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Basic Principles and
Concepts of M. TB and
Resistance
Basic Principles and Concepts
of M. TB and Resistance
1. Biological Characteristics and
Condition of M. Tuberculosis Growth
2. Definitions and Basic Concepts in
Resistances
3. Likelihood Generating MDR under NTP
conditions
1. Biological Characteristics and
Condition of M. Tuberculosis
Growth
1. Biological Characteristics and Condition
of M. Tuberculosis Growth
1. Causal Agent
2. Reservoir. Source of infection
3. Mechanism of Transmission
4. Susceptible Host
1. Causal Agent
Causal Agent
- Mycobacterium tuberculosis complex
- M. tuberculosis
- M. bovis
- M. africanum
- M. microti
- M. caneti
- M. pinnipedii
- M. caprae
Difficult to Fight
Causal Agent
- Mycobacterium tuberculosis complex
- Resistant to:
Cold,
Freezing
and
Desiccation
Causal Agent
- Mycobacterium tuberculosis complex
.
- Very sensitive to Heat, Sunlight and U.V. radiation
Causal Agent
- Mycobacterium tuberculosis complex
- Strictly aerobic (depends on Oxygen and pH)
Causal Agent
- Mycobacterium tuberculosis complex
- Polyvalent
behaviour
depending
on medium.
Bacillary populations
■ In a tuberculosis patient, there are
different bacillary populations formed of
bacilli in different situations
- Location
- pH
- Replication rate, susceptibility to drugs, …
Bacillary populations
1. Rapidly multiplying bacilli
Failure
- Optimum medium: Extracellular. PH 6.5-7, maximum
oxygenation (cavern wall)
- Large number of bacilli → High probability of spontaneous
natural mutations
Many Millions
Natural Resistant Mutants
Bacillary populations
2. Slow multiplication Bacilli
Relapses
- Intramacrophagic location. Acid pH. Population<105
No Naturally Resistant Mutants
Bacillary populations
3. Intermittently growing bacilli
Relapses
- Unfavourable conditions. Solid caseum. Extracellular
- Relapse capacity
- Population <105
No Naturally Resistant Mutants
Bacillary populations
1. Rapidly multiplying bacilli
→ INH
- Optimum medium: Extracellular. PH 6.5-7, maximum oxygenation (cavern wall)
- Large number of bacilli → High probability of spontaneous mutations
2. Slowly multiplying bacilli
→ PZ
- Intramacrophagic location. Acid pH. Population<105
3. Intermittently growing bacilli
→ RIF
- Unfavourable conditions. Solid caseum. Extracellular
- Population <105. Relapse capacity
4. Bacilli in latent state: Not susceptible to drugs
- Reactivations and relapses
M tuberculosis. Very Slow Division Capacity
- M. tuberculosis delay 16-24 h. to be divided (60 < Estafiloc.)
- Slow and Little Alarmant
Clinical Presentation
- Excessive Delay to Consult the HC
- Very Late Diagnosis
Long time to be contagious when the Cases are Diagnosed
1. Biological Characteristics and Condition
of M. Tuberculosis Growth
1. Causal Agent
2. Reservoir. Source of infection
3. Mechanism of Transmission
4. Susceptible Host
Caminero JA. Tuberculosis Guide for Specialist Physicians. The Union 2004
2. Reservoir. Source of Infection
2. Reservoir. Source of Infection
- MAN:
* Infected, healthy
World Population:
M. TB Infection:
6.100 Millions
2.000 Millions
¡¡ Possible Reservoir MDR-TB: 50 Millions !!
2. Reservoir. Source of Infection
- MAN:
* Active
disease
TB Cases:
16 million
MDR-TB Cases: + 500.000
2. Reservoir. Source of Infection
- MAN:
* Infected, healthy
* Active disease
- Animals:
* Bovine cattle (M. bovis)
* Others: Monkeys, Dogs, Cats, etc
2. Reservoir. Source of Infection
- MAN:
* Infected, healthy
* Active disease
- Animals:
* Bovine cattle (M. bovis)
* Others: Monkeys, Dogs, Cats, etc
- Not Reservoir: Kitchen and cleaning utensils, etc
1. Biological Characteristics and Condition
of M. Tuberculosis Growth
1. Causal Agent
2. Reservoir. Source of infection
3. Mechanism of Transmission
4. Susceptible Host
Mechanism of Transmission
- Fundamentally AEROGEN
- Very Uncommon:
- Cutaneous-Mucosal
- Urogenital
- Inoculation
- Tran placental, etc
TB Transmission. Contagious aerosol (droplets < 5 micras)
The TB MDR/XDR-TB have the same capacity to generate Aerosols
Patients with TUBERCULOSIS
must cover their Mouth when Coughing
Surgical Masks only work if used
by the Patient
Greatest TB Transmitters
1.- Persons with bad Coughs
2.- Sputum Sm+ Patients
3.- Untreated patients
4.- Patients who have just commenced treatment
5.- Cases with poor response to treatment
1. Biological Characteristics and Condition
of M. Tuberculosis Growth
1. Causal Agent
2. Reservoir. Source of infection
3. Mechanism of Transmission
4. Susceptible Host
Epidemiological Sequence of TB
Host Susceptible to Disease
- Age Distribution
TB Risk Groups
Relative Risk of developing TB
(compared with control population, regardless of PPD)
-
HIV/AIDS
Silicosis
Diabetes
Chronic renal failure / Haemodial.
Gastrectomy
Jejunoileal by-pass
Kidney transplant
Heart
“
Head or neck carcinoma
150
30
2 – 4.1
10 – 25.3
2-5
27 - 63
37
20 - 74
16
ATS/CDC. Am J Respir Crit Care Med 2000; 161 (part 2)
Basic Principles and Concepts
of M. TB and Resistance
1. Biological Characteristics and
Condition of M. Tuberculosis Growth
2. Definitions and Basic Concepts in
Resistances
3. Likelihood Generating MDR under NTP
conditions
2. Definitions
and Basic
Concepts in
Resistances
M. tuberculosis Resistance
Basic Concepts and Definitions
•
•
•
•
•
•
•
•
Natural resistance
Resistance in previously treated patients
Resistance in previously untreated patients
Poly-resistance
Multidrug-resistance (MDR)
Extensive-resistance (XDR)
Failure
Relapse and Poor Adherence
Basic Concepts in TB
Resistance
All these concepts are related
to the growth and
multiplication
characteristics of
M. tuberculosis
Basic Concepts in TB
Resistances
NATURAL
Resistance
M. Tuberculosis Resistances
1.
The ORIGIN
M. Tuberculosis Resistance
Natural Resistance (1)
- When all live species, - for the purpose of perpetuating the species
reach a certain number of divisions, they undergo genomic
mutations at random, which gives rise to organisms with certain
altered functions.
- This always occurs in the
successive divisions of each
species. It is therefore a
dynamic function
15 million
12 hours
M. Tuberculosis Resistance
Natural Resistance (2)
• Therefore, when the live species attain a number above
10,000 or 1 million, many of the organisms that make up the
species present genetic mutations.
• Fortunately, the majority of these mutations do not have an
obvious phenotypic expression.
• Sometimes it is necessary to subject the species to
selective pressure for it to express the selected mutation
M. Tuberculosis Resistance
Natural Resistance (3)
• Ever since M. tuberculosis has attacked man, way back in
time, it has always presented multiple genomic mutations
in its continuous divisions.
• Some of these mutations affect the genes in which antituberculosis drugs work
• This means that these antibiotics cannot work against M.
tuberculosis, and therefore phenotypically they show
resistance to them.
M. tuberculosis Resistance
Natural Resistant Mutants according to Bacillary Population
•
•
•
•
•
•
•
INH
RIF
SM
EMB
PZ
Quinolones
Others
1 x 105-106 Bacilli
1 x 107-108 Bacilli
1 x 105-106 Bacilli
1 x 105-106 Bacilli
1 x 102-104 Bacilli ?
1 x 105-106 Bacilli ?
1 x 105-106 Bacilli ?
M. tuberculosis Resistance
Bacillary Population in different TB Lesions
•
•
•
•
•
•
•
TB Sm+
107-109 Bacilli
Cavitary
107-109 Bacilli
Infiltrated
104-107 Bacilli
Nodules
104-106 Bacilli
Adenopathies 104-106 Bacilli
Renal TB
107-109 Bacilli
Extrapul. TB 104-106 Bacilli
M. Tuberculosis Resistance
Selection of Resistant Mutants
• If Smear positive TB is treated with just ONE drug (H),
for each million bacilli, it will kill 999,999, but it will
select the resistant mutant (1) that exists.
• If this TB has a minimum of 1,000 million (109), in 2-8
weeks it will have selected the 1,000 mutant bacilli
(10-6 Bacilli) that are resistant in this population
M. Tuberculosis Resistance
Selection of Resistant Mutants
• These 1,000 bacilli are insufficient to cause
clinical symptoms or to be smear +.
• The problem is that these 1,000 will soon be 109
Appearance of resistance to INH administrated in Monotherapy
Resistant Mutants
Sensitive Bacilli
No. of
viable bacilli
Months after Start of Treatment
Mitchison DA. En: Heaf F, et al. Churchill, London, 1968
M. tuberculosis Resistance
Resistant Mutants according to Bacillary Population
• As each drug has a different target to attack the
bacilli, the genomic mutation that causes the
resistance is different for each one of them.
• This is why the probability of finding a bacillus with
2 genetic mutations, that express resistance to 2
drugs, is equal to the exponential sum of their
respective mutation rates:
• 1014 for INH+RIF
• 1020 for INH+RIF+EMB
Selection of Resistant Mutants
to M. tuberculosis
Anti-TB Drugs select
the resistant mutants
They do not cause
the mutation
Bacteriological Fundaments
of TB Treatment
1. Drug combinations
The combination of drugs prevents the
appearance of resistance,
because it avoids the selection of
naturally resistant mutants
Basic Concepts in TB
Resistance
Resistance in Previously
Treated Patients
ACQUIRED Resistance
M. Tuberculosis Resistance
ACQUIRED OR SECONDARY Resistance
• A patient with selection of resistant mutants from poor
treatment will present a resistant TB  ACQUIRED
RESISTANCE, also named “in previously treated patients”
• Therefore, acquired R. is always an expression of poor
treatment:
– Direct Monotherapy
– Indirect Monotherapy (adding just one drug to an inefficient association)
• Behind an MDR TB patient, there is usually a long and
unfortunate list of therapeutic errors (successive indirect
monotherapies)
Selection of Natural Resistance,
Acquired and Initial Resistance
SUSCEPTIBLE
to Drugs
RESISTANT
to Drugs
Latent
Develop
into TB
Latent
transmission
Develop into
DR TB
transmission
Contagious
Contagious
acquire DR-TB
acquire (M)DR-TB
Basic Concepts in TB
Resistance
Resistance in Preivously
Untreated Patients
Primary or INITIAL Res.
M. Tuberculosis Resistance
PRIMARY or INITIAL Resistance
• If a person is infected by a patient with selected
resistant mutants (Acquired R.), he/she may
suffer TB with the same resistance pattern
PRIMARY RESISTANCE
• Primary resistance is that which presents in TB
patients who have never received treatment
(< 1 month)
M. Tuberculosis Resistance
PRIMARY or INITIAL Resistance
• Initial R. is the same concept as primary R., but it
is a practical term, and includes all patients who
state they have Never been treated (some do not
remember, others lie)
Resistance in “previously untreated patients”
Basic Concepts in TB
Resistance
Poly-Resistance
to Anti-TB Drugs
M. tuberculosis Resistance
Poly-Resistance
• Resistance to 2 or more drugs, independent of
the drug.
• The worst situation is resistance to H+R, very
difficult to cure
• For this reason, these patients receive an
special name ---> M.D.R.
Basic Concepts in TB
Resistance
M.D.R.
M. Tuberculosis Resistance
Multidrug-resistance (MDR)
• Defined as resistance at a minimum to
“INH+RIF”
• It is extremely dangerous, as this TB is very
difficult to cure
• MDR may be:
– Primary or Initial
– Acquired
Will it determine
the future of TB?
Basic Concepts in TB
Resistance
X.D.R.
Extensively-Drug-Resistant TB (XDR)
WHO, October 10, 2006
- MDR.
- Resistance, at least, to 3 of the 6
D.S.L. Groups:
-Quinolones
-Aminoglycosides: Kn, Ak
-Polypeptids: Cm
-Thioamides (Eth-Pth)
-PAS
-Cicloserine / terizidone
- MDR.
- Resistance, at least, to:
-Quinolones
- One or More of the Injectable:
- Aminogliyosides: Kn, Ak
- Polypeptids: Cm
The most Basic Concept in
TB Resistance
In TB, resistance is always
the expression of poor
individual or general
management of patients
Basic Concepts in TB
Resistance
Pharmacological
Failure
Pharmacological Failure
- This is when a patient does not achieve a
negative sputum smear at the end of the 4th5th month, or after achieving a negative one, it
then becomes positive.
Pharmacological Failure
- It is caused by continually growing bacilli.
- Theoretically, It is accompanied by resistance
to drugs used (not always in the field)
- Drug Susceptibility Test (DST) should be
performed
Basic Concepts in TB
Resistance
Bacteriological
Relapse
Bacteriological Relapse
- This is when a patient has concluded
treatment and has been cured and then
presents TB symptoms with positive
bacteriology again.
Bacillary populations
2. Slow multiplication Bacilli
Relapses
- Intramacrophagic location. Acid pH. Population<105
No Naturally Resistant Mutants
Bacillary populations
3. Intermittently growing bacilli
Relapses
- Unfavourable conditions. Solid caseum. Extracellular
- Relapse capacity
- Population <105
No Naturally Resistant Mutants
Bacteriological Relapse
- It may be early (< 24 months) or late
- Theoretically, it keep the same initial pattern of
resistance (not always in the field).
- DST should be performed.
Treatment After Default
- A patient is defined if he/she returns to treatment
bacteriologically positive after stopping taking
treatment for more than 1-2 months.
- Default in taking medication may be:
- Total: Like a relapse
Probably sensitive to drugs taken
- Partial:
Like a failure
Probably resistant to the drugs taken
The High Risk of the
Bad Adherence to
Select Resistances
in TB
Post-Antibiotic Effects with M. tuberculosis
Lag Periods before Commencement of Growth after Exposure in 7H10 Medium
streptomycin
Isoniazid
Ethambutol
Sequential
Monotherapy INH
Rifampicin
0
1
2
3
4
5
6
7
8
9
10
Lag after 24 hr exposure to drug (days)
Mitchison DA, et al. Postgr Med J 1971;47:737-41
Post-Antibiotic Effects with M. tuberculosis
Lag Periods before Commencement of Growth after Exposure in 7H10 Medium
streptomycin
Isoniazid
Ethambutol
Sequential
Monotherapy INH
Rifampicin
0
1
2
3
4
5
6
7
8
9
10
Lag after 24 hr exposure to drug (days)
Mitchison DA, et al. Postgr Med J 1971;47:737-41
Bacteriopausal Effects During Regrowth
Regrowth starting
Number of viable bacilli
Mutants
resistant
to A
Lag due to drug A
Mutants
resistant
to B
Killing phase
Lag due to drug B
Regrowth
Mitchison DA. In J Tuberc Lung Dis 1998;2:10-15
TB Re-treatment and Selection of
Resistance
- Theoretically:
- Relapses and total defaulters have the same initial pattern
of drug susceptibility
- Failures and partial defaulters could amplify resistance
- However,
in the Field:
- Relapses and total defaulters have an increased risk of
resistance
- A substantial proportion of failures are susceptible
Can the Relapses and
Defaulters increase the
Initial Pattern of
Resistance?
YES, because in the Field are
influencing a lot of circumstances
The possible change in the Pattern of Resistances
of the Relapses in the last 20-30 years
- 20-30 years ago, when most of the TB cases in the
community were susceptible to the anti-TB
drugs, usually the relapses came from the
dormant bacillus do not killed by the drugs.
- However, currently, when the initial resistance to H
is high in many settings, a lot of these failures
are coming from the initial H resistant cases
 selecting R resistance in the continuation
phase
Why the Relapses and Defaulters can
increase the Initial Pattern of Resistance?
- Many times the Relapse is coming for the Initial
resistance to a H  at the end of the
continuation phase the Resistance to R has
been selected
- Definition of Cured Cases based in Sm  Some
patients could be Sm-, but Culture +  In NTP
they are classified as Cured but are Failures
- A lot of times after a Relapse there is a patient with
maintained Bad Adherence Danger to select Res.
Can a Failure be
Susceptible ?
YES, above all the Failures
to Category I
Failures to Category I and MDR
- In the field, Not all patients who fail a
Cat. I regimen has MDR-TB, and the
percentage may depend on a number
of factors, above all:
- Including whether rifampicin was
used in the continuation phase
- Whether DOT was used throughout
treatment
- Some other Circumstances
Why a Failure can
be Susceptible ?
5 Possibilities in the Field
Why an Operational Failure can be Susceptible?
5 POSSIBILITIES
1. Very Delayed Negativization (Later than 4º m.)
2. Bad Adherence (Supervision) to the Treatment
3. Nontuberculous Mycobacteria
4. Bacillary Escapes
5. Died Bacillus
However, this possibility
that a Failure was
Susceptible decrease
very much in the
Failures to Category II?
3. Likelihood Generating MDR
under NTP conditions.
Inadequate Strategies
Known Factors contributing to the MDR-TB
1.
2.
3.
4.
5.
6.
7.
8.
9.
No DOTS
Bad Adherence / Supervision
No Standard Treatments
Frequent drug stock-outs
Anti-TB Drugs of Poor Quality
Important Private Sector
No Hospital Infection Control
High Virulent Strains M. TB
HIV in some settings
Is it Possible to Generate MDR and XDR in NTP Conditions ?
The possibility to generate MDR
in NTP conditions
The Risk to Amplify
Resistances with Non
Adequate Strategies
The possibility to generate MDR
in NTP conditions
2 HRZE / 4 HR
Pansusceptible
Initial Res. H
Initial MDR
The possibility to generate MDR and XDR in
NTP conditions
2 HRZE / 4 HR
Strict DOT
Pansusceptible
Bad Maintained
Adherence
CURE
Danger !
Intermittent Tr.
Post-Antibiotic Effects with M. tuberculosis
Lag Periods before Commencement of Growth after Exposure in 7H10 Medium
streptomycin
Isoniazid
Ethambutol
Sequential
Monotherapy INH
Rifampicin
0
1
2
3
4
5
6
7
8
9
10
Lag after 24 hr exposure to drug (days)
Mitchison DA, et al. Postgr Med J 1971;47:737-41
Bacteriopausal Effects During Regrowth
Regrowth starting
Number of viable bacilli
Mutants
resistant
to A
Lag due to drug A
Mutants
resistant
to B
Killing phase
Lag due to drug B
Regrowth
Mitchison DA. In J Tuberc Lung Dis 1998;2:10-15
The possibility to generate MDR in NTP conditions
2 HRZE / 4 H R
Sm (-) 2ºMonth
% CURE
Extend 1ª Phase
Initial Res. H
Sm (+) 2º M.
Go to 2ª Phase
¡ High Risk MDR-TB !, but Susceptible ZE
The Risk to Amplify Resistance in the Failures to Cat. I
receiving Category II Regime (2)
2 HRZE/ 4 HR
FAILURE
2. Initial Resistance to H (+%)
2 HRZE/4 H R
2HRZES/1HRZE/5H R E
MDR, but suscpt. Z+E
Risk to Amplify Resistance E
(Avoidable if DST before 3rd Month)
The possibility to generate MDR in NTP conditions
2 HRZE / 4 H R
CURE (20-50%)
Initial MDR
MDR-TB, Amplifying Resist. to Z+E
The Risk to Amplify Resistance in the Failures to Cat. I
receiving Category II Regime (3)
FAILURE
2 HRZE/4 HR
3. Initial M.D.R. (-%)
2 HRZE/4 H R
Resistance to HR+E+Z
2HRZES/1HRZE/5H R E
Risk to Amplify
Resistance to S
The possibility to generate MDR in NTP
conditions
- The Regimen Category I could:
1.) Produce MDR , when:
- Bad Maintained Adherence
- Drugs Not Associated In the same Tablet
- To Pass to 2ª Phase with Sm+,
- Above all, if there is Initial Resistance to H
2.) Amplify Res. to ZE in Initial MDR and Sm+
The possibility to generate MDR and XDR in
NTP conditions
- The Regimen Category I could:
1.) Produce MDR , when:
- Bad Maintained Adherence
- Drugs Not Associated In the same Tablet
- To Pass to 2ª Phase with Sm+,
- Above all, if there is Initial Resistance to H
2.) Amplify Res. to ZE in Initial MDR and Sm+
- Recommendations:
1. To Assure, at the maximum, the Adherence
2. To Prolong 1 month 1st phase if Sm+ at 2º Month.
3. To Give all the Drugs associated in the same Tablet.
4. To evaluate DST at the start of treatment in Cases and
Risk Populations
The possibility to generate MDR
in NTP conditions
- The Regimen Category II could:
1.) Amplify Resistance to EMB in cases with Initial
Res. to H  MDR with Cat.I
2.) Amplify Resistance to SM in cases with Initial
MDR  Amplification ZE with Cat. I
BUT THE CATEGORY II DO NOT GENERATE M.D.R.
 The MDR come from the Category I
The possibility to generate MDR
in NTP conditions
- The Regimen Category II could:
1.) Amplify Resistance to EMB in cases with Initial Res. to H  MDR with Cat.I
2.) Amplify Resistance to SM in cases Initial MDR  Amplification ZE with Cat. I
BUT THE CATEGORY II DO NOT GENERATE M.D.R. The MDR come from the Category I
- Recommendations:
1. Culture + DST to all the Sm+ at the end of the
2-3 month MDR
2. To Evaluate Rate of MDR-TB in Failures Cat. I 3.
To Evaluate Rate of MDR-TB in Relapses and
Defaulters Cat. I
Under Special Conditions, the
NTP have the Risk to Amplify
Resistances with Not
Adequate Strategies
NTP should Address
all the Strategies to Minimize this Risk
M. tuberculosis Resistance
In TB, resistance is always
the expression of poor
individual or general
management of patients