College of Pharmacy, University of Florida, Gainesville, FL, USA.
National Center for Tuberculosis and Lung Diseases, Tbilisi, Georgia.
J Antimicrob Chemother. 2018 Feb 1;73(2):477-483. doi: 10.1093/jac/dkx421.
Moxifloxacin is a second-line anti-TB drug that is useful in the treatment of drug-resistant TB. However, little is known about its target site pharmacokinetics. Lower drug concentrations at the infection site (i.e. in severe lung lesions including cavitary lesions) may lead to development and amplification of drug resistance. Improved knowledge regarding tissue penetration of anti-TB drugs will help guide drug development and optimize drug dosing.
Patients with culture-confirmed drug-resistant pulmonary TB scheduled to undergo adjunctive surgical lung resection were enrolled in Tbilisi, Georgia. Five serum samples per patient were collected at different timepoints including at the time of surgical resection (approximately at Tmax). Microdialysis was performed in the ex vivo tissue immediately after resection. Non-compartmental analysis was performed and a tissue/serum concentration ratio was calculated.
Among the seven patients enrolled, the median moxifloxacin dose given was 7.7 mg/kg, the median age was 25.2 years, 57% were male and the median creatinine clearance was 95.4 mL/min. Most patients (71%) had suboptimal steady-state serum Cmax (total drug) concentrations. The median free moxifloxacin serum concentration at time of surgical resection was 1.23 μg/mL (range = 0.12-1.80) and the median free lung tissue concentration was 3.37 μg/mL (range = 0.81-5.76). The median free-tissue/free-serum concentration ratio was 3.20 (range = 0.66-28.08).
Moxifloxacin showed excellent penetration into diseased lung tissue (including cavitary lesions) among patients with pulmonary TB. Moxifloxacin lung tissue concentrations were higher than those seen in serum. Our findings highlight the importance of moxifloxacin in the treatment of MDR-TB and potentially any patient with pulmonary TB and severe lung lesions.
莫西沙星是一种二线抗结核药物，在治疗耐药结核病方面很有用。然而，人们对其靶部位药代动力学知之甚少。感染部位（即在包括空洞性病变在内的严重肺部病变中）的药物浓度较低可能导致耐药性的发展和放大。提高对抗结核药物组织穿透性的认识将有助于指导药物开发和优化药物剂量。
格鲁吉亚第比利斯招募了计划接受辅助手术肺切除的经培养证实的耐药性肺结核患者。每位患者采集 5 个血清样本，分别在不同时间点采集，包括手术切除时（大约在 Tmax 时）。切除后立即对离体组织进行微透析。进行非房室分析，并计算组织/血清浓度比。
在纳入的 7 名患者中，莫西沙星的中位剂量为 7.7mg/kg，中位年龄为 25.2 岁，57%为男性，中位肌酐清除率为 95.4ml/min。大多数患者（71%）的稳态血清 Cmax（总药物）浓度不理想。手术切除时莫西沙星游离血清浓度的中位数为 1.23μg/ml（范围=0.12-1.80），游离肺组织浓度的中位数为 3.37μg/ml（范围=0.81-5.76）。游离组织/游离血清浓度比的中位数为 3.20（范围=0.66-28.08）。
莫西沙星在肺结核患者的病变肺部组织（包括空洞性病变）中具有良好的穿透性。莫西沙星肺组织浓度高于血清中的浓度。我们的研究结果强调了莫西沙星在治疗耐多药结核病以及任何患有肺结核和严重肺部病变的患者中的重要性。
