Multidrug resistant tuberculosis

drug resistant tuberculosisMDR-TB, XMDR-TB : 

Dr.T.V.Rao MD drug resistant tuberculosisMDR-TB, XMDR-TB Dr.T.V.Rao MD 1

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Dr.T.V.Rao MD 2

Why INH and Rifampin are important : 

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. Dr.T.V.Rao MD 3

Definitions : 

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. Dr.T.V.Rao MD 4

Drug–Resistant M. tuberculosis : 

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). Dr.T.V.Rao MD 5

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Dr.T.V.Rao MD 6

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. What is multidrug-resistant tuberculosis (MDR TB)? Dr.T.V.Rao MD 7

Challenges: : 

Accurately diagnose infections Prevent transmission Provide appropriate treatment Correctly classify the organism Challenges:

Genesis of MDR TB : 

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. Dr.T.V.Rao MD 9

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Dr.T.V.Rao MD 10

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11 4 x increase in volume as compared to 1960 - 75 Source: Population Action International 1994 Does Microbes, will travel faster… With Migrating populations increasing ? Compared to 1960-75, four-fold increase in migration Dr.T.V.Rao MD

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Definition of MTB drug resistance Dr.T.V.Rao MD 12

Mechanism of resistance : 

INH Chromosomally mediated Loss of catalase/peroxidase Mutation in my colic acid synthesis Regulators of peroxide response Mechanism of resistance Dr.T.V.Rao MD 13

Mechanism of resistance : 

Rifampin Reduced binding to RNA polymerase Clusters of mutations at “Rifampin Resistance Determining Region” (RRDR) Reduced Cell wall permeability Mechanism of resistance Dr.T.V.Rao MD 14

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15 Spontaneous mutations develop as bacilli proliferate to >108 Dr.T.V.Rao MD

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16 INH Drug-resistant mutants in large bacterial population Multidrug therapy: No bacteria resistant to all 3 drugs Monotherapy: INH-resistant bacteria proliferate Dr.T.V.Rao MD

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17 INH RIF INH Spontaneous mutations develop as bacilli proliferate to >108 INH mono-resist. mutants killed, RIF-resist. mutants proliferate  MDR TB INH resistant bacteria multiply to large numbers 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 18

XDR-TB a global threat : 

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) Dr.T.V.Rao MD 19

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Donald et al. NEJM 2009 MDR- and XDR- tuberculosis Dr.T.V.Rao MD 20

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 21

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Dr.T.V.Rao MD 22

Role of the Laboratory : 

23 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 : 

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 Dr.T.V.Rao MD 24

Drug Susceptibility Testing : 

25 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 : 

26 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 : 

Drug resistance testing Antimycobacterial Susceptibility Tests (ASTs) Two methods Agar based Broth based Creighton University does NE surveillance

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 ASTs by Agar proportion method

2. Prevent transmission : 

2. Prevent transmission Identifying suspected sources Understanding transmission patterns Genotyping provides tool

Genotyping Analysis : 

Genotyping Analysis Isolate A Isolate B Likely Related

Genotyping Analysis : 

Genotyping Analysis Isolate A Isolate B Not Related

Genotyping Methods : 

Two PCR-based methods: Spoligotyping MIRU-VNTR Results converted to numeric code Matches can be further investigated by other technologies Genotyping Methods

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 Spoligotyping

Spoligotyping : 

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 resistant Genes in Tuberculosis Drug Gene Rifampicin rpoB Streptomycin rpsL Isoniazid No: base pairs katG inhA Dr.T.V.Rao MD 35

Problems with drug resistance surveillance : 

Problems with drug resistance surveillance Quality of laboratory sensitivity testing Maintenance of standards over time Selection of specimens Only 1% of patients surveyed Dr.T.V.Rao MD 36

Epidemiology information of MDR-TB : 

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. Dr.T.V.Rao MD 37

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

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. Dr.T.V.Rao MD 38

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 39

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 WHO report Dr.T.V.Rao MD 40

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 41

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. Role of Health Care Workers Dr.T.V.Rao MD 42

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 43

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

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. Dr.T.V.Rao MD 44

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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 45

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46 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? : 

47 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. MMWR June 19, 1992 / 41(RR-11);59-71 Dr.T.V.Rao MD

Be united eliminate tuberculosis : 

Be united eliminate tuberculosis Dr.T.V.Rao MD 48

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Dr.T.V.Rao MD 49 Programme created by Dr. T.V.Rao MD for Medical , Paramedical , and Health care Workers in the Developing World Email doctortvrao@gmail.com