This slideshow describes the possible benefits of using thioridazine as a adjunct in therapy for MDR-TB and XDR-TB

1. Patricia G. Nelson, MPH

2. • 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

3. 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

4. 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.

5. 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

6. Second line Drugs
There 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 possible
reasons:
• 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) oxifloxacin
Thioamides: e.g., ethionamide, prothionamide

7. Third line drugs
These drugs may be considered "third-line drugs" and are listed here
either because they are not very effective (e.g., clarithromycin) or
because their efficacy has not been proven (e.g., linezolid, R207910).
Rifabutin is effective, but is not included on the WHO list because for
most developing countries, it is impractically expensive.
Rifabutin
Macrolides such as clarityromycin (CLR)
Linezolid (LZD)
Thioacetazone (T)
Thioridazine
Arginine
Vitamin D
R207910

8. 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

9. 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.

10. Thioridazine: our new magic
bullet 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

11. 12 of 14 patients treated with
thioridazine 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

12. 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

13. Use of phenothiazines significantly
enhances antibiotic effect

14. Amount of CO2 produced with variations of
critical concentration of Rifampicin against PDRTB

15. Any questions?

16. 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.