Cardiac safety of bedaquiline, delamanid and moxifloxacin co-administered with or without varying doses of sutezolid or delpazolid for the treatment of drug-susceptible TB

PanACEA consortium; Simon E Koele; Krista Stoycheva; Cyprian Mtweve; Christina Manyama; Stellah Mpagama; Francis Mhimbira; Robert Wallis; Nyanda Elias Ntinginya; Alphonce Liyoyo; Beno Huglin; Lilian Tina Minja; Larissa Wagnerberger; Tresphory Zumba; Ivan Noreña; Daud D Peter; Trevor Beattie; Heeran Makkan; Derek J Sloan; Lindsey Te Brake; Rob E Aarnoutse; Timothy D McHugh; Leticia Wildner; Jodie Schildkraut; Brian H Aldana; Patrick P J Phillips; Michael Hoelscher; Elin M Svensson; Norbert Heinrich

doi:10.1093/jac/dkaf210

Cardiac safety of bedaquiline, delamanid and moxifloxacin co-administered with or without varying doses of sutezolid or delpazolid for the treatment of drug-susceptible TB

PanACEA consortium
, Simon E Koele^*
, Krista Stoycheva
, Cyprian Mtweve
, Christina Manyama
, Stellah Mpagama
, Francis Mhimbira
, Robert Wallis
, Nyanda Elias Ntinginya
, Alphonce Liyoyo
, Beno Huglin
, Lilian Tina Minja
, Larissa Wagnerberger
, Tresphory Zumba
, Ivan Noreña
, Daud D Peter
, Trevor Beattie
, Heeran Makkan
, Derek J Sloan
, Lindsey Te Brake

Rob E Aarnoutse, Timothy D McHugh, Leticia Wildner, Jodie Schildkraut, Brian H Aldana, Patrick P J Phillips, Michael Hoelscher, Elin M Svensson, Norbert Heinrich

^*Corresponding author for this work

Radboud University Medical Center
Occupational and Environmental Epidemiology & NetTeaching Unit, Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, University Hospital of Munich (LMU), Munich, Germany.
National Institute for Medical Research-Mbeya Medical Research Centre
Kibon'goto Infectious Disease Hospital
Ifakara Health Institute
The Aurum Institute
University College London
University of California at San Francisco

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

INTRODUCTION: Many drugs for the treatment of TB prolong the QTc interval, which is associated with an increased risk of developing a life-threatening arrhythmia known as torsades de pointes. Sutezolid and delpazolid are novel oxazolidinones with demonstrated bactericidal activity. We aimed to assess the effects of sutezolid or delpazolid co-administered with bedaquiline, delamanid and moxifloxacin on the QTcF interval (Fridericia's correction). Furthermore, we developed a population pharmacodynamic model to assess the effects of drug exposure on the QTcTBT interval (TB-specific correction).

METHODS: Participants were randomized to receive standard-dose bedaquiline, delamanid and moxifloxacin with varying doses of either sutezolid (no sutezolid, 600 mg daily, 1200 mg daily, 600 mg twice daily, 800 mg twice daily) or delpazolid (no delpazolid, 400 mg daily, 800 mg daily, 1200 mg daily, 800 mg twice daily). The QTc interval was determined using weekly ECG assessments.

RESULTS: Data from 149 participants, yielding 2373 ECG observations were available for analysis. Nine participants (6.0%) experienced a Grade 3 QTcF prolongation as defined by the Common Terminology Criteria for Adverse Events v5.0. The population pharmacodynamic model predicted a 13.2 ms (95% CI: 10.9-15.3) increase of the QTcTBT in the first week of treatment, but no further increase after that. The exposure of bedaquiline's M2 metabolite was found to drive part of the QTcTBT. No exposure-response relationship was identified for the other drugs investigated.

CONCLUSIONS: The drug regimens containing standard doses of bedaquiline, delamanid and moxifloxacin, and varying doses of sutezolid or delpazolid were not found to pose a high cardiac risk in a population without further QTc-relevant risk factors. However, close monitoring of the QTc interval remains essential in patients with TB treated with combination drug therapy with known QTc-prolonging drugs.

Original language	English
Pages (from-to)	2305-2313
Number of pages	9
Journal	Journal of Antimicrobial Chemotherapy
Volume	80
Issue number	8
Early online date	4 Jul 2025
DOIs	https://doi.org/10.1093/jac/dkaf210
Publication status	Published - Aug 2025

Bibliographical note

Publisher Copyright:
© The Author(s) 2025.

Funding

This study was conducted by the PanACEA consortium, funded by the EDCTP2 programme (grant number TRIA2015-1102) with support from the German Ministry for Education and Research (BMBF; 01KA1701); further funding was contributed by the German Center for Infection Research (DZIF), the Swiss State Secretariat for Education, Research, and Innovation (SERI) and Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO). Otsuka provided delamanid for these studies at no cost to the consortium. We thank the participants involved in this study, all investigators, clinical nurses, laboratory personnel and trial support team. We would also like to acknowledge the members of the data safety monitoring board (Prof. Robert Horsburgh Jr, Prof. Ndeky Orio, Prof. Andrew Nunn, Prof. Gary Maartens). Further, we would like to acknowledge the team from TECRO Research for invaluable data management. This study was conducted by the PanACEA consortium, funded by the EDCTP2 programme (grant number TRIA2015-1102) with support from the German Ministry for Education and Research (BMBF; 01KA1701); further funding was contributed by the German Center for Infection Research (DZIF), the Swiss State Secretariat for Education, Research, and Innovation (SERI) and Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO). Otsuka provided delamanid for these studies at no cost to the consortium.

Funders	Funder number
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
Spine Education and Research Institute
Staatssekretariat für Bildung, Forschung und Innovation
Deutsches Zentrum für Infektionsforschung
Bundesministerium für Bildung und Forschung	01KA1701
TECRO	TRIA2015-1102

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Cardiac safety of bedaquiline, delamanid and moxifloxacin co-administered with or without varying doses of sutezolid or delpazolid for the treatment of drug-susceptible TBFinal published version, 1 MBLicence: CC BY

Cite this

PanACEA consortium , Koele, S. E., Stoycheva, K., Mtweve, C., Manyama, C., Mpagama, S., Mhimbira, F., Wallis, R., Ntinginya, N. E., Liyoyo, A., Huglin, B., Minja, L. T., Wagnerberger, L., Zumba, T., Noreña, I., Peter, D. D., Beattie, T., Makkan, H., Sloan, D. J., ... Heinrich, N. (2025). Cardiac safety of bedaquiline, delamanid and moxifloxacin co-administered with or without varying doses of sutezolid or delpazolid for the treatment of drug-susceptible TB. Journal of Antimicrobial Chemotherapy, 80(8), 2305-2313. https://doi.org/10.1093/jac/dkaf210

@article{c914a6f6da7a4e0f82e1e2fe60a3ae0d,

title = "Cardiac safety of bedaquiline, delamanid and moxifloxacin co-administered with or without varying doses of sutezolid or delpazolid for the treatment of drug-susceptible TB",

abstract = "INTRODUCTION: Many drugs for the treatment of TB prolong the QTc interval, which is associated with an increased risk of developing a life-threatening arrhythmia known as torsades de pointes. Sutezolid and delpazolid are novel oxazolidinones with demonstrated bactericidal activity. We aimed to assess the effects of sutezolid or delpazolid co-administered with bedaquiline, delamanid and moxifloxacin on the QTcF interval (Fridericia's correction). Furthermore, we developed a population pharmacodynamic model to assess the effects of drug exposure on the QTcTBT interval (TB-specific correction).METHODS: Participants were randomized to receive standard-dose bedaquiline, delamanid and moxifloxacin with varying doses of either sutezolid (no sutezolid, 600 mg daily, 1200 mg daily, 600 mg twice daily, 800 mg twice daily) or delpazolid (no delpazolid, 400 mg daily, 800 mg daily, 1200 mg daily, 800 mg twice daily). The QTc interval was determined using weekly ECG assessments.RESULTS: Data from 149 participants, yielding 2373 ECG observations were available for analysis. Nine participants (6.0\%) experienced a Grade 3 QTcF prolongation as defined by the Common Terminology Criteria for Adverse Events v5.0. The population pharmacodynamic model predicted a 13.2 ms (95\% CI: 10.9-15.3) increase of the QTcTBT in the first week of treatment, but no further increase after that. The exposure of bedaquiline's M2 metabolite was found to drive part of the QTcTBT. No exposure-response relationship was identified for the other drugs investigated.CONCLUSIONS: The drug regimens containing standard doses of bedaquiline, delamanid and moxifloxacin, and varying doses of sutezolid or delpazolid were not found to pose a high cardiac risk in a population without further QTc-relevant risk factors. However, close monitoring of the QTc interval remains essential in patients with TB treated with combination drug therapy with known QTc-prolonging drugs.",

author = "\{PanACEA consortium\} and Koele, \{Simon E\} and Krista Stoycheva and Cyprian Mtweve and Christina Manyama and Stellah Mpagama and Francis Mhimbira and Robert Wallis and Ntinginya, \{Nyanda Elias\} and Alphonce Liyoyo and Beno Huglin and Minja, \{Lilian Tina\} and Larissa Wagnerberger and Tresphory Zumba and Ivan Nore{\~n}a and Peter, \{Daud D\} and Trevor Beattie and Heeran Makkan and Sloan, \{Derek J\} and \{Te Brake\}, Lindsey and Aarnoutse, \{Rob E\} and McHugh, \{Timothy D\} and Leticia Wildner and Jodie Schildkraut and Aldana, \{Brian H\} and Phillips, \{Patrick P J\} and Michael Hoelscher and Svensson, \{Elin M\} and Norbert Heinrich",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

month = aug,

doi = "10.1093/jac/dkaf210",

language = "English",

volume = "80",

pages = "2305--2313",

journal = "Journal of Antimicrobial Chemotherapy",

issn = "0305-7453",

publisher = "Oxford University Press",

number = "8",

}

PanACEA consortium , Koele, SE, Stoycheva, K, Mtweve, C, Manyama, C, Mpagama, S, Mhimbira, F, Wallis, R, Ntinginya, NE, Liyoyo, A, Huglin, B, Minja, LT, Wagnerberger, L, Zumba, T, Noreña, I, Peter, DD, Beattie, T, Makkan, H, Sloan, DJ, Te Brake, L, Aarnoutse, RE, McHugh, TD, Wildner, L, Schildkraut, J, Aldana, BH, Phillips, PPJ, Hoelscher, M, Svensson, EM & Heinrich, N 2025, 'Cardiac safety of bedaquiline, delamanid and moxifloxacin co-administered with or without varying doses of sutezolid or delpazolid for the treatment of drug-susceptible TB', Journal of Antimicrobial Chemotherapy, vol. 80, no. 8, pp. 2305-2313. https://doi.org/10.1093/jac/dkaf210

Cardiac safety of bedaquiline, delamanid and moxifloxacin co-administered with or without varying doses of sutezolid or delpazolid for the treatment of drug-susceptible TB. / PanACEA consortium ; Koele, Simon E; Stoycheva, Krista et al.
In: Journal of Antimicrobial Chemotherapy, Vol. 80, No. 8, 08.2025, p. 2305-2313.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Cardiac safety of bedaquiline, delamanid and moxifloxacin co-administered with or without varying doses of sutezolid or delpazolid for the treatment of drug-susceptible TB

AU - PanACEA consortium

AU - Koele, Simon E

AU - Stoycheva, Krista

AU - Mtweve, Cyprian

AU - Manyama, Christina

AU - Mpagama, Stellah

AU - Mhimbira, Francis

AU - Wallis, Robert

AU - Ntinginya, Nyanda Elias

AU - Liyoyo, Alphonce

AU - Huglin, Beno

AU - Minja, Lilian Tina

AU - Wagnerberger, Larissa

AU - Zumba, Tresphory

AU - Noreña, Ivan

AU - Peter, Daud D

AU - Beattie, Trevor

AU - Makkan, Heeran

AU - Sloan, Derek J

AU - Te Brake, Lindsey

AU - Aarnoutse, Rob E

AU - McHugh, Timothy D

AU - Wildner, Leticia

AU - Schildkraut, Jodie

AU - Aldana, Brian H

AU - Phillips, Patrick P J

AU - Hoelscher, Michael

AU - Svensson, Elin M

AU - Heinrich, Norbert

PY - 2025/8

Y1 - 2025/8

N2 - INTRODUCTION: Many drugs for the treatment of TB prolong the QTc interval, which is associated with an increased risk of developing a life-threatening arrhythmia known as torsades de pointes. Sutezolid and delpazolid are novel oxazolidinones with demonstrated bactericidal activity. We aimed to assess the effects of sutezolid or delpazolid co-administered with bedaquiline, delamanid and moxifloxacin on the QTcF interval (Fridericia's correction). Furthermore, we developed a population pharmacodynamic model to assess the effects of drug exposure on the QTcTBT interval (TB-specific correction).METHODS: Participants were randomized to receive standard-dose bedaquiline, delamanid and moxifloxacin with varying doses of either sutezolid (no sutezolid, 600 mg daily, 1200 mg daily, 600 mg twice daily, 800 mg twice daily) or delpazolid (no delpazolid, 400 mg daily, 800 mg daily, 1200 mg daily, 800 mg twice daily). The QTc interval was determined using weekly ECG assessments.RESULTS: Data from 149 participants, yielding 2373 ECG observations were available for analysis. Nine participants (6.0%) experienced a Grade 3 QTcF prolongation as defined by the Common Terminology Criteria for Adverse Events v5.0. The population pharmacodynamic model predicted a 13.2 ms (95% CI: 10.9-15.3) increase of the QTcTBT in the first week of treatment, but no further increase after that. The exposure of bedaquiline's M2 metabolite was found to drive part of the QTcTBT. No exposure-response relationship was identified for the other drugs investigated.CONCLUSIONS: The drug regimens containing standard doses of bedaquiline, delamanid and moxifloxacin, and varying doses of sutezolid or delpazolid were not found to pose a high cardiac risk in a population without further QTc-relevant risk factors. However, close monitoring of the QTc interval remains essential in patients with TB treated with combination drug therapy with known QTc-prolonging drugs.

AB - INTRODUCTION: Many drugs for the treatment of TB prolong the QTc interval, which is associated with an increased risk of developing a life-threatening arrhythmia known as torsades de pointes. Sutezolid and delpazolid are novel oxazolidinones with demonstrated bactericidal activity. We aimed to assess the effects of sutezolid or delpazolid co-administered with bedaquiline, delamanid and moxifloxacin on the QTcF interval (Fridericia's correction). Furthermore, we developed a population pharmacodynamic model to assess the effects of drug exposure on the QTcTBT interval (TB-specific correction).METHODS: Participants were randomized to receive standard-dose bedaquiline, delamanid and moxifloxacin with varying doses of either sutezolid (no sutezolid, 600 mg daily, 1200 mg daily, 600 mg twice daily, 800 mg twice daily) or delpazolid (no delpazolid, 400 mg daily, 800 mg daily, 1200 mg daily, 800 mg twice daily). The QTc interval was determined using weekly ECG assessments.RESULTS: Data from 149 participants, yielding 2373 ECG observations were available for analysis. Nine participants (6.0%) experienced a Grade 3 QTcF prolongation as defined by the Common Terminology Criteria for Adverse Events v5.0. The population pharmacodynamic model predicted a 13.2 ms (95% CI: 10.9-15.3) increase of the QTcTBT in the first week of treatment, but no further increase after that. The exposure of bedaquiline's M2 metabolite was found to drive part of the QTcTBT. No exposure-response relationship was identified for the other drugs investigated.CONCLUSIONS: The drug regimens containing standard doses of bedaquiline, delamanid and moxifloxacin, and varying doses of sutezolid or delpazolid were not found to pose a high cardiac risk in a population without further QTc-relevant risk factors. However, close monitoring of the QTc interval remains essential in patients with TB treated with combination drug therapy with known QTc-prolonging drugs.

UR - https://www.scopus.com/pages/publications/105012758486

U2 - 10.1093/jac/dkaf210

DO - 10.1093/jac/dkaf210

M3 - Article

C2 - 40613338

SN - 0305-7453

VL - 80

SP - 2305

EP - 2313

JO - Journal of Antimicrobial Chemotherapy

JF - Journal of Antimicrobial Chemotherapy

IS - 8

ER -

Cardiac safety of bedaquiline, delamanid and moxifloxacin co-administered with or without varying doses of sutezolid or delpazolid for the treatment of drug-susceptible TB

Abstract

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