Introduction to
Drug-Resistant TB
Session 2
1
Classification of drug-resistant TB
“Drug-resistant TB” is a general term to describe a strain of M.
tuberculosis that is resistant to one or more anti-TB drugs.
Terminology
Resistance to
Mono-resistance
One drug
Poly-resistance
At least two drugs (excluding both H and R)
Multidrug resistance (MDR)
At least H and R
Extensive drug resistance
(XDR)
H and R plus a second line injectable and a
quinolone
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What is drug resistance?
“When we say that a strain of tubercle bacilli is drug-resistant we
usually mean that a patient yielding such organisms would fail to
respond to treatment with the drug concerned in normal dosage,
i.e. a dosage that will cause a response in patients infected with
sensitive organisms.”
– Mitchison DA. “What is drug resistance?” Tubercle Suppl 1969; 50: 44-47.
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How is drug resistant TB created?
“…any sensitive strain of tubercle bacilli contains a few
organisms which are naturally resistant, sometimes to high drug
concentrations. They have arisen by a process of mutation and
are called mutants…When this population comes into contact with
the therapeutic concentrations of either streptomycin or isoniazid,
the sensitive bacilli are killed, whereas the few resistant mutants
can multiply and eventually constitute the whole strain…”
– Mitchison DA. “Problems of drug resistance,” British Medical Bulletin 1954;
10: 115-124.
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Selecting for drug resistance
S
R H
S
streptomycin
treatment
S S S
S
S
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S
“Fall and rise” phenomenon
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International Union Against
Tuberculosis.”The clinical significance
of bacterial resistance tests.” Bull Int
Un Tuberc 1957; 27: 214-79.
Average mutation rates in M. tuberculosis
Isoniazid
2.56*10-8 mutations per 1 bacterium/generation
Rifampicin
2.25*10-10 mutations per 1 bacterium/generation
Ethambutol
1.0*10-7 mutations per 1 bacterium/generation
Streptomycin
2.95*10-8 mutations per 1 bacterium/generation
Resistance to
isoniazid +
rifampicin:
2.56*10-8 X 2.25*10-10 = 5.76*10-18
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Development of resistance during treatment
with a single drug
Drug
Patients with resistant cultures
Streptomycin
28/40 (70%)
PAS
9/37 (24%)
Isoniazid
31/45 (69%)
Mitchison DA.” Problems of drug resistance”. British Medical Bulletin 1954; 10: 115-124.
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Development of resistance during treatment
with two drugs
Streptomycin
resistance
Treatment
Patients with resistant
cultures
Sensitive
H
33/93 (35%)
Resistant
H
1/4 (25%)
Sensitive
SH
3/109 (3%)
Resistant
SH
4/7 (57%)
Mitchison DA. “Problems of drug resistance”. British Medical Bulletin 1954; 10: 115-124.
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“Effective” monotherapy during treatment of
DR-TB with SCC
Pre-existing
resistance
Treatment regimen
Effective monotherapy
H monoresistance
Category I
(2HREZ/4HR)
R monotherapy in the
continuation phase
HR resistance
Category II
E monotherapy in the
2SHREZ/1HREZ/5HRE continuation phase
HREZ resistance
Category II
S monotherapy in the
2SHREZ/1HREZ/5HRE intensive phase
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Drug resistance can increase after failed
SCC
Quy HTW, Lan NTN, Borgdorff MW, et al. “Drug resistance among failure and relapse cases of tuberculosis: is the standard re-treatment
regimen adequate?” Int J Tuberc Lung Dis 2003; 7: 631-6.
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Amplifier effect of short-course
chemotherapy
2HREZ/4HR
(Category I)
2SHREZ/1HREZ/5HRE
(Category II)
2SHREZ/1HREZ/5HRE
(Category II)
Resistance Patterns
H
S
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H
R
S
H
R
E
Z
S
The impact of resistance amplification on the
DR TB epidemic
Drug
resistance
Nosocomial or
community
transmission
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Inadequate
treatment
Resistance
amplification
Category II is no longer acceptable
“With the availability of funding from international financial
partners, lack of resources for MDR-TB treatment is no longer an
acceptable rationale for providing the 8-month retreatment
regimen with first-line regimen drugs (formerly called the
‘Category II’) to patients with a high likelihood of MDR; this
regimen is ineffective in treating MDR-TB and may result in
amplification of drug resistance.”
– World Health Organization (WHO). Treatment of Tuberculosis:
Guidelines. Fourth Edition. Geneva: WHO, 2010.
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Principles of MDR-TB management
What improves outcomes:
• Early identification (and treatment) of MDR-TB;
• Use of an "effective" regimen (at least 4 susceptible second line
drugs plus Z);
• Adequate patient support:
– Directly Observed Treatment (DOT)
– Prompt treatment of side-effects
– Social economic support
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