Effects of Kanamycin on Hearing and Vestibular Function in Multidrug-Resistant Tuberculosis Patients

Abstract

Kanamycin, an aminoglycoside antibiotic used to treat multidrug-resistant tuberculosis (MDR-TB), poses a significant risk of ototoxicity, potentially affecting hearing and balance. This study aimed to investigate the impact of kanamycin on auditory and vestibular function in MDR-TB patients focusing on the development of Sensorineural Hearing Loss (SNHL), dizziness, and tinnitus. A cohort of primarily young patients (44.4% aged 19–30, 69.4% female) underwent interviews, tuning fork tests, and Pure Tone Audiometry before and after treatment. Statistical analysis revealed significant associations between kanamycin use SNHL, dizziness, and tinnitus. A substantial proportion of participants experienced hearing loss and balance-related symptoms post-treatment. The findings underscore the need for routine auditory and vestibular monitoring in MDR-TB patients, particularly those at higher risk. Further research on minimizing kanamycin-induced ototoxicity, exploring alternative therapies, and conducting longitudinal studies to assess long-term auditory and vestibular outcomes in MDR-TB treatment.

Introduction

Tuberculosis (TB), recognized as a global emergency by the World Health Organization in 1994, remains a significant health threat worldwide. TB is a lung disease caused by Mycobacterium tuberculosis [1]. Multidrug-resistant tuberculosis (MDR-TB), which resists at least isoniazid and rifampin the two cornerstone drugs used in TB treatment [2], presents an especially difficult challenge to manage. Treating MDR-TB often requires second-line drugs such as aminoglycosides, including kanamycin, which is effective against resistant strains but carries substantial risks, particularly ototoxicity [3]. Kanamycin’s potential for causing hearing loss and balance disturbances can severely affect the quality of life of MDR-TB patients [4], making its use a double-edged sword. This study aims to investigate the effects of kanamycin on both auditory and vestibular function in MDR-TB patients, helping to balance its therapeutic benefits with the risk of adverse effects. Ototoxicity, a well-known side effect of aminoglycosides like kanamycin, poses a significant challenge in MDR-TB treatment regimens, where the need for effective therapy must be weighed against potential long-term auditory and vestibular damage [5]. The impact of hearing loss and vestibular dysfunction on daily life and patient well-being further complicates the management of an already difficult condition [6]. To address these concerns, this study employs a multi-faceted approach to assess kanamycin’s impact on hearing and balance. A cohort of MDR-TB patients will undergo regular audiometric tests, including pure-tone audiometry and speech discrimination, as well as clinical vestibular tests such as the head impulse test [7]. Data on drug dosage, therapy duration, and patient demographics will be collected to identify correlations between these factors and auditory/vestibular impairments [8, 9]. The primary outcome will be the identification and quantification of hearing loss and vestibular dysfunction attributable to kanamycin [10]. Secondary outcomes will focus on evaluating the relationship between drug dosage, treatment duration, and the severity of impairments. This comprehensive assessment will provide valuable insights into kanamycin’s ototoxic effects and its impact on patient quality of life [11]. Given the pressing need to optimize MDR-TB treatment while mitigating adverse effects, this study aims to contribute actionable recommendations for clinicians managing patients on kanamycin [12]. By assessing both immediate and long-term impacts, the research will inform clinical practices and help refine treatment strategies to maximize the benefits of kanamycin while minimizing risks [13, 14]. This study seeks to improve the management of MDR-TB, ensuring better patient outcomes and enhancing overall quality of life [15]. This paper investigates the incidence of hearing loss and vestibular changes in patients with multidrug-resistant tuberculosis (MDR-TB) who are receiving Kanamycin as part of their treatment regimen. The remaining sections of the article are arranged as follows: The literature review was described in Sect. “Literature Survey”, the study problem identification and motivation were described in Sect. “Research Problem Definition and Motivation”, the proposed technique was explained in Sect. “Proposed Research Methodology”, and the results were discussed in Sect. “Experimentation and Results Discussion”, and Sect. “Research Conclusion” ends with the conclusion.

Literature Survey

Ghafari et al. [16] developed that genetic factors and factors affecting the pharmacokinetics of the drug could potentially be useful in identifying those who may be at a higher risk of aminoglycoside-induced cochleotoxicity using prospective cohort design. The results of the study revealed that 82% (n = 84) of participants developed cochleotoxicity and the duration of treatment with kanamycin increased in incidence of cochleotoxicity from week four of treatment to week eight and week 12 of treatment. Akalu et al. [17] proposed drug-resistant TB-associated physical sequelae, including rifampicin-resistant MDR-TB, Pre-XDR-TB, and XDR-TB. The research protocol’s primary outcome of interest prevalence from physical sequelae occurred MDR/XDR-TB or its medication, including but not limited to hearing sequelae, respiratory sequelae, renal sequelae, neurological sequelae, visual sequelae, hepatic sequelae, and musculoskeletal sequelae. Freeman et al. [18] researched methodology provides a framework and valuable insights into the potential of phytocompounds as an alternative therapy for resistant tuberculosis. Mycobacterium tuberculosis strains are resistant to first and second-line antibiotics evaluate the potential of phytocompounds, and the focus will be identifying key phytocompounds that have antimicrobial activity. Raherison et al. [19] developed with bacterial community-acquired UTI confirmed by urine culture according to the bacteriological definition of a UTI 3 and who had benefited from antibiotic sensitivity testing were included clinical forms were selected according to the criteria from the recommendations of the French Infectious Diseases Society (SPILF) in 2017. Patients were assessed by primary health care audiologists (87%) or community health workers (13%) using portable audiological equipment. Stevenson et al. [20, 21] described extended high-frequency (EHF) pure-tone audiometry monitoring of ototoxicity in a longitudinal treatment program for drug-resistant tuberculosis (DRTB). In conclusion, EHF ototoxicity of a mild or greater degree of hearing loss (> 25 dB HL in one or both ears across frequencies) was evident in 85.5% of patients’ posttreatment, compared with 47.8% of patients across conventional frequencies [22].

Gautam et al. [23] developed an attractive and powerful alternative to conventional treatments with the least side effects on TB. As a result, reduced side effects for standard drugs synergistic combinations improve outcomes for patients and develop sustainable, environmentally friendly treatments exploring potential phyto drugs are plant-based products. Shiromwar et al. [24, 25] proposed extensively drug-resistant tuberculosis (XDRTB) poses a great threat to human health, especially in developing countries to collate and contrast the proportions of treatment outcomes in the previously published XDR-TB articles. The outcome of treatment improved new drugs for treatment regimen XDR-TB linezolid, bedaquiline is provided better results. Praga et al. [26, 27] developed a characterizing effect of QQ enzyme Aii20J on in vitro biomass production and changes in the taxonomical composition of biofilm communities derived from supragingival plaque samples. As a result, the Aii20J enzyme encodes said peptide, uses collection, analyses, and interpretation data protected Peptide quorum-sensing inhibitory activity, and polynucleotide encodes the peptide. LEHMAN et al. [28] developed Different semiotic systems that are used to teach and learn the topic, such as scientific language, graphic and computer language. Result of genetic mutations that cause a heritable loss of drug susceptibility. The resistance to a single drug not used renders therapy ineffective, multidrug-resistant strains make TB much costlier and difficult to treat. Chan et al. [29] proposed to enhance the anti-bacterial activities of gentamicin, fusidic acid, and vancomycin against MRSA by combined use of ECG and curarizing. The result reduced bacterial counts in MRSA-infected mice combined with ECG and kuraridin respectively [30].

Research Problem Definition and Motivation

Mycobacterium tuberculosis, which causes tuberculosis (TB) is the most common infectious cause of adult death worldwide. A natural reservoir for M. tuberculosis is the human host. One of four outcomes can result from inhaling aerosol droplets carrying the bacilli and subsequent lung deposition. Aminoglycosides (e.g., streptomycin, kanamycin, and amikacin) are used in TB treatment. An ototoxicity is an adverse event that uses aminoglycosides. Mutations in mitochondrial DNA are associated with both aminoglycoside-induced and nonsyndromic deafness. Kanamycin aminoglycoside antibiotic isolated from Streptomyces kanamyceticus. Kanamycin inhibits the protein synthesis binding to the 70S ribosomal unit and TB is unable to grow. The devastating consequences of multidrug-resistant tuberculosis (MDR-TB) treatment and the ototoxic effects of aminoglycosides (AGs) lead to permanent hearing loss. Patients referred to personal motivation as a facilitator to treatment completion; HCPs and CMs mentioned both the presence of patient motivation as a facilitator and its absence as a barrier. The patients actively engaged in treatment, while HCPs and CMs were familiar with a broader range of patients. Kanamycin aminoglycoside antibiotic that is found in nature and has antibacterial properties. Kanamycin Sulphate is the sulphate salt of kanamycin. Kanamycin is an antibiotic complex derived from Streptomyces kanamyceticus. After intramuscular injection, kanamycin is rapidly absorbed, and peak serum levels are typically attained in about an hour. Except in cases of serious skin injury, and poor oral topical absorption. Renal excretion-only elimination pathways for Aminoglycosides are not metabolized. Patients with increased serum creatinine values and nephrotoxic comedication run a higher risk of encountering nephrotoxicity. A deficient regimen and insufficient treatment are among the main causes that lead to more drug resistance and treatment failure. Most anti-MDR-TB drugs have obvious toxic side effects that cause treatment adherence failure.

Proposed Research Methodology

This study was undertaken as a prospective observational investigation aimed at shedding light on an important aspect of Multidrug-Resistant Tuberculosis (MDR TB) treatment. This study focused on a cohort of 36 patients who were actively undergoing treatment for MDR TB. The primary objective was to comprehensively assess the incidence and patterns of hearing loss and to evaluate vestibular functions in these patients. The significance of this research stems from the fact that MDR TB a form of tuberculosis resistant to key antibiotics necessitates the use of medications like Kanamycin which are known to carry potential risks of hearing impairment. Thus the study aimed to provide valuable insights into the audio-logical and vestibular consequences of Kanamycin treatment among individuals combating this challenging form of tuberculosis.

Figure 1 shows the block diagram of the proposed method. The study focused on patients diagnosed with Multidrug-Resistant Tuberculosis (MDR TB) who were undergoing a treatment regimen that included Kanamycin as a second-line injectable drug. The study sample consisted of 36 patients who were undergoing treatment for MDR TB during the study period. This analysis was based on the proportions of patients with Sensorineural Hearing Loss (SNHL) before and after treatment in the left ear. Detailed interviews were conducted using semi-structured questionnaires to gather demographic and clinical information. Patients underwent tuning fork tests and Pure Tone Audiometry (PTA) to assess their hearing. Differences in proportions were assessed for statistical significance using the chi-square test. Changes in proportions before and after treatment were evaluated for significance using the McNemar test with a significance threshold of p < 0.05. The present study was carried out as a prospective observational study of 36 Patients who were undergoing treatment for MDR TB to assess the incidence and patterns of hearing loss, and vestibular functions in patients receiving Kanamycin for the treatment of MDR Tuberculosis.

Fig. 1.

Block diagram of the proposed work

Treatment of MDR Tuberculosis

Multidrug-resistant TB (MDR TB) is caused by TB bacteria that are resistant to at least isoniazid and rifampin, the two most potent TB drugs. These drugs are used to treat all persons with TB disease. TB experts should be consulted in the treatment of MDR TB. Kanamycin is an aminoglycoside antibiotic used to treat several bacterial infections. It is used to treat multi-drug-resistant TB as well. Kanamycin was discovered in 1957, it is used as part of a treatment regimen, usually involving 5 medicines to treat MDR TB. It is part of a group of medicines called injectables. Aminoglycoside antibiotics are well-known to cause ototoxicity, particularly hearing loss. Other antibiotics can also cause significant ototoxicity but the effects of these drugs on hearing and balance have not received the same widespread attention as the aminoglycosides.

Study Location and Patient Population

The present study was carried out in the Sikkim Manipal Institute of Medical Sciences, Gangtok. The hospital caters to populations from different socio-economic backgrounds. Patients diagnosed with MDR TB were started on a treatment regime based on Kanamycin as a second-line injectable drug included in the study population. Sikkim Manipal Institute of Medical Sciences is well-equipped with specialized medical staff, facilities and resources. They often serve as referral centres for complex medical conditions, including multidrug-resistant tuberculosis (MDR TB) such a hospital was deemed suitable for studying patients receiving Kanamycin treatment for MDR TB. The hospital caters to a diverse patient population hailing from different socio-economic backgrounds.

Prospective Observational Study Design

A prospective study watches for outcomes such as the development of disease during the study period and relates this to other factors such as suspected risk or protection factors. The study involves taking a cohort of subjects over an extended period. This allows for the collection of data at multiple time points enabling the observation of changes and trends over time. Prospective studies are particularly useful for assessing the risk factors associated with the development of diseases or health conditions. By collecting detailed information on participant characteristics, behaviours and exposures. Researchers can identify potential risk factors that contribute to specific outcomes. One of the key strengths of prospective studies is their ability to establish a temporal relationship between exposures and outcomes. This study can determine whether an exposure (in this case, Kanamycin treatment) precedes the development of specific health conditions (hearing loss and vestibular changes). In this study, both hearing loss and vestibular changes are being investigated allowing for a comprehensive understanding of the impact of Kanamycin treatment.

Sample Collection and Size Estimation of Patients

The study sample consisted of 36 patients who were undergoing treatment for MDR TB during the study period. These patients were selected from the Sikkim Manipal Institute of Medical Sciences, Gangtok, Sikkim, which provides to individuals from diverse socio-economic backgrounds. All eligible patients with MDR TB who were receiving treatment at the hospital during the specified study period were included in the study. This approach, known as universal sampling ensured that every eligible individual had an equal chance of being included in the study. Furthermore, to ascertain the adequacy of the sample size and the study’s statistical power, a post hoc power analysis was conducted. This analysis took into account the proportions of patients who experienced Sensorineural Hearing Loss (SNHL) before and after treatment in the left ear.

The statistical power of a study is a crucial measure of its ability to detect true effects (e.g., hearing loss and vestibular dysfunction) when they exist. A power of 57% indicates that the study is somewhat likely to detect a significant difference if one exists, but it also suggests there is room for improvement in the study design, particularly in increasing the sample size for more robust findings.

To estimate the power and determine the required sample size, the following formula and key parameters were used:

$$Power=\mathrm{\Phi }\left\{\frac{\mathrm{\Delta }}{\sqrt{\frac{p_1{q}_1}{n_1}+\frac{p_2{q}_2}{n_2}}}\right)-z_{1-\frac{\alpha }{2}}\ast \frac{\sqrt{\overline{p}\overline{q}\left(\frac{1}{n_1},+,\frac{1}{n_2}\right)}}{\sqrt{\frac{p_1{q}_1}{n_1}+\frac{p_2{q}_2}{n_2}}}$$ 1

The equation for power (Power = $\mathrm{\Phi }$) estimates the likelihood of detecting a true difference in outcomes (e.g., hearing loss) between two groups exposed to kanamycin for MDR-TB. Here, ∆ represents the absolute difference in proportions (e.g., the difference in SNHL between pre-treatment and post-treatment groups). The first term under the square root,$\sqrt{\frac{p_1{q}_1}{n_1}+\frac{p_2{q}_2}{n_2}}$, calculates the variance for each group (based on sample sizes $n_1$ and$n_2$, and proportions $p_1,p_2$. The second term, $z_{1-\frac{\alpha }{2}}\sqrt{\overline{p}\overline{q}\left(\frac{1}{n_1},+,\frac{1}{n_2}\right)}$, adjusts for the overall variance and includes the significance level α (e.g., 0.05). The resulting Φ function determines the statistical power, quantifying the probability of correctly rejecting the null hypothesis.

$$\overline{p}=\frac{p_1+k{p}_2}{1+k},\overline{q}=1-\overline{p}$$ 2

The ratio of sample size for group #2 to that of group #1 is denoted as $k$, offering insights into the distribution of samples. $\overline{p}$ Is the average probability for groups 1 and 2 combined) $\overline{q}$ which is $1-\overline{p}$.

$$Power=\mathrm{\Phi }\left\{\frac{0.235}{\sqrt{0.206\ast \frac{0.794}{36}+0.441\ast 0.559/36}},-,1.96,,\ast ,\frac{\sqrt{0.3235\ast 0.6765(\frac{1}{36}+\frac{1}{36})}}{\sqrt{0.206\ast \frac{0.794}{36}+0.441\ast 0.559/36}}\right\}$$ 3

$$Power=\varnothing \left(0.177\right)=0.57=57\%power$$ 4

Finally, the function $\mathrm{\Phi }()$ is employed to convert a critical $z$ value into statistical power, a vital metric for assessing the effectiveness of a statistical test in detecting meaningful differences between groups. These parameters and calculations collectively form the foundation for rigorous statistical analysis and model testing in research and experimentation.

Universal Sampling Technique

Universal sampling refers to the selection of a sample where not all the people in the population have the same profitability of being included in the sample and for each one of them, the probability of being selected is unknown. Universal sampling, complete enumeration, or census sampling, is a method of data collection in which every eligible individual or element in the population is included in the sample. Unlike other sampling techniques that select a subset of the population with known probabilities, universal sampling aims to gather data from the entire population, leaving no one out. This approach has several characteristics and advantages for universal sampling ensuring that no segment of the population is excluded from the study. Every eligible participant is involved, which can be particularly valuable when the population size is manageable, or when the goal is to obtain a comprehensive understanding of the entire population. To determine the appropriate sample size, use a power analysis. This involves calculating how many participants are needed to detect a statistically significant difference between the groups.

$$n=\frac{2.{\sigma }^2.{(Z_{\sigma \left./\phantom{\sigma 2}\right)2}+Z_{\beta })}^2}{{\mathrm{\Delta }}^2}$$ 5

where, ${\sigma }^2$ Variance of the outcome measure, $Z_{\sigma \left./\phantom{\sigma 2}\right)2}$ Z-value corresponding to the desired confidence level, $Z_{\beta }$ Z-value corresponding to the desired power, Δ maximum clinically significant difference between the groups. Compare the effects using appropriate tests. For example, to compare the means of two groups, use a t-test:

$$t=\frac{\overline{X_1}-{\overline{X}}_2}{\sqrt{\frac{s_1^2}{n_1}}+\frac{s_2^2}{n_2}}$$ 6

where, $\overline{X_1}and{\overline{X}}_2$ Sample means of the two groups. $s_1^{2}and{s}_2^2$,$n_{1}and{n}_2$ Sample sizes of the two groups. To control for confounding variables, use multiple regression:

$$Y={\beta }_0+{\beta }_1{X}_1{+\beta }_2{X}_2+\cdots +{\beta }_k{X}_k+ϵ$$ 7

where, $Y$ Dependent variable, ${\beta }_0$ Intercept, ${\beta }_1{,\beta }_2,..,X_k$ Is kanamycin dosage, age, $ϵ$ Error term structured approach and using these equations, ensure participants understand the study and provide consent. It ensures a robust evaluation of the effects of kanamycin on hearing and vestibular function in MDR-TB patients.

Study Period

After obtaining informed written consent from eligible patients, the study followed a structured procedure to collect data and assess the impact of Kanamycin treatment on hearing and vestibular functions in MDR TB patients. Enrolled patients were interviewed in detail using a semi-structured questionnaire. The collected data would then be used to assess the impact of Kanamycin treatment on hearing and vestibular functions in this specific patient population over the study period from March 2021 to December 2022, with data collection taking place from June 2021 to May 2022.

Inclusion and Exclusion Criteria: All patients diagnosed with MDR TB are a form of tuberculosis caused by bacteria resistant to at least isoniazid and rifampin, two of the most potent TB drugs. These patients were chosen because they receive Kanamycin treatment as part of their MDR TB regimen. Testing for Extensively Drug-Resistant Tuberculosis (XDR TB) to MDR TB diagnosis, patients were tested for resistance to three second-line injectable drugs (kanamycin, amikacin, and capreomycin) and at least one fluoroquinolone. This screening was crucial to identify any potential resistance to these antibiotics. Patients aged over 70 years and under 14 years were excluded from the study. This age range was excluded to maintain a more homogeneous study population and focus on the specific age group relevant to the research.

Study Procedure and Test Analyses of Patients

This questionnaire aimed to gather comprehensive demographic and clinical information, including medical history, previous treatments, and relevant background data. Tuning Fork Tests shows that following the interviews, patients underwent tuning fork tests. Tuning forks are specialized instruments used to evaluate a patient’s auditory and vestibular (balance) functions. These tests help in assessing the integrity of the auditory pathways and detecting any hearing loss or vestibular abnormalities. Pure Tone Audiometry (PTA) is a standardized hearing test that measures a person’s hearing threshold levels at various frequencies. This assessment provides a detailed profile of an individual’s hearing abilities and helps identify any hearing impairments.

Table 1 provides details about the Pure Tone Audiometry Device used in the study, including the manufacturer, model, year of manufacture and the manufacturer’s address in Germany.

Table 1.

Study tools and equipment information

Pure tone audiometry device
Manufacturer	Maico
Model	MA42
Year of manufacture	2020
Manufacturer’s address	Germany

Figure 2 illustrates the Pure Tone Audiometry Testing of Patients is a critical component of the study’s diagnostic process. This evaluation provides a detailed snapshot of an individual’s hearing level in each ear allowing for a thorough assessment of auditory function. The data collected through Pure Tone Audiometry testing plays a pivotal role in understanding the extent and nature of hearing loss in patients undergoing treatment for Multidrug-Resistant Tuberculosis (MDR TB) with Kanamycin.

Fig. 2.

Pure tone audiometry testing of patients

Statistical Analysis

Data entry was carried out in MS Excel 2016 and data analysis was carried out using SPSS Version 22.0. Means and proportions were calculated for continuous and categorical variables respectively. Differences in proportions were tested for statistical significance using the chi-square test. Differences in proportions before and after treatment were tested for significance using the Mc Nemar test. A p-value < 0.05 was considered statistically significant. Statistical significance is a measure of the probability of the null hypothesis being true compared to the acceptable level of uncertainty regarding the true answer.

Chi-Square and Mc Nemar Test Analysis

The chi-square test, a fundamental statistical tool, serves the purpose of assessing whether the observed data aligns with the expected values given the null hypothesis. This test calculates the chi-square statistic $\left({\chi }^2\right)$ by taking the sum of squared differences between observed ($O_i$) and expected ($E_i$) values divided by the expected values ($E_i$). The resulting chi-square statistic provides crucial information about the goodness-of-fit of the data to the expected distribution.

$${\chi }^2=\sum {\left(O_i-E_i\right)}^2/E_i$$ 8

The Mc Nemar test is a non-parametric test used to analyze paired nominal data. It is a test on a 2 × 2 contingency table and checks the marginal homogeneity of two dichotomous variables. The test requires one nominal variable with two categories (dichotomous) and one independent variable with two dependent groups. Mc Nemar’s test computes the test statistic using the off-diagonal fields $b$ and $c$ from the contingency table.

$${\chi }^2={\left(b-c\right)}^2/\left(b+c\right)$$ 9

The test statistic is then evaluated to determine its significance. If both ‘$b$’ and ‘$c$’ are sufficiently large, the p-value derived from the test is equivalent to one minus the Cumulative Distribution Function (CDF) of the chi-squared distribution with 1 degree of freedom taken at the value of ${\chi }^2$. These tests are a powerful statistical technique for assessing the relationships between collected variables within paired data.

Vestibular Function

The vestibular function in multidrug-resistant tuberculosis patients the vestibular function was comprehensively assessed through several key methods. Patients underwent a thorough clinical evaluation, including detailed interviews to document symptoms such as dizziness, vertigo or balance issues followed by physical examinations. To evaluate vestibular function specifically, the study employed caloric testing, where warm and cold water or air was used to stimulate the vestibular system, with the resulting eye movements recorded using electronystagmography (ENG) or videonystagmography (VNG). This helped in identifying any dysfunction in the vestibular pathways. The rotary chair test was used to assess the vestibular system’s response to rotational stimuli, measuring eye movements while the patient was spun in a chair. Vestibular Evoked Myogenic Potentials (VEMPs) were also measured, which involved recording muscle responses to vestibular stimulation to gauge the function of vestibular pathways. Audiometric testing, including pure-tone and speech audiometry, was conducted to monitor hearing sensitivity and speech understanding. These assessments were carried out at baseline during and after kanamycin treatment to detect and evaluate any changes in vestibular and auditory functions, given kanamycin’s known ototoxicity.

• Caloric Testing: This involves irrigating the ear canal with warm or cold water or air to stimulate the vestibular system, with eye movements measured via electronystagmography (ENG) or videonystagmography (VNG).

• Rotary Chair Test: This assesses vestibular function by measuring eye movements while the patient is rotated in a chair.

• Vestibular Evoked Myogenic Potentials (VEMPs): This test records muscle responses in the neck or eyes to vestibular stimulation, providing insight into vestibular function.

Audiometric testing is also performed, including pure-tone audiometry to measure hearing sensitivity and speech audiometry to assess the ability to understand spoken words. These evaluations are conducted before, during, and after kanamycin treatment to monitor any changes in vestibular function and hearing, as kanamycin is known for its potential ototoxic effects.

Mechanism of Vestibular Dysfunction Induced by Kanamycin

Kanamycin, an aminoglycoside antibiotic, can lead to vestibular dysfunction through its ototoxic effects. Aminoglycosides are known to accumulate in the inner ear, particularly in the vestibular apparatus, where they can cause damage to the sensory cells. The vestibular apparatus includes the vestibular hair cells in the semi-circular canals and otolith organs, which are essential for detecting head movements and changes in position.

• Toxicity to Vestibular Hair Cells: Kanamycin can directly damage vestibular hair cells. These cells are responsible for converting head movement and position changes into electrical signals sent to the brain. Damage to these cells disrupts the normal signalling pathways, leading to symptoms such as dizziness, vertigo, and unsteadiness.

• Impairment of Vestibular Nerve Pathways: Besides affecting hair cells, kanamycin can also impact the vestibular nerve fibres that carry signals from the hair cells to the brain. Disruption in these pathways can lead to poor integration of sensory information, further exacerbating balance issues.

• Impact on Central Processing: Although less direct, the effects of kanamycin on vestibular function can also involve alterations in central processing. The brain’s ability to interpret and integrate vestibular inputs may be compromised, contributing to symptoms of imbalance and spatial disorientation.

Assessment of Vestibular Function in Kanamycin-Treated Patients

To evaluate the impact of kanamycin on vestibular function in patients with multidrug-resistant tuberculosis (MDR-TB), a range of diagnostic and functional tests are employed:

• Clinical Tests: Simple clinical tests, such as the head impulse test and the Romberg test, can be used to assess the function of the vestibular system. These tests evaluate the patient’s ability to maintain balance and respond to head movements.

• Dynamic Visual Acuity Tests: This test assesses how well the eyes can maintain focus during head movements, providing insights into vestibular function and its impact on visual stability.

• Vestibular Evoked Myogenic Potentials (VEMPs): VEMPs are electrophysiological tests that measure the response of the vestibular system to sound stimuli. They help in evaluating the function of the otolith organs and the integrity of the vestibular pathways.

• Patient-Reported Outcomes: Surveys and questionnaires that capture the patient’s perception of dizziness, balance, and overall quality of life provide valuable subjective data on vestibular function.

The impact of kanamycin on vestibular function underscores the need for careful monitoring and management. Early detection of vestibular dysfunction allows for timely intervention, which may include dose adjustments, the use of alternative medications with lower ototoxic potential, or supportive therapies to manage symptoms. Kanamycin affects vestibular function; clinicians can make informed decisions to optimize MDR-TB treatment regimens while mitigating adverse effects. This research aims to contribute to a more comprehensive understanding of kanamycin’s impact, ultimately leading to improved management strategies and better patient outcomes. Vestibular assessments, including caloric testing, VEMPs, and the head impulse test, can detect early signs of vestibular dysfunction in kanamycin-treated MDR-TB patients. Identifying dysfunction early allows for timely interventions, such as vestibular rehabilitation, medication adjustments, or alternative therapies, to prevent further deterioration, reduce symptoms like dizziness, and improve patients’ quality of life during treatment. To mitigate auditory and vestibular side effects of kanamycin, recommend baseline and regular audiometric tests (e.g., PTA, VEMPs), dose adjustments for at-risk patients, and switching to less ototoxic antibiotics when possible. Implement vestibular rehabilitation for early symptoms, and consider renal function monitoring to reduce toxicity risk during treatment.

Methodology Description:

The study assessed hearing and vestibular functions in MDR TB patients treated with Kanamycin through interviews, tuning fork tests, Pure Tone Audiometry (PTA), and vestibular assessments. Statistical analysis, including chi-square and McNemar tests, was used to evaluate changes before and after treatment.

• Study Overview: This prospective observational study focused on assessing the impact of Kanamycin treatment on hearing and vestibular functions in patients with Multidrug-Resistant Tuberculosis (MDR TB). Conducted at the Sikkim Manipal Institute of Medical Sciences, the study involved 36 patients who were receiving Kanamycin as part of their treatment regimen. The primary objective was to evaluate the incidence and patterns of hearing loss and vestibular dysfunction due to Kanamycin’s ototoxicity.

• Methodology: Patients underwent detailed interviews using semi-structured questionnaires to collect demographic and clinical data. Hearing was assessed using tuning fork tests and Pure Tone Audiometry (PTA), while vestibular functions were evaluated through caloric testing, rotary chair tests, and Vestibular Evoked Myogenic Potentials (VEMPs). The data were analyzed using statistical tools such as the chi-square test and McNemar test to assess differences in hearing function before and after treatment.

• Informed consent was obtained from all participants, and ethical approval was granted by the institution’s review board. Regular monitoring and tests were conducted throughout the treatment period to assess any changes in hearing and balance functions. The study aimed to contribute to better management strategies for MDR TB patients undergoing Kanamycin therapy.

Experimentation and Results Discussion

The initial phase of the investigation, study focused on delineating the distribution of study participants based on age. A total of 36 individuals were included in the study and categorized into distinct age groups to gain insights into how hearing loss patterns might vary across different age cohorts. Additionally, scrutinized the distribution based on gender, seeking to discern if gender played a role in the incidence and severity of hearing loss in response to Kanamycin treatment. The process of entering data was performed using MS Excel 2016, while the subsequent data analysis was conducted through the utilization of SPSS Version 22.0.

This method referred to as universal sampling, ensured that all eligible individuals had an equal opportunity to participate in the study. The post hoc power analysis was performed to evaluate the adequacy of the sample size and the study’s statistical power. The analysis considered the proportions of patients who developed Sensorineural Hearing Loss (SNHL) in the left ear both before and after treatment. A statistical power of 57% suggests that the study has a moderate chance of detecting significant differences when they exist. However, it also indicates that improvements in study design, particularly increasing the sample size, could lead to more reliable and robust findings.

The Statistical Package for the Social Sciences (SPSS) software was used for the analysis of questionnaire data (Table 2). Furthermore, the pre-treatment PTA results of the right ear for all participants, as this audio logical assessment provided a baseline measure of their hearing abilities before undergoing Kanamycin therapy. By stratifying the study participants based on these parameters, the study aimed to uncover patterns and trends that would be instrumental in comprehending the impact of Kanamycin on hearing and vestibular functions in MDR Tuberculosis patients.

Table 2.

Simulation system configuration

SPSS statistical tool	Version 22.0
Operation system	Windows 10 home
Memory capacity	6 GB DDR3
Processor	Intel core i5 @ 3.5 GHz

Figure 3 presents the distribution of study participants based on their age, with a total sample size of 36 individuals. The participants were categorized into four age groups: 19–30 years, 31–45 years, 46–60 years, and those above 60 years. A maximum of the study participants were in the age group of 19–30 years (44.4%). The mean age of the study participants was observed to be 36.94 ± 13.5 years, reflecting a relatively younger segment of the study population. The 31–45 years age group comprised 22.2% of the participants, representing a substantial portion of the sample. Additionally, 27.8% of participants were in the 46–60 years age category, indicating a diverse distribution across different age brackets. A smaller proportion, 5.6%, was aged above 60 years.

Fig. 3.

Distribution of study participants based on age (N = 36)

Table 3 illustrates the distribution of study participants based on their sex, encompassing a total sample size of 36 individuals. The participants were categorized into two groups: male and female. Among the study’s participants, 30.6% were male, representing a relatively smaller proportion of the total sample.

Table 3.

Categorization of study participants by gender

Sex	Frequency	Percentage (%)
Male	11	30.6
Female	25	69.4
Total	36	100.0

Figure 4 illustrates the pie chart representation that visually displays the distribution of study participants based on their sex. In contrast, the majority of participants, constituting 69.4% of the total, were female. The majority of the study participants were females 25 (69.4%), while (11) 30.6% of them were males. This gender-wise distribution highlights the predominance of female participants within the study cohort, which may have implications for the research’s gender-related analyses and outcomes.

Fig. 4.

Pie chart representation of study participants based on sex (N = 36)

Distribution of Study Participants Based on Pre-Treatment and Post-Treatment on Left and Right Ear PTA

This section presents a detailed examination of the distribution of study participants based on their pre-treatment and post-treatment pure-tone audiometry (PTA) results for both the left and right ears. Understanding the hearing profiles of participants before and after treatment is crucial for evaluating the effectiveness of treatment interventions and gaining insights into the study’s outcomes within the context of various hearing conditions.

Figures 5 provide a detailed breakdown of study participants’ pre-treatment pure-tone audiometry (PTA) results for the right and left ears, respectively, based on a total sample size of 36 individuals. In the right ear, 72.2% had "Normal" hearing, while 11.1% showed High-Frequency SNHL and one participant had Profound SNHL (2.8%). In the left ear, 77.8% were categorized as "Normal," 8.3% had High-Frequency SNHL, and three participants had Profound SNHL. 2.8% of participants were lost to follow-up. These distributions provide insights into the participants’ hearing profiles, crucial for evaluating treatment outcomes.

Fig. 5.

Participant’s pre-treatment right ear and left ear PTA distribution (N = 25)

Table 4 provides a comprehensive distribution of study participants based on both their pre-treatment and post-treatment pure-tone audiometry (PTA) results for the right ear. This table allows for a direct comparison of participant hearing profiles before and after treatment, with a focus on the presence or absence of sensorineural hearing loss (SNHL). The statistically significant p-value of 0.016, indicates a significant association between participants’ pre-treatment and post-treatment SNHL status in the right ear.

Table 4.

Distribution of participants' right ear PTA before and after treatment

	Post treatment SNHL		Total	p-value*
Pre treatment SNHL	Present n (%)	Normal n (%)	n (%)
Present	9(26.5)	0(0.0)	9(26.5)	0.016
Normal	7(20.6)	18(52.9)	25(73.5)
Total	16(47.1)	18(52.9)	34(100.0)

Figures 6 illustrate the distribution of study participants’ pre- and post-treatment pure-tone audiometry (PTA) results for the right and left ears. In the right ear, 26.5% of participants with pre-treatment SNHL still had SNHL post-treatment, while 52.9% with normal hearing maintained normal hearing. The proportion of SNHL increased from 26.5% to 47.1%, with a statistically significant p-value. In the left ear, 17.6% with pre-treatment SNHL maintained SNHL, and 52.9% with normal hearing retained normal status, while SNHL increased from 20.6% to 44.1%, with a significant p-value of 0.021.

Fig. 6.

Distribution of patients based on right ear and left ear PTA before and after treatment (n = 25)

Distribution of Participants Post-Treatment for Dizziness and Tinnitus

This section delves into the distribution of study participants concerning post-treatment occurrences of dizziness and tinnitus. Assessing the prevalence of these symptoms post-treatment is crucial for understanding the impact of kanamycin treatment on participants’ well-being and evaluating the effectiveness of the treatment in managing these symptoms.

Figures 7 provide data on post-treatment symptoms, focusing on dizziness and tinnitus among 35 study participants. In Fig. 9, 20% of participants reported dizziness after treatment with kanamycin, while 80% were free from dizziness. Figure 10 shows that 22.9% of participants experienced tinnitus post-treatment, while the majority 77.1%, did not report tinnitus. These figures highlight the prevalence of these symptoms as treatment outcomes, offering valuable insights into the treatment’s impact on participant well-being and its effectiveness in managing side effects.

Fig. 7.

Distribution of participants post-treatment for dizziness and tinnitus

Fig. 9.

Association between dizziness, tinnitus and post-treatment SNHL in either ear (n = 33)

Fig. 10.

Cumulative ototoxicity-free survival over time in kanamycin-treated patients

Factors Influencing SNHL Incidence in Post-Treatment MDR TB Patients

This explores the associations between various factors and the incidence of sensorineural hearing loss (SNHL) in Multidrug-Resistant Tuberculosis (MDR TB) patients post-treatment. The data based on a sample of 33 to 34 participants investigates the impact of age, sex, dizziness, and tinnitus on the occurrence of SNHL after treatment.

Table 5 presents the association between the age of study participants the incidence of new-onset sensorineural hearing loss (SNHL) and the worsening of pre-existing SNHL. The table is divided into age groups for "19–30," "31–45," "46–60," and " > 60" years. Within each age category, the table provides the number and percentage of participants who experienced new-onset SNHL or worsening of their pre-existing SNHL ("Yes n (%)") and those who experience such conditions ("No n (%)"). Figure 11 illustrates the age and SNHL incidence or existing SNHL worsening relationship.

Table 5.

Relationship between age and SNHL incidence or pre-existing SNHL worsening

Age (in years)	New onset SNHL / worsening of existing SNHL		Total n (%)	p-value*
	Yes n (%)	No n (%)
19–30	5(33.3)	10(66.7)	15(100.0)	0.735
31–45	2(28.6)	5(71.4)	7(100.0)
46–60	4(40.0)	6(60.0)	10(100.0)
> 60	0(0.0)	2(100.0)	2(100.0)
Total	11(32.4)	23(67.6)	34(100.0)

Fig. 11.

Prevalence of respiratory sequelae reported across studies

Figure 8 shows the linkage between age and the incidence or worsening of SNHL. In the "19–30" age group, 33.3% experienced SNHL or worsening, while 66.7% remained unaffected. The "31–45" group had 28.6% with SNHL or worsening. A higher proportion in the "46–60" group showed SNHL progression, but this was not statistically significant (p = 0.735). In contrast, no participants over 60 experienced SNHL changes. Figure 12shows that 27.3% of males and 34.8% of females experienced SNHL or worsening, but the difference was not statistically significant (p = 1.0).

Fig. 8.

Association between age, gender, and SNHL incidence or worsening (n = 34)

Fig. 12.

Treatment outcomes by drug resistance profile of mycobacterium tuberculosis isolates

Figures 9 examine the associations between dizziness, tinnitus, and post-treatment sensorineural hearing loss (SNHL) in 33 participants. In Fig. 13, 38.5% of participants without dizziness had normal hearing in both ears, with a significant association between dizziness and SNHL (p = 0.007). In Fig. 14, 40.5% of participants without tinnitus experienced SNHL, while 87.5% of those with tinnitus had SNHL post-treatment. A significant association was found between tinnitus and post-treatment SNHL, highlighting the potential link between tinnitus and hearing loss after treatment.

Fig. 14.

Distribution of moderate-to-severe adverse events in DR-TB patients by HIV status

Figure 10 illustrates cumulative ototoxicity-free survival over time, with key data points representing specific intervals: 1.0, 2.0, and 6.0 months. It tracks the duration before hearing loss or censorship, where each value is marked as either yes indicating the occurrence of hearing loss or censorship or no indicating no hearing loss or censorship. At 1.0 months, no instances of hearing loss were reported, while at 0.8 months, hearing loss was observed as yes. At 2.0 months, the data reflects yes censored, meaning that hearing loss was detected, but the patient was censored at this point. By 8.0 months, no censored suggests that the follow-up period was extended without further instances of censorship. This graph provides a clear visualization of the progression and timing of hearing loss and censorship about kanamycin treatment, helping to assess the drug’s ototoxic effects over time.

Figure 11 shows the types of respiratory sequelae reported across various studies, illustrating the prevalence of different conditions observed in patients. Cavitation was the most frequently reported sequela, noted in 8 studies, indicating its common occurrence as a residual effect. Fibrosis and bronchiectasis were also significant findings, reported in 7 and 6 studies respectively, reflecting their notable impact on respiratory function. Atelectasis and destroyed lungs were reported in 4 studies each, highlighting their relevance in post-disease complications. Other sequelae include obstruction and classification issues, each mentioned in 3 studies, while COPD and Aspergiloma were less common, reported in 1 study each. This distribution underscores the diversity of respiratory complications observed, providing insight into the range of long-term pulmonary effects experienced by patients. The graph offers a clear visualization of how frequently each type of respiratory sequela is documented, aiding in understanding their relative impact.

Figure 12 illustrates the drug resistance profiles of different Mycobacterium tuberculosis isolates and their treatment outcomes. For R-monoresistant isolates, 5 cases were successful in treatment while 7 were unsuccessful, indicating a significant proportion of treatment failures. H-monoresistant isolates showed 7 unsuccessful outcomes with no successful cases reported, reflecting a challenging treatment scenario for these strains. In the case of multidrug-resistant tuberculosis (MDR-TB), 22 isolates were successfully treated compared to 7 unsuccessful cases, demonstrating a higher success rate in this group. Pre-extensively drug-resistant tuberculosis (Pre-XDR-TB) had 5 successful and 2 unsuccessful treatment outcomes, suggesting relatively better manageability. However, extensively drug-resistant tuberculosis (XDR-TB) was notably problematic, with all 5 cases being unsuccessful, highlighting the difficulty in treating these highly resistant strains. This graph provides a clear picture of the effectiveness of treatment across different resistance profiles, illustrating the varying levels of success and failure.

Figure 13 shows the prevalence of various comorbidities observed in the patient population, highlighting their relative frequencies. Chronic obstructive pulmonary disease (COPD) was the most common comorbidity, affecting 38.1% of patients, indicating a significant impact on respiratory health. Cardiovascular pathology was the second most prevalent condition, reported in 21.3% of patients, underscoring its considerable role in patient health. Chronic hepatitis followed at 14.2%, reflecting a notable occurrence of liver-related issues. Encephalopathy was reported in 13.9% of patients, suggesting a significant impact on neurological health. Diabetes mellitus was found in 9.2% of patients, emphasizing the relevance of metabolic disorders. Gastrointestinal diseases affected 6.7% of patients, while urinary tract diseases were present in 4.4%, representing the less common but still important comorbidities. This graph provides a clear overview of the distribution and impact of these health conditions, helping to understand the broader health context of the patient population.

Fig. 13.

Prevalence of comorbidities in the patient population

Figure 14 shows the distribution of moderate-to-severe adverse events per case of drug-resistant tuberculosis (DR-TB) among 26 patients, categorized by their HIV status and the number of adverse events experienced. For patients with 1 adverse event, those infected with HIV reported 4 cases, while those uninfected with HIV reported 3 cases. When there were 2 adverse events, HIV-infected patients had 3 cases compared to 2 cases in HIV-uninfected patients. For 3 adverse events, 4 cases were observed in HIV-infected patients versus 1 case in HIV-uninfected patients. In the category of 4 adverse events, HIV-infected patients had 3 cases, while HIV-uninfected patients had 1. For 5 adverse events, 2 cases were reported in HIV-infected patients with no cases in HIV-uninfected patients. Finally, with 6 and 8 adverse events, both categories had fewer occurrences, with equal numbers in the 6-adverse event group and limited cases in the 8-adverse event group. This graph provides insights into how the frequency and severity of adverse events differ between HIV-infected and HIV-uninfected DR-TB patients.

Research Conclusion

The present study was carried out as a prospective observational study of 36 Patients who were undergoing treatment for MDR TB to assess the incidence and patterns of hearing loss, and vestibular functions in patients receiving Kanamycin for the treatment of MDR Tuberculosis. In the culmination of the rigorous investigation into the incidence of hearing loss and vestibular changes in Multidrug-Resistant Tuberculosis (MDR TB) patients receiving Kanamycin treatment, several noteworthy findings have emerged. The present study was carried out as a prospective observational study of 36 Patients who were undergoing treatment for MDR TB to assess the incidence and patterns of hearing loss, and vestibular functions in patients receiving Kanamycin for the treatment of MDR Tuberculosis. Throughout this study, meticulously assessed 36 MDR TB patients undergoing Kanamycin treatment, evaluating their hearing status and vestibular functions. Data entry was carried out in MS Excel 2016 and data analysis was carried out using SPSS Version 22.0. The findings revealed that Kanamycin treatment was associated with a significant incidence of hearing loss among the study participants. Kanamycin treatment in MDR-TB patients is associated with significant auditory and vestibular side effects, including hearing loss and dizziness. To mitigate these risks, regular auditory and vestibular monitoring through tests such as audiometry, VEMPs, and head impulse testing is recommended. Early detection of dysfunction enables timely intervention, such as dose adjustments or alternative treatments, to prevent further deterioration in patients’ quality of life and treatment adherence.

The maximum of the study participants was in the age group of 19–30 years (44.4%) and the majority were females (69.4%). 11.1% of the patients while Profound SNHL was observed in one patient before initiation of treatment, while in the left ear, high-frequency SNHL was noticed in 8.3%. The proportion of study participants with SNHL in their right ear was 26.5% before treatment, however after treatment, this proportion increased to 47.1%, which was statistically significant. The proportion of study participants with SNHL in their left ear was 20.6% before treatment, however after treatment, this proportion increased to 44.1%, which was statistically significant. A statistically significant association was observed between the presence of dizziness (p-value—0.007), tinnitus (p-value -0.039) and SNHL in either of the ears at the end of treatment. The investigation underscored the need for comprehensive audiological monitoring and early intervention in MDR TB patients receiving Kanamycin. The assessment of hearing loss patterns and the identification of susceptible age groups are critical steps toward ensuring the well-being of patients undergoing this treatment regimen. In conclusion, this research has contributed valuable insights into the audiological implications of Kanamycin treatment for MDR TB. Future studies may focus on larger and more diverse patient populations to enhance the generalizability of findings and facilitate the development of personalized treatment regimens for MDR Tuberculosis patients.