Multi-drug-resistant tuberculosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alejandro Lemor, M.D. [2]; Ammu Susheela, M.D. [3]

Multi-drug resistant tuberculosis (MDR-TB) is defined as TB that is resistant at least to isoniazid (INH) and rifampicin (RMP). Isolates that are resistant to any other combination of anti-TB drugs but not to INH and RMP are not classed as MDR-TB.

Mycobacterium tuberculosis was first described by Robert Koch in 1882 and in 1970 drug-resistant tuberculosis was first reported. Since then, several drugs and strategies have been implemented to control the disease. Cases in the US have decreased, however worldwide MDR-TB diagnosis is increasing, specially in developing countries.

Classification of drug resistant tuberculosis is based on drug susceptibility , pathophysiology, clinical classification and molecular classification. According to drug susceptibility it is classified as monoresistance, poly resistance, multidrug resistance, extensive drug resistance and rifampicin resistance. Clinically it is classified as acquired and primary resistance. The restriction fragment length polymorphism helps for molecular classification into unique and cluster type.

Tuberculosis is a granulomatous infection tansmitted mainly through droplets and can have pulmonary and extra pulmonary manifestations. Multi drug resistant strains of tuberculosis have been emerging at an alarming rate and they might be developed due to primary resistance or acquired resistance. These type of resistance are mainly through genetic mutations in genes like inhA, katG and rpob genes. These molecular pathophysiology can be detected through pyrosequencing, DNA sequencing and electrophoresis.

Mycobacterium tuberculosis is the bacterium responsible for tuberculosis. It is an aerobic, non-encapsulated, non-motile, acid-fast bacillus. M. tuberculosis belongs to the Mycobacterium tuberculosis complex, that also includes bacteria, such as M. bovis and M. africanum. The bacterium has a very slow rate of replication, and its genetic variations account for the geographical distribution of different strains, and are involved in drug resistance. M. tuberculosis has tropism for different kinds of human cells, with preference for cells of the lung. It may infect different species, yet human beings are its frequent natural reservoir.

Pulmonary tuberculosis must be differentiated from other diseases that cause cough, fever, night sweats, hemoptysis and weight loss, such as: brucellosis, bronchogenic carcinoma, Hodgkin lymphoma, bacterial pneumonia, sarcoidosis, mycoplasmal pneumonia.

Risk factors for multi-drug resistant tuberculosis include exposure to an individual with MDR-TB, previous TB treatment, HIV infection, and a low socioeconomic status.

Screening for tuberculosis is generally done with using a mantoux tuberculin skin test, also known as a tuberculin skin test or a PPD. The test involves injecting a small amount of a purified protein derivative of the tuberculosis bacterium intradermally, and watching for a reaction in the following days.

Tuberculosis has been classified as primary and post primary infection. It can have pulmonary and extra pulmonary manifestations as well as severe parenchymal, vascular, pleural and chest wall complications. The post primary infection can be due to a recent infection or reactivation of an old infection. Further multi drug resistant strains can develop through acquired resistance through inadequate treatment / treatment failure as well as slow gradual genetic mutation resulting in primary resistance. These are transmitted to healthy people resulting in emerging multi drug resistant strains. They can be rifampicin resistant, multi drug resistant, extensively drug resistant and totally drug resistant. The more the number of drugs the strain is resistant to , the poorer is the prognosis.

The general symptoms of MDR-TB will be the same as drug suceptible tuberculosis, these include weakness, weight loss, fever, and night sweats. Symptoms of pulmonary tuberculosis include cough, chest pain, and hemoptysis. Tuberculosis is particularly difficult to diagnose in children, as these may not present with common findings.

A physical examination can provide valuable information about the patient’s overall condition and other factors that may affect how tuberculosis is treated, such as HIV infection or other illnesses. The most common physical findings include fever, decreased breath sounds, tachypnea and tachycardia. Physical findings will depend on the location of the tuberculosis infection.

Routine laboratory exams are usually in the normal ranges. The presence of acid-fast-bacilli (AFB) on a sputum smear or other specimen often indicates TB disease and a positive culture for M. tuberculosis confirms the diagnosis. Other laboratory test include peritoneal fluid or CSF analysis, urinalysis, and Interferon-Gamma release assays. The Xpert MTB/RIF test is a molecular test that detects the DNA of the M. tuberculosis and resistance to rifampin. The use of this test has increased in the past years.

An X-ray is a very important diagnostic tool in pulmonary tuberculosis. Chest X-ray findings include parenchymal infiltrates, hiliar adenopathy, cavitation, nodules and pleural effusion. The most common location of a pulmonary tuberculosis lesion is the upper lobes.

The majority of patients with pulmonary tuberculosis will have abnormal findings in a chest CT, which include micronodules, interlobular septal thickening, cavitation and consolidation. CT scan is more sensitive than an X-ray to detect lymphadenopathies.

MRI is used for the assessment of extrapulmonary tuberculosis, such as CNS tuberculosis, osteoarticular tuberculosis, Pott’s disease, and parotid gland tuberculosis.

The abreugraphy is a smaller variant of the chest X-ray that allows the identification of lung abnormalities that may suggest the diagnosis of TB. With the decrease of incidence of TB, the abreugraphy is no longer recommended in most countries for low risk populations. However, depending on the screening resources of each country, it may be used for the screening of high-risk groups, such as HIV-positive patients and alcoholics.

Other diagnostic studies that could be performed in a patient with tuberculosis are the adenosine deaminase test and Nucleic Acid Amplification Test(NAAT).

Medical therapy for MDR-TB is based on the combination at least 4 drugs, one drug from each of the drug groups for TB. The duration of the treatment should be at least 18 months, depending on the culture results and clinical improvement.

Primary prevention of tuberculosis is targeted to avoid the disease transmission and infection of healthy individuals. The BCG vaccines is used in children susceptible to TB infection. Infection control measures for multi drug resistant tuberculosis include prompt diagnosis and treatment, isolation of patients already infected with Mycobacterium tuberculosis , early diagnosis and treatment of HIV infected tuberculosis. Primary prevention also includes enviornmental control measures like improving ventilation and use of personal respiratory protection like respiratory masks.

Secondary prevention for tuberculosis includes methods for screening and early diagnosis, such as tuberculin skin test (TST) and IGRAs; and to guarantee the correct treatment regimen at the right time to prevent disease progression.

Treatment of tuberculosis must be analysed for relative cost effectiveness of inpatient and outpatient models of care as it will benefit regions where tuberculosis is highly prevalent. Unless there is severe complications it is highly recommended to treat the TB patient in ambulatory care rather than inpatient services.^[1]

Since new drug resistant tuberculosis have been emerging, the role of future therapies is vital in curbing outbreaks. The new drugs should be more effective than the current regimen and a few drugs in clinical trials have been showing good results.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alejandro Lemor, M.D. [2]

Mycobacteria tuberculosis was first described by Robert Koch in 1882 and in 1970 drug-resistant tuberculosis was first reported. Since then, several drugs and strategies have been implemented to control the disease. Cases in US have decreased, however worldwide MDR-TB is increasing in developing countries.

• Tuberculosis has been present in humans since antiquity. The earliest unambiguous detection of Mycobacterium tuberculosis was in the remains of bison, dated 18,000 BC.^[1]
• However, whether tuberculosis originated in cattle and then transferred to humans, or diverged from a common ancestor, is currently unclear.^[2]
• Through history tuberculosis had many names, such as phthisis and Wasting disease, which were mostly derived from its symptoms.
• The rod-shaped bacteria Mycobacterium tuberculosis was only identified in 1882 by Robert Koch.
• In the 19th and early 20th centuries, tuberculosis caused the most widespread public concern, being considered an endemic disease of the urban poor. In 1946, the development of streptomycin made possible the treatment and cure for tuberculosis.
• During the 1970s, a multi-drug resistant mycobacterium tuberculosis was first described. ^[3]
• In 1990, the DOTS strategy was first introduced by WHO to prevent patient’s drop-out from the medical regimen.^[4]
• Since 1993 the proportion of patients with primary multidrug-resistant (MDR) TB decreased from 3% to 1% by 1998. ^[4]
• During 2009 through 2013, the percentage of primary MDR TB cases has remained stable at approximately 1%. ^[4]
• Since 1997, the percentage of U.S.-born patients with primary MDR TB has remained below 1%. ^[4]
• However, of the total number of reported primary MDR TB cases, the proportion occurring in foreign-born persons increased from 25% (103 of 407) in 1993 to 92% (75 of 82) in 2013.^[4]
• In 2012, an estimated of 450 000 cases of MDR-TB were reported and there were an estimated 170 000 deaths from MDR-TB.^[5]
• Also, the WHO reported that 3.6% of newly diagnosed TB cases were drug resistant and 20% of previously treated patients developed multi-drug resistant TB.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]

Classification of drug resistant tuberculosis is based on drug susceptibility , pathophysiology, clinical classification and molecular classification. According to drug susceptibility it is classified as monoresistance, poly resistance, multidrug resistance, extensive drug resistance and rifampicin resistance. Clinically it is classified as acquired and primary resistance. The restriction fragment length polymorphism helps for molecular classification into unique and cluster type.

Based on the drug susceptibility testing of cinical isolates confirmed to be Mycobacterium tuberculosis, the strains are classified as follows. ^[1]

Classification	Description
Monoresistance	Strain resistant to any one of the first line anti tubercular drugs
Polydrug resistance	Strain resistant to more than one first line anti tubercular drugs. (Other than both rifampicin and isoniazid)
Multidrug resistance	Strain resistant to both rifampicin and isoniazid
Extensive drug resistance	In addition to the multi drug resistance, strain is resistant to any fluroquinolone and to atleast one of the three second line injectable anti TB drugs like amikacin, capreomycin and kanamycin.
Rifampicin resistance	Using genotypic or phenotypic method, strain has been detected to have resistance to rifampicin with or without resistance to other anti TB drugs. It can include monoresistance, multi drug resistance, poly drug resistance or extensive drug resistance.

Clinically drug resistant tuberculosis can be classified into acquired drug resistance and primary drug resistance according to pathophysiology.^[2]

According to WHO , acquired resistance is defined as the isolation of drug resistant M. tuberculosis from a patient who has been treated for TB for one month or longer. Strains can acquire resistance against anti tubercular drugs in the following conditions.

• Inadequately treated by errors by caregivers in prescribing or administering drugs or supplying a poor quality drug
• Patients not completing the full course of treatment
• Patient receiving only partial treatment.

Such conditions can lead to the bacterial population to live for several months during the course of treatment thereby developing resistance against such drugs.

WHO defines primary resistanc as the isolation of a drug resistant strain from a patient without a history of previous treatment. When a patient gets infected with strains already resistant to anti tubercular drugs it is called as primary resistance. It could be against one drug of 1st line anti tubercular drugs or many drugs in the first and second line of drugs.

The restriction fragment length polymorphism helps in molecular classification of drug resistance into unique strains of drug resistance.

The restriction fragment length polymorphism helps in molecular classification of drug resistance into cluster of strains of drug resistance.

Below is a table with the current classification system of tuberculosis (TB), based on its pathogenesis:^[3]

Class	Type of Tuberculosis	Description
0	No TB exposure Not infected	No history of TB exposure Negative result to a TST or IGRA
1	TB exposure No evidence of infection	History of TB exposure Negative result to a TST (given at least 8-10 weeks after exposure) or IGRA
2	TB infection No TB disease	Positive result to a TST or IGRA Negative smears and cultures (if done) No clinical or x-ray evidence of active TB disease
3	Clinically active TB	Positive culture (if done) for M. tuberculosis Positive result to a TST or IGRA, and clinical, bacteriological, or x-ray evidence of TB disease
4	Previous TB disease (not clinically active)	Medical history of TB disease Abnormal but stable x-ray findings Positive result to a TST or IGRA Negative smears and cultures (if done) No clinical or x-ray evidence of active TB disease
5	Suspected TB	Signs and symptoms of TB disease, but incomplete evaluation

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Tuberculosis is a granulomatous infection tansmitted mainly through droplets and can have pulmonary and extra pulmonary manifestations. Multi drug resistant strains of tuberculosis have been emerging at an alarming rate and they might be developed due to primary resistance or acquired resistance. These type of resistance are mainly through genetic mutations in genes like inhA, katG and rpob genes. These molecular pathophysiology can be detected through pyrosequencing, DNA sequencing and electrophoresis.

Tuberculosis is a granulomatous infection which is chiefly transmitted through droplets. The granuloma prevents the dissemination of mycobacteria and provides a pathway for immune cell communication. Within the granuloma, T lymphocytes (CD4) secrete cytokines, such as interferon gamma, which activate local macrophages to kill the bacteria with which they are infected It is asymptomatic in 90% of immunocompetent individuals. In symptomatic patients it can present as pulmonary or extra pulmonary manifestations. The primary infection can progress to certain complications like disseminated infection. Tuberculosis can influence the progression of HIV if concomitantly present. Depending on the age of the patient, tuberculosis may have different clinical manifestations, progression, and prognosis.

MDR-TB can develop in the course of the treatment of fully sensitive TB and this is always the result of patients missing doses or failing to complete a course of treatment but MDR-TB strains appear to be less fit and less transmissible. This is known as acquired resistance to to anti tubercular drugs. Usually MDR strains do not dominate and isoniazid INH resistant tuberculosis is less potent. Also it is usually the people who are immunocompromised who are more susceptible to catching tuberculosis.

Drug resistance in Mycobacterium tuberculosis bacteria arises mainly through genetic mutations in the following aspects.

• Produce an activity of gene that binds or destroys the drug (e.g., mutations in inhA increase the amount of InhA protein which interferes with the activity of isoniazid by binding sufficient isoniazid to reduce its effective concentration in the bacterium to below an inhibitory level) ^[1]. ^[2]
• Block activation of a prodrug (e.g., mutations in katG lead to loss of the ability of catalase to activate the prodrug isoniazid to its active form),
• Block the activity of a drug (mutations in rpoB prevent binding of rifampicin to RNA polymerase and inhibition of transcription)

• The mutations that cause resistance to many of the antituberculosis drugs have been established, though much work remains to be done to identify the molecular basis of resistance for some of the drugs and to determine the predictive value of finding a particular mutation in a strain of M. tuberculosis . For example, approximately 95% of rifampin-resistant M. tuberculosis strains carry mutations within the rifampin-resistance determining region (RRDR), an 81-bp region encoding codons 507 through 533 of the rpoB gene.
• PCR is used to amplify a target sequence followed by a second assay to determine if the sequence contains a mutation associated with resistance. Methods that have been described for the latter include the following

• Pyrosequencing
• DNAsequencing
• Finding mismatches in heteroduplexes (e.g., branch migration inhibition or temperature gradient HPLC analysis ), and hybridization assays (e.g., membrane hybridization, molecular beacons,microarrays, or line-probe assays).
• Electrophoretic detection methods (e.g., single strand conformation polymorphism)

• Kits for detecting mutations associated with rifampicin resistance that are commercially available in Europe and elsewhere include line-probe assays . Some also detect mutations associated with isoniazid resistance. In-house PCR-based tests using molecular beacons have also been used for diagnostic purposes in a few clinical laboratories.
• For the assays that are subjected to hybridization, target gene causing resistance is amplified by PCR, and the PCR labeled products hybridized to oligonucleotide probes that are immobilized in a microarray or on a nitrocellulose strip. Mutations are detected by lack of binding to wild-type probes and/or by binding to probes specific for commonly occurring mutations. The performance of the line-probe assays relative to culture-based DS tests was evaluated in meta-analyses ^[3][4]
• Hybridization probes which emit fluorescence only when hybridized to their target is called molecular beacons. Molecular beacons can discriminate between targets differing by a single nucleotide. Because molecular beacons can use different fluorophores, real-time [[PCR] assays can be designed in which different DNA fragments or mutations can be amplified and detected simultaneously in the same tube. For example, a single-well assay has been developed that uses five molecular beacons to detect mutations associated with rifampicin resistance in M. tuberculosis bacteria and appears to perform similarly as the line-probe assays. In the California Microbial Diseases Laboratory, molecular beacons were designed to detect mutations in rpoB, katG, and inhA promoter region genes and directly applied to clinical specimens or to cultures. Comparison of molecular beacons results with results of culture-based drug-susceptibility testing showed 96% to 97% agreement in a series of approximately 1,000 clinical specimens and cultures ^[5]

• An approach that combines rapid (< 2hrs) DNA sequencing (K. Musser, personal communication) with PCR-amplification of the RRDR with was conducted at the Wadsworth Center . Two primers was developed to sequence the 81-bp RRDR of the rpoB gene and to gain a clear and accurate pyrogram. Evaluation of the pyrosequencing approach was in primary specimens positive for M. tuberculosis complex DNA by real-time PCR. Final results were compared with conventional susceptibility testing results or DNA sequencing.^[6] This test has a detection limit of <1 colony forming unit,99% agreement in the 188 cultures and specimens tested and 100% specificity.

• Molecular genetic tests for the other antituberculosis drugs are much less developed and studied than the tests for rifampicin resistance. A meta-analysis of the performance of the Hain MTBDR(plus) assay for detecting isoniazid revealed a pooled sensitivity of 0.85 (95%CI 0.77– 0.90) which ranged from 57%–100% and a pooled specificity of 0.99 (95%CI 0.98–1.00) which was fairly consistent across studies. Validation studies conducted in the California Microbial Diseases Laboratory that used archived cultures revealed that the molecular beacon test displayed 82.7% sensitivity, 100% specificity, 100% positive predictive value, and 98.1% negative predictive value for detecting isoniazid resistance ^[5]. Experiments for detetcting the XDR TB defining resistances, are in various stages of development from discovery of the mutations associated with resistance to development of prototype assays and laboratory-based evaluations.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2]

Synonyms and keywords: M. Tuberculosis

Mycobacterium tuberculosis is the bacterium responsible for tuberculosis. It is an aerobic, non-encapsulated, non-motile, acid-fast bacillus. M. tuberculosis belongs to the Mycobacterium tuberculosis complex, that also includes bacteria, such as M. bovis and M. africanum. The bacterium has a very slow rate of replication, and its genetic variations account for the geographical distribution of different strains, and are involved in drug resistance. M. tuberculosis has tropism for different kinds of human cells, with preference for cells of the lung. It may infect different species, yet human beings are its frequent natural reservoir.

Cellular organisms; Bacteria; Actinobacteria; Actinobacteria; Actinobacteridae; Actinomycetales; Corynebacterineae; Mycobacteriaceae; Mycobacterium; Mycobacterium tuberculosis complex; M. tuberculosis^[3]

Mycobacterium tuberculosis belongs to the Mycobacterium tuberculosis complex. This complex includes M. tuberculosis, M. bovis, M. africanum, M. canetti, and M. microti.^[4]

M. tuberculosis is an obligate aerobe, non-encapsulated, non-motile, acid-fast bacillus. Slender, straight or slightly curved bacillus with rounded ends, occuring singly, in pairs or in small clumps. It does not form spores and its ideal growing environment includes tissues with high levels of oxygen. It cannot be considered gram positive or gram negative due to its high lipid cell wall, which is impermeable to the dyes until combined with an alcohol. On microscopic examination of sputum samples, the bacteria cannot be distinguished from other acid-fast bacteria, such as Nocardia app.^[4]

M. tuberculosis has a very slow rate of replication, taking about 15 to 20 hours to divide. This characteristic, added to its ability to remain in the latent state for long periods of time, account for the long treatment duration required.^[4]

Genetic variances in the genome of M. tuberculosis lead to important phenotypical changes. There are many different strains of the bacteria, however, 6 of them were noted to be associated with specific geographic areas. This data is important since 3 strains, the Beijing family, strain W and the W-like strains, were noted to be associated with resistance to treatment drugs.^[5][6]

M. tuberculosis can infect different cells of the human body, however, due to its preference for tissues with high oxygen levels, its cellular tropism is mostly directed towards lung cells.^[4]

Human beings are the main natural reservoir for M. tuberculosis, however, the bacteria may infect other species.^[4]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alejandro Lemor, M.D. [2]

Pulmonary tuberculosis must be differentiated from other diseases that cause cough, fever, night sweats, hemoptysis and weight loss, such as: brucellosis, bronchogenic carcinoma, Hodgkin lymphoma, bacterial pneumonia, sarcoidosis, mycoplasmal pneumonia.

Disease	Findings
Bacterial pneumonia	Sudden onset of symptoms, such as high fever, cough, purulent sputum, chest pain. Consolidation on chest X-ray, leukocytosis.
Bronchogenic carcinoma	Can be asymptomatic, usually at older ages (> 50 years old); Symptoms include cough, hemoptysis, weight loss
Brucellosis	Fever, anorexia, night sweats, malaise,back pain , headache, and depression. History of exposure to infected animal
Hodgkin lymphoma	Fever, night sweats, pruritus, painless adenopathy, mediastinal mass
Mycoplasmal pneumonia	Gradual onset of dry cough, headache, malaise, sore throat. Diffuse bilateral infiltrates in chest X-ray.
Sarcoidosis	Non-caseating granulomas in lungs and other organs, bilateral hiliar adenopathy, predominantly in African American females.
Adapted from Mandell, Douglas, and Bennett’s principles and practice of infectious diseases 2010 [1]

Extra-Pulmonary Location	Differential Diagnosis
Tuberculous Lymphadenitis	Lymphoma, squamous cell carcinoma, papillary thyroid cancer, pyogenic infection
Skeletal Tuberculosis	Multiple myeloma, bone metastasis, spinal cord abscess, osteoporosis
Tuberculous Arthrits	Bacterial septic arthritis, pseudogout
Central Nervous System Tuberculosis	Bacterial meningitis, viral meningitis, encephalitis
Tuberculosis Peritonitis	Bacterial peritonitis, chronic peritoneal dialysis
Adapted from Asian Spine J. Feb 2014; 8(1): 97–111[2]; Handbook of Clinical Neurology[3]; Circulation Dec 2005 vol.112 no.23 3608-3616[4]; Am J Trop Med Hyg 2013 vol. 88 no. 1 54-64[5] Clin Infect Dis.(2011)53(6):555-562.[6]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]

Multi drug resistant tuberculosis has been emerging as an alarming threat due to the drug resistance developed due to inadequate treatment as well as slow gradual genetic mutations. People who are immunosupressed with diseases like HIV has a high chance of developing infection with multi drug resistant tuberculosis. The incidence of MDR varies substantially among countries. Prisons have a high incidence of multi drug resistant tuberculosis as well as people from soviet union have a high incidence of MDR TB

A 1997 survey of 35 countries found rates above 2% in about a third of the countries surveyed. The highest rates were in the former USSR, the Baltic states, Argentina, India and China, and was associated with poor or failing national Tuberculosis Control programmes. Likewise, the appearance of high rates of MDR-TB in New York city in the early 1990s was associated with the dismantling of public health programmes by the Reagan administration.^[1][2]

MDR-TB can develop in the course of the treatment of fully sensitive TB and this is always the result of patients missing doses or failing to complete a course of treatment.

Thankfully, MDR-TB strains appear to be less fit and less transmissible. It has been known for many years that INH-resistant TB is less virulent in guinea pigs, and the epidemiological evidence is that MDR strains of TB do not dominate naturally. A study in Los Angeles found that only 6% of cases of MDR-TB were clustered. This should not be a cause for complacency: it must be remembered that MDR-TB has a mortality rate comparable to lung cancer. It must also be remembered that people who have weakened immune systems (because of diseases such as HIV or because of drugs) are more susceptible to catching TB.

A 1997 survey of 35 countries found mortality rates above 2% in about a third of the countries surveyed. The highest rates were in the former USSR, Argentina, India and China, and was associated with poor or failing national tuberculosis control programs. Likewise, the appearance of high rates of MDR-TB in New York city in the early 1990s was associated with the dismantling of public health programmes.^[3][4]

MDR-TB strains appear to be less fit and less transmissible.^[5] It has been known for many years that INH-resistant TB is less virulent in guinea pigs, and the epidemiological evidence is that MDR strains of TB do not dominate naturally. A study in Los Angeles found that only 6% of cases of MDR-TB were clustered. MDR-TB has a mortality rate comparable to lung cancer. People who have weakened immune systems (because of diseases such as HIV or because of drugs) are more susceptible to catching TB.

Since late 2006, there has been an epidemic of XDR-TB in South Africa. The outbreak was first reported as a cluster of 53 patients in a rural hospital in KwaZulu-Natal of whom 52 died.^[6] What was particularly worrisome was that the median survival from sputum specimen collection to death was only 16 days and that the majority of patients had never previously received treatment for tuberculosis. This is the epidemic for which the acronym XDR-TB was first used, and although TB strains that fulfill the current definition have been identified retrospectively,^[7][8] this was the largest group of linked cases ever found. Since the initial report in September 2006,^[9] cases have now been reported in most provinces in South Africa. As of 16 March 2007, there were 314 cases reported, with 215 deaths.^[10] It is clear that the spread of this strain of TB is closely associated with a high prevalence of Aids and poor infection control; in other countries where XDR-TB strains have arisen, drug resistance has arisen from mismanagement of cases or poor patient compliance with drug treatment instead of being transmitted from person to person.^[11] This strain of TB does not respond to any of the drugs currently available in South Africa for first- or second-line treatment. It is now clear that the problem has been around for much longer than health department officials have suggested, and is far more extensive.^[12] By 23 November 2006, 303 cases of XDR-TB had been reported, of which 263 were in KwaZulu-Natal.^[13] Serious thought has been put to isolation procedures that may deny some patients their mobility. This has been seen as unconstitutional by the government and patients come and go as they see fit. The few that do get quarantined start riots and stone security guards. Quarantining patients is necessary to prevent further spread of this strain of TB.

• 3.6 % of the new tubercular cases have multi drug resistant strains.
• About 20% of the previously treated strains have drug resistance.
• The frequency of MDR TB varies substantially among countries.
• 10 % of MDR- TB cases are also resistant to two second line drug classes or XDR (Extensively drug resistant TB)
• 92 countries have reported at least oe XDR case by September 2013.
• About 450 000 people developed MDR-TB in the world in 2012. More than half of these cases were in India, China and the Russian Federation.
• It is estimated that about 9.6% of MDR-TB cases had XDR-TB.

The highest amount of MDR-TB and resistance in United States is found in foreign born population especially from Soviet Union with 8.5 % and 33.5% of any resistance of TB in 2000.

A rise in multi drug resistant strains of tuberculosis infection is found in prisons of developing countries as well as spanish prison and outbreaks in some prisons in New york city. ^[14]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alejandro Lemor, M.D. [2]

Risk factors for multi-drug resistant tuberculosis include exposure to an individual with MDR-TB, previous TB treatment, HIV infection, and a low socioeconomic status.

• The risk factor for developing multi-drug resistant tuberculosis include:^[1][2][3]

• Exposure to a patient with MDR-TB
• Previous TB treatment
• HIV infection
• Previous incarceration
• Failed TB treatment
• Relapse following standard TB treatment
• Low income and low socioeconomic class
• Individuals that come from areas of the world where drug-resistant TB is common
• Individuals that have spent time with someone known to have drug-resistant TB disease

• Adverse reactions of the drugs used in the treatment of tuberculosis contribute to the cease of the drug regimen and increases the probability of multi-drug resistance.
• Direct observed treatment plays an important role to avoid drop-outs from tuberculosis medical regimen, which is an important risk factor for developing resistance to the standard medical regimen.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alejandro Lemor, M.D. [2]

Screening for tuberculosis is generally done with using a mantoux tuberculin skin test, also known as a tuberculin skin test or a PPD. The test involves injecting a small amount of a purified protein derivative of the tuberculosis bacterium intradermally, and watching for a reaction in the following days.

The Mantoux tuberculin skin test (TST) is the standard method of determining whether a person is infected with Mycobacterium tuberculosis. Reliable administration and reading of the TST requires standardization of procedures, training, supervision, and practice. The TST is performed by injecting 0.1 ml of tuberculin purified protein derivative (PPD) into the inner surface of the forearm. The injection should be made with a tuberculin syringe, with the needle bevel facing upward. The TST is an intradermal injection. When placed correctly, the injection should produce a pale elevation of the skin (a wheal) 6 to 10 mm in diameter.

The skin test reaction should be read between 48 and 72 hours after administration. A patient who does not return within 72 hours will need to be rescheduled for another skin test.

The reaction should be measured in millimeters of the induration (palpable, raised, hardened area or swelling). The reader should not measure erythema (redness). The diameter of the indurated area should be measured across the forearm (perpendicular to the long axis).

TST is contraindicated only for persons who have had a severe reaction (e.g., necrosis, blistering, anaphylactic shock, or ulcerations) to a previous TST. It is not contraindicated for any other persons, including infants, children, pregnant women, persons who are HIV-infected, or persons who have been vaccinated with BCG.

In some persons who are infected with M. tuberculosis, the ability to react to tuberculin may wane over time. When given a TST years after infection, these persons may have a false-negative reaction. However, the TST may stimulate the immune system, causing a positive, or boosted reaction to subsequent tests. Giving a second TST after an initial negative TST reaction is called two-step testing.

Two-step testing is useful for the initial skin testing of adults who are going to be retested periodically, such as health care workers or nursing home residents. This two-step approach can reduce the likelihood that a boosted reaction to a subsequent TST will be misinterpreted as a recent infection.

Skin test interpretation depends on two factors:

• Measurement in millimeters of the induration.
• Person’s risk of being infected with TB and of progression to disease if infected.

Tuberculin Reaction	Considered a Positive Result in:
≥ 5 mm	HIV-positive person Recent contacts of TB case Persons with nodular or fibrotic changes on CXR consistent with old healed TB Patients with organ transplants and other immunosuppressed patients
≥ 10 mm	Recent arrivals (less than 5 years) from high-prevalent countries Injection drug users Residents and employees of high-risk congregate settings (e.g., prisons, nursing homes, hospitals, homeless shelters) Mycobacteriology lab personnel Persons with clinical conditions that place them at high risk (e.g., diabetes, prolonged corticosteroid therapy, leukemia, end-stage renal disease, chronic malabsorption syndromes, low body weight) Children less than 4 years of age, or children and adolescents exposed to adults in high-risk categories
≥ 15 mm	Persons with no known risk factors for TB
Table adapted from CDC[1]

False-Positive Reactions	False-Negative Reactions
Some persons may react to the TST even though they are not infected with M. tuberculosis. The causes of these false-positive reactions may include, but are not limited to, the following: Infection with nontuberculosis mycobacteria Previous BCG vaccination Incorrect method of TST administration Incorrect interpretation of reaction Incorrect bottle of antigen used	Some persons may not react to the TST even though they are infected with M. tuberculosis. The reasons for these false-negative reactions may include, but are not limited to, the following: Cutaneous anergy (anergy is the inability to react to skin tests because of a weakened immune system) Recent TB infection (within 8-10 weeks of exposure) Very old TB infection (many years) Very young age (less than 6 months old) Recent live-virus vaccination (e.g., measles and smallpox) Overwhelming TB disease Some viral illnesses (e.g., measles and chicken pox) Incorrect method of TST administration Incorrect interpretation of reaction
Table adapted from CDC[1]

• CDC recommends HIV screening for all TB patients after the patient is notified that testing will be performed, unless the patient declines (i.e., opt-out screening). This includes persons with TB disease and persons with latent TB infection.
• Routine HIV testing is also recommended for persons suspected of having TB disease, persons diagnosed with latent TB infection, and contacts to TB patients.
• Prevention counseling and separate written consent for HIV testing should no longer be required.
• These recommendations are aimed at eliminating missed opportunities for HIV screening and reducing significant barriers to HIV testing in health care settings by:

• Using opt-out HIV screening.
• Annually screening persons at high risk for HIV.
• Eliminating the need for separate written consent for HIV testing.
• Eliminating the need for prevention counseling as part of routine HIV screening.

• Opt-out screening is defined as performing HIV testing after notifying the patient that the test will be performed, and although the patient may decline or defer testing, it is strongly recommended. Assent is inferred unless the patient declines testing.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]

Tuberculosis has been classified as primary and post primary infection. It can have pulmonary and extra pulmonary manifestations as well as severe parenchymal, vascular, pleural and chest wall complications. The post primary infection can be due to a recent infection or reactivation of an old infection. Further multi drug resistant strains can develop through acquired resistance through inadequate treatment / treatment failure as well as slow gradual genetic mutation resulting in primary resistance. These are transmitted to healthy people resulting in emerging multi drug resistant strains. They can be rifampicin resistant, multi drug resistant, extensively drug resistant and totally drug resistant. The more the number of drugs the strain is resistant to , the poorer is the prognosis.

Tuberculosis has been classified as primary or secondary (post primary) infection. It can have pulmonary and extra pulmonary manifestations as well as severe parenchymal, vascular, pleural and chest wall complications. Pulmonary complications include pleural effusions, cavitations, lymphadenopathy, airway obstruction, pneumonia and bronchiectasis. The hematogenous dissemination of infection can lead to miliary tuberculosis. The post primary infection can be due to a recent infection or reactivation of an old infection. Without treatment, 1/3 of patients with active tuberculosis dies within 1 year of the diagnosis, and more than 50% during the first 5 years. But with early diagnosis and treatment it has a good prognosis.

• Drug resistant strains of Mycobacterium tuberculosis can develop due to failure of the full course of treatment for primary tuberculosis or indirect treatment of direct or indirect monotherapy. This mechanism is called as acquired resistance.
• Mycobacterium tuberculosis also has the ability to undergo slow , constant mutation resulting in resistant mutant organism. This process is known as primary resistance. The natural phenomenon of this mutation varies from drug to drug as follows.

• Isoniazid : One in every 10⁶ cell division
• Pyrazinamide : One in every 10⁵ cell division
• Streptomycin : One in every 10⁶ cell division
• Ethambutol : One in every 10⁵ cell division
• Rifampicin : One in every 10⁹ cell division

The anti tubercular drugs kills the susceptible bacteria , resulting in the selection of resistant mutants in the bacterial population and the emergence of multi drug resistant tuberculosis. The figure depicts the emergence of multi drug resistance strains by both the mechanisms. Due to inadequate treatment and failure of monotherapy , acquired drug resistance can occur in patients infected with Mycobacterium tuberculosis. Such strains can pass the drug resistance to the following generation as well as spread the multi drug resistant organism to other people. Also slow gradual genetic mutation can occur in the strains resulting in the primary resistance development and emergence of multi drug resistant strains.^[1]

• A rare type of MDR TB, Extensively drug resistant 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 the most powerful 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.

• MDR-TB is more difficult to treat than drug susceptible strains of Tuberculosis and one third of the people affected with MDR-TB die. The prognosis is worse for XDR than MDR. ^[2]
• The second line of drugs used in MDR has more side effects and are usually less effective. ^[3]

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