Medical Abstracts

Keyword: tuberculosis

1. N Engl J Med. 2018 Nov 15;379(20):1915-1925. doi: 10.1056/NEJMoa1800762.

Prednisone for the Prevention of Paradoxical Tuberculosis-Associated IRIS.

Meintjes G(1), Stek C(1), Blumenthal L(1), Thienemann F(1), Schutz C(1), Buyze

J(1), Ravinetto R(1), van Loen H(1), Nair A(1), Jackson A(1), Colebunders R(1),

Maartens G(1), Wilkinson RJ(1), Lynen L(1); PredART Trial Team.

Author information:

(1)From the Wellcome Centre for Infectious Diseases Research in Africa, Institute

of Infectious Disease and Molecular Medicine (G. Meintjes, C. Stek, L.B., F.T.,

C. Schutz, A.N., A.J., R.J.W.), the Department of Medicine (G. Meintjes, C. Stek,

F.T., C. Schutz, R.J.W.), and the Division of Clinical Pharmacology, Department

of Medicine (G. Maartens), University of Cape Town, Cape Town, South Africa; the

Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium

(C. Stek, J.B., R.R., H.L., R.C., L.L.); the Department of Internal Medicine,

University Hospital of Zurich, Zurich, Switzerland (F.T.); and the Department of

Medicine, Imperial College London and the Francis Crick Institute, London

(R.J.W.).

BACKGROUND: Early initiation of antiretroviral therapy (ART) in human

immunodeficiency virus (HIV)-infected patients who have tuberculosis reduces

mortality among patients with low CD4 counts, but it increases the risk of

paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome

(IRIS).

METHODS: We conducted this randomized, double-blind, placebo-controlled trial to

assess whether prophylactic prednisone can safely reduce the incidence of

paradoxical tuberculosis-associated IRIS in patients at high risk for the

syndrome. We enrolled HIV-infected patients who were initiating ART (and had not

previously received ART), had started tuberculosis treatment within 30 days

before initiating ART, and had a CD4 count of 100 cells or fewer per microliter.

Patients received either prednisone (at a dose of 40 mg per day for 14 days, then

20 mg per day for 14 days) or placebo. The primary end point was the development

of tuberculosis-associated IRIS within 12 weeks after initiating ART, as

adjudicated by an independent committee.

RESULTS: Among the 240 patients who were enrolled, the median age was 36

(interquartile range, 30 to 42), 60% were men, and 73% had microbiologically

confirmed tuberculosis; the median CD4 count was 49 cells per microliter

(interquartile range, 24 to 86), and the median HIV type 1 RNA viral load was 5.5

log10 copies per milliliter (interquartile range, 5.2 to 5.9). A total of 120

patients were assigned to each group, and 18 patients were lost to follow-up or

withdrew. Tuberculosis-associated IRIS was diagnosed in 39 patients (32.5%) in

the prednisone group and in 56 (46.7%) in the placebo group (relative risk, 0.70;

95% confidence interval [CI], 0.51 to 0.96; P=0.03). Open-label glucocorticoids

were prescribed to treat tuberculosis-associated IRIS in 16 patients (13.3%) in

the prednisone group and in 34 (28.3%) in the placebo group (relative risk, 0.47;

95% CI, 0.27 to 0.81). There were five deaths in the prednisone group and four in

the placebo group (P=1.00). Severe infections (acquired immunodeficiency

syndrome-defining illnesses or invasive bacterial infections) occurred in 11

patients in the prednisone group and in 18 patients in the placebo group

(P=0.23). One case of Kaposi's sarcoma occurred in the placebo group.

CONCLUSIONS: Prednisone treatment during the first 4 weeks after the initiation

of ART for HIV infection resulted in a lower incidence of tuberculosis-associated

IRIS than placebo, without evidence of an increased risk of severe infections or

cancers. (Funded by the European and Developing Countries Clinical Trials

Partnership and others; PredART ClinicalTrials.gov number, NCT01924286 .).

DOI: 10.1056/NEJMoa1800762

PMID: 30428290 [Indexed for MEDLINE]

2. Chem Rev. 2018 Nov 26. doi: 10.1021/acs.chemrev.8b00285. [Epub ahead of print]

Iron Acquisition in Mycobacterium tuberculosis.

Chao A, Sieminski PJ, Owens CP(1), Goulding CW.

Author information:

(1)Schmid College of Science and Technology , Chapman University , Orange ,

California 92866 , United States.

The highly contagious disease tuberculosis (TB) is caused by the bacterium

Mycobacterium tuberculosis (Mtb), which has been evolving drug resistance at an

alarming rate. Like all human pathogens, Mtb requires iron for growth and

virulence. Consequently, Mtb iron transport is an emerging drug target. However,

the development of anti-TB drugs aimed at these metabolic pathways has been

restricted by the dearth of information on Mtb iron acquisition. In this Review,

we describe the multiple strategies utilized by Mtb to acquire ferric iron and

heme iron. Mtb iron uptake is a complex process, requiring biosynthesis and

subsequent export of Mtb siderophores, followed by ferric iron scavenging and

ferric-siderophore import into Mtb. Additionally, Mtb possesses two possible heme

uptake pathways and an Mtb-specific mechanism of heme degradation that yields

iron and novel heme-degradation products. We conclude with perspectives for

potential therapeutics that could directly target Mtb heme and iron uptake

machineries. We also highlight how hijacking Mtb heme and iron acquisition

pathways for drug import may facilitate drug transport through the notoriously

impregnable Mtb cell wall.

DOI: 10.1021/acs.chemrev.8b00285

PMID: 30474981

3. Nat Med. 2018 Nov;24(11):1708-1715. doi: 10.1038/s41591-018-0224-2. Epub 2018 Nov 5.

A patient-level pooled analysis of treatment-shortening regimens for

drug-susceptible pulmonary tuberculosis.

Imperial MZ(1), Nahid P(1), Phillips PPJ(1), Davies GR(2), Fielding K(3), Hanna

D(4)(5), Hermann D(5), Wallis RS(6), Johnson JL(7)(8), Lienhardt C(9)(10), Savic

RM(11).

Author information:

(1)University of California, San Francisco, San Francisco, CA, USA.

(2)University of Liverpool, Liverpool, UK.

(3)London School of Hygiene and Tropical Medicine, London, UK.

(4)Critical Path Institute, Tucson, AZ, USA.

(5)Bill and Melinda Gates Foundation, Seattle, WA, USA.

(6)Aurum Institute and ACT4TB/HIV, Johannesburg, South Africa.

(7)Case Western Reserve University, Cleveland, OH, USA.

(8)University Hospitals Cleveland Medical Center, Cleveland, OH, USA.

(9)Global Tuberculosis Programme, World Health Organization, Geneva, Switzerland.

(10)Unité Mixte Internationale TransVIHMI (UMI 233 IRD-U1175 INSERM-Université de

Montpellier), Institut de Recherche pour le Développement (IRD), Montpellier,

France.

(11)University of California, San Francisco, San Francisco, CA, USA.

rada.savic@ucsf.edu.

Erratum in

Nat Med. 2019 Jan;25(1):190.

Tuberculosis kills more people than any other infectious disease. Three pivotal

trials testing 4-month regimens failed to meet non-inferiority margins; however,

approximately four-fifths of participants were cured. Through a pooled analysis

of patient-level data with external validation, we identify populations eligible

for 4-month treatment, define phenotypes that are hard to treat and evaluate the

impact of adherence and dosing strategy on outcomes. In 3,405 participants

included in analyses, baseline smear grade of 3+ relative to <2+, HIV

seropositivity and adherence of ≤90% were significant risk factors for

unfavorable outcome. Four-month regimens were non-inferior in participants with

minimal disease defined by <2+ sputum smear grade or non-cavitary disease. A

hard-to-treat phenotype, defined by high smear grades and cavitation, may require

durations >6 months to cure all. Regimen duration can be selected in order to

improve outcomes, providing a stratified medicine approach as an alternative to

the 'one-size-fits-all' treatment currently used worldwide.

DOI: 10.1038/s41591-018-0224-2

PMID: 30397355

4. Nat Immunol. 2018 Nov;19(11):1159-1168. doi: 10.1038/s41590-018-0225-9. Epub 2018 Oct 17.

The value of transcriptomics in advancing knowledge of the immune response and

diagnosis in tuberculosis.

Singhania A(1), Wilkinson RJ(2)(3)(4), Rodrigue M(5), Haldar P(6), O'Garra

A(7)(8).

Author information:

(1)Laboratory of Immunoregulation and Infection, The Francis Crick Institute,

London, UK.

(2)Laboratory of Tuberculosis, The Francis Crick Institute, London, UK.

(3)Department of Medicine, Imperial College London, London, UK.

(4)Wellcome Centre for Infectious Diseases Research in Africa, University of Cape

Town, Observatory, 7925, Cape Town, Republic of South Africa.

(5)Medical Diagnostic Discovery Department, bioMerieux SA, Marcy l'Etoile,

France.

(6)Respiratory Biomedical Research Centre, Institute for Lung Health, Department

of Infection Immunity and Inflammation, University of Leicester, Leicester, UK.

(7)Laboratory of Immunoregulation and Infection, The Francis Crick Institute,

London, UK. anne.ogarra@crick.ac.uk.

(8)National Heart and Lung Institute, Imperial College London, London, UK.

anne.ogarra@crick.ac.uk.

Blood transcriptomics analysis of tuberculosis has revealed an

interferon-inducible gene signature that diminishes in expression after

successful treatment; this promises improved diagnostics and treatment

monitoring, which are essential for the eradication of tuberculosis. Sensitive

radiography revealing lung abnormalities and blood transcriptomics have

demonstrated heterogeneity in patients with active tuberculosis and exposed

asymptomatic people with latent tuberculosis, suggestive of a continuum of

infection and immune states. Here we describe the immune response to infection

with Mycobacterium tuberculosis revealed through the use of transcriptomics, as

well as differences among clinical phenotypes of infection that might provide

information on temporal changes in host immunity associated with evolving

infection. We also review the diverse blood transcriptional signatures, composed

of small sets of genes, that have been proposed for the diagnosis of tuberculosis

and the identification of at-risk asymptomatic people and suggest novel

approaches for the development of such biomarkers for clinical use.

DOI: 10.1038/s41590-018-0225-9

PMID: 30333612

5. Lancet Infect Dis. 2019 Jan;19(1):46-55. doi: 10.1016/S1473-3099(18)30480-8. Epub 2018 Nov 23.

Substitution of ethambutol with linezolid during the intensive phase of treatment

of pulmonary tuberculosis: a prospective, multicentre, randomised, open-label,

phase 2 trial.

Lee JK(1), Lee JY(2), Kim DK(3), Yoon HI(4), Jeong I(2), Heo EY(1), Park YS(5),

Jo YS(5), Lee JH(4), Park SS(1), Park JS(6), Kim J(2), Lee SM(7), Joh JS(2), Lee

CH(5), Lee J(5), Choi SM(5), Park JH(1), Lee SH(6), Cho YJ(6), Lee YJ(6), Kim

SJ(6), Kwak N(5), Hwang YR(1), Kim H(5), Ki J(2), Lim JN(2), Choi HS(6), Lee

M(8), Song T(8), Kim HS(9), Han J(9), Ahn H(9), Hahn S(10), Yim JJ(11).

Author information:

(1)Division of Pulmonary and Critical Care Medicine, Department of Internal

Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical

Center, Seoul, South Korea.

(2)Division of Pulmonary and Critical Care Medicine, Department of Internal

Medicine, National Medical Center, Seoul, South Korea.

(3)Division of Pulmonary and Critical Care Medicine, Department of Internal

Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical

Center, Seoul, South Korea; Department of Internal Medicine, Seoul National

University College of Medicine, Seoul, South Korea.

(4)Division of Pulmonary and Critical Care Medicine, Department of Internal

Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea;

Department of Internal Medicine, Seoul National University College of Medicine,

Seoul, South Korea.

…

BACKGROUND: Linezolid improves the treatment outcomes of multidrug-resistant

tuberculosis substantially. We investigated whether use of linezolid instead of

ethambutol increases the proportion of sputum culture conversion at 8 weeks of

treatment in patients with pulmonary tuberculosis.

METHODS: We did a phase 2, multicentre, randomised, open-label trial for patients

with pulmonary tuberculosis at the three affiliated hospitals to Seoul National

University and National Medical Center (Seoul-Seongnam, South Korea). Patients,

aged 20-80 years, with a positive sputum for pulmonary tuberculosis, but without

resistance to rifampicin, and current treatment administered for 7 days or fewer,

were randomly assigned at a 1:1:1 ratio into three groups. The control group

received ethambutol (2 months) with isoniazid, rifampicin, and pyrazinamide. The

second group used linezolid (600 mg/day) for 2 weeks and the third group for 4

weeks instead of ethambutol for 2 months. We used a minimisation method to

randomise, and stratified according to institution, cavitation on chest

radiographs, and diabetes. The primary endpoint was the proportion of patients

with negative culture conversion of sputum in liquid media after 8 weeks of

treatment. The results of this trial were analysed primarily in the modified

intention-to-treat population. The trial is registered with ClinicalTrials.gov,

number NCT01994460.

FINDINGS: Between Feb 19, 2014, and Jan 13, 2017, a total of 429 patients were

enrolled and 428 were randomly assigned into either the control group (142

patients), the linezolid 2 weeks group (143 patients), or the linezolid 4 weeks

group (143 patients). Among them, 401 were eligible for primary efficacy

analyses. In the modified intention-to-treat analyses, negative cultures in

liquid media at 8 weeks of treatment were observed in 103 (76·9%) of 134 control

patients, 111 (82·2%) of 135 in the linezolid 2 weeks group, and 100 (75·8%) of

132 in the linezolid 4 weeks groups. The difference from the control group was

5.4% (95% CI -4·3 to 15·0, p=0·28) for the linezolid 2 weeks group and -1·1%

(-11·3 to 9·1, p=0·83) for the linezolid 4 weeks group. Numbers of patients who

experienced at least one adverse event were similar across the groups (86 [62·8%]

of 137 in control, 79 [57·2%] of 138 in the linezolid 2 weeks group, and 75

[62·0%] of 121 in the linezolid 4 weeks group). Resistance to linezolid was not

identified in any patient.

INTERPRETATION: Higher rates of culture conversion at 8 weeks of treatment with

short-term use of linezolid were not observed. However, safety analyses and the

resistance profile suggested the potential role of linezolid in shortening of

treatment for drug-susceptible tuberculosis.

FUNDING: Ministry of Health and Welfare, South Korea.

Copyright © 2019 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S1473-3099(18)30480-8

PMID: 30477961

6. Annu Rev Med. 2018 Nov 7. doi: 10.1146/annurev-med-040717-051150. [Epub ahead of print]

The Global Landscape of Tuberculosis Therapeutics.

Tornheim JA(1), Dooley KE(1)(2)(3).

Author information:

(1)Division of Infectious Diseases, Johns Hopkins University School of Medicine,

Baltimore, Maryland 21287, USA; email: kdooley1@jhmi.edu.

(2)Division of Clinical Pharmacology, Johns Hopkins University School of

Medicine, Baltimore, Maryland 21287, USA.

(3)Center for Tuberculosis Research, Johns Hopkins University School of Medicine,

Baltimore, Maryland 21287, USA.

Tuberculosis (TB) is one of the oldest infections afflicting humans yet remains

the number one infectious disease killer worldwide. Despite decades of experience

treating this disease, TB regimens require months of multidrug therapy, even for

latent infections. There have been important recent advances in treatment options

across the spectrum of TB, from latent infection to extensively drug-resistant

(XDR) TB disease. In addition, new, potent drugs are emerging out of the

development pipeline and are being tested in novel regimens in multiple currently

enrolling trials. Shorter, safer regimens for many forms of TB are now available

or are in our near-term vision. We review recent advances in TB therapeutics and

provide an overview of the upcoming clinical trials landscape that will help

define the future of worldwide TB treatment. Expected final online publication

date for the Annual Review of Medicine Volume 70 is January 27, 2019. Please see

http://www.annualreviews.org/page/journal/pubdates for revised estimates.

DOI: 10.1146/annurev-med-040717-051150

PMID: 30403551

7. J Exp Med. 2018 Nov 5;215(11):2919-2935. doi: 10.1084/jem.20180508. Epub 2018 Oct 18.

Mycobacterium tuberculosis-induced IFN-β production requires cytosolic DNA and

RNA sensing pathways.

Cheng Y(1), Schorey JS(2).

Author information:

(1)Department of Biological Sciences, Eck Institute for Global Health, Center for

Rare and Neglected Diseases, University of Notre Dame, Notre Dame, IN.

(2)Department of Biological Sciences, Eck Institute for Global Health, Center for

Rare and Neglected Diseases, University of Notre Dame, Notre Dame, IN

schorey.1@nd.edu.

RNA sensing pathways are key elements in a host immune response to viral

pathogens, but little is known of their importance during bacterial infections.

We found that Mycobacterium tuberculosis (M.tb) actively releases RNA into the

macrophage cytosol using the mycobacterial SecA2 and ESX-1 secretion systems. The

cytosolic M.tb RNA induces IFN-β production through the host RIG-I/MAVS/IRF7 RNA

sensing pathway. The inducible expression of IRF7 within infected cells requires

an autocrine signaling through IFN-β and its receptor, and this early IFN-β

production is dependent on STING and IRF3 activation. M.tb infection studies

using Mavs-/- mice support a role for RNA sensors in regulating IFN-β production

and bacterial replication in vivo. Together, our data indicate that M.tb RNA is

actively released during an infection and promotes IFN-β production through a

regulatory mechanism involving cross-talk between DNA and RNA sensor pathways,

and our data support the hypothesis that bacterial RNA can drive a host immune

response.

© 2018 Cheng and Schorey.

DOI: 10.1084/jem.20180508

PMCID: PMC6219742 [Available on 2019-05-05]

PMID: 30337468

8. Am J Respir Crit Care Med. 2018 Nov 1;198(9):1208-1219. doi:

10.1164/rccm.201711-2333OC.

Drug-Penetration Gradients Associated with Acquired Drug Resistance in Patients

with Tuberculosis.

Dheda K(1)(2), Lenders L(1), Magombedze G(3), Srivastava S(3), Raj P(4), Arning

E(5), Ashcraft P(5), Bottiglieri T(5), Wainwright H(6), Pennel T(7), Linegar

A(7), Moodley L(7), Pooran A(1), Pasipanodya JG(3), Sirgel FA(8), van Helden

PD(8), Wakeland E(4), Warren RM(8), Gumbo T(1)(3).

Author information:

(1)1 Center for Lung Infection and Immunity, Division of Pulmonology and

University of Cape Town Lung Institute, Department of Medicine.

(2)2 Institute of Infectious Disease and Molecular Medicine, Faculty of Health

Sciences, University of Cape Town, Cape Town, South Africa.

(3)3 Center for Infectious Diseases Research and Experimental Therapeutics and.

(4)4 Department of Immunology, University of Texas Southwestern Medical Center,

Dallas, Texas.

…

RATIONALE: Acquired resistance is an important driver of multidrug-resistant

tuberculosis (TB), even with good treatment adherence. However, exactly what

initiates the resistance and how it arises remain poorly understood.

OBJECTIVES: To identify the relationship between drug concentrations and drug

susceptibility readouts (minimum inhibitory concentrations [MICs]) in the TB

cavity.

METHODS: We recruited patients with medically incurable TB who were undergoing

therapeutic lung resection while on treatment with a cocktail of second-line

anti-TB drugs. On the day of surgery, antibiotic concentrations were measured in

the blood and at seven prespecified biopsy sites within each cavity.

Mycobacterium tuberculosis was grown from each biopsy site, MICs of each drug

identified, and whole-genome sequencing performed. Spearman correlation

coefficients between drug concentration and MIC were calculated.

MEASUREMENTS AND MAIN RESULTS: Fourteen patients treated for a median of 13

months (range, 5-31 mo) were recruited. MICs and drug resistance-associated

single-nucleotide variants differed between the different geospatial locations

within each cavity, and with pretreatment and serial sputum isolates, consistent

with ongoing acquisition of resistance. However, pretreatment sputum MIC had an

accuracy of only 49.48% in predicting cavitary MICs. There were large

concentration-distance gradients for each antibiotic. The location-specific

concentrations inversely correlated with MICs (P < 0.05) and therefore acquired

resistance. Moreover, pharmacokinetic/pharmacodynamic exposures known to amplify

drug-resistant subpopulations were encountered in all positions.

CONCLUSIONS: These data inform interventional strategies relevant to drug

delivery, dosing, and diagnostics to prevent the development of acquired

resistance. The role of high intracavitary penetration as a biomarker of

antibiotic efficacy, when assessing new regimens, requires clarification.

DOI: 10.1164/rccm.201711-2333OC

PMCID: PMC6221573 [Available on 2019-11-01]

PMID: 29877726

9. Clin Infect Dis. 2018 Nov 28;67(suppl_3):S336-S341. doi: 10.1093/cid/ciy626.

The Sterilizing Effect of Intermittent Tedizolid for Pulmonary Tuberculosis.

Srivastava S(1), Deshpande D(1), Nuermberger E(2)(3), Lee PS(1), Cirrincione

K(1), Dheda K(4), Gumbo T(1)(4).

Author information:

(1)Center for Infectious Diseases Research and Experimental Therapeutics, Baylor

Research Institute, Baylor University Medical Center, Dallas, Texas.

(2)Center for Tuberculosis Research, Department of Medicine.

(3)Department of International Health, Johns Hopkins University School of

Medicine, Baltimore, Maryland.

(4)Lung Infection and Immunity Unit, Division of Pulmonology and University of

Cape Town Lung Institute, Department of Medicine, Observatory, South Africa.

Background: Linezolid exhibits remarkable sterilizing effect in tuberculosis;

however, a large proportion of patients develop serious adverse events. The

congener tedizolid could have a better side-effect profile, but its sterilizing

effect potential is unknown.

Methods: We performed a 42-day tedizolid exposure-effect and dose-fractionation

study in the hollow fiber system model of tuberculosis for sterilizing effect,

using human-like intrapulmonary pharmacokinetics. Bacterial burden was examined

using time to positivity (TTP) and colony-forming units (CFUs). Exposure-effect

was examined using the inhibitory sigmoid maximal kill model. The exposure

mediating 80% of maximal kill (EC80) was defined as the target exposure, and the

lowest dose to achieve EC80 was identified in 10000-patient Monte Carlo

experiments. The dose was also examined for probability of attaining

concentrations associated with mitochondrial enzyme inhibition.

Results: At maximal effect, tedizolid monotherapy totally eliminated 7.1 log10

CFU/mL Mycobacterium tuberculosis over 42 days; however, TTP still demonstrated

some growth. Once-weekly tedizolid regimens killed as effectively as daily

regimens, with an EC80 free drug 0- to 24-hour area under the concentration-time

curve-to-minimum inhibitory concentration (MIC) ratio of 200. An oral tedizolid

of 200 mg/day achieved the EC80 in 92% of 10000 patients. The susceptibility

breakpoint was an MIC of 0.5 mg/L. The 200 mg/day dose did not achieve

concentrations associated with mitochondrial enzyme inhibition.

Conclusions: Tedizolid exhibits dramatic sterilizing effect and should be

examined for pulmonary tuberculosis. A tedizolid dose of 200 mg/day or 700 mg

twice a week is recommended for testing in patients; the intermittent tedizolid

dosing schedule could be much safer than daily linezolid.

DOI: 10.1093/cid/ciy626

PMCID: PMC6260152 [Available on 2019-11-28]

PMID: 30496463

10. Clin Infect Dis. 2018 Nov 28;67(suppl_3):S293-S302. doi: 10.1093/cid/ciy611.

Levofloxacin Pharmacokinetics/Pharmacodynamics, Dosing, Susceptibility

Breakpoints, and Artificial Intelligence in the Treatment of Multidrug-resistant

Tuberculosis.

Deshpande D(1), Pasipanodya JG(1), Mpagama SG(2), Bendet P(1), Srivastava S(1),

Koeuth T(1), Lee PS(1), Bhavnani SM(3), Ambrose PG(3), Thwaites G(4)(5), Heysell

SK(6), Gumbo T(1).

Author information:

(1)Center for Infectious Diseases Research and Experimental Therapeutics, Baylor

Research Institute, Baylor University Medical Center, Dallas, Texas.

(2)Kibong'oto Infectious Diseases Hospital, Sanya Juu, Tanzania.

(3)Institute for Clinical Pharmacodynamics, Schenectady, New York.

(4)Nuffield Department of Medicine, Centre for Tropical Medicine and Global

Health, Churchill Hospital, Oxford, United Kingdom.

(5)Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.

(6)Division of Infectious Diseases and International Health, University of

Virginia, Charlottesville.

Background: Levofloxacin is used for the treatment of multidrug-resistant

tuberculosis; however the optimal dose is unknown.

Methods: We used the hollow fiber system model of tuberculosis (HFS-TB) to

identify 0-24 hour area under the concentration-time curve (AUC0-24) to minimum

inhibitory concentration (MIC) ratios associated with maximal microbial kill and

suppression of acquired drug resistance (ADR) of Mycobacterium tuberculosis

(Mtb). Levofloxacin-resistant isolates underwent whole-genome sequencing. Ten

thousands patient Monte Carlo experiments (MCEs) were used to identify doses best

able to achieve the HFS-TB-derived target exposures in cavitary tuberculosis and

tuberculous meningitis. Next, we used an ensemble of artificial intelligence (AI)

algorithms to identify the most important predictors of sputum conversion, ADR,

and death in Tanzanian patients with pulmonary multidrug-resistant tuberculosis

treated with a levofloxacin-containing regimen. We also performed probit

regression to identify optimal levofloxacin doses in Vietnamese tuberculous

meningitis patients.

Results: In the HFS-TB, the AUC0-24/MIC associated with maximal Mtb kill was 146,

while that associated with suppression of resistance was 360. The most common

gyrA mutations in resistant Mtb were Asp94Gly, Asp94Asn, and Asp94Tyr. The

minimum dose to achieve target exposures in MCEs was 1500 mg/day. AI algorithms

identified an AUC0-24/MIC of 160 as predictive of microbiologic cure, followed by

levofloxacin 2-hour peak concentration and body weight. Probit regression

identified an optimal dose of 25 mg/kg as associated with >90% favorable response

in adults with pulmonary tuberculosis.

Conclusions: The levofloxacin dose of 25 mg/kg or 1500 mg/day was adequate for

replacement of high-dose moxifloxacin in treatment of multidrug-resistant

tuberculosis.

DOI: 10.1093/cid/ciy611

PMCID: PMC6260169 [Available on 2019-11-28]

PMID: 30496461

11. Clin Infect Dis. 2018 Nov 20. doi: 10.1093/cid/ciy835. [Epub ahead of print]

A Novel, 5-Transcript, Whole-blood Gene-expression Signature for Tuberculosis

Screening Among People Living With Human Immunodeficiency Virus.

Rajan JV(1), Semitala FC(2), Mehta T(3), Seielstad M(4), Montalvo L(5), Andama

A(6), Asege L(6), Nakaye M(6), Katende J(6), Mwebe S(6), Kamya MR(2), Yoon C(3),

Cattamanchi A(3).

Author information:

(1)Division of Experimental Medicine, Department of Medicine, Zuckerberg San

Francisco General Hospital, University of California, San Francisco.

(2)Department of Medicine, Makerere University School of Medicine, Kampala,

Uganda.

(3)Division of Pulmonary and Critical Care Medicine, Department of Medicine,

Zuckerberg San Francisco General Hospital, San Francisco.

(4)Institute for Human Genetics, Department of Laboratory Medicine, Department of

Epidemiology and Biostatistics, University of California, San Francisco.

(5)Blood Systems Research Institute, San Francisco, California.

(6)Infectious Diseases Research Collaboration, Kampala, Uganda.

Background: Gene-expression profiles have been reported to distinguish between

patients with and without active tuberculosis (TB), but no prior study has been

conducted in the context of TB screening.

Methods: We included all the patients (n = 40) with culture-confirmed TB and

time-matched controls (n = 80) enrolled between July 2013 and April 2015 in a TB

screening study among people living with human immunodeficiency virus (PLHIV) in

Kampala, Uganda. We randomly split the patients into training (n = 80) and test

(n = 40) datasets. We used the training dataset to derive candidate signatures

that consisted of 1 to 5 differentially-expressed transcripts (P ≤ .10) and

compared the performance of our candidate signatures with 4 published TB

gene-expression signatures, both on the independent test dataset and in 2

external datasets.

Results: We identified a novel, 5-transcript signature that met the accuracy

thresholds recommended for a TB screening test. On the independent test dataset,

our signature had an area under the curve (AUC) of 0.87 (95% confidence interval

[CI] 0.72-0.98), with sensitivity of 94% and specificity of 75%. None of the 4

published TB signatures achieved desired accuracy thresholds. Our novel signature

performed well in external datasets from both high (AUC 0.81, 95% CI 0.74-0.88)

and low (0.81, 95% CI 0.77-0.85) TB burden settings.

Conclusions: We identified the first gene-expression signature for TB screening.

Our signature has the potential to be translated into a point-of-care test to

facilitate systematic TB screening among PLHIV and other high-risk populations.

DOI: 10.1093/cid/ciy835

PMID: 30462176

12. Thorax. 2018 Nov 12. pii: thoraxjnl-2017-211120. doi:

10.1136/thoraxjnl-2017-211120. [Epub ahead of print]

Predicting tuberculosis relapse in patients treated with the standard 6-month

regimen: an individual patient data meta-analysis.

Romanowski K(1), Balshaw RF(2), Benedetti A(3)(4)(5), Campbell JR(4)(5), Menzies

D(3)(4)(5), Ahmad Khan F(3)(5), Johnston JC(1)(5)(6).

Author information:

(1)TB Services, British Columbia Centre for Disease Control, Vancouver, British

Columbia, Canada.

(2)Centre for Healthcare Innovation, University of Manitoba, Winnipeg, Manitoba,

Canada.

(3)Respiratory Epidemiology and Clinical Research Unit, Centre for Outcomes

Research and Evaluation, Research Institute of the McGill University Health

Centre, Montreal, Quebec, Canada.

…

BACKGROUND: Relapse continues to place significant burden on patients and

tuberculosis (TB) programmes worldwide. We aimed to determine clinical and

microbiological factors associated with relapse in patients treated with the WHO

standard 6-month regimen and then evaluate the accuracy of each factor at

predicting an outcome of relapse.

METHODS: A systematic review was performed to identify randomised controlled

trials reporting treatment outcomes on patients receiving the standard regimen.

Authors were contacted and invited to share patient-level data (IPD). A one-step

IPD meta-analysis, using random intercept logistic regression models and receiver

operating characteristic curves, was performed to evaluate the predictive

performance of variables of interest.

RESULTS: Individual patient data were obtained from 3 of the 12 identified

studies. Of the 1189 patients with confirmed pulmonary TB who completed therapy,

67 (5.6%) relapsed. In multipredictor analysis, the presence of baseline cavitary

disease with positive smear at 2 months was associated with an increased odds of

relapse (OR 2.3(95% CI 1.3 to 4.2)) and a relapse risk of 10%. When area under

the curve for each multipredictor model was compared, discrimination between

low-risk and higher-risk patients was modest and similar to that of the reference

model which accounted for age, sex and HIV status.

CONCLUSION: Despite its poor predictive value, our results indicate that the

combined presence of cavitary disease and 2-month positive smear status may be

the best currently available marker for identifying individuals at an increased

risk of relapse, particularly in resource-limited setting. Further investigation

is required to assess whether this combined factor can be used to indicate

different treatment requirements in clinical practice.

© Author(s) (or their employer(s)) 2018. No commercial re-use. See rights and

permissions. Published by BMJ.

DOI: 10.1136/thoraxjnl-2017-211120

PMID: 30420407

Conflict of interest statement: Competing interests: None declared.

13. Clin Infect Dis. 2018 Nov 12. doi: 10.1093/cid/ciy967. [Epub ahead of print]

Development and Validation of a Deep Learning-Based Automatic Detection Algorithm

for Active Pulmonary Tuberculosis on Chest Radiographs.

Hwang EJ(1), Park S(2), Jin KN(3), Kim JI(4), Choi SY(5), Lee JH(1), Goo JM(1),

Aum J(2), Yim JJ(6), Park CM(1); DLAD Development and Evaluation Group.

Author information:

(1)Department of Radiology, Seoul National University College of Medicine, Seoul,

Korea.

(2)Lunit Inc., Seoul, Korea.

(3)Department of Radiology, Seoul National University Boramae Medical Center,

Seoul, Korea.

(4)Department of Radiology, Kyung Hee University Hospital at Gangdong, Seoul,

Korea.

(5)Department of Radiology, Eulji University Medical Center, Daejon, Korea.

(6)Division of Pulmonary and Critical Care Medicine, Department of Internal

Medicine, Seoul National University College of Medicine, Seoul, Korea.

Background: Detection of active pulmonary tuberculosis (TB) on chest radiographs

(CR) is critical for the diagnosis and screening of TB. An automated system may

help streamline the TB screening process and improve diagnostic performance.

Methods: We developed a deep-learning-based automatic detection (DLAD) algorithm,

using 54,221 normal CRs and 6,768 CRs with active pulmonary TB, which were

labeled and annotated by 13 board-certified radiologists. The performance of DLAD

was validated using six external multi-center, multi-national datasets. To

compare the performances of DLAD with physicians, an observer performance test

was conducted by 15 physicians including non-radiology physicians,

board-certified radiologists, and thoracic radiologists. Image-wise

classification and lesion-wise localization performances were measured using area

under the receiver operating characteristic (ROC) curves, and area under the

alternative free-response ROC curves, respectively. Sensitivities and

specificities of DLAD were calculated using two cutoffs [high sensitivity (98%)

and high specificity (98%)] obtained through in-house validation.

Results: DLAD demonstrated classification performances of 0.977-1.000 and

localization performance of 0.973-1.000. Sensitivities and specificities for

classification were 94.3-100% and 91.1-100% using the high sensitivity cutoff and

84.1-99.0% and 99.1-100% using the high specificity cutoff. DLAD showed

significantly higher performance in both classification (0.993 vs. 0.746-0.971)

and localization (0.993 vs. 0.664-0.925) compared to all groups of physicians.

Conclusion: Our DLAD demonstrated excellent and consistent performance in the

detection of active pulmonary TB on CR, outperforming physicians including

thoracic radiologists.

DOI: 10.1093/cid/ciy967

PMID: 30418527

14. Clin Infect Dis. 2018 Nov 1. doi: 10.1093/cid/ciy937. [Epub ahead of print]

Evaluation of the impact of a sequencing assay for detection of drug resistance

on the clinical management of tuberculosis.

Lowenthal P(1), Lin SG(2), Desmond E(2), Shah N(1)(3), Flood J(1), Barry PM(1).

Author information:

(1)Tuberculosis Control Branch, Division of Communicable Disease, Center for

Infectious Disease, California Department of Public Health.

(2)Microbial Disease Laboratory, Division of Communicable Disease, Center for

Infectious Disease, California Department of Public Health.

(3)Centers for Disease Control and Prevention.

Background: In 2012, the California Department of Public Health began using

pyrosequencing (PSQ) to detect mutations associated with resistance to isoniazid,

rifampin, quinolones and injectable drugs in Mycobacterium tuberculosis complex.

We evaluated the impact of the PSQ assay on the clinical management of

tuberculosis (TB) in California.

Methods: TB surveillance and laboratory data for specimens submitted

8/1/2012-12/31/2016 were analyzed to determine time to effective treatment

initiation. A survey of clinicians was used to assess how PSQ results influenced

clinical decision-making.

Results: Of 1,957 specimens tested with PSQ, 52% were sediments and 46% were

culture isolates, submitted 8 and 35 days (median) after collection,

respectively. Among 36 patients with multidrug-resistant TB (MDR-TB) who had a

sediment specimen submitted for PSQ, median time from specimen collection to

MDR-TB treatment initiation was 12 days vs 51 days when PSQ was not used. Of 303

TB patients with a completed survey, 126 (42%) clinicians reported PSQ as a

reason for treatment change. Twenty-one patients either had an MDR-TB risk factor

and a smear positive sputum specimen, but had PSQ performed on a culture isolate

(9 of 36; 25%); or, didn't have PSQ used for MDR-TB diagnosis (12 of 38; 32%) and

thus, had an opportunity for earlier MDR-TB diagnosis with PSQ on sediment.

Conclusions: Patients with MDR-TB initiated effective treatment five weeks

earlier when PSQ was used compared to those without PSQ. Survey data suggest

clinicians use PSQ to devise effective TB drug regimens. To maximize the benefit

of PSQ, earlier submission of specimens should be prioritized.

DOI: 10.1093/cid/ciy937

PMID: 30383209

15. Nucleic Acids Res. 2018 Nov 2;46(19):10106-10118. doi: 10.1093/nar/gky714.

RbpA relaxes promoter selectivity of M. tuberculosis RNA polymerase.

Sudalaiyadum Perumal A(1), Vishwakarma RK(1), Hu Y(2), Morichaud Z(1), Brodolin

K(1).

Author information:

(1)IRIM, CNRS, Univ Montpellier, 1919 route de Mende, 34293 Montpellier, France.

(2)Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China.

The transcriptional activator RbpA associates with Mycobacterium tuberculosis RNA

polymerase (MtbRNAP) during transcription initiation, and stimulates formation of

the MtbRNAP-promoter open complex (RPo). Here, we explored the influence of

promoter motifs on RbpA-mediated activation of MtbRNAP containing the

stress-response σB subunit. We show that both the 'extended -10' promoter motif

(T-17G-16T-15G-14) and RbpA stabilized RPo and allowed promoter opening at

suboptimal temperatures. Furthermore, in the presence of the T-17G-16T-15G-14

motif, RbpA was dispensable for RNA synthesis initiation, while exerting a

stabilization effect on RPo. On the other hand, RbpA compensated for the lack of

sequence-specific interactions of domains 3 and 4 of σB with the extended -10 and

the -35 motifs, respectively. Mutations of the positively charged residues K73,

K74 and R79 in RbpA basic linker (BL) had little effect on RPo formation, but

affected MtbRNAP capacity for de novo transcription initiation. We propose that

RbpA stimulates transcription by strengthening the non-specific interaction of

the σ subunit with promoter DNA upstream of the -10 element, and by indirectly

optimizing MtbRNAP interaction with initiation substrates. Consequently, RbpA

renders MtbRNAP promiscuous in promoter selection, thus compensating for the weak

conservation of the -35 motif in mycobacteria.

DOI: 10.1093/nar/gky714

PMCID: PMC6212719

PMID: 30102406

16. Thorax. 2018 Nov;73(11):1062-1070. doi: 10.1136/thoraxjnl-2018-211715. Epub 2018 Jul 7.

Evaluating latent tuberculosis infection diagnostics using latent class analysis.

Stout JE(1), Wu Y(2), Ho CS(3), Pettit AC(4), Feng PJ(3), Katz DJ(3), Ghosh S(3),

Venkatappa T(3), Luo R(5); Tuberculosis Epidemiologic Studies Consortium.

Collaborators: Flood J, Pascopella L, Higashi J, Moore M, Garfein R, Benson C,

Belknap R, Reves R, Ahmed A, Sterling T, Pettit A, Blumberg HM, Oladele A,

Lauzardo M, Séraphin MN, Brostrom R, Khurana R, Cronin W, Dorman S, Narita M,

Horne D, Miller T.

Author information:

(1)Division of Infectious Diseases and International Health, Department of

Medicine, Duke University Medical Center, Durham, North Carolina, USA.

(2)Northrop Grumman, McLean, Virginia, USA.

(3)Division of Tuberculosis Elimination, Centers for Disease Control and

Prevention, Atlanta, Georgia, USA.

(4)Division of Infectious Diseases, Department of Medicine, Vanderbilt University

Medical Center, Nashville, Tennessee, USA.

(5)Department of Epidemiology and Biostatistics, Georgia State University, School

of Public Health, Atlanta, Georgia, USA.

BACKGROUND: Lack of a gold standard for latent TB infection has precluded direct

measurement of test characteristics of the tuberculin skin test and interferon-γ

release assays (QuantiFERON Gold In-Tube and T-SPOT.TB).

OBJECTIVE: We estimated test sensitivity/specificity and latent TB infection

prevalence in a prospective, US-based cohort of 10 740 participants at high risk

for latent infection.

METHODS: Bayesian latent class analysis was used to estimate test

sensitivity/specificity and latent TB infection prevalence among subgroups based

on age, foreign birth outside the USA and HIV infection.

RESULTS: Latent TB infection prevalence varied from 4.0% among foreign-born,

HIV-seronegative persons aged <5 years to 34.0% among foreign-born,

HIV-seronegative persons aged ≥5 years. Test sensitivity ranged from 45.8% for

the T-SPOT.TB among foreign-born, HIV-seropositive persons aged ≥5 years to 80.7%

for the tuberculin skin test among foreign-born, HIV-seronegative persons aged ≥5

years. The skin test was less specific than either interferon-γ release assay,

particularly among foreign-born populations (eg, the skin test had 70.0%

specificity among foreign-born, HIV-seronegative persons aged ≥5 years vs 98.5%

and 99.3% specificity for the QuantiFERON and T-SPOT.TB, respectively). The

tuberculin skin test's positive predictive value ranged from 10.0% among

foreign-born children aged <5 years to 69.2% among foreign-born, HIV-seropositive

persons aged ≥5 years; the positive predictive values of the QuantiFERON (41.4%)

and T-SPOT.TB (77.5%) were also low among US-born, HIV-seropositive persons aged

≥5 years.

CONCLUSIONS: These data reinforce guidelines preferring interferon-γ release

assays for foreign-born populations and recommending against screening

populations at low risk for latent TB infection.

TRIAL REGISTRATION NUMBER: NCT01622140.

© Author(s) (or their employer(s)) 2018. No commercial re-use. See rights and

permissions. Published by BMJ.

DOI: 10.1136/thoraxjnl-2018-211715

PMID: 29982223

Conflict of interest statement: Competing interests: None declared.