E u r R e s p ir J 2 0 1 1 ; 3 7 : 4 4 1 - 4 6 2 D O

I: 1 0 .1 1 8 3 /0 9 0 3 1 9 3 6 .0 0 0 3 3 0 1 0
C o p y r ig h t© E R S 2 0 1 1

SERIES "UPDATE ON TUBERCULOSIS"

Edited by C. Lange, M. Raviglione, W.W. Yew and G.B.
Migliori Number 4 in this Series

Treatment of tuberculosis: update 2010

W.W. Yew*, C. Lange# and C.C. Leung*

KEYWORDS Review, emerging extensively drug- tuberculosis

tuberculosis, treatment resistant (XDR) tuberculosis is drug action
defined as MDR tuberculosis with would be
additional bacillary resistance to beneficial.

I
n 2008, 11.5 million people
any fluoroquinolone and one or
were estimated to be living
more of the three (second-line) SCIENTIFIC
with tuberculosis, with 9.4
injectable drugs: amikacin, BASIS OF
million of them having
capreomycin and kanamycin. SHORT-
incident disease. Among the 1.9
Approximately 5.4% of MDR COURSE
million people who died of
tuberculosis reported worldwide CHEMOTH
tuberculosis, 0.5 million were
could be categorised as XDR ERAPY
seropositive for HIV [1]. While the
tuberculosis, with the proportion Mycobacterium
present chemotherapy for
exceeding 10% in some countries tuberculosis,
tuberculosis is highly efficacious,
[2]. This article examines the the causative
it has the disadvantages of being
current status and future organism of
lengthy and complex, and does
prospects of treatment of tuberculosis, is
not live up to the expectation of
tuberculosis. Where appropriate, a slow-growing
adequately controlling the current
evidence levels for the bacterium that
global tuberculosis situation. In
recommended treatment can also enter
2008, an estimated 390,000-
regimens and modalities are a phase of
510,000 cases of multidrug-
given in accordance with the dormancy,
resistant (MDR) tuberculosis with
grading system of the Scottish which appears
bacillary resistance to at least
Intercollegiate Guidelines Network to be drug-
isoniazid (H) and rifampicin (R) are
(see Appendix) [3]. refractory. Four
estimated to emerge every year
worldwide, with China and India Before discussing recommended hypothetical
together accounting for —50% of drug regimens for treating of populations of
this global burden. In 2008, MDR pulmonary tuberculosis, an under- organisms [4]
tuberculosis caused an estimated standing of basic may exist in a

ABSTRACT: Currently, the standard short-course chemotherapy for tuberculosis

comprises a 6-month regimen, with a four-drug intensive phase and a two-drug
continuation phase. Alternative chemotherapy using more costly and toxic
drugs, often for prolonged durations generally >18 months, is required for
multidrug-resistant and extensively drug-resistant tuberculosis. Directly
observed treatment, as part of a holistic care programme, is a cost-effective
strategy to ensure high treatment success and curtail development of drug
resistance in tuberculosis. New antituberculosis drugs are urgently needed to
improve the present standard short-course and alternative chemotherapies, by
shortening administration durations and increasing cure rates, through the
greater potency of these agents. At the same time, the role of adjunctive
surgery for drug-resistant tuberculosis has to be better defined.
Immunotherapy might improve treatment outcomes of both drug-susceptible
and -resistant tuberculosis, and warrants further exploration.

150,000 deaths [2]. Recently mycobacteriology and anti- patient with

tuberculosis: 1) actively growing organisms surviving under P a r k a lle e 3 5
organisms, usually present in anaerobic conditions. B o rs te l 2 3 8 4 5
A F F IL IA T IO N S G e rm a n y
abundance (extracellularly) within
'T u b e r c u lo s is and Chest U n it, G ra n th a m HE -m
o s paita
il: l, c la n g e @ fz -
aerated cavities; 2) slow,
" T u b e r c u lo s is a n d C h e s t S e rv ic e , D e p t o f H e a lth
b o, rsHtoenl.d
ge
intermittently growing organisms K o n g , C h in a . ^ D iv is io n o f C lin ic a l In fe c tio u s D is e a s e s .
in an unstable part of the lesion; M e d ic a l C lin ic , R e s e a r c h C e n te r B o rs te l. RBeoc rs e ivteel,d :
3) organisms surviving under G e rm a n y . M a rc h 0 2
microaerobic conditions in a low 2010
CO RRESPO N DEN C E C. Lange A cc e p te d
environmental pH, either in
D iv is io n o f C lin ic a l In fe c tio u s a ft e r
inflammatory lesions or within D is e a s e s r e v is io n : M a y
phagolysosomes of macrophages; M e d ic a l C lin ic 20 2010
and 4) completely dormant R e s e a r c h C e n te r B o r s te l

M t, A b u b a k a et
Previous articles in this Series: No. 1: E r k e nCs G M K, a m p h o rs r I, al. T u b e rc u lo s is c o n ta c t in v e s tig a tio n in lo w p r e v a le n c e
c o u n ts: i

E u ro p e a n c o n s e nEurResp
sus.
n e crc s s ^ r: -
;
rJ 2 0 1 0 : 3 6 : 9 2 5 - 9No.
4 9 . 2: S o lo v ic I, S e s te r M , G o m e z - etal.
R e in o JJ,
T h e r is k o f tu b e r c u lo s is r e la te d to tu m o u r

'5 :o ry Jo u r n a l
a n ta g o n is t t h e r a p ie s : a T B N E T c o n s e n s u Eur
s s taRespir
te m e nJt.2 0 1 0 ; 3 6 : 1 1 8 5 - 1 No.
2 0 6 .3: S c h u tCz , M e in tje s G , A lm a jid F , e / a / . C lin ic a l r

'

; r 1 3 -1 9 3 6
tu b e rc u lo s is a n d H IV - 1 c o - inEur
fe c tio
Respir
n . J 2 0 1 0 ; 3 6 :1 4 6 0 -1 4 8 1 .

> -

S S M 3 9 9 -3 0 0 3

EUROPEAN RESPIRATORY JOURNAL

4
VOLUME 37 4
NUMBER 2 1
SERIES» TUBERCULOSIS
The three major actions of antituberculosis
drugs [5] are: 1) bactericidal action, defined
as their ability to kill actively growing bacilli
rapidly, e.g. isoniazid, and to a lesser
extent, rifampicin and streptomycin (S); 2)
sterilising action, defined as their capacity
to kill the semi-dormant organisms, e.g.
rifampicin and pyrazinamide (Z); 3)
prevention of emergence of bacillary
resistance to drugs, e.g. isoniazid and
rifampicin; less so for streptomycin,
ethambutol (E) and pyrazinamide; least for
thiacetazone and ^^-aminosalicylic acid.
CHEMOTHERAPY OF PULMONARY
TUBERCULOSIS Short-course
chemotherapy regimens
Based on a number of clinical trials
performed previously, much knowledge has
accumulated regarding chemotherapy
regimens for new cases of smear-positive
pulmonary tuberculosis [6-15]. The shortest
duration of treatment required is, at
present, 6 months (grade A). The standard
regimen today, as categorically
recommended by the World Health
Organization (WHO) and International Union
Against Tuberculosis and Lung Disease
(IUATLD) [16], comprises the combination of
HRZE for 2 months, followed by HR for a
further 4 months. The aminoglycoside
streptomycin is not generally recommended
as a fourth drug in the intensive phase,
largely because of its higher resistance rate
than that of ethambutol [17], and its
requirement for the parenteral route of
administration. However, in rare occasions
when ethambutol use is contraindicated, the
streptomycin may be considered. Dosages
for the conventional first-line
antituberculosis drugs are well established,
and can be found in standard references
[16, 18].
Although an 8-month regimen consisting of
2 months of SHRZ, followed by 6 months of
isoniazid and thiacetazone, combined with
hospitalisation in the first 2 months, has
previously been shown to be effective in
controlled clinical trials and programme
settings in Africa [11], a randomised study
initiated by IUATLD revealed that the 8-
month regimen 2HRZE/6HE was significantly
inferior to the 6-month regimen 2HRZE/4HR
[19]. A systematic review has also shown
that regimens utilising rifampicin only for
the first 1-2 months had significantly higher
rates of failure, relapse and acquired drug
resistance compared with regimens that
used rifampicin for 6 months [20]. The WHO
currently recommends phasing out of the 8-
month regimen [16]. Thus, short-course
antituberculosis chemotherapy regimen
W . W Y. E W
ET
with both rifampicin and pyrazinamide
should contain 6 months, rather than 2
months, of rifampicin for better efficacv
(grade A).
A regimen without pvrazinamide in the
initial intensive phase must be given for
>6 months (grade A). Such a regimen
based on isoniazid and rifampicin [13-15]
is only good for pansus- ceptible
tuberculosis with limited bacillary load,
and has to be given for 9 months (namely
2HRE/7HR or 9HR). This 9-month regimen
is usually not recommended for patients in
countries with high rates of isoniazid-
resistant tuberculosis, except those who
cannot tolerate pyrazinamide.
The administration of pyrazinamide
beyond 2 months has not been shown to
offer any advantage on treatment
outcome (grade A) [21, 22]. Also, in cohort
and case-control analyses, from ^ 12
weeks after starting treatment, the
estimated risk of hepatotoxicity was 2.6%
for regimens incorporating pyrazinamide,
isoniazid and/or rifampicin and 0.8% for
standard regimens containing isoniaizid
and rifampicin. Thus, adc pyrazinamide to
isoniazid and rifampicin increases the ris]
hepatotoxicity appreciably [23].
For individual cases with extensive
disease and slow spui bacteriological
conversion, administration of pyrazinarr
with or without ethambutol beyond 2
months may se acceptable. This
prolongation of intensive phase is
currently supported by WHO [16].
However, WHO recently raised the
possible advantage of using rifampi
isoniazid and ethambutol rather than
rifampicin and isonia in the continuation
phase of treatment of tuberculosis
populations with known or suspected high
levels of bacill resistance to isoniazid [16].
Initial cavitation and posil sputum culture
after 2 months of treatment have been
founc be associated with increased risk of
failure or relapse, i possibly justify
prolongation of the continuation phase
antituberculosis therapy to give a total
duration of 9 mor [24] (grade B).
Intermittent regimens comprising two
drugs in the contin tion phase, following
an intensive phase of four drugs given a
daily basis, have been proven to be highly
efficaci< (2HRZS/4H3R3 or 2HRZS/4H2R2)
(grade A) [7,10]. WHO d not generally
recommend twice-weekly regimens,
because the higher risk of treatment
failure when missing doses oc [16].
Intermittent short-course regimens
administered th times weekly throughout
 have been shown to have larg equivalent
efficacy to daily regimens [8]. A recent
nested ca control study raised concerns
regarding the efficacy of thr times-weekly
6-month regimens in preventing disease
rela] in the presence of cavitation [25]. The
systematic revi mentioned earlier [20] did
not show any significant differe] in failure or
relapse with daily or intermittent scheduling
treatment administration, apart from
insufficient publisl evidence for the efficacy
of twice-weekly rifampicin admir tration
throughout therapy. However, major
confound: factors, such as cavitation and 2-
month culture status, mi« be
heterogeneous across the included studies
and i adequately controlled for in that
systematic revk Furthermore, rates of
acquired drug resistance among failures 1
and relapses have been shown to be higher
with thr times-weekly therapy [20]. Dosing
schedules in the fi 9 weeks did not appear
to have impact on the risk hepatotoxicity in
another case-control study [26]. Logie
regression analysis showed that sex was
nonsignificant t ageing increased the odds
of hepatitis, the risk of which r( from 2.6%
to 4.1% as age exceeded 49 yrs.
WHO currently recommends the use of
daily dosing duri both the intensive and
continuation phase as the most optin
approach (table 1).
HIV-infected patients who received 6-
month rifampicin- rifabutin-based
regimens were shown to have a higher
relap rate than those on longer therapy in
an early clinical trial and a more recent
treatment cohort [28]. Possibly because
the poor prognosis associated with the
underlying H infection before the
availability of antiretroviral therapy, t
lower relapse rate did not translate into
improved survival the former trial [27].
WHO currently recommends tl
tuberculosis patients who are living with
HIV should recei

E U R O P E A N R E S P IR A T O R Y JO O R fc

VOLUME 37 NUMBER
442
2
// Daily 3
times per week
nes per
week
3 times per
week

YEW ET AL. SERIES: TUBERCULOSIS

Recommended dosing frequency for standard 6-month

ing Dosing Comments
frequency: frequency:
nsive continuation
phase phase
regimen

east the same duration of treatment as Retreatment drug regimens

HIV-negative mts. Increased risk of
treatment failure and acquired nycin
resistance have also been shown to be
associated l intermittent regimens among
HIV-infected patients 31]. WHO currently
recommends that HIV-positive mts with
tuberculosis and all tuberculosis patients
living IIV-prevalent settings should
receive daily treatment, at t during the
intensive phase [16].
rtany countries, nearly 50% of patients
are diagnosed as Lng active pulmonary
tuberculosis on clinical and radio- >hic
grounds, without immediate
bacteriological confirma- . In the two
smear-negative studies conducted in
Hong g, China it was found that with 2
and 3 months of daily ^S treatment, the
relapse rates were 32% and 13%,
•ectively, for culture-positive patients
[32], but the rates e much lower with 4-
month treatment (2% for drug- :eptible
tuberculosis and 8% for isoniazid- and
ptomycin-resistant tuberculosis) [33].
s, it appears that months of treatment is
required for ar-negative pulmonary
tuberculosis in non-HIV-infected ents
(grade C). WHO currently recommends
the use of a onth regimen of daily HRZE
for 2 months followed by dailv iree-times-
weekly HR for a further 4 months in the
treatment ew smear-negative pulmonary
tuberculosis patients [16].
relapse rates during the 6-30 months
following til standard 6-month short-
course chemothe
;.men are
erally <5% [6-10]. 78% of relapses
occurred within 6 m ?nths topping
treatment, and 91% within 12 months
For treatment of smear-positive relapse
cases of pulmonary tuberculosis, as well as
retreatment after interruption, an 8-month
regimen has been recommended by WHO
and the IUATLD, namely
2HRZES/1HRZE/5HRE (grade D) [16]. With
the increasing availability of rapid tests for
bacillary drug susceptibilities, such as line
probe assays, it would be possible to modify
this approach according to the results,
particularly in areas with high prevalence of
MDR and XDR tuberculosis [16]. Using
conventional drug susceptibility testing, it
might be necessary to start an empirical
retreatment regimen active against MDR
disease when the levels of MDR tuberculosis
are high in different patient registration
groups in the geographical area (grade D).
Patients who have failed two rifampicin-
containing regimens, the initial and
retreatment regimens, are very likely to have
MDR tuberculosis. These updated
recommendations are now incorporated in
the current WHO guidelines (table 2) [16].
Directly observed treatment,
short-course
Directly observed treatment (DOT) was
shown to be highly efficacious in ensuring
patient adherence by experience gained in
Chennai (then Madras), India and Hong Kong
many decades ago. In 1993, WHO officially
announced the new global strategy for
tuberculosis control known as directly
observed treatment, short-course (DOTS)
that implements the 6-month short-course
regimen in a programmatic setting z 36J. The
DOTS strategy has five key components,
which include: 1 a network of trained
healthcare or community workers to
administer DOT; 2) properly equipped
laboratories

previously treated patients

Suggested antituberculosis retreatment regimens for
ÍT Likelihood of MDR-TB
utinely available
TB to guide treatment regimen used
»nventional phenotypic tests
results are available)*
results are available)*
High rfa ca:e~ts
Medium; iov. relapse oefai>: patients) .pid molecular tests
DST resufts ava table n 1-2 days to confirm or exclude MDR-
While awaiting DST es^'s emp - cal MDR-TB regimen (to be modified once DST
While awaiting DST -est. "5 2-RZES HRZE'SHRE (to be modified once DST

jT: drug susceptibility testing; MDR-TB: multidrug-resistant tuberculosis. stanca'disec individualised regimen if MDR-TB is
confirmed. Reproduced and modified ■m [16] with permission from the publisher.

O P E A NR E S P IR A T O R Y JO U R N A L

volume 37 number 44
2 3
5: TUBERCULOSIS
rained personnel to perform sputum
microscopy for tuberculosis; 3) a reliable
supply of high-quality preferably at no
cost to patients); 4) an accurate record-
^ and cohort analysis system for
monitoring case- g, treatment and
outcomes; and 5) sustained political
::ment and funding. An effectively
functioning tubercu- ntrol programme is
clearly essential for good patient re [36].
Although some patient characteristics,
such as .essness, alcohol or substance
abuse, behavioural prob- mental
retardation, and lack of social or family
support, ore commonly associated with
nonadherence to therapy, ften difficult to
identify poorly adherent patients
because nderlving reasons for such
behaviour are not only faceted and
complex, but range from characteristics
of dividual patients to qualities of the
societal and economic rment [37].
Although a Cochrane database
systematic concluded that the results of
randomised controlled conducted in low-,
middle- and high-income countries lot
provide assurance that DOT, compared
with self- nistered treatment, could
impart quantitatively important s on cure
or treatment completion in tuberculosis
patient the merit of reduction of acquired
drug resistance with was not addressed
[39]. The DOTS strategy is more than
alone: it should be viewed as a
comprehensive service, or re^ra! rart
thereof, which includes enablers,
incentives, 2r or mc r ~:>tk care that are
conducive to the success of -eatmer.:
rrccramme. In a cluster randomised
controlled ~ -arrlrir c the effectiveness of
a strategy to improve rrr ;f ::
r_:r«erailosis treatment in a resource-
poor setting, niervention package based
on improved patient counsel- nd
communication, decentralisation of
treatment delivery, r: choice of DOT
supporter, and reinforcement of super- r
activities led to improved patient
outcome compared the usual
tuberculosis control procedures [40]. In
addition od communication skills in
healthcare workers, attention e Although rifampicin hepatotoxicity was
management of the treatment
associated side-effects and or
nonadherence, and maintaining respect
for patient nomy and integrity are of
paramount importance [41]. One v has
further demonstrated that both family-
member and munitv DOTS strategies can
attain international targets for ment
success under programme conditions
[42].
W.W. YEW ET
AL.
d-dose combination
formulations
use of fixed-dose combination (FDC)
formulations com- xtg two, three or even
four drugs may enhance ease of cription for
physicians, reduce inadvertent medication
r> simplify drug procurement and supply,
improve tment adherence by patients, and,
thereby, decrease the : development of
MDR tuberculosis [43, 44]. In a study c
«mpared the levels of acquired drug
resistance in er:> who had rifampicin and
isoniazid FDC, under self- r ~:~::don
settings, the rate was as low as 0.2%, given
the r - : the investigation [45]. WHO has
included some r'.ets m its list of essential
drugs [46]. Only formulations rr c xxl quality
should be used [47]. The majority of round
no significant difference between FDC
tablets fir.^r crags regarding sputum smear
conversion rates, inc relapses [48, 49].
However, a Singapore study ; - relapse rates
at 2 and 5 yrs of follow-up in ts r. received
FDC tablets [50]. Furthermore, FDC 13 canr.
i replace treatment supervision completely,
as
there is still a potential risk of the
emergence of drug resistance when these
combination tablets are taken irregularly
[51].
Future possibilities for
rifamycin use
Studies have demonstrated the bactericidal
and sterilising activities of rifampicin, as well
as their dose and concentration dependence
[52-54]. In one study, the maximum dosage
of rifampicin tested was 20 mg-kg"1 [53].
Rifampicin at a dosage of >10 mg-kg"1 may
also suppress or delay emergence of
resistance [54]. Early chemotherapy trials
that evaluated the use of high-dose
rifampicin have shown better 1- or 2-month
bacteriological conversion but not a more
favourable relapse rate, probably due to
absence of the inclusion of pyrazinamide in
the treatment regimens [55]. The safety and
tolerability of high-dose rifampicin were not
meticulously assessed in the early
chemotherapy trials, leaving potential
concern over these issues.
thought to be idiosyncratic in nature [56], it
is not possible to exclude interactive toxicity
between isoniazid and rifampicin [57]. Thus,
it may not be entirely appropriate to
extrapolate safety data from the use of high-
dose rifampicin in treatment of other
bacterial infections, such as brucellosis [55].
In fact, mild hepatotoxicity occurred more
frequently in a study among patients who
received high-dose rifampicin for
tuberculosis treatment, although no patient
 developed serious hepatotoxicity [58].
"Flu-like" syndrome has also been
associated with high-dose rifampicin, but
mainly for intermittent rifampicin
administration, and it generally occurs
after 3 months of drug administration
[59]. Thrombocytopenia, haemolytic
anaemia and acute renal failure may also
occur. Since these reactions are
immunological in origin, they are not
likely to occur more frequently when a
higher dosage of rifampicin is used [59].
Further clinical trials would be needed to
examine whether such a strategy could
enhance bacillary sterilisation and
shorten tuberculosis therapy without
excessive adverse effects [60]. A phase II
clinical trial is being conducted to
compare the pharmacokinetics and
pharmacodynamics of daily doses of 900
and 1,200 mg rifampicin with the
standard 600-mg dose during the 2-
month intensive phase of treatment [61].
Early trials of rifapentine, a long-acting
cyclopentyl rifamycin with a plasma half-
life of 14 h, given in a 600-mg dose
volume 37 number EUROPEAN RESPIRATORY JOURNAL
2
together with isoniazid on a once-weekly
basis during the continuation phase of
treatment in patients with tuberculosis have
shown satisfactory efficacy in a subgroup of
HIV-negative patients with noncavitary
disease and limited bacterial burden, despite
an overall failure/relapse rate of 10% [62,
63], and emergence of rifamycin
monoresistance in relapse cases among HIV-
positive subjects [29]. It has been shown that
a 900-mg dose of rifapentine had superior
pharmacokinetics to the 600-mg dose [64,
65], and that a 1,200-mg dose of rifapentine
produced an optimum pulse and post-
antibiotic lag on the growth of M.
tuberculosis [52]. In a murine model, twice-
weekly regimens containing rifapentine (15-
20 mg-kg"1) have shown marked
antituberculosis potency by enhancing the
rifamycin exposure [66] and preliminary data
using daily dosing of rifapentine have also
been encouraging [67]. Rifapentine
autoinduction of metabolism has also been
noted with interest [68]. Currently, there are
only sufficient data on the safety and good
tolerance of rifapentine dosed at 900 mg
once-weekly [69]. However, in
W.W. YEW ET AL. S E R IE STUBERCULOSIS
:
an ongoing phase II clinical trial, rifapentine
dosed at 10 mg-kg"1 5 days-week"1 is being
administered [70], and no unusual
preponderance of adverse events was
reported by the Data and Safety Monitoring
Committee so far.
CHEMOTHERAPY OF PULMONARY
MDR AND XDR TUBERCULOSIS
The clinical relevance of antituberculosis
drug resistance will be reviewed first as a
background to the treatment of drug-
resistant tuberculosis, especially the MDR
and XDR forms.
Clinical relevance of
antituberculosis drug
resistance
Resistance to an antituberculosis drugs
arises spontaneously through chromosomal
mutation at a frequency of 10~6-10~8
bacterial replications [36].
chromosomal loci involved are distinct for
the major classes of drugs. Thus, when
three or more effective drugs are used in
combination, spontaneous emergence of
mutants resistant to all drugs is most
unlikely with the usual bacterial load in the
diseased host. However, sequential genetic
mutations may be amplified through
human error, resulting in clinically drug-
resistant tuberculosis. These include
"monotherapy" due to irregular drug
supply, inappropriate doctor prescription
and poor patient adherence to treatment
[36]. Subsequent transmission of resistant
M. tuberculosis strains from the index
patient to others, as facilitated by
diagnostic delay and infection-control
breach, aggravates the problem [71]. A
recent review regarding epidemiology of
MDR tuberculosis showed that the risk
factors for drug resistance pertain to those
facilitating the selection of resistance in the
community and the specific conditions that
appear to increase the vulnerability of
some patients, such as in certain HIV or
malabsorption settings.
epidemiological situation is principally
related to poor treatment practices and
poor implementation of control
programmes [71].
Isoniazid resistance is the most common
form of drug resistance encountered,
whether in isolation or in combination with
other drugs [2]. Standard short-course
chemotherapy for isoniazid-resistant
tuberculosis can achieve good success
(>95% cure rate) when all four drugs are
used throughout the 6 months of treatment
(grade B) [21]. When the four drugs are
reduced to only rifampicin and isoniazid
after 2 months, the relapse rate after 6
months of treatment rises to 10% [22]. As
there may be a genuine chance of
resistance amplification with additional
resistance to rifampicin [20, 72] (especially
for HIV status and/or intermittent dosing
[20, 28, 31]) some authorities recommend
changing to alternative regimens, such as
REZ or RE, for more prolonged durations of
administration, often yr (grade D) [73, 74].
Currently, the most optimal regimen for
treatment of isoniazid-resistant
tuberculosis appears unknown [16].
Rifampicin-resistant tuberculosis carries a
much more ominous prognosis, as the
outcome of standard short-course regimens
for such disease is poor, in terms of both
disease status on cessation of treatment
and subsequent relapse [75]. A
recommendation has been made to treat
such disease with EHZ for 18-24 months
The
(grade D) [76]. Some authorities feel that
the duration of treatment can be shortened
to 12 months by the addition of a
fluoroquinolone to this three-drug regimen
(grade D) [24]. Furthermore, rifampicin
monoresistance in
M. tuberculosis is usually rare, except
perhaps in HIV-infected patients [28, 31,
76, 77]. Thus, rifampicin resistance
generally serves as a surrogate marker for
dual resistance to rifampicin and isoniazid,
i.e. MDR tuberculosis [78, 79], especially
for previously treated patients. Short-
course chemotherapy can cure <60% of
MDR tuberculosis cases [80], with a high
recurrence rate of ~28:o among those with
apparent success [81]. A recent analysis
has shown that the currently recommended
short-course treatment regimens for both
initial and retreatment purposes could not
achieve good outcome- - failures, relapses
and deaths) in countries having initial rates
>3% [82]. It is quite clear today that
alternative specific chemotherapy using
second-line management of this formidable
conditic r ^ :
The
Increased risk for development of bac:liar.
~:
ethambutol and pyrazinamide likely occ ; -
four-drug regimen for initial treatment and
a drug retreatment regimen are repeatedly
administer :: j-^r.:. observed treatment
failure with the conventional sr. .--e
regimens for tuberculosis [84-86].
Pyrazinamide and or etr rr- butol
resistance, in addition to dual resistance to
isoniazid and rifampicin, generally portends
a more adverse prognosis in MDR
tuberculosis [87], particularly when
patients receive on]. standardised second-
line antituberculosis drug regimens with
pyrazinamide and ethambutol plus a
fluoroquinolone and aminoglycoside or
capreomycin.
Fluoroquinolones are generally regarded as
having a pivotal role in the treatment of
MDR tuberculosis [88-90]. In : : resistance
to fluoroquinolones has been shown to
predict a poor outcome in the treatment of
MDR tuberculosis [88,91, 92 Most
fluoroquinolone resistance in M.
tuberculosis is associated with the
injudicious use of this class of drugs in the
management of tuberculosis, particularly
MDR tuberculosis [93, 94" including the use
of suboptimal second-line drug regimens
comprising an inadequate number, dosage
and/or quality o: accompanying agents
[84]. Overzealous use of this class of
antimicrobials in the treatment of lower
respiratory tract and other community-
acquired infections might also contribute to
development of fluoroquinolone-resistant
tuberculosis [95].
As the aminoglycosides and capreomycin
have potent antituberculosis activity, the
loss of these second-line injectables
together with fluoroquinolones, through
EUROPEAN RESPIRATORY JOURNAL
their suboptimal us«r in the management
of MDR tuberculosis would result in XDR
tuberculosis, which, in general, carries a
worse prognosis
Programme strategies and
implementation
The emergence of drug resistance in M.
tuberculosa h^s prompted WHO to modify
the DOTS strategy to a rr comprehensive
approach, the Stop TB strategy [97] Tr -
strategy comprises the following
components: 1) pursu:: high-quality DOTS
expansion and enhancement; 21 addre — _
tuberculosis in HIV patients, MDR
tubercuosis and the r — s * poor and
vulnerable populations; 3) contribution ::
system strengthening based on primary
healthcare : - _ _ _ all care providers; 5)
empowering people with tuberc- sis ; : *
and communities through partnership; and
6 enar „:: : - : promoting research. The
management of MDR
-s
through the use of alternative second-line
anr.7„ r - - : _ chemotherapy mandates its
delivery on a pro^rarrjr i
volume 37 number
2
 SERIES» TUBERCULOSIS
with five key components built on the DOTS
framework (fig. 1). The capacity for
performing drug susceptibility testing and
availability of second-line drugs are not
adequate to achieve cure. Other factors,
such as a set of standard procedures, clear
guidelines on treatment and follow-up of
patients and administration of DOT, must
be included in the programme for MDR
tuberculosis management to attain good
results [83]. There are basically three
possible programmatic approaches for the
management of MDR tuberculosis [83]: 1)
standardised treatment, in which regimens
are designed on the basis of representative
drug-resistance surveillance data of specific
treatment categories, with all patients in
the same group or category being treated
by the same regimen; 2) empirical
treatment, in which each patient's regimen
is individually designed on the basis of the
previous history of antituberculosis therapy
with the help of representative drug-
resistance surveillance data, followed by
regimen adjustment when the individual
drug susceptibility testing results are
known; 3) individualised treatment, in
which each patient's regimen is designed
on the basis of previous history of
antituberculosis treatment and individual
drug susceptibility testing results.
While a standardised regimen enables
simple operation and broadens access to
care, there may be concern over the
amplification of multidrug resistance if the
number of available second-line drugs in
the regimen is low [98, 99]. Individualised
treatment strategies rely heavily on
capable laboratory services, but have the
advantage of avoiding placing patients on
toxic and expensive drugs to which the M.
tuberculosis strain is resistant. One caveat,
however, is the unsatisfactory reliability of
second-line drug susceptibility testing
results for many agents aside from the
fluoroquinolones and the injectables,
Rational case-finding
strategy: quality-
FIGURE 1. Directly
Uninterrupted
assured culture observed
supply
and treatment, antituberculosis
ofSustained
applied to thesusceptibility
management
quality-assured
drug ofpolitical
second-line drug-resistant tuberculosis.
modifiedantituberculosis
testing
from [83] drugscommitment
with permission
from the publisher.
W.W. YEW ET
Al
arising partly from the difficulty in
standardising testing methodology [100-
102]. However, some progress has been
made accordingly [103]. Patients who had
previous treatment with second-line drugs
would probably benefit more from the
administration of individualised regi mens.
When re-treated patients are presumed to
have a higl likelihood of MDR tuberculosis,
an empirical regimen can b( administered
while awaiting the results of conventional
dru£ susceptibility testing [16].
Regardless of the strategy advocated,
there are significant cos! issues in the
management of MDR tuberculosis patients
[104]. In a previous decision analysis, it
was shown that more patients would die
from tuberculosis if the implementation of a
drug resistance programme is associated
with even minimal decreases in the
effectiveness of DOTS [105]. Nevertheless,
the feasibility and cost-effectiveness of
treatment of MDR tuberculosis is now quite
well established, even in resource-limited
settings [106, 107]. In countries with
significant financial difficulties, additional
support, besides technical assistance, from
international organisations and
governments of industrialised countries
would be needed, further to that obtained
from local governments [108]. In this
regard, the Green Light Committee of the
Stop TB Partnership, involving WHO and
collaborators, has played a significant role
in helping the implementation of these
programmes in countries with an
affordability problem in the management of
MDR tuberculosis [109].
Design of drug regimens
Guidelines on the treatment of MDR
tuberculosis are often formulated based on
experience and observational studies, as
data from randomised trials are lacking. A
detailed review has addressed the
evidence and controversy of treatment of
MDR tuberculosis, focusing on the
number of antituberculosis drugs
required to treat MDR tuberculosis,
the most rational use of effective
drugs against the disease, the
advisable length of parenteral drug
administration or of the initial phase
of therapy, the contribution of
surgery to the management of MDR
tuberculosis, and the optimal
approach for treating MDR disease
(standardised versus individualised
regimens). However, little evidence,
but much controversy, was found
regarding the the treatment of MDR
tuberculosis [110]. Randomised
Standardised
/ Appropriate treatment \
recording
strategies using and
second-line
short-course (DOTS)
reporting system framework
drugsfor
under
proper Reproduced X
case management
drug-resistant and
conditions /
tuberculosis
control
 controlled trials regarding chemotherapy of
MDR tuberculosis should be undertaken to
provide more evidence-based
recommendations [111]. The updated WHO
guidelines in 2008 and 2009 recommend
designing treatment regimens with a
consistent approach based on the hierarchy
of five categories of antituberculosis drugs
(table 3) [16,112]. The potency of these
drugs is in a descending order; thus, the
drugs are selected from these five groups
accordingly. A brief review of the utility of
these drugs is detailed below.
While isoniazid in conventional doses has
limited usefulness, high-dose isoniazid
(>10 mg-kg"1) has demonstrated some
EUROPEAN RESPIRATORY JOURNAL
JET
volume 37 number
448
2
efficacy (clinical, bacteriological and
radiographic) as well as reasonable patient
tolerance in a recent study [113]. After
adjustment for potential confounders,
subjects who received high-dose isoniazid
had a 2.37-fold higher likelihood of
becoming culture-negative at 6 months.
Isoniazid-resistant M. tuberculosis
organisms belonging to the low-resistance
phenotype often have cross-resistance to
ethionamide, while those of the high-
resistance phenotype are more susceptible.
Adding high-dose isoniazid kills the former,
leaving the latter that are more susceptible
to the ethionamide included in the MDR
tuberculosis regimen. Ethambutol and
pyrazinamide
W.W. YEW ET AL. SERIES"
TUBERCULOSIS

iylJ^jKjl
Categori 2
es of
:
antitube
rculosis
drugs f
l
Category
u
1: first-
o
line oral
r
drugs
o
I
q
s
u
o
i
n
n
i
o
a
l
z
o
i
n
d
e
s
R
i
f L

a e

m v

p o

i f

c l

i o

n x
a

E c

t i

h n

a
m M

b o

u x

t i

o f

l l
o

P x

y a

r c

a i

z n

i
n O

a f

m l

i o

d x

e a
c

C
i

a
n

t
C
e
a
g
t
o
e
r
g
y
o n
r Category
y 4: oral
bacteriost
3 atic
: second-
line
i agents
n E
j t
e h
c i
t o
a n
b a
l m
e i
d
a e
g
e P
n r
t o
s t
h
C i
a o
p n
r a
e m
o i
m d
y e
c
i P
n a
r
A a
m -
i a
k m
a i
c n
i o
n s
a
K l
a i
n c
a y
m l
y i
c c
i
n a
c
S i
t d
r
e C
p y
t c
o l
m o
y s
c e
i r
i aid be
n include
e d in
Terizidon the
e treatm
Categor ent
y 5: regime
agents n if
with they
efficacy are
that is likely e
not effectiv
totally e from
clear
laborat
(not
ory
generall
eviden
y
ce or
ecomme
clinical
nded by
history.
WHO
for »roqui
routine nolone
use in (Categ
treating ory 2)
patients therap
with y is
rug- indepe
resistan ndentl
t y asso-
tubercul 'd with
osis) better
Isoniazid treatm
(high- ent
dose; outco
>10 mg- mes.
kg"1) Losing
Linezolid this
Amoxicilli drug
n- ^ory
clavulana increas
te es risk
Clarithro of
mycin death
Clofazimi and
ne failure
Meropen [89,
em plus 114].
clavulana Thus, a
te 'oquino
Thiacetaz lone
one should
Rifabutin be
include
HO:
d
World
whene
Health
ver
Organizat
possibl
ion.
e,
Reprodue
>ugh
d and
potenti
modified
al
from [16]
cross-
with
resista
rmission
nce
from the
publisher.
among
the
class
 memb MDR
ers ary
hampe strai
r their ns,
utility an
in XDR injec
tuberc table
ulosis agen
[115]. t
Older from
oquino Cate
lones, gory
especi 3,
ally amik
ciprofl acin,
oxacin, omy
are not cin
recom- or
led, as kana
there myci
could n,
be a shoul
slower d
sputu form
m part
culture of
conver the
sion a regi
higher men,
relaps as
e rate possi
[116]. ble.
Newer Capr
fluoroq eom
uinolo ycin
nes, may
floxaci have
n and a
levoflo furth
xacin, er
can be adva
active ntag
agains e, 5
t some to its
acin- inco
resista mple
nt te
strains cross
of M. -
tuberc resis
ulosis tanc
[117, e
118]. with
the kana
high mvci
rate n
of and
stre icin
pto in
myci som
n e M.
resis tube
tanc rculo
e sis
amo strai
ng ns
 [119 ne/terizi
, done
120] have
. potential
How ly
ever, serious
>le neurotox
cros icity. The
s- use of
resis thioamid
tanc es and
e para-
exist aminosal
s icylic
amo acid are
ng notoriou
thes sly
e associat
thre ed with
e gastro-
seco intestinal
nd- reactions
line and
ibles other
. adverse
Injec events
table [83,117].
agen They are
ts added
are accordin
gene g to
rally estimate
reco d
mme bacillary
nded suscepti
for bility,
^6 drug
months, history,
or 4 efficacy,
months side-
after effect
culture profile
conversi and cost.
on, with Category
modifica 5 drugs,
tion including
accordin linezolid,
g to amoxicill
bacillary in-
resistanc clavulan
e or ate,
patient meropen
intoleran em/clavu
ce [83]. lanate
Category and
4 agents clofazimi
are ne, are
generall not
y less generally
efficacio recomm
us and ended in
more drug-
difficult resistant
to tubercul
tolerate. osis,
Cycloseri because
their and
roles are neurolog
uncertai ical
n [112]. toxicities
However [123].
, they Use of
have linezolid
potential at half
role in dose
situation (600 mg-
s day"1)
without helped
other to
options, reduce
especiall bone
y in marrow
patients suppress
with ion, but
XDR not
tubercul peripher
osis [16, al and
121]. optic
Clinical neuropat
experien hy [124].
ce on Fatal
linezolid lactic
has acidosis
been can also
slowly occur
accumul after
ating prolonge
after the d
first therapy
report of [125]. A
its good sizeable
in vitro retrospe
activities ctive
against study
M. has
tubercul confirme
osis a d these
decade adverse
ago effects
[122]. In [126].
one Most of
study, them
nine out occurred
of 10 after 60
MDR days of
tubercul therapy
osis [126].
patients More
given major
linezolid side-
and effects
other occurred
drugs in with
a DOT twice-
setting daily
were than
cured, once-
despite daily
substant dosing,
ial with no
haemato differenc
logical e in
efficacy. available
Outcome . Further
s were evaluatio
similar n of
in linezolid
patients at a dose
treated of 600
with or mg-day"1
without is being
linezolid, conducte
although d in a
linezolid phase I/II
use was clinical
assocate trial in
d with South
more Africa
extensiv [127].
e Linezolid
resistanc (300 mg-
e to first- day"1), in
and addition
second- to good
line toleranc
drugs. e,
Thus, it appeare
appears d to
that have
linezolid reasonab
(600 mg le
once- efficacy
daily), in a
when recent
added to study
an [128].
individu However
alised ,
multidru concerns
g have
regimen, been
may raised
improve regardin
bacteriol g the
ogical method
conver- of
sion and analysis
treatme and
nt possible
success emergen
in the ce of
most drug
complica resistanc
ted MDR e [129].
or XDR Another
tubercul oxazolidi
osis none,
cases PNU-
[126]. Its 100480,
use has
might demonst
not be rated
warrante more
d where potent
better activity
tolerated in vitro
alternati and in a
ves are murine
model m/
[130], cilastatin
while is active
AZD584 against
7 is MDR and
undergoi XDR
ng strains
phase I M.
trial in tubercul
healthy osis in
voluntee vitro
rs [131]. [137].
Amoxicill There
in- are also
clavulan some
ate has limited
some efficacy
early data of
bacterici imipene
dal m in
effect mice and
against humans
M. [138].
tubercul When
osis meropen
[132] em, a
and carbape
distinct nem (a
inhibitor newer
y congene
activity r of
on MDR imipene
strains m), was
[133]. combine
Other p- d with
lactam- the (3-
p- lactamas
lactamas e
e inhibitor
inhibitor clavulan
combina ate,
tions potent
have activity
also against
shown laborator
similar y strains
in vitro of M.
activity tubercul
[134], osis was
but observed
clinical , with
efficacy sterilisati
data are on of
limited aerobical
[135, lv grown
136]. cultures
Imipene achieved
within

AN RESPIRATORY JOURNAL volume 37 number

2

44
7
SERIES* W.W. YEW ET
TUBERCULOSIS AL

14 days its
[139]. In analogu
addition, es, have
this been
combina shown to
tion possess
exhibite in vitro
d and in
activity vivo
against activities
anaerobi against
cally M.
grown tubercul
cultures osis,
that including
mimic drug-
the resistant
mycoba strains
cterial [141,
persister 142].
s, and Clofazim
inhibited ine is
the primarily
growth used in
of 13 the
XDR treatme
strains nt of
of M. leprosy
tubercul but is
osis at sometim
the es
same incorpor
levels as ated in
observe the
d for treatme
drug- nt
suscepti regimen
ble s for
strains MDR
[139]. tubercul
Thus, osis,
meropen although
em- data on
clavulan its
ate clinical
might efficacy
have a [143]
potential and
role in toleranc
the e [144]
treatme are
nt of limited
tubercul and
osis conflictin
[140]. g.
Clofazim Rifabutin
ine, a has very
riminoph limited
enazine, potential
and utility in
some of treatme
nt of who
MDR have
tubercul previousl
osis due y
to its received
high second-
cross- line
resistanc drugs
e rate are more
with likely to
rifampici need a
n [16]. higher
MDR and number
XDR of drugs,
tubercul as do
osis patients
should with
be more
treated extensiv
aggressi e
vely. The radiogra
fluoroqui phic
nolones disease
and and
injectabl more
es are formid-
the most able
potent drug
second- resistanc
line e
agents patterns.
for MDR The use
tubercul of
osis capreom
(grade ycin/
C). In kanamyc
the in/amika
initial 6 cin,
months, fluoroqui
the nolone,
treatme ethambu
nt tol,
regimen pyrazina
should - mide
consist and
of at ethiona
least mide/pro
four thionami
noncross de for
-reacting disease
drugs to with
which bacil-
the lary
organis resistanc
m is, or e to RH
is likely (with or
to be, without
suscepti S), and
ble the use
(grade of
C). capreom
Generall ycin/kan
y amycin/a
speaking mikacin,
, those fluoroqui
patients nolone,
ethiona- newly
mide develop
/prothion ed
amide, antitube
cycloseri rculosis
ne and drugs.
jPtfra- Linezolid
aminosal resistanc
icylic e among
acid for M.
disease tubercul
with osis is
bacillary fairly
resistanc well
e to known
RHEZ today,
(with or and may
without serve as
S) a
constitut warning
e [145,
importan 146].
t The
example dosages
s of of
these second-
regimen line
s. The drugs
possibilit used in
y of the
further treatme
acquired nt of
resistanc MDR and
e should XDR
be tubercul
consider osis are
ed. A listed in
single table 4
drug [83, 112,
should 147].
never be The
added to maximu
a failing m
regimen, dosage
for fear of
of cycloseri
selecting ne and
mutants ethiona
that are mide/
resistant prothion
to the amide
newly should
added generall
drug y be 750
(addition mg
phenom when
enon) once-
[84]. daily
Care is dosing is
also used, as
warrante there is
d in concern
chemoth over
erapy toxicity
trials for
involving higher
doses. nt
The duration
same of ^ 18
likely months
applies after
also for culture
aminogl conversi
ycosides on, even
/ for HIV-
capreom negative
ycin patients
given (grade
three to D) [83].
five However
times , a
per proporti
week on of
[147]. immuno
Some of compete
the nt
patients patients
weighing who
>70 kg manage
might d to
tolerate achieve
1,000 sustaine
mg for d
these sputum
three culture
classes conversi
of drugs on early
[112]. might be
The adequat
maximu ely
m once- treated
daily with 12
dosage months
of of
moxiflox fluoroqui
acin and nolone-
levofloxa containi
cin is ng
400 mg regimen
and 750- s
800 mg, [88,149]
respecti . It
vely. appears,
While however
the , that
efficacy patients
of 1,000 who are
mg immuno
levofloxa compro
cin per mised
day is (includin
high g those
[148], with
the diabetes
toleranc mellitus
e data and
are still silicosis),
limited. or have
WHO extensiv
recomm e
ends a radiogra
treatme phic
evidence tolerate.
of In a
disease study on
(particul MDR
arly with tubercul
cavities), osis in
extensiv Hong
e drug Kong, —
resistanc 40% of
e, the
delayed patients
sputum experien
culture ced
conversi adverse
on (i.e. drug
after >3 reaction
months s of
of varying
chemoth severity
erapy) [88].
or However
extrapul , only
monary half of
involvem the
ent patients
should required
receive modifica
>12 tion of
months their
of drug
therapy regimen
[88]. s. These
results
Another
corrobor
importan
ated the
t
findings
principle
of a
in the
study of
chemoth
MDR
erapy of
tubercul
MDR and
osis
XDR
patients
tubercul
in Peru,
osis is to
where
exercise
the
vigilance
adverse
to
drug
prevent
reaction
and
s never
manage
resulted
adverse
in
reaction
discontin
s.
uation of
Second- antitube
line rculosis
drugs for therapy
treating and only
MDR occasion
tubercul ally
osis are (11.7%)
generall resulted
y more in
toxic suspensi
and on of an
difficult agent
to [150]. In
a in
reported resource
series of -limited
MDR settings
tubercul [107].
osis
The
patients
second-
in
line
Turkey,
antitube
—70% of
rculosis
the
drugs
patients
are
experien
handled
ced
in
adverse
patients
effects
by
to the
different
second-
pathway
line
s,
agents
including
and
diverse
55.5%
metaboli
required
c ones.
treatme
There is
nt
a
modifica
potential
tion
for their
[151].
interacti
With
on with
timely
different
and
classes
appropri
of
ate
antiretro
manage
viral
ment,
drugs
the
[152].
treatme
nt Close
success clinical
rate monitori
(77.6%) ng is
did not necessar
appear y to
to be ensure
markedl that
y adverse
compro drug
mised. effects
Indeed, are
the recognis
results ed
from quickly.
Turkey Apart
largely from
parallele clinical
d those monitori
pooled ng,
from five ancillary
sites investiga
(Estonia, tions,
Latvia, such as
Peru, audiome
The try
Philippin screenin
es and g,
Russia) vestibula
r d course
assessm of
ent and antitube
biochemi rculosis
cal tests, therapy
including can
those of emerge
liver and within a
renal few
function days.
s, When an
electroly adverse
tes, and reaction
thyroid is mild
function and not
s, are dangero
helpful. us, such
In as a
addition gastroint
to estinal
assessm one,
ent of continua
visual tion of
acuity, therapy
tests to alongsid
detect e
peripher supporti
al ve
neuropat treatme
hy are nt is
occasion sufficien
ally t. If an
needed. adverse
The event is
optimal severe
intervals or
at which potential
these ly
investiga dangero
tions us, such
should as a
be neurolog
perform ical
ed are effect, a
unknown more
. intensive
Physicia manage
ns ment
should strategy
be embraci
aware ng
that supporti
some of ve
the treatme
adverse nt and
effects drug
that can discontin
occur uation or
during dosage
the adjustm
continua ent is
tion required
phase of [83].
an Psychos
extende ocial
 support of
is also treatme
an nt with
importan aminogl
t ycosides
element and
in the received
manage a higher
ment of total
adverse dose.
reaction Predispo
s. sing
Educatio factors
n, for
counselli ototoxici
ng and ty of
encoura aminogl
gement ycosides
can all are less
contribut well
e to a characte
successf rised,
ul except
outcome perhaps
[83]. for old
age,
Patients
renal
developi
impairm
ng
ent and
nephroto
prolonge
xicity
d
were
therapy
found to
[153].
have a
Ototoxici
significa
ty due to
ntly
aminogl
longer
ycosides
duration
can be

EUROPEAN RESPIRATORY
JOURNAL

volume 37 number
448 2
W.W. YEW ET AL. SERIES:
TUBERCwLOStS

Dosages of
antituberculosis
drugs used in
treatment of
multidrug-resistant
tuberculosis in adults
Daily dosage#

Usual daily do

A
TABLE
Drug 4 m
S
tP
a
C
lA
m
7
5
0

7
5
0
'
1
7 5
5 1
0 5
r 1
5
7 15
5
0
"

6
1
0
5
0
1
-
5
8
0
1
0
c 5
20
-
5
30
0
0
15
-
15
7
20
5
0
0
2.
*
5

4
0
0
*
;

5
0
0
-

: drugs are generally given on

#

a daily basis except for

aminoglycosides and the allied
injectable antibiotics, which are
given three to five times per
week, as well as those
otherwise specified; * : usually
the maximum daily dosage
(some of the patients weighing
>70 kg can tolerate higher
dosages: see main text); higher
dosage usually given for
fluoroquinolone-resistant
disease; §: optimal dosage not
fully delineated;f: may require
administration in two split
doses per day; requires
administration in split doses per
day; should only be used in
patients documented to be HIV-
negative, and usually not be
chosen over other oral
bacteriostatic second-line
drugs; ++ : long-term safety not
fully confirmed.

irreversi variation
ble and s in
patients method
need to of
be analysis,
counselle definition
d to of
report treatmen
symptom t success
s at the and
earliest failure,
signs of drug
occurren suscepti
ce. bility
testing,
Treat clinical
ment follow-
outco up, and
mes missing
Treatme data. The
nt outcome
outcome s also
s of MDR likely
and XDR depend
tuberculo on
sis vary adverse
greatly events
between due to
studies drugs
[88-90, and their
92, 154- manage
167], ment, as
possibly well as
related supply
to and
availabili higher
ty of the success
agents rate
for (64°o)
treatmen than
t. standardi
For MDR sed
tuberculo regimens
sis, (54%),
success although
rates the
(cures differenc
and e was
treatmen not
t statistica
completi lly
ons) are significan
around t. In
50-70% general,
[88-90. patients
92 154- with XDR
167]. In tubercu-
a recent losis had
systemat worse
ic review treatmen
[168], t success
the MDR rates
tuberculo (^50%)
sis treat- [164-
ment 166],
success although
rate one
improved study
with has
treatmen shown a
t remarka
duration ble
of ^18 treatmen
months t success
and DOT rate of
througho 60.4%,
ut which is
treatmen compara
t. Studies ble with
that that
combine (66.3%)
d both of MDR
factors tuberculo
had sis in the
significa same
ntly locality
higher [169].
pooled Prior
success antituber
rate than culosis
other therapy
studies [89, 90,
(69 92, 154,
versus 157,
58°o). 167],
Individua extensiv
lised e in vitro
treatmen drug
t resistanc
regimens e [87,
conferre 89, 92,
d a
157, [160],
165], and
fluoroqui early
nolone (<1 yr of
resistanc treatmen
e [88, t) default
90, 92, [163]
158, constitut
167] or e
prior importan
fluoroqui t risk
nolone factors
use for poor
[158], outcome
capreom s.
ycin In a
resistanc recent
e [96], systemat
positive ic review
sputum of XDR
smear tubercul
[167], osis, it
radiologi was
cal shown
cavitatio that
n [88, strategie
89, 158], s to
HIV support
seroposit adheren
ivity ce, as
[156, well as
161, psycholo
163, gical,
166, nutrition
167], al and
other even
immuno- financial
compro intervent
mised ions,
states might
[159], further
history contribut
of e to
incarcer improve
ation d
[92], low outcome
body s in
mass patients
index with XDR
(<18.5 tubercul
or <20 osis
kg-rrf2) [170].
[92, Encoura
160], ging
hypoalbu results
- from
minaemi some
a [164], countries
older in Asia
age [89, and
158], Europe
male sex have
[154], also
low suggeste
haemato d that
crit manage
ment in success
specialis rates
ed could be
referenc achieved
e with
centres treatmen
could t in
improve some
outcome commun
, ity
although settings
high [170].

EUROPEAN RESPIRATORY volume 37 number

JOURNAL 2

44
9
SERIES" W.W. YEW ET
TUBERCULOSIS AL.

The [170], it
impact was
of HIV remarke
on the d that
outcome addition
s of al data
MDR for HIV-
and XDR infected
tubercul individu
osis has als
been would
most be
serious required
in South to
Africa. determi
Among ne the
272 role of
MDR HIV
and 382 coinfecti
XDR on in
tubercul XDR
osis tubercul
patients osis
with HIV treatme
coinfecti nt
on rates outcome
of 90% , and to
and evaluate
98%, 1- interven
yr tions
mortalit that
y was might
71% and contribu
83%, te to
respecti improve
vely. out-
This comes
mortalit in HIV-
y infected
improve XDR
d, tubercul
however osis. The
, from high
2005 to case-
2007, fatality
though rate in
the the
majority Tugela
of death Ferry
still outbrea
occurred k could
within represe
the first nt a
30 days combina
[166]. In tion of
the factors
systema at play,
tic not only
review host
mention immuno
ed compro
earlier misation
, but end of
also lack life for
of the
access patient
to [83,
adequat 147].
e
diagnosi MEW
s and DRUGS
treatme FOR
nt [170]. TREATM
ENT OF
Pallia TUBERC
tive ULOSIS
mana
geme
Mew

nt
antitube

and
rculosis

end-
drugs

of-life
are

care
needed
to
At a simplify
certain treatme
point in nt )f
time, drug-
recourse suscepti
to ble
palliativ tubercul
e care is osis and
indicate to
d for improve
selected outcome
patients of irug-
with resistant
"difficult tubercul
" MDR osis
or XDR [171].
tubercul Only
osis, in four
the compou
interest nds will
of both be
the liscusse
individu d in
al detail
patient for the
and :he purpose
commun of this
ity as a article,
whole. as these
Such drugs
manage ippear
ment to have
aims to sufficien
provide t
uninterr potentia
upted l for use
medical in
and improvin
psychol g
ogical uberculo
care, as sis
well as therapy
to in the
ensure a coming
dignified decade.
Sloxif However
loxaci , a study
n with
Moxiflox nearly
acin is the ame
an 8- design
methoxy conduct
fluoroqu ed in
inolone Brazil
with a has
long shown
>lasma better
half-life culture
of —11 onversio
h. It has n (80%)
potent in
bacterici patients
dal and receivin
terilising g
activity moxiflox
against acin
M. during
tubercul the litial
osis, as phase of
shown treatme
in nt
murine compare
tudies d with
[172, the
173]. In ethamb
the TB utol arm
Trials 33%)
Consorti [175].
um Another
(TBTC) similar
Study . phase II
7, a clinical
phase II study
trial, has also
substitut hown
ing that
moxiflox patients
acin for in the
ethamb moxiflox
utol in acin arm
he first cleared
8 weeks their
of putum
therapy bacilli
did not more
change quickly
the 2- [176].
month Based
culture on the
tegativit rapid
y rates terilisati
(71%), on
but results
there of the
appeare isoniazid
d to be -sparing
higher regimen
activity t in
earlier murine \
time odels,
point TBTC
[174]. Study
28 was studies,
designe moxiflox
d as a acin
double- speared
blind, to be
lacebo- well
controlle tolerate
d study d by
to most
evaluate patients,
2-month apart
culture from i
conver- increase
on rates d
with the incidenc
substitut e of
ion of nausea.
moxiflox QTc
acin for interval
isoniazid prolonga
in \e 2- tion as
month observe
intensiv d in
e phase some
of patients,
treatme but this
nt of might
pulmona not have
ry inical
iberculo significa
sis. Only nce
a small [175,
nonsigni 177].
ficant Further
increase evaluati
in the 2- on of
lonth the
culture fluoroqu
negativi inolone
ty was is
achieve ongoing
d [177]. in a
More phase III
rapid REMox
:>utum study
culture [179].
conversi This
on was study
also will
observe explore
d with whether
the moxiflox
ddition acin
of substitut
moxiflox ion for
acin to isoniazid
the or
standar ethamb
d short- utol can
course shorten
regimen the
t a conventi
nonrand onal
omised therapy
study from 6
[178]. In to 4
these months.
Moxiflox d for
acin- bacterici
and dal
rifapenti activity
ne- and
based treatme
regimen nt-
s are shorteni
also ng
under potential
investig . The
ation. It duration
should of
be noted treatme
that, nt
when necessar
these y to
drugs achieve
are stable
given cure was
together 10
, weeks
rifapenti for daily
ne may regimen
induce s and 12
enzymes weeks
that for
metabo- three-
lise times-
moxiflox weekly
acin, regimen
resulting s,
in regardle
modestl ss of
y whether
reduced isoniazid
moxiflox or
acin moxiflox
concentr acin was
ations used
[68]. with
Using a rifapenti
murine ne and
model of pyrazina
tubercul mide
osis, [180].
regimen By
s contrast,
consistin under
g of the 12-
isoniazid week
or regimen
moxiflox of RHZ,
acin plus all mice
rifapen- relapsed
tine and . The
pyrazina treatme
mide, nt-
administ shorteni
ered ng
either potential
daily or of more
three- frequent
times- and/or
weekly, higher
were doses of
evaluate rifapenti
ne than of
600 mg sputum
once- conversi
weekly on rates
are and
being treatme
explored nt
in both outcome
animal s, as
experim well as
ents and safety
clinical and
trials, as tolerabili
discusse ty of the
d in the rifapenti
section ne-
on moxiflox
treatme acin-
nt of containi
smear- ng
positive regimen
pulmona s, will
ry thus be
tubercul evaluate
osis. d
Further 181].
more, in
a phase Notwiths
II clinical tanding
trial that these
commen somewh
ced in at
2009, encoura
smear- ging
positive results,
pulmona the high
ry rates of
tubercul fluoroqui
osis nolone-
patients resistant
were tubercul
randomi osis in
sed in many
the parts of
initial 2 the
months world,
to especiall
receive y when
either H- coincidin
rifapenti g with
ne-Z- high
moxiflox disease
acin or burden,
RHEZ, pose
followed concern
by the regardin
standard g the
nonexpe potential
rimental utility of
regimen the new
in the fluoroqui
continua nolones
tion in
phase. shorteni
The ng
efficacy tubercul
in terms osis
treatme ble M.
nt tubercul
182]. osis, as
well as
Regardin other
g the mycobac
role of terial
moxiflox species.
acin in It has a
the long
treatme half-life
nt of in
MDR and plasma
XDR and
tubercul tissues
osis, of nearly
there 24 h.
have Data
been have
some also
promisin suggest
g results ed that
lately TMC207
[183], might
although kill
the issue dormant
of partial bacilli as
cross- effective
resistanc ly as
e among aerobica
M. lly
tubercul grown
osis bacilli.
strains is TMC207
still is
cause metaboli
for sed by
concern cytochro
[184]. me P450
3A4;
TMC2 thus, its
07 plasma
TMC207 level
is a may be
novel reduced
diarylqui by half
noline through
with interacti
unique on with
activity rifampici
on the n.
mycobac However
terial , data
adenosin from a
e mouse
triphosp model
hate have
(ATP) demonst
synthase rated
[185]. It that
is active TMC207
against had
both significa
drug- nt
resistant activity,
and even
-suscepti when its
 exposur TMC207
e was probably
reduced acts
by 50% synergis
and it - tically
was with
added to pyrazina
a strong mide to
backgro exert
und sterilisat
regimen ion
of RHZ. activity.
The In the
bacterici mouse
dal model,
effect of 2-month
TMC207 treatme
in mice nt
was regimen
modest s
during containi
the first ng
week of TMC207
treatme and
nt but pyrazina
increase mide led
d in the to
following sterilisat
three ion,
weeks suggesti
[186]. ng

EUROPEAN RESPIRATORY
JOURNAL

volume 37 number
>0 2
W.W. YEW ET AL. SERIES»
TUBERCULOSIS

treatme evaluate
nt- the use
shorteni of
ng TMC207
potential in MDR
[187]. In tubercul
another osis,
mouse treatme
model nt was
study, given
the triple five
combina times
tion of per
TMC207- week
rifapenti with
ne- TMC207
pvrazi- alone or
namide, various
given combina
once tions of
weekly, TMC207
was plus
more pyrazina
active mide or
than the other
current second-
regimen line
of RHZ drugs
given [189]. All
five TMC207-
times containi
per ng
week regimen
and led s were
to significa
satisfact ntly
ory lung more
culture active
negativit than the
y at 2 non-
months TMC207-
[188]. containi
Such ng
unprece regimen
dented s after 1
activity month of
has therapy.
suggeste
An early
d that it
bacterici
might be
dal
feasible
activity
to
study
develop
with
a fully
ascendin
intermitt
g doses
ent,
of
once-
TMC207
weekly
has
regimen.
demonst
In a rated a
mouse delayed
model to onset of
bacteriol sputum
ysis, smear-
with positive
significa patients
nt with
activity MDR
from day tubercul
4-7 osis
when were
given at randomi
a daily sed to
dose of receive
400 mg, either
which TMC207
was or
similar placebo
in for 8
magnitu weeks
de to on top of
those of a
isoniazid backgro
and und
rifampici regimen.
n over The
the dosing
same scheme
period for
[190]. TMC207
was
A
validate
double-
d for
blind,
further
randomi
testing
sed
in the
phase II
second
clinical
stage,
trial with
being
TMC207
400 mg
in MDR
daily for
tubercul
2 weeks
osis
followed
patients
by 200
began in
mg
2007
three
[191].
times
The
weekly.
study is
In the
being
second
conduct
stage
ed in
planned
two
for proof
consecut
of
ive
effective
stages.
ness,
In the
patients
first
are
explorat
randomi
ory
sed to
stage for
receive
safety
either
and
TMC207
dose
or
determin
placebo
ation,
for 24
newly
weeks
diagnose
on top of
d
a
backgro TMC207
und [192].
regimen. Further
After results
finishing are
24 awaited
weeks of with
treatme great
nt, interest.
patients Like
will moxiflox
continue acin,
to QTc
receive prolonga
MDR tion with
tubercul uncertai
osis n clinical
treatme significa
nt as per nce was
national observe
treatme d in
nt some
guidelin patients,
es. aside
Study from
subjects gastroint
will be estinal
followed upset
for [192].
safety, TMC207
tolerabili can have
ty, a role in
pharmac treatme
okinetics nt of
and MDR and
microbio XDR
logical tubercul
efficacy osis,
for 96 subjecte
weeks d to
after confirma
receivin tion of
g their its
last dose toleranc
of e and
TMC207 safety
[191]. on long-
Prelimin term
ary use. Its
results interacti
from the on with
first rifampici
stage n might
indicate hamper
d high its utility
efficacy in
(faster treatme
rate and nt of
higher drug-
proporti suscepti
on of ble
culture tubercul
conversi osis.

OPC-
on) and

67683
good
toleranc
e of OPC-
67683 is drugs. In
a addition,
nitroimid it has
azole promisin
with g
high intracell
potency ular
in vitro post-
and in antibioti
vivo c effects
against against
M. M.
tubercul tubercul
osis, osis,
inclusive compara
of MDR ble to
strains. those of
It rifampici
probably n [193].
acts In mice,
through 2
inhibitio months
n of cell of OPC-
wall 67683-
biosynth rifampici
esis, a n-
mechani pyrazina
sm mide
similar followed
to that by a
of PA- further 2
824 months
[193], of OPC-
but is 67683-
~20 rifampici
times n led to
more complet
potent. e culture
OPC- negativit
67683 y,
and PA- suggesti
824 are ng that
closely OPC-
related 67683 in
compou combina
nds and tion with
appear other
to show existing
cross- drugs
resistanc could
e. OPC- potential
67683 ly
has a shorten
long tubercul
half-life osis
at ~7-8 therapy
h, with [193]. A
no cross- randomi
resistanc sed,
e or double-
antagoni blind,
stic multicen
activity tre
with phase II
first-line clinical
antitube trial has
rculosis been
underwa against
y since drug-
2008 to suscepti
evaluate ble and
its -resistan
safety, t, and
efficacy both
and dividing
pharmac and
okinetics nonrepli
in the cating
treatme M.
nt of tubercul
MDR osis
tubercul [195].
osis. In From
the first studying
56 days,
colony-
patients
forming
receivin
unit
g an
counts in
optimise
the
d
lungs of
backgro
mice,
und
PA- 824
regimen
showed
were
randomi bacterici
sed to dal
receive activity
either compara
placebo ble to
or OPC- that of
67683 at isoniazid
a dose in the
of 100 or first 8
200 mg weeks
twice- and
daily. sterilisin
Thereaft g
er, the activity
study compar-
subjects able to
will that of
complet HR in
e their the
optimise continua
d tion
backgro phase
und [196]. A
regimen follow-
[194]. up
experim
PA- ent in
824 mice
PA-824 showed
is a advanta
nitroimid ges in
azopyra relapse
n, a rate with
class of the
novel same
antibact combina
erial tion of
agents. drugs
It is when
active
PA-824 was
was conduct
given at ed
a higher recently
dose of in South
100 mg- Africa,
kg-1 evaluati
[197]. ng the
With the efficacy,
novel safety
combina and
tion of pharmac
PA-824- okinetics
moxiflox in newly
acin- diagnose
pyrazina d
mide, sputum
mice smear-
were positive
cured patients
more with
rapidly drug-
than suscepti
with the ble
first-line tubercul
regimen osis
of RHZ, [200].
suggesti Based
ng that on
this findings
combina from the
tion pre-
might clinical
radically and
shorten phase I
the studies,
treatme escalatin
nt of g doses
MDR of PA-
tubercul 824
osis in were
humans administ
ered for
[198].
14
No consecut
serious ive days
adverse to four
events groups
were of
reported patients
in phase and
I single- compare
and d with a
multiple- fifth
dose cohort
trials in receivin
healthy g
voluntee standard
rs [199]. first-line
An antitube
extende rculosis
d early treatme
bacterici nt. The
dal study
activity showed
study substant
ial and suscepti
continue ble and
d early -resistan
bacterici t
dal tubercul
activity osis.
over 14 Again,
days the most
with critical
equivale determin
nt ant
efficacy would be
at all their
doses safety
from a profiles.
daily
dose of Other
200- potent
1,200 ial
mg. One candi
importan dates
t feature Two
of PA- importan
824 is its t
high example
protein s of
binding other
(94%). potential
Thus, it candidat
is es
necessar include a
y to pyrrole
ensure derivativ
that e,
sufficien LL3858,
tly high and a
concentr diamine
ations of compou
the free nd,
drug can SQ109.
be Both
reached have
in been
cavities subjecte
of d to
pulmona phase I
ry testing
tubercul and
osis to further
exert
progress
bacterici
is
dal
ongoing
activity
[55, 202,
[201].
203].
Both
Other
OPC-
potential
67683
candidat
and PA-
es would
824
be those
appear
have
to have
both
potential
potent
roles in
bacterici
treatme
dal and
nt of
sterilisin
drug-
g
activities neurolep
. tic
Example thioridaz
s might ine with
include impressi
ATP ve
synthase antitube
inhibitor rculosis
s, gyrase activity
inhibitor might
s and also
peptide warrant
deformyl repurpos
ase ing to
inhibitor constitut
s [203]. e a new
Aside agent
from for
these treating
new MDR and
drugs XDR
under tubercul
develop osis
ment, a [204].

EUROPEAN RESPIRATORY
journal

45
volume 37 number
2 1
SERIES; W.W. YEW ET
TUBERCULOSIS £_.

A pulmona
D ry
J tubercul
U osis,
N emergen
C ce of
T MDR and
I XDR
V tubercul
E osis has
rekindle
S d the
U enthusia
R sm in
G recourse
E to
R adjuncti
Y ve
surgery
F to
O improve
R the
chance
P of cure
U in some
L patients
M in these
O drug-
N resistant
A scenario
R s [205].
Y Other
indicatio
T ns of
U surgical
B treatme
E nt of
R tubercul
C osis
U centre
L on
O manage
S ment of
I empyem
S a, post-
While tuber-
chemoth culous
erapy bronchie
using ctasis
antitube and
rculosis myceto
drugs ma
constitut [206].
es the There
primary are
treatme three
nt basic
modality selection
for criteria
for is
adjuncti sufficien
ve t to
surgery diminish
in MDR the
tubercul mycobac
osis terial
patients burden
[205]. to
These facilitate
include: healing
1) drug of
resistanc bronchia
e, as l stump
revealed after
by in lung
vitro resectio
suscepti n
bility Patients
testing, should
is so receive
severe chemoth
or erapy
extensiv prior to
e that surgery
there is for
a high months
probabili [205,
ty of 207]. If
failure or possible,
relapse they
with should
medical be
therapy rendere
alone; 2) d
the culture-
disease negative
is before
sufficien lung
tly resectio
localised n.
that the However
great , this
prepond may not
erance always
of radio- occur. In
graphica some
lly cases,
discernib sputum
le culture
disease conversi
can be on only
resected appears
with an with
expectat prolonge
ion of d
adequat medical
e therapy
cardiopu after
lmonary surgery.
capacity Ventilati
after on/perfu
surgery; sion
and 3) scan,
drug pulmona
activity ry
function n has
tests been
and found to
compute be
d rather
tomogra rewardin
phy of g. The
the cure
chest rates
are could
importan reach
t ^90%
investig with
ations pos:-
for pre- surgery
operativ chemoth
e erapy
assessm (table 5)
ent [209-
[205, 222]. In
206]. For resource
some -limitec
patients, areas,
assessm the cure
ent of rates
pulmona might be
ry lower
arterial (63-
pressure 75%),
and but
bronchia lunz
l tree resectio
anatomy n still
/patholo appears
gy need useful as
to be adjuncti
perform ve
ed. manage
Bilateral ment for
disease this
does not formidab
necessar le
ily disease
preclude [218].
surgical However
inter- ,
vention, adjuncti
unless ve
extensiv surger.
e [208]. necessit
Such ates
disease expertis
would, e and
however financial
, require instillatio
staged n, which
bilateral are ofter
resectio not
n. In readily
experien available
ced in many
hands, areas
the where
outcome MDR
of lung tubercul
resectio osa
prevail line
[223]. antitube
Two rculosis
rather chemoth
sizable erapy in
cohort patients
studies with
have MDR and
shown XDR
that the tubercu-
bes: losis
outcome [225].
s in MDR This
tubercul finding
osis suggests
patients the
were possibilit
achieved y of ar.
by the indepen
use of dent role
fluoroqui of lung
nolones resectio
and n in the
adjuncti manage
ve ment of
surgery these
[89, 224 difficult
Although drug-
there resistant
has scenario
been no s.
randomi With the
sed emergen
study to ce of
compare XDR
chemoth tubercul
erapy osis,
alone adjuncti
versus ve
combine surger.
d becomes
chemoth more
erapy relevant
and [121,
surgery 226].
in the Notwiths
manage tanding
ment of its use in
MDR some
tubercul patients,
osis, one the
recen: outcome
small of XDR
series tubercul
reported osis is
significa generall
nt and y worse
durable than
improve that of
men: MDR
with tubercul
lung osis,
resectio with an
n and overall
post- success
operativ rate of
e first- -50%
[121, low body
227]. mass
However index
, in (<18.5
selected kg-rrf"
patients, bacillary
sustaine resistanc
d e to
sputum fluoroqui
bacteriol nolones
ogical and
conversi presenc
on can e of
be cavity
satisfact beyond
orily the
maintain range of
ed surgical
[228]. resectio
From n
two portende
large d poor
series, prognosi
patients s in a
who had carefully
adjuvant perform
surgery ed study
experien [219].
ced The
better major
outcome complica
s [89, tions of
229]. surgical
Regardin treatme
g the nt of
factors pleuropu
governin lmonarv
g tubercul
outcome osis
of include
surgery broncho
for drug- pleural
resistant fistula,
tubercul residual
osis, a space

rCT^gHj Surgical
treatment of
muitidrug-resistant
tubercuiosis#
First author [ref.] Patients Treatment Operative Post-operative
n success % mortality % complications %
TREASURE [209] 19 89 0 9
VAN LEUVEN [210] 62 75 ÏÏÊSÊÈÊSÊÊÊSÊËffÊÊÊÊÊliÊÎË 23
:
SUNG [211] 27 96 0 26
POMERANTZ [212] 172 98 3 12
CHIANG [213] 27 92 4 11
PARK [214] 49 94 0 16
NAIDOO [215] 23 96 0 17
TAKEDA [216] 26 89 3 14

KIR [217] 79 95 3 5

SOMOCURCIO [218] 121 63 5 23

KIM [219] 79 72 ; 1 . 23
MOHSEN [220] 23 96 4 35
WANG [221] 56 87 0 25
SHIRAISHI [222] 56 98 0 16
# : most patients had lung resections in the form of pneumonectomy or lobectomy (a minority also had segmentectomy),

452

volume 37 number 2

EUROPEAN RESPIRATORY
journal
 W.W. YEW ET SERIES: TUBE
AL.

TB granuloma Miliary/
disseminated
TB

Chemoki
nes
CCRs

Cytolysis
Opsonisatio
n Apoptosis
ADCC
Granul
ysin
FIGURE 2, perfori
7IL-
Caseatio
PM n 17 ?ll
N
nFas-21
TNF-ot

Immunopathogenesis of
tuberculosis. ADCC: antibody-
dependent cell-mediated
cytotoxicity; CCR: CC
chemokine receptor; DN:
double negative; Fas: cell
receptor inducing apoptosis;
IFN: interferon; IL: interleukin;
LpAg: lipopolysaccharide
antigen; M0: macrophage;
MHC: major histocompatibility
complex antigen; NK: natural
killer cell; PAg: peptide
antigen; PpAg: phospho-
antigen; PMN:
polymorphonuclear neutrophil;
RNI: reactive nitrogen
intermediates; ROI: reactive
oxygen intermediates; TB:
tuberculosis; TGF:
transforming growth factor; Th:
T-helper cell; TNF: tumour
necrosis factor; Treg: T-
regulatory cell.
problems versus
and nothing
empyem or
a. Other stapling
complica versus
tions suturing
include as a
wound means of
and closure
other of the
infection stump.
s, Many
bleeding, authoriti
cardiovas es,
cular however,
embarras have
sment, recomme
atelectas nded
is and reinforce
recurrent ment of
laryngeal the
nerve bronchial
injury. stump,
The risk especiall
factors y in
for selected
bronchop patients
leural at risk
fistula from
mainly such
include complica
sputum- tions
smear [222,
positivity 230].
, low In some
forced frail
expirator patients
y volume with MDR
in 1 s, tuberculo
old age, sis, who
and usually
perhaps have
the limited
techniqu cardiopul
e of monary
stump reserve
closure and,
and thus,
reinforce would
ment not
230]. withstan
d lung
There resection
have , collapse
been no therapy
randomis using
ed thoracopl
controlle asty
d studies 231],
that
compare plombag
d e [232]
bronchial and
stump artificial
reinforce pneumot
ment horax

european respiratory
journal
[233] can ion
be group,
consider culture
ed. negativit
Thoracop y was
lasty, achieved
aside in all new
from cases
causing and
cosmetic 81.1% of
ally retreatm
unappeal ent cases
ing (-80% of
deformit the
y of the patients
thoracic had MDR
cage, tuberculo
can be sis).
associate Cavity
d with closure
obstructi occurred
ve and in 94.6%
restrictiv and
e lung 67.9%,
function respectiv
defects ely. In
after the the
procedur control
e. group,
Extrapleu culture
ral lucite negativit
sphere y was
plombag achieved
e can in 70.9%
give rise and
to 40.0%,
pressure respectiv
effects, ely, and
migration cavity
and closure
foreign- occurred
body in 56.3%
irritation and
problems 24.0%
. The use respectiv
of ely.
artificial
pneumot ADJUNCT
horax IVE
has been IMMUNO
reapprais THERAP
ed in a Y IN
recent TUBERC
study ULOSIS
with Macroph
rather ages,
encourag dendritic
ing radio- cells,
graphic natural
and killer
bacteriol cells,
ogical yST-cells
and CDl-
results
restricted
[233]. In
T-cells
the
are
intervent

volume 37 number
2 453
involved largely
in the secrete
initial or induce
cell- IL-4, -5,
mediated -6 and
immune -10. IL-12
response produced
to M. by
tubercul macroph
osis, and ages
determin expands
e the Thl cell
local or populatio
distant n and
progressi upregula
on of tes its
infection functions
to . Cell-
disease mediated
versus protectiv
containm e
ent of immunitv
the appears
infection. to be
Antigens
of M.
tubercul
osis are
processe
d bv the
antigen-
presentin
g cells.
Subsequ
ently,
CD4+
cells are
involved.
T-helper
(Th)
cells,
largely
CD4+
cells,
generally
mature
into two
functiona
lly
different
phenotvp
es, often
termed
Thl and
Th2 cells.
The
former
secrete
principall
y
interleuki
n (IL)-2
and
interfero
n (IFN)-v,
while the
latter
associate athogene
d with a sis of
Thl tuber-
response culosis.
[234]. IL- Thus, the
18, complex
another immunop
cytokine athogene
linked to sis of
Thl tubercu-
pathway, losis
may also embrace
have a s host
putative tissue
role in inflamma
cell- tion and
mediated damage,
protectio in
n against addition
mycobac to
terial protectiv
infection e
[235]. immunity
Tumour against
necrosis the
factor tubercle
(TNF)-a, bacilli.
released Athough
largely a recent
from in-depth
macro- review
phages, on the
contribut immunot
es to herapy
protectin for
g the tubercul
host by
osis has
promotin
revealed
g
a
granulom
number
a
of
formatio
potential
n [236].
ly useful
However,
agents
TNF-a
for
can also
immunor
cause
egulatio
tissue
n,
necrosis
immuno
under
augment
subversiv
ation or
e T-cell
immuno
influence
. There is sup-
some pression,
evidence no
this evidence
sabotage -based
effect recomm
comes endation
from IL-4 can yet
overactiv be
ity [237]. formulat
Figure 2 ed
summari regardin
ses the g their
immunop clinical
utility steroids
[238]. are
Adjuncti effective
ve in
corticost tubercul
eroids ous
have pleural
been effusion
used as [241]. In
an HIV-
attempt infected
to patients,
ameliora steroids
te have
inflamm been
ation. shown to
Cochran be
e beneficia
reviews l in
have tubercul
shown ous
improve meningit
d is,
mortality although
of the
patients overall
with prognosi
tubercul s is still
ous poor
pericardi [242].
tis [239] Steroid
and use in
meningit tubercul
is [240] ous
with pleural
steroid effusion
therapy, in HIV-
but infected
incon- patients
clusive was
effects associat
for ed with
pericardi a higher
al incidenc
constrict e of
ion. Kaposi's
Neurolog sarcoma
ical [243].
deficit or An
disability addition
was al
improve concern
d among is that
survivors adjuvant
with steroid
tubercul therapy
ous of HIV-
meningit related
is. There tubercul
is osis has
currently been
inadequ associat
ate ed with
evidence a
on transient
whether increase
 in viral resistant
load forms.
[244]. In Table 6
these depicts
two the
latter results
studies, of a
the number
dosages of
of prelimin
predniso ary
lone studies
used regardin
were 50 g the
mg- use of
day"1 cytokine
and 2.75 s
mg-kg"1 (especial
-day"1, ly IFN-y)
respecti [246-
vely, 251] and
with Mycobac
gradual terium
tapering vaccae
off in 8 (NCTC
weeks 11659)
[243, [252], an
244]. avirulent
SERIES' TUBERCULOSIS W.W. YEW ET AL

Preliminary studies on adjunctive immunotherapy of multidrug-resistant tuberculosis

First author [réf.] Immunomodulator/cytokine Outcome

CONDOS [246] IFN-y (aerosotised) Baciilary load lowering, radiographic improvement (CT)

JOHNSON [247] rhulL-2 (subcutaneous) Reduced baciilary load, radiographic improvement

PALMERO [248] rlFN-a2b (subcutaneous) Baciilary load reduction
GIOSUE [249] IFN-a (aerosolised) Baciilary load reduction, radiographic improvement (CT)
GRAHMANN [250] IFN-y (aerosolised) Baciilary load lowering, radiographic improvement
PARK [251] IFN-y (subcutaneous) No bacteriological conversion on smear and culture, no radiographic
improvement (CT)
STANFORD [252]
Mycobacterium vaccae
Disease yr: cure rate 82% (1-2 doses); chronic cases: cure rates

(intradermal)
7.6% (1 dose), 37.9% (7 doses), 41.6% (12 doses)
I FN: interferon; CT: computed tomography; r: recombinant; hu: human; IL: interleukin.

Cytokine vaccine
supplem from a
entation nontuber
was culous
initially mycobac
thought terial
to be species,
promis- in the
ing manage
adjuncti ment of
ve MDR
therapy tubercul
in osis. In a
tubercul more
osis recent
[245], study,
including nebulise
drug- d IFN-ylb
adjuvant allied
therapy forms of
was also immunot
found to herapy
improve in
constitut tubercul
ional osis
sympto treatme
ms, nt.
reduce By
inflamm enhancin
atory g
cytokine mycobac
s in terial
broncho killing in
alveolar macroph
lavage ages,
and vitamin
improve D might
clearanc have the
e of potential
acid-fast to
bacilli enable
from shorteni
sputum ng of
in treatme
cavitary nt
pulmona duration
ry for
tubercul tubercul
osis osis,
[253]. reducing
While infectiou
the sness
results and
from improvin
some of g
these response
in drug-
studies
resistant
are
forms of
encoura
the
ging, the
disease
limited
[254].
number
However
of
, a
enrolled
double-
patients,
blind,
alongsid
randomi
e often sed,
uncontro placebo-
lled controlle
experim d trial
ental [255]
designs, has
leaves recently
great shown
uncertai that
nty vitamin
regardin D, as a
g the supplem
definitiv entary
e role of therapy
these did not
cytokine improve
s and clinical
outcome addition,
(as there
assessed appear
by to be
clinical some
score agents
severity that can
and promote
sputum intracell
smear ular
conversi killing of
on) M.
among tubercul
patients osis by
with macroph
tubercul ages,
osis. through
There affecting
was also the
no transpor
overall t of K+
effect on and Ca2+
tubercul from the
osis phagolys
mortality osome,
at 12 thereby
months. resulting
One in better
caveat acidificat
might be ion and
the activatio
possiblv n of
insufficie hydrolas
nt dose es [256].
of This
vitamin might be
D used. a
The promisin
clinical g
role of direction
vitamin of
D in developi
immunot ng
herapy therapy
of for drug-
tubercul resistant
osis is tubercul
currently osis.
uncertai
n. CONCL
USION
In
In 2010, the prevailing
challenges of HIV
infection and drug
resistance still
undermine the global
control of
tuberculosis. With
clear indications that
XDR tuberculosis
results from
mismanaged cases of
drug-susceptible and
MDR tuberculosis, it is
imperative to treat
drug-susceptible
tuberculosis appro-
 priately to completion,
and to provide rapid
diagnosis, and
aggressive as well as
appropriate treatment
of MDR tuberculosis to
avoid the unnecessary
development of
additional cases of
XDR tuberculosis. The
main priority
interventions would
be: 1) strengthening
control of
tuberculosis, through
sound implementation
of the Stop TB
Strategy, with special
focus on laboratory
capacities and
infection control
(including HIV

EUROPEAN RESPIRATORY
journal

volume 37 number
454 2
 W.W. YEW ET AL.
Grading of evidences for recommendations according to the Scottish Intercollegiate
Guidelines Network
Study rating Study design
TABLE 7
High-quality meta-analyses, systematic reviews of RCTs or RCTs with a very low
risk of bias Well-conducted meta-analyses, systematic reviews, or RCTs with a
low risk of bias As above
High-quality case-control/cohort studies or their systemic reviews, with very low
risk of confounding/bias and high probability of causal relationship Well-conducted
case-control/cohort studies with low risk of confounding/bias and a moderate
probability of causal relationship Nonanalytic studies, e.g. case reports, case
series Expert opinion
Directly applicable
RCT: randomised controlled trial.
+ control); 2) improvement of programmatic management
of drug-resistant tuberculosis, based on updated
+ guidelines, largely from WHO; and 3) promotion of
research and development of new diagnostics, vaccines
1 and drugs, as well as other modalities of therapy.
While scientific advancement is crucial to better the care
+ of tuberculosis patients and is earnestly awaited, existing
144 tools must be harnessed in sound public health settings
-/1 to curb the epidemic of tuberculosis today [257].
+
APPENDIX
2 For Appendix, see table 7.
+ >1
STATEMENT OF INTEREST study
+
None declared.
2+
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