Professional Documents
Culture Documents
Part 1
Principles of resistance
to antituberculosis drugs
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Learning objectives
At the end of this module you will understand:
the objectives of and rationale for combined
antituberculosis therapy;
the basic definitions of drug resistance in TB;
how drug resistance develops;
the rationale for using a critical concentration of drug
in laboratory assays;
the rationale for determining what proportion of
resistant bacteria is clinically significant .
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Content outline
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Drug-resistant TB exists worldwide,
wherever treatment is available
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Introduction of
more effective anti-TB drugs
• Isoniazid (INH), a more potent drug, introduced in
1952:
– combination therapy with SM + PAS + INH (1950s) proved
highly effective in preventing emergence of resistance
– 18 months of treatment required to ensure adequate cure.
• Pyrazinamide (PZA), ethambutol (EMB) and
rifampicin (RMP)
– PZA (1952), EMB (1962) and RMP (1963) effectively
combined with INH for combination therapy.
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Current four-drug TB therapy
• Requirements for effective cure:
– treatment with multiple antibiotics (first-line, most effective
drugs);
– long therapy (6 months).
• Initial two months with RMP, INH and PZA plus either
EMB or SM
• Another four months with RMP and INH
• This regimen:
– combines antibacterial activity;
– inhibits development of resistance;
– eliminates persisting organisms.
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Objectives of anti-TB therapy
1. Quickly kill large numbers of rapidly growing bacilli in
the infected tissue:
– to cure the patient and increase chances of survival;
– to reduce the infectiousness of the patient.
2. Prevent the emergence of drug-resistant mutants.
3. Sterilization (elimination) of the dormant but still
viable bacilli in infected tissue:
– to avoid therapeutic failure and relapse;
– to reduce the chance of transmission.
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Compartmentalization of
M. tuberculosis in infected tissue
• Population A
– large number of rapidly dividing bacilli in pulmonary
cavities.
• Population B
– bacilli multiplying less rapidly because of local
adverse conditions (most often acidic).
• Population C
– dormant but still viable bacilli (often sequestered in
granulomas).
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Anti-TB drugs act on different populations:
bactericidal activity
• Drugs that kill Pop. A
are considered to have
rapid bactericidal
activity.
• Bactericidal activity is
measured by rapidity of
sputum and culture
conversion (from + to –)
• These drugs are most
effective in preventing
the emergence of drug-
resistant cells that arise
Adapted from: Iseman M. A clinician‘s guide to in the large populations.
tuberculosis. Philadelphia, Lippincott, Williams &
Wilkins, 2000. 10
Sterilizing effect
• Drugs that are more
effective against
Populations B and C are
regarded as sterilizing
agents.
• The potency of sterilizing
activity is reflected in a
high cure rate with limited
relapses in patients
completing therapy.
catalase (katG);
– primary bactericidal drug;
Mycolic
Acids
– blocks synthesis of cell wall,
acts on other targets in cell.
INH
• RMP:
Arabino-
galactan – most effective anti-TB drug
with both bactericidal and
sterilizing activities;
– inhibits bacterial RNA
transcription by binding to RNA
PZA
polymerase.
Short chain fatty acid precursors
Cytoplasm
• PZA:
RNA
Polymerase (ß-subunit)
– excellent sterilizing effect on
Chromosomal DNA
Pop. B (in acidic environment);
RNA Transcription – pro-drug, must be activated by
RMP pyrazinamidase;
– proposed target interferes with
fatty acid synthesis. 12
Adapted from: Somoskovi et al. Respir Res 2001, 2: 164-168.
Natural drug resistance
in the MTB complex
• MTB complex members
– most common – M. tuberculosis, M. bovis;
– vaccine strain – M. bovis BCG;
– rarely seen – M. africanum, M. canettii, M. microti, M.
bovis ssp. caprae.
• Natural resistance to antibiotics
– hydrophobic cell envelope (permeability barrier);
– drug efflux systems and drug-modifying enzymes;
– PZA resistance in M. canettii, M. bovis and BCG
(other members are usually susceptible to PZA).
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Common types of resistance
to first-line drugs
• Drug resistance in newly identified patients
– previously defined as primary drug resistance.
• Multidrug-resistant TB (MDR-TB)
– strains of TB resistant at least to INH and RMP;
– results in treatment failure and fatal outcomes more
often than with resistance to other drugs.
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Proportion method for determining
drug resistance in M. tuberculosis
• Laboratory assays compare the growth of a
1:100 dilution of the TB isolate on media without
drug with growth of the undiluted suspension on
media containing each drug.
• If the undiluted suspension grows faster or more
abundantly in the presence of the drug than
does the 1:100 dilution without the drug, the
isolate is considered to contain a resistant
population greater than 1%, and is reported as
resistant. 21
True and false exercise
1. TB treatment induces M. tuberculosis
resistance.
2. Monotherapy is recommended to treat TB.
3. The critical concentration is the amount of drug
in the medium that inhibits the growth of
susceptible organisms but not that of the
resistant mutants.
4. Primary drug resistance is defined as the
presence of drug-resistant organisms in a
previously untreated person.
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Module review: take-home messages I
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