Journal Article

A ‘shock and awe’ thioridazine and moxifloxacin combination-based regimen for pulmonary <i>Mycobacterium avium–intracellulare</i> complex disease

Shashikant Srivastava, Devyani Deshpande, Carleton M. Sherman and Tawanda Gumbo

in Journal of Antimicrobial Chemotherapy

Published on behalf of British Society for Antimicrobial Chemotherapy

Volume 72, issue suppl_2, pages i43-i47
Published in print September 2017 | ISSN: 0305-7453
Published online September 2017 | e-ISSN: 1460-2091 | DOI: http://dx.doi.org/10.1093/jac/dkx308
A ‘shock and awe’ thioridazine and moxifloxacin combination-based regimen for pulmonary Mycobacterium avium–intracellulare complex disease

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Abstract

Objectives

To develop a thioridazine/moxifloxacin-based combination regimen for treatment of pulmonary infection due to Mycobacterium avium–intracellulare complex (MAC) that kills bacteria faster than the standard treatment regimen.

Methods

Monocytes were infected with MAC and inoculated into the hollow-fibre system model for pulmonary MAC disease (HFS-MAC). We co-administered ethambutol plus azithromycin daily for 28 days, to achieve the same human concentration–time profiles that result from standard doses, in three HFS-MAC systems. Two experimental regimens consisted of thioridazine at an exposure associated with optimal kill, given intermittently on days 0, 3, 7 and 10. Regimen A consisted of thioridazine in combination with standard dose azithromycin for the entire study duration. Regimen B was thioridazine plus moxifloxacin at concentration–time profiles achieved by the standard daily dose administered for 14 days, followed by daily azithromycin. Each HFS-MAC was sampled for bacterial burden every 7 days.

Results

The bacteria in the non-treated HFS-MAC grew at a rate of 0.11 ± 0.01 log10 cfu/mL/day. The azithromycin/ethambutol regimen decreased bacterial burden by 1.21 ± 0.74 log10 cfu/mL below baseline during the first 7 days, after which it failed. Regimen A killed 3.28 ± 0.32 log10 cfu/mL below baseline up to day 14, after which regrowth occurred once thioridazine treatment stopped. Regimen B killed bacteria to below the limits of detection in 7 days (≥5.0 log10 cfu/mL kill), with rebound in the azithromycin continuation phase.

Conclusions

The thioridazine/moxifloxacin regimen demonstrated that rapid microbial kill could be achieved within 7 days. This is a proof of principle that short-course chemotherapy for pulmonary MAC is possible.

Journal Article.  3246 words.  Illustrated.

Subjects: Medical Oncology ; Critical Care

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