An estimated one third of the world's population is infected with Mycobacterium tuberculosis, and nearly 9 million persons develop disease caused by M. tuberculosis each year. Although tuberculosis (TB) occurs predominantly in resource-limited countries, it also occurs in the United States.  During 1985-1992, the United States was confronted with an unprecedented TB resurgence. This resurgence was accompanied by a rise in multidrug-resistant TB (MDR TB), which is defined as TB that is resistant to the two most effective first-line therapeutic drugs, isoniazid and rifampin. In addition, virtually untreatable strains of M. tuberculosis are emerging globally. Extensively drug-resistant (XDR) TB is defined as MDR TB that also is resistant to the most effective second-line therapeutic drugs used commonly to treat MDR TB: fluoroquinolones and at least one of three injectable second-line drugs used to treat TB (amikacin, kanamycin, or capreomycin). XDR TB has been identified in all regions of the world, including the United States. In the United States, the cost of hospitalization for one XDR TB patient is estimated to average $483,000, approximately twice the cost for MDR TB patients. Because of the limited responsiveness of XDR TB to available antibiotics, mortality rates among patients with XDR TB are similar to those of TB patients in the preantibiotic era. In January 1992, CDC convened a Federal TB Task Force to draft an action plan to improve prevention and control of drugresistant TB in the United States (CDC. National action plan to combat multidrug-resistant tuberculosis. MMWR 1992;41(). In November 2006, CDC reconvened the Task Force to draft an updated action plan to address the issue of MDR TB and XDR TB. Task Force members were divided into nine response areas and charged with articulating the most pressing problems, identifying barriers to improvement, and recommending specific action steps to improve prevention and control of XDR TB within their respective areas. Although the first priority of the Federal TB Task Force convened in 2006 was to delineate objectives and action steps to address MDR TB and XDR TB domestically, members recognized the necessity for TB experts in the United States to work with the international community to help strengthen TB control efforts globally. TB represents a substantial public health problem in low-and middle-income countries, many of which might benefit from assistance by the United States. In addition, the global TB epidemic directly affects the United States because the majority of all cases of TB and 80% of cases of MDR TB reported in the United States occur among foreign-born persons. For these reasons, the Action Plan also outlines potential steps that U.S. government agencies can take to help solve global XDR TB problems. Unless the fundamental causes of MDR TB and XDR TB are addressed in the United States and internationally, the United States is likely to experience a growing number of cases of MDR TB and XDR TB that will be difficult, if not impossible, to treat or prevent. The recommendations provided in this report include specific action steps and new activities that will require additional funding and a renewed commitment by government and nongovernment organizations involved in domestic and international TB control efforts to be implemented effectively. The Federal TB Task Force will coordinate activities of various federal agencies and partner with state and local health departments, nonprofit and TB advocacy organizations in implementing this plan to control and prevent XDR TB in the United States and to contribute to global efforts in the fight against this emerging public health crisis.# Introduction Global Health Burden of Tuberculosis
Tuberculosis (TB) is among the most common infectious diseases and frequent causes of death worldwide (1). TB is caused by Mycobacterium tuberculosis and is spread most commonly by airborne transmission. M. tuberculosis can affect any part of the body but is found most often in the lungs. Persons with pulmonary TB generally have a cough that produces small airborne droplet nuclei containing tubercle bacilli that can remain in the air for hours. Vulnerable persons exposed to tubercle bacilli in airborne droplets might become infected. The majority of persons who become infected remain noncontagious and without a cough or other symptoms. These persons have latent M. tuberculosis infection (LTBI) and can be treated with a single drug (isoniazid) for 9 months to prevent disease.
Infected persons who do not have underlying medical problems and do not receive LTBI treatment have a 5%-10% lifetime risk for progressing to TB disease (2). However, the risk for disease progression increases substantially in the presence of immunosuppression, such as that caused by the human immunodeficiency virus (HIV) and immunosuppressive medications (2). Persons with pulmonary TB can be cured with a 6-month course of antibiotics that includes isoniazid, rifampin, pyrazinamide, and ethambutol during the first 2 months. In the United States, diagnosis and treatment for TB is accessible and effective (3). However, many developing countries have limited resources to diagnose TB illness and treat persons with TB. Worldwide, 2 billion persons (one third of the world's population) are thought to have LTBI. Nearly 9 million persons develop TB disease each year, and close to 2 million TB-related deaths occur annually (1). In the United States, approximately 13,000 new cases of TB are reported annually, and 650 persons die from TB each year (4). TB is the leading cause of mortality among persons infected with HIV (5).

# Emergence of Drug-Resistant Tuberculosis
During 1985-1992, the United States experienced an unprecedented TB resurgence marked by a substantial number of patients with TB who did not respond to treatment and who eventually died (6). Physicians and epidemiologists quickly determined that these persons had multidrug-resistant TB (MDR TB), which is defined as TB that is resistant to both isoniazid and rifampin (7). Although persons with MDR TB usually can be treated effectively by relying on second-line drugs (amikacin, kanamycin, or capreomycin), these have more side effects and are more expensive and less effective than first-line drugs and require regimens lasting 18-24 months (3). In addition, the cure rate for persons with MDR TB is 50%-60%, compared with 95%-97% for persons with drug-susceptible TB (3). In response to several MDR TB outbreaks in hospitals and correctional facilities in New York and Florida during 1988-1991 (8,9), CDC convened a Federal TB Task Force- with representatives from multiple U.S. agencies  to produce recommendations for a nationwide response to the MDR TB outbreaks. In June 1992, the Federal TB Task Force published an action plan that provided a framework for response and specific action steps for state and local health departments and federal agencies (7). These action steps were grouped into nine categories: 1) surveillance and epidemiology, 2) laboratory diagnosis, 3) patient management, 4) screening and preventive therapy, 5) infection control, 6) outbreak control, 7) program evaluation, 8) information dissemination/training and education, and 9) research. Emergency federal funding was appropriated to CDC in 1993 and again in 1994 to allow the Federal TB Task Force and state and local health departments to implement certain parts of the plan. For example, CDC investigative teams were deployed to assist local programs in defining and organizing appropriate response to MDR TB outbreaks (CDC, personal communication, 2007). State and local health departments enhanced diagnostic laboratory capacity, increased the sensitivity of their surveillance systems, improved infection-control practices, and reemphasized the need for optimal treatment of all forms of TB to prevent the development and further transmission of MDR TB. Other federal agencies that are members of the task force also contributed substantially to implementation of the plan; a description of their activities follows.
The need for increased biomedical research and product development for TB was recognized by the National Institutes of Health (NIH) as part of the implementation of the 1992 Action Plan. The National Institute for Allergy and Infectious Diseases (NIAID) established extramural and intramural research programs in all areas of fundamental, translational, and clinical research in TB to create a platform of knowledge and the research tools needed to study M. tuberculosis and its interaction with the host and to characterize TB in animal models and humans. In June 2007, NIAID released a research agenda describing the specific biomedical research challenges and priorities that should be addressed in response to the emergence of drug-resistant TB (10).
The National Heart, Lung, and Blood Institute (NHLBI) supported studies with a strong emphasis on pulmonary TB, including complications through coinfection with HIV, and developed a training curriculum in TB for health professionals at medical institutions through the National Tuberculosis Curriculum Consortium (NTCC) (11,12). The Fogarty International Center (FIC) supported TB research and research training for developing country scientists through collaborative grants with U.S. institutions (13). The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) focused on international clinical research for optimizing TB treatment in children and women coinfected with HIV (14). The more recently created National Institute of Biomedical Imaging and Bioengineering (NIBIB) has a substantial investment in diagnostic platform technologies (point-of-care and imaging) that can help improve TB diagnosis through advances in medical imaging methods (15).
In May 1994, the Food and Drug Administration (FDA) approved Rifater (a fixed-dose combination of rifampin, isoniazid, and pyrazinamide) to facilitate patient adherence with lengthy and complex multidrug therapy (16). In addition, FDA granted a priority new drug application review for the drug rifapentine, which was approved in July 1998 for the treatment of TB (17). In 1993, the United States Marshals Service (USMS) established a formal medical program for prisoners with TB (USMS, personal communication, 2007). As part of this activity, USMS drafted a series of advisory memoranda to provide education information and guidance to USMS field offices to support TB screening for staff and prisoners. USMS also collaborated with the Texas Department of Health to conduct presentations on TB control in correctional facilities highlighting patient tracking and follow-up issues that arise when transferring prisoners between and outside jurisdictions. The Department of Housing and Urban Development (HUD) developed web-based information and training activities on acquired immune deficiency syndrome (AIDS) and TB (HUD, personal communication, 2007).
Since 1998, with the creation of specific international TB programs (e.g., directly observed treatment, short-course  expansion; research; training; and TB/HIV coinfection), the U.S. Agency for International Development (USAID) has provided technical and financial support to strengthen TB control programs worldwide (18). USAID also has supported drug-resistance surveys with biannual global reports and pilot programs to optimize MDR TB treatment and the Green Light Committee (GLC), which helps countries gain access to high-quality second-line TB drugs so they can provide treatment for persons with MDR TB (19). More recently, the Division of Immigration Health Services (DIHS) of the Health Resources and Services Administration (HRSA) implemented a national TB Continuity of Care Program for persons who are detained by U.S. Immigration and Customs Enforcement (ICE) agents in the Department of Homeland Security (DHS) and who are to be deported before completing TB therapy (20); in October 2007, DIHS was transferred from HRSA to ICE. In addition, U.S. government agencies have worked with their counterparts in Mexico and in U.S. state agencies to develop initiatives (e.g., Ten Against TB) to address TB, including drug-resistant TB, along the U.S.-Mexico border (21). During 1993-2007, as a result of implementation of the 1992 Action Plan, the reported annual incidence of MDR TB in the United States declined 75%, from 485 cases in 1993 to 119 cases in 2007 (4).

# Emergence of Extensively Drug-Resistant Tuberculosis
Since 1993, both incidence of TB and the total number of TB cases in the United States have decreased, although the rate of decline has slowed since 2000. Worldwide, the number of TB cases has continued to increase, but the incidence rate has decreased since 2003. Recently, highly drug-resistant forms of TB have emerged worldwide. In 2006, CDC, the World Health Organization (WHO) and the International Union Against Tuberculosis and Lung Disease (IUATLD) reported the results of a survey regarding drug-resistant TB conducted by 25 reference laboratories comprising the Global Supranational TB Reference Laboratory Network (2000)(2001)(2002)(2003)(2004), the National TB Surveillance System in the United States (1993)(1994)(1995)(1996)(1997)(1998)(1999)(2000)(2001)(2002)(2003)(2004), the national reference laboratory of South Korea (2004), and the national MDR TB patient registry in Latvia (2000-2002) (22). The findings indicated that 20% of M. tuberculosis isolates were MDR, and 2% also were resistant to multiple second-line drugs. This highly resistant form of TB was identified in every region of the world, including the United States, where 4% of MDR TB isolates also were resistant to multiple second-line drugs. In a report published in 2006, this highly resistant form of TB was named extensively drug-resistant TB (XDR TB) (22). XDR TB is a subset of MDR TB that is resistant both to isoniazid and rifampin and to any fluoroquinolone drug and at least one of three second-line injectable drugs (amikacin, kanamycin, or capreomycin) (23).
The emergence of XDR TB raises concerns about the possibility of epidemics of virtually untreatable TB. Such epidemics could result in excessive mortality and substantial financial and infrastructure burden for public health and TB control programs. XDR TB is much more expensive to treat, with hospitalization costs in the United States estimated to average $483,000 per case. A major outbreak of XDR TB in the United States would constitute a substantial drain on public health resources and could quickly deplete the existing state and local TB budgets and have a negative impact on progress toward TB elimination. This is especially true in an era of diminishing resources for TB control at the national, state, and local levels (6). Treatment failures and subsequent death are more common among patients with XDR TB, and the drugs available to treat XDR TB are associated with serious adverse effects. Because persons who are infected with HIV or who have other immune-compromising conditions (e.g., diabetes) are more vulnerable to progressing to active TB disease, infection with XDR TB is of particular concern among these persons. In countries with high rates of HIV and limited health-care resources, substantial numbers of XDR TB cases are likely present. As of April 2007, South Africa (where HIV prevalence was estimated at 10.8% in 2005) had reported 352 cases of XDR TB, with the actual prevalence likely being much higher (24) because cultures and susceptibility testing are performed on only a small fraction of TB patients, and many drug-resistant cases will go undetected.

# Methodology
After an outbreak of XDR TB among HIV-infected persons in Kwazulu Natal, South Africa, reported in August 2006, urgent expert consultations were organized by the South African Medical Research Council (SAMRC) and WHO in September and October 2006 (25). The result of these consultations was the 2007 publication of a global MDR TB and XDR TB response plan with eight overarching objectives (26). Several U.S. government agencies, including CDC, participated in the expert consultations. The U.S. Federal TB Task Force was recognized as the appropriate venue to coordinate U.S. involvement in the global response to XDR TB.
In November 2006, following participation in the SAMRC and WHO XDR TB consultations, CDC convened members of the Federal TB Task Force to discuss the emergence of XDR TB and coordinate U.S. government agency involvement in the domestic and international response to this problem. After several teleconferences, the Task Force agreed that a U.S. government agency action plan should be written. The action plan that had been published in 1992 to respond to MDR TB was selected as a basis for drafting the XDR TB response plan (7). Several members of the 2006 Task Force also had contributed to the 1992 Action Plan to combat MDR TB. This MDR TB expertise contributed substantially to a well-informed and effective discussion and the creation of an Action Plan to Combat Extensively Drug-Resistant TB. As had occurred in the process to create the 1992 Action Plan, members of the Federal TB Task Force were divided into sections to address critical areas of response. The 1992 action plan distributed the objectives and implementation steps needed to address 38 problems among nine response areas (surveillance and epidemiology, laboratory diagnosis, patient management, screening and preventive therapy, infection control, outbreak control, program evaluation, information dissemination/training and education, and research). Although largely overlapping with the 1992 action plan, the response areas for the XDR TB plan were reorganized as follows: 1) diagnostic laboratory; 2) surveillance, epidemiology, and outbreak investigations; 3) infection control; 4) clinical and programmatic interventions; 5) ethical and legal issues; 6) communication and education; 7) research; 8) partnerships; and 9) cost analysis. These response areas also are closely aligned with WHO's seven-point Global Action Plan to Combat XDR TB (26), which calls for public health authorities to 1) conduct rapid surveys of XDR TB to determine the burden, 2) enhance laboratory capacity with an emphasis on rapid drug-sensitivity testing, 3) improve the technical capacity of clinical and public health practitioners to respond effectively to XDR TB outbreaks and manage patients, 4) implement infection-control precautions, 5) increase research support for TB drug development, 6) increase research support for rapid diagnostic test development, and 7) promote universal access to antiretroviral drugs under joint TB/HIV activities. In addition, the implementation steps were renamed "action steps."
In January 2007, each subgroup of the Federal TB Task Force that was responsible for addressing a critical response area began by reviewing the relevant sections of the 1992 action plan to determine which problems, objectives, and action (formerly implementation) steps needed to be deleted or updated and revised. The subgroups also determined if gaps existed requiring the identification of additional problems, objectives and action steps. In particular, because the 1992 plan had focused primarily on domestic MDR TB, the subgroups were instructed to expand the scope of the new plan to address the role of U.S. government agencies in the international response to XDR TB. To reflect this distinction, the new plan labels objectives as domestic, international, or both. The expanded scope and a greater emphasis on detail resulted in a substantial increase in the number of problems, objectives, and action steps identified compared with the 1992 plan. For example, the number of problems increased from 38 in 1992 to 67 in the current plan. An emphasis also was placed on being as inclusive as possible when designating lead federal agencies and potential external partners. To provide a basis for revisions, the subgroup members reviewed pertinent literature published since 1992, which is substantially more voluminous, especially for drug-resistant TB, compared with that available before 1992, and available unpublished data. After drafts of the sections were completed, the sections were compiled into a single document that was distributed to the entire Federal TB Task Force for review and comment. In June 2007, the Federal TB Task Force met in Rockville, Maryland, to make additional revisions, especially to eliminate redundancies between sections. These revisions were incorporated into a final draft that was submitted for multiple agency clearance in September 2007.

# Recommendations to Combat Extensively Drug-Resistant Tuberculosis Diagnostic Laboratory
The diagnosis of XDR TB is established by laboratory methods. Accurate, reliable, and prompt TB laboratory services should be coordinated fully with provider and public health practitioners caring for persons with TB. Test results must be available in a time frame that allows clinicians to make prompt and informed patient management decisions. For this goal to be met, laboratory capacity for the diagnosis of TB and the detection of drug resistance must be rapidly enhanced, both in the United States and worldwide. Adequate infrastructure must be built where it does not exist, a stable and well-trained work force must be developed and maintained, and a systems approach (27) must be implemented to maximize efficiency and proficiency. Laboratory methods and reporting, especially for susceptibility to second-line drugs, should be standardized through expert consensus. Rapid tests for TB diagnosis and drug-susceptibility testing on the basis of newer molecular methods must be evaluated promptly to determine their feasibility, especially for low-resource settings, and, if appropriately validated, their use should be promoted and facilitated. Internationally, competent, high-quality reference laboratory services with capacity to perform required testing of samples and to report results in a prompt fashion to providers and health officials must be available to jurisdictions in need.

# Surveillance, Epidemiology, and outbreak Investigation
Domestic XDR TB surveillance must include accurate and complete reporting of second-line drug-susceptibility testing, real-time reporting, and active case finding. Central notification of MDR TB and XDR TB is essential to identify cross-jurisdictional issues and to provide potential for rapid emergency federal support, when needed. Internationally, rapid drug-susceptibility test (DST) surveys and more sustained systematic capture of DST information are highlighted as areas to be addressed as part of a comprehensive response to XDR TB. Epidemiologic studies that make use of genotyping tools are recommended to elucidate XDR TB risk factors and transmission dynamics. Strategies also are needed to rapidly identify and respond to domestic and international XDR TB outbreaks.

# Infection Control
Effective infection-control practices are critical to prevent the transmission and further spread of MDR and XDR TB in health-care settings and other congregate settings (e.g., correctional facilities and homeless shelters). CDC infectioncontrol guidelines were updated in December 2005 and should continue to be updated as needed (28). Further studies are needed to assess the effectiveness and feasibility of various infection-control strategies in different institutional settings. Testing workers for TB in various institutional settings is an important strategy for identifying workers infected with TB and detecting unsuspected transmission.

# Clinical and Programmatic Interventions
Prevention and control of TB in the United States require a robust public health infrastructure that includes a workforce trained in TB prevention, diagnosis, treatment, and case management. Because some patients fail to recognize TB symptoms, health care often is not sought during early stages of disease. In addition, providers who are unfamiliar with signs and symptoms of TB and with diagnostic standards might not suspect TB, delaying the start of effective treatment. Access to comprehensive and affordable clinical TB services (i.e., preventive, diagnostic, and treatment/case management) should be provided to all persons with TB or those suspected to have TB. Health-care providers who screen persons for TB should use up-to-date diagnostic and treatment guidelines. More health-care workers are needed to provide directly observed therapy (DOT) for TB patients to ensure successful treatment and help prevent development of disease attributable to drug-resistant TB.

# Ethical and Legal Issues
Strict infection-control measures are necessary to prevent the spread of XDR TB. Patients with XDR TB might need to be placed in airborne infectious isolation while initial treatment response is monitored in order to prevent disease transmission to others. Guidance is needed regarding the ethical and legal issues involved in identifying and treating persons with XDR TB. The adequacy of current public health laws in the United States to address drug-resistant TB has not been studied comprehensively since 1993 (29). All states have laws to compel isolation for persons with certain infectious diseases (including TB); however, these laws vary by state, and those for TB might be contingent on patient nonadherence and failure of voluntary measures. Public health authorities must balance the interests of the public with individual rights. Legal and ethical issues become even more complicated when persons have XDR TB because prolonged isolation might be necessary even when a patient is adherent. In addition, for some patients, no effective treatment is available that would allow for release from isolation on completion. Additional complexity also exists regarding non-U.S. citizens with infectious XDR TB who are scheduled to be repatriated to their native countries. U.S. public health officials might not be familiar with public health laws of other countries.

# Communication and Education
As a result of TB incidence rates decreasing in the United States, health-care providers have received little training regarding TB and consequently might not recognize the signs and symptoms of TB, which can lead to incorrect diagnosis and treatment, creation of drug resistance, and continued spread of TB in the community (30,31). Health-care providers should be educated about the signs and symptoms of TB, diagnostic methods, prevention, and treatment. In addition, education materials on MDR TB and XDR TB should be developed for the general public, populations at high-risk for TB on the basis of demographic and clinical characteristics, TB patients, TB prevention advocacy organizations, and policy makers, including legislators. Education materials should include informational pamphlets, instructions for therapy, behaviors to prevent transmission, medical alerts, and descriptions of TB programs. Distribution of these materials should be coordinated across federal and state agencies and updated as necessary. Advocacy is critical to make the public aware of the importance of TB control to the public's health, and to educate policy makers on the magnitude of the problems that will result if resources to state and local TB control programs continue to decline.

# Research
The biomedical research challenges represented by drugresistant TB in the context of overall TB research activities have been described previously (10). Knowledge gaps remain regarding the genetics and growth characteristics of M. tuberculosis, the physiology and biochemistry of both the host and pathogen during infection, and the disease and genotypic and biologic markers that facilitate surveillance and indicate infection, disease, and drug resistance. Basic research needs to be supported to advance understanding of these issues and to help design new approaches to diagnosis and treatment. The emergence of drug-resistant TB illustrates the pressing need to develop new and effective drug regimens for the treatment of TB, including drugs to cure MDR TB and XDR TB and to prevent development of active disease among persons who are infected latently with drug-resistant M. tuberculosis. Because poor patient adherence to therapy is one factor that can lead to development of MDR TB and XDR TB, research of associated behavioral and social factors should be conducted to identify ways to improve patient adherence and treatment completion. New, rapid, and cost-effective diagnostic methods are needed, particularly for use in rural areas and developing countries. Ultimately, an effective vaccine is needed to eliminate TB.

# Partnerships
To coordinate efforts to control XDR TB, existing partnerships must be strengthened, and new partnerships are needed between countries and within both the public and private sectors, including government and nongovernment organizations. Partnerships are necessary to focus existing resources on the most affected geographic areas, increase current public and private resources (both financial and human resources), coordinate the efforts (including research, education, laboratory, and programmatic), and raise awareness of the problem and consequences.

# Cost Analysis
Comprehensive information is not available on the cost of treating and implementing programs and interventions to prevent XDR TB. Research on the cost of treating and preventing XDR TB is needed to calculate the cost-effectiveness and benefits of interventions and strategies to combat XDR TB.

# Action Plan to Combat Extensively Drug-Resistant Tuberculosis Diagnostic Laboratory
The laboratory plays a critical role in the diagnosis and management of drug-resistant TB. Test results must be available in a time frame that allows clinicians to make prompt patient management decisions. Many laboratory techniques used to confirm a TB diagnosis and to identify drug resistance were developed in the 1950s, 1960s, and 1970s. Substantial improvements have been made in culture techniques and in rapid methods in the past decade. However, these more accurate, rapid, and sophisticated methods have not been implemented widely, particularly in regions of the world where MDR TB and XDR TB are common and optimized algorithms for providing rapid point-of-care laboratory confirmation of TB and detection of drug resistance have not been established. To combat the growing problem of resistance to TB drugs, the most current methods need to be applied to their fullest capacity while better diagnostic tests are developed. The needs of the TB laboratory must be addressed to make laboratory services for TB, MDR TB, and XDR TB more rapid, sensitive, reliable, and more responsive to the needs for patient management, infection control, and TB control efforts. Although the challenges and potential solutions vary by setting, domestic and international TB laboratories face many of the same challenges.

# Problem 1
Many clinicians, laboratorians, health-care professionals, public health officials, and policy makers do not possess upto-date knowledge of what constitutes appropriate laboratory capabilities and capacities or the appropriate use of tests to arrive at a prompt and accurate diagnosis of TB. Increase awareness of the need to develop necessary capacity and capabilities for the laboratory diagnosis of TB. This includes proper use of diagnostic tests, prompt reporting of results, and appropriate interpretation of test results for establishing a definite diagnosis and for guiding management of TB (domestic and international).

# Problem 4
The quality of and proficiency in TB laboratory diagnosis varies within the United States and internationally because a well-trained and stable laboratory workforce is not universally available.

# Problem 5
TB laboratory services at certain local public health laboratories are limited and might depend on access to networks of other public and private laboratories with better diagnostic capabilities, which often leads to substantial delays in diagnosis and treatment of TB. Develop a systems approach to improving TB laboratory services at the local level (domestic).

# Action Steps
5.1.1. Assess available TB laboratory services in a jurisdiction to determine the status and capacity of services and to identify unmet needs, obstacles to obtaining services, and opportunities for improvement.
5.1.2. Assess the actual costs of providing TB laboratory services through existing programs and develop a business plan for providing these services through an integrated system of laboratory services in the United States.
5.1.3. Develop a strategic plan for implementing and maintaining a systems approach to TB laboratory services.
5.1.4. Develop outcome measures to assess performance of and improvements in laboratory services and overall TB control programs.
Lead federal agencies: HHS (CDC). 5.2.4. Develop program-specific plans and phased approaches to improving laboratory services in national, country-level regional and peripheral (local) laboratories.
5.2.5. Develop local, district, regional, and national laboratories, including referral laboratories, that provide reliable services through conventional and rapid methods for TB diagnosis, drug-susceptibility testing and patient care.
5.2.6. Develop or ensure access to effective external quality assessment programs for laboratory services (e.g., acid fast bacillus -smear microscopy, culture, and drug-susceptibility testing) provided at each level.
5.2.7. Support development of laboratory standards and accreditation programs with an emphasis on culture and drug-susceptibility testing to facilitate assessment and quality improvement of national and regional laboratories.
5.2.8. Explore options to increase TB laboratory capacity as part of efforts to improve general diagnostic laboratory service capacity and overall health sector reform. 5.2.9. Identify interim laboratory support services until local and regional capacity is developed.
5.2.10. Support research to develop inexpensive, high-quality diagnostic tools that can be used in resource-limited settings.
Lead federal agencies: HHS (CDC and NIH), and USAID.
Suggested collaborators: DoD, DOS, NTCA, APHL, ASM, WHO, and IUATLD. Culture-based laboratory tests to identify persons with XDR TB are slow, lack sensitivity, and have poor reliability, resulting in delayed diagnosis, treatment, and public health control efforts. objective 6.1
Improve the ability of TB laboratories to identify and report drug-resistant M. tuberculosis (domestic).

# Action Steps
6.1.1. Develop local, district, state, regional, or referral laboratories that are able to rapidly identify M. tuberculosis bacteria in patient specimens and determine drug susceptibilities to first-and second-line agents using state-of-the-art conventional or rapid methods.
6.1.2. Encourage the use of state-of-the-art rapid tests for detection of M. tuberculosis and drug-susceptibility testing through focused laboratory funding.
6.1.3. Develop a bank of M. tuberculosis isolates for use in proficiency testing and research.
6.1.4. Implement proficiency testing programs and external quality assessment programs for new drug-susceptibility tests and rapid methods.
6.1.5. Assist laboratories in developing and implementing an integrated information management system for inventory, specimen tracking, reporting, and information sharing.
6.1.6. Identify interim laboratory support services until local and regional capacities are developed.
Lead federal agencies: HHS (CDC and NIH). Suggested collaborators: APHL and NTCA.

# Problem 7
The lack of guidelines for the use of conventional and rapid culture-based or molecular methods for detection of M. tuberculosis and drug resistance impedes the widespread use of these tests. Develop consensus guidelines to address TB laboratory testing in the United States, in high-burden and in focus countries (domestic and international). Action Steps 7.1.1. Develop consensus guidelines for culture, drug-susceptibility, and rapid diagnostic testing to be used in local, district, state, national, and country-level regional laboratories.
7.1.2. Develop consensus guidelines for the use of rapid methods (e.g., nucleic acid amplification tests) to detect M. tuberculosis directly from patient specimens. 7.1.3. Develop consensus guidelines for the use of rapid, molecular methods for drug-susceptibility testing.
7.1.4. Develop consensus guidelines for culture-based methods to determine resistance to second-line TB drugs.
7.1.5. Conduct operational and implementation research to develop guidelines for optimal algorithms for TB laboratory testing, specimen referral, and reporting.
Lead federal agencies: HHS (CDC and NIH) and USAID.
Suggested collaborators: APHL, ATS, IDSA, CLSI, WHO, IUATLD, and academia.

# Problem 8
The current process for evaluating newly developed diagnostic tests can be time consuming and delay implementation for routine clinical use. Develop strategies for expedited evaluation and implementation of new rapid methods for laboratory confirmation of TB and identification of drug-resistance patterns (domestic and international). 8.1.10. Determine and promote the most effective pointof-care drug-susceptibility testing methods and diagnostic algorithms and strategies, including molecular testing at the local level followed by transport of positive specimens to fullservice laboratories for further evaluation.
8.1.11. Provide access to or conduct clinical trials in partnership with high-burden countries to validate new microbiologic drug-susceptibility tests as part of local diagnostic procedures/ algorithms.
8.1.12. Discuss with FDA criteria that will be required for approval of new tests for identification of drug-resistant TB and to perform rapid drug-susceptibility testing.
Lead federal agencies: HHS (CDC, FDA, and NIH), and USAID.
Suggested collaborators: DoD, Foundation for Innovative New Diagnostics (FIND), WHO Special Programme for Research and Training in Tropical Diseases ), academia, public health laboratories, and IUATLD.

# Problem 9
The laboratory confirmation of TB in HIV-infected persons is difficult and time consuming because of the need for highly sensitive, sophisticated and technically challenging diagnostic tests that are not universally available in all settings with a high burden of HIV and TB. Suggested collaborators: DOS, DoD, FIND, WHO (TDR), ASM, APHL, academia, IUATLD, and public health laboratories.

# Problem 10
Current technical assistance for laboratory capacity building is sporadic and not well coordinated or integrated often leading to unclear and inconsistent guidance.

# Develop consistent and well-coordinated approaches to technical assistance and consultation for TB laboratories in high-burden and focus countries (international).
Action Steps 10.1.1. Develop technical assistance approaches and practices that are coordinated, consistent, and compatible with the efforts of international partners such as WHO and IUATLD.
10.1.2. Establish a cadre of well-trained consultants to help guide coordinated approaches to building TB laboratory capacity in high-burden and focus countries.
10.1.3. Contribute to the coordinated development of standardized checklists and templates for laboratory evaluation and training materials for laboratory capacity building efforts.
10.1.4. Contribute to the coordinated development of external quality assessment guidance and documents for microscopic and culture identification of M. tuberculosis and drug-susceptibility testing.
10.1.5. Contribute to the coordinated development of widely compatible laboratory information systems to facilitate transfer of information within and between TB control programs.
10.1.6. Promote expansion of the Supranational Laboratory Network through inclusion of reference laboratories that can assist in capacity building and external quality assessment.
10.1.7. Promote expansion of the Supranational Laboratory Network proficiency testing to include second-line drugsusceptibility testing.
10.1.8. Promote and coordinate partnering of public health laboratories in the United States with public health laboratories in high-burden and focus countries.
Lead federal agencies: HHS (CDC and NIH), and USAID.
Suggested collaborators: DoD, DOS, NTCA, APHL, ASM, WHO, and IUATLD.

# Problem 11
Providing technical assistance is logistically difficult. objective 11.1 Establish international regional centers of excellence to facilitate implementation of technical assistance provided by the United States to TB endemic or TB-focus countries (international).

# Action Steps
11.1.1. Build expertise for technical assistance to TB laboratories at selected centers of excellence in high-burden countries. February 13, 2009 11.1.2. Provide opportunities for peer-to-peer training and exchange of laboratory personnel in resource limited settings.
11.1.3. Assist centers of excellence in developing training programs for program staff, laboratory managers and bench workers on establishing methods for external quality assessment processes through site visits and monitoring.
11.1.4. Assist centers of excellence in establishing reference laboratory services for identification of M. tuberculosis and susceptibility testing for first-and second-line drugs that would qualify them as Supranational Reference Laboratories and that could be made available to partner programs.
Lead federal agencies: HHS (CDC and NIH) and USAID. Suggested collaborators: DOS, DoD, WHO, IUATLD, APHL, ASM, KNCV, RIT, academia, and public health laboratories.

# Problem 12
Resources available to TB laboratories are often inadequate for building and maintaining the necessary infrastructure and competencies to provide consistently high-quality diagnostic services. Mobilize resources and support international efforts to strengthen and sustain TB laboratory capacity (international).

# Action Steps
12.1.1. Identify funding opportunities through the President's Emergency Plan for AIDS Relief, USAID, and the Global Fund to contribute to strengthening international laboratory efforts. 12.1.2. Support global efforts (e.g., WHO's strategic approach to the strengthening of laboratory services for TB control).
12.1.3. Support the Stop TB Partnership's Global Laboratory Initiative and the DOTS (directly observed therapy, short course) Expansion Working Group.
Lead federal agencies: USAID and HHS (CDC). Suggested collaborators: DOS, WHO, the Bill & Melinda Gates Foundation, APHL, and the American Lung Association (ALA).

# Problem 13
The role of public and private TB laboratories in the diagnosis of persons latently infected with XDR M. tuberculosis has not been defined clearly.

# Develop laboratory services to identify persons with drug-resistant latent M. tuberculosis infection (DR LTBI) (domestic).

# Action Steps
13.1.1. Assess the capacity of public and private TB laboratories to support DR LTBI diagnostic testing by determining the status and capacity of currently available services and identifying gaps, obstacles and opportunities for improvement.
13.1.2. Develop materials and programs to train laboratory personnel in DR LTBI diagnostic testing.
13.1.3. Develop consensus laboratory guidelines for DR LTBI testing methods.
13.1.4. Conduct operational research to optimize testing and referral algorithms.
13.1.5. Develop proficiency testing and external quality assessment modules for DR LTBI diagnosis.
13.1.6. Conduct Phase 4 clinical studies of new technologies for DR LTBI diagnosis and management.
Lead federal agencies: HHS (CDC, FDA, NIH). Suggested collaborators: DoD, NTCA, APHL, CLSI, ATS, and IDSA.

# Problem 14
International laboratory services used by physicians under provisions of the United States Immigration and Nationality Act often are not equipped to the standards of U.S. TB programs and might not be able to reliably identify persons with drug-susceptible or MDR TB and XDR TB. Evaluate and improve the ability of international laboratories employed to identify M. tuberculosis and perform drug-susceptibility testing for potential U.S. immigrants (international). Suggested collaborators: DoD, FIND, and academia.

# Surveillance, Epidemiology, and outbreak Investigations
Identifying outbreaks of XDR TB to prevent further transmission requires a rapid, accurate, and adaptable surveillance system and coordinated response strategies. In the United States, individual states require reporting of TB cases by health-care providers and facilities to public health authorities. By mutual agreement, state health authorities report TB cases to CDC. Substantial delays can occur in reporting to CDC because many states report on a quarterly basis or at the end of the year. Key domestic surveillance needs include immediate case reporting, accurate and complete reporting of second-line drug susceptibility and genotyping results, and active case finding among contacts and other high risk groups. Central notification of MDR and XDR TB is essential to identify crossjurisdictional issues and to outline specific areas that should be targeted for rapid emergency (federal) support. Improved, unambiguous technical guidance (including outcome standards) is needed for collection, reporting, and data-quality procedures at the local, state, and federal levels. Internationally, areas that require increased attention and improvement include capacity for rapid DST surveys and more sustained, systematic capture of DST information. Epidemiologic studies, including genetic analyses of host and pathogen, are recommended to elucidate risk factors for acquiring XDR TB, transmission dynamics and determinants of host survival.

# Problem 16
No requirement exists for rapid reporting of TB cases to the National TB Surveillance System (NTSS), and many state and city TB programs report to NTSS only quarterly or at the end of the year, thus substantially limiting the ability to identify rapidly and respond promptly to outbreaks of MDR TB and XDR TB.

# Problem 23
In areas where XDR TB has been identified, the actual prevalence of resistance to first-and second-line drugs among TB cases is unknown.

# Problem 24
The risk factors for and transmission dynamics of XDR TB in domestic and international settings are not completely understood.

# Problem 25
The survival rates among patients with TB that is resistant to first-and second-line therapeutics have not been adequately analyzed, and host/pathogen determinants of survival, including the effect of co-morbidities, remain to be elucidated.

# Infection Control
Because TB is spread by the airborne route, anyone who breathes air containing viable tubercle bacilli is at risk for acquiring M. tuberculosis infection. This includes persons caring for and exposed to infectious TB patients, especially patients without an established diagnosis. To prevent the spread of disease and maintain the best possible care for patients, special infection-control practices and procedures must be available.
Effective infection control depends on early detection and diagnosis of TB disease, prompt initiation of effective therapy, and airborne infection isolation to prevent further disease transmission. Each institutional setting that might house persons with undiagnosed TB disease or in which TB patients are treated should have infection-control programs available that minimize the risk for TB transmission, including MDR TB and XDR TB, to patients, workers, and others within the institutional setting.
Various infection-control strategies are available depending on whether a setting will provide primary care or triage and refer patients with suspected or confirmed TB disease. All infection-control strategies should be on the basis of a three-level hierarchy: administrative controls, environmental controls, and personal respiratory protection. Combinations of these infection-control strategies have been demonstrated to be effective at preventing TB transmission. However, these strategies are not implemented consistently, and their individual effectiveness and feasibility are not well-characterized.

# Problem 27
Although administrative controls, environmental controls, and respiratory protection have been effective when used in combination, ethical issues have prevented assessment of their individual effectiveness in settings in which TB transmission occurs. Resulting knowledge gaps hamper efforts to prioritize interventions for optimal cost-benefit in resource-limited settings.
-bjective 27.1
Ensure dissemination and implementation of currently recommended infection-control strategies across a range of highrisk institutional settings (e.g., health-care facilities, substance abuse clinics, residential treatment centers, homeless shelters, and correctional and detention facilities) through education and regulatory programs (domestic and international). 28.1.2. Recommend considering positive tuberculin skin test (TST) or blood assay (BAMT) for identification of M. tuberculosis infection among health-care workers as an outcome measure of the effectiveness of TB infection-control programs in health-care facilities that are in the medium risk category or have been classified as having potential ongoing transmission.
28.1.3. Provide health departments with support in recruitment of and assistance to health-care centers, correctional facilities, homeless shelters, and substance-abuse treatment centers to implement and assess the effectiveness of programs for systematic TB screening of workers employed in mediumor high-risk settings.
Lead federal agencies: HHS (CDC). Suggested collaborators: OSHA, JCAHO, and state and local health departments.

# Clinical and Programmatic Interventions
The fundamental principles and practices of TB control have been described previously (3,33). These principles and practices underlie the clinical and programmatic components of diagnosis, reporting, treatment and prevention of drugresistant TB addressed in this Task Force Plan Persons at risk for TB disease often fail to access health-care systems for a variety of complex reasons. A lack of understanding of TB and its symptoms, lack of financial resources (e.g., health insurance or transportation to the clinic), lack of awareness of free clinical services for TB, concerns of deportation and stigmatization, and existence of competing priorities (e.g., shelter and food) all contribute to delays in TB diagnosis and result in prolonged TB transmission in the community. Clinical and programmatic services must be integrated with and closely coordinated with TB laboratory services through a systems approach to ensure successful diagnosis and case management. Once patients access care, lack of familiarity with TB by health-care providers might result in misdiagnosis and inappropriate treatment, which in turn can lead to development of drug resistance and continued transmission of M. tuberculosis. Once a TB diagnosis has been established, providing clinical TB services (preventive, diagnostic, and treatment/ case-management) that are culturally acceptable, affordable and logistically accessible to patients is a prerequisite for successful TB management and treatment completion.
Throughout the process of clinical care of TB patients, infection-control practices must be implemented properly, and health-care providers (physicians, nurses, pharmacists, dentists, laboratorians, other allied health professionals, traditional healers) must be educated thoroughly and trained in all principles and practices of TB care. To sustain consistent high quality and prompt care of TB patients, monitoring and evaluation programs must be established to identify rapidly systems failures and implement corrective measures. The elements of the health system that are necessary to prevent the  development and transmission of MDR TB and XDR TB have been identified (Figure). Failures at any of the necessary steps related to proper TB diagnosis, treatment and infectioncontrol measures can lead to the development or transmission of drug-resistant TB.

# Figure. Prevention of development and transmission of drug-resistant tuberculosis (TB)
The United States needs to assist international TB control programs in the development of clinical and programmatic practices that follow international standards for TB diagnosis and care, laboratory services, and infection control. Support should be provided to ensure that TB patients receive services free of charge and have access to DOT through the completion of treatment. The implementation of international informa-tion sharing mechanisms is critical for the prevention of drug resistance and the successful control of TB worldwide.

# Problem 30
Initial point-of-contact (POC) providers (e.g., emergency, urgent, primary, and correctional care providers; university health service and occupational medicine clinicians; health department clinicians; civil surgeons   ; and traditional healers) might not suspect TB or have current or complete information about the diagnosis and/or treatment of TB (see Problem 44). Provide POC providers who serve at-risk persons with education and guidance to increase their knowledge of TB and increase their access to resources to avoid misdiagnosis, prolonged transmission, and inappropriate treatment (domestic).

# Action Steps
30.1.1. Promote general knowledge of TB among providers through specific TB curricula and self-study modules. Educate providers about the critical importance of patient-centered case management and how to deliver high-quality services needed to ensure patient adherence and treatment completion.
Explain the risks associated with undiagnosed, misdiagnosed, and inappropriately or inadequately treated TB.
30.1.2. Promote practices such as use of treatment regimens on the basis of national guidelines, DOT, prompt adjustment of treatment in response to DST results, patient incentives and enablers to maintain adherence, monitoring of response to treatment, and comprehensive case management in close collaboration with the local TB control program and treatment experts to prevent development and amplification of drug resistance among all TB patients.
30.1.3. Conduct a national media campaign to raise awareness of TB for the general public and health-care providers.
30.1.4. Engage medical professional associations to raise awareness of TB and TB guidelines.
30.1.5. Review TB screening procedures and protocols for institutional facilities and primary care providers to assure competency and develop links between POC providers, local and state health departments and RTMCCs for diagnosis and referral of suspects.
30.1.6. Develop and distribute current regional, national and international MDR/XDR surveillance charts to healthcare providers and public health programs to inform them of high-prevalence areas for MDR TB and XDR TB.
30.1.7. Address health-care provider fears about MDR TB and XDR TB through discussions with medical societies, formal and informal presentations with health-care professionals at meetings, and through targeted mailings.
30 31.1.3. Educate health-care providers on the need for expedited drug-susceptibility testing immediately after an initial TB diagnosis, especially in high-risk congregate settings and in immunocompromised persons, to reduce morbidity and mortality in persons with drug-resistant TB.
31.1.4. Update TB care guidelines to recommend routine HIV testing during initial patient evaluation for TB on the basis of opt-out testing   recommended by CDC.
31.1.5. Develop and distribute regularly updated regional, national and international MDR TB and XDR TB surveillance charts to health-care providers and public health programs to increase awareness of the extent of drug-resistant disease in patients who do not respond to first-line therapy.
31.1.6. Develop a system of consultation and patient referral between primary care physicians (including HRSA Community Health Centers, primary care HIV clinics, and homeless programs), physicians in correctional or detention settings, departments of health, and RTMCCs to improve diagnosis and management of TB patients, especially those with MDR TB and XDR TB.
31.1.7. Discuss with FDA requirements for review and approval of rapid tests to detect rifampin resistance (RIF) as a primary/surrogate indicator for MDR TB and XDR TB and define special situation where use of rapid RIF assays and other molecular tests to diagnose drug resistance would be appropriate.
Lead federal agencies: HHS (CDC, FDA, and HRSA). Suggested collaborators: NTCA, RTMCCs, state and local health departments, and health-care provider professional societies.

# Problem 32
Existing diagnostic protocols used for screening foreign-born persons entering, or already residing in the United States, are not sufficient to detect XDR reliably.

# Problem 34
The quality of currently available services and treatment for XDR TB patients has not been monitored or evaluated sufficiently. Improve the quality and effectiveness of free clinical services, medications and treatment regimens as part of patient-centered management for patients with XDR TB (domestic).

# Action Steps
34.1.1. Develop and implement fully supported, improved patient-centered clinical services for outpatient management of persons with XDR TB that ensure full cooperation and maximum chance of success.
34.1.2. Develop and implement procedures and due process and recommendations for legal recourse for management of   Defined as performing HIV testing after notifying the patient that the test will be performed and consent is inferred unless the patient specifically declines.
XDR TB patients refusing treatment or care to minimize risk to communities (see Problems 39, 41, and 42).
34.1.3. Identify centers of excellence for in-patient treatment of MDR TB and XDR TB that are available for consultation on and referral of XDR TB patients to optimize care and increase likelihood of cure.
34.1.4. Evaluate whether XDR TB centers of excellence might be developed as national referral centers for all patients with XDR TB to provide the best possible care, increase treatment success and reduce transmission to others.
34.1.5. Develop procedures for transfer of patients to referral centers and identify funding to support the cost of treating and managing XDR TB patients.
34.1.6. Establish programs to facilitate collaboration between XDR TB centers of excellence and the RTMCCs for ongoing medical education, consultation, and technical assistance to community providers on all aspects of care of MDR TB and XDR TB patients.
34.1.7. Develop processes and procedures for referral and care of patients who are in legal custody during inpatient or outpatient treatment to ensure appropriate discharge and continuity of care when released from custody or transferred to a different detention facility or law enforcement agency.
34.1.8. Develop processes to request a stay of removal for patients slated for deportation to a country where treatment is not likely to be available and establish procedures and resources to complete TB treatment in the United States, including provision of secure environments, if appropriate.
Lead 38.1.5. Review the technical instructions for panel physicians   who conduct TB screening as part of immigration procedures with regard to XDR TB diagnosis and contact management and develop a process to certify panel physicians.
38.1.6. Support and recommend the use of fixed-dose drug combinations when appropriate and provide training and technical assistance to improve TB drug management.
38.1.7. Provide technical assistance through full-time consultants to ministries of health in countries that are sources of large numbers of U.S. immigrants and countries with a high burden of drug-resistant TB to support completion of ongoing drug-resistance surveys and the establishment of drug-resistance surveillance systems.
38.1.8. Provide resources and support to establish U.S.transnational TB case management programs such as international referral programs and information-sharing system.
Lead federal agencies: USAID, HHS (CDC, HRSA), and DHS (ICE).
Suggested collaborators: DOS, WHO, IUATLD, Green Light Committee (GLC), Medicins Sans Frontieres (MSF), and KNCV.

# Ethical and Legal Issues
TB is a reportable infectious disease, and public health protection and TB control activities are described in specific state laws. Many existing laws were established before the contemporary public health recommendations for the prevention and control of TB became available (6,35). As a result, the Advisory Committee for the Elimination of Tuberculosis (ACET) and CDC conducted a survey of state TB control laws and regulations and developed recommendations that addressed legal issues of TB control in the United States. Since these recommendations were published (29), no systematic follow up has been conducted to determine the extent to which these recommendations were implemented.

# Problem 39
Laws and regulations permitting authorities to compel treatment and isolation of patients with tuberculosis vary by state. Suggested collaborators: state and local health departments, law schools, and national justice and health ministries.

# Problem 41
The effectiveness of mandated isolation or quarantine to compel treatment for TB patients as compared to less restrictive measures, and the ethical issues associated with these measures, have not been evaluated closely. Develop guidelines and a research agenda to determine the effectiveness of and ethical issues associated with compelling treatment and isolation for TB patients who are considered a threat to public health (domestic).

# Action Steps
41.1.1. Conduct research to determine the impact and effectiveness of mandatory isolation to compel treatment for tuberculosis as compared with less restrictive measures. 41.1.2. Conduct research on ethical issues of mandated isolation (or quarantine) and less restrictive measures to compel treatment for tuberculosis. 41.1.3. Convene a workshop for bioethicists and TB control, care, and research professionals to identify and catalog key ethical issues likely to be confronted as part of the XDR TB response.
Lead federal agencies: HHS (CDC and NIH), DHS, and DOJ.
Suggested collaborators: state and local health departments, law schools, and academia (biomedical ethicists).

# Problem 42
Patients with XDR TB could require prolonged isolation measures regardless of the patient's adherence to treatment, which might present an ethical dilemma in balancing the interests of public health with those of the patient. Develop guidance on ethical issues pertaining to prolonged isolation of patients with XDR TB who are fully adherent to treatment (domestic).

# Action Steps
42.1.1. Conduct research on ethical considerations of prolonged, mandated isolation including contexts of fully adherent patients and those who are in the terminal stages of disease.
Lead federal agencies: HHS (CDC and NIH), DHS, and DOJ.
Suggested collaborators: state and local health departments, law schools, and academia (biomedical ethicists).

# Problem 43
Obstacles to compassionate use of experimental chemotherapeutic agents for patients with XDR TB limit critically important therapeutic options.

# Communication and Education
Comprehensive and tailored information on TB and drugresistant TB including XDR is needed for many different audiences. In the United States, private health-care providers (i.e., those not in public health departments) receive little education or training on detection and appropriate treatment of TB (11,30,31,(36)(37)(38). As a consequence, infectious TB often goes unrecognized, even if a patient presents to a physician with apparent signs and symptoms of active disease. This has led to incorrect treatment, prolonged transmission of TB in the community, and creation of drug-resistant organisms.
Education and communication must be appropriately targeted to health-care providers and patients to improve awareness and guide access to competent clinical services. Community leaders and health policy makers, including public health officials, must be well informed about the need to communicate and address issues that can fuel the development and spread of drug-resistant TB in their communities. Education efforts should clearly outline the critical elements that must be applied to prevent and control TB in various settings and risk populations (34).
Clear, concise messages, easy to understand yet comprehensive education materials and medical alerts should be developed and disseminated to the general public, TB patients, physicians and other health-care workers, health advocacy organizations, and decision makers, including legislators. These communications should be coordinated across Federal agencies and updated as necessary. Increasing awareness of the signs and symptoms of TB and the appropriate treatment and control strategies, must become a priority in the United States to ensure TB is recognized and treated as a public health threat with the potential to result in virtually untreatable forms of disease, such as XDR TB.
In TB-endemic countries where cases of drug-resistant TB are increasing, health authorities must also remain informed about the risk for and incidence of XDR TB. There, provider education initiatives must also focus on the need for appropri-ate case management, including knowledge regarding locally and regionally available specialty resources and medications and the consequences of inappropriate or inadequate treatment of drug-resistant TB.

# Problem 44
Health-care providers and the general public are not wellinformed about the symptoms, appropriate, diagnosis, treatment, and prevention of drug-susceptible and drug-resistant TB including XDR TB. Develop education mechanisms and materials, targeted to public and private health-care providers and other workers who might come into contact with populations with a high prevalence of TB infection and disease in settings such as health-care facilities, homeless shelters and correctional facilities, about drug-susceptible and drug-resistant TB including XDR, heighten awareness and encourage appropriate prevention, diagnosis, treatment, and referral (domestic).

# Action Steps
44.1.1. Review and update existing education materials and communication products on TB to include relevant information about drug-resistant forms of disease.
44.1.2. Identify communication gaps and special needs for education and communication products regarding drugsusceptible and drug-resistant TB and develop new materials as needed.
44.1.3. Communicate to health-care providers appropriate measures to prevent MDR TB and XDR TB, including the importance of detecting and treating LTBI and TB disease and the importance of prompt reporting of TB cases to proper health authorities.
44.1.4. Communicate to health-care providers the importance of consulting and engaging TB experts in the medical management of MDR TB patients to avoid the development of XDR TB and to ensure that appropriate specialized resources for treatment of drug-resistant TB are optimally used.
44.1.5. Familiarize health-care providers serving high-risk patients with TB training and medical consultation resources that are available through the RTMCCs.
44.1.6. Contribute to the dissemination and promotion of infection-control guidelines and supporting education materials in the United States (28) and globally (39).
44.1.7. Develop strategies and materials on TB and MDR TB and XDR TB diagnosis, treatment, and reporting for dissemination at national medical and laboratory meetings.
44.1.8. Develop education materials for digital mass media, such as the Internet, personal digital assistants, and podcasts to reach and inform health-care providers about control of all forms of TB. 44.1.9. Develop and distribute targeted education material to health-care providers and nontraditional partners who are not usually engaged in TB control activities such as primary care and nurse practitioners, physician assistants, emergency care and urgent care specialists, health-care providers in correctional facilities, civil surgeons, pharmacists, foreign-trained clinicians, non-U.S. health-care providers, university health service, occupational medicine specialists, rheumatologists, oncologists, radiologists, laboratories, traditional healers, NGOs, and CBOs.
44.1.10. Present specialty-specific information about care and control of all forms of TB at professional conferences.
44.1.11. Develop targeted TB training and education for other workers who might be exposed to TB in settings such as health-care facilities, homeless shelters and correctional facilities.
Lead federal agencies: HHS (CDC, NIH, and HRSA). Suggested collaborators: RTMCCs, NTCA, ATS, American College of Chest Physicians (ACCP), IDSA, American Medical Association (AMA), American Association of Family Practitioners (AAFP), and APHL. Develop education mechanisms and materials to inform decision makers in the public and private sectors about priorities and strategies for the prevention and control of TB and MDR TB and XDR TB (domestic). Establish and maintain mechanisms to facilitate regular communication among federal agencies, and with state and local TB control programs (domestic).

# MMWR February 13, 2009
Action Steps 44.4.1. Regularly update and disseminate information by the CDC, WHO, and other agencies on MDR TB and XDR TB to federal staff, TB control programs, HIV/AIDS programs, and other public health agencies and interested organizations to ensure that U.S. public health programs are well informed about the incidence and prevalence of drug-resistant TB in the United States and globally.
44.4.2. Identify federal TB Task Force members to serve as key spokespersons for issues related to MDR TB and XDR TB while ensuring that all Task Force members are well informed to contribute to the ongoing dissemination of information on all forms of TB.
44.4.3. Communicate on a regular basis efforts and relevant results and outcomes related to prevention and control of MDR TB and XDR TB by federal agencies.
Lead federal agencies: HHS (CDC and NIH). Suggested collaborators: NTCA and state and local health departments.

# Research
Biomedical research in TB creates a foundation of knowledge that informs the development of new health-care interventions as well as control and prevention strategies for drug-resistant TB. While U.S. federal agencies have substantially contributed to research in TB and the identification of drugs, vaccines and diagnostics, the emergence of more difficult to treat forms of drug-resistant TB will require renewed and more targeted efforts to help control and prevent the development and transmission of drug-resistant forms of TB. One compilation of biomedical research priorities related to MDR TB and XDR TB has been published (7).
TB therapy was revolutionized in the 1940s by the development of antibiotics by academic and for-profit organizations, and the demonstration of their efficacy and safety in randomized clinical trials largely conducted by the public sector. These therapies became the basis for the global DOTS strategy for TB control. Although initially highly effective in reducing the incidence and prevalence of TB in endemic countries, the continued success of the DOTS strategy is now seriously threatened by the emergence of highly drug-resistant strains of M. tuberculosis. Furthermore, interactions between TB and HIV medications and drugs used in the treatment of specialized problems such as diabetes, drug addiction and mental disorders (conditions that are encountered in populations at risk for TB) might substantially complicate the development of effective new TB drugs. To ensure the continued availability of effective therapeutics against all forms of TB, the development of new, safe, and effective TB drugs must remain a high priority. Success in TB drug development will also heavily rely on the establishment and continued support of competent, experienced trial sites in TB and TB/HIV endemic countries for all phases of clinical testing.

# Problem 45
Few new TB drugs are in preclinical and clinical development. Increase the number of candidates in all stages of the TB drug development pipeline to increase the likelihood that new agents will become available for clinical use within the next 5-10 years (domestic and international).

# Action Steps
45.1.1. Increase communication between private not-forprofit and commercial organizations and relevant public sector agencies to identify opportunities for public/private collaborations in TB drug development.
45.1.2. Reevaluate, refine, and optimize support for drug discovery and preclinical studies for pharmaceutical companies and academic/not-for profit organizations (in vitro and animal models).
45.1.3. Encourage pharmaceutical companies, academic researchers and nonprofit organizations to engage in TB drug development research and development efforts.
Lead federal agencies: HHS (CDC, FDA, and NIH) and USAID.
Suggested collaborators: Global Alliance for TB Drug Development, pharmaceutical industry, and academia.

# Problem 46
The global capacity to conduct clinical trials for new drugs that treat TB and MDR TB and XDR TB is limited.

# Problem 47
Well-validated surrogate markers do not exist to rapidly assess clinical efficacy of new chemotherapeutic agents and regimens against drug-susceptible and MDR TB and XDR TB.  Lead federal agencies: HHS (CDC, FDA, and NIH). Suggested collaborators: Global Alliance for TB Drug Development, pharmaceutical industry, other national research agencies (e.g., BMRC, SAMRC, and TRC-Chennai), and academia.

# Problem 49
The types of clinical data needed to support registration of new chemotherapeutic agents against TB have not been clearly defined making it difficult to design effective clinical development plans and timelines. Establish a forum for discussion between U.S. and international regulatory agencies to define specific guidance for clinical development and approval of chemotherapeutic agents indicated for use in MDR TB and XDR TB (domestic and international).

# Fundamental Science
The foundation for development of new health-care interventions in TB is a solid understanding of the interaction between M. tuberculosis and the host and how infection transitions to active disease. Knowledge acquired through basic research in these areas must be effectively leveraged in translational science (i.e., research that translates basic scientific discoveries into clinical applications). As a consequence of the sequencing of the genome of both the host and pathogen, the development of molecular tools to manipulate the pathogen, the establishment of genomic and postgenomic technologies and tools, and the expansion of animal models available to study TB, many important questions in the pathogenicity of TB now can be addressed.
Although considerable progress in fundamental science (basic and translational) of TB has been made over the past decade, the availability of more tools, technologies and advanced methodologies has made it possible to create new hypotheses and revisit earlier observations to contribute to a more detailed understanding of the best points of intervention in TB treatment, necessary characteristics of potential new TB vaccines, and what host/pathogen factors might be early indicators of infection, disease, drug resistance, and transmission. In addition, the effectiveness of current and new infection-control measures, such as negative pressure, high-efficiency particulate air filters, laminar flow, ventilation design on the basis of modeling approaches (e.g., computational fluid dynamics, ultraviolet germicidal irradiation, room air cleaners, and alternative air disinfection methodologies) should be evaluated in appropriate research settings.

# Problem 52
The characteristics of M. tuberculosis (e.g., growth, physiology, biochemistry, genetics, and molecular biology) are incompletely understood. 52.1.6. Continue to provide high quality research reagents to facilitate TB research. 52.1.7. Expand efforts to identify and validate novel drug targets, vaccine strategies, diagnostic markers and research tools.
52.1.8. Encourage and support research on genomics of both M. tuberculosis and human/animal hosts, linking to genetic epidemiologic research to direct studies in transmission, pathogenicity, microbial host interactions, and disease progression.
52.1.9. Support studies to characterize manifestations of TB in pediatric and immunocompromised populations.
Lead federal agencies: HHS (CDC and NIH) Suggested collaborators: Global Alliance for TB Drug Development, pharmaceutical industry, other national research agencies (e.g., BMRC, SAMRC, and TRC-Chennai), and academia.

# Problem 53
The effectiveness of various individual strategies for preventing TB transmission has not been sufficiently evaluated in domestic and international health-care settings. 53.1.3. Support research and efforts to develop effective, affordable methods for expedient isolation of contagious patients that do not require major facility modifications.
53.1.4. Encourage and support cost analyses for modifying existing health-care settings, correctional and detention facilities, homeless shelters, community residences for special needs populations and other high-risk institutional settings to achieve compliance with current and future infection-control requirements.
53.1.5. Support research to characterize dose-infection relationships for airborne M. tuberculosis to inform risk assessment of infection in relation to reductions in exposure.
53.1.6. Develop protocols and support studies to evaluate the effectiveness of various administrative controls on the reduction of TB transmission.
53.1.7. Support research to objectively document and improve the ability of various environmental controls to reduce exposure to airborne M. tuberculosis.
53.1.8. Support research to develop objective measures to document and compare the ability of various respiratory protective devices to reduce exposure to M. tuberculosis and to establish evidence-based recommendations for use of nationally certified respirators providing the appropriate level of protection.
Lead federal agencies: HHS (CDC and NIH), DHS (ICE), and DOJ (USMS and BOP).
Suggested collaborators: OSHA, WHO, health-care facilities, academia, other national research agencies (e.g., BMRC, SAMRC, and TRC-Chennai)

# Diagnostics
The prompt and correct diagnosis of drug-susceptible and drug-resistant TB is one of the cornerstones of effective TB control. Current diagnosis of pulmonary TB in endemic countries is limited to clinical evaluation combined with low sensitivity microbiologic tests. Available diagnostics do not offer the speed and sophistication needed to provide physicians in the field in high-burden countries with the information required to accurately diagnose drug-susceptible and drugresistant TB and to prescribe the most appropriate treatment regimens. Although certain diagnostics platforms might be technologically too advanced for field use in resource limited countries, these tests might nevertheless provide a substantial contribution to the advancement of new therapeutics for TB by allowing rapid assessment of response to therapy in clinical trials. Such measures are critical in settings with patients with extrapulmonary TB and those where drug-susceptibility testing is not possible or delayed. Furthermore, rapid assessment of response to therapy will help determine whether adequate regimens have been prescribed and might contribute to limiting the development of drug resistance.

# Problem 54
Rapid, point-of-care identification of drug-sensitive and drug-resistant pulmonary and extrapulmonary TB among HIV-negative and HIV-positive adults and pediatric populations ands reliable early identification of latent M. tuberculosis infection are not yet possible (see Problem 15). Develop rapid, point-of-care diagnostics for the reliable identification of drug-sensitive and drug-resistant pulmonary and extrapulmonary TB disease and latent infection including in HIV infected patients and pediatric populations (domestic and international).

# Vaccines
Long-term control and ultimate elimination of TB likely will require an effective vaccine (40). Research to characterize needs for an effective vaccine, on the basis of immunological responses of persons infected with M. tuberculosis who do not become ill and animal models and comparisons with the currently used vaccine M. bovis Bacille Calmette-Guerin (BCG) have been supported for over a decade. BCG vaccine, usually administered once in infancy in countries with a moderate and high incidence of TB, is effective in preventing TB meningitis and disseminated TB in children but has highly variable efficacy in preventing other forms of TB, especially in adults (41). Strategic plans for a TB vaccine have been developed, and support for biomedical research for the development of new, more effective vaccines and vaccinations strategies has resulted in progress to the point where several new vaccine candidates are now being evaluated in clinical trials. Nevertheless, a highly effective vaccine has remained elusive.
Increased capacity to allow entry of novel vaccine candidates into Phase I clinical studies and comparative studies of vaccine platforms in human trials will contribute substantially to understanding development needs for effective TB vaccines. However, assays and methodologies for preclinical validation and clinical characterization need to be standardized globally. Clinical trial protocols for the assessment of vaccination strategies and the development of expertise to conduct clinical trials and immunological assays in TB endemic countries are needed to establish a robust infrastructure for TB vaccine research and development (R&D).

# Problem 56
Current preclinical and clinical efforts in TB vaccine development are not optimally coordinated.

# Behavioral, Social, Clinical, and operational Science
Current TB therapy is complex and lengthy, and it can be associated with adverse reactions to medications. Patient adherence often is difficult, leading to discontinuation of therapy; this results in relapse, continued transmission of disease, and, in some cases, the development of drug-resistant TB. Adherence is influenced by patient characteristics, differences in healthcare seeking behavior, assumptions about disease, the healthcare environment, the availability of adherence-enhancing interventions, the quality of communication between patients and providers, the availability and use of education materials to inform patients and families about TB, treatment and consequences of defaulting, the convenience of access to drugs for supervised treatment, and the quality of drugs available through TB control programs.
The complexity of factors underlying patient adherence and the importance of completing treatment for TB necessitates increased emphasis on patient-centered treatment options and a thorough understanding of behavioral and social interventions that have to be in place to augment traditional TB control approaches. Operational research to improve care programs must include studies to characterize TB health services, case and data management practices, staff selection, training and retention incentives, physician training, management and organizational structure, relationships with the community, community perceptions of services, community resistance to public health services, and clinic policies and practices to provide the best possible environment for ensuring patient trust and treatment completion.

# Problem 57
Patient adherence to TB chemotherapy is not optimal, and alternative methods for ensuring completion of therapy are not fully developed. Identify alternatives and adjuncts to currently used treatment protocols through behavioral research to improve adherence to therapy (domestic and international).

# Problem 58
Operational and clinical questions related to patient adherence and optimal organization and structure of health services to ensure effective TB care remain unanswered.

# Partnerships
Because XDR TB presents a worldwide threat, a coordinated international response will rely on effective partnerships between all organizations and governments that are involved in TB control programs, TB biomedical research and product development (Box). In addition, the establishment of new alliances is needed to fill the critical gaps in the global response identified in this report. Currently, government agencies at all levels, international organizations, nongovernment organizations (NGOs), academic institutions, and the private sector are coordinating their efforts as members of the STOP TB Partnership. Furthermore, cross-disciplinary research and product development efforts are brought together through various nonprofit organizations focused on developing affordable and effective drugs, vaccines and diagnostics. Representatives from United States government agencies are actively involved in these partnerships and contribute their knowledge and expertise to help address the national and global aspects of XDR TB. The U.S. Federal Tuberculosis Task Force serves as a mechanism to coordinate activities of various federal agencies that are involved in domestic and international TB prevention and elimination programs. Domestically, U.S. government agencies work closely with local and state TB control programs, academic institutions, professional associations, and pharmaceutical companies to assure the most effective use of available resources and to minimize duplication of effort. The expansion of existing partnerships to include management and prevention of XDR TB and other forms of drug-resistant TB will be important if TB is to be eliminated in the United States and worldwide.

# Problem 59
Differing jurisdictions among public health agencies, scopes of work among nongovernment organizations, and varying country-specific public health policies, economic conditions, and political commitments pose a substantial barrier to launching and focusing a coordinated response to TB (MDR TB and XDR TB and HIV/TB) in high-burden settings with the greatest needs. Optimize integration, coordination and synergy between U.S. government agencies, international organizations, and national TB/HIV programs to achieve reduction in disease rates through more focused prevention/intervention activities for MDR TB and XDR TB and HIV/TB and nonduplicative allocation of funding, staff and resources (international).

# Action Steps
59.1.1. Develop programs or working groups to maximize cooperation between international organizations and to align resources for an efficient, resource sparing response in highburden countries.
59.1.2. Establish additional interagency agreements to formalize existing cooperative efforts, where feasible.
Lead federal agencies: USAID and HHS (CDC). Suggested collaborators: WHO, STOP TB, IUATLD, KNCV, ministries of health, and national and local National TB Program (NTP) staff.

# Problem 60
Currently available global funds are insufficient to mount a comprehensive response to XDR TB, particularly in settings with high rates of HIV/TB co-infection. Resources need to be focused on this emerging threat, on the basis of identification of specific needs.

# Problem 61
Globally, human resources at all levels in national TB programs are insufficient and maintaining a well qualified workforce has been difficult due to the continuous exodus of qualified, experienced TB and/or HIV staff. Domestically, the number of medical professionals with experience in managing TB patients, much less MDR TB and XDR TB patients, has declined in parallel with TB cases. A critical need is to strengthen human resources at the local and state/provincial/ district level.

# Problem 63
Biomedical and product development activities and regulatory activities are not coordinated optimally between U.S. and international governmental and private agencies. Insufficient coordination of research activities exists among the various international entities with commitments to support TB research, or with involvement in related activities such as medical regulation. Establish and maintain partnerships with appropriate organizations within and outside the public health community to increase awareness of XDR TB among policy makers and the general public (domestic and international).

# Action Steps
64.1.1. In collaboration with appropriate partners, develop coordinated and consistent education material to promote informed awareness of XDR TB in the U.S. and internationally.
Lead federal agencies: HHS (CDC, NIH, and HRSA), USAID, and HUD.
Suggested collaborators: WHO, IUATLD, Results International, American Lung Association, Treatment Action Group, local and state health departments, academia, and national ministries of health.

# Problem 65
Current public health partnerships are not sufficient to ensure continuity of care for TB patients and their contacts who either reside temporarily in the United States or frequently February 13, 2009 cross its borders. More than half the TB cases in the United States occur among immigrants who become infected before their arrival in the United States. Lack of continuity of care contributes to treatment default, ongoing transmission, and prolonged illness. Partnerships are needed for effective transnational case management. Identify appropriate partners and programs to contribute to projects and strategies that ensure continuity of TB care for patients traveling or migrating into or out of the United States (domestic and international).

# Action Steps
65.1.1. Identify domestic and international partners to participate in an assessment of barriers to continuity of care for migrants or traveling TB patients.
65.1.2. Develop and implement transnational partnerships that allow establishment of cross-border TB care and management programs, such as the Bi-National TB Card and transnational referral programs for continuity of TB therapy.
65.1.3. Strengthen partnerships between ICE and TB Programs in countries to which patients are deported while on TB treatment that was initiated in the United States.
Lead federal agencies: HHS (CDC and HRSA), USAID, DHS (ICE, CBP), federal courts, and USMS.
Suggested collaborators: foreign NTPs and ministries of health, local and state TB programs in the United States and other countries, Cure TB, and TB Net.

# Cost Analysis
A realistic national estimate of the costs of diagnosing, treating, and managing XDR TB will be an important prerequisite for measuring the benefit and savings to the United States that would be realized through prevention of XDR TB. CDC has estimated the costs for hospitalization of one XDR TB patient at approximately $483,000 (CDC, unpublished data 2007) whereas outpatient treatment costs, productivity losses, patient out-of-pocket expenses, and quality of life changes attributable to XDR TB are unknown. Some of the existing interventions and strategies for TB care and management, such as the use of DOT, already have been demonstrated to be cost effective in preventing the development of MDR TB, but information about additional strategies is currently not available. Analysis of such cost-benefit and cost-effectiveness data will be critical to prioritize programs and advocate for resources to implement specific interventions to help prevent XDR TB.

# Problem 66
A comprehensive and up-to-date estimate of the costs of diagnosing, treating, and managing XDR TB in the United States in not available. Conduct a study on the basis of health-care system and societal perspectives to calculate the costs of diagnosing, treating, and managing all cases of XDR TB identified through surveillance for patients and their contacts (domestic).

# Action Steps
66.1.1. Identify representative samples or cohorts of XDR TB patients during 2004-2007 (verified and reported, unreported incident and prevalent cases), and their contacts for estimating costs associated with health care and personal productivity.
66.1.2. Estimate from representative samples or cohorts of XDR TB patients the average medical costs incurred on the basis of the extent and pattern of drug resistance, medically indicated procedures and examinations needed to diagnose drug-resistant TB, the length of inpatient and outpatient treatment, management of adverse events and treatment and disease associated chronic sequelae, and the cost of case management of contacts.
66.1.3. Estimate from representative samples or cohorts of XDR TB patients that were employed prior or during XDR TB diagnosis associated losses in personal productivity and salary losses on the basis of the extent and pattern of drug resistance, chronic disease, and the impact of patient mortality (age at death and time to death).
66.1.4. From a survey of XDR TB survivors and their family members, estimate loss of quality-adjusted life years on the basis of extent and patterns of drug-resistant TB disease. 66.1.5. Conduct patient interviews to estimate out-of-pocket medical expenses associated with XDR TB disease.
Lead federal agencies: HHS (CDC). Suggested collaborators: state/local Departments of Health, public and private outpatient providers and hospitals, laboratories, former patients, and family members.

# Problem 67
Cost-effective strategies to prevent XDR TB remain to be established. 67.1.4. Determine the cost benefit for each prevention strategy in relation to cost that would have been incurred to treat XDR TB.
Lead federal agencies: HHS (CDC). Suggested collaborators: state and local health departments, and academia.

# Conclusion
The nine response areas addressed in this report are closely aligned with WHO's seven-point Global Action Plan to Combat XDR TB (26), which calls for public health authorities to 1) conduct rapid surveys of XDR TB to determine the burden, 2) enhance laboratory capacity with an emphasis on rapid drug sensitivity testing, 3) improve technical capacity of clinical and public health practitioners to respond effectively to XDR TB outbreaks and manage patients, 4) implement infection-control precautions, 5) increase research support for TB drug development, 6) increase research support for rapid diagnostic test development, and 7) promote universal access to antiretroviral drugs under joint TB/HIV activities.
The Federal TB Task Force Plan and the Global Action Plan will require a renewed commitment by all public health workers as well as new resources from both the public and private sectors. In the United States, federal funding has remained relatively level since 2000, and state and local funding has declined in many states since 2000. As a result, TB prevention and control capacity in the United States has eroded. For example, many states have decided to implement selective rather than universal patient-centered DOT to ensure adherence to treatment until complete. These decisions are made on the basis of financial constraints but place the patient at high risk for treatment failure and subsequently the potential creation of MDR TB or XDR TB. In the absence of shorter treatment regimens, and without adherence-promoting measures such as DOT, the TB patient is more likely to experience drug resistance that could result from interruptions in treatment. These choices place the public and the nation in a vulnerable position, risking outbreaks of MDR or XDR TB if conditions facilitate rapid spread and possibly causing public health crises. (42,43) The Federal TB Task Force Plan provides an effective framework to detect, prevent, and control XDR TB, but it also highlights the existence of substantial unmet needs. There is concern that progress in TB prevention and control is waning as manifested by the decrease in the rate of decline in TB incidence since 2000. The United States responded successfully to the MDR TB problem in the 1990s and is capable of preventing and controlling XDR TB; however, this will require a united commitment and effort similar to that which occurred in 1992.