Activity of nitazoxanide and tizoxanide against Mycobacterium tuberculosis in vitro and in whole blood culture - 09/05/16

Doi : 10.1016/j.tube.2016.03.002

Elizabeth P. Harausz ^a,^⁎ , Keith A. Chervenak ^a , Caryn E. Good ^b , Michael R. Jacobs ^b , Robert S. Wallis ^c , Manuel Sanchez-Felix ^d,^{^{1
Present address: Novartis Institute for Biomedical Research, Cambridge, MA 02139, USA.}} , W. Henry Boom ^a
for the
TB Research Unit (TBRU) at Case Western Reserve University
^a Department of Medicine, Case Western Reserve University, University Hospitals Case Medical Center, 10900 Euclid Ave, Cleveland, OH 44106, USA
^b Department of Pathology, Case Western Reserve University, University Hospitals Case Medical Center, 10900 Euclid Ave, Cleveland, OH 44106, USA
^c Aurum Institute, 29 Queens Rd, Parktown, Johannesburg, South Africa
^d Lilly Research Laboratories, USA

^∗Corresponding author. Tuberculosis Research Unit, Case Western Reserve University School of Medicine, 10900 Euclid Ave, Cleveland, OH 44106, USA. Tel.: +1 216 368 1949; fax: +1 216 368 0105.

Summary

Nitazoxanide (NTZ) and its metabolite tizoxanide (TIZ) were studied as antimycobacterial agents in vitro (in mycobacterial growth indicator tube [MGIT] cultures) and in a whole blood bactericidal assay. Both NTZ and TIZ show high protein binding. In MGIT cultures (albumin concentration = 78 μM), inhibition of Mycobacterium tuberculosis growth occurred at total drug concentrations of ≥16 μg/ml, whereas in whole blood cultures (albumin concentration = 350 μM), ≥128 μg/ml was required. Free drug fractions at these two conditions were estimated to be 69% and 2%, respectively. Co-incubation of NTZ and TIZ in human plasma for 72 h nearly completely eliminated their ability to inhibit mycobacterial growth in MGIT. Interactions with plasma proteins may limit the potential of NTZ and TIZ as drugs for human tuberculosis.

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Keywords : Mycobacterium tuberculosis, Nitazoxanide, Tizoxanide, Mycobacteria growth indicator tube, BCG, Whole blood assay

Plan

Introduction

Materials and methods

Preparation of NTZ and TIZ

Preparation of MTB, Mycobacterium bovis BCG and use of MGIT system

Preparation of direct inoculation experiments

Plasma experiments

Whole blood assay

Estimation of protein binding

Statistical analysis

Results

Direct effect of NTZ and TIZ on MTB growth in MGIT

Effect of plasma on NTZ and TIZ's ability to inhibit mycobacterial growth

WBA of NTZ and TIZ

Discussion

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Vol 98

P. 92-96 - mai 2016 Retour au numéro

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Activity of nitazoxanide and tizoxanide against Mycobacterium tuberculosis in vitro and in whole blood culture - 09/05/16

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