# Presentation: 704530

## 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 

**Assistant Surgeon General, USPHS**
**Director, D****ivis****ion o****f ****Tuberculosis Elimination**
**National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention**

**Welcome and Introduction**** **

## 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

**Notes:**
Since 2005 CDC has funded four Regional Training and Medical Consultation Centers which are geographically located throughout the United States The Frances J. Curry National TB Center in San Francisco CA, the Heartland National TB Center in San Antonio TX , the South eastern TB  Center in Gainesville Florida, and New Jersey Medical Center Global Tuberculosis Institute in  Newark, NJ  as seen in this slide.

These four Centers of excellence were funded to carry out their Mission in providing : (next slide)

## 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

**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**

**Learning Objectives**

## 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 |

## 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

**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.**

## 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**

**Notes:**
definitions for drug resistance...
MDR TB implies resistance to at least isoniazid and rifampin
XDR TB is defined as MDR TB and resistance to the 2 most important classes of 2nd-line agents used in MDR TB treatment:  fluoroquinolones and 1 of the 3 injectable agents
Patients with XDR TB are usually resistant to all four 1st line agents
Primary drug resistance means the the patient has drug resistance due to transmission of a drug resistant strain from a drug resistant source. In other words, the patient became infected with a strain that was already drug resistant.
Secondary drug resistance means that the resistance was acquired during the course of TB treatment
MDR TB
Resistance to at least isoniazid and rifampin
MDR TB Importance:  No short course treatment regimen available  and requires use of more toxic drugs
   XDR TB Importance:  Significantly poorer outcome

## 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**

## 2006 Global Distribution of MDR TB Among New Cases				Source: Zignol, Dye et al, JID 2006:194

**2006 Global Distribution of MDR TB Among New Cases****	****	****	****	****Source: Zignol, Dye et al, JID 2006:194**

**Notes:**
This 2006 map shows that MDR TB is not evenly distributed in the world.  
The light green areas indicate the 3-6% of incident cases are MDR.  This includes China, the most populous country in the world.
The yellow countries have the highest rates of MDR TB of over 6%.  This include 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 (eg. Estonia !7.4%, Azerbaijan 14.6%, Kazakhstan 14.6%)

**Notes:**
Global WHO/IUATLD/CDC Survey 
Convenience sample (17,690 isolates) submitted to participating international SRL network, 2000-2004
3520 (20%) of isolates MDR TB
  347 (  2%) of isolates XDR TB 
XDR TB in all regions, more common FSU and Asia (Republic of Korea
Denominator information unavailable

## 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 2****nd**** line drugs **
**	**** ****(Global Plan to Stop TB 2006-2015)**

## Primary MDR TBUnited States, 1993–2005

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

**No. of Cases**

**Percentage**

## Primary MDR TB inU.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.**

## 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**

**Notes:**
Can we determine from this data if XDR was acquired here in the US or not?  IF so, has the trends changed over time?  I would expect that more US-born acquired XDR in the past.  What about now?  Is XDR being acquired or imported?

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

**2**

**1**

**1**

**8**

**11**

**2**

**1**

**2**

**NYC**** 16**

**New Jersey**** 3**

**1**

***  Preliminary data- not for distribution**

## 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**

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

|  | 1993-1999 | 2000-2007 |
| --- | --- | --- |
| U.S.-born | 17 (65%) | 5 (25%) |
| Foreign-born | 9 (35%) | 15 (75%) |

**+**** Two cases of unknown origin**

***  Preliminary data- not for distribution**

**XDR TB Cases (Initial DST) in U.S.-born vs. Foreign-born Persons ****+*******

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

## Outcomes of XDR TB Counted Cases Defined on Initial DST, 1993–2007*

| 
Alive at Diagnosis

Completed Therapy
Died While on Therapy                                              
Moved
Currently on Treatment
Removed from Meds
Other
Lost | N     (%)
46

16  (35%)
15  (33%)
7    (15%)
4    (9%)
2    (4%)
1    (2%)
1    (2%) |
| --- | --- |

***  Preliminary data- not for distribution**

## Death of XDR TB Counted Cases Defined on Initial DST, 1993–2007

| Dead at Diagnosis
Died During Therapy

Total Deaths

Percent of Death Among Total XDR Cases (17/48)

Percent of Death Among XDR Cases with a Known OutcomeŦ (17/33) | 2
15

17

35%

52% |
| --- | --- |

**Ŧ ****Known Outcomes are cases who died or completed therapy**

***  Preliminary data- not for distribution**

## Have germs, will travel... 

**4 x increase in volume as compared to 1960**

**-**

**75**

***Source: Population Action International 1994***

**Have germs, will travel... **
**Migrating populations in the 1990s**

***Compared to 1960-75, four-fold increase in migration***

**Notes:**
This map show the travel has increased 4 fold from the 60s and 70s  and note the heavist arrows – most frequent paths have US as destination. 
USING CALIF. AS THE EXAMPLE
~10 million Californians are foreign-born 
~400 million crossing US Mexico border each year 
~3.5 million visitors to CA
~2 million undocumented enter CA	
~250,000 new entrants with perm residence visa 	
~100,000 new entrants with student visa
CA in particular is a major destination , 10 million of 35 million residents are FB. Very large volume of travel and migation for temp and perm residence. Human migration links low and high income, low and high incidence, near and far
Air is the vehicle and  shared universally

There is major flow from Asia to Oceania,
SE Asia & the Middle East
Europe & the Americas & all points on the globe

The even travel to & within Africa has increased

In fact the volume of migration has increased 4 times as compared with 20 to 40 years ago 

## 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**

**Notes:**
Thank you.  Before discussing the laboratory aspects of drug-resistant tuberculosis, I’ll briefly describe how drug-resistant bacteria arise in the human host.

## Spontaneous mutations

**    ****develop as bacilli**
**        ****proliferate to >10****8**

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

**Notes:**
M. tuberculosis bacteria become resistant to anti-TB drugs by acquiring mutations that confer resistance.  Such mutations develop spontaneously as the bacteria proliferaet in the host.
Rif-R mutants arise at a frequency of 1 in 10exp-8
INH-R and PZA-R mutants arise at a frequency of 10exp-6
So, prior to treatment, the population of bacteria in a TB pateint already contains drug-resistant bacteria.

## INH

**INH**

**Drug-resistant mutants in **_**large**_** bacterial population**

**Multidrug therapy: **
**No bacteria resistant to all 3 drugs**

**Monotherapy: INH-resistant bacteria proliferate**

**Notes:**
If one treats this population with three effective drugs, all bacteria are killed.
However, if one treats with only one drug, say INH, one selects for INH resistant bacteria.  --

## INH

**INH**

**RIF**

**INH**

**Spontaneous mutations**
**    ****develop as bacilli**
**        ****proliferate to >10****8**

**INH mono-resist. **
**mutants killed, **
**RIF-resist. mutants proliferate ******** MDR TB**

**INH resistant bacteria multiply **
**to large numbers**

**Notes:**
These bacteria then can multiply to large numbers and once again spontaneous mutations can arise.  In this case acquisition of a second drug resistance.  Treatment with two drugs then leads to selection of the MDR strain and its proliferation can lead to the acquisition of additional resistance.  This sort of amplification of drug resistance can occur one drug  at a time to ultimately lead to XDR 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**

**Notes:**
The role of the laboratory is to ....   And to prevent the acquisition of drug resistance.
Current recommendations are ...
-  drug susceptibility test methods include ...

## Drug Susceptibility Testing

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

**Notes:**
drug susceptibility test methods include ...
The proportion method is commonly used in the U.S.
First-line drugs are typically tested in liquid media.  Second-line drugs are typically tested on solid media.
-

## 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 **

**Notes:**
For the agar proportion method .....

To distinguish the drug resistant bacteria from drug resistant bacteria, isolates are usually tested against the critical concentration, which is also sometimes called the breakpoint concentration.  -

## Critical Concentration

**The lowest concentration of a drug that**
**Inhibits growth of all susceptible strains**** **
**AND**
**Allows growth of all resistant strains**

**Notes:**
In an ideal world, the critical concentration would be the concentration of a drug at which all susceptible strains would fail to grow and all resistant strains would grow.  So if you saw a colony on a drug-containing plate, you would know that the bacteria were drug resistant.  If there were no colonies, you would know the bacteria were drug susceptible.
However, the world is not ideal and it is difficult to find a drug concentration that actually meets this definition.  So we often have to settle for the concentration that best discriminates between susceptible and resistant strains. 
The next slide shows how critical concentrations were determined. 

## Critical Concentrations

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

**Rifampin**

**Isoniazid**

**Notes:**
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.  By the way, 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.   -

## Critical Concentration

**Ethambutol**

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

**Notes:**
For ethambutol, the picture is very complicated and 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.  -

## 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**

**Notes:**
Other reasons for discordant results include...
- Here is an example of what I mean by problem drugs

## 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% |

**Notes:**
- Here is an example of what I mean by problem drugs
Each year, a panel of well-behaved strains is sent to the members of the WHO SNRL network as part of a proficiency testing program.
These state-of-the-art laboratories were able to accurately identify rifampin and isoniazid resistance with sensitivities and specificities of 97-98%.  On the other hand, even these reference labs had difficulties identfying streptomycin and ethambutol resistant strains with sensitivities on only about 90%.
This indicates that DST with streptomycin and ethambutol are somewhat less reliable than DST with isoniazid and rifampin.   DST for many of the second line drugs is even less reliable than DST for strep or EMB.
In addition to these concerns, not all Mtb strains are as well behaved as the strains sent out in this proficiency test panel.   -

## Difficult Strains

**Strains sent to >100 laboratories for analysis**

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

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

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

**Notes:**
Here is what I mean by difficult strains.  
As part of a performance evaluation program, CDC sent strains to more than 100 laboratories for DST.
Most strains were consistently identified as susceptibly or resistant by the labs.  However, for some strains, agreement between the labs was less than 80%.  That is, laboratories disagreed more than 20% of the time for 3 of 19 rifampin rersistant starins and for 10 of 40 INH resistant strains. 
For example, only about 1/3 of the labs found strain 1 to be INH-R, 2/3 found it to be INH-S.
About 2/3 of the labs found strain 2 to be Rif-R, 1/3 found it to be Rif-S.
These problem strains may represent strains that have MICs close to the critical concentration.   -

## 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.**

**Notes:**
In Summary ...

## 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

**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**

**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**

**RJM**

## Treatment History (cont.)

**1/12/87 (approx. 6 mos. after treatment initiation): **
**AFB smear positive (1+)**
**Continue INH, RIF, and B****6**** **
**Add EMB (800 mg/d)**** **
**11/20/87 (approx. 11⁄2 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**

## Treatment History (cont.)

**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**

**12-8-89**

**RJM**

## Drug-O-Gram*:  Initial Regimens

**RJM**

- * Chronological display of treatment and bacteriology

## 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**

**Notes:**
This patient was lost to follow-up three and half years after his initial diagnosis of tuberculosis.  At the time he was lost he remained culture positive. This represents treatment failure.  A crucial factor leading to his poor outcome was the failure of public health and of his providers to ensure adherence to treatment.  Drug susceptible TB which this patient had is readily treatable and curable.  His alcohol abuse, homelessness, and poor attendance at medical appointments are characteristics associated with poor adherence.  These factors should have been recognized and addressed. Directly Observed Therapy, a treatment strategy in which a trained health care worker watches the patient take every dose of TB medication is the standard care for all TB patients in the US and is associated with significantly better treatment outcomes.  DOT should have been ORDERED for this patient.

The medical management of this patient was inadequate. His initial regimen of INH and RIF was an acceptable regimen for drug susceptible TB in 1986 but six months into treatment he remained sputum smear positive and therefore a treatment failure.  The provider’s response was addition of a single drug to a failing regimen.  Because a failing regimen is a possible indication of developing drug resistance, the correct action should have been to add at least two and preferably three new drugs to his treatment regimen.  Ideally one of these drugs should have been an injectable agent. 
Retreatment after patient had been “lost” for one year and after 2 years of failure used only drugs which were part of the prior failed regimen.
New drug susceptibility studies should be ordered whenever the culture remains positive after three months. Despite the glaring possibility of drug resistance, this risk was not recognized, and repeat drug susceptibility tests were not ordered. 

DISCUSSION SLIDE 1
Poor outcome: treatment failure with positive smear and culture after 3 1⁄2 years of medical management
Failure of public health and private provider to ensure adherence to treatment
DOT not used
Self administered therapy for 3 1⁄2 years despite poor adherence and treatment abandoned for one year
Factors placing patient at risk not addressed
Homelessness
Alcohol abuse

DISCUSSION SLIDE 2
Inadequate medical management with poor outcome over 3 1⁄2 years
Treatment failure not recognized and managed
Addition of EMB as single drug at 6 months
Failure to repeat drug susceptibility study for 31⁄2 yrs

DISCUSSION SLIDE 3
Inadequate medical management with poor outcome over 3 1⁄2 years
Retreatment after patient was “lost” for one year and after failure of prior treatment over 2 years used only drugs part of prior failed regimen and was self administered
Despite compromised regimen cultures convert initially but become positive 3 months after streptomycin stopped
Probable improved adherence during streptomycin

## Ten Years Later...Patient History (cont.)

**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**

**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**

**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) |

**RJM**

**  ****The patient now not only has MDR TB, but also XDR TB **

## 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**

| 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 |

**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 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**** **

**BS**

**Good response does not justify continuation of an inadequate treatment regimen**

**Notes:**
9 1⁄2 years after abandoning a failing treatment regimen this patient was located.  The possibility of drug resistance was recognized by his providers and drug susceptibility tests were ordered.  Non-adherence was addressed with implementation of DOT.  A standard 4-drug treatment regimen was started.  Many experts would have considered an expanded treatment regimen in which 2 or 3 additional drugs are started because of the possibility of drug resistance.   

2 months later the lab reported resistance to INH and RIf documenting a diagnosis of acquired MDR-TB.  By this time he had improved clinically and was  smear and culture negative.  INH and RIF were stopped and SM, ofloxacin and clofazamine were added.

By adjusting his therapy in response to the susceptibility results, his providers followed an important principle of treatment of drug resistant tuberculosis.  They recognized that a good initial response does not justify continuation of an inadequate treatment regimen as further drug resistance and ultimate treatment failure is likely to develop.

## 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**

**BS**

**Notes:**
The treatment regimen chosen was too weak and short to adequately treat MDR-TB. When initiating or revising therapy, it is important to always attempt to employ at least 3 previously unused drugs to which there is in vitro susceptibility The patient was treated with three drugs, EMB, PZA, and SM which were compromised by their inclusion in a failed treatment regimen. Also, EMB and PZA were the only drugs the isolate was susceptible to  during the initial 9 weeks of this treatment and PZA is not active against rapidly growing populations of mycobacteria. Thus most of the population would have only been treated with EMB. 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.  The report of ciprofloxacin resistance should have alerted  providers to ofloxacin resistance. Bactericidal drugs with proven efficacy should be used. Clofazimine is a weak drug with unproven efficacy.  

## 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**

**BS**

**Notes:**
The regimen was fatally compromised when streptomycin was stopped after only six months. The CDC, ATS, IDSA, and most experts recommend at least 6 and preferably 12 months of injectable therapy after conversion of cultures to negative.  This is especially important  when it is combined with a weak oral regimen..  Usually twenty four months of treatment following culture conversion is recommended for MDR-TB. Selected patients with limited disease may be adequately treated with 18 months of therapy. All treatment was stopped after only 13 months

## BS

**BS**

**Notes:**
Building a Treatment Regimen
 Let’s look at this 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.  These generally should be used if the organism is susceptible, even if they have been used as part of a failed treatment regimen. Next a fluoroquinolone which will likely be the most important and active drug in the regimen should be added if one is available.  When a fluroquinolone is not included in the treatment regimen the likelihood of a good outcome is significantly less.  The high mortality of XDR TB is especially related to resistance to fluoroquinolones. Moxifloxacin is regarded by many to be the most active fluroquinolone.  Finally an injectable agent should be added.  Any of these agents is generally considered equally efficacious but slight differences in toxicity profiles exist.  Because the incidence of streptomycin resistance is >10% in many areas of the world, it should only be used if there is documented sensitivity.
After incorporation of drugs in step one, 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.  When possible consider the medical co-morbidities of your patient. For example you would want to avoid cycloserine in patients with seizures or serious underlying psychiatric diagnoses and ethionamide in those with serious underlying liver disease.  
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. The drug that is most helpful from this group is linezolid. The CDC recommends consulting an expert for the management of all drug resistant cases, but especially those requiring the use of drugs in step 3. 

## Slide 55

## BS

**BS**

**Notes:**
Building a Treatment Regimen
 Let’s look at this 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.  These generally should be used if the organism is susceptible, even if they have been used as part of a failed treatment regimen. Next a fluoroquinolone which will likely be the most important and active drug in the regimen should be added if one is available.  When a fluroquinolone is not included in the treatment regimen the likelihood of a good outcome is significantly less.  The high mortality of XDR TB is especially related to resistance to fluoroquinolones. Moxifloxacin is regarded by many to be the most active fluroquinolone.  Finally an injectable agent should be added.  Any of these agents is generally considered equally efficacious but slight differences in toxicity profiles exist.  Because the incidence of streptomycin resistance is >10% in many areas of the world, it should only be used if there is documented sensitivity.
After incorporation of drugs in step one, 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.  When possible consider the medical co-morbidities of your patient. For example you would want to avoid cycloserine in patients with seizures or serious underlying psychiatric diagnoses and ethionamide in those with serious underlying liver disease.  
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. The drug that is most helpful from this group is linezolid. The CDC recommends consulting an expert for the management of all drug resistant cases, but especially those requiring the use of drugs in step 3. 

## 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**

**RJM**

## Drug Susceptibility Test Results from National Reference Lab

| 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) |  |  |

**RJM**

**Specimen Collected: 6-16-00**

**Date Reported: 2-21-01**

**  ****8 months, slow growing subculture**

## 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 |

**RJM**

## Drug-O-Gram: Retreatment

**RJM**

**Notes:**
NOTE Break in treatment for two months in summer 2000 (June16-Aug 18 2000)  Treatment stopped prematurely after 13 months, followed by relapse

NOTE: After information regarding 2nd line drugs was obtained in Feb 2001,  no new drugs were addeduntil Nov 2001 and ultimately this was too little too late the patient died in Jan 2002

## 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 **

**BS**

**Notes:**
Drug susceptibility studies confirmed further amplification of drug resistance with reported  resistance to ofloxacin and pyrazinamide. The patient’s management continued to be inadequate. When initiating or revising therapy, it is important to try to use at least 3 new drugs to which there is laboratory confirmed susceptibility.   Instead of using three new drugs, treatment was started with the same regimen that had just failed and consisted of only oral drugs. Sputum cultures should be done monthly during treatment of MDR-TB in order to follow the patient’s response to treatment. Sputum cultures remained positive for three months after restarting treatment  and then were not collected for another eight months. Repeat DST should be performed when culture remains positive for 3 months and Extended drug susceptibility studies should be done on all patients with MDR TB   
Expert consultation should be sought on patients with drug resistant tuberculosis.  Expert consultation was not requested until after 15 months of failing therapy by which time the patient was desperately ill.
The recommendations of expert consultants were only partially followed and his treatment included only a single drug likely to be effective, cycloserine. 
At this point every available drug should have been used but, the possibility of a good outcome was unlikely. 

## 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 **

**BS**

**Notes:**
This slide represents many of the key principles to follow when treating a patient with multiple drug resistant or XDR TB.  Most of these principles were violated by his providers.  These principles include:

## 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**

**BS**

**Notes:**

Most of these principles were violated by his providers and contributed to the development of XDR TB and ultimate death of this patient.  His disease should have been readily treatable and curable.  His management represented complete systematic failure..  

## 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.**

## 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**

## 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.***

## 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.**

## 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 |

**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*****.**** **

## 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 ***

## 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***

## 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.**

## 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**

## 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***

## 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***

## 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.**

## 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***

## 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***

## 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”**

## Lee B. Reichman, MD, MPH
Executive Director
New Jersey Medical School Global Tuberculosis Institute
University of Medicine and Dentistry of New Jersey

**Lee B. Reichman, MD, MPH**
**Executive Director**
**New Jersey Medical School Global Tuberculosis Institute**
**University of Medicine and Dentistry of New Jersey**

**MDR and XDR TB:****Lessons & Resources**

## 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**

## 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**

## 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 **

## 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**_

## Regional Training and Medical Consultation Centers

**Regional Training and Medical Consultation Centers**

## 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**

## RTMCC Educational Products & Resources for XDR/MDR

**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/

_**www.cdc.gov/tb/xdrtb/**_

## 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****) **

## 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**

## Acknowledgements

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

##  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**_

## 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**