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A High-throughput Compatible Assay to Evaluate Drug Efficacy against Macrophage Passaged Mycobacterium tuberculosis

A High-throughput Compatible Assay to Evaluate Drug Efficacy against Macrophage Passaged Mycobacterium tuberculosis

Published on: March 24, 2017

Prevalence of p-glycoprotein (PGP) expression, function and its effect on efficacy of rifampicin in patients with

Alok Nath¹, Mohit Kumar Rai², Zia Hashim¹

¹Department of Pulmonary Medicine, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareilly Road, Lucknow, 226014, India.

The Indian Journal of Tuberculosis

|June 20, 2020

Abstract

Objective:

P-glycoprotein (PGP) overexpression may be one of the operating mechanisms of suboptimal responses to antitubercular treatment (ATT) in patients with lymph node tuberculosis. This might become responsible for the development of drug resistance later due to exposure of subtherapeutic concentrations to the mycobacteria. In this study we aim to study the prevalence of PGP expression and function and its relationship with serum concentrations of Rifampicin in consecutive patients with lymph node tuberculosis.

Methods:

All newly diagnosed treatment naïve subjects with a confirmed diagnosis of tubercular lymphadenopathy were included in the study and the expression and function of PGP in blood was determined by flowcytometry at baseline and after two months of treatment. Serum levels of Rifampicin was measured at 2 months by high performance liquid chromatography (HPLC). The mean net PGP expression expressed as percent and relative fluorescence indices (RFI) of PGP expression and function respectively was compared at baseline at 2 months and was also correlated with serum rifampicin levels.

Results:

The mean net PGP expression, RFI of PGP expression and RFI of PGP function were significantly higher in patients with lymph node tuberculosis as compared to healthy controls and the mean net PGP expression and RFI of PGP expression were significantly higher at 2 months as compared to baseline (25.64 ± 5.18% vs. 27.68 ± 4.89%, 4.34 ± 1.09% vs. 4.95 ± 1.55). There was no significant difference in RFI of PGP expression and RFI of PGP function between the poor-responders and responders at baseline and 2 months however there was a trend towards significantly higher net PGP expression amongst poor responders at baseline. The mean serum rifampicin levels were 10.74 ± 2.36 μg/ml in the responder group and 7.86 ± 1.21 μg/ml in the non-responder group and the difference between the two was statistically significant (p = 0.004).

Conclusions:

Overexpression of PGP is common in patients with lymph node tuberculosis and leads to lower concentrations of Rifampicin in blood which subsequently may give rise to development of drug resistance. This is also responsible for poor therapeutic responses in these patients. Nonspecific inhibitors of PGP may be used in conjunction with ATT to augment therapeutic response in such cases.

Insights

P-glycoprotein (PGP) overexpression in lymph node tuberculosis patients leads to lower Rifampicin blood concentrations, potentially causing drug resistance and poor treatment response. Targeting PGP may improve tuberculosis treatment outcomes.

Area of Science:

Medical Research
Pharmacology
Infectious Diseases

Background:

P-glycoprotein (PGP) overexpression is implicated in suboptimal responses to antitubercular treatment (ATT).
This overexpression may lead to drug resistance by exposing mycobacteria to sub-therapeutic drug concentrations.
Understanding PGP's role is crucial for improving tuberculosis treatment efficacy.

Purpose of the Study:

To investigate the prevalence and function of PGP in lymph node tuberculosis patients.
To determine the relationship between PGP expression and serum Rifampicin concentrations.
To correlate PGP activity with treatment response in tuberculosis.

Main Methods:

Flow cytometry was used to assess PGP expression and function in blood at baseline and after two months of ATT.
Serum Rifampicin levels were quantified using high-performance liquid chromatography (HPLC) at two months.
Comparisons were made between baseline and follow-up, and correlations were drawn with treatment outcomes.

Main Results:

Patients with lymph node tuberculosis showed significantly higher PGP expression and function compared to healthy controls.
PGP expression increased significantly from baseline to two months of treatment.
Lower serum Rifampicin levels were observed in non-responders compared to responders, with a trend towards higher PGP expression in poor responders at baseline.

Conclusions:

PGP overexpression is prevalent in lymph node tuberculosis and contributes to reduced Rifampicin concentrations.
This mechanism likely drives poor therapeutic responses and the development of drug resistance.
Co-administration of PGP inhibitors with ATT could potentially enhance treatment efficacy.

Read full analysis

Keywords:

Drug resistance PGP over-expression Tuberculosis p-glycoprotein

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