Rev Soc Bras Med Trop 50(5):646-651, September-October, 2017

doi: 10.1590/0037-8682-0465-2016

Major Article

The importance of audiometric monitoring in patients

with multidrug-resistant tuberculosis
Karla Anacleto de Vasconcelos[1], Silvana Maria Monte Coelho Frota[1],[2],
Antonio Ruffino-Netto[3] and Afrânio Lineu Kritski[2],[4]

[1]. Departamento de Fonoaudiologia, Hospital Universitário Clementino Fraga Filho, Faculdade de Medicina, Universidade Federal do Rio de Janeiro,
Rio de Janeiro, RJ, Brasil. [2]. Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brasil.
[3]. Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil.
[4]. Programa de Pós-Graduação em Clínica Médica, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brasil.

Abstract
Introduction: A total of 771 cases of multidrug-resistant tuberculosis (MDR-TB) were reported in Brazil in 2014. Treatment of
MDR-TB with aminoglycosides can produce serious side effects such as permanent and irreversible hearing loss, which occurs in
5-64% of cases, and severely compromise patient quality of life. The goal of this research was to evaluate auditory and vestibular
side effects in patients treated for MDR-TB and to identify associations between these complaints and the type of aminoglycoside
used. Methods: We performed a retrospective review of 599 medical records from patients with MDR-TB who were treated at
the Hélio Fraga/Fiocruz Reference Center between 2006 and 2010. Cases without auditory or vestibular complaints and patients
who were not treated with aminoglycoside drugs were excluded from the study. Results: Of 164 eligible cases, 55 (33.5%)
reported an auditory or vestibular complaint and medication was subsequently suspended, although hearing damage was not
confirmed in all cases. Audiometric testing confirmed hearing loss in 11 (21.7%) of 12 cases submitted for evaluation. Hearing
loss related to ototoxicity was confirmed in 15 (62.5%) cases. Tinnitus was significantly associated with the use of amikacin and
streptomycin. Conclusions: Evaluations of ototoxicity symptoms were not usually reported in the routine care of patients with
MDR-TB. Complaints of tinnitus were associated with amikacin and streptomycin use. These results require confirmation in
future studies.
Keywords: Aminoglycoside. Hearing. Hearing loss. Tuberculosis.

INTRODUCTION and middle-income countries2,3. Yet, aminoglycoside use for the

In recent years, the increasing incidence of multidrug-
resistant tuberculosis (MDR-TB) has become a significant
concern for policy makers. The World Health Organization1
estimated that in 2014, there were 480,000 new cases of MDR-
TB worldwide and approximately 190,000 deaths related to
MDR-TB1. Brazil is ranked 17 among the 22 countries with
the highest number of cases of MDR-TB, reporting 70,000 new
cases and 4,600 related deaths annually1,2. Moreover, an increase
in the number of MDR-TB cases was recently reported in Rio
de Janeiro State in the year 20152.
Patients with MDR-TB characterized by bacilli resistant to
first-line treatments including rifampicin and isoniazid require
the use of second-line medications such as aminoglycosides.
Aminoglycosides have been used to treat TB for more than 40
years3. These agents are cost-effective and widely used in low-
treatment of MDR-TB is associated with ototoxicity in 5-64%
in cases3-11. Ototoxicity can produce hearing loss and associated
psychosocial changes that negatively affect quality of life12.
Recent research has highlighted the importance of auditory
monitoring in patients receiving aminoglycosides3,5,11,. Auditory
monitoring facilitates the early identification of injury before
the onset of hearing loss of tonal thresholds in the range
of conventional frequencies used in speech. Consequently,
screening and appropriate treatment can reduce the effect of
aminoglycoside-related ototoxicity on quality of life. There is
little data on ototoxicity in patients receiving aminoglycosides
for the treatment of MDR-TB in Brazil7,11. Therefore, the goal of
this study was to retrospectively evaluate auditory and vestibular
complaints in patients treated for MDR-TB at a reference center
in Rio de Janeiro State, and to analyze relationships between
these complaints and the type of aminoglycoside used.

METHODS
Corresponding author: Fga. Karla Anacleto de Vasconcelos.
e-mail: karla.fono@hotmail.com
We retrospectively enrolled patients with MDR-TB who
Received 15 November 2016 attended the outpatient clinic at Helio Fraga Reference Center/
Accepted 18 October 2017 FIOCRUZ between January 2006 and December 2010. Clinical

646

and socio-demographic data were obtained from the medical
records of the National Surveillance System for MDR-TB.
Secondary data were obtained from clinic medical records.
Clinical variables included hearing complaints such as hearing
loss (difficulty hearing or understanding speech), tinnitus, and
dizziness were verified in this study. Information about the
discontinuation of aminoglycosides due to auditory or vestibular
complaints and requests for audiometric evaluation were also
recorded. Hearing test results were recorded from medical charts
and analyzed separately for each ear. Cases of MDR-TB were
excluded from the analysis if there were no auditory or vestibular
data or if an aminoglycoside was not administered.
Associations between the most frequent symptoms and the
variables studied (aminoglycoside, sex, age, schooling, previous
use of an aminoglycoside, and previous treatment) were tested
using Chi-square tests. The threshold for statistical significance
was p < 0.05. The epiinfo version 7 program was used.
Ethical considerations
This study was approved by the Research Ethics Committee of
the Hospital Universitário Clementino Fraga Filho/Universidade
Federal do Rio de Janeiro (approval no. 75676/12).
The procedures used were in accordance with the ethical
standards of the responsible human experimentation committee
(institutional, regional or national) and in accordance with the
Declaration of Helsinki of 1964, revised in 1975, 1983, 1989,
1996 and 2000.
RESULTS
Of 599 medical records analyzed, 417 (69.6%) were excluded
from the analysis due to the absence of auditory/vestibular
complaints and 10 (1.7%) were excluded due to use of a non-
aminoglycoside treatment regimen. In the remaining 172 (28.7%)
cases, amikacin was administered in 145 (84.3%) patients and
streptomycin was administered in 19 (11%) patients (Figure 1).
One or more auditory/vestibular complaints were reported
in 164 (95.3%) cases; hypoacusis was reported in 116 (70.7%)
cases, tinnitus was reported in 88 (53.6%) cases, and dizziness
was reported in 28 (17%) cases (Figure 2). Fifty-five (33.5%)
patients discontinued the medication after reporting a hearing or
vestibular complaint; however, only 12 (21.8%) of these cases
underwent evaluation. Audiometric testing confirmed hearing
loss in 11 (91.7%) of 12 cases, with 8 exhibiting sensorineural-
type hearing loss with a downward curve compatible with
ototoxicity. The grade of hearing loss ranged from mild to
severe. It is worth noting in the Figure 3 that classifications
of hearing loss were conducted at all frequencies (i.e., from
0.25kHz to 8kHz).
An analysis of the time period between treatment initiation
with aminoglycosides and the report of a hearing complaint
revealed that both tinnitus and hearing loss were associated
with duration of use (Table 1). Tinnitus was also associated
with amikacin use and young age, and while hearing loss was
associated with male gender. In contrast, vestibular complaints
(dizziness) had the highest frequency at the beginning of
treatment (Figure 3).
de Vasconcelos KA et. al - Hearing loss after MDR-TB treatment
DISCUSSION
Although the ototoxic effects of aminoglycosides were first
described in the 1940s, the underlying mechanisms remain
unclear. Hearing damage associated with aminoglycoside use
can include permanent hearing loss and tinnitus secondary to
the degradation of sensorineural hair cells of the cochlea and/
or vestibule. Damage to cochlear hair cells is thought to be
mediated by oxidative stress, starting at the base where high-
frequency sounds are decoded and advancing to the apex6,8,13,14,15.
In the present study, we identified hearing complaints after
aminoglycoside use in 27% of medical records analyzed, similar
to what has been described in the literature (27.8%)11. Higher
frequencies of TB and hearing complaints among male subjects
in our study were also consistent with previous reports. This
finding may be related to the increased tendency for ototoxicity
risk factor exposure in men compared to women4,11,13.
In this study, we examined the relationship between hearing
complaints and the type of aminoglycoside used, as different
types of aminoglycosides affect different areas of the auditory and
vestibular systems. Amikacin is described in the literature as a
synthetic aminoglycoside that can cause damage to cochlear cells
to produce clinical presentations including tinnitus and hearing
loss. In contrast, streptomycin preferentially affects cells of the
vestibule, but can also cause damage to the cells of the cochlea.
In such cases, the first symptom is dizziness, followed by tinnitus
and hearing loss. These mechanisms are partly consistent with our
observation that amikacin and streptomycin use were associated
with tinnitus. The lack of a significant association between use
of these medications and hearing loss may have been due to the
small number of cases included in this study. It is also noteworthy
that by the time individuals perceive hearing loss, the lesion has
already progressed to affect the area of the cochlea responsible
for the transduction of sound in the frequencies of human speech.
Therefore, some subjects may have had yet undetectable hearing loss.
Some phonemes such as [s], [f], and [t] have low intensities,
such that any loss in high frequencies can hinder their
perception5,9. Difficulty hearing but not understanding what is
being said can cause embarrassment and lead to social isolation,
often with occupational consequences5. Because of this, it is
essential to carefully consider patient complaints of hearing loss
or difficulty understanding speech. A hearing aid is one possible
solution in patients with damage related to aminoglycoside use;
however, hearing aids are expensive, especially considering the
socioeconomic level of the majority of individuals with TB in
low- and middle-income countries16. The referral of patients
with hearing loss to centers of medium- and high-complexity
Hearing Health Programs of the Ministry of Health operated in
conjunction with state governments is the most suitable option
given the socioeconomic profile of the population studied.
Tinnitus was the second most frequent hearing complaint in
this study. Tinnitus is defined as an auditory perception in the
absence of an actual stimulus. The subjective characteristics
of tinnitus complicate investigations of its pathophysiology.
Tinnitus is fairly common in clinical practice; although there are
no studies about its prevalence in Brazil, tinnitus affects nearly
40 million people in the United States and England5,9. Previous
647
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FIGURE 1 - The study on the organization chart data colletion in CRPHF (2006-2010). CRPHF: Centro de Referência Professor Helio Fraga;
MDR-TB: multidrug-resistant tuberculosis.

studies have described an association between tinnitus and the

use of amikacin and streptomycin as well as the appearance of
tinnitus prior to hearing loss9. At present, there is no treatment
for tinnitus induced by ototoxicity, as the hearing damage is More of a
irreversible. Rather, strategies to mask the perception of tinnitus
complaint
can be used to prevent symptoms from interfering with day-to-
day life. The most frequent strategies indicated are the use of n. 55
background music to fall asleep, relaxation techniques, and a Hiyoacusis
noise-generating hearing aid. Dizzines n.116
Dizziness is a vestibular complaint defined as an illusory n.28
sense of rotation associated with impaired perception of mobile
environments5. Damage to the hair cells of the vestibular system
(the bulb and otolith organs) can activate the reflex responses
generated by head, eye, and body movements triggering
dizziness5,9,15. Although the relationship between streptomycin
use and dizziness is well characterized in the literature5, we did Tinitus
not identify this association in our population. Nevertheless, n.88
dizziness was the most frequently reported complaint at the
beginning of treatment. This can be explained by the normal
physiological response to damage caused by vestibulotoxic
agents; injury to the vestibular system is followed by FIGURE 2 - Distribution of hearing/vestibular complaints in the studied
neurological reorganization to restore corporal equilibrium population.

648
 TABLE 1
Statistical analysis between the type of aminoglycoside and hearing complaints in population evaluated.

  Number   Hypoacusis Tinitus Dizziness

  included excluded yes no total yes no total yes no total
p-value p-value p-value p-value
Aminoglycoside n % n % n % n % n n % n % n n % n % n

amikacin 145 88,4 339 77,9 101 69,7 44 30,3 145 82 56,6 63 43,4 145 23 15,9 122 84,1 145
<0,01 0,40 0,04 0,24
streptomycin 19 11,6 86 19,8 15 78,9 4 21,1 19 6 31,6 13 68,4 19 5 26,3 14 73,7 19

Sex

male 87 53,0 273 62,8 70 80,5 17 19,5 87 43 49,4 44 50,6 87 10 11,5 77 88,5 87
0,04 <0,01 0,25 0,07
female 77 47,0 162 37,2 46 59,7 31 40,3 77 45 58,4 32 41,6 77 17 22,1 60 77,9 77

Age group

12 - 39 78 47,6 210 48,3 55 70,5 23 29,5 78 49 62,0 30 38,0 79 11 14,1 67 85,9 78

40 - 59 76 46,3 196 45,1 0,76 54 71,1 22 28,9 76 0,95 33 42,3 45 57,7 78 0,04 15 19,7 61 80,3 76 0,44

> 60 10 6,1 29 6,7 7 70,0 3 30,0 10 6 85,7 1 14,3 7 1 10,0 9 90,0 10

Education

illiterate 7 4,3 28 6,4 5 71,4 2 28,6 7 3 42,9 4 57,1 7 1 14,3 6 85,7 7

elementary school 88 53,7 285 65,5 60 68,2 28 31,8 88 53 60,2 35 39,8 88 12 13,3 78 86,7 90
0,49 0,11 0,14
high school 49 29,9 72 16,6 0,04 37 75,5 12 24,5 49 23 46,9 26 53,1 49 10 20,0 40 80,0 50

higher education 8 4,9 18 4,1 5 62,5 3 37,5 8 3 37,5 5 62,5 8 3 37,5 5 62,5 8

no information 12 7,3 32 7,4 9 75,0 3 25,0 12 6 50,0 6 50,0 12 1 11,1 8 88,9 9

Previous treatments

0-1 24 14,6 89 20,5 16 66,7 8 33,3 24 11 45,8 13 54,2 24 4 16,7 20 83,3 24

≥2 118 72,0 314 72,2 0,23 84 71,2 34 28,8 118 0,66 64 54,2 53 44,9 118 0,43 20 16,9 98 83,1 118 0,97

no information 22 13,4 32 7,4 16 72,7 6 27,3 22 13 59,1 9 40,9 22 3 13,6 19 86,4 22

Previous aminoglycoside

yes 103 71,0 234 53,8 72 69,9 31 30,1 103 59 57,3 44 42,7 103 14 13,6 89 86,4 103

no 49 33,8 175 40,2 0,03 35 71,4 14 28,6 49 0,84 22 44,9 27 55,1 49 0,20 11 22,4 38 77,6 49 0,25
de Vasconcelos KA et. al - Hearing loss after MDR-TB treatment

no information 12 8,3 26 6,0 9 75,0 3 25,0 12 7 58,3 5 41,7 12 2 16,7 10 83,3 12

649
Rev Soc Bras Med Trop 50(5):646-651, September-October, 2017

50
45
40
35
30
25
20
15
10
5
0
1 to 30 days 31 to 60 days 3 to 12 months after termination More than 18
of use (period months of use
indicated, Ministry (treatment failure )
of Health)

Tinutus Hypoacusis Dizziness

FIGURE 3 - Distribution of the relationship between the time of use and the reporting of auditory/vestibular complaints.

over time. Therefore, patients exposed to vestibulotoxic agents
may initially experience some imbalance or dizziness and
recover thereafter. Vestibular rehabilitation or labyrinthine
rehabilitation can accelerate the process of compensation in
cases of dizziness resulting from the use of ototoxic drugs.
In the present study, approximately 70% of records analyzed
were excluded because there were no reported adverse events
of interest. Auditory and vestibular complaints should have a
prominent place in the medical records of patients with MDR-
TB who are treated with aminoglycosides. When a complaint
was reported, physicians discontinued aminoglycoside treatment
without laboratorial confirmation of hearing loss. Awareness of
the consequences of a hearing loss and delays for diagnosis in
the public health system likely caused physicians and patients to
decide against the continuation of treatment. In our study, only
27% patients were referred for hearing assessment and of these,
91% of cases were confirmed to have hearing loss. The addition
of an on-site or referral team of otolaryngologists and audiologists
to TB clinics can enable the proper testing and monitoring of
auditory and vestibular function in patients treated for MDR-TB.
The present study had some limitations. First, the effects or
contributions of confounding variables for hearing loss such as
smoking and noise exposure were not studied and are not currently
known in the context of aminoglycoside ototoxicity. Our results
suggest that cases of hearing loss identified in this study were due
to aminoglycoside use, given the types of impairment, the period
of onset, and the audiometric configuration. A high prevalence
of sensorineural bilateral loss with downward curves among
individuals tested suggests a possible association that should
be examined in future studies. Second, the study was limited
by a retrospective design and the availability of data in patient
medical records/missing data. The attending medical specialists
at MDR-TB reference centers do not habitually document data on
auditory or vestibular complaints. Proper auditory monitoring and
the careful assessment of hearing complaints should be routine
procedures in treating patients with MDR-TB.
The development of standard operating protocols for
monitoring hearing has not been a priority in medical practice;
however, a systematic investigation into the hearing conditions
of patients exposed to ototoxic drugs would: 1) support clinical
decisions; 2) provide an assessment of the overall effectiveness
of current clinical methods for monitoring ototoxicity; and 3)
aid the development of programs for clinical application.
Acknowledgments
We thankful to the team members of the outpatient clinic at Hélio Fraga
Reference Center/Fundação Oswaldo Cruz (FIOCRUZ), especially
Dr. Margareth Dalcolmo and nurse Suzanne Leite.
Conflicts of interest
The authors declare that there is no conflict of interest.
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