# In vitro activity of rifampicin, rifapentine and rifabutin in combination with their 25-deacetyl-metabolites against various Mycobacterium tuberculosis lineages

## TL;DR

This study examines how rifamycin drugs and their metabolites work together against tuberculosis bacteria, finding that they have additive effects.

## Contribution

The study reveals that rifamycin metabolites additively interact with their parent drugs against various tuberculosis lineages.

## Key findings

- Rifamycin metabolites showed additive effects with their parent drugs, with no antagonism observed.
- MICs varied across rifamycins, with RIF and its metabolite showing the highest MICs.
- The additive effects were consistent across different Mycobacterium tuberculosis complex lineages.

## Abstract

Rifamycin agents (rifampicin (RIF), rifapentine (RFP), rifabutin (RFB)) are the cornerstone of tuberculosis (TB) therapy. Rifamycins are metabolized into 25-deacetyl-metabolites, which have been described has active and may contribute to in vivo drug effect. However, little is known about the combined effect of rifamycins and their metabolites across different Mycobacterium tuberculosis complex (MTBC) lineages.

This study included 14 MTBC strains representing the main lineages. Minimum inhibitory concentrations (MICs) were determined using microdilution assays for the three rifamycins and their metabolites. A checkerboard assay was used to assess drug interactions, with the fractional inhibitory concentration (FIC) index calculated for synergy or antagonism.

MICs varied across rifamycins, RIF and its metabolite showed the highest MICs, followed by RFP and RFB and their respective metabolites. FIC indices for rifamycin-metabolite combinations indicated additive effects (FIC between 0.5 and 1.25), with no antagonism observed, even at clinically relevant metabolite-to-parent drug ratios, and without impact of MTBC lineage.

Rifamycin metabolites exhibit additive effects with parent drugs, potentially enhancing bactericidal activity. This highlights that rifamycin susceptibility testing should account for both parent drugs and their metabolites, as these metabolites also exhibit antimicrobial activity. Additionally, these findings support further pharmacokinetic/pharmacodynamic studies to optimize TB treatment regimens, particularly in relation to metabolite-to-parent drug ratios in patients.