The early bactericidal activity of antituberculosis drugs

Abstract

Early bactericidal activity studies measure the ability of antituberculosis treatments to reduce the burden of Mycobacterium tuberculosis in sputum specimens collected overnight from smear-positive pulmonary tuberculosis patients during the first 14 days of therapy. This confirms the efficacy of novel agents or drug combinations in human patients, allows comparison of different drug dosages and a preliminary assessment of the drugs' pharmacokinetics and toxicity in closely observed patients. In the past few years several novel antituberculosis agents have demonstrated significant early bactericidal activity and progressed to studies of longer duration. Most recently the early bactericidal activity of drug combinations was found to be similar to results predicted by murine studies. This may contribute to expediting the future progress of drug evaluation.

Keywords::

• bedaquiline
• delamanid
• early bactericidal activity
• PA-824
• rifampicin
• sutezolid
• treatment
• tuberculosis

Acknowledgement

We thank Dr L van der Merwe for drawing the original figures.

Financial & competing interests disclosure

PR Donald is supported by the South African National Research Foundation. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• For the first time in four decades, new antituberculosis drugs have entered clinical evaluation and there is every prospect of new regimens being registered for clinical use in the near future.

• There is now an established pathway of evaluation for new antituberculosis agents and regimens commencing in the laboratory, leading to evaluation in animal models, most often using mice, and then to studies in healthy humans and finally pulmonary tuberculosis patients.

• Encouragement comes from the recent finding that certain drug combinations have similar patterns of synergistic and antagonistic activity in mouse models and in human early bactericidal activity (EBA) studies. This promises to reduce the time needed to develop new treatment regimens.

• EBA studies provide the first opportunity to demonstrate antituberculosis efficacy in patients; there are no currently used antituberculosis agents that have not shown efficacy in 14-day studies of EBA.

• Several single drugs and combinations have now progressed to Phase III clinical trials and in due course it will become easier to retrospectively confirm (or refute) the value of early bactericidal studies and interpret their findings more accurately.

• Studies of EBA in pulmonary tuberculosis patients provide an opportunity for the evaluation of toxicity in small groups of hospitalized patients under careful observation and for the conduct of pharmacokinetic studies allowing study of efficacy in relation to drug exposure in tuberculosis patients. From these results, a drug dosage can be selected to take forward to later Phase II and III studies.

• Together with later stage evaluations, EBA studies also allow the evaluation of the potential value for drug assessment of other biomarkers based on sputum or other body fluids.

Notes