Correlation between pyrazinamidase activity and the short-term clinical efficacy of multidrug-resistant pulmonary tuberculosis

doi:10.3969/j.issn.1000-6621.2021.12.014

Abstract

Abstract:

Objective To explore the correlation between pyrazinamidase (PZase) activity and the short-term efficacy of multidrug-resistant pulmonary tuberculosis (MDR-PTB), and to provide guidance for the choice of chemotherapy for MDR-PTB patients. Methods A prospective cohort study was conducted on 85 MDR-PTB patients admitted to Guangzhou Chest Hospital from July 2018 to December 2019. All the patients received 6Am-Mfx-PZA-Pto-Cs/18Mfx-PZA-Pto-Cs (Am: amikacin; Mfx: moxifloxacin; PZA: pyrazinamide; Pto: protionamide; Cs: cycloserine) regimen recommended by WHO. Of the 85 MDR-PTB patients, 9 patients were excluded, including those who lost, interrupted treatment or lost to follow-up, and 76 patients were included in the final study. Wayne method was used to detect PZase activity, and BACTEC MGIT 960 system was used to detect the drug sensitivity to PZA. The sputum negative conversion, lesion absorption and cavity closure in patients positive or negative for PZase at the end of 2, 4 and 6 months after treatment were compared. Results Of the 76 patients, PZase was positive in 32 cases (42.1%) and negative in 44 cases (57.9%); 36 cases (47.4%) PZA were with phenotypic resistance and 40 cases (52.6%) were with PZA phenotypic sensitivity. High consistency was found between PZA drug sensitivity test and PZase activity test (Kappa=0.687, P=0.000). At the end of the 4th month of the treatment, the lesion absorption rate in PZase-positive patients were significantly higher than those in PZase-negative patients (59.4% (19/32) vs 36.4% (16/44), χ²=3.949, P=0.047; 65.5% (19/29) vs 36.8% (14/38), χ ²=5.411, P=0.020). After 6-month treatment, the effective rate of cavity closure in PZase-positive patients was significantly higher than that in PZase-negative patients (86.2% (25/29) vs 63.2% (24/38), χ ²=4.447, P=0.035). Conclusion The efficacy of MDR-PTB patients is related to PZase activity. The effect of lesion absorption and cavity closure in PZase-positive patients treated with standard regimen of MDR-PTB containing PZA is better than that in PZase-negative patients.

Key words: Pyrazinamide, Tuberculosis,pulmonary, Tuberculosis,multidrug-resistant, Treatment outcome

WU Bi-tong, CAI Xing-shan, KUANG Hao-bin, LIU Zhi-hui, MENG Fan-rong, WANG Nan, GAO Jun-wen, TAN Shou-yong. Correlation between pyrazinamidase activity and the short-term clinical efficacy of multidrug-resistant pulmonary tuberculosis[J]. Chinese Journal of Antituberculosis, 2021, 43(12): 1308-1313. doi: 10.3969/j.issn.1000-6621.2021.12.014

Figures/Tables 5

特征	吡嗪酰胺酶阳性(32例)	吡嗪酰胺酶阴性(44例)	检验值	P值
年龄(岁, $x ¯$ ±s)	40.6±10.4	41.4±10.6	t=0.312	0.763
性别[例(构成比,%)]			χ²=0.441	0.507
男性	22(68.8)	27(61.4)
女性	10(31.2)	17(38.6)
治疗分类[例(构成比,%)]			χ²=0.105	0.746
初治	6(18.8)	7(15.9)
复治	26(81.2)	37(84.1)
病灶位置[例(构成比,%)]			χ²=0.215	0.643
单侧	10(31.2)	16(36.4)
双侧	22(68.8)	28(63.6)
并发空洞[例(发生率,%)]	29(90.6)	38(86.4)	χ²=0.322	0.570
吡嗪酰胺表型药敏[例(构成比,%)]			Kappa=0.687^a	0.000
敏感	30(93.8)	10(22.7)
耐药	2(6.2)	34(77.3)

References 19

[1]	Huy NQ, Lucie C, Hoa TTT, et al. Molecular analysis of pyrazinamide resistance in Mycobacterium tuberculosis in Vietnam highlights the high rate of pyrazinamide resistance-associated mutations in clinical isolates. Emerg Microbes Infect, 2017, 6(10):e86. doi: 10.1038/emi.2017.73. doi: 10.1038/emi.2017.73
[2]	Hoffner S, Angeby K, Sturegård E, et al. Proficiency of drug susceptibility testing of Mycobacterium tuberculosis against pyrazinamide: the Swedish experience. Int J Tuberc Lung Dis, 2013, 17(11):1486-1490. doi: 10.5588/ijtld.13.0195. doi: 10.5588/ijtld.13.0195 pmid: 24125455
[3]	Daum LT, Konstantynovska OS, Solodiankin OS, et al. Characterization of novel Mycobacterium tuberculosis pncA gene mutations in clinical isolates from the Ukraine. Diagn Microbiol Infect Dis, 2019, 93(4):334-338. doi: 10.1016/j.diagmicrobio.2018.10.018. doi: 10.1016/j.diagmicrobio.2018.10.018 URL
[4]	Ramirez-Busby SM, Rodwell TC, Fink L, et al. A Multinational Analysis of Mutations and Heterogeneity in PZase, RpsA, and PanD Associated with Pyrazinamide Resistance in M/XDR Mycobacterium tuberculosis. Sci Rep, 2017, 7(1):3790. doi: 10.1038/s41598-017-03452-y. doi: 10.1038/s41598-017-03452-y pmid: 28630430
[5]	World Health Organization. WHO treatment guideline for drug-resistant tuberculosis (2016 update). Geneva: World Health Organization, 2016.
[6]	Njire M, Tan Y, Mugweru J, et al. Pyrazinamide resistance in Mycobacterium tuberculosis: Review and update. Adv Med Sci, 2016, 61(1):63-71. doi: 10.1016/j.advms.2015.09.007. doi: 10.1016/j.advms.2015.09.007 URL
[7]	Iacobino A, Piccaro G, Giannoni F, et al. Fighting tuberculosis by drugs targeting nonreplicating Mycobacterium tuberculosis bacilli. Int J Mycobacteriol, 2017, 6(3):213-221. doi: 10.4103/ijmy.ijmy_85_17. doi: 10.4103/ijmy.ijmy_85_17 pmid: 28776518
[8]	Shi W, Zhang X, Jiang X, et al. Pyrazinamide inhibits trans-translation in Mycobacterium tuberculosis. Science, 2011, 333(6049):1630-1632. doi: 10.1126/science.1208813. doi: 10.1126/science.1208813 URL
[9]	Khan MT, Khan A, Rehman AU, et al. Structural and free energy landscape of novel mutations in ribosomal protein S1 (rpsA) associated with pyrazinamide resistance. Sci Rep, 2019, 9(1):7482. doi: 10.1038/s41598-019-44013-9. doi: 10.1038/s41598-019-44013-9 URL
[10]	Bouzouita I, Cabibbe AM, Trovato A, et al. Is sequencing better than phenotypic tests for the detection of pyrazinamide resistance? Int J Tuberc Lung Dis, 2018, 22(6):661-666. doi: 10.5588/ijtld.17.0715. doi: 10.5588/ijtld.17.0715 pmid: 29862951
[11]	车洋, 杨天池, 林相, 等. 浙江省宁波市耐多药结核分枝杆菌吡嗪酰胺耐药特征及与二线抗结核药物耐药关系. 疾病监测, 2020, 35(3):237-241. doi: 10.3784/j.issn.1003-9961.2020.03.013. doi: 10.3784/j.issn.1003-9961.2020.03.013
[12]	Yee DP, Menzies D, Brassard P. Clinical outcomes of pyrazinamide-monoresistant Mycobacterium tuberculosis in Quebec. Int J Tuberc Lung Dis, 2012, 16(5):604-609. doi: 10.5588/ijtld.11.0376. doi: 10.5588/ijtld.11.0376 pmid: 22409887
[13]	吴碧彤, 邝浩斌, 刘志辉, 等. 标准耐多药结核病化疗方案中是否对吡嗪酰胺耐药的疗效对比研究. 中国防痨杂志, 2019, 41(4):447-451. doi: 10.3969/j.issn.1000-6621.2019.04.015. doi: 10.3969/j.issn.1000-6621.2019.04.015
[14]	Njire M, Tan Y, Mugweru J, et al. Pyrazinamide resistance in Mycobacterium tuberculosis: Review and update. Adv Med Sci, 2016, 61(1):63-71. doi: 10.1016/j.advms.2015.09.007. doi: 10.1016/j.advms.2015.09.007 URL
[15]	Gupta UD, Vemuri N, Gupta P, et al. Efficacy of moxifloxacin & econazole against multidrug resistant (MDR) Mycobacterium tuberculosis in murine model. Indian J Med Res, 2015, 142(3):323-329. doi: 10.4103/0971-5916.166599. doi: 10.4103/0971-5916.166599 pmid: 26458349
[16]	Sun F, Li Y, Chen Y, et al. Introducing molecular testing of pyrazinamide susceptibility improves multidrug-resistant tuberculosis treatment outcomes: a prospective cohort study. Eur Respir J, 2019, 53(3):1801770. doi: 10.1183/13993003.01770-2018. doi: 10.1183/13993003.01770-2018 URL
[17]	关平. 广东地区结核分枝杆菌吡嗪酰胺耐药的pncA、rpsA、panD基因分型特征研究. 国际检验医学杂志, 2019, 40(17):2066-2069. doi: 10.3969/j.issn.1673-4130.2019.17.004. doi: 10.3969/j.issn.1673-4130.2019.17.004
[18]	Werngren J, Alm E, Mansjö M. Non-pncA Gene-Mutated but Pyrazinamide-Resistant Mycobacterium tuberculosis: Why Is That? J Clin Microbiol, 2017, 55(6):1920-1927. doi: 10.1128/JCM.02532-16. doi: 10.1128/JCM.02532-16 pmid: 28404681
[19]	洪创跃, 杨婷婷, 李金莉, 等. 深圳市耐多药结核分枝杆菌耐药基因突变特征分析. 中国防痨杂志, 2020, 42(6):583-589. doi: 10.3969/j.issn.1000-6621.2020.06.009. doi: 10.3969/j.issn.1000-6621.2020.06.009

分类	2个月末	4个月末	6个月末
吡嗪酰胺酶阴性(44例)	18(40.9)	23(52.3)	28(63.6)
吡嗪酰胺酶阳性(32例)	19(59.4)	22(68.8)	25(78.1)
χ²值	2.529	2.083	1.843
P值	0.112	0.149	0.175

分类	2个月末	4个月末	6个月末
吡嗪酰胺酶阴性(44例)	15(34.1)	16(36.4)	30(68.2)
吡嗪酰胺酶阳性(32例)	17(53.1)	19(59.4)	26(81.3)
χ²值	2.753	3.949	1.632
P值	0.097	0.047	0.201

分类	2个月末	4个月末	6个月末
吡嗪酰胺酶阴性(38例)	13(34.2)	14(36.8)	24(63.2)
吡嗪酰胺酶阳性(29例)	14(48.3)	19(65.5)	25(86.2)
χ²值	1.352	5.411	4.447
P值	0.245	0.020	0.035

分类	2个月末	4个月末	6个月末
吡嗪酰胺酶阴性(44例)	5(11.4)	7(15.9)	11(25.0)
吡嗪酰胺酶阳性(32例)	4(12.5)	6(18.8)	7(21.9)
χ²值	0.000^a	0.105	0.101
P值	1.000	0.750	0.750