Transcript Multi-drug Resistant Tuberculosis

Multi-drug Resistant
Tuberculosis
Hail M. Al-Abdely
Consultant, Infectious
Diseases, KFSH&RC
Presentation Outline
 Definition
of MDR TB
 Epidemiology of MDR TB
 Genesis of MDR
 Mechanism of resistance
 Treatment
 Chemoprophylaxis for MDR TB
exposure
Definition of MDR TB
 1950s-1970s:
– M. tb resistant to INH, streptomycin
and/or PAS
 1980s-current:
– M. tb resistant to at least INH and
Rifampin
Why INH and Rifampin
Most potent and bacteriocidal
 Tb can be treated effectively with INH+Rif
alone
 Mono-resistance to one of them can be
treated effectively with a regimen
containing the other agent with very low
failure rate (2.5-5%)
 Failure rate when INH+Rif resistant is
44% in non-HIV and 70% in HIV patients
 Duration required for cure doubles to
triples.

Tuberculosis notification rates, 2000
Rate per 100 000
0-9
10 - 24
25 - 49
50 - 99
100 or more
No report
The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World
Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or
boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement.
Global Tuberculosis Control. WHO Report 2002. WHO/CDS/TB/2002.295
Estimated TB incidence rates, 2000
Rate per 100 000
0-9
10 - 24
25 - 49
50 - 99
100 - 300
300 or more
No estimate
The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World
Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or
boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement.
Global Tuberculosis Control. WHO Report 2002. WHO/CDS/TB/2002.295
Epidemiology of MDR TB
Geographic region
No. of MDR TB cases (% of all new cases)
All countries (n = 136)
272,906 (3.2)
Established market economies
882 (0.7)
Latin America
8508 (2.2)
Eastern Europe
17,269 (5.5)
Africa, low HIV
15,014 (1.9)
Africa, high HIV
25,199 (1.8)
Eastern Mediterranean
45,964 (7.9)
Southeast Asia
75,062 (2.5)
Western Pacific
85,008 (4.5)
Dye et al. Global Burden of Multidrug-Resistant TB. JID 185(8), 2002
WHO Surveillance and Incidence of
MDR TB
Country
% MDR TB of all new cases
Estonia
14.1
Latvia
9.0
China (non-DOTS)
7.7
China (DOTS)
2.8
Russia
6.0
India
3.4
Iran
5.8
Dominican
6.6
Ivory Cost
5.3
Dye et al. Global Burden of Multidrug-Resistant TB. JID 185(8), 2002
WHO Estimates of MDR TB in Some Arabian Countries
Country
% MDR TB of all new cases
Morocco*
2.2
Oman*
0.8
Algeria
0.7
Egypt
5.6
Jordan
2.8
Kuwait
3.3
Lebanon
3.4
Saudi Arabia
3.0
Sudan
10.1
Syria
6.7
Yemen
12.4
* Surveyed
Dye et al. Global Burden of Multidrug-Resistant TB. JID 185(8), 2002
Genesis of MDR TB

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Resistance is a man-made amplification of a
natural phenomenon.
Inadequate drug delivery is main cause of
secondary drug resistance.
Secondary drug resistance is the main cause of
primary drug resistance due to transmission of
resistant strains.
MDR due to spontaneous mutations is not
possible as the genes encoding resistance for anti
TB are unlinked.
Development of anti-tuberculosis drug resistance
Wild M. TB strain
Spontaneous mutation
Strains with genetic
drug resistance
Selection: inadequate treatment
Acquired drug
resistance
Transmission
Primary drug
resistance
Pablos-Mendez et al. WHO, 1997
Clinical factors promoting resistance
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
Delayed diagnosis and isolation
Inappropriate drug regimen.
–
–
–
–
–
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Inadequate initial therapy
Incomplete course of treatment
Inappropriate treatment modifications
Adding single drug to a failing regimen
Inappropriate use of chemoprophylaxis
Poor adherence and incomplete F/U
Failure to isolate MDR TB patients
Failure to employ DOT
Over the counter anti TB
Faked drugs
Mechanism of Resistance
 TB
specific drugs
– INH, PZA, ETH
 Antibiotics
with activity against TB
– RIF
– Aminogycosides
– Flouroquinolones
Mechanism of resistance
 INH
– Chromosomally mediated
– Loss of catalase/peroxidase
– Mutation in mycolic acid synthesis
– Regulators of peroxide response
Mechanism of resistance
 Rifampin
– Reduced binding to RNA polymerase
 Clusters
of mutations at “Rifampin
Resistance Determining Region” (RRDR)
– Reduced Cell wall permeability
Treatment of MDR TB
 Factors
determining Success
– Culture of MDR TB
– Reliable susceptibility
– Reliable history of previous drug
regimens
– Program to assure delivery of prescribed
drugs (DOT)
– Correct choice of modified treatment
regimen
– Reliable follow up
Iseman M. NEJM, 329:784, 1993
New Chemotherapeutic Agents


Not many. Low interest from industry
Derivatives of Rifamycin
– Rifabutin: Sensitive subset of Rifampin resistant strains
– Rifapentine: Extended half-life but more monoresistance to rifamycins
– KRM-1648. benzoxazinorifamycin. In vitro and animal
models.

New flouroquinolones
– Gatifloxacin, Moxifloxacin, levofloxacin, sparfloxacin

Nitroimidazoles
– related to metronidazole. May work better against latent
bacilli

Avoiding pro-drug problems
Chemoprophylaxis
 Determinants
of intervention
– Likelihood of infection with MDR TB
 Low
 Intermediate
 High
– Likelihood of developing MDR TB
 Immune
suppression
Likelihood of infection with MDR TB
Low
Intermediate to high
High possibility
for disease
No
Yes
Confirmed R
to INH+RIF
Standard
recommendation
For non-MDR TB contacts
Consider Multidrug
prophylaxis