The treatment of multi drug resistant tuberculosis (mdr-tb) with sirturo (bedaquiline)(1)

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The treatment of multi drug resistant tuberculosis (mdr-tb) with sirturo (bedaquiline)(1)

  1. 1. THE TREATMENT OF MULTI-DRUG RESISTANT TUBERCULOSIS (MDR-TB) WITH SIRTURO(BEDAQUILINE) I.INTRODUCTION Tuberculosis, MTB, or TB (short for tubercle bacillus) is a common, and in many cases lethal, infectious disease caused by various strains of mycobacterium, usually Mycobacterium tuberculosis. Tuberculosis typically attacks the lungs, but can also affect other parts of the body. It is spread through the air when people who have an active TB infection cough, sneeze, or otherwise transmit their saliva through the air. Most infections are asymptomatic and latent, but about one in ten latent infections eventually progresses to active disease which, if left untreated, kills more than 50% of those so infected (Centers for Disease Control and Prevention ,2012). Tuberculosis (TB) is an infection caused by slow-growing bacteria that grow best in areas of the body that have lots of blood and oxygen. That’s why it is most often found in the lungs. This is called pulmonary TB. But TB can also spread to other parts of the body, which is called extrapulmonary TB. Treatment is often a success, but it is a long process. It usually takes about 6 to 9 months to treat TB. But some TB infections need up to 2 years to treat (http://www.cdc.gov/tb/). Tuberculosis is either latent or active: Latent TB means that you have the TB bacteria in your body, but your body’s defenses (immune system) are keeping it from turning into active TB. This means that you don't have any symptoms of TB right now and can't spread the disease to others. If you have latent TB, it can become active TB. Active TB means that the TB bacteria are growing and causing symptoms. If your lungs are infected with active TB, it is easy to spread the disease to others. II. EPIDEMIOLOGY One third of the world's population is thought to have been infected with M. tuberculosis, with new infections occurring at a rate of about one per second. In 2007, there were an estimated 13.7 million chronic active cases globally, while in 2012, there were an estimated 8.8 million new cases and 1.5 million associated deaths, mostly occurring in developing countries. The absolute number of tuberculosis cases has been decreasing since 2006, and new cases have decreased since 2002. The distribution of tuberculosis is not uniform across the globe; about 80% of the CMR College of Pharmacy, (Pharmacology), Page 1
  2. 2. THE TREATMENT OF MULTI-DRUG RESISTANT TUBERCULOSIS (MDR-TB) WITH SIRTURO(BEDAQUILINE) population in many Asian and African countries test positive in tuberculin tests, while only 5– 10% of the United States population tests positive. More people in the developing world contract tuberculosis because of compromised immunity, largely due to high rates of HIV infection and the corresponding development of AIDS (World Health Organization). III. TB DEFINITIONS 3.1 Tuberculosis (TB): Tuberculosis, commonly known as TB, is a contagious and an often severe airborne disease caused by a bacterial infection. TB typically affects the lungs, but it also may affect any other organ of the body. It is usually treated with a regimen of drugs taken for 6 months to 2 years, depending on the type of infection.(World Health Organization 2012, http://www.cdc.gov/tb). 3.2 Multidrug-Resistant Tuberculosis (MDR TB): MDR TB is a form of drug-resistant TB in which TB bacteria can no longer be killed by at least the two best antibiotics, isoniazid (INH) and rifampin (RIF), commonly used to cure TB. As a result, this form of the disease is more difficult to treat than ordinary TB and requires up to 2 years of multidrug treatment ( World Health Organization 2012, http://www.cdc.gov/tb). 3.3 Extensively Drug-Resistant Tuberculosis (XDR TB): XDR TB is a less common form of multidrug-resistant TB in which TB bacteria have changed enough to circumvent the two best antibiotics, INH and RIF, as well as most of the alternative drugs used against MDR TB. These second-line drugs include any fluoroquinolone, and at least one of the other three injectable anti-TB drugs: amikacin, kanamycin, or capreomycin. As a result, XDR TB needs up to 2 years of extensive drug treatment and is the most challenging to treat (World Health Organization 2012). IV. ETIOLOGY 4.1 Causative organism: Tuberculosis is an infection caused by the rod-shaped, non–spore-forming, aerobic bacterium Mycobacterium tuberculosis.Mycobacteria typically measure 0.5 μm by 3 μm, are classified as acid-fast bacilli, and have a unique cell wall structure crucial to their survival. The well-developed cell wall contains a considerable amount of a fatty acid, mycolic acid, covalently CMR College of Pharmacy, (Pharmacology), Page 2
  3. 3. THE TREATMENT OF MULTI-DRUG RESISTANT TUBERCULOSIS (MDR-TB) WITH SIRTURO(BEDAQUILINE) attached to the underlying peptidoglycan-bound polysaccharide arabinogalactan, providing an extraordinary lipid barrier. This barrier is responsible for many of the medically challenging physiological characteristics of tuberculosis, including resistance to antibiotics and host defense mechanisms. The composition and quantity of the cell wall components affect the bacteria’s virulence and growth rate. The peptidoglycan polymer confers cell wall rigidity and is just external to the bacterial cell membrane, another contributor to the permeability barrier of mycobacteria. Another important component of the cell wall is lipoarabinomannan, a carbohydrate structural antigen on the outside of the organism that is immunogenic and facilitates the survival of mycobacteria within macrophages.The cell wall is key to the survival of mycobacteria, and a more complete understanding of the biosynthetic pathways and gene functions and the development of antibiotics to prevent formation of the cell wall are areas of great interest. The M. tuberculosis complex (MTBC) includes four other TB-causing mycobacteria: M. bovis, M. africanum, M. canetti, and M. microti. M. africanum is not widespread, but it is a significant cause of tuberculosis in parts of Africa. M. bovis was once a common cause of tuberculosis, but the introduction of pasteurized milk has largely eliminated this as a public health problem in developed countries. M. canetti is rare and seems to be limited to the Horn of Africa, although a few cases have been seen in African emigrants. M. microti is also rare and is mostly seen in immunodeficient people, although the prevalence of this pathogen has possibly been significantly underestimated. Other known pathogenic mycobacteria include M. leprae, M. avium, and M. kansasii. The latter two species are classified as "nontuberculous mycobacteria" (NTM). NTM cause neither TB nor leprosy, but they do cause pulmonary diseases that resemble TB (Harsh Mohan 2006). 4.2 Pathophysiology: Infection with M tuberculosis results most commonly through exposure of the lungs or mucous membranes to infected aerosols. Droplets in these aerosols are 1-5 μm in diameter; in a person with active pulmonary TB, a single cough can generate 3000 infective droplets, with as few as 10 bacilli needed to initiate infection. CMR College of Pharmacy, (Pharmacology), Page 3
  4. 4. THE TREATMENT OF MULTI-DRUG RESISTANT TUBERCULOSIS (MDR-TB) WITH SIRTURO(BEDAQUILINE) When inhaled, droplet nuclei are deposited within the terminal airspaces of the lung. The organisms grow for 2-12 weeks, until they reach 1000-10,000 in number, which is sufficient to elicit a cellular immune response that can be detected by a reaction to the tuberculin skin test. Mycobacteria are highly antigenic, and they promote a vigorous, nonspecific immune response. Their antigenicity is due to multiple cell wall constituents, including glycoproteins, phospholipids, and wax D, which activate Langerhans cells, lymphocytes, and polymorphonuclear leukocytes. When a person is infected with M tuberculosis, the infection can take 1 of a variety of paths, most of which do not lead to actual TB. The infection may be cleared by the host immune system or suppressed into an inactive form called latent tuberculosis infection (LTBI), with resistant hosts controlling mycobacterial growth at distant foci before the development of active disease. Patients with LTBI cannot spread TB. The lungs are the most common site for the development of TB; 85% of patients with TB present with pulmonary complaints. Extrapulmonary TB can occur as part of a primary or late, generalized infection. An extrapulmonary location may also serve as a reactivation site; extrapulmonary reactivation may coexist with pulmonary reactivation. The most common sites of extrapulmonary disease are as follows (the pathology of these lesions is similar to that of pulmonary lesions): Mediastinal, retroperitoneal, and cervical (scrofula) lymph nodes - The most common site of tuberculous lymphadenitis (scrofula) is in the neck, along the sternocleidomastoid muscle; it is usually unilateral and causes little or no pain; advanced cases of tuberculous lymphadenitis may suppurate and form a draining sinus Vertebral bodies Adrenals Meninges GI tract CMR College of Pharmacy, (Pharmacology), Page 4
  5. 5. THE TREATMENT OF MULTI-DRUG RESISTANT TUBERCULOSIS (MDR-TB) WITH SIRTURO(BEDAQUILINE) Infected end organs typically have high regional oxygen tension (as in the kidneys, bones, meninges, eyes, and choroids, and in the apices of the lungs). The principal cause of tissue destruction from M tuberculosis infection is related to the organism's ability to incite intense host immune reactions to antigenic cell wall proteins. Uveitis caused by TB is the local inflammatory manifestation of a previously acquired primary systemic tubercular infection. There is some debate with regard to whether molecular mimicry, as well as a nonspecific response to noninfectious tubercular antigens, provides a mechanism for active ocular inflammation in the absence of bacterial replication (Harsh Mohan 2006). 4.3 TB lesions: The typical TB lesion is an epithelioid granuloma with central caseation necrosis. The most common site of the primary lesion is within alveolar macrophages in subpleural regions of the lung. Bacilli proliferate locally and spread through the lymphatics to a hilar node, forming the Ghon complex. Early tubercles are spherical, 0.5- to 3-mm nodules with 3 or 4 cellular zones demonstrating the following features: A central caseation necrosis An inner cellular zone of epithelioid macrophages and Langhans giant cells admixed with lymphocytes An outer cellular zone of lymphocytes, plasma cells, and immature macrophages A rim of fibrosis (in healing lesions) Initial lesions may heal and the infection become latent before symptomatic disease occurs. Smaller tubercles may resolve completely. Fibrosis occurs when hydrolytic enzymes dissolve tubercles and larger lesions are surrounded by a fibrous capsule. Such fibrocaseous nodules usually contain viable mycobacteria and are potential lifelong foci for reactivation or cavitation. Some nodules calcify or ossify and are seen easily on chest radiographs. CMR College of Pharmacy, (Pharmacology), Page 5
  6. 6. THE TREATMENT OF MULTI-DRUG RESISTANT TUBERCULOSIS (MDR-TB) WITH SIRTURO(BEDAQUILINE) Tissues within areas of caseation necrosis have high levels of fatty acids, low pH, and low oxygen tension, all of which inhibit growth of the tubercle bacillus. If the host is unable to arrest the initial infection, the patient develops progressive, primary TB with tuberculous pneumonia in the lower and middle lobes of the lung. Purulent exudates with large numbers of acid-fast bacilli can be found in sputum and tissue. Subserosal granulomas may rupture into the pleural or pericardial spaces and create serous inflammation and effusions. With the onset of the host immune response, lesions that develop around mycobacterial foci can be either proliferative or exudative. Both types of lesions develop in the same host, since infective dose and local immunity vary from site to site. Proliferative lesions develop where the bacillary load is small and host cellular immune responses dominate. These tubercles are compact, with activated macrophages admixed, and are surrounded by proliferating lymphocytes, plasma cells, and an outer rim of fibrosis. Intracellular killing of mycobacteria is effective, and the bacillary load remains low. Exudative lesions predominate when large numbers of bacilli are present and host defenses are weak. These loose aggregates of immature macrophages, neutrophils, fibrin, and caseation necrosis are sites of mycobacterial growth. Without treatment, these lesions progress and infection spreads (Harsh Mohan 2006, World Health Organization 2012 ). V. Latent TB Infection and TB Disease Not everyone infected with TB bacteria becomes sick. As a result, two TB-related conditions exist: latent TB infection and TB disease 5.1 Latent TB Infection: TB bacteria can live in the body without making you sick. This is called latent TB infection. In most people who breathe in TB bacteria and become infected, the body is able to fight the bacteria to stop them from growing. People with latent TB infection do not feel sick and do not have any symptoms. People with latent TB infection are not infectious and cannot spread TB CMR College of Pharmacy, (Pharmacology), Page 6
  7. 7. THE TREATMENT OF MULTI-DRUG RESISTANT TUBERCULOSIS (MDR-TB) WITH SIRTURO(BEDAQUILINE) bacteria to others. However, if TB bacteria become active in the body and multiply, the person will go from having latent TB infection to being sick with TB disease. 5.2 TB Disease: TB bacteria become active if the immune system can't stop them from growing. When TB bacteria are active (multiplying in your body), this is called TB disease. People with TB disease are sick. They may also be able to spread the bacteria to people they spend time with every day. Many people who have latent TB infection never develop TB disease. Some people develop TB disease soon after becoming infected (within weeks) before their immune system can fight the TB bacteria. Other people may get sick years later when their immune system becomes weak for another reason. Person with LTBI (Infected) Person with TB Disease (Infectious) Has a small amount of TB bacteria in his/her Has a large amount of active TB bacteria in body that are alive, but inactive his/her body Cannot spread TB bacteria to others May spread TB bacteria to others Does not feel sick, but may become sick if the May feel sick and may have symptoms such as bacteria become active in his/her body a cough, fever, and/or weight loss Usually has a TB skin test or TB blood test Usually has a TB skin test or TB blood test reaction indicating TB infection reaction indicating TB infection Radiograph is typically normal Radiograph may be abnormal Sputum smears and cultures are negative Sputum smears and cultures may be positive Should consider treatment for LTBI to prevent Needs treatment for TB disease TB disease Does not require respiratory isolation May require respiratory isolation Not a TB case A TB case Table. no 5.2a. Deference between LTBI and TB Disease CMR College of Pharmacy, (Pharmacology), Page 7
  8. 8. THE TREATMENT OF MULTI-DRUG RESISTANT TUBERCULOSIS (MDR-TB) WITH SIRTURO(BEDAQUILINE) Persons at Increased Risk • Persons infected with HIV; • Children younger than 5 years of age; • Persons who were recently infected with M. tuberculosis (within the past 2 years); • Persons with a history of untreated or inadequately treated TB disease, including persons with fibrotic changes on chest radiograph consistent with prior TB disease; • Persons who are receiving immunosuppressive therapy such as tumor necrosis factor-alpha (TNF) antagonists, systemic corticosteroids equivalent to/greater than 15 mg of prednisone per day, or immunosuppressive drug therapy following organ transplantation; • Persons with silicosis, diabetes mellitus, chronic renal failure, leukemia, or cancer of the head, neck, or lung; • Persons who have had a gastrectomy or jejunoileal bypass; • Persons who weigh less than 90% of their ideal body weight; • Cigarette smokers and persons who abuse drugs and/or alcohol; and • Populations defined locally as having an increased incidence of disease due to M. tuberculosis, including medically underserved, low-income populations. Table. no 5.2b. Persons at Increased Risk for Progression of LTBI to TB Disease For people whose immune systems are weak, especially those with HIV infection, the risk of developing TB disease is much higher than for people with normal immune systems (World Health Organization (2012). 5.2.1 Signs and Symptoms of TB Disease: Symptoms of TB disease depend on where in the body the TB bacteria are growing. TB bacteria usually grow in the lungs (pulmonary TB). TB disease in the lungs may cause symptoms such as A bad cough that lasts 3 weeks or longer pain in the chest coughing up blood or sputum (phlegm from deep inside the lungs) Other symptoms of TB disease are CMR College of Pharmacy, (Pharmacology), Page 8
  9. 9. THE TREATMENT OF MULTI-DRUG RESISTANT TUBERCULOSIS (MDR-TB) WITH SIRTURO(BEDAQUILINE) weakness or fatigue weight loss no appetite fever sweating at night VI. Transmission: Mycobacterium tuberculosis is spread by small airborne droplets, called droplet nuclei, generated by the coughing, sneezing, talking, or singing of a person with pulmonary or laryngeal tuberculosis. These minuscule droplets can remain airborne for minutes to hours after expectoration. The number of bacilli in the droplets, the virulence of the bacilli, exposure of the bacilli to UV light, degree of ventilation, and occasions for aerosolization all influence transmission. Introduction of M tuberculosis into the lungs leads to infection of the respiratory system; however, the organisms can spread to other organs, such as the lymphatics, pleura, bones/joints, or meninges, and cause extrapulmonary tuberculosis (Harsh Mohan 2006, World Health Organization 2012 ). Figure. no 6.1. Mode of Transmission of TB bacilli CMR College of Pharmacy, (Pharmacology), Page 9
  10. 10. THE TREATMENT OF MULTI-DRUG RESISTANT TUBERCULOSIS (MDR-TB) WITH SIRTURO(BEDAQUILINE) VII. Diagnosis: 7.1 The Standard: Definitive diagnosis of tuberculosis requires the identification of M tuberculosisin a culture of a diagnostic specimen. The most frequent sample used from a patient with a persistent and productive cough is sputum. Because most mycobacteria grow slowly, 3 to 6 weeks may be required for detectable growth on solid media. However, a newer, alternative method in which high-performance liquid chromatography is used to isolate and differentiate cell wall mycolic acids provides confirmation of the disease in 4 to 14 days. Conventionally, 3 sputum samples were also used for culture diagnosis, but the use of 2 specimens, as mentioned earlier for smears, also applies for cultures. After medications are started, the effectiveness of the therapy is assessed by obtaining sputum samples for smears. Once again, the traditional requirement of 3 sputum smears negative for M tuberculosis may be unnecessary when determining if respiratory isolation can be discontinued. A patient is considered to have achieved culture conversion when a culture is negative for the mycobacteria after a succession of cultures have been positive; culture conversion is the most important objective evaluation of response to treatment (World Health Organization 2012 ). 7.2 Alternatives: Unfortunately, not all patients with tuberculosis can be detected by culture of sputum specimens, a situation that can lead to delayed or missed diagnosis. Additionally, many critically ill patients have trouble producing the necessary material from the lungs and instead produce saliva or nasopharyngeal discharge. For patients who have difficulty generating sputum, inhalation of an aerosol of normal saline can be used to induce sputum for collection. However, if sputum specimens are still inadequate, or the index of suspicion for tuberculosis is still high despite cultures negative for M tuberculosis, alternative approaches are available. Bronchoscopy with bronchial washings or bronchoalveolar lavage can provide sputum for diagnosis. In bronchial washing, a fiberoptic bronchoscope is inserted into the lungs, and fluid is squirted in and then collected, essentially washing out a sample of cells and secretions from the alveolar and bronchial airspaces. Aliquots obtained from subsequent lavages constitute bronchoalveolar lavage specimens. CMR College of Pharmacy, (Pharmacology), Page 10
  11. 11. THE TREATMENT OF MULTI-DRUG RESISTANT TUBERCULOSIS (MDR-TB) WITH SIRTURO(BEDAQUILINE) In patients with involvement of intrathoracic lymph nodes, as indicated by adenopathy suggestive of tuberculosis, who have sputum smears negative for M tuberculosis, culture of specimens collected by transbronchial needle aspiration can be used to accurately and immediately diagnose the disease. With this technique, specimens are collected by inserting a 19-gauge flexible histology needle through a bronchoscopy tube; patients are sedated but conscious, and computed tomography scans are used for guidance (Centers for Disease Control and Prevention 2012). 7.3 Technological Advancements: Newer diagnostic techniques for faster detection of M tuberculosis include nucleic acid amplification tests. In these tests, molecular biology methods are used to amplify DNA and RNA, facilitating rapid detection of microorganisms; the tests have been approved by the Food and Drug Administration. One method is the polymerase chain reaction assay, which can be used to differentiate M tuberculosis from other Mycobacteria on the basis of genetic information and provides results within hours. Although the test can provide rapid confirmation of M.tuberculosis in sputum specimens positive for acid-fast bacilli, it has limitations, including high cost, low sensitivity, and low availability. A polymerase chain reaction assay positive for M tuberculosis in conjunction with a sputum smear positive for the organism indicates true tuberculosis, but in a patient with a sputum smear negative for the organism, the positive polymerase chain reaction assay should be considered carefully along with clinical indicators. The results of these assays cannot be relied on as the sole guide for isolation or therapy (Centers for Disease Control and Prevention 2012). 7.4 Diagnosing latency: Once patients recover from a primary M tuberculosis infection and the infection becomes latent, sputum specimens are negative for the organisms, and findings on chest radiographs are typically normal. These patients also do not have signs or symptoms of infection, and they are not infectious to others. Tuberculin skin testing is the most common method used to screen for latent M tuberculosis. 7.4.1 The tuberculin skin test is performed by intradermally injecting 0.1 mL of intermediatestrength purified protein derivative (PPD) that contains 5 tuberculin units. After 48 to 72 hours, CMR College of Pharmacy, (Pharmacology), Page 11
  12. 12. THE TREATMENT OF MULTI-DRUG RESISTANT TUBERCULOSIS (MDR-TB) WITH SIRTURO(BEDAQUILINE) the injection site is examined for induration but not redness . Although the test is useful because the PPD elicits a skin reaction via cell-mediated immunity when injected in patients previously infected with mycobacteria, it is limited because it is not specific for the species of mycobacteria. Many proteins in the PPD product are highly conserved in various species of mycobacteria. Also, the test is of limited value in patients with active tuberculosis because of its low sensitivity and specificity. False-negatives can occur in patients who are immunocompromised or malnourished, because these patients cannot mount an immune response to the injection, and in 20% to 25% of patients who have active tuberculosis, because there is a time lag of 2 to 10 weeks between infection and the T-lymphocyte response required for a positive skin reaction. False-positives can occur in patients who have infections caused by mycobacteria other than M tuberculosis or who have been given BCG vaccine. The tuberculin skin test was the only test available to detect latent tuberculosis until an interferon-release assay, called QuantiFERON-TB test, was approved by the Food and Drug Administration in 2001. Then, in 2005, a new interferon-assay, called QuantiFERON-TB Gold was approved and is intended to replace the QuantiFERON-TB test, which is no longer commercially available. In both tests, the cell-mediated reactivity to M tuberculosis is determined by incubating whole blood with an antigen and then using an enzyme-linked immunosorbent assay to measure the amount of interferon-γ released from white blood cells. In the QuantiFERON-TB Gold test, 2 synthetic antigenic proteins specific in PPD are used rather than a PPD admixture, making this test more sensitive than its predecessor. QuantiFERON-TB Gold provides results in less than 24 hours and can be used to detect both active and latent tuberculosis. The results of the QuantiFERON-TB Gold test are similar to those of the tuberculin skin test, and the Centers for Disease Control and Prevention now recommend that the QuantiFERON-TB Gold test be used in all instances in which the tuberculin skin test formerly would have been used ( www.cdc.gov/tb). CMR College of Pharmacy, (Pharmacology), Page 12
  13. 13. THE TREATMENT OF MULTI-DRUG RESISTANT TUBERCULOSIS (MDR-TB) WITH SIRTURO(BEDAQUILINE) Table.no7.4.1a.TST reaction for diagnosis of TB VIII. Drug-resistance Tuberculosis 8.1 Types of drug resistance: The three types of drug resistance are primary, secondary, and naturally occurring resistance. 8.1.1 Primary resistance: Primary resistance occurs if the organisms transmitted are resistant to one or more TB drugs. 8.1.2 Secondary resistance: Secondary resistance occurs if new resistance develops during treatment. 8.1.3 Naturally occurring drug resistance: There is a degree of naturally occurring resistance to anti-TB drugs. This resistance varies from drug to drug. The approximate rates of development of resistant organisms in vitro are: 10-3 for ethionamide, capreomycin, cycloserine and thiocetazone 10-5–10-7 for isoniazid, streptomycin, ethambutol, kanamycin and para-aminosalicylic acid 10-9 for rifampicin 10-14 for combined isoniazid and rifampicin. CMR College of Pharmacy, (Pharmacology), Page 13
  14. 14. THE TREATMENT OF MULTI-DRUG RESISTANT TUBERCULOSIS (MDR-TB) WITH SIRTURO(BEDAQUILINE) Cavities contain approximately 108–109 bacilli and there is a significantly higher risk of naturally resistant organisms being present in cavitating TB. Due to the occurrence of naturally occurring drug resistant TB it is essential that TB is treated with multiple drugs (www.cdc.gov/tb) 8.1.4 Suspected drug resistance: Additional drugs may be necessary in re-treating TB in people previously treated. If MDR-TB is a possibility and immediate treatment is clinically necessary, sufficient drugs should be used initially to avoid the development of further resistance should the isolate subsequently prove to be resistant to all first-line agents. In practice, this may necessitate use of an MDR regimen at the outset. Treatment of TB caused by drug-resistant organisms should be done by or in close consultation with an expert in the management of these difficult cases. Second-line regimens often present the patient’s best hope for cure and thus inappropriate management of a drug-resistant case can have life threatening consequences. The management of drug-resistant TB is often complicated by drug toxicities and long duration of therapy. Successful treatment outcomes for drug-resistant TB are often difficult to achieve compared with drug-susceptible disease, especially when multidrug-resistance is present (World Health Organization 2012) The most important predictors of drug-resistant TB are: a previous episode of TB treatment progressive clinical and/or radiographic findings while on TB treatment origin from, history of residence in or frequent travel to a region/country with high rates of drug resistance exposure to an individual with infectious drug-resistant TB. Multidrug-Resistant Tuberculosis (MDR TB): CMR College of Pharmacy, (Pharmacology), Page 14
  15. 15. THE TREATMENT OF MULTI-DRUG RESISTANT TUBERCULOSIS (MDR-TB) WITH SIRTURO(BEDAQUILINE) MDR TB is a form of drug-resistant TB in which TB bacteria can no longer be killed by at least the two best antibiotics, isoniazid (INH) and rifampin (RIF), commonly used to cure TB. As a result, this form of the disease is more difficult to treat than ordinary TB and requires up to 2 years of multidrug treatment. People may get MDR TB in two ways: Directly, if they spend time with an MDR TB patient and breathe in the MDR TB bacteria If they already have active TB and do not properly follow their prescribed treatment regimen or TB medicine is not reliably available to them. The inconsistent use of TB antibiotics gives the bacteria enough time to evolve and evade the first-line anti-TB medicines, and regular TB may then progress to MDR TB, which is more challenging to treat. Extensively Drug-Resistant Tuberculosis (XDR TB): XDR TB is a less common form of multidrug-resistant TB in which TB bacteria have changed enough to circumvent the two best antibiotics, INH and RIF, as well as most of the alternative drugs used against MDR TB. These second-line drugs include any fluoroquinolone, and at least one of the other three injectable anti-TB drugs: amikacin, kanamycin, or capreomycin. As a result, this form of the disease needs up to 2 years of extensive drug treatment and is the most challenging to treat. People may get XDR TB in two ways: Directly, if they spend time with an XDR TB patient and breathe in the XDR TB bacteria, and If they already have MDR TB or active TB, and do not properly follow their prescribed treatment regimen or TB medication is not reliably available to them. The inconsistent use of TB antibiotics gives the bacteria enough time to evolve and evade most if not all TB drugs, making it extremely difficult or impossible to treat XDR TB (World Health Organization 2012) IX. Treatment of drug-resistant TB The duration of treatment needs to be re-evaluated when drug resistance is encountered. The following treatment periods are a guide and represent the minimum duration of treatment CMR College of Pharmacy, (Pharmacology), Page 15
  16. 16. THE TREATMENT OF MULTI-DRUG RESISTANT TUBERCULOSIS (MDR-TB) WITH SIRTURO(BEDAQUILINE) (Table). A daily dosing schedule should be used for all patients with drug-resistant TB. Intermittent dosing schedules must not be used. It is essential that exemplary infection control practices are maintained in all case of drug resistant TB ( ttp://www.theunion.org/index.php/en/what-we-do/tuberculosis/multidrug-resistanttb-mdr-tb, www.ncbi.nlm.nih.gov ) Pattern of Suggested regimen Minimum duration Comments drug of resistance (months) H (+/- S) R,Z and E 6–9* treatment A fluoroquinolone may strengthen the regimen for patients with extensive disease H and Z R, E and moxifloxacin 9–12* A longer duration of treatment should be used for patients with extensive disease H and E R, Z and moxifloxacin 9–12* A longer duration of treatment should be used for patients with extensive disease R H, E, moxifloxacin plus 12–18* An injectable at least two months of Z strengthen the regimen for patients with agent may extensive disease CMR College of Pharmacy, (Pharmacology), Page 16
  17. 17. THE TREATMENT OF MULTI-DRUG RESISTANT TUBERCULOSIS (MDR-TB) WITH SIRTURO(BEDAQUILINE) R and E (+/- H, Z, moxifloxacin plus 18 A longer course (six months) S) an injectable agent for of the injectable agent may at least the first 2–3 strengthen the regimen for months patients with extensive disease R and Z (+/- H, E, moxifloxacin plus 18 A longer course (six months) S) an injectable agent for of the injectable agent may at least the first 2–3 strengthen the regimen for months patients with extensive disease H, E, Z (+/- R, moxifloxacin plus an 18 A longer course (six months) S) oral second-line agent, of the injectable agent may plus an injectable agent strengthen the regimen for for the first 2–3 months patients with extensive disease Table.no 9.1. Suggested regimens for mono- and poly-drug resistance (when further acquired resistance is not a factor and laboratory results are highly reliable) Isoniazid-resistant tuberculosis: Resistance to isoniazid is reported at 0.1 mcg/mL (low level) and 0.4 mcg/mL (high level). If low-level resistance is present, isoniazid should be continued as part of a regimen containing at least three other effective drugs. This is because the determination of isoniazid resistance is based on minimal inhibitory concentrations (MICs), and in practice the serum level could exceed the in vitro MIC. Rifampicin-resistant tuberculosis: Isolated resistance to rifampicin is uncommon and should raise the suspicion of MDR-TB. The loss of rifampicin from the treatment regimen requires a longer duration of treatment. CMR College of Pharmacy, (Pharmacology), Page 17
  18. 18. THE TREATMENT OF MULTI-DRUG RESISTANT TUBERCULOSIS (MDR-TB) WITH SIRTURO(BEDAQUILINE) Resistance to rifampicin is associated in most cases with cross-resistance to rifabutin. It is not clear whether laboratory-reported rifabutin susceptibility in the presence of rifampicin resistance is sufficiently reliable to allow use of rifabutin as a substitute for rifampicin. It is recommended that a regimen similar to that used for rifampicin resistance be used. Pyrazinamide-resistant tuberculosis: Mycobacterium bovis (or BCG related disease) is naturally resistant to pyrazinamide. 2RHE/7RH (or 9RH for minor extent of disease) is appropriate for treatment of patients with isolated pyrazinamide-resistant TB (www.ncbi.nlm.nih.gov) X. Tuberculosis facts Tuberculosis (TB) is an infection, primarily in the lungs (apneumonia), caused by bacteria called Mycobacterium tuberculosis. It is spread usually from person to person by breathing infected air during close contact. TB can remain in an inactive (dormant) state for years without causing symptoms or spreading to other people. When the immune system of a patient with dormant TB is weakened, the TB can become active (reactivate) and cause infection in the lungs or other parts of the body. The risk factors for acquiring TB include close-contact situations, alcohol and IV drug abuse, and certain diseases (for example,diabetes, cancer, and HIV) and occupations (for example, health-care workers). The most common symptoms and signs of TB are fatigue, fever,weight loss, coughing, and night sweats. The diagnosis of TB involves skin tests, chest X-rays, sputum analysis (smear and culture), andPCR tests to detect the genetic material of the causative bacteria. Inactive tuberculosis may be treated with an antibiotic, isoniazid (INH), to prevent the TB infection from becoming active. CMR College of Pharmacy, (Pharmacology), Page 18
  19. 19. THE TREATMENT OF MULTI-DRUG RESISTANT TUBERCULOSIS (MDR-TB) WITH SIRTURO(BEDAQUILINE) Active TB is treated, usually successfully, with INH in combination with one or more of several drugs, including rifampin (Rifadin), ethambutol (Myambutol),pyrazinamide, and streptomycin. Drug-resistant TB is a serious, as yet unsolved, public-health problem, especially in Southeast Asia, the countries of the former Soviet Union, Africa, and in prison populations. Poor patient compliance, lack of detection of resistant strains, and unavailable therapy are key reasons for the development of drug-resistant TB. The occurrence of HIV has been responsible for an increased frequency of tuberculosis. Control of HIV in the future, however, should substantially decrease the frequency of TB (www.ncbi.nlm.nih.gov). XI. TUBERCULOSIS MANAGEMENT Tuberculosis treatment refers to the medical treatment of the infectious tuberculosis (TB). The standard "short" course treatment for TB is isoniazid (along with pyridoxal phosphate to obviate peripheral neuropathy caused by isoniazid), rifampicin (also known as rifampin in the United States), pyrazinamide, and ethambutol for two months, then isoniazid and rifampicin alone for a further four months. The patient is considered cured at six months (although there is still a relapse rate of 2 to 3%). For latent tuberculosis, the standard treatment is six to nine months of isoniazid alone. If the organism is known to be fully sensitive, then treatment is with isoniazid, rifampicin, and pyrazinamide for two months, followed by isoniazid and rifampicin for four months. Ethambutol need not be used. First-line drugs Isoniazid (INH) Rifampin (RIF) Rifabutin Rifapentine CMR College of Pharmacy, (Pharmacology), Page 19
  20. 20. THE TREATMENT OF MULTI-DRUG RESISTANT TUBERCULOSIS (MDR-TB) WITH SIRTURO(BEDAQUILINE) Pyrazinamide (PZA) Ethambutol (EMB) Second-line drugs The second line drugs are considered as the reserved therapy for tuberculosis treatment. These drugs are often used in special conditions. When situations like resistance to first line therapy, extensively drug-resistant tuberculosis (XDR-TB) or multidrug-resistant tuberculosis (MDR-TB) arise, the second-line drugs are implemented for the treatment of tuberculosis.[2] There are six classes of second-line drugs (SLDs) used for the treatment of TB. A drug may be classed as second-line instead of first-line for one of three possible reasons: it may be less effective than the first-line drugs (e.g., p-aminosalicylic acid); or, it may have toxic side-effects (e.g., cycloserine); or it may be unavailable in many developing countries (e.g., fluoroquinolones): Cycloserine Ethionamide Streptomycin Amikacin/kanamycin Capreomycin P-Amniosalicylic acid (PAS) Levofloxacin Moxifloxacin Gatifloxacin 11.1 Multi-drug resistant TB: MDR-TB is defined as TB that is resistant to rifampicin and isoniazid. Resistance to other drugs may or may not be present. Key recommendations for the treatment of MDR-TB include: drug-resistant TB should be promptly diagnosed and appropriate therapy initiated CMR College of Pharmacy, (Pharmacology), Page 20
  21. 21. THE TREATMENT OF MULTI-DRUG RESISTANT TUBERCULOSIS (MDR-TB) WITH SIRTURO(BEDAQUILINE) patients with MDR-TB should always be treated with a minimum of four or more drugs to which the patient has not been previously exposed and to which the isolate is susceptible drug susceptibility testing (DST) should generally be used to guide therapy, however do not depend on DST in individual regimen design for ethambutol, pyrazinamide and group 4 and 5 drugs ciprofloxacin should not be used as an anti-tuberculosis agent treatment should be continued for at least 18 months past culture conversion adverse effects should be treated immediately and adequately daily DOT is mandatory for all patients with MDR-TB. WHO classifies five different groups of drugs available for use for the treatment of MDR-TB. These groups provide a systematic method for allocating drugs to an MDR treatment regimen (Table 11.1a ). Treatment regimens should be designed with a consistent approach based on the hierarchy of the five groups of anti-tuberculosis drugs (Centers for Disease Control and Prevention 2012). Group Drug Group 1 – first line agents (oral) Isoniazid, rifampicin, ethambutol, pyrazinamide Group 2 – injectable agents Streptomycin, amikacin, kanamycin, capreomycin Group 3 – Fluoroquinolone group Moxifloxacin, ofloxacin, levofloxacin, gatifloxacin Group 4 – Other, second line agents Ethionamide, protionamide, cyloserine, PAS (bacteriostatic) Group 5 – Agents of uncertain efficacy (not Clofazamine, amoxicillin-clavulanate, routinely recommended) clarithromycin, linezolid Table. no 11.1a . WHO classification of anti-TB drugs CMR College of Pharmacy, (Pharmacology), Page 21
  22. 22. THE TREATMENT OF MULTI-DRUG RESISTANT TUBERCULOSIS (MDR-TB) WITH SIRTURO(BEDAQUILINE) Group 1: Ethambutol and pyrazinamide can be used if there is laboratory evidence of susceptibility but previous use potentially means that these drugs may be less effective. If the laboratory demonstrates low-level isoniazid resistance then high dose isoniazid may be beneficial. Group 2: An injectable agent should be given to all MDR patients. Group 3: A fluoroquinolone antibiotic should be included if susceptible. Moxifloxacin is the preferred fluoroquinolone. Ciprofloxacin is no longer recommended for the treatment of TB. Group 4: Protionamide (or ethionamide) and cycloserine are the two most commonly used agents from this group. Para-aminosalicylic acid (PAS) is the next choice if a third drug is required. Group 5: The effectiveness of drugs in this group is unclear. They should only be considered when drug options are limited. 11.2 Extensively drug-resistant TB: Extensively drug-resistant TB (XDR-TB) is defined as MDR-TB that is resistant to one or more of the fluoroquinolones and injectable agents. Treatment of XDR-TB will involve Group 5 agents and management should always be in consultation with an expert in the management of drug-resistant TB. XDR-TB has a very high mortality rate, especially in the setting of HIV co-infection, and a low cure rate (Centers for Disease Control and Prevention 2012). XII. FDA Grants Accelerated Approval for SIRTURO (bedaquiline) as Part of Combination Therapy to Treat Adults with Pulmonary Multi-Drug Resistant Tuberculosis "The accelerated approval of SIRTURO is a significant step in the fight against MDR-TB, which is a more difficult to treat form of TB that affects approximately 630,000 people in the world . CMR College of Pharmacy, (Pharmacology), Page 22
  23. 23. THE TREATMENT OF MULTI-DRUG RESISTANT TUBERCULOSIS (MDR-TB) WITH SIRTURO(BEDAQUILINE) "This is the first time a new drug is being introduced specifically for MDR-TB, for which the current needs are so great," said Lee Reichman, M.D., Executive Director, New Jersey Medical School Global Tuberculosis Institute. "It is an important step in the development of new compounds for this serious and contagious disease." The FDA accelerated approval of SIRTURO was based on data from TMC207-C208 Study 1 and Study 2. The primary endpoint was time to sputum culture conversion, defined as the interval in days between the first dose of study drug and the date of the first of two consecutive negative sputum cultures collected at least 25 days apart during treatment. TMC207-C208 Study 1 is a placebo-controlled, double-blind, randomized trial conducted in newly diagnosed patients with multi-drug resistant pulmonary Mycobacterium tuberculosis. Patients were randomized to receive treatment with either SIRTURO and other drugs used to treat MDR-TB (SIRTURO treatment group) (n=79) or placebo plus other drugs to treat MDRTB (placebo treatment group) (n=81): the other drugs used to treat MDR-TB consisted of a combination of five other antimycobacterial drugs (ethionamide, kanamycin, pyrazinamide, ofloxacin, and cycloserine/terizidone or available alternative). SIRTURO was administered as 400 mg once daily for the first two weeks and as 200 mg three times per week for the following 22 weeks. After the 24 week study drug (SIRTURO or placebo) treatment phase patients continued to receive their other drugs used to treat MDR-TB until a total treatment duration of 18 to 24 months was achieved, or at least 12 months after the first confirmed negative culture (FDA Advisory http://www.sarpam.net ). 12.1 THE SIRTURO TREATMENT group had decreased time to culture conversion and improved culture conversion rates compared to the placebo treatment group at week 24. Median time to culture conversion was 83 days for the SIRTURO treatment group, compared to 125 days for the placebo treatment group. At week 24, culture conversation status results were: 77.6 percent of patients in the SIRTURO treatment group reached treatment success vs. 57.6 percent of patients in the placebo treatment group (p=0.014). CMR College of Pharmacy, (Pharmacology), Page 23
  24. 24. THE TREATMENT OF MULTI-DRUG RESISTANT TUBERCULOSIS (MDR-TB) WITH SIRTURO(BEDAQUILINE) 22.4 percent of patients in the SIRTURO treatment group experienced treatment failure vs. 42.4 percent of patients in the placebo treatment group. 7.5 percent of patients in the SIRTURO treatment group vs. 24.2 percent in the placebo treatment group experienced lack of conversion. Discontinuation rates were 14.9 percent for SIRTURO treatment group vs. 18.2 percent for the placebo treatment group. At week 72, culture conversation status results were: 70.1 percent of patients in the SIRTURO treatment group reached treatment success vs. 56.1 percent of patients in the placebo treatment group (p=0.092). 29.9 percent of patients in the SIRTURO treatment group experienced treatment failure vs. 43.9 percent of patients in the placebo treatment group. 4.5 percent of patients in the SIRTURO treatment group vs. 10.6 percent in the placebo treatment group experienced lack of conversion. Discontinuation rates were 25.4 percent for SIRTURO treatment group vs. 33.3 percent for placebo treatment group. TMC207-C208 Study 2 is a smaller, placebo-controlled study designed similarly to Study 1 except that SIRTURO™ or placebo was given for only 8 weeks instead of 24 weeks. Patients were randomized to either SIRTURO and other drugs used to treat MDR-TB (SIRTURO treatment group) (n=23) or placebo and other drugs used to treat MDR-TB (placebo treatment group) (n=24). Twenty-one patients randomized to the SIRTURO treatment group and 23 patients randomized to the placebo treatment group had confirmed MDR-TB based on subjects' baseline M. tuberculosis isolate obtained prior to randomization. The SIRTURO treatment group had a decreased time to culture conversion and improved culture conversion rates compared to the placebo treatment group at week 8. At weeks 8 and 24, the differences in culture conversion proportions were 38.9 percent and 15.7 percent, respectively (http://www.who.int/tb/challenges/mdr/en/). CMR College of Pharmacy, (Pharmacology), Page 24
  25. 25. THE TREATMENT OF MULTI-DRUG RESISTANT TUBERCULOSIS (MDR-TB) WITH SIRTURO(BEDAQUILINE) 12.1.1 Two Phase 2 Clinical Trials: The FDA looked at two Phase 2 clinical trials to determine Sirturo's safety and efficacy. In the first trial, patients were randomly selected to be treated with Sirturo alongside other TB medications, or a placebo alongside other TB medications. In the second trial patients received Sirturo plus other TB medications. This study is ongoing. In both studies, the aim was to determine how long it took for the patient's sputum to be free ofM. tuberculosis. In the first trial, the Sirturo-combination therapy patients' sputum became M. tuberculosis free in 83 days, versus 125 days for those on placebo. The second trial has so far supported the results of the first trial. During the two trials, the most commonly reported side effects included headache, joint pain and nausea ( Diacon AH et al June 2012 , http://www.who.int/tb/challenges/mdr/en/). 12.2 MECHANISM OF ACTION OF BEDAQULINE: The FDA approved Bedaquiline (as the fumarate salt; trade name: Sirturo; (for Bedaquiline Fumarate), and TMC-207 (for Bedaquiline)), a novel, first-in-class diarylquinoline antimycobacterial drug indicated for the treatment of pulmonary multi-drug resistant tuberculosis (MDR-TB) as part of combination therapy in adults. Tuberculosis is an infectious disease caused by the mycobacteria Mycobacterium tuberculosis, which usually affects the lungs. MDR-TB occurs when M. tuberculosis becomes resistant to the two most powerful first-line treatment anti-TB drugs, Isoniazid and Rifampin . Bedaquiline is the first anti-TB drug that works by inhibiting mycobacterial adenosine 5'-triphosphate (ATP) synthase , an enzyme essential for the replication of the mycobacteria. CMR College of Pharmacy, (Pharmacology), Page 25
  26. 26. THE TREATMENT OF MULTI-DRUG RESISTANT TUBERCULOSIS (MDR-TB) WITH SIRTURO(BEDAQUILINE) Figure.no 12.2.a The Mycobacterial ATP synthase ATP is the most commonly used energy currency of cells for most organisms. ATP synthase produces ATP from adenosine di phosphate (ADP) and inorganic phosphate using energy from a transmembrane proton-motive force generated by respiration. The above figure depicts a model of the mycobacterial ATP synthase. ATP synthase has two major structural domains, F0 and F1, that act as a biological rotary motor. The F1 domain is composed of subunits α3 (Uniprot: ), β3 (Uniprot:), γ3 (Uniprot:), δ and ε (Uniprot:); the F0 domain includes one a subunit (Uniprot), two b subunits (Uniprot) and 9 to 12 c subunits (Uniprot) arranged in a symmetrical disk. The F0 and F1 domains are linked by central stalks (subunits γ and ε) and peripheral stalks (subunits b and δ). The proton-motive force fuels the rotation of the transmembrane disk and the central stalk, which in turn modulates the nucleotide affinity in the catalytic β subunit, leading to the production of ATP (FDA Advisory http://www.sarpam.net ). It has been shown that mutation in the atpE gene, which encodes the c subunit, of the mycobacterial ATP synthase, confers resistant to Bedaquiline, suggesting that Bedaquiline binds crucially to this target (although almost certainly other components of the complex are required CMR College of Pharmacy, (Pharmacology), Page 26
  27. 27. THE TREATMENT OF MULTI-DRUG RESISTANT TUBERCULOSIS (MDR-TB) WITH SIRTURO(BEDAQUILINE) for a competent binding site), inhibiting the proton pump of M. tuberculosis and therefore interfering with the rotation properties of the transmembrane disk, leading to ATP depletion  Another notable feature is the high specificity of Bedaquiline for Mycobacteria. This is due to the fact that there is very limited sequence similarity between the mycobacterial and human atpE proteins. 12.2 .1 STRUCTURE OF BEDAQUILINE : Figure.no12.2.1a . The structure of Bedaquiline Bedaquiline is a diarylquinoline antimycobacterial drug, which displays both planar hydrophobic moieties and hydrogen-bonding acceptor and donor groups. It has a molecular weight of 555.50 Da (671.58 for the fumarate salt), an ALogP of 6.93, 4 hydrogen-bond acceptors and 1 hydrogen-bond donor, and therefore not fully rule-of-five compliant.[13][14] IUPAC Name: (1R, 2S)-1-(6-bromo-2 methoxy-3-quinolinyl)-4-(dimethylamino)-2-(1naphthalenyl)-1-phenyl-2-butanol The recommended dosage of Bedaquiline is 400 mg once daily for 2 weeks followed by 200 mg 3 times per week for 22 weeks with food. CMR College of Pharmacy, (Pharmacology), Page 27
  28. 28. THE TREATMENT OF MULTI-DRUG RESISTANT TUBERCULOSIS (MDR-TB) WITH SIRTURO(BEDAQUILINE) Bedaquiline shows volume of distribution of approximately 164 L and a plasma binding protein of > 99.9%. Bedaquiline is primarily subjected to oxidative metabolism by CYP3A4 leading to the formation of the N-monodesmethyl metabolite (M2), which is 4 to 6 times less active in terms of antimycobacterial potency. It is mainly eliminated in feces and the mean terminal half-life T1/2 of Bedaquiline and M2 is approximately 5.5 months ( Diacon AH et al June 2012). XIII. Warnings and Precautions: Increased Mortality: An increased risk of death was seen in the SIRTURO treatment group. QT Prolongation: SIRTURO prolongs the QT interval. An electrocardiogram (ECG) should be obtained before initiation of treatment, and at least 2, 12 and 24 weeks after starting treatment with SIRTURO. Serum potassium, calcium, and magnesium should be obtained at baseline and corrected if abnormal. Discontinue SIRTURO and all other QT prolonging drugs if the patient develops clinically significant ventricular arrhythmia or a QTcF interval of > 500 ms (confirmed by repeat ECG). The following may increase the risk for QT prolongation when patients are receiving SIRTURO and therefore ECGs should be monitored closely: use with other QT prolonging drugs including fluoroquinolones and macrolide antibacterial drugs and the antimycobacterial drug, clofazimine; a history of Torsade de Pointes; a history of cogenital long QT syndrome; a history of hypothyroidism and bradyarrhythmias; a history of uncompensated heart failure, serum calcium, magnesium, or potassium levels below the lower limits of normal (www.fda.gov, http://www.sarpam.net ). SIRTURO has not been studied in patients with ventricular arrhythmias or recent myocardial infarction. Hepatic-related Adverse Drug Reactions: More hepatic-related adverse drug reactions were reported with the use of SIRTURO plus other drugs to treat TB compared to other drugs used to treat TB without the addition of SIRTURO. Alcohol and other hepatotoxic drugs should be CMR College of Pharmacy, (Pharmacology), Page 28
  29. 29. THE TREATMENT OF MULTI-DRUG RESISTANT TUBERCULOSIS (MDR-TB) WITH SIRTURO(BEDAQUILINE) avoided while on SIRTURO , especially in patients with diminished hepatic reserve. Monitor liver-related laboratory tests. Discontinue SIRTURO if aminotransferase elevations are accompanied by total bilirubin elevation > 2xULN; aminotransferase elevations are > 8xULN; aminotransferase elevations persist beyond 2 weeks. Drug Interactions: Co-administration of rifamycins (e.g., rifampin, rifapentine and rifabutin) or other strong systemic CYP3A4 inducers should be avoided. Co-administration with strong systemic CYP3A4 inhibitors for more than 14 consecutive days should be avoided. Appropriate clinical monitoring for SIRTURO™-related adverse reactions is recommended. HIV-TB Co-Infected Patients: There are no clinical data on the combined use in HIV/MDR-TB co-infected patients and only limited clinical data on the use in HIV/MDR-TB co-infected patients who were not receiving antiretroviral therapy. Treatment Failure: SIRTURO should be administered by directly observed therapy. SIRTURO™ should only be administered in combination with at least 3 drugs active against the patient's TB isolate. Non-adherence to the treatment regimen could result in failure or resistance. Adverse Reactions: The most common adverse drug reactions reported in greater than or equal to 10% of patients treated with SIRTURO compared to the placebo treatment group are nausea (38% vs. 32.1%), arthralgia (32.9% vs. 22.2%), headache (27.8% vs. 12.3%) and additional adverse events reported in greater than or equal to 10% of patients are hemoptysis (17.7% vs. 11.1%) and chest pain (11.4% vs. 7.4%) ( Diacon AH et al June 2012). . CMR College of Pharmacy, (Pharmacology), Page 29
  30. 30. THE TREATMENT OF MULTI-DRUG RESISTANT TUBERCULOSIS (MDR-TB) WITH SIRTURO(BEDAQUILINE) XIV. APPENDIX TABLES: TABLE.NO NAME OF THE TABLE Table.no 5.2a Deference between LTBI and TB Disease Table.no 5.2b Persons at Increased Risk for Progression of LTBI to TB Disease Table.no7.4.1a TST reaction for diagnosis of TB Table.no9.1 Suggested regimens for mono- and poly-drug resistance (when further acquired resistance is not a factor and laboratory results are highly reliable) WHO classification of anti-TB drugs Table.no11.1a FIGURES: FIGURE.NO NAME OF THE FIGURE Figure.no 6.1 . Mode of Transmission of TB bacilli Figure.no 12.2a The Mycobacterial ATP synthase Figure.no 12.2.1a The structure of Bedaquiline CMR College of Pharmacy, (Pharmacology), Page 30
  31. 31. THE TREATMENT OF MULTI-DRUG RESISTANT TUBERCULOSIS (MDR-TB) WITH SIRTURO(BEDAQUILINE) XV. REFERENCES: 1. http://en.wikipedia.org/wiki/Tuberculosis 2. http://www.cdc.gov/tb/ 3. http://www.who.int/topics/tuberculosis/en/ 4. World Health Organization (2009). "Epidemiology".Global tuberculosis control: epidemiology, strategy, financing. pp. 6–33. ISBN 978-92-4-156380-2. Retrieved 12 November 2009. 5. Harsh Mohan p.no.149-156.(2006) Text book of pathology (p.no.149-156.) 6. Centers for Disease Control and Prevention (2006). "Emergence of Mycobacterium tuberculosis with Extensive Resistance to Second-Line Drugs — Worldwide, 2000–2004".MMWR Weekly 55 (11): 301–05. 7. Multidrug and extensively drug-resistant TB (M/XDR-TB) Drugs Used in the Treatment of Tuberculosis.(WWW.Cdc.Com) 8. http://www.medindia.net/patients/patientinfo/tuberculosis_treatment.html. 9. . http://www.webmd.com/lung/understanding-tuberculosis-treatment. 10. .http://www.ncbi.nlm.nih.gov. 11. http://www.theunion.org/index.php/en/what-we-do/tuberculosis/multidrug-resistant-tb-mdr-tb. 12. FDA Advisory Committee recommends accelerated approval of bedaquiline for drug-resistant TB (http://www.sarpam.net). 13. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm333695.html. 14. http://www.who.int/tb/challenges/mdr/en/. 15. Diacon AH et al. Randomized pilot trial of eight weeks of bedaquiline (TMC207) treatment for multidrugresistant tuberculosis: long-term outcome, tolerability, and effect on emergence of drug resistance. Antimicrobial Agents and Chemotherapy 56, no. 6: 3271-3276, June 2012. CMR College of Pharmacy, (Pharmacology), Page 31

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