The Lancet Respiratory Medicine Commission

The epidemiology, pathogenesis, transmission, diagnosis,

and management of multidrug-resistant, extensively
drug-resistant, and incurable tuberculosis
Keertan Dheda*, Tawanda Gumbo*, Gary Maartens*, Kelly E Dooley*, Ruth McNerney*, Megan Murray*, Jennifer Furin*, Edward A Nardell*,
Leslie London*, Erica Lessem*, Grant Theron, Paul van Helden, Stefan Niemann, Matthias Merker, David Dowdy, Annelies Van Rie, Gilman K H Siu,
Jotam G Pasipanodya, Camilla Rodrigues, Taane G Clark, Frik A Sirgel, Aliasgar Esmail, Hsien-Ho Lin, Sachin R Atre, H Simon Schaaf,
Kwok Chiu Chang, Christoph Lange, Payam Nahid, Zarir F Udwadia, C Robert Horsburgh Jr, Gavin J Churchyard, Dick Menzies, Anneke C Hesseling,
Eric Nuermberger, Helen McIlleron, Kevin P Fennelly, Eric Goemaere, Ernesto Jaramillo, Marcus Low, Carolina Morn Jara, Nesri Padayatchi,
Robin M Warren*

Global tuberculosis incidence has declined marginally over the past decade, and tuberculosis remains out of control Lancet Respir Med 2017;
in several parts of the world including Africa and Asia. Although tuberculosis control has been effective in some 5: 291360

regions of the world, these gains are threatened by the increasing burden of multidrug-resistant (MDR) and Published Online
March 23, 2017
extensively drug-resistant (XDR) tuberculosis. XDR tuberculosis has evolved in several tuberculosis-endemic
http://dx.doi.org/10.1016/
countries to drug-incurable or programmatically incurable tuberculosis (totally drug-resistant tuberculosis). This S2213-2600(17)30079-6
poses several challenges similar to those encountered in the pre-chemotherapy era, including the inability to cure See Comment page 241
tuberculosis, high mortality, and the need for alternative methods to prevent disease transmission. This phenomenon *Contributed equally
mirrors the worldwide increase in antimicrobial resistance and the emergence of other MDR pathogens, such as Lung Infection and Immunity
malaria, HIV, and Gram-negative bacteria. MDR and XDR tuberculosis are associated with high morbidity and Unit, Department of Medicine,
substantial mortality, are a threat to health-care workers, prohibitively expensive to treat, and are therefore a serious Division of Pulmonology and
public health problem. In this Commission, we examine several aspects of drug-resistant tuberculosis. The traditional UCT Lung Institute, University
of Cape Town, Groote Schuur
view that acquired resistance to antituberculous drugs is driven by poor compliance and programmatic failure is now Hospital, Cape Town,
being questioned, and several lines of evidence suggest that alternative mechanismsincluding pharmacokinetic South Africa (Prof K Dheda PhD,
variability, induction of efflux pumps that transport the drug out of cells, and suboptimal drug penetration into R McNerney PhD, A Esmail MBBS);
tuberculosis lesionsare likely crucial to the pathogenesis of drug-resistant tuberculosis. These factors have Center for Infectious Diseases
Research and Experimental
implications for the design of new interventions, drug delivery and dosing mechanisms, and public health policy. Therapeutics, Baylor Research
We discuss epidemiology and transmission dynamics, including new insights into the fundamental biology of Institute, Baylor University
transmission, and we review the utility of newer diagnostic tools, including molecular tests and next-generation Medical Center, Dallas, TX, USA
whole-genome sequencing, and their potential for clinical effectiveness. Relevant research priorities are highlighted, (Prof T Gumbo MD,
J G Pasipanodya PhD); Division of
including optimal medical and surgical management, the role of newer and repurposed drugs (including bedaquiline, Clinical Pharmacology,
delamanid, and linezolid), pharmacokinetic and pharmacodynamic considerations, preventive strategies (such as Department of Medicine,
prophylaxis in MDR and XDR contacts), palliative and patient-orientated care aspects, and medicolegal and ethical University of Cape Town,
issues. Cape Town, South Africa
(Prof G Maartens MMed,
Prof H McIlleron PhD); Center for
Introduction results from infection with a drug-resistant strain, Tuberculosis Research,
With the notable exception of sub-Saharan Africa, the whereas resistance that develops during therapy is Johns Hopkins University School
of Medicine, Baltimore, MD,
incidence of tuberculosis has declined over the past referred to as secondary or acquired resistance.
USA (K E Dooley PhD,
two decades in most regions of the world.1,2 However, Amplification of resistance might occur when resistance Prof E Nuermberger MD);
gains in tuberculosis control are threatened by the to additional drugs emerges during the treatment Department of Global Health
emergence of resistance to antituberculosis drugs. course, often in association with inadequate therapy. and Social Medicine
(Prof M Murray PhD, J Furin PhD);
Approximately 20% of tuberculosis isolates globally are Globally, approximately 5% of patients with tuberculosis
and TH Chan School of Public
estimated to be resistant to at least one major drug are estimated to have either MDR or XDR types, but the Health (Prof E A Nardell MD),
(first-line or group A or B second-line), with approxi distribution of cases is not uniform; it is substantially Department of Medicine,
mately 10% resistant to isoniazid. WHO has defined higher in some regions, and increasing incidence has Harvard Medical School, Boston,
MA, USA; School of Public
multidrug-resistant (MDR) tuberculosis as resistance to been reported in several countries.1 The high mortality
Health and Medicine, University
at least isoniazid and rifampicin, when first-line therapy due to most patients remaining untreated is a key of Cape Town, Cape Town,
is unlikely to cure the disease and a switch to a second- reason for this apparently stable estimated global rate of South Africa (Prof L London MD);
line drug regimen is recommended. Similarly, exten drug-resistant tuberculosis. Approximately 30% of Treatment Action Group,
New York, NY, USA
sively drug-resistant (XDR) tuberculosis is MDR MDR tuberculosis isolates are either fluoroquinolone-
(E Lessem MPH); SA MRC Centre
tuberculosis that is also resistant to the fluoroquinolones resistant or aminoglycoside-resistant, and approxi for Tuberculosis Research/DST/
and second-line injectable drugs, indicating the mately 10% of MDR tuberculosis isolates can be classed NRF Centre of Excellence for
probable failure of the standardised second-line as XDR tuberculosis, or as having resistance to Biomedical Tuberculosis
Research, Division of Molecular
treatment regimen. Two modes exist by which patients additional drugs beyond XDR tuberculosis (ie, totally Biology and Human Genetics,
contract drug-resistant tuberculosis. Primary resistance drug resistant). This expansion of resistance has

www.thelancet.com/respiratory Vol 5 April 2017 291

 The Lancet Respiratory Medicine Commission
Stellenbosch University,
Tygerberg, South Africa
(G Theron PhD,
Prof P van Helden PhD,
F A Sirgel PhD,
Prof R M Warren PhD); Molecular
and Experimental
Mycobacteriology
(Prof S Niemann Dr rer nat,
M Merker Dr rer nat) and Division
of Clinical Infectious Diseases,
German Center for Infection
Research (Prof C Lange PhD),
Research Center Borstel, Borstel,
Schleswig-Holstein, Germany;
German Centre for Infection
Research (DZIF), Partner Site
Borstel, Borstel,
Schleswig-Holstein, Germany
(Prof S Niemann); Department
of Epidemiology, Johns Hopkins
Bloomberg School of Public
Health, Baltimore, MD, USA
(D Dowdy PhD); University of
North Carolina at Chapel Hill,
Chapel Hill, NC, USA
(Prof A Van Rie PhD);
International Health Unit,
Epidemiology and Social
Medicine, Faculty of Medicine,
University of Antwerp,
Antwerp, Belgium
(Prof A Van Rie); Department of
Health Technology and
Informatics, The Hong Kong
Polytechnic University,
Hung Hom, Hong Kong SAR,
China (G K H Siu PhD);
Department of Microbiology,
P.D. Hinduja National Hospital &
Medical Research Centre,
Mumbai, India (C Rodrigues MD);
Faculty of Infectious and
Tropical Diseases and Faculty of
Epidemiology and Population
Health, London School of
Hygiene & Tropical Medicine,
London, UK (Prof T G Clark PhD);
Institute of Epidemiology and
Preventive Medicine, National
Taiwan University, Taipei,
Taiwan (H-H Lin ScD); Center for
Clinical Global Health Education
(CCGHE), Johns Hopkins
University, Baltimore, MD, USA
(S R Atre PhD); Medical College,
Hospital and Research Centre,
Pimpri, Pune, India (S R Atre);
Desmond Tutu TB Centre,
Department of Paediatrics and
Child Health, Faculty of
Medicine and Health Sciences,
Stellenbosch University,
Cape Town, South Africa
(Prof H S Schaaf MD,
Prof A C Hesseling PhD);
Tuberculosis and Chest Service,
Centre for Health Protection,
Department of Health,
Hong Kong SAR, China
(K C Chang MBBS); International
292 www.thelancet.com/respiratory Vol 5 April 2017
ushered in an era of programmatically incurable
tuberculosis, in which insufficient effective drugs
remain to construct a curative regimen. The availability
of newer drugs, such as bedaquiline and delamanid,35
has not averted this problem and resistance to both
bedaquiline and delamanid in the same patient has
already been reported.6 The effect on patients is
profound, because drug resistant tuberculosis is
associated with a higher morbidity than drug-sensitive
tuberculosis7 and is responsible for approximately
20% of the global tuberculosis mortality, with mortality
rates estimated at around 40% for patients with MDR
tuberculosis and 60% for those with XDR tuberculosis.1
Provision of effective first-line treatment was hoped to
prevent the emergence of drug-resistant tuberculosis as
a public health problem. However, data suggest that
primary transmission of MDR and XDR tuberculosis is
now driving the spread of resistance, including in high-
burden countries such as China, India, and South Africa.
The inability to cure infectious patients raises ethical
and medicolegal questions regarding the freedom of
affected individuals to work and travel and how to
prevent onward transmission. Drug-resistant tubercu
losis causes a strain on health systems because of the
chronic nature of the disease, and because of the risk of
transmission to health-care workers.7 Drug-resistant
tuberculosis also jeopardises tuberculosis control
through its economic effect, because the high cost of
managing drug-resistant tuberculosis is not sustainable
in some settings and an anticipated shortfall in global
resources has been reported by the STOP TB
partnership.1 In the USA, average inpatient costs have
been estimated to be US$81000 for patients with MDR
tuberculosis and $285 000 for those with XDR
tuberculosis.8 In South Africa, management of MDR
and XDR tuberculosis, despite only accounting for less
than 5% of all tuberculosis cases, is estimated to
consume over a third of the total tuberculosis pro
gramme resources.9 Of the US$63 billion available in
2014 to respond to the global tuberculosis epidemic,
$38 billion was used for diagnosis and treatment of
drug-susceptible tuberculosis, and $18 billion (47%) for
MDR tuberculosis.10 Tuberculosis and drug-resistant
tuberculosis are no longer the concern of individual
countries, because international travel and migration
support transmission across international boundaries
and around the world.
Addressing drug-resistant tuberculosis requires an
urgent and concerted effort to manage the disease and
prevent onward transmission with sustained research
to develop and assess new tools. In this Commission,
we report on the global status of drug-resistant
tuberculosis and how it emerges, followed by state-of-
the-art detection and patient management options;
we discuss transmission and intervention to reduce
transmission; and research needs are assessed and
prioritised. We therefore present for consideration a
contemporary situational analysis and roadmap for
combating and eradicating drug-resistant tuberculosis
as a global public health problem. An array of views is
presented on drug-resistant tuberculosis with the aim
to highlight challenges and to provide practicable
solutions and a roadmap for progress. A patient-
orientated perspective is also presented, including
audio and video interviews with patients with drug-
resistant tuberculosis (panel 1).
Epidemiology and risk factors for MDR and XDR
tuberculosis, and resistance beyond XDR
Global epidemiology of MDR and XDR tuberculosis
Historically, knowledge of drug-resistant tuberculosis has
been limited by the absence of reliable data from many of
the countries with a high burden of tuberculosis. Drug
susceptibility testing is technically challenging and
requires specialist laboratory facilities that are not widely
available in many tuberculosis-endemic countries.
In 1994, WHO and International Union Against
Tuberculosis and Lung Disease (IUATLD) launched a
global surveillance programme to standardise methods
and improve data quality. Data was collected for
susceptibility to the first-line drugs isoniazid, rifampicin,
ethambutol, and streptomycin. Pyrazinamide was
excluded because of technical difficulties and the poor
reliability of testing methods. Increased laboratory
capacity for testing and progress in surveillance activities
has made it possible to estimate the global burden of
MDR tuberculosis and look at trends over time. As of
2014, 153 countries have provided data on drug-resistant
tuberculosis to WHO.1 Some countries have undertaken
national surveillance studies, and others have submitted
subnational (regional) data. Data are provided as
resistance in new cases (<1 month of treatment, presumed
primary transmission of a drug-resistant strain)
and resistance in previously treated cases (>1 month
exposure to antituberculosis drugs). WHO estimates that
480000 new cases of MDR tuberculosis and 190000 deaths
from MDR tuberculosis occurred in 2014.1 Worldwide,
the proportion of MDR tuberculosis was 33% of new
tuberculosis cases and 200% of previously treated cases.
The percentage is highest in eastern European and
central Asian countries (>20% in new cases and >50% in
previously treated cases; figure 1 AD). However, in terms
of incidence of MDR tuberculosis in the general
population, South Africa should also be considered a
high-burden country (figure 1 C).11 India, China, and
Russia have the highest number of estimated MDR
tuberculosis cases with the three countries accounting for
over 50% of all MDR tuberculosis cases in notified
patients with pulmonary disease worldwide. Although
the global burden of MDR tuberculosis remained
unchanged between 2008 and 2013, the number of
detected rifampicin-resistant cases increased substantially
in several countries (eg, China, India, Pakistan, Nigeria,
South Africa, Indonesia, Bangladesh, and DR Congo)

from 2009 to 2013.11 Of the two drugs associated with
MDR tuberculosis, resistance to isoniazid is more
common, with an estimated global average mono
resistance in 2014 of 95% (95% CI 80110; 81% in
new cases and 140% in previously treated tuberculosis).
Regardless, routine testing for isoniazid resistance is not
done as a front-line test in most settings and as a result
most isoniazid-monoresistant tuberculosis will remain
undetected. Approximately one in five tuberculosis
isolates worldwide are resistant to at least one major first-
line (rifampicin, isoniazid, pyrazinamide, or ethambutol)
or second-line drug (fluoroquinolone or a second-line
injectable agent).11
As the incidence of MDR tuberculosis has increased,
cure rates have decreased in some countries; the WHO
southeast Asia region reported that cure rates dropped
from more than 70% in 2006 to less than 50% in 2014.1
Information on XDR tuberculosis is more scarce, but
available data suggest that 97% of MDR tuberculosis
cases also had XDR tuberculosis. The proportion of
MDR tuberculosis with XDR tuberculosis was highest
in Belarus in 2014 (29%) and Lithuania in 2013 (25%).1
Notably, the proportion of MDR tuberculosis cases
that were also resistant to any fluoroquinolone
was 21% worldwide, whereas resistance to either a
fluoroquinolone, a second-line injectable agent, or
both, was more than 30%. The global burden of drug
resistance in children has rarely been quantified;
two recent high-quality modelling studies generated
plausible estimates of 31948 cases (95% CI 2559438663)
of paediatric MDR tuberculosis in 2010 and 24800 cases
(1610037400) in 2014.12,13
Further resistance to the drugs used to treat XDR
tuberculosis has been reported in several countries and
has resulted in the phenomenon of programmatically
incurable tuberculosis (ie, when insufficient susceptible
drugs remain for a curative regimen).3,4 Of particular
concern is the occurrence of programmatically in
curable strains in countries such as China, India, and
South Africa that are poorly equipped to prevent
onward transmission.5
Determinants of drug resistance
The primary vehicle by which drug resistance arises in
Mycobacterium tuberculosis is via mutations in genes
encoding drug targets or enabling enzymes. Unlike
other bacteria that often acquire resistance through
promiscuous gene transfer systems such as plasmid
exchange, changes in the genomic DNA of M tuberculosis
usually result from single-nucleotide polymorphisms
(SNPs), indels, or, more rarely, large deletions.14
In principle, the effect of drug treatment is to diminish
the pool of susceptible bacteria, which enables the clonal
expansion and enrichment of resistant bacteria and the
emergence of a strain able to withstand drug treatment.
Sequential mutations in additional genes can lead to
resistance to additional drug targets and the emergence
www.thelancet.com/respiratory Vol 5 April 2017 293
The Lancet Respiratory Medicine Commission
Panel 1: Audiovisual material outlining a researcher perspective and interviews with
patients with MDR and XDR tuberculosis
This video, produced by Meera Senthilingam, gives an introduction to the tuberculosis
and drug-resistant tuberculosis epidemic in South Africa through the eyes of the lead
author (KD) and a patient undergoing treatment for MDR tuberculosis, and the
tribulations she faces in day to day life. The video shows the township setting in which the
majority of patients in South Africa reside to provide insight into the environment and
living conditions of those most affected and at high risk of tuberculosis.
Interview by Meera Senthilingam with Kirt Ross, a patient with XDR tuberculosis
whose treatment has failed to cure his condition and who is no longer receiving drug
treatment for tuberculosis. Kirt discusses his experiences with treatment, stigma,
and how he lives day to day knowing he carries a contagious and deadly infection.
Video showing the lifelong effects that treatment for drug-resistant tuberculosis can
have on an individual. Through her story, Phumeza Tisile shows that, although the
disease is curable, the ramifications of drug-resistant tuberculosis forever change a
patients life. The Human Spirit Project is a collaboration between Visual Epidemiology,
the Stop TB Partnership, TB PROOF, and WHO.
Courtesy of Meera Senthilingum (Multimedia producer).
of strains resistant to multiple drugs. Several studies in Health/Infectious Diseases,
individual patients who have developed progressive drug University of Lbeck, Lbeck,
Germany (Prof C Lange);
resistance over time have documented the initial Department of Medicine,
acquisition of isoniazid resistance as a result of one or Karolinska Institute,
more mutations, followed by acquisition of resistance to Stockholm, Sweden
rifampicin or ethambutol (or both), pyrazinamide, and (Prof C Lange); Department of
Medicine, University of
finally, the second-line and third-line drugs.1517 The order Namibia School of Medicine,
in which resistance is acquired might reflect the number Windhoek, Namibia
of different mutations that lead to resistance to a specific (Prof C Lange); Division of
drug,14 the relative fitness costs associated with specific Pulmonary and Critical Care,
San Francisco General Hospital,
mutations (ie, mutations might lead to less successful University of California,
survival and reproduction of the organism),18 or pheno San Francisco, CA, USA
typic changes following an initial drug-resistance (Prof P Nahid PhD); Pulmonary
mutation that might facilitate the acquisition of further Department, Hinduja Hospital
& Research Center, Mumbai,
mutations.19 When resistance to one or more drugs is India (Z F Udwadia MD); Schools
acquired in this way, it is referred to as secondary of Public Health Medicine,
resistance. Boston University, Boston, MA,
USA (Prof C R Horsburgh Jr MD);
By contrast, primary resistance occurs when resistant
Aurum Institute, Johannesburg,
strains are transmitted to a new host in the same manner South Africa
as a drug-susceptible strain. Because the mutations that (G J Churchyard PhD); School of
lead to resistance can be deleterious and produce a Public Health, University of
Witwatersrand, Johannesburg,
fitness cost, many observers hypothesised that resistant
South Africa (G J Churchyard);
strains were less virulent or less easily transmitted than Advancing Treatment and Care
drug-sensitive strains. However, recent work has shown for TB/HIV, South African
that additional mutations often follow or coincide with Medical Research Council,
Johannesburg, South Africa
drug resistance mutations, and that these mutations can
(G J Churchyard); Montreal Chest
compensate for deleterious effects, restoring their initial Institute, McGill University,
growth capacity.20,21 Although some epidemiological Montreal, QC, Canada
studies have found that drug-resistant strains are less (Prof D Menzies MD); Pulmonary
Clinical Medicine Section,
transmissible than drug-sensitive strains, others have
Division of Intramural Research,
shown the opposite,22 and the question of the effect of National Heart, Lung, and Blood
resistance on transmission remains an open one. Institute (NHLBI), National
Institutes of Health (NIH),
Bethesda, MD, USA
Risk factors (K P Fennelly MD); MSF South
Several studies have investigated host, bacterial, eco Africa, Cape Town, South Africa
logical, or health-system determinants of MDR and (E Goemaere PhD);
 The Lancet Respiratory Medicine Commission

A B

029
359 0199
6119 2001999
12179 200019 999
18 20 00049 999
No data 50 000
Subnational data only No data
Not applicable Not applicable
C D
1 100

0
19
1099
100499
500
No data
Not applicable

Figure 1: WHO maps showing the global burden of drug-resistant tuberculosis in 2014
(A) The percentage of new tuberculosis cases that are MDR. (B) Estimated number of cases of MDR tuberculosis in diagnosed patients with pulmonary tuberculosis. (C) Incidence of MDR tuberculosis
and rifampicin-resistance per 100000 individuals of the general population. Available from www.who.int/tb/data. (D) Number of patients with confirmed XDR tuberculosis who started treatment in
2014. Parts (A), (B), and (D) are from the WHO Global Tuberculosis Report, 20151. MDR=multidrug resistant. XDR=extensively drug resistant.

School of Public Health and
Family Medicine, University of
Cape Town, Cape Town,
South Africa (E Goemaere);
World Health Organization,
Geneva, Switzerland
(E Jaramillo PhD); Treatment
Action Campaign,
Johannesburg, South Africa
(M Low MA); Socios en Salud,
Lima, Peru (C Morn Jara RN);
and Centre for the AIDS
Programme of Research in South
Africa (CAPRISA), MRC HIV-TB
Pathogenesis and Treatment
Research Unit, Durban,
South Africa (N Padayatchi PhD)
Correspondence to:
Prof Keertan Dheda, Division of
Pulmonology and UCT Lung
Institute, University of Cape Town,
Groote Schuur Hospital,
Cape Town 7925, South Africa
keertan.dheda@uct.ac.za
XDR tuberculosis. Nonetheless, identifying the initial
causes of the problem by studying human populations
is challenging, in part because of the multiple steps or
transitions involved both in the pathogenesis of
tuberculosis and in the emergence and transmission of
resistance. Not only does each of the tuberculosis
transitions (exposure, infection, and disease pro
gression) have its own set of specific determinants, but
distinct risk factors for resistance exist at each of these
stages. We briefly review non-biomedical risk factors
for the acquisition of MDR tuberculosis.
Previous exposure to antituberculosis drugs is con
sistently identified as a strong risk factor for MDR, but
other host risk factors can vary in different geographical
settings.23 Few studies have examined risk factors for
primary MDR tuberculosis and the associations that
have been reported have been inconsistent. A common
finding across multiple studies is that patients with
MDR tuberculosis tend to be younger than those with a
drug-sensitive infection,24 with one meta-analysis
reporting that patients with tuberculosis younger than
65 years were 25 times more likely to have MDR than
those who are older than 65 years.24 A possible
explanation for this is that older patients might have
tuberculosis due to activation of a latent infection
acquired before the emergence of drug resistance. Such
data are consistent with findings from molecular
epidemiological studies that show that younger age is a
risk factor for recent transmission.25 Many studies have
identified socioeconomic or behavioural risk factors for
MDR, although unsurprisingly, these factors vary across
settings, most serving as indicators of poor access to
high-quality health care. For example, foreign-born
individuals in the Netherlands had almost twice the risk
for MDR as people born locally.26 In Shanghai, internal
migrants from other regions of China were 14 times
more likely to develop MDR than individuals born in
the city.27 Other groups at high risk in some settings
include prisoners, who were shown to have double the
incidence of MDR compared with civilians in Samara

294 www.thelancet.com/respiratory Vol 5 April 2017


Oblast in Russia;28 abusers of alcohol (odds ratio
[OR] 853 in patients admitted to tuberculosis hospitals
in St Petersburg and Ivanovo, Russia); intravenous drug
users; and homeless people.
Although most studies focus on individual char
acteristics, these host risk factors might not lead directly
to MDR tuberculosis but serve as indicators of poor
access to high-quality care. Rather than identifying
individual risk factors for resistance, recent research has
increasingly focused on the attributes of communities
and health systems in spatially distinct areas with a high
burden of MDR tuberculosis. For example, a study in
Moldova found that communities with a larger pro
portion of previously incarcerated patients with
tuberculosis were more likely to be MDR hotspots than
communities with fewer of these patients.29 Similarly,
using county-level data from China, another group
showed that factors such as health resources, health
services, tuberculosis treat ment, and tuberculosis de
tection, but not socioeconomic status, were associated
with drug resistance.30
Comorbidities as risk factors for MDR
Two common comorbidities, HIV and diabetes
mellitus, have been inconsistently associated with
drug-resistant tuberculosis. A systematic review31
found that several studies have reported a high
proportion of resistant cases in patients with
tuberculosis co-infected with HIV in specific outbreak
settings such as prisons and hospitals, but few studies
have systematically compared prevalence of multidrug
resistance between HIV-infected and uninfected
patients after controlling for other factors. A 2009
systematic review that summarised 32 eligible studies
noted a statistically significant association between
HIV co-infection and primary but not secondary
multidrug resistance, but most of the studies included
in the analysis were not adjusted for confounders.31
A study in Kazakhstan showed that, although risk
factors for HIV and MDR tuberculosis largely over
lapped, HIV was not a risk factor for MDR once the
socioeconomic risk factors for both diseases had been
taken into account.32
Studies on diabetes as a risk factor for MDR
tuberculosis have been similarly heterogeneous.
Although multiple studies have reported a positive
association, with ORs ranging from 12 to 85, others
have found no association.3337 Furthermore, many
studies did not control for body-mass index, which is
often high in people with type 2 diabetes, and can be
associated with subtherapeutic serum drug concen
trations that might lead to acquired resistance. In
addition, the classification of patients simply as having
type 2 diabetes without further stratification by glycaemic
control, treatment modality, or renal function might
result in the mixing of patients with substantially
differing susceptibilities to drug resistance.
www.thelancet.com/respiratory Vol 5 April 2017 295
The Lancet Respiratory Medicine Commission
Modelling MDR epidemics For the introduction to
Mathematical models provide a means to explore the TB video see https://www.
dropbox.com/s/ir6r6iaa2ednc9f/
dynamics of drug-resistant tuberculosis in different
Lancet%20video%20-%20
epidemiological and intervention contexts. The simplest Zizipho%20-%20Du%20Noon.
approach entails the construction of a compartmental mov?dl=0
model that describes the emergence of an epidemic as a For the audio interview with Kirt
function of the transmissibility of an infectious Ross see https://www.dropbox.
com/s/vk9rahnb7til3wp/
organism, the rate of person-to-person contact, and the
KirtRoss%20Mixdown%201.
duration of infectiousness. More elaborate simulations mp3?dl=0
can be generated through individual or agent-based For the Human Spirit Project
models that assign specific characteristics to each video see https://www.dropbox.
individual in a population. Early work on modelling com/s/tmzgninh7inell3/
Phumeza%20Tisile-%20Hear%20
MDR tuberculosis suggested that potential fitness costs
No%20Evil-HD.mp4?dl=0
concomitant with resistance-causing mutations might
be offset by the longer duration of infectiousness of
patients with MDR tuberculosis for whom access to
effective therapy was delayed.38,39 More recent studies
have modelled the potential effect of improving
detection of drug resistance and access to effective
treatment, or of reducing acquired resistance by
enhancing treatment of drug-susceptible tuberculosis.
These dynamic models have linked transmission
models to economic models to predict the cost-
effectiveness of specific intervention strategies.40,41 One
study examined the estimated incidence of new and
retreatment cases in countries with a high tuberculosis
burden, and concluded that more than 95% of MDR
tuberculosis is due to primary transmission of resistant
strains.42 Consistent with the results described above,
these findings suggest that a focus on early detection
and improved treatment of MDR tuberculosis is needed
to curtail future incidence.
Summary of epidemiology and risk factors for MDR and
XDR tuberculosis
Despite technical challenges in the laboratory testing of
drug susceptibilities and gaps in the data map, evidence
from WHO-monitored surveillance activities sug gests
that drug-resistant tubercu losis is a global problem.
Advanced resistance to first-line and second-line drugs
has emerged as a significant threat to public health in
several countries, including nations with a high burden of
tuberculosis. Although previous exposure to tuberculosis
drugs remains a major determinant for MDR tuberculosis,
several social and behavioural risk factors have been
identified, some of which relate to poor access to health
care and social support networks. Further monitoring of
resistance to second-line drugs is needed to enable
assessment of XDR and resistance beyond XDR, including
programmatically incurable forms of the disease.
Molecular epidemiology and transmission
dynamics of drug-resistant tuberculosis in
high-burden countries
Drug-resistant tuberculosis continues to be a threat to
tuberculosis control.43 Molecular epidemiology has been
important in advancing the knowledge of drug-resistant
 The Lancet Respiratory Medicine Commission
IS6110 restriction fragment length polymorphism
Targeted gene sequencing
Spoligotyping
MIRU-VNTR typing
Next-generation whole genome sequencing
XDR-tuberculosis
Targeted deep sequencing
outbreak in South Africa
Additional epidemiological
mechanisms leading to
Association between drug-resistant tuberculosis
mutation and drug
resistance
Exogenous re-infection with an
MDR-tuberculosis strain in
immune competent patients
Exogenous reinfection
with an MDR-tuberculosis
strain in an immune- Transmission of Genotypic classification of
compromised patient MDR-tuberculosis drug-resistant tuberculosis
1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016
Figure 2: Timeline of key molecular epidemiological findings using different genotyping tools
Genotyping tools used for each finding are indicated by different colours. MDR=multidrug resistant. MIRUVNTR=mycobacterial interspersed repetitive unitsvariable numbers of tandem repeat.
XDR=extensively drug-resistant.
tuberculosis epidemics (figure 2). First, on a population
basis, strain typing identifies strain relatedness, thus
identifying chains of transmission (a cluster of isolates
with identical genotypes according to IS6110 DNA
fingerprinting,44 mycobacterial inter spersed repetitive
unitsvariable numbers of tandem repeat [MIRUVNTR]
typing,45 or whole-genome sequencing;46 figure 2) and
providing an indication of how well a tuberculosis control
programme functions with respect to transmission
control.47,48 High clustering of drug-resistant tuberculosis
strains is indicative of high levels of transmission, which
might be because of the absence of appropriate case
detection and diagnosis-associated delays (and hence
treatment delays). By contrast, predominance of unique
drug-resistant tuberculosis strains reflects the acquisition
of drug resistance or reactivation of drug-resistant
tuberculosis acquired many years earlier49 (panel 2).
Second, on a patient level, strain typing provides insight
into the mechanism whereby drug-resistant tuberculosis
develops in an individual49,5456ie, whether resistance
developed in the patient during treatment (acquired
resistance) or whether a patient was infected with an
already resistant strain of M tuberculosis (primary
resistance).57 Third, since drug resistance is caused mainly
by particular mutations in the genome of M tuberculosis
complex strains, molecular epidemiology tools using gene
or genome sequencing are increasingly involved in the
identification of drug resistance in clinical isolates.58,59
296 www.thelancet.com/respiratory Vol 5 April 2017
Detection of mutations conferring
Heteroresistance explains resistance by targeted next generation
discordance between sequencing
genotype and phenotype
Whole genome sequencing
identifies transmission of
drug-resistant tuberculosis in Russia
Identification of compensatory
mutations in rpoA and rpoC
Rapid detection of
XDR-tuberculosis in Portugal
drug-resistant mutations
by whole genome sequencing
Whole genome
sequencing used
to differentiate
acquisition from
transmission Chronology of mutational
events leading to the
Totally drug-resistant evolution of
tuberculosis in Iran XDR-tuberculosis
Combined strain typing and targeted gene sequencing
improve the accuracy of transmission studies of
drug-resistant tuberculosis.53 Identification of resistance-
conferring mutations forms the foundation of com
mercially available molecular diagnostics tests endorsed
by WHO, including the Xpert MTB/RIF assay for simul
taneous detection of M tuberculosis and rifampicin
resistance, and the molecular line probe assays
MTBDRplus and MTBDRsl for detection of resistance to
first-line and second-line drugs.6062
The discourse around drug-resistant tuberculosis
continues to rely on two deeply-rooted epidemiological
dogmas. First, resistance has a fitness cost rendering
drug-resistant strains less transmissible (in this case, we
can regard fitness cost to be when bacilli grow more
slowly in vitro; however, whether this is relevant in a
clinical case is debatable).63,64 Second, resistance is
believed to primarily be acquired by patients who were
previously exposed to antituberculosis drugs (secondary
resistance).65 Consequently, for decades, tuberculosis
control policies have targeted prevention of drug-
resistant tuberculosis through the WHO directly
observed treatment, short course (DOTS) strategy and
focused on detection of drug-resistant tuberculosis in
individuals with a history of prior treatment for active
tuberculosis (high-risk group).65 International policies
have largely ignored patients who develop primary
resistance. Only with the advent of molecular
 The Lancet Respiratory Medicine Commission

epidemiology tools (table 1) are we now able to challenge

Panel 2: Strain typing definitions and interpretation
Cluster
Isolates collected within a defined time period and geographical
region with identical patterns on IS6110 RFLP, spoligotyping,
or MIRU-VNTR, are hypothesised to reflect recent
transmission.45,50 This definition of a cluster can be flexible to
allow for minor variation in the IS6110 RFLP or MIRU-VNTR
patterns and evolutionary events.51,52 Within the context of
drug-resistant tuberculosis, supporting the definition of a
cluster with resistance-conferring SNP data is crucial.53
When using whole-genome sequencing, two isolates differing
by several SNPs (commonly 10 SNPs) are hypothesised to
reflect transmission provided resistance-conferring SNPs are
identical (although additional resistance-conferring mutations
might be present, reflecting amplification of resistance).46
Unique
Drug-resistant isolates with unique IS6110 RFLP banding
patterns, spoligotype patterns, or MIRU-VNTR types, and
drug-resistant isolates with identical IS6110 RFLP banding
patterns, spoligotype patterns, or MIRU-VNTR types but
different mutations conferring resistance, reflect the
acquisition of drug resistance (ie, secondary resistance).49
Similarly, isolates whose whole genome sequences differ by
more than ten SNPs are interpreted to reflect the acquisition of
resistance or reactivation of a previous drug-resistant
tuberculosis infection or influx from a different community
(migration).
RFLP=restriction fragment length polymorphism. SNP=single-nucleotide
polymorphism.
these concepts.
Challenging the dogma of fitness cost of drug-resistance
mutations
The concept of reduced fitness in resistant strains stems
from the observation that isoniazid-resistant strains were
less virulent than isoniazid-susceptible strains in the
guineapig infection model.64,79 This concept of reduced
in-vitro or in-vivo fitness has been translated into a belief
that fitness costs slow the progression from infection to
active tuberculosis disease in human beings, reduce
virulence, and ultimately reduce transmission.80 On the
basis of this belief, early mathematical models suggested
that the transmission of MDR strains would not pose a
great risk to global tuberculosis control.81 This dogma has
been challenged by molecular epidemiological studies
that have shown transmission of drug-resistant strains in
several regions of the world.47,48,55,8285 However, the
transmissibility of drug-resistant strains is variable,86
which is explained by the fact that sequence variations
elicit a spectrum of fitness defects caused by functional
alterations in essential gene classes controlling functions
such as RNA or DNA replication or protein synthesis.8789
Notably, common mutations resulting in streptomycin,
isoniazid, and rifampicin resistance identified in clinical
isolates have been associated with low, or no, in-vitro and
in-vivo fitness cost.9092 These fitness deficits have been
quantified in vitro by competition assays that measure
bacterial growth rate.88 Using these assays, clinical
isolates were shown to rapidly undergo mutation
to ameliorate fitness deficits.90 These compensatory

Advantages Disadvantages Applications

IS6110 restriction fragment
length polymorphism44
Spoligotyping66
Mycobacterial interspersed
repetitive unit-variable
number tandem repeat
(MIRU-VNTR)6769
Targeted gene sequencing
(Sanger)58,70
Targeted deep
sequencing7173
Whole-genome
sequencing7478 of the pathogen
High discriminatory index
Direct genotyping of clinical specimens;
global reference database; relatively
inexpensive; requires fewer laboratory
resources
Direct genotyping of clinical specimens; Undergoes homoplasy; cannot
high discriminatory index; global
reference database
Direct genotyping of clinical specimens; Information limited to nucleotide
relatively inexpensive
Direct genotyping of clinical specimens
Comprehensive analysis of the genome
Requires culture and DNA extraction; Identification of transmission chains,
cannot differentiate between mechanism leading to primary resistance, and
drug-sensitive and drug-resistant strains temporal changes in the strain population
Low discriminatory index; undergoes Classification of strains according to
homoplasy; cannot differentiate lineages, re-infection, and strain migration For the SITVIT global database
between drug-sensitive and see http://www.pasteur-
drug-resistant strains guadeloupe.fr:8081/SITVIT_
Identification of transmission chains and ONLINE
differentiate between drug-sensitive mechanisms leading to primary resistance For the MIRU-VNTRplus global
and drug-resistant strains database see http://www.
pasteur-guadeloupe.fr:8081/
Identification of mutations conferring SITVIT_ONLINE
variants in a selected set of genes; resistance
no strain type information
Information limited to nucleotide Identification of mutations conferring
variants in a selected set of genes; resistance and heteroresistance
no strain type information; more
expensive; requires high-level
laboratory infrastructure
Requires culture (or specimen Identification of transmission chains,
enrichment); more expensive; might be mutations conferring resistance,
computationally demanding or complex heteroresistance (low resolution), mixed
infections, specimen heterogeneity, and
intrapatient evolution

Table 1: Molecular epidemiological genotyping methods

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 The Lancet Respiratory Medicine Commission
mutations might occur in genes coding the same protein
or in the same or a linked metabolic pathway or pathways,
thereby balancing fitness deficits or even raising the
comparative fitness of drug-resistant isolates to surpass
their drug-susceptible counterparts.90,91,93 Compensatory
mutations have been described for rpoA or rpoC,82,85,90
ahpC,93 and 16S rRNA.94 Highly transmissible MDR
outbreak clones with specific combinations of low-cost
resistance and compensatory mutations have already
emerged in several areas of the world.21,82,85 The
transmissibility of these drug-resistant strains remains
intact, even in the presence of up to nine resistance-
conferring mutations.82,84,95 However, even strains with
mutations associated with high fitness cost have emerged
and spread in immunocompromised hosts.84,96
Challenging the dogma that drug-resistant tuberculosis
is predominantly acquired
The 33% worldwide MDR tuberculosis prevalence in
new cases versus 20% in previously treated cases has led
to the widely held belief that most cases of MDR
tuberculosis arise from acquisition of resistance during
treatment rather than transmission of resistant strains.
Using molecular epidemiological tools, various mechan
isms for the development of drug-resistant tuberculosis
have been described: 1) primary infection with a drug-
resistant strain;57 2) re-infection with a drug-resistant
strain during treatment for drug-susceptible tuberculosis;54
3) re-infection with a drug-resistant strain after successful
treatment for drug-susceptible tuberculosis;5456,97 4) mixed
infection with a susceptible and resistant strain with
unmasking of the resistant strain during treatment for
drug-susceptible tuberculosis;54 and 5) acquisition of
resistance during therapy.98 A major outcome of large-
scale genotyping studies was that, in several high-
incidence settings, the contribution of transmission
for fuelling the drug resistance epidemic was under
estimated.49,82,99101
In most regions of the world, drug-resistant tubercu
losis is now predominantly caused by transmission rather
than acquisition of resistance, with an estimated 959%
of MDR tuberculosis in new tuberculosis cases and 613%
in previously treated cases being due to transmission.42
Even the epidemiology of XDR tuberculosisdefined as
resistance to isoniazid, rifampicin, a fluoroquinolone,
and an injectable agentis now better understood as
reflecting endemics rather than epidemics,48,95,102,103 and
population migration is recognised as a vehicle for spread
beyond the region of the strains origin. Indeed, molecular
epidemiological studies have documented the spread
of drug-resistant strains within countries, between
countries, and even across continents (figure 3).
The contribution of molecular epidemiology to the
history of drug-resistant tuberculosis
Phylogenetic analysis of DNA sequences has enabled the
study of the chronology in which drug resistance is
298 www.thelancet.com/respiratory Vol 5 April 2017
acquired.6,84,95,99 Analysis of the Tugela Ferry clone (a Latin
American Mediterranean strain) that caused the first
reported outbreak of XDR tuberculosis in 2006,48
suggested that development of extensive drug resistance
in KwaZulu-Natal originated from drug resistance that
began in the late 1950s, that isoniazid was the first drug
to which resistance was acquired, and that MDR
tuberculosis emerged in the 1980s, soon after the intro
duction of rifampicin.84 The precursors to XDR strains
emerged before the HIV pandemic, sug gesting that
transmissible XDR tuberculosis can develop in
dependently of HIV. Notably, the high HIV prevalence
combined with inadequate infection control have
undoubtedly contributed to the spread of XDR tubercu
losis in South Africa.84
Molecular analysis of MDR tuberculosis strains
worldwide shows a strong association between MDR
tubercu losis and resistance to ethambutol121,122 or
pyrazinamide.123,124 This association probably reflects first-
line treatment of undiagnosed MDR tuberculosis
resulting in acquisition of resistance to ethambutol and
pyrazinamide,125 followed by transmission. The continued
use of these two drugs, together with undetected
ethionamide resistance, weakened the MDR treatment
regimen culminating in the selection of XDR tuberculosis
strains.126,127 Clones of genetically distinct strains have
now evolved to become the dominant circulating pre-
XDR and XDR tuberculosis strains in defined geo
graphical regions, as observed in eastern Europe,82,85,104
Portugal,67 South Africa,48,95 and South America.99
Clinical implications of the findings of molecular
epidemiology
Clinical and public health practices for MDR
tuberculosis management have been slow to change,
partially reflecting the insufficient worldwide invest
ment in MDR tuberculosis diagnosis and treatment.
For example, drug susceptibility testing (DST) continues
to focus on previously treated patients,65 and universal
DST or DST beyond rifampicin is rarely done.
Pyrazinamide, isoniazid (high dose), and ethambutol
are still recom mended as add-on agents in MDR
tuberculosis treatment regimens, even in the absence of
documented sensitivityreflecting the low number of
active agents available.68 Consequently, many patients
with MDR tuberculosis are never appropriately treated
for MDR tuberculosis or are treated with ineffective
regimens, allowing for amplification of resistance and
continued transmission. In 2014, only a quarter of all
new MDR tuberculosis cases were detected and
reported.43 Furthermore, since full DST profiling and
individualised therapy are rarely done, strains with
second-line resistance often continue to transmit.
Consequently, drug-resistant strains can circulate and
persist for decades, as has been shown in Argentina,99
South Africa,84 eastern Europe,82,103 and Portugal.67
However, our knowledge of the global extent of such
 The Lancet Respiratory Medicine Commission

Figure 3: Inter-country and intra-country spread of drug-resistant tuberculosis according to M tuberculosis genotype
(A) Worldwide spread of drug-resistant strains of M tuberculosis. Red=Beijing strain.103,104,105112 Green=LAM9 strain.113 Light blue=Haarlem1 strain.114 Purple=T1 strain.115
Dark blue=untyped strains.116118 (B) Ongoing intra-country spread of extensively drug-resistant tuberculosis strains in South Africa. Red=atypical Beijing strains.
Green=LAM4 strain.53,119 Intra-country spread has also been reported in Portugal67 and Spain.120

drug-resistant tuberculosis strains is limited to The recent recommendation of a shorter-course MDR

countries in which culture and molecular strain typing
has been done.
The observation that most drug-resistant tuberculosis is
the result of transmission nevertheless raises hope,
because reducing transmission through early and effective
MDR tuberculosis treatment should halt transmission and
thus control MDR tuberculosis epidemics.42,69,128 Indeed,
some settingsfrom Estonia129,130 to New York131have
seen steeper declines in the incidence of drug-resistant
tuberculosis than in tuberculosis as a whole after adopting
interventions to control the transmission of drug-resistant
tuberculosis. Typically, these measures included universal
DST,132 individualised treatment,133 access to tuberculosis
care,134 and sustained efforts to improve treatment
completion, which is only achieved in two-thirds of cases,
even in well functioning programmes.135
tuberculosis regimen in patients with rifampicin-
resistant or MDR tuberculosis not previously treated
with second-line drugs and in whom resistance
to fluoroquinolones and second-line injectable drugs
has been excluded or is considered highly unlikely,
could substantially improve treatment compliance and
thus reduce transmission from patients who might
otherwise fail to adhere to the standard 24-month toxic
MDR tuberculosis regimen.68 For those diagnosed with
pre-XDR tuberculosis (resistance to either a
fluoroquinolone or second-line injectable drugs) and
XDR tuberculosis, the availability of new drugs,
including bedaquiline and delamanid, promises better
treatment outcomes in those patients who previously
had very low treatment success rates, potentially
interrupting the spread of drug-resistant strains.43

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 The Lancet Respiratory Medicine Commission
For the ReSeqTB see
https://platform.reseqtb.org
300 www.thelancet.com/respiratory Vol 5 April 2017
However, in the absence of careful stewardship136 the
effectiveness of these drugs might be rapidly lost6
thereby potentiating the cycle of transmission.
The future of molecular epidemiology of drug-resistant
tuberculosis: whole-genome sequencing
The advent and accessibility of whole-genome
sequencing could revolutionise the field of molecular
epidemiology because this method provides the ultimate
resolution for strain classification, and has thereby
challenged the accuracy of genotyping methods that have
been used previously.137,138 As with other typing methods,
transmission of M tuberculosis strains is measured by the
relatedness of each strains whole-genome sequencing
results. Recent reports have suggested that strains
differing by less than 10 single nucleotide variations
reflect transmission46,74,137,139,140 (figure 4). Deciphering
tuberculosis transmission dynamics is crucial for the
optimisation of local and global control measures and
the early detection of MDR and XDR outbreaks.142144
Whole-genome sequencing also provides a robust system
for differentiating clinical isolates into major lineages
and sublineages using an accurate nomenclature
framework,75 paving the way for investigations of lineage-
specific pathobiological characteristics.
Whole-genome sequencing also allows for the
simultaneous characterisation of virtually all resistance
markers in a given isolate.145,146 However, before whole-
genome sequencing information can be used in routine
clinical practice, several important issues need to be
resolved. Whole-genome sequencing is complicated by
the need for culture before DNA extraction,147
incomplete knowledge of all resistance-conferring
mutations,59,148 and the need for a validated pipeline to
accurately predict resistance.149 A relational sequencing
tuberculosis data platform (ReSeqTB) is being
developed in a partnership between the Foundation for
Innovative Diagnostics and Critical Path to TB Drug
Regimens to catalogue genotypic and phenotypic data
and to provide a validated pipeline for the analysis of
whole-genome sequencing. However, in the absence of
a complete understanding of the association between
genotype and phenotype, whole-genome sequencing or
targeted sequencing will remain a rule-in assay for the
presence of resistance. Further challenges will be the
need to rapidly process whole-genome sequencing data
and to communicate in a clinically and programmatically
relevant timeframe. This will be challenging, especially
in high-burden countries in which whole-genome
sequencing will most likely only occur at centralised
reference laboratories. Finally, data will need to be
presented in a clear, easily interpretable manner to
clinicians and programme managers who are un
familiar with sequencing technology. The application
of whole-genome sequencing information to clinical
care and tuberculosis control will thus benefit from
research by microbiologists to establish the mutations
conferring resistance and strain classification, and
by experts in implementation science to optimally
translate whole-genome sequencing results into policy
and practice.
Next-generation molecular epidemiology
The diagnostic pipeline has recently undergone
unprecedented innovation, with the development of
several new molecular tests for diagnosis of tuberculosis
and drug-resistant or MDR tuberculosis.150 WHO has
endorsed Xpert MTB/RIF60 and the MTBDRplus,
MTBDRsl, and Nipro line probe assays.61,62 New tests
such as Xpert Ultra (Cepheid) or targeted whole-genome
sequencing are in the advanced stages of development.
Used in routine care, these molecular tests not only
provide a diagnosis in an individual patient, but could
also potentially be modified to provide mutation-specific
information and phylogenetic data (eg, Xpert Ultra will
detect IS6110 transposable elements) at a population
level that could be used for monitoring drug resistance
surveillance, detecting epidemics, and contact tracing.
The potential utility of these tests (and evidence to
support their use) for public health interventions
unfortunately remains quite unexplored.
Examples of potential applications of molecular
epidemiological data from diagnostic tests do exist.
A preliminary study from South Africa151 found that
Xpert MTB/RIF probe information, which differed
substantially by geographical region, could be used for
near real-time national surveillance using connected
software, such as GXalert (open-source data connectivity
for the GeneXpert).152 By documenting the increasing
frequency of a specific mutation, these data could be
used for identifying the emergence of drug-resistant
tuberculosis or hotspots of MDR tuberculosis.69
Targeting these hotspots might be highly effective for
controlling drug-resistant tuberculosis.128 However,
as described by the routine strain typing service in the
UK, the effect of molecular epidemiological data on
patient care and public health response might not be
useful if those data are not reported and acted upon
quickly.153 To achieve this, major technical and systems
barriers must be overcome, including the strengthening
of information technology systems to facilitate timely
capture, export, and potentially automated analysis
of complex data, such as in web-based systems;148 linking
molecular data to key epidemiological data (eg,
geographical location); improving local scientific
capacity; and providing decision makers with sufficient
autonomy and resources to act in response to such data.
Summary of molecular epidemiology and transmission
dynamics
Whole-genome sequencing and new molecular diag
nostics promise to revolutionise our understanding of
the epidemiology of M tuberculosis. Advances in these
technologies have raised the prospect that molecular
 The Lancet Respiratory Medicine Commission

epidemiology could be integrated into routine care.

However, numerous challenges still remain with respect
to the utility of these methods for the direct analysis of
A
clinical specimens and whether such methods can be IS6110 RFLP Spoligotype Key
implemented in low-resource settings in which the 102401
burden of tuberculosis disease is highest. Whole-genome 3929/10
6631/04
sequencing is computationally intense, delaying its real-
10118/05
time application for diagnosis and rapid programmatic
11114/03
interventions. Furthermore, analysis tools have some 1608/04
limitations: the definition of a transmission cluster 164/04
remains poorly defined; repeat regions of the genome 2387/04
are excluded from the analyses; genomic deletions are 2651/10
missed; and the sensitivity for detecting heteroresistance 3176/05
and mixed infections is low. Resolution of these 3501/05
3543/05
problems, together with more basic clinical and
4155/03
implementation research, will allow us to address the 5829/05
knowledge gaps regarding transmission, pathophysio 629/09
logy, and the association between mutations, microbio 6577/07
logical resistance, and clinical impact. 6755/05
6821/03
The rise of drug-resistant tuberculosis 7679/03
7684/04
Historical notions on how drug resistance arises
8073/03
In the past, the proximate cause of acquired drug 8370/04
resistance had been ascribed to poor adherence.154,155 Thus, 8506/04
acquired drug resistance was dealt with using a 8779/06
programmatic approach, specifically the DOTS strategy, to 9956/03
improve adherence. The idea of DOTS arose from the 9952/07
move from sanatoria-based care to ambulatory care, on
the basis of studies in India156 and Hong Kong157 in the B
late 1950s and the 1960s, the main outcomes of which
6631-04
were for ambulatory patients to achieve the same rates of 3176-05
treatment compliance as was achieved in hospitalised
patients, to attain the same treatment success.156158 To 1

achieve this compliance, supervision of outpatient

63
therapynot just in these countries but also in Western 3543-05 4155-03
countriesand the development of intermittent therapy
regimens was needed. The Styblo model,159 which 4 1
included strict supervision and active case finding, 164-04
expanded supervised outpatient therapy into international 6557-07
2387-04 1
tuberculosis programme contexts, with trial projects in 1 2651-10
120 6755-05
east Africa.159,160 These early efforts have evolved to the 6821-03 7679-03
2 1608-04
point at which supervised treatment is now universally 10118-05 7684-04
advocated and is a pillar of the WHO DOTS policy. 3501-05 3
5829-05 1
The DOTS programme has five elements: political 2 629-09 1
8506-04
commitment from governments, improved laboratory 9952-07
8779-06 11114-03
services, a continuous supply of high-quality drugs, 8073-03
1

60
8370-04
Figure 4: IS6110 DNA fingerprint of 26 outbreak isolates
Genotypic analysis of 26 outbreak isolates. (A) IS6110 DNA fingerprint and
spoligotype patterns and (B) genome analysis (modified from Kohl and
1024-01
colleagues141). IS6110 DNA RFLP and spoligotyping patterns are identical
(clustered), suggesting transmission. Whole-genome sequence analysis identified
a total of 264 single-nucleotide polymorphisms between the different isolates 4
which allowed for a higher differentiation of the outbreak strains in the
minimum spanning tree. Four outlier strains with more than 50 single-nucleotide
polymorphisms were identified. Colours depict strains from patients with direct 3929-10
epidemiological linkssource case is coloured purple. RFLP=restriction fragment
length polymorphism.

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 The Lancet Respiratory Medicine Commission
a reporting system to document the progress (and failure)
of treatments for individual patients and for the pro
gramme, and direct observation to ensure that patients
swallow all their pills. Strengthening DOTS programmes
was credited with stopping the outbreaks of MDR
tuberculosis in many regions in the USA, especially in
New York City, the DallasFort Worth Metroplex, and
Baltimore.161164 Emergence of acquired drug resistance
eventually became equated with poor adherence, and high
rates of acquired drug resistance were considered to be an
indicator of poor performance of DOTS programmes.
Thus, high numbers of patients defaulting from therapy
is now considered an indicator of poor treatment
outcomes in its own right, as bad as therapy failure.
Acquired drug resistance continues to be a major problem
in many places, including in programmes in which
patients achieve high rates of adherence.4,165,166 Indeed,
careful historical documentation has shown that the
problem of M tuberculosis acquired drug resistance arose
as soon as drug therapy first became available, and has
continued being a problem from the 1950s to the
present.165
Several mechanisms were proposed for how poor
compliance could lead to acquired drug resistance.
In 1970, Hugo David performed fluctuation tests to
identify M tuberculosis mutation rates, and identified
average mutation rates (as mutation per bacterium per
generation) of 25610 for isoniazid, 25610 for However, this pharmacological approach does not
ethambutol, and 22510 for rifampin.167 The exclude the role of tuberculosis programmes; rather it
probability of acquired drug resistance to two or more
drugs is the product of these mutation rates, so the
probability of acquired drug resistance for these
three drugs in combination would be ~1010. In view understanding, which would strengthen the effectiveness
of this low predicted probability, the only way acquired
drug resistance was thought to be possible was with
inadvertent monotherapy because of inappropriate
prescribing, irregular drug supplies, or most importantly,
poor patient adherence.168 Four scenarios or mechanisms
were proposed for this inadvertent monotherapy.169 First,
given the high bacillary burden in which mutants
probably pre-existed, and that each antibiotic in the
combination only works on specific metabolic sub
populations of the bacteria (eg, isoniazid is the only
effective drug against rapidly growing bacteria; thus,
monotherapy is effectively being given), isoniazid-
resistant mutants would be selected if patients took the
combination treatment for 2 days and then stopped. The
second mechanism would arise during the sterilising
effect, given that pyrazinamide would be the only
effective drug for semidormant M tuberculosis under
acidic conditions, and rifampicin for non-replicating
persistent bacteria under hypoxia; mathematical models
predicted that poor compliance would lead to acquired
drug resistance in this situation.170 The third mechanism
involves regrowth during subinhibitory concentrations
of drugs, especially for drugs (such as isoniazid) that
have a high therapeutic margin and a long half-life,
302 www.thelancet.com/respiratory Vol 5 April 2017
because they remain present in the body after the
clearance of other drugs. This is essentially a version of
the pharmacokinetic mismatch hypothesis. The fourth
scenario involves differential bacteriopausal mechanisms
in which a drug such as rifampicin, whose post-antibiotic
effect is shorter than of a companion drug such as
isoniazid, selects isoniazid-resistant mutants during
regrowth.169
The lessons learned from the study of other bacteria,
such as Staphylococcus aureus and Gram-negative bacilli,
and simple evolutionary principles should not have been
ignored. In the clinical setting, poor adherence is not the
main driver of acquired drug resistance in many other
bacteria. In fact, suboptimal antibiotic concentrations
lead to acquired drug resistance as a result of simple
evolutionary pressure, and some bacterial genetic
hypermutable backgrounds could predispose some
strains to a higher propensity for acquired drug
resistance. Doses and dosing schedules that lead to
suboptimal concentrations and a bacterial genetic
background that facilitates acquired drug resistance
cannot be overcome simply by improved adherence.
Fortunately, in recent years, a better understanding that
is supported by studies in standard bacteriology and
pharmacology has emerged to explain M tuberculosis
acquired drug resistance.171173 Consideration of resistance
mechanisms beyond gene mutations has also begun.
emphasises that the policy for abrogating acquired drug
resistance that programmes implement should continue
being revised to conform to the latest scientific
of these programmes.
The role of adherence in emergence of acquired drug
resistance: preclinical models and evidence-based
clinical approaches
One explanation of how non-adherence causes acquired
drug resistance is pharmacokinetic mismatch. During
periods of non-adherence, the drugs with shorter half-
lives disappear so that M tuberculosis bacilli are exposed
to monotherapy with the drug that has the longer half-
life for periods of their growth, leading to resistance to
that drug. This concept also applies to HIV drugs such as
efavirenz with a half-life of 58 h, and stavidune and
lamivudine with half-lives of 512 h. If the viral burden is
10 virions in the body with a mutation rate of 410 to
210 per base per cell and a doubling time of 10 h, the
virus would be exposed to efivarenz monotherapy for a
period of 2 weeks (ie, >30 doubling times).174 In the
standard antituberculosis regimen, rifampicin and
isoniazid both have a short half-life of 23 h and
pyrazinamide has a half-life of 10 h, while M tuberculosis
has a doubling time of 1496 h and the mutation rates
(25610 for isoniazid, 25610 for ethambutol, and
22510 for rifampin) identified by David,167 with a

total bacterial burden of 10 in a cavity.175178 The antibiotics
are no longer present because clearance occurs before a
single M tuberculosis has replicated, and certainly by the
second and third replications. This timing makes the
probability of generation of mutants, or even amplifying
pre-existing ones, less likely, particularly for non-
replicating persistors and semi dormant bacilli, aptly
described as fat and lazy by Garton and colleagues179
because of their lipid content and slow doubling times,
which can take weeks.180 The pharmacokinetic mismatch
hypothesis for acquired drug resistance was directly
tested for isoniazid and rifampicin in the hollow fibre
model of tuberculosis, on the basis of M tuberculosis
doubling times of 24 h and 240 h.181,182 This preclinical
model was chosen because of the ease in which acquired
drug resistance arises in the model. Acquired drug
resistance did not arise with mismatched regimens, even
when the inoculum was spiked with 05% rifampicin-
resistant and isoniazid-resistant isogenic strains; rather,
microbial kill was actually better with the most
deliberately mismatched regimens compared with the
most perfectly matched regimen, supporting a role for
sequential dosing.182 The success of sequential dosing is
probably because of reduced isoniazidrifampicin
antagonism in the most mismatched regimens. Thus, at
least in the laboratory, pharmacokinetic mismatch was
not likely to be involved in the emergence of XDR and
MDR tuberculosis.
The hollow fibre model was also used to directly test the
non-compliance hypothesis for acquired drug resistance
and for amplification of pre-existent (05%) rifampicin
and isoniazid resistance.181 This experimental model
which has a forecasting accuracy of 94% for clinical
therapeutic events in patients with tuberculosis, based on
evidence gathered for regulatory approval by the US Food
and Drug Administration (FDA) and European Medicines
Agency (EMA)enables experi ments to be done that
Study design Number of subjects and study
location
Volmink and Garner Ten RCTs 3985 patients from Tanzania, Nepal,
(1997,188 updated Taiwan, Pakistan, Thailand, USA, and
2007189) South Africa
Pasipanodya and Ten RCTs and 8774 patients from Tanzania, Nepal,
Gumbo (2013)187 prospective studies Taiwan, Pakistan, Thailand, USA, and
South Africa were allocated to DOT
and 3708 patients from the same
countries were allocated to SAT
Karumbi and Garner 11 RCTs, including 5662 patients from Tanzania, Nepal,
(2015)186 nine individual Taiwan, Pakistan, Thailand, Australia,
patient RCTs and USA, and South Africa
two cluster RCTs
DOT=directly observed therapy. SAT=self-administered therapy. ADR=acquired drug resistance. RCT=randomised controlled trial. RR=relative risk.
Table 2: Evidence-based medicine approach for evaluating the effect of DOT versus SAT on tuberculosis treatment outcomes, including ADR
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The Lancet Respiratory Medicine Commission
could be too dangerous in patients (eg, the deliberate
generation of acquired drug re sistance).183 Different
degrees of adherence, from 0% to 100% of doses missed,
and different adherence patterns (onoff; onoffonoff,
random missed doses) were used, and population size of
the resistant subpopulations was captured via repetitive
sampling with treatment of up to 56 days. No emergence
of MDR tuberculosis was seen (except transient isoniazid
resistance which eventually disappeared) in any system
in a set of six repeat experiments, including those with a
pre-existent resistant population of less than 1%. Similar
findings were seen in the mouse model, in which no
MDR tuberculosis arose with non-adherence.184 Thus,
at least in two laboratory pre-clinical models, missing
doses did not seem to lead to either MDR M tuberculosis
or amplification of acquired drug resistance.
In the past, the role of non-adherence in acquired drug
resistance has been established in clinical settings by
consensus on the basis of low-quality retrospective
studies.155,164,185 These were the only type of studies available
and thus represented the best available evidence at the
time. Since then, at least five randomised controlled trials
and five prospective observational studies, in which
patients were assigned to self-administered therapy or
supervised therapy (ie, DOTS), have been reported.186188
Recent meta-analyses of these prospective studies, in which
quality was assessed and studies were ranked using
standard evidence-based medicine criteria, examined the
outcomes of therapy failure and acquired drug resistance.
These meta-analyses are summarised in table 2.186188 The
three meta-analyses were concordant in showing that
supervised therapy was effective in reducing non-adherence
and improving treatment completion. The meta-analyses
also showed that no benefits were associated with DOTS
compared with self-administered therapy when microbio
logical failure and relapse were examined as clinical
endpoints.186189 Pasipanodya and colleagues187 showed that
Hypotheses examined Conclusions
Effects of DOT on tuberculosis cure, DOT did not improve overall cure (RR 102, 95% CI 086 to 121).
tuberculosis treatment completion, There was a possible small effect with home-based DOT compared
adherence, and latent tuberculosis with clinic DOT (RR 110, 95% CI 102 to 118)
treatment efficacy and adherence
Compared DOT versus SAT on DOT was not significantly better than SAT in preventing
tuberculosis treatment failure, relapse, microbiological failure, relapse, or ADR; the pooled risk difference
and ADR was 00 (95% CI, 001 to 001) when DOT (n=415) was compared
with SAT (n=532) for ADR
Effects of different forms and intensity Proportion of patients whose disease was cured was still low and
of DOT on tuberculosis cure, ranged between 41% and 69%; DOT did not improve overall
tuberculosis treatment completion, proportion cured (RR 108, 95% CI 091127); no significant
adherence, and latent tuberculosis difference in proportion whose disease was cured was seen between
treatment efficacy and adherence different forms of DOT (facility based vs community based) or the
person supervising (health care worker, family, or community
member)
 The Lancet Respiratory Medicine Commission
acquired drug resistance developed in seven of 415 (169%)
patients randomised to supervised therapy (ie, DOTS)
versus five of 532 (094%) who were randomised to self-
administered therapy, with a risk difference of 000
(95% CI 001 to 001).187 The incidence of acquired drug
resistance was the same whether supervised therapy was
given at home, in a health facility, by a family member, or
by a community health-care provider.186 None of these
analyses identified single study effect or bias.
Despite this apparent absence of an effect, the DOTS
programme is useful because it is an example of political
commitment by governments and ensures the continu
ous supply of good-quality drugs, which directly affects
pharmacokinetic variability. Equally important are good
laboratory services, which affect the accuracy of
susceptibility testing and measurement of minimal
inhibitory concentrations (MICs), which are crucial in
defining MDR and XDR tuberculosis, and in triaging
patients to different regimens. Accumulating evidence,
based on the latest evidence-based approaches, indicate
that causes of acquired drug resistance in tuberculosis
should be sought elsewhere other than poor adherence.
Pharmacokinetic variability and acquired drug
resistance
To demonstrate the common scenarios that lead to
acquired drug resistance in patients with tuberculosis,
we refer to a paediatric case report by Garcia-Prats and
colleagues.190 They described a boy aged 25 months
infected with drug-susceptible tuberculosis, who was
treated with a meticulous directly observed therapy, but
sequentially developed isoniazid acquired drug resistance
after 2 months of therapy, and then rifampicin acquired
drug resistance after 5 months.190 The reason was
established as low serum isoniazid and rifampicin
concentrations, due in part to rapid metabolism of
isoniazid by NAT2*4/2*7B in the child, who was given
the standard therapy at the time.166,190 Thus, despite the
paucibacillary nature of this disease in children,
Start of therapy Upregulated Low-level phenotypic Drug target site
RNA for multiple resistance reversed by mutations; efflux
efflux pumps efflux pump inhibitors pump mutations
Low drug concentration exposures:
Pharmacokinetic variability
Drug penetration
Concentration gradients
Suboptimal dosing Hours to days Days Weeks to months
Low active pharmaceutical ingredient
High minimal inhibitory concentration
Figure 5: Antibiotic resistance timeline
Exposure to low drug concentrations caused by various factors often initiates the process of antibiotic resistance.
Low concentrations of active pharmaceutical ingredient is a common problem, with low-quality drugs produced
by some manufacturers as well as from counterfeit drugs. Early events include induction of multiple efflux pump
genes, with RNA upregulation of up to 50 times. Phenotypic low-level resistance can then occur, which is reversed
by efflux pump inhibitors. Over time, a subpopulation of the bacteria replicate, with mutations in the antibiotic
target site and efflux pumps. In the event that there is heteroresistance at the start of therapy, the process is still
operational for both the resistant and susceptible subpopulations. Additionally, part of the susceptible bacterial
subpopulation is killed at high drug exposures, leaving the resistant subpopulation.
304 www.thelancet.com/respiratory Vol 5 April 2017
pharmacokinetic variability was crucial in the emergence
of MDR tuberculosis. This scenario has also emerged as
an important and common proximate cause of acquired
drug resistance in adult patients with tuberculosis.
Hollow fibre studies in tandem with in-silico clinical
trial simulations predicted that, given the xenobiotic
metabolism patterns in the Western Cape in South Africa,
a proportion of patients would actually be on mono
therapy despite being given the full multidrug regimen
and being part of a DOTS programme.191 This is because
of the differential rapid elimination of some drugs in the
regimen, leading to prolonged monotherapy with the
drug that is not rapidly or extensively metabolised over
tens to hundreds of rounds of bacterial replication. The
in-silico study181 predicted that 068% of patients would
develop acquired drug resistance and MDR tuberculosis
within 2 months despite 100% adherence, because of
such differential pharmacokinetic variability of regimen
components. A prospective clinical study191 in the same
population was performed, and identified suboptimal
drug concentrations due to pharmacokinetic variability
as the cause of failure of therapy in more than 90% of
patients. Acquired drug resistance, including MDR
tuberculosis, was encountered in 07% of patients during
the first 2 months, despite adherence to standard doses
of isoniazid, rifampicin, pyrazinamide, and ethambutol.
All cases of acquired drug resistance, including MDR
tuberculosis, were preceded by suboptimal drug
concentrations due to pharmacokinetic variability.191
A meta-analysis of 13 randomised studies with 1631 rapid
isoniazid acetylators and 1751 slow acetylators showed
that rapid acetylators had 20 times higher occurrence of
microbiological failure and acquired drug resistance
compared with slow acetylators.192 This increased
microbial failure and acquired drug resistance was due
to pharmacokinetic variability to only one of the three
main drugs in the regimens. Recent studies have
extended this finding to aminoglycosides in patients with
MDR tuberculosis.192 Dheda and colleagues193 have
proposed and tested further pharmacokinetic variability
at the level of drug penetration into tuberculosis lesions,
which is dependent on the architecture of the tuberculosis
lung cavity, for more than eight drugs. The lung cavity
and surrounding fibrosis, depending on the size, will
create a physicochemical barrier to drug entry, leading
to anatomical site-based monotherapy. Indeed, this
differential penetration has also been identified in
pericardial194 and meningeal195 tuberculosis.
Some problems exist in the tuberculosis programme
that will exacerbate pharmacokinetic variability, such as
drug stock shortages, and that many drug stocks include
counterfeit drugs with low concentrations of active
pharmaceutical ingredient, so the drug is unknowingly
taken at low concentrations even when first ad
ministered. In addition, health-care workers might
prescribe lower doses than those needed to achieve the
required optimal drug concentrations because of error

or weight-based capping dosing practices (when dosing
is capped at a particular maximum for the individual
patient weight), which are often used in tuberculosis
programmes, especially when fixed-dose formulations
are given. All these factors converge to increase the
chances of delivering suboptimal drug concentrations.
The role of efflux pumps in antibiotic resistance
Laboratory experiments and clinical observations,
combined with the consideration of non-adherence,
biological variability, evolution, and efflux pumps, have
led to another theory of the mechanisms underlying
drug resistance, in which efflux pumps and chromosomal
mutations represent a single process of acquired drug
resistance.171173,196,197 In this theory of drug resistance
(figure 5) several initiating factors exist such as low drug
dosage due to poor dosing practices, pharmacokinetic
variability, or inadvertent monotherapy with, for example,
quino lones for bacterial pneumonias and other con
ditions that turn out to be tuberculosis. As part of the
bacterial stress reaction to the suboptimal antibiotic
concentrationsand to effective monotherapyefflux
pumps in the bacilli are upregulated within hours. This
increase can be demonstrated by quantifying transporter
messenger RNA, and is followed within a few days by
phenotypically demonstrable low-level resistance that is
reversed by efflux pump inhibitors such as verapamil.
This process is evolutionarily conserved in M tuberculosis,
Mycobacterium avium complex, Mycobacterium leprae,
Mycobacterium marinum, Mycobacterium abscessus, and
Mycobacterium ulcerans.172 This efflux pump-dependent
low-level resistance process allows the bacteria time to
undergo multiple rounds of replication under suboptimal
antibiotic pressure or monotherapy, allowing for
development of mutations in the canonical drug
resistance genes, in efflux pump genes, or in negative
regulators of efflux pumps.198 The mutations in efflux
pump regulators lead to high-level resistance, usually to
multiple antibiotics. The demonstration of co-occurrence
of canonical mutations in drug target genes and MICs
that decrease in the presence of an efflux pump inhibitor,
as well as recent studies in clinical isolates, seem to
support this new idea.6,197,198,199201
Some phylogenetic lineages of M tuberculosis (geno
types) and the strains of these lineages have greater
propensity to cause acquired drug resistancethis theory
has been especially recognised since the Beijing strain
started gaining notoriety in the MDR tuberculosis
epidemic.202 Ford and colleagues203 did Luria-Delbrck
fluctuation analysis on a panel of laboratory and clinical
isolates from lineage 2 and lineage 4, to which the Beijing
strain belongs, and found the number of mutants per cell
plated in a single culture ranged from 24210 for the the same, and data show that M tuberculosis is no exception.
CDC-1551 strain (lineage 2) to 19410 for the HN878 Using pharmacokineticpharmacodynamic principles,
strain (lineage 4), which was a significant difference.203 In
the case of M tuberculosis genotypes associated with
higher mutation rates, there could be a pre-existing
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The Lancet Respiratory Medicine Commission
Standard or Proposed MIC Breakpoint, Lowest MIC in mutants
WHO MIC above* which carrying resistance mutations
therapy fails
Isoniazid 02; 10 003; 0125 00312 0030125
Rifampicin 1 00625 0125 0125; 006025
Ethambutol 5; 75 4 4
Pyrazinamide 100 50 50 25
Moxifloxacin 1 1 05
MIC=minimal inhibitory concentrations. shows a range. =unknown value. *Since MICs are determined on the basis
of two-fold dilution steps, but classification and regression tree analyses calculate exact MIC breakpoints, the values
presented in the table indicate the nearest observed MICs that fulfil the non-strict inequality values. Where two values
are given, this indicates the high and low level of resistance. Data are from several sources.209221
Table 3: Clinical and microbial evidence to support proposed susceptibility breakpoints of different
antibiotics
subpopulation already resistant to one or two antibiotics
before commencement of therapy.203 Indeed, math
ematical modelling predicted a probability of the
emergence of resistance to both isoniazid and rifampicin
of 110 to 110 before commencement of therapy,
suggesting that prior existence of MDR might be
common.204 These patients would have a mixture of both
drug-susceptible M tuberculosis and drug-resistant
M tuberculosis that have arisen from a single strain.
By contrast, there are also groups of patients infected by
mixed strains, one resistant and the other susceptible.
These scenarios lead to so-called heteroresistance, which
is encountered in 725% of patients with MDR
tuberculosis, patients previously treated for tuberculosis,
and those in whom first-line therapy failed.70,205,206
Treatment with standard regimens or MDR tuberculosis
regimens would lead to rapid selection of the drug-
resistant subpopulations, either on the basis of classic
Luria-Delbrck considerations, or the antibiotic resistance
process shown in figure 5.207
Redefining drug resistance, MDR tuberculosis, and XDR
tuberculosis by changing susceptibility breakpoints
M tuberculosis is considered drug resistant when >1% of
M tuberculosis cultures grow in the presence of critical drug
concentrations. Critical concentrations are derived from
epidemiological cutoff values on the basis of their ability to
kill 95% of wild-type isolates or the 95% MIC on a normal
distribution curve.208 The problem with this definition is
logical and mathematical: what do the parameters of the
Gaussian curve of the MIC distribution have to do with
how well a patient will respond to therapy?209 Wild-type
MIC distributions of any organism vary between regions
because of local evolutionary drivers, so it in unclear which
to use.210 The idea that all wild-type distributions are the
same is assumed in general microbiologybut they aren't
and the knowledge that microbial kill with a fixed celling
concentration decreases as MIC of the drug increases,
Gumbo211 proposed that drug resistance should be defined
 The Lancet Respiratory Medicine Commission

Common mutations Compensatory mutations

Isoniazid: inhibition of cell wall mycolic acid synthesis
katG Thr275Pro, Trp300Gly, Ser315Thr or Ser315Asn, Gln434X, Intergenic region between oxyR and ahpC: 9GA, 15CT
Ala478del
Rv1910c-furA intergenic 12GA, 10AC, 7GA Unknown
region
furA-katG intergenic region Truncation of 134-bp fragment (21565922156726)* Unknown
mabA (fabG)-inhA 17GT, 15CT, 8tA, Ser94Ala Unknown
Rifampicin: inhibition of transcriptional activity
rpoB Asp516Val or Asp516Tyr, His526Arg or His526Asp or rpoA mutations: Arg186Cys, Thr187Pro/Ala, Glu319Lys; rpoC
His526Tyr, Ser531Leu mutations: Val483Ala, Asp485Asn, Gly594Glu, Asn689Ser,
Asn826Lys
Pyrazinamide: interference with membrane energy transduction, inhibition of trans-translation, inhibition of pantothenate and inhibition of CoA
biosynthesis
pncA Diverse mutations scattered along entire gene Unknown
rpsA Thr5Ser, Asp123Ala, Ala438del Unknown
panD Met117Ile, Pro134Ser Unknown
Ethambutol: inhibition of biosynthesis of cell wall arabinogalactan
embB Met306Val or Met306Ile, Gly406Ser or Gly406Ala or Unknown
Gly406Asp or Gly406Cys, Gln497Arg
ubiA Val188Ala, Ala237Val, Arg240Cys, Ala249Gly Unknown
Fluoroquinolones: inhibition of DNA replication, transcription, and recombination
gyrA Ala74Ser, Gly88Ala or Gly88Cys, Ala90Val, Ser91Pro, Asp94Gly gyrA mutations: Thr80Ala, Ala90Gly
or Asp94His or Asp94Ala
gyrB Asp461His or Asp461Asn or Asp461Ala, Gly470Ala, Unknown
Asp494Ala, Asn499Asp, Glu501Val
Streptomycin: inhibition of protein synthesis
rpsL Lys43Arg, Lys88Arg Unknown
rrs 462CT, 492CT, 514AC, 517CT Unknown
gidB n/a Unknown
Kanamycin and amikacin: inhibition of protein synthesis
rrs 1401AG, 1484GT 1409CA, 1491GT
eis 10GA, 14CT, 37GT Unknown
whiB7 86del C, 124del C, 128del G, 133del C, 133_134insC, 179del G Unknown
Capreomycin: inhibition of protein synthesis
rrs 1401AG, 1484GT Unknown
tlyA Asn236Lys Unknown
Linezolid: inhibition of protein synthesis
rrl 2061GT, 2270GC or 2270GT, 2576GT, 2746GA Unknown
rplC Cys154Asn, His155Asp Unknown
Bedaquiline: inhibition of mycobacterial ATP synthase
atpE Asp28Val, Glu61Asp, Ala63Pro Unknown
Rv0678 Ser68Gly, Arg94Gln, Glu138Gly, Trp92_Phe93insGly, Unknown
Arg38_Leu39insAla
Ethionamide: inhibition of cell wall mycolic acid synthesis
ethA Diverse mutations scattered along entire gene Unknown
ethR Ala95Thr, Phe110Leu Unknown
mabA (fabG)-inhA 17GT, 15CT, 8TA, Ser94Ala Unknown
(Table 4 continues on next page)

as the MIC at which the antibiotic fails to kill M tuberculosis
in a patient taking the maximum tolerated dose. If the
drug cannot kill the bacteria in the lungs of patients
because its MIC is high, then the bacteria are resistant. In
view of this, mathematical modelling and simulations
have identified the MICs at which isoniazid, rifampicin,
ethambutol, pyrazinamide, and moxifloxacin fail
(table 3).211 These MIC values differ substantially from the
consensus breakpoints that are used by WHO, suggesting
that the problem of MDR tuberculosis, and thus also XDR
tuberculosis and incurable tuberculosis, is much more
severe than appreciated.

306 www.thelancet.com/respiratory Vol 5 April 2017

 The Lancet Respiratory Medicine Commission

Common mutations Compensatory mutations

(Continued from previous page)
Para-aminosalicylic acid: inhibitor of folic acid and thymine nucleotide metabolism
ribD 11 GA Unknown
thyA Gln111X, Leu143Pro, Ala182Pro, Thr202Ala, Tyr251X, Unknown
Val261Gly X264Arg
dfrA Val54Ala, Ser66Cys, Cys110Arg Unknown
folC Glu40Ala or Glu40Gly, Ile43Ala or Ile43Thr Unknown
D-cycloserine: inhibition of cell wall peptidoglycan synthesis
alr 26 GT|| Unknown
ddl None identified Unknown
cycA Gly122Ser** Unknown

*Nucleotide positions refer to H37Rv genome (NC_000962.3). No particular mutations in gidB have been shown to have causal relationship with streptomycin resistance in
clinical strains, although deletion of gidB by homologous recombination can confer low-level streptomycin resistance. Promoter mutations in eis confer only kanamycin
resistance but not amikacin resistance. The listed mutations in whiB7 were identified in spontaneous mutants derived from laboratory strains. The listed mutations in
Rv0678 were identified in spontaneous mutants derived from laboratory strains. ||The mutation was identified in a DCS-resistant M smegmatis strain. **The mutation was
identified in a DCS-resistant M bovis strain.

Table 4: Common target mutations and compensatory mutations in drug-resistant Mycobacterium tuberculosis isolates

Confirmation of these lower critical concentrations have
come from clinical studies209213 and several investi
gations214221 of drug resistance-associated mutations in
isolates with MICs below the standard breakpoint. Clinical
studies using assumption-free methods such as machine
learning have confirmed that these values (table 3) are in
fact the MICs above which tuberculosis patients fail
combination therapy.209,212,213 As an example, on the basis of
an analysis of 207 patients with MDR tuberculosis in
China, Zheng and colleagues213 identified the same
proposed susceptibility breakpoint for pyrazinamide as
the pharmacokineticpharmacodynamic breakpoint
(table 3), and calculated a sensitivity of 89% and a
specificity of 93% for treatment success. Thus, the
proposed breakpoints are relevant in terms of patient
outcomes. Additionally, studies have been done in which
treatment failed in patients who were infected with
M tuberculosis who had drug target site mutations, but
MICs were lower than current breakpoints, and were
more consistent with the newly proposed breakpoints.214221
Therefore, the proposed concentrations have higher
sensitivity for clinical decision making, and should be
used to estimate the global burden of MDR tuberculosis.
Mutations identified by whole-genome sequencing
that are associated with XDR or MDR tuberculosis
Acquired drug resistance in M tuberculosis is considered to
be mostly caused by chromosomal mutations that lead to
drug-target modification, as is the case with rifampicin
and rpoB. Mutations can also occur in enzymes that
convert prodrugs to active moietyeg, catalase-peroxidase
and isoniazid. Another common mechanism resulting in
acquired drug resistance involves mutations that lead to
activation of efflux pumps. Traditional sequencing
targeted at some antibiotic targets and the use of
whole-genome sequencing for an unbiased identification
of mutations associated with drug resistance have revealed
a myriad of mutations directly leading to resistance on the
basis of these three mechanisms, as well as compensatory
mutations. A comprehensive list of these mutations is
provided in table 4.199,222,76,223225,77
Summary of the rise in drug-resistant tuberculosis
New efforts have been made to establish how acquired
drug resistance and MDR tuberculosis arise in patients
Preclinical studies, prospective clinical studies, and meta-
analyses have not identified the role of adherence in
acquired drug resistance, contrary to common beliefs.
Pharmacokinetic variability has emerged as an important
proximate cause of acquired drug resistance in vitro, in
mathematical simulations, in prospective clinical studies,
and in meta-analyses. Another new hypothesis is that
efflux pumps and final-target mutations associated with
acquired drug resistance are linked and part of
one process. One pivotal study203 proposed different
mutation rates for the different phylogenetic lineages of
M tuberculosis, which could explain why drug resistance
emerges commonly in some locations. Finally, we propose
that the susceptibility breakpoints should be revised
on the basis of pharmacokineticpharmacodynamic
approaches and patient outcomes.
Diagnosis of MDR and XDR tuberculosis
Drug-resistant tuberculosis occurs when M tuberculosis
bacilli undergo mutations that enable it to survive the
effects of tuberculosis drug treatments. Unlike many
other bacteria, no horizontal acquisition of resistance has
been shown in M tuberculosis, and a drug-resistant strain
can be defined as one that differs significantly from wild
strains in its degree of susceptibility because of the
increased proportion of resistant mutants.226 Testing the
susceptibility of M tuberculosis to antituberculosis drugs
might be done either for patient management or as part
of a surveillance programme to monitor the effectiveness

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 The Lancet Respiratory Medicine Commission
of local treatment protocols. An important distinction
between the two is the need for urgency; patients on
inappropriate treatment are unlikely to recover. They
could remain infectious and therefore a source of onward
transmission. Drug resistance testing reveals drugs of
reduced or no curative benefit, thus facilitating
construction of an individualised, optimised treatment
regimen. Other factors deserving consideration in the
treatment of drug-resistant tuberculosis are drug toxicity
and individual patient tolerance. In most high-income
countries with a low prevalence of tuberculosis, all
patient isolates are routinely screened for susceptibility
to the major antituberculosis drugs.227 In settings with a
high incidence of disease or scarce resources, testing is
often restricted to those cases for which drug resistance
is suspected. Previously, in high-burden countries and in
locations where second-line drug therapies were not
available, routine drug susceptibility testing was not
considered a priority.228 However, the emergence of MDR
and XDR tuberculosis prompted a change in WHO
strategy in 2006229 and the capacity for testing has been
expanded since.230 Despite these efforts, access to tests
for MDR remains poor (figure 6). Facilities for drug
susceptibility testing are scarce in many parts of the
world, and less than a quarter of the estimated
tuberculosis cases with resistance to rifampicin are
confirmed by laboratory tests.
Phenotypic testing
Culture-based phenotypic drug-susceptibility testing
(DST) methods provide a measure of the susceptibility of
No data
>80%
6180%
4160%
2140%
<20%
Figure 6: MDR tuberculosis detection in diagnosed cases of tuberculosis
Estimated rifampicin-resistant and MDR tuberculosis cases with laboratory confirmation, as a percentage of the total diagnosed tuberculosis cases by country.
Compiled with data from the WHO TB Control Report, 2015.1
308 www.thelancet.com/respiratory Vol 5 April 2017
bacteria to a drug. Routine DST is normally based on
qualitative methods that assess in-vitro growth using a
single critical concentration of the drug.231 The results are
typically reported as susceptible or resistant and are less
precise than those generated by semiquantitative
methods, whereby bacteria are grown at a range of drug
concentrations so the MIC can be established.232 Semi
quantitative data have therapeutic implications because
it differentiates between susceptible and resistant strains,
and it also detects moderate or low-level resistance where
increased dosage might be beneficial to the patient.233,234
The first DST methods were developed and validated
for solid culture using Lwenstein-Jensen slopes or agar
plates. For the proportion method, bacteria are grown on
drug-containing and drug-free media.233 The numbers of
colonies on the drug-containing media are counted and
expressed as a percentage of those on the drug-free
media. If the proportion exceeds the critical proportion
for that drug then the strain is classed as resistant. To
ascertain the MIC, the bacteria are exposed to a series of
media containing serial two-times (log) dilutions of the
drug. MICs of test strains are compared with the upper
MIC limit or the epidemiological cutoff value of wild-
type strains.232 WHO defines the MIC for M tuberculosis
as the lowest concentration of drug that inhibits 95% of a
wild-type strain (that has never been exposed to drug)
while allowing clinically resistant strains to grow.
DST is also performed in the commercial automated
liquid-based culture systems such as the MGIT 960,
for which results can be obtained in 712 days.233
Alternative low-cost DST methods have been developed

that use microscopic observation of colonies or oxidation-
reduction dyes to indicate growth of bacteria.233,235
From a clinical perspective, the main drawback of DST
is the time taken to obtain a result. To increase the speed
of detection, clinical specimens can be screened directly
so that the delays incurred during isolation and pre
culture are avoided.236 However, this is only feasible for a
small number of drugs and is not a suitable method for
measuring MICs.
Phenotypic testing is technically demanding and can be
affected by interactions of the drug with the culture media
and the propensity of hydrophobic M tuberculosis bacilli to
form clumps. Different critical drug concentrations have
been adopted for different culture systems.237 In 1994,
WHO and the IUATLD established a Global Surveillance
Project with a network of supra national reference
laboratories to standardise methods and introduce
international quality standards for drug susceptibility
testing.238 DST is considered the reference standard by
which new genotypic tests are compared. However,
discrepancies between methods are not uncommon and
it has been suggested that for rifampicin, genotypic
analysis offers a more reliable reference standard.239,240
Simple binary classification on the basis of a single critical
concentration into susceptible and resistance is evidently
not sufficient. Drug susceptibility tests for pyrazinamide,
ethambutol, ethionamide, and para-aminosalicylic acid are
less reproducible than phenotypic tests for the drugs for
which resistance defines MDR and XDR tuberculosis
(isoniazid, rifampicin, fluoroquinolones, and second-line
injectable drugs) and the data obtained are considered
less reliable.240 The critical concentrations need to be
reconsidered in accordance with modern principles
of setting clinical breakpoints (wild-type MIC distributions,
pharmacokineticpharmacodynamic considerations, and
outcome data).
Genotypic testing
Genotypic tests predict resistance to a drug but do not
establish susceptibility, and a negative genotypic test
result is usually reported as no resistance detected. Drug
resistance in M tuberculosis can arise from mutations in
the bacterial DNA that render the organism immune to
the action of the drug. The most frequently observed
cause of resistance are SNPs in genes encoding drug
targets or converting enzymes, but large deletions might
also result in resistance.71,241 A summary of loci implicated
in resistance to antituberculosis drugs is presented in
table 4. A review of the loci is not included in this
Commission, and for a comprehensive list of resistance-
causing mutations (1325 polymorphisms [SNPs and
indels] at 992 nucleotide positions from 31 loci,
6 promoters, and 25 coding regions) and corresponding
aminoacid changes, we refer the reader to the London
School of Hygiene & Tropical Medicine TB Profiler.
M tuberculosis is naturally resistant to several
antibiotics because of the impermeable nature of the
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The Lancet Respiratory Medicine Commission
cell wall.242 Transmembrane transporter molecules and
efflux pumps might aid in the emergence of resistance,
but no putative diagnostic efflux gene polymorphisms
have been identified. Epigenetic factors are likely to be
involved in the regulation of such transporter mech
anisms but have not been extensively investigated in
M tuberculosis.243 Considerable progress has been made
in understanding the mechanisms of resistance for
most key first-line and second-line antituberculosis
drugs, but further work is needed to identify the full
range of mutations and to define their clinical
efficacy.244
Resistance to rifampicin is almost entirely due to
changes in the subunit of DNA-dependent RNA
polymerase, which is encoded by the rpoB gene.245
Molecular tests targeting this gene are more accurate
than using phenotypic DST.241 However, caution must be
used when interpreting data from some molecular tests
because not all mutations have the same effect. Silent
mutations can occur, where replacement of a nucleotide
does not necessarily result in resistance. An example of a
silent mutation can be seen in rpoB (TTCTTT;
Phe514Phe), which does not result in an aminoacid
change, and tests that only detect changes at that
nucleotide position without identifying the nucleotide
involved might give false-positive resistance results.246
Regardless, the high sensitivity and specificity of the
molecular targets (SNPs) for rifampicin resistance,247 and
their value as a tool for predicting MDR tuberculosis has
supported commercial in-vitro diagnostic products to
enter the market.
Xpert MTB/RIF
Xpert MTB/RIF is an easy-to-use automated PCR-based
test that diagnoses tuberculosis and detects mutations
predictive of resistance to rifampicin in less than 2 h.
The test was endorsed by WHO in 2010248 and is
recommended as a front-line diagnostic test and tool to
assist in the management of MDR tuberculosis.249
Regulatory approval has also been granted by the FDA
who recognised the potential for false-negative results,
with the recommendation that phenotypic testing should
also be performed.250 Concerns about the accuracy of the
Xpert MTB/RIF test and reports of false-positive
rifampicin resistance results have led countries such as
Brazil and South Africa to adopt a policy of confirmatory
testing.247,251254 The manufacturers have reported that a
new version of the Xpert MTB/RIF test is under
development (Xpert ULTRA) in which the diagnostic
targets and rifampicin-resistance detection chemistry
have been changed, with the aim of increasing test
accuracy. The test is being assessed by its developers and
is expected to be released for sale and independent
assessment in 2017. For the London School of
The GeneXpert test combines sample extraction and Hygeine & Tropical Medicine
TB profiler see http://tbdr.
analysis within a single sample cassette that is processed
lshtm.ac.uk/
and analysed by placing it within the GeneXpert
 The Lancet Respiratory Medicine Commission

instrument, thus is very simple to use; however, the test A newer version of the Hain XDR test is available
has high costs associated with manufacture. A four- (GenoType MTBDRsl-v20), which incorporates an
module GeneXpert instrument and ancillary equipment extended range of loci using 27 probes for the detection of
costs ~US$20000 (ex-factory) and a single-use test cassette resistance to fluoroquinolones and aminoglycosides.
costs ~$10.249 To test every individual with suspected Fewer data have been published on this new test, but a
tuberculosis the estimated cost is $434468 million European study258 found similar sensitivity to the previous
per year.255 A consortium of international donors led by version of the test when testing isolates for detection of
UNITAID is providing financial support to facilitate fluoroquinolone resistance (836%; 95% CI 734903)
reduced pricing for public-sector procurers in countries and a high specificity of 100% (976100). For detection of
with a high tuberculosis burden. However, annual resistance to second-line injectable drugs, sensitivity was
maintenance costs and periodic replacement of the 864% (799910) and specificity was 901% (817949).
modules might mean that affordability and sustainability Similar results were obtained when testing smear-positive
of this technology for routine use in countries with a high clinical samples for fluoroquinolone resistance with a
burden of tuberculosis is unlikely. sensitivity of 930% (833972) and a specificity of 988%
(951994), and for resistance to second-line injectable
Line probe assays (LPAs) drugs; 889% (788945), and 917% (865950).258
In addition to the GeneXpert technology, WHO has LPA requires an operator who is skilled in molecular
endorsed LPA molecular technology for detecting drug techniques, and precautions are needed to avoid amplicon
resistance. Following amplification of the target gene, LPA contamination that would render the results invalid.
technology reverse-hybridises samples to a series of Additionally, considerable laboratory infrastructure is
oligonucleotide probes immobilised on a membrane.256 needed, so LPA is only suited for use in tertiary centres
The most widely studied tests are the GenoType and reference laboratories. Semi-automated and robotic
MTBDRplus for rifampicin and isoniazid and the systems are available to assist sample preparation, and
GenoType MTBDRsl-v1.0 assay for fluoroquinolones, although colorimetric readouts can be read by eye,
amino glycosides, and ethambutol. The GenoType instrumentation is highly recommended. The costs of
MTBDRsl-v1.0 was the first commercially available test for LPA technology are negotiable and vary according to
XDR tuberculosis. A Cochrane systematic review257 of location and customer status, and preferential pricing for
published performance data found a pooled sensitivity Hain Biosciences products is available for the public
compared with DST of 831% (95% CI 787867) and a sector in low-income and middle-income countries with a
pooled specificity of 977% (943991) when testing high burden of tuberculosis. Start-up equipment costs
cultured bacteria for resistance to fluoroquinolones. The are approximately US$50000 and the test and DNA
test maintained similar accuracy to that seen when testing extraction kit cost is approximately $15 per patient. Three
cultured bacteria when used to test samples of smear- other manufacturers have developed LPA products for
positive sputum, with a sensitivity of 851% (71927) drug-resistant tuberculosis, including the REBA MTB-
and specificity of 982% (968990).257 When testing XDR test (YD Diagnostics, Korea), which tests for
cultured isolates for resistance to second-line injectable rifampicin and isoniazid or ofloxacin, or kanamycin and
drugs, pooled sensitivities were 879% (821920) for streptomycin; the tuberculosis resistance module
amikacin, 669% (441838) for kanamycin, and 795% (Autoimmun Diagnostika GmbH, Germany), which
(583914) for capreomycin. Specificities were 995% tests for rifampicin and isoniazid, streptomycin,
(975999) for amikacin, 986% (961995) for fluoroquinolones, second-line injectable drugs and
kanamycin, and 958% (934973) for capreomycin. Few ethambutol; and TM/MDR TB LPA (Nipro Co, Japan),
studies reported testing smear-positive sputum for second- which tests for rifampicin and isoniazid, or pyrazinamide
line injectable drugs; the pooled sensitivity was 944% or fluoroquinolones. These tests have not yet been
(252999) and the pooled specificity was 982% subjected to extensive independent assessment, and
(889997). Wide variation in sensitivities was observed robust data on their performance and pricing was not
across study sites, ranging from 1% to 100%. Clonal spread available at the time of writing.
during transmission of resistant strains increases the
prevalence of particular polymorphisms and the sensitivity Compensatory mutations
and predictive value of a test might vary by geographical One of the challenges when assessing the effect of
location and population.241 The suboptimal sensitivity of polymorphisms on drug efficacy is the accumulation of
the LPA tests for extensive drug resistance suggests that a compensatory mutations.90 These changes can abrogate
negative test result does not rule out resistance, and DST the negative effects of resistance mutations on the
should be undertaken to confirm the susceptibility of the bacteria, restoring fitness and giving selective advantage.259
strain. High specificity is crucial because false-positive Such compensatory changes in the genome might be
results might lead to the unnecessary rejection of effective strongly associated with resistance but are not causative and
drugs and, in some cases, misclassification of patients as so should not be used to diagnose resistance. A second
having MDR or XDR tuberculosis. form of compensatory mutation has recently been described

310 www.thelancet.com/respiratory Vol 5 April 2017


in which susceptibility of a drug-resistant mutant is restored
by additional mutations in the gene.260 Fluoroquinolone
resistance often arises because of changes in DNA gyrase
caused by mutations in GyrA. However, susceptibility to
ofloxacin can be restored by additional mutations in the
gene that infers hypersensitivity.261 Therefore, strains should
be checked for the resistance-conferring mutations and
the restorative compensatory mutations. Although this
phenomenon is rare, it has great significance for patients,
because a false-positive test for fluoroquinolone resistance
could result in a misdiagnosis of XDR tuberculosis and
unnecessary treatment with drugs of heightened toxicity.
Commercial tests for fluoroquinolones do not incorporate
the hypersensitivity mutations in their analysis and so
might overdiagnose XDR tuberculosis. Notably, phenotypic
tests are not affected by compensatory mutations.
Differentiating resistance levels
Phenotypic identification of MICs shows variation in the
tolerance of bacteria to antituberculosis drugs. The
degree of disruption caused by a mutation is associated
with its position within a gene, and the part played by
that gene in the action of the drug. Increased dosage can
provide a therapeutic solution for some drugs for which
there is low-level resistance, because the resistance can
be overcome by high-dose treatment. An example is the
common first-line drug rifampicin, in which changes in
the conformation of the drug binding site cause high-
level resistance, but mutations at sites outside of that
region result in lower MICs.262 Similarly, mutations in
inhA typically confer low-level resistance to isoniazid,
whereas katG mutations confer high-level resistance.263
Mutation analysis also offers some advantages in
differentiating susceptibilities to closely related drugs;
cross-resistance in drug families is common, but not
universal. DST for each fluoroquinolone, aminoglycoside,
and rifamycin used in the treatment of tuberculosis
would be slow and costly; however, mutation analysis can
be used to predict susceptibility for individual drugs
within a family. Thus, the Ala90Val mutation in gryrA
causes lower resistance to levofloxacin (2 g/mL) and
moxifloxacin (1 g/mL) than to ofloxacin (4 g/mL), and
for such cases, treatment with a higher dose of
moxifloxacin might succeed while treatment with
ofloxacin might be unsuccessful.264 Similarly, mutations
at codon 516 in rpoB cause resistance to rifampicin but
do not increase the MIC of rifabutin to above the critical
threshold of 05 g/mL.265 Further studies are required to
validate these observations, but providing additional
treatment options for patients with extensive resistance
would be highly beneficial. One phenomenon that
neither genotypic or phenotypic testing can assess is
environmentally induced phenotypic changes. Bacilli
that have become dormant might resist the action of
bacteriostatic drugs, and changes in cell wall structures
can hinder drugs from entering the bacilli. Such
conditions, if temporary, will not be observed during
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The Lancet Respiratory Medicine Commission
in-vitro growth and do not represent the emergence of a
transmissible drug-resistant strain.
Sequencing approaches
For patients with rifampicin-resistant tuberculosis,
follow-on testing to identify resistance to additional
drugs is advisable because it will allow treatment
regimens to be optimised. Use of ineffective second-line
drugs might inadvertently promote amplification of
resistance and the emergence of XDR tuberculosis.
Timely access to curative treatment would reduce
opportunities for onward transmission and might reduce
morbidity and mortality.The use of multidrug cocktails to
treat tuberculosis has resulted in the identification of a
complex array of polymorphisms that are responsible for
resistance. Although a single gene is involved for
rifampicin resistance (rpoB), several genes might be
involved for some other drugs (table 4 presents a summary
list of loci and common mutations). Molecular tests are
limited in the number of loci they can analyse at one time,
and although sequential testing of a few drugs at a time is
possible, it will increase costs and might delay access to
effective therapy. DNA sequencing examines all nucleotide
positions, can provide higher accuracy,241 and in some
settings might be more time-efficient and cost-efficient
than the LPA and probe-based tests. Several sequencing
strategies are available, including targeted sequencing,
where specific genes or loci are amplified before
sequencing, and can be performed directly from sputum
samples.266 Pyrosequencing is a real-time method for rapid
sequencing of small segments of genomic DNA, and is
capable of reliably detecting mutations that confer first-
line and second-line drug resistance in M tuberculosis.
Pyrosequencing not only shows the presence or absence of
these mutations, but also displays detailed sequence data,
which enables users to distinguish mutations conferring
resistance from silent mutations as well as from those
conferring different levels of resistance.267 Commercial kits
are available but have not yet received regulatory approval
for diagnostic use. For example, the Ion AmpliSeq TB
Research Panel examines eight genes involved in
resistance to first-line and second-line drugs (embB, eis,
gyrA, inhA, katG, pncA, rpoB, and rpsL).
Considered the ultimate drug resistance test by some,
whole-genome sequencing has the potential to provide
resistance profiles for all drugs within a single analysis
(figure 7). Sequencing has previously been the preserve of
sophisticated research laboratories, but reductions in
costs and development of more robust and user-friendly
instrumentation has led to its introduction in clinical
settings and pathology laboratories. Sequencing is
considered a referral-level test to be used in tertiary
centres in which, if found to be cost-effective, it might
eventually replace LPA. A comparison of whole-genome
sequencing with the follow-on tests (DST and LPA) for
samples found positive for resistance to rifampicin is
presented in table 5. Whole-genome sequencing should
 The Lancet Respiratory Medicine Commission

Bacterial DNA is extracted and purified

CCAT
TGCA
T TGAA
CCTG
A

Library is prepared of short Sequencing: amplification and assembly Amplicons are aligned to reference genome or
DNA fragments that are is done with multiple reads, giving de-novo assembly to give the genetic code
labelled and tagged coverage across the whole genome (genome)

Known drug resistance and strain-type mutations

Whole-genome are identified in the samples genome
sequencing result

Resistance to:
Rifampicin
Isoniazid
Ethambutol M tuberculosis
Moxifloxacin
mutations
M tuberculosis library
lineage 2.2.1
Seen before
Patient management
M tuberculosis
in silico profile

Figure 7: Process of next-generation sequencing

The first step in detecting drug resistance by whole-genome sequencing is extraction of the Mycobacterium tuberculosis DNA from the clinical specimen or cultured
isolate. After the creation of a library of DNA fragments, an amplification step creates multiple amplicons, which are aligned using computing technology to give
multiple overlapping layers of sequence reads across the genome. Comparison (alignment) to a reference genome permits mutations to be detected, and those
associated with drug resistance can be recognised by software using databases of the known resistance-causing mutations. The end readout will be a report of the
genotypic resistance patterns to assist selection of an effective cocktail of drugs for treating the patient. With small bacterial genomes such as M tuberculosis, multiple
samples can be analysed in a single run, greatly reducing costs.

Phenotypic tests Xpert MTB/RIF Line probe assays Whole-genome sequencing

Time to result Slow (weeks or months)
Sensitivity for detecting resistance High
Resistance levels Ability to determine MICs
Safety High risk, requiring
sophisticated microbiological
protection
Quality assessment Quality assurance via WHO and Test-specific quality assurance schemes not Test-specific quality assurance
International Union Against
Tuberculosis and Lung Disease
reference laboratory network
Efficiency Separate tests for each drug
Less than 2 h Rapid (hours or days) when
done directly from samples
High for rifampicin; no other drugs Sensitivity limited by the
included number of loci incorporated in
test; high for rifampicin
Does not assess MIC Does not assess MICs; some
tests provide knowledge of
mutations that can be used to
predict levels of resistance but
have poor clinical validity
Low risk Moderate microbiological risk
when testing clinical samples.
High risk if bacterial cultures are used
used
widespread schemes not widespread
Detects resistance to one drug only Two or three drugs per test
Rapid (hours or days) if done directly
from samples
Dependent on knowledge of
polymorphisms; high for rifampicin
Does not assess MICs; ability to predict
extent of resistance for some drugs from
knowledge of mutations, but not yet
validated for clinical use
Moderate risk when testing clinical
samples. High risk if bacterial cultures are
Quality assurance schemes not available
Single analysis for all drugs

MIC=minimum inhibitory concentration.

Table 5: Comparison of test characteristics of whole-genome sequencing with current drug-resistance tests

be introduced for tuberculosis control for two main
reasons: first, it can potentially accelerate access to
effective treatment for individuals who are likely to fail
standardised treatment for MDR or XDR, and it can
prevent amplification of resistance through inadequate
treatment. Second, it reduces the hazards associated with
handling highly resistant and sometimes incurable
strains of M tuberculosis. Molecular approaches for de
tecting drug resistance promise rapidity, safety, accuracy,
and accessibility, but developers of tests for tuberculosis

312 www.thelancet.com/respiratory Vol 5 April 2017


have some considerable improvements to make. Whole-
genome sequencing requires more M tuberculosis DNA
than is usually found in sputum samples, and sequencing
is performed on cultured isolates. For genotypic tests to
fully exploit their potential they need the capacity to test
clinical specimens directly without recourse to culture.
The scarcity of M tuberculosis bacilli in sputum and the
complexity of the sample matrix provides a serious
challenge to the provision of a user-friendly DNA isolation
device at an affordable manufacturing cost.
Efforts to enhance sequencing directly from sputum
are ongoing and proof of concept has been obtained,
but further studies are required. Strategies being
investigated include selective removal of human DNA
and enrichment of samples for M tuberculosis DNA.147,268
However, selective whole-genome amplification ap
proaches, which have been used across a range of other
pathogens might provide a cost-effective alternative.269
The use of whole-genome sequencing for the rapid
drug susceptibility profiling of M tuberculosis for
tuberculosis treatment management will be dependent
on a routinely curated high-quality drug resistance
database.241 Building on the TBdream database, the
tuberculosis profiling tool241 provides the most complete
knowledge of the relationship between mutations and
resistance in M tuberculosis, with high predictive ability
for 14 drugs. However, concerted efforts in tuberculosis
research are required to identify new markers of
resistance, and develop knowledge databases containing
clinical, phenotypic, and sequence data that can be used
routinely in tuberculosis research and health care. One
such initiative is the Relational Sequencing TB Data
Platform (ReSeqTB), which is a collaborative project
funded by the Bill & Melinda Gates Foundation. Once
established, the platform will provide a validated whole-
genome sequencing analysis pipeline and a one-stop
source of curated, clinically relevant genetic data and
associated metadata for drug-resistant tuberculosis.244
The economic benefits of sequencing approaches
remain a matter of speculation because studies have
not been done, and the cost of sequencing is highly
dependent on throughput. M tuberculosis has a
relatively small genome of approximately 45 million
basepairs compared with 3 billion in the human
genome, so batched analysis of multiple samples is
possible, greatly reducing costs. The capacity of
sequencing platforms vary widely, with instruments
costing from thousands to hundreds of thousands of
US dollars. Whole-genome sequencing costs for
each tuberculosis genome (excluding data analysis)
are approximately $30100. Whichever technology is
preferred, studies are needed to inform sampling
strategies. To assess cost-effectiveness, clinical trials
are needed to measure the effect of rapid diagnostic
testing on treatment practices and on important
patient outcomes such as treatment success, morbidity,
and mortality.
www.thelancet.com/respiratory Vol 5 April 2017 313
The Lancet Respiratory Medicine Commission
Summary of diagnosis of drug-resistant tuberculosis
Susceptibility testing remains severely inaccessible
in most high-burden countries. For patients with drug-
resistant disease, inaccessibility prevents or delays effective
treatment and provides opportunity for transmission, and
in some cases it allows amplification of resistance to
further drugs. Urgent action is needed to address this gap
in service provision. New technology might aid this
situation, and molecular testing methods have the
advantage of speed, with results available in hours or days,
compared with days or weeks for phenotypic methods.
Molecular testing is also considered safer, removing the
need to culture and manipulate large numbers of highly
infectious bacteria. However, major reservations about the
use of molecular testing include the imperfect under
standing of the clinical effect of some polymorphisms and
the cost and sophistication of the technology required.
A further impediment is the technical challenge of
sequencing directly from clinical specimens to avoid the
need for isolation and culture of the bacteria.
We suggest that improved access to effective
treatment for people with resistance to multiple drugs
will require tests capable of assessing the full range of For the TB Drug Resistance
available drugs. The most promising technology to Mutation Database
see https://tbdreamdb.ki.se
deliver improved access is whole-genome sequencing.
Further development of this technology is needed to
allow direct testing of sputum samples, complemented
by the construction of a well characterised library of
resistance mutations to profile drug resistance. New
diagnostics, including portable targeted sequencing,
are yet to show their full potential, and greater
convergence of technologies and approaches is needed For the ReSeqTB platform see
to accelerate the development of improved tests to https://platform.reseqtb.org
provide rapid access to effective treatment for all
patients. Above all, greater investment is urgently
needed, to implement the tools already available and to
develop and assess new tools for the detection of drug-
resistant tuberculosis.
Medical and surgical management of
drug-resistant tuberculosis: general principles
and treatment of children, patients with HIV,
and in other specific clinical contexts
The management of drug-resistant tuberculosis is
complex and several factors must be considered,
including the prioritisation of effective treatment.
Priorities should be decided upon while accounting for
multiple clinical contexts, including HIV co-infection,
diabetes, and vulnerable populations, such as pregnant
women and children. More effective new and repurposed
drugs are now routinely being used to treat drug-resistant
tuberculosis, but resistance to these agents is already
emerging. The key principles of developing a treatment
regimen for MDR and XDR tuberculosis are outlined in
panel 3; however, these recommendations are mostly
based on observational studies. Other important aspects
of management include well-functioning laboratories for
 The Lancet Respiratory Medicine Commission
bacteriology and DST, infection control in health - two from group C, and additional drugs from group D
care facilities to minimise transmission, adherence-
promoting mechanisms, attention to psychosocial factors
and patient-specific economic matters, access to quality
drugs, appropriate training of health-care workers,
rolling out appropriate information systems to track
patients and audit data, and overall strengthening of
national tuberculosis programmes.
Empirical regimens in use
WHO recommendations (2016) state that the conventional
treatment for rifampicin-resistant tuberculosis or MDR
tuberculosis should include at least five drugs (panel 4) that
are likely to be effective in a regimen, including
pyrazinamide and four core second-line drugsone
chosen from group A, one from group B, and at least
Panel 3: Recommended principles to be used when designing a regimen for the medical management of MDR and XDR
tuberculosis
MDR tuberculosis
Ideally use at least four drugs, in addition to pyrazinamide,
to which the strain has proven or probable susceptibility
(drugs previously taken for 1 month are generally
avoided)238
Use a backbone of a later-generation fluoroquinolone
(eg, moxifloxacin or levofloxacin; group A drug), plus a
second-line injectable drug (amikacin or kanamycin,
or capreomycin; group B drugs; used for 4 months after
culture conversion and for a minimum of 6 months)238
Add any first-line drug and additional group C drugs
(eg, cycloserine or terizidone, ethionamide or
prothionamide, clofazimine, or linezolid if appropriate) to
which the isolate is susceptible
The WHO recommended treatment duration is 20 months;
however, this recommendation is based on very low-quality
evidence)238
Bedaquiline or delamanid (group D2) can be added to the
regimen if toxicity or resistance precludes formulation of
a regimen containing 4 drugs that are likely to be
effective, particularly if a group A or B drug cannot be
used (both prolong QT interval, and thus require
monitoring)270,271
Oxazolidinones (linezolid) can be used (group C drug),
particularly in fluoroquinolone-resistant MDR or
XDR tuberculosis, but monitoring for toxicity (neuropathy
and bone marrow suppression) is required272,273,274
Given the specific and conditional nature of the
recommendation (poor-quality evidence), the decision to
use the newer WHO-recommended 912-month short
course versus the ~20-month regimen in selected
patients will be dependent on several factors, including
previous treatment, local resistance profiles, patient
acceptance, and the requirement for proven or highly
likely fluoroquinolone and aminoglycoside isolate
susceptibility, and absence of probable or proven
314 www.thelancet.com/respiratory Vol 5 April 2017
when appropriate.68 This approach is an attempt to improve
the poor efficacy (favourable outcome ~50%) of
conventional MDR tuberculosis treatment. Nevertheless,
drawbacks of significant toxicity and pill burden, poor
adherence, and 68 months of painful injections with
second-line injectable drugs remain. Also in 2016, WHO
has recommended a standardised shorter MDR
tuberculosis treatment regimen that has been used with
second-line drug treatment-nave patients with MDR
tuberculosis in Bangladesh,277 Niger,278 and Cameroon.279
The shorter MDR tuberculosis regimen (912 months) is
successful in approximately 90% of cases, and includes
three drugs (kanamycin, prothionamide, and high-dose
isoniazid) for 46 months, with additional drugs
(moxifloxacin, clofazimine, pyrazinamide, and ethambutol)
resistance to any of the components of the regimen
(except isoniazid)68
Whatever the duration of the regimen used, psychosocial
and financial support are crucial elements to maintain
adherence
Patients should be monitored for adverse drug reactions,
which are common275
A single drug should not be added to a failing regimen
The patients HIV status should be established and
antiretroviral therapy initiated in all HIV-infected patients
XDR tuberculosis and resistance beyond XDR tuberculosis
Regimens should be constructed on the basis of prevailing
patterns of drug resistance and on similar principles to those
outlined for MDR tuberculosis (use of 4 drugs is likely to be
effective)
We recommend a backbone of bedaquiline or delamanid, or
both, plus linezolid, inclusion of a later-generation
fluoroquinolone, and addition of other drugs such as
clofazimine, para-aminosalicylic acid, pyrazinamide,
high-dose isoniazid, and other drugs depending on the
likelihood of susceptibility
Bedaquiline and delamanid can be used in combination
(with careful monitoring for corrected QT prolongation
eg, every 2 weeks for the first 12 weeks)
Adverse events such as renal failure, hypokalaemia,
hypomagnesaemia, and hearing loss are associated with
capreomycin, which has high levels of cross-resistance with
aminoglycosides275
Differential susceptibility to fluoroquinolones might occur276
Group D3 drugs such as meropenem plus clavulanate can be
used, but their clinical effectiveness is uncertain
WHO classification of drugs used for the treatment of MDR tuberculosis:
group A=fluoroquinolones; group B=second-line injectable agents; group C=other core
second-line agents; group D=add-on agents. MDR=multidrug resistant.
XDR=extensively drug resistant. Adapted from Dheda K.2

given throughout the course of treatment. WHO now
recommends the shorter MDR tuberculosis regimen for
selected patients with MDR tuberculosis or rifampicin-
resistant-tuberculosis irrespective of patient age or HIV
status, on the basis of a systematic review of the
observational studies68 and following their standard practice
for making recommendations on the treatment of MDR
tuberculosis.68,280 Patients are eligible for this regimen
unless they have confirmed or suspected resistance to any
of the shorter MDR tuberculosis regimen drugs (except
isoniazid, but especially to fluoroquinolones or second-line
injectable drugs), prior exposure to any second-line drug
contained within the shorter MDR tuberculosis regimen
for more than 1 month, intolerance or toxicity to any of the
drugs, unwanted drugdrug interactions, pregnancy, extra
pulmonary disease, or drug inaccessi bility. This newly
recommended 912-month MDR tuberculosis regimen
might be limited to specific patients and regional settings
for various reasons, including the high frequency
of M tuberculosis drug resistance to pyrazinamide,
ethambutol or second-line antituberculosis drugs, hesi
tance of patients and clinicians to use clofazimine because
of adverse events like hyper pigmentation and potential
induction of bedaquiline resistance, and substantial rates
of previous tuberculosis in settings with high prevalence of
MDR tuberculosis.281 Use of this conditional recom
mendation (weak evidence based only on a few small
cohort studies) must be guided by patient and geographical
context. Thus, until the results of the STREAM 1 study are
available, the shorter MDR tuberculosis treatment regimen
can be conditionally recommended in carefully selected
patients, taking into account prevailing drug resistance
profiles and previous treatment. Adherence is expected to
be much better with the short duration regimen. Ineligible
patients should receive the 20-month 5-drug regimen
unless they have resistance or intolerance to the injectable
agents or fluoroquinolones, in which case they should
receive bedaquiline or delamanid, according to WHO
guidelines.68
Principles of formulating a treatment regimen for MDR
and XDR tuberculosis
Several factors that might affect the selection of drugs and
regimens are outlined in panel 4; these include the presence
of HIV co-infection, age of the patient, presence of
extrapulmonary tuberculosis, history of previous first-line
or second-line antituberculosis treatment, disease severity,
and access to reliable DST results, including second-line
DST (often no standardisation of testing methods exists or
testing is unavailable). Treatment is often complicated by a
high rate of adverse drug reactions, which is more common
in MDR and XDR tuberculosis than in drug-susceptible
tuberculosis.282 The scarcity of comprehensive and rapid
susceptibility readouts directly from sputum means that
empirical regimens are still frequently necessary.
Randomised controlled trials are required to establish
the minimum number of drugs, duration of treatment,
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The Lancet Respiratory Medicine Commission
and what specific drugs should constitute an effective
regimen (table 6). However, better outcomes are
associated with use of a greater number of effective
drugs, the use of antiretroviral therapy in HIV-infected
persons, and the use of new and repurposed drugs, such
as bedaquiline, delamanid, and linezolid.283 The high
mortality of patients with MDR and XDR tuberculosis
has been strongly linked to the scarcity of effective drugs.
Although capreomycin is an option in patients with
XDR tuberculosis, it is associated with substantial toxicity,
and there is a high level of cross-resistance with amino
glycosides.284 Capreomycin, or aminoglycosides, can be
dosed three times per week after culture conversion to
decrease toxicity. High-dose isoniazid can be a useful
addition for patients with inhA gene mutations conferring
Panel 4: WHO categorisation68 of second-line
antituberculosis drugs recommended for the treatment of
rifampicin-resistant and multidrug-resistant tuberculosis
Group A: fluoroquinolones*
Levofloxacin
Moxifloxacin
Gatifloxacin
Group B: second-line injectable agents
Amikacin
Capreomycin
Kanamycin
Streptomycin
Group C: other core second-line agents*
Ethionamide or prothionamide
Cycloserine or terizidone
Linezolid
Clofazimine
Group D: add-on agents (not part of the core
multidrug-resistant tuberculosis regimen)
D1
Pyrazinamide
Ethambutol
High-dose isoniazid
D2
Bedaquiline
Delamanid
D3
Para-aminosalicylic acid
Imipenem plus cilastatin
Meropenem
Amoxicillin plus clavulanate
Thioacetazone
This grouping is intended to guide the design of conventional regimens. *These medicines
are shown by decreasing order of usual preference for use. Streptomycin might substitute
other injectable agents under specific conditions. Resistance to streptomycin alone does not
qualify for the definition of extensively drug-resistant tuberculosis. Carbapenems and cla-
vulanate are meant to be used together; clavulanate is only available in formulations com-
bined with amoxicillin. HIV status must be tested and confirmed to be negative before
thioacetazone is started.
 The Lancet Respiratory Medicine Commission

New drug in Official trial title Description Status Phase Trial Registry Identifier (link)
regimen
Otsuka 233 Delamanid Phase 2, open-label, multiple-dose Safety, efficacy, and pharmacokinetic Enrolment Phase 2 NCT01859923
trial to assess the safety, tolerability, study of delamanid in paediatric completed for
pharmacokinetics, and efficacy of patients with MDR tuberculosis participants aged
delamanid in paediatric patients (aged 6 years or older;
0 to <18 years) with MDR tuberculosis enrolment open for
on therapy with an optimised participants younger
background regimen of than 6 years in the
antituberculosis drugs receive Phillipines
delamanid over a 6-month treatment
period
Janssen C211 Bedaquiline A phase 2, open-label, multicentre, Investigate the pharmacokinetics, Currently enrolling Phase 2 NCT02354014
single-arm study to assess the safety, tolerability, and participants in
pharmacokinetics, safety, tolerability antimycobacterial activity of Russia and South
and antimycobacterial activity of bedaquiline in combination with MDR Africa
TMC207 in combination with a tuberculosis therapy for HIV-negative
background regimen of MDR children and adolescents
tuberculosis medications for the
treatment of children and adolescents
younger than 18 years who have
confirmed or probable pulmonary
MDR tuberculosis
NC-005 Pretomanid and A phase 2, open-label, partially Study of combinations of bedaquiline, Fully enrolled Phase 2 NCT02193776
bedaquiline randomised trial to assess the efficacy, moxifloxacin, pretomanid, and
safety, and tolerability of pyrazinamide for 8 weeks in patients
combinations of bedaquiline, with drug-sensitive or MDR
moxifloxacin, pretomanid, and tuberculosis, with one arm for patients
pyrazinamide during 8 weeks of with MDR tuberculosis adding
treatment in adult subjects with moxifloxacin to bedaquiline,
newly diagnosed drug-sensitive pretomanid, and pyrazinamide
tuberculosis, MDR tuberculosis,
or smear-positive pulmonary
tuberculosis
ACTG 5343 Bedaquiline and A trial of the safety, tolerability, and Study of drug-drug interactions and Enrolling Phase 2 NCT02583048
delamanid pharmacokinetics of bedaquiline and combined QT effects of bedaquiline and participants in South
delamanid separately and in delamanid Africa
combination, in participants taking
multidrug treatment for
drug-resistant tuberculosis
ACTG 5312 Isoniazid The early bactericidal activity of Safety and efficacy study of different Currently enrolling Phase 2 NCT01936831
high-dose or standard-dose isoniazid in doses and generic variants of participants in
adult participants with isoniazid-resistant tuberculosis South Africa
isoniazid-resistant or drug-sensitive
tuberculosis
Opti-Q Levofloxacin Prospective, randomised, blinded Efficacy and safety study of increasing Fully enrolled Phase 2 NCT01918397
phase 2 pharmacokinetic/ doses of levofloxacin in combination
pharmacodynamic study of the efficacy with optimised background therapy
and tolerability of levofloxacin in
combination with optimised
background regimen for the treatment
of MDR tuberculosis
MDR-END Delamanid Shortening treatment of MDR Comparing efficacy of a treatment Currently enrolling Phase 2 NCT02619994
tuberculosis using existing and new regimen that consisted of delamanid, participants in South
drugs linezolid, levofloxacin, and Korea
pyrazinamide for 912 months, with a
control arm of the standard treatment
regimen (including an injectable drug)
for 2024 months for the treatment of
quinolone-sensitive MDR tuberculosis
Janssen Japan Trial Bedaquiline An open-label study to explore the Open-label, single-arm, multicentre trial Enrolling Phase 2 NCT02365623
safety, efficacy, and pharmacokinetics to explore safety, efficacy, and participants in Japan
of TMC207 in Japanese patients with pharmacokinetics of bedaquiline in
pulmonary MDR tuberculosis Japanese participants with pulmonary
MDR tuberculosis
(Table 6 continues on next page)

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New drug in Official trial title Description Status Phase Trial Registry Identifier (link)
regimen
(Continued from previous page)
TB-PRACTECAL Bedaquiline and Pragmatic clinical trial for a more TB PRACTECAL is a multicentre, Enrolling Phase NCT02589782
pretomanid effective, concise, and less toxic MDR open-label, multi-arm, randomised, participants in 23
tuberculosis treatment regimen controlled, phase 23 trial, assessing Uzbekistan
short treatment regimens containing
bedaquiline and pretomanid in
combination with existing and
repurposed antituberculosis drugs for
the treatment of biologically confirmed
pulmonary MDR tuberculosis
STREAM Stage 1 Modified The assessment of a standardised Comparison of standard WHO MDR Recruitment Phase 3 ISRCTN78372190
Bangladesh treatment regimen of antituberculosis tuberculosis regimen with 9-month complete; follow-up
regimen drugs for patients with MDR modified Bangladesh regimen ongoing
tuberculosis: a multicentre
international parallel group
randomised controlled trial
Otsuka 213 Delamanid A phase 3, multicentre, randomised, Safety and efficacy study of delamanid vs Recruitment Phase 3 NCT01424670
double-blind, placebo-controlled, placebo for 6 months in combination complete; follow-up
parallel group trial to assess the safety with optimised background therapy for ongoing
and efficacy of delamanid 1824 months
administered orally as 200 mg total
daily dose for 6 months in patients
with pulmonary sputum
culture-positive, MDR-TB
STREAM Stage 2 Bedaquiline Assessment of a standard treatment Comparison of a 6-month (containing Enrolling Phase 3 NCT02409290
regimen of antituberculosis drugs for an injectable) and 9-month (all oral) participants in
patients with MDR tuberculosis bedaquiline-containing regimen versus Ethiopia, Vietnam,
the WHO and Bangladesh regimen Mongolia, and
South Africa
NeXT Bedaquiline Investigating a new treatment Open label RCT of a 69-month Enrolling Phase 3 NCT02454205,
regimen for patients with MDR injection-free regimen containing participants in PACTR201409000848428
tuberculosis: a prospective open-label bedaquiline, linezolid, levofloxacin, South Africa
randomised controlled trial ethionamide or high-dose isoniazid,
and pyrazinamide
NiX-TB Bedaquiline, A phase 3 open-label trial assessing Study of bedaquiline, pretomanid, and Enrolling Phase 3 NCT02333799
pretomanid, the safety and efficacy of bedaquiline linezolid in patients with XDR participants in
linezolid plus PA-824 plus linezolid in subjects tuberculosis and MDR tuberculosis for South Africa
with pulmonary infection of either 6 months with an option of 9 months
XDR tuberculosis, treatment
treatment-intolerant tuberculosis, or
pre-XDR non-responsive MDR
tuberculosis
STAND Pretomanid A phase 3 open-label, partially Efficacy, safety, and tolerability of a On hold; participant Phase 3 NCT02342886
randomised trial to assess the efficacy, combination of moxifloxacin, PA-824, recruitment
safety, and tolerability of the and pyrazinamide treatments after suspended
combination of moxifloxacin plus 6 months of treatment in patients with
PA-824 plus pyrazinamide after MDR tuberculosis compared with a
4 and 6 months of treatment in adults combination of moxifloxacin, PA-824,
with smear-positive pulmonary and pyrazinamide treatments in
drug-sensitive tuberculosis, and after drug-sensitive tuberculosis subjects;
6 months of treatment in adults with there will be a comparator arm for MDR
smear-positive pulmonary MDR tuberculosis
tuberculosis
China PZA Trial Pyrazinamide Optimisation of an MDR tuberculosis Efficacy study of introducing molecular Unknown Phase 3 NCT02120638
treatment regimen based on the testing of pyrazinamide susceptibility in
molecular drug susceptibility results of optimising the MDR tuberculosis
pyrazinamide treatment regimen
Open label, multicentre trial with a
cluster-randomised superiority design
to compare the efficacy and safety of 26
weeks of delamanid versus 26 weeks of
isoniazid for preventing confirmed or
probably active tuberculosis during 96
weeks of follow-up in high-risk
household contacts of patients with
MDR tuberculosis
(Table 6 continues on next page)

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 The Lancet Respiratory Medicine Commission

New drug in Official trial title
regimen
(Continued from previous page)
endTB Bedaquiline, Evaluating newly approved drugs for
delamanid multidrug-resistant tuberculosis:
a clinical trial
FS-1 Trial FS-1* Randomised, placebo-controlled
study of safety and therapeutic
efficacy of the drug FS-1 in the oral
dosage form in drug-resistant
pulmonary tuberculosis
V-QUIN Levofloxacin A randomised controlled trial of
6 months of daily levofloxacin for the
prevention of tuberculosis in
household contacts of patients with
MDR tuberculosis
TB-CHAMP Levofloxacin Tuberculosis child and adolescent
multidrug-resistant preventive
therapy trial
PHOENIx MDR TB Delamanid Protecting households on exposure to
newly diagnosed index multidrug-
resistant tuberculosis patients
(A5300B/I2003B/PHOENIx)
Description Status Phase Trial Registry Identifier (link)
This is a phase 3, randomised, Not yet recruiting Phase 3 NCT02754765
controlled, open-label, non-inferiority,
multicountry trial assessing the efficacy
and safety of new combination
regimens for MDR tuberculosis
treatment
Safety and efficacy of FS-1 administered Enrolling Phase 3 NCT02607449
orally to patients with drug-resistant participants in
pulmonary tuberculosis Kazakhstan and
Kyrgyzstan
Investigating 6 months of daily Enrolling Phase 3 ACTRN12616000215426
levofloxacin versus placebo as participants in
preventive therapy in contacts of MDR Vietnam
tuberculosis; enrolling HIV-positive and
HIV-negative household contacts with a
positive tuberculin skin test. Enrolment
of children <15 years is on hold.
Household randomisation
Randomised double-blind placebo- Not yet recruiting Phase 3 ISRCTN92634082
controlled, multicentre superiority trial to
assess the efficacy of levofloxacin versus
placebo for the prevention of MDR
tuberculosis in child and adolescent
household contacts
Open label, multi-centre trial with a Not yet recruiting Phase 3 A5300B
cluster- randomised superiority design to
compare the efficacy and safety of
delamanid versus isoniazid for 26 weeks
for preventing confirmed or probable
active tuberculosis during 96 weeks of
follow-up in high-risk household
contacts of patients with MDR
tuberculosis

MDR=multidrug resistant. XDR=extensively drug resistant. *FS-1 is an immunomodulatory agent that is only available in Kazakhstan.

Table 6: Currently registered phase 2 and 3 clinical trials for MDR-tuberculosis

isoniazid resistance (in the absence of katG gene
mutations), although the rate of hepatotoxic and neuro
toxic adverse events are quite high.285 A dose of
1015 mg/kg three times per week is often better tolerated
than 1618 mg/kg per day, except in children, in whom
1618 mg/kg is well tolerated.285 This tolerance is present
because children eliminate isoniazid faster than adults,
especially young children.286 Clofazimine might be a
useful drug because it has been shown to have sterilising
properties in experimental studies; it might require co-
administration with pyrazinamide for optimal activity, but
is a less potent antituberculosis agent with minimal early
bactericidal activity, and could theoretically induce cross-
resistance to bedaquiline (though this remains unproven
in clinical practice). Clofazimine is also associated with
several problematic adverse effects, including pro
longation of the corrected QT (QTc) interval and
hyperpigmentation, which often affects adherence. The
potential usefulness of meropenem plus clavulanate or
imipenem plus clavulanate has been highlighted, but it is
expensive, requires long-term intravenous access, and
insufficient clinical evidence of its usefulness or effective
ness exists.287,288
Use of linezolid, bedaquiline, and delamanid
For the first time in nearly half a century, multiple promising
new and repurposed agents are available to treat MDR
tuberculosis; and experience of the new drugs bedaquiline
and delamanid and the repurposed drug linezolid is
increasing. These drugs should be considered part of the
routine management of highly resistant strains of
tuberculosis.289 Recommendations for the use of bedaquiline
and delamanid are outlined in panel 3, mechanisms of
action, drug interactions, and key adverse events are
described in table 7, and planned and ongoing clinical trials,
including MDR tuberculosis regimen shortening to 6 or
9 months are presented in table 6. Although the merits of
the regimen composition, duration, and adverse event
profile in these trials can be debated, we view the different
studies as complementary because they address different
questions and regimens that are relevant to different cases,
depending on the clinical and programmatic context.

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 The Lancet Respiratory Medicine Commission

WHO group Mechanism of action Mechanism of resistance Common adverse events Pharmacology and drug Important shared toxicity
or cautions interactions with rifampicin* with antiretrovirals
and antiretrovirals*
Bedaquiline/TMC D2 Inhibition of AtpE gene mutation (encodes Increased rates of Rifampicin reduces steady-state Hepatotoxicity; caution use
207 Mycobacterium subunit c of ATP synthase); unexplained deaths in the bedaquiline concentrations by with nevirapine, lopinavir
(diarylquinoline) tuberculosis ATP mutations in Rv067 coding for bedaquiline arm 79%; efavirenz reduces plus ritonavir, and NRTIs
synthase repressors of M tuberculosis (114 vs 25% in the control steady-state bedaquiline
efflux pump; some resistance group),290 not apparent in concentrations by 52%;291
with clofazimine; high barrier to pharmacovigilance studies lopinavir plus ritonavir
resistance to date; prolonged significantly increases
corrected QT interval; steady-state bedaquiline
caution in patients with concentration (uncertain clinical
liver dysfunction significance);292 nevirapine shows
no significant interaction
Pretomanid/ Unclassified Inhibition of mycolic Mutations in fbiA, fbiB, fbiC Hepatotoxicity; caution Rifampicin reduces pretomanid Hepatotoxicity; caution use
PA-824 acid biosynthesis and leads to impaired coenzyme in patients with renal by 66%; efavirenz reduces with nevirapine, lopinavir
(nitroimidazole) generation of F420 synthesis; mutation in dysfunction; pretomanid 35%293 plus ritonavir, and NRTIs
mycobactericidal Rv3547 coding for gastrointestinal tract
nitrogen oxide deazaflavin-dependent toxicity
derivatives (dormant nitroreductase (inhibit
M tuberculosis) activation of pro-drug); could
have a low barrier to resistance
Delamanid/OPC D2 Inhibits mycolic acid Mutation in mycobacterial Prolonged corrected QT Rifampicin reduced delamanid Potentially no significant
67683 biosynthesis Rv3547 prevents activation of interval (linked to concentrations by 45%; anticipated drugdrug
(nitroimidazole) delamanid; could have a low metabolite); potential no clinically significant interactions with
barrier to resistance CNS toxicity when used interaction with efavirenz;294 antiretrovirals
with isoniazid or lopinavir plus ritonavir might
fluoroquinolone; caution increase delamanid
with hypoalbuminaemia concentration294 (uncertain
(<28 g/dL) clinical significance);
twice daily dosing (once daily
dosing during maintenance
phase is under study); taken
separately from other
companion drugs
SQ-109 Unclassified Inhibits mycobacterial Mutation in the mmpL3 gene Gastrointestinal tract No clinical data available No clinical data available
(diamines) cell wall synthesis could potentially confer toxicity
specifically targeting resistance
the transmembrane
transporter encoded
by mmpL3 gene
Linezolid or C Inhibits protein Mutations in the 23S rRNA; Peripheral neuropathy; Rifampicin induces clearance of Peripheral neuropathy:
sutezolid/PNU- synthesis mutations in the rplC encoding hepatotoxicity linezolid, possibly through caution use with high-dose
100480 ribosomal protein L3; other P-glycoprotein expression; isoniazid (InhA mutation)
(oxazolidinones) mechanisms with possible sutezolid is metabolised by flavin and with antiretrovirals such
involvement of efflux pumps; mono oxygenases with small as didanosine and stavudine;
might have high barrier to contribution by cytochrome myelosuppression: caution
resistance P450 isoenzyme 3A use with zidovudine

NRTI=nucleoside reverse transcriptase inhibitors. *A reduction in the concentrations of the parent drug due to a co-administered inducing drug might be compensated for by an increase in concentrations of the
active metabolite. Unless otherwise stated, the % changes are in the area under the curve. Phase 2B trials completed. This mechanism might confer resistance to clofazimine, but the clinical significance of this
is unclear. The STAND study investigating a 4-month regimen for drug-sensitive tuberculosis has been stopped because of concerns of hepatotoxicity. Phase 2A trials completed.

Table 7: Novel, repurposed, and conventional drugs for the treatment of drug-resistant tuberculosis, including mechanism of action, key adverse events, and drug interactions

Monitoring treatment response and predicting
outcome
The monitoring of patients on MDR tuberculosis
treatment regimens should follow a holistic approach
with consideration given to clinical, laboratory, micro
biological, and radiological parameters.295 WHO guide
lines suggest monthly sputum smear microscopy and
culture as an adjunct to clinical monitoring of patients to
assess treatment outcome.296 For example, the duration of
second-line injectable drug therapy and the definition of
treatment failure are based on this information. However,
sputum culture conversion at 23 months has poor
sensitivity for predicting successful final treatment
outcomes using the conventional MDR tuberculosis
regimen297299 (many culture positives later converted and
had a successful outcome). 6-month conversion has a
high sensitivity (approaching 90% because some con
verters will revert back to being culture positive later) but
modest specificity (some of those who failed to convert
by 6 monthsinitially suggesting an unfavourable
outcomelater converted), and 710-month timepoint
sensitivity was higher (approaching 100%) but specificity
was still modest (~50%ie, many cultures converters
reverted). In 2015, an analysis of patients with MDR

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 The Lancet Respiratory Medicine Commission
tuberculosis from two large observational studies came to
similar timepoint-specific conclusions; sensitivity at
6 months was high but with modest specificity (~60%),
and the best maximum combined sensitivity and
specificity occurred between month 6 and month 10 of
treatment.300 In 2016, analysis of European data also
showed that 6-month culture conversion had high
sensitivity for predicting disease-free relapse.301 Thus, late
culture conversion is associated with poor outcomes.302,303
However, a time-specific cutpoint is dependent on the
effectiveness and sterilising activity of the regimen used.
Thus, finding a suitable pathogen-specific biomarker will
be useful. Regardless, biomarkers (particularly host-
related ones) will vary because of many factors, such as
disease extent, and high rates of between-person variability
will exist. Given the caveats of obtaining expectorated
sputum, culture conversion when used in isolation, is an
inaccurate tool for predicting treatment outcomes. This is
analogous to the situation in drug-sensitive tuberculosis
in which culture conversion has poor predictive value.302
Other factorssuch as HIV co-infection, previous
history of tuberculosis treatment, resistance profile
(MDR vs XDR vs other), extent of total and cavitary
disease on chest radiograph, presence of comorbid
conditions such as diabetes mellitus, and initial micro
biological burdenmight all have some role in
predicting treatment response.304306 Therefore, the need
to develop a composite tool that can predict long-term
outcomes of failure and relapse is urgent. Such a tool,
Panel 5: Recommended principles for the surgical
management of MDR and XDR tuberculosis
Patient selection for surgery and management should be
interdisciplinary
Candidates include patients with unilateral disease
(or apical bilateral disease in selected cases) with adequate
lung function who have failed medical treatment309
In patients with rifampicin-resistant or MDR tuberculosis,
elective partial lung resection (lobectomy or wedge
resection) was associated with improved treatment
success310
Surgical intervention might be appropriate in patients at
high risk of relapse or failure despite response to therapy
(eg, XDR tuberculosis or resistance beyond XDR)309
Facilities for surgical lung resection are scarce and often
inaccessible
PET-CT might be useful for clarifying the significance of
contralateral disease and could have prognostic
significance, but its role in this context requires
validation311,312
The optimal duration of therapy after resection remains
unclear
Surgery should be performed at a centre with relevant
experience
MDR=multidrug resistant. XDR=extensively drug resistant. Adapted from Dheda K.2
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once validated, would have the potential to significantly
shorten the approval of new interventions for MDR
tuberculosis.
Managing treatment failure, resistance beyond XDR
tuberculosis, and programmatically incurable
tuberculosis
Treatment failure is generally defined as the presence of
two consecutive positive cultures approximately 30 days
apart (one intervening culture might be missed or
contaminated), and either the need for a permanent
regimen change of at least two major antituberculosis
drugs, or treatment is terminated (stopping 2 or more
drugs) at a specified timepoint, or both. A consensus
definition has been proposed.307 Treatment failure might
occur in the context of no culture conversion from the
outset, initial response with subsequent culture re
version, or the need for a regimen change because of
adverse events or acquired drug resistance.
Despite the presence of significant drug-specific
resistance, patients might improve transiently. A rescue
regimen will depend on the results of patient DST and
prevailing DST profiles. However, other factors must
first be considered, including adherence and mal
absorption of drugs (eg, in patients who are HIV-
positive), and drug quality might occasionally be a
problem. When appropriate, a concomitant alternative
diagnosis must be considered. In areas where the MDR
tuberculosis prevalence is less than 10%, a significant
proportion of Xpert MTB/RIF rifampicin-resistant
results could theoretically be false positive (approximately
1015%). Although confirmation by additional methods
is advocated, this often does not occur in tuberculosis-
endemic countries. Occasionally, despite considering all
other factors, patients who persistently remain culture
positive with bacilli susceptible to aminoglycosides and
fluoroquinolones fail to respond to MDR treatment and
might have heteroresistance. Resistance profiles that are
not detectable in the sputum using tools such as DNA
amplification techniques, or an MIC in the cutpoint grey
zone are often the cause. In such cases, empirical use of
an XDR tuberculosis regimen, after exclusion of other
causes, is reasonable.
Totally drug-resistant tuberculosis has been used in the
literature to refer to strains of M tuberculosis that show
in-vitro resistance to all medications that are available for
testing.308 However, this term is a misnomer, since many
of the new and repurposed agents that have been shown
to be effective against tuberculosis are not assessed in
in-vitro resistance testing panels.4 Such individuals
would probably benefit from inclusion in clinical trials of
new drugs or regimens, or consideration of surgical
resection (panel 5). Regardless, many patients with
resistance beyond XDR tuberculosis are not given
effective medical treatment options, which has already
been highlighted as a problem in South Africa3 and is
likely occurring in other countries such as India, China,

and Russia. Indeed, in Indiathe region with the
majority of the worlds patients with MDR tuberculosis
there is no widespread access to new life-saving drugs
such as bedaquiline and delamanid, despite these drugs
having received approvals by the FDA in 2012, and the
EMA in 2014. However, a small compassionate use
programme and an early pilot project for bedaquiline
access has begun. Apart from some initial attempts to
access these drugs via compassionate use programmes
and vigorous campaigning by activists, these drugs
remain unavailable to the patients who need them the
most.313 Many patients with treatment failure reside in
the community because tuberculosis hospitals are full,
which raises several ethical and medicolegal issues.
Thus, the provision of palliative care and long-term-stay
community facilities is urgently needed.5 Access to these
services is extremely difficult in most tuberculosis
programmes and must be improved as part of the
patient-centred approach to treatment.314
Management in special situations
Patients with HIV, those who are pregnant, and those
with liver or kidney disease need to be optimally
managed in a comprehensive fashion in which specific
treatment regimens are designed that take into account
the risks of poor outcomes from drug-resistant
tuberculosisincluding the development of adverse
eventsversus the risks of the comorbid conditions
(panel 6).
HIV is commonly encountered in people with drug-
resistant tuberculosis, and in some settings, as many as
80% of drug-resistant tuberculosis patients are also HIV
positive. For this reason, it is imperative that all people
with MDR tuberculosis be screened for HIV at the time
of diagnosis.321 Management of HIV-infected patients is
complicated by several factors, including higher rates
of drug toxicity, HIV-related organ dysfunction
(eg, nephropathy, neuropathy, and anaemia), drugdrug
interactions and overlapping toxicities, pill burden, and
immune reconstitution inflammatory syndrome322
(table 7). However, when there is good control of HIV
disease, excellent treatment outcomes can be achieved in
persons with drug-resistant tuberculosis and HIV.323 As a
set of general management principles, people with MDR
tuberculosis and HIV should be started on antiretroviral
therapy as soon as possibleusually within 28 weeks of
starting MDR tuberculosis treatmentregardless of
CD4 count.238 The selection of the drug-resistant
tuberculosis regimen should be done on the basis of
WHO principles, but should also minimise the use of
drugs with overlapping toxicities if at all possible.
Although people with HIV were largely excluded from
the phase IIb clinical trials of both bedaquiline and
delamanid, some data on the safety and efficacy of
bedaquiline have emerged in cohorts in South Africa and
Swaziland.324 Bedaquiline should not be given with
efavirenz, however, since efavirenz decreases the serum
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The Lancet Respiratory Medicine Commission
concentration of bedaquiline. Delamanid does not
appear to have significant interactions with any of the
antiretroviral mediations (table 7).
Decision on the timing of drug-resistant tuberculosis
treatment during pregnancy should account for the
clinical condition of the mother, gestational age of the
fetus, and risks of teratogenicity. Women who are
pregnant and develop drug-resistant tuberculosis should
be included in all discussions on management plans
with a multidisciplinary team. All women of childbearing
age should be offered contraception free of charge as part
of the management of drug-resistant tuberculosis.
Compared with children born to women who have
untreated drug-resistant tuberculosis, children born to
women treated for drug-resistant tuberculosis during
pregnancy appear to have excellent birth outcomes (ie,
no evidence of neurological dysfuction or hearing or
visual abnormalities), and long-term follow-up of small
cohorts of such children do not document any negative
effects.325
Surgical management
Various principles underlie the surgical management of
patients with drug-resistant tuberculosis (panel 5).
Although no controlled trials have been performed and
patients undergoing surgery are selected for low severity
of disease (thus biasing towards a favourable outcome),
recent meta-analyses using observational data found that
surgical intervention was associated with better outcomes
compared with medical treatment, particularly in patients
with XDR tuberculosis.310,326 Newer, non-invasive broncho
scopic approaches using valves and other methods might
offer alternative approaches in selected patients who
refuse surgery or are not surgical candidates.327 Surgical
mortality is <5%, but the rate of complications varies
between 12% and 30%.295 Several questions remain
unanswered, including timing of surgery, use of
adjunctive therapy, and optimal investigation in those
patients with borderline lung function who might be
eligible for surgery, and these have been reviewed in
detail by Calligaro and colleagues.295 The 2016 WHO
update68 on the MDR tuberculosis treatment guidelines
examined the effectiveness of surgery for MDR
tuberculosis and suggested (on the basis of low quality
evidence) that elective partial lung resection (lobectomy
or wedge resection), when used alongside a recommended
MDR tuberculosis regimen, improves prognosis
compared with chemotherapy alone. The duration of
antituberculous therapy for people undergoing surgery
should be a minimum of 1824 months from the time of
culture conversion, which is often 1824 months after
surgery has been done. In patients with minimal disease
burden, as assessed by PET or CT, shorter treatment
durations could be considered depending on patient
tolerance, but no data exist to guide the optimal timing
and duration of medical therapy after surgical resection
of disease.328
 The Lancet Respiratory Medicine Commission
Panel 6: Management of MDR tuberculosis in different clinical contexts
Patients with HIV and MDR tuberculosis
Commence antiretroviral therapy, irrespective of
CD4 count, usually within 812 weeks of tuberculosis
treatment initiation238
Start antiretroviral therapy within 2 weeks of tuberculosis
treatment initiation in those with CD4 count less than
50 cells/mL, which is the case with drug-susceptible
tuberculosis (given the higher mortality) despite the additional
risk of immune reconstitution inflammatory syndrome315317
Bedaquiline can be combined with two nucleoside reverse
transcriptase inhibitors and nevirapine, or a combination of
lopinavir plus ritonavir (use with caution given increased
concentrations of drugs; see table 7), or an integrase strand
transfer inhibitor
Delamanid is potentially safe when co-administered with
antiretroviral therapy
If treatment for hepatitis B is indicated, antiretroviral
therapy should be initiated with the combination of at least
two agents active against hepatitis B viruseg,
tenofovir+emtricitabine or tenofovir+lamivudine.
In hepatitis C and hepatitis B virus coinfection, drug
interactions and overlapping toxicities must be considered
Pregnancy
Start treatment immediately if medically indicated, using
the principles outlined in panel 3
Given the high risk of teratogenicity in the first trimester,
in stable and selected cases, treatment with second-line
drugs can be deferred until the second trimester with
appropriate monitoring
Avoid aminoglycosides regardless of gestational age
(concern about fetal ototoxicity)
If deemed to be lifesaving for the mother, capreomycin can
be given (three times per week, if appropriate, to decrease
fetal drug exposure and the risk of ototoxicity)
Avoid ethionamide because of concerns about
teratogenicity and worsening of pregnancy-associated
nausea and vomiting
Ethionamide and aminoglycosides or other second-line
injectable drugs may be reintroduced after delivery to
strengthen the regimen
Management of MDR and XDR tuberculosis in children
A substantial proportion of worldwide MDR tuberculosis
cases occur in children. Conservative estimates suggest
that about 32000 children (younger than 15 years)
developed MDR tuberculosis in 2010.12 Children with
MDR tuberculosis usually have considerably better
treatment outcomes than adults; treatment is successful
in 8090% of children given individualised therapy,
probably due to the paucibacillary nature of most
paediatric tuberculosis. MDR tuberculosis in children
usually results from direct transmission from an adult,
and treatment of MDR tuberculosis in children is
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The teratogenicity of bedaquiline and delamanid in human
beings remains unclarified. However, bedaquiline appears
to be relatively safe in animal studies,318 and existing
protocols allow the recruitment of pregnant patients into
delamanid-based studies and the companys
compassionate use protocol
Contraception should be offered, preferably free of charge,
to all women being treated for MDR tuberculosis
Liver disease
Ethionamide, prothionamide, high-dose isoniazid,
para-aminosalicylic acid, and bedaquiline might be
hepatotoxic; use with caution in chronic stable liver disease
with close monitoring
Avoid pyrazinamide in patients with underlying chronic liver
disease
Avoid other potentially hepatotoxic non-tuberculosis
agents in patients with underlying chronic liver disease
No formal studies of drugdrug interactions between the
hepatitis C protease inhibitors and the second-line
tuberculosis drugs have been done; if a patient has stable
liver function, treatment of MDR tuberculosis should be
initiated first
Alcohol use might substantially exacerbate liver disease in
some settings, although studies have found that no
increased risk of hepatic adverse events exists in people with
MDR tuberculosis319
Renal disease
Frequency and dosage should be adjusted by creatinine
clearance for aminoglycosides, capreomycin, pyrazinamide,
ethambutol, cycloserine, either ethionamide or
prothionamide, and para-aminosalicylic acid320
Bedaquiline is often used to substitute second-line
injectable drugs in cases of significant pre-existing or
aminoglycoside-related renal dysfunction
Bedaquiline does not require any dose adjustments for
patients with mild to moderate renal dysfunction (ie, not on
dialysis) and may be used with caution in advanced renal
failure
MDR=multidrug resistant.
particularly challenging. Bacteriological confirmation of
MDR tuberculosis in children could be complicated
because of its paucibacillary nature, because the
tuberculosis is often extrapulmonary, and because
sample collection is challenging. Although bacterial
confirmation should be attempted, most children can be
presumptively diagnosed with MDR tuberculosis on the
basis of the presence of signs and symptoms of
tuberculosis and a positive contact history, because there
is high concordance between DST patterns of children
and their source cases.329,330 The hesitance of health-care
providers to treat probable MDR tuberculosis in children

is a major reason for few children with drug-resistant
tuberculosis receiving adequate treatment.
The principles of MDR tuberculosis treatment in
adults and children are the same; all second-line drugs
are used in children, although formal pharmacokinetic
studies are sparse and child-friendly formulations are
not usually available (panel 7). Notably, theoretical
concerns about the effects of the fluoroquinolones on
developing bones and joints that emerged from animal
studies have not been observed in children on long-
term fluoroquinolone use for the treatment of MDR
tuberculosis or for other chronic infectious diseases.331
Shorter overall treatment durations (1215 months) can
be considered in children with non-severe disease.332,333
Shorter 912 month regimens were recently recom children, with maximum daily dose in brackets
mended by WHO for use in selected patients, including
children.
Disseminated forms of extrapulmonary tuberculosis
such as miliary tuberculosis and tuberculosis meningitis
are common in infants and young children, and have
important implications. Treatment of these forms of
tuberculosis requires medication with good penetration
into cerebrospinal fluid, such as fluoroquinolones,
thioamides, cycloserine or terizidone, and linezolid.
Children experience fewer adverse effects from second-
line antituberculosis drugs than adults, with a meta-
analysis of 315 children showing that 391% of the
children had an adverse event compared with 573% in
an adult cohort meta-analysis from a similar time
period.334,335 However, high-quality, prospective studies of
adverse effects in children on MDR tuberculosis
treatment are rare. Additionally, adverse effects are more
difficult to assess in children, and could therefore be
underestimated.333 A notable exception is irreversible
sensorineural hearing loss caused by the injectable
drugs, which is seen in up to 25% of children.336 Hence,
a high-priority research objective is developing an all-oral
regimen for children.
Summary of medical and surgical management
We have described the key principles for designing an
effective regimen for MDR and XDR tuberculosis
(panel 3) and the management of MDR tuberculosis
in special situations, including in HIV-infected
individuals (table 7 and panel 6). However, several
other factors are critical for successful treatment
outcomes, including ensuring adherence support,
a good laboratory infrastructure, and a well-functioning
tuberculosis programme.
Furthermore, we suggest that an entirely new framework
for the treatment of drug-resistant tuberculosis be adopted
and that the conventional regimen no longer be used to
treat the majority of individuals with drug-resistant
tuberculosis. Rather, we suggest a precision medicine-
orientated treatment approach in which universal access
to rapid DST for isoniazid, rifampicin, the second-line
injectables, and the fluoroquinolones is available, to guide
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The Lancet Respiratory Medicine Commission
individualised therapy. In the interim, patients without
resistance to the second-line drugs would receive the
shortened drug-resistant tuberculosis treatment regimen,
and those with resistance to the second-line drugs would
receive novel agents such as bedaquiline or delamanid, or
both, in combination with other drugs shown to be
effective in randomised trials, such as linezolid and
clofazimine. All-oral regimens that maximise potency and
minimise toxicity should be rapidly implemented as
evidence emerges. The ideal length of therapy would be
calculated, taking into account clinical, laboratory,
microbiological, and radiographic parameters, and
Panel 7: Recommended dosing of second-line drugs in
Pyrazinamide
3040 mg/kg per day (2000 mg)
Kanamycin, amikacin, or capreomycin
1520 mg/kg per day (1000 mg)
Levofloxacin
1520 mg/kg per day (1000 mg)
Moxifloxacin
10 mg/kg per day (400 mg)
Ethionamide or prothionamide
1520 mg/kg per day (1000 mg)
Cycloserine or terizidone
1520 mg/kg per day (750 mg)
Para-aminosalicylic acid
150200 mg/kg per day (12 g)
Clofazimine
23 mg/kg per day (100 mg)
Linezolid
In children 10 years or older: 10 mg/kg per day (600 mg)
In children younger than 10 years: 10 mg/kg twice daily
(600 mg)
Delamanid
Weight of 35 kg or more: 100 mg twice daily
Weight of 2034 kg: 50 mg twice daily
Weight of less than 20 kg: consult with expert
Bedaquiline
Weight of 33 kg or more: 400 mg daily for 14 days
followed by 200 mg three times a week for 22 weeks
Weight of less than 33 kg: consult with expert
Amoxicillin plus clavulanate
80 mg/kg of amoxicillin component divided into
two doses (4000 mg amoxicillin plus 500 mg clavulanate)
Meropenem*
2040 mg/kg intravenously every 8 h (6000 mg)
*Meropenem is only to be used in combination with amoxicillin plus davulanate.
 The Lancet Respiratory Medicine Commission
comorbidities that affect outcomes, including poorly
controlled HIV, malnutrition, and diabetes. Thus,
improved biomarkers and scoring systems are urgently
required to accurately predict outcomes, facilitate clinical
management, and streamline the assessment of new
therapeutic interventions for MDR tuberculosis.
Patients with XDR tuberculosis and additional
resistance to second-line drugs should be offered access
to clinical trials and to new medications through
compassionate use and expanded access programmes.
Surgical therapy should be considered a key adjuvant to
medical management of highly resistant forms of
tuberculosis. Children merit special attention in the
diagnosis, prevention, and treatment of drug-resistant
tuberculosis, and the long delays in access to innovation
in this vulnerable population must be eliminated. Other
vulnerable populations, including pregnant women,
people with hepatic disease, and those with other risk
factors for poor outcomes such as diabetes, HIV, or renal
disease, can have successful outcomes if they are treated
in a comprehensive programme. In tandem, adherence-
promoting mechanisms, antibiotic steward ship, and
attention to appropriate dosing and monitoring is crucial
to prevent the amplification of resistance and rapid loss
of these agents. Insufficient effective approaches will
only enlarge the pool of patients with programmatically
incurable tuberculosis, which is a substantial problem
in tuberculosis-endemic countries. Other innovative
approaches such as community-based isolation facilities
will be required to deal with this ongoing problem.
New drugs and strategies for treating
drug-resistant tuberculosis
Developing new regimens for drug-resistant tuberculosis
is challenging. Tuberculosis drugs work in combination,
and an effective regimen should include at least one drug
with potent bactericidal activity to rapidly reduce
mycobacterial burden. This role is filled by isoniazid
in drug-susceptible tuberculosis. Drugs with potent
sterilising activity (eg, rifampicin and pyrazinamide in
drug-susceptible tuberculosis), which effectively kill
semidormant, persisting organisms that will cause
relapse if they are not eradicated, are even more
important. Companion drugs with different mechanisms
of action that protect these main bactericidal and
sterilising drugs against the emergence of resistance
(like ethambutol in drug-susceptible tuberculosis) are
also essential. Additionally, an ideal regimen that can be
used for drug-resistant tuberculosis worldwide will have
the following features: compatibility with antiretroviral
therapy, good penetration into cavitary lung lesions and
areas undergoing caseous necrosis, few requirements for
safety monitoring, ease of use in programmatic settings,
and oral formulations.
Tuberculosis is a millennia-old disease and to defeat it
(or even abate the advance of ever more drug-resistant
tuberculosis), scientists must think creatively and
324 www.thelancet.com/respiratory Vol 5 April 2017
marshal all available resources, including repurposing
existing drugs and developing new ones. Fortunately,
a pipeline of drugs is now in development for tuberculosis.
However, this pipeline is not yet robust, several drugs are
newly in clinical use or are in clinical development, and
some old drugs are being reassessed or optimised for
drug-resistant tuberculosis (tables 7 and 8).
New or repurposed drugs for drug-resistant
tuberculosis: the building blocks
Repurposed drugs are antimicrobials that were developed
for other bacterial infections, but which have useful
antimycobacterial activity. Substantial information on
the pharmacokinetics and pharmacodynamics, safety
and tolerability, and drugdrug interactions is typically
available for repurposed drugs, which accelerates their
adoption for tuberculosis treatment. However, further
optimisation of drug dosing for safety and efficacy, as is
being done for levofloxacin (OptiQ Study; NCT01918397),
is needed in the context of the long treatment durations
and multidrug regimens used to treat drug-resistant
tuberculosis.
Fluoroquinolones
Fluoroquinolones are well-tolerated oral agents that are
used to treat a wide variety of bacterial infections. These
drugs are already considered cornerstone agents for the
treatment of MDR tuberculosis, and the use of late-
generation drugs of this class against susceptible
isolates was associated with an adjusted odds ratio of
25 for treatment success in an individual patient meta-
analysis.337 Fluoroquinolones form complexes with
bacterial DNA and topoisomerase enzymes to inhibit
bacterial replication. However, their bactericidal effect
is mediated through subsequent chromosomal frag
mentation and generation of reactive oxygen species, as
well as at least one other poorly characterised mech
anism.338 Available fluoroquinolones differ in their MIC
against M tuberculosis, with the late-generation
fluoroquinolones moxifloxacin and gatifloxacin being
most potent, followed by levofloxacin and then
ofloxacin, but clinical trials comparing fluoroquinolones
are few in number and narrow in scope. Ofloxacin has
been shown to be less efficacious than the others and
should be abandoned for tuberculosis therapy.339
Moxifloxacin, gatifloxacin, and high-dose (ie, 1 g daily
for patients weighing >50 kg) levofloxacin display
similar early bactericidal activity in drug-susceptible
tuberculosis.340 Sputum culture conversion rates were
similar for levofloxacin and moxifloxacin in a small
randomised controlled trial in patients with MDR
tuberculosis.341 Evidence is emerging that moxifloxacin
and gatifloxacin might retain activity against some
ofloxacin-resistant isolates, especially those with A90V
and D94A mutations in gyrA.342 Increasing the
moxifloxacin or gatifloxacin dose would be expected to
further increase the activity against such isolates and
 The Lancet Respiratory Medicine Commission

Standard Shortened Key role Adverse events and tolerability Comments

Fluoroquinolone: levofloxacin
or moxifloxacin
Injectable agent: amikacin,
kanamycin, or capreomycin
Ethionamide or prothionamide
Cycloserine or terizidone
Linezolid
Clofazimine
High-dose isoniazid
Pyrazinamide
Ethambutol
treatment* treatment
Yes Yes Key bactericidal agent Generally well tolerated; Optimal dose unclear; little to no sterilising activity
tendinitis; insomnia;
QT prolongation
Yes Yes Undefined Ototoxicity, common and often No measurable bactericidal activity; no measurable
irreversible; nephrotoxicity; sterilising activity; candidate for replacement in novel
injections painful regimens because of poor tolerability; should generally
be avoided with tenofovir
Yes Yes Treat isolates whose Nausea and vomiting common Candidate for replacement in novel regimens because of
isoniazid resistance is toxicity
mediated by katG
mutation
Yes No Bacteriostatic drug Neuropsychiatric side-effects Candidate for replacement in novel regimens because of
common toxicity
No No Protect against emergence Peripheral neuropathy and bone Optimal dose and duration to optimise efficacy and
of resistance marrow toxicity common minimise toxicity not defined
No Yes Sterilising drug Skin discoloration in almost all Synergistic with pyrazinamide; some cross-resistance
people; QT prolongation with bedaquiline
No Yes Treat isolates whose Peripheral neuropathy, Optimal dose unclear
isoniazid resistance is preventable by vitamin B6 Avoid use with stavudine or didanosine to prevent
mediated by inhA peripheral neuropathy
mutation
Yes Yes Sterilising drug; synergy Arthralgias common; hepatitis Synergistic with clofazimine
with other drugs High proportion of MDR isolates are resistant
Should be used with caution when combined with other
potentially hepatotoxic ART
No Yes Protection against Optic neuritis, rarely High proportion of MDR isolates are resistant
resistance

*In 2016, WHO recommendations were updated to recommend the following as standard treatment: a fluoroquinolone, an injectable, two of the followingethionamide or prothionamide, cycloserine or
terizidone, linezolid, and clofazimineand pyrazinamide. Other agents (ethambutol, bedaquiline, delamanid, etc) could be added, if needed, to construct a regimen. Before 2016, linezolid and clofazimine were
not components of WHO-recommended standard MDR-TB treatment, but they now are.

Table 8: Drugs used in current WHO standard or shortened treatment of multidrug-resistant tuberculosis

suggests opportunities for more personalised ap
proaches to MDR tuberculosis therapy in conjunction
with resistance genotype information.339 However,
gatifloxacin poses a risk of hyperglycaemia or
hypoglycaemia, so has been removed from the market
in many regions. Further study should establish
whether higher doses of levofloxacin or moxifloxacin
would be more efficacious with acceptable toxicity.
Fluoroquinolones cause modest QT interval pro
longation (with the effects of moxifloxacin greater than
those of levofloxacin), and this should be kept in mind
when constructing multidrug regimens or treating
concurrent illnesses with drugs that also have this risk.
Oxazolidinones
Oxazolidinones are orally available drugs developed for
resistant Gram-positive infections, which inhibit
bacterial protein synthesis by binding to 23S ribosomal
RNA. Mutations in the rrl gene encoding 23S rRNA
confer high-level resistance to oxazolidinones, whereas
mutations in the rplC gene encoding ribosomal
L4 protein confer low-level resistance.343 Because these
mutations occur spontaneously in only approximately
1 in 10 bacilli, this class has a high genetic barrier to
drug resistance. Linezolid, the first drug in this class, has
good in-vitro activity against M tuberculosis, and is the
best-studied oxazolidinone in tuberculosis. Linezolid
also has good pulmonary and cerebrospinal fluid
penetration.343
Linezolid has been used off-label in patients with MDR
tuberculosis with promising efficacy in observational
studies.272 The addition of linezolid to a failing regimen
in patients with XDR tuberculosis resulted in culture
conversion in 87% of patients by 6 months, and resistance
emerged in 4 of 38 patients.344 In another trial in which
patients with XDR tuberculosis were randomised to
receive linezolid or placebo, added to an individually
optimised treatment regimen, culture conversion at
24 months was significantly higher for patients receiving
linezolid (79% vs 38%).345
Linezolid commonly causes haematological or neuro
pathic toxicity by virtue of its inhibition of protein
synthesis in human mitochondria, and sometimes
treatment must be stopped temporarily or permanently.
This toxicity is both dose-dependent and duration-
dependent. Although the approved dose for Gram-
positive bacterial infections is 600 mg twice daily,
clinicians treating MDR or XDR tuberculosis commonly
initiate therapy with 300600 mg once daily in an effort
to mitigate toxicity. However, increasing bactericidal

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 The Lancet Respiratory Medicine Commission
activity has been observed with increasing total daily
doses between 300 and 1200 mg. Administration of
higher doses intermittently (eg, 9001200 mg three times
per week), with or without an initial phase of daily
therapy, might be a promising strategy to better separate
the efficacy of linezolid from its toxicity. Linezolid is a
weak inhibitor of monoamine oxidase A and B and
cannot be given with serotonin reuptake inhibitors
because this might result in development of the serotonin
syndrome. Cost has restricted linezolid usage, but the
availability of generic linezolid and the inclusion of
linezolid in the WHO Model List of Essential Medicines346
since 2015 have improved drug accessibility.
Newer oxazolidinones with potential for more favour
able risk-to-benefit ratios than linezolid need to be
explored for use in drug-resistant tuberculosis. Tedizolid
is an oxazolidinone that is newly approved for the
treatment of bacterial skin and soft tissue infections. In
vitro it is active against M tuberculosis and might have
less mitochondrial toxicity than linezolid, but tedizolid
has not been tested in patients with tuberculosis or given
for prolonged periods.347,348 Sutezolid is an investigational
oxazolidinone in phase 2 testing for tuberculosis (table 8).
Preclinical data suggest it could be more efficacious than
linezolid, but a high incidence (14%) of liver enzyme
elevations in an early bactericidal activity study was
reported.349
Clofazimine
Clofazamine is an oral riminophenazine dye that is used
to treat leprosy. Although its mechanisms of action are not
completely understood, it results in the intracellular
generation of reactive oxygen species via redox cycling that
involves a mycobacterial NADH dehydrogenase and
molecular oxygen. In mouse models, clofazamine shows
delayed-onset bactericidal activity as monotherapy, and
significant sterilising activity in combination with first-line
and second-line regimens.350352 However, in C3HeB/FeJ
mice that develop large caseous granulomas, clofazimine
is less effective, perhaps because of the hypoxic conditions
or reduced diffusion through caseous tissue, or both.353,354
Clofazimine shows no bactericidal activity in patient
sputum over the first 14 days of treatment.355 However, in a
phase 2 clinical trial, adding clofazimine at a dose of
100 mg daily for 21 months to multidrug background
therapy (ie, the MDR tuberculosis treatment regimen)
improved MDR tuberculosis treatment success versus
placebo (74% vs 54%).356 Clofazimine is also considered a
key component of a short-course regimen (ie, 912 months)
recently endorsed by WHO for treatment of MDR
tuberculosis after several observational cohorts reported
good treatment success.277279
Clofazimine is highly lipophilic, it has a very large
volume of distribution, and has a terminal half-life of
70 days. The drug becomes highly concentrated in fat,
organs, and skin with long-term use.357 Clofazimine
accumulation causes slowly reversible red-black skin
326 www.thelancet.com/respiratory Vol 5 April 2017
discolouration in nearly all patients, which is a barrier to
widespread implementation because there is a stigma
against hyperpigmentation in many countries in which
tuberculosis is endemic. The extent of hyperpigmentation
and the time to resolution depends on both dose and
duration and might, therefore, be mitigated by shorter
treatment durations or lower doses, or both, should they
prove effective. Clofazimine also causes modest QT
extension.
-lactams
-lactams as a class of drugs have received little atten
tion as antituberculosis drugs, primarily because
M tuberculosis has a constitutively active broad-spectrum
-lactamase (BlaC). However, carbapenems such as
meropenem are inefficiently hydrolysed by BlaC. Further,
carbapenems are active against M tuberculosis in vitro, and
clavulanate, an irreversible inhibitor of BlaC, further
enhances the activity of carbapenems.358,359 The com
bination of a carbapenem and a penicillin might also have
additive or synergistic effects.360 To examine the activity of
a carbapenempenicillinclavulanate combin ation in
vivo, a recent phase 2A proof-of-concept trial was done. In
this study, a combination of meropenem, amoxicillin, and
clavulanate showed quantifiable early bactericidal activity
in patients with pulmonary drug-susceptible tubercu
losis.361 However, all drugs were administered three times
per day, and meropenem (like imipenem) requires
intravenous infusion. Faropenem, an oral penem,
in combination with amoxicillin-clavulanate had no
bactericidal activity, perhaps because the drug exposure
was too low at the tested dose.
Bedaquiline
Bedaquiline is a new oral diarylquinoline drug developed
for tuberculosis that inhibits the M tuberculosis ATP
synthase. Bedaquiline is the first representative of a new
class of drugs to be approved for treatment of tuberculosis
in over 40 years. In preclinical testing, bedaquiline plus
pyrazinamide had better sterilising activity than
rifampicin, pyrazinamide, and isoniazid.362 Bedaquiline
displays notable synergy with pyrazinamide.362 Spon
taneous mutations conferring resistance to bedaquiline
occur in approximately 1 in 10 or 10 bacteria (similar to
rifampicin).363 High-level resistance to bedaquiline
results from mutations in the ATP synthase binding site,
but such mutants have yet to be observed in clinical
isolates. A lower level of resistance occurs via up
regulation of mycobacterial efflux pumps because of
inactivation of the negative transcriptional regulator,
Rv0678. These resistant mutants show cross-resistance
to clofazimine and have been selected for during
treatment of patients with pre-XDR and XDR tuberculosis
with bedaquiline.199
In human beings, bedaquiline is highly protein-
bound (999%), is metabolised by cytochrome P450
isoenzyme 3A (CYP3A) to a less active metabolite (M2),

and has a very long terminal half-life (about 5 months).364
Clearance of the drug is 52% higher in black people, sug
gesting an undiscovered pharmacogenomic determinant
of exposure. Several important drugdrug interactions
exist between bedaquiline and antiretroviral drugs:
bedaquiline concentrations are estimated to be reduced
by about 50% with concurrent efavirenz treatment, and
increased two-times with concurrent lopinavir and
ritonavir.292
In phase 2 trials, 2-month sputum culture conversion
increased after 8-week therapy from 9% with multidrug
background therapy and placebo to 48% with background
therapy and bedaquiline, and the increase was sustained
at 6 months.365,366 Mortality was higher in the bedaquiline
group than the placebo group, but most of the deaths in
the bedaquiline group occurred after completion of the
6-month course of bedaquiline treatment, and causes of
death were widely variable. This suggests that the
increased mortality associated with bedaquiline in the
small phase 2 study is a chance finding. In post-
marketing studies, an increase in mortality was not
seen.324 WHO recommends that bedaquiline be given for
6 months for treatment of MDR tuberculosis in adult
patients who dont have other treatment options.270
Mortality concerns in the phase 2 study and the reduction
in bedaquiline concentrations by more than 50% with
the concurrent use of rifampicin has prevented
its investigation as a first-line treatment-shortening
regimen.
Bedaquiline causes moderate prolongation (1015 ms) of
the QT interval,365 so clinicians should minimise the use of
other QT-prolonging drugs, including non-tuberculosis
drugs and tuberculosis drugs such as clofazimine,
delamanid, and the fluoroquinolones (apart from
levofloxacin, which has a minor effect on QT) and
undertake rapid correction of electrolyte abnormalities and
regular ECG monitoring. Substantial hepatotoxicity has
been reported (77% in the bedaquiline arm vs 25% in the
control arm).290 In-vitro studies using human mononuclear
cells suggest that bedaquiline induces phospholipidosis
with ultrastructural cellular changes;283 however, the
implications for toxicity from this drug-induced
phospholipidosis are unclear. Drug interactions with the
concurrent use of bedaquiline and antiretroviral therapy is
outlined in table 7. The extremely long terminal elimination
half-life (6 months) and intracellular drug accumulation
might have beneficial mycobactericidal effects, although
concerns have been raised about the development of
resistance in individuals lost to follow-up who could have
been exposed to long periods of bedaquiline monotherapy.
The need for rapid use of bedaquiline in sub-
populations with significant mortality and toxicity
(eg, people with pre-XDR or XDR tuberculosis, and those
with MDR tuberculosis with intolerance of other drugs
such as aminoglycoside ototoxicity) but at the same time
clarify important unknowns through phase 3 trials
(efficacy, optimum duration and use with companion
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The Lancet Respiratory Medicine Commission
drugs, and adverse events), raises important ethical and
medicolegal questions.
Although encouraging initial observations have been
made of faster culture conversion in early bactericidal
activity and phase 2 studies of bedaquiline,365,366 and high
rates of culture conversion in French367 and South African
patients with XDR tuberculosis (100% in the French
cohort and 85% in the South African cohort),324 another
analysis368 indicated that the 120-week culture conversion
rate was 70% in patients with pre-XDR tuberculosis
and 62% in XDR tuberculosis when bedaquiline was
used with companion drugs and an optimised background
regimen. Thus, even with newer drugs such as
bedaquiline, treatment failure will be common in patients
with XDR tuberculosis or those with resistance beyond
XDR tuberculosis, for which no effective therapy is
available and so it remains programmatically incurable.
Measures will need to be taken to strengthen the drug
development pipeline and to minimise drug resistance.
In addition to addressing patient-specific and programme-
specific issues that promote the development of drug
resistance, novel drug dosing and administration
strategies, monitoring strategies, and adjunct therapies
(eg, efflux pump inhibitors and immune modulation
strategies) will need to be investigated.
Nitroimidazoles
Nitroimidazoles have been developed specifically for
tuberculosis. They have two mechanisms of actionthe
inhibition of mycolic acid (mycobacterial cell wall)
synthesis and the liberation of toxic nitric oxide within
M tuberculosis.369,370 These drugs act against actively
dividing and non-replicating bacilli and show potent
sterilising activity in mouse models.
Delamanid is a nitroimidazole registered for use in the
treatment of drug-resistant tuberculosis and is a prodrug
that is activated by an F420-dependent mycobacterial
nitroreductase. Mutations across the nitroreductase
gene, or in any of four genes involved in the synthesis or
activation of the F420 cofactor, could cause high-level
delamanid resistance.371 Spontaneous mutations con
ferring resistance to delamanid are relatively frequent,
occurring in approximately one in 100000 to
1000000 bacilli.369,372374 In human beings, delamanid is
highly protein bound (>995%), is metabolised by
albumin,375 has a half-life of 34 h, and its DM-6705
metabolite has a half-life of more than 150 h.375 Delamanid
has low oral bioavailability, so it has to be given with
food, and dosing must be separated in time from dosing
of other medications. Co-administration with ritonavir-
boosted protease inhibitors or efavirenz does not
markedly affect delamanid exposure.
In a phase 2 randomised controlled trial in patients with
MDR tuberculosis,376 treatment with delamanid resulted
in higher rates of culture conversion at 2 months
compared with placebo (454% vs 296%, p=0008) after
8 weeks of treatment compared with placebo; the
 The Lancet Respiratory Medicine Commission
For more on the Global Drug
Facility see http://www.stoptb.
org/gdf
For more on the TB Alliance see
https://www.tballiance.org
328 www.thelancet.com/respiratory Vol 5 April 2017
carry-over observational study377 showed higher rates of
favourable treatment outcome in participants who
received 6 months or more versus 2 months or less of
delamanid treatment (745% vs 55%; p<0001).377
Delamanid causes moderate QT prolongation (1015 ms)
but is otherwise well tolerated. QT prolongation appears
to be associated with concentrations of the DM-6705
metabolite. A phase 3 trial of delamanid (NCT01424670)
has completed the enrolment and treatment phase
(table 6), and full results are expected in 2018.
Global access to delamanid has been poor, but the drug
has been made available through the Global Drug
Facility378 and there is increasing experience of its use.
Delamanid has a low threshold for resistance
development, therefore it should be used in combination
with drugs with higher genetic barriers to resistance,
such as bedaquiline (with careful ECG monitoring).
Delamanid is contraindicated in people who have an
allergy to metronidazole. The twice-daily dosing regimen
complicates the use of delamanid in DOT programmes,
and a single daily dose of delamanid is being assessed in
clinical trials. Delamanid is recommended for 24 weeks
of therapy, but longer courses have been given without
additional safety issues both in the industry-sponsored
observational study and in individual patients. Patients
given delamanid should have a baseline and monthly
ECG to measure the QTc interval and a baseline albumin
test because the drug is metabolised by albumin and
there might be an increase in adverse events with
albumin concentrations below 28 g/L. Delamanid is not
recommended in patients with moderate to severe
hepatic impairment. Delamanid has few drugdrug
interactions and no significant interactions have been
seen with the antiretrovirals efavirenz and lopinavir
ritonavir.294
Pretomanid (PA-824) is another nitroimidazole agent
that is being developed as part of combination therapy
for tuberculosis and MDR tuberculosis by the
TB Alliance. Pretomanid is in phase 3 testing, and its
characteristics are shown in table 7. On the basis of early
bactericidal activity studies355 and the superior bactericidal
activity of pretomanid, moxifloxacin, and pyrazinamide
versus rifampicin, isoniazid, pyrazinamide, and
ethambutol for drug-sensitive tuberculosis at 8 weeks,379
the phase 3 STAND study was launched (table 6;
NCT02342886), but this study was placed on partial
clinical hold because of hepatotoxicity and further
enrolment was stopped, but follow up will continue as
per protocol. Pretomanid is also being studied as part of
combination therapy for XDR tuberculosis (NiX Trial,
NCT02333799; table 6). Complete cross-resistance exists
between delamanid and pretomanid.
Constructing regimens: tools and strategies
Although the majority of MDR tuberculosis strains are
resistant to additional drugs beyond isoniazid and
rifampicin, detailed susceptibility profiles are rarely
available at the initiation of treatment. The standard of
care to construct empirical drug-resistant tuberculosis
regimens, pending the outcome of full susceptibility
results, or for standardised drug-resistant tuberculosis
regimens used in low-resource settings is given in panel 3.
Treatment with a large number of tuberculosis drugs is
commenced in an effort to provide at least 34 active drugs
(ie, drugs that the organism is susceptible to). Standardised
MDR tuberculosis treatment regimens typically consist
of a fluoroquinolone, a second-line injectable drug,
ethionamide or prothionamide, and cycloserine or
terizidone; however, these drugs do not have good
sterilising activity. The first-line drugs pyrazinamide and
ethambutol are often included, despite high prevalence of
resistance in MDR tuberculosis isolates. In 2016, WHO
recommended68 a 912 month, 7-drug MDR tuberculosis
regimen for selected patients that uses largely the same
drugs, with the addition of clofazimine and high-dose
isoniazid. There is a need for a more rational approach to
selecting newer drug-resistant tuberculosis regimens, with
a focus on safer and shorter regimens.
With the new or repurposed drugs that we have
described in this Commission, existing first-line and
second-line drugs commonly used in drug-resistant
tuberculosis, and experimental drugs that have entered or
will be entering the clinical research pipeline, the number
of potential combinations of drugs, durations, and doses
to construct new regimens appears almost limitless.
However, considering that the regimen ought to be rapidly
bactericidal (to interrupt transmission), have good
sterilising activity (to completely cure), minimise
resistance emergence (to be durable), and to be well
tolerated (considering overlapping toxicities and drug
drug interactions), the number of promising regimens
shrinks substantially, and assessing them becomes more
manageable.
The absence of a validated surrogate efficacy marker
that can be measured early in the course of treatment
and predict long-term treatment outcomes is a major
impediment to the clinical development of new
tuberculosis drugs and regimens. Non-clinical models
therefore fulfil an essential role, enabling exploration of
exposureresponse relationships and the efficacy of
novel drug combinations. The ultimate goal of non-
clinical efficacy studies is to inform the design of clinical
trials that will establish the optimal dose of individual
drugs, the contribution of individual drugs to the efficacy
of novel regimens, and the efficacy of novel regimens
relative to the standard of care. A variety of non-clinical
models have been used, each with advantages and
disadvantages.380 Largely for reasons of availability, cost,
and tractability, murine models have been used most
extensively. Although the lung pathology produced in the
commonly used mouse strains does not reproduce the
caseous pathology observed in human tuberculosis,
demonstration of the treatment-shortening potential of
rifampicin and pyrazinamide have established the utility

of murine models.381,382 Studies in mice were used to
justify phase 3 trials investigating the potential of late-
generation fluoroquinolones to shorten the treatment of
drug-susceptible tuberculosis. However, the failure of
these treatment-shortening trials showed potential
pitfalls in the way non-clinical and early clinical data
have been used to inform trial design, including over-
reliance on murine models that might not fully represent
the distribution and activity of drugs in caseating lung
lesions, and underappreciation of the effect of inter
individual pharmacokinetics and drugdrug interactions
on efficacy.383
A key lesson that has been learned is that defining optimal
drug doses is a necessary step in optimising regimen effi
cacy and preventing the emergence of resistance.384387
Astonishingly, 50 years has passed since the introduction of
rifampicin into clinical use, and the optimal dose of this key
sterilising drug has yet to be established. Some data suggest
that dose optimisation of rifampicin or rifapentine alone
might deliver a 4-month regimen that is less likely to select
for isoniazid-resistant and MDR disease than the 6-month
regimen.384387 Repetition of the mistake of underdosing with
new drugs should be avoided in drug-resistant tuberculosis
regimens, because resistance could rapidly emerge. For
repurposed drugs, doses used to treat other infections should
not be assumed to be optimal for drug-resistant tuberculosis
treatment, in which disease-specific pharmacokinetic
pharmacodynamic associations, longer treatment durations,
overlapping toxicities, and drugdrug interactions associated
with combin ation therapy are important factors in
establishing optimal doses. Even for new drugs specifically
developed for drug-resistant tuberculosis, such as
bedaquiline and delamanid, it should not be assumed that
doses used for regulatory approval are necessarily optimal.
Although additive or synergistic drug combinations could be
exploited to lower individual drug doses, this could
undermine the ability of regimens to suppress the emergence
of drug resistance. The role of rifabutin in MDR tuberculosis
also requires clarification (panel 8).
A more revolutionary approach uses non-clinical
model results together with early clinical data
to rapidly advance novel, short-duration drug
combinations containing two or more new drugs or
multiple regimens. The combination of pretomanid
with moxifloxacin and pyrazinamide was first shown
to be superior to the first-line regimen for drug-
susceptible tuberculosis in a murine model388 and has
subsequently shown activity that is superior to the
standard of care over the first 2 months of treatment
in patients with drug-susceptible tuberculosis.379
Pyrazinamide also appeared to be effective in patients
with pyrazinamide-susceptible and fluoroquinolone-
susceptible MDR tuberculosis.379 A confirmatory
phase 3 study of pyrazinamide in patients with MDR
tuberculosis is underway (China PZA trial; table 6).
Similarly, following the promising effects in mice, the
three-drug combination of bedaquiline, pretomanid,
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The Lancet Respiratory Medicine Commission
Panel 8: Potential role for rifabutin in drug-resistant
tuberculosis
Evidence has shown that there is not complete
cross-resistance between rifamycins in MDR tuberculosis,
because some strains remain susceptible to rifabutin99
A multinational study of 60 M tuberculosis isolates from
patients with MDR tuberculosis showed
that 15 of 60 isolates had mutations in the rpoB gene,
which conferred resistance to rifampicin but not rifabutin
These findings have important implications given the key
role that rifamycins have in treating tuberculosis
Future genotypic resistance tests should identify rpoB
mutations that distinguish between rifabutin and
rifampicin resistance
Clinical studies are required to establish the efficacy of
rifabutin in this setting
RHZE
0
Relative change in treatment duration (months)
1
PaMZ BPaL
2
BPaM
3
BPaZ
BPaMZ
4
BPaLZ
5
6
Figure 8: Treatment-shortening effects of novel regimens relative to the
first-line regimen (RHZE) in a murine model of tuberculosis
Red font indicates new drugs to which minimal resistance exists.
B=bedaquiline. L=linezolid. M=moxifloxacin. Pa=pretomanid.
RHZE=rifampicin+isoniazid+pyrazinamide+ethambutol. Z=pyrazinamide.
With courtesy and permission from CAPRISA.
and pyrazinamide is under investigation in patients
with drug-sensitive tuberculosis, with the addition of
moxifloxacin in patients with MDR tuberculosis
(STAND; table 6). Combining bedaquiline and
pretomanid (or delamanid) with linezolid could be the
best opportunity for a much-desired three-drug
regimen that is effective against virtually all circulating
drug-resistant and drug-sensitive M tuberculosis
isolates. This combination has shown sterilising
activity superior to the first-line drug-susceptible
tuberculosis regimen in mice389 and is now being
studied in patients with XDR tuberculosis or MDR
tuberculosis with intolerance of other regimens.
A graphic summary of the effect of relevant novel
regimens on duration of therapy in murine models is
shown in figure 8. However, when developing
regimens containing two or more new drugs for which
safety data are scarce, special attempts should be made
 The Lancet Respiratory Medicine Commission
to assign causality of adverse events to individual
drugs, and to understand the mechanisms of toxicity.
The proposal to use a new phase 2C trial design,390 which
is a hybrid phase 2/3 study, to accelerate the development
of novel treatment-shortening regimens in drug-
susceptible tuberculosis is equally applicable to drug-
resistant tuberculosis, and is being pursued by several
groups.
Challenges and opportunities for the treatment of
paediatric MDR tuberculosis
Although the second-line antituberculosis drugs are
routinely used for treating paediatric MDR tuberculosis,
all are prescribed off-label and none had been
prospectively assessed in pharmacokinetic studies in
children until recently. These studies391,392 show sub
stantially lower exposures to key second-line tubercu
losis drugs, including levofloxacin and moxifloxacin,
compared with adult target values, indicating con
siderable opportunity for dose optimisation. There are
few palatable, child-friendly formulations of the
second-line antituberculosis drugs, making safe and
appropriate dosing difficult, especially in young
children, complicating adherence, and making both
providers and families reluctant to initiate MDR
tuberculosis therapy for children. The high pill burden
(figure 9) and paucity of child-friendly formulations are
even more challenging in children who are co-infected
with HIV. Available MDR tuberculosis regimens with
existing second-line antituberculosis drugs are long,
often require hospitalisation, and are associated with
frequent and serious toxicity, including permanent
sensorineural hearing loss due to injectable tuberculosis
drugs in up to 24% of children.336 Safer, shorter, simpler,
and injectable-sparing treatment regimens are urgently
needed. Trials investigating such regimens are already
underway in adults.
Children have traditionally been excluded from trials of
novel tuberculosis treatment regimens because of the
perceived low public health significance of paediatric
tuberculosis, a disregard for the significant tuberculosis-
associated morbidity and mortality in children, few
A B
Figure 9: Pill burden for patients with MDR tuberculosis
(A) Pill burden for a child aged 8 years. (B) Pill burden in an adult, including morning dose (left panel) and evening dose (right panel). These photos exclude any
injectable agents, which are usually given in addition to pills, for 68 months intramuscularly without anaesthesia. Images with courtesy and permission of CAPRISA.
330 www.thelancet.com/respiratory Vol 5 April 2017
regulatory incentives, practical challenges of including
children in trials, and scarce commercial incentives.393 For
novel tuberculosis drugs, given proof of efficacy from
phase 2B or 3 trials in adults, the priority for children is
pharmacokinetic and safety studies to establish the optimal
and safe doses in children of different ages and weights. In
parallel to the opening of adult efficacy trials, paediatric
formulations should therefore already be developed to allow
for the clinical assessment of these drugs in paediatric-
appropriate regimens. Considering the extensive clinical
assessment and licensure of the novel drugs bedaquiline
and delamanid in adults with MDR tuberculosis, the rare
assessment of these drugs in children to date represents a
serious neglect of paediatric tuberculosis by researchers.
Delamanid seems to be safe and well tolerated in
children aged 617 years, and with appropriate exposures
achieved using the adult formulation, but very few
controlled data for children have been collected.394 Studies
in younger age groups are ongoing. Paediatric studies for
bedaquiline are ongoing. Such studies are urgently needed
to improve childrens access to trials assessing injectable-
sparing short-course MDR tuberculosis therapy and for
routine care. Paediatric formulations should be developed
and used in these trials.
Summary of new drugs and strategies
The approach of assessing new drugs by comparing them
with placebo added to multidrug background therapy has
identified drugs that are promising candidates for new
regimens. Murine models are used extensively to assess
novel regimens, several of which are now being studied
in phase 2 and 3 clinical studies. Enough new drugs now
exist to enable discontinuation of the use of toxic drugs
with low efficacy, at least for MDR tuberculosis. The
912-month regimen now recommended by WHO for
selected patients with MDR tuberculosis is welcome, but
it includes seven drugs, some of which are quite toxic or
unlikely to be effective (table 8). With the new drugs,
much better regimens can be constructed. Injection-free
regimens of 69 months are highly likely to replace the
problematic drug-resistant tuberculosis regimens in the
medium term. New regimens that are shown to be

effective should be rapidly available to all patients with
drug-resistant tuberculosis, including children and
individuals with HIV co-infection.
Pharmacokineticpharmacodynamic factors in
drug-resistant tuberculosis
A direct association exists between acquired drug
resistance and drug pharmacokinetics181 and is best
explained by use of antimicrobial pharmacokinetic
pharmacodynamic science. Similarly, drug exposures
predict the clearing of viable M tuberculosis from the
sputum.191,395
Capturing pharmacokinetic variability
Each patient treated with a fixed dose achieves a different
concentration-time curve from the next. This difference
between patients is due to differences in absorption,
speed of xenobiotic metabolism, elimination, and volume
of distribution. Evolution, lifestyle habits such as smoking
and diet, and anthropometric factors such as weight,
nutritional state, height, and other immeasurable factors,
are responsible for this between-patient pharmacokinetic
variability. For example, obesity has emerged as a major
driver of pharmacokinetic variability over the past few
decades.396,397 In children, age is an important determinant
of pharmacokinetic variability, based on changes in organ
size and physiological maturation, including that of
enzymes responsible for xenobiotic metabolism.398403
Furthermore, variation exists from day to day in the same
patient, which is termed inter-occasion variability. Thus, a
given dose of a drug (even when given in mg/kg rather
than an absolute concentration) will achieve many
different peak concentrations (Cmax) and area under the
curve (AUC) values, as well as different lengths of time
for which the drug concentration persists above the
MIC (TMIC). This variability is captured and quantified
in population pharmacokinetic analyses. Therefore,
population pharmaco kinetic parameter values of anti
tuberculosis drugs should be established for each locale
in which the tuberculosis burden is high. The
pharmacokinetic parameters for standard first-line drugs
and for drugs used in both MDR and XDR tuberculosis
are shown in table 9, mainly based on publications from
South Africa, India, and the USA.404416 Predicting what
concentration a patient will achieve is difficult, given the
multiple determinants of pharmacokinetic variability.191
Therefore, to identify the specific concentration-time
profile, the drug concentrations should be measured in
the patient directly.
Pharmacokineticpharmacodynamic indices and
microbial kill versus acquired drug resistance:
fraternal twins
The pharmacokineticpharmacodynamic exposure is the
drug concentration at a site divided by the MIC. This
calculation is based on the fact that the drug concentration
(Cmax or AUC) achieved as well as the MIC will affect how
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The Lancet Respiratory Medicine Commission
well an antibiotic kills M tuberculosis. M tuberculosis MICs
for antibiotics are variable, and have a distribution. Thus,
commonly used statements that specify a typical MIC do
not reflect the distribution of susceptibility to a particular
drug.210,417 As a result of this MIC distribution and the
pharmacokinetic variability, when patients are given the
same dose of antibiotics, wide distributions of Cmax divided
by MIC, AUC024 divided by MIC, and TMIC are achieved in
different individuals. Since it is difficult to guess the
effect of such distributions from patient to patient, the
drug concentration and MIC should be measured in each
patient to establish the exact exposure achieved.
The associations between pharmacokineticpharmaco
dynamic exposure and microbial kill or acquired drug
resistance were first established using preclinical models
such as the hollow fibre system, murine models,
and guineapig models. Since the pharmacokinetic
pharmacodynamic relationships are intrinsic to the inter
action between bacteria and different drug exposures, the
relationships are invariant, and follow the exposure
response curves shown in figure 10A, on the basis of an
inhibitory sigmoid maximal effect (Emax) model. The
model has four parameters: 1) the effect without any drug
treatment; 2) Emax; 3) the exposure associated with 50% of
Emax (EC50); and 4) the slope on the steep portion of the
curve (Hill factor). This relationship can be translated
from preclinical models to humans. In some models
these data have been found to accurately forecast
therapeutic events with 94% accuracy.183,421425 The
bactericidal effect of isoniazid is an example that has
been shown in several preclinical models and patients
(table 10).421 The pharmacokineticpharmacodynamic
exposure patterns or indices important in preventing
or amplifying acquired drug resistance have been
established for several agents in preclinical models, and
at least in the case of first-line antituberculosis drugs and
quinolones, they have been validated in clinical
studies.380,426,419 Table 11 shows the pharmacokinetic
pharmacodynamic exposure and pharmacokinetic
pharmacodynamic index associated with the suppression
of acquired drug resistance for several drugs that are used
in clinical practice; these often differ from those
associated with opti mal microbial kill for the same
drug.173,180,191,192,196,380,395,417,419431 Mistakenly, many regi
mens
were designed for the treatment of tuberculosis with a
focus on microbial kill, ignoring the problem of acquired
drug resistance. The theory was that directly observing
the patients swallowing the pills, and using one drug to
prevent resistance to another, would solve the acquired
drug resistance problem.192 As a result, MDR and XDR
tuberculosis developed. Each drug in a given combination
will need optimisation for both microbial kill and
acquired drug resistance, which can be achieved with
awareness of pharmacokinetic variability, followed by
understanding the relationship between pharmaco
kinetics and pharmacodynamics, and pharmacokinetics
and acquired drug resistance.
 The Lancet Respiratory Medicine Commission

Age range Total clearance in L/h Central volume in Absorption constant

(interindividual L (interindividual per h (interindividual
variability) variability) variability)
Children
Isoniazid404,405 (n=191; India)* Younger than 15 years 78 (678%) 52 (343%) 08 (648%)
Rifampicin404,405 (n=191; India) Younger than 15 years 110 (1300%) 218 (170%) 11 (1260%)
Pyrazinamide404,405 (n=191; India) Younger than 15 years 13 (419%) 128 (484%) 25 (772%)
Ethambutol406 (n=31; South Africa) Younger than 15 years 206 (2961%) 135 (157%) 17 (1235%)
Linezolid407 (n=100; USA), full term (per kg) Full-term birth to 031 (220%) 066 (290%)
28 days
Linezolid407 (n=100; USA), infants (per kg) 28 days to 3 months 032 (320%) 079 (270%)
Linezolid407 (n=100; USA), child (per kg) Aged 3 months to 023 (530%) 069 (280%)
11 years
Moxifloxacin408 (n=23; USA), infants (per kg) 01 years 035 (270%) 223 (3135%)
Moxifloxacin408 (n=23; USA), toddlers (per kg) 14 years 026 (2434%) 161 (2293%)
Moxifloxacin408 (n=23; USA), school age (per kg) 49 years 025 (3687%) 208 (3337)
Adults
Isoniazid409 (n=235; South Africa) 18 years or older 216, fast acetylator 577 (165%) 185
(184%); 97, slow
acetylator (184%)
Rifampicin410 (n=261; South Africa) 18 years or older 192 (528%) 532 (434%) 115 (663%)
Ethambutol411 (n=189; South Africa) 18 years or older 399 (20%) 824 05 (39%)
Pyrazinamide397 (n=227; South Africa) 18 years or older 34 292 356, fast absorbers
125, slow absorbers
Linezolid412 (n=455; Japan, USA) 18 years or older 13 (466%) 470 (259%) 06
Moxifloxacin300 (n=241; South Africa) 18 years or older 106 (186%) 114 15 (699%)
Levofloxacin413 (n=272; USA) 18 years or older 93 (465%) 648 (513%)
Bedaquiline414 (n=480)|| 18 years or older 278 (504%) 164 (391%)
Para-aminosalicylic acid415 (n=73; South Africa) 18 years or older 94 (475%) 518 (748%)
Amikacin416 (n=88; Belgium)** 18 years or older 22 (719%) 192 (390%)

Values for which there is no inter-individual variability published have no percentage indicated. The clearance and central volume in children are expressed as per kg because
children's weights change rapidly and regularly. =not estimated. *Isoniazid intercompartmental clearance in children was 154 L/h (169%), and volume of peripheral
compartment 75 L (210%); Isoniazid intercompartmental clearance in adults was 334 L/h (931%), and volume of peripheral compartment 1730 L. Ethambutol
intercompartmental clearance in adults was 343 L/h, and volume of peripheral compartment 623L. Slope of effect of weight on clearance (per kg) was 005; slope of effect of
weight on volume (per kg) was 043. Linezolid intercompartmental clearance was 21 L/h (329%), and volume of peripheral compartment 898 L. ||A 4-compartment
disposition model. **Amikacin intercompartmental clearance was 43 L/h (165%), and volume of peripheral compartment 93 L (34%).

Table 9: Pharmacokinetic parameter estimates and variability of antituberculosis agents in adults and children

The relationship between the pharmacokinetic
pharmacodynamic exposure and acquired drug re
sistance is described by a system of quadratic functions
(figure 10). This U-shaped relationship, first described in
hollow-fibre models for isoniazid and pyrazinamide for
M tuberculosis, has since been identified with other
antibiotics in their relationships with other mycobacteria,
including M abscessus.432,433 For M tuberculosis, the
relationship between exposure and the bacterial burden
of the drug-resistant subpopulation forms a U-shaped
curve early during therapy (figure 10). As drug exposure
increases (eg, as Cmax/MIC increases) there is a pro
gressive decrease in the size of the drug-resistant
subpopulation, indicating suppression of acquired drug
resistance. However, a point is reached that as exposure
increases the drug-resistant subpopulation begins to
increase again, then as therapy duration increases, the
curve starts to flatten, eventually flipping into an inverted
U-shape. Thus, as drug exposure increases from zero,
amplification of the drug-resistant subpopulation
occurs. This amplification of the drug-resistant sub
population reaches a point after which increases in
exposure lead to a decrease in the size of the resistant
population, eventually to zero. That drug concentration
or exposure, which is associated with a zero size of drug-
resistant subpopulation, is the target for suppression of
acquired drug resistance. However, with increasing
duration of therapy at concentrations below this point,
acquired drug resistance is amplified and a high level of
drug resistance is established that cannot be overcome
with any achievable drug exposures. Thus, acquired
drug resistance is determined by both pharmacokinetic
pharmacodynamic exposure and duration of therapy;
longer is not necessarily better. Thus, in dosing to

332 www.thelancet.com/respiratory Vol 5 April 2017

 The Lancet Respiratory Medicine Commission

suppress acquired drug resistance, it would be necessary
to achieve the pharmacokineticpharmacodynamic
exposure that suppresses resistance (ie, target con
centration) but delivered for shorter durations that mini
mise resistance. The idea of increased drug resistance
with longer therapy duration is counterintuitive, because
in clinical practice the tendency is to lengthen therapy
duration to improve outcome.
therapeutic drug monitoring could be used to ameliorate
concentration-dependent toxicity, for example with
aminoglycosides, many second-line drugs, and even new
antituberculosis compounds. For example, Modongo
and colleagues456 examined the main determinants of
amikacin ototoxicity and identified them to be an
amikacin cumulative AUC of 87232 days per mg/h/L,
a patient weight of less than 51 kg, and duration of

The importance of drug penetration to the infection site

A
Antituberculosis drugs are administered at a site that is 9
remote from the infection that is being treated, so whether 8
antibiotics are administered orally, intramuscularly, or
7
intravenously, they need to reach infections in different Maximal kill (Emax)
M tuberculosis log10 CFU/mL

anatomical compartments. The physical barriers to drug 6

transit toward the site of infection include the normal 5

histopathology of the infected organ, physiological 4
barriers such as the bloodbrain barrier, and the 3 EC80
pathological lesion such as a lung tuberculosis cavity that
2
has layers of different cells and tissues. The concentration-
time profiles that M tuberculosis will be exposed to are 1

defined by these barriers; these local profiles will either 0

0 25 50 75 100 125
kill the M tuberculosis, amplify acquired drug resistance, AUC/MIC
or suppress acquired drug resistance. Antituberculosis
B
drug penetration indices into the lung cavity,434,435 macro 7 t1
phages,428,401,433 epithelial lining fluid,437443 bone,444,445 the t2
t3
pericardial space,194 and the meninges are shown in 6
M tuberculosis burden log10 CFU/mL

table 12.446455 In 2016, Dheda and colleagues193 showed that 5

entry into the human tuberculosis cavity leads to a
concentration gradient map, and they directly linked this 4
gradient to the MICs (and hence resistance) in the
3
different parts of the lung cavity for several
antituberculosis drugs that patients were taking.193 2
Studies are ongoing that aim to associate this drug
1
penetration at the site of infection to more accessible
drug concentrations in media such as the serum, to allow 0
for better therapeutic drug monitoring. However, the 0 10 20 30 40 50

clinician will have to choose drugs that penetrate a Drug exposure (AUC/MIC or %TMIC or peak/MIC)

particular site of infection (eg, pericardial fluid), and not

simply copy the regimen that works in one site for
another site (table 12).
Therapeutic drug monitoring
Three main aims exist for therapeutic drug monitoring.
First, drug concentration measurements should be used
to individualise the dose to achieve optimal exposures in
patients, giving them a better possibility of cure. This
measurement is especially important in patients with
comorbid conditions associated with worse tuberculosis
outcomes, such as immunosuppressed patients or those
with diabetes. Ideally, if resources permit, then specific
measurements should be done in all tuberculosis
patients, as is already the case in several countries.
Second, therapeutic drug monitoring could be used to
suppress resistance emergence, especially for those
drugs whose mutation frequencies have weak barriers to
acquired drug resistance. Third, implementation of
Figure 10: Microbial kill and acquired drug resistance versus exposure
(A) The inhibitory sigmoid Emax curve for the relationship between drug exposure
(linezolid AUC/MIC in this case) and the total bacterial population, modelled from
receptor theory. At low exposures, no change in effect is seen with large exposure
changes, until the exposure reaches an inflection point. After that, small exposure
changes result in large changes in effect, with steep bacterial burden decline.
An inflection point is eventually reached, probably because most target sites are
occupied by the antibiotic. Increased exposure does not result in much change in
effect beyond that. Adapted from Deshpande and colleagues.418 (B) System of
quadratic functions explaining the size of the drug-resistant subpopulation with
time versus exposure, based on the model by Gumbo and colleagues.419,420 At time
t1, there is a decline in the size of the resistant subpopulation with increasing
exposure, until a nadir is reached after which, paradoxically, increasing exposure
leads to an increase in the drug-resistant subpopulation towards baseline. This
shows suppression of acquired drug resistance over time. As the duration of
therapy increases, the graph straightens and then flips, so that at t2, the
relationship is opposite, indicating resistance amplification. However, at high
exposures, resistance is suppressed below baseline. As the duration of therapy
increases beyond that, the descending arm straightens out, and no amount of drug
exposure can suppress the acquired drug-resistant subpopulation. AUC=area under
the curve. CFU=colony-forming units. EC80=80% of maximum efficacy.
Emax=maximum efficacy. MIC=minimal inhibitory concentration. TMIC=length of time
for which the drug concentration persists above the MIC.

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 The Lancet Respiratory Medicine Commission

therapy of 166 days. Peak and trough concentrations a good strategy is intermittent dosing with these targets,
were not predictive of ototoxicity. These observations with identification of both Cmax and AUC during the
were also made in carefully planned amikacin first week to calculate the duration of therapy upfront in
experiments in guineapigs based on audiometry:457 order to avoid the cumulative AUC of 87232 days
cumulative AUC was associated with hearing loss but per mg/h/L that is associated with toxicity. In this
not peak or trough. By contrast, a Cmax more than 67 mg/L scenario, the practice of also measuring trough
and a Cmax/MIC more than ten were identified as the concentration would be abandoned. Another potential
drivers of amikacin efficacy in tuberculosis.417,431 Thus, drug for therapeutic drug monitoring and MIC identifi
cation could be pyrazinamide, especially when used for
patients with MDR tuberculosis. For pyrazinamide
Hollow fibre Mouse Guineapig Human patients
treatment, exposures and MICs are the major
EC50, AUC024/minimal inhibitory concentration 62 28 63 823 215 (13 mg/kg)* determinants of clinical outcomes. Accounting for both
Hill slope 09 04 10 16 13 10 04 the pyrazinamide exposures and actual MIC in each
Emax (as early bactericidal activity), log10 CFU/mL 09 02 06 01 patient is crucial since the much lower proposed
r for inhibitory sigmoid Emax regression 097 083 099 095 susceptibility breakpoint of 50 mg/L means that many
patients will probably have isolates naturally resistant to
Hill slope is the slope on the steep portion of the inhibitory Emax curve. AUC=area under curve. Emax=efficacy. =data not
available. *EC50 given as mg/kg dose. Adapted from Pasipanodya and Gumbo426 and Gumbo and colleagues.419 pyrazinamide. Furthermore, many patients might not
achieve the serum AUC/MIC ratio of 113, which has
Table 10: The invariant relationship between isoniazid exposure and microbial effect in different disease
been associated with optimal sterilising effect.191,213,395
models and patients
Increasing the pyrazinamide dose would of course entail

Microbial kill Acquired drug resistance

Preclinical models Clinic Preclinical models Clinic
Isoniazid AUC024/MIC AUC024; Cmax AUC024/MIC; Cmax/MIC AUC024/MIC; Cmax/MIC
Rifampicin Cmax/MIC; AUC024/MIC Cmax; AUC024 Cmax/MIC; AUC024/MIC Cmax/MIC
Ethambutol Cmax/MIC; AUC024/MIC Cmax/MIC %TMIC
Pyrazinamide AUC024/MIC AUC024/MIC; AUC024 %TMIC
Moxifloxacin AUC024/MIC AUC024/MIC AUC024/MIC
Linezolid AUC024/MIC
Amikacin Cmax/MIC Cmax; Cmax/MIC
Thioridazine Cmax/MIC Cmax/MIC
Pretomanid %TMIC %TMIC

Pharmacokineticpharmacodynamic exposures are given as ratios of AUC and Cmax to MIC and are associated with microbiological kill as well as with acquired drug resistance
suppression. Pharmacokineticpharmacodynamic paramaters identified in preclinical models are compared with those observed in patients in the clinic. MIC=minimal
inhibitory concentration. Cmax=peak concentration. AUC024=24-h area under the concentration time curve. TMIC=percentage of time in the 24 h during which concentration
persists above MIC.

Table 11: Antimicrobial pharmacokineticpharmacodynamic parameters linked to microbial kill and resistance suppression

Cerebrospinal fluid446455 Pericardial194 Bone444,445 Lung cavity434,435 Epithelial lining Intracellular

fluid437443 404,418,436

Rifampicin 003 060 00:005:05* ~20 034 8808

Isoniazid 08 090 00:001:04* 1232 4017
Pyrazinamide 10 103 00:003:02* 1722 2689
Ethambutol 04 065 11 1121
Moxifloxacin 0304 08 50 320
Levofloxacin 07 08 133 1435 58
Linezolid 10 11 1133 01507
Amikacin 03 014030 007
Bedaquiline 0

=data not available. *Bone-to-serum ratio for foci inside sclerotic wall: sclerotic wall of vertebrae: other apparently abnormal bone. Single-point sampling, not AUC or Cmax,
thus could be subject to hysteresis. Estimated from published graph of caseum-to-plasma ratio at steady state by Prideaux and colleagues.434 Pericardial fluid in tuberculosis
pericarditis had pH 734 (thus pyrazinamide might not work), and a protein 61 g/L which would bind most rifampicin.

Table 12: Tissue-to-serum penetration ratio for drug AUCs

334 www.thelancet.com/respiratory Vol 5 April 2017


closer follow-up of adverse events, and frequent liver
function tests.
Summary of pharmacokineticpharmacodynamic
factors
Given the pharmacokinetic variability and the variability
of MICs in patients, drug exposures that could lead to
acquired drug resistance and therapy failure could be
achieved. More data about drug exposure targets that
would minimise therapy failure is available. Most data
about acquired drug resistance was collected from
preclinical models,380,419,420,426431 except for one analysis of
clinical studies in which all acquired drug resistance was
preceded by low drug concentrations.191,426 Drug con
centrations are also likely to be lower than the optimal
concentration in some anatomical compartments, such as
the meninges and pericardial fluid, because of poor
penetration of drugs into those compartments. Thus, to
choose the most effective therapy for different anatomical
locations, having an idea of drug penetration indices is
crucial. The research agenda should involve examining
the penetration of alternative antibiotics for sites such as
the pericardial fluid in which rifampicin, ethambutol, and
pyrazinamide do not achieve high enough concentrations
to be effective. Therapeutic drug monitoring targets must
be those that were derived to optimise patient response,
and to minimise toxicity. Work still needs to be done to
validate concentration targets associated with suppression
of acquired drug resistance in patients, using knowledge
garnered from preclinical models.
Prevention and containment of transmission of
highly drug-resistant (MDR and XDR)
tuberculosis
Managing patients with highly drug-resistant tubercu
losis is a rigorous process, so prevention of these
infections is a far better option than treatment. Therefore,
health-care delivery systems are crucial in ensuring that
treatment of tuberculosis is effective, thereby preventing
the emergence of drug resistance (panel 9). A full
discussion of the effect of health-care delivery systems
(private, public, inpatient, ambulatory, community-
based, vertical, integrated) on the prevention of MDR
tuberculosis is beyond the scope of this Commission;
however, here we will discuss interventions that aim to
prevent the generation, transmission, and reactivation of
highly drug-resistant tuberculosis.
Sources of drug resistance
Mutations in M tuberculosis that confer drug resistance can
be acquired through several processes. These drug-
resistant bacilli can then be transmitted from an infectious
patient to another person.459 Knowing the relative
contributions of acquired drug resistance and person to
person transmission to the burden of drug-resistant
tuberculosis is crucial to target setting-specific tuberculosis
control measures. For example, if most drug resistance is
www.thelancet.com/respiratory Vol 5 April 2017 335
The Lancet Respiratory Medicine Commission
Panel 9: Effective treatment: the role of health-care
delivery systems
Community-based treatment of drug-susceptible and
drug-resistant tuberculosis is more likely to be effective
because of better adherence and cost-effective because of
reduced hospital admissions thus preventing both the
emergence of MDR tuberculosis and its transmission
Successful community-based programmes have credited
various key features, including the employment of paid
and trained community members (rather than
volunteers)eg, in Cambodia, Haiti, Peru, and Rwanda
together with incentives and enablers such as food
baskets, transportation vouchers, telephone credits,
contracts, bonds, cash payments, and patient support
groups
Community-based programmes have been shown to be
as effective or more effective than hospitalisation, and
their cost is 3370% less458
Unfortunately, with insufficient beds and resources for
the growing numbers of patients with MDR tuberculosis,
some programmeseg, those in South Africahave
rapidly transitioned from hospital-based care, without
first building the community-based infrastructure that is
needed to assure treatment success
acquired, interventions to correct pharmacokinetic mis
match, promote adherence, and return patients to
treatment with quality-assured drugs, are more likely to be
effective. However, if most drug-resistant tuberculosis is
transmitted (figure 11), interventions to rapidly reduce the
infectiousness of patients (eg, by active case finding, rapid
diagnosis, prompt and effective treatment, and trans
mission control interventions) are required. Molecular
epidemiology studies in high-burden settings have shown
high degrees of strain clusteringwhich is indicative of
transmission rather than acquisitionin the majority of
known MDR tuberculosis cases and a significant
proportion of XDR tuberculosis cases.83,119 Indeed, the
proportion of drug-resistant tuberculosis cases that are
new tuberculosis cases, and hence have not had an
opportunity to acquire resistance, has increased and is up
to 80% in some settings.460 Some previously treated
patients assumed to be due to acquired drug resistance,
would likely be attributed to transmission if molecular
typing were more widely available. Furthermore, a recent
mechanistic mathematical modelling approach42 based on
WHO prevalence data estimated the proportion of MDR
tuberculosis due to transmission in different settings.42
Although the transmission-attributable fraction varied
widely from 48% in Bangladesh to 99% in Uzbekistan,
with the remainder probably being driven by acquired
resistance, this model furthers underscores the importance
of interrupting MDR tuberculosis transmission to prevent
new cases. For several years, it has been established that
only 20% of patients with MDR tuberculosis are given
 The Lancet Respiratory Medicine Commission
100
Proportion of retreatment cases of tuberculosis that are MDR (%)
75
50
25
% of incident MDR tuberculosis that results from transmission
0 25 50 75
0 on the speed of diagnosis and effective treatment for the
0 22 47 10 20
Proportion of new cases of tuberculosis that are MDR (%)
Figure 11: Proportion of cases of MDR tuberculosis that arise by transmission
Drug-resistant tuberculosis can spread by acquisition, but the majority of incident MDR tuberculosis is caused by
person-to-person transmission. The graph shows modelling data estimating the proportion of incident MDR
tuberculosis that is due to transmission, on the basis of WHO estimates. Acquired rates of resistance are only high
when the ratio of MDR prevalence in retreatment versus new cases is high (red and yellow). The prevalence of MDR
tuberculosis estimated by WHO (area demarcated with the dashed black line) suggests that the vast majority of
global MDR tuberculosis is caused by transmission (purple). MDR=multidrug resistant. Adapted from Kendall and
colleagues.42
effective treatment (and less than half of these successfully
treated), and thus the infectious pool of patients with
undiagnosed, often unsuspected, drug resistance will
continue to grow unabated. Estimating the burden due to
ineffective or poorly adherent treatment is further
complicated by data that suggest that approximately 1% of
patients will still acquire resistance despite having
uninterrupted treatment.181 Additionally, the association
between treatment effectiveness (which can vary widely)
and the degree of acquisition of drug resistance is not well
understood.
Importance of unsuspected drug resistance
Tuberculosis transmission commonly and efficiently
occurs in congregate settings from patients with
unsuspected or undiagnosed drug-resistant disease,
people not on therapy at all, or those on inadequate
treatment.461,462 For example, in Tomsk, Russia,
Gelmanova and colleagues463 reported a six-times greater
risk of MDR tuberculosis for drug-susceptible, adherent
patients with a history of hospitalisation compared with
drug-susceptible, adherent patients treated entirely on an
ambulatory basis. Commonly in Russia and around the
world, patients diagnosed by sputum smear or radi
ography are treated for drug-susceptible tuberculosis in a
room with many other patients with tuberculosis. In
many regions of the world, drug susceptibility testing is
only ordered when patients fail to clinically respond to
336 www.thelancet.com/respiratory Vol 5 April 2017
treatment, with long delays in obtaining results using
culture-based conventional methods. Commonly, MDR
tuberculosis is recognised several months into treatment,
and then effective treatment started, but during those
months MDR tuberculosis transmission and re-infection
of other patients and staff can occur. With the increasing
use of Xpert MTB/RIF and other rapid molecular
diagnostic tests, exposure to patients with unsuspected
tuberculosis or unrecognised MDR tuberculosis can be
substantially reduced. In a tuberculosis hospital in
Veronesh, Russia, 932 patients with suspected pulmonary
tuberculosis were hospitalised from May, 2013, to
March, 2014; 923 underwent Xpert MTB/RIF testing, of
whom 863 (935%) were tested within 2 days of
admission. 407 (44%) of 923 that underwent testing were
positive for tuberculosis; of these, 161 (40%) were
rifampicin-resistant, of whom 159 (99%) were started on
MDR tuberculosis treatment within three working days
100 of receiving the result. An initiative to refocus attention
30
purpose of transmission control has been branded FAST:
Find cases Actively, Separate, and Treat effectively.464
Following the widely publicised and high-mortality
outbreak of XDR tuberculosis at the Church of Scotland
Hospital in KwaZulu-Natal, South Africa, a series of
similar targeted interventions have dramatically reduced
transmission in the hospital and in the community.
Insights into the effect of treatment on transmission
using the guineapig and cough aerosol sampling
models
Once diagnosed and started on effective treatment,
another important practical issue is how long patients
remain infectious. How long, if at all, do patients with
MDR tuberculosis require isolation or separation in
hospital, and do they actually require hospitalisation for
transmission-control purposes? On the basis of house
hold contact studies, Rouillon and colleagues465 in 1976
first proposed 2 weeks of effective treatment as the
minimum duration necessary to render tuberculosis
patients non-infectious. The authors emphasise that
most patients are not smear-negative or culture-negative
after 2 weeks (converting, on average, at about 2 months),
concluding that smear and culture predicted patient
infectiousness before the onset of effective therapy, but
not once started. Three human to guineapig natural
transmission studies spanning more than 50 years on
three continents all found that transmission occurred
almost exclusively from patients not on effective therapy.
The original Riley study466 found that the 98% reduction
in infectiousness from patients with drug-susceptible
tuberculosis occurred almost immediately, since treat
ment was started only on hospital admission, not 2 weeks
before. Since then, in South Africa, Dharmadhikari and
colleagues467 found transmission only from patients
with unsuspected XDR tuberculosis who were in
adequately treated with MDR drugs rather than those
 The Lancet Respiratory Medicine Commission

patients that received effective treatment. In their study,

A B
more than a hundred patients with MDR tuberculosis
just started on effective therapy were exposed to hundreds
of sentinel guineapigs. 27 patients without molecular
mutations for XDR tuberculosis and given effective
treatment infected just one guineapig over 3 months,
suggesting the effectiveness of MDR treatment in halting
transmission.
By contrast, Fennelly and colleagues468 cultured bacilli
from captured cough aerosol sampling using novel
apparatus (figure 12), and found that aerosol cultures in
four patients with MDR tuberculosis who were on
effective treatment declined exponentially and much

2016 American Thoracic Society

faster than sputum smears or cultures. However, aerosol
cultures in one patient remained positive for up to
3 weeks, suggesting the potential for transmission. These
data raise concerns, because cough aerosol cultures of
M tuberculosis have been found to be the best predictors of
recent infection in contacts of untreated patients and Figure 12: Cough aerosol sampling system
have also been associated with incident disease in View inside of chamber with two Andersen cascade impactors and settle plate (A), and set-up in procedure room
contacts. Thus, once a patient is on antimycobacterial ready for use (B). Reprinted with permission of the American Thoracic Society.
therapy with an appropriate threshold of effective drugs
(ie, drugs to which the isolate is susceptible), the sputum
smear for acid-fast bacilli is not a good marker of
infectiousness.
Following current national guidelines, many hospital
infection control practitioners assume infectiousness
while sputum remains positive by smear or culture,
resulting in prolonged isolation or hospitalisation, with
important resource implications for the inpatient
management of drug-resistant tuberculosiseven as
ambulatory and community-based treatment expands
globally. Some studies469 show that patients on effective
therapy based on rapid drug susceptibility testing require
little, if any, added precautions. They can be treated at
home or in the hospital and do not require isolation.
Other studies470 have indicated that despite effective Figure 13: Germicidal UV fixture and air mixing fan
therapy, patients with positive sputum smears or positive A hospital in South Africa. The upper-room germicidal UV fixture can be seen
cough aerosol cultures might pose a risk of transmission. on the back wall (another similar fixture is offset from centre on the opposite
wall) and a centre mounted low-velocity air-mixing fan can be seen on the
However, to our knowledge, there are no reports of ceiling.
transmission to contacts by patients with tuberculosis
who were on effective therapy. In the absence of a broad because it is widely available in areas with suitable
consensus on this important question, it remains an climates, and presumably much more sustainable than
important topic for additional research, including the the alternative engineering strategies such as mechan
effect of newer drugs on XDR tuberculosis transmission. ical ventilation, germicidal UV air disinfection, and air
filtration (room air cleaners). Little high-level evidence
Environmental controls exists to support any tuberculosis infection environ
Although rapid diagnosis and effective treatment are the mental control interventions. Although natural venti
most effective means to stop transmission, not all cases lation should be the centrepiece of environmental
of tuberculosis will be rapidly diagnosed and treated, control strategies, it has its limitations. Many buildings
even with active case finding. Traditional environmental have not been designed for effective natural ventilation,
control strategies and respiratory protection have a role wind direction and speed are usually unpredictable,
in reducing the risk in congregate settings, especially in windows are often closed on cold nights even in tropical
emergency rooms, general medical and specialty areas, or temperate climates, and access to outdoor waiting
and non-medical settings, such as jails and prisons. areas might not be feasible in many urban settings.
In the WHO tuberculosis infection prevention and Natural ventilation cannot be used in very cold climates,
control guidelines,471 natural ventilation is emphasised and even in hot climates, windows are often closed as

www.thelancet.com/respiratory Vol 5 April 2017 337

 The Lancet Respiratory Medicine Commission
split-system cooling is increasingly introduced for
comfort. If available, mechanical ventilation systems in
high-burden settings often simply cannot be maintained
by most hospital engineering staff because they do not
have the expertise or targeted resources. Room air
cleaners are attractive to hospital administrators, but
are often oversold, and invariably undersized in terms
of clean air delivery rateusually producing no more
than a fraction of one equivalent room air change per
hour (ACH) when tested in situations in which
612 ACH are recommended. Another option is upper-
room germicidal ultraviolet air disinfection with air
mixing, which, unfortunately, has usually been poorly
applied and poorly maintained (figure 13). However, of
the three technologies available to supplement or
replace natural ventilation (at night, for example),
germicidal ultraviolet air disinfection holds the greatest
potential for sustainable effectiveness. Some studies472,473
have shown effectiveness under experimental hospital
conditions in Peru and South Africa, and recent
advances in dosing and fixture technology and
maintenance strategies promise wider use of this
highly cost-effective interventionespecially as LED
technology eventually replaces conventional low-
pressure mercury lamps and fixtures, with the potential
for solar and battery power.
Respiratory protection
The third and final recourse in the transmission control
hierarchy are personal respirators, which are tight-fitting
masks designed to protect the wearer from inhalation
hazards. By contrast, surgical masks are loose fitting,
originally designed to prevent the exhalation of infectious
particles onto a sterile field. Surgical masks on patients
were shown to be about 50% effective in preventing
transmission of tuberculosis from people to guineapigs.467
This risk reduction is equivalent to doubling the building
TB-CHAMP
Intervention Levofloxacin vs placebo for 6 months
Design Cluster randomised; superiority;
community based
Target population 05 years regardless of TST or HIV status
Assumptions Levofloxacin decreases tuberculosis
incidence by 50% from 7%; 80% power
Sample size 778 households; 1556 contacts
Sites South Africa
Start of recruitment Open (fourth quarter of 2016)
TST=tuberculin skin test.
Table 13: Planned treatment trials for the prevention of MDR-TB infection. All have a cluster randomised, superiority design targeting household contacts
338 www.thelancet.com/respiratory Vol 5 April 2017
ventilation, so is neither insignificant, nor completely
effective.
The majority of commonly used respirators are the
disposable variety, invariably having at least two elastic
straps and a nose clip to reduce air leakage between the
face and the respirator, which is the major cause of
reduced protection. Optimal protection requires formal
fit testing, and the availability of a variety of respirator
models and sizes to find one that effectively fits the shape
of their face. Fit testing is not often available in high-
burden settings, contributing to respiratory protection of
no more than 7080% for most disposable N95-type
respirators. Again, this is neither insignificant, nor
complete protection. Furthermore, modelling studies474,475
suggest that combining simple disposable respirators
with enhanced air disinfection can lower the risk
substantially. For very high-risk procedures, for example,
for chest surgery, bronchoscopy, or autopsy of patients
with known or suspected MDR tuberculosis, powered air
purifying respirators (PAPRs) can be used, which
increase the protection factor to more than 90% because
the breathing space is under positive pressure. Important
limitations of respiratory protection include that respir
ators cannot be worn continuously, that they are more
likely to be used for known, non-infectious patients with
MDR tuberculosis who are on effective therapy, and are
not worn for unsuspected cases.
Treatment of latent tuberculosis infection
The treatment of latent tuberculosis infection is
considered crucial to global tuberculosis elimination,
and can also have life-saving implications for individual
patients. Targeted contact investigations of MDR
tuberculosis cases could prevent future cases and avert
deaths. In a systematic review and meta-analysis of
household contacts of drug-resistant tuberculosis cases,476
household contacts had a high yield of tuberculosis
V-QUIN PHOENIx
Levofloxacin vs placebo for 6 months Delamanid vs standard dose isoniazid daily for
6 months
Cluster randomised; superiority; Cluster randomised; superiority; community
community based based
TST-positive and paediatric enrolment on HIV-positive; children 05 years
hold TST-positive or interferon gamma release
assay-positive if older than 5 years
Levofloxacin decreases tuberculosis Delamanid decreases tuberculosis incidence
incidence by 70% from 3%; 80% power by 50% from 5%; 90% power
1326 households; 2785 contacts 1726 households; 3452 contacts
Vietnam AIDS Clinical Trials Group and International
Maternal, Pediatric, Adolescent AIDS Clinical
Trials network sites, including Botswana,
Brazil, Haiti, Kenya, India, Peru, South Africa,
Tanzania, Thailand, and Zimbabwe
Open (first quarter of 2016) Fourth quarter of 2017

disease (78%) and latent infection (472%). The majority
of secondary cases occurred within a year of the source
case diagnosis. More than 50% of secondary cases had
drug susceptibility patterns concordant with the source
case, particularly in children, who have greater exposure
in the household than in the community.
Young children (aged <5 years) and HIV-infected
children of all ages who are exposed to a source case with
MDR tuberculosis are at high risk of developing MDR
tuberculosis disease. Although no formal guidelines on
preventive therapy regimens exist, analysis of many
studies477 suggest efficacy and safety of a fluoroquinolone-
based 612-month preventive therapy regimen.478 How
ever, because of the scarce evidence from randomised
clinical trials, WHO does not recommend treatment, but
advises 2 years of follow up for any person who has been
exposed to tuberculosis in the household. Three clinical
trials investigating the use of levofloxacin (TB-CHAMP,
V-Quin) or delamanid (PHOENIx MDR TB/A5300B) for
treatment of child and adult household contacts are
underway or will be starting soon (table 13). Until clinical
trial evidence becomes available, the WHO guidelines
advise clinicians as part of good clinical practice to
consider individually tailored preventive treatment, for
which operational guidelines now exist. Challenges to
treating MDR tuberculosis infection include the few tests
available to identify whether tuberculosis infection is
drug resistant and whether the treatment results in a
cure; adhering to long courses of potentially toxic drugs;
and concerns of generating resistance. In addition to
treatment, an effective tuberculosis vaccine could also
contribute to preventing MDR tuberculosis.
Summary of drug-resistant tuberculosis prevention
We have discussed an unconventional approach to
preventing drug-resistant tuberculosis transmission,
focusing not on patients with identified drug resistance
who are already on effective treatment, but on pre
venting the transmission from patients with un
suspected tuberculosis or unsuspected drug-resistant
disease. We maintain that MDR tuberculosis is best
prevented by earlier diagnosis and more effective
treatment of susceptible and resistant disease, in order
to prevent acquired mutations and to prevent their
transmission. One intensified, refocused administrative
approach to preventing transmission through active
case finding, rapid diagnosis, and prompt effective
therapy (FAST) is reducing exposure duration in
a variety of settings. Preventing transmission in
congregate settings by conventional environmental
control interventions remains important, but wide
spread sustainable implementation proves challenging.
Although natural ventilation can be sustainable, greater
use of rationally applied upper-room germicidal
ultraviolet air disinfection, including new LED tech
nology, should be anticipated. Contact investigations
and preventive therapy have some potential to prevent
www.thelancet.com/respiratory Vol 5 April 2017 339
The Lancet Respiratory Medicine Commission
the reactivation of latent MDR tuberculosis infection,
but evidence to inform policy is needed. Children
exposed to MDR cases are an especially compelling risk
population for the treatment of latent drug-resistant
infection. Health-care workers risk their own lives in
the interest of treating drug-resistant tuberculosis cases,
often themselves becoming infected, and also deserve
consideration for preventive treatment because of their
enhanced exposure.
Patient-centred care for drug-resistant
tuberculosis
The treatment of drug-resistant tuberculosis requires
careful attention not only to the medical aspects of the
disease but also to the psychosocial aspects. A patient-
centred approach to tuberculosis is a central pillar in
WHOs new End TB strategy, and there are multiple For WHO's End TB strategy see
opportunities to enhance this type of care in the treatment http://www.who.int/tb/strategy/
end-tb/en
of drug-resistant tuberculosis, including adherence
support, treatment discontinuation, and palliative care.
The fundamental underpinning of the patient-centred
strategy is a diagnostic and treatment programme that is
grounded in human rights.
Patient-centred adherence support
Successful therapy for drug-resistant tuberculosis requires
patient adherence for the entire treatment course.479
However, drug-resistant tuberculosis adherence is
challenging for many reasons, including the high pill
burden, the frequency of drug-related adverse events, the
lengthy duration of treatment, low efficacy of the regimen,
and the added common burden of HIV co-infection
(panel 1). People with MDR tuberculosis, particularly
those with highly resistant strains, are often hospitalised
for treatment, which increases costs for the health-care
system and the patient, increases the chance of nosocomial
transmission of disease, and also loss to follow-up,
compared with community-based care.480 Although drug-
resistant tuberculosis therapy is still almost always given
as DOT, a recent Cochrane systematic review186 questioned
the effectiveness of DOT. Indeed, some evidence showed
that DOT might actually represent a barrier to adherence
through increased transportation costs, inability to work
or go to school, and discrimination experienced from
health-care providers, other patients, and the community.
The successful decentralisation of drug-resistant
tuberculosis care in Khayelitsha, Cape Town, showed
that improved cure rates could be achieved simul
taneously with the delivery of a more patient-responsive
service closer to patients homes; indeed, much of the
improvement in cure rates was likely to be due to these
patient-responsive services (figure 14 A).481 Programmes
in Lesotho, India, and Peru led by non-governmental
organisations have challenged health services to
recognise different ways, appropriate to the local context,
to manage drug-resistant tuberculosis other than in
hospitals.482
 The Lancet Respiratory Medicine Commission
A
B psychological factors or the denial that is commonly seen
Figure 14: The impact of tuberculosis
(A) Four women living with MDR tuberculosis pictured at a hospital in rural
Bangladesh. The masks they are wearing are to reduce the risk of tuberculosis
spread and are part of an income-generation project for hospitalised patients.
With courtesy and permission of Jennifer Furin. (B) A painting on a store in
Khayelitsha, Cape Town, showing the tremendous impact that tuberculosis has
on this community, and the types of structures that serve as homes and
businesses in this region. With courtesy and permission of Jennifer Furin.
Supporting adherence is therefore one of the most
important aspects of drug-resistant tuberculosis treatment
and might be achievable outside the strict confines of
DOT.483 Counselling and treatment literacy delivered by
trained and paid lay health counsellors or drug-resistant
tuberculosis survivors are crucial.484 Such counselling
should be individualised and include ongoing assessments
of barriers to adherence and strategies for addressing
them, because an individuals ability to adhere can change
over time depending on his or her life circumstances.485
Since many people living with drug-resistant tuberculosis
face other pressing health and social concernsincluding
catastrophic illness-related costsnutritional, economic,
and transportation support are essential for continued
adherence to therapy and in keeping with the WHOs goal
to eliminate such costs by 2020. Peer support groups are
also a key part of patient-centred care.486
The development of drug-resistant tuberculosis was
previously thought to be amplified from drug-susceptible
tuberculosis as the result of inadequate adherence. As
340 www.thelancet.com/respiratory Vol 5 April 2017
a result, patients with drug-resistant tuberculosis were
often labelled as problematic (non-adherent) and sub
sequent management decisions were coloured by this
erroneous perception of patient irresponsibility. Attributing
treatment failure to the behavioural choices of the patient,
without making any effort to address these underlying risk
factors for non-adherence, is both an ethical failure on the
part of the health system and a likely violation of patient
rights (figure 14 B). As recent South African evidence
shows,487,488 drug-resistant tuberculosis is often contracted
via primary transmission and that when amplification is
responsible for the development of drug-resistant
tuberculosis, it is usually due to service and regimen
failings rather than poor adherence.
Nonetheless, some individuals will be non-adherent
even when optimal support is provided, as a result of
in people with serious illness.489 Denial might be more
common in people with drug-resistant tuberculosis,
given the high degree of stigma and discrimination.490
Difficulties in adherence should prompt careful investi
gation of underlying factors associated with non-
adherence, preferably by a multidisciplinary team. If an
individual is unable to adhere after individualised
interventions are attempted, then cessation of treatment
could be considered but must be based on objective
evidence of likely future non-adherence rather than
judgments about patient behaviour.
Patient-centred approach to treatment discontinuation
and palliative care
Deciding when treatment is failing and needs to be
discontinued is not a simple task, given the paucity of
data on the natural course of treated drug-resistant
tuberculosis. A study in the Western Cape province of
South Africa using cohort data from four South African
treatment sites,483 identified criteria for treatment failure,
including duration of uninterrupted treatment for
12 months, three consecutive positive sputa, and a
declining clinical condition. Decisions on treatment
discontinuation should always be made by a multi
disciplinary team, including the individual being treated
and his or her support network.
Treatment discontinuation raises ethical questions
about health risks posed by infectious patients to
household contacts, close family, and to the community
(panel 1). Should such patients be confined involuntarily
to a health facility to protect third parties from infection,
heralding a return to the days of the sanatorium?5 This is
the classic trade-off between the rights of the individual
(to autonomy, freedom of movement, and respect) and
that of the community (to an environment that is not
harmful to health).491 Although forced isolation and
treatment might be a consideration in some settings, this
should only be done as a last resort if there is
demonstrable evidence of the risk of infection to
vulnerable contacts (eg, children or HIV-positive people)
 The Lancet Respiratory Medicine Commission

and after all other treatment and infection control options
have been exhausted.492
Relying on enforced confinement of patients with
drug-resistant tuberculosis that has failed treatment to
achieve control of infection risk to third parties is
problematic for many reasons. Patients might abscond
from confinement, and court orders compelling them
back to hospital are largely ineffective in practice.493
Other methods exist for infection control, including
increasing ventilation in the home and providing
patients with surgical masks, which might be effective
and less invasive of patient rights.494,495 Furthermore,
from a programmatic point of view, focusing solely on
prevention of infection risk late in the course of the
disease overlooks the fact that most transmission
probably occurs before diagnosis in the community.496499
Enforced confinement is a poor strategy to prevent
transmission at a community level, might drive the
epidemic underground, and is not justified as a routine
measure.
Discontinuation of tuberculosis treatment is often
associated with the discontinuation of any form of care,
essentially abandoning the patient when he or she is in
greatest need of palliative care, and contact with the
health system remains essential. Given that palliative
care pertains to the provision of services aimed at
providing individuals with relief from the pain, physical
symptoms, and mental distress that accompany chronic
and serious diseases, palliative care should clearly be
offered to all individuals diagnosed with drug-resistant
tuberculosis. This should include counselling and
psychological support for people living with drug-
resistant tuberculosis and their families, oxygen
therapy, inhaler therapy for reactive airways disease,
aggressive prevention and management of adverse
events, pain control, physical and occupational therapy,
and pulmonary rehabilitation and nutritional support.500
The component of palliative care that includes end-of-
life care is particularly important for patients whose
treatment has failednot only to ensure dignity and
respect for the dying person and that they are able to die
in comfort without pain, but also to restrict the
opportunity for transmission by including infection
control in the palliative care received. In high-burden
settings, the need to strike a balance between inpatient
palliation and palliative care delivered in the home must
be tailored to local conditions. The transmissibility of the
disease might lead to strong feelings of guilt or shame
about the risk to others in the household, where most
people receive end-of-life services, which complicates
end-of-life care for drug-resistant tuberculosis.501 Even
though antiretroviral therapy continuation in co-infected
patients might increase opportunities for drug-resistant
tuberculosis transmission though prolonged survival,
it would be unethical to withdraw antiretroviral treatment
in these patients.
Apart from isolation and natural ventilation,
engineering interventions applicable in congregate
settings, such as germicidal ultraviolet irradiation, air
filtration, or mechanical ventilation, are impractical for
home use and respirators are difficult for family
members to wear continuously. One potentially novel
intervention being investigated to reduce infectiousness
during end-of-life care is the use of the inhaled anti
biotic, dry powder colistin, commonly used for patients
with cystic fibrosis.502

Component Rationale Key elements

Integration with HIV Intensified screening of those with high risk for tuberculosis Integration of tuberculosis screening and treatment with HIV services,
and other services or high risk of poor outcomes; facilitation of seeking care;
coordinated management of multiple medications and
side-effects
Decentralisation Reduces need for hospital beds or other infrastructure,
which can be costly and lead to delayed care or loss to
follow-up; people with tuberculosis can continue working
or other daily activities and still receive care
Supportive health-care People with tuberculosis disease or infection are more likely
system to seek and stay in care if it is provided in a comfortable,
safe environment; an effective health-care system can
reduce many barriers that people with tuberculosis face
with obtaining a diagnosis and completing treatment
Optimal diagnosis and Poor availability of and access to optimal biomedical
treatment interventions nationally and locally contribute to
undiagnosed cases of drug-resistant tuberculosis, lower
cure rates because of less effective or less tolerable
treatment, and increased transmission due to longer
infectiousness and inadequate preventive measures
Supportive environment Many factors outside the health-care system influence a
for addressing persons ability to seek and stay in care; when someone has
tuberculosis beyond the tuberculosis, the health and wellbeing of others around
health-care system them are also affected and need attention
maternal and child health services, and diabetes services (and screening
for and treating diabetes and HIV in people with tuberculosis)
Provision of care close to home where supportive structures are more
likely; strong health-care systems
Sound infrastructure with proper infection control and necessary
resources (electricity, clean water, and medical and laboratory
supplies); professional and respectful clinical and administrative staff;
provision of nutritional or other support; peer support, treatment
literacy training, and counselling
Rapid diagnosis of tuberculosis; drug susceptibility testing to guide
treatment choice; screening, treatment, counselling, and support for
families of people with tuberculosis; effective prevention and treatment
that is safe, tolerable, and easy to complete, and appropriate for all ages;
auxiliary care such as monitoring for and managing side-effects
Education about tuberculosis in communities to reduce stigma and
encourage care-seeking behaviour; infection control in homes, public
spaces, prisons, and schools; improved transportation and
infrastructure to facilitate care seeking

Table 14: Components of optimal care for multidrug-resistant and extensively drug-resistant tuberculosis

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 The Lancet Respiratory Medicine Commission
Panel 10: Patient case histories illustrating the real-world challenges and practical realities of dealing with drug-resistant
tuberculosis in low-resource settings
Patient story 1
KP is a woman aged 27 years who was living in a one-room
shanty home in South Africa with her boyfriend and her
three children, who are aged 3, 6, and 7 years. Her boyfriend
had returned to the household after a 6-month period of
incarceration for petty theft. KP occasionally works selling
sunglasses on the street, but the family struggles to earn
enough to survive.
The familys tenuous situation took a turn for the worse
when KPs boyfriend started coughing up blood. She took
him to the health centre where they tested him for HIV and
tuberculosis, and his HIV test came back positive and the
Xpert MTB/RIF test done on his sputum showed
M tuberculosis with rifampin resistance. He was told by the
nurse he has strong tuberculosis and that he must come to
the clinic daily to take his medication and receive his daily
injection. He and KP were deeply frightened and, because he
was too exhausted to walk, they arranged for a small taxi to
take him to the clinic daily so he could start on his daily
treatment of kanamycin, high-dose isoniazid, ethionamide,
pyrazinamide, moxifloxacin, and terizidone. Unfortunately,
he developed severe nausea and vomiting with the
medication, and everyone in the household feared that he
would die.
1 month after starting this gruelling treatment regimen,
KPs boyfriend went to the clinic but did not return. KP went
to the health centre to find him, only to be told by the nurse
that he was taken to the hospital after additional test results
showed he had killer tuberculosis. The clinic had received a
report that morning from second-line line probe assay
testing that showed additional resistance to both ofloxacin
and kanamycin, and KPs boyfriend was taken to the hospital
for admission, as is required of all patients with XDR
tuberculosis. KP was told that he would probably die and
that the family could not visit him because they might get
sick too. The nurse also told KP that this killer tuberculosis
that her boyfriend had was a result of him not taking his
medication properly, which made KP afraid and
embarrassed.
KPs worry intensified when she herself began to develop a
cough and fever and to lose weight, which she attributed to a
change in the weather and to having less food to eat since
her boyfriend was hospitalised. Understandably, KP was
reluctant to go to the clinic because she was worried that the
nursing sister would scold her again and because she didnt
want to be sent to the hospital, where people only go to
die. However, when her 5-year-old child began to cough and
have drenching nightsweats, she took him to the health
centre. The clinic team examined the child and KP and
diagnosed both of them with tuberculosis on the basis of
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clinical findings, chest radiograph, and Xpert MTB/RIF tests
showing the presence of M tuberculosis and rifampin
resistance.
Her son was taken to the paediatric ward and placed under the
care of physicians there, and the nurse caring for KP noted
during her contact screening questions that KPs boyfriend
had XDR tuberculosis and was worried that KP might have it
as well. The nurse wanted to have KP admitted to the hospital,
but KP refused, reporting that she will have nobody to care for
her other two children. The nurse asked for assistance from
the MDR tuberculosis counsellor working in the clinicwho
herself had survived MDR tuberculosisand the
counsellor and KP spent almost an hour talking. Meanwhile,
the nurse learned that no open beds were available for
women in the MDR tuberculosis hospital and that KP had to
wait to begin therapy until a bed opens, which can take
several weeks.
Given KPs situation, her contact history, and the low availability
of beds, she was offered treatment through a community-based
project that is being run by the National TB Programme in
partnership with a local non-governmental organisation.
The programme uses new drugs to treat people with XDR
tuberculosis, and they were able to start KP on a regimen of
bedaquiline, linezolid, clofazimine, pyrazinamide, high-dose
levofloxacin, pyrazinamide, and terizidone. She was also started
on antiretroviral therapy, because she also has HIV. She received
ongoing support from her counsellor, in addition to taking
treatment daily at the health centre. She also attended a
support group twice a month for people who are on new
tuberculosis drugs.
KP was devastated when she heard her boyfriend had died in
the hospital. This news increased her anxiety for her
two children at home and the one in the hospital, who was
also being treated for XDR tuberculosis. KP has been hoping
that her son too can get one of the new drugs for his XDR
tuberculosis, so her nurse got in touch with the childrens
hospital (KP was unable to visit him because of her own XDR
tuberclosis). However, the drug was not available for children
younger than 6 years or those who weigh less than 20 kg;
and although her son, aged 5 years, weighed 21 kg, he did
not qualify to get the medication because it is only available
straight from the drug company, and not licensed for use in
the country. So KP was told that they screened her son for
participation in a trial of the drug but he did not qualify, and
she did not understand why they could consider her child for
drug testing in the trial, but he cannot get the drug for
treatment. Now all she can do is worry almost about her
other two children, and what might happen if they too
become ill.
(Panel 10 continues on next page)

(Continued from previous page)
Patient story 2
PI is a man aged 32 years, who works in a garment factory
outside of Kolkata in eastern India. He was grateful for the
jobwhich opened when one of his cousins who was
working at the factory died of pneumoniabecause it allows
him to better support his wife, sister, and the five children
they have living with them in an informal settlement on the
edge of town. He usually worked for 16 h per day, 7 days per
week, so he ignored the fatigue and weight loss that he had
had since his second month of work. Only when his incessant
cough caught the attention of his co-workers, was he taken
to the nearby health clinic. The doctor suspected tuberculosis,
and a sputum smear confirmed the presence of acid-fast
bacilli. PIs chest radiograph showed a right upper lobe
cavitary lesion, so he was started on directly-observed
therapy and fired from his job.
PI lived far away from the factory, and the clinic at which he
was diagnosed, and he was deeply ashamed of having
tuberculosis. He confided in his sister who helped him locate
a hospital nearby that he could attend for his treatment. He
reported almost daily for his medications, but occasionally
he found some work picking scrap metal out of a nearby
dump, so could not go to the clinic for his treatment,
because it was only open during his work hours. Despite the
treatment, he continued to cough and lose weight, and after
6 months he was told he had failed treatment and must
start second-line therapy, which includes a daily injection.
During his treatment he couldnt work, and his infant
daughter was hospitalised with malnutrition. His sputum
smears never converted, his treatment was stopped, and an
additional sputum was sent for culture and drug
susceptibility testing.
6 weeks later, a community health worker visited PI at home,
because he could no longer get out of bed, and the family
reported that he coughssometimes with bloodand has
shivers all the time. The family was distraught, because their
infant daughter died 3 weeks before and they were about to be
evicted from their home. The health worker found a taxi and
took PI to the hospital, telling them he had tuberculosis. The
nurse at the hospital contacted his clinic and found out that his
sputum tests showed he has MDR tuberculosis, with resistance
to isoniazid, rifampin, ethambutol, and streptomycin. He was
Patient-centred care and human rights
The problem of drug-resistant tuberculosis is essen
tially a consequence of a systematic violation of human
rights arising from the failure to develop pharma
ceuticals for this neglected disease.503 The unpalatable
decisions forced on health-care providers to stop
treatment or to confine infectious patients with drug-
resistant tuberculosis would not be as pressing had
new drugs been developed for tuberculosis since
rifampicin, the last major tuberculosis drug, which was
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The Lancet Respiratory Medicine Commission
started on a regimen of kanamcyin, levofloxacin, ethionamide,
pyrazinamide, cycloserine, and ethionamide, and admitted to
the hospital. He shared a single bed in an open ward with
17 other men who had also been diagnosed with MDR
tuberculosis.
Initially PI experienced some improvement because he was
given nutritional support along with his medications.
However, after 1 month of therapy he began to hear a
buzzing in his ears, and one morning he woke up completely
deaf. This caused deep depression in PI, and although
psychological support was offered to him, he had trouble
participating since he could not hear and was unable to read
or write.
After 3 months on treatment, PIs sputum cultures became
positive for M tuberculosis once again, and a chest radiograph
showed progression of the disease, with bilateral upper lobe
cavities seen as well as scarring, fibrosis, and near-total
destruction of the right lung. His left lung also had
ulceroinfiltrative disease throughout the upper lobe, and
scarce normal lung tissue remained. Another sputum sample
was sent for culture, and a research study also investigated
the sputum using rapid second-line drug susceptibility
testing. Unfortunately, his sputum sample came back with
resistance to all the drugs tested, including isonizid, rifampin,
ethambutol, streptomycin, amikacin, kanamycin,
ethionamide, cycloserine, ofloxacin, low-dose moxifloxacin,
and para-aminosalicylic acid. In view of this, his physicians
considered starting him on a regimen containing new drugs,
but although bedaquiline was registered in the country, it was
only available at a small number of sites, and none of these
were in Kolkata.
PI was considered a terminal case and the nurses tried to
contact his family to let them know to come and collect him.
However, when the community health worker went to the
familys old house there was nobody there, and the neighbours
told her the family left long ago. The hospital staff were
frightened of catching tuberculosis from PI, and refused to help
him eat or wash. The other patients were also frightened of
him, and he was moved to an isolated corner of the hospital
ward. Eventually, he died in isolation of untreatable
tuberculosis.
licensed in the 1970s. With the recent recognition of the
global tuberculosis crisis and the formation of global
initiatives to accelerate drug development, some new
and repurposed drugs have appeared in the tuberculosis
drug development pipeline. Preliminary studies290,344,376,504
with linezolid, bedaquiline, and delamanid suggests
that they substantially improve treat ment outcomes,
offering hope to patients who would previously have
been considered untreatable. However, without sus
tained investment in the promotion of access to new
 The Lancet Respiratory Medicine Commission
Panel 11: Key messages
Resistance to antituberculosis drugs is a global problem of considerable public health
importance that threatens to derail efforts to eradicate the disease. Advocacy is
needed in national and transnational fora to ensure the urgency of the situation is
understood and that appropriate funding is made available.
Practices for the management of individual patients in settings with a high
tuberculosis burden are not sufficient to prevent the emergence, amplification, and
spread of drug-resistant tuberculosis. These practices include empirical treatment with
standardised second-line drug regimens for people who are found to have
rifampicin-resistant tuberculosis.
Access to drug resistance testing is scarce in most countries and urgently needs to
be expanded to allow curative second-line treatment regimens to be
implemented.
Knowledge regarding the safe useincluding dose and length of treatmentof new
and repurposed drugs must be improved through clinical trials.
Models of care for people with drug-resistant tuberculosis, including
programmatically incurable disease, must ensure that the rights and dignity of
individual patients are respected.
Assessment of the performance, health effects, and potential economic benefits of
molecular tools such as genome sequencing for detecting resistance, must be
accelerated to facilitate effective implementation.
Greater investment is needed in the development of new drugs and diagnostics.
treatments, including shorter regimens with fewer
adverse effects, effective drugs will become scarce again
as resistance develops to the newest treatment options.
Furthermore, even as new life-saving drugs become
available, access to these drugs might be compromised
by cumbersome regis tration processes, highlighting
state responsibilities to ensure optimal access to life-
saving medicines as part of its obligation to realising
the right to enjoy the benefits of scientific progress.505
Summary of patient-centred care
For the individual patient, pursuing the best possible
treatment regimen or keeping a patient on a costly but
failing regimen has opportunity costs and might lead to
fewer available options for other patients with a better
chance of cure if treated early. However, at a pro
grammatic level, the current approach of pro tecting
new drugs from development of resistance has
restricted access to potentially life-saving treatments
when fears of resistance might not be evidence-based.
Increasingly, better treatment is being recognised
earlier in the course of the disease, and will not only
improve individual patient outcomes, but likely
enhance programmatic effectiveness in terms of cure
rates and reduced community transmission. We suggest
expanding models of care, providing comprehensive
packages of support for people who are living with
drug-resistant tuberculosis, to replace any remaining
restrictive tuberculosis delivery approaches. Patient-
centred care for all forms of drug-resistant tuberculosis
must become the norm, linked to community-based
models, with hospitalisation reserved only for those
344 www.thelancet.com/respiratory Vol 5 April 2017
with clinical indications. Access to new shorter
regimens, as recommended by WHO in 2016,281 is
already a reality in some countries, and should be
increasingly common as new tuberculosis drugs
become available, which will help considerably to
alleviate the ethical problem of stopping drug-resistant
tuberculosis treatment that is suspected to be failing.
However, patients who are unable to adhere to
treatment or those whose drug-resistant tuberculosis
cannot be cured require palliative care interventions
from multidisciplin ary teams aimed at maintaining
their dignity while minimising transmission risk. In
the interim, retention of patients with XDR tuberculosis
in care, even if their treatment has failed and cure is no
longer a realistic prospect, is crucial for reducing
community transmission. Develop ment of robust
evidence-based protocols for reducing community
transmission is an important research priority in this
context.
Components of patient-centred and
community-centred care for MDR and XDR
tuberculosis: an advocacy perspective
The weak, vertical, unsupportive approach to treating
MDR and XDR tuberculosis is failing. Of the estimated
480000 new MDR tuberculosis cases in 2014, only 26%
were diagnosed and only 23% were treated.1 People on
treatment suffer from toxic side-effects of drugs, stigma,
and economic loss. About 50% of patients who get
treatment for MDR tuberculosis and 26% of those treated
for XDR tuberculosis are cured. The failure of approaches
to combat tuberculosis can be overcome; through not
only patient-centred but also family-centred and
community-centred approaches to care. We outline the
key components of a framework for ideal MDR and XDR
tuberculosis care, most of which are achievable
immediately (table 14).
Integration: one patient, one file, one health-care worker
Tuberculosis is a leading cause of illness and death in
people who are HIV-positive.506 Initiating antiretroviral
therapy during tuberculosis treatment improves sur
vival;315,317 integrating tuberculosis and HIV care is cost-
effective;507 early initiation of antiretroviral therapy in
people with MDR tuberculosis and HIV substantially
reduces mortality;508 and, in patients with XDR
tuberculosis and HIV, more deaths occur among those
not receiving antiretroviral therapy.509 Despite this
overwhelming supportive evidence and guidelines for
integration, implementation is scarce. Globally, only a
third of people with tuberculosis and HIV receive
antiretroviral therapy.510 Patients with tuberculosis and
HIV who are in care must make multiple visits to health-
care centres and interact with multiple clinicians, which
is challenging for the patient and complicates the
management of adverse effects, dosing, and regimen
adjustments.

2-year goals
Improve knowledge of genetic predictors of resistance to the key
first-line and second-line drugs
Expand current rapid software tools to include all drugs and provide Software tool for predicting resistance and minimum
estimated accuracy data from in-silico validation studies
Develop DNA extraction and sequencing methodology suitable for
routine use in a diagnostic laboratory
Complete studies of the clinical significance of heteroresistance as
detected by molecular methods
Complete epidemiological studies to determine the contribution of
diabetes to drug resistance
Complete intervention studies to assess the effect of different
psychosocial and behavioural interventions on MDR tuberculosis
transmission, progression, and treatment outcomes
Strengthen engagement with civil society and affected community
organisations to ensure research is applicable and accessible to all
those affected by MDR tuberculosis
Complete and launch studies to confirm the efficacy of dispersible
formulations, other dosing strategies, and pharmacokinetic
assessments of the second-line drugs in adolescents and children
5-year goals
Develop and validate technology platforms for assessing genetic
markers of resistance
Initiate economic and health system service delivery studies to
understand how to include genome sequencing technologies
Develop affordable tests that could be used in routine diagnostic
laboratories
Complete pharmacokinetic and pharmacodynamic studies to
determine the contribution of subtherapeutic serum drug
concentrations to the acquisition of drug resistance
Investigate the biological mechanisms by which diabetes
contributes to the emergence of drug resistance
Initiate interventional studies to reduce acquisition and transmission
of MDR tuberculosis in prisons and in other high-risk institutions
Complete studies to determine community and health system risk
factors for spread of drug resistance
Develop and test innovative procedures for personal protection and Strategies for interrupting transmission
sterilisation
Strengthen joint initiatives to explore and assess the contribution
of community groups and faith-based organisations to prevent
emergence and spread of drug-resistant tuberculosis
Assess how targeted drug delivery (to the lung) affects drug
concentrations in the various lung compartments
Undertake interventional studies on enhanced adherence support
strategies, especially those that allow for dignified partnerships
between people living with tuberculosis and their care providers
Complete formal studies on specific psychosocial, nutritional, and
economic strategies that address the links between tuberculosis
and poverty
Develop and test models of integrated care to address medical,
housing, and infection control needs
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The Lancet Respiratory Medicine Commission
Outcome Barriers to achievement
Accurate genetic markers for predicting multidrug and Poor knowledge regarding clinical effect of genetic markers
extensive drug resistance, and pyrazinamide resistance of resistance
Several such tools are being developed but independent
inhibitory concentration values to antituberculosis drugs assessment of their comparative performance and regulatory
from genome sequence data approval have not been done
Methodology for sequencing from clinical specimens Technical challenges might be insurmountable using current
technology
Improved documentation of the significance of Low availability of funding might restrict the geographical
heteroresistance in clinical outcomes spread of data collection
Overview of the effect of diabetes on drug-resistant Low funding might restrict the geographical spread of data
tuberculosis collection
Targeted interventions to address the social and Buy-in from the necessary agencies and stakeholders might
behavioural factors associated with morbidity and be difficult to achieve in some countries. Low funding might
mortality from MDR tuberculosis and the emergence of also restrict the geographical spread of studies; prioritisation
further resistance, including substance abuse of various interventions will need to be done
A research agenda grounded in a human rights approach to Low engagement because of poor communication with civil
preventing, diagnosing, and successfully treating society; input of civil society not valued by tuberculosis
drug-resistant tuberculosis policy makers; insufficient interest (political will) from
service providers in the formal sector
Child-friendly formulations and dosing recommendations Insufficient investment from pharmaceutical companies and
for all second-line drugs, including novel therapeutic agents public or philanthropic funding bodies; regulatory challenges
for drug developers and stringent regulatory authorities;
small market in the paediatric population
Affordable rapid tests for MDR and XDR tuberculosis for use Insufficient financial investment; failure to develop technology
at the point at which care is provided that is considered affordable in low-income countries
Strategies for providing full resistance profiles for patients Failure of countries or donor agencies to use such
with MDR tuberculosis that is also resistant to additional technologies for regimen design
drugs
A test to monitor drug concentrations at the point at which Insufficient financial investment; failure to develop technology
care is provided that is considered affordable in low-income countries
Contribution of subtherapeutic serum drug concentrations Availability of funding
to the emergence of resistance
Improved strategies for managing diabetic patients with Tuberculosis immunology and metabolism in the diabetic
tuberculosis host is not fully understood; availability of funding
Strategies to reduce risk of nosocomial and Insufficient human rights-based approach to tuberculosis
institutionalised spread of resistance transmission in congregate settings; insistence on
hospitalisation for treatment of MDR tuberculosis, XDR
tuberculosis, or use of new drugs; Not enough buy-in from
stakeholders
Strategies to eliminate spread of drug resistance Complicated social networks with migration playing a major
role in transmission; availability of funding
Insufficient investment
Strategies for community involvement for ending Not enough buy-in from stakeholders; low recognition of
drug-resistant tuberculosis the importance of such groups in optimal management of
drug-resistant tuberculosis
Improved strategies for drug delivery Technical difficulties in ascertaining drug concentrations;
failure to attain ethical review approval
Improved strategies for individualised adherence support Buy-in from care providers; failure to identify acceptable
other than directly observed therapy strategies
Support package for patients living with highly Failure to identify effective generalisable interventions;
drug-resistant tuberculosis scarce systems, funding, and will to implement effective
interventions in these areas
Care package for patients living with highly drug-resistant In many countries, tuberculosis control measures are highly
tuberculosis vertical and housing needs might be considered outside the
scope of tuberculosis programmes
(Table 15 continues on next page)
 The Lancet Respiratory Medicine Commission

Outcome Barriers to achievement

(Continued from previous page)
5-year goals
Clinical trials, including safety and efficacy of (i) oxazolidinones
(linezolid, tedizolid, and sutezolid) and (ii) delamanid and
pretomanid in drug-resistant tuberculosis; the optimum dose and
duration of linezolid, moxifloxacin, and levofloxacin for
drug-resistant tuberculosis; phase 3 trial of bedaquiline, delamanid
or pretomanid, and moxifloxacin for drug-resistant tuberculosis;
and phase 3 trial of bedaquiline, delamanid or pretomanid, and
linezolid for drug-resistant tuberculosis (or combinations of the
abovementioned drugs to optimise favourable outcome)
Complete clinical trials and observational studies on post-exposure
prevention of MDR tuberculosis, including clinical trials on the use
of the fluoroquinolones, isoniazid, and delamanid
Continue clinical trials to measure the effect of active case finding
and early treatment of previously undiagnosed MDR tuberculosis
on individual treatment outcomes and transmission
Develop and validate an affordable portable tool for rapid
identification of infectious patients
Launch formal studies on MDR tuberculosis elimination strategies
in multiple high-burden countries, regions, or cities
Continue and report on findings of clinical trials to measure
contribution of new-generation sequencing to personalised
treatment
Implementation policies for novel therapeutic approaches
10-year goals
Continue and expand research and development to identify and
explore new drug targets and potential compounds through basic
science research
Continue and expand the programme of all clinical trials
Launch interventional studies of targeted drug delivery with
optimised doses and drugs levels at the site of disease
Continue to adapt, validate, and adopt new and improved
detection platforms and incorporate new drugs
Complete and analyse early vaccine trials and identify appropriate
candidates to move forward
Scale-up interventions, including treatment of MDR tuberculosis
infection, active case finding, improved management of comorbid
disease, and poverty reduction, which have been pilot-tested at
high-burden sites
Knowledge on safety and efficacy of new drugs, and when
used in novel, injection free, shortened (<12 months
duration) regimens
Strategies to prevent MDR tuberculosis, including
treatment of infection before progression to active disease
Polices to improve case finding and identification of
resistance
A tool to assess infectiousness of individuals
Pilot strategies of comprehensive packages of services that
might be effective in eliminating MDR tuberculosis in
high-burden settings
Implementation policies for new detection technologies
Complete and report on findings of clinical trials of novel
therapeutic regimens
New candidate drugs
An all-oral regimen of less than 12 months duration that
can cure 90% of people with all forms of MDR tuberculosis
Refined treatment algorithms and delivery systems to
provide optimum dosage
Expanded access to resistance testing
Candidate vaccine for large-scale testing in vulnerable
populations
Comprehensive package of services that have been effective Insufficient sustained funding from national governments
in eliminating MDR tuberculosis at selected sites and international donors; poor political leadership in
high-burden countries
Low investment from pharmaceutical companies; insufficient
funding from public and philanthropic bodies; not enough
new trial sites and low capacity or fatigue of existing sites
Few networks able to carry out such trials; regulatory
approvals complicated for preventive therapy; scarce access
to funding
Access to funding; effect of intensified case finding activities
confounded by empirical treatment practices
Failure to develop technology that is considered affordable in
low-income countries
Insufficient funding; not enough involvement of people
outside of public health (eg, mayors or urban planners) who
are key to success
Insufficient funding for studies; scarce use of individualised
care for patients with drug-resistant tuberculosis by National
TB Control Programmes and WHO
Requires acceptance and buy-in from national tuberculosis
control programmes, and for those countries that depend on
donor funding, from WHO and the Global Fund to Fight
AIDS, Tuberculosis, and Malaria
Insufficient investment from pharmaceutical companies and
public or philanthropic funding bodies
Insufficient investment from pharmaceutical companies;
insufficient funding from public and philanthropic bodies;
insufficient new trial sites and low capacity or fatigue of
existing sites
Requires acceptance and buy-in from national tuberculosis
control programmes
Dependent on funding and the emergence and availability of
new drugs
Incomplete understanding of host protective immunity
leading to unsatisfactory vaccine candidates; reduced
funding from public and philanthropic bodies

For drug-resistant tuberculosis to be controlled and eradicated, increased investment is needed in tools for case detection and for developing shortened treatment regimens and drugs with low toxicity. Lists of
such research priorities have previously been published by WHO and STOP-TB Partnership.521,523 In addition, considerable gaps remain in our understanding of the emergence and spread of resistance and how to
interrupt transmission. We highlight here only critical research topics to be addressed and their outcomes. The major challenge facing the goals is access to adequate funding, which reflects the insufficient
political will of some governments and international bodies to resolve this public health crisis. MDR=multidrug resistant. XDR=extensively drug resistant.

Table 15: Research goals and activities with anticipated outcomes and deliverables: a 10-year programme of priority research to control drug-resistant tuberculosis

Integrating diabetes and tuberculosis screening and
management, and tuberculosis screening in maternal and
child health programmes, is also crucial. Integration will
increase detection and survival, and would also reduce
numbers of visits and streamline care for individuals,
which could positively affect adherence and mental
wellbeing.
Decentralisation: take treatment to the people
With centralised MDR tuberculosis care, patients must
travel further to access care, disrupting work and social
life. Decentralisation improves access to treatment
without compromising treatment outcomes and is cost
effective.511515 Successful decentralisation requires
relatively robust health-care infrastructure.516

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Supportive health-care systems: make care-seeking a
positive experience
Supportive health-care systems that create a positive
experience, including physical infrastructure, human
resources, and nutritional support, are important to
retention in care. The environment should be comfortable,
safe, and clean, should have appropriate infection control,
a stable electrical and potable water supply, and
uninterrupted medication and supply stocks.471 Food
supplementation can enhance supportive health care.517
Providers must show commitment, capability, pro
activity, respect for confidentiality, and empathy for
several aspects of the patient experience, including drug
toxicity and the considerable pill burden (figure 9).
Psychosocial support, patient involvement, education,
and treatment literacy are important for good outcomes.518
DOT for tuberculosis is disempowering. Preferential
adherence to antiretroviral therapy over MDR and XDR
tuberculosis treatment might be because antiretroviral
therapy is the patients responsibility; patients receive
education and counselling for antiretroviral therapy and
understand it, whereas tuberculosis notification is
incriminating and XDR tuberculosis is clinically isolating.
Improved diagnosis and treatment
Access to culture, line probe assays, and nucleic acid
amplification testing can greatly improve the scarce
MDR and XDR tuberculosis detection perpetuated by a
reliance on sputum smear microscopy, which has low
sensitivity and is unable to detect drug resistance.
Active case finding by identifying and screening
individuals at riskincluding those with close contacts
with smear-positive tuberculosisnot just people who
present to the health-care system with symptoms,
is essential for early detection and prevention of
transmission.
But merely finding cases is insufficient: rapid initiation
of acceptable, effective treatment must follow. The pill
burden of MDR tuberculosis treatment (figure 9), lengthy
duration, poor tolerability, and inadequate efficacy
contribute to adherence challenges and poor outcomes.
Wider and more effective MDR and XDR tuberculosis
treatment options are urgently needed, as well as
validated MDR tuberculosis prevention options and
child-friendly formulations for the 30000 children who
develop MDR tuberculosis each year.12 Additionally,
improved access to underused drugs such as delamanid,
bedaquiline, linezolid, and clofazimine could improve
outcomes. Screening for hearing loss, nerve damage,
and depression to mitigate toxicities of older drugs, such
as the injectables and cycloserine, can and should be
widely implemented immediately to save lives and
prevent disability.
A holistic approach: creating a supportive environment
Addressing tuberculosis requires a multi-angle approach.
The real-world challenges and practical realities of
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The Lancet Respiratory Medicine Commission
dealing with drug-resistant tuberculosis in low-resource
settings are difficult (panel 10). People with HIV and
XDR tuberculosis report far more stigma and isolation
associated with their tuberculosis than with their HIV
status, which deters health-care seeking.519 Community
education about tuberculosis symptoms and trans
mission should emphasise that the disease can be cured,
and should explain simple infection control strategies
such as ventilation. With increased understanding of and
confidence in preventing disease, we anticipate decreased
stigma. Improved transportation options and roads,
economic opportunities, and uncrowded housing options
can facilitate care seeking, improve overall health, and
reduce transmission.
Summary of community-centred care for MDR and XDR
tuberculosis
With new and repurposed drugs to treat tuberculosis,
improved diagnostic tests, and more research underway,
progress is being made in addressing the clinical drivers
of MDR and XDR tuberculosis, but much more can be
done with existing tools. Investment in tuberculosis
research and development was US$674 million in 2014,
which is a third of the $2 billion needed annually to
eliminate tuberculosis, estimated by the Stop TB
Partnership.520,521 Investment in health-care systems and
the social factors surrounding tuberculosis, such as
poverty, overcrowding, and stigma, is essential to
empower patients with MDR and XDR tuberculosis and
communities, to reduce stigma, and create supportive
environments for detection and treatment.
Conclusion
MDR tuberculosis, XDR tuberculosis, and resistance
beyond XDR tuberculosis remains a major threat to
global tuberculosis control because of the increasing
burden it creates on health-care systems, economies,
and societies, the threat to health-care workers in
tuberculosis-endemic countries, the high mortality, and
the unsustainably high costs of treating drug-resistant
tuberculosis. Additionally, the development of totally
drug-resistant or programmatically incurable tubercu
losis has raised several ethical and medicolegal
challenges. The global epidemiology of drug-resistant
tuberculosis shows a worrying increase in the preva
lence and incidence of drug-resistant tuberculosis in
several countries and regions. Also, the proportion of
cases of tuberculosis that are MDR and fluoroquinolone-
resistant or aminoglycoside-resistantie, pre-XDRor
that are programmatically incurable has increased
greatly. New molecular tools such as next-generation
whole-genome sequencing are shedding further light
on the transmission, diagnosis, and pathogenesis of
drug-resistant tuberculosis.522 Particularly, several lines
of evidence challenge the traditional view that resistance
is acquired through non-adherence promoted by poor
programmatic functioning. Although adherence is
 The Lancet Respiratory Medicine Commission
clearly important for the prevention of drug-resistant
tuberculosis, several other factors that promote
pharmaco kinetic mismatch drive the acquisition of
drug-resistant tuberculosis even when adherence
is good. However, newer methods to enable whole-
genome sequencing directly from sputum and to assess
its effect on clinical outcomes are needed.
Furthermore, a paradigm shift is required to take
testing from the clinical setting into the community,
thus promoting active case finding, and the detection
of the undiagnosed and unsuspected cases of
community-based drug-resistant tuberculosis. Newer
drugs have improved the efficacy of the treatment of
MDR and XDR tuberculosis, and therefore the
prognosis, but resistance amplification will need to
be minimised through strengthening tuberculosis
programmes and other innovative approaches to
prevent pharmacokinetic mismatch. Novel ways to
reduce or eliminate the transmission of drug-resistant
tuberculosis and to understand the fundamental
biology of transmission are urgently required. These
key messages are summarised in panel 11, and timeline-
orientated research priorities and goals for drug-
resistant tuberculosis are shown in table 15. All these
priorities will need to be urgently addressed in tandem
with the strengthening of health systems, reduction of
poverty, and changing of political will.
Contributors
KD wrote the outline of the Commission and the text for the abstract,
introduction, and conclusion sections. KD, JF, and RM reviewed and
edited the entire Commission as it was developed by the other
authors. Epidemiology and risk factors for MDR and XDR
tuberculosis, and resistance beyond XDR: MMu was lead author;
H-HL, SRA, RM, and KD were contributors. Molecular epidemiology
and transmission dynamics of drug-resistant tuberculosis in
high-burden countries: RMW was lead author; GT, PvH, SN, MMe,
DD, AVR, and TGC were contributors. The rise of drug-resistant
tuberculosis: TG and KD were lead authors; GKHS and JGP were
contributors. Diagnosis of MDR and XDR tuberculosis: RM was the
lead author; CR, TGC, and FAS were contributors. Medical and
surgical management of drug-resistant tuberculosis: general
principles and treatment of children, patients with HIV, and in other
specific clinical contexts: KD and JF were lead authors; HSS, KCC,
CL, PN, ZFLU, CRH, GJC, AE, and DM were contributors. New drugs
and strategies for treating drug-resistant tuberculosis: KED and GM
were lead authors; ACH and EN were contributors. Pharmacokinetic
pharmacodynamic factors in drug-resistant tuberculosis: TG was the
lead author; HM was a contributor. Prevention and containment of
transmission of highly drug-resistant (MDR and XDR) tuberculosis:
EAN was the lead author; GT, GJC, and KPF were contributors.
Patient-centred care for drug-resistant tuberculosis: LL and JF were
lead authors; EG and EJ were contributors. Components of patient-
centred and community-centred care for MDR and XDR tuberculosis:
an advocacy perspective: EL was the lead author; ML, CMJ, and NP
were contributors.
Declaration of interests
KD reports grants from Foundation of Innovative New Diagnostics,
eNose Company, Statens Serum Institut, bioMeriux, ALERE, Oxford
Immunotec, Cellestis (now Qiagen), Cepheid, Antrum Biotec, and Hain
Lifescience. KD is supported by the SA MRC, NIH, and the EDCTP. KD
has a patent Characterisation of novel tuberculosis-specific urinary
biomarkers granted, a patent A smart mask for monitoring cough-
related infectious diseases granted, and a patent Device for diagnosing
EPTB issued. GM served on the data safety and monitoring board for
348 www.thelancet.com/respiratory Vol 5 April 2017
Janssen for the TMC207 C208 and C207 phase 2 trials in patients with
multidrug-resistant tuberculosis, 200712. KPF is supported by the
Intramural Research Program of the NIH/NHLBI. EJ is staff member
of WHO; he alone is responsible for the views expressed in this
publication and they do not necessarily represent the decisions or
policies of WHO. All other authors declare no competing interests.
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