REVIEW

Korean J Intern Med 2016;31:15-29

http://dx.doi.org/10.3904/kjim.2016.31.1.15

Emerging strategies for the treatment of

pulmonary tuberculosis: promise and limitations?
Wing Wai Yew1 and Won-Jung Koh2

1
Stanley Ho Centre for Emerging A worsening scenario of drug-resistant tuberculosis has increased the need for
Infectious Diseases, The Chinese new treatment strategies to tackle this worldwide emergency. There is a press-
University of Hong Kong, Hong
Kong; 2Division of Pulmonary and ing need to simplify and shorten the current 6-month treatment regimen for
Critical Care Medicine, Department of drug-susceptible tuberculosis. Rifamycins and fluoroquinolones, as well as sever-
Medicine, Samsung Medical Center,
Sungkyunkwan University School of
al new drugs, are potential candidates under evaluation. At the same time, treat-
Medicine, Seoul, Korea ment outcomes of patients with drug-resistant tuberculosis should be improved
through optimizing the use of f luoroquinolones, repurposed agents and newly
Received : May 6, 2015
Accepted : May 11, 2015 developed drugs. In this context, the safety and tolerance of new therapeutic ap-
proaches must be addressed.
Correspondence to
Wing Wai Yew, M.D.
Stanley Ho Centre for Emerging Keywords: Tuberculosis; Drug resistance; Therapeutics
Infectious Diseases, The Chinese
University of Hong Kong, Hong
Kong
Tel: +852-2252-8884
Fax: +852-2635-4977
E-mail: yewww@cuhk.edu.hk

INTRODUCTION need to achieve: (1) shortening and simplification of the

treatment regimens of drug-susceptible TB and (2) an
Tuberculosis (TB) is a major infectious disease that improvement of the treatment of MDR-TB and XDR-
causes significant morbidity and mortality [1,2]. The TB. These strategies can be viewed as preventative, to
principal challenge in its treatment is the emergence forestall the emergence of forms of TB that are difficult
of drug-resistant forms leading to worsening scenar- to treat, and definitive, to tackle the established scenar-
ios worldwide [3,4]. Multidrug-resistant (MDR)-TB is ios of drug resistance, respectively.
defined as bacillary resistance to isoniazid and rifam- To help our understanding, this mini-review is lim-
picin. Extensively drug-resistant (XDR)-TB is usually ited to strategies for the treatment of pulmonary TB
defined as MDR-TB with additional bacillary resis- only; those concerning latent infections due to Myco-
tance to fluoroquinolones and one or more of the sec- bacterium tuberculosis are beyond the scope of this review.
ond-line injectable drugs of kanamycin, amikacin and Human immunodeficiency virus (HIV) coinfection is-
capreomycin. The spread of drug resistance is a cause sues are also only mentioned briefly. Furthermore, im-
for concern and totally drug-resistant-TB has been re- munotherapy and other adjunctive treatment options
ported in some parts of the world, such as India and for TB, such as surgery, are not included in this article.
South Africa [5-7].
Given this worsening scenario, new strategies to meet
the therapeutic challenge of drug-resistant TB would

Copyright © 2016 The Korean Association of Internal Medicine pISSN 1226-3303

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 The Korean Journal of Internal Medicine Vol. 31, No. 1, January 2016

SHORTENING AND SIMPLIFYING SHORT- ethambutol for 2 months, followed by a continuation

COURSE CHEMOTHERAPY FOR PULMONARY TB phase that comprises the concomitant use of rifampi-
cin and isoniazid for another 4 months [11]. Thus, the
total duration of therapy lasts for 6 months. A strate-
The biology of M. tuberculosis and the scientific basis gy known as directly observed treatment, short-course
of short-course TB treatments (DOTS), focusing on supervised therapy and holistic
In theory, there exist different populations of M. tu- care, is generally recommended to achieve a good pa-
berculosis within pathological TB lesions in the body tient cure rate, and to curtail the development of bac-
(commonly in the lungs) of the host, or within dif- illary resistance to drugs. However, a 6-month treat-
ferent parts of the same lesion. This phenomenon of ment is lengthy and patient adherence throughout can
heterogeneity is highly relevant to our understanding be difficult to guarantee. In addition, the amount of
of the scientific basis of short-course chemotherapies resources required to deliver DOTS, even with enlist-
used to treat TB [8,9]. In general, there are abundant ment of community participation, can be substantial,
bacilli undergoing continuous growth and rapid repli- especially in countries with a high TB burden. As a re-
cation that constitute a distinct mycobacterial popula- sult, it is easy to understand why a shorter treatment
tion commonly found in highly aerobic environments, duration should be investigated as an alternative meth-
such as the lumen of a pulmonary cavity. Other bacilli od to treat TB [12,13].
undergoing spurts of metabolism or even hibernation
are also present. These organisms are known as per- Possible approaches to shorten drug-susceptible TB
sisters [10]. Such hibernating mycobacteria develop chemotherapy and its associated limiting issues
through stochastic evolutionary processes and are in- The most successful and workable approach would be to
duced by environmental clues such as antibiotic stress explore more effective means of dosing and scheduling
and nutrient deprivation, and are believed to reside of currently available agents to enable efficacious and
in unstable pulmonary lesions, such as the biofilms efficient treatment of TB. In this context, two groups
on the inner wall of cavities, or in inflammatory ar- of drugs can readily be considered; the rifamycins and
eas in the lung parenchyma, or even intracellularly the fluoroquinolones. Newly developed drugs for the
within macrophages. Unlike the rapidly growing or- treatment of TB also offer considerable promise (Fig. 1).
ganisms, which are susceptible to bactericidal activ-
ity of antimicrobial drugs, the persisters can only be Rifamycins
tackled by agents that have a sterilizing activity [9]. In Rifamycins have a dose-dependent, early bactericidal
the treatment of TB, drugs with distinct bactericidal activity (EBA) against M. tuberculosis, with a linear rela-
activity usually include isoniazid and sometimes also
aminoglycosides, whereas drugs that have a predomi-
nant sterilizing activity include the rifamycins and the
fluoroquinolones (which also have some bactericidal Rifamycins
activity). Pyrazinamide, however, only has a sterilizing High-dose rifampicin?
High-dose rifampentine?
activity. The totally dormant organisms are assumed to Current
reside largely in densely fibrotic and calcified areas of drugs with
Fluoroquinolones bactericidal
the lungs, and it is believed that they cannot be readily Optimal dose?? & sterilizing
killed by antimicrobial therapies [10]. activities

Rationale for shortening the current short-course

TB chemotherapy New drugs
The conventional or standard short-course treatment
for pulmonary TB comprises an intensive phase with Figure 1. Potential candidates for a reduced 6-month treat-
rifampicin and isoniazid, as well as pyrazinamide and ment duration of drug-susceptible tuberculosis.

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Yew WW and Koh WJ. Treatment of pulmonary TB

tionship to a logarithmic dose at lower doses and a cur- initially enrolled into a control group receiving the
vilinear response at higher doses [14]. Thus, enhancing standard rifampicin dose of 10 mg/kg, whereas the ex-
the rifamycin delivery method by increasing the dose perimental groups each received 20, 25, 30, and 35 mg/
and frequency of administration might boost its activ- kg, respectively, for 14 days. Over the last 7 days, each
ity against M. tuberculosis. In addition, rifamycins have patient also received isoniazid, ethambutol, and pyr-
a sterilizing activity that can eliminate the mycobacte- azinamide in the usual doses. Peak serum rifampicin
rial persisters (mainly semi-dormant or near-dormant levels and total rifampicin exposure showed a higher
organisms) within the host [15]. This anti-persister than proportional escalation with higher doses and a
mechanism is highly relevant in attempts to shorten larger than estimated reduction in the bacillary load in
the duration of TB treatment, as the persisters are gen- the two highest dose groups. Safety and tolerance were
erally regarded as the culprits of relapses of TB disease within normal levels for all doses, but the study dura-
[16]. tion and number of subjects were limiting factors and
A randomized controlled trial (RCT) on drug-suscep- did not enable complete confidence in the toxicity as-
tible TB, involving patients treated with rifapentine, a sessment. In a case-control study in India, a peak plas-
long-acting cyclopentyl rifamycin, at a dose of 10 mg/ ma rifampicin concentration of 12.5 mg/L or more on
kg versus rifampicin at a dose of 10 mg/kg, both for 5 day 7 possibly predicted the subsequent development of
days per week, did not reveal significantly better activi- drug-induced hepatitis in the vast majority of patients
ty of the former over the latter with respect to an 8-week [20]. Other high-dose rifampicin studies are listed in
sputum culture conversion from positive to negative, Table 1. Some of these have already been completed and
although the longer-acting rifapentine was found to the results are currently being analyzed. The reports
be safe and was well-tolerated at the explored dose are awaited with great interest.
and frequency of administration [17]. Higher rifapen- Furthermore, while all these enhanced rifamycin
tine exposure (20 mg/kg daily, for 7 days per week) was trials have alluded to greater efficacy in terms of en-
significantly associated with a higher sputum culture hanced bactericidal activity in the early weeks of treat-
conversion from positive to negative on completion of ment (with reduced culture times and an increased
an 8-week intensive phase of treatment [18]. Greater ex- proportion of subjects showing bacteriological im-
posure to rifapentine, via a higher dosage, was also tol- provement), the potential for these parameters to act as
erated by patients. Two other RCTs of rifapentine-based robust markers for sterilizing activity remains conten-
regimens are awaiting analysis of the results. One of tious. The relapse rate on follow up after completion of
the trials compares rifapentine 600 mg/450 mg versus the full course of TB treatment remains the gold stan-
rifampicin 600 mg (NCT00814671), and the other com- dard to evaluate the sterilizing activity of a drug/drug
pares rifapentine 7.5 mg/kg and moxifloxacin versus regimen and the potential of the agent(s) to shorten the
rifampicin 10 mg/kg and ethambutol (NCT 00728507). length of the TB treatment [21]. Improved understand-
The results of an EBA study on the use of high-dose ing of M. tuberculosis persister will increase the poten-
rifampicin have also been published recently [19]. In tial to discover biomarkers better suited to identify
this study, patients with drug-susceptible TB were viable, nonculturable mycobacteria and, thus, assess

Table 1. Clinical trials of high-dose rifampicin in the treatment of drug-susceptible tuberculosis

Trial registration number Trial drug regimen Trial phase
ISRCTN 55670677 Rifampicin: 20 mg/kg vs. 15 mg/kg vs. 10 mg/kg IIB
NCT00760149 Rifampicin: 1,200 mg vs. 900 mg vs. 600 mg IIB
NCT01408914 Rifampicin: 20 mg/kg vs. 15 mg/kg vs. 10 mg/kg IIB
NCT01785186 Rifampicin 35 mg/kg + Ethambutol vs. Rifampicin 10 mg/kg + SQ109 vs. IIB
Rifampicin 20 mg/kg + SQ109 vs. Rifampicin 20 mg/kg + Moxifloxacin vs.
Rifampicin 10 mg/kg + Ethambutol

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 The Korean Journal of Internal Medicine Vol. 31, No. 1, January 2016

the chances of relapse from the proportion of myco- Fluoroquinolones

bacterial persisters, during and after short-course TB Prompted by the encouraging results from murine TB
treatments [22,23]. Possible approaches, phenotypic and models of the possible sterilizing effects of later gen-
transcriptomic in nature, are now under active investi- eration fluoroquinolones [26,27], a number of studies,
gation [24,25]. many of which are RCTs [28-36], have aimed to identi-
fy whether fluoroquinolones could be used to shorten

Table 2. Clinical trials on the use of fluoroquinolones in drug-susceptible tuberculosis

Source Study design Findings summary
Burman et al. RCT Substituting moxifloxacin for ethambutol during the intensive phase of
(2006) [28] treatment did not affect the 2-month sputum culture status (71% in both groups),
but did increase the proportion of negative cultures at earlier time points.
Patients treated with moxifloxacin more commonly suffered from nausea, but
similar proportions in both groups completed the study treatment (88% vs. 89%).
Dorman et al. RCT Substituting moxifloxacin for isoniazid during an intensive phase of treatment
(2009) [29] resulted in a small but nonsignificant increase in culture negativity after 8
weeks (60.4% vs. 54.9%).
Wang et al. Cohort study Adding moxifloxacin to isoniazid, rifampicin, pyrazinamide and ethambutol
(2010) [30] shortened the time to culture conversion, and significantly increased the
proportion of culture conversion after 6 weeks (82% vs. 61%).
Conde et al. RCT Adding moxifloxacin instead of ethambutol to isoniazid, rifampicin and
(2009) [31] pyrazinamide significantly improved the proportion of converted cultures after
8 weeks (80% vs. 63%).
Jawahar et al. RCT Administering gatifloxacin or moxifloxacin instead of ethambutol in the first
(2013) [32] 2 months, with isoniazid, rifampicin and pyrazinamide for 6 months
(thrice weekly) resulted in significantly more recurrences in the gatifloxacin
group than the control group (15% vs. 6%).
Gillespie et al. RCT Substituting moxifloxacin for either ethambutol or isoniazid in the first 17
(2014) [33] weeks followed by a placebo for 8 weeks resulted in significantly more unfavorable
outcomes (treatment failure or relapse within 18 months) in a 4-month regimen
compared to the standard 6-month regimen (difference: 11.4% and 6.1%, respectively).
Merle et al. RCT A 4-month regimen comprising isoniazid, rifampicin, and gatifloxacin
(2014) [34] supplemented by pyrazinamide during a 2-month intensive phase yielded
significantly more unfavorable outcomes (treatment failure, recurrence, death,
or dropout during treatment) than the standard 6-month regimen (difference: 3.5%).
Recurrence rates of the 4- and 6-month regimens were 14.6% vs. 7.1%, respectively).
Jindani et al. RCT A 4-month daily regimen comprising moxifloxacin, rifampicin, pyrazinamide
(2014) [35] and ethambutol in the first 2 months followed by moxifloxacin and rifapentine
twice weekly for 2 months was compared with a 6-month regimen
(continuation phase: moxifloxacin and rifapentine weekly for 4 months) and
a 6-month standard regimen. The 4-month moxifloxacin-based regimen
resulted in significantly more unfavorable responses (treatment failure or
relapse), with a difference of 13.6% per protocol analysis and 13.1% by modified
intention-to-treat analysis. The 6-month moxifloxacin-based regimen was found
to be as effective as the 6-month standard regimen.
Velayutham et al. RCT A daily regimen comprising moxifloxacin, isoniazid, rifampicin, ethambutol,
(2014) [36] and pyrazinamide yielded a significantly higher proportion of culture conversion
after 2 months of treatment (95% vs. 81%).
RCT, randomized controlled trial.

18 www.kjim.org http://dx.doi.org/10.3904/kjim.2016.31.1.15
Yew WW and Koh WJ. Treatment of pulmonary TB

the duration of TB chemotherapy. These studies are A randomized dose-ranging study regarding the EBA
listed in Table 2. For example, one RCT suggested that of delamanid at 100, 200, 300, and 400 mg over 14 days
moxifloxacin might have sterilizing activity due to the revealed exposure-dependent activity [39]. The drug
rate of conversion of a sputum culture from positive to exposure, however, plateaued at 300 mg, presumably
negative after 8 weeks of treatment [31]; however, the due to absorption limitations resulting in less than
relapse rate after cessation of treatment would reflect proportional exposure increases.
the sterilizing capacity of the drug/drug regimen more A 14-day EBA study randomized patients to receive
accurately. Currently, 4-month moxifloxacin-/gatiflox- 200, 600, 1,000, and 1,200 mg of pretomanid and
acin-containing regimens have not been shown to be the results indicated an optimal performance at the
non-inferior to the standard 6-month short-course relatively low dose of 200 mg [40]. Another random-
regimen currently in use [33-35]. Although one RCT ized dose-ranging phase II study of 14-day EBA of a
suggested that adding moxifloxacin to the standard once-daily pretomanid dose at 50, 100, 150, and 200
4-drug short-course regimen would enhance the bac- mg demonstrated acceptable safety and tolerance at all
tericidal activity of the combination substantially, doses [41]. A lower EBA was observed in those patients
interpretation of the results might be limited by the given pretomanid 50 mg once daily, but this was not
confounding difference in the dosing schedules be- statistically significant. A further phase IIA EBA study
tween the test regimens and the control regimen [36]. evaluated patients randomized to receive 5-drug combi-
It is possible that the potential sterilizing activity of nations in comparison with the standard 4-drug short-
the later generation fluoroquinolones is related to the course regimen, i.e., pretomanid with bedaquiline,
size of the dose, similar to the rifamycins. More work pretomanid with pyrazinamide, pretomanid with
is needed to explore this, and the safety and tolerance moxifloxacin and pyrazinamide, bedaquiline, and be-
of these compounds with dose escalation must also be daquiline with pyrazinamide [42]. The dosages of pre-
evaluated. tomanid and bedaquiline were 200 and 400 mg once
daily, respectively. The 14-day EBA of pretomanid with
New drugs moxifloxacin and pyrazinamide was comparable with
Several new drugs, including bedaquiline (a diaryquin- those of pretomanid with pyrazinamide and the stan-
oline that interferes with ATP synthesis), delamanid (a dard 4-drug combination, and was significantly higher
nitro-dihydro-imidazooxazole derivative that inhib- than the other groups. The favorable results shown by
its mycolic acid biosynthesis), pretomanid or PA-824 this 3-drug combination have been corroborated by a
(a nitroimidazo-oxazine with a similar mechanism of subsequent phase IIB open-label, partly- randomized
action to delamanid), and sutezolid (an oxazolidinone study that compared the bactericidal activity of the
that acts on ribosomal protein synthesis) have all com- combination of pretomanid, moxifloxacin, and pyra-
pleted evaluation in phase II clinical trials for efficacy zinamide with that of rifampicin, isoniazid, ethambu-
and safety as anti-TB drugs. tol, and pyrazinamide, which demonstrated the superi-
Bedaquiline has significant EBA at a dose of 400 ority of the former regimen [43]. Thus, the combination
mg [37]. Another 14-day EBA study selected patients of pretomanid, moxifloxacin, and pyrazinamide could
with drug-susceptible TB randomly to receive com- be useful for treating TB, and a phase III study is now
binations of bedaquiline with pyrazinamide-clofaz- underway (STAND trial: GATB NC-006).
imine, pretomanid-pyrazinamide, pretomanid-pyra- Sutezolid is a newer member of the oxazolidinones,
zinamide-clofazimine and pretomanid-clofazimine, of which linezolid is a known repurposed drug used
or clofazimine, or pyrazinamide alone, or the stan- in the treatment of TB. Repurposed drugs are agents
dard 4-drug combination [38]. The combination of that were initially not intended for the treatment of
bedaquiline-pretomanid-pyrazinamide yielded the TB when launched. A 14-day EBA study of sutezolid
most favorable activity. It should be noted that two in the sputum, as well as an assessment of intracel-
newly developed drugs were included in this novel lular bactericidal effects using whole blood cultures,
regimen. showed favorable results when the drug was utilized at

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 The Korean Journal of Internal Medicine Vol. 31, No. 1, January 2016

a dosage of 600 mg twice daily or 1,200 mg once daily did not appear to be active on its own or to enhance
[44]. AZD5847, another member of this class of com- the activity of rifamycin [49]. In a similar fashion, as
pounds, has been assessed in an extended EBA study bedaquiline constitutes a substrate for the cytochrome
(NCT01516203) involving a dose-ranging evaluation P450 isozymes (isoenzymes), expected interactions with
in comparison with the standard rifampicin-isonia- inducers such as rifampicin would occur and might
zid-ethambutol-pyrazinamide combination. The re- lead to attenuation of the therapeutic activity of the di-
sults are currently being analyzed. arylquinoline [50]. Some TB patients also suffer from
As bedaquiline, delamanid and pretomanid all have HIV coinfection, and in these cases the potential for
proven sterilizing activity, as demonstrated in animal complex pharmacokinetic and pharmacodynamic in-
models, there is the distinct possibility that these com- teractions between antiretroviral drugs and new an-
pounds can be included in the design of novel drug ti-TB drugs can be daunting. Overlapping toxicities,
regimens to shorten current TB chemotherapies [45]. notably dermatopathy, neurotoxicity, cardiotoxicity,
The 14-day EBA (phase IIA)/phase IIB studies can help nephrotoxicity, and other adverse effects might also
to demonstrate the bactericidal activity of these agents pose a significant challenge in the clinical manage-
and possibly shed some light on their sterilizing activi- ment of these patients [45]. Aside from HIV infection,
ties against mycobacterial persisters [46]. One major is- other populations also vulnerable to drug-drug inter-
sue with regard to the long-term use of these new drugs actions include elderly patients and those with organ
in a clinical setting concerns the limited amount of transplants [51].
data regarding their safety and tolerance. This could be Bedaquiline is a substrate of cytochrome P450 (CYP)
addressed through evaluations in phase III trials [45]. 3A4, and is actively metabolized to a N-monodesmeth-
Likewise, the newer oxazolidinone congeners, sutezol- yl derivative. As mentioned above, the rifampicin-be-
id and AZD5847, which have potential roles for treating daquiline interaction hampers the development of
drug-susceptible and drug-resistant forms of TB, also diarylquinoline for the treatment of drug-susceptible
face similar problems. TB when rifamycin is included in the drug regimen.
The rising resistance rates of M. tuberculosis strains Interaction of bedaquiline with efavirenz, a non-nu-
to fluoroquinolones and pyrazinamide, especially in cleoside reverse transcriptase inhibitor, has been re-
patients with acquired MDR-TB, but also in those with ported, albeit with some variability in the severity of
a high risk of transmitted bacillary resistance, pose the outcomes [52,53]. Bedaquiline should only be ad-
possible limitations on the use of these “new” drug ministered with caution to patients receiving ritona-
regimens [47]. Clearly any adverse bacillary resistance vir-boosted lopinavir, as there would be a resultant
would hamper the efficacy of such regimens concomi- escalation of bedaquiline exposure due to pharmaco-
tantly containing fluoroquinolones and pyrazinamide, kinetic inhibition [54]. An estimated 30% of sutezolid
which are also intended to contribute to the sterilizing and 20% of pretomanid doses are also metabolized by
activity of these novel treatment regimen options [45]. CYP3A4 [55]. Efavirenz reduced the exposure of preto-
Drug-drug interaction is another hurdle in the de- manid by ~30%, but lopinavir-ritonavir exerted much
velopment of regimens to shorten the duration of TB less effect [56]. Delamanid has no known association
chemotherapy. The interaction between rifampicin with the CYP isozymes and; thus, has a low potential
and moxifloxacin, possibly through induction of ef- for pharmacokinetic interactions with this family of
fects of the former on the glucuronidation or sulpha- isozymes [57]. The metabolism of SQ109 is not associat-
tion of the latter, was shown to result in reduced plas- ed with CYP3A4 but this ethylenediamine is a substrate
ma concentrations of fluoroquinolone [48]. In a study to of CYP2D6 and CYP2C19, which can be significantly
evaluate the safety, tolerability, pharmacokinetics and inhibited by some triazoles, albeit with uncertain clin-
bacteriological effects of different doses of SQ109 (an ical implications [55,58].
ethylenediamine derivative analogous to ethambutol), In the future, as novel regimens for the treatment of
a 300 mg dose yielded a higher exposure than the 150- TB may include more than one newly developed agent,
mg dose upon coadministration of rifampicin. SQ109 thorough study is needed of their interactions in the

20 www.kjim.org http://dx.doi.org/10.3904/kjim.2016.31.1.15
Yew WW and Koh WJ. Treatment of pulmonary TB

context of efficacy and toxicity. At present there are lim- ing activities of the later generation fluoroquinolones.
ited data regarding the favorable interactions between In addition, the high dose would also lessen the risk
SQ109 and bedaquiline with respect to the efficacy of of the development of fluoroquinolone resistance in M.
both agents [59]. Interactions between pretomanid and tuberculosis strains. As the Bangladesh regimen also in-
bedaquiline, as well as between delamanid and be- corporates other drugs, there has been much enthusi-
daquiline, especially in terms of safety and tolerability, asm in attributing the efficacy of the regimen to these
also require further investigation. A study for the latter accompanying agents, especially clofazimine [64-66].
is soon to be launched (ACTG A5343). Table 3 summarizes the pertinent findings from these
studies.
However, the good long-term treatment outcomes
IMPROVING THE TREATMENT OF MDR-TB in this observational cohort of patients, except among
AND XDR-TB those with bacillary resistance to fluoroquinolone at
phenotypically high levels, affirms the key therapeutic
There are two major strategies to capitalize on the role of the high-dose fluoroquinolone in the Bangla-
current tools available to treat MDR-TB and XDR-TB. desh regimen [67]. The regimen also highlights the
These are (1) optimizing the use of later generation flu- paramount importance of programmed management
oroquinolones, and (2) review the use of repurposed of MDR-TB to minimize the development of bacillary
agents. In the face of the suboptimal treatment success resistance to fluoroquinolones, alongside the prudent
rates of MDR-TB in many countries worldwide [60], use of short-course fluoroquinolones in the treatment
there is clearly a genuine need for newly-developed of bacterial infections, especially those pertaining to
drugs/drug regimens to stop the looming epidemic of the lower respiratory tract [68].
XDR-TB, which develops through both acquired and More importantly, tolerance to the Bangladesh
transmitted resistance mechanisms [7,61]. regimen was remarkable [63]. Less than 10% of pa-
tients experienced major adverse reactions, and this
Possible new approaches to improving the out- included dysglycemic reactions in diabetic subjects.
comes of drug-resistant TB Unfortunately, due to a dwindling supply of gatiflox-
acin worldwide, the efficacy and safety of other, later
High-dose fluoroquinolones generation fluoroquinolones that can be used at high
There is unequivocal evidence that the fluoroquino- dosages must be explored, despite the associated in-
lones are pivotal agents in the treatment of drug-re- creased costs. Currently, there are two ongoing studies;
sistant TB. The later generation fluoroquinolones are the STREAM trial, which is evaluating moxifloxacin
likely to have greater efficacy compared to the earlier [69], and the Opti-Q trial, which is evaluating levoflox-
agents, especially for use in fluoroquinolone-resistant acin (NCT01918397). The STREAM trial has recently
MDR-TB and XDR-TB [62]. The Bangladesh regimen included an additional section to evaluate the benefit
is based on the use of high-dose gatifloxacin, up to 800 and safety of incorporating bedaquiline, but the fluo-
mg once daily, alongside clofazimine, ethambutol, and roquinolone used in this case is levofloxacin. Careful
pyrazinamide taken over 9 months and supplemented evaluation of the safety of different later generation flu-
by kanamycin, prothionamide, and a moderately high oroquinolones is clearly justified, as the risk of adverse
dose of isoniazid (~10 mg/kg/day) for a minimum of 4 reactions, especially cardiotoxicity [45], might differ
months; this regimen has achieved a relapse-free cure substantially among these later congeners. The poten-
rate of 88% in patients with MDR-TB who were pre- tial pharmacodynamic interaction of bedaquiline and
viously untreated with second-line drugs [63]. The re- high-dose fluoroquinolone, specifically the additive
markable efficacy of this shortened MDR-TB treatment risks of cardiotoxicity, are discussed below.
regimen, compared with the 20-month regimes, as rec-
ommended by World Health Organization [62], might Repurposed agents
attest to the dose-dependent bactericidal and steriliz- The principal agents considered for the management

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 The Korean Journal of Internal Medicine Vol. 31, No. 1, January 2016

Table 3. Recent studies of clofazimine in drug-resistant tuberculosis

Source Study design Findings summary
Grosset et al. (2013) [64] Animal study Mice infected with isoniazid-resistant M tuberculosis were treated with
a combination of moxifloxacin, ethambutol, pyrazinamide, and amikacin.
Half of the mice also received clofazimine. The decline in lung bacillary load
after 2 months was significantly better in animals in the clofazimine group,
with culture negativity by 5 months, whereas mice in the other group
remained culture-positive throughout the entire 9 months of the study.
The relapse rate was only 7% among mice treated with clofazimine.
Padayatchi et al. (2014) [65] Retrospective Patients were treated with either a clofazimine- or non-clofazimine-contain
cohort study ing extensively drug-resistant tuberculosis treatment regimen. Most patients
(86%) were human immunodeficiency virus-infected and receiving
antiretrovirals (90%). In the clofazimine- and non-clofazimine groups,
40% and 28.6% had culture conversion to negativity, respectively. The hazard
rate ratio of conversion at 6 months was 2.54 for the clofazimine group.
Adverse reactions due to clofazimine were minor and rarely life threatening.
Tang et al. (2015) [66] Randomized Patients were randomized to either a clofazimine or a control group, and
controlled trial received ~21 months of individualized treatment regimens based on their
medication history and drug susceptibility testing results. Sputum culture
conversion was earlier in the clofazimine group than in the control group, and
cavitary closure was also earlier. The treatment success rate in the clofazimine
group was 73.6%, which was significantly higher than the 53.8% in the contro
l group, but there was no significant difference in cure rates between the two
groups. Skin discoloration and ichthyosis were common in the clofazimine
recipients.

of drug-resistant TB largely include linezolid, clofazi- and XDR-TB, linezolid use significantly increased the
mine, and meropenem-clavulanate [70]. Two systemat- probability of a favorable outcome (culture conversion
ic reviews have suggested the importance of linezolid from positive to negative, cure, completion without
in the treatment of MDR-TB, highlighting the benefit death, default, failure, or relapse) by 57% [76]. The con-
of a lower dose of 600 mg daily with an equivalent effi- tribution of clofazimine and meropenem-clavulanate
cacy, in light of the substantial and serious hematologi- in the management of these difficult drug-resistance
cal and neurological toxicities (over 50% in total) among scenarios, independent of that of linezolid, require
recipients of linezolid therapy [71,72]. However, a lower confirmation [77-80]. However, an underestimation of
dose, whilst effective in reducing bone marrow toxicity, the add-on benefits of these two repurposed agents is
remains associated with a substantial risk of periph- likely to be due to the limited data available and selec-
eral neuropathy. A further lowering of the daily dose tion bias, as the study [76] was concerned only with a
of linezolid to 300 mg cut the incidence of peripheral highly selective group of difficult TB patients with for-
neuropathy to ~27% [73,74]. The use of linezolid inter- midable bacillary resistance. The role of a high-dose of
mittently three-times a week during the continuation isoniazid in the management of MDR-TB patients also
phase after an initial 2 to 3 months of an intensive phase needs further clarification [76].
of daily dosing could possibly reduce the risk of periph-
eral neuropathy, even over prolonged administration, New drugs
as is often necessary in complicated cases of MDR-TB A phase IIB RCT has shown that addition of be-
and XDR-TB [75]. Research is needed to find the opti- daquiline to an optimized background regimen short-
mal balance between efficacy and toxicity for the use ened the length of time for sputum culture conversion
of linezolid in the treatment of MDR-TB and XDR-TB. from positive to negative and improved the proportion
In a systematic review of cohort- and meta-analyses of patients with converted cultures, compared with a
of patients with fluoroquinolone-resistant MDR-TB placebo group, after 2 months of therapy (48% vs. 9%),

22 www.kjim.org http://dx.doi.org/10.3904/kjim.2016.31.1.15
Yew WW and Koh WJ. Treatment of pulmonary TB

and at 24 weeks during follow up (79% vs. 58%) [81,82]. A 14-day RCT on EBA showed that bedaquiline-pre-
Incorporation of bedaquiline also helped to prevent tomanid-pyrazinamide had substantial activity [38].
the development of bacillary resistance to the accom- However, a phase IIB/phase III RCT is required to
panying drugs in the regimen [82]. A similar RCT of confirm the clinical efficacy of this regimen, given the
6-months bedaquiline treatment showed that the ad- limitations of using EBA to fully evaluate the steriliz-
dition of this diarylquinoline reduced the time to cul- ing activity of drugs. This regimen, using these two
ture conversion (125 days vs. 83 days), and increased the new agents, shows potential for the treatment of MDR-
proportion of culture conversion at 24 (79% vs. 58%) TB patients. A further study is now underway that
and 120 weeks (62% vs. 44%), as well as significantly incorporates moxifloxacin into the bedaquiline-pre-
improved the cure rate at 120 weeks (58% vs. 32%) [83]. tomanid-pyrazinamide combination described above
However, of concern was the 5-fold increase in mortali- (GATB NC-005).
ty of patients receiving bedaquiline, compared to those Finally, the NExT trial will soon be launched in South
who were not [83]. The cause of these deaths requires Africa. This study will evaluate a short-course (6 to 9
in-depth investigation, as bedaquiline is known to pro- months) regimen of bedaquiline, linezolid, levofloxa-
long the QT interval in some patients [84]. cin, ethionamide, or high-dose isoniazid, and pyrazin-
A phase IIB RCT of delamanid, administered at 100 amide for the treatment of MDR-TB. In this case, the
and 200 mg twice daily to treat MDR-TB, showed a drug regimen includes the strategic “big three,” i.e., a
higher proportion of 2-month sputum culture con- fluoroquinolone, a repurposed agent and a new drug.
version in those on the new drug (45.4% and 41.9% vs. As the regimen is entirely based on oral drugs, it would
29.6%, for low-dose and high-dose delamanid, respec- be particularly suitable for treating patients with HIV
tively vs. the placebo) [85]. In a cohort of patients sub- coinfection.
jected to open-label evaluation, a favorable outcome oc-
curred in 74.5% of patients administered with at least 6 Drug interaction and toxicity
months of delamanid, but in only 55% of those who had Although pharmacokinetic interactions through cyto-
taken the drug for 2 months [86]. There was also a sig- chrome P450 isozymes might occur with a lower fre-
nificant reduction in the mortality rate with longer use quency in drugs used to treat drug-resistant TB, the
compared to the shorter duration of administration: possibility of interactive toxicity of a pharmacodynam-
2.9% vs. 12.0% [87]. However, QT prolongation on elec- ic nature cannot be dismissed. Cardiototoxicity, due
trocardiograms was also significantly more frequent to its potential for fatality, is of particular concern [45].
among the delamanid users, although without any ad- High-dose fluoroquinolones as well as newly developed
verse clinical events [85]. A phase III multicentre RCT drugs, such as bedaquiline and delamanid, could have
of delamanid in MDR-TB (NCT01424670) has recently additive risks for such toxicity with coadministration.
been completed and the results are being analyzed. In The potential risk of cardiotoxicity associated with the
this study, delamanid was used at 100 mg twice daily use of clofazimine cannot be completely ignored.
for 2 months, followed by 200 mg daily for 4 months, Potential overlapping drug toxicities in patients with
and results on its safety and tolerability data are keenly HIV-MDR-TB, related to the use of antiretrovirals and
anticipated. the anti-MDR-TB agents, have been reported previous-
Pretomanid-moxifloxacin-pyrazinamide appears to ly [88]. Examples include gastrointestinal reactions,
be a potentially promising combination for the treat- neurotoxicity and metabolic disturbances. In addition,
ment of drug-susceptible TB [42,43]. Although the regi- there might be adverse effects related to organ dysfunc-
men was also found to be efficacious in a small number tion, such as nephropathy, as well as immune recon-
of MDR-TB patients [43], the expected compromise in stitution inflammatory syndrome and pharmacoki-
regimen efficacy in the presence of bacillary resistance netic or pharmacodynamic drug-drug interactions in
to fluoroquinolones and pyrazinamide, which can be a an HIV-infected population. Among the latter type of
genuine issue in some MDR-TB settings [47,67], war- interactions, nephrotoxicity and peripheral neuropa-
rants further investigation. thy are of particular concern. The need for therapeutic

http://dx.doi.org/10.3904/kjim.2016.31.1.15 www.kjim.org 23
 The Korean Journal of Internal Medicine Vol. 31, No. 1, January 2016

drug monitoring on an individualized basis, to opti- availability that might inadvertently lead to undesirable
mize efficacy and monitor the toxicity of treatment in adverse reactions. This strategy is of greatest relevance
these HIV/MDR-TB coinfected patients warrants fur- in drug-resistant TB settings. There have been some
ther evaluation [89,90]. preliminary results in the use of aminoglycosides and
the other injectables [99], fluoroquinolones [100] and
riminophenazines [101], as well as pretomanid, which is
CONCLUSIONS a new agent [102]. It might also be pertinent to explore
the potential use of the inhaled route as an adjunct to
In the search for, and use of, new drugs to fight TB, oral therapy, when the use of orally administered drugs
the key priorities are to benefit and protect the patients, at a high dose is compromised by systemic toxicity. It
and also to protect the drugs [91]. Drug safety and tol- may be an option to explore such enhanced therapies
erability have been widely discussed. Pharmaco-vigi- with later generation fluoroquinolones [45].
lance must be in place at many different levels during The coming decade will probably witness an exciting
the administration of these drugs, especially the newly period of development of new strategies in the treat-
developed agents. The issue is particularly relevant in ment of pulmonary TB. This new era in fighting the
the context of the treatment duration of TB, which gen- disease will hopefully be realized through a rational
erally lasts for many months. exploration of the limitations of these new therapeutic
Regarding the issue of the emergence of drug resis- agents.
tance in repurposed agents and new drugs, prevention
is of paramount importance and; therefore, clear and Conflict of interest
stringent regulatory guidance cannot be overempha- WWY is a consultant to Otsuka Pharmaceutical Co.
sized. The deterioration of bacillary susceptibility of Ltd.
M. tuberculosis to linezolid is of concern [92,93], espe-
cially with the likely increase in the use of this agent for
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