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Early Depressing Effect on Abundancy and Diversity of Sputum Microbiome Followed by Recovery During Anti-Tuberculosis Treatment: A Multi-Regimen Analysis of the High-Rifampicin II- and Multi-Arm-Multi-Stage Clinical Trials

47 Pages Posted: 27 Jul 2022

See all articles by Emmanuel Musisi

Emmanuel Musisi

University of St. Andrews - Division of Infection and Global Health

Adam Wyness

University of Mpumalanga - School of Biology and Environmental Sciences

Sahar Eldirdiri

NHS Foundation Trust - Department of Microbiology

Evelin Dombay

University of St. Andrews - Division of Infection and Global Health

Bariki Mtafya

University of St. Andrews - Division of Infection and Global Health

Nyanda Elias Ntinginya

National Institute for Medical Research (NIMR)

Norbert Heinrich

Ludwig Maximilian University of Munich (LMU) - Division of Infectious Diseases and Tropical Medicine

Gibson Sammy Kibiki

Kilimanjaro Christian Medical University College - Kilimanjaro Christian Medical Centre

Michael Hoelscher

Ludwig Maximilian University of Munich (LMU) - Division of Infectious Diseases and Tropical Medicine

Martin Boeree

Radboud University Nijmegen - Department of Lung Disease

Stephen Henry Gillespie

University of St. Andrews - Division of Infection and Global Health

Wilber Sabiti

University of St. Andrews - Division of Infection and Global Health

PanACEA Consortium Group

Independent

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Abstract

Background: Respiratory tract microbiota has been described as the gate keeper for respiratory health. Using new drug combinations, attempts have been made to shorten treatment of tuberculosis (TB), but the impact of such drug combinations on the respiratory microbiome have not been studied.

Methods: Using total RNA and V3-V4 16S rRNA gene sequencing, sputum microbiome of participants under the HIGHRIF2 and Multi-Arm-Multi-Stage clinical trials were analysed across a 3-month treatment period. Participants were treated with standard TB regimen Isoniazid(H)-Rifampicin-(R600mgor10mg/kg)-Pyrazinamide(Z)-Ethambutol(E) in comparison to investigational regimens containing fixed dose, R900mg and R1200mg under HIGHRIF2 and/or differing doses of rifampicin (10mg/kg, 20mg/kg, 35mg/kg including novel combinations replacing ethambutol with SQ109(Q) or moxifloxacin(M) in the Multi-Arm-Multi-Stage study.  

Findings: Sequence data was obtained from 397 pre- and post-treatment samples across seven treatment regimens. Pre-treatment microbiome (n=206 genera) was dominated by firmicutes, 44%, and Streptococcus, 36% at phyla and genus levels, respectively. All regimens had a depressing effect on microbiome abundancy and diversity in the first two weeks of treatment, but this was only significant under the HR20mg/kgZM and HR35mg/kgZE, Shannon diversity index p=0.003 and p=0·03 respectively. Gram negative bacteria were the most sensitive to bactericidal activity of treatment with the highest number of species suppressed being under the moxifloxacin regimen. By week-12, microbiome had recovered to pre-treatment level except with the Rif35mg/kg regimen and genus Mycobacterium that did not show recovery across all regimens. TB culture conversion-to-negative by week-8 of treatment was associated with clearance of genus Neisseria, 98% reduction of the pre-treatment level. 

Interpretation of the findings: Within the first-line regimen, changing rifampicin dose alone required as high as 35mg/kg to significantly reduce microbiome diversity, an outcome achieved by less rifampicin-20mg/kg supplemented with moxifloxacin without limiting microbiome recovery. An effective anti-TB regimen to shorten treatment may be achieved without harming the commensal microbiota. 

Funding: European and Developing Countries Clinical Trials Partnership and German Ministry of Education and Research.

Declaration of Interest: Wilber Sabiiti and Stephen Gillespie provide a pro bono advice for
a company that is developing TB-MBLA for clinical use. All other members declare a no
conflict of interest.

Ethical Approval: Sputum samples for the microbiome analysis were obtained from participants in the Multi-Arm-Multi-Stage (MAMS) and High Rifampicin 2 (HIGHRIF 2) clinical trials in Tanzania. Approval of the MAMS study was obtained from Tanzania National Institute for Medical Research (NIMR)-Mbeya Medical Research centre ethics review committee, the NIMR-National Health Research Ethics Committee (NatHREC) and University of Munich (study sponsor) ethics committee. HIGHRIF 2 study was approved by the Kilimanjaro Christian Medical College Research Ethics and Review Committee, the Ifakara Health Institute Institutional Review Board, and NatHREC. Both studies were conducted according to Good Clinical Practice guidelines.

Keywords: Sputum microbiome surrogate for respiratory microbiome, anti-tuberculosis antibiotics, tuberculosis treatment, impact on microbiome, anti-tuberculosis drug development strategies.

Suggested Citation

Musisi, Emmanuel and Wyness, Adam and Eldirdiri, Sahar and Dombay, Evelin and Mtafya, Bariki and Ntinginya, Nyanda Elias and Heinrich, Norbert and Kibiki, Gibson Sammy and Hoelscher, Michael and Boeree, Martin and Gillespie, Stephen Henry and Sabiti, Wilber and Group, PanACEA Consortium, Early Depressing Effect on Abundancy and Diversity of Sputum Microbiome Followed by Recovery During Anti-Tuberculosis Treatment: A Multi-Regimen Analysis of the High-Rifampicin II- and Multi-Arm-Multi-Stage Clinical Trials. Available at SSRN: https://ssrn.com/abstract=4172089 or http://dx.doi.org/10.2139/ssrn.4172089

Emmanuel Musisi

University of St. Andrews - Division of Infection and Global Health ( email )

Adam Wyness

University of Mpumalanga - School of Biology and Environmental Sciences ( email )

Sahar Eldirdiri

NHS Foundation Trust - Department of Microbiology ( email )

Evelin Dombay

University of St. Andrews - Division of Infection and Global Health ( email )

Bariki Mtafya

University of St. Andrews - Division of Infection and Global Health ( email )

Nyanda Elias Ntinginya

National Institute for Medical Research (NIMR) ( email )

Mwanza
Tanzania

Norbert Heinrich

Ludwig Maximilian University of Munich (LMU) - Division of Infectious Diseases and Tropical Medicine ( email )

Gibson Sammy Kibiki

Kilimanjaro Christian Medical University College - Kilimanjaro Christian Medical Centre ( email )

Moshi
Tanzania

Michael Hoelscher

Ludwig Maximilian University of Munich (LMU) - Division of Infectious Diseases and Tropical Medicine ( email )

Martin Boeree

Radboud University Nijmegen - Department of Lung Disease ( email )

Stephen Henry Gillespie

University of St. Andrews - Division of Infection and Global Health ( email )

Wilber Sabiti (Contact Author)

University of St. Andrews - Division of Infection and Global Health ( email )

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