title: Comparing amikacin and kanamycin-induced hearing loss in multidrug-resistant tuberculosis treatment under programmatic conditions in a Namibian retrospective cohort.
abstract: BACKGROUND
  Amikacin and kanamycin are mainly used for treating multidrug-resistant tuberculosis (MDR-TB), especially in developing countries where the burden of MDR-TB is highest. Their protracted use in MDR-TB treatment is known to cause dose-dependent irreversible hearing loss, requiring hearing aids, cochlear implants or rehabilitation. Therapeutic drug monitoring and regular audiological assessments may help to prevent or detect the onset of hearing loss, but these services are not always available or affordable in many developing countries. We aimed to compare the cumulative incidence of hearing loss among patients treated for MDR-TB with amikacin or kanamycin-based regimens, and to identify the most-at-risk patients, based on the real-life clinical practice experiences in Namibia.
  
  
  METHODS
  We conducted a retrospective cohort study of patients treated with amikacin or kanamycin-based regimens in four public sector MDR-TB treatment sites in Namibia between June 2004 and March 2014. Patients were audiologically assessed as part of clinical care. The study outcome was the occurrence of any hearing loss. Data were manually extracted from patients' treatment records. We compared proportions using the Chi-square test; applied stratified analysis and logistic regression to study the risk of hearing loss and to identify the most-at-risk patients through effect-modification analysis. A P-value < 0.05 was statistically significant.
  
  
  RESULTS
  All 353 patients had normal baseline hearing, 46 % were HIV co-infected. Cumulative incidence of any hearing loss was 58 %, which was mostly bilateral (83 %), and mild (32 %), moderate (23 %), moderate-severe (16 %), severe (10 %), or profound (15 %). Patients using amikacin had a greater risk of developing the more severe forms of hearing loss than those using kanamycin (adjusted odds ratio (OR) = 4.0, 95 % CI: 1.5-10.8). Patients co-infected with HIV (OR = 3.4, 95 % CI: 1.1-10.6), males (OR = 4.5, 95 %1.5-13.4) and those with lower baseline body weight (40-59 kg, OR = 2.8, 95 % CI: 1.1-6.8), were most-at-risk of developing hearing loss.
  
  
  CONCLUSIONS
  Amikacin use in the long-term MDR-TB treatment led to a higher risk of occurrence of the more severe forms of hearing loss compared to kanamycin use. Males, patients with low baseline body weight and those co-infected with HIV were most-at-risk. MDR-TB treatment programmes should consider replacing amikacin with kanamycin and strengthen the routine renal, serum therapeutic drug levels and audiometric monitoring in the most-at-risk patients treated with aminoglycosides.
authors.affiliation: Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands. esagwa@gmail.com.
authors.forename: Evans L
authors.initials: EL
authors.lastname: Sagwa
authors.affiliation: National Tuberculosis and Leprosy Program, Windhoek, Namibia.
authors.forename: Nunurai
authors.initials: N
authors.lastname: Ruswa
authors.affiliation: National Tuberculosis and Leprosy Program, Windhoek, Namibia.
authors.forename: Farai
authors.initials: F
authors.lastname: Mavhunga
authors.affiliation: University of Namibia School of Pharmacy, Windhoek, Namibia.
authors.forename: Timothy
authors.initials: T
authors.lastname: Rennie
authors.affiliation: Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors.forename: Hubert G M
authors.initials: HG
authors.lastname: Leufkens
authors.affiliation: Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors.forename: Aukje K
authors.initials: AK
authors.lastname: Mantel-Teeuwisse
mesh_terms: D000293:Adolescent; D000328:Adult; D000583:Amikacin / Q000009:adverse effects*; D000900:Anti-Bacterial Agents / Q000009:adverse effects; D001835:Body Weight; D016009:Chi-Square Distribution; D002648:Child; D002675:Child, Preschool; D060085:Coinfection / Q000188:drug therapy* / Q000382:microbiology / Q000821:virology; D015658:HIV Infections / Q000188:drug therapy*; D034381:Hearing Loss / Q000139:chemically induced / Q000175:diagnosis* / Q000453:epidemiology; D006320:Hearing Tests / Q000379:methods; D006801:Humans; D015994:Incidence; D007223:Infant; D007231:Infant, Newborn; D007612:Kanamycin / Q000009:adverse effects*; D016015:Logistic Models; D008875:Middle Aged; D009276:Namibia / Q000453:epidemiology; D012189:Retrospective Studies; D018570:Risk Assessment / Q000379:methods / Q000706:statistics & numerical data; D012307:Risk Factors; D012737:Sex Factors; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy*
chemical_list: D000900:Anti-Bacterial Agents; D007612:Kanamycin; D000583:Amikacin