Doing the Math:

The Dilemma of Drug Resistant

Tuberculosis
Frances Jamieson, MD, FRCPC
PHO Rounds, April 17th, 2012

Tuberculosis : A Global Problem

WHO Estimates (2010 data):

8.8 million New Infections
1.1 million Deaths
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TB by the numbers
One third of the worlds population is infected
with M. tuberculosis
5-10% will develop active disease
Almost 2 million persons die annually almost
5,000 every day
It is estimated that each case left untreated
can infect an average of 10 15 persons
annually before death
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Drug Resistant Tuberculosis: Definitions*

Multi-drug Resistant Tuberculosis: MDRTB
-resistant to isoniazid (INH) and rifampin (RMP)
Extensively-drug Resistant Tuberculosis: XDRTB
-resistant to INH, RMP (ie MDRTB) PLUS any of the
fluoroquinolones (e.g levofloxacin, moxifloxacin or
gatifloxacin) and at least one of the 3 injectable drugs
(capreomycin, kanamycin, amikacin)
*MMWR November 3rd,2006
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The global TB situation

Estimated number of
cases, 2010

All forms of TB

8.8 million
(8.59.2 million)

HIV-associated TB
Multidrugresistant TB

Estimated number of
deaths, 2010

1.1 million*
(0.91.2 million)

1.1 million

350,000

(1.01.2 million)

(320,000390,000)

~ 650,000
out of 12 million (11-14 million)
prevalent TB cases

* Excluding deaths attributed to HIV/TB

Source: WHO Global Tuberculosis Control Report 2011 (www.who.int/tb/publications/global_report/2011/gtbr11_full.pdf)
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Time trends in MDR-TB

Available data from 74 countries and territories with
measurements for at least two years could not
answer the question of whether the proportion of
previously untreated TB cases with MDR was
increasing, decreasing or stable over time at a global
or regional level.

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Global Tuberculosis Control: WHO report 2011

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Public Health Agency of Canada: Tuberculosis in Canada 2007

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Public Health Agency of Canada: Tuberculosis in Canada 2007

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No one is spared

John Keats

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George Orwell

Davies RPO et al, Int J Tuberc Lung Dis 1999;3(12):1051-54

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Tuberculosis incidence rate and counts Canada: 1980-2007

15

3,000

Cases

10

2,000

1,500

Rate

1,000

500

0
1980

1983

1986

1989

1992

1995

1998

2001

2004

2007

Public Health Agency of Canada

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Number of Cases

Rate per 100,000 population

2,500

Pathogenesis of Tuberculosis

Stuart GR et al, Nature Rev Microbiol 2003;1:97-100

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Chest X-Ray with Cavity in Tuberculosis

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14

Biology of M. tuberculosis

Very long generation time approx. 18 20 hours

Can remain dormant in cells (inactive, low metabolic activity)
Cavitary lesions form with large numbers of organisms
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M. tuberculosis isnt like other bacteria

M. tuberculosis (Mtb) infection usually acquired early
in life; organisms enter latency (metabolically
inactive)
Mtb organisms do not interact and exchange genetic
information (unlike other bacteria, e.g. S. aureus
colonizing the nasopharynx)
Resistance can only occur through chromosomal
mutation

Mutation rate for individual genes varies between

and within genes
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Doing the Math: The Development of

Drug Resistance in M. tuberculosis
Risk of drug resistant mutants emerging in a patient depends on
the product of the risks of mutation for each agent and the
size of the bacterial population within compartments (e.g.
lung cavities):
P = 1 - (1 r)n
where P = probability of drug resistance emerging; r is the mutation rate,

and n is the number of bacilli in a lesion (usually estimated at 108)

Gillespie SH, Antimicrob Agents and Chemotherapy, 2002
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Doing a lot more math

Emergence of mono-resistance before treatment:

Emergence of multi-drug resistance before treatment:

Emergence of multi-drug resistance during treatment:

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Colijn C et al, Plos ONE 2011;6(3):e1832718

Doing the Math risk of drug resistance

Single drug therapy with a risk of mutation of 10-6:
Probability = 100%

Two drug therapy with combined risks of mutation of 10-12:

Probability = 0.01%

Above two drug therapy with a bacterial population in a lesion of

1010:
Probability = 1.0%
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Spontaneous mutation rates for first-line TB drug therapy

Rifampin:

3.32 X 10-9

Isoniazid:

2.56 X 10-8

Ethambutol:

1.0 X 10-7

[Streptomycin:

2.29 X 10-8]

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Ghandi NR et al, Lancet 2010; May 19 ePub

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Acquired and Primary Drug Resistance:

Zhang Y et al, Int J Tuberc Lung Dis 2009;13(11):1320-30

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Treatment of Tuberculosis

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23

Ma Z et al, Lancet; May 19 2010 epub

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What is a First-line drug?

Canadian Tuberculosis Standards, 6th Edition, 2007

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Drug Susceptibility Testing of MTB - Determining

Resistance
All first isolates of MTB from patients are tested for
susceptibility to the first line panel of drugs :
Isoniazid ( INH)
Rifampin ( RIF)
Ethambutol (EMB)
Pyrazinamide) ( PZA)
Testing is by MGIT/BT 960 method

First-line drug therapy for fully-susceptible TB

National Institute of Allergy and Infectious Diseases

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Drug Resistant Tuberculosis: Definitions*

Multi-drug Resistant Tuberculosis: MDRTB
-resistant to isoniazid (INH) and rifampin (RMP)
Extensively-drug Resistant Tuberculosis: XDRTB
-resistant to INH, RMP (ie MDRTB) PLUS any of the
fluoroquinolones (e.g levofloxacin, moxifloxacin or
gatifloxacin) and at least one of the 3 injectable drugs
(capreomycin, kanamycin, amikacin)
*MMWR November 3rd,2006
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MDRTB requires treatment with second-line drugs

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29

Drug Susceptibility Testing of MtbC:

Second-line*
Drug Name

Critical Concentration mg/ml

Amikacin

1.0

Capreomycin

2.5

Ethionamide

5.0

Kanamycin

2.5

Linezolid

1.0

Moxifloxacin

0.25

Ofloxacin (for Ciprofloxacin)

2.0

PAS

4.0

Rifabutin

0.5

Streptomycin

1.0

*Using MGIT/960 as of October 1st, 2010

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MDRTB and possible effective treatments

National Institute of Allergy and Infectious Diseases

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Proportion of MDR among new TB cases

Latest available data, 1994-2010

0-<3
3-<6
6-<12
12-<18
>18
No data available
Subnational data only
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.
WHO 2011. All rights reserved

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Proportion of MDR among previously treated TB cases

Latest available data, 1994-2010

0-<6
6-<12
12-<30
30-<50
>50
No data available
Subnational data only
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.
WHO 2011. All rights reserved

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OntarioOntario

Public Health Agency of Canada: Tuberculosis: Drug Resistance in Canada - 2010

Public Health Agency of Canada: Tuberculosis: Drug Resistance in Canada - 2010
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XDR-TB

Public Health Agency of Canada: Tuberculosis: Drug Resistance in Canada - 2010

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Countries Reporting at Least One Case of

XDRTB by October 2011

Argentina
Burkina Faso
Armenia
Bhutan
Australia
Cambodia
Austria
Canada
Azerbaijan Chile
Bangladesh China
Belarus
Colombia
Belgium
Czech Republic
Benin
Dominican Republic
Botswanawww.oahpp.ca
Ecuador
Brazil
Egypt

Estonia
Japan
France
Kazakhstan
Georgia
Kenya
Germany
Kyrgyzstan
Greece
Latvia
India
Lesotho
Indonesia
Lithuania
Iran (Islamic Rep. of) Mexico
Ireland
Mongolia
Israel
Mozambique
Italy
Myanmar

Namibia
Nepal
Netherlands
Niger
Norway
Pakistan
Peru
Philippines
Poland
Portugal
Qatar

Republic of Korea
Republic of Moldova
Romania
Russian Federation
Slovenia
South Africa
Spain
Swaziland
Sweden
Tajikistan
Thailand

The Former Yugoslav Republic of Macedonia

Togo
Tunisia
Turkey
Ukraine
United Arab Emirates
United Kingdom
United Republic of Tanzania
United States of America
Uzbekistan
Viet Nam

WHO 2011

Is there Totally Drug Resistant TB (TDR)?

After reports from Iran in 2009 of Extremely Drug Resistant
(XXDR-TB), and more recently from India of Totally Drug
Resistant (TDR-TB), WHO convened an expert panel on March
21-22nd, 2012:
Cannot validate new definitions of TDR or XXDR due to
technical challenges with drug susceptibility testing of many
second-line anti-TB drugs
DST for drugs used to define MDRTB and XDRTB are accurate
and reproducible

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37

XDRTB and diminishing options for therapy

National Institute of Allergy and Infectious Diseases

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www.oahpp.ca

New drug therapies on the horizon

National Institute of Allergy and Infectious Diseases

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Tuberculosis and Drug Resistance:

A Global Problem

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Thank-you!

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