Globally,
tuberculosis infections continue to increase their resistance to
antibiotics.
Multidrug resistant tuberculosis infections (MDR TB) have progressed to extensively drug resistance status (
XDR TB) and the latter have evolved in some parts of the world to totally
drug resistant (TDR TB)
infections. MDR TB is difficult to treat successfully, and when
therapy is ineffective, a single case can cost almost $500,000. When the
infection is
XDR TB therapy is mostly unsuccessful and is accompanied with high mortality. TDR TB-a yet to be defined
infection, is resistant to all forms of
therapy and mortality is almost certain. We have, over a period of 14 years, studied
thioridazine (TZ) an old
neuroleptic that we have shown to: i) have in vitro activity against all
antibiotic resistant forms of Mycobacterium tuberculosis; ii) have activity against intracellular Mycobacterium tuberculosis regardless of its antibiotic resistance status; iii) cure the infected mouse of an
antibiotic susceptible and MDR TB
infections; and, iv) when used in combination with
antibiotics used for
therapy of
tuberculosis, would render the organism significantly more susceptible. These studies have guided our Argentinian colleagues to treat successfully
XDR TB infections with
thioridazine in combination with three
antibiotics to which the
infection was initially resistant. This mini review will describe our further work and the mechanisms by which TZ alone and in combination with
antibiotics cures an
XDR TB infection and why it is expected to cure TDR TB
infections as well. The concepts presented are totally new and because they focus on the activation of killing by non-killing macrophages where Mycobacterium tuberculosis normally resides during
infection, and coupled to the inhibition of efflux pumps which contribute to the
antibiotic resistant status, effective
therapy of any
antibiotic resistant TB
infection is possible. Because TZ is cheap and therefore affordable to any economically disadvantaged country, and will produce no harm when appropriate measures are taken, it is the ideal
drug for immediate use in countries that have high frequencies of MDR, XDR and TDR TB
infections.