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  1. Drug ResistantTuberculosisA Great Human Concern Dr.T.V.Rao MD

  2. MDR TB –Great Human Concern

  3. HISTORY ofTuberculosis Tuberculosis Is an Ancient Disease Identified as Spinal Tuberculosis in Egyptian Mummies History dates to 1550 – 1080 BC Identified by PCR

  4. A Tribute to Robert Koch Discoverer of MycobacteriumTuberculosis

  5. Global Status • Nine million people suffer from tuberculosis • Two million people die each year. • Tuberculosis accounts for one-third of AIDS deaths world wide every year.

  6. USAIDReport on Tuberculosis in India • India has more new tuberculosis (TB) cases annually than any other country, ranking first among the 22 high-burden TB countries worldwide, according to the World Health Organization’s (WHO’s) Global TB Report 2009. TB remains one of the leading infectious causes of mortality in India, causing more than 331,000 deaths in 2007. There were approximately 1.96 million new TB cases in India in 2007, representing more than 21 percent of all TB cases worldwide

  7. Nobody is absolutely Immune to Tuberculosis

  8. Pharmacological discoveries • 1908-1920 (Calmette and Guerin) • Vaccine (BCG) • Attenuated strain Mycobacterium Bovis • 1943 • Streptomycin developed • 20th November 1944 • Critically ill TB patient injected dramatically recovered

  9. Selman Abraham WaksmanNobel Prize for his discovery in 1952. 

  10. Pharmacological discoveries • 1956-1960 • Combination therapy of INH and PZA cures TB • 1955 Cycloserine • 1962 Ethambutol • 1963 Rifampicin • 1970-1977 • Combination of Rifampicin and Isoniazid adopted as International regime for treatment of TB

  11. Introduction • Tuberculosis is an ancient disease & it remains the leading cause of death of human being. • It is mainly caused by Mycobacterium tuberculosis

  12. Typical tubercle bacilli • Human type M.tuberculosis. • Bovine type M.bovis. • Vole type M.microti. • Human type M.africanum.

  13. Multi Drug Resistant TuberculosisMDR-TB

  14. Definition • MDR-TB caused by strains of Mycobacterium Tuberculosis resistant both Rifampicin and Isoniazid with or without resistance to other drugs. • Single Isoniazid or Rifampicin resistance is not MDR - TB • MDR TB is a laboratory diagnosis

  15. MDR-TB & XDR-TBTHE 2008 REPORT% of MDR-TB among new TB cases 1994-2007

  16. Classification of Drugs • 3 Groups depending upon the degree of effectiveness and potential side effects • First Line: (Primary agents) • are the most effective and have lowest toxicity. IsoniazidRifampin • Second Line: • Less effective and more toxic effects • include (in no particular order): p-amino salicylic acid, Streptomycin, Ethambutol • Third Line • are least effective and most toxic. Amikacin, Kanamycin, Capreomycin, Viomycin, Kanamycin, Cycloserine

  17. Several Drugs becoming resistant

  18. Basic concepts – Keep facts Primary (Initial) resistance • TB patient’s initial Mycobacterium tuberculosis population resistant to drugs Secondary (Acquired) resistance • Drug-resistant M. tuberculosis in initial population selected by inappropriate drug use (inadequate treatment or non-adherence)

  19. When to suspect MDR TB • Re-treatment patients who’s sputum smear remains positive after three months’ of intensive therapy • Treatment failure and interruption cases • Close contacts of MDR tuberculosis cases • Positive diagnoses with; • TB culture and susceptibility testing

  20. What is extensively drug resistant tuberculosis (XDR TB)? • Extensively drug resistant TB (XDR TB) is a relatively rare type of MDR TB. XDR TB is defined as TB which is resistant to isoniazid and rifampin, plus resistant to any fluoroquinoloneand at least one of three injectable second-line drugs (i.e., amikacin, kanamycin, or capreomycin).

  21. Why XDR - TB a grave concern • Because XDR TB is resistant to first-line and secondline drugs, patients are left with treatment options that are much less effective. • XDR TB is of special concern for persons with HIV infection or other conditions that can weaken the immune system. These persons are more likely to develop TB disease once they are infected, and also have a higher risk of death once they develop TB.

  22. Global Estimates

  23. Extensively Drug-Resistant Mycobacterium tuberculosis, India • The first XDR TB cases in India and the emergence of XDR TB is reported by Rajesh Mondal* and Amita Jain**King George's Medical University, Lucknow, IndiaVolume 13, Number 9–September 2007 in Emerging Infectious Diseases.

  24. Global incidence of tuberculosis Still rising as a result of the growing epidemic in Africa 600 AFR high HIV 500 400 300 Incidence per 100,000 per year AFR low HIV 200 Sth East Asia World West. Pacific 100 East. Medit. East. Europe Lat. America Cent. Euro, 0 Est Market 1990 1995 2000 2005 2010 2015

  25. Are we Returning to a Pre-antibiotic Era Drug susceptible TB*§ MDR-TB 1990§ XDR-TB 2006§ Total DR ? *or limited resistance manageable with 4 drug regimen - DOTS Resistance to H&R – Treatable with 2nd line drugs Resistance to 2nd line drugs –Treatment options seriously restricted Resistance to all available drugs – No treatment options

  26. WHO Surveillance and Incidence of MDR TB Dye et al. Global Burden of Multidrug-Resistant TB. JID 185(8), 2002

  27. Genesis of MDR TB • Resistance is a man-made amplification of a natural phenomenon. • Inadequate drug delivery is main cause of secondary drug resistance. • Secondary drug resistance is the main cause of primary drug resistance due to transmission of resistant strains. • MDR due to spontaneous mutations is not possible as the genes encoding resistance for anti TB are unlinked.

  28. Development of anti-tuberculosis drug resistance Wild M. TB strain Spontaneous mutation Strains with genetic drug resistance Selection: inadequate treatment Acquired drug resistance Transmission Primary drug resistance Pablos-Mendez et al. WHO, 1997

  29. Factors Contributing to Development and Spread of MDR and XDR TB • Weak TB programs (DOTS) • Low completion/cure rates • Lack of treatment follow up and patient support • Unreliable drug supply • Diagnostic delay • Absent or inadequate infection control measures • Uncontrolled use of 2nd line drugs

  30. Mechanism of resistance • INH • Chromosomally mediated • Loss of catalase/peroxidase • Mutation in mycolic acid synthesis • Regulators of peroxide response

  31. Mechanism of resistance • Rifampin • Reduced binding to RNA polymerase • Clusters of mutations at “Rifampin Resistance Determining Region” (RRDR) • Reduced Cell wall permeability

  32. Gene location associated Drug-Resistant M.tuberculosis Drug Gene Isoniazid Kat G, Inh A, Kas A Rifampicin rpo B Ethambutol emb B Streptomycin rps L Pyrazinamide pnc A Fluoroquinolones gyr A Dubaniewicz A, et al. Molecular sub-type of the HLA-DR antigens in pulmonary tuberculosis. Int J Infect Dis2000;4:129-33.

  33. Drug Susceptibility Testing

  34. Susceptibility Testing • 􀂄 Direct and indirect testing • 􀂄 Primary Drugs testing • 􀂄 Isoniazid • 􀂄 Rifampicin • 􀂄 Ethambutol (*) • 􀂄 Pyrizinamide (*)

  35. Drug susceptibility testing (DST) • DST is recommended for all new cases for all first line drugs with specimens taken before initiating treatment.? • Accuracy is more important than speed • DST results should come from a small number of well-equipped, experienced laboratories who participate and perform well in an international DST quality control scheme. • The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this

  36. Drug susceptibility Testing • Assessment of grwoth inhibition on solid media containing various dilutions of the drug, in comparison with the test strains. • As the method depend observation of grwoth Results are not available until several weeks after isolation of the organism.

  37. Other accredited Methods • Radiometric and Non radiometric methods • Nucleicacid technology – effective upto 95% in mutations to rifampicin resistance to gene rpoB gene

  38. Drug susceptibility testing (DST) • As a minimum, laboratories supplying DST data, should correctly identify resistance to isoniazid and rifampicin in over 90% of quality control samples in two out of the last three quality control rounds.

  39. Detection of Rifampicin Drug susceptibility testing (DST) is more important. • Early identification of mycobacterial growth as M. tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB. • Laboratories should aim to identify isolates as M. tuberculosis complex and perform rifampicin resistance in 90% of isolates within 1-2 working days. This is technologically feasible.

  40. Drug susceptibility testing • For DST laboratories, modern molecular techniques permit the successful identification of isoniazid resistance in at least 75% of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance.

  41. Secondary Drugs testing:[lack of standardized methods!] • Ofloxacin, quinolones • Ethionamide Kanamycin • Capreomycin • ! Ensure quality control and quality assurance ?

  42. MODSMicroscopicObservation ofDrug Susceptibility Testing

  43. MODS affordable Technically Feasible • MODS arose during experiments conducted by Luz Caviedes under the guidance of Professor Robert Gilman at Universidad Peruana Cayetano Heredia in Lima, Peru in the late 1990s in which a colorimetric test for TB growth was being investigated. The observation that microcolonies could be seen under the microscope long before a colour change occurred prompted the development of MODS.

  44. Review Article in Indian Journal of Medical Microbiology • Caviedes L, Moore DA. Introducing mods: A low-cost, low-tech tool for high-performance detection of tuberculosis and multidrug resistant tuberculosis. Indian J Med Microbial 2007;25:87-8

  45. Observation of Grwoth in liquid Media • MODS depends upon three key principles (which have been known for decades): (1) Mycobacterium tuberculosis grows faster in liquid (broth) than on solid media, (2) in liquid cultures M. tuberculosis grows in a visually characteristic manner (tangles, cording) which can be observed under the microscope long before the naked eye could visualize colonies on solid agar

  46. Least time required for detection of MDR • Incorporation of anti-TB drugs into broth cultures at the outset enables direct susceptibility testing from sputum samples

  47. MODS more streamlined • Recently completed operational field studies have served to refine and streamline the methodology further and importantly validate MODS as a test for TB detection and MDRTB detection directly from sputum.

  48. Inverted Microscope a minimal need • Characteristic “ tangles “ of M.tuberculosis can be visualised under microscope long before colonies to the naked eye

  49. MODS for detection of MDR - TB • The scientific observations have proved that a single MODS culture of sputum sample offers more rapid and sensitive detection of tuberculosis and Multidrug-resistant tuberculosis than the existing gold standard methods used.

  50. Advantages of MODS methodology in MDR detection • All the chemical ingredients are available locally, except few which can be acquired easily. • Existing infrastructure in District and Teaching hospital can be adopted for implementation of MODS • Risk to technician handling the specimens is minimal, there is no absolute need to obtain grade III safety cabinets, • Technology transfer is easier all the new technical manpower can be trained easily.