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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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slide2

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
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.
slide11

Bacillary populations

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

- Location

- pH

- Replication rate, susceptibility to drugs, …

slide12

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

slide13

Bacillary populations

2. Slow multiplication Bacilli

- Intramacrophagic location. Acid pH. Population<105

Relapses

No Naturally Resistant Mutants

slide14

Bacillary populations

3. Intermittently growing bacilli

- Unfavourable conditions. Solid caseum. Extracellular

- Population <105 - Relapse capacity

Relapses

No Naturally Resistant Mutants

slide15

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 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
slide25

TB Transmission. Contagious aerosol (droplets < 5 micras)

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

slide26

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
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/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)

slide31

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

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
slide34

Basic Concepts in TB Resistance

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

M. tuberculosis

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
  • 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 ?
m tuberculosis resistance bacillary population in different tb lesions
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
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
slide44

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
slide46

Selection of Resistant Mutants

to M. tuberculosis

Anti-TB Drugs select

the resistant mutants

They do not cause the mutation

slide47

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

slide48

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)
slide50

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

slide51

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”

slide54

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.
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?

slide59

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
slide60

The most Basic Concept in TB Resistance

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

slide61

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

slide64

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.

slide66

Bacillary populations

2. Slow multiplication Bacilli

- Intramacrophagic location. Acid pH. Population<105

Relapses

No Naturally Resistant Mutants

slide67

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

slide71

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

slide72

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

slide73

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

slide75

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

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

slide76

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

slide77

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.

slide78

Can a Failure be Susceptible ?

YES, above all the Failures to Category I

slide79

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

slide80

Why a Failure can be Susceptible ?

5 Possibilities in the Field

slide81

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

slide82

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

slide84

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 ?

slide85

The possibility to generate MDR in NTP conditions

The Risk to Amplify Resistances with Non Adequate Strategies

slide86

Initial Res. H

Initial MDR

Pansusceptible

The possibility to generate MDR

in NTP conditions

2 HRZE / 4 HR

slide87

The possibility to generate MDR and XDR in NTP conditions

2 HRZE / 4 HR

CURE

Strict DOT

Pansusceptible

Bad Maintained

Adherence

Danger !

Intermittent Tr.

slide88

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

slide89

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

slide90

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

slide91

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

slide92

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

slide93

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

slide94

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+
slide95

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
slide96

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

slide97

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 ofMDR-TB in Relapses and
  • DefaultersCat. I
slide98

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

ad