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Title: Emergence and selection of isoniazid and rifampin resistance in tuberculosis granulomas

Abstract

Drug resistant tuberculosis is increasing world-wide. Resistance against isoniazid (INH), rifampicin (RIF), or both (multi-drug resistant TB, MDR-TB) is of particular concern, since INH and RIF form part of the standard regimen for TB disease. While it is known that suboptimal treatment can lead to resistance, it remains unclear how host immune responses and antibiotic dynamics within granulomas (sites of infection) affect emergence and selection of drug-resistant bacteria. We take a systems pharmacology approach to explore resistance dynamics within granulomas. We integrate spatio-temporal host immunity, INH and RIF dynamics, and bacterial dynamics (including fitness costs and compensatory mutations) in a computational framework. We simulate resistance emergence in the absence of treatment, as well as resistance selection during INH and/or RIF treatment. There are four main findings. First, in the absence of treatment, the percentage of granulomas containing resistant bacteria mirrors the non-monotonic bacterial dynamics within granulomas. Second, drug-resistant bacteria are less frequently found in non-replicating states in caseum, compared to drug-sensitive bacteria. Third, due to a steeper dose response curve and faster plasma clearance of INH compared to RIF, INH-resistant bacteria have a stronger influence on treatment outcomes than RIF-resistant bacteria. Finally, under combination therapy with INH and RIF, fewmore » MDR bacteria are able to significantly affect treatment outcomes. Overall, our approach allows drug-specific prediction of drug resistance emergence and selection in the complex granuloma context. Since our predictions are based on pre-clinical data, our approach can be implemented relatively early in the treatment development process, thereby enabling pro-active rather than reactive responses to emerging drug resistance for new drugs. Furthermore, this quantitative and drug-specific approach can help identify drug-specific properties that influence resistance and use this information to design treatment regimens that minimize resistance selection and expand the useful life-span of new antibiotics.« less

Authors:
 [1];  [2]; ORCiD logo [2];  [3]
  1. Univ. of Michigan, Ann Arbor, MI (United States); Purdue Univ., West Lafayette, IN (United States)
  2. Univ. of Michigan, Ann Arbor, MI (United States)
  3. Univ. Autònoma de Barcelona (Spain)
Publication Date:
Research Org.:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). National Energy Research Scientific Computing Center (NERSC)
Sponsoring Org.:
USDOE
OSTI Identifier:
1544032
Resource Type:
Accepted Manuscript
Journal Name:
PLoS ONE
Additional Journal Information:
Journal Volume: 13; Journal Issue: 5; Journal ID: ISSN 1932-6203
Publisher:
Public Library of Science
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; Science & Technology; Other Topics

Citation Formats

Pienaar, Elsje, Linderman, Jennifer J., Kirschner, Denise E., and Cardona, Pere -Joan. Emergence and selection of isoniazid and rifampin resistance in tuberculosis granulomas. United States: N. p., 2018. Web. doi:10.1371/journal.pone.0196322.
Pienaar, Elsje, Linderman, Jennifer J., Kirschner, Denise E., & Cardona, Pere -Joan. Emergence and selection of isoniazid and rifampin resistance in tuberculosis granulomas. United States. doi:10.1371/journal.pone.0196322.
Pienaar, Elsje, Linderman, Jennifer J., Kirschner, Denise E., and Cardona, Pere -Joan. Thu . "Emergence and selection of isoniazid and rifampin resistance in tuberculosis granulomas". United States. doi:10.1371/journal.pone.0196322. https://www.osti.gov/servlets/purl/1544032.
@article{osti_1544032,
title = {Emergence and selection of isoniazid and rifampin resistance in tuberculosis granulomas},
author = {Pienaar, Elsje and Linderman, Jennifer J. and Kirschner, Denise E. and Cardona, Pere -Joan},
abstractNote = {Drug resistant tuberculosis is increasing world-wide. Resistance against isoniazid (INH), rifampicin (RIF), or both (multi-drug resistant TB, MDR-TB) is of particular concern, since INH and RIF form part of the standard regimen for TB disease. While it is known that suboptimal treatment can lead to resistance, it remains unclear how host immune responses and antibiotic dynamics within granulomas (sites of infection) affect emergence and selection of drug-resistant bacteria. We take a systems pharmacology approach to explore resistance dynamics within granulomas. We integrate spatio-temporal host immunity, INH and RIF dynamics, and bacterial dynamics (including fitness costs and compensatory mutations) in a computational framework. We simulate resistance emergence in the absence of treatment, as well as resistance selection during INH and/or RIF treatment. There are four main findings. First, in the absence of treatment, the percentage of granulomas containing resistant bacteria mirrors the non-monotonic bacterial dynamics within granulomas. Second, drug-resistant bacteria are less frequently found in non-replicating states in caseum, compared to drug-sensitive bacteria. Third, due to a steeper dose response curve and faster plasma clearance of INH compared to RIF, INH-resistant bacteria have a stronger influence on treatment outcomes than RIF-resistant bacteria. Finally, under combination therapy with INH and RIF, few MDR bacteria are able to significantly affect treatment outcomes. Overall, our approach allows drug-specific prediction of drug resistance emergence and selection in the complex granuloma context. Since our predictions are based on pre-clinical data, our approach can be implemented relatively early in the treatment development process, thereby enabling pro-active rather than reactive responses to emerging drug resistance for new drugs. Furthermore, this quantitative and drug-specific approach can help identify drug-specific properties that influence resistance and use this information to design treatment regimens that minimize resistance selection and expand the useful life-span of new antibiotics.},
doi = {10.1371/journal.pone.0196322},
journal = {PLoS ONE},
number = 5,
volume = 13,
place = {United States},
year = {2018},
month = {5}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record

Figures / Tables:

Fig 1 Fig 1: Antibiotic resistance emergence and selection over bacterial through population scales. Resistance develops upon mutation conferring genetic resistance (A). Resistant bacteria grow (B) within the host, giving rise to hetero-resistance (C), which can spread resistant bacteria to others (D). Improper treatment (E) selects for resistant bacteria, resulting in drug-resistantmore » TB (F), which can spread in a community. (G) The influence of bacterial and drug dynamics on resistance emergence and selection in the context of granulomas remains unclear. Arrows between scales represent a series of potential events, but influences can occur in both directions.« less

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Works referenced in this record:

The spectrum of latent tuberculosis: rethinking the biology and intervention strategies
journal, October 2009

  • Barry, Clifton E.; Boshoff, Helena I.; Dartois, Véronique
  • Nature Reviews Microbiology, Vol. 7, Issue 12
  • DOI: 10.1038/nrmicro2236

Management of latent Mycobacterium tuberculosis infection: WHO guidelines for low tuberculosis burden countries
journal, September 2015

  • Getahun, Haileyesus; Matteelli, Alberto; Abubakar, Ibrahim
  • European Respiratory Journal, Vol. 46, Issue 6
  • DOI: 10.1183/13993003.01245-2015

Isoniazid Preventive Therapy and Risk for Resistant Tuberculosis
journal, May 2006

  • Balcells, Maria Elvira; Thomas, Sara L.; Godfrey-Faussett, Peter
  • Emerging Infectious Diseases, Vol. 12, Issue 5
  • DOI: 10.3201/eid1205.050681

Clinical Characteristics and Treatment Outcomes of Patients with Isoniazid‐Monoresistant Tuberculosis
journal, January 2009

  • Cattamanchi, Adithya; Dantes, Raymund B.; Metcalfe, John Z.
  • Clinical Infectious Diseases, Vol. 48, Issue 2
  • DOI: 10.1086/595689

Sterilization of granulomas is common in active and latent tuberculosis despite within-host variability in bacterial killing
journal, December 2013

  • Lin, Philana Ling; Ford, Christopher B.; Coleman, M. Teresa
  • Nature Medicine, Vol. 20, Issue 1
  • DOI: 10.1038/nm.3412

Quantitative Comparison of Active and Latent Tuberculosis in the Cynomolgus Macaque Model
journal, July 2009

  • Lin, P. L.; Rodgers, M.; Smith, L.
  • Infection and Immunity, Vol. 77, Issue 10
  • DOI: 10.1128/IAI.00592-09

Pharmacokinetic Evaluation of the Penetration of Antituberculosis Agents in Rabbit Pulmonary Lesions
journal, October 2011

  • Kjellsson, Maria C.; Via, Laura E.; Goh, Anne
  • Antimicrobial Agents and Chemotherapy, Vol. 56, Issue 1
  • DOI: 10.1128/AAC.05208-11

A computational tool integrating host immunity with antibiotic dynamics to study tuberculosis treatment
journal, February 2015

  • Pienaar, Elsje; Cilfone, Nicholas A.; Lin, Philana Ling
  • Journal of Theoretical Biology, Vol. 367
  • DOI: 10.1016/j.jtbi.2014.11.021

In silico evaluation and exploration of antibiotic tuberculosis treatment regimens
journal, November 2015

  • Pienaar, Elsje; Dartois, Véronique; Linderman, Jennifer J.
  • BMC Systems Biology, Vol. 9, Issue 1
  • DOI: 10.1186/s12918-015-0221-8

Concentration-Dependent Mycobacterium tuberculosis Killing and Prevention of Resistance by Rifampin
journal, August 2007

  • Gumbo, T.; Louie, A.; Deziel, M. R.
  • Antimicrobial Agents and Chemotherapy, Vol. 51, Issue 11
  • DOI: 10.1128/AAC.01533-06

Failure of drug penetration and acquisition of drug resistance in chronic tuberculous empyema
journal, October 1995


Contribution of mathematical modeling to the fight against bacterial antibiotic resistance
journal, January 2011

  • Opatowski, Lulla; Guillemot, Didier; Boëlle, Pierre-Yves
  • Current Opinion in Infectious Diseases, Vol. 24, Issue 3
  • DOI: 10.1097/QCO.0b013e3283462362

Burden of transmitted multidrug resistance in epidemics of tuberculosis: a transmission modelling analysis
journal, December 2015


Classification of drug-resistant tuberculosis in an epidemic area
journal, July 2000


Outwitting Evolution: Fighting Drug-Resistant TB, Malaria, and HIV
journal, March 2012


Mechanisms of drug resistance in <I>Mycobacterium tuberculosis</I>: update 2015
journal, November 2015

  • Zhang, Y.; Yew, W-W.
  • The International Journal of Tuberculosis and Lung Disease, Vol. 19, Issue 11
  • DOI: 10.5588/ijtld.15.0389

Modeling epidemics of multidrug-resistant M. tuberculosis of heterogeneous fitness
journal, September 2004

  • Cohen, Ted; Murray, Megan
  • Nature Medicine, Vol. 10, Issue 10
  • DOI: 10.1038/nm1110

Evolution of Drug Resistance in Tuberculosis: Recent Progress and Implications for Diagnosis and Therapy
journal, June 2014


Resistance to Isoniazid and Ethionamide in Mycobacterium tuberculosis: Genes, Mutations, and Causalities
journal, August 2014


Antimicrobial agent resistance in mycobacteria: molecular genetic insights.
journal, October 1995


DnaE2 Polymerase Contributes to In Vivo Survival and the Emergence of Drug Resistance in Mycobacterium tuberculosis
journal, April 2003


Mutation rate and the emergence of drug resistance in Mycobacterium tuberculosis
journal, September 2013

  • McGrath, M.; Gey van Pittius, N. C.; van Helden, P. D.
  • Journal of Antimicrobial Chemotherapy, Vol. 69, Issue 2
  • DOI: 10.1093/jac/dkt364

Mycobacterium tuberculosis mutation rate estimates from different lineages predict substantial differences in the emergence of drug-resistant tuberculosis
journal, June 2013

  • Ford, Christopher B.; Shah, Rupal R.; Maeda, Midori Kato
  • Nature Genetics, Vol. 45, Issue 7
  • DOI: 10.1038/ng.2656

The Influence of Host and Bacterial Genotype on the Development of Disseminated Disease with Mycobacterium tuberculosis
journal, March 2008


The Competitive Cost of Antibiotic Resistance in Mycobacterium tuberculosis
journal, June 2006


Exploring the collaboration between antibiotics and the immune response in the treatment of acute, self-limiting infections
journal, May 2014

  • Ankomah, P.; Levin, B. R.
  • Proceedings of the National Academy of Sciences, Vol. 111, Issue 23
  • DOI: 10.1073/pnas.1400352111

Two-Drug Antimicrobial Chemotherapy: A Mathematical Model and Experiments with Mycobacterium marinum
journal, January 2012


The population dynamics of antimicrobial chemotherapy.
journal, February 1997

  • Lipsitch, M.; Levin, B. R.
  • Antimicrobial Agents and Chemotherapy, Vol. 41, Issue 2
  • DOI: 10.1128/AAC.41.2.363

The population genetics of antibiotic resistance: integrating molecular mechanisms and treatment contexts
journal, June 2010

  • MacLean, R. Craig; Hall, Alex R.; Perron, Gabriel G.
  • Nature Reviews Genetics, Vol. 11, Issue 6
  • DOI: 10.1038/nrg2778

Minimizing Potential Resistance: A Population Dynamics View
journal, September 2001

  • Levin, Bruce R.
  • Clinical Infectious Diseases, Vol. 33, Issue s3
  • DOI: 10.1086/321843

Antibiotic exposure and resistance in mixed bacterial populations
journal, December 1987


Within-host population dynamics of antibiotic-resistant M. tuberculosis
journal, March 2007

  • Alavez-Ramírez, Justino; Castellanos, J. Rogelio Avendano; Esteva, Lourdes
  • Mathematical Medicine and Biology: A Journal of the IMA, Vol. 24, Issue 1
  • DOI: 10.1093/imammb/dql026

A network-based approach for resistance transmission in bacterial populations
journal, January 2010

  • Gehring, Ronette; Schumm, Phillip; Youssef, Mina
  • Journal of Theoretical Biology, Vol. 262, Issue 1
  • DOI: 10.1016/j.jtbi.2009.09.002

Spontaneous Emergence of Multiple Drug Resistance in Tuberculosis before and during Therapy
journal, March 2011


Evolution of Drug Resistance in Mycobacterium tuberculosis: Clinical and Molecular Perspective
journal, February 2002


Phagocytes, Antibiotics, and Self-Limiting Bacterial Infections
journal, November 2017

  • Levin, Bruce R.; Baquero, Fernando; Ankomah, Peter (Pierre)
  • Trends in Microbiology, Vol. 25, Issue 11
  • DOI: 10.1016/j.tim.2017.07.005

Metronidazole prevents reactivation of latent Mycobacterium tuberculosis infection in macaques
journal, July 2012

  • Lin, P. L.; Dartois, V.; Johnston, P. J.
  • Proceedings of the National Academy of Sciences, Vol. 109, Issue 35
  • DOI: 10.1073/pnas.1121497109

Multiscale Computational Modeling Reveals a Critical Role for TNF-α Receptor 1 Dynamics in Tuberculosis Granuloma Formation
journal, February 2011

  • Fallahi-Sichani, Mohammad; El-Kebir, Mohammed; Marino, Simeone
  • The Journal of Immunology, Vol. 186, Issue 6
  • DOI: 10.4049/jimmunol.1003299

Synergy between Individual TNF-Dependent Functions Determines Granuloma Performance for Controlling Mycobacterium tuberculosis Infection
journal, March 2009

  • Ray, J. Christian J.; Flynn, JoAnne L.; Kirschner, Denise E.
  • The Journal of Immunology, Vol. 182, Issue 6
  • DOI: 10.4049/jimmunol.0802297

Identifying control mechanisms of granuloma formation during M. tuberculosis infection using an agent-based model
journal, December 2004

  • Segovia-Juarez, Jose L.; Ganguli, Suman; Kirschner, Denise
  • Journal of Theoretical Biology, Vol. 231, Issue 3
  • DOI: 10.1016/j.jtbi.2004.06.031

Damaging role of neutrophilic infiltration in a mouse model of progressive tuberculosis
journal, January 2014


Multiscale Model of Mycobacterium tuberculosis Infection Maps Metabolite and Gene Perturbations to Granuloma Sterilization Predictions
journal, March 2016

  • Pienaar, Elsje; Matern, William M.; Linderman, Jennifer J.
  • Infection and Immunity, Vol. 84, Issue 5
  • DOI: 10.1128/IAI.01438-15

Tuneable resolution as a systems biology approach for multi-scale, multi-compartment computational models: Tuneable resolution as a systems biology approach
journal, July 2014

  • Kirschner, Denise E.; Hunt, C. Anthony; Marino, Simeone
  • Wiley Interdisciplinary Reviews: Systems Biology and Medicine, Vol. 6, Issue 4
  • DOI: 10.1002/wsbm.1270

Tuberculous Granulomas Are Hypoxic in Guinea Pigs, Rabbits, and Nonhuman Primates
journal, March 2008

  • Via, L. E.; Lin, P. L.; Ray, S. M.
  • Infection and Immunity, Vol. 76, Issue 6
  • DOI: 10.1128/IAI.01515-07

Dosage Regimens of Antibacterials: Implications of a Pharmacokinetic/Pharmacodynamic Model
journal, January 1996


Review on Pharmacokinetics and Pharmacodynamics and the Aging Kidney
journal, January 2010

  • Aymanns, Christian; Keller, Frieder; Maus, Sebastian
  • Clinical Journal of the American Society of Nephrology, Vol. 5, Issue 2
  • DOI: 10.2215/CJN.03960609

Use of whole genome sequencing to estimate the mutation rate of Mycobacterium tuberculosis during latent infection
journal, April 2011

  • Ford, Christopher B.; Lin, Philana Ling; Chase, Michael R.
  • Nature Genetics, Vol. 43, Issue 5
  • DOI: 10.1038/ng.811

Induction of Mycobacterial Resistance to Quinolone Class Antimicrobials
journal, May 2012

  • Malik, Muhammad; Chavda, Kalyan; Zhao, Xilin
  • Antimicrobial Agents and Chemotherapy, Vol. 56, Issue 7
  • DOI: 10.1128/AAC.00474-12

Immune activation of the host cell induces drug tolerance in Mycobacterium tuberculosis both in vitro and in vivo
journal, April 2016

  • Liu, Yancheng; Tan, Shumin; Huang, Lu
  • The Journal of Experimental Medicine, Vol. 213, Issue 5
  • DOI: 10.1084/jem.20151248

Microbial phenotypic heterogeneity and antibiotic tolerance
journal, February 2007


Stress and Host Immunity Amplify Mycobacterium tuberculosis Phenotypic Heterogeneity and Induce Nongrowing Metabolically Active Forms
journal, January 2015


Asymmetry and Aging of Mycobacterial Cells Lead to Variable Growth and Antibiotic Susceptibility
journal, December 2011

  • Aldridge, Bree B.; Fernandez-Suarez, Marta; Heller, Danielle
  • Science, Vol. 335, Issue 6064
  • DOI: 10.1126/science.1216166

The Spectrum of Drug Susceptibility in Mycobacteria
journal, October 2014


Effect of Mutation and Genetic Background on Drug Resistance in Mycobacterium tuberculosis
journal, April 2012

  • Fenner, Lukas; Egger, Matthias; Bodmer, Thomas
  • Antimicrobial Agents and Chemotherapy, Vol. 56, Issue 6
  • DOI: 10.1128/AAC.06460-11

Contribution of Efflux to the Emergence of Isoniazid and Multidrug Resistance in Mycobacterium tuberculosis
journal, April 2012


Comparison of Fitness of Two Isolates of Mycobacterium tuberculosis, one of Which had Developed Multi-drug Resistance During the Course of Treatment
journal, September 2000

  • Davies, A. P.; Billington, O. J.; Bannister, B. A.
  • Journal of Infection, Vol. 41, Issue 2
  • DOI: 10.1053/jinf.2000.0711

Fitness cost of drug resistance inMycobacterium tuberculosis
journal, January 2009


Effect of rpoB Mutations Conferring Rifampin Resistance on Fitness of Mycobacterium tuberculosis
journal, March 2004


Evaluation of wild-type MIC distributions as a tool for determination of clinical breakpoints for Mycobacterium tuberculosis
journal, July 2009

  • Schon, T.; Jureen, P.; Giske, C. G.
  • Journal of Antimicrobial Chemotherapy, Vol. 64, Issue 4
  • DOI: 10.1093/jac/dkp262

The heterogeneous evolution of multidrug-resistant Mycobacterium tuberculosis
journal, March 2013


Fitness cost of antibiotic susceptibility during bacterial infection
journal, July 2015


Strain diversity, epistasis and the evolution of drug resistance in Mycobacterium tuberculosis
journal, June 2011


Fitness-compensatory mutations in rifampicin-resistant RNA polymerase: Fitness compensation of RifR
journal, May 2012


Putative Compensatory Mutations in the rpoC Gene of Rifampin-Resistant Mycobacterium tuberculosis Are Associated with Ongoing Transmission
journal, December 2012

  • de Vos, M.; Muller, B.; Borrell, S.
  • Antimicrobial Agents and Chemotherapy, Vol. 57, Issue 2
  • DOI: 10.1128/AAC.01541-12

Compensatory ahpC Gene Expression in Isoniazid-Resistant Mycobacterium tuberculosis
journal, June 1996


Integrating Antimicrobial Therapy with Host Immunity to Fight Drug-Resistant Infections: Classical vs. Adaptive Treatment
journal, April 2016


Drug-resistance in patients with pulmonary tuberculosis presenting at chest clinics in Hong Kong
journal, June 1964


T cell repertoire scanning is promoted by dynamic dendritic cell behavior and random T cell motility in the lymph node
journal, January 2004

  • Miller, M. J.; Hejazi, A. S.; Wei, S. H.
  • Proceedings of the National Academy of Sciences, Vol. 101, Issue 4
  • DOI: 10.1073/pnas.0306407101

A methodology for performing global uncertainty and sensitivity analysis in systems biology
journal, September 2008

  • Marino, Simeone; Hogue, Ian B.; Ray, Christian J.
  • Journal of Theoretical Biology, Vol. 254, Issue 1
  • DOI: 10.1016/j.jtbi.2008.04.011

Tuberculosis Drug Resistance Mutation Database
journal, February 2009


Detection of mutations associated with isoniazid resistance in multidrug-resistant Mycobacterium tuberculosis clinical isolates
journal, May 2014

  • Jagielski, Tomasz; Bakuła, Zofia; Roeske, Katarzyna
  • Journal of Antimicrobial Chemotherapy, Vol. 69, Issue 9
  • DOI: 10.1093/jac/dku161

Evolution and transmission of drug-resistant tuberculosis in a Russian population
journal, January 2014

  • Casali, Nicola; Nikolayevskyy, Vladyslav; Balabanova, Yanina
  • Nature Genetics, Vol. 46, Issue 3
  • DOI: 10.1038/ng.2878

PET/CT imaging correlates with treatment outcome in patients with multidrug-resistant tuberculosis
journal, December 2014


Epistasis between antibiotic resistance mutations drives the evolution of extensively drug-resistant tuberculosis
journal, January 2013

  • Borrell, Sònia; Teo, Youjin; Giardina, Federica
  • Evolution, Medicine, and Public Health, Vol. 2013, Issue 1
  • DOI: 10.1093/emph/eot003

Intracellular growth and drug susceptibility of Mycobacterium tuberculosis in macrophages
journal, March 2007


Differential drug susceptibility of intracellular and extracellular tuberculosis, and the impact of P-glycoprotein
journal, May 2007


Pharmacokinetics-Pharmacodynamics of Rifampin in an Aerosol Infection Model of Tuberculosis
journal, July 2003


Isoniazid Pharmacokinetics-Pharmacodynamics in an Aerosol Infection Model of Tuberculosis
journal, July 2004


Comprehensive physicochemical, pharmacokinetic and activity profiling of anti-TB agents
journal, November 2014

  • Lakshminarayana, Suresh B.; Huat, Tan Bee; Ho, Paul C.
  • Journal of Antimicrobial Chemotherapy, Vol. 70, Issue 3
  • DOI: 10.1093/jac/dku457

The association between sterilizing activity and drug distribution into tuberculosis lesions
journal, September 2015

  • Prideaux, Brendan; Via, Laura E.; Zimmerman, Matthew D.
  • Nature Medicine, Vol. 21, Issue 10
  • DOI: 10.1038/nm.3937

Time-kill kinetics of anti-tuberculosis drugs, and emergence of resistance, in relation to metabolic activity of Mycobacterium tuberculosis
journal, October 2010

  • de Steenwinkel, J. E. M.; de Knegt, G. J.; ten Kate, M. T.
  • Journal of Antimicrobial Chemotherapy, Vol. 65, Issue 12
  • DOI: 10.1093/jac/dkq374

Acquired Resistance to Bedaquiline and Delamanid in Therapy for Tuberculosis
journal, November 2015

  • Bloemberg, Guido V.; Keller, Peter M.; Stucki, David
  • New England Journal of Medicine, Vol. 373, Issue 20
  • DOI: 10.1056/NEJMc1505196

Rapid emergence of Mycobacterium tuberculosis bedaquiline resistance: lessons to avoid repeating past errors
journal, December 2016

  • Veziris, Nicolas; Bernard, Christine; Guglielmetti, Lorenzo
  • European Respiratory Journal, Vol. 49, Issue 3
  • DOI: 10.1183/13993003.01719-2016

Mutations Prevalent among Rifampin- and Isoniazid-Resistant Mycobacterium tuberculosis Isolates from a Hospital in Vietnam
journal, July 2006

  • Caws, M.; Duy, P. M.; Tho, D. Q.
  • Journal of Clinical Microbiology, Vol. 44, Issue 7
  • DOI: 10.1128/JCM.00330-06

Mycobacterium tuberculosis and Rifampin Resistance, United Kingdom
journal, May 2006

  • Sam, I-Ching; Drobniewski, Francis; More, Philip
  • Emerging Infectious Diseases, Vol. 12, Issue 5
  • DOI: 10.3201/eid1205.041339

Characterization of Host and Microbial Determinants in Individuals with Latent Tuberculosis Infection Using a Human Granuloma Model
journal, February 2015


A 3D Human Lung Tissue Model for Functional Studies on <em>Mycobacterium tuberculosis</em> Infection
journal, January 2015

  • Braian, Clara; Svensson, Mattias; Brighenti, Susanna
  • Journal of Visualized Experiments, Issue 104
  • DOI: 10.3791/53084

A Bioengineered Three-Dimensional Cell Culture Platform Integrated with Microfluidics To Address Antimicrobial Resistance in Tuberculosis
journal, February 2017

  • Bielecka, Magdalena K.; Tezera, Liku B.; Zmijan, Robert
  • mBio, Vol. 8, Issue 1
  • DOI: 10.1128/mBio.02073-16

Relapse, re-infection and mixed infections in tuberculosis disease
journal, February 2017

  • McIvor, Amanda; Koornhof, Hendrik; Kana, Bavesh Davandra
  • Pathogens and Disease, Vol. 75, Issue 3
  • DOI: 10.1093/femspd/ftx020

Minimal inhibitory concentration of isoniazid in isoniazid-resistant Mycobacterium tuberculosis isolates from children
journal, February 2007

  • Schaaf, H. S.; Victor, T. C.; Engelke, E.
  • European Journal of Clinical Microbiology & Infectious Diseases, Vol. 26, Issue 3
  • DOI: 10.1007/s10096-007-0257-9

Treatment Outcomes in Low-Level Isoniazid Resistant Tuberculosis
journal, January 2016

  • Isaac, Abraam; Kunimoto, Dennis
  • Open Forum Infectious Diseases, Vol. 3, Issue suppl_1
  • DOI: 10.1093/ofid/ofw172.422

High-dose rifampicin: how do we proceed? [Correspondence]
journal, August 2011

  • Boeree, M. J.; Plemper van Balen, G.; Aarnoutse, R. A.
  • The International Journal of Tuberculosis and Lung Disease, Vol. 15, Issue 8
  • DOI: 10.5588/ijtld.11.0198

High-Dose Rifapentine with Moxifloxacin for Pulmonary Tuberculosis
journal, October 2014

  • Jindani, Amina; Harrison, Thomas S.; Nunn, Andrew J.
  • New England Journal of Medicine, Vol. 371, Issue 17
  • DOI: 10.1056/NEJMoa1314210

High-dose rifampicin, moxifloxacin, and SQ109 for treating tuberculosis: a multi-arm, multi-stage randomised controlled trial
journal, January 2017


Factors associated with default from treatment among tuberculosis patients in nairobi province, Kenya: A case control study
journal, September 2011

  • Muture, Bernard N.; Keraka, Margaret N.; Kimuu, Peter K.
  • BMC Public Health, Vol. 11, Issue 1
  • DOI: 10.1186/1471-2458-11-696

Combined Use of Delamanid and Bedaquiline to Treat Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis: A Systematic Review
journal, February 2017

  • Migliori, Giovanni; Pontali, Emanuele; Sotgiu, Giovanni
  • International Journal of Molecular Sciences, Vol. 18, Issue 2
  • DOI: 10.3390/ijms18020341

Current strategies to treat tuberculosis
journal, January 2016


Applying Optimization Algorithms to Tuberculosis Antibiotic Treatment Regimens
journal, August 2017

  • Cicchese, Joseph M.; Pienaar, Elsje; Kirschner, Denise E.
  • Cellular and Molecular Bioengineering, Vol. 10, Issue 6
  • DOI: 10.1007/s12195-017-0507-6