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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.

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Basic principles and concepts of m tb and resistance

Basic Principles and Concepts of M. TB and Resistance


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


Basic principles and concepts of m tb and resistance

1. Biological Characteristics and Condition of M. Tuberculosis Growth


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


Basic principles and concepts of m tb and resistance

  • 1. Causal Agent


Causal agent

CausalAgent

  • - Mycobacterium tuberculosiscomplex

    • - M. tuberculosis

    • - M. bovis

    • - M. africanum

    • - M. microti

    • - M. caneti

    • - M. pinnipedii

    • - M. caprae

Difficult to Fight


Causal agent1

CausalAgent

  • - Mycobacterium tuberculosis complex

    • - Resistant to:

      • Cold,

      • Freezing

        • and

      • Desiccation


Causal agent2

CausalAgent

  • - Mycobacterium tuberculosis complex

    • .

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


Causal agent3

CausalAgent

  • - Mycobacterium tuberculosis complex

    - Strictly aerobic (depends on Oxygen and pH)


Causal agent4

CausalAgent

  • - Mycobacterium tuberculosis complex

    • - Polyvalent

      • behaviour

      • depending

      • on medium.


Basic principles and concepts of m tb and resistance

Bacillary populations

■ In a tuberculosis patient, there are different bacillary populations formed of bacilli in different situations

- Location

- pH

- Replication rate, susceptibility to drugs, …


Basic principles and concepts of m tb and resistance

Bacillary populations

  • 1. Rapidly multiplying bacilli

    • - 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

    Failure


    Basic principles and concepts of m tb and resistance

    Bacillary populations

    2. Slow multiplication Bacilli

    - Intramacrophagic location. Acid pH. Population<105

    Relapses

    No Naturally Resistant Mutants


    Basic principles and concepts of m tb and resistance

    Bacillary populations

    3. Intermittently growing bacilli

    - Unfavourable conditions. Solid caseum. Extracellular

    - Population <105- Relapse capacity

    Relapses

    No Naturally Resistant Mutants


    Basic principles and concepts of m tb and resistance

    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.)

    - Excessive Delay to Consult the HC

    - Very Late Diagnosis

    Long time to be contagious when the Cases are Diagnosed

    M tuberculosis. Very Slow Division Capacity

    - Slow and Little Alarmant

    Clinical Presentation


    1 biological characteristics and condition of m tuberculosis growth1

    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


    2 reservoir source of infection1

    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 !!


    2 reservoir source of infection2

    2. Reservoir. Source of Infection

    • - MAN:

      • * Active disease

    TB Cases: 16 million

    MDR-TB Cases:+ 500.000


    2 reservoir source of infection3

    2. Reservoir. Source of Infection

    • - MAN:

      • * Infected, healthy

      • * Active disease

  • - Animals:

    • * Bovine cattle (M. bovis)

    • * Others: Monkeys, Dogs, Cats, etc


  • 2 reservoir source of infection4

    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 growth2

    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

    Mechanism of Transmission

    • - Fundamentally AEROGEN

    • - Very Uncommon:

      • - Cutaneous-Mucosal

      • - Urogenital

      • - Inoculation

      • - Tran placental, etc


    Basic principles and concepts of m tb and resistance

    TB Transmission. Contagious aerosol (droplets < 5 micras)

    The TB MDR/XDR-TB have the same capacity to generate Aerosols


    Basic principles and concepts of m tb and resistance

    Patients with TUBERCULOSIS

    must cover their Mouth when Coughing

    Surgical Masks only work if used

    by the Patient


    Greatest tb transmitters

    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 growth3

    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

    Epidemiological Sequence of TBHost Susceptible to Disease

    • - Age Distribution


    Tb risk groups relative risk of developing tb compared with control population regardless of ppd

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

    - HIV/AIDS150

    -Silicosis30

    -Diabetes2 – 4.1

    -Chronic renal failure / Haemodial.10 – 25.3

    -Gastrectomy2-5

    -Jejunoileal by-pass 27 - 63

    -Kidney transplant37

    -Heart “ 20 - 74

    -Head or neck carcinoma 16

    ATS/CDC. Am J Respir Crit Care Med 2000; 161 (part 2)


    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


    Basic principles and concepts of m tb and resistance

    2. Definitions and Basic Concepts in Resistances


    M tuberculosis resistance basic concepts and definitions

    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


    Basic principles and concepts of m tb and resistance

    Basic Concepts in TB Resistance

    All these concepts are related to the growth and multiplication characteristics of

    M. tuberculosis


    Basic principles and concepts of m tb and resistance

    Basic Concepts in TB Resistances

    NATURAL Resistance


    Basic principles and concepts of m tb and resistance

    M. Tuberculosis Resistances

    1. The ORIGIN


    M tuberculosis resistance natural resistance 1

    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


    M tuberculosis resistance natural resistance 2

    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

    M. Tuberculosis Resistance Natural Resistance (3)

    • Ever since M. tuberculosis has attacked man, way back in time, it has always presented multiple genomic mutationsin 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.


    M tuberculosis resistance natural resistant mutants according to bacillary population

    M. tuberculosis Resistance Natural Resistant Mutants according to Bacillary Population

    • INH1 x 105-106 Bacilli

    • RIF1 x 107-108 Bacilli

    • SM 1 x 105-106 Bacilli

    • EMB1 x 105-106 Bacilli

    • PZ1 x 102-104 Bacilli ?

    • Quinolones 1 x 105-106 Bacilli ?

    • Others 1 x 105-106 Bacilli ?


    M tuberculosis resistance bacillary population in different tb lesions

    M. tuberculosis Resistance Bacillary Population in different TB Lesions

    • TB Sm+ 107-109 Bacilli

    • Cavitary107-109 Bacilli

    • Infiltrated104-107 Bacilli

    • Nodules104-106 Bacilli

    • Adenopathies104-106 Bacilli

    • Renal TB 107-109 Bacilli

    • Extrapul. TB104-106 Bacilli


    M tuberculosis resistance selection of resistant mutants

    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 mutants1

    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


    Basic principles and concepts of m tb and resistance

    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

    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


    Basic principles and concepts of m tb and resistance

    Selection of Resistant Mutants

    to M. tuberculosis

    Anti-TB Drugs select

    the resistant mutants

    They do not cause the mutation


    Basic principles and concepts of m tb and resistance

    The combination of drugs prevents the

    appearance of resistance,

    because it avoids the selection of

    naturally resistant mutants

    Bacteriological Fundaments

    of TB Treatment

    1. Drug combinations


    Basic principles and concepts of m tb and resistance

    Basic Concepts in TB Resistance

    Resistance in Previously Treated Patients

    ACQUIRED Resistance


    M tuberculosis resistance acquired or secondary 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)


    Basic principles and concepts of m tb and resistance

    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


    Basic principles and concepts of m tb and resistance

    Basic Concepts in TB Resistance

    Resistance in Preivously Untreated Patients

    Primary or INITIAL Res.


    M tuberculosis resistance primary or initial resistance

    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 resistance1

    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 principles and concepts of m tb and resistance

    Basic Concepts in TB Resistance

    Poly-Resistance

    to Anti-TB Drugs


    M tuberculosis resistance poly resistance

    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 principles and concepts of m tb and resistance

    Basic Concepts in TB Resistance

    M.D.R.


    M tuberculosis resistance multidrug resistance mdr

    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 principles and concepts of m tb and resistance

    Basic Concepts in TB Resistance

    X.D.R.


    Basic principles and concepts of m tb and resistance

    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


    Basic principles and concepts of m tb and resistance

    The most Basic Concept in TB Resistance

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


    Basic principles and concepts of m tb and resistance

    Basic Concepts in TB Resistance

    Pharmacological Failure


    Pharmacological failure

    Pharmacological Failure

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


    Pharmacological failure1

    Pharmacological Failure

    It is caused by continually growingbacilli.

    - Theoretically, It is accompanied by resistance to drugs used (not always in the field)

    - Drug Susceptibility Test (DST) should be performed


    Basic principles and concepts of m tb and resistance

    Basic Concepts in TB Resistance

    Bacteriological Relapse


    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.


    Basic principles and concepts of m tb and resistance

    Bacillary populations

    2. Slow multiplication Bacilli

    - Intramacrophagic location. Acid pH. Population<105

    Relapses

    No Naturally Resistant Mutants


    Basic principles and concepts of m tb and resistance

    Bacillary populations

    3. Intermittently growing bacilli

    - Unfavourable conditions. Solid caseum. Extracellular

    - Population <105- Relapse capacity

    Relapses

    No Naturally Resistant Mutants


    Bacteriological relapse1

    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

    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


    Basic principles and concepts of m tb and resistance

    The High Risk of the Bad Adherence to Select Resistances in TB


    Basic principles and concepts of m tb and resistance

    Sequential

    Monotherapy INH

    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 1971;47:737-41


    Basic principles and concepts of m tb and resistance

    Sequential

    Monotherapy INH

    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 1971;47:737-41


    Basic principles and concepts of m tb and resistance

    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 1998;2:10-15


    Tb re treatment and selection of resistance

    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


    Basic principles and concepts of m tb and resistance

    Can the Relapses and Defaulters increase the Initial Pattern of Resistance?

    YES, because in the Field are influencing a lot of circumstances


    Basic principles and concepts of m tb and resistance

    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


    Basic principles and concepts of m tb and resistance

    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.


    Basic principles and concepts of m tb and resistance

    Can a Failure be Susceptible ?

    YES, above all the Failures to Category I


    Basic principles and concepts of m tb and resistance

    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


    Basic principles and concepts of m tb and resistance

    Why a Failure can be Susceptible ?

    5 Possibilities in the Field


    Basic principles and concepts of m tb and resistance

    Why an Operational Failure can be Susceptible?

    5 POSSIBILITIES

    • Very Delayed Negativization (Later than 4º m.)

    2. Bad Adherence (Supervision) to the Treatment

    3. Nontuberculous Mycobacteria

    4. Bacillary Escapes

    5. Died Bacillus


    Basic principles and concepts of m tb and resistance

    However, this possibility that a Failure was Susceptible decrease very much in the Failures to Category II?


    Basic principles and concepts of m tb and resistance

    3. Likelihood Generating MDR under NTP conditions.

    Inadequate Strategies


    Basic principles and concepts of m tb and resistance

    Known Factors contributingto the MDR-TB

    • 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 ?


    Basic principles and concepts of m tb and resistance

    The possibility to generate MDR in NTP conditions

    The Risk to Amplify Resistances with Non Adequate Strategies


    Basic principles and concepts of m tb and resistance

    Initial Res. H

    Initial MDR

    Pansusceptible

    The possibility to generate MDR

    in NTP conditions

    2 HRZE / 4 HR


    Basic principles and concepts of m tb and resistance

    The possibility to generate MDR and XDR in NTP conditions

    2 HRZE / 4 HR

    CURE

    Strict DOT

    Pansusceptible

    Bad Maintained

    Adherence

    Danger !

    Intermittent Tr.


    Basic principles and concepts of m tb and resistance

    Sequential

    Monotherapy INH

    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 1971;47:737-41


    Basic principles and concepts of m tb and resistance

    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 1998;2:10-15


    Basic principles and concepts of m tb and resistance

    The possibility to generate MDR in NTP conditions

    2 HRZE / 4 H R

    Sm (-) 2ºMonth

    Extend 1ª Phase

    Initial Res. H

    % CURE

    Sm (+) 2º M.

    Go to 2ª Phase

    ¡ High Risk MDR-TB !, but Susceptible ZE


    Basic principles and concepts of m tb and resistance

    FAILURE

    2. Initial Resistance to H (+%)

    2 HRZE/4 HR

    MDR, but suscpt.Z+E

    2HRZES/1HRZE/5H R E

    Risk to Amplify Resistance E

    (Avoidable if DST before 3rd Month)

    The Risk to Amplify Resistance in the Failures to Cat. I receiving Category II Regime (2)

    2 HRZE/ 4 HR


    Basic principles and concepts of m tb and resistance

    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


    Basic principles and concepts of m tb and resistance

    FAILURE

    3. Initial M.D.R. (-%)

    2 HRZE/4 HR

    Resistance to HR+E+Z

    Risk to Amplify

    Resistance to S

    2HRZES/1HRZE/5HRE

    The Risk to Amplify Resistance in the Failures to Cat. I receiving Category II Regime (3)

    2 HRZE/4 HR


    Basic principles and concepts of m tb and resistance

    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+


  • Basic principles and concepts of m tb and resistance

    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


    Basic principles and concepts of m tb and resistance

    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


    Basic principles and concepts of m tb and resistance

    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. I3. To Evaluate Rate ofMDR-TB in Relapses and

    • DefaultersCat. I


    Basic principles and concepts of m tb and resistance

    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

    M. tuberculosis Resistance

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


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