Additional drug resistance for Mycobacterium tuberculosis during turnaround time for drug-susceptibility testing in China: A multicenter observational cohort study

•One third developed extra drug resistance within turnaround time for DST results.•One fourth of MDR Mtb acquired PZA/EMB resistance within turnaround time for DST.•Exogenous reinfection played a ponderous role in the drug resistance acquisition. Although phenotypic drug susceptibility testing (DST)...

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Published in:	International journal of infectious diseases Vol. 108; pp. 81 - 88
Main Authors:	Zhu, Jiahui, Bao, Ziwei, Xie, Yan, Werngren, Jim, Hu, Yi, Davies Forsman, Lina, Bruchfeld, Judith, Hoffner, Sven
Format:	Journal Article
Language:	English
Published:	Canada Elsevier Ltd 01.07.2021 Elsevier
Subjects:	Additional drug resistance Drug-susceptibility testing Exogenous reinfection Mixed infection Turnaround time Mixed infection Turnaround time Drug-susceptibility testing Additional drug resistance Exogenous reinfection
ISSN:	1201-9712, 1878-3511, 1878-3511
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Abstract	•One third developed extra drug resistance within turnaround time for DST results.•One fourth of MDR Mtb acquired PZA/EMB resistance within turnaround time for DST.•Exogenous reinfection played a ponderous role in the drug resistance acquisition. Although phenotypic drug susceptibility testing (DST) of Mycobacterium tuberculosis (Mtb) takes up to 6–8 weeks, little is known about how drug susceptibility is affected during this period. We performed a prospective cohort study to investigate the development of drug resistance (DR) during turnaround time (TAT), including 359 pulmonary tuberculosis (PTB) patients with a baseline DST result of an Mtb isolate collected at TB diagnosis and a follow-up DST result of an Mtb isolate collected when baseline DST result was available between 2013 and 2018. Whole-genome sequencing (WGS) was used to differentiate between acquired drug resistance, exogenous reinfection, and mixed infection. Among the studied patients, during TAT for DST, 116 (32.3%) developed DR to four first-line drugs (rifampicin, isoniazid, pyrazinamide, ethambutol). Among 116 pairs of isolates included for WGS, 21 pairs were classified as acquired drug resistance with single nucleotide polymorphisms (SNPs) differences less than 12. Four pairs with an intermediate SNPs differences displayed minor differences in related genotypes and were assessed as mixed infection. The remaining 91 pairs had high SNPs differences consistent with exogenous reinfection. The exogenous reinfection of drug-resistant strains played a vital role in the development of DR of Mtb isolates during TAT for DST, highlighting the need for both rapid DST methods and improved infection control.
AbstractList	Although phenotypic drug susceptibility testing (DST) of Mycobacterium.Tuberculosis (Mtb) takes up to 6-8 weeks, little is known about how drug susceptibility is affected during this period. We performed a prospective cohort study to investigate the development of drug resistance (DR) during turnaround time (TAT), including 359 pulmonary tuberculosis (PTB) patients with a baseline DST result of a Mtb isolate collected at TB diagnosis and a follow-up DST result of a Mtb isolate collected when baseline DST result was available between 2013 and 2018. Whole-genome sequencing (WGS) was used to differentiate between acquired drug resistance, exogenous reinfection, and mixed infection. Among the studied patients, during TAT for DST, 116 (32.3%) developed DR to four first-line drugs (rifampicin, isoniazid, pyrazinamide, ethambutol). Among 116 pairs of isolates included for WGS, 21 paired was classified as acquired drug resistance with single nucleotide polymorphisms (SNPs) differences less than 12. Four pairs with an intermediate SNPs differences displayed minor differences in related genotypes and were assessed as mixed infection. The remaining 91 pairs had high SNPs differences consistent with exogenous reinfection. The exogenous reinfection of drug-resistant strains played a vital role in the development of DR of Mtb isolates during TAT for DST, highlighting the need for both rapid DST methods and improved infection control. •One third developed extra drug resistance within turnaround time for DST results.•One fourth of MDR Mtb acquired PZA/EMB resistance within turnaround time for DST.•Exogenous reinfection played a ponderous role in the drug resistance acquisition. Although phenotypic drug susceptibility testing (DST) of Mycobacterium tuberculosis (Mtb) takes up to 6–8 weeks, little is known about how drug susceptibility is affected during this period. We performed a prospective cohort study to investigate the development of drug resistance (DR) during turnaround time (TAT), including 359 pulmonary tuberculosis (PTB) patients with a baseline DST result of an Mtb isolate collected at TB diagnosis and a follow-up DST result of an Mtb isolate collected when baseline DST result was available between 2013 and 2018. Whole-genome sequencing (WGS) was used to differentiate between acquired drug resistance, exogenous reinfection, and mixed infection. Among the studied patients, during TAT for DST, 116 (32.3%) developed DR to four first-line drugs (rifampicin, isoniazid, pyrazinamide, ethambutol). Among 116 pairs of isolates included for WGS, 21 pairs were classified as acquired drug resistance with single nucleotide polymorphisms (SNPs) differences less than 12. Four pairs with an intermediate SNPs differences displayed minor differences in related genotypes and were assessed as mixed infection. The remaining 91 pairs had high SNPs differences consistent with exogenous reinfection. The exogenous reinfection of drug-resistant strains played a vital role in the development of DR of Mtb isolates during TAT for DST, highlighting the need for both rapid DST methods and improved infection control. Although phenotypic drug susceptibility testing (DST) of Mycobacterium tuberculosis (Mtb) takes up to 6-8 weeks, little is known about how drug susceptibility is affected during this period.BACKGROUNDAlthough phenotypic drug susceptibility testing (DST) of Mycobacterium tuberculosis (Mtb) takes up to 6-8 weeks, little is known about how drug susceptibility is affected during this period.We performed a prospective cohort study to investigate the development of drug resistance (DR) during turnaround time (TAT), including 359 pulmonary tuberculosis (PTB) patients with a baseline DST result of an Mtb isolate collected at TB diagnosis and a follow-up DST result of an Mtb isolate collected when baseline DST result was available between 2013 and 2018. Whole-genome sequencing (WGS) was used to differentiate between acquired drug resistance, exogenous reinfection, and mixed infection.METHODSWe performed a prospective cohort study to investigate the development of drug resistance (DR) during turnaround time (TAT), including 359 pulmonary tuberculosis (PTB) patients with a baseline DST result of an Mtb isolate collected at TB diagnosis and a follow-up DST result of an Mtb isolate collected when baseline DST result was available between 2013 and 2018. Whole-genome sequencing (WGS) was used to differentiate between acquired drug resistance, exogenous reinfection, and mixed infection.Among the studied patients, during TAT for DST, 116 (32.3%) developed DR to four first-line drugs (rifampicin, isoniazid, pyrazinamide, ethambutol). Among 116 pairs of isolates included for WGS, 21 pairs were classified as acquired drug resistance with single nucleotide polymorphisms (SNPs) differences less than 12. Four pairs with an intermediate SNPs differences displayed minor differences in related genotypes and were assessed as mixed infection. The remaining 91 pairs had high SNPs differences consistent with exogenous reinfection.RESULTSAmong the studied patients, during TAT for DST, 116 (32.3%) developed DR to four first-line drugs (rifampicin, isoniazid, pyrazinamide, ethambutol). Among 116 pairs of isolates included for WGS, 21 pairs were classified as acquired drug resistance with single nucleotide polymorphisms (SNPs) differences less than 12. Four pairs with an intermediate SNPs differences displayed minor differences in related genotypes and were assessed as mixed infection. The remaining 91 pairs had high SNPs differences consistent with exogenous reinfection.The exogenous reinfection of drug-resistant strains played a vital role in the development of DR of Mtb isolates during TAT for DST, highlighting the need for both rapid DST methods and improved infection control.CONCLUSIONSThe exogenous reinfection of drug-resistant strains played a vital role in the development of DR of Mtb isolates during TAT for DST, highlighting the need for both rapid DST methods and improved infection control. Background: Although phenotypic drug susceptibility testing (DST) of Mycobacterium tuberculosis (Mtb) takes up to 6–8 weeks, little is known about how drug susceptibility is affected during this period. Methods: We performed a prospective cohort study to investigate the development of drug resistance (DR) during turnaround time (TAT), including 359 pulmonary tuberculosis (PTB) patients with a baseline DST result of an Mtb isolate collected at TB diagnosis and a follow-up DST result of an Mtb isolate collected when baseline DST result was available between 2013 and 2018. Whole-genome sequencing (WGS) was used to differentiate between acquired drug resistance, exogenous reinfection, and mixed infection. Results: Among the studied patients, during TAT for DST, 116 (32.3%) developed DR to four first-line drugs (rifampicin, isoniazid, pyrazinamide, ethambutol). Among 116 pairs of isolates included for WGS, 21 pairs were classified as acquired drug resistance with single nucleotide polymorphisms (SNPs) differences less than 12. Four pairs with an intermediate SNPs differences displayed minor differences in related genotypes and were assessed as mixed infection. The remaining 91 pairs had high SNPs differences consistent with exogenous reinfection. Conclusions: The exogenous reinfection of drug-resistant strains played a vital role in the development of DR of Mtb isolates during TAT for DST, highlighting the need for both rapid DST methods and improved infection control.
Author	Hu, Yi Hoffner, Sven Werngren, Jim Xie, Yan Davies Forsman, Lina Bao, Ziwei Bruchfeld, Judith Zhu, Jiahui
Author_xml	– sequence: 1 givenname: Jiahui surname: Zhu fullname: Zhu, Jiahui organization: School of Public Health and Key Laboratory of Public Health Safety, Fudan University, Shanghai, China – sequence: 2 givenname: Ziwei surname: Bao fullname: Bao, Ziwei organization: The Fifth People’s Hospital of Suzhou, Infectious Disease Hospital Affiliated to Soochow University, Suzhou, China – sequence: 3 givenname: Yan surname: Xie fullname: Xie, Yan organization: Department Tuberculosis Control, Zigong Center for Disease Control and Prevention, Zigong, China – sequence: 4 givenname: Jim surname: Werngren fullname: Werngren, Jim organization: Department of Microbiology, The Public Health Agency of Sweden, Stockholm, Sweden – sequence: 5 givenname: Yi surname: Hu fullname: Hu, Yi email: yhu@fudan.edu.cn organization: School of Public Health and Key Laboratory of Public Health Safety, Fudan University, Shanghai, China – sequence: 6 givenname: Lina surname: Davies Forsman fullname: Davies Forsman, Lina organization: Department of Infectious Disease, Karolinska University Hospital, Stockholm, Sweden – sequence: 7 givenname: Judith surname: Bruchfeld fullname: Bruchfeld, Judith organization: Department of Infectious Disease, Karolinska University Hospital, Stockholm, Sweden – sequence: 8 givenname: Sven surname: Hoffner fullname: Hoffner, Sven organization: Department of Global Public Health, Karolinska Institute, Stockholm, Sweden
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Keywords	Mixed infection Turnaround time Drug-susceptibility testing Additional drug resistance Exogenous reinfection
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Snippet	•One third developed extra drug resistance within turnaround time for DST results.•One fourth of MDR Mtb acquired PZA/EMB resistance within turnaround time for... Although phenotypic drug susceptibility testing (DST) of Mycobacterium.Tuberculosis (Mtb) takes up to 6-8 weeks, little is known about how drug susceptibility... Although phenotypic drug susceptibility testing (DST) of Mycobacterium tuberculosis (Mtb) takes up to 6-8 weeks, little is known about how drug susceptibility... Background: Although phenotypic drug susceptibility testing (DST) of Mycobacterium tuberculosis (Mtb) takes up to 6–8 weeks, little is known about how drug...
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SubjectTerms	Additional drug resistance Drug-susceptibility testing Exogenous reinfection Mixed infection Turnaround time
Title	Additional drug resistance for Mycobacterium tuberculosis during turnaround time for drug-susceptibility testing in China: A multicenter observational cohort study
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