Abstract
To estimate the prevalence of Sensorineural hearing loss and evaluate the severity of hearing impairment in patients undergoing second line injectable antitubercular treatment. To study the effects of duration of treatment, dose schedule and demographic factors which aggravates anti TB drug induced ototoxicity. Design–prospective and retrospective study Setting-ENT & TB clinic at our hospital and TB Hospital of Subject-18–50 year age , diagnosed MDR or XDR TB Method–baseline puretone audiometry was done of all patients. all patients divided in 3 group depending on aminoacid (amikacin , kanamycin, capreomycin). Follow up PTA was done at 3rd month, 6th month and 6 month after stopping treatment 35.48% of Group 1 (kanamycin) patients show High frequency hearing loss and 16% of patient have both high and low frequency hearing loss High frequency hearing loss 21% of Group 2 (amikacin) patients show High frequency hearing loss and 5% of patient have both high and low frequency hearing loss 20% of Group 3 (capreomycin) patients show High frequency hearing loss with no patient resulted low frequency loss Patients treated FOR MDR-TB develop significant adverse effects. Clinicians must consider risk benefit analysis during treatment as ototoxicity of injectable aminoglycoside ATT is permanent. Early detection of hearing loss through pure tone audiometry helps preventing and progression of hearing loss without compromising the treatment.
Keywords: MDRTB, ATT, Hearing loss, SNHL, Aminoglycoside
Introduction
Tuberculosis (TB) remains a major global health problem. The latest estimate report that there were 8.6 million new TB cases in 2012 and 1.3 million TB deaths (just under 1.0 million among HIV-negative people and 0.3 million HIV associated TB deaths) [1]. The World Health Organization (WHO) estimated there to be 650,000 cases globally of multidrug resistant tuberculosis (MDR-TB) (Mycobacterium Tuberculosis resistant to rifampicin and isoniazid) [1]. The treatment of drug- resistant (DR-) TB requires the use of second line anti-TB medications many of which are associated with significant adverse events [2].
The injectable drugs, the aminoglycosides and polypeptides, are associated with a risk to renal function, hearing and the vestibular system. The injectable anti-TB drugs selectively destroy the basal hair cells of basilar membrane, which are required for high frequency hearing [3]. After parenteral administration, aminoglycosides enter the inner ear fluids of the organ of corti and the sensory hair cells where they are thought to react with heavy metal ions to form highly reactive free radicals that damage the steriocilia of sensory hair cells. Hearing loss in those treated with aminoglycosides and polypeptides usually starts with high frequency loss first, with later progression to the frequencies more associated with speech communication. Damage is usually permanent. These drugs can also destroy the hair cells of vestibule [3]. Nephrotoxicity is generally reversible but damage to auditory and vestibular system is usually permanent. These drugs can destroy the hair cells of the vestibular system is usually permanent. The monitoring of hearing loss is important for two reasons. First, if detected early it may be possible to alter the regimen to stop or reduce the dose of the responsible drug, preventing progression of hearing loss to the point where it would impact on communication. Second, if significant hearing loss has been developed and detected, interventions can be implemented to assist in communication. These include hearing aids, cochlear implants or other hearing tools, teaching and training.
Methods
A prospective and retrospectives was conducted on 60 patients who are second line Anti tubercular treatment at MY Hospital and govt. TB hospital, Indore during 2011–2016. All relevant data were recorded on MDR-TB patient sheets including baseline and follow-up investigations. Patient of age group 18–50 years diagnosed and under treatment for MDR and XDR –TB were included in the study.
Baseline Pure tone audiometry was performed on all the patients on their first visit and follow up PTA was done on 3rd month, 6th month and 6 month after stopping the treatment. PTA was also done on these patients whenever they presented with any of symptomatology related to the ototoxic effects of the treatment. Patients with the evidence suggestive of hearing loss prior to commencement of study were excluded. The patients were subjected to detailed history, physical examination and routine otolaryngology examination. Patients were subjected to tuning fork test, tympanometry to exclude any middle ear pathology and pure tone audiometry.
These patients were divided into 3 groups depending on ototoxic aminoglycoside used.
Group 1 patients received Amikacin (dose according to weight band)
Group 2 patients received Kanamycin (dose according to weight band)
Group 3 patients received Capreomycin (dose according to weight band)
All the patients who have just started second line ATT treatment already on the treatment were subjected to baseline Pure Tone Audiometry. Patients who have clinically or audio metrically hearing loss were excluded from the study. The patients were followed up every 3 month and 6 month after stopping the treatment. Patients were also asked to follow up whenever they present with any symptomology related to the toxicity of the treatment [4, 5]. The results obtained were studied with regards to the different factors like duration of treatment, drug dosage, type of drug used in the treatment.
The criteria used for determining ototoxic threshold shift from baseline audiogram were (CAPS ASHA CRITERIA)
10 decibel or greater decrease of any two adjescent frequencies
20 decibel of greater decrease of any one test frequency
Loss of response at 3 consecutive frequencies where responses were previously obtained
Hearing losses observed were notify to the TB hospital Indore
Results
In this study all the patients were age group of 18–50 year with male constituting 58.33% and female constituting 41.6% (n = 60).(Figure 1). Most of the patients were from rural background (61.66%) while 38.33% were from urban areas
Of the 60 patients studied, 31 patients were on injection kanamycin (51.66%), 19 patients were on Amikacin(31.66%) and 10 patients on capreomycin (16.66%). (Figure 2).
The most common age group in which hearing loss was commonly seen was 46-55 years (66%) 2nd being 36–45 years (38%), 3rd common being 26–35 years (27%) (Fig. 3).
Overall incidence of High frequency loss (HFL) was 28.33%, whereas incidence of FLAT loss where lower hearing frequency was also involve was 10% in this study
35.48% of Group 1 (kanamycin) patients show High frequency hearing loss and 16% of patient have both high and low frequency hearing loss High frequency hearing loss
21% of Group 2 (amikacin) patients show High frequency hearing loss and 5% of patient have both high and low frequency hearing loss
20% of Group 3 (capreomycin) patients show High frequency hearing loss with no patient resulted low frequency loss (Fig. 4).
Most of the patients who presented with hearing loss were of the range of moderately to severe sensorineural hearing loss 56–70 decibel (10%), send common being in the range of profound hearing loss > 90 decibel (8.3%), in this study most commonly drug used is Kanamycin in 51.6% of the patient, Amikacin in 31.6% and capreomycin in 20% of the patient.
The most common symptomatology with which the patient presented was tinnitus (25%) followed by hearing loss (11.66%), vertigo (8.33%), unsteadiness (3.33%)
The hearing loss was statistically related to a large cumulative dose (P = 0.02) and a higher age (P = 0.03), though the duration of the treatment was statistically insignificant with the degree of hearing loss (Figure 5).
(Tables 1, 2, 3) the above table implies that table the hearing loss was statistically related to large cumulative dose and a higher age, though the duration of treatment was statistically insignificant
Fig. 1.
Classification of cases on the basis of their sex
Fig. 2.
Distribution of injection anti TB drug in study
Fig. 3.
Classification of cases on the basis of age and hearing loss type
Fig. 4.
Distribution of patients with hearing loss in relation to the drugs used
Fig. 5.
Distribution of patients with hearing loss in relation to the drugs used
Table 1.
Kanamycin distribution of drug, dose, and duration schedule with hearing loss
| Age (in years) | No. of patients with the dose (as per weight band) | Men duration (Days) | Mean hearing loss (dB) | |
|---|---|---|---|---|
| < 25 | 1 | 0 | 180 | 41 |
| 26–35 | 4 | 0 | 202 | 64.5 |
| 36–45 | 0 | 2 | 187.5 | 85 |
| > 46 | 3 | 1 | 187.5 | 89.25 |
Table 2.
Amikacin distribution of drug, dose, and duration schedule with hearing loss
| Age (in years) | No. of patients with the dose (as per weight band) | Men duration (Days) | Mean hearing loss (dB) |
|---|---|---|---|
| < 25 | – | – | – |
| 26–35 | – | – | – |
| 36–45 | 2 | 162.5 | 61.5 |
| > 46 | 2 | 185 | 85 |
Table 3.
Capreomycin distribution of drug, dose, and duration schedule with hearing loss
| Age (in years) | No. of patients with the dose (as per weight band) | Men duration (Days) | Mean hearing loss (dB) | |
|---|---|---|---|---|
| < 25 | – | – | – | – |
| 26–35 | – | 1 | 180 | 65 |
| 36–45 | 1 | – | 180 | 70 |
| > 46 | – | – | – | – |
Discussion
Emergence of resistance to drugs uses to treat tuberculosis and particularly multidrug resistant (MDR-TB) has become an obstacle to effective global TB control. to other major issues of importance which affect the outcome in MDR-TB compared to drug susceptible disease are the increased cost (up to 100 times higher) and higher toxicity
In this study, all the patients were in the age group of 18–50 years with male In this study all the patients were age group of 18–50 year with male constituting 58.33% and female constituting 41.6% (n = 60). Most of the patients were from rural background (61.66%) while 38.33% were from urban areas. The most common age group in which hearing loss was commonly seen was 46-55 years (66%) 2nd being 36–45 years (38%), 3rd common being 26–35 years (27%)
Vishal sharma [6] in 2016, in his study on 100 patients using Kanamycin of age group 15–16 years found that maximum toxicity was seen in the age group of 36–45 years.
Overall incidence of High frequency loss (HFL) was 28.33% whereas incidence of FLAT loss where lower frequency also involved was 10% in this study.
Most patients who presented with hearing loss were of range moderately—severe sensory neural hearing loss of 56–7-dB (10%), second common being in the range of profound hearing loss > 90 dB (8.3%). Ashish kumar [7], in 2015 found ototoxicity in 35% (more of mild to moderate SNHL) of the total patients using kanamycin over a period of 6 months.
In the group of patients who were on Kanamycin (n = 31), 11 patients (35.48%) showed sensorineural hearing loss (SNHL) involving th higher frequencies (HFL). Kanamycin was stopped on the first report of hearing loss and patient shifted to another second line drug. Follow up PTA showed no deterioration after drug is stopped. Development of SNHL involving lower frequencies FLAT was seen in 5 patients (16.1%)
Vishal sharma [6] in 2016, in his study on 100 patients using Kanamycin found ototoxicity in 18%of the subjects. HFL was present in 25 at first week, 12% at 6 weeks and 4% has FLAT type hearing loss at week 6. The mean duration of use of Kanamycin was 181.38 days, the mean dose being 580.645 mg. the duration was lesser in those whom the drug was stopped due to first report of hearing loss [7].
In the group of patients who were on Amikacin (n = 19), 4 patients (21%) developed SNHL involving higher frequencies (HFL). Amikacin was discontinued on first report of SNHL and shifted to another drug.
Development of SNHL involving the lower frequencies (FLAT) was seen in 1 patient (5.2%). Mean duration of Amikacin was 174.26 days, the mean dose being 500 mg. except in those whom the drug was stopped due to hearing loss.
In patients who were on Capreomycin (n = 10), 2 patient developed SNHL involving higher frequencies (HFL). Capreomycin was discontinued on first report of SNHL and shifted to another drug.
Mean duration of Capreomycin was 182.2 days, the mean dose being 600 mg. except in those whom the drug was stopped due to hearing loss.
The study showed that ototoxicity was associated with a large cumulative dose and older age. None of the patients in any group had any recovery in pure tone thresholds after stopping the injectable treatment. Peloquin et al. [8] in 2004, who looked at the incidence of toxicities associated with two recommended design regimen (daily vs. three times per week of intravenous streptomycin, kanamycin, amikacin) in TB patients; the magnitude of the dose and frequency of administration were not associated with ototoxicity; Ototoxicity was associated with a larger cumulative dose and older age [9, 10, 11].
Duggal [12], in 2007, found ototoxicity in 18.75% of the 64 subjects studied. None of the patients had any recovery in pure tone thresholds after stopping the treatment.
The finding that higher frequencies are involved before the lower frequencies may be used as a monitoring procedure for the detection of ototoxicity and has the potential for the detection of ototoxicity and has the potential for minimizing irreversible loss may have been reduced because the aminoglycoside was stopped immediately at the onset of ototoxicity and substituted with another second line drug. The entire group of patient included in the study completed the remaining part of the therapy.
Conclusion
A large number of Patients being treated for MDR-TB develop significant adverse effects that can impair their quality of life. The effect on development of children is profound. Careful audiological monitoring may help in limiting the damage which once developed is permanent.
Clinicians must consider risk benefit analysis during treatment as ototoxicity of injectable aminoacid ATT is permanent. This study throws light on the incidence of hearing loss among patients on second line injectable anti tubercular drugs, early detection of hearing loss through pure tone audiometry helps preventing and progression of hearing loss without compromising the treatment.
So PTA should be done on all MDR and XDR TB patients before starting the second line ATT aand should be shifted to another treatment schedule if hesrimng;oss is found in PTA.
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