• Caused by Mycobacterium tuberculosis• Most often affects the lungs• Can affect the brain, kidneys, spine• The body can form granulomas in the lungs to ‘wall it off’• Compromised immune system can trigger active infection
How prevalent is TB? One third of the world is infected with TB A new infection occurs every second. Each person who develops an active infection passes it on to roughly 10 - 15 people WHO estimates that about 2 million deaths due to TB annually, but only for cases that were identified More than 90% of TB cases occur in developing nations that have poor hygiene and health-care resources and high numbers of people infected with HIV. 11,181 cases in US in 2010
What drugs are used to treat TB? The standard "short" course treatment TB: isoniazid, rifampicin (rifampin) pyrazinamide and ethambutol for two months, then isoniazid and rifampicin alone for four months. For latent TB, the standard treatment is six to nine months of isoniazid alone.
What about drug-resistance? TB that is resistant to the two main front-line drugs, isoniazid and rifampicin, is called MDR-TB. More difficult to treat, must use second-line drugs, injectables, drugs with more side effects and less effective against TB. What about XDR-TB? Nearly impossible to treat, resistant to isoniazid, rifampicin, all fluoroquinolones and at least one of three injectable second-line drugs (i.e., amikacin, kanamycin, or capreomycin
Second line DrugsThere are six classes of second-line drugs (SLDs) used for the treatment of TB. A drug may be classed as second-line instead of first-line for one of 3 possiblereasons:• it may be less effective• toxic side-effects (e.g., cycloserine);• may be unavailable in many developing countries (e.g., fluoroquinolones):amikacin (AMK), kanamycin (KM);capreomycin, viomycin, enviomycin;Fluoroquinolones: eg, ciprofloxacin, (CIP)moxifloxacin, (MXF) oxifloxacinThioamides: e.g., ethionamide, prothionamide
Third line drugsThese drugs may be considered "third-line drugs" and are listed hereeither because they are not very effective (e.g., clarithromycin) orbecause their efficacy has not been proven (e.g., linezolid, R207910).Rifabutin is effective, but is not included on the WHO list because formost developing countries, it is impractically expensive.RifabutinMacrolides such as clarityromycin (CLR)Linezolid (LZD)Thioacetazone (T)ThioridazineArginineVitamin DR207910
Cases of MDR and XDR-TB 440,000 cases of MDR-TB globally per year over 25,000 cases yearly of XDR-TB (WHO, 2011) MDR-TB is now present in nearly every country in the world, and XDR-TB is in at least 69 countries Multidrug-resistant (MDR) and extensively drug- resistant (XDR) tuberculosis (TB) have emerged in high-HIV-prevalence settings Highest rates of XDR-TB are in Asia and Eastern Europe Totally drug-resistant cases (TDR-TB) in India
Why are we worried in the US? The majority of cases of MDR-TB, XDR-TB, and all TDR-TB are outside the US. TB is a reportable disease US Counties are required to investigate & treat all TB cases One case can financially break a county Total costs per person ranged from $28,217 to $181492 (average $89,594) for those who survived, and from $509490 to $1278066 (average $717555) for those who died.
Thioridazine: our new magicbullet against tuberculosis? In a class of drugs known as phenothiazines Known for decades to have antimicrobial properties Mental patients treated with it recovered from TB faster Used for decades with generally no severe side effects Has been proven to cure mice of both antibiotic- susceptible and MDR-TB infection Acts synergistically with antibiotics Can actually somewhat restore susceptibility to antibiotics Inexpensive Patent protection expired, can be reapproved for other use
12 of 14 patients treated withthioridazine cured of XDR-TB In a study in Buenos Aires, Argentina, 17 patients were given combination therapy , including 14 with linezolid, plus moxifloxacin and/or thioridazine (TDZ) TDZ started at 25 mg/day X 2 weeks, then gradually increased to 200 mg/day Strict cardiac monitoring while receiving TDZ Decreased night sweats, increase in appetite, weight gain
Why does thioridazine work? TDZ kills both antibiotic susceptible and MDR-TB in vitro Inhibits the genetic expression of efflux pumps of M. tuberculosis that extrude antibiotics Inhibits the activity of existing efflux pumps that contribute to the multidrug-resistant phenotype of M. tuberculosis Enhances the killing of intracellular M. tuberculosis by non-killing macrocytes in the alveoli of the lungs where the drug is concentrated by the body
Use of phenothiazines significantlyenhances antibiotic effect
Amount of CO2 produced with variations ofcritical concentration of Rifampicin against PDRTB
References http://en.widipedia.org/wiki/Tuberculosis_treatment#Extra-pulmonary_tuberculosis Rajbhandary SS, Marks SM, Bock NN. Costs of patients hospitalized for multidrug- resistant tuberculosis. Int J Tuberc Lung Dis. 2004 Aug;8(8):1012-6 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 Viveiros, M, Amaral, L (2001). Enhancement of antibiotic activity against poly-drug resistant Mycobacterium tuberculosis by thenothiazines. International Journal of Antimicrobial Agents 17, 225 – 228. 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 Abbate, E, Vescovo, M, Natiello, M, Cufre, M, Garcia, A, Gonzalez, P et al. (2011). Successful alternative treatment of extensively drug-resistant tuberculosis in Argentina with a combination of linezolid, moxifloxacin and thioridazine. Journal of Antimicrobial Chemotherapy, Dec 2011. Amaral, L, Viveiros, M (2012). Why thioridazine in combination with antibiotics cures extensivey drug-resistant Mycobacterium tuberculosis infections. IJAA 39,376-380.