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Drug Resistant Tuberculosis


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Drug Resistant Tuberculosis

Drug Resistant Tuberculosis

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  • 1. Drug Resistant TuberculosisEmerging Human Concern Dr.T.V.Rao MD Dr.T.V.Rao MD 1
  • 2. HISTORY of TuberculosisTuberculosis Isan AncientDiseaseIdentified asSpinalTuberculosis inEgyptianMummiesHistory dates to1550 – 1080 BCIdentified by PCR Dr.T.V.Rao MD 2
  • 3. A Tribute to Robert KochDiscoverer of Mycobacterium Tuberculosis Dr.T.V.Rao MD 3
  • 4. Historical Background ► Neolithic Time  2400 BC - Egyptian mummies spinal columns ► 460 BC  Hippocrates, Greece ► Firstclinical description: Phthisis / Consumption (I am wasting away) ► 500-1500 AD  Roman occupation of Europe it spread to Britain ► 1650-1900 AD  White plague of Europe, causing one in five deaths Dr.T.V.Rao MD 4
  • 5. Diagnostic discoveries► 24th March 1882 (Robert Koch) TB Day  Discovery of staining technique that identified Tuberculosis bacillus  Definite diagnosis made possible 1890 (Robert Koch)  Tuberculin discovered  Diagnostic use when injected into skin► 1895 (Roentgen)  Discovery of X-rays  Early diagnosis of pulmonary disease Dr.T.V.Rao MD 5
  • 6. From Tuberculosis to Tuberculin Failure of Robert Koch Tuberculin therapy did in fact work in Kochs laboratory, even though it failed to do so almost anywhere else.. his reliance an animal experiments, which essentially differed from what many of his Dr.T.V.Rao MD contemporaries, many 6 differed with his ideas
  • 7. 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. Dr.T.V.Rao MD 7
  • 8. USAID Report 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 per cent Dr.T.V.Rao MD 8 of all TB cases worldwide
  • 9. Pharmacological discoveries►1908-1920 (Chalmette and Guerin)  Vaccine (BCG) ►Attenuated strain Mycobacterium Bovis►1943  Streptomycin developed►20th November 1944  Critically ill TB patient injected dramatically recovered Dr.T.V.Rao MD 9
  • 10. Selman Abraham WaksmanNobel Prize for his discovery in 1952. Dr.T.V.Rao MD 10
  • 11. 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 Dr.T.V.Rao MD 11
  • 12. No one is Immune to TuberculosisNot only infects poor, but famous too Dr.T.V.Rao MD 12
  • 13. Multi Drug Resistant Tuberculosis MDR-TB Dr.T.V.Rao MD 13
  • 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 Dr.T.V.Rao MD 14
  • 15. 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. Isoniazid Rifampin  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 Dr.T.V.Rao MD 15
  • 16. Basic concepts – Keep factsPrimary (Initial) resistance►TB patient‟s initial Mycobacterium tuberculosis population resistant to drugsSecondary (Acquired) resistance► Drug-resistant M. tuberculosis in initial population selected by inappropriate drug use (inadequate treatment or non- adherence) Dr.T.V.Rao MD 16
  • 17. 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 Dr.T.V.Rao MD 17
  • 18. 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 fluoroquinolone and at least one of three injectable second- line drugs (i.e., amikacin, kanamycin, or capreomycin). Dr.T.V.Rao MD 18
  • 19. Why XDR - TB a grave concern► Because XDR TB is resistant to first-line and second line 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. Dr.T.V.Rao MD 19
  • 20. Global EstimatesClassificat Estimated Number Estimated ion of Cases Number of DeathsAll forms 8.8 million 1.6 million TB MDR TB 4,24,000 1,16,000, XDR TB 27,000 16,000 Dr.T.V.Rao MD 20
  • 21. Extensively Drug-ResistantMycobacterium tuberculosis, India►The first XDR TB cases in Indiaand the emergence of XDR TBis reported by RajeshMondal* and Amita Jain**King Georges MedicalUniversity, Lucknow, India Volume13, Number 9–September 2007 in EmergingInfectious Diseases. Dr.T.V.Rao MD 21
  • 22. Are we Returning to a Pre-antibiotic Era ??? Drug susceptible MDR-TB XDR-TB Total DR TB* 1990 2006 ?*or limited Resistance Resistance Resistance toresistance to H&R – to 2nd line all availablemanageable drugs – drugs –with 4 drug Treatable Treatmentregimen - with 2nd options NoDOTS line drugs seriously treatment restricted Dr.T.V.Rao MD options 22
  • 23. 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 23
  • 24. 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► Fluroquinolones ? Dr.T.V.Rao MD 24
  • 25. Mechanism of resistance►INH  Chromosomally mediated  Loss of catalase/peroxidase  Mutation in mycolic acid synthesis  Regulators of peroxide response Dr.T.V.Rao MD 25
  • 26. 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 26
  • 27. Gene location associated Drug-Resistant M.tuberculosis Drug GeneIsoniazid Kat G, Inh A, Kas ARifampicin rpo BEthambutol emb BStreptomycin rps LPyrazinamide pnc AFluoroquinolones gyr A Dubaniewicz A, et al. Molecular sub-type of the HLA-DRantigens in pulmonary tuberculosis. Int J Infect Dis2000;4:129- Dr.T.V.Rao MD 2733.
  • 28. Current ScientificDocumentations onDrug Resistance in Tuberculosis Dr.T.V.Rao MD 28
  • 29. Alarming Rise of Resistant Tuberculosis WHO Report on Anti- ► 490,000 new cases of MDR-TB each year, TB Drug Resistance with >110,000 deaths1 ► Accounts for 5% of 9 million new cases of TB2 ► MDR-TB rates higher than ever (up to 22.3%), particularly in former Soviet Union countries ► XDR-TB reported by as many as 49 countries (by June 2008)3 ► Recent WHO/IUATLD Global Surveillance report indicated 7.5% (301/4012) of MDR TB to be XDR4 ► Around 40,000 XDR-TB cases emerge every year11Tuberculosis:MDR-TB & XDR-TB—The 2008 Report. The Stop TB Department, WHO.2Hargreaves S., Vol 8, April 2008, p.2203Raviglione MC. NEJM 2008;359:636-8.4Anti-TB Drug Resistance in the World: Report No. 4. The WHO/IUATLD Global Project on Anti-Tuberculosis Drug Dr.T.V.Rao MD 29Resistance Surveillance 2002-2007. World Health Organization, 2008 (WHO/HTM/TB2008.394).
  • 30. MDR-TB & XDR-TB THE 2008 REPORT% of MDR-TB among new TB cases 1994-2007 Dr.T.V.Rao MD 30
  • 31. MDR-TB rates higher than ever (up to22.3%), particularly in former Soviet Union countries Dr.T.V.Rao MD 31
  • 32. Alarming Rise of Resistant TB ► Resistant TB burden in countries of former Soviet Union  about 50% of cases resistant to at least one drug  about 20% MDR  XDR-TB proportions also higher (as high as 24% in Estonia)1 ► MDR/XDR TB – essentially a man-made problem2 ► High numbers of resistant cases (>400,000 MDR-TB cases every year) due mainly to:  Underinvestment in basic TB control  Poor management of anti-TB drugs  Transmission of drug resistant strains11Anti-TB Drug Resistance in the World: Report No. 4. The WHO/IUATLD Global Project on Anti-TuberculosisDrug Resistance Surveillance 2002-2007. World Health Organization, 2008 (WHO/HTM/TB2008.394). Dr.T.V.Rao MD 322Reichman. The Lancet 2008:371:1052-3.
  • 33. The Much Discussed Article on XDR TB in the Lancet* ► Of the 221 multi-drug resistant (MDR- TB) cases, 53 (24%) were XDR. ► Almost all (52 of 53) of the XDR-TB patients died, with a median survival of only 16 days from the time of diagnosis (in the 42 patients with confirmed dates of death) ► All the 44 XDR TB patients who were tested for HIV were found co-infected ► 55% patents had never received anti-TB drugs, suggesting primary transmission of XDR pathogen ► 67% patients had been admitted to the hospital in the preceding 2 years, suggesting potential role of nosocomial transmission. Dr.T.V.Rao MD 33 * Gandhi et al. Lancet 2006;368:1575-80.
  • 34. Poor mangement of infected lead to grwoing resistance►Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care. Problems include incorrect drug prescribing practices by providers, poor quality drugs or erratic supply of drugs, and also patient non- adherence Dr.T.V.Rao MD 34
  • 35. Susceptibility Testing► 􀂄 Direct and indirect testing► 􀂄 Primary Drugs testing► 􀂄 Isoniazid► 􀂄 Rifampicin► 􀂄 Ethambutol (*)► 􀂄 Pyrizinamide (*) Dr.T.V.Rao MD 35
  • 36. 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 Dr.T.V.Rao MD 36
  • 37. 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 37
  • 38. Other accredited Methods►Radiometric and Non radiometric methods►Nucleic acid technology – effective upto 95% in mutations to rifampicin resistance to gene rpoB gene Dr.T.V.Rao MD 38
  • 39. 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 39
  • 40. Detection of Rifampicin Drugsusceptibility 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 40
  • 41. 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. Dr.T.V.Rao MD 41
  • 42. Secondary Drugs testing:[lack of standardized methods!]►Ofloxacin,quinolones►Ethionamide Kanamycin►Capreomycin►! Ensure quality control and quality assurance ? Dr.T.V.Rao MD 42
  • 43. WHO Controls the Tuberculosis related work►The laboratory methods for anti- tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended, and all laboratory processes should be quality- assured in cooperation with a partner Supranational Reference Laboratory (SRL) Dr.T.V.Rao MD 43
  • 44. 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 44
  • 45. BacT/ALERT® Dr.T.V.Rao MD 45
  • 46. CDC Updates Guidelines for Nucleic Acid Amplification Techniques to Diagnose Tuberculosis►NAAT results should be interpreted in conjunction with the AFB smear results.► NAAT and smear positive: start Rx despite pending culture results. PPV 95%►Smear negative, NAAT positive: use clinical judgment to either treat or await culture Dr.T.V.Rao MD 46
  • 47. Selection from automated systems for molecular and bacteriological rapid diagnostics► PCR:► Roche/COBAS®: Amplicor® amplification kits► Roche/COBAS® : LightCycler® (real- time-PCR)► Roche/COBAS® : TaqMan 48®► (increases the specificity of real-time- PCR) Dr.T.V.Rao MD 47
  • 48. Molecular Fingerprinting► 26 of 30 (87%) XDR TB isolates found to be genetically similar Majority of patients had no previous history of TB treatment Suggestive of recent infection with drug- resistant strain Dr.T.V.Rao MD 48
  • 49. Is PCR methods a solution ?►PCR cant yetreplaceneithermicroscopy,culturing andcompetentclinicalexamination. Dr.T.V.Rao MD 49
  • 50. No testing method replaces Clinical assessment Dr.T.V.Rao MD 50
  • 51. XDR-TB► The description of XDR-TB was first used earlier in 2006, following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC) Dr.T.V.Rao MD 51
  • 52. How x-MDR generated►Acquired resistance is that which occurs as a result of specific previous treatment. The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past, while the level of acquired resistance is a measure of on-going TB control measures Dr.T.V.Rao MD 52
  • 53. Extreme Drug resistant Tuberculosis (XDR-TB)► Resistantto all first line drugs namely; Isoniazid and Rifampin and Three or more second line drugs (SLD‟S) that are used to treat MDR-TB  Thequinalones like Ofloaxin Or  Aminoglycosides like Capreomycin & Kanamycin►No third-line drugs available to treat XDR-TB since none has been developed in the last 40 years. Dr.T.V.Rao MD 53
  • 54. Background Extensively drug- resistant tuberculosis ► Extensively drug- resistant tuberculosis has been reported in 45 countries, including countries with limited resources and a high burden of tuberculosis. Dr.T.V.Rao MD 54
  • 55. Dr.T.V.Rao MD 55
  • 56. Transmission of X -MDR► Likeother forms of TB, XDR-TB is spread through the air. When a person with infectious TB coughs, sneezes, talks or spits, they propel Mycobacterium into the air. Dr.T.V.Rao MD 56
  • 57. Best options to diagnose X-MDR tuberculosis►. To evaluate drug susceptibility, the bacteria need to be cultivated and tested in a suitable laboratory. Final diagnosis in this way for TB, and especially for XDR-TB, may take from 6 to 16 weeks To reduce the time needed for diagnosis, new tools for rapid TB diagnosis are urgently needed. Dr.T.V.Rao MD 57
  • 58. When to suspect MDR TB ? Patients not showing any reduction in bacillary population after 3-months of regular treatment with Cat II regimen Sputum positive patients who are contacts of a known MDR TB patient Dr.T.V.Rao MD 58
  • 59. How to evaluate MDR TB ? MDR TB is only a laboratory proved HR resistance Clinical suspicion should be followed by lab. Confirmation Laboratories should be quality controlled Dr.T.V.Rao MD 59
  • 60. Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS► Itcan also be contracted without a patient receiving any previous treatment for TB► Mostly associated with HIV positive patients► HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic► Average survival period for patients infected with XDR-TB is 16 days. Dr.T.V.Rao MD 60
  • 61. Responding to MDR/XDR-TB Augment A mathematical model projected by DOTS Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by Program by bringing synergistic effects through: ► New diagnostics ► Use of masks ► New drugs ► Reduced time as in-patient ► New vaccines ► Improved ventilation ► HIV incidence ► Rapid resistance testing reduction ► HIV treatment ► Advocacy1 ► TB isolation facilities21Marteens and Wilkinson. Lancet 2007;370:2030-432Basu et al. Quoted in: Porco and Getz. Lancet 2007;370:1464-5. MD Dr.T.V.Rao 61
  • 62. Second Line Drug Treatment (SLD’s)Less effective, more costly and more toxic, 50% cure rate►Four months intensive phase (5 drugs)  Kanamycins  Ethionamide  Pyrazinamide  Ofloxacin  Cycloserine or Ethambutol Dr.T.V.Rao MD 62
  • 63. World Health Organisation (WHO)Guidelines for treatment of MDR-TB ► Strengthen basic TB care to prevent the emergence of drug-resistance ► Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission ► Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients ► Increase investment in laboratory infrastructures to enable better detection and management of resistant cases. Dr.T.V.Rao MD 63
  • 64. Treatment Guidelines►Sensitivity testing for all smear positive specimens►Patient, Family and staff counselling & education►Correct and thorough hand washing protocol and procedure!!!►Personal protection is very important!! Dr.T.V.Rao MD 64
  • 65. THE NEW MDR-TB Guidelines►A flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions► But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation► Reflect GLC expert consensus and evidence and experience from GLC projects thus far Dr.T.V.Rao MD 65
  • 66. Effective laboratory Diagnosis  Sputum smear examinations – rapid classification of species (atypical mycobacteria common in AIDS)  Culture examinations  Rapid drug sensitivity Dr.T.V.Rao MD testing 66
  • 67. MDR TB and HIV► MDR TB occurs with the same frequency in HIV patients as in TB patients who are smear negative► Transmission of drug-resistant strains among HIV-infected patients in congregate settings occurs leading to „outbreaks‟ of MDR TB in such settings► Infection control measures absolutely essential in settings where large number of HIV TB patients stay together. Dr.T.V.Rao MD 67
  • 68. Transmission is dependent on closeness and time of contact► In penitentiary care contacts are very close and prolonged – culture positive cases can also transmit TB especially to HIV positive population Dr.T.V.Rao MD 68
  • 69. To Know more on MDR –TB Current Guidelines of WHO► Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb]► Visit ……….► WHO/HTM/TB/2011.6 Dr.T.V.Rao MD 69
  • 70. Are there any solutions for effective Diagnosis in TB ? Dr.T.V.Rao MD 70
  • 71. ► Programme Created by Dr.T.V.Rao MDfor Medical and Health Care Workers in the Developing World ►Email ► Dr.T.V.Rao MD 71