在坦桑尼亚，含吡嗪酰胺方案治疗敏感和耐多药结核病时，如果低估了吡嗪酰胺耐药率，可能会影响治疗结局。

Underestimated pyrazinamide resistance may compromise outcomes of pyrazinamide containing regimens for treatment of drug susceptible and multi-drug-resistant tuberculosis in Tanzania.

机构信息

Kilimanjaro Clinical Research Institute, Moshi, Tanzania.

Kilimanjaro Christian Medical Centre and Kilimanjaro Christian Medical University College, Kilimanjaro, Tanzania.

出版信息

BMC Infect Dis. 2019 Feb 7;19(1):129. doi: 10.1186/s12879-019-3757-1.

DOI:10.1186/s12879-019-3757-1

PMID:30732572

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6367741/

Abstract

BACKGROUND

Tuberculosis (TB) is the leading cause of death from an infectious disease and the roll-out of rapid molecular diagnostics for rifampin resistance has resulted in a steady rise in the number of patients with multidrug-resistant (MDR)-TB referred for treatment. Pyrazinamide is used in susceptible TB treatment for 6 months when used in combination with rifampin, isoniazid and ethambutol and is an important companion drug in novel MDR-TB trials. This study was undertaken to determine the prevalence of pyrazinamide resistance by either phenotypic or pncA testing among patients admitted to a referral hospital in Tanzania for drug-susceptible and MDR-TB treatment.

METHODS

Surveillance sputa were sent among subjects beginning TB therapy at the national MDR-TB referral hospital during a 6 month period in 2013-2014. Mycobacterial cultures of pretreatment sputa were performed at the Kilimanjaro Clinical Research Institute (KCRI) in the BACTEC mycobacterial growth indicator tubes (MGIT) 960 system. Speciation of M. tuberculosis complex was confirmed by MTBc assay. Isolates were sub-cultured on to Lowenstein-Jensen (LJ) slants. Phenotypic resistance to pyrazinamide was performed in the MGIT system while a real-time PCR with High Resolution Melt (HRM) technique was used to determine mutation in the pncA gene from the same pure subculture. Sputa were then collected monthly to determine the time to culture negativity. Final treatment outcome was determined.

RESULTS

Ninety-one M. tuberculosis isolates from individual patients were available for analysis of which 30 (32.9%) had MDR-TB, the mean (±SD) age was 33 ± 10 years, and the majority 23 (76.7%) were males. Of the 30 MDR-TB patients, 15(50%) had isolates with pyrazinamide resistance by conventional MGIT testing. This proportion expectedly exceeded the number with pyrazinamide resistance in the 61 patients without MDR-TB, 13 (21.3%) (p = 0.008). Six (20%) of MDR-TB patients had a poor outcome including treatment failure. Among patients with treatment failure, 5 (83%) had pyrazinamide resistance compared to only 10 (41.6%) with treatment success (p = 0.08). Two patients died, and both had isolates with pyrazinamide resistance. No other pretreatment characteristic was associated with treatment outcome.

CONCLUSION

Pyrazinamide susceptibility appears to be important in clinical outcomes for MDR-TB patients, and susceptibility testing appears to be a critical adjunct to TB care. The high proportion of PZA resistance in non-MDR TB cases calls for further local investigation.

摘要

背景

结核病（TB）是传染病导致死亡的主要原因，快速分子诊断方法的推出导致耐利福平的耐药结核病（MDR-TB）患者数量稳步上升，需要接受治疗。吡嗪酰胺在利福平、异烟肼和乙胺丁醇联合使用时用于敏感结核病治疗 6 个月，是新型 MDR-TB 试验中的重要伴随药物。本研究旨在通过表型或 pncA 检测确定坦桑尼亚转诊医院接受药物敏感和 MDR-TB 治疗的患者中吡嗪酰胺耐药的流行率。

方法

2013-2014 年期间，在国家 MDR-TB 转诊医院开始结核病治疗的患者中，每 6 个月发送一次监测痰液。在基利马尼临床研究所（KCRI）的 BACTEC 分枝杆菌生长指示剂管（MGIT）960 系统中对预处理痰液进行分枝杆菌培养。使用 MTBc 检测确认结核分枝杆菌复合体的种属。分离物在 Lowenstein-Jensen（LJ）斜面上进行亚培养。在 MGIT 系统中进行吡嗪酰胺表型耐药性检测，同时使用实时 PCR 与高分辨率熔解（HRM）技术从同一纯亚培养物中确定 pncA 基因的突变。然后每月收集痰液以确定培养物阴性的时间。确定最终治疗结果。

结果

91 份来自个体患者的结核分枝杆菌分离物可用于分析，其中 30 份（32.9%）患有 MDR-TB，平均（±SD）年龄为 33±10 岁，大多数 23 名（76.7%）为男性。在 30 名 MDR-TB 患者中，15 名（50%）患者的分离物通过常规 MGIT 检测显示出吡嗪酰胺耐药性。这一比例明显高于没有 MDR-TB 的 61 名患者中 13 名（21.3%）的吡嗪酰胺耐药患者（p=0.008）。6 名（20%）MDR-TB 患者预后不良，包括治疗失败。在治疗失败的患者中，5 名（83%）患者的吡嗪酰胺耐药性，而治疗成功的患者中只有 10 名（41.6%）（p=0.08）。有 2 名患者死亡，他们的分离物均具有吡嗪酰胺耐药性。没有其他治疗前特征与治疗结果相关。