Pharmacokinetics and other risk factors for kanamycin-induced hearing loss in patients with multi-drug resistant tuberculosis.

Objective: The toxicity associated with the use of kanamycin includes irreversible hearing loss. There are limited data describing the relationship between hearing loss and kanamycin pharmacokinetics (PK). We explored the association of kanamycin PK with hearing loss in patients on MDR-TB treatment.Design: We prospectively recruited patients on kanamycin-based MDR-TB treatment in Cape Town. Hearing thresholds from 0.25 to 16 kHz were tested at baseline and at 4, 8 and 12 weeks. We determined kanamycin concentrations at steady-state in serial plasma samples over 10 h, and explored factors associated with hearing loss.Study sample: One hundred and two participants including 58 (56.9%) men had analysable audiometric data; median age was 34.9 years, 65 (63.7%) were HIV-positive, and 24 (23.5%) had been treated for MDR-TB previously.Results: Eighty-four participants (82.4%) developed hearing loss. We found a 3% (95% CI: 1-6%, p = 0.028) increased risk of cochleotoxicity for each 10 µg h/L increase in 0-10 h AUC.Conclusion: We describe a high incidence of hearing loss in MDR-TB patients treated with kanamycin, with higher AUC0-10 significantly associated with hearing loss.

Generation of Cochlear Hair Cells from Sox2 Positive Supporting Cells via DNA Demethylation.

Regeneration of auditory hair cells in adult mammals is challenging. It is also difficult to track the sources of regenerated hair cells, especially in vivo. Previous paper found newly generated hair cells in deafened mouse by injecting a DNA methyltransferase inhibitor 5-azacytidine into the inner ear. This paper aims to investigate the cell sources of new hair cells. Transgenic mice with enhanced green fluorescent protein (EGFP) expression controlled by the Sox2 gene were used in the study. A combination of kanamycin and furosemide was applied to deafen adult mice, which received 4 mM 5-azacytidine injection into the inner ear three days later. Mice were followed for 3, 5, 7 and 14 days after surgery to track hair cell regeneration. Immunostaining of Myosin VIIa and EGFP signals were used to track the fate of Sox2-expressing supporting cells. The results show that (i) expression of EGFP in the transgenic mice colocalized the supporting cells in the organ of Corti, and (ii) the cell source of regenerated hair cells following 5-azacytidine treatment may be supporting cells during 5-7 days post 5-azacytidine injection. In conclusion, 5-azacytidine may promote the conversion of supporting cells to hair cells in chemically deafened adult mice.

Treatment Outcomes of Patients Switching From an Injectable Drug to Bedaquiline During Short Standardized Treatment for Multidrug-resistant Tuberculosis in Mozambique.

Bedaquiline was recommended by the World Health Organization as the preferred option in treatment of multidrug-resistant tuberculosis (MDR-TB) with long regimens. However, no recommendation was given for the short MDR-TB regimen. Data from our small cohort of patients who switched from injectable drug to bedaquiline suggest that a bedaquiline-based short regimen is effective and safe.

Human mesenchymal stromal cell therapy for damaged cochlea repair in nod-scid mice deafened with kanamycin.

BACKGROUND: Kanamycin, mainly used in the treatment of drug-resistant-tuberculosis, is known to cause irreversible hearing loss. Using the xeno-transplant model, we compared both in vitro and in vivo characteristics of human mesenchymal stromal cells (MSCs) derived from adult tissues, bone marrow (BM-MSCs) and adipose tissue (ADSCs). These tissues were selected for their availability, in vitro multipotency and regenerative potential in vivo in kanamycin-deafened nod-scid mice. METHODS: MSCs were isolated from informed donors and expanded ex vivo. We evaluated their proliferation capacity in vitro using the hexosaminidase assay, the phenotypic profile using flow-cytometry of a panel of surface antigens, the osteogenic potential using alkaline phosphatase activity and the adipogenic potential using oil-red-O staining. MSCs were intravenously injected in deafened mice and cochleae, liver, spleen and kidney were sampled 7 and 30 days after transplantation. The dissected organs were analyzed using lectin histochemistry, immunohistochemistry, polymerase chain reaction (PCR) and dual color fluorescence in situ hybridization (DC-FISH). RESULTS: MSCs showed similar in vitro characteristics, but ADSCs appeared to be more efficient after prolonged expansion. Both cell types engrafted in the cochlea of damaged mice, inducing regeneration of the damaged sensory structures. Several hybrid cells were detected in engrafted tissues. DISCUSSION: BM-MSCs and ADSCs showed in vitro characteristics suitable for tissue regeneration and fused with resident cells in engrafted tissues. The data suggest that paracrine effect is the prevalent mechanism inducing tissue recovery. Overall, BM-MSCs and ADSCs appear to be valuable tools in regenerative medicine for hearing loss recovery.

Reduced Chance of Hearing Loss Associated with Therapeutic Drug Monitoring of Aminoglycosides in the Treatment of Multidrug-Resistant Tuberculosis.

Hearing loss and nephrotoxicity are associated with prolonged treatment duration and higher dosage of amikacin and kanamycin. In our tuberculosis center, we used therapeutic drug monitoring (TDM) targeting preset pharmacokinetic/pharmacodynamic (PK/PD) surrogate endpoints in an attempt to maintain efficacy while preventing (oto)toxicity. To evaluate this strategy, we retrospectively evaluated medical charts of tuberculosis (TB) patients treated with amikacin or kanamycin in the period from 2000 to 2012. Patients with culture-confirmed multiresistant or extensively drug-resistant tuberculosis (MDR/XDR-TB) receiving amikacin or kanamycin as part of their TB treatment for at least 3 days were eligible for inclusion in this retrospective study. Clinical data, including maximum concentration (Cmax), Cmin, and audiometry data, were extracted from the patients' medical charts. A total of 80 patients met the inclusion criteria. The mean weighted Cmax/MIC ratios obtained from 57 patients were 31.2 for amikacin and 12.3 for kanamycin. The extent of hearing loss was limited and correlated with the cumulative drug dose per kg of body weight during daily administration. At follow-up, 35 (67.3%) of all patients had successful outcome; there were no relapses. At a median dose of 6.5 mg/kg, a correlation was found between the dose per kg of body weight during daily dosing and the extent of hearing loss in dB at 8,000 Hz. These findings suggest that the efficacy at this lower dosage is maintained with limited toxicity. A randomized controlled trial should provide final proof of the safety and efficacy of TDM-guided use of aminoglycosides in MDR-TB treatment.

D-methionine (D-met) significantly reduces kanamycin-induced ototoxicity in pigmented guinea pigs.

OBJECTIVE: Test D-methionine (D-met) as an otoprotectant from kanamycin-induced ototoxicity and determine the lowest maximally protective D-met dose. DESIGN: Auditory brainstem responses (ABR) were measured at 4, 8, 14, and 20 kHz at baseline and two, four, and six weeks after kanamycin and D-met administration initiation. ABR threshold shifts assessed auditory function. Following six-week ABR testing, animals were decapitated and cochleae collected for outer hair cell (OHC) quantification. STUDY SAMPLE: Eight groups of 10 male pigmented guinea pigs were administered a subcutaneous kanamycin (250 mg/kg/dose) injection once per day and an intraperitoneal D-met injection (0 (saline), 120, 180, 240, 300, 360, 420, or 480 mg/kg/day) twice per day for 23 days. RESULTS: Significant ABR threshold shift reductions and increased OHC counts (p ≤ 0.01) were measured at multiple D-met-dosed groups starting at two-week ABR assessments. A 300 mg/kg/day optimal otoprotective D-met dose provided 34-41 dB ABR threshold shift reductions and OHC protection. Lesser, but significant, D-met otoprotection was measured at lower and higher D-met doses. CONCLUSIONS: D-met significantly reduced ABR threshold shifts and increased OHC percentages compared to kanamycin-treated controls. Results may be clinically significant particularly for multidrug-resistant tuberculosis patients who frequently suffer from kanamycin-induced hearing loss in developing countries.

Gitelman-like Syndrome with Kanamycin Toxicity.

A 22 year-old lady with multi-drug-resistant pulmonary tuberculosis was on Kanamycin, Cycloserine, Ethionamide, Pyrazinamide and Moxifloxacin since more than two months. She presented with muscle cramps and carpopedal spasm. Investigation revealed hypokalemia and metabolic alkalosis. She also had hypomagnesemia, hypochloremia and hypocalciuria. Serum urea and creatinine levels were normal. Patient was treated with intravenous and oral potassium chloride. Kanamycin was stopped. Metabolic alkalosis and hypokalemia improved gradually over one month. Biochemical parameters were like Gitelman's syndrome but it reversed with stoppage of Kanamycin. Gitelman-like syndrome with Kanamycin toxicity has not been reported in literature previously.

Bicarbonate enhances the in vitro antibiotic activity of kanamycin in Escherichia coli.

UNLABELLED: Growth of enteropathogenic Escherichia coli E2348/69 was inhibited by bicarbonate in a dose-dependent manner, showing approximately 5% growth reduction at 5 mmol l(-1) while kanamycin at 3·12 µg ml(-1) inhibited growth by 15%, yet when kanamycin and bicarbonate were combined at these concentrations, inhibition increased to 80%. Unexpectedly, at bicarbonate concentrations >20 mmol l(-1) enhancement of the antibiotic activity virtually disappeared, i.e. there was a paradoxical Eagle-like effect. How bicarbonate acts is unclear, but neutral or alkaline pH also enhanced the activity of kanamycin. However, several differences indicated a separate effect of bicarbonate. First, bicarbonate inhibited growth more than the corresponding increments in pH. Second, at low concentration, the antibiotic enhancing effect of bicarbonate was stronger than the effect of pH alone. Third, 5 mmol l(-1) bicarbonate significantly enhanced the activity of kanamycin while the corresponding pH had no effect. Fourth, the Eagle-like effect was exclusive of bicarbonate because changes in pH did not induce an analogous behaviour. Notwithstanding the mechanism, the enhancing effect of bicarbonate was indubitable. Consequently, it seems worthwhile to explore further its potential to improve the efficacy of aminoglycosides and maybe even other antibiotics. SIGNIFICANCE AND IMPACT OF THE STUDY: Bicarbonate at a low concentration enhanced the in vitro antibiotic activity of kanamycin and gentamicin. Even though the action mechanism of bicarbonate is hitherto unknown, it seems worthwhile to explore further its capacity to improve the efficacy of aminoglycosides. Clearly, the well-known harmful side-effects of aminoglycosides are a concern. However, it has recently been shown in a fish model that bicarbonate may protect ciliary cells against the damage caused by aminoglycosides. So, it seems possible that bicarbonate could help reduce aminoglycoside dosage at the same time that it might help lessen the damage to auditory ciliary cells in humans.

Impact of kanamycin on melanogenesis and antioxidant enzymes activity in melanocytes--an in vitro study.

Aminoglycosides, broad spectrum aminoglycoside antibiotics, are used in various infections therapy due to their good antimicrobial characteristics. However, their adverse effects such as nephrotoxicity and auditory ototoxicity, as well as some toxic effects directed to pigmented tissues, complicate the use of these agents. This study was undertaken to investigate the effect of aminoglycoside antibiotic-kanamycin on viability, melanogenesis and antioxidant enzymes activity in cultured human normal melanocytes (HEMa-LP). It has been demonstrated that kanamycin induces concentration-dependent loss in melanocytes viability. The value of EC50 was found to be ~6.0 mM. Kanamycin suppressed melanin biosynthesis: antibiotic was shown to inhibit cellular tyrosinase activity and to reduce melanin content in normal human melanocytes. Significant changes in the cellular antioxidant enzymes: SOD, CAT and GPx were stated in melanocytes exposed to kanamycin. Moreover, it was observed that kanamycin caused depletion of antioxidant defense sytem. It is concluded that the inhibitory effect of kanamycin on melanogenesis and not sufficient antioxidant defense mechanism in melanocytes in vitro may explain the potential mechanisms of undesirable side effects of this drug directed to pigmented tissues in vivo.

Refinement of systemic guinea pig deafening in hearing research: Sensorineural hearing loss induced by co-administration of kanamycin and furosemide via the leg veins.

Auditory disabilities have a large impact on the human population worldwide. Research into understanding and treating hearing disabilities has increased significantly in recent years. One of the most relevant animal species in this context is the guinea pig, which has to be deafened to study several of the hearing pathologies and develop novel therapies. Applying kanamycin subcutaneously and furosemide intravenously is a long-established method in hearing research, leading to permanent hearing loss without surgical intervention at the ear. The intravenous application of furosemide requires invasive surgery in the cervical area of the animals to expose the jugular vein, since a relatively large volume (1 ml per 500 g body weight) must be injected over a period of about 2.5 min. We have established a gentler alternative by applying the furosemide by puncture of the leg veins. For this, custom-made cannula-needle devices were built to allow the vein puncture and subsequent slow injection of the furosemide. This approach was tested in 11 guinea pigs through the foreleg via the cephalic antebrachial vein and through the hind leg via the saphenous vein. Frequency-specific hearing thresholds were measured before and after the procedure to verify normal hearing and successful deafening, respectively. The novel approach of systemic deafening was successfully implemented in 10 out of 11 animals. The Vena saphena was best suited to the application. Since the animals' condition, post leg vein application, was better in comparison to animals deafened by exposure of the Vena jugularis, the postulated refinement that reduced animal stress was deemed successful.

The ototoxic effect of locally applied kanamycin and furosemide in guinea pigs.

BACKGROUND: Hearing impairment is a growing social and economic issue. New technical or biological approaches aiming hearing rehabilitation or regeneration require animal testing. Therefore, a reproducible and safe model for hearing-impaired animals is essential. NEW METHOD: Intratympanic injection of kanamycin and furosemide was administered for BFA bunt pigmented guinea pigs for either 1 or 2 h. Hearing loss was regularly measured with compound action potential response to click and tone burst stimuli for up to 26 weeks. Hair cell loss and the density of spiral ganglion neurons were histologically analyzed. RESULTS: One week after the exposure, complete hearing loss was observed in 34 ears from the 36 ears treated for 2 h and remained stable during the follow-up. Histology revealed near complete hair cell loss and secondary degeneration of spiral ganglion neurons. COMPARISON WITH EXISTING METHODS: Animal deafening is usually achieved by systemic application of aminoglycoside antibiotics or chemotherapy drugs, although side effects such as nephrotoxicity may occur which can be avoided by local application. With our procedure, unilateral hearing loss model can also be established. CONCLUSIONS: The single intratympanic application of a solution of 200 mg/ml kanamycin and 50 mg/ml furosemide is a stable and reliable deafening method.

N-methyl-D-aspartate antagonists limit aminoglycoside antibiotic-induced hearing loss.

The use of aminoglycoside antibiotics is limited by ototoxicity that can produce permanent hearing loss. We report that concurrent administration of N-methyl-D-aspartate (NMDA) antagonists markedly attenuates both the hearing loss and destruction of cochlear hair cells in guinea pigs treated with aminoglycoside antibiotics. These findings indicate that aminoglycoside-induced hearing loss is mediated, in part, through an excitotoxic process. The high correlation (Spearman correlation coefficient: 0.928; P < 0.01) obtained between the relative cochleotoxicities of a series of aminoglycosides in humans and the potencies of these compounds to produce a polyamine-like enhancement of [3H]dizocilpine binding to NMDA receptors is consistent with this hypothesis, and provides a simple in vitro assay that can predict this aspect of aminoglycoside-induced ototoxicity.

Impact of drug-resistant tuberculosis treatment on hearing function in South African adults: Bedaquiline versus kanamycin.

BACKGROUND: Ototoxicity linked to medications used to treat tuberculosis (TB) remains a global challenge. OBJECTIVES: The aim was to describe the audiological function in a group of adults with drug-resistant tuberculosis (DR-TB) on bedaquiline (G-BDQ) treatment attending a TB hospital in South Africa and compare this with patients on kanamycin (G-KCIN). METHODS: A quantitative paradigm was adopted within a non-experimental retrospective record review design. The sample consisted of 30 records of adults with DR-TB between the ages of 18 and 50 years, recruited from a Tropical Diseases Hospital in South Africa. Data were analysed through both descriptive and inferential statistical measures. RESULTS: Clear and statistically significant differences in the audiological function were found between the two groups. The group receiving G-KCIN presented with ototoxicity that was clearly demonstrated by sensorineural hearing loss of high-frequency worsening of thresholds in over 73% of the records, which was statistically (p 0.05) and clinically significant, over the three testing sessions, demonstrating the cumulative effects of dosage. Increased evidence of tinnitus was also found in this group. The group receiving G-BDQ presented with neither statistically (p 0.05) nor clinically significant changes in hearing thresholds across all frequencies over the same monitoring timeframe. Additionally, only one report (7%) of tinnitus was found in this group. CONCLUSION: The results indicating that bedaquiline does not cause hearing loss when compared with G-KCIN highlight the need for increased availability of bedaquiline for the treatment of DR-TB within the South African context, to preserve both the quantity and quality of life of those infected.

Involvement of calpain-I and microRNA34 in kanamycin-induced apoptosis of inner ear cells.

Inner ear cells, including hair cells, spiral ganglion cells, stria vascularis cells and supporting cells on the basilar membrane, play a major role in transducing hearing signals and regulating inner ear homoeostasis. However, their functions are often damaged by antibiotic-induced ototoxicity. Apoptosis is probably involved in inner ear cell injury following aminoglycoside treatment. Calpain, a calcium-dependent protease, is essential for mediating and promoting cell death. We have therefore investigated the involvement of calpain in the molecular mechanism underlying ototoxicity induced by the antibiotic kanamycin in mice. Kanamycin (750 mg/kg) mainly induced cell death of cochlear cells, including stria vascularis cells, supporting cells and spiral ganglion cells, but not hair cells within the organ of Corti. Cell death due to apoptosis occurred in a time-dependent manner with concomitant up-regulation of calpain expression. Furthermore, the expression levels of two microRNAs, mir34a and mir34c, were altered in a dose-dependent manner in cochlear cells. These novel findings demonstrated the involvement of both calpain and microRNAs in antibiotic-induced ototoxicity.

[Kanamycin-induced ototoxicity during treatment of multidrug-resistant tuberculosis]. / Ototoxicité liée à la kanamycine au cours du traitement de la tuberculose multirésistante.

INTRODUCTION: Aminoglycosides are commonly used in the treatment of multidrug-resistant tuberculosis (MDR-TB). Their use can cause ototoxicity with irreversible hearing loss. The aim of this study was to determine the incidence and to identify factors associated to kanamycin-induced ototoxicity during MDR-TB treatment in Yaounde. METHODS: The records of patients hospitalized in the pulmonology department of the Jamot Hospital of Yaounde between May 2008 and July 2015 (7 years) for treatment of MDR-TB with regimens containing kanamycin were analyzed. Logistic regression was used to identify for factors associated with ototoxicity during this treatment. RESULTS: Of the 79 patients included, 60.7% were male and their median age (25th-75th percentile) was 31 (25-43) years. Eighteen (22.8%) patients had HIV infection. During treatment, the incidence of kanamycin-induced ototoxicity [95% confidence interval (95% CI)] was 36.7 (26.9-47.7) %. Factors independently associated with this ototoxicity [odds ratio (95% CI)] during MDR-TB treatment were age>40 years [13.47 (3.66-49.49)] and a body mass index<18.5kg/m2 [4.58 (1.36-15.44)]. CONCLUSION: The incidence of kanamycin-induced ototoxicity during MDR-TB treatment is relatively high. Taking these factors into consideration at the initiation of MDR-TB treatment would allow to reduce the occurrence of irreversible functional impairment induced by the treatment of MDR-TB.

Prevalence of Pre-Existing Hearing Loss Among Patients With Drug-Resistant Tuberculosis in South Africa.

Purpose Hearing loss, resulting from aminoglycoside ototoxicity, is common among patients with drug-resistant tuberculosis (DR-TB). Those with pre-existing hearing loss are at particular risk of clinically important hearing loss with aminoglycoside-containing treatment than those with normal hearing at baseline. This study aimed to identify factors associated with pre-existing hearing loss among patients being treated for DR-TB in South Africa. Method Cross-sectional analysis nested within a cluster-randomized trial data across 10 South African TB hospitals. Patients ≥ 13 years old received clinical and audiological evaluations before DR-TB treatment initiation. Results Of 936 patients, average age was 35 years. One hundred forty-two (15%) reported pre-existing auditory symptoms. Of 482 patients tested by audiometry, 290 (60%) had pre-existing hearing loss. The prevalence of pre-existing hearing loss was highest among patients ≥ 50 years (adjusted prevalence ratio [aPrR] for symptoms 5.53, 95% confidence interval (CI) [3.63, 8.42]; aPrR for audiometric hearing loss 1.63, 95% CI [1.31, 2.03] compared to age 13-18 years) and among those with a prior history of second-line TB treatment (aPrR for symptoms 1.73, 95% CI [1.66, 1.80]; PrR for audiometric hearing loss 1.33, 95% CI [1.03, 1.73]). Having HIV with cluster of differentiation 4 cell count < 200 cells/mm3 and malnutrition were risk factors but did not reach statistical significance in adjusted analyses. Conclusion Pre-existing hearing loss is common among patients presenting for DR-TB treatment in South Africa, and those older than the age of 50 years or who had prior second-line TB treatment history were at highest risk.

Etiology of Childhood Bilateral Sensorineural Hearing Loss in Shandong Province, China.

Objectives The purpose of this study is to ascertain the etiology of bilateral sensorineural hearing loss (SNHL) in children aged ≤ 18 years living in Shandong province. Method Data were taken from a cross-sectional study, which was conducted between 2015 and 2017. The study included children aged ≤ 18 years, recruited from special schools for children with hearing loss and from hearing rehabilitation centers in Shandong province of China. Children were screened for bilateral SNHL through audiological testing. Clinical examination, genetic testing, and structured interviews were conducted for those children who were identified as having hearing loss to identify the potential cause. Results The etiology of bilateral SNHL in our sample was genetic in 874 (39.3%), acquired in 650 (29.3%), and unknown in 697 (31.4%) children. Among children with acquired SNHL, the cause was maternal viral infection in 75 (11.5%); perinatal factors in 238 (36.6%); meningitis, measles, and mumps in 146 (22.5%); and ototoxic exposure in 117 (18%) children. Among the children with genetic SNHL, only 44 (4.9%) were identified as having syndromic hearing loss, and the remainder (95.1%) were classified as nonsyndromic hearing loss. Conclusion The findings indicated that nearly 30% of bilateral SNHL in Shandong province could be preventable through immunization, early prenatal diagnosis, proper treatment of infections, and avoidance of prescription of ototoxic drugs. This finding emphasizes the need for programs aimed at improving the health services at primary and secondary levels of health care, which will in turn prevent childhood hearing loss.

Synergistic ototoxicity due to noise exposure and aminoglycoside antibiotics.

Acoustic exposure to high intensity and/or prolonged noise causes temporary or permanent threshold shifts in auditory perception, reflected by reversible or irreversible damage in the cochlea. Aminoglycoside antibiotics, used for treating or preventing life-threatening bacterial infections, also induce cytotoxicity in the cochlea. Combined noise and aminoglycoside exposure, particularly in neonatal intensive care units, can lead to auditory threshold shifts greater than simple summation of the two insults. The synergistic toxicity of acoustic exposure and aminoglycoside antibiotics is not limited to simultaneous exposures. Prior acoustic insult which does not result in permanent threshold shifts potentiates aminoglycoside ototoxicity. In addition, exposure to subdamaging doses of aminoglycosides aggravates noise-induced cochlear damage. The mechanisms by which aminoglycosides cause auditory dysfunction are still being unraveled, but likely include the following: 1) penetration into the endolymphatic fluid of the scala media, 2) permeation of nonselective cation channels on the apical surface of hair cells, and 3) generation of toxic reactive oxygen species and interference with other cellular pathways. Here we discuss the effect of combined noise and aminoglycoside exposure to identify pivotal synergistic events that can potentiate ototoxicity, in addition to a current understanding of aminoglycoside trafficking within the cochlea. Preventing the ototoxic synergy of noise and aminoglycosides is best achieved by using non-ototoxic bactericidal drugs, and by attenuating perceived noise intensity when life-saving aminoglycoside therapy is required.

Nephrotoxicity and ototoxic symptoms of injectable second-line anti-tubercular drugs among patients treated for MDR-TB in Ethiopia: a retrospective cohort study.

BACKGROUND: Nephrotoxicity and ototoxicity are clinically significant dose-related adverse effects associated with second-line anti-tubercular injectables drugs (aminoglycosides and capreomycin) used during intensive phase of treatment of multi-drug resistant tuberculosis (MDR-TB) patients. Data are scarce on injectable-induced nephrotoxicity and ototoxicity in Ethiopian MDR-TB patients. The aim of this study was to assess the prevalence, management of nephrotoxicity and ototoxic symptoms and treatment outcomes of patients treated for MDR-TB with injectable-based regimens. METHOD: This was retrospective cohort study based on review of medical records of about 900 patients on MDR-TB treatment from January 2010 to December 2015 at two large TB referral hospitals in Addis Ababa, Ethiopia. Nephrotoxicity in study participants was screened using baseline and monthly measurement of serum creatinine and clinical diagnosis and patient reports. RESULTS: Overall, 473 (54.2%) of participants were male. Children accounted for 47 (5.5%) of cases and the mean age of participants was 32 ± 12.6 years with range of 2-75 years. The majority (n = 788, 84.6%) of participants had past history of TB. The most commonly used injectable anti-TB drug was capreomycin (n = 789, 84.7%), while kanamycin and amikacin were also used. There was a statistically significant increment (p<0.05) in the mean serum creatinine values from baseline throughout intensive phase of treatment with a 10-18% prevalence of nephrotoxicity. Based on clinical criteria, nephrotoxicity was detected in 62 (6.7%) and ototoxic symptoms were detected in 42 (4.8%) participants. Nephrotoxicity and ototoxic symptoms were clinically managed by modification of treatment regimens including dose and frequency of drug administration. CONCLUSION: Nephrotoxicity and ototoxic symptoms were significant problems among patients on follow-up for MDR-TB treatment. Based on laboratory criteria (serum creatinine), nephrotoxicity remained significant adverse events throughout intensive phase of treatment, indicating close monitoring of patients for successful outcome is mandatory until countries adopt the recent injectable-free WHO guideline and under specific conditions.