Transcript Full Webinar Slides - Heartland National TB Center

Multidrug-Resistant Tuberculosis
(MDR TB) and
Extensively-Drug Resistant (XDR) TB:
A Web-Based Seminar
Presented by the Division of Tuberculosis Elimination
Centers for Disease Control and Prevention (CDC)
In joint sponsorship with:
Francis J. Curry National Tuberculosis Center
Heartland National Tuberculosis Center
Southeastern National Tuberculosis Center
New Jersey Medical School Global Tuberculosis Institute
Welcome and Introduction
Kenneth G. Castro, MD
Assistant Surgeon General, USPHS
Director, Division of Tuberculosis
Elimination
National Center for HIV/AIDS, Viral
Hepatitis, STD, and TB Prevention
SAFER
HEALTHIER
PEOPLE
Collaboration
• Division of Tuberculosis Elimination, Centers
for Disease Control and Prevention
• Regional Training and Medical Consultation
Centers (RTMCCs)
– Francis J. Curry National Tuberculosis
Center
– Heartland National Tuberculosis Center
– New Jersey Medical School Global
Tuberculosis Institute
– Southeastern National Tuberculosis Center
TB Regional Training and Medical
Consultation Centers
4
Learning Objectives
At the end of the webinar, participants will be able to:
•
•
•
•
•
•
Describe the global and national epidemiology of
MDR and XDR TB
Describe the development of drug-resistant TB
Describe the laboratory diagnosis of drug-resistant
TB
List the general principles of treatment of MDR and
XDR TB
Discuss the challenges in managing contacts of
MDR and XDR TB cases
Identify resources for education, training, and expert
consultation on management and treatment of MDR
and XDR TB
Agenda
Time
Title
5 min Welcome/Introduction
Speaker
Dr. Ken Castro
10 min MDR/XDR Epidemiology
Dr. Masae Kawamura
15 min Laboratory Aspects of
Drug-Resistant TB
20 min Principles of Preventing
and Managing DrugResistant TB
10 min Management of Contacts
Dr. Tom Shinnick
Dr. Reynard McDonald
and Dr. Barbara
Seaworth
Dr. Michael Lauzardo
30 min Lessons, Resources, and Dr. Lee Reichman
Discussion
Continuing Education Credits
• For information on obtaining continuing
education credits go to:
www.cdc.gov/tb/CE/webinars.htm
Credits Type of Continuing Education Credit
1.5
Continuing Medical Units (CMEs)
1.5
Continuing Nursing Units (CNEs)
0.15
Continuing Education Units (CEUs)
1.5
Continuing Education Contact Hours
(CECH)
Continuing Education Disclaimer
Statement
•
•
8
CDC, our planners, and our presenters wish to
disclose they have no financial interests or other
relationships with the manufacturers of commercial
products, suppliers of commercial services, or
commercial supporters.
Presentations will not include any discussion of the
unlabeled use of a product or a product under
investigational use with the exception of Dr.
Seaworth’s discussion on Treatment of MDR/XDR TB.
She may discuss the use of fluoroquinolone and
linezolid therapy for MDR and XDR TB which are not
FDA approved for this purpose.
MDR/XDR TB: Global Problem,
Domestic Implications
L. Masae Kawamura, MD
Director, TB Control Section, San
Francisco Department of Public Health
Francis J. Curry National Tuberculosis
Center
University of California, San Francisco
MDR TB is a manmade
problem…..It is costly, deadly,
debilitating, and the biggest threat to our
current TB control strategies.
10
Definitions
MDR TB: TB isolate that is resistant to both
isoniazid and rifampin
XDR TB: MDR + resistance to fluoroquinolone
and 1 of the 3 injectable drugs (amikacin,
kanamycin, capreomycin)
• Primary drug resistance:
– Infected with TB which is already
drug resistant
• Secondary (acquired) drug resistance:
– Drug resistance develops during
11
treatment
Global Drug-Resistant
TB: How Bad Is It?
•
2004 MDR TB estimates: 424,203 (4.3%)
(estimate includes new and previously treated cases)
2000 MDR TB estimates: 272,906 (1.1%)
•
•
(estimate includes new cases only)
Estimated 43% of global MDR TB cases
have had prior treatment
China, India, and Russian Federation
account for 62% of the MDR burden
Zignol, Dye et al, JID 2006:194
12
Prevalence of XDR TB not known
2006 Global Distribution of MDR TB Among New
Cases
Source: Zignol, Dye et al, JID 2006:194
13
14
Global Drug-Resistant TB:
MDR/XDR TB Fuel
•
•
•
•
15
Suboptimal TB control practices (e.g., poor
DOT, infection control, and treatment without
drug susceptibilities or culture)
MDR TB is pre-XDR TB: poor use of second-line
TB drugs in low and middle income countries
HIV amplification of disease and transmission
(example: KwaZulu-Natal (KZN) South Africa)
Fact in 2005: only ~2% of estimated culture
proven MDR TB cases are treated with 2nd line
drugs
(Global Plan to Stop TB 2006-2015)
Primary MDR TB
United States, 1993–2005
No. of Cases
Percentage
500
400
300
200
100
0
3
2
1
0
93 94 95 96 97 98 99 00 01 02 03 04 05
No. of Cases
Percentage
Note: Based on initial isolates from persons with no prior history of TB.
16 MDR TB defined as resistance to at least isoniazid and rifampin.
% Resistant
Primary MDR TB in
U.S.-born vs. Foreign-born Persons,
United States, 1993–2005
3
2
1
0
1993
1995
1997
1999
U.S.-born
17
2001
2003
Foreign-born
Note: Based on initial isolates from persons with no prior history
of TB.
MDR TB defined as resistance to at least isoniazid and rifampin.
2005
XDR TB in the US: 1993-2007*
18
Counted
Uncounted
Primary XDR TB
48
2
Acquired XDR TB
33
5
Total
81
7
* Preliminary data- not for
distribution
XDR TB Cases in the United States (Initial DST),
1993–2007*
1
2
8
1
1
11
2
19
NYC 16
New Jersey 3
2
1
* Preliminary data- not for
distribution
Primary U.S. XDR TB Counted Cases
as Defined on Initial DST by Year,
1993–2007*
12
Case Count
10
8
6
4
2
0
3 94 95 96 97 98 99 00 01 02 03 04 05 06 07
9
19 19 19 19 19 19 19 20 20 20 20 20 20 20 20
Year of Diagnosis
20
* Preliminary data- not for distribution
Unknown,
2%
Black, 21%
Hispanic,
35%
XDR TB counted cases by
Race/Ethnicity, 1993–2007*
Asian, 21%
White, 21%
XDR TB Cases (Initial DST) in U.S.-born vs. Foreign-born Persons +*
1993-1999 2000-2007
U.S.-born
17 (65%)
5 (25%)
Foreign-born
9 (35%)
15 (75%)
+
21
Two cases of unknown origin
* Preliminary data- not for
distribution
Outcomes of XDR TB Counted Cases
Defined on Initial DST, 1993–2007*
22
Alive at Diagnosis
N (%)
46
Completed Therapy
Died While on Therapy
Moved
Currently on Treatment
Removed from Meds
Other
Lost
16
15
7
4
2
1
1
(35%)
(33%)
(15%)
(9%)
(4%)
(2%)
(2%)
* Preliminary data- not for
distribution
Death of XDR TB Counted Cases
Defined on Initial DST, 1993–2007
Dead at Diagnosis
Died During Therapy
2
15
Total Deaths
17
Percent of Death Among Total XDR Cases
(17/48)
35%
Percent of Death Among XDR Cases with a
Known OutcomeŦ (17/33)
Ŧ Known
23
52%
Outcomes are cases who died or completed
therapy
* Preliminary data- not for distribution
Have germs, will travel…
Migrating populations in the
1990s
Compared
to 1960-75,
four-fold
increase intomigration
4 x increase
in volume
as compared
1960-75
24 Source: Population Action International 1994
Laboratory Aspects of
Drug-Resistant Tuberculosis
Thomas M. Shinnick, Ph.D.
Mycobacteriology Laboratory Branch
Division of Tuberculosis Elimination
National Center for HIV/AIDS, Viral
Hepatitis, STD, and TB Prevention
SAFER
HEALTHIER
PEOPLE
Spontaneous mutations
develop as bacilli
proliferate to >108
Drug
Mutation Rate
Rifampin
10-8
Isoniazid
10-6
Pyrazinamide
10-6
26
Drug-resistant
mutants in large
bacterial population
Multidrug therapy:
No bacteria resistant to all 3 drugs
INH
RIF
PZA
Monotherapy: INH-resistant
bacteria proliferate
INH
27
Spontaneous mutations
develop as bacilli
proliferate to >108
INH resistant
bacteria multiply
to large numbers
INH
RIF
INH
28
INH mono-resist.
mutants killed,
RIF-resist. mutants
proliferate  MDR TB
Role of the Laboratory
• Detect drug resistance to enable clinician to
design effective multidrug regimen
• Initial M. tuberculosis isolate should be tested
against primary drugs
– INH, RIF, PZA, EMB
• For Rif-R isolates, test secondary drugs as
needed
– FQ, AMI, KAN, CAP
29
Drug Susceptibility Testing
• Culture-based methods
– Proportion method
• Solid media
• Liquid media
– Absolute concentration method
– Relative ratio method
• Molecular methods
30
Agar Proportion Method
• Plate bacteria on media containing
– No drugs
– Critical concentrations of a drug
• Incubate for 3 weeks
• Count colonies
Isolate is resistant if the number of
colonies on drug-containing media is
>1% of the colonies on drug-free media
31
Critical Concentration
The lowest concentration of a drug that
• Inhibits growth of all susceptible strains
AND
• Allows growth of all resistant strains
32
Critical Concentrations
Rifampin
33
Isoniazid
S.J. Kim. 2005. Eur Respir J 25:564.
Critical Concentration
Ethambutol
34
S.J. Kim. 2005. Eur Respir J 25:564.
Reasons for Discordant DST Results
• Bacterial population (isolate vs. subculture)
• Differential growth kinetics
• Different inoculation methods (size, clumps)
• Different methods or media
• Cross-contamination
• Transcription, labeling errors
• Problem strains and drugs
– MIC ≈ critical concentration
35
Problem Drugs
• Proficiency testing panel of well-behaved
strains sent yearly to WHO SNRL
Drug
Rifampin
Isoniazid
Streptomycin
Ethambutol
36
Sensitivity
97.2%
98.7%
90.8%
89.3%
Specificity
96.8%
98.5%
93.9%
94.0%
Difficult Strains
• Strains sent to >100 laboratories for analysis
Resistant Strains
Rifampin (n=19)
Isoniazid (n=40)
Strain
1
2
37
Agree
16
30
INH-R
31/88 (35%)
112/112
Disagree
3
10
RIF-R
106/108
74/117 (62%)
*CDC unpublished data. J. Ridderhof, P. Angra
Summary
• DST results must be available as soon as
possible to guide treatment choices
– Testing algorithms including molecular tests for rif-R
may speed decisions
• Lab tests don’t replace clinical judgment
• Clinicians need data to interpret results
– Performance parameters of the test
– Potential impact of prevalence of resistance on
predictive value, etc.
38
Averting Disaster:
Principles in Preventing and
Managing Drug-Resistant TB
Reynard McDonald, MD
Medical Director, NJMS Global
Tuberculosis Institute
Barbara Seaworth, MD
Medical Director, Heartland
National Tuberculosis Center
Patient History
•
•
A 60 year old homeless black
male presented to a local
hospital in July 1986 with a
positive TST (15 mm) and an
abnormal CXR
Initial bacteriology
– Smear +
– Culture M.tb
– Pan-sensitive
•
The patient was diagnosed
with pulmonary tuberculosis
5-5-86
40
RJM
Treatment History
• On July 19, 1986, the patient was started
on self administered treatment with INH
(300 mg/d) and RIF (600 mg/d)
• Patient was non-adherent in taking
medications
– History of alcohol abuse
– Uncooperative in keeping his medical
appointments
41
RJM
Treatment History (cont.)
•
1/12/87 (approx. 6 mos. after treatment initiation):
•
11/20/87 (approx. 1½ yrs after treatment initiation):
– AFB smear positive (1+)
– Continue INH, RIF, and B6
– Add EMB (800 mg/d)
–
–
–
–
Patient again missed appointment and is still drinking
Recent CXR shows no change
Sputum remains positive on smear and culture
Discontinue INH and RIF due to increased AST (269
U/L)
– Start PZA (1.5 gm/d) and SM (1gm 5x/wk), continue
EMB (800 mg/d)
NOTE: Failure to manage toxicity correctly
42
– PZA added when AST>5 x normal
RJM
Treatment History (cont.)
•
•
•
Patient was lost to followup from April 1988 until
March 1989 when he
presented to the
emergency department at
a local hospital with a
complaint of cough
Treatment was restarted
under self administration
with RIF, INH, PZA, and SM
In December 1989 he was
again lost to follow-up
12-8-89
43
RJM
Drug-O-Gram*: Initial Regimens
44
* Chronological display of treatment and bacteriology
RJM
Poor Patient Outcome with Failure
to Follow Principles of Care
•
Providers should assess barriers to adherence and
address them
– All patients should receive Directly Observed Therapy
(DOT)
•
•
•
•
45
Acquired drug resistance may be associated with
treatment failure
Repeat drug susceptibility studies should be ordered
when cultures remain positive after three months
A single drug should never be added to a failing
regimen
At least two and preferably three new drugs with
proven or suspected susceptibility should be added
BS
Ten Years Later…
Patient History (cont.)
•
•
•
•
46
On 4-30-99, the patient, who
was now 73 years old and
homeless, was discharged
from a local hospital with a
diagnosis of pulmonary TB
CXR was abnormal
Sputum specimens
collected on 4-29 & 4-30-99
were smear positive for AFB
Patient stated he had
previously been treated from
1986-1989 for pulmonary TB,
but had taken his
medications very irregularly
5-7-99
RJM
Retreatment Regimen
• On 5-7-99, a decision was made to start
treatment while awaiting drug
susceptibility test (DST) results
• DOT was started with the following:
–
–
–
–
INH 300 mg/d
RIF 600 mg/d
PZA 1500 mg/d
EMB 1200 mg/d
47
RJM
Drug Susceptibility Testing from Commercial
Lab (Specimen collected 4-29-99)
Susceptible
Resistant
Ethambutol (EMB)
Isoniazid (INH)
Streptomycin (SM)
Rifampin (RIF)
Capremycin (CM)
Kanamycin (KM)
Cycloserine (CS)
Amikacin (AK)
Pyrazinamide (PZA)
Ciprofloxicin (CFX)
Ethionamide (ETA)
• The patient now not only has MDR TB, but also XDR TB
48
RJM
Retreatment Course
•
•
•
On 7-16-99, although patient appeared to be responding
to treatment, the regimen was revised as follows:
Stopped
Continued
Added
INH 300 mg/d
RIF 600 mg/d
EMB 1200 mg/d
PZA 1500 mg/d
SM 1 gm 5x/wk
Ofloxacin 400 mg/d
Clofazimine 300 mg/d
On 12-10-99, Ofloxacin was increased to 800 mg/d
and all other drugs were continued
On 1-14-00, SM was stopped and treatment continued
with EMB, PZA, Ofloxacin, and Clofazimine
49
RJM
Treatment Failure
• On 6-16-00, the treating physician felt that
treatment was adequate
– The patient had completed 13 months of
treatment and was 12 months post sputum
culture conversion to negative
• Treatment with EMB, PZA, Ofloxacin, and
Clofazimine was stopped
• On 6-21-00, 5 days after treatment was
50
stopped, the state TB lab reported that a
sputum sample collected 6-16-00 was smear
positive for AFB
RJM
Discussion of Retreatment:
Appropriate Management Decisions
•
Prior poor adherence recognized and addressed:
– DOT ordered
•
Risk of drug resistance due to non-adherence and
treatment failure identified
– Drug susceptibility tests ordered
– BUT - Standard treatment regimen with RIPE
•
•
Many experts would have used an expanded regimen
Correct response to report of MDR
– Treatment changed after report of drug resistance despite a
good initial response
Good response does not justify continuation of an
inadequate treatment regimen
51
BS
Approach to Treatment of MDR TB:
Errors in Management
•
When initiating or revising therapy, always attempt to
employ at least 3 previously unused drugs to which
there is in vitro susceptibility
– Used 3 drugs that were part of previous failed Rx
– Ethambutol and PZA used alone for 9 weeks
•
The use of drugs to which there is demonstrated in
vitro resistance is not encouraged because there is
little or no efficacy of these drugs
– Ciprofloxacin resistance should have alerted providers to
ofloxacin resistance
•
52
Bactericidal drugs with proven efficacy should be
used
– Clofazamine is a weak drug with unknown efficacy
BS
Approach to Treatment of MDR TB:
Errors in Management (cont.)
•
12 months of injectable therapy following culture
conversion is generally recommended
– Exact duration determined by extent of disease
and drug resistance
• Streptomycin stopped after month 6
•
Two years of total treatment after conversion of
cultures to negative is usually recommended
– Occasional patients with limited disease are
cured after 18 months
• Treatment stopped at 13 months
53
BS
Step 1
Use any
available
Begin with any
First line agents to
Which the isolate is
Susceptible
Add a
Fluoroquinolone
And an injectable
Drug based on
susceptibilities
First-line drugs
Pyrazinamide
Ethambutol
PLUS
One of
these
Fluoroquinolones
Levofloxacin
Moxifloxacin
PLUS
One of
these
Injectable agents
Amikacin
Capreomycin
Streptomycin
Kanamycin
54
BS
Step 1
Use any
available
Begin with any
First line agents to
Which the isolate is
Susceptible
First-line drugs
Add a
Fluoroquinolone
And an injectable
Drug based on
susceptibilities
Pyrazinamide
Ethambutol
Step 2
Add 2nd line drugs until
you have 4-6 drugs to
which isolate is
susceptible (which have
not been used previously)
55
PLUS
One of
these
Fluoroquinolones
PLUS
Injectable agents
Levofloxacin
Moxifloxacin
Pick one or more of these
Oral second line drugs
Cycloserine
Ethionamide
PAS
One of
these
Amikacin
Capreomycin
Streptomycin
Kanamycin
Step 1
Use any
available
Begin with any
First line agents to
Which the isolate is
Susceptible
PLUS
Pyrazinamide
Amikacin
Capreomycin
Streptomycin
Kanamycin
Pick one or more of these
Step 2
Add 2nd line drugs until
you have 4-6 drugs to
which isolate is
susceptible (which have
not been used previously)
Oral second line drugs
Step 3
56
Injectable agents
Levofloxacin
Moxifloxacin
Ethambutol
One of
these
PLUS
Fluoroquinolones
First-line drugs
Add a
Fluoroquinolone
And an injectable
Drug based on
susceptibilities
One of
these
If there are not
4-6 drugs
available
consider 3rd line
in consult with
MDRTB experts
Cycloserine
Ethionamide
PAS
Consider use of these
Third line drugs
Imipenem Linezolid
Amoxicillin/Clavulanate
Macrolides
BS
Retreatment Course Continued
•
On 8-18-2000, after a lapse of approximately 2
months, treatment was restarted with:
–
–
–
–
EMB
PZA
Ofloxacin
Clofazimine
•
12-8-00 Streptomycin added
•
7-31-01 Streptomycin discontinued
57
RJM
Drug Susceptibility Test Results from
National Reference Lab
Specimen Collected: 6-16-00
Date Reported: 2-21-01
Susceptible
Resistant
Intermediate
Ethambutol (EMB)
Isoniazid (INH)
Clarithromycin (CLR)
Ethionamide (ETA)
Rifampin (RIF)
Streptomycin (SM)
Kanamycin (KM)
Capreomycin (CM)
Amikacin (AK)
Cycloserine (CS)
Ciprofloxacin (CFX)
PAS
Ofloxacin (OFX)
Clofazimine (CF)
Levofloxacin (LFX)
Pyrazinamide (PZA)
• 8 months, slow growing subculture
58
RJM
Retreatment Course
•
On 11-20-01 regimen was revised as follows:
Stopped
Continued
Added
Ofloxacin 800
mg/d
EMB 1200 mg/d
PZA 1500 mg/d
Clofazimine 200
mg/d
CS 750 mg/d
RBT 300 mg/d
LFX 500 mg/d
59
RJM
Drug-O-Gram: Retreatment
60
RJM
Approach to Treatment of MDR TB:
Errors in Management
•
When initiating or revising therapy, always attempt to
employ at least 3 previously unused drugs to which
there is in vitro susceptibility
– Oral drugs used previously; compromised or known to be resistant
– Single drug added to failing regimen
•
Cultures should be done monthly to monitor response
of MDR TB to therapy
– Cultures usually not done
•
•
61
Repeat DST should be performed when culture remains
positive for 3 months and extended DSTs should be
done for all patients with MDR TB
Expert medical consultation should be sought
BS
Principles for Managing MDR TB
American Thoracic Society, Centers for Disease Control & Prevention, & Infectious
Diseases Society of America, 2003
•
Patients should receive either hospital-based or domiciliary
DOT
•
•
A single drug should never be added to a failing regimen
•
Sufficient numbers of oral drugs should be started at onset of
therapy to make sure there is an adequate regimen once the
injectable agent is discontinued
•
Do not limit the regimen to 3 agents if other previously unused
drugs that are likely to be active are available
62
When initiating or revising therapy, always attempt to employ
at least 3 previously unused drugs to which there is in vitro
susceptibility
BS
Principles for Managing MDR TB (cont.)
American Thoracic Society, Centers for Disease Control & Prevention, & Infectious
Diseases Society of America, 2003
•
•
Intermittent therapy should not be used in treating MDR TB
•
A good response does not justify continuation of an
inadequate regimen
•
Serum therapeutic drug level monitoring should generally be
utilized, especially for the bactericidal drugs and those most
toxic
•
Resistance to RIF is associated in most cases with cross
resistance to rifabutin and in all cases to rifapentine
•
Consultation with an expert in the care of drug resistant
tuberculosis should be sought
63
The use of drugs to which there is demonstrated in vitro
resistance is not encouraged because there is little or no
efficacy of these drugs
BS
Management of
Contacts to Cases of MDR
and XDR
Michael Lauzardo, MD
Principal Investigator
Southeastern National Tuberculosis Center
University of Florida
Deputy Health Officer for Tuberculosis
Florida Department of Health
Transmission of Tuberculosis
• The spread of M. tuberculosis
involves a 3-step process:
– transmission of
bacteria,
– establishment of
infection, and
– progression to
disease.
65
Challenges to an Evidence-Based
Approach to Management of Contacts to
MDR and XDR TB
• Questions regarding “fitness” of MDR/XDR
strains
• Questions regarding the relationship
between the genotype and phenotype of
MDR/XDR strains
• Questions regarding the ideal management
of contacts to these cases
66
Are drug-resistant strains as
transmissible as drug-susceptible
strains?
•
•
67
A case-control study by Snider et al demonstrated
that contacts of patients with drug-resistant and
drug-susceptible cases of TB had an equal
prevalence of positive tuberculin skin test.
In contrast, animal studies have shown that
isoniazid-resistant strains caused significantly less
disease in guinea pigs than drug-susceptible strains.
Snider et al Am Rev Respir Dis 1985; 132:125 32,
Middlebrook Am Rev Tuberc 1954; 69:471 2, Riley
Am Rev Respir Dis 1962; 85:511 25.
Are drug-resistant strains likely to
progress to active disease once
infection is established?
•
•
•
68
In San Francisco, Burgos et al found that strains that
were resistant to isoniazid either alone or in
combination with other drugs were less likely to
result in secondary cases than were drugsusceptible strains.
In this setting, isoniazid-resistant and MDR TB cases
were not likely to produce new, incident drugresistant TB cases.
This presumed effect on pathogenicity may be
related to mutations in the katG gene.
Secondary Case Rate Ratio (SR) of Drug-Resistant
(DR) Strains, by (HIV) Serostatus and Place of Birth
Burgos et al. J Infect Dis. 2003 Dec 15;188(12):1878-84.
Secondary cases
from DR case
Secondary cases
from DS case
SR (95% CI)
P
42
424
0.51 (0.37 - 0.69)
<.001
Positive
19
146
0.49 (0.30 - 0.80)
.003
Negative
23
278
0.45 (0.30 - 0.69)
<.001
US
29
268
0.66 (0.43 - 1.02)
.055
Foreign-Born
13
156
0.41 (0.24 - 0.70)
.004
Characteristics
Resistant to ≥ 1
drug
HIV serostatus
Place of birth
69
Are drug-resistant strains likely to
progress to active disease once
infection is established?
•
•
70
In addition to these data, other molecular
epidemiologic studies observed that cases of TB
caused by drug-resistant strains were less likely
to be in clusters.
The implication is that drug-resistant strains were
less likely to be transmitted and/or to cause
active TB.
Van Soolingen et al J Infect Dis 1999; 180:726 36,
Garcia-Garcia et al Arch Intern Med 2000; 160:630 6
Conflicting Data
•
•
•
71
Texeira et al (2001) in Brazil found 37% PPD +
among DS contacts and 44% PPD + contacts
among MDR TB.
Conover et al (2001) discovered 18.5% (56/303) of
contacts at a methadone treatment program
converted their skin tests.
Thirteen secondary cases were identified among
462 clients and staff (2.8%), but limited HIV data
was available.
Texeira et al. IJTLD 5(4):321-328,
Conover et al IJTLD 5(1):59-64
Are drug-resistant strains likely to
progress to active disease once infection
is established?
•
•
•
72
In 1991, the first documented MDR outbreak was
published in the MMWR.
During 1990 and 1991, outbreaks of multi-drug
resistant tuberculosis (MDR TB) in four hospitals
were investigated.
Of the 87 patients involved in the outbreaks, 82
(94%) were HIV(+) and 70 (80%) were dead within 416 weeks of being diagnosed with TB.
Are drug-resistant strains as likely to
progress to active disease?
•
It will depend on various
factors:
– Pathogen related
• Undefined virulence
•
•
factors
Variability in virulence
between genotypes
Size of the infecting
inoculum
– Host related
• Presence of
•
73
immunosuppression
Ethnic susceptibility to
various strains
Are all MDR and XDR strains equally
virulent?
•
•
•
74
Sun et al (2007) in a study in Singapore found that
MDR isolates (n=41, OR 2.66, 95% CI 1.28-5.50) were
more common among Beijing strains than among
non-Beijing strains.
Estimated transmission rate of MDR TB was 7.7%.
The transmission rate of DR TB was significantly
higher among Beijing genotype strains than nonBeijing strains (12.9% vs. 4.4%; P=0.034).
Sun et al. IJTLD 11(4):436-442
Should we treat or follow
contacts to MDR/XDR?
• The answer is….yes.
• Guidelines for MDR and drug resistance
recommend following the contact for at least
two years.
• Data to support strategies for managing
contacts is very sparse.
75
MMWR June 19, 1992 / 41(RR-11);59-71
Practical Points in Treating
MDR/XDR Contacts
• Recommended regimens are supported by
very little data.
• Usually oral regimens combining PZA with a
quinolone or EMB.
• Tolerance is generally poor compared to INH.
• Published reports are non-randomized
series.
76
Treatment Outcomes of MDR
Contacts
• Schaaf et al followed 119 children who
were contacts to active cases of MDR TB.
• Sixty-one children were infected (51%) and
14 (12%) had active disease.
• Two (5%) of 41 children who received
preventive therapy developed TB,
compared to 13 (20%) who did not (OR
4.97).
77
Schaaf et al. Pediatrics 2002 109:765-771
Treatment Outcomes of MDR
Contacts (cont.)
•
•
•
78
In the Conover study, during two years of followup no further cases of MDR-TB were identified.
Preventive regimens were determined by the
treating physician and were typically a
combination of two of the following
– EMB
– PZA
– Ofloxacin
All medications were given by DOT.
Conover et al IJTLD 5(1):59-64
Summary
• Little data to support our current
recommendations for MDR TB contacts
• Outcomes of contacts may be
influenced by the specific organism’s
genetics
• Close follow-up is prudent despite
some questions about “fitness”
79
MDR and XDR TB:
Lessons & Resources
Lee B. Reichman, MD, MPH
Executive Director
New Jersey Medical School Global
Tuberculosis Institute
University of Medicine and Dentistry of
New Jersey
Lessons from US Traveler with
XDR/MDR TB
•
•
•
•
81
TB has not gone away, it remains with us,
highly prevalent and transmissible
Anyone can get tuberculosis, not only poor
people, minorities, or the foreign born
TB anywhere is TB everywhere
All resistant TB, MDR and Extensively Drug
Resistant TB is preventable by proper TB
diagnosis and treatment
Lessons from US Traveler with
XDR/MDR TB (cont.)
•
•
•
•
82
Good public health can be silent, but when
there is a glitch, it can become major news
We desperately need new tools for TB
diagnosis
We desperately need new drugs and treatments
for regular, drug-sensitive TB as well as drugresistant TB
You don’t want to sit on an airplane for 8 hours
next to an untreated coughing person with any
kind of TB, be it drug sensitive, MDR, or XDR
Consultation
• Be sure to notify your state and local TB
programs of all TB cases
• Always bring in expert consultation when
managing a person with drug-resistant TB
and TB treatment failure
• Experts are available at your state TB
program and also at the 4 CDC-funded
Regional Training and Medical
Consultation Centers
83
Regional Training and Medical
Consultation Centers
•
•
•
•
84
Francis J. Curry National Tuberculosis Center
– 1-877-390-NOTB or 1-877-390-6682
– www.nationaltbcenter.edu
Heartland National Tuberculosis Center
– 1-800-TEX-LUNG or 1-800-839-5864
– www.heartlandntbc.org
New Jersey Medical School Global Tuberculosis
Institute
– 1-800-4TB-DOCS or 1-800-482-3627
– www.umdnj.edu/globaltb
Southeastern National Tuberculosis Center
– 1-800-4TB-INFO or 1-800-482-4636
– http://sntc.medicine.ufl.edu
Regional Training and Medical
Consultation Centers
85
RTMCC Training
• Series of national webinars on legal
interventions, laboratory diagnostics,
TB/HIV, and genotyping
• Stand-up training courses such as
Clinical Intensives, Case
Management, Contact Investigation,
Program Management, and Updates
on topical issues
86
RTMCC Educational Products &
Resources for XDR/MDR
•
•
•
•
87
Drug-Resistant Tuberculosis: A Survival Guide
for Clinicians
– Francis J. Curry National Tuberculosis
Center
MDR TB Care Plan
– Heartland National Tuberculosis Center
Drug-o-Gram
– New Jersey Medical School Global
Tuberculosis Institute
Medical Consultation Database
– Southeastern National Tuberculosis Center
Additional XDR and MDR TB
Educational Resources
Division of Tuberculosis Elimination
Centers for Disease Control and Prevention
www.cdc.gov/tb/xdrtb/
89
CDC’s Extensively Drug-Resistant
Tuberculosis (XDR TB) Webpage
About XDR TB
• Overview
• XDR TB Fact Sheet
• Podcast
• MDR TB Fact Sheet
About XDR TB (translated)
• Español (Spanish)
• 德凱胡赤兒 (Chinese)
• Français (French)
• Italiano (Italian)
90
CDC’s XDR TB Webpage (cont.)
www.cdc.gov/tb/XDRTB/
More About XDR TB
• Morbidity and Mortality Weekly Reports
• Fact Sheets
• Drug Susceptibility Testing for TB:
Questions and Answers
• TB and air travel: Guidelines for
prevention and control
• State TB Control Offices
• City TB Control Offices
• WHO: XDR-TB Website
91
Acknowledgements
•Nisha
•Kashef
Ijaz
•John
•Pawan Angra
•Amera
Khan
•Gisela
Schecter
•Lori
Armstrong
•Anita
Khilal
•James
Sederberg
•Ken
Castro
•Sang
Jae Kim
•Karen
•Peter
Ahamed
Cegielski
92
Lardizabal
•Wanda
Mangura
•Anne
Williamson
Metchock
•Scott
Wilson
Napolitano
•Dan Ruggiero
•WHO
Chen
•Bonita
•Nick
DeLuca
•Beverly
Flood
•Johnny Griffin
Simpson
•Alfred
•Lisa
•Jennifer
Ridderhof
•Eileen
Walton
Subgroup Lab
Capacity Strengthening
•WHO Supranational
Reference Lab Network
CDC and Regional Training and
Medical Consultation Centers
•
•
•
•
•
93
CDC Division of Tuberculosis Elimination
– www.cdc.gov/tb
Francis J Curry National Tuberculosis Center
– 1-877-390-NOTB or 1-877-390-6682
– www.nationaltbcenter.edu
Heartland National Tuberculosis Center
– 1-800-TEX-LUNG or 1-800-839-5864
– www.heartlandntbc.org
New Jersey Medical School Global Tuberculosis Institute
– 1-800-4TB-DOCS or 1-800-482-3627
– www.umdnj.edu/globaltb
Southeastern National Tuberculosis Center
– 1-800-4TB-INFO or 1-800-482-4636
– http://sntc.medicine.ufl.edu
94
Panel Discussion
•
Infection Control
•
International Epidemiology
– Kevin Fennelly, MD, MPH, New Jersey Medical
School Global Tuberculosis Institute
– Tim Holtz, MD, and Peter Cegielski, MD, CDC
•
Nurse Case Management
•
Outbreak Investigations
•
Pediatric TB
– Todd Braun, BSN, RN, MPH, Heartland National
Tuberculosis Center
– Ann Buff, MD, and Theresa Harrington, MD
CDC
– Anne Loeffler, MD, Francis J. Curry National
Tuberculosis Center