South Africa is one of the countries with a high incidence of multidrug-resistant tuberculosis (MDR-TB) and rifampicin resistance tuberculosis (RR-TB). The standard MDR/RR-TB regimen prescribed in South Africa, at the time of the present study included Kanamycin, an aminoglycoside with a known cochleotoxic effect. Although kanamycin has recently been removed from the WHO MDR/RR-TB regimen, amikacin, another aminoglycoside derived from kanamycin, with similar structure and cochleotoxic side effects, has remained as part of the regimen for MDR/RR-TB patients with limited treatment options. In addition, some countries (e.g. India and Nigeria) have not completely removed kanamycin from their treatment regimen for MDR/RR-TB. Research has shown that genetic factors and factors affecting the pharmacokinetic of the drug could potentially be useful in identifying those who may be at a higher risk of aminoglycoside-induced cochleotoxicity. However, not much is known about the pharmacokinetics of Kanamycin and there is currently limited research available on the role of mutations involved in aminoglycoside-induced cochleotoxicity in South Africa. Therefore, this study aimed to determine: (1) the incidence of cochleotoxicity in MDR/RR-TB patients who are receiving kanamycin, (2) the pharmacokinetic properties of kanamycin that are associated with increased risk of cochleotoxicity, and (3) the association between participant's susceptibility to develop cochleotoxicity and two potentially pathogenic mitochondrial mutations (T15312C (I189T in MT-CYB) and T10114C (I19T in MT-ND3)). The current study used a prospective cohort design. A total of 102 patients (median age was 34.9 years) on kanamycin-based MDR/RR-TB treatment participated in this study. The study site was the Metro Tuberculosis Hospital Centre, Cape Town. The majority of the participants were males (n = 58, 56.9%,). Sixty five (63.7%) participants were HIVpositive, and 24 (23.5%) had been treated for MDR/RR-TB previously. Participants' hearing thresholds (0.25 to16kHz) were prospectively monitored for cochleotoxicity at the start of their treatment (baseline), and at 4, 8 and 12 weeks. The American SpeechLanguage- Hearing Association criteria (ASHA, 1994) were used to identify significant threshold shift (STS). Kanamycin concentrations were determined using liquid chromatography tandem mass spectrometry (LC-MS/MS), at steady-state in serial plasma samples over 10 hours. The T15312C (I189T in MT-CYB) and T10114C (I19T in MTND3) mutations was detected using PCR, ABI PRISM® 3130xl Genetic Analyser and UniPro UGene. The results of the study revealed 82% (n = 84) of participants developed cochleotoxicity. The duration of treatment with kanamycin was associated with cochleotoxicity with a 120% and 220% increase in incidence of cochleotoxicity from week four of treatment to week eight and week 12 of treatment, respectively. Kanamycin exposure was significantly associated with cochleotoxicity with about 3% increased risk of hearing loss for every 10µg•hr/L increase in kanamycin AUC0-10. The statistical analysis of the relationship between cochleotoxicity and two potentially pathogenic mutations, T15312C and T10114C, was not possible due to the low frequency of these mutations in the sample size. However, T15312C and T10114C were detected in 4.5% and 6%, respectively. Based on the MAF cut-off of 0.01 (1%), they are considered as common mutations. In addition, as T15312C and T10114C were just detected among participants who developed cochleotoxicity and not those who did not, they may be potentially pathogenic. However, since the presence of the known mutations associated with aminoglycoside-induced hearing loss in participants who carry T15312C and T10114C mutations had not been 17 investigated, it was not possible to draw a definite conclusion about the pathogenicity of T15312C and T10114C. The results of the current study indicate that: (1) a high incidence of cochleotoxicity was detected among MDR/RR-TB patients receiving kanamycin, (2) the longer duration of treatment with kanamycin was associated with higher risk of cochleotoxicity, (3) higher Kanamycin AUC0-10 was strongly associated with an increased incidence of cochleotoxicity, and (4) the T15312C and T10114C were common mutations in South African MDR/RR-TB patients who participated in this study and they may be potentially pathogenic for cochleotoxicity, and that should be assessed in future studies. This study recommends that aminoglycoside-sparing regimens should be used for MDR/RR-TB patients. A routine ototoxic monitoring programme (at least once a month) including ultra-high frequency audiometry should be implemented for MDR/RR-TB patients who receive aminoglycosides, from the time of ototoxic drug exposure until six months post treatment. Therapeutic drug monitoring should be implemented for all the MDR/RR-TB patients on aminoglycosides and AUC value should be used for clinical decision making to reduce the risk of cochleotoxicity. Screening for the known mutations that contribute to the risk of cochleotoxicity, prior to the start of aminoglycoside therapy is recommended to lower the incidence of aminoglycoside induced hearing loss, especially in countries such as South Africa with a high incidence of MDR/RR-TB.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:uct/oai:localhost:11427/37992 |
| Date | 28 June 2023 |
| Creators | Ghafari, Nazanin |
| Contributors | Ramma, Lebogang |
| Publisher | Faculty of Health Sciences, Department of Health and Rehabilitation Sciences |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Thesis / Dissertation |
| Format | application/pdf |
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