#Global #burden of #latent #MDR #tuberculosis: #trends and #estimates based on mathematical modelling (Lancet Infect Dis., abstract)

[Source: The Lancet Infectious Diseases, full page: (LINK). Abstract, edited.]

Global burden of latent multidrug-resistant tuberculosis: trends and estimates based on mathematical modelling

Gwenan M Knight, PhD, C Finn McQuaid, PhD, Peter J Dodd, PhD †, Rein M G J Houben, PhD †

Open Access / Published: July 04, 2019 / DOI: https://doi.org/10.1016/S1473-3099(19)30307-X




To end the global tuberculosis epidemic, latent tuberculosis infection needs to be addressed. All standard treatments for latent tuberculosis contain drugs to which multidrug-resistant (MDR) Mycobacterium tuberculosis is resistant. We aimed to estimate the global burden of multidrug-resistant latent tuberculosis infection to inform tuberculosis elimination policy.


By fitting a flexible statistical model to tuberculosis drug resistance surveillance and survey data collated by WHO, we estimated national trends in the proportion of new tuberculosis cases that were caused by MDR strains. We used these data as a proxy for the proportion of new infections caused by MDR M tuberculosis and multiplied trends in annual risk of infection from previous estimates of the burden of latent tuberculosis to generate trends in the annual risk of infection with MDR M tuberculosis. These estimates were used in a cohort model to estimate changes in the global and national prevalence of latent infection with MDR M tuberculosis. We also estimated recent infection levels (ie, in 2013 and 2014) and made predictions for the future burden of MDR tuberculosis in 2035 and 2050.


19·1 million (95% uncertainty interval [UI] 16·4 million–21·7 million) people were latently infected with MDR tuberculosis in 2014—a global prevalence of 0·3% (95% UI 0·2–0·3). MDR strains accounted for 1·2% (95% UI 1·0–1·4) of the total latent tuberculosis burden overall, but for 2·9% (95% UI 2·6–3·1) of the burden among children younger than 15 years (risk ratio for those younger than 15 years vsthose aged 15 years or older 2·65 [95% UI 2·11–3·25]). Recent latent infection with MDR M tuberculosis meant that 1·9 million (95% UI 1·7 million–2·3 million) people globally were at high risk of active MDR tuberculosis in 2015.


We estimate that three in every 1000 people globally carry latent MDR tuberculosis infection, and prevalence is around ten times higher among those younger than 15 years. If current trends continue, the proportion of latent tuberculosis caused by MDR strains will increase, which will pose serious challenges for management of latent tuberculosis—a cornerstone of tuberculosis elimination strategies.


UK Medical Research Council, Bill & Melinda Gates Foundation, and European Research Council.

Keywords: Antibiotics; Drugs Resistance; Tuberculosis; Worldwide.



Acquisition of cross- #resistance to #Bedaquiline and #Clofazimine following #treatment for #Tuberculosis in #Pakistan (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Acquisition of cross-resistance to Bedaquiline and Clofazimine following treatment for Tuberculosis in Pakistan

Arash Ghodousi, Alamdar Hussain Rizvi, Aurangzaib Quadir Baloch, Abdul Ghafoor, Faisal Masood Khanzada, Mehmood Qadir, Emanuele Borroni, Alberto Trovato, Sabira Tahseen,Daniela Maria Cirillo

DOI: 10.1128/AAC.00915-19



We report on the first six cases of acquired-resistance to bedaquiline in Pakistan. Seventy sequential isolates from 30 drug-resistant tuberculosis patients on bedaquiline-containing regimens were retrospectively tested for bedaquiline resistance by MIC test and by detection of mutations in relevant genes. We documented cases failing therapy developed specific mutations in Rv0678 and increased MICs associated with cross-resistance to clofazimine during treatment. This study underlines the relevance of surveillance programs following the introduction of new drugs.

Copyright © 2019 Ghodousi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

Keywords: Antibiotics; Drugs Resistance; Tuberculosis; Pakistan; Bedaquiline; Clofazimine.


Managing #tuberculosis in the #Baltic states (Lancet Resp Med., summary)

[Source: Lancet Respiratory Medicine, full page: (LINK). Summary, edited.]

Managing tuberculosis in the Baltic states

Vijay Shankar Balakrishnan

Published: June 17, 2019 / DOI: https://doi.org/10.1016/S2213-2600(19)30219-X


In March, WHO and the European Centre for Disease Prevention and Control (ECDC) jointly released the latest tuberculosis surveillance and monitoring report. The report included a mixture of good and bad news about the management of tuberculosis in the Baltic states (Estonia, Latvia, and Lithuania), which are in fierce competition to eliminate tuberculosis by 2030.



Copyright © 2019 Elsevier Ltd. All rights reserved.

Keywords: Tuberculosis; Public Health; Estonia; Lithuania; Latvia.


High rate of #transmission in a pulmonary #tuberculosis #outbreak in a primary #school, north-eastern #Italy, 2019 (Euro Surveill., abstract)

[Source: Eurosurveillance, full page: (LINK). Abstract, edited.]

High rate of transmission in a pulmonary tuberculosis outbreak in a primary school, north-eastern Italy, 2019

Sandro Cinquetti1, Maria Dalmanzio1, Elisa Ros1, Davide Gentili1,2, Mauro Ramigni3, Adriano Grossi4,5, Xanthi D Andrianou5,6, Leonardo Ermanno La Torre7, Roberto Rigoli8, Pier Giorgio Scotton9, Angela Taraschi10, Vincenzo Baldo11, Giuseppina Napoletano12, Francesca Russo12, Patrizio Pezzotti5, Giovanni Rezza5, Antonietta Filia5

Affiliations: 1 Public Health Office , Local Health Unit 2 Marca Trevigiana, Treviso, Italy; 2 Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy; 3 Epidemiology Office, Local Health Unit 2 Marca Trevigiana, Treviso, Italy; 4 University Cattolica del Sacro Cuore, Rome, Italy; 5 Department of Infectious Diseases, National Health Institute (Istituto Superiore di Sanità), Rome, Italy; 6 European Programme for Intervention Epidemiology Training (EPIET), European Centre for Disease Prevention and Control (ECDC), Stockholm, Sweden; 7 Department of Radiology, Oderzo Hospital, Local Health Unit 2 Marca Trevigiana, Treviso, Italy; 8 Department of Microbiology, Treviso Hospital, Local Health Unit 2 Marca Trevigiana, Treviso, Italy; 9 Department of Infectious Diseases, Treviso Hospital, Local Health Unit 2 Marca Trevigiana, Treviso, Italy; 10 Department of Pediatrics, Oderzo Hospital, Local Health Unit 2 Marca Trevigiana, Treviso, Italy; 11 Hygiene and Public Health Unit, University of Padua, Padua, Italy; 12 Prevention Department, Veneto Regional Health Authority, Venice, Italy

Correspondence: Antonietta Filiaantonietta.filiaiss.it

Citation style for this article: Cinquetti Sandro, Dalmanzio Maria, Ros Elisa, Gentili Davide, Ramigni Mauro, Grossi Adriano, Andrianou Xanthi D, La Torre Leonardo Ermanno, Rigoli Roberto, Scotton Pier Giorgio, Taraschi Angela, Baldo Vincenzo, Napoletano Giuseppina, Russo Francesca, Pezzotti Patrizio, Rezza Giovanni, Filia Antonietta. High rate of transmission in a pulmonary tuberculosis outbreak in a primary school, north-eastern Italy, 2019. Euro Surveill. 2019;24(24):pii=1900332. https://doi.org/10.2807/1560-7917.ES.2019.24.24.1900332

Received: 24 May 2019;   Accepted: 13 Jun 2019



Italy is a low-incidence country for tuberculosis (TB). We describe a TB outbreak in a primary school in north-eastern Italy, involving 10 cases of active pulmonary disease and 42 cases of latent infection. The index case was detected in March 2019, while the primary case, an Italian-born schoolteacher, was likely infectious since January 2018. Administration of a pre-employment health questionnaire to school staff with sustained contact with children should be considered in low-incidence countries.

© This work is licensed under a Creative Commons Attribution 4.0 International License.

Keywords: TB; Institutional outbreaks; Italy.


Boosting #BCG with proteins or #rAd5 does not enhance #protection against #tuberculosis in rhesus macaques (npj Vaccines, abstract)

[Source: npj Vaccines, full page: (LINK). Abstract, edited.]

Article | OPEN | Published: 28 May 2019

Boosting BCG with proteins or rAd5 does not enhance protection against tuberculosis in rhesus macaques

Patricia A. Darrah, Robert M. DiFazio, Pauline Maiello, Hannah P. Gideon, Amy J. Myers, Mark A. Rodgers, Joshua A. Hackney, Thomas Lindenstrom, Thomas Evans, Charles A. Scanga, Victor Prikhodko, Peter Andersen, Philana Ling Lin, Dominick Laddy, Mario Roederer, Robert A. Seder & JoAnne L. Flynn

npj Vaccines 4, Article number: 21 (2019)



Tuberculosis (TB) is the leading cause of death from infection worldwide. The only approved vaccine, BCG, has variable protective efficacy against pulmonary TB, the transmissible form of the disease. Therefore, improving this efficacy is an urgent priority. This study assessed whether heterologous prime-boost vaccine regimens in which BCG priming is boosted with either (i) protein and adjuvant (M72 plus AS01E or H56 plus CAF01) delivered intramuscularly (IM), or (ii) replication-defective recombinant adenovirus serotype 5 (Ad5) expressing various Mycobacterium tuberculosis (Mtb) antigens (Ad5(TB): M72, ESAT-6/Ag85b, or ESAT-6/Rv1733/Rv2626/RpfD) administered simultaneously by IM and aerosol (AE) routes, could enhance blood- and lung-localized T-cell immunity and improve protection in a nonhuman primate (NHP) model of TB infection. Ad5(TB) vaccines administered by AE/IM routes following BCG priming elicited ~10–30% antigen-specific CD4 and CD8 T-cell multifunctional cytokine responses in bronchoalveolar lavage (BAL) but did not provide additional protection compared to BCG alone. Moreover, AE administration of an Ad5(empty) control vector after BCG priming appeared to diminish protection induced by BCG. Boosting BCG by IM immunization of M72/AS01E or H56:CAF01 elicited ~0.1–0.3% antigen-specific CD4 cytokine responses in blood with only a transient increase of ~0.5–1% in BAL; these vaccine regimens also failed to enhance BCG-induced protection. Taken together, this study shows that boosting BCG with protein/adjuvant or Ad-based vaccines using these antigens, by IM or IM/AE routes, respectively, do not enhance protection against primary infection compared with BCG alone, in the highly susceptible rhesus macaque model of tuberculosis.

Keywords: Tuberculosis; BCG; Vaccines; Animal models.


#Linezolid #resistance in patients with drug-resistant #TB and treatment failure in South Africa (J Antimicrob Chemother., abstract)

[Source: Journal of Antimicrobial Chemotherapy, full page: (LINK). Abstract, edited.]

Linezolid resistance in patients with drug-resistant TB and treatment failure in South Africa

Sean Wasserman, Gail Louw, Limpho Ramangoaela, Garrick Barber, Cindy Hayes, Shaheed Vally Omar, Gary Maartens, Clifton Barry, III, Taeksun Song, Graeme Meintjes

Journal of Antimicrobial Chemotherapy, dkz206, https://doi.org/10.1093/jac/dkz206

Published: 12 May 2019




Limited data exist on clinical associations and genotypic correlates of linezolid resistance in Mycobacterium tuberculosis. We aimed to describe mutations and clinical factors associated with phenotypic linezolid resistance from patients with drug-resistant TB at two public sector facilities in South Africa.


Adults and adolescents with treatment failure (culture positivity ≥4 months) on a linezolid-containing regimen were retrospectively identified. Phenotypic resistance, as defined by a linezolid MIC >1 mg/L, was assessed for retrieved isolates using broth microdilution. Targeted sequencing of rrl and rplC was performed, irrespective of growth on subculture.


Thirty-nine patients with linezolid-based treatment failure were identified, 13 (33%) of whom had phenotypic or genotypic linezolid resistance after a median duration of 22 months (range = 7–32) of linezolid therapy. Paired MIC testing and genotyping was performed on 55 unique isolates. All isolates with phenotypic resistance (n = 16) were associated with known resistance mutations, most frequently due to the T460C substitution in rplC (n = 10); rrlmutations included G2814T, G2270C/T and A2810C. No mutations were detected in isolates with MICs at or below the critical concentration.


Linezolid resistance occurred in a third of patients with drug-resistant TB and treatment failure. Resistance occurred late and was predicted by a limited number of mutations in rrl and rplC. Screening for genotypic resistance should be considered for patients with a positive culture after 4 months of linezolid therapy in order to optimize treatment and avoid the toxicity of ineffective linezolid therapy.

Topic: phenotype – mutation – south africa – treatment failure – linezolid
– drug-resistant tuberculosis


Keywords: Antibiotics; Drugs Resistance; Linezolid; Tuberculosis; S. Africa.


#Chemical disarming of #isoniazid resistance in #Mycobacterium tuberculosis (Proc Natl Acad Sci USA, abstract)

[Source: Proceedings of the National Academy  of Sciences of the United States of America, full page: (LINK). Abstract, edited.]

Chemical disarming of isoniazid resistance in Mycobacterium tuberculosis

Kelly Flentie, Gregory A. Harrison, Hasan Tükenmez, Jonathan Livny, James A. D. Good, Souvik Sarkar, Dennis X. Zhu, Rachel L. Kinsella, Leslie A. Weiss, Samantha D. Solomon, Miranda E. Schene, Mette R. Hansen, Andrew G. Cairns, Martina Kulén, Torbjörn Wixe, Anders E. G. Lindgren, Erik Chorell, Christoffer Bengtsson, K. Syam Krishnan, Scott J. Hultgren, Christer Larsson, Fredrik Almqvist, and Christina L. Stallings

PNAS first published May 6, 2019 / DOI: https://doi.org/10.1073/pnas.1818009116

Edited by Caroline S. Harwood, University of Washington, Seattle, WA, and approved April 5, 2019 (received for review October 22, 2018)



Mycobacterium tuberculosis (Mtb) causes the disease tuberculosis (TB), which kills more people than any other infection. The emergence of drug-resistant Mtb strains has exacerbated this already alarming epidemic. We have identified a small molecule, C10, that potentiates the activity of the frontline antibiotic isoniazid (INH) and prevents the selection for INH-resistant mutants. We find that C10 can even reverse INH resistance in Mtb. Therefore, our study reveals vulnerabilities that can be exploited to reverse INH resistance in Mtb.



Mycobacterium tuberculosis (Mtb) killed more people in 2017 than any other single infectious agent. This dangerous pathogen is able to withstand stresses imposed by the immune system and tolerate exposure to antibiotics, resulting in persistent infection. The global tuberculosis (TB) epidemic has been exacerbated by the emergence of mutant strains of Mtb that are resistant to frontline antibiotics. Thus, both phenotypic drug tolerance and genetic drug resistance are major obstacles to successful TB therapy. Using a chemical approach to identify compounds that block stress and drug tolerance, as opposed to traditional screens for compounds that kill Mtb, we identified a small molecule, C10, that blocks tolerance to oxidative stress, acid stress, and the frontline antibiotic isoniazid (INH). In addition, we found that C10 prevents the selection for INH-resistant mutants and restores INH sensitivity in otherwise INH-resistant Mtb strains harboring mutations in the katG gene, which encodes the enzyme that converts the prodrug INH to its active form. Through mechanistic studies, we discovered that C10 inhibits Mtb respiration, revealing a link between respiration homeostasis and INH sensitivity. Therefore, by using C10 to dissect Mtb persistence, we discovered that INH resistance is not absolute and can be reversed.

Mycobacterium tuberculosis – drug tolerance – antibiotic resistance – isoniazid – respiration



1 K.F. and G.A.H. contributed equally to this work.

2 To whom correspondence may be addressed. Email: fredrik.almqvist@umu.se or stallings@wustl.edu.

Author contributions: K.F., G.A.H., and C.L.S. designed research; K.F., G.A.H., H.T., J.L., D.X.Z., R.L.K., L.A.W., S.D.S., M.E.S., and C.L. performed research; J.L., J.A.D.G., S.S., M.R.H., A.G.C., M.K., T.W., A.E.G.L., E.C., C.B., K.S.K., and F.A. contributed new reagents/analytic tools; K.F., G.A.H., H.T., J.L., J.A.D.G., D.X.Z., R.L.K., L.A.W., S.D.S., M.E.S., S.J.H., C.L., F.A., and C.L.S. analyzed data; and K.F., G.A.H., and C.L.S. wrote the paper.

Conflict of interest statement: C.L.S., S.J.H., and F.A. have ownership interests in Quretech Bio AB, which licenses C10.

This article is a PNAS Direct Submission.

Data Deposition: The RNA-sequencing data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, https://www.ncbi.nlm.nih.gov/geo (accession no. GSE129835).

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1818009116/-/DCSupplemental.

Published under the PNAS license.

Keywords: Tuberculosis; Antibiotics; Drugs Resistance; Isoniazid.