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Introduction
It has been sixty years since the treatment for tuberculosis has been developed which mainly includes vaccination and chemotherapy; still, it remains the major cause of casualty around the world occurring from a single infectious agent. It has even surpassed the prevalence of human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) for the first time in the history of medicine ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"eJE467o3","properties":{"formattedCitation":"(Bloom et al.)","plainCitation":"(Bloom et al.)","noteIndex":0},"citationItems":[{"id":"M9fxualC/a8uFQlm8","uris":["http://zotero.org/users/local/CKNkWnK9/items/EAETEG4E"],"uri":["http://zotero.org/users/local/CKNkWnK9/items/EAETEG4E"],"itemData":{"id":473,"type":"chapter","abstract":"Despite 90 years of vaccination and 60 years of chemotherapy, tuberculosis (TB) remains the world’s leading cause of death from an infectious agent, exceeding human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) for the first time (WHO 2015b, 2016a). The World Health Organization (WHO) estimates that there are about 10.4 million new cases and 1.8 million deaths from TB each year. One-third of these new cases (about 3 million) remain unknown to the health system, and many are not receiving proper treatment. Tuberculosis is an infectious bacterial disease caused by Mycobacterium tuberculosis (Mtb), which is transmitted between humans through the respiratory route and most commonly affects the lungs, but can damage any tissue. Only about 10 percent of individuals infected with Mtb progress to active TB disease within their lifetime; the remainder of persons infected successfully contain their infection. One of the challenges of TB is that the pathogen persists in many infected individuals in a latent state for many years and can be reactivated to cause disease. The risk of progression to TB disease after infection is highest soon after the initial infection and increases dramatically for persons co-infected with HIV/AIDS or other immune-compromising conditions. Treatment of TB disease requires multiple drugs for many months. These long drug regimens are challenging for both patients and health care systems, especially in low- and middle-income countries (LMICs), where the disease burden often far outstrips local resources. In some areas, the incidence of drug-resistant TB, requiring even longer treatment regimens with drugs that are more expensive and difficult to tolerate, is increasing. Diagnosis in LMICs is made primarily by microscopic examination of stained smears of sputum of suspected patients; however, smear microscopy is capable of detecting only 50–60 percent of all cases (smear-positive). More sensitive methods of diagnosing TB and detecting resistance to drugs have recently become available, although they are more expensive. The time between the onset of disease and when diagnosis is made and treatment is initiated is often protracted, and such delays allow the transmission of disease. Although bacille Calmette–Guérin (BCG) remains the world’s most widely used vaccine, its effectiveness is geographically highly variable and incomplete. Modeling suggests that more effective vaccines will likely be needed to drive tuberculosis toward elimination in high-incidence settings. The basic strategy to combat TB has been, for 40 years, to provide diagnosis and treatment to individuals who are ill and who seek care at a health facility. The premise is that, if patients with active disease are cured, mortality will disappear, prevalence of disease will decline, transmission will decline, and therefore incidence should decline. The reality in many countries is more complex, and overall the decline in incidence (only about 1.5 percent per year) has been unacceptably slow. Chemotherapy for TB is one of the most cost-effective of all health interventions (McKee and Atun 2006). This evidence has been central to the global promotion of the WHO and Stop TB Partnership policy of directly observed therapy, short course (DOTS) strategy, the package of measures combining best practices in the diagnosis and care of patients with TB (UN General Assembly 2000). The DOTS strategy to control tuberculosis promotes standardized treatment, with supervision and patient support that may include, but is far broader than, direct observation of therapy (DOT), where a health care worker personally observes the patient taking the medication (WHO 2013a). Thanks in part to these efforts and national and international investments, much progress has been made in TB control over the past several decades. Between 1990 and 2010, absolute global mortality from TB declined 18.7 percent, from 1.47 million to 1.20 million (Lozano and others 2012) and by 22 percent between 2000 and 2015 (WHO 2016a). By 2015, an estimated 49 million lives had been saved (WHO 2016a). The internationally agreed targets for TB, embraced in the United Nations (UN) Millennium Development Goals (MDGs), sought “to halt and reverse the expanding incidence of tuberculosis by 2015,” and this target has been met to some extent in all six WHO regions and in most, but not all, of the world’s 22 high-burden countries (WHO 2014c). Despite progress, major gaps persist. Although the Sustainable Development Goals (SDGs) seek to end the tuberculosis epidemic altogether (WHO 2015a, 2015c), the decline in incidence has been disappointing. One of every three TB patients remains “unknown to the health system,” many are undiagnosed and untreated, and case detection and treatment success rates remain too low in the high-burden countries. Ominously, rates of multidrug-resistant (MDR) TB—defined as resistance to the two major TB drugs, isoniazid and rifampicin—are rising globally (WHO 2011a) with the emergence of extensively drug-resistant (XDR) TB, resistant to many second-line drugs, as well as strains resistant to all current drugs (Dheda and others 2014; Udwadia and others 2012; Uplekar and others 2015). These are now primarily the result of transmission rather than inadequate treatment (Shah and others 2017). Moreover, the TB problem has become more pressing because of co-infection with HIV/AIDS. While globally HIV/AIDS and TB co-infection represents only 11 percent of the total TB burden, in some areas of Sub-Saharan Africa with a high burden of TB, as many as three-quarters of TB patients are co-infected with HIV/AIDS. In those countries, efforts to control TB are overwhelmed by the rising number of TB cases occurring in parallel with the HIV/AIDS epidemic. And after decades of steady decline, the incidence of TB is also increasing in some high-income countries (HICs), mainly as the result of outbreaks in vulnerable groups (WHO 2015b). If the ultimate goal of controlling an infectious disease is to interrupt transmission, turning the tide on TB will require early and accurate case detection, rapid commencement of and adherence to effective treatment that prevents transmission, and, where possible, preventive treatment of latent TB. It is universally understood that new strategies and more effective tools and interventions will be required to reach post-2015 targets (Bloom and Atun 2016; WHO 2015a). These interventions must be not only cost-effective, but also affordable and capable of having an impact on a very large scale. TB control will need three new advances—development of new point-of-care diagnostics, more effective drug regimens to combat drug-susceptible and drug-resistant TB, and more effective vaccines. As argued in this chapter, these require new strategies and tools that include moving away from the traditional DOTS passive case finding and toward more active case finding in high-burden regions; service delivery that is targeted to the most vulnerable populations and integrated with other services, especially HIV/AIDS services; and care that is based at the primary health care and community levels. Specifically, in high-burden countries, many individuals with TB are asymptomatic, such that waiting for patients to become sick enough to seek care has not been sufficient to reduce transmission and incidence markedly (Bates and others 2012; Mao and others 2014; Willingham and others 2001; Wood and others 2007). A more active and aggressive approach is needed that tackles health system barriers to effective TB control. The strategies for controlling TB recommended by the WHO have evolved significantly over time. In the early formulations, the central tenets of the global TB control strategy were clinical and programmatic in nature, focusing principally on the delivery of standardized drug regimens; the underlying assumption was that the problem could be solved largely by existing biomedical tools (Atun, McKee, and others 2005; Schouten and others 2011). Yet, in many LMICs, health system weaknesses in governance, financing, health workforce, procurement and supply chain management, and information systems have impeded TB control (Elzinga, Raviglione, and Maher 2004; Marais and others 2010; Travis and others 2004) and not been adequately addressed by TB control efforts. The current global TB strategy, formulated as the End TB Strategy, is the most comprehensive ever, with three major pillars: Integrated, patient-centered care and prevention. Social and political action to address determinants of disease. Recognition of the urgent need for research to provide new tools (WHO 2015a). Health systems are important and need to be strengthened. As with other health interventions, the success of tuberculosis treatment and control in a country is often determined by the strength of its health system (McKee and Atun 2006; WHO 2003). A health system can be defined in many ways, perhaps best as “all the activities whose primary purpose is to promote, restore, or maintain health” (WHO 2000, 5). In a sense, the major risk factor for acquiring TB is breathing. Thus, people of all social and economic statuses are at risk. While TB disproportionately affects the poor, the narrative that TB is a disease only of the poor is misleading and counterproductive, if it leads either to further stigmatization of the disease or to the view that middle- and high-income countries need not worry about the disease. In the case of co-infection with HIV/AIDS, evidence suggests that HIV/AIDS is often more prevalent in better-off populations in Africa that suffer high rates of TB. The analytical framework underlying this chapter defines key functions of the health system, ultimate goals, and contextual factors that affect the health system (figure 11.1). It builds on the WHO framework (WHO 2000) as well as health system frameworks developed by Frenk (1994), Hsiao and Heller (2007), and Roberts and others (2004), and national accounts (OECD, Eurostat, and WHO 2011). It also draws on earlier studies by Atun (2012); Atun and Coker (2008); Atun, Samyshkin, and others (2006); Samb and others (2009); and Swanson and others (2012). The four key health system functions represented in the framework are as follows: Governance and organization. The policy and regulatory environment; stewardship and regulatory functions of the ministry of health and its relation to other levels of the health system; and structural arrangements for insurers and purchasers, health care providers, and market regulators. Financing. The way funds are collected, funds and risks are pooled, finances are allocated, and health care providers are remunerated. Resource management. The way resources—physical, human, and intellectual—are generated and allocated, including their geographic and needs-based allocation. Service delivery. Both population- and individual-level public health interventions and health care services provided in community, primary health care, hospitals, and other health institutions. Each of these functions is influenced by the economic, demographic, legal, cultural, and political context. As the framework suggests, health system goals include better health, financial protection, and user satisfaction. Personal health services and public health interventions should be organized to achieve an appropriate balance of equity (including reducing out-of-pocket [OOP] expenditures and impoverishment of individuals and families), efficiency, effectiveness (that is, the extent to which interventions are evidence based and safe), responsiveness, equity, and client satisfaction (as perceived by the users of services). This chapter is organized as follows. First, we provide a detailed discussion of the global burden of disease and clinical context, followed by a review of approaches to diagnosis, treatment, and prevention. The aim throughout is to approach TB through a health system lens and, in the latter part of the chapter, to provide recommendations for improving delivery strategies and strengthening health systems, including care, supply chain, and information systems. Because the current tools for combating TB are seriously inadequate, we conclude with sections on critical research and development and economic analyses of new interventions for diagnosis, treatment, and vaccines. Throughout, emphasis is placed on data or modeling of the economic costs and benefits, where available, of current or possible future interventions to combat this disease. The chapter recommends moving toward active case finding in high-burden countries; greater investments in health systems; community-based rather than hospital-based service delivery; and greater support for research on new tools—that is, developing better diagnostics, treatment regimens, and vaccines. Most of these approaches were included in earlier WHO policies, but were not emphasized. They are now part of the WHO’s End TB Strategy, with which this report is fully consistent (WHO 2015a, 2015c).","call-number":"NBK525174","container-title":"Major Infectious Diseases","edition":"3rd","event-place":"Washington (DC)","ISBN":"978-1-4648-0524-0","language":"eng","note":"PMID: 30212088","publisher":"The International Bank for Reconstruction and Development / The World Bank","publisher-place":"Washington (DC)","source":"PubMed","title":"Tuberculosis","URL":"http://www.ncbi.nlm.nih.gov/books/NBK525174/","author":[{"family":"Bloom","given":"Barry R."},{"family":"Atun","given":"Rifat"},{"family":"Cohen","given":"Ted"},{"family":"Dye","given":"Christopher"},{"family":"Fraser","given":"Hamish"},{"family":"Gomez","given":"Gabriela B."},{"family":"Knight","given":"Gwen"},{"family":"Murray","given":"Megan"},{"family":"Nardell","given":"Edward"},{"family":"Rubin","given":"Eric"},{"family":"Salomon","given":"Joshua"},{"family":"Vassall","given":"Anna"},{"family":"Volchenkov","given":"Grigory"},{"family":"White","given":"Richard"},{"family":"Wilson","given":"Douglas"},{"family":"Yadav","given":"Prashant"}],"editor":[{"family":"Holmes","given":"King K."},{"family":"Bertozzi","given":"Stefano"},{"family":"Bloom","given":"Barry R."},{"family":"Jha","given":"Prabhat"}],"accessed":{"date-parts":[["2019",12,9]]},"issued":{"date-parts":[["2017"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (Bloom et al.). According to the World Health Organization, It is estimated that the year 2018 contributed to the death of almost one and a half million individuals with Tuberculosis as the sole cause of these casualties ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"uhMsdhIW","properties":{"formattedCitation":"({\\i{}Tuberculosis (TB)})","plainCitation":"(Tuberculosis (TB))","noteIndex":0},"citationItems":[{"id":"M9fxualC/Mgygk9fH","uris":["http://zotero.org/users/local/CKNkWnK9/items/8YFYSFYH"],"uri":["http://zotero.org/users/local/CKNkWnK9/items/8YFYSFYH"],"itemData":{"id":476,"type":"webpage","abstract":"Tuberculosis is caused by bacteria that most often affect the lungs. TB is curable and preventable and is spread from person to person through the air.","language":"en","title":"Tuberculosis (TB)","URL":"https://www.who.int/news-room/fact-sheets/detail/tuberculosis","accessed":{"date-parts":[["2019",12,9]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (Tuberculosis (TB)). An estimated number of individuals that were diagnosed with tuberculosis are ten million including five million males, three million females and the rest of them comprising, children. Among these cases, almost one-third remain untreated due to not having proper knowledge of the new forms of disease ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"0treDNAQ","properties":{"formattedCitation":"(Snider and Roper)","plainCitation":"(Snider and Roper)","noteIndex":0},"citationItems":[{"id":"M9fxualC/g1rr4GCr","uris":["http://zotero.org/users/local/CKNkWnK9/items/6QV6CTAK"],"uri":["http://zotero.org/users/local/CKNkWnK9/items/6QV6CTAK"],"itemData":{"id":478,"type":"article-journal","container-title":"New England Journal of Medicine","DOI":"10.1056/NEJM199203053261011","ISSN":"0028-4793, 1533-4406","issue":"10","journalAbbreviation":"N Engl J Med","language":"en","page":"703-705","source":"DOI.org (Crossref)","title":"The New Tuberculosis","volume":"326","author":[{"family":"Snider","given":"Dixie E."},{"family":"Roper","given":"William L."}],"issued":{"date-parts":[["1992",3,5]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (Snider and Roper). Tuberculosis refers to the disease of the respiratory system which is caused by bacterial infection of Mycobacterium tuberculosis (Mtb). An infection is a communicable disease that is transmitted through the air to other human beings. During cough, spitting or sneezing, the bacteria is transmitted into the air from where it enters into the respiratory tract of other human beings and causes infection in the lungs ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"MINOZBZj","properties":{"formattedCitation":"(Bloom et al.)","plainCitation":"(Bloom et al.)","noteIndex":0},"citationItems":[{"id":"M9fxualC/a8uFQlm8","uris":["http://zotero.org/users/local/CKNkWnK9/items/EAETEG4E"],"uri":["http://zotero.org/users/local/CKNkWnK9/items/EAETEG4E"],"itemData":{"id":473,"type":"chapter","abstract":"Despite 90 years of vaccination and 60 years of chemotherapy, tuberculosis (TB) remains the world’s leading cause of death from an infectious agent, exceeding human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) for the first time (WHO 2015b, 2016a). The World Health Organization (WHO) estimates that there are about 10.4 million new cases and 1.8 million deaths from TB each year. One-third of these new cases (about 3 million) remain unknown to the health system, and many are not receiving proper treatment. Tuberculosis is an infectious bacterial disease caused by Mycobacterium tuberculosis (Mtb), which is transmitted between humans through the respiratory route and most commonly affects the lungs, but can damage any tissue. Only about 10 percent of individuals infected with Mtb progress to active TB disease within their lifetime; the remainder of persons infected successfully contain their infection. One of the challenges of TB is that the pathogen persists in many infected individuals in a latent state for many years and can be reactivated to cause disease. The risk of progression to TB disease after infection is highest soon after the initial infection and increases dramatically for persons co-infected with HIV/AIDS or other immune-compromising conditions. Treatment of TB disease requires multiple drugs for many months. These long drug regimens are challenging for both patients and health care systems, especially in low- and middle-income countries (LMICs), where the disease burden often far outstrips local resources. In some areas, the incidence of drug-resistant TB, requiring even longer treatment regimens with drugs that are more expensive and difficult to tolerate, is increasing. Diagnosis in LMICs is made primarily by microscopic examination of stained smears of sputum of suspected patients; however, smear microscopy is capable of detecting only 50–60 percent of all cases (smear-positive). More sensitive methods of diagnosing TB and detecting resistance to drugs have recently become available, although they are more expensive. The time between the onset of disease and when diagnosis is made and treatment is initiated is often protracted, and such delays allow the transmission of disease. Although bacille Calmette–Guérin (BCG) remains the world’s most widely used vaccine, its effectiveness is geographically highly variable and incomplete. Modeling suggests that more effective vaccines will likely be needed to drive tuberculosis toward elimination in high-incidence settings. The basic strategy to combat TB has been, for 40 years, to provide diagnosis and treatment to individuals who are ill and who seek care at a health facility. The premise is that, if patients with active disease are cured, mortality will disappear, prevalence of disease will decline, transmission will decline, and therefore incidence should decline. The reality in many countries is more complex, and overall the decline in incidence (only about 1.5 percent per year) has been unacceptably slow. Chemotherapy for TB is one of the most cost-effective of all health interventions (McKee and Atun 2006). This evidence has been central to the global promotion of the WHO and Stop TB Partnership policy of directly observed therapy, short course (DOTS) strategy, the package of measures combining best practices in the diagnosis and care of patients with TB (UN General Assembly 2000). The DOTS strategy to control tuberculosis promotes standardized treatment, with supervision and patient support that may include, but is far broader than, direct observation of therapy (DOT), where a health care worker personally observes the patient taking the medication (WHO 2013a). Thanks in part to these efforts and national and international investments, much progress has been made in TB control over the past several decades. Between 1990 and 2010, absolute global mortality from TB declined 18.7 percent, from 1.47 million to 1.20 million (Lozano and others 2012) and by 22 percent between 2000 and 2015 (WHO 2016a). By 2015, an estimated 49 million lives had been saved (WHO 2016a). The internationally agreed targets for TB, embraced in the United Nations (UN) Millennium Development Goals (MDGs), sought “to halt and reverse the expanding incidence of tuberculosis by 2015,” and this target has been met to some extent in all six WHO regions and in most, but not all, of the world’s 22 high-burden countries (WHO 2014c). Despite progress, major gaps persist. Although the Sustainable Development Goals (SDGs) seek to end the tuberculosis epidemic altogether (WHO 2015a, 2015c), the decline in incidence has been disappointing. One of every three TB patients remains “unknown to the health system,” many are undiagnosed and untreated, and case detection and treatment success rates remain too low in the high-burden countries. Ominously, rates of multidrug-resistant (MDR) TB—defined as resistance to the two major TB drugs, isoniazid and rifampicin—are rising globally (WHO 2011a) with the emergence of extensively drug-resistant (XDR) TB, resistant to many second-line drugs, as well as strains resistant to all current drugs (Dheda and others 2014; Udwadia and others 2012; Uplekar and others 2015). These are now primarily the result of transmission rather than inadequate treatment (Shah and others 2017). Moreover, the TB problem has become more pressing because of co-infection with HIV/AIDS. While globally HIV/AIDS and TB co-infection represents only 11 percent of the total TB burden, in some areas of Sub-Saharan Africa with a high burden of TB, as many as three-quarters of TB patients are co-infected with HIV/AIDS. In those countries, efforts to control TB are overwhelmed by the rising number of TB cases occurring in parallel with the HIV/AIDS epidemic. And after decades of steady decline, the incidence of TB is also increasing in some high-income countries (HICs), mainly as the result of outbreaks in vulnerable groups (WHO 2015b). If the ultimate goal of controlling an infectious disease is to interrupt transmission, turning the tide on TB will require early and accurate case detection, rapid commencement of and adherence to effective treatment that prevents transmission, and, where possible, preventive treatment of latent TB. It is universally understood that new strategies and more effective tools and interventions will be required to reach post-2015 targets (Bloom and Atun 2016; WHO 2015a). These interventions must be not only cost-effective, but also affordable and capable of having an impact on a very large scale. TB control will need three new advances—development of new point-of-care diagnostics, more effective drug regimens to combat drug-susceptible and drug-resistant TB, and more effective vaccines. As argued in this chapter, these require new strategies and tools that include moving away from the traditional DOTS passive case finding and toward more active case finding in high-burden regions; service delivery that is targeted to the most vulnerable populations and integrated with other services, especially HIV/AIDS services; and care that is based at the primary health care and community levels. Specifically, in high-burden countries, many individuals with TB are asymptomatic, such that waiting for patients to become sick enough to seek care has not been sufficient to reduce transmission and incidence markedly (Bates and others 2012; Mao and others 2014; Willingham and others 2001; Wood and others 2007). A more active and aggressive approach is needed that tackles health system barriers to effective TB control. The strategies for controlling TB recommended by the WHO have evolved significantly over time. In the early formulations, the central tenets of the global TB control strategy were clinical and programmatic in nature, focusing principally on the delivery of standardized drug regimens; the underlying assumption was that the problem could be solved largely by existing biomedical tools (Atun, McKee, and others 2005; Schouten and others 2011). Yet, in many LMICs, health system weaknesses in governance, financing, health workforce, procurement and supply chain management, and information systems have impeded TB control (Elzinga, Raviglione, and Maher 2004; Marais and others 2010; Travis and others 2004) and not been adequately addressed by TB control efforts. The current global TB strategy, formulated as the End TB Strategy, is the most comprehensive ever, with three major pillars: Integrated, patient-centered care and prevention. Social and political action to address determinants of disease. Recognition of the urgent need for research to provide new tools (WHO 2015a). Health systems are important and need to be strengthened. As with other health interventions, the success of tuberculosis treatment and control in a country is often determined by the strength of its health system (McKee and Atun 2006; WHO 2003). A health system can be defined in many ways, perhaps best as “all the activities whose primary purpose is to promote, restore, or maintain health” (WHO 2000, 5). In a sense, the major risk factor for acquiring TB is breathing. Thus, people of all social and economic statuses are at risk. While TB disproportionately affects the poor, the narrative that TB is a disease only of the poor is misleading and counterproductive, if it leads either to further stigmatization of the disease or to the view that middle- and high-income countries need not worry about the disease. In the case of co-infection with HIV/AIDS, evidence suggests that HIV/AIDS is often more prevalent in better-off populations in Africa that suffer high rates of TB. The analytical framework underlying this chapter defines key functions of the health system, ultimate goals, and contextual factors that affect the health system (figure 11.1). It builds on the WHO framework (WHO 2000) as well as health system frameworks developed by Frenk (1994), Hsiao and Heller (2007), and Roberts and others (2004), and national accounts (OECD, Eurostat, and WHO 2011). It also draws on earlier studies by Atun (2012); Atun and Coker (2008); Atun, Samyshkin, and others (2006); Samb and others (2009); and Swanson and others (2012). The four key health system functions represented in the framework are as follows: Governance and organization. The policy and regulatory environment; stewardship and regulatory functions of the ministry of health and its relation to other levels of the health system; and structural arrangements for insurers and purchasers, health care providers, and market regulators. Financing. The way funds are collected, funds and risks are pooled, finances are allocated, and health care providers are remunerated. Resource management. The way resources—physical, human, and intellectual—are generated and allocated, including their geographic and needs-based allocation. Service delivery. Both population- and individual-level public health interventions and health care services provided in community, primary health care, hospitals, and other health institutions. Each of these functions is influenced by the economic, demographic, legal, cultural, and political context. As the framework suggests, health system goals include better health, financial protection, and user satisfaction. Personal health services and public health interventions should be organized to achieve an appropriate balance of equity (including reducing out-of-pocket [OOP] expenditures and impoverishment of individuals and families), efficiency, effectiveness (that is, the extent to which interventions are evidence based and safe), responsiveness, equity, and client satisfaction (as perceived by the users of services). This chapter is organized as follows. First, we provide a detailed discussion of the global burden of disease and clinical context, followed by a review of approaches to diagnosis, treatment, and prevention. The aim throughout is to approach TB through a health system lens and, in the latter part of the chapter, to provide recommendations for improving delivery strategies and strengthening health systems, including care, supply chain, and information systems. Because the current tools for combating TB are seriously inadequate, we conclude with sections on critical research and development and economic analyses of new interventions for diagnosis, treatment, and vaccines. Throughout, emphasis is placed on data or modeling of the economic costs and benefits, where available, of current or possible future interventions to combat this disease. The chapter recommends moving toward active case finding in high-burden countries; greater investments in health systems; community-based rather than hospital-based service delivery; and greater support for research on new tools—that is, developing better diagnostics, treatment regimens, and vaccines. Most of these approaches were included in earlier WHO policies, but were not emphasized. They are now part of the WHO’s End TB Strategy, with which this report is fully consistent (WHO 2015a, 2015c).","call-number":"NBK525174","container-title":"Major Infectious Diseases","edition":"3rd","event-place":"Washington (DC)","ISBN":"978-1-4648-0524-0","language":"eng","note":"PMID: 30212088","publisher":"The International Bank for Reconstruction and Development / The World Bank","publisher-place":"Washington (DC)","source":"PubMed","title":"Tuberculosis","URL":"http://www.ncbi.nlm.nih.gov/books/NBK525174/","author":[{"family":"Bloom","given":"Barry R."},{"family":"Atun","given":"Rifat"},{"family":"Cohen","given":"Ted"},{"family":"Dye","given":"Christopher"},{"family":"Fraser","given":"Hamish"},{"family":"Gomez","given":"Gabriela B."},{"family":"Knight","given":"Gwen"},{"family":"Murray","given":"Megan"},{"family":"Nardell","given":"Edward"},{"family":"Rubin","given":"Eric"},{"family":"Salomon","given":"Joshua"},{"family":"Vassall","given":"Anna"},{"family":"Volchenkov","given":"Grigory"},{"family":"White","given":"Richard"},{"family":"Wilson","given":"Douglas"},{"family":"Yadav","given":"Prashant"}],"editor":[{"family":"Holmes","given":"King K."},{"family":"Bertozzi","given":"Stefano"},{"family":"Bloom","given":"Barry R."},{"family":"Jha","given":"Prabhat"}],"accessed":{"date-parts":[["2019",12,9]]},"issued":{"date-parts":[["2017"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (Bloom et al.). The symptoms include a cough that persists for two to three weeks, fever, chills, loss of appetite, weight loss, and lethargy. Treatments of tuberculosis involve the use of various antibiotics over a different course of time depending upon the type of tuberculosis. There are mainly three types of Tuberculosis: Latent Tuberculosis, Active Tuberculosis, and Multiple Drug-Resistant Tuberculosis. The treatment for all these forms require different drugs due to the phenomena of antimicrobial resistance ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"gtlNFSyZ","properties":{"formattedCitation":"(Gillespie)","plainCitation":"(Gillespie)","noteIndex":0},"citationItems":[{"id":"M9fxualC/3STEUtXj","uris":["http://zotero.org/users/local/CKNkWnK9/items/JGKW2T7F"],"uri":["http://zotero.org/users/local/CKNkWnK9/items/JGKW2T7F"],"itemData":{"id":484,"type":"article-journal","container-title":"Antimicrobial Agents and Chemotherapy","DOI":"10.1128/AAC.46.2.267-274.2002","ISSN":"0066-4804","issue":"2","journalAbbreviation":"Antimicrob Agents Chemother","note":"PMID: 11796329\nPMCID: PMC127054","page":"267-274","source":"PubMed Central","title":"Evolution of Drug Resistance in Mycobacterium tuberculosis: Clinical and Molecular Perspective","title-short":"Evolution of Drug Resistance in Mycobacterium tuberculosis","volume":"46","author":[{"family":"Gillespie","given":"Stephen H."}],"issued":{"date-parts":[["2002",2]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (Gillespie). The essay will focus on tuberculosis associated antimicrobial resistance phenomena in detail.
Discussion
Latent tuberculosis is a stage where the infection is present in your body but remains inactive. This inactive infection can be activated later in life and develop into tuberculosis. Anyone of these two antibiotics: Isoniazid (INH), Rifampin (Rifadin, Rimactane) or a combination of Isoniazid and rifapentine varying in duration are used to treat this form of infection ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1aPVBOo5","properties":{"formattedCitation":"(Bloom et al.)","plainCitation":"(Bloom et al.)","noteIndex":0},"citationItems":[{"id":"M9fxualC/a8uFQlm8","uris":["http://zotero.org/users/local/CKNkWnK9/items/EAETEG4E"],"uri":["http://zotero.org/users/local/CKNkWnK9/items/EAETEG4E"],"itemData":{"id":473,"type":"chapter","abstract":"Despite 90 years of vaccination and 60 years of chemotherapy, tuberculosis (TB) remains the world’s leading cause of death from an infectious agent, exceeding human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) for the first time (WHO 2015b, 2016a). The World Health Organization (WHO) estimates that there are about 10.4 million new cases and 1.8 million deaths from TB each year. One-third of these new cases (about 3 million) remain unknown to the health system, and many are not receiving proper treatment. Tuberculosis is an infectious bacterial disease caused by Mycobacterium tuberculosis (Mtb), which is transmitted between humans through the respiratory route and most commonly affects the lungs, but can damage any tissue. Only about 10 percent of individuals infected with Mtb progress to active TB disease within their lifetime; the remainder of persons infected successfully contain their infection. One of the challenges of TB is that the pathogen persists in many infected individuals in a latent state for many years and can be reactivated to cause disease. The risk of progression to TB disease after infection is highest soon after the initial infection and increases dramatically for persons co-infected with HIV/AIDS or other immune-compromising conditions. Treatment of TB disease requires multiple drugs for many months. These long drug regimens are challenging for both patients and health care systems, especially in low- and middle-income countries (LMICs), where the disease burden often far outstrips local resources. In some areas, the incidence of drug-resistant TB, requiring even longer treatment regimens with drugs that are more expensive and difficult to tolerate, is increasing. Diagnosis in LMICs is made primarily by microscopic examination of stained smears of sputum of suspected patients; however, smear microscopy is capable of detecting only 50–60 percent of all cases (smear-positive). More sensitive methods of diagnosing TB and detecting resistance to drugs have recently become available, although they are more expensive. The time between the onset of disease and when diagnosis is made and treatment is initiated is often protracted, and such delays allow the transmission of disease. Although bacille Calmette–Guérin (BCG) remains the world’s most widely used vaccine, its effectiveness is geographically highly variable and incomplete. Modeling suggests that more effective vaccines will likely be needed to drive tuberculosis toward elimination in high-incidence settings. The basic strategy to combat TB has been, for 40 years, to provide diagnosis and treatment to individuals who are ill and who seek care at a health facility. The premise is that, if patients with active disease are cured, mortality will disappear, prevalence of disease will decline, transmission will decline, and therefore incidence should decline. The reality in many countries is more complex, and overall the decline in incidence (only about 1.5 percent per year) has been unacceptably slow. Chemotherapy for TB is one of the most cost-effective of all health interventions (McKee and Atun 2006). This evidence has been central to the global promotion of the WHO and Stop TB Partnership policy of directly observed therapy, short course (DOTS) strategy, the package of measures combining best practices in the diagnosis and care of patients with TB (UN General Assembly 2000). The DOTS strategy to control tuberculosis promotes standardized treatment, with supervision and patient support that may include, but is far broader than, direct observation of therapy (DOT), where a health care worker personally observes the patient taking the medication (WHO 2013a). Thanks in part to these efforts and national and international investments, much progress has been made in TB control over the past several decades. Between 1990 and 2010, absolute global mortality from TB declined 18.7 percent, from 1.47 million to 1.20 million (Lozano and others 2012) and by 22 percent between 2000 and 2015 (WHO 2016a). By 2015, an estimated 49 million lives had been saved (WHO 2016a). The internationally agreed targets for TB, embraced in the United Nations (UN) Millennium Development Goals (MDGs), sought “to halt and reverse the expanding incidence of tuberculosis by 2015,” and this target has been met to some extent in all six WHO regions and in most, but not all, of the world’s 22 high-burden countries (WHO 2014c). Despite progress, major gaps persist. Although the Sustainable Development Goals (SDGs) seek to end the tuberculosis epidemic altogether (WHO 2015a, 2015c), the decline in incidence has been disappointing. One of every three TB patients remains “unknown to the health system,” many are undiagnosed and untreated, and case detection and treatment success rates remain too low in the high-burden countries. Ominously, rates of multidrug-resistant (MDR) TB—defined as resistance to the two major TB drugs, isoniazid and rifampicin—are rising globally (WHO 2011a) with the emergence of extensively drug-resistant (XDR) TB, resistant to many second-line drugs, as well as strains resistant to all current drugs (Dheda and others 2014; Udwadia and others 2012; Uplekar and others 2015). These are now primarily the result of transmission rather than inadequate treatment (Shah and others 2017). Moreover, the TB problem has become more pressing because of co-infection with HIV/AIDS. While globally HIV/AIDS and TB co-infection represents only 11 percent of the total TB burden, in some areas of Sub-Saharan Africa with a high burden of TB, as many as three-quarters of TB patients are co-infected with HIV/AIDS. In those countries, efforts to control TB are overwhelmed by the rising number of TB cases occurring in parallel with the HIV/AIDS epidemic. And after decades of steady decline, the incidence of TB is also increasing in some high-income countries (HICs), mainly as the result of outbreaks in vulnerable groups (WHO 2015b). If the ultimate goal of controlling an infectious disease is to interrupt transmission, turning the tide on TB will require early and accurate case detection, rapid commencement of and adherence to effective treatment that prevents transmission, and, where possible, preventive treatment of latent TB. It is universally understood that new strategies and more effective tools and interventions will be required to reach post-2015 targets (Bloom and Atun 2016; WHO 2015a). These interventions must be not only cost-effective, but also affordable and capable of having an impact on a very large scale. TB control will need three new advances—development of new point-of-care diagnostics, more effective drug regimens to combat drug-susceptible and drug-resistant TB, and more effective vaccines. As argued in this chapter, these require new strategies and tools that include moving away from the traditional DOTS passive case finding and toward more active case finding in high-burden regions; service delivery that is targeted to the most vulnerable populations and integrated with other services, especially HIV/AIDS services; and care that is based at the primary health care and community levels. Specifically, in high-burden countries, many individuals with TB are asymptomatic, such that waiting for patients to become sick enough to seek care has not been sufficient to reduce transmission and incidence markedly (Bates and others 2012; Mao and others 2014; Willingham and others 2001; Wood and others 2007). A more active and aggressive approach is needed that tackles health system barriers to effective TB control. The strategies for controlling TB recommended by the WHO have evolved significantly over time. In the early formulations, the central tenets of the global TB control strategy were clinical and programmatic in nature, focusing principally on the delivery of standardized drug regimens; the underlying assumption was that the problem could be solved largely by existing biomedical tools (Atun, McKee, and others 2005; Schouten and others 2011). Yet, in many LMICs, health system weaknesses in governance, financing, health workforce, procurement and supply chain management, and information systems have impeded TB control (Elzinga, Raviglione, and Maher 2004; Marais and others 2010; Travis and others 2004) and not been adequately addressed by TB control efforts. The current global TB strategy, formulated as the End TB Strategy, is the most comprehensive ever, with three major pillars: Integrated, patient-centered care and prevention. Social and political action to address determinants of disease. Recognition of the urgent need for research to provide new tools (WHO 2015a). Health systems are important and need to be strengthened. As with other health interventions, the success of tuberculosis treatment and control in a country is often determined by the strength of its health system (McKee and Atun 2006; WHO 2003). A health system can be defined in many ways, perhaps best as “all the activities whose primary purpose is to promote, restore, or maintain health” (WHO 2000, 5). In a sense, the major risk factor for acquiring TB is breathing. Thus, people of all social and economic statuses are at risk. While TB disproportionately affects the poor, the narrative that TB is a disease only of the poor is misleading and counterproductive, if it leads either to further stigmatization of the disease or to the view that middle- and high-income countries need not worry about the disease. In the case of co-infection with HIV/AIDS, evidence suggests that HIV/AIDS is often more prevalent in better-off populations in Africa that suffer high rates of TB. The analytical framework underlying this chapter defines key functions of the health system, ultimate goals, and contextual factors that affect the health system (figure 11.1). It builds on the WHO framework (WHO 2000) as well as health system frameworks developed by Frenk (1994), Hsiao and Heller (2007), and Roberts and others (2004), and national accounts (OECD, Eurostat, and WHO 2011). It also draws on earlier studies by Atun (2012); Atun and Coker (2008); Atun, Samyshkin, and others (2006); Samb and others (2009); and Swanson and others (2012). The four key health system functions represented in the framework are as follows: Governance and organization. The policy and regulatory environment; stewardship and regulatory functions of the ministry of health and its relation to other levels of the health system; and structural arrangements for insurers and purchasers, health care providers, and market regulators. Financing. The way funds are collected, funds and risks are pooled, finances are allocated, and health care providers are remunerated. Resource management. The way resources—physical, human, and intellectual—are generated and allocated, including their geographic and needs-based allocation. Service delivery. Both population- and individual-level public health interventions and health care services provided in community, primary health care, hospitals, and other health institutions. Each of these functions is influenced by the economic, demographic, legal, cultural, and political context. As the framework suggests, health system goals include better health, financial protection, and user satisfaction. Personal health services and public health interventions should be organized to achieve an appropriate balance of equity (including reducing out-of-pocket [OOP] expenditures and impoverishment of individuals and families), efficiency, effectiveness (that is, the extent to which interventions are evidence based and safe), responsiveness, equity, and client satisfaction (as perceived by the users of services). This chapter is organized as follows. First, we provide a detailed discussion of the global burden of disease and clinical context, followed by a review of approaches to diagnosis, treatment, and prevention. The aim throughout is to approach TB through a health system lens and, in the latter part of the chapter, to provide recommendations for improving delivery strategies and strengthening health systems, including care, supply chain, and information systems. Because the current tools for combating TB are seriously inadequate, we conclude with sections on critical research and development and economic analyses of new interventions for diagnosis, treatment, and vaccines. Throughout, emphasis is placed on data or modeling of the economic costs and benefits, where available, of current or possible future interventions to combat this disease. The chapter recommends moving toward active case finding in high-burden countries; greater investments in health systems; community-based rather than hospital-based service delivery; and greater support for research on new tools—that is, developing better diagnostics, treatment regimens, and vaccines. Most of these approaches were included in earlier WHO policies, but were not emphasized. They are now part of the WHO’s End TB Strategy, with which this report is fully consistent (WHO 2015a, 2015c).","call-number":"NBK525174","container-title":"Major Infectious Diseases","edition":"3rd","event-place":"Washington (DC)","ISBN":"978-1-4648-0524-0","language":"eng","note":"PMID: 30212088","publisher":"The International Bank for Reconstruction and Development / The World Bank","publisher-place":"Washington (DC)","source":"PubMed","title":"Tuberculosis","URL":"http://www.ncbi.nlm.nih.gov/books/NBK525174/","author":[{"family":"Bloom","given":"Barry R."},{"family":"Atun","given":"Rifat"},{"family":"Cohen","given":"Ted"},{"family":"Dye","given":"Christopher"},{"family":"Fraser","given":"Hamish"},{"family":"Gomez","given":"Gabriela B."},{"family":"Knight","given":"Gwen"},{"family":"Murray","given":"Megan"},{"family":"Nardell","given":"Edward"},{"family":"Rubin","given":"Eric"},{"family":"Salomon","given":"Joshua"},{"family":"Vassall","given":"Anna"},{"family":"Volchenkov","given":"Grigory"},{"family":"White","given":"Richard"},{"family":"Wilson","given":"Douglas"},{"family":"Yadav","given":"Prashant"}],"editor":[{"family":"Holmes","given":"King K."},{"family":"Bertozzi","given":"Stefano"},{"family":"Bloom","given":"Barry R."},{"family":"Jha","given":"Prabhat"}],"accessed":{"date-parts":[["2019",12,9]]},"issued":{"date-parts":[["2017"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (Bloom et al.). Active Tuberculosis is a form in which active infection can spread to others. It is treated with various antibiotics such as Ethambutol (Myambutol), Isoniazid, Pyrazinamide and Rifampin over six to nine months. These medications are prescribed to the patient based upon the ability of bacteria to develop a resistance against a certain drug. These initially formulated drugs are used in combinations so, if one or two drugs are resisted by a strain of bacteria, others can have a possible effect on inhibiting the growth and development and prevent antimicrobial resistance ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"iFs3BND1","properties":{"formattedCitation":"(Lew et al.)","plainCitation":"(Lew et al.)","noteIndex":0},"citationItems":[{"id":"M9fxualC/NEeem3hF","uris":["http://zotero.org/users/local/CKNkWnK9/items/FQIV4JRQ"],"uri":["http://zotero.org/users/local/CKNkWnK9/items/FQIV4JRQ"],"itemData":{"id":481,"type":"article-journal","container-title":"Annals of Internal Medicine","DOI":"10.7326/0003-4819-149-2-200807150-00008","ISSN":"0003-4819","issue":"2","journalAbbreviation":"Ann Intern Med","language":"en","page":"123","source":"DOI.org (Crossref)","title":"Initial Drug Resistance and Tuberculosis Treatment Outcomes: Systematic Review and Meta-analysis","title-short":"Initial Drug Resistance and Tuberculosis Treatment Outcomes","volume":"149","author":[{"family":"Lew","given":"Woojin"},{"family":"Pai","given":"Madhukar"},{"family":"Oxlade","given":"Olivia"},{"family":"Martin","given":"Daniel"},{"family":"Menzies","given":"Dick"}],"issued":{"date-parts":[["2008",7,15]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (Lew et al.). In most cases, through plasmid, bacteria can pass the gene of antibiotic resistance to other organisms. There are three main mechanisms through which bacteria acquire resistance towards a certain antibiotic. First, through the cell wall which acts as a barrier to the entry of drugs into cells. Second, through the drug inactivating enzymes, present on its surface which can inactivate the drugs. Third, through the drug efflux systems which expel the drug out of system actively. Final, through mutations, which changes the target proteins thus rendering it inactive ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"bkpMQNbk","properties":{"formattedCitation":"(Sandhu and Akhter)","plainCitation":"(Sandhu and Akhter)","noteIndex":0},"citationItems":[{"id":"M9fxualC/CDTSbhjX","uris":["http://zotero.org/users/local/CKNkWnK9/items/YE9FLRMG"],"uri":["http://zotero.org/users/local/CKNkWnK9/items/YE9FLRMG"],"itemData":{"id":482,"type":"article-journal","abstract":"Drug resistance is a major concern due to the evolution and emergence of pathogenic bacterial strains with novel strategies to resist the antibiotics in use. Mycobacterium tuberculosis (Mtb) is one of such pathogens with reported strains, which are not treatable with any of the available anti-TB drugs. This scenario has led to the need to look for some novel drug targets in Mtb, which may be exploited to design effective treatment strategies against the infection. The goal of this review is to discuss one such class of emerging drug targets in Mtb. MmpL (mycobacterial membrane protein large) proteins from Mtb are reported to be involved in multi-substrate transport including drug efflux and considered as one of the contributing factors for the emergence of multidrug-resistant strains. MmpL proteins belong to resistance nodulation division permeases superfamily of membrane transporters, which are viably and pathogenetically important and their inhibition could be lethal for the bacteria.","container-title":"Archives of Microbiology","DOI":"10.1007/s00203-017-1434-6","ISSN":"1432-072X","issue":"1","journalAbbreviation":"Arch. Microbiol.","language":"eng","note":"PMID: 28951954","page":"19-31","source":"PubMed","title":"Evolution of structural fitness and multifunctional aspects of mycobacterial RND family transporters","volume":"200","author":[{"family":"Sandhu","given":"Padmani"},{"family":"Akhter","given":"Yusuf"}],"issued":{"date-parts":[["2018",1]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (Sandhu and Akhter).
As opposed to several other bacteria, M. tuberculosis does not exhibit plasmids of resistance however; drug resistance emerges by acquiring particular chromosome mutations ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"FZLSCAo7","properties":{"formattedCitation":"(M\\uc0\\u252{}ller et al.)","plainCitation":"(Müller et al.)","noteIndex":0},"citationItems":[{"id":26,"uris":["http://zotero.org/users/local/Fw9DaQie/items/XYUERV2R"],"uri":["http://zotero.org/users/local/Fw9DaQie/items/XYUERV2R"],"itemData":{"id":26,"type":"article-journal","abstract":"Recent surveillance data of multidrug-resistant tuberculosis (MDR-TB) reported the highest rates of resistance ever documented. As further amplification of resistance in MDR strains of Mycobacterium tuberculosis occurs, extensively drug-resistant (XDR) and totally drug resistant (TDR) TB are beginning to emerge. Whilst for the most part, the epidemiological factors involved in the spread of MDR-TB are understood, insights into the bacterial drivers of MDR-TB have been gained only recently, largely owing to novel technologies and research in other organisms. Herein, we review recent findings on how bacterial factors such as persistence, hypermutation, the complex interrelationship between drug resistance and fitness, compensatory evolution, and epistasis affect the evolution of multidrug resistance in M. tuberculosis. Improved knowledge of these factors will help better predict the future trajectory of MDR-TB, and contribute to the development of new tools and strategies to combat this growing public health threat.","container-title":"Trends in genetics : TIG","DOI":"10.1016/j.tig.2012.11.005","ISSN":"0168-9525","issue":"3","journalAbbreviation":"Trends Genet","note":"PMID: 23245857\nPMCID: PMC3594559","page":"160-169","source":"PubMed Central","title":"The Heterogeneous Evolution of Multidrug-Resistant Mycobacterium tuberculosis","volume":"29","author":[{"family":"Müller","given":"Borna"},{"family":"Borrell","given":"Sonia"},{"family":"Rose","given":"Graham"},{"family":"Gagneux","given":"Sebastien"}],"issued":{"date-parts":[["2013",3]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (Müller et al.). The demographic orientation of M. Tb is predominantly clonal, indicating a minor role throughout the genetics of M. tuberculosis for horizontal gene transfer (HGT). The latest survey has criticized this view but it is continuously illustrated that HGT serves a presumed function in the development of antibiotic resistance in M. tuberculosis ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"oJnN3b9o","properties":{"formattedCitation":"(M\\uc0\\u252{}ller et al.)","plainCitation":"(Müller et al.)","noteIndex":0},"citationItems":[{"id":26,"uris":["http://zotero.org/users/local/Fw9DaQie/items/XYUERV2R"],"uri":["http://zotero.org/users/local/Fw9DaQie/items/XYUERV2R"],"itemData":{"id":26,"type":"article-journal","abstract":"Recent surveillance data of multidrug-resistant tuberculosis (MDR-TB) reported the highest rates of resistance ever documented. As further amplification of resistance in MDR strains of Mycobacterium tuberculosis occurs, extensively drug-resistant (XDR) and totally drug resistant (TDR) TB are beginning to emerge. Whilst for the most part, the epidemiological factors involved in the spread of MDR-TB are understood, insights into the bacterial drivers of MDR-TB have been gained only recently, largely owing to novel technologies and research in other organisms. Herein, we review recent findings on how bacterial factors such as persistence, hypermutation, the complex interrelationship between drug resistance and fitness, compensatory evolution, and epistasis affect the evolution of multidrug resistance in M. tuberculosis. Improved knowledge of these factors will help better predict the future trajectory of MDR-TB, and contribute to the development of new tools and strategies to combat this growing public health threat.","container-title":"Trends in genetics : TIG","DOI":"10.1016/j.tig.2012.11.005","ISSN":"0168-9525","issue":"3","journalAbbreviation":"Trends Genet","note":"PMID: 23245857\nPMCID: PMC3594559","page":"160-169","source":"PubMed Central","title":"The Heterogeneous Evolution of Multidrug-Resistant Mycobacterium tuberculosis","volume":"29","author":[{"family":"Müller","given":"Borna"},{"family":"Borrell","given":"Sonia"},{"family":"Rose","given":"Graham"},{"family":"Gagneux","given":"Sebastien"}],"issued":{"date-parts":[["2013",3]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (Müller et al.). Drug-resistant genetic changes in M. tuberculosis were identified in genetic makeup that encode proteins that are specifically aimed by antibiotic treatment, in the gene regulatory regions, or in gene product lines that activate anti-drugs. Traditional evolutionary scientists predict that immunity-conferring variants occur quantum mechanically and regardless of medication intake within bacterial communities ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"Ispb9pAd","properties":{"formattedCitation":"(M\\uc0\\u252{}ller et al.)","plainCitation":"(Müller et al.)","noteIndex":0},"citationItems":[{"id":26,"uris":["http://zotero.org/users/local/Fw9DaQie/items/XYUERV2R"],"uri":["http://zotero.org/users/local/Fw9DaQie/items/XYUERV2R"],"itemData":{"id":26,"type":"article-journal","abstract":"Recent surveillance data of multidrug-resistant tuberculosis (MDR-TB) reported the highest rates of resistance ever documented. As further amplification of resistance in MDR strains of Mycobacterium tuberculosis occurs, extensively drug-resistant (XDR) and totally drug resistant (TDR) TB are beginning to emerge. Whilst for the most part, the epidemiological factors involved in the spread of MDR-TB are understood, insights into the bacterial drivers of MDR-TB have been gained only recently, largely owing to novel technologies and research in other organisms. Herein, we review recent findings on how bacterial factors such as persistence, hypermutation, the complex interrelationship between drug resistance and fitness, compensatory evolution, and epistasis affect the evolution of multidrug resistance in M. tuberculosis. Improved knowledge of these factors will help better predict the future trajectory of MDR-TB, and contribute to the development of new tools and strategies to combat this growing public health threat.","container-title":"Trends in genetics : TIG","DOI":"10.1016/j.tig.2012.11.005","ISSN":"0168-9525","issue":"3","journalAbbreviation":"Trends Genet","note":"PMID: 23245857\nPMCID: PMC3594559","page":"160-169","source":"PubMed Central","title":"The Heterogeneous Evolution of Multidrug-Resistant Mycobacterium tuberculosis","volume":"29","author":[{"family":"Müller","given":"Borna"},{"family":"Borrell","given":"Sonia"},{"family":"Rose","given":"Graham"},{"family":"Gagneux","given":"Sebastien"}],"issued":{"date-parts":[["2013",3]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (Müller et al.). The mean level of incidence of isoniazid and rifampicin random tolerance alterations in M. tuberculosis was measured at 10−8 and 10−9 mutations/bacterium/cell division, correspondingly ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"AucsVbvl","properties":{"formattedCitation":"(M\\uc0\\u252{}ller et al.)","plainCitation":"(Müller et al.)","noteIndex":0},"citationItems":[{"id":26,"uris":["http://zotero.org/users/local/Fw9DaQie/items/XYUERV2R"],"uri":["http://zotero.org/users/local/Fw9DaQie/items/XYUERV2R"],"itemData":{"id":26,"type":"article-journal","abstract":"Recent surveillance data of multidrug-resistant tuberculosis (MDR-TB) reported the highest rates of resistance ever documented. As further amplification of resistance in MDR strains of Mycobacterium tuberculosis occurs, extensively drug-resistant (XDR) and totally drug resistant (TDR) TB are beginning to emerge. Whilst for the most part, the epidemiological factors involved in the spread of MDR-TB are understood, insights into the bacterial drivers of MDR-TB have been gained only recently, largely owing to novel technologies and research in other organisms. Herein, we review recent findings on how bacterial factors such as persistence, hypermutation, the complex interrelationship between drug resistance and fitness, compensatory evolution, and epistasis affect the evolution of multidrug resistance in M. tuberculosis. Improved knowledge of these factors will help better predict the future trajectory of MDR-TB, and contribute to the development of new tools and strategies to combat this growing public health threat.","container-title":"Trends in genetics : TIG","DOI":"10.1016/j.tig.2012.11.005","ISSN":"0168-9525","issue":"3","journalAbbreviation":"Trends Genet","note":"PMID: 23245857\nPMCID: PMC3594559","page":"160-169","source":"PubMed Central","title":"The Heterogeneous Evolution of Multidrug-Resistant Mycobacterium tuberculosis","volume":"29","author":[{"family":"Müller","given":"Borna"},{"family":"Borrell","given":"Sonia"},{"family":"Rose","given":"Graham"},{"family":"Gagneux","given":"Sebastien"}],"issued":{"date-parts":[["2013",3]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (Müller et al.).⠀ It suggests that considering the average percentage of estimated 108 enteric bacteria present in person Tuberculosis tumors, the presence of resistant strains will almost eventually occur throughout monotherapy ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"q5LFNC3n","properties":{"formattedCitation":"(M\\uc0\\u252{}ller et al.)","plainCitation":"(Müller et al.)","noteIndex":0},"citationItems":[{"id":26,"uris":["http://zotero.org/users/local/Fw9DaQie/items/XYUERV2R"],"uri":["http://zotero.org/users/local/Fw9DaQie/items/XYUERV2R"],"itemData":{"id":26,"type":"article-journal","abstract":"Recent surveillance data of multidrug-resistant tuberculosis (MDR-TB) reported the highest rates of resistance ever documented. As further amplification of resistance in MDR strains of Mycobacterium tuberculosis occurs, extensively drug-resistant (XDR) and totally drug resistant (TDR) TB are beginning to emerge. Whilst for the most part, the epidemiological factors involved in the spread of MDR-TB are understood, insights into the bacterial drivers of MDR-TB have been gained only recently, largely owing to novel technologies and research in other organisms. Herein, we review recent findings on how bacterial factors such as persistence, hypermutation, the complex interrelationship between drug resistance and fitness, compensatory evolution, and epistasis affect the evolution of multidrug resistance in M. tuberculosis. Improved knowledge of these factors will help better predict the future trajectory of MDR-TB, and contribute to the development of new tools and strategies to combat this growing public health threat.","container-title":"Trends in genetics : TIG","DOI":"10.1016/j.tig.2012.11.005","ISSN":"0168-9525","issue":"3","journalAbbreviation":"Trends Genet","note":"PMID: 23245857\nPMCID: PMC3594559","page":"160-169","source":"PubMed Central","title":"The Heterogeneous Evolution of Multidrug-Resistant Mycobacterium tuberculosis","volume":"29","author":[{"family":"Müller","given":"Borna"},{"family":"Borrell","given":"Sonia"},{"family":"Rose","given":"Graham"},{"family":"Gagneux","given":"Sebastien"}],"issued":{"date-parts":[["2013",3]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (Müller et al.). Tuberculosis must, therefore, be handled with combination therapy with at least four antibiotic drugs.
In the case of Tuberculosis, the mechanism of bacterial resistance for rifampin is quite fascinating. The rpo gene is mainly involved in the synthesis of the beta subunit of RNA polymerase where rifampin acts and inhibits transcription. Rop gene mutation causes the gene to change the sequence of amino acids and thus altering the protein configuration. The configuration renders rifampin inactive because of the absence of a binding subunit ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"Bw6LtHQR","properties":{"formattedCitation":"(Gillespie)","plainCitation":"(Gillespie)","noteIndex":0},"citationItems":[{"id":"M9fxualC/3STEUtXj","uris":["http://zotero.org/users/local/CKNkWnK9/items/JGKW2T7F"],"uri":["http://zotero.org/users/local/CKNkWnK9/items/JGKW2T7F"],"itemData":{"id":484,"type":"article-journal","container-title":"Antimicrobial Agents and Chemotherapy","DOI":"10.1128/AAC.46.2.267-274.2002","ISSN":"0066-4804","issue":"2","journalAbbreviation":"Antimicrob Agents Chemother","note":"PMID: 11796329\nPMCID: PMC127054","page":"267-274","source":"PubMed Central","title":"Evolution of Drug Resistance in Mycobacterium tuberculosis: Clinical and Molecular Perspective","title-short":"Evolution of Drug Resistance in Mycobacterium tuberculosis","volume":"46","author":[{"family":"Gillespie","given":"Stephen H."}],"issued":{"date-parts":[["2002",2]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (Gillespie). The bacterium is immune to other medicines by other genetic variations. For instance, there are several genetic defects in the genes katG, inhA, ahpC, and others which generate resistance to isoniazid (INH) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"vultcSRU","properties":{"formattedCitation":"(Gillespie)","plainCitation":"(Gillespie)","noteIndex":0},"citationItems":[{"id":"M9fxualC/3STEUtXj","uris":["http://zotero.org/users/local/CKNkWnK9/items/JGKW2T7F"],"uri":["http://zotero.org/users/local/CKNkWnK9/items/JGKW2T7F"],"itemData":{"id":484,"type":"article-journal","container-title":"Antimicrobial Agents and Chemotherapy","DOI":"10.1128/AAC.46.2.267-274.2002","ISSN":"0066-4804","issue":"2","journalAbbreviation":"Antimicrob Agents Chemother","note":"PMID: 11796329\nPMCID: PMC127054","page":"267-274","source":"PubMed Central","title":"Evolution of Drug Resistance in Mycobacterium tuberculosis: Clinical and Molecular Perspective","title-short":"Evolution of Drug Resistance in Mycobacterium tuberculosis","volume":"46","author":[{"family":"Gillespie","given":"Stephen H."}],"issued":{"date-parts":[["2002",2]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (Gillespie). Amino acid modifications in InhA's NADH binding site seem to aid in INH tolerance by causing mycolic acid biosynthesis inhibition which occurs in the bacterial cell wall. Defects in the katG gene render it impossible for the protein catalase-peroxidase to transform INH to its pharmacologically active state. Therefore, INH is unsuccessful and bacteria develop resistance. Studies have established that to solve drug-resistant issues, the creation of new biochemical mechanisms is mandatory ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"s2uQfz6h","properties":{"formattedCitation":"(Sandhu and Akhter)","plainCitation":"(Sandhu and Akhter)","noteIndex":0},"citationItems":[{"id":"M9fxualC/CDTSbhjX","uris":["http://zotero.org/users/local/CKNkWnK9/items/YE9FLRMG"],"uri":["http://zotero.org/users/local/CKNkWnK9/items/YE9FLRMG"],"itemData":{"id":482,"type":"article-journal","abstract":"Drug resistance is a major concern due to the evolution and emergence of pathogenic bacterial strains with novel strategies to resist the antibiotics in use. Mycobacterium tuberculosis (Mtb) is one of such pathogens with reported strains, which are not treatable with any of the available anti-TB drugs. This scenario has led to the need to look for some novel drug targets in Mtb, which may be exploited to design effective treatment strategies against the infection. The goal of this review is to discuss one such class of emerging drug targets in Mtb. MmpL (mycobacterial membrane protein large) proteins from Mtb are reported to be involved in multi-substrate transport including drug efflux and considered as one of the contributing factors for the emergence of multidrug-resistant strains. MmpL proteins belong to resistance nodulation division permeases superfamily of membrane transporters, which are viably and pathogenetically important and their inhibition could be lethal for the bacteria.","container-title":"Archives of Microbiology","DOI":"10.1007/s00203-017-1434-6","ISSN":"1432-072X","issue":"1","journalAbbreviation":"Arch. Microbiol.","language":"eng","note":"PMID: 28951954","page":"19-31","source":"PubMed","title":"Evolution of structural fitness and multifunctional aspects of mycobacterial RND family transporters","volume":"200","author":[{"family":"Sandhu","given":"Padmani"},{"family":"Akhter","given":"Yusuf"}],"issued":{"date-parts":[["2018",1]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (Sandhu and Akhter). In certain Tuberculosis bacteria, the development of these defects can be interpreted by several modifications in the Genetic recombination, identification and repairing machinery. Genetic variations resulting in mutation enable the bacteria to have a significantly higher frequency of mutations as well as to acquire more mutations rapidly that generate antibiotic resistance ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"3Ur2RU2Y","properties":{"formattedCitation":"(Gillespie)","plainCitation":"(Gillespie)","noteIndex":0},"citationItems":[{"id":"M9fxualC/3STEUtXj","uris":["http://zotero.org/users/local/CKNkWnK9/items/JGKW2T7F"],"uri":["http://zotero.org/users/local/CKNkWnK9/items/JGKW2T7F"],"itemData":{"id":484,"type":"article-journal","container-title":"Antimicrobial Agents and Chemotherapy","DOI":"10.1128/AAC.46.2.267-274.2002","ISSN":"0066-4804","issue":"2","journalAbbreviation":"Antimicrob Agents Chemother","note":"PMID: 11796329\nPMCID: PMC127054","page":"267-274","source":"PubMed Central","title":"Evolution of Drug Resistance in Mycobacterium tuberculosis: Clinical and Molecular Perspective","title-short":"Evolution of Drug Resistance in Mycobacterium tuberculosis","volume":"46","author":[{"family":"Gillespie","given":"Stephen H."}],"issued":{"date-parts":[["2002",2]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (Gillespie).
The most severe form of tuberculosis corresponds to the resistance of bacteria towards several powerful anti TB drugs simultaneously and called as “Multiple Drug-Resistant Tuberculosis” ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"exiF64lM","properties":{"formattedCitation":"(Wood and Iseman)","plainCitation":"(Wood and Iseman)","noteIndex":0},"citationItems":[{"id":"M9fxualC/uBIDEGiU","uris":["http://zotero.org/users/local/CKNkWnK9/items/A4X8UQMD"],"uri":["http://zotero.org/users/local/CKNkWnK9/items/A4X8UQMD"],"itemData":{"id":487,"type":"article-journal","container-title":"New England Journal of Medicine","DOI":"10.1056/NEJM199309093291108","ISSN":"0028-4793, 1533-4406","issue":"11","journalAbbreviation":"N Engl J Med","language":"en","page":"784-791","source":"DOI.org (Crossref)","title":"Treatment of Multidrug-Resistant Tuberculosis","volume":"329","author":[{"family":"Wood","given":"Alastair J.J."},{"family":"Iseman","given":"Michael D."}],"issued":{"date-parts":[["1993",9,9]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (Wood and Iseman). In this case, the treatment is provided by the use of second-line anti TB drugs such as fluoroquinolones, amikacin, capreomycin, ethionamide, and para-aminosalicylic acid ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"xVxryYuC","properties":{"formattedCitation":"(Ginsburg et al.)","plainCitation":"(Ginsburg et al.)","noteIndex":0},"citationItems":[{"id":"M9fxualC/EzjU9Sh1","uris":["http://zotero.org/users/local/CKNkWnK9/items/BKAQ86IB"],"uri":["http://zotero.org/users/local/CKNkWnK9/items/BKAQ86IB"],"itemData":{"id":479,"type":"article-journal","abstract":"Although the fluoroquinolones are presently used to treat tuberculosis primarily in cases involving resistance or intolerance to first-line antituberculosis therapy, these drugs are potential first-line agents and are under study for this indication. However, there is concern about the development of fluoroquinolone resistance in Mycobacterium tuberculosis, particularly when administered as monotherapy or as the only active agent in a failing multidrug regimen. Treatment failures as well as relapses have been documented under such conditions. With increasing numbers of fluoroquinolone prescriptions and the expanded use of these broad-spectrum agents for many infections, the selective pressure of fluoroquinolone use results in the ready emergence of fluoroquinolone resistance in a diversity of organisms, including M tuberculosis. Among M tuberculosis, resistance is emerging and may herald a significant future threat to the long-term clinical utility of fluoroquinolones. Discussion and education regarding appropriate use are necessary to preserve the effectiveness of this antibiotic class against the hazard of growing resistance.","container-title":"The Lancet Infectious Diseases","DOI":"10.1016/S1473-3099(03)00671-6","ISSN":"1473-3099","issue":"7","journalAbbreviation":"The Lancet Infectious Diseases","language":"en","page":"432-442","source":"ScienceDirect","title":"Fluoroquinolones, tuberculosis, and resistance","volume":"3","author":[{"family":"Ginsburg","given":"Amy Sarah"},{"family":"Grosset","given":"Jacques H"},{"family":"Bishai","given":"William R"}],"issued":{"date-parts":[["2003",7,1]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (Ginsburg et al.). Multi-Drug Resistant Tuberculosis can further become resilient to major categories of second-line Tuberculosis medications such as fluoroquinolones including drugs moxifloxacin, ofloxacin and intravenous aminoglycosides including amikacin, capreomycin, kanamycin. It is categorized as Extensively Drug-Resistant Tuberculosis when MDR-TB is resilient to at least one stimulant from each group ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"R9dekkIo","properties":{"formattedCitation":"(Ginsburg et al.)","plainCitation":"(Ginsburg et al.)","noteIndex":0},"citationItems":[{"id":"M9fxualC/EzjU9Sh1","uris":["http://zotero.org/users/local/CKNkWnK9/items/BKAQ86IB"],"uri":["http://zotero.org/users/local/CKNkWnK9/items/BKAQ86IB"],"itemData":{"id":479,"type":"article-journal","abstract":"Although the fluoroquinolones are presently used to treat tuberculosis primarily in cases involving resistance or intolerance to first-line antituberculosis therapy, these drugs are potential first-line agents and are under study for this indication. However, there is concern about the development of fluoroquinolone resistance in Mycobacterium tuberculosis, particularly when administered as monotherapy or as the only active agent in a failing multidrug regimen. Treatment failures as well as relapses have been documented under such conditions. With increasing numbers of fluoroquinolone prescriptions and the expanded use of these broad-spectrum agents for many infections, the selective pressure of fluoroquinolone use results in the ready emergence of fluoroquinolone resistance in a diversity of organisms, including M tuberculosis. Among M tuberculosis, resistance is emerging and may herald a significant future threat to the long-term clinical utility of fluoroquinolones. Discussion and education regarding appropriate use are necessary to preserve the effectiveness of this antibiotic class against the hazard of growing resistance.","container-title":"The Lancet Infectious Diseases","DOI":"10.1016/S1473-3099(03)00671-6","ISSN":"1473-3099","issue":"7","journalAbbreviation":"The Lancet Infectious Diseases","language":"en","page":"432-442","source":"ScienceDirect","title":"Fluoroquinolones, tuberculosis, and resistance","volume":"3","author":[{"family":"Ginsburg","given":"Amy Sarah"},{"family":"Grosset","given":"Jacques H"},{"family":"Bishai","given":"William R"}],"issued":{"date-parts":[["2003",7,1]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (Ginsburg et al.). In a survey of MDR-TB victims in different parts of the world from the year 2005 to 2008, forty-three percent were reported to develop resistance to the minimum of one second-line medication. Approximately nine percent of MDR-TB instances were immune to both medications and were known as XDR-TB ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"qwjQ8vfT","properties":{"formattedCitation":"({\\i{}MDR_TB_FactSheet.Pdf})","plainCitation":"(MDR_TB_FactSheet.Pdf)","noteIndex":0},"citationItems":[{"id":25,"uris":["http://zotero.org/users/local/Fw9DaQie/items/PLPRHN8Y"],"uri":["http://zotero.org/users/local/Fw9DaQie/items/PLPRHN8Y"],"itemData":{"id":25,"type":"article","title":"MDR_TB_FactSheet.pdf","URL":"https://www.who.int/tb/challenges/mdr/MDR_TB_FactSheet.pdf","accessed":{"date-parts":[["2019",12,10]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (MDR_TB_FactSheet.Pdf).
Conclusion
Tuberculosis is a leading cause of causalities around the world and its prevalence has now surpassed the percentage occurrence of HIV AIDS. However, the treatment of Tuberculosis is well recognized in the field of medicine still, most of the cases remain unsolved due to the emergence of the new strains. The treatment includes the use of multiple drug therapy which includes the administration of several different drug combinations because of the phenomenon of bacterial drug resistance. It has been evident from the studies that the emergence of new strains day by asks for the immediate development of new drug strategies so the prevalence of this epidemic can be taken under control.
Works Cited
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Ginsburg, Amy Sarah, et al. “Fluoroquinolones, Tuberculosis, and Resistance.” The Lancet Infectious Diseases, vol. 3, no. 7, July 2003, pp. 432–42. ScienceDirect, doi:10.1016/S1473-3099(03)00671-6.
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