New and Repurposed Drugs For The Treatment of Active Tuberculosis - An Update For

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RESPIRATION Karger Publishers
Respiration. 2023 Feb; 102(2): 83–100. PMCID: PMC9932851

Published online 2022 Dec 14. doi: 10.1159/000528274 PMID: 36516792
New and Repurposed Drugs for the Treatment of Active Tuberculosis: An

Update for Clinicians
Jessica M Aguilar Diaz, a Ahmed A Abulfathi, b , c , d Lindsey HM te Brake, e Jakko van Ingen, f
Saskia Kuipers, f Cecile Magis-Escurra, a Jelmer Raaijmakers, f Elin M Svensson, e , g and
Martin J Boeree a ,*
Abstract
Although tuberculosis (TB) is preventable and curable, the lengthy treatment (generally 6
months), poor patient adherence, high inter-individual variability in pharmacokinetics (PK),
emergence of drug resistance, presence of comorbidities, and adverse drug reactions
complicate TB therapy and drive the need for new drugs and/or regimens. Hence, new
compounds are being developed, available drugs are repurposed, and the dosing of existing
drugs is optimized, resulting in the largest drug development portfolio in TB history. This
review highlights a selection of clinically available drug candidates that could be part of
future TB regimens, including bedaquiline, delamanid, pretomanid, linezolid, clofazimine,
optimized (high dose) rifampicin, rifapentine, and para-aminosalicylic acid. The review
covers drug development history, preclinical data, PK, and current clinical development.
Keywords: Drugs, Treatment, Tuberculosis
Introduction
In the last century, the incidence of tuberculosis (TB) has declined considerably with a
setback in the past few years due to the COVID-19 pandemic. The decline in TB incidence
was accelerated by the introduction of anti-TB treatment after the Second World War, which
stopped in the 1980s among other factors due to the emergence of HIV and drug-resistant TB
(DR-TB). At that moment, new drugs were not specifically developed for TB. However in the
last 2 decades, a new impulse in drug treatment was given through the development of global
coordination in the fight against the poverty-related diseases HIV/acquired
immunodeficiency syndrome, malaria, and TB. The efforts resulted in the formation of
several research consortia sometimes in collaboration with the pharmaceutical industry,
leading to an enhanced effort to develop new compounds, repurpose already available drugs,
or optimize doses of first-line TB drugs: Pan-African Consortium for the Evaluation of
Antituberculosis Antibiotics (PanACEA), International Consortium for Trials of
Chemotherapeutic Agents in Tuberculosis (INTERTB), Tuberculosis Trials Consortium
(TBTC), Acquired Immunodeficiency Syndrome Clinical Trials Group (ACTG), Project to
Accelerate New Treatments for Tuberculosis (PAN-TB), and most recently the UNITE4TB
consortium. Currently, there is a portfolio of novel/repurposed/redeveloped TB drugs in
preclinical and clinical development, representing the largest pipeline in history of TB drug
development. This review will highlight a selection of the clinically available drug candidates
that could be part of future TB regimens. We selected registered and clinically available
drugs, which were selected because they are new (bedaquiline, delamanid, and pretomanid),
repurposed (linezolid), revived (clofazimine), or optimized (rifampicin, rifapentine, and para-
aminosalicylic acid [PAS]). The selected drugs will potentially be suitable for an optimized
or shortened regimen for drug-sensitive TB (DS-TB) or DR-TB in the near future. The
review describes drug development history, preclinical data, pharmacokinetics (PK), and
current clinical development.
New Drugs
Bedaquiline
The antimycobacterial properties of diarylquinolines were patented in 2004. The first

scientific report on the activity of bedaquiline (formerly known as TMC207 and R207910)
was published in Science in 2005 [1]. The compound was developed by Johnson & Johnson,
which obtained conditional market approval for the treatment of DR-TB from the US Food
and Drug Administration (FDA) in 2012. Bedaquiline was then the first anti-TB drug with a
novel mechanism of action to reach TB patients in more than 40 years (Table 1).
Table 1
Characteristics of each drug in the treatment of TB
Drug Molecule name Class Mechanism of Clinical Dose adults

action indication
Bedaquiline C32H31 (Diaryl) Inhibits ATP DR-TB, 400 mg once-

BrN202 quinoline synthesis by investigated daily orally for 2
targeting in DS-TB weeks and 200
mycobacterial mg 3 times a
ATP synthase weekafterward
for 22 weeks [20]
Delamanid C25H25F3N406 Nitro-dihydro- Inhibits mycolic DR-TB 100 mg twice a

imidazooxazole acid synthesis and day for 24 weeks
cellular [37]
respiration
PA C14H12F3N305 Nitro-dihydro- Inhibits mycolic DR-TB, 200 mg once

imidazooxazole acid synthesis investigated daily for 26
in DS-TB weeks [49]
Linezolid C16H20FN3O4 Oxazolidinone Inhibits protein DR-TB 600 mg once or

synthesis, binds twice daily [20];
to the 23S RNA 6 months in
peptidyl newest BPaLM
transferase center regimen; higher
(PTC) of the once-daily doses
prokaryotic are under
ribosomal 50S investigation for
subunit TB meningitis
Clofazimine C27H22CI2N4 Phenazine Incompletely DR-TB 100 mg once

understood, daily [20] at least
includes 9 months;
Bedaquiline targets mycobacterial ATP synthases and thereby the energy metabolism of the
bacteria (shown in Fig. 1 [2]) [3]. The minimum inhibitory concentration (MIC) of
bedaquiline is typically 0.012–1.0 mg/L when tested by broth microdilution with the
Mycobacterium Growth Indicator Tube (MGIT) system, and a clinical cut-off at 1 mg/L has
been suggested [4]. A dose-fractionation study in mice identified total exposure (AUC) as the
main driver of bactericidal effect [5]. In a murine model of latent TB, bedaquiline
demonstrated at least as good sterilizing activity as rifampicin [6].
Fig. 1
Bacterial representation of M. tuberculosis with mechanism of action for each drug, adapted with
permission from Hoelscher [2].
Bedaquiline is primarily metabolized through n-demethylation by hepatic isoenzyme

CYP3A4 to the approximately 5 times less active M2 metabolite [7]. The terminal half-life
(T1/2) of bedaquiline is extremely long (>5 months), and the approved dosing regimen
therefore includes a loading-phase (2 weeks of 400 mg once daily) and a maintenance phase
(200 mg 3 times per week) (Table 1) [7]. The plasma protein binding of bedaquiline is
>99.9% [7]. Bedaquiline exposures are affected by drugs interacting with CYP3A4, and
important examples are rifampicin and rifapentine (decreasing bedaquiline exposures almost
4- to 5-fold) and antiretroviral drugs such as efavirenz (decreasing bedaquiline exposures by
half) and lopinavir/ritonavir (increasing bedaquiline exposures by 2- to 3-fold increase) [8, 9,
10, 11].
Bedaquiline has limited early bactericidal activity (EBA) on its own, and the effect can only
be seen after about 1 week of treatment [12]. In phase 2 trials including multi-DR-TB (MDR-
TB) patients, it was shown that the addition of bedaquiline to an optimized background
regimen shortened the time-to-culture conversion and increased the proportion of favorable
outcomes at follow-up [13]. Model-based analyses found that the weekly average bedaquiline
concentration is associated with the rate of decline in bacterial load and suggest that the
currently used dosing regimen is not achieving maximal possible efficacy [14]. The main side
effect of bedaquiline is QT prolongation, driven primarily by the exposure to the M2
metabolite [15]. This raised concerns regarding combining bedaquiline with delamanid, a
drug that also causes QT prolongation, but recent data indicate that the combined effect of
the two is clinically modest and no more than additive [16]. Bedaquiline for treatment of
MDR-TB is currently being tested in a phase 3 setting through the STREAM trial (stage 2),
with results expected in 2022 [17]. Bedaquiline in combination with pretomanid and
linezolid has demonstrated 90% (95% CI: 83–95%) favorable outcomes in extensively DR-TB
(XDR-TB) and treatment-intolerant MDR-TB patients, enabling the recent approval of this
specific regimen (bedaquiline, pretomanid, and linezolid [BPaL]) [18]. Furthermore, in May
2022, the WHO published a rapid communication endorsing the 6-month bedaquiline,
pretomanid, linezolid, and moxifloxacin (BPaLM) regimen based on data of the ZeNix-TB
study and TB-PRACTECAL, which are described in further sections of this review [19]. If
there is resistance to fluoroquinolones, moxifloxacin should not be given [19].
In the latest update of WHO guidance on treatment of DR-TB, bedaquiline was categorized
as a group A drug that is considered highly effective and strongly recommended for inclusion
in all regimens unless contraindicated [20]. Very limited data on the use of bedaquiline in
children are available [21]. A child-friendly, 20 mg scored, dispersible tablet has been
developed. Pediatric PK and safety studies are still ongoing, but FDA and European
Medicines Agency (EMA) already recommend bedaquiline for use in children 5 years and
older, weighing at least 15 kg. The WHO published consolidated guidelines in 2022, where it
conditionally recommends bedaquiline use in all children [22]. Experience with bedaquiline
for DR-TB in programmatic use is growing, and reports are mainly positive with relatively
high rates of culture conversion (80–95%) and few serious adverse events [23, 24, 25, 26, 27,
28, 29]. Bedaquiline can be used during pregnancy and in a South African cohort including
108 pregnant women where about half were treated with bedaquiline, and 88% of babies
exposed to bedaquiline in utero were thriving and developing normally at 12 months
compared to 82% of the babies not exposed [30]. It is unclear how well bedaquiline
penetrates into the central nervous system, enabling effective treatment of TB meningitis.
One case report noted that concentrations of bedaquiline in cerebrospinal fluid were
undetectable [31], but a recent study reported bedaquiline levels in cerebrospinal fluid in the
same order of magnitude as unbound plasma concentrations [32].
Few concerns regarding emergence of resistance to bedaquiline and MIC-increasing

mutations in the atpE, mmpR (Rv0678), and pepQ (Rv2535c) genes have been described
[33]. Notably, cross-resistance with clofazimine has also been detected [34, 35].
Delamanid
Delamanid (Deltyba®), a nitro-dihydro-imidazooxazole derivative, formerly known as OPC-

67683 [36], was patented in the 1990s. In 2014, shortly following the approval of
bedaquiline, delamanid obtained EMA's approval for early release to the market as the
second new drug for DR-TB treatment in over 40 years (Table 1).
Delamanid's exact target is yet to be determined. However, delamanid is known to inhibit

mycolic acid synthesis and cellular respiration (shown in Fig. 1 [2], Table 1). The inhibitory
effect probably involves the release of reactive radicals such as nitric oxide, which are crucial
in the mammalian defense mechanism against mycobacterial infections [37].
The drug has a low MIC90: 0.006–0.024 μg/mL and is found to be active against DS and DR
M. tuberculosis isolates [38]. It inhibits replicating and dormant bacilli, both extracellularly
and intracellularly. In murine experiments, the combination of delamanid with rifampicin and
pyrazinamide resulted in more rapid sterilization of lung tissue than the standard regimen of
first-line anti-TB drugs. Its activity against intracellular M. tuberculosis was equivalent to
that of rifampicin at a concentration of 1–3 μg/mL [37].
Delamanid has a time to peak concentration (Tmax) of 4 h, with the peak concentration
(Cmax) varying from 175 to 286 ng/mL in the dose range of 100–400 mg [39]. The area under
the plasma concentration-time curve from 0 to 24 h (AUC0–24) ranged from 2,500 to 5,483
h*ng/mL at the dose range of 100–400 mg, indicating that the increase in exposure is not
dose-proportional, and reaches a plateau at 300 mg dose [39]. When taken with food,
delamanid bioavailability increases 2- to 4-fold. The apparent T1/2 is 30–38 h, while the T1/2
of its main metabolite is approximately 150–600 h. Delamanid is metabolized to M1, a
unique metabolite formed by plasma albumin. Nonhepatic formation of M1 and multiple
separate pathways for metabolism of M1, including CYP3A4, suggest that clinically
significant drug-drug interactions with delamanid and M1 are limited, although concurrent
administration with medicines known to induce/inhibit CYP3A4 may modestly alter
delamanid exposures [40]. Delamanid and its major metabolites do not inhibit or induce CYP
enzyme activity and thus have little potential for interaction with antiretroviral drugs [40,
41]. Its high plasma protein binding (≥99.5%), especially to albumin, alters its volume of
distribution [42].
The 14-day EBA in a phase 1 trial with a 200 mg daily dose was 0.052 log10 cfu/mL sputum
per day supporting the bactericidal potential of this drug. The EBA of delamanid was
monophasic and not significantly different between dosages, in line with the overlapping
exposure profiles. Adverse events in this 14-day trial were of either mild or moderate
severity. No serious adverse events occurred, and QT intervals were not prolonged [39]. The
first randomized placebo-controlled-phase 2 trial (2012) showed an increase in 2-month
culture conversion rates in patients with DR-TB treated with delamanid in combination with
a backbone regimen compared to placebo [43]. However, a randomized, double-blind,
placebo-controlled phase 3 multicenter trial, published in 2019, could not show any
difference in efficacy between the two groups at 6 months of evaluation [44]. A multicenter
observational study (n = 53) showed that 67.6% of a difficult-to-treat cohort of DR-TB
patients successfully culture converted by 6 months of treatment with delamanid. A total of
31 serious adverse events were reported in 14 patients (26.4%); most common were
hepatotoxicity (5), electrolyte imbalance (5), and QT prolongation (3) [45].
A recent meta-analysis of seven studies that used a bedaquiline and delamanid combination
to treat 87 cases of DR-TB showed promising outcomes. Most M/XDR-TB patients were
concomitantly treated with bedaquiline and delamanid, and in most cases for a duration >6
months. The sputum culture conversion rate after 6 months of treatment was considerably
higher (81.4%) than in historical M/XDR-TB patient cohorts. Out of 87 patients, 23 (26.4%)
had slight increases in QTc. However, only 2.3% of treatments were interrupted because of
life-threatening cardiac adverse events [46]. In children (aged 3 years and above), delamanid
shows an excellent safety and side effect profile [47].
Currently, there are several ongoing studies but because of paucity and weaknesses of the
existing evidence the efficacy of delamanid is still challenging to define [48]. Therefore,
pivotal clinical trials are needed to clarify its clinical value.
Pretomanid
Pretomanid (Dovprela®) (PA), another nitro-dihydro-imidazooxazole derivative, formerly

known as PA-824, was approved in 2019 by the FDA for XDR-TB or treatment-intolerant or
nonresponsive MDR-TB in the BPaL regimen, and in 2020 it received conditional approval
by the EMA (Table 1) [49, 50, 51]. PA was first identified in 1995 and is co-licensed by the
TB Alliance and Mylan with affordable access agreements for low- and middle-income
countries.
PA inhibits mycolic acid synthesis, a necessary step in cell wall formation (shown in Fig. 1
[2]) [52, 53]. PA is metabolized to reactive nitrogen species, which permits its activity
against nonreplicating bacilli. In vitro activity is shown with an MIC of <1 μg/mL and a
MIC90 of 0.063 μg/mL [54]. PA was found to be highly active in mice, especially in
combination with bedaquiline and linezolid [55]. Five genes are associated with the
emergence of resistance (ddn, fgd1, fbiA, fbiB, and fbiC) [56, 57]. Cross-resistance with
delamanid has been observed.
PA is administered orally as a tablet once daily. Following administration of a single dose of

200 mg with food, the mean Cmax is 2.0 μg/mL, the median Tmax is 5 h, and the mean AUC∞
is 51.6 μg*h/mL (Table 1) [49]. It is 86% protein-bound, and steady state is achieved after 4–
6 days. PA is metabolized via several pathways, 20% of which is via CYP3A4. PA is cleared
in urine and feces mainly as metabolites. PA's co-administration with rifampicin,
lopinavir/ritonavir, or efavirenz reduces its exposures, in the case of rifampicin by 53–85%
[58]. PA inhibits OAT3 transporter, suggesting that it may increase exposures of OAT3
substrates such as methotrexate.
PA has been investigated in several phase 2 trials for DS-TB. A phase 2A 14-day study with
PA evaluating various combinations bedaquiline, pretomanid, and pyrazinamide showed
equal EBA compared to the standard control [59]. In a phase 2B study (NC002) for 8 weeks,
a regimen combining moxifloxacin, pretomanid 200 mg, and pyrazinamide showed that there
was a significant increase of sputum culture conversion compared to the control [60]. In a
later phase 2B trial (NC005), adding bedaquiline to the regimen of moxifloxacin, pretomanid,
and pyrazinamide (BPaMZ) increased the bactericidal activity over 2 months considerably, in
both DS- and DR-TB [61].
Recently, two phase 3 trials for PA were performed with a focus on DR-TB. The BPaL
regimen was successfully investigated in the Nix-TB trial and was licensed for XDR-TB,
treatment-intolerant or nonresponsive MDR pulmonary TB [18]. TB-PRACTECAL, a phase
2/3 clinical trial, investigated the 6-month BPaLM regimen, against the locally accepted
standard of care. It found that 89% of patients in the group of patients receiving a 6-month
regimen of BPaLM were cured versus 52% of patients who had been prescribed the standard
regimen of up to 20 months of treatment, but this has not been published yet [62]. The
BPaLM regimen has now been included in the recent WHO rapid communication [19].
For both DS- as DR-TB, the TB Alliance has initiated the pivotal SimpliciTB trial. The trial
is almost finished, and the results will be presented at the Union World Conference on Lung
Health in November 2022. SimpliciTB is the continuation of the STAND trial that was
changed from PaMZ into BPaMZ when the results came available of the NC005 trial.
Further trials with PA are the phase 3 ZeNix trial (aimed to reduce linezolid toxicity) and the
phase 2B APT trial evaluating PA added to a first-line regimen with either rifampicin or
rifabutin, isoniazid, and pyrazinamide [63].
The most common adverse events of PA are gastrointestinal symptoms and vomiting and
suggested to be dose related [64], and the following described symptoms are not dose related:
transaminase increase, hepatotoxicity, and headache. The presence of hepatoxicity is
unfortunate as it reduces the value of a regimen to be used in low resources settings.
Repurposed Drugs
Linezolid
In 1987, when the antimicrobial activity of oxazolidinones against plant pathogens was
discovered [65], one of these agents was developed into linezolid (DuP721, PNU-100766, S-
N-3-3-fluoro-4-[4-morpholinyl]phenyl-2-oxo-5-oxazolidinylmethyl-acetamide). Linezolid
was marketed for treating gram-positive bacterial infections of the lungs, skin, and soft
tissues in 2000 and considered for the treatment of MDR-TB as a group 5 agent in 2006 by
the WHO [66].
Oxazolidinones inhibit protein synthesis by decreasing mRNA translation through binding to

the 23S RNA peptidyl transferase center of the prokaryotic ribosomal 50S subunit (shown in
Fig. 1 [2], Table 1) [67]. The binding of linezolid to human mitochondria can cause
myelosuppression, peripheral and optic neuropathy, and hyperlactatemia [68, 69].
The critical linezolid concentration for M. tuberculosis is 1 mg/L in 7H10 and MGIT
medium [70, 71]. Median linezolid MIC of 4,470 strains tested in M7H9 medium is 0.5 mg/L
(range 0.06–16 mg/L) [72].
In mice, 25–260 mg/kg of linezolid showed anti-tuberculous activity against replicating and
nonreplicating bacilli [73, 74]. A once daily linezolid hollow fiber model demonstrated
substantial activity against M. tuberculosis in acid-phase and nonreplicating persister states
[75].
Linezolid has an excellent oral bioavailability approaching 100%, low plasma protein binding
of 31%, and good tissue penetration including cerebrospinal fluid [76], alveolar macrophages
[77], and bone [78]. Plasma Cmax is 15–27 mg/L, and Tmax is 0.5–2 h [79]. When dosed 600
mg every 12 h, linezolid has an elimination half-life of 4.8–5.5 h (Table 1). Children under
12 years have a faster clearance and a shorter elimination half-life than adults [80].
Sixty-five percent of linezolid is oxidized into two inactive metabolites. About 30% of
linezolid and 50% of the metabolites are excreted via urine [81]. Although metabolism via
CYP3A4 plays a minor role in linezolid elimination, rifampicin co-administration reduces
linezolid exposure. Concomitant use of monoamine oxidase inhibitors with oxazolidinones is
contraindicated because of the risk of serotonin syndrome. Linezolid trough plasma
concentrations and AUC0-24 are linearly related, and trough concentrations are predictive of
linezolid exposure [82, 83]. Linezolid's EBA is modest in HIV-positive TB patients [84].
Currently, the WHO categorizes linezolid as a group A drug for rifampicin-resistant or

MDR-TB [47]. Several studies provide evidence for this choice. The addition of linezolid to
the ongoing regimen in 41 XDR-TB patients without response to earlier treatment showed
sputum culture conversion after 4 months in 15 out of 19 patients (79%) in the group that
started immediately and a negative sputum culture after 6 months of treatment in 34 out of
39 patients (87%) [85]. Improved 24-month treatment outcome, based on the WHO
definition, was found for an oral 6-month regimen including linezolid, levofloxacin, and
bedaquiline compared to the conventional empiric injection-based regimen, although it was
stopped early due to a new standard of care [86]. In the Nix-TB study, where 1,200 mg
linezolid daily was given with PA and bedaquiline anemia developed in 37% of patients, and
peripheral neuropathy in 81%, mainly attributed to linezolid toxicity. Only 34% completed
treatment, warranting careful monitoring of side effects of linezolid [18]. The phase 3 ZeNix
trial investigates the efficacy and toxicity of 600 mg versus 1,200 mg linezolid daily in
combination with PA and bedaquiline, and aims to reduce linezolid toxicity. Presented
results, which are not published yet, showed that the lower doses and/or shorter duration
treatment arms of linezolid had similar success rates and less toxicity in comparison with the
treatment arm including 1,200 mg of linezolid for 6 months [87]. As described in the PA
section, the BPaLM regimen was found to be efficacious in the TB-PRACTECAL trial [62,
88] and is included in the newest WHO rapid communication [19]. Another study including
linezolid is the MDR-END study, which compares the effectiveness and safety of oral
linezolid, delamanid, levofloxacin, and pyrazinamide for 9–12 months with the WHO 2016
MDR-TB regimen for 20–24 months [89]. [62].
Thus, a major concern and drawback in long-term linezolid use are its toxicity, which was a
reason to conduct the ZeNix trial, described above. A meta-analysis of twelve studies of
linezolid-containing TB regimens showed adverse events in 58.9% (63/107) of patients.
Anemia was found in 38.1% (32/84) of patients, peripheral neuropathy in 47.1% (40/85),
gastrointestinal disorders in 16.7% (14/84), optic neuritis in 13.2% (10/76), and
thrombocytopenia in 11.8% (10/85) of patients, especially with doses above 600 mg [90].
Monitoring hemoglobin levels and neuropathy may guide linezolid dosing optimization [91].
Therapeutic drug monitoring of linezolid is helpful when the daily dose is below 300 mg
[92]. A trough concentration of 2.5 mg/L should be evaluated as a target for therapeutic drug
monitoring [93].
Phenotypic linezolid resistance in M. tuberculosis, defined by an MIC >1 mg/L, emerged in

2007 and is mainly linked to mutations in or close to the PTC-binding site like the ribosomal
protein L3 rplC gene and the 23S rRNA rrl gene [33, 94]. In a South African study of MDR-
TB patients, linezolid resistance developed after 7–32 months of therapy. Sixteen
phenotypically resistant strains most frequently showed the T460C substitution in rplC, and
G2814T, G2270 C/T, and A2810C mutations in the rrl gene. No mutations were detected in
isolates with MICs at or below the critical concentration [95]. Mutations in rrl led to growth
impairment and decreased fitness which could limit spread in clinical settings [96]. Other
resistance mechanisms need further elucidation.
Revived Drugs
Clofazimine
Clofazimine was first synthesized and reported from Trinity College Dublin in 1957; it is the
prototype riminophenazine antibiotic [97]. While initially developed for TB treatment, its
preclinical development stalled as its in vivo activity proved inconsistent in particular animal
models, i.e., guinea pig and primates. This lack of in vivo activity was later linked to poor
absorption, low plasma concentrations, and/or high burden of extracellular mycobacteria.
Thus, for decades, its use remained limited to leprosy treatment [98].
Its exact mechanism of action remains incompletely understood but includes inhibition of
mycobacterial respiration via intracellular redox cycling as well as membrane disruption [99,
100]. Other proposed mechanisms of action include generation of reactive oxygen species,
inhibition of mycobacterial phospholipase A2, microbial K+ transport inhibition, and efflux
pump inhibition (shown in Fig. 1; Table 1) [97, 98, 99, 101, 102]. Recently, studies have
shown that upregulation of the MmpS5/MmpL5 efflux system after mutations in its repressor
gene (Rv0678) leads to increased MICs against clofazimine as well as cross-resistance with
bedaquiline [33]. In addition, mutations in the pepQ (Rv2535c) and Rv1979c genes,
encoding an aminopeptidase and a permease transporter, increase clofazimine MICs by
unknown mechanisms [33, 103, 104].
In vitro, clofazimine is highly active against M. tuberculosis complex isolates with a reported
MIC90 of 0.25 mg/L in wild-type isolates using broth microdilution [98, 105]. It took mouse
models with long treatment durations to demonstrate that clofazimine has potent, albeit
delayed and dose-independent, anti-TB activity (across the range of doses investigated) and
that clofazimine adds significant activity to first- and second-line TB treatment regimens, at
serum concentrations above the MIC [106, 107]. Clofazimine also exhibits a sustained
antimycobacterial activity after treatment cessation, yet again most prominent if serum
concentrations during treatment were ≥0.25 mg/L (the MIC90), suggesting a potential for
treatment shortening with clofazimine [108]. This treatment shortening effect was further
investigated in first-line regimens where rifampicin was replaced with rifapentine and
clofazimine was added; in two distinct mouse models of more acute (Balb/c) and caseous-
necrotic disease (C3HeB/FeJ), adding clofazimine and rifapentine increased the bactericidal
and sterilizing activity of the regimens, more than either drug alone [109]. This confirmed
the potential for treatment shortening by clofazimine-containing regimens [109].
Compared to administration during fasting, the oral bioavailability of clofazimine is

increased by ingestion with a fatty-meal, whereas aluminum/magnesium antacid has the
opposite effect [110]. Clofazimine is highly lipophilic and has peculiar PK including long
time-to-steady state, low serum concentrations (0.4–1 mg/L at 100 mg once-daily dose), high
protein binding, accumulation in skin, fatty tissues, reticuloendothelial organs and
macrophages, and a very long half-life (up to 70 days with long-term repeating dosing)
(Table 1) [99, 110]. Although clofazimine is a weak inducer of CYP3A4 itself [111], its PK
is not affected by concomitant rifamycin administration [112]. Despite its long use, the
optimal dose remains undetermined (Table 1). A 100 mg once-daily dose is standard, but a
recent modeling study showed that 200 mg once-daily loading doses in the first 2–4 weeks
shorten the time to effective steady-state concentrations by a month [113].
Clofazimine as a monotherapy showed no detectable 14-day EBA, nor did it add to EBA of
regimens with other drugs [59]; subsequent modeling revealed that it did have concentration-
dependent effects, primarily on the persister subpopulation, and therefore contributes
sterilizing activity to regimens [114]. In a randomized controlled trial, adding clofazimine to
personalized MDR-TB treatment regimens led to accelerated time-to-culture conversion and
higher treatment success rates (74% vs. 54%, p = 0.035) [115]. Subsequent meta-analyses of
individual patient data have presented conflicting conclusions on the efficacy of clofazimine
as part of MDR-TB treatment, with 2017 meta-analyses reporting no beneficial effect of
clofazimine [116]. However, a follow-up meta-analysis in 2018 reported greater treatment
success with the use of clofazimine than without it, with an adjusted risk difference of 0.06
(95% CI: 0.01–0.10) [117]. Very recent results from the TB-PRACTECAL study showed that
the bedaquiline, pretomanid, linezolid, and clofazimine regimen was effective and safe, but it
was not the most effective and safe regimen within the trial, but this has not been published
yet [88, 118]. Based on its performance in clinical trials and meta-analyses, clofazimine was
categorized as a group B drug in the 2019 WHO consolidated guidelines on MDR-TB
treatment [20]. With only three drugs in group A, it implicitly recommends adding
clofazimine to all MDR-TB regimens, where it is available. Yet, clofazimine availability is
limited and its cost further impairs access to the drug for MDR-TB treatment [119].
Clofazimine is well tolerated; in a meta-analysis, 1.6% (95% CI 0.5–5.3%) of MDR-TB

patients interrupt or stop therapy because of adverse events [120]. Adverse events associated
with clofazimine use include skin discoloration (reported in frequencies ranging from 3% to
94% [99, 115, 116, 120]). Informing patients about the possibility of clofazimine causing
reddish-black discoloration of skin and body secretions could mitigate against unnecessary
anxiety and nonadherence. Other adverse events include gastrointestinal discomfort, nausea,
vomiting, and QTc interval prolongation [99, 115, 121]. QTc interval prolongation is
important particularly when clofazimine is combined with other QTc interval prolonging
drugs, e.g., bedaquiline, fluoroquinolones, delamanid, and oxazolidinones (linezolid,
sutezolid) [99].
Optimized Drugs
Optimized Dose (High Dose) Rifampicin
Rifampicin is considered to be the cornerstone in the treatment of TB. A review concluded

that the current dose (10 mg/kg) for the short-course treatment regimen was chosen because
the drug was expensive at the time due to fear of adverse events/toxicity and because serum
concentrations were above the minimal inhibitory concentration of M. tuberculosis. Twenty
years ago, Dennis Mitchison already suggested that high dose of rifampicin should be
investigated because of an increased sterilizing effect [122].
According to a murine aerosol infection model and a hollow fiber model, rifampicin shows
concentration-dependent killing and the most adequate parameter for the killing of bacteria is
AUC/MIC [123, 124]. Also in mice, it was shown that the maximum tolerated dose was 160
mg/kg daily and a dose of 80 mg/kg per day reduced treatment duration to 9 weeks, without
adverse effects [125]. Other murine studies showed that a higher dose led to faster culture
conversion, a shortened treatment period, a decreased relapse rate, and an increase in
bactericidal and sterilizing activity [123, 126, 127].
The concentration of rifampicin increases more than proportional with dose, up to 7-fold
[128, 129, 130, 131]. Modeling and simulations showed that higher exposures of rifampicin
led to greater EBA [132]. Rifampicin induces CYP450 enzymes which leads to decreased
concentrations of many drugs, but not the other standard drugs [133, 134, 135]. There is
probably a ceiling in the maximal inductive capacity of rifampicin at relatively low doses of
rifampicin [133]. Currently, the PHENORIF study is looking at the interaction potential of
high-dose rifampicin.
A systematic review found an advantage in terms of likelihood of culture conversion in

patients that received at least 900 mg rifampicin based on historical clinical trials [136]. In
two phase 2B clinical trials, it was found that 20 mg/kg rifampicin for 2 months was safe and
tolerated by patients [137, 138]. Findings of a dose ranging trial showed that 40 mg/kg
rifampicin was safe and tolerated by patients for 2 weeks and that 50 mg/kg was poorly
tolerated [139]. In another phase 2B trial, it was found that a regimen containing 35 mg/kg
rifampicin for 12 weeks was safe and reduced time to stable culture conversion in liquid
media [134]. Increasing rifampicin doses (up to 30 mg/kg orally) and exposures resulted in a
better survival of patients with TB meningitis [130, 140], although this was not confirmed in
a larger trial with an increase of 15 mg/kg orally (Table 1) [141].
Based on a change in international guidelines in 2010, rifampicin is administered at a higher

dose (15 mg/kg) [142] in children than in adults because 10 mg/kg in children leads to lower
serum concentrations than in adults [142, 143, 144, 145, 146, 147]. The results of the SHINE
trial showed that with the revised WHO doses of all drugs a 4-month treatment regimen was
noninferior to a 6-month treatment regimen in children with regard to efficacy [148], which
has led to the recommendation of a 4-month regimen by the WHO [149]. Furthermore, high
doses of rifampicin up to 60 mg/kg in children for a period of 2 weeks were found to be safe
based on the Opti-Rif trial [150].
Suboptimal concentrations of rifampicin could induce resistance at standard doses, explained

by poor penetration into cavities [131, 151]. In one study, it was shown that rifampicin
reaches adequate concentrations in critical lesions such as necrotic caseum after multiple
doses [152]. Other drugs do not achieve adequate concentrations; thus, it was suggested that
there can be monotherapy at specific time and locations, which could lead to the emergence
of resistance [152].
Optimized doses of rifampicin have not been implemented in guidelines, and the WHO is
awaiting additional evidence, which includes phase 3 clinical trials, and a systematic review
on all available literature. A phase 2C trial is planned within the PanACEA consortium to
investigate 3- and 4-month combination regimens with isoniazid, pyrazinamide in a standard
dose and an optimized dose of rifampicin, pyrazinamide, and moxifloxacin [153].
Furthermore, a pragmatic randomized trial will be conducted in Europe to study the safety of
an optimized dose of rifampicin in an operational setting. There is an increasing amount of
evidence to suggest that the time has come to reconsider the guidelines in special situations
(meningitis, severe TB, children, diabetes mellitus, HIV, etc.).
Rifapentine
Rifapentine is a cyclopentyl-substituted semi-synthetic derivative of rifampicin. Like other
rifamycins, rifapentine selectively binds to bacterial DNA-dependent RNA polymerase, and
inhibition will occur already after short periods of drug exposure (shown in Fig. 1; Table 1).
Specific mutations in the β subunit of the RNA polymerase gene (rpoB) lead to the
development of cross-resistance to all rifamycins, including rifapentine and rifampicin [154].
The MIC against M. tuberculosis of rifapentine is approximately 0.02 μg/mL [155]. MIC and
the minimum bactericidal concentration of rifapentine for intracellular bacteria are 2- to 4-
fold lower than those of rifampicin; for extracellular bacteria, this difference was
approximately 2-fold [156]. The prolonged effect of rifapentine and its potential for
intermittent use found in this study may be associated with high intracellular accumulation,
which were 4- to 5-fold higher than those found for rifampicin [156].
PK of rifapentine has been investigated at various doses, frequencies, regimens, and

populations [157, 158, 159, 160, 161]. In general, time to Cmax is observed in 4–6 h and the
half-life is relatively long with about 12–15 h [154]. This is significantly longer than for
rifampicin (1.5–5.0 h) and supports a more intermittent use, e.g., for latent TB treatment.
Rifapentine peak exposures have been found to be dose linear [161] or less than dose linear
[159]. AUCs are less than dose-proportional [162]. The latter is in contrast to the greater than
dose-proportional PK observed for rifampicin. The rifapentine Cmax (15 μg/mL) at a dose of
600 mg sufficiently exceeds the MIC [154, 162]. However, rifapentine is about 98% plasma
protein-bound [154], which is 4- to 10-fold higher than for rifampicin (about 8–25% protein-
unbound [163]), compensating for the lower MIC of rifapentine and possibly explaining the
suboptimal efficacy of historically recommended doses of rifapentine.
Recently, a systematic review was published describing rifapentine population PK in a large

cohort of nine clinical studies [164]. The analysis showed that rifapentine bioavailability was
clinically relevant and was affected by HIV status, food, and dose. With intermittent dosing,
autoinduction of clearance was minimal to moderate. With daily dosing, maximum induction
was achieved with doses of 300 mg or more. The maximum effect was a 72% increase in
clearance after 21 days [164]. Month 2 culture conversion was found to be less likely in
individuals with low weight (<50 kg) and in those with low rifapentine exposure. Body
weight was not a clinically relevant predictor of clearance, suggesting weight-band dosing of
rifapentine should be removed from latent TB infection (LTBI) dosing guidelines [164]. Of
note, very limited PK data are available for LTBI: only one study is available that collected
PK data in LTBI in 77 participants [160].
Similar to rifampicin, daily/intermittent rifapentine administration significantly reduces

exposures of co-administered drugs [154], such as midazolam/bedaquiline (CYP3A4
substrate) [11, 165] and moxifloxacin (UGT1A1) [166]. While in vitro rifampicin seemed to
have a superior drug interaction potential [167], oral midazolam clearance was reduced to
significantly greater extent (74 vs. 93%) by rifapentine than rifampicin in vivo [159].
Induction of enzyme activities by rifapentine occurs within 4 days after the first dose,
returning to baseline levels 14 days after discontinuing rifapentine [154]. In general, less
drug-drug interactions are anticipated for once weekly dosing of rifapentine. For example,
moxifloxacin exposures remained almost unaffected when rifapentine was dosed once weekly
[168]. Rifapentine given once weekly also did not affect concentrations of efavirenz, an HIV
drug that is a CYP2B6 substrate [169].
Several rifapentine-based short courses of LTBI treatment have been evaluated to date. A 1-
month regimen of rifapentine plus isoniazid was noninferior to 9 months of isoniazid alone
for preventing TB in HIV-infected patients [170]. However, the rifapentine-based LTBI
regimen with the most extensive track record at present is 12 weeks weekly
rifapentine/isoniazid (3HP). Multiple large-scale clinical trials and analyses have shown that
3HP is noninferior to standard INH and has significantly higher rates of treatment completion
and lower rates of adverse events [171, 172, 173, 174]. Completion of 3HP in routine
healthcare settings seems even greater than rates reported from clinical trials, and greater
than historically observed using other regimens among reportedly nonadherent populations
[175].
For pulmonary TB treatment, more frequent rifapentine administrations seem desirable, as

once weekly or less frequent use of rifapentine increases the risk of bacteriological relapse
compared to intermittent use of rifampicin [176]. In phase 2 clinical trials, no obvious safety
concerns have been noted with the use of daily rifapentine during the first 8 weeks of
combination therapy for pulmonary TB [177], and increasing the PK exposure to rifapentine
was associated with improved sterilization at the end of the intensive phase as compared to
standard dose rifampicin in mice and humans [177, 178]. In a pivotal, ground-breaking
recent phase III trial the threshold of shortening to 4 months was finally reached: the efficacy
of this 4-month rifapentine-based regimen containing moxifloxacin was noninferior to the
standard 6-month regimen in the treatment of TB, and it was similar in regard to safety [179].
This was the first study supporting the treatment shortening potential of a rifamycin when
combined with moxifloxacin. The WHO now conditionally recommends the use of a 4-
month regimen consisting of rifapentine, isoniazid, pyrazinamide, and moxifloxacin in
patients with drug-susceptible TB that are 12 years or older (Table 1) [149].
PAS
PAS, first discovered in 1902 by Seidel and Bittner, was rediscovered in 1943 by Jorgen
Lehmann, a Swedish clinician-scientist [180, 181]. PAS is arguably the first synthetic drug
used in the clinic to successfully treat TB patients in 1944 [182, 183, 184].
The precise mechanism of action of PAS remains elusive, and PAS is considered an
antimetabolite, which is structurally similar to para-aminobenzoic acid, a substrate of
dihydropteroate synthase [185, 186]. In turn, the generation of hydroxyl dihydrofolate
antimetabolite in turn inhibits dihydrofolate reductase [186]. An additional potential PAS
mechanism of action is its inhibition of mycobactin, a component of the mycobacterial cell
wall resulting in reduced iron uptake by M. tuberculosis (Fig. 1; Table 1) [187]. A PAS MIC
≤1 mg/L defines susceptibility in clinical isolates [188, 189]. Concentration-dependent
activity of PAS was demonstrated in an in vitro study, in which PAS concentration of 100
mg/L was decidedly better than 10 mg/L in suppressing resistance emergence in the
companion drugs streptomycin and isoniazid [182, 190]. Animal models of TB show the
dose and concentration-dependent bacteriostatic effects of PAS [182, 191].
The PK of PAS varies with the formulation. PAS salts are readily absorbed when
administered orally and achieve higher Cmax in plasma than with PAS acid or the widely
available granular slow-release PAS formulation (PASER) [188, 192, 193, 194]. Under the
influence of N-acetyltransferase 1, PAS undergoes first-pass metabolism to acetyl-PAS in the
gut and liver, which might explain acetyl-PAS appearance in blood earlier than PAS [181,
195]. PAS is metabolized to glycine-PAS in the liver [195]. N-acetyltransferase 1 and N-
acetyltransferase 2 genetic polymorphisms have been recognized to influence PAS clearance
[182, 196]. Approximately 80% of the administered dose is excreted in urine as PAS and its
two major metabolites, acetyl-PAS and glycine-PAS [181, 195]. PAS has an elimination half-
life of 0.5–2.5 h and a modest plasma protein binding [181, 187, 193, 197].
Oral administration of PASER with food increases the oral bioavailability of PAS, Cmax, and
overall systemic exposure, while reducing intolerance particularly when taken with acidic
beverages [182, 197]. The gastrointestinal intolerance to PAS is primarily because of its
direct irritant effect while in the gastrointestinal tract and PAS decarboxylation to meta-
aminophenol toxin [182, 187].
The early appreciation that gastrointestinal intolerance to PAS could be formulation related
led to the development of many formulations [181, 182, 198]. With improving intolerance in
mind, PASER is enteric-coated and designed to slowly release PAS in the intestine rather
than in the stomach [187]. Furthermore, the gastrointestinal intolerance is neither related to
plasma concentrations nor to the conjugated metabolites [182, 194, 196, 199, 200].
Clinical trials conducted in the 1950s by the British Medical Research Council established
the role of PAS in suppressing resistance emergence in companion drugs, allowing the
construction of an efficacious anti-TB regimen for the next three decades [201, 202, 203,
204]. This ability to suppress resistance emergence is clearly dose-dependent, with 20 g/day
sodium PAS outperforming 10 g/day and 5 g/day doses administered in four divided doses
[203]. A subsequent study found that a sodium PAS dose of 20 g/day has no advantage over
10 g/day in the ability of PAS to suppress resistance emergence to isoniazid [204]. It is
however important to note that the individual PAS dosage administered in the study was 5 g
because 20 g/day and 10 g/day were administered in 4 and 2 divided doses, respectively.
These findings and preclinical evidence of the PAS concentration-dependent effect could
indicate that Cmax and, by extension, Cmax/MIC are the parameters linked to the prevention of
resistance in companion drugs [190, 202, 203, 204].
In addition, an EBA study showed PAS might have a bactericidal effect if used at a high
enough dose and, consequently, a high Cmax could be reached with a single-daily dose [205].
In this study, 15 g once-daily PAS resulted in a 2-day EBA similar to that of once-daily 10
mg/kg rifampicin [205]. Furthermore, two clinical studies conducted in the early days of PAS
use provided an early indication of the potential of PAS to be a bactericidal agent [206, 207].
The Cmax/MIC ratio has been suggested to be linked to PAS' ability to prevent resistance
emergence in companion drugs; if that hypothesis is correct, the plasma PAS concentrations
reached with PASER are low [182, 188, 196, 208] and maybe inadequate at the current
dosing regimen of 12 g/day in 2–3 divided doses. Therefore, there remains an urgent need for
a prospective EBA study with a PK component to evaluate different once daily PASER
regimens. This prospective study should clarify the most appropriate PK/pharmacodynamics
determinant of PAS efficacy.
In its 2019 MDR-TB treatment guideline, the WHO downgraded the use of PAS (group C) to
only when there is resistance or toxicity to the more preferred anti-TB agents (group A and
B) [20]. A meta-analysis of observational studies at least in part was responsible for the
WHO recommendation regarding PAS use [117]. The limitations inherent in observational
studies strengthen the need for prospective studies to clearly outline the use of PAS, as we are
likely not using PASER optimally. Thus, to win the fight against the DR-TB epidemic, all
drugs including PAS in a regimen must be optimally utilized, especially in the face of
resistance emergence in newly approved drugs such as bedaquiline and delamanid.
Conclusion
We have arrived at a promising stage in the fight against TB, with several academic,
governmental, and nongovernmental organizations facilitating and accelerating TB drug
development. There have been recommendations and communication of new treatment
regimens, with progress been made in treatment shortening for DS- and DR-TB. Moreover,
currently new drugs with new targets and existing or repurposed drugs are investigated in
clinical trials, with another series of new and repurposed drugs in earlier stages of
development. This review highlighted a selection of clinically available drug candidates for
current and future TB regimens. Nevertheless, studies are still ongoing to further investigate
these drugs and their optimal application. The most recent developments are a shortened
treatment regimen for DS-TB in guidelines and recent guidelines and a rapid communication
for DR-TB, including new definitions of multi- and extensive drug resistance. For DS-TB, a
short (4 months) rifapentine and moxifloxacin-based regimen has now been adopted in
guidelines for people of 12 years or older [149]. Optimized (high dose) dose rifampicin is
already implemented in severe cases of TB in some clinical settings and is currently being
investigated in a study with a large sample size. Furthermore, for children with nonsevere TB
a short (4 months) treatment regimen has been recommended [149]. The newest WHO rapid
communication on DR-TB now stresses the importance of bedaquiline, pretomanid,
linezolid, and, to a lesser extent, clofazimine [19]; for rifampicin- and MDR-TB, the (6
months) BPaLM regimen is endorsed, and if there is resistance to fluoroquinolones it can be
used without moxifloxacin [19].
Newer oxazolidinones with a lower toxicity profile than linezolid are being studied.
Moreover, a universal regimen for both DS- and DR-TB is also currently being investigated,
the BPaMZ regimen was meant to become such a regimen, although this could be questioned
considering the rapid emergence of resistance to bedaquiline and the current resistance to
quinolones and pyrazinamide.
In this review, we have outlined various anti-TB drugs that to a greater or lesser extent could
potentially contribute to improved treatment regimens. Some drugs are new, some are
repurposed, and some are optimized with increased dosages. In order to achieve the targets of
the End TB strategy [209], increasing efforts still need to be made of which the development
of new treatment regimens for active (and latent) TB is essential.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
This research did not receive grants from any funding agency in the public, commercial, or
not-for-profit sectors.
Author Contributions
Jessica Maria Aguilar Diaz: abstract, introduction, section about an optimized dose of
rifampicin, conclusion, table, adaptation figure, lay-out article, general comments, references,
and end-editing. Ahmed Aliyu Abulfathi: section about para-aminosalicylic acid, English
edits, general comments. Lindsey Hendrika Maria te Brake: abstract, introduction, section
about rifapentine, conclusion, and general comments. Jakko van Ingen: section about
clofazimine, general comments, and conclusion. Saskia Kuipers: section about linezolid and
general comments. Cecile Magis-Escurra: section about delamanid and general comments.
Jelmer Raaijmakers: references and general comments. Elin Margareta Svensson: section
about bedaquiline and general comments. Martin Johan Boeree: abstract, introduction,
section about pretomanid, conclusion, and end-editing.
Funding Statement
This research did not receive grants from any funding agency in the public, commercial, or
not-for-profit sectors.
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RESPIRATION Karger Publishers

Respiration. 2023 Feb; 102(2): 83–100. PMCID: PMC9932851

New and Repurposed Drugs for the Treatment of Active Tuberculosis: An

Keywords: Drugs, Treatment, Tuberculosis

The antimycobacterial properties of diarylquinolines were patented in 2004. The first

Characteristics of each drug in the treatment of TB

Drug Molecule name Class Mechanism of Clinical Dose adults

Bedaquiline C32H31 (Diaryl) Inhibits ATP DR-TB, 400 mg once-

Delamanid C25H25F3N406 Nitro-dihydro- Inhibits mycolic DR-TB 100 mg twice a

PA C14H12F3N305 Nitro-dihydro- Inhibits mycolic DR-TB, 200 mg once

Linezolid C16H20FN3O4 Oxazolidinone Inhibits protein DR-TB 600 mg once or

Clofazimine C27H22CI2N4 Phenazine Incompletely DR-TB 100 mg once

Bedaquiline is primarily metabolized through n-demethylation by hepatic isoenzyme

Few concerns regarding emergence of resistance to bedaquiline and MIC-increasing

Delamanid (Deltyba®), a nitro-dihydro-imidazooxazole derivative, formerly known as OPC-

Delamanid's exact target is yet to be determined. However, delamanid is known to inhibit

Pretomanid (Dovprela®) (PA), another nitro-dihydro-imidazooxazole derivative, formerly

PA is administered orally as a tablet once daily. Following administration of a single dose of

Oxazolidinones inhibit protein synthesis by decreasing mRNA translation through binding to

Currently, the WHO categorizes linezolid as a group A drug for rifampicin-resistant or

Phenotypic linezolid resistance in M. tuberculosis, defined by an MIC >1 mg/L, emerged in

Compared to administration during fasting, the oral bioavailability of clofazimine is

Clofazimine is well tolerated; in a meta-analysis, 1.6% (95% CI 0.5–5.3%) of MDR-TB

Optimized Dose (High Dose) Rifampicin

Rifampicin is considered to be the cornerstone in the treatment of TB. A review concluded

A systematic review found an advantage in terms of likelihood of culture conversion in

Based on a change in international guidelines in 2010, rifampicin is administered at a higher

Suboptimal concentrations of rifampicin could induce resistance at standard doses, explained

PK of rifapentine has been investigated at various doses, frequencies, regimens, and

Recently, a systematic review was published describing rifapentine population PK in a large

Similar to rifampicin, daily/intermittent rifapentine administration significantly reduces

For pulmonary TB treatment, more frequent rifapentine administrations seem desirable, as

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

2. Hoelscher M. Netherlands: Nijmegen; 2022. 24 March, Presentation TB treatment-new drugs, ESCMID

3. Koul A, Dendouga N, Vergauwen K, Molenberghs B, Vranckx L, Willebrords R, et al. Diarylquinolines target

45. Hewison C, Ferlazzo G, Avaliani Z, Hayrapetyan A, Jonckheere S, Khaidarkhanova Z, et al. Six-month

94. Richter E, Rüsch-Gerdes S, Hillemann D. First linezolid-resistant clinical isolates of Mycobacterium

118. MSF TB-Practecal Clinical Trial MSF. 2022.

127. Hu Y, Liu A, Ortega-Muro F, Alameda-Martin L, Mitchison D, Coates A. High-dose rifampicin kills

187. Jacobus Pharmaceutical Company I Paser 2010. Available from https://medlibrary.org/lib/rx/meds/paser/

206. Para-aminosalicylic acid treatment in pulmonary tuberculosis Am Rev tuberculosis. 1950;61((5)):597–612.

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