A Multistrain Mathematical Model To Investigate the Role of Pyrazinamide in the Emergence of Extensively Drug-Resistant Tuberculosis

ABSTRACT Several infectious diseases of global importance—e.g., HIV infection and tuberculosis (TB)—require prolonged treatment with combination antimicrobial regimens typically involving high-potency core agents coupled with additional companion drugs that protect against the de novo emergence of mutations conferring resistance to the core agents. Often, the most effective (or least toxic) companion agents are reused in sequential (first-line, second-line, etc.) regimens. We used a multistrain model of Mycobacterium tuberculosis transmission in Southeast Asia to investigate how this practice might facilitate the emergence of extensive drug resistance, i.e., resistance to multiple core agents. We calibrated this model to regional TB and drug resistance data using an approximate Bayesian computational approach. We report the proportion of data-consistent simulations in which the prevalence of pre-extensively drug-resistant (pre-XDR) TB—defined as resistance to both first-line and second-line core agents (rifampin and fluoroquinolones)—exceeds predefined acceptability thresholds (1 to 2 cases per 100,000 population by 2035). The use of pyrazinamide (the most effective companion agent) in both first-line and second-line regimens increased the proportion of simulations in which the prevalence exceeded the pre-XDR acceptability threshold by 7-fold compared to a scenario in which patients with pyrazinamide-resistant TB received an alternative drug. Model parameters related to the emergence and transmission of pyrazinamide-resistant TB and resistance amplification were among those that were the most strongly correlated with the projected pre-XDR prevalence, indicating that pyrazinamide resistance acquired during first-line treatment subsequently promotes amplification to pre-XDR TB under pyrazinamide-containing second-line treatment. These findings suggest that the appropriate use of companion drugs may be critical to preventing the emergence of strains resistant to multiple core agents.

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Evaluation of Pyrosequencing for Detecting Extensively Drug-Resistant Mycobacterium tuberculosis among Clinical Isolates from Four High-Burden Countries

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.03614-14 ◽

2014 ◽

Vol 59 (1) ◽

pp. 414-420 ◽

Cited By ~ 20

Author(s):

Kanchan Ajbani ◽

Shou-Yean Grace Lin ◽

Camilla Rodrigues ◽

Duylinh Nguyen ◽

Francine Arroyo ◽

...

Keyword(s):

Drug Resistance ◽

Mycobacterium Tuberculosis ◽

The Philippines ◽

Drug Susceptibility Testing ◽

Clinical Isolates ◽

Drug Resistant ◽

Second Line ◽

Additional Advantage ◽

Content Type ◽

Extensively Drug Resistant

ABSTRACTReliable molecular diagnostics, which detect specific mutations associated with drug resistance, are promising technologies for the rapid identification and monitoring of drug resistance inMycobacterium tuberculosisisolates. Pyrosequencing (PSQ) has the ability to detect mutations associated with first- and second-line anti-tuberculosis (TB) drugs, with the additional advantage of being rapidly adaptable for the identification of new mutations. The aim of this project was to evaluate the performance of PSQ in predicting phenotypic drug resistance in multidrug- and extensively drug-resistant tuberculosis (M/XDR-TB) clinical isolates from India, South Africa, Moldova, and the Philippines. A total of 187 archived isolates were run through a PSQ assay in order to identifyM. tuberculosis(via the IS6110marker), and to detect mutations associated with M/XDR-TB within small stretches of nucleotides in selected loci. The molecular targets includedkatG, theinhApromoter and theahpC-oxyRintergenic region for isoniazid (INH) resistance; therpoBcore region for rifampin (RIF) resistance;gyrAfor fluoroquinolone (FQ) resistance; andrrsfor amikacin (AMK), capreomycin (CAP), and kanamycin (KAN) resistance. PSQ data were compared to phenotypic mycobacterial growth indicator tube (MGIT) 960 drug susceptibility testing results for performance analysis. The PSQ assay illustrated good sensitivity for the detection of resistance to INH (94%), RIF (96%), FQ (93%), AMK (84%), CAP (88%), and KAN (68%). The specificities of the assay were 96% for INH, 100% for RIF, FQ, AMK, and KAN, and 97% for CAP. PSQ is a highly efficient diagnostic tool that reveals specific nucleotide changes associated with resistance to the first- and second-line anti-TB drug medications. This methodology has the potential to be linked to mutation-specific clinical interpretation algorithms for rapid treatment decisions.

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Prevalence and Genetic Characterization of Second-Line Drug-Resistant and Extensively Drug-Resistant Mycobacterium tuberculosis in Rural China

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00102-13 ◽

2013 ◽

Vol 57 (8) ◽

pp. 3857-3863 ◽

Cited By ~ 22

Author(s):

Yi Hu ◽

Sven Hoffner ◽

Linlin Wu ◽

Qi Zhao ◽

Weili Jiang ◽

...

Keyword(s):

Drug Resistance ◽

Mycobacterium Tuberculosis ◽

Dna Sequences ◽

Rural China ◽

Multidrug Resistant ◽

Drug Resistant ◽

Second Line ◽

Content Type ◽

Extensively Drug Resistant ◽

Line Drug

ABSTRACTThis study aimed to investigate the prevalence of resistance to second-line antituberculosis (anti-TB) drugs and its association with resistance-related mutations inMycobacterium tuberculosisisolated in China. In the present study, we collected 380 isolates from a population-based study in China and tested the drug susceptibility to first- and selected second-line drugs. These results were compared with polymorphisms in the DNA sequences of genes associated with drug resistance and MIC values of the studied second-line drugs. Of 43 multidrug-resistantM. tuberculosisisolates, 13 showed resistance to fluoroquinolones or injectable second-line drugs (preextensively drug-resistant TB [pre-XDR-TB]), and 4 were resistant to both and thus defined as extensively drug-resistant TB (XDR-TB). Age and previous TB therapy, including use of second-line drugs, were two independent factors associated with increased resistance to both first- and second-line drugs. Molecular analysis identified the most frequent mutations in the resistance-associated genes: D94G ingyrA(29.1%) and A1401G inrrs(30.8%). Meanwhile, all 4 XDR-TB isolates had a mutation ingyrA, and 3 of them carried the A1401G mutation inrrs. Mutations ingyrAandrrswere associated with high-level resistance to fluoroquinolones and the second-line injectable drugs. In addition to the identification of resistance-associated mutations and development of a rapid molecular test to diagnose the second-line drug resistance, it should be a priority to strictly regulate the administration of second-line drugs to maintain their efficacy to treat multidrug-resistant TB.

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Sensititre MycoTB Plate Compared to Bactec MGIT 960 for First- and Second-Line Antituberculosis Drug Susceptibility Testing in Tanzania: a Call To Operationalize MICs

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01117-15 ◽

2015 ◽

Vol 59 (11) ◽

pp. 7104-7108 ◽

Cited By ~ 29

Author(s):

Scott K. Heysell ◽

Suporn Pholwat ◽

Stellah G. Mpagama ◽

Saumu J. Pazia ◽

Happy Kumburu ◽

...

Keyword(s):

Susceptibility Testing ◽

Acquired Resistance ◽

Drug Susceptibility ◽

Drug Susceptibility Testing ◽

Drug Resistant ◽

Second Line ◽

Drug Resistant Tuberculosis ◽

Content Type ◽

Resistant Tuberculosis ◽

Extensively Drug Resistant

ABSTRACTMIC testing forMycobacterium tuberculosisis now commercially available. Drug susceptibility testing by the MycoTB MIC plate has not been directly compared to that by the Bactec MGIT 960. We describe a case of extensively drug-resistant tuberculosis (XDR-TB) in Tanzania where initial MIC testing may have prevented acquired resistance. From testing on archived isolates, the accuracy with the MycoTB plate was >90% for important first- and second-line drugs compared to that with the MGIT 960, and clinically useful quantitative interpretation was also provided.

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Drug resistance profile among multi-drug resistant tuberculosis patients at diagnosis and correlation with history of anti-tubercular treatment in a tertiary care center

International Journal of Advances in Medicine ◽

10.18203/2349-3933.ijam20195251 ◽

2019 ◽

Vol 6 (6) ◽

pp. 1918

Author(s):

Rahul Kumar ◽

Rajiv Garg ◽

Silpa Kshetrimayum ◽

Amita Jain

Keyword(s):

Drug Resistance ◽

Drug Sensitivity ◽

Drug Resistant ◽

Second Line ◽

Drug Resistant Tuberculosis ◽

Resistant Tuberculosis ◽

Extensively Drug Resistant ◽

Primary Drug Resistance ◽

Mdr Tb ◽

History Of

Background: Drug Resistant Tuberculosis (DR-TB) is a major threat to the realization of the goal of a TB free world in the near future. It is important to study the reasons for the increasing number of such cases so that effective action can be taken to control this growing epidemic.Methods: Sputum from 36 patients diagnosed with acquired pulmonary Multidrug Resistant Tuberculosis (MDR-TB) were subjected to first- and second-line Drug Sensitivity Testing (DST) after liquid culture in mycobacterium growth Indicator Tube (MGIT). Primary MDR-TB cases were excluded. The relation of the drug sensitivity profile with the history of prior treatment taken was statistically analysed.Results: Majority of the patients had received appropriate treatment, and most had adhered to prescribed treatment. Among the 36 patients, 24(66.7%) were found to be Pre-Extensively Drug Resistant (Pre-XDR-TB) and 4(11.1%) were extensively drug resistant XDR-TB cases. Inappropriate prescription of fluoroquinolone (FQ) was found to be most common. Prior intake of any drug was not found to significantly affect subsequent resistance to that drug.Conclusions: Fluoroquinolone resistance is quite common in patients with DR-TB (66.7%). This study did not find the prior use of FQ or any other drug to significantly affect subsequent resistance to the drug. Primary drug resistance is thus a major concern. 11.1% patients were found to be XDR-TB cases. Hence DST for first- and second-line drugs should be done at the time of diagnosis to avoid failure of treatment with a predesigned regimen.

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Extensively drug-resistant tuberculosis in Myanmar: burden and mutations causing second-line drug resistance

The International Journal of Tuberculosis and Lung Disease ◽

10.5588/ijtld.17.0321 ◽

2018 ◽

Vol 22 (1) ◽

pp. 47-53 ◽

Cited By ~ 2

Author(s):

P. W. Ei ◽

W. W. Aung ◽

W. W. Nyunt ◽

T. L. Swe ◽

M. M. Htwe ◽

...

Keyword(s):

Drug Resistance ◽

Drug Resistant ◽

Second Line ◽

Drug Resistant Tuberculosis ◽

Resistant Tuberculosis ◽

Extensively Drug Resistant ◽

Line Drug

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Molecular Detection of Mutations Associated with First- and Second-Line Drug Resistance Compared with Conventional Drug Susceptibility Testing of Mycobacterium tuberculosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01550-10 ◽

2011 ◽

Vol 55 (5) ◽

pp. 2032-2041 ◽

Cited By ~ 236

Author(s):

Patricia J. Campbell ◽

Glenn P. Morlock ◽

R. David Sikes ◽

Tracy L. Dalton ◽

Beverly Metchock ◽

...

Keyword(s):

Drug Resistance ◽

Mycobacterium Tuberculosis ◽

Dna Sequencing ◽

Susceptibility Testing ◽

Drug Susceptibility ◽

Drug Susceptibility Testing ◽

Second Line ◽

First Line ◽

Content Type ◽

Line Drug

ABSTRACTThe emergence of multi- and extensively drug-resistant tuberculosis is a significant impediment to the control of this disease because treatment becomes more complex and costly. Reliable and timely drug susceptibility testing is critical to ensure that patients receive effective treatment and become noninfectious. Molecular methods can provide accurate and rapid drug susceptibility results. We used DNA sequencing to detect resistance to the first-line antituberculosis drugs isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB) and the second-line drugs amikacin (AMK), capreomycin (CAP), kanamycin (KAN), ciprofloxacin (CIP), and ofloxacin (OFX). Nine loci were sequenced:rpoB(for resistance to RIF),katGandinhA(INH),pncA(PZA),embB(EMB),gyrA(CIP and OFX), andrrs,eis, andtlyA(KAN, AMK, and CAP). A total of 314 clinicalMycobacterium tuberculosiscomplex isolates representing a variety of antibiotic resistance patterns, genotypes, and geographical origins were analyzed. The molecular data were compared to the phenotypic data and the accuracy values were calculated. Sensitivity and specificity values for the first-line drug loci were 97.1% and 93.6% forrpoB, 85.4% and 100% forkatG, 16.5% and 100% forinhA, 90.6% and 100% forkatGandinhAtogether, 84.6% and 85.8% forpncA, and 78.6% and 93.1% forembB. The values for the second-line drugs were also calculated. The size and scope of this study, in numbers of loci and isolates examined, and the phenotypic diversity of those isolates support the use of DNA sequencing to detect drug resistance in theM. tuberculosiscomplex. Further, the results can be used to design diagnostic tests utilizing other mutation detection technologies.

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Drug Resistance Among Adolescents and Young Adults with Virologic Failure of First-Line Antiretroviral Therapy and Response to Second-Line Treatment

AIDS Research and Human Retroviruses ◽

10.1089/aid.2019.0232 ◽

2020 ◽

Vol 36 (7) ◽

pp. 566-573

Author(s):

Vinie Kouamou ◽

Bhavini Varyani ◽

Tinei Shamu ◽

Tichaona Mapangisana ◽

Cleophas Chimbetete ◽

...

Keyword(s):

Drug Resistance ◽

Young Adults ◽

Antiretroviral Therapy ◽

Virologic Failure ◽

Adolescents And Young Adults ◽

Line Treatment ◽

Second Line ◽

First Line

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Pathogenesis of drug resistant epilepsy

Epilepsia and paroxyzmal conditions ◽

10.17749/2077-8333.2019.11.1.79-87 ◽

2019 ◽

Vol 11 (1) ◽

pp. 79-87

Author(s):

S. M. Malyshev ◽

T. M. Alekseeva ◽

W. A. Khachatryan ◽

M. M. Galagudza

Keyword(s):

Drug Resistance ◽

Antiepileptic Drugs ◽

Mechanisms Of Action ◽

Drug Resistant ◽

Line Treatment ◽

First Line ◽

Receptor Proteins ◽

Per Se ◽

Drug Resistant Epilepsy ◽

First Line Treatment

Pharmacotherapy is the first-line treatment modality for epilepsy. However, in 20-40% of patients, epilepsy is resistant to pharmacotherapy. These numbers have not changed for decades despite the development and use of antiepileptic drugs with novel mechanisms of action. Drug-resistant epilepsy is now considered a separate pathophysiologic and clinical entity. The existing hypotheses on its pathogenesis could be divided in two groups. Firstly, drug-resistance might be caused by an abnormal pharmacokinetics or pharmacodynamics of antiepileptic drugs as a result of congenital or acquired dysfunction of the transporter or receptor proteins. Secondly, it might be a consequence of inherent features of epilepsy per se, such as the so-called “intrinsic severity” or some disorder of the connectome. Taking into account the complexity of this phenomenon, the issue of drug resistance continues to remain in the focus of the current research efforts.

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Early Detection of Emergent Extensively Drug-Resistant Tuberculosis by Flow Cytometry-Based Phenotyping and Whole-Genome Sequencing

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01834-18 ◽

2019 ◽

Vol 63 (4) ◽

Cited By ~ 2

Author(s):

Max R. O’Donnell ◽

Michelle H. Larsen ◽

Tyler S. Brown ◽

Paras Jain ◽

Vanisha Munsamy ◽

...

Keyword(s):

Drug Resistance ◽

Genome Sequencing ◽

Low Frequency ◽

Whole Genome ◽

Drug Resistant ◽

Drug Resistant Tuberculosis ◽

Content Type ◽

Resistant Tuberculosis ◽

Extensively Drug Resistant

ABSTRACTA critical gap in tuberculosis (TB) treatment is detection of emergent drug resistance. We hypothesized that advanced phenotyping with whole-genome sequencing (WGS) will detect low-frequencyMycobacterium tuberculosisdrug resistance. We assessed a reporter mycobacteriophage (Φ2GFP10)in vitroto detect drug-resistant subpopulations and predictM. tuberculosisbactericidal activity in this pilot study. Subsequently, we prospectively studied 20 TB patients with serial Φ2GFP10, Xpert MTB/RIF, andM. tuberculosisculture through end of treatment. WGS was performed, and single nucleotide polymorphisms (SNPs) were examined to detect mixed infection in selectedM. tuberculosisisolates. ResistantM. tuberculosisisolates were detected at 1:100,000, and changes in cytometry-gated events were predictive ofin vitroM. tuberculosisbactericidal activity using the Φ2GFP10 assay. Emergent drug resistance was detected in one patient by Φ2GFP10 at 3 weeks but not by conventional testing (M. tuberculosisculture and GeneXpert). WGS revealed a phylogeographically distinct extensively drug-resistant tuberculosis (XDR-TB) genome, identical to an XDR-TB isolate from the patient’s spouse. Variant lineage-specific SNPs were present early, suggesting mixed infection as the etiology of emergent resistance with temporal trends providing evidence for selection during treatment. Φ2GFP10 can detect low-frequency drug-resistantM. tuberculosisand with WGS characterize emergentM. tuberculosisresistance. In areas of high TB transmission and drug resistance, rapid screening for heteroresistance should be considered.

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