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Multidrug-Resistant Tuberculosis (MDR TB) and Extensively-Drug Resistant (XDR) TB: A Web-Based Seminar

Multidrug-Resistant Tuberculosis (MDR TB) and Extensively-Drug Resistant (XDR) TB: A Web-Based Seminar. Presented by the Division of Tuberculosis Elimination Centers for Disease Control and Prevention (CDC) In joint sponsorship with: Francis J. Curry National Tuberculosis Center

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Multidrug-Resistant Tuberculosis (MDR TB) and Extensively-Drug Resistant (XDR) TB: A Web-Based Seminar

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  1. Multidrug-Resistant Tuberculosis (MDR TB) and Extensively-Drug Resistant (XDR) TB:A Web-Based Seminar Presented by the Division of Tuberculosis Elimination Centers for Disease Control and Prevention (CDC) In joint sponsorship with: Francis J. Curry National Tuberculosis Center Heartland National Tuberculosis Center Southeastern National Tuberculosis Center New Jersey Medical SchoolGlobal Tuberculosis Institute

  2. SAFER HEALTHIER PEOPLE Welcome and Introduction Kenneth G. Castro, MD Assistant Surgeon General, USPHS Director, Division of Tuberculosis Elimination National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention

  3. Collaboration • Division of Tuberculosis Elimination, Centers for Disease Control and Prevention • Regional Training and Medical Consultation Centers (RTMCCs) • Francis J. Curry National Tuberculosis Center • Heartland National Tuberculosis Center • New Jersey Medical School Global Tuberculosis Institute • Southeastern National Tuberculosis Center

  4. TB Regional Training and Medical Consultation Centers

  5. Learning Objectives At the end of the webinar, participants will be able to: • Describe the global and national epidemiology of MDR and XDR TB • Describe the development of drug-resistant TB • Describe the laboratory diagnosis of drug-resistant TB • List the general principles of treatment of MDR and XDR TB • Discuss the challenges in managing contacts of MDR and XDR TB cases • Identify resources for education, training, and expert consultation on management and treatment of MDR and XDR TB

  6. Agenda

  7. Continuing Education Credits • For information on obtaining continuing education credits go to: www.cdc.gov/tb/CE/webinars.htm

  8. Continuing Education Disclaimer Statement • CDC, our planners, and our presenters wish to disclose they have no financial interests or other relationships with the manufacturers of commercial products, suppliers of commercial services, or commercial supporters. • Presentations will not include any discussion of the unlabeled use of a product or a product under investigational use with the exception of Dr. Seaworth’s discussion on Treatment of MDR/XDR TB. She may discuss the use of fluoroquinolone and linezolid therapy for MDR and XDR TB which are not FDA approved for this purpose.

  9. MDR/XDR TB: Global Problem, Domestic Implications L. Masae Kawamura, MDDirector, TB Control Section, San Francisco Department of Public HealthFrancis J. Curry National Tuberculosis CenterUniversity of California, San Francisco

  10. MDR TB is a manmade problem…..It is costly, deadly, debilitating, and the biggest threat to our current TB control strategies.

  11. Definitions MDR TB: TB isolate that is resistant to both isoniazid and rifampin XDR TB: MDR + resistance to fluoroquinolone and 1 of the 3 injectable drugs (amikacin, kanamycin, capreomycin) • Primary drug resistance: • Infected with TB which is already drug resistant • Secondary (acquired) drug resistance: • Drug resistance develops during treatment

  12. Global Drug-Resistant TB: How Bad Is It? • 2004 MDR TB estimates: 424,203 (4.3%)(estimate includes new and previously treated cases) 2000 MDR TB estimates: 272,906 (1.1%)(estimate includes new cases only) • Estimated 43% of global MDR TB cases have had prior treatment • China, India, and Russian Federation account for 62% of the MDR burden Prevalence of XDR TB not known Zignol, Dye et al, JID 2006:194

  13. 2006 Global Distribution of MDR TB Among New CasesSource: Zignol, Dye et al, JID 2006:194

  14. Global Drug-Resistant TB: MDR/XDR TB Fuel • Suboptimal TB control practices (e.g., poor DOT, infection control, and treatment without drug susceptibilities or culture) • MDR TB is pre-XDR TB: poor use of second-line TB drugs in low and middle income countries • HIV amplification of disease and transmission (example: KwaZulu-Natal (KZN) South Africa) • Fact in 2005: only ~2% of estimated culture proven MDR TB cases are treated with 2nd line drugs (Global Plan to Stop TB 2006-2015)

  15. Primary MDR TBUnited States, 1993–2005 No. of Cases Percentage Note: Based on initial isolates from persons with no prior history of TB. MDR TB defined as resistance to at least isoniazid and rifampin.

  16. Primary MDR TB inU.S.-born vs. Foreign-born Persons, United States, 1993–2005 % Resistant Note: Based on initial isolates from persons with no prior history of TB. MDR TB defined as resistance to at least isoniazid and rifampin.

  17. XDR TB in the US: 1993-2007* * Preliminary data- not for distribution

  18. XDR TB Cases in the United States (Initial DST), 1993–2007* 1 NYC 16 8 New Jersey 3 1 2 1 2 11 1 2 * Preliminary data- not for distribution

  19. Primary U.S. XDR TB Counted Cases as Defined on Initial DST by Year, 1993–2007* Case Count Year of Diagnosis * Preliminary data- not for distribution

  20. XDR TB counted cases by Race/Ethnicity, 1993–2007* XDR TB Cases (Initial DST) in U.S.-born vs. Foreign-born Persons +* + Two cases of unknown origin * Preliminary data- not for distribution

  21. Outcomes of XDR TB Counted Cases Defined on Initial DST, 1993–2007* * Preliminary data- not for distribution

  22. Death of XDR TB Counted Cases Defined on Initial DST, 1993–2007 Ŧ Known Outcomes are cases who died or completed therapy * Preliminary data- not for distribution

  23. Have germs, will travel… Migrating populations in the 1990s Compared to 1960-75, four-fold increase in migration 4 x increase in volume as compared to 1960 - 75 Source: Population Action International 1994

  24. SAFER HEALTHIER PEOPLE Laboratory Aspects of Drug-Resistant Tuberculosis Thomas M. Shinnick, Ph.D.Mycobacteriology Laboratory BranchDivision of Tuberculosis EliminationNational Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention

  25. Spontaneous mutations develop as bacilli proliferate to >108

  26. INH RIF PZA Multidrug therapy: No bacteria resistant to all 3 drugs Drug-resistant mutants in large bacterial population Monotherapy: INH-resistant bacteria proliferate INH

  27. Spontaneous mutations develop as bacilli proliferate to >108 INH resistant bacteria multiply to large numbers INH RIF INH INH mono-resist. mutants killed, RIF-resist. mutants proliferate  MDR TB

  28. Role of the Laboratory • Detect drug resistance to enable clinician to design effective multidrug regimen • Initial M. tuberculosis isolate should be tested against primary drugs • INH, RIF, PZA, EMB • For Rif-R isolates, test secondary drugs as needed • FQ, AMI, KAN, CAP

  29. Drug Susceptibility Testing • Culture-based methods • Proportion method • Solid media • Liquid media • Absolute concentration method • Relative ratio method • Molecular methods

  30. Agar Proportion Method • Plate bacteria on media containing • No drugs • Critical concentrations of a drug • Incubate for 3 weeks • Count colonies Isolate is resistant if the number of colonies on drug-containing media is >1% of the colonies on drug-free media

  31. Critical Concentration The lowest concentration of a drug that • Inhibits growth of all susceptible strains AND • Allows growth of all resistant strains

  32. Critical Concentrations Rifampin Isoniazid S.J. Kim. 2005. Eur Respir J 25:564.

  33. Critical Concentration Ethambutol S.J. Kim. 2005. Eur Respir J 25:564.

  34. Reasons for Discordant DST Results • Bacterial population (isolate vs. subculture) • Differential growth kinetics • Different inoculation methods (size, clumps) • Different methods or media • Cross-contamination • Transcription, labeling errors • Problem strains and drugs • MIC ≈ critical concentration

  35. Problem Drugs • Proficiency testing panel of well-behaved strains sent yearly to WHO SNRL

  36. Difficult Strains • Strains sent to >100 laboratories for analysis *CDC unpublished data. J. Ridderhof, P. Angra

  37. Summary • DST results must be available as soon as possible to guide treatment choices • Testing algorithms including molecular tests for rif-R may speed decisions • Lab tests don’t replace clinical judgment • Clinicians need data to interpret results • Performance parameters of the test • Potential impact of prevalence of resistance on predictive value, etc.

  38. Averting Disaster: Principles in Preventing andManaging Drug-Resistant TB Reynard McDonald, MDMedical Director, NJMS Global Tuberculosis Institute Barbara Seaworth, MDMedical Director, Heartland National Tuberculosis Center

  39. A 60 year old homeless black male presented to a local hospital in July 1986 with a positive TST (15 mm) and an abnormal CXR Initial bacteriology Smear + Culture M.tb Pan-sensitive The patient was diagnosed with pulmonary tuberculosis Patient History 5-5-86 RJM

  40. Treatment History • On July 19, 1986, the patient was started on self administered treatment with INH (300 mg/d) and RIF (600 mg/d) • Patient was non-adherent in taking medications • History of alcohol abuse • Uncooperative in keeping his medical appointments RJM

  41. Treatment History (cont.) • 1/12/87 (approx. 6 mos. after treatment initiation): • AFB smear positive (1+) • Continue INH, RIF, and B6 • Add EMB (800 mg/d) • 11/20/87 (approx. 1½ yrs after treatment initiation): • Patient again missed appointment and is still drinking • Recent CXR shows no change • Sputum remains positive on smear and culture • Discontinue INH and RIF due to increased AST (269 U/L) • Start PZA (1.5 gm/d) and SM (1gm 5x/wk), continue EMB (800 mg/d) NOTE: Failure to manage toxicity correctly • PZA added when AST>5 x normal RJM

  42. Patient was lost to follow-up from April 1988 until March 1989 when he presented to the emergency department at a local hospital with a complaint of cough Treatment was restarted under self administration with RIF, INH, PZA, and SM In December 1989 he was again lost to follow-up Treatment History (cont.) 12-8-89 RJM

  43. Drug-O-Gram*: Initial Regimens * Chronological display of treatment and bacteriology RJM

  44. Poor Patient Outcome with Failure to Follow Principles of Care • Providers should assess barriers to adherence and address them • All patients should receive Directly Observed Therapy (DOT) • Acquired drug resistance may be associated with treatment failure • Repeat drug susceptibility studies should be ordered when cultures remain positive after three months • A single drug should never be added to a failing regimen • At least two and preferably three new drugs with proven or suspected susceptibility should be added BS

  45. On 4-30-99, the patient, who was now 73 years old and homeless, was discharged from a local hospital with a diagnosis of pulmonary TB CXR was abnormal Sputum specimens collected on 4-29 & 4-30-99 were smear positive for AFB Patient stated he had previously been treated from 1986-1989 for pulmonary TB, but had taken his medications very irregularly Ten Years Later…Patient History (cont.) 5-7-99 RJM

  46. Retreatment Regimen • On 5-7-99, a decision was made to start treatment while awaiting drug susceptibility test (DST) results • DOT was started with the following: • INH 300 mg/d • RIF 600 mg/d • PZA 1500 mg/d • EMB 1200 mg/d RJM

  47. Drug Susceptibility Testing from Commercial Lab (Specimen collected 4-29-99) • The patient now not only has MDR TB, but also XDR TB RJM

  48. Retreatment Course • On 7-16-99, although patient appeared to be responding to treatment, the regimen was revised as follows: • On 12-10-99, Ofloxacin was increased to 800 mg/d and all other drugs were continued • On 1-14-00, SM was stopped and treatment continued with EMB, PZA, Ofloxacin, and Clofazimine RJM

  49. Treatment Failure • On 6-16-00, the treating physician felt that treatment was adequate • The patient had completed 13 months of treatment and was 12 months post sputum culture conversion to negative • Treatment with EMB, PZA, Ofloxacin, and Clofazimine was stopped • On 6-21-00, 5 days after treatment was stopped, the state TB lab reported that a sputum sample collected 6-16-00 was smear positive for AFB RJM

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