Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Department of Pulmonary Diseases and Tuberculosis, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
BMJ Open. 2020 Jun 16;10(6):e035350. doi: 10.1136/bmjopen-2019-035350.
Global multidrug-resistant tuberculosis (MDR-TB) treatment success rates remain suboptimal. Highly active WHO group A drugs moxifloxacin and levofloxacin show intraindividual and interindividual pharmacokinetic variability which can cause low drug exposure. Therefore, therapeutic drug monitoring (TDM) of fluoroquinolones is recommended to personalise the drug dosage, aiming to prevent the development of drug resistance and optimise treatment. However, TDM is considered laborious and expensive, and the clinical benefit in MDR-TB has not been extensively studied. This observational multicentre study aims to determine the feasibility of centralised TDM and to investigate the impact of fluoroquinolone TDM on sputum conversion rates in patients with MDR-TB compared with historical controls.
Patients aged 18 years or older with sputum smear and culture-positive pulmonary MDR-TB will be eligible for inclusion. Patients receiving TDM using a limited sampling strategy (t=0 and t=5 hours) will be matched to historical controls without TDM in a 1:2 ratio. Sample analysis and dosing advice will be performed in a centralised laboratory. Centralised TDM will be considered feasible if >80% of the dosing recommendations are returned within 7 days after sampling and 100% within 14 days. The number of patients who are sputum smear and culture-negative after 2 months of treatment will be determined in the prospective TDM group and will be compared with the control group without TDM to determine the impact of TDM.
Ethical clearance was obtained by the ethical review committees of the 10 participating hospitals according to local procedures or is pending (online supplementary file 1). Patients will be included after obtaining written informed consent. We aim to publish the study results in a peer-reviewed journal.
ClinicalTrials.gov Registry (NCT03409315).
全球耐多药结核病（MDR-TB）的治疗成功率仍然不理想。高度有效的世界卫生组织（WHO）A 组药物莫西沙星和左氧氟沙星显示出个体内和个体间的药代动力学变异性，这可能导致药物暴露不足。因此，推荐对氟喹诺酮类药物进行治疗药物监测（TDM），以实现个体化药物剂量，预防耐药性的发展，并优化治疗效果。然而，TDM 被认为繁琐且昂贵，并且其在 MDR-TB 中的临床获益尚未得到广泛研究。本观察性多中心研究旨在确定集中 TDM 的可行性，并研究与历史对照相比，氟喹诺酮 TDM 对 MDR-TB 患者痰培养转阴率的影响。
符合纳入标准的患者为年龄在 18 岁或以上、痰涂片和培养阳性的肺部 MDR-TB 患者。接受 TDM 的患者将采用有限采样策略（t=0 时和 t=5 小时）进行匹配，以 1:2 的比例与未接受 TDM 的历史对照进行匹配。将在中央实验室进行样本分析和剂量建议。如果在采样后 7 天内返回了 >80%的剂量建议，并且在 14 天内返回了 100%的剂量建议，则认为集中 TDM 是可行的。将确定前瞻性 TDM 组中在治疗 2 个月后痰涂片和培养阴性的患者数量，并与未接受 TDM 的对照组进行比较，以确定 TDM 的影响。
根据当地程序，10 家参与医院的伦理审查委员会已获得伦理批准（在线补充文件 1），或正在等待批准。患者将在获得书面知情同意后纳入研究。我们的目标是在同行评议的期刊上发表研究结果。
ClinicalTrials.gov 注册（NCT03409315）。
