Multidrug-resistant Mycobacterium
tuberculosis: The Next Threat to
Humanity
Natalia Grob
April 28, 2005
http://www.i-volume.com/stoptb/details.asp?id=660
Outline
 M. tuberculosis



History
Pathogenicity
Infection
 MDR-TB




1st and 2nd line drugs
Public Health
Treatment
Future
Worldwide Concern
 20 million people will
die in the next decade
 Most common cause
of death due to single
infectious agent
 Disease of poverty
http://stoptb.lpipserver.com/library_new.asp
History
 Eradication: 2010
 Re-emergence & resurgence





Immigration
HIV epidemic
Deteriorating health infrastructure
Inadequate institutional control
MDR-TB
Basic Biology
 Gram positive
 Slow growing
 No basic virulence
factors (exotoxins,
capsules, etc.)
 Facultative
intracellular parasite
of macrophages
http://www-medlib.med.utah.edu/WebPath/INFEHTML/INFEC033.html
Genome




H37Rv
4,411,529 base pairs
4,000 genes
Aerobic and
anaerobic enzymes
Cole et al. (1998)
Pathogenicity
 Slow generation time
 High lipid concentration in cell wall
 Impermeability and resistance to
antimicrobials
 Resistance to killing by acidic/alkaline
compounds
 Resistance to osmotic lysis via complement
deposition and attack by lysozyme
 Phagosome maturation arrest
Blocking Phagolysosome Fusion
 No phagolysosome formation
persistence of tubercule bacillus
 Key players:




Ca2+
LAM
EEA1
Syntaxin 6
Calcium Cascade
Ca2+
CaMKII
LAM
*LAM
EEA1
hVPS34
Phagosome maturation
Maturation cascade
EEA1 & Syntaxin 6
Lysosome hydrolases
Acidification
Maturation
ATPase
Acidification
Maturation
Transmission
 One droplet = 3 bacilli
 Talking five minutes =
3000 droplets = 9000
bacilli!
http://catalog.cmsp.com/datav3/it060009.htm
Infection
 T-lymphocytes more macrophages
 Spherical granulomas  tubercles
http://www-medlib.med.utah.edu/WebPath/TUTORIAL/MTB/MTB008.html
Necrosis: Soft White Cheese
http://www-medlib.med.utah.edu/WebPath/TUTORIAL/MTB/MTB002.html
Outline
 M. tuberculosis



History
Pathogenicity
Infection
 MDR-TB




1st and 2nd line drugs
Public Health
Treatment
Future
Drug Resistance
 Types:
 Acquired resistance
 Transmitted resistance/Primary resistance
 Amplified resistance
 MDR-TB: isoniazid + rifampicin
 Statistics
 Diagnosis: mycobacterial culture and in vitro
sensitivity testing.
First-line Drugs
Sharma & Mohan (2004)
First-line Drugs: Rifampin
MDR-TB marker
Affects transcription of RNA
Cheruvu et al. (2001)
 rpoB gene
 RRDR
 New mutations continually arise
First-line Drugs: Mutations
Cheruvu et al. (2001)
Second-line Drugs
 Increased treatment
difficulties




Expensive,unavailable
More side effects
Difficult Ab penetration
Longer treatment
 Controversy
 Standard treatments
 Everything it takes
http://www.tbcta.org/Pages/home.php
Second-line Drugs: SQ109
 EMB analog;
enhanced efficacy
 Penetrates
macrophage
phagosome
 High concentration in
target organs
Jia et al. (2004)
Second First-Line Drugs: Hope?
 40 years!
 Standard regime
 Promise of R207910
Andries et al. (2005)
DOTS
 WHO guidelines
 Political commitment
 Detection of TB
 Standardized shortcourse chemotherapy
(SCC)
 Uninterrupted supply
drugs
 Recording and
reporting system
http://www.tbcta.org/Pages/home.php
Emergence of MDR-TB
 Errors in treatment
 monotherapy
 Errors in diagnosis
 Pre-existing MDR
 Noncompliance
 Drug addiction, mental illness
 Low socioeconomic status, age, race,
education level
History
 Little action from
WHO
 NYC outbreak
global attention
 Dr. Paul Farmer
 “Mountains Beyond
Mountains”
http://www.brighamandwomens.org/socialmedicine/farmerbio.asp
The Irony
 Model of MDR-TB emergence
 Poor control of TB leads to MDR-TB
 Less infectious than wild-type
 Successful TB program hot zones
Treatment: Where?
Pablos-Mendez et al. (2002)
Treatment: How?
 First-line drugs whenever possible
 Injectable agent
 Second-line drugs
Treatment: Who?
 Children = important
special cases
 Difficulty in obtaining
sample
 Cost constraints
 Importance of medical
history
 Importance of early
diagnosis
http://stoptb.lpipserver.com/library_new.asp
What Now?
 Control is priority
 Locally severe problem
 Three-part response:
 SCC implementation
 Surveillance and testing
 Second-line drugs?
What Now?
 DOTS and DOTS-Plus
 Promotion of adherence
 Monitor adverse effects
 Enablers and enhancers
Concluding Remarks
 Big issue, many
opinions, many (often
opposing) theories
 New drugs needed
 Medicine and public
health
 Read “Mountains
Beyond Mountains”
Thanks a bunch!
 Peer reviewers Amy
Malhowski and Caitlin
Reed
 Professor Christine
White-Ziegler
 Emerging Infectious
Diseases Class
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