Advancing the chemotherapy of tuberculous meningitis: a consensus view

Sean Wasserman¹, Joseph Donovan², Evelyne Kestelyn³, James A Watson³, Robert E Aarnoutse⁴, James R Barnacle⁵, David R Boulware⁶, Felicia C Chow⁷, Fiona V Cresswell⁸, Angharad G Davis⁹, Kelly E Dooley¹⁰, Anthony A Figaji¹¹, Diana M Gibb¹², Julie Huynh¹³, Darma Imran¹⁴, Suzaan Marais¹⁵, David B Meya¹⁶, Usha K Misra¹⁷, Manish Modi¹⁸, Mihaja Raberahona¹⁹, Ahmad Rizal Ganiem²⁰, Ursula K Rohlwink²¹, Rovina Ruslami²², James A Seddon²³, Keira H Skolimowska¹, Regan S Solomons²⁴, Cari J Stek²⁵, Nguyen Thuy Thuong Thuong³, Reinout van Crevel⁴, Claire Whitaker²⁵, Guy E Thwaites¹³, Robert J Wilkinson²⁶

Affiliations

¹ Institute of Infectious Disease and Molecular Medicine and Department of Medicine, University of Cape Town, Cape Town, South Africa; Infection and Immunity, St George's University of London, London, UK.
² Department of Clinical Research, London School of Hygiene & Tropical Medicine, London, UK.
³ Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam.
⁴ Radboud University Medical Center, Nijmegen, Netherlands.
⁵ Institute of Infectious Disease and Molecular Medicine and Department of Medicine, University of Cape Town, Cape Town, South Africa; The Francis Crick Institute, London, UK; Department of Infectious Diseases, Imperial College London, London, UK.
⁶ Division of Infectious Diseases and International Medicine, Department of Medicine, University of Minnesota, Minneapolis, MN, USA.
⁷ Departments of Neurology and Medicine (Infectious Diseases), University of California San Francisco, San Francisco, CA, USA.
⁸ Infectious Diseases Institute, School of Medicine, College of Health Sciences, Makerere University, Kampala, Uganda; HIV Interventions, Medical Research Council-Uganda Virus Research Institute MRC and London School of Hygiene & Tropical Medicine Uganda Research Unit, Entebbe, Uganda; Global Health and Infection, Brighton and Sussex Medical School, Brighton, UK.
⁹ Institute of Infectious Disease and Molecular Medicine and Department of Medicine, University of Cape Town, Cape Town, South Africa; The Francis Crick Institute, London, UK.
¹⁰ Division of Infectious Diseases, Vanderbilt University Medical Center, Nashville, TN, USA.
¹¹ Division of Neurosurgery, Neuroscience Institute, Department of Surgery, University of Cape Town, Cape Town, South Africa.
¹² Medical Research Council Clinical Trials Unit, London, UK.
¹³ Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, Oxford, UK.
¹⁴ Dr Cipto Mangunkusumo Hospital, Jakarta, Indonesia.
¹⁵ Division of Neurology, Neuroscience Institute, Department of Medicine, University of Cape Town, Cape Town, South Africa.
¹⁶ Infectious Diseases Institute, School of Medicine, College of Health Sciences, Makerere University, Kampala, Uganda; Department of Medicine, School of Medicine, College of Health Sciences, Makerere University, Kampala, Uganda.
¹⁷ Prof Emeritus T S Misra Medical College, Vivekanand Polyclinic and Institute of Medical Sciences and Apollo Medics Super Speciality Hospital, Lucknow, India.
¹⁸ Postgraduate Institute of Medical Education and Research, Chandigarh, India.
¹⁹ University Hospital Joseph Raseta Befelatanana, Antananarivo, Madagascar.
²⁰ Department of Neurology, Faculty of Medicine, Universitas Padjadjaran-Hasan Sadikin Hospital, Bandung, Indonesia.
²¹ Institute of Infectious Disease and Molecular Medicine and Department of Medicine, University of Cape Town, Cape Town, South Africa; Division of Neurosurgery, Neuroscience Institute, Department of Surgery, University of Cape Town, Cape Town, South Africa.
²² Department of Biomedical Sciences, Faculty of Medicine, Universitas Padjadjaran-Hasan Sadikin Hospital, Bandung, Indonesia.
²³ Department of Infectious Diseases, Imperial College London, London, UK; Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Stellenbosch, South Africa.
²⁴ Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Stellenbosch, South Africa.
²⁵ Institute of Infectious Disease and Molecular Medicine and Department of Medicine, University of Cape Town, Cape Town, South Africa.
²⁶ Institute of Infectious Disease and Molecular Medicine and Department of Medicine, University of Cape Town, Cape Town, South Africa; The Francis Crick Institute, London, UK; Department of Infectious Diseases, Imperial College London, London, UK. Electronic address: r.j.wilkinson@imperial.ac.uk.

PMID: 39342951
PMCID: PMC7616680
DOI: 10.1016/S1473-3099(24)00512-7

Advancing the chemotherapy of tuberculous meningitis: a consensus view

Sean Wasserman et al. Lancet Infect Dis. 2025 Jan.

. 2025 Jan;25(1):e47-e58.

doi: 10.1016/S1473-3099(24)00512-7. Epub 2024 Sep 26.

Authors

Affiliations

¹ Institute of Infectious Disease and Molecular Medicine and Department of Medicine, University of Cape Town, Cape Town, South Africa; Infection and Immunity, St George's University of London, London, UK.
² Department of Clinical Research, London School of Hygiene & Tropical Medicine, London, UK.
³ Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam.
⁴ Radboud University Medical Center, Nijmegen, Netherlands.
⁵ Institute of Infectious Disease and Molecular Medicine and Department of Medicine, University of Cape Town, Cape Town, South Africa; The Francis Crick Institute, London, UK; Department of Infectious Diseases, Imperial College London, London, UK.
⁶ Division of Infectious Diseases and International Medicine, Department of Medicine, University of Minnesota, Minneapolis, MN, USA.
⁷ Departments of Neurology and Medicine (Infectious Diseases), University of California San Francisco, San Francisco, CA, USA.
⁸ Infectious Diseases Institute, School of Medicine, College of Health Sciences, Makerere University, Kampala, Uganda; HIV Interventions, Medical Research Council-Uganda Virus Research Institute MRC and London School of Hygiene & Tropical Medicine Uganda Research Unit, Entebbe, Uganda; Global Health and Infection, Brighton and Sussex Medical School, Brighton, UK.
⁹ Institute of Infectious Disease and Molecular Medicine and Department of Medicine, University of Cape Town, Cape Town, South Africa; The Francis Crick Institute, London, UK.
¹⁰ Division of Infectious Diseases, Vanderbilt University Medical Center, Nashville, TN, USA.
¹¹ Division of Neurosurgery, Neuroscience Institute, Department of Surgery, University of Cape Town, Cape Town, South Africa.
¹² Medical Research Council Clinical Trials Unit, London, UK.
¹³ Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, Oxford, UK.
¹⁴ Dr Cipto Mangunkusumo Hospital, Jakarta, Indonesia.
¹⁵ Division of Neurology, Neuroscience Institute, Department of Medicine, University of Cape Town, Cape Town, South Africa.
¹⁶ Infectious Diseases Institute, School of Medicine, College of Health Sciences, Makerere University, Kampala, Uganda; Department of Medicine, School of Medicine, College of Health Sciences, Makerere University, Kampala, Uganda.
¹⁷ Prof Emeritus T S Misra Medical College, Vivekanand Polyclinic and Institute of Medical Sciences and Apollo Medics Super Speciality Hospital, Lucknow, India.
¹⁸ Postgraduate Institute of Medical Education and Research, Chandigarh, India.
¹⁹ University Hospital Joseph Raseta Befelatanana, Antananarivo, Madagascar.
²⁰ Department of Neurology, Faculty of Medicine, Universitas Padjadjaran-Hasan Sadikin Hospital, Bandung, Indonesia.
²¹ Institute of Infectious Disease and Molecular Medicine and Department of Medicine, University of Cape Town, Cape Town, South Africa; Division of Neurosurgery, Neuroscience Institute, Department of Surgery, University of Cape Town, Cape Town, South Africa.
²² Department of Biomedical Sciences, Faculty of Medicine, Universitas Padjadjaran-Hasan Sadikin Hospital, Bandung, Indonesia.
²³ Department of Infectious Diseases, Imperial College London, London, UK; Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Stellenbosch, South Africa.
²⁴ Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Stellenbosch, South Africa.
²⁵ Institute of Infectious Disease and Molecular Medicine and Department of Medicine, University of Cape Town, Cape Town, South Africa.
²⁶ Institute of Infectious Disease and Molecular Medicine and Department of Medicine, University of Cape Town, Cape Town, South Africa; The Francis Crick Institute, London, UK; Department of Infectious Diseases, Imperial College London, London, UK. Electronic address: r.j.wilkinson@imperial.ac.uk.

PMID: 39342951
PMCID: PMC7616680
DOI: 10.1016/S1473-3099(24)00512-7

Erratum in

Correction to Lancet Infect Dis 2025; 25: e47-58.
[No authors listed] [No authors listed] Lancet Infect Dis. 2025 Jan;25(1):e13. doi: 10.1016/S1473-3099(24)00829-6. Lancet Infect Dis. 2025. PMID: 39734086 No abstract available.

Abstract

Tuberculous meningitis causes death or disability in approximately 50% of affected individuals and kills approximately 78 200 adults every year. Antimicrobial treatment is based on regimens used for pulmonary tuberculosis, which overlooks important differences between lung and brain drug distributions. Tuberculous meningitis has a profound inflammatory component, yet only adjunctive corticosteroids have shown clear benefit. There is an active pipeline of new antitubercular drugs, and the advent of biological agents targeted at specific inflammatory pathways promises a new era of improved tuberculous meningitis treatment and outcomes. Yet, to date, tuberculous meningitis trials have been small, underpowered, heterogeneous, poorly generalisable, and have had little effect on policy and practice. Progress is slow, and a new approach is required. In this Personal View, a global consortium of tuberculous meningitis researchers articulate a coordinated, definitive way ahead via globally conducted clinical trials of novel drugs and regimens to advance treatment and improve outcomes for this life-threatening infection.

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Conflict of interest statement

Declaration of interests FVC has received grant funding from Johnson & Johnson and ViiV. GET has acted as a consultant for Bioversys. RJW and JRB are funded by the Francis Crick Institute, which receives support from the Wellcome Trust (CC2112), UKRI-Medical Research Council (CC2112), and Cancer Research UK (CC2112). RJW declares support from the National Institutes of Health (NIH; R01AI145436), Meningitis Now UK, European & Developing Countries Clinical Trials Partnership (RIA2017T-2019 109237), and the NIHR Biomedical Research Centre of Imperial College NHS Trust. RJW and MR declare funding from the European & Developing Countries Clinical Trials Partnership (RIA2017T-2019 109237). DRB declares support from the National Institute of Allergy and Infectious Diseases (R01AI162786, R01AI145437). SW declares support from the NIH (K43TW011421, U01AI170426, and UM1AI068636) and the Bill & Melinda Gates Foundation. RvC, GET, ARG, DI, and NTTT receive funding for tuberculous meningitis research from the NIH (R01AI145781 and R01AI165721). AAF declares funding from the Wellcome Trust (227950) and the South African Medical Research Council. KHS declares funding from the Wellcome Trust (223029/Z/21/Z). SM receives funding from the National Research Foundation of South Africa (132051). JAW is a Sir Henry Dale Fellow funded by the Wellcome Trust (223253/Z/21/Z). FVC is funded by the Wellcome Trust (300088/Z/23/Z). AGD receives funding from Meningitis Now UK. UKR is supported by the Wellcome Trust (224176/Z/21/Z). RSS received funding from the National Research Foundation of South Africa (150174). All other authors declare no competing interests. This work was funded by an Academy of Medical Sciences Global Challenges Research Fund Networking Grant awarded to SW and JD (GCRFNGR8\1090), with additional support provided by Wellcome (203135).

Figures

**Figure 1. Potential regimens based on individual drug rankings.**
B = bedaquiline, H = isoniazid, L = linezolid, M = moxifloxacin, O = DprE1 inhibitor, Pa = pretomanid, Rb = rifabutin, S = sutezolid, AlpE = alpibectir/ethionamide, Z = pyrazinamide, R = rifampicin (high dose), Fq = fluoroquinolone, E = ethambutol. Coloured cells relate to individual drug scores on the ranking system, indicated in Table 3: green ≥ 12; orange 9 – 11; yellow < 9; red not currently manufactured.

See this image and copyright information in PMC

References

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Advancing the chemotherapy of tuberculous meningitis: a consensus view

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Advancing the chemotherapy of tuberculous meningitis: a consensus view

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