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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 School Global Tuberculosis Institute 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 SAFER HEALTHIER PEOPLE 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 TB Regional Training and Medical Consultation Centers 4 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 Agenda Time Title 5 min Welcome/Introduction Speaker Dr. Ken Castro 10 min MDR/XDR Epidemiology Dr. Masae Kawamura 15 min Laboratory Aspects of Drug-Resistant TB 20 min Principles of Preventing and Managing DrugResistant TB 10 min Management of Contacts Dr. Tom Shinnick Dr. Reynard McDonald and Dr. Barbara Seaworth Dr. Michael Lauzardo 30 min Lessons, Resources, and Dr. Lee Reichman Discussion Continuing Education Credits • For information on obtaining continuing education credits go to: www.cdc.gov/tb/CE/webinars.htm Credits Type of Continuing Education Credit 1.5 Continuing Medical Units (CMEs) 1.5 Continuing Nursing Units (CNEs) 0.15 Continuing Education Units (CEUs) 1.5 Continuing Education Contact Hours (CECH) Continuing Education Disclaimer Statement • • 8 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. MDR/XDR TB: Global Problem, Domestic Implications L. Masae Kawamura, MD Director, TB Control Section, San Francisco Department of Public Health Francis J. Curry National Tuberculosis Center University of California, San Francisco MDR TB is a manmade problem…..It is costly, deadly, debilitating, and the biggest threat to our current TB control strategies. 10 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 11 treatment 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 Zignol, Dye et al, JID 2006:194 12 Prevalence of XDR TB not known 2006 Global Distribution of MDR TB Among New Cases Source: Zignol, Dye et al, JID 2006:194 13 14 Global Drug-Resistant TB: MDR/XDR TB Fuel • • • • 15 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) Primary MDR TB United States, 1993–2005 No. of Cases Percentage 500 400 300 200 100 0 3 2 1 0 93 94 95 96 97 98 99 00 01 02 03 04 05 No. of Cases Percentage Note: Based on initial isolates from persons with no prior history of TB. 16 MDR TB defined as resistance to at least isoniazid and rifampin. % Resistant Primary MDR TB in U.S.-born vs. Foreign-born Persons, United States, 1993–2005 3 2 1 0 1993 1995 1997 1999 U.S.-born 17 2001 2003 Foreign-born Note: Based on initial isolates from persons with no prior history of TB. MDR TB defined as resistance to at least isoniazid and rifampin. 2005 XDR TB in the US: 1993-2007* 18 Counted Uncounted Primary XDR TB 48 2 Acquired XDR TB 33 5 Total 81 7 * Preliminary data- not for distribution XDR TB Cases in the United States (Initial DST), 1993–2007* 1 2 8 1 1 11 2 19 NYC 16 New Jersey 3 2 1 * Preliminary data- not for distribution Primary U.S. XDR TB Counted Cases as Defined on Initial DST by Year, 1993–2007* 12 Case Count 10 8 6 4 2 0 3 94 95 96 97 98 99 00 01 02 03 04 05 06 07 9 19 19 19 19 19 19 19 20 20 20 20 20 20 20 20 Year of Diagnosis 20 * Preliminary data- not for distribution Unknown, 2% Black, 21% Hispanic, 35% XDR TB counted cases by Race/Ethnicity, 1993–2007* Asian, 21% White, 21% XDR TB Cases (Initial DST) in U.S.-born vs. Foreign-born Persons +* 1993-1999 2000-2007 U.S.-born 17 (65%) 5 (25%) Foreign-born 9 (35%) 15 (75%) + 21 Two cases of unknown origin * Preliminary data- not for distribution Outcomes of XDR TB Counted Cases Defined on Initial DST, 1993–2007* 22 Alive at Diagnosis N (%) 46 Completed Therapy Died While on Therapy Moved Currently on Treatment Removed from Meds Other Lost 16 15 7 4 2 1 1 (35%) (33%) (15%) (9%) (4%) (2%) (2%) * Preliminary data- not for distribution Death of XDR TB Counted Cases Defined on Initial DST, 1993–2007 Dead at Diagnosis Died During Therapy 2 15 Total Deaths 17 Percent of Death Among Total XDR Cases (17/48) 35% Percent of Death Among XDR Cases with a Known OutcomeŦ (17/33) Ŧ Known 23 52% Outcomes are cases who died or completed therapy * Preliminary data- not for distribution Have germs, will travel… Migrating populations in the 1990s Compared to 1960-75, four-fold increase intomigration 4 x increase in volume as compared 1960-75 24 Source: Population Action International 1994 Laboratory Aspects of Drug-Resistant Tuberculosis Thomas M. Shinnick, Ph.D. Mycobacteriology Laboratory Branch Division of Tuberculosis Elimination National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention SAFER HEALTHIER PEOPLE Spontaneous mutations develop as bacilli proliferate to >108 Drug Mutation Rate Rifampin 10-8 Isoniazid 10-6 Pyrazinamide 10-6 26 Drug-resistant mutants in large bacterial population Multidrug therapy: No bacteria resistant to all 3 drugs INH RIF PZA 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 28 INH mono-resist. mutants killed, RIF-resist. mutants proliferate MDR TB 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 33 Isoniazid S.J. Kim. 2005. Eur Respir J 25:564. Critical Concentration Ethambutol 34 S.J. Kim. 2005. Eur Respir J 25:564. 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 Drug Rifampin Isoniazid Streptomycin Ethambutol 36 Sensitivity 97.2% 98.7% 90.8% 89.3% Specificity 96.8% 98.5% 93.9% 94.0% Difficult Strains • Strains sent to >100 laboratories for analysis Resistant Strains Rifampin (n=19) Isoniazid (n=40) Strain 1 2 37 Agree 16 30 INH-R 31/88 (35%) 112/112 Disagree 3 10 RIF-R 106/108 74/117 (62%) *CDC unpublished data. J. Ridderhof, P. Angra 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 and Managing Drug-Resistant TB Reynard McDonald, MD Medical Director, NJMS Global Tuberculosis Institute Barbara Seaworth, MD Medical Director, Heartland National Tuberculosis Center Patient History • • 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 5-5-86 40 RJM 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 41 RJM Treatment History (cont.) • 1/12/87 (approx. 6 mos. after treatment initiation): • 11/20/87 (approx. 1½ yrs after treatment initiation): – AFB smear positive (1+) – Continue INH, RIF, and B6 – Add EMB (800 mg/d) – – – – 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 42 – PZA added when AST>5 x normal RJM Treatment History (cont.) • • • Patient was lost to followup 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 12-8-89 43 RJM Drug-O-Gram*: Initial Regimens 44 * Chronological display of treatment and bacteriology RJM 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) • • • • 45 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 Ten Years Later… Patient History (cont.) • • • • 46 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 5-7-99 RJM 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 47 RJM Drug Susceptibility Testing from Commercial Lab (Specimen collected 4-29-99) Susceptible Resistant Ethambutol (EMB) Isoniazid (INH) Streptomycin (SM) Rifampin (RIF) Capremycin (CM) Kanamycin (KM) Cycloserine (CS) Amikacin (AK) Pyrazinamide (PZA) Ciprofloxicin (CFX) Ethionamide (ETA) • The patient now not only has MDR TB, but also XDR TB 48 RJM Retreatment Course • • • On 7-16-99, although patient appeared to be responding to treatment, the regimen was revised as follows: Stopped Continued Added INH 300 mg/d RIF 600 mg/d EMB 1200 mg/d PZA 1500 mg/d SM 1 gm 5x/wk Ofloxacin 400 mg/d Clofazimine 300 mg/d 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 49 RJM 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 50 stopped, the state TB lab reported that a sputum sample collected 6-16-00 was smear positive for AFB RJM Discussion of Retreatment: Appropriate Management Decisions • Prior poor adherence recognized and addressed: – DOT ordered • Risk of drug resistance due to non-adherence and treatment failure identified – Drug susceptibility tests ordered – BUT - Standard treatment regimen with RIPE • • Many experts would have used an expanded regimen Correct response to report of MDR – Treatment changed after report of drug resistance despite a good initial response Good response does not justify continuation of an inadequate treatment regimen 51 BS Approach to Treatment of MDR TB: Errors in Management • When initiating or revising therapy, always attempt to employ at least 3 previously unused drugs to which there is in vitro susceptibility – Used 3 drugs that were part of previous failed Rx – Ethambutol and PZA used alone for 9 weeks • The use of drugs to which there is demonstrated in vitro resistance is not encouraged because there is little or no efficacy of these drugs – Ciprofloxacin resistance should have alerted providers to ofloxacin resistance • 52 Bactericidal drugs with proven efficacy should be used – Clofazamine is a weak drug with unknown efficacy BS Approach to Treatment of MDR TB: Errors in Management (cont.) • 12 months of injectable therapy following culture conversion is generally recommended – Exact duration determined by extent of disease and drug resistance • Streptomycin stopped after month 6 • Two years of total treatment after conversion of cultures to negative is usually recommended – Occasional patients with limited disease are cured after 18 months • Treatment stopped at 13 months 53 BS Step 1 Use any available Begin with any First line agents to Which the isolate is Susceptible Add a Fluoroquinolone And an injectable Drug based on susceptibilities First-line drugs Pyrazinamide Ethambutol PLUS One of these Fluoroquinolones Levofloxacin Moxifloxacin PLUS One of these Injectable agents Amikacin Capreomycin Streptomycin Kanamycin 54 BS Step 1 Use any available Begin with any First line agents to Which the isolate is Susceptible First-line drugs Add a Fluoroquinolone And an injectable Drug based on susceptibilities Pyrazinamide Ethambutol Step 2 Add 2nd line drugs until you have 4-6 drugs to which isolate is susceptible (which have not been used previously) 55 PLUS One of these Fluoroquinolones PLUS Injectable agents Levofloxacin Moxifloxacin Pick one or more of these Oral second line drugs Cycloserine Ethionamide PAS One of these Amikacin Capreomycin Streptomycin Kanamycin Step 1 Use any available Begin with any First line agents to Which the isolate is Susceptible PLUS Pyrazinamide Amikacin Capreomycin Streptomycin Kanamycin Pick one or more of these Step 2 Add 2nd line drugs until you have 4-6 drugs to which isolate is susceptible (which have not been used previously) Oral second line drugs Step 3 56 Injectable agents Levofloxacin Moxifloxacin Ethambutol One of these PLUS Fluoroquinolones First-line drugs Add a Fluoroquinolone And an injectable Drug based on susceptibilities One of these If there are not 4-6 drugs available consider 3rd line in consult with MDRTB experts Cycloserine Ethionamide PAS Consider use of these Third line drugs Imipenem Linezolid Amoxicillin/Clavulanate Macrolides BS Retreatment Course Continued • On 8-18-2000, after a lapse of approximately 2 months, treatment was restarted with: – – – – EMB PZA Ofloxacin Clofazimine • 12-8-00 Streptomycin added • 7-31-01 Streptomycin discontinued 57 RJM Drug Susceptibility Test Results from National Reference Lab Specimen Collected: 6-16-00 Date Reported: 2-21-01 Susceptible Resistant Intermediate Ethambutol (EMB) Isoniazid (INH) Clarithromycin (CLR) Ethionamide (ETA) Rifampin (RIF) Streptomycin (SM) Kanamycin (KM) Capreomycin (CM) Amikacin (AK) Cycloserine (CS) Ciprofloxacin (CFX) PAS Ofloxacin (OFX) Clofazimine (CF) Levofloxacin (LFX) Pyrazinamide (PZA) • 8 months, slow growing subculture 58 RJM Retreatment Course • On 11-20-01 regimen was revised as follows: Stopped Continued Added Ofloxacin 800 mg/d EMB 1200 mg/d PZA 1500 mg/d Clofazimine 200 mg/d CS 750 mg/d RBT 300 mg/d LFX 500 mg/d 59 RJM Drug-O-Gram: Retreatment 60 RJM Approach to Treatment of MDR TB: Errors in Management • When initiating or revising therapy, always attempt to employ at least 3 previously unused drugs to which there is in vitro susceptibility – Oral drugs used previously; compromised or known to be resistant – Single drug added to failing regimen • Cultures should be done monthly to monitor response of MDR TB to therapy – Cultures usually not done • • 61 Repeat DST should be performed when culture remains positive for 3 months and extended DSTs should be done for all patients with MDR TB Expert medical consultation should be sought BS Principles for Managing MDR TB American Thoracic Society, Centers for Disease Control & Prevention, & Infectious Diseases Society of America, 2003 • Patients should receive either hospital-based or domiciliary DOT • • A single drug should never be added to a failing regimen • Sufficient numbers of oral drugs should be started at onset of therapy to make sure there is an adequate regimen once the injectable agent is discontinued • Do not limit the regimen to 3 agents if other previously unused drugs that are likely to be active are available 62 When initiating or revising therapy, always attempt to employ at least 3 previously unused drugs to which there is in vitro susceptibility BS Principles for Managing MDR TB (cont.) American Thoracic Society, Centers for Disease Control & Prevention, & Infectious Diseases Society of America, 2003 • • Intermittent therapy should not be used in treating MDR TB • A good response does not justify continuation of an inadequate regimen • Serum therapeutic drug level monitoring should generally be utilized, especially for the bactericidal drugs and those most toxic • Resistance to RIF is associated in most cases with cross resistance to rifabutin and in all cases to rifapentine • Consultation with an expert in the care of drug resistant tuberculosis should be sought 63 The use of drugs to which there is demonstrated in vitro resistance is not encouraged because there is little or no efficacy of these drugs BS Management of Contacts to Cases of MDR and XDR Michael Lauzardo, MD Principal Investigator Southeastern National Tuberculosis Center University of Florida Deputy Health Officer for Tuberculosis Florida Department of Health Transmission of Tuberculosis • The spread of M. tuberculosis involves a 3-step process: – transmission of bacteria, – establishment of infection, and – progression to disease. 65 Challenges to an Evidence-Based Approach to Management of Contacts to MDR and XDR TB • Questions regarding “fitness” of MDR/XDR strains • Questions regarding the relationship between the genotype and phenotype of MDR/XDR strains • Questions regarding the ideal management of contacts to these cases 66 Are drug-resistant strains as transmissible as drug-susceptible strains? • • 67 A case-control study by Snider et al demonstrated that contacts of patients with drug-resistant and drug-susceptible cases of TB had an equal prevalence of positive tuberculin skin test. In contrast, animal studies have shown that isoniazid-resistant strains caused significantly less disease in guinea pigs than drug-susceptible strains. Snider et al Am Rev Respir Dis 1985; 132:125 32, Middlebrook Am Rev Tuberc 1954; 69:471 2, Riley Am Rev Respir Dis 1962; 85:511 25. Are drug-resistant strains likely to progress to active disease once infection is established? • • • 68 In San Francisco, Burgos et al found that strains that were resistant to isoniazid either alone or in combination with other drugs were less likely to result in secondary cases than were drugsusceptible strains. In this setting, isoniazid-resistant and MDR TB cases were not likely to produce new, incident drugresistant TB cases. This presumed effect on pathogenicity may be related to mutations in the katG gene. Secondary Case Rate Ratio (SR) of Drug-Resistant (DR) Strains, by (HIV) Serostatus and Place of Birth Burgos et al. J Infect Dis. 2003 Dec 15;188(12):1878-84. Secondary cases from DR case Secondary cases from DS case SR (95% CI) P 42 424 0.51 (0.37 - 0.69) <.001 Positive 19 146 0.49 (0.30 - 0.80) .003 Negative 23 278 0.45 (0.30 - 0.69) <.001 US 29 268 0.66 (0.43 - 1.02) .055 Foreign-Born 13 156 0.41 (0.24 - 0.70) .004 Characteristics Resistant to ≥ 1 drug HIV serostatus Place of birth 69 Are drug-resistant strains likely to progress to active disease once infection is established? • • 70 In addition to these data, other molecular epidemiologic studies observed that cases of TB caused by drug-resistant strains were less likely to be in clusters. The implication is that drug-resistant strains were less likely to be transmitted and/or to cause active TB. Van Soolingen et al J Infect Dis 1999; 180:726 36, Garcia-Garcia et al Arch Intern Med 2000; 160:630 6 Conflicting Data • • • 71 Texeira et al (2001) in Brazil found 37% PPD + among DS contacts and 44% PPD + contacts among MDR TB. Conover et al (2001) discovered 18.5% (56/303) of contacts at a methadone treatment program converted their skin tests. Thirteen secondary cases were identified among 462 clients and staff (2.8%), but limited HIV data was available. Texeira et al. IJTLD 5(4):321-328, Conover et al IJTLD 5(1):59-64 Are drug-resistant strains likely to progress to active disease once infection is established? • • • 72 In 1991, the first documented MDR outbreak was published in the MMWR. During 1990 and 1991, outbreaks of multi-drug resistant tuberculosis (MDR TB) in four hospitals were investigated. Of the 87 patients involved in the outbreaks, 82 (94%) were HIV(+) and 70 (80%) were dead within 416 weeks of being diagnosed with TB. Are drug-resistant strains as likely to progress to active disease? • It will depend on various factors: – Pathogen related • Undefined virulence • • factors Variability in virulence between genotypes Size of the infecting inoculum – Host related • Presence of • 73 immunosuppression Ethnic susceptibility to various strains Are all MDR and XDR strains equally virulent? • • • 74 Sun et al (2007) in a study in Singapore found that MDR isolates (n=41, OR 2.66, 95% CI 1.28-5.50) were more common among Beijing strains than among non-Beijing strains. Estimated transmission rate of MDR TB was 7.7%. The transmission rate of DR TB was significantly higher among Beijing genotype strains than nonBeijing strains (12.9% vs. 4.4%; P=0.034). Sun et al. IJTLD 11(4):436-442 Should we treat or follow contacts to MDR/XDR? • The answer is….yes. • Guidelines for MDR and drug resistance recommend following the contact for at least two years. • Data to support strategies for managing contacts is very sparse. 75 MMWR June 19, 1992 / 41(RR-11);59-71 Practical Points in Treating MDR/XDR Contacts • Recommended regimens are supported by very little data. • Usually oral regimens combining PZA with a quinolone or EMB. • Tolerance is generally poor compared to INH. • Published reports are non-randomized series. 76 Treatment Outcomes of MDR Contacts • Schaaf et al followed 119 children who were contacts to active cases of MDR TB. • Sixty-one children were infected (51%) and 14 (12%) had active disease. • Two (5%) of 41 children who received preventive therapy developed TB, compared to 13 (20%) who did not (OR 4.97). 77 Schaaf et al. Pediatrics 2002 109:765-771 Treatment Outcomes of MDR Contacts (cont.) • • • 78 In the Conover study, during two years of followup no further cases of MDR-TB were identified. Preventive regimens were determined by the treating physician and were typically a combination of two of the following – EMB – PZA – Ofloxacin All medications were given by DOT. Conover et al IJTLD 5(1):59-64 Summary • Little data to support our current recommendations for MDR TB contacts • Outcomes of contacts may be influenced by the specific organism’s genetics • Close follow-up is prudent despite some questions about “fitness” 79 MDR and XDR TB: Lessons & Resources Lee B. Reichman, MD, MPH Executive Director New Jersey Medical School Global Tuberculosis Institute University of Medicine and Dentistry of New Jersey Lessons from US Traveler with XDR/MDR TB • • • • 81 TB has not gone away, it remains with us, highly prevalent and transmissible Anyone can get tuberculosis, not only poor people, minorities, or the foreign born TB anywhere is TB everywhere All resistant TB, MDR and Extensively Drug Resistant TB is preventable by proper TB diagnosis and treatment Lessons from US Traveler with XDR/MDR TB (cont.) • • • • 82 Good public health can be silent, but when there is a glitch, it can become major news We desperately need new tools for TB diagnosis We desperately need new drugs and treatments for regular, drug-sensitive TB as well as drugresistant TB You don’t want to sit on an airplane for 8 hours next to an untreated coughing person with any kind of TB, be it drug sensitive, MDR, or XDR Consultation • Be sure to notify your state and local TB programs of all TB cases • Always bring in expert consultation when managing a person with drug-resistant TB and TB treatment failure • Experts are available at your state TB program and also at the 4 CDC-funded Regional Training and Medical Consultation Centers 83 Regional Training and Medical Consultation Centers • • • • 84 Francis J. Curry National Tuberculosis Center – 1-877-390-NOTB or 1-877-390-6682 – www.nationaltbcenter.edu Heartland National Tuberculosis Center – 1-800-TEX-LUNG or 1-800-839-5864 – www.heartlandntbc.org New Jersey Medical School Global Tuberculosis Institute – 1-800-4TB-DOCS or 1-800-482-3627 – www.umdnj.edu/globaltb Southeastern National Tuberculosis Center – 1-800-4TB-INFO or 1-800-482-4636 – http://sntc.medicine.ufl.edu Regional Training and Medical Consultation Centers 85 RTMCC Training • Series of national webinars on legal interventions, laboratory diagnostics, TB/HIV, and genotyping • Stand-up training courses such as Clinical Intensives, Case Management, Contact Investigation, Program Management, and Updates on topical issues 86 RTMCC Educational Products & Resources for XDR/MDR • • • • 87 Drug-Resistant Tuberculosis: A Survival Guide for Clinicians – Francis J. Curry National Tuberculosis Center MDR TB Care Plan – Heartland National Tuberculosis Center Drug-o-Gram – New Jersey Medical School Global Tuberculosis Institute Medical Consultation Database – Southeastern National Tuberculosis Center Additional XDR and MDR TB Educational Resources Division of Tuberculosis Elimination Centers for Disease Control and Prevention www.cdc.gov/tb/xdrtb/ 89 CDC’s Extensively Drug-Resistant Tuberculosis (XDR TB) Webpage About XDR TB • Overview • XDR TB Fact Sheet • Podcast • MDR TB Fact Sheet About XDR TB (translated) • Español (Spanish) • 德凱胡赤兒 (Chinese) • Français (French) • Italiano (Italian) 90 CDC’s XDR TB Webpage (cont.) www.cdc.gov/tb/XDRTB/ More About XDR TB • Morbidity and Mortality Weekly Reports • Fact Sheets • Drug Susceptibility Testing for TB: Questions and Answers • TB and air travel: Guidelines for prevention and control • State TB Control Offices • City TB Control Offices • WHO: XDR-TB Website 91 Acknowledgements •Nisha •Kashef Ijaz •John •Pawan Angra •Amera Khan •Gisela Schecter •Lori Armstrong •Anita Khilal •James Sederberg •Ken Castro •Sang Jae Kim •Karen •Peter Ahamed Cegielski 92 Lardizabal •Wanda Mangura •Anne Williamson Metchock •Scott Wilson Napolitano •Dan Ruggiero •WHO Chen •Bonita •Nick DeLuca •Beverly Flood •Johnny Griffin Simpson •Alfred •Lisa •Jennifer Ridderhof •Eileen Walton Subgroup Lab Capacity Strengthening •WHO Supranational Reference Lab Network CDC and Regional Training and Medical Consultation Centers • • • • • 93 CDC Division of Tuberculosis Elimination – www.cdc.gov/tb Francis J Curry National Tuberculosis Center – 1-877-390-NOTB or 1-877-390-6682 – www.nationaltbcenter.edu Heartland National Tuberculosis Center – 1-800-TEX-LUNG or 1-800-839-5864 – www.heartlandntbc.org New Jersey Medical School Global Tuberculosis Institute – 1-800-4TB-DOCS or 1-800-482-3627 – www.umdnj.edu/globaltb Southeastern National Tuberculosis Center – 1-800-4TB-INFO or 1-800-482-4636 – http://sntc.medicine.ufl.edu 94 Panel Discussion • Infection Control • International Epidemiology – Kevin Fennelly, MD, MPH, New Jersey Medical School Global Tuberculosis Institute – Tim Holtz, MD, and Peter Cegielski, MD, CDC • Nurse Case Management • Outbreak Investigations • Pediatric TB – Todd Braun, BSN, RN, MPH, Heartland National Tuberculosis Center – Ann Buff, MD, and Theresa Harrington, MD CDC – Anne Loeffler, MD, Francis J. Curry National Tuberculosis Center