Transcript tb_june_2010.pul..ppt

Tuberculosis Overview & Update
June 2010
Stephan L. Kamholz, MD
Objectives
• Understand epidemiology, clinical
presentation & immunopathogenesis of TB
• Gain familiarity with standard and newer
diagnostic modalities for TB
• Review therapies and approaches to TB
control
Disclosure
• No stocks, bonds, salaried board positions
• No direct industry research grant funds
• No personal financial interest in any
product, device or drug
Case Presentation
56 year old woman with rheumatoid
arthritis…new cough
56 yo woman h/o RA, GERD p/w three wks of
weakness, night sweats, & chills. Patient had a
flu shot 5 weeks ago at medicine clinic (went for
routine check up) and had flu-like symptoms
(chills, body aches, cough with little sputum)
since then. No sick contacts, no recent travel
within two years. Seen by rheumatologist 3
weeks ago c/o flu symptoms but told that she
didn't have an infections. Weakness gradually
worsened over the 3 weeks respiratory
symptoms (cough/yellow sputum) persisted,
developed appetite loss & fatigue  ED.
56 year old woman with rheumatoid
arthritis …new cough
Past History:
PPD 2 years ago, non reactive (? RA rx at
that time?); Came to USA from Bolivia 30
years ago
RA (Rheumatoid Arthritis) (ICD9 714.0)
GERD (Gastroesophageal Reflux Disease)
(ICD9 530.81):
Surgical History:
CS (Cesarean Section) (ICD9 669.70)
Meds:
Leflunomide [Arava]; Adalimumab [Humira].
56 year old woman with rheumatoid
arthritis …new cough
56 year old woman with rheumatoid
arthritis …new cough
56 year old woman with rheumatoid
arthritis …new cough
Guerra RL et al. Use of the amplified mycobacterium tuberculosis
direct test in a public health laboratory: test performance and
impact on clinical care. Chest. 2007 Sep;132(3):946-51
• The Amplified Mycobacterium tuberculosis Direct Test (MTD;
Gen-Probe; San Diego, CA) is a nucleic-acid amplification test
for rapid pulmonary tuberculosis (PTB) diagnosis.
• RESULTS: A total of 1,151 respiratory specimens from 638 PTB
suspects were analyzed. MTD sensitivity, specificity, positive
predictive value, and negative predictive value were 91.7%,
98.7%, 96.7%, and 96.5% overall, respectively; and 98.7%,
97.8%, 98.7%, and 97.8% for smear-positive patients; and
62.2%, 98.9%, 85.2%, and 96.1% for smear-negative patients.
• In the MTD group, concordance between definitive and clinician
presumptive diagnoses was 78% (95% confidence interval [CI],
64 to 88%), similar to that for the non-MTD group (79%; 95% CI,
68.4 to 89.6%).
• Concordance between definitive diagnosis and the MTD test
was 98% (95% CI, 94.1 to 100%).
• CONCLUSION: For smear-positive PTB suspects, MTD had
excellent concordance with definitive diagnosis,
Dixon WG et al. Drug-specific risk of tuberculosis in patients with
rheumatoid arthritis treated with anti-TNF therapy: Results from
the British Society for Rheumatology Biologics Register.
Ann Rheum Dis. 2009 Oct 22. [Epub ahead of print]
•
•
•
•
•
Risk of TB in patients with RA is felt to be increased following anti-TNF rx.
Proposed differential risk between the anti-TNF drugs etanercept (ETA),
infliximab (INF) and adalimumab (ADA).
Compare directly the risk between drugs, to explore time to event, site of
infection and the role of ethnicity, using data from the British Society for
Rheumatology Biologics Register compared TB rates in 10712 anti-TNF
treated patients (3913 ETA, 3295 INF, 3504 ADA) and 3232 patients with active
RA treated with traditional DMARDs.
RESULTS: As of 04/08, 40 cases of TB were reported, all in the anti-TNF
cohort. The rate of TB was higher for the monoclonal antibodies ADA (144
events/ 100,000 person years (pyrs)) and INF (136/100,000 pyrs) than ETA (39/
100,000 pyrs). After adjustment, the incidence rate ratio compared to ETAtreated patients was 3.1 (95% CI 1.0, 9.5) for INF and 4.2 (1.4, 12.4) for ADA.
13/40 cases occurred after stopping therapy. 25/40 (62%) cases were extrapulmonary, of which 11 were disseminated. Patients of non-white ethnicity
had a six-fold increased risk of TB compared to white patients treated with
anti-TNF therapy.
CONCLUSION: The rate of TB in patients with RA treated with anti-TNF
therapy was 3-4 fold higher in patients receiving INF and ADA compared to
ETA.
TB Epidemiology
W.H.O. 2009 TB Report
W.H.O. 2009 TB Report
2009 - 13th annual report on global control of
tuberculosis (TB) - World Health Organization
• Globally, estimated 9.27 million incident cases of TB in
2007.
• Increase from 9.24 million cases in 2006, 8.3 million cases
in 2000 and 6.6 million cases in 1990.
• Most of the cases in 2007 were in Asia (55%) and Africa
(31%), with small proportions of cases in the Eastern
Mediterranean Region (6%), the European Region (5%)
and the Americas (3%).
• The five countries that rank first to fifth in terms of total
numbers of cases in 2007 are India (2.0 million), China
(1.3 million), Indonesia (0.53million), Nigeria (0.46 million)
and South Africa (0.46 mill).
• Of the 9.27 million incident TB cases in 2007,an estimated
1.37 million (15%) were HIV-positive; 79% of these HIVpositive cases were in the African Region and 11% were in
the South-East Asia Region.
2009 - 13th annual report on global control of
tuberculosis (TB) - World Health Organization
• Although incident cases of TB increased in absolute
terms as a result of population growth, the number of
cases per capita is falling.
• The rate of decline is slow, at less than 1% per year.
• Globally, rates peaked at 142 cases per 100 000
population in 2004.
• In 2007, there were an estimated 139 incident
cases per 100 000 population.
• Incidence rates are falling in five of the six WHO
regions (the exception is the European Region,
where rates are approximately stable).
2009 - 13th annual report on global control of
tuberculosis (TB) - World Health Organization
• Estimated 13.7 million prevalent cases of TB in 2007
(206 per 105 population), a decrease from 13.9 million
cases (210 per 105 population) in 2006.
• Estimated 1.3 million deaths occurred among HIV
negative incident cases of TB (20 per 105 population) in
2007.
• There were an additional 456 000 deaths among incident
TB cases who were HIV-positive; these deaths are
classified as HIV deaths in the International Statistical
Classification of Diseases (ICD-10).
2009 - 13th annual report on global control of
tuberculosis (TB) - World Health Organization
• Estimated 0.5 million cases of multi drug
resistant TB (MDR -TB) in 2007.
• 27 countries (of which 15 are in the European
Region) that account for 85% of all such cases.
• The countries ranking 1 to 5 in terms of MDR TB cases are India (131 000), China (112 000),
the Russian Federation (43 000), South Africa
(16 000) and Bangladesh (15 000).
• By the end of 2008, 55 countries and territories
had reported at least one case of extensively
drug resistant TB (XDR -TB).
TB – USA – 2008
www.cdc.gov/.../dsTB2008Data
TB – New York State – 2008
NYSDOH Report - March 24, 2009
• TB cases were reported in all regions of the state and in all age groups.
• In NYS there were 1,200 cases of TB in 2008, a 2% increase over 2007.
• 76% of cases were among persons born outside the United States,
reflecting the high burden of TB in Latin America, East Asia, Africa, and
the Indian subcontinent.
• In New York City there were 895 cases, for a rate of 11.2 cases per
100,000, a 2% decrease from 2007 and a 21.3% decrease over 5 years.
• In the 57 counties outside New York City, 305 cases (2.8 cases per
100,000 population) were reported, a 17% increase from 2007. But
overall there has been a 10% decrease in cases over the last five years.
• More than half (56 percent) of the cases outside New York City were
reported in three counties: Nassau, Westchester, and Suffolk.
• In 2008 12 cases of multi-drug resistant TB were reported, compared
with 20 to 30 cases of multi-drug resistant TB annually in recent years.
Patients with drug-resistant TB must be treated for longer periods with
less effective drugs.
Tuberculosis
• The pathway from transmission to
infection to disease
Transmission of TB
• Patient with active pulmonary tuberculosis
coughs, releasing AFB into atmosphere
• Each organism is surrounded by a sphere of
hydration known as the droplet nucleus
• Mass median diameter of droplet nuclei is 1 2 microns
• Host inhales droplet nuclei which evade the
mucociliary clearance mechanism and
impact in peripheral alveoli of the mid and
lower lung zones
Macrophage phagocytosis
of tubercle bacilli
Intra-cytoplasmic events
• Inhaled mycobacteria phagocytosed by alveolar
macrophage...phagosomal vacuole also contains
components of class II MHC
• Anticipated fusion of lysosome with phagosome is
inhibited, perhaps by sulfolipids, leading to
unimpeded proliferation of M. tb. in macrophage
• Evidence of specific inhibition of fusion of vesicular
proton-ATPase which results in less than adequate
acidification of vacuole
Sturgill-Koszycki et al. Science 1994;263:678-681.
Antigen presentation
Cell-cell interactions post-phagocytosis
Immunopathogenetic Steps
• Ultimately, mycobacterial antigens processed for
presentation [with MHC] to CD4+ T-helper cells
which have been primed by macrophage release of
Il-1
• Lymphocyte secretes lymphokines leading to clonal
expansion of antigen specific CD4+ cells and
stimulation of macrophages. . .a subset of cytotoxic
T cells may lyse infected macrophages permitting M.
tb. to be phagocytosed by activated macrophages
[IFN-gamma, etc]
• Positive tuberculin skin test develops in
immunocompetent individuals
{Delayed hypersensitivity}
Symptomatology
• Constitutional illness is attributable to the
immune response
• Cytokines [TNF, interferon-gamma, Il-1] can
evoke many of the classic symptoms of
tuberculosis, e.g., fever, sweats, weight loss,
anorexia
• Localizing symptoms [e.g., cough] related to
impingement of lesions on airways or
stimulation of interstitial stretch
receptors
• Dyspnea occurs only with very extensive
lung involvement
Possible outcomes post infection
Progressive Primary TB
• Initial parenchymal focus progresses
• Characteristic of tuberculosis in the pediatric
age group and occurs with increased
frequency in immunocompromised hosts
• Tuberculous pneumonia, often accompanied
by hilar and/or mediastinal lymph node
enlargement
Progressive Primary
Case Vignette
• 27 year old woman from West Indies with one
month fever, achy left chest pain, mucopurulent cough, night sweats and 7 lb.
weight loss; HIV risks ????
• WBC 19.K, Na+ 133; sputum C/S = N.O.F.;
Sputum AFB smears X 3 (-)
CXR
Initial Hematogenous Dissemination
• May occur with primary or reactivation
disease
• Tubercle bacilli gain access to lung
lymphatics, reach hilar nodes and undergo
lympho-hematogenous dissemination
• Lung apices, meninges, epiphyses of bones,
kidneys, adrenals, liver are seeded
• Primary lung lesion and peripheral foci heal
in the immunocompetent host
• Disseminated [miliary] disease develops in
some individuals [children, HIV, etc]
Miliary TB
• Diffuse tiny pulmonary nodules 1 - 2 mm in
diameter [resembling millet seeds]
representing hematogenous dissemination
to lung
• Multiple other organs affected
• Patients extremely ill with spiking fevers,
sweats, weight loss, hematologic
abnormalities …can have respiratory failure,
shock
Miliary TB Case Vignette
• 27 yr. old woman, known HIV , S/P
intrathecal chemorx. for B-cell
lymphoma [pre-antiretroviral era]
• Fevers, night sweats, anorexia, weight
loss, mild DOE
• Lymphopenia & hyponatremia
CXR
Post FA, Wood R, Pillay GP. Pulmonary tuberculosis in HIV infection:
radiographic appearance is related to CD4+ T-lymphocyte count
Tuber Lung Dis. 1995 Dec;76(6):518-21
• CD4+ T-lymphocyte count was used as a marker of HIV disease
progression.
• Upper zone infiltrate typical of Pulmonary TB reactivation was
present in 18 patients. This pattern was associated with early HIV
infection (mean CD4+ T-cell count 389) and had 78% positive
predictive value for identifying patients with > 200 CD4+ Tlymphocytes/microL.
• Pleural effusion was present in 32 patients and occurred over a wide
intermediate range of CD4+ T-cell counts (mean 185).
• Lower or midzone infiltrates, adenopathy, interstitial pattern or
normal radiograph occurred in 136 patients and were associated
with advanced HIV disease (mean CD4+ T-cell count 105).
• These patterns had 84%, 89%, 89% and 100% positive predictive
value, respectively, for identifying patients with < 200 CD4+ Tcell/microL.
• CONCLUSION: Pulmonary tuberculosis in HIV-positive patients
presents with a spectrum of radiographic abnormalities predictive of
stage of HIV disease progression.
“Pleural TB”
• Often develops 3 to 6 up to 24 months after
initial infection, however, can accompany
parenchymal reactivation
• Lymphocytic exudative pleural effusion is a
common manifestation
• Probably represents rupture of sub-pleural
[parenchymal] focus of viable mycobacteria
into pleural space followed by exuberant
lymphocytic inflammatory response
Pleural TB Case Vignette
• 40 year old woman with acute
severe right chest pain and T
38.5oC
• Known tuberculin skin test
conversion 11 months ago, refused
isoniazid chemoprophylaxis
CXR 
Diagnosis of Tuberculous
Pleurisy
• Lymphocytic exudative effusion: CD4 cells as
high as 65%, CD8 cells up to 19%
• High protein, normal or low glucose
• Elevated adenosine deaminase {> 53 U/ml}
with pleural/serum ADA ratio > 1.5
• Elevated interferon- and interferon-
• Demonstration of caseating granulomata on
biopsy; growth of AFB from fluid or biopsy
• Positive direct AFB smear of fluid unusual
except in HIV-associated TB pleural effusion
Reactivation TB
{a.k.a. Post-Primary TB}
• Characteristically upper lobe disease with
cavitation
• Occurs in previously infected individuals due
to some diminution in immune surveillance,
usually older patients
• May have extra-pulmonary involvement
• Represents the most common type of
tuberculosis encountered in the U.S.,
probably 2/3 to ¾ cases
Reactivation TB - Case Vignette
(“Mr. XDR of the 1990’s”)
• 44 year old “street person” admitted
with cough, fatigue, night sweats,
dyspnea
• Past history of admissions for inpatient
TB treatment X 7 over 4 year period
• Known resistant isolate
CXR 
Confirmed the etiology
• Robert Koch, MD
Acid Fast Stain
• Cell wall lipids make cell surface
hydrophobic, conferring resistance to
staining with basic aniline dyes
• Ziehl Nielsen acid fast stain often applied
with heat; once stained , AFB resist
decolorization; acid/alcohol decolorizer
used, however organisms remain reddish
• Fluorescent staining possible using
fluorochrome methodology
Fluorochrome Stain
“Invasive” sampling
techniques
• Bronchoscopic sampling
• Pleural Disease
[already discussed re: case]
• Other extra-pulmonary sites…site
specific sampling
Tuberculosis
• Newer diagnostic modalities
– Identification & sensitivity testing of
clinical specimens
– Immunodiagnostic testing pf
patients
Luciferase Reporter Assay
Luciferase Reporter Assay
Hazbón MH, Guarín N, Ferro BE, Rodríguez AL, Labrada LA, Tovar R, Riska PF,
Jacobs WR Jr. J Clin Microbiol. 2003 Oct;41(10):4865-9.
Photographic and luminometric detection of luciferase reporter phages for drug
susceptibility testing of clinical Mycobacterium tuberculosis isolates.
Luminometric detection of LRP activity offers higher sensitivity and
quantitative results, while a Polaroid film detection method offers a
"low-tech" inexpensive alternative that is called the Bronx box. In
this work we evaluated, improved, and compared the performance
of the luminometer and the Bronx box formats for drug susceptibility
testing with LRPs by using 51 clinical isolates of M. tuberculosis,
with the agar proportion method (PM) serving as reference. The
sensitivity in detecting resistance to isoniazid and rifampin,
antibiotics that define multidrug resistance (MDR), was 100% for
both methods. The turnaround time for results was reduced from 3
weeks for PM to 54 or 94 h for luminometry or the Bronx box,
Luciferase Reporter Assay
(A) Bronx box. The Polaroid film cassette is placed over
the microtiter plate containing the LRP-infected
mycobacterial cultures. The door is closed, and the
overnight film exposure begins. (B) Drug susceptibility
test result gained from the Bronx box [turnaround time = 94 hours]
[Ref: Hazbon MH et al. J Clin Microbiol. 2003 October; 41(10): 4865–4869]
Dusthackeer A et al. Construction and evaluation of luciferase
reporter phages [LRP] for the detection of active and nonreplicating tubercle bacilli. J Microbiol Methods. 2008
Apr;73(1):18-25
• Improved sensitivity and specificity with new
LRP…Che12, the first true temperate phage
infecting M. tuberculosis
• LRP constructs exhibited detectable luciferase
activity in dormant as well as in actively growing
M. tuberculosis.
• TB cases among the HIV infected population
often result from the reactivation of latent bacilli,
it would be useful to develop LRP that can
detect dormant bacteria
Polymerase Chain Reaction Tests for TB
• 1,090 tissue and body fluid specimens from 1,032 patients
with suspected TB were subjected to acid-fast bacillus (AFB)
smear, culture, and the AMPLICOR MTB PCR test.
• The PCR was negative for all eight specimens that yielded MAC
only
• The sensitivity, specificity, positive predictive value, and
negative predictive value for the AMPLICOR MTB PCR test were
76.4%, 99.8%, 92.8%, and 99.2%, respectively.
• PCR results were available within 6.5 hours, compared with an
average of 3 weeks for culture of M tuberculosis.
• Conclusions: These data establish the utility of the AMPLICOR
MTB PCR test for the rapid detection of M tuberculosis in tissue
and body fluid specimens other than respiratory secretions.
(CHEST 1998; 113:1190-94)
Quantiferon Test
•
•
Interferon Gamma Release Assays
take advantage of this natural
process in infected
immunocompetent individuals.
When antigens specific for a given
infecting agent (often in the form of
purified protein derivatives) are
applied to whole-blood samples
from infected individuals, T cells
sensitized to the antigens will be
present in the blood, and will bind
to the antigen. The T cells will then
release Interferon-Gamma; the
presence of sensitized T-cells in
infected individuals will result in far
higher levels of IFN-G release than
among uninfected individuals.
The presence of IFN-G can then be
quantified using a single step
enzyme-linked immunosorbent
assay (ELISA) using anti-IFN-G
antibodies.
Quantiferon Test
(NY City DOH offers QFTB-Gold)
•
Studies assessing QFT-G suggest a specificity of 98.1% and a
sensitivity of 89.0% was reported in 118 patients with cultureconfirmed TB.
•
QFT-G was compared with TST by using two tuberculin units of RT-23.
In a group of 99 healthy, BCG-vaccinated medical students in Korea,
the specificity of QFT-G was 96%, compared with 49% for the TST.
•
Among 54 patients with pulmonary TB disease, the sensitivity of the
QFT-G was 81%, compared with 78% for the TST.
•
QFT-G and the TST were compared in an unselected population of 318
hospitalized patients . QFT-G had greater sensitivity for TB disease
(67%) than did TST (33%), but indeterminate QFT-G responses were
common (21%) among patients with negative TST results, the majority
of whom were thought to be immunocompromised or
immunosuppressed.
Use of Quantiferon Test
• FDA approved QFT-G as an in vitro diagnostic aid using
peptide mixtures simulating ESAT-6 and CFP-10 proteins to
stimulate cells in heparinized whole blood.
• Detection of IFN-g by ELISA is used to identify in vitro
responses to ESAT-6 and CFP-10 that are associated with M.
tuberculosis infection
• QFT-G can be used in all circumstances in which the TST is
used, including contact investigations, evaluation of recent
immigrants who have had BCG vaccination, and TB screening
of health-care workers and others undergoing serial evaluation
for M. tuberculosis infection. QFT-G usually can be used in
place of (and not in addition to) the TST.
• A positive QFT-G result should prompt the same public health
and medical interventions as a positive TST result. No reason
exists to follow a positive QFT-G result with a TST. Persons
who have a positive QFT-G result, regardless of symptoms or
signs, should be evaluated for TB disease before LTBI is
diagnosed. At a minimum, a chest radiograph should be
examined for abnormalities consistent with TB disease.
Tuberculosis
• Approaches to treatment & prevention
– Historical
– Current
– Future [prevention]
Edward L. Trudeau, MD
Trudeau Sanatorium–Saranac NY
Why sanatoria might have been beneficial…
Ustianowski A et al. Prevalence and associations of vitamin D
deficiency in foreign-born persons with tuberculosis in London.
J Infect. 2005 Jun;50(5):432-7
•
•
•
•
•
•
Incidence of tuberculosis is high amongst foreign-born persons resident in
developed countries.
Vitamin D is important in the host defense against TB in vitro and deficiency
may be an acquired risk factor for this disease.
Study to determine the incidence and associations of vitamin D deficiency in
TB patients diagnosed in London, UK.
METHODS: Case-note analysis of 210 unselected patients diagnosed with TB
who had plasma vitamin D (25(OH)D3) levels routinely measured. Prevalence of
25(OH)D3 deficiency and its relationship to ethnic origin, religion, site of TB,
sex, age, duration in the UK, month of 25(OH)D3 estimation and TB diagnosis
were determined.
RESULTS: Of 210 patients 76% were 25(OH)D3 deficient and 56% had
undetectable levels. 70/82 Indian, 24/28 East African Asian, 29/34 Somali, 14/19
Pakistani and Afghani, 16/22 Sri Lankan and 2/6 other African patients were
deficient (with 58, 17, 23, 9, 6 and 1 having undetectable levels, respectively).
Only 0/6 white Europeans and 1/8 Chinese/South East Asians had low plasma
25(OH)D3 levels. Muslims, Hindus and Sikhs all had equivalent rates of
deficiency though Hindus were more likely to have undetectable levels (odds
ratio 1.87, 95% CI 1.27-2.76).
CONCLUSIONS: 25(OH)D3 deficiency commonly associates with TB among all
ethnic groups apart from white Europeans, and Chinese/South East Asians.
Our data support a lack of sunlight exposure and potentially a vegetarian diet
as contributors to this deficiency.
TB Treatment
• Latent TB Infection (LTBI)
• Active, drug sensitive disease
• Drug Resistant Disease
TB Rx Regimens
www.uspharmacist.com/content/c14112
TB TREATMENT
•
Start a Four drug regimen:
INH, RIF, EMB, PZA begin for suspected/confirmed case [unless MDRTB suspected or re-treatment case]
•
•
Notify public health authorities within 24 hours
Initiate contact screening
•
Armamentarium - First line agents:
Isoniazid, rifampin, ethambutol, pyrazinamide (in the past:
streptomycin)
Traditional second line drugs: ethionamide, cycloserine, paraaminosalicylic acid, viomycin, kanamycin, capreomycin
Newer agents in use: quinolones, substituted macrolides, rifabutin,
rifapentine, amoxicillin-clavulanate, clofazimine
Need for expanded therapeutic arsenal because of prevalence of
resistant
•
•
•
Fixed Dose Combination Tablets
• IUATLD & WHO recommendation to
ensure proper treatment
• Requires high quality FDCs which have
high rifampin bioavailability
• Problems have been attributed to poor
drug quality rather than low absorption
Blomberg B et al. Bull World Health Organ 2001:79(1):61-68
Fixed combination drugs
• Strategy: increase compliance and
reduce risk of resistance
• Rifater®
= INH + RIF + PZA
• Rifamate® = INH + RIF
• Patients cannot take single drugs
Issues in Therapy
Drug Resistance
XDR TB – Treatment Issues
Probability of Resistance
to anti-TB Drugs
• High probability [10-3]: Ethionamide,
cycloserine, viomycin, capreomycin,
thiacetazone
• Intermediate probability [10-6]:
Isoniazid, streptomycin, kanamycin
ethambutol, p-aminosalicylic acid
• Low probability [10-8]: Rifampin
Mechanisms of Resistance
•
•
•
•
•
•
Isoniazid
Rifampin
Ethambutol
Pyrazinamide
Streptomycin
Fluoroquinolones
•
•
•
•
•
•
katG inhA mutations
rpoB
EmbCAB sequence 
Amidase [pncA]
rpsL rrs
Single amino acid
substitutions
Principles of MDR-TB Rx.
• A regimen with at least two
[preferably 3] drugs to which the isolate
is sensitive
• Supervised treatment until cure
• Compliance with treatment is often
difficult to achieve, due to the presence
of multiple co-morbidities, psychiatric
disorders, substance abuse, and social
disorganization in some patients…
Surgical Management of MDR-TB
Indications:
1-Medical rx. failed  failure highly likely
2-predominantly localized disease
3-adequate cardiopulmonary status
4-rx. regimen contains  2 effective drugs
27 MDR-TB patients [42 mos. mean followup]: 1 peri-op death; 11% complications;
92% sputum conversion +/or (-) post-op
Chiang CY et al. Int J Tuberc Lung Dis 2001;5(3):272-77.
Emerg Infect Dis. 2007 Mar;13(3):380-7. Links
Worldwide emergence of
extensively drug-resistant tuberculosis.
Shah NS, Wright A, Bai GH, Barrera L, Boulahbal F, Martín-Casabona N,
Drobniewski F, Gilpin C, Havelková M, Lepe R, Lumb R, Metchock B, Portaels
F, Rodrigues MF, Rüsch-Gerdes S, Van Deun A, Vincent V, Laserson K, Wells
C, Cegielski JP.Centers for Disease Control and Prevention, Atlanta, Georgia,
USA. [email protected]
Mycobacterium tuberculosis strains that are resistant to an increasing
number of second-line drugs used to treat multidrug-resistant tuberculosis
(MDR TB) are becoming a threat to public health worldwide. We surveyed the
Network of Supranational Reference Laboratories for M. tuberculosis isolates
that were resistant to second-line anti-TB drugs during 2000-2004. We defined
extensively drug-resistant TB (XDR TB) as MDR TB with further resistance to
> or = 3 of the 6 classes of second-line drugs. Of 23 eligible laboratories, 14
(61%) contributed data on 17,690 isolates, which reflected drug susceptibility
results from 48 countries. Of 3,520 (19.9%) MDR TB isolates, 347 (9.9%) met
criteria for XDR TB. Further investigation of population-based trends and
expanded efforts to prevent drug resistance and effectively treat patients with
MDR TB are crucial for protection of public health and control of TB
XDR TB Cases – WHO – June 2008
The TB Alliance
The TB Alliance is a not-for-profit, product
development partnership accelerating the discovery
and development of new TB drugs that will shorten
treatment, be effective against susceptible and
resistant strains, be compatible with antiretroviral
therapies for those HIV-TB patients currently on
such therapies, and improve treatment of latent
infection.
The TB Alliance is committed to ensuring that
approved new drug regimens are affordable, widely
adopted and available to those who need them.
• Support of the TB Alliance
TB Drugs in Development
Tuberculosis Vaccine
Past, Present & Future
• TB Vaccine Timeline
Candidate TB Vaccines
• Recombinant BCG vaccines – expressing immunodominant
antigens and/or cytokines.
• Live, attenuated strains of M. tuberculosis – including singly and
doubly auxotrophic mutants.
• Nonpathogenic mycobacteria – including M. vaccae (a soil
mycobacterium, which has been tested as an adjunctive
immunotherapeutic in adult pulmonary TB patients. M. microti (the
vole bacillus; tested in humans by the British MRC), M. smegmatis
(a rapidly-growing, non-pathogen) and M. habana (a slow-growing
photochromogen originally isolated from monkeys).
• Non-mycobacterial microbial vectors – including attenuated
Salmonella and Vaccinia virus, expressing immunodominant
mycobacterial antigens.
• Subunit vaccines – protein-, lipid, and carbohydrate-based, but
mostly protein/peptide antigens have been the focus to date.
• DNA vaccines - with various adjuvants; independently and in primeBCG boost paradigms.
TB Control – The Funding Gap
• Extensively drug-resistant TB (XDR-TB). The spread of XDR-TB
poses a serious threat to progress and could even reverse recent
gains.
• It will take an additional US$ 650 million globally to implement
control of both XDR-TB and multi-drug-resistant TB (MDR-TB) in
2007 alone, (Dr Mario Raviglione, Director of the WHO Stop TB
Department) "Beyond that, because of the threat of XDR-TB,
research to identify new diagnostics, drugs and vaccines is more
vital than ever."
• Overall funding gap. Although funds for TB control have risen
substantially since 2002, reaching US$ 2 billion, an additional US$
1.1 billion will be needed to meet the 2007 funding requirements set
by the Global Plan to Stop TB (2006-2015). A total of US$ 56 billion-half of which should be funded by endemic countries and the other
half by donors--is needed for the 10-year plan, but current funding
commitments indicate a gap of at least US$ 31 billion.
Summary
• Mankind’s most important infectious
disease
• Concerted efforts by WHO and
local/national health authorities provide
greatest hope of control
• New diagnostic modalities are available
• New drugs and promising vaccines “in
the pipeline”