Tuberculosis mycobacterium (TB) is one of the oldest infectious bacteria known to man, and one of the most deadly. One third of the world is infected with TB, either actively, or in a latent phase, which could become active depending on the circumstances of the individual. TB is a disease that can be easily passed on to another person simply by being around someone who has an active case of TB, whether the person coughs, sings, or even just speaks. You don’t have to drink after the other person, or even shake hands. Being in close quarters with a person who has active TB several times is usually all it takes. It is impossible to know with certainty if the person near you is coughing because they have a chest cold, asthma, the pneumonia, or TB without diagnostic testing.
The fight against TB using antibiotic therapy was initiated following Selman Abraham Waksman’s discovery of streptomycin in 1944. Since that time, in the space of about 60 years, some strains of TB have managed to develop resistance to the front-line drugs isoniazid and rifampicin, which is referred to as Multi-drug resistant TB (MDR-TB). Other strains have developed resistance to the front-line drugs, any fluoroquinolones, and at least one of the second-line injectable antibiotic treatments, capreomycin, kanamicin, and amikacin (Amaral et al., 2008) used to treat TB, resulting in what has been coined by the CDC as Extensively Drug Resistant TB (XDR-TB). These resistant strains are much more difficult to treat, often requiring taking a regimen of various drugs for over two years with more undesireable side effects and less effectiveness than the standard therapy. In most cases, XDR-TB patients don’t survive.
The World Health Organization (WHO) declared TB to be a global emergency In 1993, and since then, important measures have been taken in 189 countries to better diagnose and treat TB, including the use of Direct Observation Therapy – Short Course (DOTS), better laboratory and drug delivery services, and of course, more research and development of vaccines and new drugs and that can be used on more resistant strains. Despite the best efforts of World Health Organization’s Stop TB program and The Global Plan to Stop TB, these new resistant strains of MDR-TB and XDR-TB, plus coinfection with HIV/AIDS threaten the progress made over the last few years. As of 2009, 1.8 million people die each year from TB (Bill and Melinda Gates Foundation, 2009), and as of last spring, there were 440,000 cases of MDR-TB globally per year, and 25,000 cases yearly of XDR-TB (WHO, 2011). MDR-TB is now present in nearly every country in the world, and neither Africa nor Eastern Europe will achieve globally set targets for TB control, mainly due to MDR-TB and TB/HIV. In the African country of Lesotho, it is estimated that 10% of the population has MDR-TB.
As of 2009, cases of Totally Drug-Resistant TB (TDR-TB) have emerged, initially in Iran, and now cases are being reported as of January 2012 in Indian hospitals in Mumbai (Udwadia, Amale, Ajbani, and Rodrigues, 2012)
In view of the increasingly common global resistance to our current arsenal of drugs, we are clearly losing the battle and we need to take another approach. If we had a ‘magic bullet’, that would work on all TB, irrespective of susceptibility, and could work either in conjunction with other drugs or alone, to which the bacterium could not develop resistance – and it was inexpensive as well — shouldn’t we be using it?
It seems that we already do have a magic bullet. Thioridazine is a drug which is in the class of phenothiazines, which can serve as antimicrobial drugs. Thioridazine has been used extensively as an antipsychotic drug, generally without causing severe side effects. Many studies, both in vitro and in vivo have been performed to demonstrate its efficacy as an antimicrobial to TB.
Here are just a few examples:
“We tested thioridazine monotherapy in the Balb/c mouse model for its activity to treat both susceptible and multidrug-resistant tuberculosis by a two months daily oral administration of 32 and 70 mg/kg. In addition, we tested its additive value when combined with a standard first-line regimen for susceptible tuberculosis. Thioridazine treatment resulted in a significant reduction of colony-forming-units of the susceptible (−4.4 log CFU, p<0.05) and multidrug-resistant tuberculosis bacilli (−2.4 log CFU, p<0.009) in the lung both at one and two months after infection, compared to controls. Moreover, when thioridazine was added to a regimen containing rifampicin, isoniazid and pyrazinamide for susceptible tuberculosis, a significant synergistic effect was achieved (−6.2 vs −5.9 log CFU, p<0.01).”
“…. The Balb/c tuberculosis model has been used extensively to test different forms of therapy [12]–[14], confirming that it is highly suitable to explore the efficiency of new drugs or immunotherapy; this is the first study to explore efficacy of a novel drug in MDR-TB infection. The model is based on the airway route of infection which is the most common pathway of infection in humans; intratracheal infection ensures equal distribution over both lungs and accurate control of the infecting dose. The highest rate of bacterial multiplication in the lung correlates with the extent of tissue damage (pneumonia), in coexistence with a bias to Th2 pattern, decline of Th1 response and death of infected animals [9], [14]. We started treatment two months post-infection, a timepoint at which infected animals suffer from progressive tuberculosis with high number of viable bacilli and lung consolidation and mount an increasingly Th2-driven response, to mimic the situation at initial presentation of patients in high-burden, low-income settings.” (van Sooligan et al., 2010).
“…Both chlorpromazine (CPZ) and thioridazine (TZ) killed intracellular antibiotic-sensitive and -resistant M. tuberculosis organisms when they were used at concentrations in the medium well below those present in the plasma of patients treated with these agents. These concentrations in vitro were not toxic to the macrophage, nor did they affect in vitro cellular immune processes. TZ thus appears to be a serious candidate for the management of a freshly diagnosed infection of pulmonary tuberculosis or as an adjunct to conventional antituberculosis therapy if the patient originates from an area known to have a high prevalence of multidrug-resistant M. tuberculosis isolates.” (Ordway et al, 2003).
“The in vitro activities of phenothiazines against Mycobacterium tuberculosis have been known for many decades (28, 29, 31). Since the introduction of the phenothiazine chlorpromazine (CPZ) in 1953 by Rhône-Poulenc (9), sporadic reports have indicated that CPZ has in vitro activity similar to those of other phenothiazines in vivo (15, 30, 24). Nevertheless, CPZ has not been considered for use in the management of pulmonary tuberculosis due to the severe side effects associated with its chronic use……… Thioridazine (TZ), a sister phenothiazine of CPZ used for the treatment of psychosis, is equal to CPZ with respect to its in vitro antimycobacterial properties (1, 4, 8, 37). Because this compound is concentrated by human macrophages (10, 20, 23) and is active against intracellular Staphylococcus aureus, regardless of its susceptibility or resistance to methicillin (32), we have repeated the latter studies with M. tuberculosis in place of staphylococci. The results of this study provide strong direct evidence that TZ, a neuroleptic that is milder and less toxic than CPZ, kills intracellular M. tuberculosis isolates that are resistant to two or more antibiotics when the concentration of TZ in the medium approaches that in the plasma of a patient chronically managed with this compound.” (Ordway et al, 2003).
“Whereas human neutrophils are effective and efficient killers of bacteria, macrophages such as those derived from monocytes are almost devoid of killing activity. Nevertheless, monocytes can be transformed into effective killers of mycobacteria or staphylococci when exposed to clinical concentrations of a phenothiazine or to inhibitors of efflux pumps (reserpine and verapamil), or to ouabain, an inhibitor of K+ transport. Because the rates of multidrug-resistant Mycobacterium tuberculosis (MDR-TB) continue to escalate globally, and because no new effective drug has been made available for almost 40 years, compounds that enhance the killing activity of monocytes against MDR-TB are obviously needed. This review covers the specific characteristics of MDR-TB, identifies a variety of agents that address these characteristics and therefore have potential for managing MDR-TB. Because the mechanism by which these agents enhance the killing of intracellular bacteria is important for the intelligent design of new anti-tubercular agents, the review correlates the mechanisms by which these agents manifest their effects. Lastly, a model is presented which describes the mechanisms by which distinct efflux pumps of the phagosome–lysosome complex are inhibited by agents that are known to inhibit K+ flux. The model also predicts the existence of a K+ activated exchange (pump) that is probably located in the membrane that delineates the lysosome. This putative pump, which is immune to inhibitors of K+ flux, is identified as being the cause for the acidification of the lysosome thereby activating its hydrolytic enzymes. Because the non-killer macrophage can be transformed into an effective killer by a variety of compounds that inhibit K+ transport, perhaps it would be wise to develop drugs that enhance the killing activity of these cells inasmuch as this approach would not be subject to any resistance, as is the eventual case for conventional antibiotics.“ (Amaral L, Martins, M and Viveiros, M. (2007).
“Thioridazine (TDZ) has been shown to have in vitro activity against multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis, to promote the killing of intracellular MDR and XDR strains and to cure the mouse of antibiotic-susceptible and -resistant pulmonary tuberculosis (TB) infections. Recently, TDZ was used to cure 10 of 12 XDR-TB patients in Buenos Aires, Argentina. At the time of writing, it is being used for the therapy of non-antibiotic-responsive terminal XDR-TB patients in Mumbai, India, on the basis of compassionate therapy and although it is too early to determine a cure, the patients have improved appetite, weight gain, are afebrile and free of night sweats, and their radiological picture shows great improvement. Because XDR-TB is essentially a terminal disease in many areas of the world and no new effective agents have yet to yield successful clinical trials, global clinical trials for the therapy of XDR-TB are urgently required.” (Amaral, L., Boeree, M. Gillespie, S., Udwadia, Z., & van Soolingen, D., 2010).
At a cost of a few pennies per pill, Thioridazine is an attractive, sensible drug to be used as an adjunct to standard therapy, at least, unless larger clinical trials reveal that its efficacy as a standalone drug.
Currently, there is a rush to develop new drugs that can be used as TB antibiotic therapy, and new vaccines are hopefully in the pipelines. For people who already have TB, a vaccine is too late. However, we have something in our hands that has already worked, it’s very available, and it’s cheap. Each year, millions of people lose everything they have fighting a battle that they have no hope of winning. The drugs alone are losing their effectiveness. We have seen the pictures, the wasting, the terror in the faces of TB victims. Sometimes people aren’t moved to act until a condition touches them or someone they care about. Any one of those people could be our brother, our sister, our mother, or our daughter. It’s not someone else’s problem. It’s Our problem. Just say yes to thioridazine.
TB victims are dying to try something new.
References
Amaral, L., Boeree, M. Gillespie, S., Udwadia, Z., & van Soolingen, D. (2010). Thioridazine cures extensively drug-resistant tuberculosis (XDR-TB) and the need for global trials is now! International Journal of Antimicrobial Agents, 35, 524 – 526.
Amaral, L., Martins, M., Viveiros, M., Molnar, J., Kristiansen, J. (2008). Promising Therapy of XDR-TB/MDR-TB with Thioridazine an Inhibitor of Bacterial Efflux Pumps. Current Drug Targets, Volume 9, pp. 816 – 819.
Amaral, L, Martins, M and Viveiros, M. (2007). Enhanced killing of intracellular multidrug-resistant Mycobacterium tuberculosis by compounds that affect the activity of efflux pumps. Journal of. Antimicrobial Chemotherapy (2007)59 (6): 1237-1246. Retrieved on January 30, 2012 from http://jac.oxfordjournals.org/content/59/6/1237.full
Bill and Melinda Gates Foundation (2009) Tuberculosis Strategy Overview. Retrieved on January 31, 2012 from http://www.gatesfoundation.org/global-health/Documents/tuberculosis-strategy.pdf
Calver, A., Falmer, Al, Murray, M., Strauss, O., Streicher, E., Hanefom, M., et al. (2010). Emergence of Increased Resistance and Extensively Drug-Resistant Tuberculosis Despite Treatment Adherence,South Africa. Emerging Infectious Diseases, 16(2), p. 264 – 271. DOI: 10.3201/eid0210.090968.
Ordway, D. et al. (2003). Clinical Concentrations of Thioridazine Kill Intracellular Multidrug-Resistant Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2003 March; 47(3): 917–922. Retrieved on January 30, 2012 from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC149316/
WHO (2011). Tuberculosis MDR-TB and XDR-TB 2011 Progress Report, retrieved on 1/30/12 from http://www.who.int/tb/challenges/mdr/factsheet_mdr_progress_march2011.pdf
Van Sooligan et al., (2010). The Antipsychotic Thioridazine Shows Promising Therapeutic Activity in a Mouse Model of Multidrug-Resistant Tuberculosis. PLoS One. 2010; 5(9): e12640. Retrieved on January 30, 2012 from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2936563/pdf/pone.0012640.pdf
Zarir F. Udwadia, Rohit A. Amale, Kanchan K. Ajbani, Camilla Rodrigues (2012). Totally Drug-Resistant Tuberculosis in India. Clinical Infectious Diseases. February 1, 2012 54 (4), 579 -584. doi: 10.1093/cid/cir889
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