MECHANISM OF

DRUG
RESISTANCE (M.tb)

MECHANISM OF DR-TB
Learning Objectives:
• At the end of the session participants should be
able to:
• Understand the definition of Drug resistant TB.
• Understand the pattern of drug resistance.
• Understand type of drug resistance
• Understand the mechanism of drug resistant
and meaning of cross resistance
• Understand the amplification of drug resistance.
• Understand the factors that promote drug
resistance.
 MDR TB
Patient

“Ihave been treated several

times over the past five
years & I’m still coughing &
can’t gain weight!”
 What is Drug resistance?

• Drug resistance: The ability of bacteria &

other microorganisms to withstand a drug
to which they were sensitive to (slowed in
growth or killed outright).

• Drug-resistant TB occurs when drug-

resistant bacilli outgrow drug-susceptible
bacilli.
-r
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 Mono resistance
• Strains that are resistant to only one of
the five first line drugs

1. Rifampicn
2. Isonazid
3. Streptomycin Resistant to any
4. Ethambutol one of them
5. Pyraziamide
 Poly resistance
• Strains that are resistant to two or more
drugs, but not to both Isonazid &
Rifampicin

1. Rifampicin
2. Isonazid
3. Streptomycin Resistant to 2 or more
4. Ethambutol
5. Pyraziamide
 Multidrug Resistant TB
(MDR)
• Is a patient with laboratory-confirmed in
vitro resistance to at least isoniazid (H) &
Rifampicin (R).

1. Rifampicin Resistant must include

2. Isonazid these 2 drugs &/or >
3. Streptomycin
4. Ethambutol
5. Pyraziamide
 Extensive Drug Resistant TB
(XDR)
(Extreme Drug Resistance)
• Resistance to at least isoniazid & rifampicin
(i.e., MDR TB)
PLUS

• Resistance to any fluoroquinolone

(i,e.,Ofloxacin, Levofloxacin , Moxifloxacin)
AND

• At least one injectable second-line drug

(i.e.,amikacin, kanamycin, or capreomycin).
 What is the significance of
DR?
• INH resistance is of minor importance.

• RIF resistance is of vital importance.

(Key sterilizing drug)
• INH & RIF resistance (MDR) changes
everything.
 Types of Drug Resistance

1. Drug resistance among new cases

(formerly primary drug resistance)

2. Drug resistance among previously treated

cases (formerly acquired drug resistance)
 Drug resistance
among new cases
• Resistant strain to single or several drugs
in a patient who has never received anti
TB drugs or has received anti TB drugs for
less the one month.
Source:
• As a result of infection with a resistant
strain from another patient.

Resistant
M.tuberculosis
 Drug resistance among previously
treated cases
• The strain of tubercle bacilli shifts from a
susceptible to resistant phenotype during or
following a course of chemotherapy
for>1month
Source:
• Non adherence
• mono-therapy,
• No DOT
• poor absorption of drug,
• undiagnosed primary resistance to one of the drugs
prescribed (amplification phenomenon)
How Dose Drug Resistance
Develop?:
 Pathogenesis of Drug Resistance TB

• The drug-resistant organisms are produced

by random mutations in the bacterial
chromosome which occur spontaneously in
wild-type strains, even before the strains
come in contact with an anti TB drug.
• Mutations can produce bacilli resistant to
any of the anti TB drugs, although they
occur more frequently for some drugs than
others.
 Development & spread of DR TB
Wild strain M.tb
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Selection of strains with genetic drug resistance

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Acquired drug resistance, to one drug, then MDR

Spreading of infection due to delay in
diagnosing, overcrowding, inadequate
infection control

Primary drug resistance to one drug or MDR TB

Pa thoge nesis of Drug Re sis tance – 1

I NH
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PATHOGENESS OF DRUG RESISTANCE 1

PZA

Pathogenesis of Drug Resistance

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 Pathogene sis of Drug Res is tance – 1

INH INH
2 2
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PATHOGENESS OF DRUG RESISTANCE

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PATHOGENESS OF DRUG RESISTANCE

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H H
H H
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H H R
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Probabilities of spontaneous mutations of micro
organisms in relation to anti-TB drugs resistance

• Rifampicin (R) 1 in 100.000.000 (108)

• Isoniazide (H) 1 in 1.000.000 (106)
• Ethambutol (E) 1 in 1.000.000 (106)
• Streptomycin (S) 1 in 100.000 (105)

• Probability of spontaneous resistance of a micro

organism to two antibiotics equals the product of their
probabilities (e.g. for H together with R is 1 to 1014)
Molecular Mechanism of
Drug Resistance
 Action

Inhibit Mycolic Acid Synthesis

 Action

Bind to DNA - dependent RNA polymerase of

mycobacteria, thus Inhibit protein synthesis by
prevention of messenger RNA formation

Mutation locus Molecular target Result

RNA polymerase-
Bacteria continue to
rpoB
subunit B synthesize protein.
Loss of drug effect
 PYRAZINAMIDE
Exerts a lethal effect via inhibition
of various intracellular target & mainly
the pathway of mycolic acid synthesis

Molecular Target
Mutation Locus Result

In activation &
Mycobacterial
pcrA drug resistance
amidase
 ETHAMBUTOL

Inhibit protein bacteria cell wall

polysacharide &inhibit cell wall building
blocks arabinolacton &lipoarabinomannan

Molecular Target
Mutation Locus Result

Over expression of the

embAB Arabinosyl transferase enzyme & blunt affect
of EMB
 Action

Bind to bacterial ribosome

blocking protein synthesis

Mutation locus Molecular target Result

rpsl 1. Ribosomal protein Alteration in ribosomal

rrs subunit 12 binding site interfere
2. 16s ribosomal RNA with drug Transport
&production of
inactivation enzyme
 Using single drug
willingly or unwillingly

• Sensitive bacilli are eliminated

• Resistant bacilli multiply without
obstacles

• Resistant bacilli become dominant

 Amplification of
resistance
• As noted, patients with drug-resistant TB
who are treated with DOTS are at high risk
of remaining sick & infectious, even if they
are completely adherent with therapy.

• Proper Short course chemotherapy (SCC)

can worsen resistance in patients already
resistant to first line drugs e.g. a patient
resistant to HES if he receives standard
SCC, he might develop resistance to R.
This phenomenon is called “the amplifier
effect of short-course chemotherapy”.
 Emergence of Resistance
Inappropriate Therapy

Date 8/07 11/07 2/08

Treatment
H I
R I
E
Smear + + +
Culture + + +
Susceptibility

H R R R
R S R R
S S R
E
 Emergence of Resistance
Nonadherence

Date 6/07 9/07 12/07 3/08 6/08

Treatment
H I
R I ? I
E I
DOT
Smear + + – +
+
Culture + + + + +
Susceptibility

H S R S RR
R S S R RR
E S S R RR
 ALL OR NONE
• If the patient starts an effective TB
regimen & then stops taking all the TB
drugs at the same time, the population of
bacteria usually remains susceptible.
This is the major advantage of DOT:
1. either the patients take all the drugs or
none of the drugs.
2. This is also the benefit of fixed dose
combination
3. The patient either takes all drugs or none
reducing risk of development of resistance.
 Cross
Resistance?
• Resistance to other medications from the
same class of drugs.
• Cross-resistance arises because the
mechanism of resistance to several drugs
is the same & arises through the identical
genetic mutations
 Drug Cross resistance Comments
Isoniazid Ethionamide Cross-resistance to ethionamide may
occur whent here is low-level resistance
to isoniazid.

Rifampicin Rifamycins Cross-resistance among the Ramycin

class of drugs is typical. In a few strains
that are resistant To Rampin, Rabutin
may retain susceptibility in vitro

Kanamycin Amikacin High likelihood of cross-resistance since

it is associated with the same mutation.

Fluoroqu. Other There is a complete cross resistance

fluoroquinolones among fluoroquinolones invitro.

No cross resistance for Ethambutol, Pyraziamide,Streptomycin Cycloserine , PAS or

Capreomycin
 Factors contributing
to the development
of drug resistance
• No proper DOT.
• Inadequate dosage.
• Inadequate treatment regimens.
• Poor quality drugs.
• Sale of medications over the counter.
• Poor infection control practices.
• Poor patient treatment adherence counseling
• Malabsorption
• High bacillary load
Thank
s for
your
attenti
on