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

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

Delayed diagnosis and isolation

Inappropriate drug regimen.

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 mono-resistance
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