MultiDrug Resistant Tuberculosis


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MultiDrug Resistant Tuberculosis

  1. 1. Multi Drug Resistant Tuberculosis Basics, Concerns and Diagnosis Dr.T.V.Rao MD
  2. 2. A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculosis Dr.T.V.Rao MD 2
  3. 3. Nobody is absolutely Immune to Tuberculosis Dr.T.V.Rao MD 3
  4. 4. 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) Dr.T.V.Rao MD 4
  5. 5. Changing Definition of MDR TB 1950s-1970s: M. tb resistant to INH, streptomycin and/or PAS 1980s-current: M. tb resistant to at least INH and Rifampin
  6. 6. Definition of MDR - TB 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, Not a Clinical assumption Dr.T.V.Rao MD 7
  7. 7. Why INH and Rifampin Most potent and bactericidal drugs for Tuberculosis Tb can be treated effectively with INH+Rif alone Mono-resistance to one of them can be treated effectively with a regimen containing the other agent with very low failure rate (2.5- 5%) Failure rate when INH+Rif resistant is 44% in non-HIV and 70% in HIV patients Duration required for cure doubles to triples. Dr.T.V.Rao MD 8
  8. 8. MDR-TB & XDR-TB THE 2008 REPORT % of MDR-TB among new TB cases 1994-2007 Dr.T.V.Rao MD 11
  9. 9. Dr.T.V.Rao MD 12
  10. 10. Epidemiology of MDR TB
  11. 11. 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.Dr.T.V.Rao MD 14
  12. 12. When to suspect MDR TBRe-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 Dr.T.V.Rao MD 16
  13. 13. 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 Dr.T.V.Rao MD 17
  14. 14. Mechanism of resistance INH Chromosomally mediated Loss of catalase/peroxidase Mutation in mycolic acid synthesis Regulators of peroxide response Dr.T.V.Rao MD 18
  15. 15. Mechanism of resistance Rifampin Reduced binding to RNA polymerase Clusters of mutations at “Rifampin Resistance Determining Region” (RRDR) Reduced Cell wall permeability Dr.T.V.Rao MD 19
  16. 16. LABORATORY DIAGNOSIS OF MDR-TB AND XDR-TB The laboratory is an essential component in TB control programs, and broader access to DST is a priority for most countries. Early choice of appropriate treatment is an essential determinant of favourable outcome, and rapid determination of drug resistance can allow a customized approach to treatment early in the course of the disease and can potentially reduce morbidity, mortality and infectiousness Dr.T.V.Rao MD 20
  17. 17. CONVENTIONAL CULTURE-BASED METHODS Using standardized DST procedures with conventional methods, eight to 12 weeks are required to identify drug-resistant microorganisms on solid media (ie, Lowenstein-Jensen medium). In general, such methods assess inhibition of M tuberculosis growth in the presence of antibiotics to distinguish between susceptible and resistant strains Dr.T.V.Rao MD 21
  18. 18. Proportion method The proportion method allows precise determination of the proportion of resistant mutants to a certain drug; the resistance ratio method compares the resistance of an unknown strain with that of a standard laboratory strain. While relatively inexpensive and undemanding of sophisticated equipment, results usually take weeks and this is challenging; inappropriate choice of treatment regimen may result in death within weeks of initiation, such as in the case of XDR-TB (especially in HIV-infected patients) Dr.T.V.Rao MD 22
  19. 19. Conventional Methods are Outdated In addition, delayed identification of drug resistance results in inadequate treatment, which may generate additional drug resistance and continued transmission in the community.
  20. 20. LIQUID CULTURE-BASED METHODS The BACTEC 460 TB radiometric system (Becton Dickinson, USA) was considered to be a major advancement when it was introduced, but has been replaced by the Mycobacteria Growth Indicator Tube system (Becton Dickinson, USA). Several published studies have shown the excellent performance of the Mycobacteria Growth Indicator Tube system for the rapid detection of resistance to first- and second-line anti-TB drugs . Detection of drug resistance can be accomplished in days rather than weeks, although still constrained by high cost (equipment and consumables).
  21. 21. Diagnosis of MDR-TB and XDR-TB The diagnosis of MDR-TB and XDR-TB is hampered by the absence of effective and affordable rapid diagnostic techniques for drug sensitivity. Several approaches, phenotypic and molecular, have been explored to develop rapid, reliable and accurate methods for the rapid detection of drug resistance in M tuberculosis. These methods should also be evaluated and applied in high-incidence areas Dr.T.V.Rao MD 25
  22. 22. Susceptibility Testing 􀂄 Direct and indirect testing 􀂄 Primary Drugs testing 􀂄 Isoniazid 􀂄 Rifampicin 􀂄 Ethambutol (*) 􀂄 Pyrazinamide (*) Dr.T.V.Rao MD 26
  23. 23. 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. Dr.T.V.Rao MD 27
  24. 24. Drug susceptibility Testing Assessment of growth inhibition on solid media containing various dilutions of the drug, in comparison with the test strains. As the method depend observation of growth Results are not available until several weeks after isolation of the organism. Dr.T.V.Rao MD 28
  25. 25. MODS Microscopic Observation of Drug Susceptibility Testing Dr.T.V.Rao MD 29
  26. 26. 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 micro colonies could be seen under the microscope long before a colour change occurred prompted the development of MODS. Dr.T.V.Rao MD 30
  27. 27. Observation of Growth 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 Dr.T.V.Rao MD 31
  28. 28. 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 Dr.T.V.Rao MD 32
  29. 29. 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. Dr.T.V.Rao MD 33
  30. 30. Other accredited Methods Radiometric and Non radiometric methods Nucleic acid technology – effective up to 95% in mutations to rifampicin resistance to gene rpoB gene
  31. 31. 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. Dr.T.V.Rao MD 35
  32. 32. 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. Dr.T.V.Rao MD 36
  33. 33. 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.
  34. 34. Secondary Drugs testing: [lack of standardized methods!] Ofloxacin, quinolones Ethionamide Kanamycin Capreomycin ! Ensure quality control and quality assurance ?
  35. 35. Other WHO-Endorsed Tools Liquid culture (e.g. MGIT, BacT/ALERT) Capilia TB Rapid strip test that detects a TB-specific antigen from culture Molecular line probe assays (e.g. Genotype MTBDRplus, INNO-LiPA Rif.TB) Strip test for detection of TB and drug-resistance conferring mutations Dr.T.V.Rao MD 39
  36. 36. NOVEL, RAPID MOLECULAR METHODS The identification of specific mutations responsible for drug resistance has facilitated the development of novel, rapid molecular tools for DST. The detection of RIF resistance is traditionally used as a predictor of MDR-TB – its positive predictive value is a function of the sensitivity and specificity of RIF resistance testing and the prevalence of MDR and non-MDR RIF resistance, which is highest among previously treated cases in settings with high MDR prevalence and low non-MDR RIF resistance. Dr.T.V.Rao MD 40
  37. 37. Xpert MTB/RIF
  38. 38. The Xpert MTB/RIF The Xpert MTB/RIF is a cartridge-based, automated diagnostic test that can identify Mycobacterium tuberculosis (MTB)DNA and resistance to rifampicin (RIF)by nucleic acid amplification technique(NAAT Dr.T.V.Rao MD 42
  39. 39. WHO Endorses Xpert MTB/RIF In December 2010, the World Health Organization (WHO) endorsed the Xpert MTB/RIF for use in TB endemic countries[2] and declared it a major milestone for global TB diagnosis. Dr.T.V.Rao MD 44
  40. 40. Xpert MTB/RIF detects DNA sequences The Xpert MTB/RIF detects DNA sequences specific for Mycobacterium tuberculosis and rifampicin resistance by polymerase chain reaction It is based on the Cepheid GeneXpert system, a platform for rapid and simple-to-use nucleic acid amplification tests (NAAT). Dr.T.V.Rao MD 45
  41. 41. How Xpert® MTB/RIF Works The Xpert® MTB/RIF purifies and concentrates Mycobacterium tuberculosis bacilli from sputum samples, isolates genomic material from the captured bacteria by sonication and subsequently amplifies the genomic DNA by PCR. Dr.T.V.Rao MD 46
  42. 42. Xpert® MTB/RIF Helps in Faster Diagnosis of Resistance to Rifampicin The process identifies all the clinically relevant Rifampicin resistance inducing mutations in the RNA polymerase beta (rpoB) gene in the Mycobacterium tuberculosis genome in a real time format using fluorescent probes called molecular beacons. Results are obtained from unprocessed sputum samples in 90 minutes, with minimal biohazard and very little technical training required to operate.This test was developed as an on- demand near patient technology which could be performed even in a doctor's office if necessary.
  43. 43. Summary Drug resistant TB Drug-resistant TB poses a grave public health threat especially in high HIV prevalence settings XDR-TB strains have been found in all regions of the world XDR-TB occurs as a result inadequate TB control programmes XDR-TB, if identified early, can be treated and cured but experience limited to low HIV prevalence settings Infection control measures must be strengthened XDR-TB underlines the need for investment in basic TB control plus development of new TB diagnostics, treatments and vaccines Dr.T.V.Rao MD 49
  44. 44. No testing method replaces clinical assessment for Tuberculosis Dr.T.V.Rao MD 50
  45. 45. Progress in diagnosing multidrug- resistant tuberculosis 20 March 2014 | Geneva - Almost half a million people fell ill with multidrug- resistant tuberculosis (MDR-TB) in 2012, yet less than one in 4 of these people was diagnosed, mainly due to a lack of access to quality diagnostic services. Dr.T.V.Rao MD 51
  46. 46. Koch failed to conquer tuberculosis, which still causes enormous health problems worldwide 100 years after his Nobel award. The scientific academies noted that the triumphant discovery of 1882 was followed by a succession of failures: first of all, the failed attempt to present tuberculin as a remedy against tuberculosis in 1890-91, which severely damaged Koch's reputation Medical History, 2001, 45: 1-32 CHRISTOPH GRADMANN* Dr.T.V.Rao MD 52
  47. 47. Tuberculosis is a Concern for Everyone Dr.T.V.Rao MD 53
  48. 48. MDR Tuberculosis is Global Emergency Dr.T.V.Rao MD 54
  49. 49. Visit me for more Articles of Interest on Infectious Diseases Dr.T.V.Rao MD 55
  50. 50. Programme Created by Dr.T.V.Rao MD for Medical and Health Professionals in the Developing World Email