Pharmacokinetics of Ethionamide Delivered in Spray-Dried Microparticles to the Lungs of Guinea Pigs

The use of ethionamide (ETH) in treating multidrug-resistant tuberculosis is limited by severe side effects. ETH disposition after pulmonary administration in spray-dried particles might minimize systemic exposure and side effects. To explore this hypothesis, spray-dried ETH particles were optimized for performance in a dry powder aerosol generator and exposure chamber. ETH particles were administered by the intravenous (IV), oral, or pulmonary routes to guinea pigs. ETH appearance in plasma, bronchoalveolar lavage, and lung tissues was measured and subjected to noncompartmental pharmacokinetic analysis. Dry powder aerosol generator dispersion of 20% ETH particles gave the highest dose at the exposure chamber ports and fine particle fraction of 72.3%. Pulmonary ETH was absorbed more rapidly and to a greater extent than orally administered drug. At T_max, ETH concentrations were significantly higher in plasma than lungs from IV dosing, whereas insufflation lung concentrations were 5-fold higher than in plasma. AUC_(0-t) (area under the curve) and apparent total body clearance (CL) were similar after IV administration and insufflation. AUC_(0-t) after oral administration was 6- to 7-fold smaller and CL was 6-fold faster. Notably, ETH bioavailability after pulmonary administration was significantly higher (85%) than after oral administration (17%). These results suggest that pulmonary ETH delivery would potentially enhance efficacy for tuberculosis treatment given the high lung concentrations and bioavailability.     

丙硫乙烟胺抗结核分枝杆菌临床耐药界限的研究

目的通过测定丙硫乙烟胺（Th）对128株临床分离的结核分枝杆菌的最低抑菌浓度（MIC）,分析MIC与既往Th的用药史及经过含Th方案治疗的疗效相关性,以期确定Th的临床耐药界限。方法住院的结核病患者128例,留取痰或体液进行结核分枝杆菌培养、药敏试验及MIC测定,并系统观察47例肺结核患者接受Th治疗方案的痰菌阴转率,各组间率的比较用x^2检验。结果（1）既往未接受Th药物治疗的临床分离株中,MIC=2．5μg／mL者占72．5％,MIC≤5．0μg／mL者占77．5％;（2）既往曾接受Th药物治疗的临床分离株中,MIC〉5．0μg／mL者占96．4％;（3）如以MIC≥5．0μg／mL为临床耐药界限。MIC〈5．0μg／mL与MIC≥5．0μg／mL比较,3、6、12个月患者痰菌阴转率分别为53．6％、75．0％、82．1％及≥5．0μg／mL 3、6、12个月患者痰菌阴转率分别为53.6%,75.0%,82.1%及15．8％,31．6％、42．1％,两组比较差异均有非常显著性（P〈0．01）。结论（1）曾接受Th药物治疗的结核病患者分离株MIC显著高于未接受Th治疗的患者,随着用药时间的延长,MIC随之升高;（2）根据MIC与临床疗效分析结果,提示采用MIC≥5．0μg／mL为临床耐药界限为宜;（3）既往曾接受Th药物治疗的结核病患者,应进行Th的药敏试验,并坚持合理、联合用药的原则,防止耐药株的产生。     

结核分枝杆菌异烟肼和丙硫异烟胺耐药及其交叉耐药相关机制研究进展

结核病是一种严重危害人类健康的呼吸道传染病。据世界卫生组织估算,2018年全球耐多药结核病患者数为48.4万。异烟肼是重要的一线抗结核药物,但其目前耐药情况比较严重。丙硫异烟胺,作为异烟肼耐药患者的替代治疗药物,与异烟肼存在部分的交叉耐药性。本文综述了异烟肼和丙硫异烟胺交叉耐药的相关机制,为异烟肼耐药及耐多药结核病患者的治疗提供科学依据。     

Low Serum Concentrations of Moxifloxacin,Prothionamide, and Cycloserine on Sputum Conversion in Multi-Drug Resistant TB

Purpose

Low serum concentrations of drugs used to treat multi-drug resistant tuberculosis (MDR-TB) have occasionally been associated with treatment failure. We determined the frequencies of low serum concentrations of anti-MDR-TB drugs, and assessed the effects of these concentrations on 2-month sputum conversion.

Materials and Methods

The serum levels of moxifloxacin (MF), prothionamide (PTH), and cycloserine (CS) were determined for 89 serum samples by high-pressure liquid chromatography-tandem mass spectrometry.

Results

Low serum concentrations of MF, PTH, and CS below the minimal levels of the normal ranges were 83.3% (20/24), 59.2% (29/49), and 71.2% (47/66), respectively. There were no significant differences between the 2-month sputum conversion group (n=25) and the 2-month sputum non-conversion group (n=4) in median drug concentrations (µg/mL) of MF (1.46 vs. 1.60), PTH (0.91 vs. 0.70), and CS (14.90 vs. 14.90). However, a poor compliance rate was significantly greater in the 2-month sputum non-conversion group (75.0%, 3/4) than in the 2-month sputum conversion group (0%, 0/25) (p=0.001).

Conclusion

The frequency of low serum concentrations of anti-MDR-TB drugs was substantial and might not affect the 2-month sputum conversion rate. Larger prospective studies with timely sampling are needed to investigate the role of therapeutic drug monitoring in MDR-TB.     

Rifampin Induces Expression of P-glycoprotein on the THP1 Cell–Derived Macrophages,Causing Decrease Intramacrophage Concentration of Prothionamide

Rifampin (RIF) has been widely used for the treatment of bacterial infections, including tuberculosis (TB). Treatment of drug-resistant TB is a global problem because of reduced drug efficacy. The present study determined the effect of RIF on MDR1 gene (P-glycoprotein, P-gp) expression in THP1 macrophages and analyzed the intracellular concentration of the anti-TB drug prothionamide in the presence of RIF. RIF treatment significantly induced MDR1 protein and mRNA levels in phorbol 12-myristate 13-acetate–stimulated THP1 macrophages (p < 0.001 and 0.01, respectively). The pregnane X receptor inhibitors resveratrol and ketoconazole significantly suppressed RIF-induced P-gp expression in THP1 macrophages (p < 0.05). RIF-treated THP1 macrophages also exhibited strong efflux of P-gp substrate, resulting in a reduced intracellular concentration of rhodamine-123 and prothionamide (p < 0.01 and 0.05, respectively). By contrast, the P-gp inhibitor cyclosporine A significantly increased intracellular concentration of rhodamine-123 and prothionamide (p < 0.001 and 0.05, respectively). The present results suggest that the usage of RIF together with P-gp–substrate drugs to treat TB may lead to deteriorated treatment efficacy because of the lower intracellular drug concentration. Further studies would be necessary to know the influence of RIF-induced P-gp induction on the treatment outcome of patients with TB.     

重庆地区结核分枝杆菌异烟肼和丙硫异烟胺耐药及其交叉耐药相关基因突变研究

目的 研究结核分枝杆菌(MTB)对异烟肼(INH)和丙硫异烟胺(Pto)的耐药情况,分析INH耐药相关基因(katG、inhA、ahpC、kasA)及与Pto交叉耐药相关基因的突变特点。方法 对233株INH耐药MTB临床分离株(37株对Pto同时耐药)的katG、inhA、ahpC、kasA基因进行扩增及序列分析。结果 耐异烟肼菌株中未发现katG完全缺失,223株 (96.5%)耐药株katG存在点突变、插入,其中 2个突变位点未见报道。195株 (83.6%)耐药株的第 315位点突变;189株 (81.1%)耐药株第463位点突变(R463L),其中166株 (71.2%)与第 315位点联合突变;在其他位点发生突变的菌株4株,包括D448G 1株、D419H 1株和2株同义突变。 11株(4.72%) INH耐药菌株中inhA点突变,包括S94A 1株、I194T 1株,C-15T 9株。37株Pto耐药的菌株中,8株点突变且均为inhA C-15T(4株为inhA单基因点突变C-15T,4株发生katG S315T和inhA C-15T的双基因联合突变)。全部耐药菌中有1株为ahpC基因突变,未发现有kasA基因突变。结论 进一步证实katG315和inhA-15基因位点突变与MTB对INH耐药密切相关;INH与Pto存在着交叉耐药,但耐药率较低,Pto耐药的发生与inhA-15位点突变密切相关。