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 Organization’s (WHO’s) 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 percent of all TB cases worldwide
TB patient’s 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 non-adherence )
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
Re-treatment patients who’s 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
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 second-line drugs (i.e., amikacin, kanamycin, or capreomycin).
Because XDR TB is resistant to first-line and secondline 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.
Global Estimates 16,000 27,000 XDR TB 1,16,000, 4,24,000 MDR TB 1.6 million 8.8 million All forms TB Estimated Number of Deaths Estimated Number of Cases Classification
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 9–September 2007 in Emerging Infectious Diseases.
Global incidence of tuberculosis Still rising as a result of the growing epidemic in Africa 0 100 200 300 400 500 600 1990 1995 2000 2005 2010 2015 Incidence per 100,000 per year World Cent. Euro, East. Europe Est Market East. Medit. Lat. America West. Pacific Sth East Asia AFR high HIV AFR low HIV
Are we Returning to a Pre-antibiotic Era Drug susceptible TB*§ MDR-TB 1990§ XDR-TB 2006§ Total DR ? Resistance to H&R – Treatable with 2 nd line drugs Resistance to 2 nd line drugs – Treatment options seriously restricted Resistance to all available drugs – No treatment options *or limited resistance manageable with 4 drug regimen - DOTS
WHO Surveillance and Incidence of MDR TB Dye et al. Global Burden of Multidrug-Resistant TB. JID 185(8), 2002 5.3 Ivory Cost 6.6 Dominican 5.8 Iran 3.4 India 6.0 Russia 2.8 China (DOTS) 7.7 China (non-DOTS) 9.0 Latvia 14.1 Estonia % MDR TB of all new cases Country
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 .
Strains with genetic drug resistance Wild M. TB strain Acquired drug resistance Primary drug resistance Spontaneous mutation Selection: inadequate treatment Transmission Development of anti-tuberculosis drug resistance Pablos-Mendez et al. WHO, 1997
Factors Contributing to Development and Spread of MDR and XDR TB
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.
Detection of Rifampicin Drug susceptibility testing (DST) is more important .
Early 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.
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.
Secondary Drugs testing:[lack of standardized methods!]
! Ensure quality control and quality assurance ?
MODS M icroscopic O bservation of D rug Susceptibility T esting
MODS arose during experiments conducted by Luz Caviedes under the guidance of Professor Robert Gilman at Universidad Peruana Cayetano Heredia in Lima, Peru in the late 1990s in which a colorimetric test for TB growth was being investigated. The observation that microcolonies could be seen under the microscope long before a colour change occurred prompted the development of MODS.
Review Article in Indian Journal of Medical Microbiology
Caviedes L, Moore DA. Introducing mods: A low-cost, low-tech tool for high-performance detection of tuberculosis and multidrug resistant tuberculosis. Indian J Med Microbial 2007;25:87-8
MODS depends upon three key principles (which have been known for decades): (1) Mycobacterium tuberculosis grows faster in liquid (broth) than on solid media, (2) in liquid cultures M. tuberculosis grows in a visually characteristic manner (tangles, cording) which can be observed under the microscope long before the naked eye could visualize colonies on solid agar
Recently completed operational field studies have served to refine and streamline the methodology further and importantly validate MODS as a test for TB detection and MDRTB detection directly from sputum.
The scientific observations have proved that a single MODS culture of sputum sample offers more rapid and sensitive detection of tuberculosis and Multidrug-resistant tuberculosis than the existing gold standard methods used.
Advantages of MODS methodology in MDR detection
All the chemical ingredients are available locally, except few which can be acquired easily.
Existing infrastructure in District and Teaching hospital can be adopted for implementation of MODS
Risk to technician handling the specimens is minimal, there is no absolute need to obtain grade III safety cabinets,
Technology transfer is easier all the new technical manpower can be trained easily.
Four in control wells, no drug was used and each of the remaining 8 wells, contained one of the four drugs at one of the two concentrations tested.
The cultures were examined under an inverted light microscope at magnification of 40x every day ( except weekends ) from 4 to day 15, on alternative days from 16 today 25 and twice weekly from 26 to 40day.
Sample layout on MODS plate (2 samples per plate) No plate contained 2 samples from the same patient
Per specimen, there was concordance between MODS and LJ culture in 94.2% MODS tests were also less prone to contamination than LJ cultures. 62 [3.8%] vs (95 [5.8%] of 1,639 samples, respectively (P ≤0.01).
PCR: Molecular susceptibility testing RMP resistance INH resistance Hain Genotype MTBDR Hain Genotype MTBDR INNO-LiPA Rif.TB assay
Spacer Oligonucleotide typing Spoligotyping , polymerase chain reaction with multiple primers, or both were applied to all isolates from each of the three types of cultures in order to confirm the presence of M.tuberculosis.
Legitimate concerns about biosafety with other liquid culture systems do not really apply to MODS, indeed the converse is the case. After inoculation with decontaminated sample the MODS plates are permanently sealed in ziplock polythene bags through which the microscopic examination is made, thus spillage of the mycobacterial "soup" cannot occur.
As no secondary sub-culture is needed (because this is direct and not indirect susceptibility testing) no further manipulation is required - this zero potential for aerosolisation or accident compares favourably with the hazard associated with preparation of a standardized inoculum for indirect DST.
Computer pattern recognition of Mycobacterium tuberculosis in MODS culture
One possible drawback however, could be the inability of the laboratory technicians to distinguish between TB and some NTM. This could potentially have clinical impact in settings where NTM prevalence is high and not all mycobacteria respond to anti-TB treatment.
The laboratory methods for anti-tuberculosis drug susceptibility testing should be selected from among those that are WHO-recommended, and all laboratory processes should be quality-assured in cooperation with a partner Supranational Reference Laboratory (SRL)
“ Rapidly Fatal in South Africa” Tugela Ferry, KwaZulu-Natal
10% isolates resistant to ALL 1 st and 2 nd line agents
51/52 XDR dead in median 16 days after first positive sputum
67% AIDS deaths w/ MDR TB
Czech Republic The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the WHO concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. WHO 2005. All rights reserved Ecuador Georgia Argentina Bangladesh Germany Republic of Korea Armenia Russian Federation South Africa Portugal Latvia Mexico Peru USA Brazil UK Sweden Thailand Chile Based on information provided to WHO Stop TB Department 13 September 2007 Spain Islamic Republic of Iran China, Hong Kong SAR France Japan Norway Canada Italy Netherlands Estonia Lithuania Ireland Romania Israel Azerbaijan Poland Slovenia India Australia Mozambique Vietnam Countries with confirmed XDR-TB cases as of September 2007
High risk – Prolonged closed contact with infectious patients
Smear positive MDR TB patients
Medium risk –Primary health care centres involved
Sputum collection on TB suspects
Low risk –Health care support staff e.g. cleaners
Porters and admin staff
Koch failed to conquer tuberculosis, which still causes enormous health problems worldwide 100 years after his Nobel award.
The scientific academies noted that the triumphant discovery of 1882 was followed by a succession of failures: first of all, the failed attempt to present tuberculin as a remedy against tuberculosis in 1890-91, which severely damaged Koch's reputation
Medical History, 2001, 45: 1-32 CHRISTOPH GRADMANN *
Are there any solutions for effective Diagnosis in TB ?
Many more powerful hands needed to Control Tuberculosis
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