatment audiogram, and 64% of worsening was compared to pretreatment OAEs.

The guidelines for the audiologic management of individuals receiving cochleotoxic drug therapy published by the American Speech-Language-Hearing Association and the American Academy of Audiology have recommended audiometry including high frequency, distortion OAE, and tympanometry with questionnaires.[15],[16] All are important in monitoring ototoxicity. Hope these recommendations are included in every tertiary care center as a routine.

Individual variability in developing ototoxicity may be explained by the genetic predisposition of an individual. Hence, it is better if we can find out genetic variants that may develop ototoxicity. Pharmacogenetic studies have drawn parallel between genotypes and ototoxicity.

The ototoxic effects can be minimized using otoprotective agents such as N-acetyl cysteine, amifostine, sodium thiosulfate, Vitamin E, ginkgo biloba extract, and dexamethasone.

Ejigu and Abay prove that there was a decreased ototoxicity with giving N-acetyl cysteine with it.[17] If cochleotoxicity features are diagnosed, we can modify the choice of aminoglycoside like Souleymane et al. where giving linezolid instead of kanamycin can prevent ototoxicity.[18]

Moreover, OAE screening as a sensitive marker can be time-saving and can help screen more patients. Further, it would be of immense value if advanced techniques like high-frequency audiometry covering frequencies above 8kHz, which can detect changes much earlier than conventional audiometry are available.

The following measures can be taken: reduction in the frequency to alternate days, or three times a week or changing to capreomycin with a comparatively lower risk of ototoxicity. Audiometry can be done every week, and depending on the results, the drug choice can be altered. A more essential step would be rehabilitation of the patient with hearing support devices or aids. In future, we may have cochlear gene therapy or stem cell therapy.

Ototoxicity includes both cochleotoxicity and vestibulotoxicity. Although we are able to diagnose cochleotoxicity to some extent, no standard investigations are available to diagnose vestibulotoxicity until the patient becomes symptomatic. Even after having vestibular symptoms, other comorbidities may be thought of as causes preceding a diagnosis of vestibulotoxicity.

  Conclusion Top

Otoacoustic emissions are a simple, essential tool for early diagnosis of ototoxicity; wherein the present study, 52.3% of the population receiving aminoglycoside antibiotics for the treatment of MDR-TB had changes detected in OAE before the change of the grade of hearing loss detected by pure-tone audiometry in the population studied. Therefore, the inclusion of OAEs for the regular audiological monitoring of ototoxicity in MDR-TB patients at a periodic interval of 1 month can be a valuable tool in detecting early hair cell damage.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Davis A, McMahon CM, Pichora-Fuller KM, Russ S, Lin F, Olusanya BO, et al. Aging and hearing health: The life-course approach. Gerontologist 2016;56 Suppl 2:S256-67.  Back to cited text no. 1
Chakaya J, Khan M, Ntoumi F, Aklillu E, Fatima R, Mwaba P, et al. Global tuberculosis report 2020 – Reflections on the global TB burden, treatment and prevention efforts. Int J Infect Dis 2021;113 Suppl 1:S7-12.  Back to cited text no. 2
Verbeeck RK, Günther G, Kibuule D, Hunter C, Rennie TW. Optimizing treatment outcome of first-line anti-tuberculosis drugs: The role of therapeutic drug monitoring. Eur J Clin Pharmacol 2016;72:905-16.  Back to cited text no. 3
World Health Organization. WHO Treatment Guidelines for Multidrug- and Rifampicin-Resistant Tuberculosis. Geneva, Switzerland: World Health Organization; 2018.  Back to cited text no. 4
World Health Organization. WHO Consolidated Guidelines on Drug-Resistant Tuberculosis Treatment. World Health Organization; 2019. Available from: https://www.who.int/publications/i/item/9789241550529. [Last accessed on 2019 Mar 20].  Back to cited text no. 5
Dillard LK, Martinez RX, Perez LL, Fullerton AM, Chadha S, McMahon CM. Prevalence of aminoglycoside-induced hearing loss in drug-resistant tuberculosis patients: A systematic review. J Infect 2021;83:27-36.  Back to cited text no. 6
Hong H, Budhathoki C, Farley JE. Increased risk of aminoglycoside-induced hearing loss in MDR-TB patients with HIV coinfection. Int J Tuberc Lung Dis 2018;22:667-74.  Back to cited text no. 7
Duggal P, Sarkar M. Audiologic monitoring of multi-drug resistant tuberculosis patients on aminoglycoside treatment with long term follow-up. BMC Ear Nose Throat Disord 2007;7:5.  Back to cited text no. 8
Khan F, Nizamuddin S, Khan A, Kamaal C. Assessment of hearing loss in multi-drug resistant tuberculosis (MDR-TB) patients undergoing Aminoglycoside treatment. Int J Res Med Sci 2015;3:1734-40.  Back to cited text no. 9
Sogebi OA, Fadeyi MO, Adefuye BO, Soyinka FO. Hearing thresholds in patients with drug-resistant tuberculosis: Baseline audiogram configurations and associations. J Bras Pneumol 2017;43:195-201.  Back to cited text no. 10
Fausti SA, Rappaport BZ, Schechter MA, Frey RH, Ward TT, Brummett RE. Detection of aminoglycoside ototoxicity by high-frequency auditory evaluation: Selected case studies. Am J Otolaryngol 1984;5:177-82.  Back to cited text no. 11
Vasconcelos KA, Lima MA, Frota S, Ruffino Netto A, Kritski AL. Audiometric evaluation of patients treated for pulmonary tuberculosis. J Bras Pneumol 2012;38:81-7.  Back to cited text no. 12
Md Daud MK, Mohamadl H, Haron A, Rahman NA. Ototoxicity screening of patients treated with streptomycin using distortion product otoacoustic emissions. B-ENT 2014;10:53-8.  Back to cited text no. 13
Knight KR, Kraemer DF, Winter C, Neuwelt EA. Early changes in auditory function as a result of platinum chemotherapy: Use of extended high-frequency audiometry and evoked distortion product otoacoustic emissions. J Clin Oncol 2007;25:1190-5.  Back to cited text no. 14
American Speech-Language-Hearing Association. Guidelines for the audiologic management of individuals receiving cochleotoxic drug therapy. ASHA 1994;36 Suppl 12:11-9.  Back to cited text no. 15
American Academy of Audiology Position Statement and Clinical Practice Guidelines: Ototoxicity monitoring; 2009. Available from: http://www.audiology.org/publications-resources/document-library/ototoxicity-monitoring. [Last accessed on 2016 Jan 05].  Back to cited text no. 16
Ejigu DA, Abay SM. N-Acetyl cysteine as an adjunct in the treatment of tuberculosis. Tuberc Res Treat 2020;2020:5907839. doi: 10.1155/2020/5907839.  Back to cited text no. 17
Souleymane MB, Piubello A, Lawan IM, Hassane-Harouna S, Assao-Neino MM, Soumana A, et al. High rifampicin-resistant TB cure rates and prevention of severe ototoxicity after replacing the injectable by linezolid in early stage of hearing loss. Eur Respir J 2021;57:2002250. DOI: 10.1183/13993003.02250-2020.  Back to cited text no. 18


  [Table 1]


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