Basic Principles and Concepts of M. TB and Resistance

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Basic Principles and Concepts of M. TB and
Resistance
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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
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1. Biological Characteristics and Condition of
M. Tuberculosis Growth
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1. Biological Characteristics and Condition of
M. Tuberculosis Growth

• 1. Causal Agent
• 2. Reservoir. Source of infection
• 3. Mechanism of Transmission
• 4. Susceptible Host

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• 1. Causal Agent

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Causal Agent

• - Mycobacterium tuberculosis complex
• - M. tuberculosis
• - M. bovis
• - M. africanum
• - M. microti
• - M. caneti
• - M. pinnipedii
• - M. caprae

Difficult to Fight
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Causal Agent

• - Mycobacterium tuberculosis complex
• - Resistant to
• Cold,
• Freezing
• and
• Desiccation

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Causal Agent

• - Mycobacterium tuberculosis complex
• .
• - Very sensitive to Heat, Sunlight and U.V.
  radiation

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Causal Agent

• - Mycobacterium tuberculosis complex
• - Strictly aerobic (depends on Oxygen and pH)

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Causal Agent

• - Mycobacterium tuberculosis complex
• - Polyvalent
• behaviour
• depending
• on medium.

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Bacillary populations
In a tuberculosis patient, there are different
bacillary populations formed of bacilli in
different situations - Location - pH -
Replication rate, susceptibility to drugs,
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Failure
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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.
Populationlt105 3. Intermittently growing
bacilli ? RIF - Unfavourable conditions. Solid
caseum. Extracellular - Population lt105. Relapse
capacity 4. Bacilli in latent state Not
susceptible to drugs - Reactivations and relapses
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M tuberculosis. Very Slow Division Capacity
- Slow and Little Alarmant Clinical Presentation
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Causal Agent

• - M. tuberculosis complex
• - Differentiate from
• Environmental M.
• (Atypical)

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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
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2. Reservoir. Source of Infection
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2. Reservoir. Source of Infection

• - MAN
• Infected, healthy

World Population 6.100 Millions M. TB
Infection 2.000 Millions
Possible Reservoir MDR-TB 50 Millions !!
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2. Reservoir. Source of Infection

• - MAN
• Active disease

TB Cases 16 million MDR-TB Cases 500.000
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2. Reservoir. Source of Infection

• - MAN
• Infected, healthy
• Active disease
• - Animals
• Bovine cattle (M. bovis)
• Others Monkeys, Dogs, Cats, etc

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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

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1. Biological Characteristics and Condition of
M. Tuberculosis Growth

• 1. Causal Agent
• 2. Reservoir. Source of infection
• 3. Mechanism of Transmission
• 4. Susceptible Host

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Mechanism of Transmission

• - Fundamentally AEROGEN
• - Very Uncommon
• - Cutaneous-Mucosal
• - Urogenital
• - Inoculation
• - Tran placental, etc

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TB Transmission. Contagious aerosol (droplets lt 5
micras)
The TB MDR/XDR-TB have the same capacity to
generate Aerosols
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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

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1. Biological Characteristics and Condition of
M. Tuberculosis Growth

• 1. Causal Agent
• 2. Reservoir. Source of infection
• 3. Mechanism of Transmission
• 4. Susceptible Host

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Epidemiological Sequence of TBHost Susceptible
to Disease

• - Age Distribution

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TB Risk Groups Relative Risk of developing
TB(compared with control population, regardless
of PPD)

• - HIV/AIDS 150
• - Silicosis 30
• - Diabetes 2 4.1
• - Chronic renal failure / Haemodial. 10 25.3
• - Gastrectomy 2-5
• - Jejunoileal by-pass 27 - 63
• - Kidney transplant 37
• - Heart 20 - 74
• - Head or neck carcinoma 16

ATS/CDC. Am J Respir Crit Care Med 2000 161
(part 2)
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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
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2. Definitions and Basic Concepts in Resistances
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M. tuberculosis ResistanceBasic 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

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Basic Concepts in TB Resistance

• All these concepts are related to the growth and
  multiplication characteristics of
• M. tuberculosis

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Basic Concepts in TB Resistances
NATURAL Resistance
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M. Tuberculosis Resistances
1. The ORIGIN
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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.

15 million
- This always occurs in the successive divisions
of each species. It is therefore a dynamic
function
12 hours
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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

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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
  anti-tuberculosis drugs work
• This means that these antibiotics cannot work
  against M. tuberculosis, and therefore
  phenotypically they show resistance to them.

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M. tuberculosis Resistance Natural Resistant
Mutants according to Bacillary Population

• INH 1 x 105-106 Bacilli
• RIF 1 x 107-108 Bacilli
• SM 1 x 105-106 Bacilli
• EMB 1 x 105-106 Bacilli
• PZ 1 x 102-104 Bacilli ?
• Quinolones 1 x 105-106 Bacilli ?
• Others 1 x 105-106 Bacilli ?

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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

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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

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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

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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
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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 INHRIF
• 1020 for INHRIFEMB

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M. TuberculosisCellular Wall target point of
Drugs
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Selection of Resistant Mutants to M. tuberculosis
Anti-TB Drugs select the resistant mutants
They do not cause the mutation
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Bacteriological Fundaments of TB Treatment
1. Drug combinations
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Basic Concepts in TB Resistance
Resistance in Previously Treated
Patients ACQUIRED Resistance
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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)

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Selection of Natural Resistance, Acquired and
Initial Resistance
SUSCEPTIBLE to Drugs
RESISTANT to Drugs
Latent
Latent
Develop into TB
Develop into DR TB
transmission
transmission
Contagious
Contagious
acquire (M)DR-TB
acquire DR-TB
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Basic Concepts in TB Resistance
Resistance in Preivously Untreated
Patients Primary or INITIAL Res.
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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
  (lt 1 month)

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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
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Basic Concepts in TB Resistance
Poly-Resistance to Anti-TB Drugs
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M. tuberculosis Resistance Poly-Resistance

• Resistance to 2 or more drugs, independent of the
  drug.
• The worst situation is resistance to HR, very
  difficult to cure
• For this reason, these patients receive an
  special name ---gt M.D.R.

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Basic Concepts in TB Resistance
M.D.R.
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M. Tuberculosis Resistance Multidrug-resistance
(MDR)

• Defined as resistance at a minimum to
  INHRIF
• 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?
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Basic Concepts in TB Resistance
X.D.R.
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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

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The most Basic Concept in TB Resistance

• In TB, resistance is always the expression of
  poor individual or general management of patients

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Basic Concepts in TB Resistance
Pharmacological Failure
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Pharmacological Failure

• - This is when a patient does not achieve a
  negative sputum smear at the end of the 4th-5th
  month, or after achieving a negative one, it then
  becomes positive.

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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

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Basic Concepts in TB Resistance
Bacteriological Relapse
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Bacteriological Relapse

• This is when a patient has concluded treatment
  and has been cured and then presents TB symptoms
  with positive bacteriology again.

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Bacteriological Relapse

• - It may be early (lt 24 months) or late
• - Theoretically, it keep the same initial pattern
  of resistance (not always in the field).
• - DST should be performed.

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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

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The High Risk of the Bad Adherence to Select
Resistances in TB
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Post-Antibiotic Effects with M. tuberculosis Lag
Periods before Commencement of Growth after
Exposure in 7H10 Medium
streptomycin
Isoniazid
Ethambutol
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 197147737-41
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Post-Antibiotic Effects with M. tuberculosis Lag
Periods before Commencement of Growth after
Exposure in 7H10 Medium
streptomycin
Isoniazid
Ethambutol
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 197147737-41
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Bacteriopausal Effects During Regrowth
Regrowth starting
Mutants
resistant
to A
Lag due to drug A
Number of viable bacilli
Mutants
Lag due to drug B
resistant
to B
Regrowth
Killing phase
Mitchison DA. In J Tuberc Lung Dis 1998210-15
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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
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Can the Relapses and Defaulters increase the
Initial Pattern of Resistance?
YES, because in the Field are influencing a lot
of circumstances
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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
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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.
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Can a Failure be Susceptible ?
YES, above all the Failures to Category I
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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
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Why a Failure can be Susceptible ?
5 Possibilities in the Field
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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
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However, this possibility that a Failure was
Susceptible decrease very much in the Failures to
Category II?
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3. Likelihood Generating MDR under NTP
conditions. Inadequate Strategies
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Known Factors contributing to the MDR-TB

1. No DOTS
2. Bad Adherence / Supervision
3. No Standard Treatments
4. Frequent drug stock-outs
5. Anti-TB Drugs of Poor Quality
6. Important Private Sector
7. No Hospital Infection Control
8. High Virulent Strains M. TB
9. HIV in some settings

Is it Possible to Generate MDR and XDR in NTP
Conditions ?
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The possibility to generate MDR in NTP
conditions
The Risk to Amplify Resistances with Non
Adequate Strategies
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The possibility to generate MDR in NTP
conditions
2 HRZE / 4 HR
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The possibility to generate MDR and XDR in NTP
conditions
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Post-Antibiotic Effects with M. tuberculosis Lag
Periods before Commencement of Growth after
Exposure in 7H10 Medium
streptomycin
Isoniazid
Ethambutol
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 197147737-41
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Bacteriopausal Effects During Regrowth
Regrowth starting
Mutants
resistant
to A
Lag due to drug A
Number of viable bacilli
Mutants
Lag due to drug B
resistant
to B
Regrowth
Killing phase
Mitchison DA. In J Tuberc Lung Dis 1998210-15
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The possibility to generate MDR in NTP
conditions
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The Risk to Amplify Resistance in the Failures to
Cat. I receiving Category II Regime (2)
2 HRZE/ 4 HR
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The possibility to generate MDR in NTP
conditions
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The Risk to Amplify Resistance in the Failures to
Cat. I receiving Category II Regime (3)
2 HRZE/4 HR
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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
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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

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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
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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

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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
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M. tuberculosis Resistance

• In TB, resistance is always the expression of
  poor individual or general management of patients