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.

Venous thrombotic events in patients admitted to a tuberculosis centre.

BACKGROUND: Considering the relationship between inflammation and thrombosis, patients with tuberculosis (TB) patients might be at high risk of venous thrombosis. AIM: To evaluate the risk of venous thromboembolism in patients admitted to the Beatrixoord Tuberculosis Centre (BTBC), a tertiary centre for TB. We specifically explored which cofactors elevate the risk of venous thrombosis (VTE), and whether the timing of venous thrombotic events would justify extended primary prophylaxis. DESIGN: retrospective cohort study. METHODS: We performed a retrospective chart review of all patients with TB discharged from BTBC between 2000 and 2010. We excluded patients who were already on therapeutic anticoagulation before their TB episode, below the age of 18 years and patients in which TB diagnosis was withdrawn. For evaluating the timing of venous thrombosis, we calculated the time between commencement of anti TB therapy and the VTE. RESULTS: Of 750 included in the final analysis, 18 (2.4%) suffered a venous thrombotic event. 3 of these events were not related to classic risk factors or hospitalization. Most (13/18) VTE's occurred in the time window of two weeks before starting TB medication.In the multivariate analysis, only Human Immunodeficiency Virus (HIV) infection was strongly associated with risk of VTE (adjusted Odds ratio 8.2 (95% confidence interval: 2.9-22.7)). CONCLUSIONS: This high risk in HIV co-infected TB patients suggests that standard thrombo-prophylaxis should be routinely considered in this group. However, our findings might not be generalizable due to referral bias. Further prospective studies in unselected HIV co-infected TB patients are needed to corroborate our findings.