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REVIEW

CURRENT
OPINION Multi and extensively drug-resistant pulmonary
tuberculosis: advances in diagnosis
and management
Emanuele Pontali a, Dina Visca b, Rosella Centis c, Lia D’Ambrosio c,d,
Antonio Spanevello b,e, and Giovanni Battista Migliori c

Purpose of review
Multidrug-resistant (MDR) tuberculosis (TB) and extensively drug-resistant (XDR)-TB epidemics are key
obstacles towards TB control and elimination.

Recent findings
Diagnosis of MDR/XDR-TB is difficult and requires several weeks. New diagnostic tools are being tested
and proposed allowing for shorter time to diagnosis and reduced delays in starting an adequate treatment
regimen. MDR/XDR-TB treatment strategies are currently on an evolving stage. New shortened treatments
based on the recommended ’Bangladesh regimen’ or on the newer anti-TB drugs, delamanid and
bedaquiline may represent part of the future scenario. In addition, more information on safety and efficacy
of delamanid and bedaquiline has been published, allowing to better position these drugs. Recent
information on treatment regimens for the paediatric age, with or without delamanid or bedaquiline, has
become available. This is of great help in designing safer and more efficacious regimens for the treatment
of MDR/XDR-TB in children and adolescents.

Summary
The accessibility, sustainability and scale-up of new diagnostic technologies are lagging behind and more
efforts are needed. In addition, we need high-quality information on safety and efficacy of various
combinations of drugs to obtain the best possible regimens to treat the largest possible proportion of
patients.

Keywords
bedaquiline, delamanid, extensively drug-resistant tuberculosis, multidrug-resistant tuberculosis, paediatric tuber-
culosis

INTRODUCTION drugs within adequate national management strat-

&&

Multidrug-resistant (MDR) tuberculosis (TB) (i.e. egies [2 ,3].

TB due to strains resistant to rifampicin and isoni-
azid) and extensively drug-resistant (XDR) TB (i.e.
MDR-TB with additional resistance to a fluoro-
quinolone and a second-line injectable drug) con-
tinue to be major challenges in the fight against
the ‘white plague’ [1]. The WHO in its latest report
estimated that during 2016 about 490 000 new
MDR-TB cases and 110 000 rifampicin-resistant
cases occurred globally (50% of them in China,
India and the Russian Federation) [1] (Table 1;
Figs. 1 and 2). In 2016, an estimated 6.2% of
people with MDR-TB had XDR-TB [1]. The difficul-
ties in facing the epidemic of MDR/XDR-TB are
because of the suboptimal availability of rapid
diagnostics and the difficulty to use second-line
Several significant reports have been published
in 2016, providing new information on diagnosis
and management of drug-resistant TB.
a
Department of Infectious Diseases, Galliera Hospital, Genoa, bRespir-
Respiratory Medicine Unit, cWHO Collaborating Centre for TB and Lung
Diseases, Maugeri Care and Research Institute, IRCCS, Tradate, Italy,
d
Public Health Consulting Group, Lugano, Switzerland and eDepartment
of Medicine and Surgery, Respiratory Diseases, University of Insubria,
Varese-Como, Italy
Correspondence to Giovanni Battista Migliori, MD, WHO Collaborating
Centre for TB and Lung Diseases, Maugeri Care and Research Institute,
IRCCS, via Roncaccio 16, 21049 Tradate (VA), Italy.
Tel: +390331829404; e-mail: giovannibattista.migliori@icsmaugeri.it
Curr Opin Pulm Med 2018, 24:000–000
DOI:10.1097/MCP.0000000000000477

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KEY POINTS
 The MDR/XDR-epidemic continues to be a major
challenge for TB control. The number of cases is
decreasing, but treatment outcomes are
still unsatisfactory.
 Today, it is possible to early diagnose rifampicin
resistance and to obtain information on resistance to
first-line drugs and to some second-line drugs quite
rapidly. Still traditional DST is required to obtain
definitive certainty on the exact resistance profile of
each strain. There is the need for better diagnostic tests
that would allow for rapid and trustable results.
 Delamanid and bedaquiline are the newest anti-TB
drugs. They are proving, cohort after cohort, their
capability in improving treatment outcomes of MDR-TB
and XDR-TB patients. There is growing evidence on
their safety in different settings, even for prolonged
treatment durations.
 The possibility to use a short-course treatment – at
given and precise conditions – opens a new horizon
for a cheap and effective regimen in several settings. In
the future, different combinations of drugs that would
include delamanid or bedaquiline need to be explored
to obtain shorter or better tolerated regimens for most
patients with MDR-TB or XDR-TB.
DIAGNOSIS
MDR-TB management requires the diagnosis of TB
and resistance to at least rifampicin and isoniazid.
Getting to diagnosis of XDR-TB requires additional
detection of resistance to fluoroquinolones and
injectables. Thus, accurate and rapid diagnostic
tools are required. Currently, WHO recommends
to use biomolecular test as the initial diagnostic tool
in case of presumed TB: Xpert Mycobacterium tuber-
culosis (MTB)/RIF assay (Cepheid, Sunnyvale, CA,
USA) [1]. Such tools are useful to rapidly
identify patients with rifampicin resistance (proxy
Table 1. Major epidemiological estimates from 2017 WHO Global Tuberculosis Report with particular emphasis on drug-
resistant tuberculosis
New tuberculosis cases in 2016
Deaths attributed to tuberculosis in 2016
New rifampicin-resistant or MDR/XDR cases in 2016
New rifampicin-resistant (non MDR) TB cases in 2016
New MDR-TB cases in 2016
New XDR TB cases in 2016
People starting treatment for drug resistant TB in 2016
Deaths attributed to rifampicin-resistant or MDR/XDR in 2016
MDR, multidrug-resistant; TB, tuberculosis; XDR, extensively drug-resistant.
Data from [1].
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of MDR-TB). So far, Xpert MTB/RIF remains the most
efficient tool; it is suitable for implementation at the
point-of-care level in resource-constrained settings,
but its implementation is not proceeding rapidly
enough where it is mostly needed [4,5]. MTB/RIF is
able to detect TB in several biological fluids and
specimens [1,6–8]. Further testing is needed to
detect resistances beyond rifampicin. Nevertheless,
standard/traditional drug susceptibility testing
(DST) on solid or liquid culture is essential to con-
firm MDR-TB diagnosis [9]. Xpert MTB/RIF has
proved to significantly reduce the time to MDR-
TB treatment in a deprived rural setting, resulting
in a shorter diagnosis delay [10].
Line probe assays (LPAs) are rapid molecular diag-
nostics detecting both MTB and drug resistance. Geno-
type MTBDRplusV1 was WHO-endorsed in 2008 but
newer LPAs are now available. LPAs can be used as
alternative to conventional DST, although their imple-
mentation is still challenged by high costs and
complex technical requirements. New LPAs have
better sensitivity and specificity [11]. A systematic
review by Nathavitharana et al. [12] compared Hain
Genotype MTBDRplusV1, MTBDRplusV2 and Nipro
NTMþMDRTB. Sensitivity estimates for rifampicin
and isoniazid resistance were almost identical for
LPA performed directly on sputum specimens and
indirectly on culture isolates (96.3 and 96.9%, respec-
tively, for rifampicin, 89.2 and 91.0% for isoniazid).
LPAs demonstrated high accuracy overall for the detec-
tion of rifampicin resistance in pulmonary TB [12].
LPAs demonstrated high specificity for isoniazid-resis-
tance detection with good sensitivity [12]. Genotype
MTBDRplus version 2.0 has also been specifically eval-
uated in real-life setting showing to be reliable in
detecting MTB in sputum smear-negative samples [13].
Recent evidence is available on the new Xpert
versions. The results from a clinical trial carried out
in Uganda proved that Xpert Ultra performed signifi-
cantly better than the standard Xpert in diagnosing TB
10 400 000
1 714 000
600 000; 4.1% of new cases (highest in Belarus: 38%) and
19% of previously treated cases (highest in Belarus: 72%)
110 000
490 000
30 380 (6.2% of MDR-TB cases)
129 689 (precise figures as per reports from countries to WHO)
240 000
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Drug-resistant pulmonary tuberculosis Pontali et al.

FIGURE 1. Percentage of new TB cases with MDR/RR-TB per country. Source: Global tuberculosis report 2017. WHO/HTM/
TB/2017.23. Geneva: World Health Organization; 2017. [1]. MDR, multidrug-resistant; RR, rifampicin-resistant; TB,
tuberculosis. Reproduced with permission from [1].

FIGURE 2. Percentage of previously treated TB cases with MDR/RR-TB per country. Source: Global tuberculosis report 2017.
WHO/HTM/TB/2017.23. Geneva: World Health Organization; 2017. [1]. MDR, multidrug-resistant; TB, tuberculosis.
Reproduced with permission from [1].

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Infectious diseases

meningitis [14]. A study from China and South Korea
tested new Xpert cartridges able to detect katG and
inhA promoter for isoniazid, gyrA for fluoroquinolones
(ofloxacin and moxifloxacin) and rrs for kanamycin
&&
and amikacin [15 ]. The assay was able to accurately
detect MTB mutations associated with resistance to
isoniazid, fluoroquinolones and aminoglycosides
&&
[15 ]. As the Xpert platform technology is undergoing
continuous improvements, these tests are likely to be
repositioned by WHO in the coming future.
Direct sequencing of DNA extracted from sputum
samples or cultures are promising techniques to
obtain fast and reliable resistance profiles well before
phenotypic DST becomes available. There are pres-
ently interlaboratory differences in sensitivity of this
assay as different primers are used. A recent article
from China reported very high specificity and good
sensitivity for rifampicin, but lower sensitivity for
isoniazid and fluoroquinolones [16]. Interestingly,
the resistance results were available within 3 days.
MANAGEMENT
Prevention
A core priority of MDR/XDR-TB control and man-
agement is preventing its transmission. An interest-
ing article revised the relevant interventions to
reduce the transmission of resistant strains [17]. In
particular, the authors identified the following use-
ful interventions: rapid detection and timely initia-
tion of effective treatment (rendering MDR/XDR TB
cases noninfectious), scale-up of rapid molecular
testing (reducing diagnosis delay), optimization of
infection control measures in hospitals and clinics,
and targeted screening of high-risk communities
(enhancing early case-detection).
Treatment strategies
&&
Early in 2017, Falzon et al. [2 ] summarized the key
elements of the new WHO guidelines on MDR-TB
&&
treatment (Table 2) [2 ].
Globally, in the 2014 cohort, the proportion of
MDR/rifampicin-resistant-TB patients who success-
fully completed treatment (i.e. cured or treatment
completed) was 54%, with 8% treatment failure,
16% death, 15% loss to follow-up and 7% no out-
come information [1].
Growing evidence was published on treatment
outcomes from several cohorts in China, India and
Ukraine. Reports from China described different
aspects of the MDR/XDR-TB epidemic. Authors from
Beijing reported an increasing trend in isolation of
XDR-TB strains [18]. They also described outcomes
of patients affected by strains with resistance
beyond XDR; in this population, the inclusion of
linezolid increased the favourable outcome by 27
times [18]. Another article from Shandong showed
growing incidence of XDR-TB strains and unsatis-
factory treatment outcomes of MDR and XDR-TB
patients (44.6 and 14.6%, respectively) [19]. More
than one quarter of patients were lost to follow-up,
making adherence and retention in care key areas
for improvement [19]. A study from Hunan
achieved higher favourable outcomes (57%) among
MDR/XDR-TB cases [20]. However, as in the previ-
ous study, the main issue affecting treatment was
loss to follow-up (27% of patients); this prompted
authors to develop a tracing programme to investi-
gate reasons behind loss to follow-up and retain
patients in treatment [20].
A report from Ukraine showed very low favour-
able outcomes (18.1%) with high prevalence of
deaths (36.4%) and loss to follow-up (31.9%) [21].
The individuals at highest risk of death were
untreated HIV-infected patients and XDR-TB cases;
the authors recommended treatment centres to
follow national guidelines and promptly initiate
antiretroviral treatment among HIV-infected
patients [21].
Furthermore, a systematic review on pulmonary
MDR/XDR treatment including 17 494 patients
showed favourable treatment outcomes (26 and

Table 2. Key elements of the new WHO guidelines on multidrug-resistant-tuberculosis treatment (2016)
1. A second-line treatment is recommended for all RR-TB patients, regardless of whether isoniazid resistance of the mycobacterial
isolate is confirmed
2. A shorter MDR-TB treatment regimen is conditionally recommended for MDR/RR-TB patients, under specific eligibility criteria
3. Recommendations for the treatment of children with MDR/RR-TB are based on the first-ever individual paediatric patient data meta-
analysis on treatment outcomes
4. MDR-TB medicines are now differently regrouped, based on updated information about their efficacy and safety. In particular,
clofazimine and linezolid are now recommended as core second-line MDR-TB drugs, whereas p-aminosalicylic acid has been
moved to the list of add-on agents. Clarithromycin and other macrolides are no longer included for the treatment of MDR/RR-TB.
Delamanid may also be used in patients aged 6–17 years old
5. An evidence-informed recommendation on partial resection lung surgery is now included

MDR, multidrug-resistant; RR, rifampicin-resistant; TB, tuberculosis; XDR, extensively drug-resistant.

&&
Adapted from [2 ] with permission of the ß ERS 2018: European Respiratory Journal Mar 2017, 49 (3) 1602308; DOI: 10.1183/13993003.02308–2016

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Drug-resistant pulmonary tuberculosis Pontali et al.

Table 3. Proposed basic requirements to create a standard regimen for pre-extensively drug-resistant and extensively drug-
resistant-tuberculosis patients
1. At least four new drugs (never used before), likely to be effective, need to be present
2. Two of them should be ‘core’ drugs, at least one having a good bactericidal activity and one a good sterilizing activity.
Ideally, both (or at least the sterilizing drug) should be given for the entire duration of treatment
3. The other two drugs are the so-called ‘companion’ drugs, whose function is to protect the action of the core drugs
4. Treatment should be administered for sufficient time to cure patients while preventing relapse. Compounds with higher
sterilizing activity (rifampicin, pyrazinamide and, probably, moxifloxacin, levofloxacin, linezolid, bedaquiline and
delamanid) are potentially useful to reduce the treatment duration, although some of them will not be eligible for this
regimen

TB, tuberculosis; XDR, extensively drug-resistant.

Reproduced from [30] with permission of the ß ERS 2018: European Respiratory Journal Jul 2017, 50 (1) 1700648; DOI: 10.1183/13993003.00648–2017

60% in XDR and MDR-TB, respectively) [22]. In The drugs used to treat MDR/XDR-TB had been
addition, the authors noted that patients receiving traditionally classified by WHO into five groups; this
individualized treatment achieved significantly bet- classification was recently modified by reclassifying
&&
ter outcomes than those receiving standard treat- drugs into groups A–D (Table 4) [24,2 ].
ment (64 vs. 52%) [22].
Recently, a new short-course treatments strategy
proved to be efficacious and was proposed as a new Table 4. New classification of WHO-recommended drugs
standard for MDR-TB treatment (the so-called used to treat multidrug-resistant-tuberculosis and extensively
&&
’Bangladesh regimen’) [2 ,23]. This 9–12 month reg- drug-resistant-tuberculosis
imen includes 4–6 months of kanamycin, moxiflox-
A – later-generation Levofloxacin (Lfx)
acin, prothionamide, clofazimine, pyrazinamide, fluoroquinolones
high-dose isoniazid and ethambutol, followed by Moxifloxacin (Mfx)
5 months of moxifloxacin, clofazimine, pyrazina-
Gatifloxacin (Gfx)
mide and ethambutol. WHO stated that this regimen
B – second-line injectable Amikacin (Am)
is indicated for adults and children with rifampicin- agents
resistant and MDR-TB who have not been previously Capreomycin (Cm)
treated with second-line drugs and in whom resis-
Kanamycin (Km)
tance to fluoroquinolones and second-line injectable
(Streptomycin) (S)a
agents has been excluded or considered highly
&& C – second-line agents Ethionamide/prothionamide (Eto/Pto)
unlikely [2 ,24]. At least 35 countries have imple-
mented this strategy as of June 2017 [1]. Nevertheless, Cycloserine/terizidone (Cs/Trd)
some authors reported that, by applying the WHO Linezolid (Lzd)
inclusion criteria, only a fraction of the affected pop- Clofazimine (Cfz)
ulation will benefit from it [25–28]. A careful selection D1 – pyrazinamide and Pyrazinamide (Z)
of patients is therefore necessary to prescribe any other
first-line agent (if they
this regimen.
can help strengthen the
One of the key challenges at programmatic level is regimen)
the management of patients with resistance beyond Ethambutol (E)
XDR-TB in settings where all the needed drugs (beda- High-dose isoniazid (Hh)
quiline, linezolid, delamanid, rifabutin and carbape-
D2 – bedaquiline and Bedaquiline (Bdq)
nems) cannot be available [29]. If not properly treated, delamanid
such patients are likely to disseminate further their Delamanid (Dlm)
MDR/XDR-TB strains within the family, in healthcare D3 – other agents p-aminosalicylic acid (PAS)
settings and within the community.
Imipenem–cilastatin (Ipm-Cln) or
Some authors discussed the possibility of build- Meropenem (Mpm) þ Amoxicillin–
ing a standard treatment for patients with pre-XDR clavulanate (Amx-Clv)
or XDR-TB [30]. They identified the basic require- Thioacetazone (T)
ments to create an adequate regimen for each
patient with a standardized approach (Table 3) MDR, multidrug-resistant; TB, tuberculosis; XDR, extensively drug-resistant.
a
Streptomycin may substitute other injectable agents when the other three
[30]. They also extensively discussed the limits of
cannot be used.
the proposed approach and the need for further &&
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This new classification of anti-TB drugs is based
on the need to build a regimen including at least
four drugs likely to be effective; two of them are
essential (or ‘core’ drugs), whereas the other two are
called companion drugs [31]. The core drugs are
chosen for their capacity to kill MTB in any of its
metabolic phases. Differently, the companion
drugs protect the core ones in their action thus
preventing selection of further resistance. Although
one of the core drugs should have a good bacteri-
cidal activity, the other should have a good steriliz-
ing activity; they both need to be maintained for the
entire duration of treatment [32,33]. A new reclas-
sification is likely to occur in the future, as new
information is becoming available on safety and
efficacy for all drugs (especially on new and repur-
posed ones) [33].
A recent study evaluated the drugs used in MDR/
XDR-TB belonging to the (former) group 5, that is
amoxicillin/clavulanic acid, thioacetazone, macro-
lides, linezolid, clofazimine and terizidone [34].
Authors did not find any improvement in treatment
success among patients taking clofazimine, amoxi-
cillin/clavulanic acid or macrolides, despite apply-
ing a number of statistical approaches to control
confounding. Thioacetazone was associated with
increased treatment success when patients treated
with it were compared with others not receiving any
other (former) group 5 drug. Thus, these findings
prevent from drawing definitive conclusions on this
group of drugs: additional information is needed.
Other authors from Brazil reported interesting
information on safety of clofazimine in real life [35].
As part of global efforts to improve MDR/XDR-
TB outcomes, by June 2017, 89 countries and terri-
tories started using bedaquiline and 54 delamanid
[1]. Several articles reporting new and relevant infor-
mation on bedaquiline and delamanid use were
published in 2016 and 2017.
Bedaquiline
A review of bedaquiline use has been published in
&&
ERJ in early 2017 [36 ]. It described the scanty
information available on safety and tolerability of
this key drug [30] and reported the latest news on
bedaquiline effectiveness in the treatment of MDR/
XDR-TB for prolonged periods (i.e. more than 24
weeks, an area of current debate) [30,37,38].
Later in 2017, treatment outcomes and safety
information from the largest cohort of bedaquiline-
&&
treated patients (428) were published [39 ]. The
authors showed interesting and promising results:
sputum smear and culture conversion rates in MDR-
TB cases were 85.5 and 80.5%, respectively, at
90ødays. Out of 247 culture-confirmed MDR-TB cases
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completing treatment, 71.3% achieved success (62.4%
cured; 8.9% completed treatment).
Additional information on cardiac safety came
from a review on bedaquiline use in healthy volun-
teers and patients affected by TB (96.4%) and other
&&
mycobacteriosis [40 ]. This is particularly impor-
tant because bedaquiline is often prescribed with
concomitant anti-TB drugs having the potential to
prolong QTc, that is fluoroquinolones, clofazimine,
pretomanid, delamanid and azithromycin. This arti-
cle reports about 1293 individuals who received
bedaquiline and were assessed for the cardiac safety
in the selected studies, and whose information on
&&
QTc was available [40 ]. In general, bedaquiline was
well tolerated with a very limited number of treat-
ments’ discontinuation because of safety concerns
or poor tolerability. In particular, 44 patients dis-
continued bedaquiline due to adverse events (3.5%
of 1256 treatments). Nevertheless, only eight
patients out of 44 (0.6% of the total) discontinued
bedaquiline because of QTc prolongation and two of
these last patients restarted bedaquiline after reso-
&&
lution of the acute episode [40 ].
Regarding safety, a case-report from France
showed safe and effective use of bedaquiline during
&
pregnancy (third trimester) [41 ].
Delamanid
New information on delamanid use has become
&&
available. Hewison et al. [42 ] reported data on 53
patients in seven countries from Africa, Asia and
Europe, who were prescribed a delamanid-based
regimen. Treatment results were encouraging, with
almost three quarters of patients achieving a favour-
able response (as per authors’ definition) with cul-
ture conversion in at least two of three patients
at month 6. In three cases, QTc prolongation
(>500 ms) occurred due to electrolyte imbalance;
delamanid was temporarily discontinued, but
&&
restarted after imbalance correction [42 ].
Another report about 78 patients (15% HIV coin-
fected) from Europe, Asia and Africa treated under a
compassionate use programme suggests the drug is
effective and safe [43]. The vast majority (84.6%) of
patients completed treatment; only one patient had
to discontinue delamanid because of safety/tolerabil-
ity (QT prolongation) [43]. QTcF prolongation
(defined as frequency-corrected QT > 500 ms) was
noted in 3.8% (three out of 78) of the patients
exposed to delamanid (any duration). Among those
completing 24 weeks of treatment, 80% (53 out of 66)
achieved culture-conversion at 24 weeks [43].
&
Mok et al. [44 ] reported interim results of real-
life use of delamanid in South Korea. Thirty-two
patients received delamanid; culture conversion at
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24 weeks occurred in 94.4% of patients. Delamanid
was well tolerated; in particular, a transient increase
of QTcF more than 500 ms was observed in three
&
patients only [44 ].
A small report from Latvia added interesting
information on safety and efficacy of delamanid in
programmatic conditions [45]. Notwithstanding the
use of delamanid in association with fluoroquino-
lones and prolonged use beyond 24 weeks in some
patients, no case of QT increase (>500 ms) was
observed. In addition, although average duration
of treatment was shorter than the conventional
one in the Latvian programme (15 vs. 18–24 months,
respectively), excellent results were observed, that is
84.2% cure, whereas the remaining patients were lost
to follow up when already culture negative.
In addition, some authors started to report infor-
mation on the association of bedaquiline and
delamanid in complex and challenging MDR/
&&
XDR-TB cases [46,47,48 ]. In these preliminary
reports, the association of the two drugs seems
sufficiently tolerated and effective. Nevertheless,
significantly greater evidence will be required to
provide specific recommendations on regimens
including such association.
Paediatric treatment of multidrug-resistant/
extensively drug-resistant-tuberculosis
The paediatric epidemic of MDR-TB and XDR-TB is
not very well defined, but modelling studies suggest
that more than 30 000 MDR-TB cases occurred in
children below 15 years of age with a third of them
&
being actually XDR cases [49 ]. There is unfulfilled
need of information on well-designed and tolerated
regimens in this special population. Many of the
drugs employed in paediatric treatment regimens
are not registered for children and/or proper formu-
lations are not available. Even for the new anti-TB
drugs, that is bedaquiline and delamanid, although
Table 5. Key open issues on bedaquiline and delamanid
Issue Bedaquiline
Prolonged use beyond 24 weeks Some experience; interesting perspectives [30,37,38]
Pregnancy One case report [40 ]
&&
Cardiac safety Reassuring; variables affecting QTc not yet clear;
not unequivocal data on companion drugs
with QTc prolongation potential [40 ]
Best companion drugs Not identified
Abbreviated duration of treatment Possible shorter treatments
with regimens containing this drug
Paediatric use Limited information [49 ]
&
Association of the two drugs Limited information [47,48 ]
&&
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Drug-resistant pulmonary tuberculosis Pontali et al.
&&
their use is recommended [50,51,52 ], experience is
very limited. During 2016 and 2017, some studies
reported encouraging results on their use in paedi-
atric populations. In this regard, practice-based rec-
ommendations on bedaquiline, delamanid and
other repurposed drugs used in MDR/XDR-TB treat-
ment in children have been issued by an expert
&&
group [52 ].
Bedaquiline has been prescribed in a cohort of
27 children (aged 10–17) from South Africa, Tajiki-
&
stan, Uzbekistan and Belarus [49 ]. Most children
received bedaquiline with linezolid and clofazi-
mine, a few with the addition of moxifloxacin.
Treatment was very effective; all patients still on
treatment at the time of the analysis (85% of the
initial cohort) were culture negative. The only
observed bedaquiline-related adverse events were
on the QTcF. Four patients experienced increases
in QTcF more than 60 ms above baseline (managed
by electrolyte replacement); one patient had QTcF
prolongation more than 500 ms (clofazimine and
moxifloxacin were discontinued). None of the cases
&
ever discontinued bedaquiline [49 ].
A revision of delamanid use in children was
published during 2017, summarizing the results from
19 paediatric cases (four MDR, 15 XDR; mean age 14.4
years). Unfortunately, at the time of publication,
only a small proportion of cases (31.6%) had com-
pleted the 24 weeks of delamanid treatment, and a
single case the whole treatment regimen [53]. Never-
theless, information is insufficient to draw final con-
clusions on safety and tolerability of delamanid in the
paediatric population.
CONCLUSION
The epidemic of MDR/XDR-TB keeps posing
severe challenges towards TB control in several
high-burden and medium-burden countries. During
2016, several steps towards faster and more precise
Delamanid
Some information from Latvia [45]
No information
Reassuring; variables affecting
QTc not yet clear [42 ,43,44 ,45]
&& &
&&
Not identified
Possible shorter treatments
Limited information [53]
Limited information [47,48 ]
&&
www.co-pulmonarymedicine.com 7
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MCP 240303
Infectious diseases
diagnosis of drug resistant TB have been done. The
accessibility, sustainability and scale-up of these
new technologies are lagging behind and more
efforts are therefore needed.
From the treatment side, we start observing the
positive effect of real-life use of bedaquiline and
delamanid in different population and at the pro-
grammatic level. Nevertheless, older drugs differ-
ently combined showed the potential of creating
short-course highly efficacious regimens. The reality
is that at present time, we urgently need high-qual-
ity information on safety and efficacy of the various
combinations of drugs (e.g. randomized clinical
trials) to obtain – at the programmatic level – the
best possible regimens to treat the largest possible
proportion of patients.
Several issues remain open in the treatment of
MDR/XDR-TB with regimens including bedaquiline,
delamanid or both; the most relevant ones are
&& & &&
reported in Table 5 [30,37,38,40 ,49 ,47,48 ,45,
&& & &&
42 ,43,44 ,45,53,47,48 ].
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
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