Drugs (2019) 79:161–171

https://doi.org/10.1007/s40265-018-1043-y

REVIEW ARTICLE

The Role of Fluoroquinolones in the Treatment of Tuberculosis in 2019

A. D. Pranger1,5   · T. S. van der Werf2,3 · J. G. W. Kosterink1,4 · J. W. C. Alffenaar1

Published online: 7 January 2019

© The Author(s) 2019

Abstract
The inability to use powerful antituberculosis drugs in an increasing number of patients seems to be the biggest threat towards
global tuberculosis (TB) elimination. Simplified, shorter and preferably less toxic drug regimens are being investigated for
pulmonary TB to counteract emergence of drug resistance. Intensified regimens with high-dose anti-TB drugs during the
first weeks of treatment are being investigated for TB meningitis to increase the survival rate among these patients. Moxi-
floxacin, gatifloxacin and levofloxacin are seen as core agents in case of resistance or intolerance against first-line anti-TB
drugs. However, based on their pharmacokinetics (PK) and pharmacodynamics (PD), these drugs are also promising for
TB meningitis and might perhaps have the potential to shorten pulmonary TB treatment if dosing could be optimized. We
prepared a comprehensive summary of clinical trials investigating the outcome of TB regimens based on moxifloxacin, gati-
floxacin and levofloxacin in recent years. In the majority of clinical trials, treatment success was not in favour of these drugs
compared to standard regimens. By discussing these results, we propose that incorporation of extended PK/PD analysis into
the armamentarium of drug-development tools is needed to clarify the role of moxifloxacin, gatifloxacin and levofloxacin for
TB, using the right dose. In addition, to prevent failure of treatment or emergence of drug-resistance, PK and PD variability
advocates for concentration-guided dosing in patients at risk for too low a drug-exposure.

Key Points  1 Introduction

The optimal fluoroquinolone dose should be investigated To end tuberculosis (TB) by 2035, as mentioned in the
for tuberculosis treatment. United Nations Sustainable Development Goals, may be an
over-ambitious target as evidence is emerging that the TB
Patients at risk for a too low drug exposure should be
incidence is not declining at all [1, 2]. Optimization of drug-
selected and monitored.
resistant TB prevention and treatment is a known challenge
of global TB elimination [3]. According to the latest annual
* A. D. Pranger WHO report (2018), 558,000 new TB patients were infected
a.d.pranger@lumc.nl with rifampicin-resistant (RR) M. tuberculosis (MTB) iso-
lates, resistant against the most important first-line anti-TB
1
Department of Clinical Pharmacy and Pharmacology, agent [4], and in Italy, Iran and India, notation has been
University of Groningen, University Medical Center
Groningen, Groningen, The Netherlands made of TB cases resistant against (almost) all second-line
2 anti-TB drugs [5–7]. The biggest threat towards TB elimina-
Department of Pulmonary Diseases and Tuberculosis,
University of Groningen, University Medical Center tion could therefore well be the increase of resistance against
Groningen, Groningen, The Netherlands powerful anti-TB agents.
3
Department of Internal Medicine/Infectious Diseases, Fluoroquinolones, i.e. moxifloxacin, gatifloxacin and lev-
University of Groningen, University Medical Center ofloxacin, are the most valuable second-line anti-TB agents
Groningen, Groningen, The Netherlands according to the current WHO guidelines (update October
4
PharmacoTherapy, Epidemiology and Economics, Groningen 2016) [8]. These recommendations were consistent with our
Research Institute of Pharmacy, University of Groningen, forecasts on particularly moxifloxacin and gatifloxacin based
Groningen, The Netherlands on a review on pharmacokinetics (PK) and pharmacodynam-
5
Department of Clinical Pharmacy and Toxicology, Leiden ics (PD) of 14 fluoroquinolones for TB [9]. Although moxi-
University Medical Center, P.O. Box 9600, 2300 RC Leiden, floxacin was not recommended until the WHO guidelines
The Netherlands

Vol.:(0123456789)

162 A. D. Pranger et al.

were updated in 2011, our main finding was that the role of are preferred components of this shorter regimen, which is
moxifloxacin for drug-resistant TB, possibly at a dose of 600 restricted to TB patients with no history of second-line drugs
or 800 mg once daily, was underestimated. This conclusion and no resistance against pyrazinamide, fluoroquinones or
was based on excellent penetration of moxifloxacin in alveo- aminoglycosides [8]. From 2011 onwards, in TB research
lar macrophages, epithelial lining fluid, bone and cerebro- and WHO guidelines, fluoroquinolones (moxifloxacin, gati-
spinal fluid; the highest bactericidal and sterilizing activity; floxcin, levofloxacin) have been given an important share in
and bactericidal activity against ofloxacin-resistant strains regimens for drug-susceptible and drug-resistant TB. This
[9]. For moxifloxacin, gatifloxacin and levofloxacin, and for role seems justified based on its PK and PD [9]. The aim of
the four high-potential fluoroquinolones for TB as defined this review was to update, summarize and discuss the treat-
in 2011 [9], the current marketing and clinical development ment outcome of regimens based on moxifloxacin, gatifloxa-
status is described in Table 1. The four high potentials have cin or levofloxacin for TB.
never been under clinical development for TB, and the gen-
eral marketing status of all seven fluoroquinolones has not
changed compared to 2011 [9]. 2 Methods
Since rifampicin was authorised for treatment of TB more
than half a century ago, the US Food and Drug Administra- A PubMed search was preformed using the keywords
tion (FDA) and/or European Medicines Agency (EMA) have “moxifloxacin” OR “levofloxacin” OR “gatifloxacin” AND
only approved bedaquiline (2012) and delamanid (2014) for “tuberculosis”. The limitations “human”, “English” and
TB as a last remedy in the case of extensive drug resistance a publication date of the last “5 years”, and article types
[10, 11]. Currently, the TB pipeline is working on simpli- “clinical trial”, “randomized controlled trial”, “controlled
fication of regimens (shorter, less toxic, oral) to counteract clinical trial” and “comparative study” were added to the
drug resistance by promoting drug adherence [12]. Unfor- searches. We included articles reporting bacteriological and/
tunately, the results of a short-course drug-susceptible TB or clinical treatment outcome. Publications reporting only
regimen based on moxifloxacin were disappointing [13, 14]. pharmacokinetic outcome and/or early bactericidal results
However, in 2016, the WHO adopted a shorter regimen— were excluded. Trials were included regardless of the extent
still 9–12 months—for selected patients with multidrug- of drug-resistance and regardless of the localization of TB.
resistant TB (MDR-TB) [8]. Moxifloxacin or gatifloxacin

Table 1  State of clinical development in tuberculosis (TB) treatment and general marketing status as at 2019
­ BA,B
Marketing status other than T Registered strength (mg) Clinical development
phase for TB (2011–
2018)C, D

WHO recommended fluoroquinolones (2019)

 Gatifloxacin Discontinued (USA) – III
 Levofloxacin Approved (USA/EU)E 250, 500 and 750 IVF, II, III
 Moxifloxacin Approved (USA/EU)E 400 IIF, III
High-potential fluoroquinolones based on PK/PD
 Sparfloxacin Discontinued (USA) – None
 Sitafloxacin None – None
 Trovafloxacin Discontinued (USA/EUE) – None
 DC-159a None – None

Searches were conducted in March 2018. A second search in December 2018 revealed no change in marketing or clinical development status
Table format partly adopted from Pranger et al. Current Pharmaceutical Design 2011
Oral formulation unless indicated otherwise
PK/PD pharmacokinetics/pharmacodynamics
A
 Marketing status is indicated as the state of the fluoroquinolone on the market of the USA and/or the European Union (EU)
B
 Marketing status ‘none’: registered data was not available on fda.gov or ema.europa.eu
C
 Clinical development status ‘none’: no registered trial (Phase I–IV) on clinicaltrials.gov or available as literature on PubMed
D
 Pulmonary TB unless otherwise indicated
E
 Intravenous and oral formulation
F
 For pulmonary TB as well as TB meningitis
Fluoroquinolones in the Treatment of Tuberculosis 163

All searches were conducted in June 2017. Searches up to included 4 months of once-a-week dosing of moxifloxacin
and including December 2018 revealed no new articles. and rifapentine was similar to that of the standard DS-TB
regimen [14]. For MDR-TB treatment success, moxifloxacin
and levofloxacin (750 mg/day) were equally effective in one
3 Results clinical trial [15].

3.1 Pulmonary Tuberculosis 3.2 Tuberculosis Meningitis

Five clinical trials investigated the treatment outcome of Three clinical trials investigated the survival benefit of
moxifloxacin, gatifloxacin and/or levofloxacin for pulmo- a fluoroquinolone added to, or replacing, a drug from
nary TB (Tables 2, 3). In one clinical trial [15], moxifloxacin the standard regimen for the treatment of TB meningitis
was compared with levofloxacin as part of an MDR-TB regi- (TBM) (Table 4). A significant survival benefit (hazard
men. In the remaining four clinical trials [13, 14, 16, 17], ratio: 2.13, 95% CI 1.04–4.34, P = 0.04) was observed for
results of seven fluorquinolone-based regimens (moxifloxa- TBM patients, regardless of stage of TBM, treated with levo-
cin: five, gatifloxacin: two) compared to a standard WHO- floxacin (10 mg/kg/day, maximum 500 mg/day) instead of
recommended daily (five times) or thrice-weekly (two times, rifampicin, next to isoniazid, pyrazinamide and ethambutol.
moxifloxacin: one, gatifloxacin: one) drug-susceptible (DS) Although the proportion of patients with an unfavourable
TB treatment, were published. A thrice-weekly DS-TB regi- outcome did not change in the per-protocol analysis (exclud-
men is no longer recommended in the WHO guidelines [18]. ing patients with serious adverse events) for both treatment
groups, it was striking that levofloxacin had to be discon-
3.1.1 Four‑month Fluoroquinolone‑Containing Regimens tinued in 16 of 60 patients mainly due to seizures [19]. In
the remaining two clinical trials [20, 21], intensified TBM
A 2-month shorter regimen was investigated in six out of regimens for DS-TB were investigated that included high-
seven fluoroquinolone regimens for DS-TB, but none of dose fluoroquinolone (levofloxacin or moxifloxacin) and/or
these regimens demonstrated a favourable outcome after a high-dose rifampicin during the first weeks of treatment.
follow-up period of at least 6 months, compared to the stand- Adding levofloxacin (20 mg/kg/day) plus rifampicin (5 mg/
ard DS-TB regimen (Tables 2, 3, S). A remarkably higher TB kg/day) to the standard drug combination during the first
recurrence rate was observed in the experimental compared 8 weeks of treatment did not contribute to reducing death
to the control arms [13, 14, 17], leading to premature termi- after 9 months of treatment [20]. Although the sample size
nation of both the moxifloxacin- and gatifloxacin-containing was small and the study was exploratory, replacing ethambu-
arm in one clinical trial [17]. Additionally, in one of the tol with moxifloxacin (400 or 800 mg) in the first 2 weeks of
other clinical trials, non-inferiority was not observed after standard DS-TB treatment was also not associated with any
12 months of follow-up, but was observed at the end of treat- survival benefit [21]. On the other hand, in this study high-
ment for two moxifloxacin-containing regimens [13]. More- dose rifampicin (600 mg intravenously) in the first 2 weeks
over, in the preliminary terminated study [17], with the only of treatment was associated with a lower 6-month mortality
thrice-weekly control and experimental regimens, a higher compared to the standard rifampicin dose (450 mg orally)
TB recurrence rate was observed for gatifloxacin (16%) [21].
compared to moxifloxacin (10%), and almost all recurrences
occurred before the sixth month post-treatment. A minimal
increase in unfavourable outcome was observed at the end 4 Discussion
of treatment [17]. Finally, one clinical trial suggested that
standard DS-TB treatment might even benefit specific patient 4.1 Pulmonary Tuberculosis
populations, like DS-TB patients with an HIV-negative sta-
tus, if a daily 4-month gatifloxacin regimen is the alternative The main finding of this review is that the 4-month moxi-
treatment option [16]. floxacin- or gatifloxacin-containing regimens successfully
treated 75–90% of pulmonary TB patients, but none of them
3.1.2 Moxifloxacin demonstrated a favourable outcome after a follow-up period
of at least 6 months, compared to the standard DS-TB regi-
The treatment-shortening potential of moxifloxacin has been men (Tables 2, 3). Particularly, the TB relapse rate after
the most studied subject in recent years with regard to fluo- treatment was remarkable.
roquinolones for pulmonary TB (Tables 2, 3). Contrary to MTB has the capacity to survive in a hypoxic environ-
the results of these 4-month regimens, the efficacy, includ- ment by switching to a low-replicating and low-metabolic
ing the relapse rate after treatment, of a 6-month course that rate, resulting in a difficult-to-treat sub-population of

164

Table 2  Treatment outcomes of fluoroquinolone (FQ)-containing regimens for pulmonary tuberculosis (TB)

FQ (mg) Treatment ­regimenA Study Treatment outcome

FQ (months) Control Type No.C Patient Primary endpoint(s) End-pointD End-point ­FQC End-point FQ minus FQ non- Refs.
(months) ­controlC ­controlC,E inferiorB

M 400 S MRZE (2) HRZE (2) Non-inferiority, 193 (M) Drug- Unfavourable outcome (culture- ≥ 6 27I% 14% 13.1 (5.6 to No [14]
MRi900mg (2)F HR (4) RCT​ 188 (C) sensitiveG, positive, or death, or clinical 20.6) %
smear- need to change treatment, or
positive incomplete treatment with
positive culture at the end of
follow-up)H
M 400 MRZE (2) HRZE (2) Non-inferiority, 212 (M) Drug- Unfavourable outcome (culture- ≥ 6 14% 14% 0.4 (− 5.7 to Yes [14]
MRi1200mg (4)J HR (4) RCT​ 188 (C) sensitiveG, positive, or death, or clinical 6.6) %
smear- need to change treatment, or
positive incomplete treatment with
positive culture at the end of
follow-up)H
M 400 S HRZM (2) HRZE (2) Placebo- 568 (M) R- and FQ- Unfavourable outcome (bac- 12 23K% 16% 7.8 (2.7 to 13.0) No [13]
HRM (2) HR (4) controlled, 555 (C) sensitive, teriologically or clinically 0.48 (− 2.16 to
double-blind, smear- defined failure or relapse) 3.11)L
non-inferior- positive
ity, RCT​
M 400 S MRZE (2) HRZE (2) Placebo- 551 (M) R- and FQ- Unfavourable outcome (bac- 12 24K% 16% 9.0 (3.8 to 14.2) No [13]
RM (2) HR (4) controlled, 555 (C) sensitive, teriologically or clinically 1.96 (− 0.90 to
double-blind, smear- defined failure or relapse) 4.83)L
non-inferior- positive
ity, RCT​

C control, E ethambutol, FQ fluoroquinolone, H isoniazid, M moxifloxacin, RCT​randomized controlled trial, Ri rifapentine, R rifampicin, S short-course, Z pyrazinamide
A
 Daily regimen unless indicated otherwise
B
 (Modified) intention-to-treat and per-protocol population unless indicated otherwise
C
 (Modified) intention-to-treat population unless indicated otherwise
D
 Months after the end of control treatment
E
 Point-difference (95% or 97.5% CI)
F
 Administered twice weekly
G
 R, H and M sensitive TB. Most patients with unfavourable DST results were excluded after randomization (late exclusions, excluded from modified intention-to-treat analysis)
H
 Patients with re-infection and pregnant patients were excluded
I
 Remarkable high relapse rate compared to control
J
 Administered once weekly
K
 Approx. 10% relapse rate after the end of treatment
L
 Sensitivity analyses: non-inferior status at the end of treatment
A. D. Pranger et al.
Table 3  Treatment outcomes of fluoroquinolone (FQ)-containing regimens for pulmonary tuberculosis (TB)
FQ (mg) Treatment ­regimenA Study Treatment outcome Refs.
C
FQ (months) Control Type No. Patient Primary endpoint(s) End- End-point End-point FQ minus FQ non-
(months) pointD ­FQC ­controlC ­controlC,E inferiorB

G 400 S GHRZ (2) HRZE (2) Non- 1356 R-sen- Unfavourable outcome 24 21% 17% 3.5 (− 0.7 to No [16]
GHR (2) HR (4) inferiority, sitive, (culture-positive at 7.7) %F
open- smear- the end of treatment,
label, positive relapse or re-infec-
RCT​ tion, or death, or
study drop-out)
G 400 S GHRZ (2)G HRZE (2)G Open-label, 136 (G)H Culture- Unfavourable outcome 0 5%I 3%I – N/a [17]
GHR (2)G HR (4)G RCT​ 165 (C)H positive (culture-positive, or 24 16%I,J 6%I
death, or clinical need
Fluoroquinolones in the Treatment of Tuberculosis

to change treatment)
recurrence
L 750 LB (3 +)K – Open-label, 77 (L)L MDR, Treatment success 0 84% (L) – M-L: N/a [15]
M 400 MB (3 +)K RCT​ 74 (M)L culture- (sum of cure and 0 80% (M) − 4.7 (− 17.0 to
positive completion)M 8% (L) 7.6) %
treatment failure 7% (M) M-L:
(sum of death and − 1.0 (− 10.1 to
failure) 8.1) %
M 400 S MHRZ (2)G HRZE (2)G Open-label, 115 (M)H Culture- Unfavourable outcome 0 2%I 3%I – N/a [17]
MHR (2)G HR (4)G RCT​ 165 (C)H positive (culture-positive, or 24 10%I 6%I
death, or clinical need
to change treatment)
recurrence

B background regimen according to WHO guidelines, C control, E ethambutol, FQ fluoroquinolone, G gatifloxacin, H isoniazid, L levofloxacin, M moxifloxacin, MDR multi-drug resistance, O
ofloxacin, RCT​randomized controlled trial, R rifampicin, S short-course, Z pyrazinamide
A
 Daily regimen unless indicated otherwise
B
 (Modified) intention-to-treat and per-protocol population unless indicated otherwise
C
 (Modified) intention-to-treat population unless indicated otherwise
D
 Months after the end of treatment
E
 Point-difference (95% CI)
F
 Subgroups HIV-negative, cavitation, BMI ≥ 16: 95% CI in favour of Control
G
 Thrice-weekly
H
 Premature termination due to the extent of TB recurrence in the G- and M-arm
I
 Drug-susceptible (DS) TB patients (tested drugs: H,R,E,O): 94% (G), 97% (M) and 84% (C): DS-TB patients: equivalent frequencies for primary endpoints compared to the total group
J
 FQ vs. control: p < 0.05
K
 3 months’ trial medication, thereafter according to WHO guidelines
L
 Premature termination due to drop of patient enrollment
M
 Follow-up analysis comparing all WHO definitions of treatment outcome. Initial study had primary outcome = sputum culture conversion
165

166

Table 4  Treatment outcomes of fluoroquinolone (FQ)-containing regimens for tuberculosis (TB) meningitis

FQ (mg) Treatment ­regimenA Study Treatment outcome Survival FQ/control
B B
FQ (months) Control Type No. Patient Primary end- End- Endpoint ­FQ Endpoint Hazard ratio P value Refs.
(months) point point ­controlB (95% CI)B
­monthsc

L 20/kg LR (8 weeks) + HRZE HRZE (3) Double-blind, 817 Clinical Death 0 28% 28% Death: 0.66 [20]
(3)D HR (6) placebo-con- diagnosis, no 0.94 (0.73–
HR (6) trolled, RCT​ ­MDRE 1.22)
L 10/kg HLZE (6) HRZE (6) Open-label, 120 Clinical diag- Death 0 22%G 38%G Survival: 0.04 [19]
(max. 500) RCT​ nosis 2.13 (1.04–
4.34)F
M 0 HRZE (2 weeks)H – Open-label, + ­R450mg Clinical diag- DeathI 0 + ­R450mg – Death: 0.55K [21]
400 HRZM (2 weeks)H RCT, facto- 12 nosis 58% 0.76 (0.30–
800 HRZM (2 weeks)H rial design 10 60% 1.94)J,K
All arms > 2 weeks: 9 78% 1.27 (0.53–
HRZE + ­R600mg + ­R600mg 3.02)J,K
(2 months–2 weeks) 10 30%
HR (4) 9 22%
10 50%

E ethambutol, FQ fluoroquinolone, H isoniazid, L levofloxacin, MDR multi-drug resistance, M moxifloxacin, RCT​randomized controlled trial, R rifampicin, Z pyrazinamide
A
 Daily regimen
B
 (Modified) intention-to-treat population
C
 Months after the end of treatment
D
 + 5 mg/kg/day rifampicin (total 15 mg/kg/day) in the first 8 weeks. Streptomycin was added for the first 3 months in treatment-experienced patients
E
 MDR proven by sputum culture or suspected
F
 Adjusted for covariates of survival such as stage of disease
G
 Levofloxaxin was withdrawn in 16 patients due to serious adverse events (SAEs). Death in the per-protocol analysis (patients with SAEs excluded): 25% (L) vs. 41% (R)
H
 Six arms: first randomization oral R
­ 450mg (standard) or intravenous R
­ 600mg (high-dose), second randomization M
­ 400mg, ­M800mg or E
I
 Secondary endpoint. No sample size calculation because of the exploratory nature of the study. Sample size was assumed to be sufficient to explore pharmacokinetics and safety of intensified
regimens based on M and/or R
J
 Adjusted for R
­ 600mg, HIV status, and Glasgow coma scale at baseline
K
 M (400 mg, 800 mg) vs. E
A. D. Pranger et al.
Fluoroquinolones in the Treatment of Tuberculosis 167

persistent TB bacilli in pulmonary TB lesions [22], and thus all anti-tuberculosis drugs could be affected by TB disease
several months of treatment are needed to attain sterilising activity (wasting, loss of lean body mass, fat and serum
treatment. The indication that moxifloxacin or gatifloxacin proteins), HIV, diabetes or drug–drug interactions [37, 38].
had the potential to shorten DS-TB treatment was based on The PK interaction between rifampicin and moxifloxacin
the in vitro bactericidal activity of moxifloxacin and gati- is well known [39, 40]. Also male gender might be a risk
floxacin against anaerobic, non-replicating TB bacilli. Also, factor for reduced moxifloxacin exposure in the early phase
a stable cure in BALB/c mice was reached after 4 instead of treatment, which is probably due to disease-related intes-
of 6 months of treatment with isoniazid replaced by moxi- tinal dysfunction (publication submitted). In healthy vol-
floxacin and a similar or higher proportion of TB patients unteers, moxifloxacin has a high penetration into alveolar
with negative sputum culture after 8 weeks of treatment was macrophages and epithelial lining fluid [9]. However, based
reached with moxifloxacin or gatifloxacin instead of isonia- on MALDI mass spectrometry imaging, the penetration of
zid or ethambutol [23–28]. A poor predictive value of the moxifloxacin into the hypoxic sites of pulmonary lesions of
pre-clinical study designs used and a sub-optimal exposure TB patients is marginal compared to the oxygen-rich sites,
of anti-TB drugs at the site of infection might explain the and compared to rifampicin [41]. All together, the opti-
unfavourable results of these shorter-course regimens. mal sterilizing dose appears to differ from one patient to
First, the standard BALB/c mouse does not exhibit the TB another, probably due to PK variability, and this advocates
lesion heterogeneity as seen in humans, making this mouse for sub-group analyses in pre-clinical animal models (e.g.
model possibly unsuitable to study in vivo activity of drugs extent of cavitation) and clinical trials (e.g. low body mass
against non-replicating TB bacilli [29]. The C3HeB/FeJ index (BMI)), and also for drug-concentration monitoring
mouse, on the other hand, may be more suitable [29]. In in patients at risk for low drug exposure during treatment.
addition, the two 4-month moxifloxacin-containing regimens Despite limited data on gatifloxacin PK, in one of the Phase
of the REMoxTB Phase III study were retrospectively evalu- III trials (OFLOTUB), the 4-month gatifloxacin-containing
ated in a pre-clinical model with C3HeB/FeJ mice [30]. In regimen was not associated with treatment success for the
accordance with the results of the Phase III trial, a stable total group of patients, but was in favour of treatment suc-
cure was also not expected after 4 months of treatment based cess for patients without cavitation, for patients with HIV
on this murine model [30]. Second, using in vitro PK/PD co-infection, and for patients with a low BMI, compared to
modelling and Monte Carlo simulations, it has been sug- the standard DS-TB regimen [16].
gested that a daily dose of 800 mg of moxifloxacin or more In recent years, one clinical trial compared two conven-
is needed for optimal kill of MTB and to suppress drug- tional MDR-TB regimens (Tables 2, 3). In accordance with
resistant mutants in log-phase growth [31, 32]. The optimal the results of this study [15], a recent individual patient data
sterilizing dose is thus unknown, but 400 mg/day is likely meta-analysis showed that incorporation of moxifloxacin or
not the optimal dosage of moxifloxacin for TB. In addition, levofloxacin in a MDR/RR-TB regimen is associated with
combination therapy with rifampicin might be synergistic for treatment success [42]. The current WHO guidelines (Octo-
suppression of drug resistance (MTB in log-phase growth), ber 2016) proposed a shorter-course—still 9–12 months—
but antagonistic for the time needed to kill the non-growing regimen for RR/MDR-TB patients [8]. This largely standard-
mycobacterial population [32]. Given the possible para- ized gatifloxacin- (or moxifloxacin-) containing regimen is
doxical effect of rifampicin on moxifloxacin, the predictive based on three observational studies of cohorts from Bang-
performance for sterilizing activity of Phase IIB studies, ladesh, Niger and Cameroon, supplemented with individual
investigating culture conversion at 2 months of moxifloxacin patient data [8, 43–45]. Although the number of patients
substituted for isoniazid or ethambutol in a standard DS-TB in follow-up was limited, MDR/RR-TB patients without
regimen, is at least questionable. Also, PD interactions (syn- previous use of second-line drugs, and without resistance
ergistic, antagonistic or additive) might be concentration against fluoroquinolones and injectable agents, were found
dependent. An in vitro hollow fibre system (HFS) has the likely enough to benefit from this shorter regimen [8]. An
ability to study both the bactericidal and sterilizing effects important note is that the short-course Bangladesh regimen
for drug combinations using a variety of concentrations over included high-dose gatifloxacin (600 mg for a bodyweight
time [29, 33]. Therefore, the HFS might be a useful model to of 33–50 kg, 800 mg for > 50 kg) [43, 45]. In the prospective
study potentially sterilizing drugs like moxifloxacin and gati- evaluation of the shorter-course regimen for MDR/RR-TB,
floxacin, as part of a standard or new TB regimen. Recently, gatifloxacin was replaced by moxifloxacin because of market
the HFS was used to select the optimal sterilizing dose of withdrawal of gatifloxacin due to dysglycaemia. Although
both linezolid and ertapenem-clavulanate for TB [34, 35]. patients with a bodyweight > 50 kg are also treated with
Furthermore, in our TB patients treated under direct 800 mg of moxifloxacin once daily in this STREAM stage 1
observation (DOT), moxifloxacin PK variability in plasma trial [46], it is still questionable if this weight-band dosing
was found to be ninefold on 400 mg/day [36]. The PK of is optimal for a sterilizing and bactericidal effect. In August

168 A. D. Pranger et al.

2018, the WHO published a rapid communication regard- be true for the third study [20], including high dosages of
ing reclassification of core anti-TB drugs. Moxifloxacin or levofloxacin and rifampicin in the first 8 weeks added to
levofloxacin have remained core agents in the conventional isoniazid, rifampicin, pyrazinamide and ethambutol, which
and shorter course MDR/RR-TB regimen [47]. As earlier did not result in a cumulative survival benefit. Remarkably,
suggested for DS-TB, and as was proposed for ertapenem- the head-to-head comparison of standard dosages of levo-
clavulanate [35], we propose a combination of studies in floxacin and rifampicin in the first study was in favour of
HFS and Monte Carlo simulations, using RR/MDR-TB levofloxacin [19], which might support further investigating
patient data, to select the sterilizing fluoroquinolone dose the relationship between drug-exposure and outcome in a
most suitable to be tested in controlled Phase III trials as multiple drug-regimen. Also, in other bacteria quinolones
part of RR/MDR-TB regimens. have a concentration-dependent killing with a post-antibiotic
effect. However, it is at least questionable if the half-life of
4.2 Tuberculosis Meningitis levofloxacin is long enough to fullfill the criteria for once-
daily dosing in TB, i.e. to prevent drug-resistant mutant
A significant survival benefit for TBM patients treated with selection [9]. Further research of the optimal dosing interval
a fluoroquinolone-containing regimen was observed in one of levofloxacin for TB is therefore also important.
of the three published clinical trials (Table 4). The idea to Finally, considering that the (protein-unbound) drug-
use moxifloxacin and levofloxacin for improvement of TBM exposure in plasma is closely linked to drug-exposure in
survival is based on favourable penetration into cerebrospi- CSF, as for plasma, CSF PK variability might play an impor-
nal fluid (CSF) [9]. Because an evidence-based regimen is tant role. Therefore, the identification of sub-groups at risk
lacking, TBM patients are often treated (for a pragmatic for inadequate CSF exposure might be important for clini-
longer period) with the standardized pulmonary TB regi- cal research and clinical practice. Inadequate drug-exposure
men, as recommended by the WHO despite the fact that may result in drug resistance and high drug exposure in tox-
rifampicin only marginally penetrates into CSF [18, 48]. In icity, and, as CSF penetration has to be sufficiently high, sec-
the only RCT with favourable results for the patients treated ond-line treatment options are even more limited for TBM
with a fluoroquinolone [19], levofloxacin was compared to compared to the second-line drug options for pulmonary TB.
rifampicin, both using a standard dose, next to isonazid, Aminoglycosides belong to the core RR/MDR-TB agents;
pyrazinamide and ethambutol. The improved outcome for however, these drugs have marginal penetration into CSF
TBM patients treated with levofloxacin might be explained [48]. In addition, a recent sub-group analysis showed that in
by the much better penetration of levofloxacin into CSF isoniazid-monoresistant TB, an intensified combination of
compared to rifampicin [9, 48]. levofloxacin and rifampicin in the early phase of treatment
As adequate early-phase treatment is important to pre- was associated with a lower 9-month mortality, although
vent patients suffering from TBM to deteriorate, the two an overall survival benefit was not observed. Levofloxacin
remaining clinical studies investigated intensified, high-dose combined with rifampicin might therefore provide a sur-
therapies during the early phase of TBM treatment [20, 21]. vival benefit for isoniazid-resistant TBM patients [20, 52].
Although the trial with moxifloxacin was not powered for With regard to the safety of high-dose fluoroquinolones, data
survival analysis, instead of the high-dose moxifloxacin are limited, but no increase of serious adverse events was
(800 mg) treatment, the ‘high-dose’ rifampicin (600 mg reported for levofloxacin or moxifloxacin in TBM patients
iv) treatment in the first 2 weeks, given in an attempt to [20, 21, 53]. However, high-dose moxifloxacin was always
increase CSF drug-exposure, was associated with survival combined with rifampicin in these studies and a high inci-
benefit [21]. In this study, the moxifloxacin dose was esca- dence of seizures was observed by using the standard dose of
lated because of the well-known drug-drug interaction with levofloxacin [19, 21, 53]. The authors of the standard-dose
rifampicin. An additional PK/PD analysis was done to inves- levofloxacin study suggested that there could have been a
tigate the extent to which exposure was related to outcome relatively high seizure potential amongst their patients due
[49]. Despite the small sample size, moxifloxacin AUC was to inter alia severe meningitis [19]. Also, recently a ‘black
not, but the AUC of rifampicin was related to TBM sur- box’ warning was launched by the FDA on potential neu-
vival, and therefore the authors concluded that increasing rotoxicity and low blood sugar levels after administration
the rifampicin dose above 600 mg might be the way forward of fluoroquinolones [54]. However, as long as there is no
to further optimize TBM treatment. However, there was a drug-exposure breakpoint for safety, ECG monitoring is still
trend to a higher moxifloxacin peak-plasma concentration for recommended for high-dose moxifloxacin, especially when
patients who survived at least 2 weeks. We therefore agree combined with bedaquiline in the newest WHO prioritized
with the authors that an extended cumulative PK/PD analy- MDR/RR-TB regimen [47, 55], and one should be aware of
sis of the TBM regimen is needed to clarify the (long-term) seizures when using (high-dose) levofloxacin.
role of moxifloxacin for TBM [50, 51]. The same might
Fluoroquinolones in the Treatment of Tuberculosis 169

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described in this manuscript or to assist with preparation of the manu- sensitive tuberculosis. N Engl J Med. 2014;371(17):1577–87.
script. 14. Jindani A, Harrison TS, Nunn AJ, Phillips PP, Churchyard GJ,
Charalambous S, Hatherill M, Geldenhuys H, Mcllleron HM,
Zvada SP, Mungofa S, Shah NA, Zizhou S, Magweta L, Shepard
Conflict of interest The authors A.D. Pranger, T.S van der Werf, J, Nyirenda S, van Dijk JH, Clouting HE, Coleman D, Bateson
J.G.W. Kosterink, and J.W.C.Alffenaar, declare that they have no con- AL, McHugh TD, Butcher PD, Mitchison DA, RIFAQUIN Trial
flicts of interest. Team. High-dose rifapentine with moxifloxacin for pulmonary
tuberculosis. N Engl J Med. 2014;371(17):1599–608.
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tive Commons Attribution-NonCommercial 4.0 International License Jang SH, Yoo KH, Jung KH, Kim KU, Choi SB, Ryu YJ, Kim
(http://creativecommons.org/licenses/by-nc/4.0/), which permits any KC, Um S, Kwon YS, Kim YH, Choi WI, Jeon K, Hwang YI,
noncommercial use, distribution, and reproduction in any medium, Kim SJ, Lee HK, Heo E, Yim JJ. Choice between levofloxacin
provided you give appropriate credit to the original author(s) and the and moxifloxacin and multidrug-resistant tuberculosis treatment
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