Drug Resistant

Tuberculosis
Emerging Human Concern
Dr.T.V.Rao MD

Dr.T.V.Rao MD

HISTORY of Tuberculosis
Tuberculosis Is an Ancient Disease Identified as Spinal Tuberculosis in Egyptian Mummies History dates to 1550 1080 BC Identified by PCR

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A Tribute to Robert Koch Discoverer of Mycobacterium Tuberculosis

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Historical Background

Neolithic Time
2400 BC - Egyptian mummies spinal columns

460 BC
Hippocrates, Greece
First

clinical description: Phthisis / Consumption (I am wasting away)

500-1500 AD
Roman occupation of Europe it spread to Britain

1650-1900 AD
White plague of Europe, causing one in five deaths
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Diagnostic discoveries

24th March 1882 (Robert Koch) TB Day Discovery of staining technique that identified Tuberculosis bacillus Definite diagnosis made possible 1890 (Robert Koch)

Tuberculin discovered Diagnostic use when injected into skin 1895 (Roentgen) Discovery of X-rays Early diagnosis of pulmonary Dr.T.V.Rao MD disease

From Tuberculosis to Tuberculin Failure of Robert Koch

Tuberculin therapy did in fact work in Koch's laboratory, even though it failed to do so almost anywhere else.. his reliance an animal experiments, which essentially differed from what many of his contemporaries, many differed with his ideas

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Global Status
Nine

million people suffer from tuberculosis Two million people die each year. Tuberculosis accounts for onethird of AIDS deaths world wide every year.
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USAID Report on Tuberculosis

in India
India

has more new tuberculosis (TB) cases annually than any other country, ranking first among the 22 high-burden TB countries worldwide, according to the World Health Organizations (WHOs) Global TB Report 2009. TB remains one of the leading infectious causes of mortality in India, causing more than 331,000 deaths in 2007. There were approximately 1.96 million new TB cases in India in 2007, representing more than 21 per cent of all TB cases worldwide
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Pharmacological discoveries
1908-1920

(Chalmette and Guerin)

strain Mycobacterium Bovis

Vaccine (BCG)
Attenuated

1943

Streptomycin developed
20th

November 1944
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Critically ill TB patient injected dramatically recovered

Selman Abraham Waksman

Nobel Prize for his discovery in 1952.

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Pharmacological discoveries
1956-1960

Combination therapy of INH and PZA cures TB

1955

Cycloserine 1962 Ethambutol 1963 Rifampicin 1970-1977

Combination of Rifampicin and Isoniazid adopted as International regime for treatment of TB
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No one is Immune to Tuberculosis Not only infects poor, but famous too

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Multi Drug Resistant Tuberculosis MDR-TB

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Definition
MDR-TB

caused by strains of Mycobacterium Tuberculosis resistant both Rifampicin and Isoniazid with or without resistance to other drugs. Single Isoniazid or Rifampicin resistance is not MDR - TB

MDR TB is a laboratory diagnosis

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Classification of Drugs
3

Groups depending upon the degree of effectiveness and potential side effects First Line: (Primary agents)
are

Isoniazid Rifampin

the most effective and have lowest toxicity.

Second Line:
Less

effective and more toxic effects include (in no particular order): p-amino salicylic acid, Streptomycin, Ethambutol

Third Line
are

least effective and most toxic. Amikacin, Kanamycin, Capreomycin, Viomycin, Kanamycin, Dr.T.V.Rao MD Cycloserine

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Basic concepts Keep facts

Primary (Initial) resistance TB patients initial Mycobacterium tuberculosis population resistant to drugs
Secondary (Acquired) resistance Drug-resistant M. tuberculosis in initial population selected by inappropriate drug use (inadequate treatment or nonadherence)
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When to suspect MDR TB

Re-treatment

patients whos sputum smear remains positive after three months of intensive therapy Treatment failure and interruption cases Close contacts of MDR tuberculosis cases Positive diagnoses with;

TB culture and susceptibility testing

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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 fluoroquinolone and at least one of three injectable secondline drugs (i.e., amikacin, kanamycin, or capreomycin).
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Why XDR - TB a grave concern

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.
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Global Estimates
Classificat Estimated Number ion of Cases All forms TB MDR TB XDR TB 8.8 million 4,24,000 27,000 Estimated Number of Deaths 1.6 million 1,16,000, 16,000

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Extensively Drug-Resistant Mycobacterium tuberculosis, India

The

first XDR TB cases in India and the emergence of XDR TB is reported by Rajesh Mondal* and Amita Jain* *King George's Medical University, Lucknow, India Volume
13, Number 9September 2007 in Emerging Infectious Diseases.
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Are we Returning to a Pre-antibiotic Era ???

Drug susceptible TB*

MDR-TB 1990

XDR-TB 2006

Total DR ?

*or limited resistance manageable with 4 drug regimen DOTS

Resistance to H&R Treatable with 2nd line drugs

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Resistance to 2nd line drugs Treatment options seriously restricted

Resistance to all available drugs

No treatment options

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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.
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Factors Contributing to Development and Spread of MDR and XDR TB

Weak TB programs (DOTS)

Low completion/cure rates Lack of treatment follow up and patient support Unreliable drug supply Diagnostic delay Absent or inadequate infection control measures Uncontrolled use of 2nd line drugs Fluroquinolones ?
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Mechanism of resistance
INH

Chromosomally mediated Loss of catalase/peroxidase Mutation in mycolic acid synthesis Regulators of peroxide response
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Mechanism of resistance
Rifampin

Reduced binding to RNA polymerase Clusters of mutations at Rifampin Resistance Determining Region (RRDR)
Reduced Cell wall permeability
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Gene location associated Drug-Resistant M.tuberculosis

Drug Isoniazid Rifampicin Ethambutol Streptomycin Pyrazinamide Fluoroquinolones Gene Kat G, Inh A, Kas A rpo B emb B rps L pnc A gyr A

Dubaniewicz A, et al. Molecular sub-type of the HLA-DR Dr.T.V.Rao MD antigens in pulmonary tuberculosis. Int J Infect Dis2000;4:12933.

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Current Scientific Documentations on Drug Resistance in Tuberculosis

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WHO Report on AntiTB Drug Resistance

Alarming Rise of Resistant Tuberculosis

490,000 new cases of MDR-TB each year, with >110,000 deaths1

Accounts for 5% of 9 million new cases of TB2 MDR-TB rates higher than ever (up to 22.3%), particularly in former Soviet Union countries XDR-TB reported by as many as 49 countries
(by June 2008)3

Recent WHO/IUATLD Global Surveillance report indicated 7.5% (301/4012) of MDR TB to be XDR4 Around 40,000 XDR-TB cases emerge every year1
1Tuberculosis: 2Hargreaves

MDR-TB & XDR-TBThe 2008 Report. The Stop TB Department, WHO. S. http://infection.thelancet.com, Vol 8, April 2008, p.220 3Raviglione MC. NEJM 2008;359:636-8. 4Anti-TB Drug Resistance in the World: Report No. 4. The Dr.T.V.Rao MD WHO/IUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007. World Health Organization, 2008 (WHO/HTM/TB2008.394).

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MDR-TB & XDR-TB THE 2008 REPORT % of MDR-TB among new TB cases 1994-2007

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MDR-TB rates higher than ever (up to 22.3%), particularly in former Soviet Union countries

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Alarming Rise of Resistant TB

Resistant TB burden in countries of former Soviet Union

about 50% of cases resistant to at least one drug about 20% MDR XDR-TB proportions also higher (as high as 24% in Estonia)1

MDR/XDR TB essentially a man-made problem2

High numbers of resistant cases (>400,000 MDR-TB cases every year) due mainly to:
Underinvestment in basic TB control Poor management of anti-TB drugs

Transmission of drug resistant strains1

1Anti-TB Drug Resistance in the World: Report No. 4. The WHO/IUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance 2002-2007. World Health Organization, 2008 (WHO/HTM/TB2008.394). Dr.T.V.Rao MD 2Reichman. The Lancet 2008:371:1052-3.
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The Much Discussed Article on XDR TB in the Lancet*

Of the 221 multi-drug resistant (MDRTB) cases, 53 (24%) were XDR. Almost all (52 of 53) of the XDR-TB patients died, with a median survival of only 16 days from the time of diagnosis
(in the 42 patients with confirmed dates of death)

All the 44 XDR TB patients who were tested for HIV were found co-infected 55% patents had never received anti-TB drugs, suggesting primary transmission of XDR pathogen

67% patients had been admitted to the hospital in the preceding 2 years, suggesting potential role of nosocomial transmission.
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* Gandhi et al. Lancet 2006;368:1575-80.

Poor mangement of infected lead to grwoing resistance

Resistance

to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care. Problems include incorrect drug prescribing practices by providers, poor quality drugs or erratic supply of drugs, and also patient nonadherence
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Susceptibility Testing

Direct and indirect testing Primary Drugs testing Isoniazid Rifampicin Ethambutol (*) Pyrizinamide (*)
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Drug susceptibility testing (DST)

DST

is recommended for all new cases for all first line drugs with specimens taken before initiating treatment.? Accuracy is more important than speed DST results should come from a small number of well-equipped, experienced laboratories who participate and perform well in an international DST quality control scheme. The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage for this
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Drug susceptibility Testing

Assessment

of growth inhibition on solid media containing various dilutions of the drug, in comparison with the test strains. As the method depend observation of growth Results are not available until several weeks after isolation of the organism.

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Other accredited Methods

Radiometric

methods Nucleic acid technology effective upto 95% in mutations to rifampicin resistance to gene rpoB gene
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and Non radiometric

Drug susceptibility testing (DST)

As

a minimum, laboratories supplying DST data, should correctly identify resistance to isoniazid and rifampicin in over 90% of quality control samples in two out of the last three quality control rounds.
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Detection of Rifampicin Drug susceptibility testing (DST) is more important.

identification of mycobacterial growth as M. tuberculosis complex and the identification of rifampicin resistance should be the first priority as rifampicin resistance invalidates standard 6 month short-course chemotherapy and is a useful marker in most countries for MDR-TB. Laboratories should aim to identify isolates as M. tuberculosis complex and perform rifampicin resistance in 90% of isolates within 1-2 working days. This is technologically feasible.
Early
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Drug susceptibility testing

For

DST laboratories, modern molecular techniques permit the successful identification of isoniazid resistance in at least 75% of mycobacterial cultures within 1-2 working days and are useful preliminary screens for isoniazid resistance.
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Secondary Drugs testing: [lack of standardized methods!]

Ofloxacin,

quinolones Ethionamide Kanamycin Capreomycin ! Ensure quality control and quality assurance ?
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WHO Controls the Tuberculosis related work

The

laboratory methods for antituberculosis drug susceptibility testing should be selected from among those that are WHO-recommended, and all laboratory processes should be qualityassured in cooperation with a partner Supranational Reference Laboratory (SRL)
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Other WHO-Endorsed Tools

Liquid

culture (e.g. MGIT, BacT/ALERT) TB

Capilia

Rapid strip test that detects a TB-specific antigen from culture

Molecular

line probe assays (e.g. GenoType MTBDRplus, INNO-LiPA Rif.TB)

Strip test for detection of TB and drugresistance conferring mutations
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BacT/ALERT

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CDC Updates Guidelines for Nucleic Acid Amplification Techniques to Diagnose Tuberculosis

NAAT

results should be interpreted in conjunction with the AFB smear results. NAAT and smear positive: start Rx despite pending culture results. PPV 95% Smear negative, NAAT positive: use clinical judgment to either treat or await culture
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Selection from automated systems for molecular and bacteriological rapid diagnostics
PCR:

Roche/COBAS:

amplification kits Roche/COBAS : LightCycler (realtime-PCR) Roche/COBAS : TaqMan 48 (increases the specificity of real-timePCR)
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Amplicor

Molecular Fingerprinting
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of 30 (87%) XDR TB isolates found to be genetically similar Majority of patients had no previous history of TB treatment Suggestive of recent infection with drugresistant strain

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Is PCR methods a solution ?

PCR

can't yet replace neither microscopy, culturing and competent clinical examination.

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No testing method replaces Clinical assessment

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XDR-TB
The

description of XDR-TB was first used earlier in 2006, following a joint survey by WHO and the US Centres for Disease Control and Prevention (CDC)
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How
Acquired

x-MDR generated

resistance is that which occurs as a result of specific previous treatment. The level of primary resistance in the community is considered to reflect the efficacy of control measures in the past, while the level of acquired resistance is a measure of on-going TB control measures
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Extreme Drug resistant Tuberculosis (XDR-TB)

Resistant

No

to all first line drugs namely; Isoniazid and Rifampin and Three or more second line drugs (SLDS) that are used to treat MDR-TB Thequinalones like Ofloaxin Or Aminoglycosides like Capreomycin & Kanamycin

third-line drugs available to treat XDR-TB since none has been developed in the last 40 years.
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Background Extensively drugresistant tuberculosis

Extensively

resistant tuberculosis has been reported in 45 countries, including countries with limited resources and a high burden of tuberculosis.
54

drug-

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Transmission of X -MDR
Like

other forms of TB, XDR-TB is spread through the air. When a person with infectious TB coughs, sneezes, talks or spits, they propel Mycobacterium into the air.

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Best options to diagnose X-MDR tuberculosis

.

To evaluate drug susceptibility, the bacteria need to be cultivated and tested in a suitable laboratory. Final diagnosis in this way for TB, and especially for XDR-TB, may take from 6 to 16 weeks To reduce the time needed for diagnosis, new tools for rapid TB diagnosis are urgently needed.
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When to suspect MDR TB ?

Patients

not showing any reduction in

bacillary population after 3-months of

regular treatment with Cat II regimen

Sputum

positive

patients

who

are

contacts of a known MDR TB patient

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How to evaluate MDR TB ?

MDR

TB is only a laboratory proved

HR resistance
Clinical

suspicion should be

followed by lab. Confirmation

Laboratories

should be quality
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controlled

Extreme Drug resistant Tuberculosis (XDR-TB) and AIDS

It

can also be contracted without a patient receiving any previous treatment for TB Mostly associated with HIV positive patients HIV has the potential to fast tracking XDR-TB into an uncontrollable epidemic Average survival period for patients infected with XDR-TB is 16 days.

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Responding to MDR/XDR-TB
Augment DOTS Program by

New diagnostics New drugs New vaccines HIV incidence reduction Advocacy1

A mathematical model projected by Basu and co-workers indicates that half of XDR-TB can be averted by 2012 by bringing synergistic effects through:

Use of masks Reduced time as in-patient Improved ventilation Rapid resistance testing HIV treatment TB isolation facilities2

1Marteens and Wilkinson. Lancet 2007;370:2030-43 2Basu et al. Quoted in: Porco and Getz. Lancet 2007;370:1464-5. Dr.T.V.Rao MD

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Second Line Drug Treatment (SLDs)

Less effective, more costly and more toxic, 50% cure rate

Four

months intensive phase (5 drugs)

Kanamycin's Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol

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World Health Organisation (WHO) Guidelines for treatment of MDR-TB

Strengthen

basic TB care to prevent the emergence of drug-resistance Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients Increase investment in laboratory infrastructures to enable better detection and management of resistant cases.
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Treatment Guidelines
Sensitivity

specimens Patient, Family and staff counselling & education Correct and thorough hand washing protocol and procedure!!! Personal protection is very important!!
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testing for all smear positive

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THE NEW MDR-TB Guidelines

A

flexible framework approach combining both clinical and programmatic aspects of DOTS Plus based on essential programme conditions But encouraging programs to tailor their case-finding and treatment strategies to the local epidemiological and Programme situation Reflect GLC expert consensus and evidence and experience from GLC projects thus far
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Effective laboratory Diagnosis

Sputum smear examinations rapid classification of species (atypical mycobacteria common in AIDS) Culture examinations

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Rapid drug sensitivity testing

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MDR TB and HIV

MDR TB occurs with the same frequency in HIV patients as in TB patients who are smear negative

Transmission of drug-resistant strains among HIV-infected

patients

in

congregate

settings

occurs

leading

to

outbreaks of MDR TB in such settings

Infection control measures absolutely essential in settings where large number of HIV TB patients stay together.

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Transmission is dependent on closeness and time of contact

In

penitentiary care contacts are very close and prolonged culture positive cases can also transmit TB especially to HIV positive population
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To Know more on MDR TB Current Guidelines of WHO

Guidelines

for the programmatic management of drug-resistant tuberculosis - 2011 update [pdf 904kb] Visit .

WHO/HTM/TB/2011.6
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Are there any solutions for effective Diagnosis in TB ?

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 Programme

Created by Dr.T.V.Rao MD for Medical and Health Care Workers in the Developing World
Email
doctortvrao@gmail.com

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