X-MDR Tuberculosis


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X-MDR Tuberculosis

  3. 3. Table of drugs used for the treatment of tuberculosis. First line drugs Second line drugs Essential Other Old NewIsoniazid Pyrazinamide Capreomycin QuinolonesRifampicin Ethambutol Amikacin ofloxacin Streptomycin Kanamycin ciprofloxacin moxifloxacin Cycloserine Ethionamide Macrolides PAS Thioacetazone clarithromycin Clofazimine Amoxycillin & Clavulanic acid LanizolidNew rifamycins Hifalutin Rifapentine MD DR.T.V.RAO 3
  4. 4. DEVELOPMENT OF DRUG RESISTANCE FROM THE PERSPECTIVE OF THE PATIENT:• The presence of drug resistant strains results from simple Darwinian pressures, brought out by the presence of antibiotics• Multiple drug resistant strains result from the step-wise accumulation of individual resistance elements therefore MDR-TB is MAN-MADEDR.T.V.RAO MD 4
  5. 5. History Elements that place a patient at-risk for MDR-TB or drug resistance1. Previous TB treatment with multiple drugs2. Failed TB Treatment that is documented3. A known chronic TB case4. Default from previous TB treatment or erratic use of TB drugs5. Exposure to a known MDR case6. Use of TB drugs of poor or unknown quality7. Prior use of an inadequate regimen8. Conditions associated with drug malabsorption or severe diarrhea DR.T.V.RAO MD 5
  6. 6. WHY INH AND RIFAMPIN ARE IMPORTANT IN TUBERCULOSIS• Most potent and bactericidal• 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 6
  7. 7. DR.T.V.RAO MD 7
  8. 8. DEFINITIONS• Multidrug-resistant tuberculosis (MDRTB) Resistance to Isoniazid and Rifampicin• Extensively (extremely) drug-resistant (XDR-TB) MDR-TB plus resistance to a second line injectable drugs such as Amikacin plus a quinolone.DR.T.V.RAO MD 8
  9. 9. Magnitude of the MDR-TB Problem WHO/IUATLD Global Projection Drug Resistance Surveillance, which surveyed fifty-eight different countries between 1996 and 1999, revealed the presence of new “hot spots” for MDR-TB in addition to those reported in the first phase of the WHO/IUATLD Global Project on Drug Resistance Surveillance. MDR-TB was shown to range from 0% to 14.1% among new TB cases. Another review (1999) compiled by Harvard Medical School has shown that drug-resistant TB exists in 104 countries in recent years.
  10. 10. MULTIDRUG-RESISTANT TUBERCULOSISWHO and IUATLD• The median prevalence of MDR-TB 1.1% in newly diagnosed patients.• The median prevalence of MDR-TB 7.0% in patients who have previously received anti-TB treatment• MDR-TB : Threatening to destabilize global tuberculosis control (Chest2006;130:261-272)DR.T.V.RAO MD 10
  11. 11. TUBERCULOSIS CONTINUES TO BE A PROBLEM….• The problem is compounded by the emergence of drug resistant strains, due to patients not completing antibiotic courses.• In 1980 50 per cent of TB bacilli were resistant to 1 drug.• Multi-drug resistant TB (MDR-TB) began to emerge. There are now an estimated 1.5m MDR cases worldwide.• Extreme drug resistance (XDR-TB) was reported in 2006.• The first completely drug resistant (CDR-TB) case was reported in Italy in 2007.DR.T.V.RAO MD 11
  12. 12. MULTI DRUG-RESISTANT TB (MDR TB) OCCURS ..• Occurs when resistance develops to first line drugs • Currently approximately 5-25% of TB cases • Non-adherence to DOTS / treatment programme • Can have direct infection with MDR strain TB • Drug use increases risk of conversion • Co-infection, especially with HIV, increases risk• Second level drugs 1000 times more expensive than first line• Patients remain infectious?DR.T.V.RAO MD Slide 12
  13. 13. 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 13
  14. 14. DRUG–RESISTANT M. TUBERCULOSISEpidemiology• Primary drug resistance • initial drug resistance• Secondary drug resistance • acquire drug resistance Treatment of tuberculosis: guidelines for national programmes, 3rd ed. Geneva, World Health Organization, 2003(WHO/CDS/TB/2003.313).DR.T.V.RAO MD 14
  15. 15. DRUG–RESISTANT M. TUBERCULOSIS• Drug resistance • Monodrug resistance • Polydrug or Combined resistance (not INH and RIF)• Multidrug resistance (MDR) (INH and RIF resistance)• Extensively Multidrug resistance (XDR) • MDR-TB and • Resist to at least 3 classes of second line drugs Treatment of tuberculosis: guidelines for national programmes, 3rd ed. Geneva, World Health Organization, 2003(WHO/CDS/TB/2003.313). DR.T.V.RAO MD 15
  16. 16. GENE LOCATION ASSOCIATED DRUG-RESISTANT 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-DR antigens in pulmonary tuberculosis. Int J Infect Dis2000;4:129-33.DR.T.V.RAO MD 16
  17. 17. EPIDEMIOLOGY INFORMATION OF MDR-TB• Incidence varies according to reported sites.• High incidence is located in some geographic area and not evenly distribution.• Data of sensitivity can not be directly compared because of different methodology.• No separation of previously treated and untreated cases.• High incidence is associated with poor compliance previous treatment history, HIV infection, contact with drug resistant case, inborn country.DR.T.V.RAO MD 17
  18. 18. MULTIDRUG RESISTANT TUBERCULOSIS TO EXTENSIVELY DRUG RESISTANT TUBERCULOSIS• Extensively drug-resistant tuberculosis (XDR-TB) is a form of tuberculosis caused by bacteria that are resistant to the most effective anti-TB drugs. Some contend that XDR-TB strains have emerged from the mismanagement of multidrug-resistant TB (MDR-TB) and once created, can spread from one person to another. The exact nature of this mismanagement is not yet known, but origin of XDR-TB may coincide with the institution of new policies to promote drug compliance, such as DOTSDR.T.V.RAO MD 18
  19. 19. DR.T.V.RAO MD 19
  20. 20. XDR – TB ON RAISE• DR-TB raises concerns of a future TB epidemic with restricted treatment options, and jeopardizes the major gains made in TB control and progress on reducing TB deaths among people living with HIV/AIDS. It is therefore vital that TB control be managed properly and new tools developed to prevent, treat and diagnose the disease.• The true scale of XDR-TB is unknown as many countries lack the necessary equipment and capacity to accurately diagnose it. It is estimated however that there are around 40,000 cases per year. As of June 2008, 49 countries have confirmed cases of XDR-TB. By 2010, that number had risen to 58.DR.T.V.RAO MD 20
  21. 21. HIGH INCIDENCE OF MDR-TB • Moldova has one of the highest rates of multi-drug resistant tuberculosis (MDR-TB) anywhere in the world. This deadly strain of the disease can emerge as a result of low quality health systems, poor quality drugs, lack of accessibility to treatment, and when a patient intermittently takes his medicine or fails to complete his treatment. After the fall of the Soviet Union,DR.T.V.RAO MD 21
  22. 22. DEFINITION OF XDR-TB• XDR-TB is defined as TB that has developed resistance to at least rifampicin and isoniazid (resistance to these first line anti- TB drugs defines Multi-drug-resistant tuberculosis, or MDR-TB), as well as to any member of the quinolone family and at least one of the following second-line anti-TB injectable drugs: kanamycin, Capreomycin, or Amikacin This definition of XDR- TB was agreed by the WHO Global Task Force on XDR-TB in October 2006. The earlier definition of XDR-TB as MDR-TB that is also resistant to three or more of the six classes of second- line drugs, is no longer used, but may be referred to in older publicationDR.T.V.RAO MD 22
  23. 23. XDR-TB A GLOBAL THREAT• Between 2000-2004, of 17,690 TB isolates in the world were MDR-TB 20% and XDR-TB 2% (Lancet2006;368:964)• Between 2003-2005, of 1,284 TB isolates in Iran were MDR-TB 9.3% and XDR-TB 1% (CID2006;316:216)DR.T.V.RAO MD 23
  24. 24. RISK FACTORS FOR INFECTION WITH DRUG-RESISTANT TUBERCULOSIS• Expose to person who has known drug-resistant tuberculosis• Exposure to a person with active tuberculosis who has prior treatment for tuberculosis (treatment failure or relapse) and whose susceptibility test results are not known• Expose to persons with active tuberculosis from areas in which there is a high prevalence of drug resistance. . DR.T.V.RAO MD 24
  26. 26. SPUTUM CULTURE FOR TB AND SUSCEPTIBILITY TESTINGHigh-risk patient who has drug resistance TBRelapse caseHistory of irregular treatmentTreatment failure caseExpose to person who has known Drug-Resistant TuberculosisHIV co-infectionAddictionsBorn in high prevalence country (Current Practice in Common Infectious Diseases2001. สมาคมโรคติดเชื้ อแห่งประเทศไทย;20:339-353.) DR.T.V.RAO MD 26
  27. 27. PROBLEMS WITH DRUG RESISTANCE SURVEILLANCE• Quality of laboratory sensitivity testing• Maintenance of standards over time• Selection of specimens• Only 1% of patients surveyedDR.T.V.RAO MD 27
  28. 28. DIAGNOSIS : MDR-TB• Isoniazid and Rifampicin resistance case• Short course treatment failure : sputum for AFB + after 5 months of treatment• “fall and rise” sputum for AFB +• Long course treatment failure : sputum for AFB + after complete 12 months• Long duration of treatment : 18 – 24 months• Susceptibility testing : MDR-TB DR.T.V.RAO MD 28
  29. 29. STANDARD SHORT COURSE REGIMEN OF ANTI-TB DRUGS (WHO)• Category I : 2HRZE/4HR New case of pulmonary TB with sputum AFB +• Category II : 2HRZES/HRZE/5HRE New case of pulmonary TB with sputum AFB + Suspected Drug-Resistant TB• Category III : 2HRZ/4HR New case of pulmonary TB without sputum AFB +, no extensive lesion• Category IV Chronic case with MDR-TB ( Management of tuberculosis modified WHO modules of managing tuberculosis at district level 1991) DR.T.V.RAO MD 29
  30. 30. SECOND LINE DRUGS (6 CLASSES)• Aminoglycosides : Streptomycin (15 MKD) no cross resistance Kanamycin, Amikacin (15 MKD) -first 2-3 mo, at least 5 days/wk -after sputum for AFB – negative 2-3 days/wk to 6 mo or patient has adverse effects (ototoxic and nephrotoxic)• Fluoroquinolones : cross resistance ofloxacin (10MKD) levofloxacin (10MKD) nausea vomiting, dizziness ciprofloxacin (30MKD) DR.T.V.RAO MD 30
  31. 31. SECOND LINE DRUGS• Polypeptides : Capreomycin• Serine analog : Cycloserine• Ethionamide(10- 20MKD)• Para-amino salicylic acid (PAS)DR.T.V.RAO MD 31
  32. 32. GUIDELINES FOR TREATMENT OF DRUG-RESISTANT ORGANISM• Never add one drug into the failing regimen• Use > 3 drug with in vitro susceptibility (1 drug should be injectable)• Should not use intermittent therapy• Need DOTS• Amikacin cross-R with Kana, SM not cross-R with other• Two-inject-drug is not recommended Frequency of resistance mutation RIF: 10‾18 INH, SM: 10‾6 ETB: 10‾5 DR.T.V.RAO MD 32
  33. 33. WHAT DO WE NEED IN MDR AND X-MDR-TB• Specialized and experienced institute.• Correct identification of drug resistance case.• Good laboratory support.• Availability and adequate drugs.• DOTS (directly observed therapy strategy).• Strictly monitoring of treatment.• Follow up patient to prevent relapse case. DR.T.V.RAO MD 33
  34. 34. NEW DRUGS FOR TUBERCULOSIS TREATMENT• Fixed dose combination (FDC)-WHO formulation • Fluoroquinolones: ofloxacin, levofloxacin, gatimoxacin, moxifloxacin • MPC below Cmax • Sterilizing activity • Oxazolidinones : linezolid • Imidazole derivatives : PA824 • Diaryquinolone : TMC207 • Ketolides : telithromycin (no activities) • Drug on latency stage : Glyoxylate shunt (Mendell, et al.Principle and Practice of INFECTIOUS DISEASES;2005:2852 -2886.) DR.T.V.RAO MD 34
  35. 35. BIOSAFETY A MUST IN LABORATORY PRACTICE• I advise all the medical microbiologists, laboratory workers not to take up project works, research work and diagnostic work on Mycobacterium ( decontamination, culturing and drug susceptibility testing with out standard Bio hazard protection which includes use grade 3 bio safety cabinet. As many strains are becoming MDR-TB and X-MDR tuberculosis . Our students and lab workers are the real victims. In spite of severe bio hazards of Mycobacterium many Doctors directors and managers do not have idea about the dangers of Tuberculosis, putting some ones life at risk. I request all the younger generation of Microbiologists to work with Biosafety precautions Even the Medical council of India should implement strict regulations on this matter Dr.T.V.Rao MDDR.T.V.RAO MD 35
  36. 36. WHO - REPORT-BE CAUTIOUS• TB drug resistance needs a frontal assault. If countries and the international community fail to address it aggressively now we will lose this battle," said Dr Mario Raviglione, Director of the WHO Stop TB Department.• "In addition to specifically confronting drug- resistant TB and saving lives, programmes worldwide must immediately improve their performance in diagnosing all TB cases rapidly and treating them until cured, which is the best way to prevent the development of drug resistance." DR.T.V.RAO MD 36
  37. 37. • Programme created by Dr.T.V.Rao MD for Medical and Health care Workers in the Developing World • Email • doctortvrao@gmail.comDR.T.V.RAO MD 37