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why inh and rifampin are important
Most potent and bactericidal

Tb can be treated effectively with INH+Rif alone

Mono-resistance to one of them can be treated effectively with a regimen containing the other agent with very low failure rate (2.5-5%)

Failure rate when INH+Rif resistant is 44% in non-HIV and 70% in HIV patients

Duration required for cure doubles to triples.

Why INH and Rifampin are important

Dr.T.V.Rao MD

definitions
Multidrug-resistant tuberculosis (MDRTB)

Resistance to Isoniazid and Rifampicin

Extensively (extremely) drug-resistant (XDR-TB)

MDR-TB plus resistance to a second line injectable drug such as Amikacin plus a quinolone.

Definitions

Dr.T.V.Rao MD

drug resistant m tuberculosis
Epidemiology

Primary drug resistance

initial drug resistance

Secondary drug resistance

acquire drug resistance

Treatment of tuberculosis: guidelines for national programmes, 3rd ed. Geneva, (World Health Organization, 2003(WHO/CDS/TB/2003.313).

Drug–Resistant M. tuberculosis

Dr.T.V.Rao MD

what is multidrug resistant tuberculosis mdr tb
What is multidrug-resistant tuberculosis (MDR TB)?
  • Multidrug-resistant TB (MDR TB) is TB that is resistant to at least two of the best anti-TB drugs, isoniazid and rifampicin. These drugs are considered first-line drugs and are used to treat all persons with TB disease.

Dr.T.V.Rao MD

challenges
Challenges:
  • Accurately diagnose infections
  • Prevent transmission
  • Provide appropriate treatment
  • Correctly classify the organism
genesis of mdr tb
Resistance is a man-made amplification of a natural phenomenon.

Inadequate drug delivery is main cause of secondary drug resistance.

Secondary drug resistance is the main cause of primary drug resistance due to transmission of resistant strains.

MDR due to spontaneous mutations is not possible as the genes encoding resistance for anti TB are unlinked.

Genesis of MDR TB

Dr.T.V.Rao MD

slide10

Development of anti-tuberculosis drug resistance

Wild M. TB strain

Spontaneous mutation

Strains with genetic

drug resistance

Selection: inadequate treatment

Acquired drug

resistance

Transmission

Primary drug

resistance

Pablo's-Mendez et al. WHO, 1997

Dr.T.V.Rao MD

slide11

Does Microbes, will travel faster…

With Migrating populations increasing ?

Compared to 1960-75, four-fold increase in migration

4 x increase in volume as compared to 1960

-

75

Dr.T.V.Rao MD

Source: Population Action International 1994

mechanism of resistance
Mechanism of resistance
  • INH
    • Chromosomally mediated
    • Loss of catalase/peroxidase
    • Mutation in my colic acid synthesis
    • Regulators of peroxide response

Dr.T.V.Rao MD

mechanism of resistance14
Mechanism of resistance
  • Rifampin
    • Reduced binding to RNA polymerase
      • Clusters of mutations at “Rifampin Resistance Determining Region” (RRDR)
    • Reduced Cell wall permeability

Dr.T.V.Rao MD

slide15

Spontaneous mutations

develop as bacilli

proliferate to >108

Dr.T.V.Rao MD

slide16

INH

RIF

PZA

Multidrug therapy:

No bacteria resistant to all 3 drugs

Drug-resistant mutants in large bacterial population

Monotherapy: INH-resistant bacteria proliferate

INH

Dr.T.V.Rao MD

slide17

Spontaneous mutations

develop as bacilli

proliferate to >108

INH resistant bacteria multiply

to large numbers

INH

RIF

INH

INH mono-resist.

mutants killed,

RIF-resist. mutants proliferate  MDR TB

Dr.T.V.Rao MD

multidrug resistant tuberculosis mdr tb
Multidrug-resistant tuberculosis (MDR-TB)
  • Multidrug-resistant tuberculosis (MDR-TB) is an increasing global problem, with most cases arising from a mixture of physician error and patient non-compliance during treatment of susceptible TB. The extent and burden of MDR-TB varies significantly from country to country and region to region.
  • As with TB itself, the overwhelming burden of MDR-TB is in high-burden resource-poor countries. The diagnosis depends on confirming the drug susceptibility pattern of isolated organisms, which is often only possible in resource-rich settings

Dr.T.V.Rao MD

xdr tb a global threat
Between 2000-2004, of 17,690 TB isolates in the world were MDR-TB 20% and XDR-TB 2% (Lancet2006;368:964)

Between 2003-2005, of 1,284 TB isolates in Iran were MDR-TB 9.3% and XDR-TB 1% (CID2006;316:216)

XDR-TB a global threat

Dr.T.V.Rao MD

slide20

MDR- and XDR- tuberculosis

Dr.T.V.Rao MD

Donald et al. NEJM 2009

who is at risk for getting mdr tb
Who is at risk for getting MDR TB?
  • Drug resistance is more common in people who:
  • do not take their TB medicine regularly
  • do not take all of their TB medicine as told by their doctor or nurse
  • develop active TB disease again, after having taken TB medicine in the past
  • come from areas of the world where drug-resistant TB is common
  • have spent time with someone known to have drug-resistant TB disease

Dr.T.V.Rao MD

role of the laboratory
Role of the Laboratory
  • Detect drug resistance to enable clinician to design effective multidrug regimen
  • Initial M. tuberculosis isolate should be tested against primary drugs
    • INH, RIF, PZA, EMB
  • For Rif-R isolates, test secondary drugs as needed
    • FQ, AMI, KAN, CAP

Dr.T.V.Rao MD

methods
Drug susceptibility testing performed on all cultures positive for M. tuberculosis

Isoniazid, rifampicin, Ethambutol, streptomycin, ciprofloxacin, kanamycin

Chart review performed for patients with strains resistant to all tested drugs (XDR TB cases)

Demographics, prior TB treatment, prior hospital admissions, HIV status, survival

Molecular fingerprinting by Spoligotyping on all XDR TB isolates

Methods

Dr.T.V.Rao MD

drug susceptibility testing
Drug Susceptibility Testing
  • Culture-based methods
    • Proportion method
      • Solid media
      • Liquid media
    • Absolute concentration method
    • Relative ratio method
  • Molecular methods

Dr.T.V.Rao MD

agar proportion method
Agar Proportion Method
  • Plate bacteria on media containing
    • No drugs
    • Critical concentrations of a drug
  • Incubate for 3 weeksCount colonies

Isolate is resistant if the number of colonies on drug-containing media is >1% of the colonies on drug-free media

Dr.T.V.Rao MD

drug resistance testing
Antimycobacterial Susceptibility Tests (ASTs)

Two methods

Agar based

Broth based

Creighton University does NE surveillance

Drug resistance testing
asts by agar proportion method
ASTs by Agar proportion method
  • Gold standard
  • Dilutions of standardized inoculum onto control and drug containing agar
  • Compare growth in absence or presence of drug
  • >1% colony growing on the drug containing agar suggests resistance
2 prevent transmission
Identifying suspected sources

Understanding transmission patterns

2. Prevent transmission

Genotyping provides tool

genotyping analysis
Genotyping Analysis

Isolate A

Isolate B

Likely Related

genotyping analysis31
Genotyping Analysis

IsolateA

Isolate B

Not Related

genotyping methods
Genotyping Methods
  • Two PCR-based methods:
    • Spoligotyping
    • MIRU-VNTR
  • Results converted to numeric code
  • Matches can be further investigated by other technologies
spoligotyping
Spoligotyping
  • Spacer Oligonucleotide Typing
  • Presence or absence of 43 spacer regions found in the Direct Repeat region of M. tb genome.
  • Results converted to 15 digit code
spoligotyping34
Original banding pattern

Binary code

14 + 1 grouping

Designation (15 digits)

Spoligotyping

1 1 1 1 0 0 1 1 0 0 1 1 1

111-100-110-011-1…..

7 4 6 3

drug resistant genes in tuberculosis
Drug Gene

Rifampicin rpoB

Streptomycin rpsL

Isoniazid No: base pairs

katG

inhA

Drug resistant Genes in Tuberculosis

Dr.T.V.Rao MD

problems with drug resistance surveillance
Quality of laboratory sensitivity testing

Maintenance of standards over time

Selection of specimens

Only 1% of patients surveyed

Problems with drug resistance surveillance

Dr.T.V.Rao MD

epidemiology information of mdr tb
Incidence varies according to reported sites.

High incidence is located in some geographic area and not evenly distribution.

Data of sensitivity can not be directly compared because of different methodology.

No seperation of previously treated and untreated cases.

High incidence is associated with poor compliance previous treatment history, HIV infection, contact with drug resistant case, inborn country.

Epidemiology information of MDR-TB

Dr.T.V.Rao MD

risk factors for infection with drug resistant tuberculosis 1
Expose to person who has known drug-resistant tuberculosis

Exposure to a person with active tuberculosis who has prior treatment for tuberculosis (treatment failure or relapse)and whose susceptibility test results are not known

Expose to persons with active tuberculosis from areas in which there is a high prevalence of drug resistance From Centers for Disease Control and Prevention. Treatment of tuberculosis. American Thoracic Society of America. MMWR Morb Mortal Wkly Rep.2003;52(RR-11):1-88.

Risk factors for infection with Drug-Resistant Tuberculosis(1)

Dr.T.V.Rao MD

what is extensively drug resistant tuberculosis xdr tb
What is extensively drug resistant tuberculosis (XDR TB)?
  • Extensively drug resistant TB (XDR TB) is a relatively rare type of MDR TB. XDR TB is defined as TB which is resistant to isoniazid and rifampin, plus resistant to any fluoroquinolones and at least one of three injectable second-line drugs (i.e., amikacin, kanamycin, or Capreomycin).
  • Because XDR TB is resistant to first-line and second line drugs, patients are left with treatment options that are much less effective.
  • XDR TB is of special concern for persons with HIV infection or other conditions that can weaken the immune system. These persons are more likely to develop TB disease once they are infected, and also have a higher risk of death once they develop TB.

Dr.T.V.Rao MD

who report
WHO report
  • The report, "Anti-tuberculosis drug resistance in the world", is based on data collected between 2002 and 2006 on 90,000 TB patients in 81 countries. It found that extensively drug-resistant tuberculosis (XDR-TB), a virtually untreatable form of the respiratory disease, has been recorded in 45 countries

Dr.T.V.Rao MD

how can mdr tb be prevented
How can MDR TB be prevented?
  • The most important thing a person can do to prevent the spread of MDR TB is to take all of their medications exactly as prescribed by their health care provider. No doses should be missed and treatment should not be stopped early. Patients should tell their health care provider if they are having trouble taking the medications. If patients plan to travel, they should talk to their health care providers and make sure they have enough medicine to last while away.

Dr.T.V.Rao MD

role of health care workers
Role of Health Care Workers
  • Health care providers can help prevent MDR TB by quickly diagnosing cases, following recommended treatment guidelines, monitoring patients’ response to treatment, and making sure therapy is completed.

Dr.T.V.Rao MD

reduction of exposure to infected cases
Reduction of exposure to infected cases
  • Another way to prevent getting MDR TB is to avoid exposure to known MDR TB patients in closed or crowded places such as hospitals, prisons, or homeless shelters. If you work in hospitals or health-care settings where TB patients are likely to be seen, you should consult infection control or occupational health experts. Ask about administrative and environmental procedures for preventing exposure to TB. Once those procedures are implemented, additional measures could include using personal respiratory protective devices.

Dr.T.V.Rao MD

the global spread of mdr and xdr tb conclusions
MDR and XDRTB is increasing

There is little likelihood of new drugs being available within the next ten years

We will have to mange with what we have

Reduction in drug resistance has been achieved in some settings

Lessons form successful areas must be adapted and deployed in problem areas.

The global spread of MDR- and XDR- TB - conclusions

Dr.T.V.Rao MD

slide45

Better Understaning of Disease

  • Drug resistant strains of MTB are increasing worldwide
  • Causes for the emergence of MTB drug resistance are variable (healthcare mismanagement, unavailability of drugs, direct transmission of MTB resistant strains in vulnerable populations)
  • The treatment prognosis is dependent upon the level of drug resistance and the availability of second line drugs
  • Therapy of MDR/XDR TB is long-lasting (> 18 months) and frequently requires modifications due to adverse effects of the drugs
  • There is a need for biomarkers to predict the duration of therapy in individual patients
  • There is a need for the development of new drugs against MTB but not much is changing for now

Dr.T.V.Rao MD

slide46

MDR TB is a manmade

problem…..It is costly, deadly,

debilitating, and the biggest threat to our current TB control strategies.

Dr.T.V.Rao MD

should we treat or follow contacts to mdr xdr
The answer is….yes.

Guidelines for MDR and drug resistance recommend following the contact for at least two years.

Data to support strategies for managing contacts is very sparse.

Should we treat or follow contacts to MDR/XDR?

MMWR June 19, 1992 / 41(RR-11);59-71

Dr.T.V.Rao MD

slide49

Programme created by Dr. T.V.Rao MD for Medical , Paramedical , and Health care Workers in the Developing World

  • Email
  • doctortvrao@gmail.com

Dr.T.V.Rao MD