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Antimicrob Agents Chemother. 2018 Nov 26;62(12). pii: e01487-18. doi: 10.1128/AAC.01487-18. Print 2018 Dec.

Predicting the Outcomes of New Short-Course Regimens for Multidrug-Resistant Tuberculosis Using Intrahost and Pharmacokinetic-Pharmacodynamic Modeling.

Doan TN1,2,3, Cao P4, Emeto TI2,5, McCaw JM6,7,8,9, McBryde ES10,2.

Author information

1
Department of Medicine at The Royal Melbourne Hospital, University of Melbourne, Melbourne, Victoria, Australia tan.doan@uqconnect.edu.au pengxing.cao@unimelb.edu.au.
2
Australian Institute of Tropical Health and Medicine, James Cook University, Townsville, Queensland, Australia.
3
Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia.
4
School of Mathematics and Statistics, University of Melbourne, Melbourne, Victoria, Australia tan.doan@uqconnect.edu.au pengxing.cao@unimelb.edu.au.
5
College of Public Health, Medical and Veterinary Sciences, James Cook University, Townsville, Queensland, Australia.
6
School of Mathematics and Statistics, University of Melbourne, Melbourne, Victoria, Australia.
7
Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia.
8
Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia.
9
Peter Doherty Institute for Infection and Immunity, Royal Melbourne Hospital and University of Melbourne, Melbourne, Victoria, Australia.
10
Department of Medicine at The Royal Melbourne Hospital, University of Melbourne, Melbourne, Victoria, Australia.

Abstract

Short-course regimens for multidrug-resistant tuberculosis (MDR-TB) are urgently needed. Limited data suggest that the new drug bedaquiline (BDQ) may have the potential to shorten MDR-TB treatment to less than 6 months when used in conjunction with standard anti-TB drugs. However, the feasibility of BDQ in shortening MDR-TB treatment duration remains to be established. Mathematical modeling provides a platform to investigate different treatment regimens and predict their efficacy. We developed a mathematical model to capture the immune response to TB inside a human host environment. This model was then combined with a pharmacokinetic-pharmacodynamic model to simulate various short-course BDQ-containing regimens. Our modeling suggests that BDQ could reduce MDR-TB treatment duration to just 18 weeks (4 months) while still maintaining a very high treatment success rate (100% for daily BDQ for 2 weeks, or 95% for daily BDQ for 1 week during the intensive phase). The estimated time to bacterial clearance of these regimens ranges from 27 to 33 days. Our findings provide the justification for empirical evaluation of short-course BDQ-containing regimens. If short-course BDQ-containing regimens are found to improve outcomes, then we anticipate clear cost savings and a subsequent improvement in the efficiency of national TB programs.

KEYWORDS:

bedaquiline; mathematical modeling; multidrug resistance; short-course regimen; tuberculosis

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