International Journal of Infectious Diseases 76 (2018) 88–90

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International Journal of Infectious Diseases

journal homepage: www.elsevier.com/locate/ijid

Case Report

The use of bedaquiline to treat patients with multidrug-resistant

tuberculosis and end-stage renal disease: A case report
Seyeon Parka , Kyu Min Leea , Insu Kima , Jeongha Moka,b,c,*
a
Department of Internal Medicine, Pusan National University Hospital, 179 Gudeok-ro, Seo-gu, Busan 49241, Republic of Korea
b
College of Medicine, Pusan National University, 2 Busandaehak-ro, Geumjeong-gu, Busan 46241, Republic of Korea
c
Biomedical Research Institute, Pusan National University Hospital, 179 Gudeok-ro, Seo-gu, Busan, 49241, Republic of Korea

A R T I C L E I N F O A B S T R A C T

Article history: The use of bedaquiline to treat patients with multidrug-resistant tuberculosis (MDR-TB) and end-stage
Received 26 July 2018 renal disease (ESRD) may raise safety concerns. Currently, no clinical information is available on the use
Received in revised form 13 September 2018 of bedaquiline to treat MDR-TB patients with ESRD. We report the use of bedaquiline to treat two patients
Accepted 13 September 2018
with MDR-TB and ESRD. This report highlights the safety and tolerability of bedaquiline as well as the
Corresponding Editor: Eskild Petersen, Aar-
hus, Denmark
treatment outcome. The use of bedaquiline in patients with ESRD is also discussed.
© 2018 The Author(s). Published by Elsevier Ltd on behalf of International Society for Infectious Diseases.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
Keywords:
Bedaquiline
nc-nd/4.0/).
Tuberculosis
Multidrug resistance
End-stage renal disease

Introduction There is currently no clinical information available on the use of

The treatment of multidrug-resistant tuberculosis (MDR-TB) is
prolonged, as second-line drugs that are less effective and more toxic
than first-line drugs must be used (Matteelli et al., 2007). Thus,
treatment outcomes are unsatisfactory. In a 2014 global MDR-TB
cohort, only 54% of patients successfully completed treatment
(World Health Organization, 2017). Effective drugs for the treatment
of MDR-TB are lacking. Bedaquiline, which inhibits mycobacterial
ATP synthase, has recently been introduced clinically. In clinical trials
and in real-world cohorts, bedaquiline combined with optimal
background regimens has afforded promising outcomes, with
acceptable safety and tolerability (Diacon et al., 2014; Pym et al.,
2016; Borisov et al., 2017; Olayanju et al., 2018).
End-stage renal disease (ESRD) is a well-known risk factor for
active TB. Atypical/serious drug reactions occur frequently during
TB treatment, and TB-specific mortality is higher in patients with
ESRD (British Thoracic Society Standards of Care Committee and
Joint Tuberculosis Committee et al., 2010; Wu et al., 2015). QT
prolongation is common in ESRD patients and may be an
independent predictor of mortality (Hage et al., 2010). Therefore,
the use of bedaquiline to treat TB patients with ESRD may raise
safety concerns.
* Corresponding author at: Department of Internal Medicine, Pusan National
University Hospital, 179 Gudeok-ro, Seo-gu, Busan 49241, Republic of Korea.
E-mail address: mokgamokga@gmail.com (J. Mok).
bedaquiline to treat MDR-TB patients with ESRD. Patients with
severe concomitant illnesses including ESRD were excluded from
earlier clinical trials. There are no real-world reports on the use of
bedaquiline for patients with ESRD. The World Health Organiza-
tion states that bedaquiline should be administered with care in
patients with severe renal impairment requiring dialysis, but the
evidence is limited (World Health Organization, 2014). Here, we
describe two patients with ESRD who were prescribed bedaquiline
to treat pulmonary MDR-TB.
Case reports
Patient 1
In August 2016, a 46-year-old HIV-negative Korean man was
referred to Pusan National University Hospital for the treatment of
pre-extensively drug-resistant (XDR)-TB. Two months before that
visit, he had been diagnosed with culture-confirmed pulmonary
and peritoneal TB and had commenced first-line drugs. Subse-
quent phenotypic drug susceptibility testing (DST) revealed pre-
XDR-TB, after which he was transferred to our hospital (Table 1).
The patient exhibited hypertension and ESRD (anuria requiring
conventional hemodialysis three times weekly). On initial exami-
nation, sputum staining and culture for Mycobacterium tuberculosis
were negative. Baseline serum creatinine levels were 8.12 mg/dl
pre-hemodialysis and 3.97 mg/dl post-hemodialysis. The baseline
QTcF interval was 441 ms on electrocardiogram (ECG) monitoring.

https://doi.org/10.1016/j.ijid.2018.09.009
1201-9712/© 2018 The Author(s). Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
 S. Park et al. / International Journal of Infectious Diseases 76 (2018) 88–90 89

Table 1
Clinical characteristics of the two patients.

Patient 1 Patient 2
Nationality South Korean South Korean
Age, years 46 53
Sex Male Male
Body weight, kg 45 72
Body mass index, kg/m2 14.9 24.9
Comorbidities Hypertension Hypertension
ESRD (on hemodialysis) Diabetes mellitus
HCV infection
Chronic kidney diseasea
Previous TB treatment None First-line drugs
Type of TB Pulmonary TB + peritoneal TB Pulmonary TB
Extent and severity of TB Unilateral disease with cavities Bilateral disease with cavities
Phenotypic DST resultb Resistant to: H, R, E, Z, Rfb, Ofx, Lfx, S, Pto, PAS Resistant to: H, R, E, S
Susceptible to: Am, Km, Cm, Mfx, Cs Susceptible to: Z, Rfb, Ofx, Lfx, Mfx, Am, Km, Cm, Pto, Cs, PAS
Treatment regimen over 1 monthb Z, 1000 mg three times weekly Z, 1,000 mg three times weeklye
Am, 500 mg three times weeklyc Lfx, 750 mg three times weekly
Mfx, 400 mg daily Pto, 250 mg daily
Cs, 250 mg daily Cs, 250 mg daily
Lzd, 300 mg dailyc PAS, 6.6 g dailye
Bdq, 200 mg three times weeklyd Bdq, 400 mg daily for 2 weeks → 200 mg three times weeklyd
Total treatment duration, days 607 653

ESRD, end-stage renal disease; HCV, hepatitis C virus; TB, tuberculosis; DST, drug susceptibility testing.
a
Did not require renal replacement therapy at baseline; maintenance hemodialysis commenced 5 months after treatment commenced, i.e., 3 months after adding
bedaquiline.
b
Am, amikacin; Bdq, bedaquiline; Cm, capreomycin; Cs, cycloserine; E, ethambutol; H, isoniazid; Km, kanamycin; Lfx, levofloxacin; Lzd, linezolid; Mfx, moxifloxacin; Ofx,
ofloxacin; PAS, para-aminosalicylic acid; Pto, prothionamide; R, rifampicin; Rfb, rifabutin; S, streptomycin; Z, pyrazinamide.
c
Duration of use was 12 months.
d
Duration of use was 24 weeks.
e
Pyrazinamide was replaced with para-aminosalicylic acid after 5 months of treatment.

Based on the DST results, the patient was commenced on
treatment with pyrazinamide, amikacin, moxifloxacin, cycloserine,
linezolid, and bedaquiline after obtaining informed consent.
Bedaquiline was started at 200 mg three times weekly and was
given for 24 weeks without any discontinuation. No adverse
reaction related to bedaquiline was encountered. One year after
treatment initiation, amikacin and linezolid were permanently
discontinued because of a hearing disturbance and peripheral
neuropathy, respectively. Sputum cultures remained negative
throughout treatment, and clinical and radiological improvements
were evident. In April 2018, he successfully completed treatment
(total duration of 607 days). ECG monitoring was conducted daily
for the first 2 weeks and monthly thereafter. Over the entire course
of treatment, the maximum QTcF interval was 469 ms (on day 2
after bedaquiline commencement). No clinically significant cardiac
event was noted.
Patient 2
In September 2016, a 53-year-old HIV-negative Korean man was
referred to Pusan National University Hospital for the treatment of
MDR-TB. He had taken first-line drugs in 2013 and 2014 to treat
drug-susceptible pulmonary TB. Three months prior to presenta-
tion, he had been diagnosed with culture-confirmed pulmonary TB
once more and placed on first-line drugs. Subsequent DST revealed
MDR-TB, and he was then transferred to our hospital (Table 1). The
patient exhibited hypertension, diabetes mellitus, hepatitis C virus
infection, and chronic kidney disease (average urine volume
1500 ml/day without a requirement for maintenance renal
replacement therapy). On initial examination, sputum staining
and culture for M. tuberculosis were negative. The baseline serum
creatinine level was 3.04 mg/dl (the estimated glomerular filtra-
tion rate was 21.7 ml/min/1.73 m2). The baseline QTcF interval was
424 ms on ECG monitoring.
Based on the DST results, the patient was commenced on
treatment with pyrazinamide, levofloxacin, amikacin,
prothionamide, and cycloserine. Unfortunately, acute kidney
injury developed 6 days later (the serum creatinine level increased
to 5.1 mg/dl, combined with oliguria), and amikacin was thus
discontinued permanently. After 2 months, bedaquiline was added
to the treatment regimen after obtaining informed consent. (Due
to administrative issues, bedaquiline could not be started
immediately after discontinuing the amikacin.) Bedaquiline was
commenced at 400 mg daily for 2 weeks, followed by 200 mg three
times weekly. In February 2017 (5 months after treatment
commencement and 3 months after the addition of bedaquiline),
the patient started conventional maintenance hemodialysis (three
times weekly) because renal impairment had progressed. Bedaqui-
line treatment was continued unchanged for a total of 24 weeks
without any discontinuation. No adverse drug reaction related to
bedaquiline was observed. Five months after treatment initiation,
pyrazinamide was replaced by para-aminosalicylic acid because
the patient developed gout. Sputum cultures remained negative
throughout treatment, and clinical and radiological improvements
were evident. In June 2018, he successfully completed treatment
(total duration of 653 days). ECG monitoring was conducted daily
for the first 2 weeks and monthly thereafter. Over the entire
treatment, the maximum QTcF interval was 463 ms (on day 2 after
bedaquiline commencement). No clinically significant cardiac
event was noted.
Discussion
In these case reports, the treatment outcomes of the bedaqui-
line-containing regimens were favorable, and its safety and
tolerability were acceptable in two MDR-TB patients with ESRD.
QT prolongation is of major concern in ESRD patients (who often
exhibit a prolonged QT interval at baseline), but no significant QT
prolongation or clinically significant cardiac event was observed in
either of the patient cases described. In a French cohort study that
included two patients with renal failure, no clinically relevant
adverse event associated with bedaquiline was reported
90 S. Park et al. / International Journal of Infectious Diseases 76 (2018) 88–90
(Guglielmetti et al., 2015). The second patient in the present report
exhibited a gradual decrease in renal function and was commenced
on maintenance hemodialysis during TB treatment. However, we
believe that this was associated with uncontrolled hypertension
and diabetes mellitus, not bedaquiline use, as the deterioration in
renal function was already evident prior to the addition of
bedaquiline. In earlier clinical trials of bedaquiline, no severe renal
impairment was observed (Diacon et al., 2014; Pym et al., 2016).
Furthermore, South African XDR-TB bedaquiline and non-bedaqui-
line cohorts exhibited similar rates of renal impairment (Olayanju
et al., 2018). However, the safety of bedaquiline may not be
generalizable based on the small number of patients. One death
attributed to renal impairment has been reported during bedaqui-
line treatment (Pontali et al., 2016).
Bedaquiline is eliminated principally in the feces. Urinary
excretion of bedaquiline and its M2 metabolite are negligible
(0.001%) (van Heeswijk et al., 2014). However, any impact of
dialysis on bedaquiline pharmacokinetics remains unknown. Renal
impairment may influence the pharmacokinetics of non-renally
eliminated drugs by affecting the levels of drug-metabolizing
enzymes or drug transporters (van Heeswijk et al., 2014). One
clinical study found that creatinine clearance did not affect
bedaquiline clearance. However, patients with ESRD requiring
dialysis were not included in that study (van Heeswijk et al., 2014).
In the first patient in the present report, bedaquiline was started at
200 mg three times weekly, rather than 400 mg daily for 2 weeks,
because we were concerned about adverse reactions, such as QT
prolongation. However, it is not clear whether dose adjustment is
required during the bedaquiline loading-dose period in patients
with ESRD. We did not load bedaquiline based on a clinical decision
without supporting evidence. Further pharmacokinetic studies of
patients with ESRD are needed.
Although ESRD is not frequently seen in MDR-TB patients,
patients with ESRD can certainly be infected with this hard-to-
treat pathogen. Further studies are needed to expand the use of
bedaquiline and to control drug-resistant TB in special popula-
tions. Therapeutic drug monitoring (TDM) may be useful in
patients with ESRD (Tiberi et al., 2018). However, the long half-life
of bedaquiline and its M2 metabolite, and the frequent interactions
between bedaquiline and other drugs, may make TDM difficult in
terms of reaching a steady-state and sampling timing (van
Heeswijk et al., 2014). Further, no detailed guidelines on TDM in
patients with ESRD are available. Additional evidence supporting
the use of bedaquiline to treat patients with MDR-TB and ESRD is
needed. Our experience may thus be helpful.
Author contributions
Mok J and Park S conceived the initial idea of this study and its
design. Mok J, Park S, Lee KM, and Kim I pooled the data and
contributed to the data analysis. Mok J and Park S drafted the
manuscript. All authors revised and approved the final manuscript.
Funding sources
The authors declare that they have no funding sources to
acknowledge.
Ethical approval
The present study was approved by the Institutional Review
Board of Pusan National University Hospital (IRB approval number
1807-014-068).
Conflict of interest
The authors declare that they have no competing interests.
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