Multidrug-Resistant Tuberculosis (MDR TB)
and Extensively-Drug Resistant (XDR) TB

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Welcome and Overview

Slide 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 School Global Tuberculosis Institute

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Slide 2: 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

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Slide 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

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Slide 4: TB Regional Training and Medical Consultation Centers

Map of the RTMCCs. Since 2005 CDC has funded four Regional Training and Medical Consultation Centers which are geographically located throughout the United States.

The Francis J. Curry National Tuberculosis Center is located in San Francisco, CA and serves: Alaska, California, Colorado, Hawaii, Idaho, Montana, Nevada, Oregon, Utah, Washington, Wyoming, Federated State of Micronesia, Northern Mariana Islands, Republic of Marshall Islands, American Samoa, Guam, and the Republic of Palau.

The Heartland National Tuberculosis Center is located in San Antonio, Texas and serves: Arizona, Illinois, Iowa, Kansas, Minnesota, Missouri, New Mexico, Nebraska, North Dakota, Oklahoma, South Dakota, Texas, and Wisconsin.

The Southeastern National Tuberculosis Center is located in Gainesville, Florida and serves: Alabama, Arkansas, Florida, Georgia, Kentucky, Louisiana, Mississippi, North Carolina, South Carolina, Tennessee, Virginia, Puerto Rico, and the U.S. Virgin Islands.

The Northeastern Regional Training and Medical Consultation Consortium serves: Connecticut, District of Columbia, Delaware, Indiana, Massachusetts, Maryland, Maine, Michigan, New Hampshire, New Jersey, New York, Ohio, Pennsylvania, Rhode Island, Vermont, and West Virginia.

The New Jersey Medical School Global Tuberculosis Institute is located in Newark, New Jersey and serves: Connecticut, District of Columbia, Delaware, Indiana, Massachusetts, Maryland, Maine, Michigan, New Hampshire, New Jersey, New York, Ohio, Pennsylvania, Rhode Island, Vermont, and West Virginia.

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Slide 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

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Slide 6: Agenda

Time	Title	Speaker
5 min	Welcome/Introduction	Dr. Ken Castro
10 min	MDR/XDR Epidemiology	Dr. Masae Kawamura
15 min	Laboratory Aspects of Drug-Resistant TB	Dr. Tom Shinnick
20 min	Principles of Preventing and Managing Drug Resistant TB	Dr. Reynard McDonald and Dr. Barbara Seaworth
10 min	Management of Contacts	Dr. Michael Lauzardo
30 min	Lessons, Resources, and Discussion	Dr. Lee Reichman

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Slide 7: 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)

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Slide 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.

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MDR/XDR TB: Global Problem, Domestic Implications

Slide 9: 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

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Slide 10: Timebomb

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

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Slide 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

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Slide 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 (Zignol, Dye et al, JID 2006:194)

Prevalence of XDR TB not known

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Slide 13: 2006 Global Distribution of MDR TB among New Cases

Source: Zignol, Dye et al, JID 2006:194

This 2006 map shows the global distribution of MDR TB among new cases.

• Most of the map is dark green, indicating less than 3% of TB incident cases are MDR TB. This includes North America, Europe, Australia, and most of Africa, the Middle East, Southeast Asia, and South America.
   
• The light green areas indicate the 3-6% of TB incident cases are MDR TB. This includes China, the most populous country in the world, as well as Iran, Mozambique, Cte d’Ivoire, Ecuador, and Peru.
   
• The yellow countries have the highest rates of MDR TB of over 6%. This includes the Russian Federation and countries of the former Soviet Union.
   
• Former Soviet Union and Eastern Block Countries with the highest rates. Some countries record >14% prevalence of MDR TB (e.g., Estonia 17.4%, Azerbaijan 14.6%, Kazakhstan 14.6%)

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Slide 14: WHO Map – Countries with XDR TB Confirmed Cases to Date

This map shows countries with confirmed cases of XDR TB.

Countries include: Argentina, Armenia, Bangladesh, Brazil, Chile, Czech Republic, Ecuador, Georgia, Germany, Korea, Latvia, Mexico, Peru, Portugal, Russia Federation, South Africa, Spain, Thailand, United Kingdom, and the United States.

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Slide 15: 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)

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Slide 16: Primary MDR TB, United States, 1993–2005

This graph focuses on trends in primary MDR TB (based on initial isolates from persons with no prior history of TB) in the United States from 1993 through 2005.

The number of MDR TB cases, represented by bars, steadily declined from 410 in 1993 to 115 in 2001. Since then the total number of MDR TB cases has fluctuated from 91 to 125 cases, with 95 cases reported for 2005. Primary MDR TB, shown by the line, decreased from 2.5% in 1993 to approximately 1.0% in 1997, and remained at this level up to and including 2005.

Graph Note: Based on initial isolates from persons with no prior history of TB. MDR TB defined as resistance to at least isoniazid and rifampin.

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Slide 17: Primary MDR TB in U.S.-born vs. Foreign-born Persons, United States, 1993–2005

This graph highlights primary MDR TB in U.S.-born versus foreign-born persons. The percentage with primary MDR TB has declined among both groups, although the decline in the U.S.-born has been greater. As a result, the proportion of primary MDR TB cases reported in foreign-born persons increased from approximately 26% of all MDR TB cases in 1993 to approximately 75% of all MDR TB cases in 1999, and continued at this proportion through 2005 (not shown on slide). Among the U.S.-born, the percentage with MDR TB remained between 0.5% and 0.7% from 1998 through 2004 and dropped to 0.4% in 2005. The percentage among foreign-born persons has fluctuated year by year, while averaging approximately 1.4% from 1998 through 2005.

Graph Note: Based on initial isolates from persons with no prior history of TB. MDR TB defined as resistance to at least isoniazid and rifampin.

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Slide 18: XDR TB in the US: 1993-2007*

	Counted	Uncounted
Primary XDR TB	48	2
Acquired XDR TB	33	5
Total	81	7

* Preliminary data- not for distribution

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Slide 19: XDR TB Cases in the United States (Initial DST), 1993–2007*

This map shows XDR TB case distribution in the United States from 1993-2007.
11 cases have been counted in California, 2 in Nevada, 2 in Texas, 1 in Minnesota, 1 in Illinois, 1 in Ohio, 8 in New York (excluding New York City), 16 in New York City, 3 in New Jersey, 2 in Virginia, and 1 in Georgia.

* Preliminary data- not for distribution

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Slide 20: Primary U.S. XDR TB Counted Cases as Defined on Initial DST by Year, 1993–2007*

This graph shows primary U.S. XDR TB counted cases as defined by initial DST 1993-2007. The number of XDR TB cases, represented by bars.

1993 – 10 counted XDR TB cases
1994 – 6 counted XDR TB cases
1995 – 1 counted XDR TB cases
1996 – 3 counted XDR TB cases
1997 – 2 counted XDR TB cases
1998 – 1 counted XDR TB cases
1999 – 5 counted XDR TB cases
2000 – 0 counted XDR TB cases
2001 – 4 counted XDR TB cases
2002 – 6 counted XDR TB cases
2003 – 0 counted XDR TB cases
2004 – 4 counted XDR TB cases
2005 – 2 counted XDR TB cases
2006 – 3 counted XDR TB cases
2007 – 1 counted XDR TB cases

* Preliminary data- not for distribution

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Slide 21: XDR TB Pie Chart and Table

XDR TB counted cases by Race/Ethnicity, 1993–2007*

• Hispanic – 35%
• Black – 21%
• Asian – 21%
• White – 21%
• Unknown – 2%

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%)

* Preliminary data- not for distribution
+ Two cases of unknown origin

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Slide 22: Outcomes of XDR TB Counted Cases Defined on Initial DST, 1993–2007*

	N	(%)
Alive at Diagnosis	46
Completed Therapy	16	(35%)
Died While on Therapy	15	(33%)
Moved	7	(15%)
Currently on Treatment	4	(9%)
Removed from Meds	2	(4%)
Other	1	(2%)
Lost	1	(2%)

* Preliminary data- not for distribution

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Slide 23: Death of XDR TB Counted Cases Defined on Initial DST, 1993–2007

Dead at Diagnosis	2
Died During Therapy	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)	52%

Ŧ Known Outcomes are cases who died or completed therapy
* Preliminary data- not for distribution

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Slide 24: Have germs, will travel… Migrating populations in the 1990s

• This world map shows different paths of immigration throughout the world in 1990s.
• Compared to 1960-75, four-fold increase in migration
Source: Population Action International 1994

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Laboratory Aspects of Drug-Resistant Tuberculosis

Slide 25: 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

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Slide 26: Spontaneous mutations develop as bacilli proliferate to >10⁸

This graphic shows that spontaneous mutations develop as bacilli proliferate to >10⁸

Drug	Mutation Rate
Rifampin	10-8
Isoniazid	10-6
Pyrazinamide	10-6

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Slide 27: Drug-resistant mutants

• The graphic shows that when drug-resistant mutants in a large bacterial population are treated with three effective drugs, all bacteria are killed.
• However, if only INH is used for treatment, INH-resistant bacteria will proliferate.

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Slide 28: Drug-resistant mutants (cont.)

• The graphic shows using only one drug for treatment, for example INH, selects for INH resistant bacteria.

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Slide 29: 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

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Slide 30: Drug Susceptibility Testing

• Culture-based methods
• Proportion method
• Solid media
• Liquid media
• Absolute concentration method
• Relative ratio method
• Molecular methods

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Slide 31: 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

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Slide 32: Critical Concentration

The lowest concentration of a drug that

• Inhibits growth of all susceptible strains
  
  AND
   
• Allows growth of all resistant strains

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Slide 33: Critical Concentrations

S.J. Kim. 2005. Eur Respir J 25:564.

Two graphs depicting the critical concentrations of rifampin and isoniazid are shown here.

The experiment to determine a critical concentration involves measuring the percentage of presumably drug susceptible bacteria (dotted lines) and presumably resistant bacteria (solid lines) whose growth is prevented by various concentrations of a drug. Presumably susceptible strains are those that come from previously untreated patients and presumably resistant strains are those that come for patients who failed therapy with that drug.

For rifampin, the presumably susceptible strains are easily distinguished from presumably resistant strains over a wide range of concentrations. The best discrimination is shown by the vertical line and this is what is used as the critical concentration. In this case it is 40 ug/ml in LJ medium.

For isoniazid, susceptible strains are also easily distinguished from presumably resistant strains, but over a much narrower range. For the laboratory this means that care must be taken to precisely make the drug-containing media to avoid having too little drug which could lead to susceptible strains being misclassified as resistant strains or too much drug which could lead to resistant strains being misclassified as susceptible

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Slide 34: Critical Concentration

S.J. Kim. 2005. Eur Respir J 25:564.

This graph shows the critical concentration for ethambutol.
For ethambutol, there is a large overlap of the inhibiting concentrations for presumable susceptible and resistant strains. Even at the most discriminatory concentration, the so-called critical concentration, there is some concern that strains may be incorrectly classified as susceptible of resistant.
These sorts of difficulties in classifying strains may be one of the reasons for different results in different laboratories.

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Slide 35: 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

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Slide 36: Problem Drugs

• Proficiency testing panel of well-behaved strains sent yearly to WHO SNRL

Drug	Sensitivity	Specificity
Rifampin	97.2%	96.8%
Isoniazid	98.7%	98.5%
Streptomycin	90.8%	93.9%
Ethambutol	89.3%	94.0%

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Slide 37: Difficult Strains

Strains sent to >100 laboratories for analysis

Resistant Strains	Agree	Disagree
Rifampin (n=19)	16	3
Isoniazid (n=40)	30	10

 

Strain	INH-R	RIF-R
1	31/88 (35%)	106/108
2	112/112	74/117 (62%)

*CDC unpublished data. J. Ridderhof, P. Angra

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Averting Disaster: Principles in Preventing and Managing Drug Resistant TB

Slide 38: 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.

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Slide 39: 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

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Slide 40: 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

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Slide 41: 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

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Slide 42: Treatment History (cont.)

• 1/12/87 (approx. 6 mos. after treatment initiation):
• AFB smear + (1+)
• Continue INH, RIF, and B6
• Add EMB (800 mg/d)
• 11/20/87 (approx. 1 yrs after treatment initiation):
• Patient again missed appointment and is still drinking
• Recent CXR shows no change
• Sputum remains + 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

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Slide 43: Treatment History (cont.)

• 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

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Slide 44: Drug-O-Gram: Initial Regimens

This graphic depicts a Drug-O-Gram which is a chronological display of treatment and bacteriology

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Slide 45: 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

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Slide 46: Ten Years Later…Patient History (cont.)

• 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

Image of a chest radiograph.

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Slide 47: 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

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Slide 48: 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

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Slide 49: 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	EMB 1200 mg/d	SM 1 gm 5x/wk
RIF 600 mg/d	PZA 1500 mg/d	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

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Slide 50: 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

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Slide 51: 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

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Slide 52: 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
• Bactericidal drugs with proven efficacy should be used
• Clofazamine is a weak drug with unknown efficacy

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Slide 53: 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

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Slide 54: Building a Treatment Regimen

• This is a diagrammatic representation of the general approach to designing a treatment regimen for MDR-TB
• In Step 1, the first action is to identify any first line drugs which have proven or likely susceptibility

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Slide 55: Building a Treatment Regimen (cont)

• After incorporation of drugs in Step 1, the next step is to add one or more of the oral second line drugs to create a regimen of at least four and preferably five to six drugs

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Slide 56: Building a Treatment Regimen (cont)

• The last step is to add a third line drug if an acceptable regimen cannot be built from drugs available in Step 1 and 2

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Slide 57: 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

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Slide 58: 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

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Slide 59: Retreatment Course

• On 11-20-01 regimen was revised as follows:

Stopped	Continued	Added
Ofloxacin 800	EMB 1200 mg/d	CS 750 mg/d
mg/d	PZA 1500 mg/d	RBT 300 mg/d
	Clofazimine 200 mg/d	LFX 500 mg/d

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Slide 60: Drug-O-Gram: Retreatment

• Break in treatment for two months in summer 2000 (June16-Aug 18 2000)
• Treatment stopped prematurely after 13 months, followed by relapse
• After information regarding 2nd line drugs was obtained in Feb 2001, no new drugs were added until Nov 2001 and ultimately this was too little too late the patient died in Jan 2002

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Slide 61: 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
• 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

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Slide 62: 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
• When initiating or revising therapy, always attempt to employ at least 3 previously unused drugs to which there is in vitro susceptibility
• 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

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Slide 63: 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
• 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
• 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

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Management of Contacts to Cases of MDR/XDR

Slide 64: 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

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Slide 65: Transmission of Tuberculosis

• The spread of M. tuberculosis involves a 3-step process:
• transmission of bacteria,
• establishment of infection, and
• progression to disease.

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Slide 66: 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

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Slide 67: Are drug-resistant strains as transmissible as drug-susceptible strains?

• 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.

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Slide 68: Are drug-resistant strains likely to progress to active disease once infection is established?

• 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 drug-susceptible strains.
   
• In this setting, isoniazid-resistant and MDR TB cases were not likely to produce new, incident drug-resistant TB cases.
   
• This presumed effect on pathogenicity may be related to mutations in the katG gene.

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Slide 69: 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.

Characteristics	Secondary cases from DR case	Secondary cases from DS case	SR (95% CI)	P
Resistant to ≥ 1 drug	42	424	0.51 (0.37 - 0.69)	<.001
HIV serostatus
Positive	19	146	0.49 (0.30 - 0.80)	.003
Negative	23	278	0.45 (0.30 - 0.69)	<.001
Place of birth
US	29	268	0.66 (0.43 - 1.02)	.055
Foreign-Born	13	156	0.41 (0.24 - 0.70)	.004

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Slide 70: Are drug-resistant strains likely to progress to active disease once infection is established?

• 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

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Slide 71: Conflicting Data

• 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

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Slide 72: Are drug-resistant strains likely to progress to active disease once infection is established?

• 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 4-16 weeks of being diagnosed with TB.

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Slide 73: 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 immunosuppression
• Ethnic susceptibility to various strains

Photo image of a sick man coughing

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Slide 74: Are all MDR and XDR strains equally virulent?

• 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 non-Beijing strains (12.9% vs. 4.4%; P=0.034).

Sun et al. IJTLD 11(4):436-442

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Slide 75: 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.

MMWR June 19, 1992 / 41(RR-11);59-71

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Slide 76: 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.

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Slide 77: 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).

Schaaf et al. Pediatrics 2002 109:765-771

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Slide 78: Treatment Outcomes of MDR Contacts (cont.)

• In the Conover study, during two years of follow-up 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

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Slide 79: 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”

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Lessons and Resources

Slide 80: 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

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Slide 81: Lessons from US Traveler with XDR/MDR TB

• 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

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Slide 82: Lessons from US Traveler with XDR/MDR TB (cont.)

• 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 drug- resistant 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

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Slide 83: 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

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Slide 84: Regional Training and Medical Consultation Centers

• 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

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Slide 85: Regional Training and Medical Consultation Centers

Map of the RTMCCs. Since 2005 CDC has funded four Regional Training and Medical Consultation Centers which are geographically located throughout the United States.

The Francis J. Curry National Tuberculosis Center is located in San Francisco, CA and serves: Alaska, California, Colorado, Hawaii, Idaho, Montana, Nevada, Oregon, Utah, Washington, Wyoming, Federated State of Micronesia, Northern Mariana Islands, Republic of Marshall Islands, American Samoa, Guam, and the Republic of Palau.

The Heartland National Tuberculosis Center is located in San Antonio, Texas and serves: Arizona, Illinois, Iowa, Kansas, Minnesota, Missouri, New Mexico, Nebraska, North Dakota, Oklahoma, South Dakota, Texas, and Wisconsin.

The Southeastern National Tuberculosis Center is located in Gainesville, Florida and serves: Alabama, Arkansas, Florida, Georgia, Kentucky, Louisiana, Mississippi, North Carolina, South Carolina, Tennessee, Virginia, Puerto Rico, and the U.S. Virgin Islands.

The Northeastern Regional Training and Medical Consultation Consortium serves: Connecticut, District of Columbia, Delaware, Indiana, Massachusetts, Maryland, Maine, Michigan, New Hampshire, New Jersey, New York, Ohio, Pennsylvania, Rhode Island, Vermont, and West Virginia.

The New Jersey Medical School Global Tuberculosis Institute is located in Newark, New Jersey and serves: Connecticut, District of Columbia, Delaware, Indiana, Massachusetts, Maryland, Maine, Michigan, New Hampshire, New Jersey, New York, Ohio, Pennsylvania, Rhode Island, Vermont, and West Virginia.

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Slide 86: 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

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Slide 87: RTMCC Educational Products & Resources for XDR/MDR

• Drug-Resistant Tuberculosis: A Survival Guide for Clinicians
(Guide cover image on right)
• Francis J. Curry National Tuberculosis Center
• MDR TB Care Plan
• Heartland National Tuberculosis Center
• Drug-o-Gram
(Drug-o-Gram image on right)
• New Jersey Medical School Global Tuberculosis Institute
• Medical Consultation Database
(Image of the database on right)
• Southeastern National Tuberculosis Center

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Slide 88: Additional XDR and MDR TB Educational Resources

Division of Tuberculosis Elimination
Centers for Disease Control and Prevention

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Slide 89: CDC’s Extensively Drug-Resistant Tuberculosis (XDR TB) Webpage

Image of CDC’s TB webpage.
www.cdc.gov/tb/xdrtb

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Slide 90: 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)
• Francais (French)
• Italiano (Italian)

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Slide 91: 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

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Slide 92: Acknowledgements

• Nisha Ahamed
• Pawan Angra
• Lori Armstrong
• Ken Castro
• Peter Cegielski
• Lisa Chen
• Nick DeLuca
• Jennifer Flood
• Johnny Griffin
• Kashef Ijaz
• Amera Khan
• Anita Khilal
• Sang Jae Kim
• Alfred Lardizabal
• Bonita Mangura
• Beverly Metchock
• Eileen Napolitano
• Dan Ruggiero
• John Ridderhof
• Gisela Schecter
• James Sederberg
• Karen Simpson
• Wanda Walton
• Anne Williamson
• Scott Wilson
• WHO Subgroup Lab Capacity Strengthening
• WHO Supranational Reference Lab Network

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Slide 93: CDC and Regional Training and Medical Consultation Centers

• 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

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Slide 94: Panel Discussion

• Infection Control
• Kevin Fennelly, MD, MPH, New Jersey Medical School Global Tuberculosis Institute
• International Epidemiology
• Tim Holtz, MD, and Peter Cegielski, MD, CDC
• Nurse Case Management
• Todd Braun, BSN, RN, MPH, Heartland National Tuberculosis Center
• Outbreak Investigations
• Ann Buff, MD, and Theresa Harrington, MD CDC
• Pediatric TB
• Anne Loeffler, MD, Francis J. Curry National Tuberculosis Center

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