title: Reduced Chance of Hearing Loss Associated with Therapeutic Drug Monitoring of Aminoglycosides in the Treatment of Multidrug-Resistant Tuberculosis.
abstract: 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 weightedCmax/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.
authors.affiliation: University of Groningen, University Medical Center Groningen, Tuberculosis Centre Beatrixoord, Haren, The Netherlands.|University of Groningen, University Medical Center Groningen, Departments of Pulmonary Diseases and Tuberculosis, Groningen, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: van Altena
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlands.
authors.forename: J A
authors.initials: JA
authors.lastname: Dijkstra
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlands.
authors.forename: M E
authors.initials: ME
authors.lastname: van der Meer
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Internal Medicine, Groningen, The Netherlands.
authors.forename: J F
authors.initials: JF
authors.lastname: Borjas Howard
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlands.|University of Groningen, Department of Pharmacy, Section Pharmacotherapy and Pharmaceutical Care, Groningen, The Netherlands.
authors.forename: J G W
authors.initials: JG
authors.lastname: Kosterink
authors.affiliation: National Mycobacteria Reference Laboratory, National Institute of Public Health and the Environment, Bilthoven, The Netherlands.|Radboud University Nijmegen Medical Center, Departments of Pulmonary Diseases and Medical Microbiology, Nijmegen, The Netherlands.
authors.forename: D
authors.initials: D
authors.lastname: van Soolingen
authors.affiliation: University of Groningen, University Medical Center Groningen, Departments of Pulmonary Diseases and Tuberculosis, Groningen, The Netherlands.|University of Groningen, University Medical Center Groningen, Department of Internal Medicine, Groningen, The Netherlands.
authors.forename: T S
authors.initials: TS
authors.lastname: van der Werf
authors.affiliation: University of Groningen, University Medical Center Groningen, Tuberculosis Centre Beatrixoord, Haren, The Netherlands j.w.c.alffenaar@umcg.nl.
authors.forename: J W C
authors.initials: JW
authors.lastname: Alffenaar
mesh_terms: D000328:Adult; D000583:Amikacin / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D000995:Antitubercular Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001299:Audiometry; D001682:Biological Availability; D004334:Drug Administration Schedule; D054796:Drug Dosage Calculations; D016903:Drug Monitoring; D054908:Extensively Drug-Resistant Tuberculosis / Q000097:blood / Q000188:drug therapy* / Q000382:microbiology; D005260:Female; D034381:Hearing Loss / Q000139:chemically induced / Q000175:diagnosis* / Q000473:pathology; D006801:Humans; D007612:Kanamycin / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000254:growth & development; D012189:Retrospective Studies
chemical_list: D000995:Antitubercular Agents; D007612:Kanamycin; D000583:Amikacin
keywords: TDM; amikacin; kanamycin; pharmacodynamics; pharmacokinetics; therapeutic drug monitoring; tuberculosis