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

Abstract

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 AUC_0–10 significantly associated with hearing loss.

Keywords:

• Cochleotoxicity
• AUC
• aminoglycosides
• kanamycin
• hearing loss
• pharmacokinetics

Acknowledgments

We would like to acknowledge the contributions of the patients who volunteered for the study.

Declaration of interest

There is no conflict of interest regarding the publication of this article.

Additional information

Funding

This study was supported by a grant from the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (R01AI116155 to H.M. and T.G.). The University of Cape Town (UCT) Clinical PK Laboratory is also supported by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health under award numbers UM1 AI068634, UM1 AI068636, and UM1 AI106701. Overall support for the International Maternal Paediatric Adolescent AIDS Clinical Trials Group (IMPAACT) at UCT was provided by the National Institute of Allergy and Infectious Diseases (U01 AI068632), the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and National Institute of Mental Health [grant No. AI068632]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. H.M. and T.G. are also supported by the National Research Foundation of South Africa [grant Nos. 90729 and 85810, respectively]. H.M. is also supported by the Wellcome Trust (206379/Z/17/Z).