Transcript Basic principles and concepts of Drug resistance-TB
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 c omplex 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
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In a tuberculosis patient, there are different bacillary populations bacilli in different situations formed of
- 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<10 5
No Naturally Resistant Mutants
Bacillary populations 3. Intermittently growing bacilli Relapses
- Unfavourable conditions. Solid caseum. Extracellular - Population <10 5 Relapse capacity
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
- Intramacrophagic location. Acid pH. Population<10 5 →
PZ
3. Intermittently growing bacilli
Unfavourable conditions. Solid caseum. Extracellular - Population <10 5.
Relapse capacity →
RIF
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.
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)
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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.
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Fortunately, the majority of these mutations do not obvious phenotypic expression .
have an
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Sometimes it is necessary to subject the species to selective pressure for it to express the selected mutation
M. Tuberculosis Resistance Natural Resistance (3)
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Ever since M. tuberculosis has attacked man, way back in time, it has always presented multiple genomic mutations in its continuous divisions.
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Some of these mutations affect the tuberculosis drugs work genes in which anti-
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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 10 5 -10 6 Bacilli 1 x 10 7 -10 8 Bacilli 1 x 10 5 -10 6 Bacilli 1 x 10 5 -10 6 Bacilli 1 x 10 2 -10 4 Bacilli ?
1 x 10 5 -10 6 Bacilli ?
1 x 10 5 -10 6 Bacilli ?
M. tuberculosis Resistance Bacillary Population in different TB Lesions
• • • • • • •
TB Sm+ Cavitary 10 7 -10 9 Bacilli 10 7 -10 9 Bacilli Infiltrated Nodules 10 4 -10 7 Bacilli 10 4 -10 6 Bacilli Adenopathies 10 4 -10 6 Bacilli Renal TB 10 7 -10 9 Bacilli Extrapul. TB 10 4 -10 6 Bacilli
M. Tuberculosis Resistance Selection of Resistant Mutants
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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.
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If this TB has a minimum of 1,000 million (10 9 ), 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
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These 1,000 bacilli are insufficient to cause clinical symptoms or to be smear +.
•
The problem is that these 1,000 will soon be 10 9
Appearance of resistance to INH administrated in Monotherapy
Resistant Mutants No. of viable bacilli Sensitive 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
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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.
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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:
• •
10 14 10 20 for INH+RIF 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
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A patient with selection of resistant mutants from poor treatment will present a resistant TB
ACQUIRED RESISTANCE , also named “in previously treated patients”
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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
Develop into TB SUSCEPTIBLE to Drugs Latent transmission RESISTANT to Drugs Latent Develop into DR TB transmission Contagious acquire DR-TB Contagious 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 )
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MDR.
Resistance, at least, to 3 of the 6 D.S.L. Groups:
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Quinolones
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Aminoglycosides: Kn, Ak
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Polypeptids: Cm
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Thioamides (Eth-Pth)
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PAS
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Cicloserine / terizidone WHO, October 10, 2006
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MDR .
Resistance, at least, to:
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Quinolones One or More of the
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Injectable : Aminogliyosides: Kn, Ak
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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 4th 5th 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<10 5
No Naturally Resistant Mutants
Bacillary populations 3. Intermittently growing bacilli Relapses
- Unfavourable conditions. Solid caseum. Extracellular - Population <10 5 Relapse capacity
No Naturally Resistant Mutants
Bacteriological Relapse
- It may be early (< 24 months) or late Theoretically resistance , it keep the same initial pattern of (not always in the field).
DST should be performed .
Treatment After Default
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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 Rifampicin Ethambutol
Sequential Monotherapy INH
0 1 2 3 4 5 6 7 Lag after 24 hr exposure to drug (days) 8 9 10
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 Rifampicin
Sequential Monotherapy INH
0 1 2 3 4 5 6 7 Lag after 24 hr exposure to drug (days) 8 9 10
Mitchison DA, et al. Postgr Med J 1971;47:737-41
Bacteriopausal Effects During Regrowth
Regrowth starting
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 of drug susceptibility have the same initial pattern 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 Susceptible be ?
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 5 can be POSSIBILITIES Susceptible ?
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 Susceptible was 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 NTP conditions in
2 HRZE / 4 HR
Pansusceptible Strict DOT 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 Rifampicin Ethambutol
Sequential Monotherapy INH
0 1 2 3 4 5 6 7 Lag after 24 hr exposure to drug (days) 8 9 10
Mitchison DA, et al. Postgr Med J 1971;47:737-41
Bacteriopausal Effects During Regrowth
Regrowth starting
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 Initial Res. H Sm (+) 2º M. Extend 1ª Phase Go to 2ª Phase ¡ High Risk MDR-TB !, but Susceptible ZE
The Risk to Amplify Resistance in the Failures receiving Category II Regime (2) to Cat. I
2 HRZE/ 4 HR FAILURE
2. Initial Resistance to H (+%)
2 HRZE/4 H R
MDR, but suscpt.
Z+E
2HRZES/1HRZE/5H R 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 receiving Category II Regime (3) to Cat. I
2 HRZE/4 HR FAILURE
3. Initial M.D.R.
(-%)
2 HRZE/4 H R 2HRZES/1HRZE/5H R E
Resistance to HR+E+Z
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 1 st 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 Res. to H
MDR with Cat.I
in cases with Initial 2.) Amplify Resistance to SM MDR
Amplification ZE in cases with Initial 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 To Evaluate Rate of MDR-TB in in Failures Cat. I Relapses and Defaulters Cat. I 3.
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