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department of health and human services

Centers for Disease Control and Prevention

Recommendations and Reports February 13, 2009 / Vol. 58 / No. RR-3

Morbidity and Mortality Weekly Reportwww.cdc.gov/mmwr

Pla t Cmbat ExtesivelyDrug-Resistat TuberculsisRecmmedatis f the

Federal Tuberculsis Task Frce


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MMWR

Editrial BardWilliam L. Roper, MD, MPH, Chapel Hill, NC, Chairman

Virginia A. Caine, MD, Indianapolis, INDavid W. Fleming, MD, Seattle, WA

William E. Halperin, MD, DrPH, MPH, Newark, NJMargaret A. Hamburg, MD, Washington, DC

King K. Holmes, MD, PhD, Seattle, WADeborah Holtzman, PhD, Atlanta, GA

John K. Iglehart, Bethesda, MDDennis G. Maki, MD, Madison, WI

Sue Mallonee, MPH, Oklahoma City, OKPatricia Quinlisk, MD, MPH, Des Moines, IA

Patrick L. Remington, MD, MPH, Madison, WIBarbara K. Rimer, DrPH, Chapel Hill, NCJohn V. Rullan, MD, MPH, San Juan, PR

William Schaner, MD, Nashville, NAnne Schuchat, MD, Atlanta, GA

Dixie E. Snider, MD, MPH, Atlanta, GAJohn W. Ward, MD, Atlanta, GA

TeMMWRseries o publications is published by the CoordinatingCenter or Health Inormation and Service, Centers or DiseaseControl and Prevention (CDC), U.S. Department o Health andHuman Services, Atlanta, GA 30333.

Suggested Citati: Centers or Disease Control and Prevention.[itle]. MMWR 2009;58(No. RR-#):[inclusive page numbers].

Ceters fr Disease Ctrl ad PrevetiRichard E. Besser, MD

(Acting) Director

anja Popovic, MD, PhDChie Science Ofcer

James W. Stephens, PhDAssociate Director or Science

Steven L. Solomon, MDDirector, Coordinating Center or Health Inormation and Service

Jay M. Bernhardt, PhD, MPHDirector, National Center or Health Marketing

Katherine L. Daniel, PhDDeputy Director, National Center or Health Marketing

Editrial ad Prducti Staff

Frederic E. Shaw, MD, JDEditor, MMWRSeries

Susan F. Davis, MD(Acting) Assistant Editor, MMWRSeries

Robert A. Gunn, MD, MPHAssociate Editor, MMWRSeries

eresa F. RutledgeManaging Editor, MMWRSeries

David C. Johnson(Acting) Lead Technical Writer-Editor

Jerey D. Sokolow, MAProject Editor

Martha F. BoydLead Visual Inormation Specialist

Malbea A. LaPeteStephen R. SpriggsVisual Inormation Specialists

Kim L. Bright, MBAQuang M. Doan, MBA

Phyllis H. KingInormation Technology Specialists

ConTEnTS

Introduction .............................................................................. 2

Recommendations to Combat Extensively

Drug-Resistant Tuberculosis ...................................................... 5

Action Plan to Combat Extensively Drug-Resistant Tuberculosis ...... 6

Conclusion .............................................................................. 39References .............................................................................. 39

Appendix ............................................................................... 41

Disclsure f Relatiship

CDC, our planners, and our content experts wish to disclose they haveno nancial interests or other relationships with the manuacturers ocommercial products, suppliers o commercial services, or commerciasupporters. Presentations will not include any discussion o the unlabeleduse o a product or a product under investigational use.


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Vol. 58 / RR-3 Recommendations and Reports 1

Pla t Cmbat Extesively Drug-Resistat TuberculsisRecmmedatis f the Federal Tuberculsis Task Frce

Reported byPhilip LoBue, MD1

Christine Sizemore, PhD2

Kenneth G. Castro, MD1

1Division o TB Elimination, National Center or HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, CDC2Division o Microbiology and Inectious Diseases, National Institute or Allergy and Inectious Diseases, National Institutes o Health, Bethesda, Maryland

Summary

An estimated one third o the worlds population is inected with Mycobacterium tuberculosis, and nearly 9 million personsdevelop disease caused byM. tuberculosis each year. Although tuberculosis (TB) occurs predominantly in resource-limited coun-tries, it also occurs in the United States.

During 19851992, the United States was conronted with an unprecedented TB resurgence. This resurgence was accompa-

nied by a rise in multidrug-resistant TB (MDR TB), which is dened as TB that is resistant to the two most eective rst-linetherapeutic drugs, isoniazid and riampin. In addition, virtually untreatable strains oM. tuberculosis are emerging globally.Extensively drug-resistant (XDR) TB is dened as MDR TB that also is resistant to the most eective second-line therapeutic

drugs used commonly to treat MDR TB: fuoroquinolones and at least one o three injectable second-line drugs used to treat TB(amikacin, kanamycin, or capreomycin). XDR TB has been identied in all regions o the world, including the United States.

In the United States, the cost o hospitalization or one XDR TB patient is estimated to average $483,000, approximately twicethe cost or MDR TB patients. Because o the limited responsiveness o XDR TB to available antibiotics, mortality rates amongpatients with XDR TB are similar to those o TB patients in the preantibiotic era.

In January 1992, CDC convened a Federal TB Task Force to drat an action plan to improve prevention and control o drug-resistant TB in the United States (CDC. National action plan to combat multidrug-resistant tuberculosis. MMWR 1992;41([No.

RR-11]). In November 2006, CDC reconvened the Task Force to drat an updated action plan to address the issue o MDR TBand XDR TB. Task Force members were divided into nine response areas and charged with articulating the most pressing prob-lems, identiying barriers to improvement, and recommending specic action steps to improve prevention and control o XDR TBwithin their respective areas.

Although the rst priority o the Federal TB Task Force convened in 2006 was to delineate objectives and action steps to addressMDR TB and XDR TB domestically, members recognized the necessity or TB experts in the United States to work with the inter-

national community to help strengthen TB control eorts globally. TB represents a substantial public health problem in low- andmiddle-income countries, many o which might benet rom assistance by the United States. In addition, the global TB epidemicdirectly aects the United States because the majority o all cases o TB and 80% o cases o MDR TB reported in the United Statesoccur among oreign-born persons. For these reasons, the Action Plan also outlines potential steps that U.S. government agenciescan take to help solve global XDR TB problems. Unless the undamental causes o MDR TB and XDR TB are addressed in the

United States and internationally, the United States is likely to experience a growing number o cases o MDR TB and XDR TBthat will be dicult, i not impossible, to treat or prevent.

The recommendations provided in this report include specic action steps and new activities that will require additional undingand a renewed commitment by government and nongovern-ment organizations involved in domestic and international TB

control eortsto be implemented eectively. The Federal TBTask Force will coordinate activities o various ederal agenciesand partner with state and local health departments, nonprotand TB advocacy organizations in implementing this planto control and prevent XDR TB in the United States and to

contribute to global eorts in the ght against this emergingpublic health crisis.

Te material in this report originated in the National Center or HIV/AIDS, Viral Hepatitis, SD, and B Prevention, Kevin Fenton, MD,PhD, Director, and the Division o uberculosis Elimination, KennethG. Castro, MD, Director.Corresponding preparer: Philip LoBue, MD, Division o BElimination, National Center or HIV/AIDS, Viral Hepatitis, SD,and B Prevention, CDC, 1600 Cliton Road, NE, MS E-10, Atlanta,GA 30333. elephone: 404-639-8120; Fax: 404-639-8604; E-mail:[email protected].


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2 MMWR February 13, 2009

Itrducti

Glbal Health Burde f Tuberculsisuberculosis (B) is among the most common inectious dis-

eases and requent causes o death worldwide (1). B is causedbyMycobacterium tuberculosisand is spread most commonlyby airborne transmission.M. tuberculosiscan aect any parto the body but is ound most oten in the lungs. Persons withpulmonary B generally have a cough that produces small air-borne droplet nuclei containing tubercle bacilli that can remainin the air or hours. Vulnerable persons exposed to tuberclebacilli in airborne droplets might become inected. Te major-ity o persons who become inected remain noncontagious andwithout a cough or other symptoms. Tese persons have latentM. tuberculosisinection (LBI) and can be treated with a singledrug (isoniazid) or 9 months to prevent disease.

Inected persons who do not have underlying medical

problems and do not receive LBI treatment have a 5%10%lietime risk or progressing to B disease (2). However, therisk or disease progression increases substantially in the pres-ence o immunosuppression, such as that caused by the humanimmunodeciency virus (HIV) and immunosuppressive medi-cations (2). Persons with pulmonary B can be cured with a6-month course o antibiotics that includes isoniazid, riampin,pyrazinamide, and ethambutol during the rst 2 months. Inthe United States, diagnosis and treatment or B is accessibleand eective (3). However, many developing countries havelimited resources to diagnose B illness and treat persons withB. Worldwide, 2 billion persons (one third o the worlds

population) are thought to have LBI. Nearly 9 million personsdevelop B disease each year, and close to 2 million B-relateddeaths occur annually (1). In the United States, approximately13,000 new cases o B are reported annually, and 650 personsdie rom B each year (4). B is the leading cause o mortalityamong persons inected with HIV (5).

Emergece f Drug-ResistatTuberculsis

During 19851992, the United States experienced anunprecedented B resurgence marked by a substantial number

o patients with B who did not respond to treatment and whoeventually died (6). Physicians and epidemiologists quicklydetermined that these persons had multidrug-resistant B(MDR B), which is dened as B that is resistant to bothisoniazid and riampin (7). Although persons with MDR Busually can be treated eectively by relying on second-linedrugs (amikacin, kanamycin, or capreomycin), these have moreside eects and are more expensive and less eective than rst-

line drugs and require regimens lasting 1824 months (3). Inaddition, the cure rate or persons with MDR B is 50%60%compared with 95%97% or persons with drug-susceptibleB (3). In response to several MDR B outbreaks in hospitaland correctional acilities in New York and Florida during19881991(8,9), CDC convened a Federal B ask Force*

with representatives rom multiple U.S. agenciesto producerecommendations or a nationwide response to the MDR Boutbreaks. In June 1992, the Federal B ask Force publishedan action plan that provided a ramework or response andspecic action steps or state and local health departmentsand ederal agencies (7). Tese action steps were groupedinto nine categories: 1) surveillance and epidemiology, 2)laboratory diagnosis, 3) patient management, 4) screening andpreventive therapy, 5) inection control, 6) outbreak control7) program evaluation, 8) inormation dissemination/trainingand education, and 9) research. Emergency ederal unding wasappropriated to CDC in 1993 and again in 1994 to allow theFederal B ask Force and state and local health departmentsto implement certain parts o the plan. For example, CDCinvestigative teams were deployed to assist local programs indening and organizing appropriate response to MDR B outbreaks (CDC, personal communication, 2007). State and locahealth departments enhanced diagnostic laboratory capacityincreased the sensitivity o their surveillance systems, improvedinection-control practices, and reemphasized the need oroptimal treatment o all orms o B to prevent the development and urther transmission o MDR B. Other ederaagencies that are members o the task orce also contributed

substantially to implementation o the plan; a description otheir activities ollows.Te need or increased biomedical research and product

development or B was recognized by the National Instituteso Health (NIH) as part o the implementation o the 1992Action Plan. Te National Institute or Allergy and InectiousDiseases (NIAID) established extramural and intramuraresearch programs in all areas o undamental, translationaland clinical research in B to create a platorm o knowledgeand the research tools needed to studyM. tuberculosisand itsinteraction with the host and to characterize B in animalmodels and humans. In June 2007, NIAID released a research

agenda describing the specic biomedical research challengesand priorities that should be addressed in response to theemergence o drug-resistant B (10).

* A list o the members o the task orce as o March 2007 appears on page 43o this report.

CDC, Food and Drug Administration, National Institutes o Health, HealthResources and Services Administration, Bureau o Prisons, Occupational Saetyand Health Administration, Health Care Financing Administration, IndianHealth Service, and National Institute on Drug Abuse.


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Te National Heart, Lung, and Blood Institute (NHLBI)supported studies with a strong emphasis on pulmonary B,including complications through coinection with HIV, anddeveloped a training curriculum in B or health proession-als at medical institutions through the National uberculosisCurriculum Consortium (NCC) (11,12). he Fogarty

International Center (FIC) supported B research and researchtraining or developing country scientists through collaborativegrants with U.S. institutions (13). Te Eunice Kennedy ShriverNational Institute o Child Health and Human Development(NICHD) ocused on international clinical research oroptimizing B treatment in children and women coinectedwith HIV (14). Te more recently created National Instituteo Biomedical Imaging and Bioengineering (NIBIB) has asubstantial investment in diagnostic platorm technologies(point-o-care and imaging) that can help improve B diag-nosis through advances in medical imaging methods (15).

In May 1994, the Food and Drug Administration (FDA)approved Riater (a xed-dose combination o riampin, iso-niazid, and pyrazinamide) to acilitate patient adherence withlengthy and complex multidrug therapy (16). In addition, FDAgranted a priority new drug application review or the drugriapentine, which was approved in July 1998 or the treat-ment o B (17). In 1993, the United States Marshals Service(USMS) established a ormal medical program or prisonerswith B (USMS, personal communication, 2007). As part othis activity, USMS drated a series o advisory memoranda toprovide education inormation and guidance to USMS eldoces to support B screening or sta and prisoners. USMS

also collaborated with the exas Department o Health toconduct presentations on B control in correctional acilitieshighlighting patient tracking and ollow-up issues that arisewhen transerring prisoners between and outside jurisdictions.Te Department o Housing and Urban Development (HUD)developed web-based inormation and training activities onacquired immune deciency syndrome (AIDS) and B (HUD,personal communication, 2007).

Since 1998, with the creation o specic international Bprograms (e.g., directly observed treatment, short-course[DOS] expansion; research; training; and B/HIV coin-ection), the U.S. Agency or International Development

(USAID) has provided technical and nancial support tostrengthen B control programs worldwide (18). USAID alsohas supported drug-resistance surveys with biannual globalreports and pilot programs to optimize MDR B treatmentand the Green Light Committee (GLC), which helps coun-tries gain access to high-quality second-line B drugs so theycan provide treatment or persons with MDR B (19). Morerecently, the Division o Immigration Health Services (DIHS)o the Health Resources and Services Administration (HRSA)

implemented a national B Continuity o Care Program orpersons who are detained by U.S. Immigration and CustomsEnorcement (ICE) agents in the Department o HomelandSecurity (DHS) and who are to be deported beore completingB therapy (20); in October 2007, DIHS was transerred romHRSA to ICE. In addition, U.S. government agencies have

worked with their counterparts in Mexico and in U.S. stateagencies to develop initiatives (e.g., en Against B) to addressB, including drug-resistant B, along the U.S.-Mexico border(21). During 19932007, as a result o implementation o the1992 Action Plan, the reported annual incidence o MDR Bin the United States declined 75%, rom 485 cases in 1993 to119 cases in 2007 (4).

Emergece f ExtesivelyDrug-Resistat Tuberculsis

Since 1993, both incidence o B and the total number o

B cases in the United States have decreased, although the rateo decline has slowed since 2000. Worldwide, the number oB cases has continued to increase, but the incidence rate hasdecreased since 2003. Recently, highly drug-resistant ormso B have emerged worldwide. In 2006, CDC, the WorldHealth Organization (WHO) and the International UnionAgainst uberculosis and Lung Disease (IUALD) reported theresults o a survey regarding drug-resistant B conducted by25 reerence laboratories comprising the Global SupranationaB Reerence Laboratory Network (20002004), the NationaB Surveillance System in the United States (19932004)the national reerence laboratory o South Korea (2004), andthe national MDR B patient registry in Latvia (20002002)(22). Te ndings indicated that 20% oM. tuberculosisisolateswere MDR, and 2% also were resistant to multiple second-linedrugs. Tis highly resistant orm o B was identied in everyregion o the world, including the United States, where 4% oMDR B isolates also were resistant to multiple second-linedrugs. In a report published in 2006, this highly resistant ormo B was namedextensively drug-resistant B (XDR B)(22). XDR B is a subset o MDR B that is resistant both toisoniazid and riampin and to any fuoroquinolone drug andat least one o three second-line injectable drugs (amikacin

kanamycin, or capreomycin) (23).Te emergence o XDR B raises concerns about the possi-bility o epidemics o virtually untreatable B. Such epidemiccould result in excessive mortality and substantial nancialand inrastructure burden or public health and B controprograms. XDR B is much more expensive to treat, withhospitalization costs in the United States estimated to aver-age $483,000 per case. A major outbreak o XDR B in theUnited States would constitute a substantial drain on public


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health resources and could quickly deplete the existing stateand local B budgets and have a negative impact on progresstoward B elimination. Tis is especially true in an era odiminishing resources or B control at the national, state, andlocal levels (6). reatment ailures and subsequent death aremore common among patients with XDR B, and the drugs

available to treat XDR B are associated with serious adverseeects. Because persons who are inected with HIV or who haveother immune-compromising conditions (e.g., diabetes) aremore vulnerable to progressing to active B disease, inectionwith XDR B is o particular concern among these persons.In countries with high rates o HIV and limited health-careresources, substantial numbers o XDR B cases are likely pres-ent. As o April 2007, South Arica (where HIV prevalence wasestimated at 10.8% in 2005) had reported 352 cases o XDRB, with the actual prevalence likely being much higher (24)because cultures and susceptibility testing are perormed ononly a small raction o B patients, and many drug-resistantcases will go undetected.

MethdlgyAter an outbreak o XDR B among HIV-inected persons

in Kwazulu Natal, South Arica, reported in August 2006,urgent expert consultations were organized by the SouthArican Medical Research Council (SAMRC) and WHO inSeptember and October 2006 (25). Te result o these con-sultations was the 2007 publication o a global MDR B andXDR B response plan with eight overarching objectives (26).Several U.S. government agencies, including CDC, partici-

pated in the expert consultations. Te U.S. Federal B askForce was recognized as the appropriate venue to coordinateU.S. involvement in the global response to XDR B.

In November 2006, ollowing participation in the SAMRCand WHO XDR B consultations, CDC convened memberso the Federal B ask Force to discuss the emergence o XDRB and coordinate U.S. government agency involvement inthe domestic and international response to this problem. Aterseveral teleconerences, the ask Force agreed that a U.S. gov-ernment agency action plan should be written. Te action planthat had been published in 1992 to respond to MDR B wasselected as a basis or drating the XDR B response plan (7).Several members o the 2006 ask Force also had contributedto the 1992 Action Plan to combat MDR B. Tis MDRB expertise contributed substantially to a well-inormedand eective discussion and the creation o an Action Plan toCombat Extensively Drug-Resistant B. As had occurred inthe process to create the 1992 Action Plan, members o theFederal B ask Force were divided into sections to addresscritical areas o response. Te 1992 action plan distributed

the objectives and implementation steps needed to address 38problems among nine response areas (surveillance and epide-miology, laboratory diagnosis, patient management, screeningand preventive therapy, inection control, outbreak controlprogram evaluation, inormation dissemination/training andeducation, and research). Although largely overlapping with

the 1992 action plan, the response areas or the XDR Bplan were reorganized as ollows: 1) diagnostic laboratory; 2)surveillance, epidemiology, and outbreak investigations; 3)inection control; 4) clinical and programmatic interventions5) ethical and legal issues; 6) communication and education; 7)research; 8) partnerships; and 9) cost analysis. Tese responseareas also are closely aligned with WHOs seven-point GlobaAction Plan to Combat XDR B (26), which calls or publichealth authorities to 1) conduct rapid surveys o XDR B todetermine the burden, 2) enhance laboratory capacity withan emphasis on rapid drug-sensitivity testing, 3) improve thetechnical capacity o clinical and public health practitionersto respond eectively to XDR B outbreaks and managepatients, 4) implement inection-control precautions, 5)increase research support or B drug development, 6) increaseresearch support or rapid diagnostic test development, and7) promote universal access to antiretroviral drugs under joinB/HIV activities. In addition, the implementation steps wererenamed action steps.

In January 2007, each subgroup o the Federal B ask Forcethat was responsible or addressing a critical response area beganby reviewing the relevant sections o the 1992 action plan todetermine which problems, objectives, and action (ormerly

implementation) steps needed to be deleted or updated andrevised. Te subgroups also determined i gaps existed requiringthe identication o additional problems, objectives and actionsteps.In particular, because the 1992 plan had ocused primar-ily on domestic MDR B, the subgroups were instructed toexpand the scope o the new plan to address the role o U.Sgovernment agencies in the international response to XDRB. o refect this distinction, the new plan labels objectivesas domestic, international, or both. Te expanded scope and agreater emphasis on detail resulted in a substantial increase inthe number o problems, objectives, and action steps identiedcompared with the 1992 plan. For example, the number o

problems increased rom 38 in 1992 to 67 in the current planAn emphasis also was placed on being as inclusive as possiblewhen designating lead ederal agencies and potential externapartners. o provide a basis or revisions, the subgroup mem-bers reviewed pertinent literature published since 1992, whichis substantially more voluminous, especially or drug-resistanB, compared with that available beore 1992, and availableunpublished data. Ater drats o the sections were completedthe sections were compiled into a single document that was


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distributed to the entire Federal B ask Force or review andcomment. In June 2007, the Federal B ask Force met inRockville, Maryland, to make additional revisions, especiallyto eliminate redundancies between sections. Tese revisionswere incorporated into a nal drat that was submitted ormultiple agency clearance in September 2007.

Recmmedatis t CmbatExtesively Drug-Resistat

Tuberculsis

Diagstic LabratryTe diagnosis o XDR B is established by laboratory meth-

ods. Accurate, reliable, and prompt B laboratory servicesshould be coordinated ully with provider and public healthpractitioners caring or persons with B. est results must be

available in a time rame that allows clinicians to make promptand inormed patient management decisions. For this goal tobe met, laboratory capacity or the diagnosis o B and thedetection o drug resistance must be rapidly enhanced, bothin the United States and worldwide. Adequate inrastructuremust be built where it does not exist, a stable and well-trainedwork orce must be developed and maintained, and a systemsapproach (27)must be implemented to maximize eciencyand prociency. Laboratory methods and reporting, especiallyor susceptibility to second-line drugs, should be standardizedthrough expert consensus. Rapid tests or B diagnosis anddrug-susceptibility testing on the basis o newer molecular

methods must be evaluated promptly to determine their ea-sibility, especially or low-resource settings, and, i appropri-ately validated, their use should be promoted and acilitated.Internationally, competent, high-quality reerence laboratoryservices with capacity to perorm required testing o samplesand to report results in a prompt ashion to providers andhealth ocials must be available to jurisdictions in need.

Surveillace, Epidemilgy, adoutbreak Ivestigati

Domestic XDR B surveillance must include accurate

and complete reporting o second-line drug-susceptibilitytesting, real-time reporting, and active case nding. Centralnotication o MDR B and XDR B is essential to identiycross-jurisdictional issues and to provide potential or rapidemergency ederal support, when needed. Internationally, rapiddrug-susceptibility test (DS) surveys and more sustainedsystematic capture o DS inormation are highlighted asareas to be addressed as part o a comprehensive response toXDR B. Epidemiologic studies that make use o genotyping

tools are recommended to elucidate XDR B risk actors andtransmission dynamics. Strategies also are needed to rapidlyidentiy and respond to domestic and international XDR Boutbreaks.

Ifecti CtrlEective inection-control practices are critical to prevent

the transmission and urther spread o MDR and XDR Bin health-care settings and other congregate settings (e.g.correctional acilities and homeless shelters). CDC inectioncontrol guidelines were updated in December 2005 and shouldcontinue to be updated as needed (28). Further studies areneeded to assess the eectiveness and easibility o variousinection-control strategies in dierent institutional settingsesting workers or B in various institutional settings is animportant strategy or identiying workers inected with Band detecting unsuspected transmission.

Cliical ad PrgrammaticItervetis

Prevention and control o B in the United States require arobust public health inrastructure that includes a workorcetrained in B prevention, diagnosis, treatment, and casemanagement. Because some patients ail to recognize Bsymptoms, health care oten is not sought during early stageso disease. In addition, providers who are unamiliar with signsand symptoms o B and with diagnostic standards might nosuspect B, delaying the start o eective treatment. Access to

comprehensive and aordable clinical B services (i.e., pre-ventive, diagnostic, and treatment/case management) shouldbe provided to all persons with B or those suspected to haveB. Health-care providers who screen persons or B shoulduse up-to-date diagnostic and treatment guidelines. Morehealth-care workers are needed to provide directly observedtherapy (DO) or B patients to ensure successul treat-ment and help prevent development o disease attributable todrug-resistant B.

Ethical ad Legal Issues

Strict inection-control measures are necessary to prevent thespread o XDR B. Patients with XDR B might need to beplaced in airborne inectious isolation while initial treatmentresponse is monitored in order to prevent disease transmissionto others. Guidance is needed regarding the ethical and legalissues involved in identiying and treating persons with XDRB. Te adequacy o current public health laws in the UnitedStates to address drug-resistant B has not been studied com-prehensively since 1993 (29). All states have laws to compe


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isolation or persons with certain inectious diseases (includingB); however, these laws vary by state, and those or B mightbe contingent on patient nonadherence and ailure o voluntarymeasures. Public health authorities must balance the interestso the public with individual rights. Legal and ethical issuesbecome even more complicated when persons have XDR B

because prolonged isolation might be necessary even when apatient is adherent. In addition, or some patients, no eec-tive treatment is available that would allow or release romisolation on completion. Additional complexity also existsregarding non-U.S. citizens with inectious XDR B whoare scheduled to be repatriated to their native countries. U.S.public health ocials might not be amiliar with public healthlaws o other countries.

Cmmuicati ad EducatiAs a result o B incidence rates decreasing in the United

States, health-care providers have received little training regard-ing B and consequently might not recognize the signs andsymptoms o B, which can lead to incorrect diagnosis andtreatment, creation o drug resistance, and continued spread oB in the community (30,31). Health-care providers shouldbe educated about the signs and symptoms o B, diagnosticmethods, prevention, and treatment. In addition, educationmaterials on MDR B and XDR B should be developed orthe general public, populations at high-risk or B on the basiso demographic and clinical characteristics, B patients, Bprevention advocacy organizations, and policy makers, includ-ing legislators. Education materials should include inorma-

tional pamphlets, instructions or therapy, behaviors to preventtransmission, medical alerts, and descriptions o B programs.Distribution o these materials should be coordinated acrossederal and stateagencies and updated as necessary. Advocacyis critical to make the public aware o the importance o Bcontrol to the publics health, and to educate policy makers onthe magnitude o the problems that will result i resources tostate and local B control programs continue to decline.

ResearchTe biomedical research challenges represented by drug-

resistant B in the context o overall B research activitieshave been described previously (10).Knowledge gaps remainregarding the genetics and growth characteristics oM. tuber-culosis, the physiology and biochemistry o both the host andpathogen during inection, and the disease and genotypicand biologic markers that acilitate surveillance and indicateinection, disease, and drug resistance. Basic research needs tobe supported to advance understanding o these issues and tohelp design new approaches to diagnosis and treatment. Te

emergence o drug-resistant B illustrates the pressing needto develop new and eective drug regimens or the treatmeno B, including drugs to cure MDR B and XDR B and toprevent development o active disease among persons who areinected latently with drug-resistantM. tuberculosis. Becausepoor patient adherence to therapy is one actor that can lead to

development o MDR B and XDR B, research o associatedbehavioral and social actors should be conducted to identiyways to improve patient adherence and treatment completionNew, rapid, and cost-eective diagnostic methods are neededparticularly or use in rural areas and developing countriesUltimately, an eective vaccine is needed to eliminate B.

Partershipso coordinate eorts to control XDR B, existing partner-

ships must be strengthened, and new partnerships are neededbetween countries and within both the public and private

sectors, including government and nongovernment organiza-tions. Partnerships are necessary to ocus existing resourceson the most aected geographic areas, increase current publicand private resources (both nancial and human resources)coordinate the eorts (including research, education, labora-tory, and programmatic), and raise awareness o the problemand consequences.

Cst AalysisComprehensive inormation is not available on the cost o

treating and implementing programs and interventions to

prevent XDR B. Research on the cost o treating and prevent-ing XDR B is needed to calculate the cost-eectiveness andbenets o interventions and strategies to combat XDR B.

Acti Pla t Cmbat ExtesivelyDrug-Resistat Tuberculsis

Diagstic LabratryTe laboratory plays a critical role in the diagnosis and

management o drug-resistant B. est results must be available in a time rame that allows clinicians to make promp

patient management decisions. Many laboratory techniquesused to conrm a B diagnosis and to identiy drug resistancewere developed in the 1950s, 1960s, and 1970s. Substantiaimprovements have been made in culture techniques andin rapid methods in the past decade. However, these moreaccurate, rapid, and sophisticated methods have not beenimplemented widely, particularly in regions o the world whereMDR B and XDR B are common and optimized algorithmsor providing rapid point-o-care laboratory conrmation o


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B and detection o drug resistance have not been established.o combat the growing problem o resistance to B drugs,the most current methods need to be applied to their ullestcapacity while better diagnostic tests are developed. Te needso the B laboratory must be addressed to make laboratoryservices or B, MDR B, and XDR B more rapid, sensitive,

reliable, and more responsive to the needs or patient manage-ment, inection control, and B control eorts. Although thechallenges and potential solutions vary by setting, domesticand international B laboratories ace many o the samechallenges.

Prblem 1

Many clinicians, laboratorians, health-care proessionals,public health ocials, and policy makers do not possess up-to-date knowledge o what constitutes appropriate laboratorycapabilities and capacities or the appropriate use o tests toarrive at a prompt and accurate diagnosis o B.

objective 1.1

Increase awareness o the need to develop necessary capac-ity and capabilities or the laboratory diagnosis o B. Tisincludes proper use o diagnostic tests, prompt reporting oresults, and appropriate interpretation o test results or estab-lishing a denite diagnosis and or guiding management o B(domestic and international).

Acti Steps

1.1.1. Educate clinicians and public health ocials aboutappropriate use o diagnostic services and tests, interpretation

o laboratory test results, and the role o the diagnostic labora-tory in monitoring treatment. Distribute current guidelineson B diagnostic testing, drug-susceptibility testing, andlaboratory services.

1.1.2. Conduct a survey o current practices and capabilitiesin private, hospital, commercial, and public B laboratoriesto assess current methods and inrastructure used or directdetection oM. tuberculosisin patient specimens, and rapidtesting or susceptibility to rst- and second-line drugs.

1.1.3. Create or update sel-assessment tools or private,hospital, commercial, and public laboratories to evaluatetheir practices in and knowledge o B diagnosis and drug-susceptibility testing to acilitate planning o continuousquality improvements.

1.1.4. Educate policy makers, national health ministryocials, program ocials, clinicians, laboratory managers,and laboratory directors about the role o prompt, reliable Blaboratory services in national and local health-care systemsand public health programs.

1.1.5. Educate laboratorians, clinicians, and public healthocials on the appropriate use o B diagnostic laboratoryservices and the need or the integration o rapid tests into Bcontrol programs to enhance patient care.

1.1.6. Identiy and use resources available rom regional juris-dictions in resource-limited settings with expected increases

in MDR B and XDR B cases to help improve capacityor drug-susceptibility testing and care o patients with drug-resistant B.

Lead ederal agencies: U.S. Department o Health andHuman Services (HHS) (CDC and NIH), USAID, and U.SDepartment o Veterans Aairs (VA).

Suggested collaborators: U.S. Department o Deense(DoD), American Toracic Society (AS), Inectious DiseaseSociety o America (IDSA), Association o Public HealthLaboratories (APHL), National B Controllers Association(NCA), Regional raining and Medical Consultation Centers(RMCCs), WHO, national health ministry, academia, andpublic health and private laboratories.

Prblem 2

Although the majority o domestic B laboratories are pre-pared to respond to MDR B, many have limited capacity torespond to XDR B.

objective 2.1

Ensure that required laboratory services are available torespond properly to XDR B (domestic).

Acti Steps

2.1.1. Assess current domestic laboratory resources andcapacity to create an integrated network o B diagnosticresources necessary or a prompt and robust response to XDRB anywhere in the United States.

2.1.2. Develop centers o excellence or B diagnosis aspart o a network o laboratories and inormation/specimenmanagement systems that use standardized procedures orreporting within 2 days o identication o MDR and XDRM. tuberculosisrom clinical specimens, tracking and reerraor B cases, and shipping o specimens.

2.1.3. Develop enhanced biosaety level 3 laboratories withappropriate acilities, trained sta, administrative controlsand monitoring programs to handle XDR M. tuberculosistrains saely.

2.1.4. Ensure second-line drug-susceptibility testing o iso-lates rom all patients identied with MDR B.

2.1.5. Develop suicient domestic laboratory capacityto accommodate rapid testing o M. tuberculosisstrains in

Organizations listed as suggested collaborators have not yet been approachedto work on any recommended action steps.


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case o domestic and international B outbreaks (surgecapacity) and to provide comprehensive, ongoing coverageor surveillance.

2.1.6. Develop a laboratory component or a rapid XDRB outbreak response plan and provide training to local, state,and ederal responders.

2.1.7. Coordinate the CDC Universal B GenotypingProgram with B genotyping programs o the European Union(EU) and other international partners to identiy genotypesassociated with XDRM. tuberculosisstrains and develop anearly warning system or the spread o XDRM. tuberculosisstrains.

Lead ederal agencies: HHS (CDC and NIH).Suggested collaborators: APHL, NCA, academia, and

public health and private laboratories.

Prblem 3

Current laboratory capacity is inadequate to identiy, charac-

terize and track drug resistantM. tuberculosisstrains in responseto the XDR B epidemic.

objective 3.1

Enhance laboratory capacity to support outbreak investiga-tions and studies o XDR B (domestic).

Acti Steps

3.1.1. Provide support or MDR and XDR B outbreakinvestigations through genotyping oM. tuberculosisisolatesand rapid drug-susceptibility testing.

3.1.2. Fully implement the CDC Universal B Genotyping

Program to track and monitorM. tuberculosisstrain transmis-sion in the United States.

3.1.3. Establish and support a nationalM. tuberculosisgeno-type and isolate archive to compare strains, epidemiologic data,and clinical outcomes rom dierent geographic regions.

3.1.4. Support eorts to determine genomic sequences oMDR and XDRM. tuberculosisstrains to characterize resistanceand aid in determining virulence mechanisms.

3.1.5. Provide overall technical laboratory assistance toinvestigate MDR B and XDR B outbreaks.

Lead ederal agencies: HHS (CDC and NIH).Suggested collaborators: NCA, APHL, academia, and

public health and private laboratories.

objective 3.2

Determine laboratory capacity needed or rapid XDR Bsurveys in WHO-designated high-burden (dened by WHO as

the 22 countries with the highest B morbidity) and B-ocuscountries (international).

Acti Steps

3.2.1. Assess capacities o national and internationalacademic, private, commercial, and public laboratories to

provide laboratory services needed to conduct rapid XDRB surveys.

3.2.2. Provide immediate (emergency) surge capacitythrough U.S. laboratory resources to aected countries inresponse to MDR B and XDR B outbreaks.

3.2.3. Develop a network o international quality-assuredlaboratories to conduct drug-susceptibility testing or XDRB surveys.

3.2.4. Develop standardized methods or rst- and sec-ond-line drug-susceptibility testing to be used in XDR Bsurveys.

3.2.5. Develop external quality assessment programs or

surveys.Lead ederal agencies: HHS (CDC and NIH) and

USAID.Suggested collaborators: U.S. Department o State (DOS)

DoD, WHO, APHL, American Society or Microbiology(ASM), NCA, IUALD, Royal Netherlands uberculosisAssociation (KNCV), Research Institute o uberculosis (RI),public health and private laboratories, and academia.

Prblem 4

Te quality o and prociency in B laboratory diagnosisvaries within the United States and internationally because a

well-trained and stable laboratory workorce is not universallyavailable.

objective 4.1

Provide training in conventional and new diagnostic meth-ods or B (domestic and international).

Acti Steps

4.1.1. Provide training to private, commercial, and publichealth laboratory managers and supervisors in laboratorymanagement and systems.

4.1.2. Provide training to B laboratory personnel or con-

ventional and new diagnostic tests.4.1.3. Provide training in biosaety and sae manipulation

o pathogenic mycobacteria.4.1.4. Develop training materials or current, new, and

emerging technologies or B laboratory personnel.

Countries that either 1) are WHO high-burden countries, 2) are countrierom which the majority o oreign-born persons with B in the United Stateoriginate (e.g. Mexico, the Philippines, and Vietnam), 3) have high HIV/Bprevalence, or 4) have a high prevalence o MDR B.


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4.1.5. Provide opportunities or exchange o person-nel between laboratories in resource-limited settings toshare knowledge about successul approaches to laboratorydiagnosis.

4.1.6. Develop programs to assist laboratory managers inmaintaining prociency in B laboratory services or to obtain

services rom reerral laboratories.4.1.7. Explore opportunities to integrate B laboratory

personnel into the general clinical laboratory workorce tostrengthen overall human resource capacity at the local, district,and provincial levels.

4.1.8. Develop programs to inorm and educate health-careproviders about new tests or B, their potential useulness inestablishing a diagnosis or monitoring therapy, and their cost/benet over existing approaches.

4.1.9. Evaluate the eectiveness o newly developed trainingactivities and programs to build laboratory capacity.

Lead ederal agencies: HHS (CDC), and USAID.Suggested collaborators: DoD, APHL, NCA, National

Laboratory raining Network (NLN), SOP B USA, WHO, IUALD, Clinical Laboratory Standards Institute(CLSI), the Global Fund, and the World Bank.

Prblem 5

B laboratory services at certain local public health labo-ratories are limited and might depend on access to networkso other public and private laboratories with better diagnosticcapabilities, which oten leads to substantial delays in diagnosisand treatment o B.

objective 5.1Develop a systems approach to improving B laboratory

services at the local level (domestic).

Acti Steps

5.1.1. Assess available B laboratory services in a jurisdictionto determine the status and capacity o services and to identiyunmet needs, obstacles to obtaining services, and opportunitiesor improvement.

5.1.2. Assess the actual costs o providing B laboratoryservices through existing programs and develop a business planor providing these services through an integrated system olaboratory services in the United States.

5.1.3. Develop a strategic plan or implementing and main-taining a systems approach to B laboratory services.

5.1.4. Develop outcome measures to assess perormanceo and improvements in laboratory services and overall Bcontrol programs.

Lead ederal agencies: HHS (CDC).

Suggested collaborators: APHL, NCA, state and locaB programs, academia, and public health and privatelaboratories.

objective 5.2

Develop integrated B laboratory systems in high-

burden countries and countries with limited resources(international).

Acti Steps

5.2.1. Inventory and assess available academic, privatecommercial and public B laboratory service providers todetermine each countrys domestic capacity to provide servicesor B program and patient care activities.

5.2.2. Develop a network o public and private B laboratories that use standardized and quality controlled methods orinormation and specimen management to meet the needs othe local and national B treatment and control programs.

5.2.3. Provide training to develop national expertise in Bdiagnostic laboratory services, patient care and B controactivities through engagement o national academic and clinical research programs.

5.2.4. Develop program-specic plans and phased approacheto improving laboratory services in national, country-leveregional and peripheral (local) laboratories.

5.2.5. Develop local, district, regional, and national laborato-ries, including reerral laboratories, that provide reliable servicesthrough conventional and rapid methods or B diagnosisdrug-susceptibility testing and patient care.

5.2.6. Develop or ensure access to eective external quality

assessment programs or laboratory services (e.g., acid ast bacil-lus [AFB]smear microscopy, culture, and drug-susceptibilitytesting) provided at each level.

5.2.7. Support development o laboratory standards andaccreditation programs with an emphasis on culture anddrug-susceptibility testing to acilitate assessment and qualityimprovement o national and regional laboratories.

5.2.8. Explore options to increase B laboratory capacity aspart o eorts to improve general diagnostic laboratory servicecapacity and overall health sector reorm.

5.2.9. Identiy interim laboratory support services until loca

and regional capacity is developed.5.2.10. Support research to develop inexpensive, high-qualitydiagnostic tools that can be used in resource-limited settings

Lead ederal agencies: HHS (CDC and NIH), andUSAID.

Suggested collaborators: DoD, DOS, NCA, APHL, ASMWHO, and IUALD.


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Prblem 6

Culture-based laboratory tests to identiy persons withXDR B are slow, lack sensitivity, and have poor reliability,resulting in delayed diagnosis, treatment, and public healthcontrol eorts.

objective 6.1Improve the ability o B laboratories to identiy and report

drug-resistantM. tuberculosis(domestic).

Acti Steps

6.1.1. Develop local, district, state, regional, or reerral labo-ratories that are able to rapidly identiyM. tuberculosisbacteriain patient specimens and determine drug susceptibilities torst- and second-line agents using state-o-the-art conventionalor rapid methods.

6.1.2. Encourage the use o state-o-the-art rapid tests ordetection o M. tuberculosisand drug-susceptibility testingthrough ocused laboratory unding.

6.1.3. Develop a bank oM. tuberculosisisolates or use inprociency testing and research.

6.1.4. Implement prociency testing programs and externalquality assessment programs or new drug-susceptibility testsand rapid methods.

6.1.5. Assist laboratories in developing and implementingan integrated inormation management system or inventory,specimen tracking, reporting, and inormation sharing.

6.1.6. Identiy interim laboratory support services until localand regional capacities are developed.

Lead ederal agencies: HHS (CDC and NIH).Suggested collaborators: APHL and NCA.

Prblem 7

Te lack o guidelines or the use o conventional andrapid culture-based or molecular methods or detection oM.tuberculosisand drug resistance impedes the widespread useo these tests.

objective 7.1

Develop consensus guidelines to address B laboratory test-ing in the United States, in high-burden and in ocus countries

(domestic and international).Acti Steps

7.1.1. Develop consensus guidelines or culture, drug-suscep-tibility, and rapid diagnostic testing to be used in local, district,state, national, and country-level regional laboratories.

7.1.2. Develop consensus guidelines or the use o rapidmethods (e.g., nucleic acid amplication tests) to detectM.tuberculosisdirectly rom patient specimens.

7.1.3. Develop consensus guidelines or the use o rapidmolecular methods or drug-susceptibility testing.

7.1.4. Develop consensus guidelines or culture-based meth-ods to determine resistance to second-line B drugs.

7.1.5. Conduct operational and implementation research todevelop guidelines or optimal algorithms or B laboratory

testing, specimen reerral, and reporting.Lead ederal agencies: HHS (CDC and NIH) and

USAID.Suggested collaborators: APHL, AS, IDSA, CLSI, WHO

IUALD, and academia.

Prblem 8

Te current process or evaluating newly developed diagnostic tests can be time consuming and delay implementation orroutine clinical use.

objective 8.1

Develop strategies or expedited evaluation and implementa-tion o new rapid methods or laboratory conrmation o Band identication o drug-resistance patterns (domestic andinternational).

Acti Steps

8.1.1. Evaluate and deploy methods to optimize AFB sputumsmear microscopy.

8.1.2. Evaluate and deploy sensitive and rapid molecular teststo detectM. tuberculosisdirectly in sputum specimens.

8.1.3. Evaluate and deploy rapid culture methods or isolatingM. tuberculosis.

8.1.4. Evaluate and deploy rapid culture-based or moleculardrug-susceptibility testing methods.

8.1.5. Develop methods to validate genotypic indicators oresistance through phenotypic susceptibility results and thepatients response to treatment.

8.1.6. Develop consensus methods and guidelines or theintroduction and use o new diagnostic methods, includingin resource-limited settings.

8.1.7. Provide access to well-characterized drug-susceptibleand drug resistant-strains oM. tuberculosisor identicationo drug-resistance markers.

8.1.8. Expand the genomic characterization o drug-resistantM. tuberculosisstrains to identiy new markers o resistance tosecond-line drugs.

8.1.9. Evaluate the cost eectiveness and appropriate use oavailable and new rapid methods and approaches to identiyo MDR/XDRM. tuberculosis.

8.1.10. Determine and promote the most eective point-o-care drug-susceptibility testing methods and diagnosticalgorithms and strategies, including molecular testing at the


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local level ollowed by transport o positive specimens to ull-service laboratories or urther evaluation.

8.1.11. Provide access to or conduct clinical trials in partner-ship with high-burden countries to validate new microbiologicdrug-susceptibility tests as part o local diagnostic procedures/algorithms.

8.1.12. Discuss with FDA criteria that will be required orapproval o new tests or identication o drug-resistant Band to perorm rapid drug-susceptibility testing.

Lead ederal agencies: HHS (CDC, FDA, and NIH), andUSAID.

Suggested collaborators: DoD, Foundation or InnovativeNew Diagnostics (FIND), WHO Special Programme orResearch and raining in ropical Diseases [DR]), academia,public health laboratories, and IUALD.

Prblem 9

Te laboratory conrmation o B in HIV-inected persons

is dicult and time consuming because o the need or highlysensitive, sophisticated and technically challenging diagnostictests that are not universally available in all settings with a highburden o HIV and B.

objective 9.1

Improve laboratory conrmation o B, MDR B, and XDRB in HIV-inected persons (domestic and international).

Acti Steps

9.1.1. Strengthen B laboratory capacity to detect AFB-smear negative B through support o global eorts to build

culture capacity in B laboratories and develop methods toincrease sensitivity o AFB-smear microscopy.

9.1.2. Develop and evaluate eective laboratory testing algo-rithms and specimen reerral systems to prioritize specimensrom HIV-inected persons appropriately.

9.1.3. Integrate B laboratory capacity building with HIVlaboratory capacity building.

9.1.4. Evaluate and deploy the use o sensitive and rapidmolecular tests to detectM. tuberculosisdirectly in sputum andother clinical specimens rom HIV-positive persons.

Lead ederal agencies: HHS (CDC and NIH), andUSAID.

Suggested collaborators: DOS, DoD, FIND, WHO(DR), ASM, APHL, academia, IUALD, and public healthlaboratories.

Prblem 10

Current technical assistance or laboratory capacity buildingis sporadic and not well coordinated or integrated oten leadingto unclear and inconsistent guidance.

objective 10.1

Develop consistent and well-coordinated approaches totechnical assistance and consultation or B laboratories inhigh-burden and ocus countries (international).

Acti Steps

10.1.1. Develop technical assistance approaches and practicesthat are coordinated, consistent, and compatible with the eortso international partners such as WHO and IUALD.

10.1.2. Establish a cadre o well-trained consultants to helpguide coordinated approaches to building B laboratory capac-ity in high-burden and ocus countries.

10.1.3. Contribute to the coordinated development o stan-dardized checklists and templates or laboratory evaluation andtraining materials or laboratory capacity building eorts.

10.1.4. Contribute to the coordinated development oexternal quality assessment guidance and documents ormicroscopic and culture identication o

M. tuberculosisand

drug-susceptibility testing.10.1.5. Contribute to the coordinated development o widely

compatible laboratory inormation systems to acilitate transero inormation within and between B control programs.

10.1.6. Promote expansion o the Supranational LaboratoryNetwork through inclusion o reerence laboratories that canassist in capacity building and external quality assessment.

10.1.7. Promote expansion o the Supranational LaboratoryNetwork prociency testing to include second-line drug-susceptibility testing.

10.1.8. Promote and coordinate partnering o public health

laboratories in the United States with public health laboratoriesin high-burden and ocus countries.Lead ederal agencies: HHS (CDC and NIH), and

USAID.Suggested collaborators: DoD, DOS, NCA, APHL, ASM

WHO, and IUALD.

Prblem 11

Providing technical assistance is logistically dicult.

objective 11.1

Establish international regional centers o excellence to

acilitate implementation o technical assistance providedby the United States to B endemic or B-ocus countries(international).

Acti Steps

11.1.1. Build expertise or technical assistance to Blaboratories at selected centers o excellence in high-burdencountries.


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11.1.2. Provide opportunities or peer-to-peer trainingand exchange o laboratory personnel in resource limitedsettings.

11.1.3. Assist centers o excellence in developing trainingprograms or program sta, laboratory managers and benchworkers on establishing methods or external quality assessment

processes through site visits and monitoring.11.1.4. Assist centers o excellence in establishing reerence

laboratory services or identication oM. tuberculosisandsusceptibility testing or rst- and second-line drugs that wouldqualiy them as Supranational Reerence Laboratories and thatcould be made available to partner programs.

Lead ederal agencies: HHS (CDC and NIH) and USAID.Suggested collaborators: DOS, DoD, WHO, IUALD,

APHL, ASM, KNCV, RI, academia, and public healthlaboratories.

Prblem 12

Resources available to B laboratories are oten inadequateor building and maintaining the necessary inrastructure andcompetencies to provide consistently high-quality diagnosticservices.

objective 12.1

Mobilize resources and support international eortsto strengthen and sustain B laboratory capacity(international).

Acti Steps

12.1.1. Identiy unding opportunities through the

Presidents Emergency Plan or AIDS Relie, USAID, andthe Global Fund to contribute to strengthening internationallaboratory eorts.

12.1.2. Support global eorts (e.g., WHOs strategicapproach to the strengthening o laboratory services or Bcontrol).

12.1.3. Support the Stop B Partnerships Global LaboratoryInitiative and the DOS (directly observed therapy, shortcourse) Expansion Working Group.

Lead ederal agencies: USAID and HHS (CDC).Suggested collaborators: DOS, WHO, the Bill & Melinda

Gates Foundation, APHL, and the American Lung Association(ALA).

Prblem 13

Te role o public and private B laboratories in the diag-nosis o persons latently inected with XDRM. tuberculosishas not been dened clearly.

objective 13.1

Develop laboratory services to identiy persons withdrug-resistant latent M. tuberculosisinection (DR LBI)(domestic).

Acti Steps

13.1.1. Assess the capacity o public and private B laborato-ries to support DR LBI diagnostic testing by determining thestatus and capacity o currently available services and identiy-ing gaps, obstacles and opportunities or improvement.

13.1.2. Develop materials and programs to train laboratorypersonnel in DR LBI diagnostic testing.

13.1.3. Develop consensus laboratory guidelines or DRLBI testing methods.

13.1.4. Conduct operational research to optimize testingand reerral algorithms.

13.1.5. Develop prociency testing and external qualityassessment modules or DR LBI diagnosis.

13.1.6. Conduct Phase 4 clinical studies o new technologiesor DR LBI diagnosis and management.

Lead ederal agencies: HHS (CDC, FDA, NIH).Suggested collaborators: DoD, NCA, APHL, CLSI, AS

and IDSA.

Prblem 14

International laboratory services used by physicians underprovisions o the United States Immigration and NationalityAct oten are not equipped to the standards o U.S. B pro-grams and might not be able to reliably identiy persons with

drug-susceptible or MDR B and XDR B.objective 14.1

Evaluate and improve the ability o international laboratoriesemployed to identiyM. tuberculosisand perorm drug-suscep-tibility testing or potential U.S. immigrants (international).

Acti Steps

14.1.1. Determine which high-burden country issues thelargest number o immigrant visas and identiy the top 20immigrant visa processing posts.

14.1.2. Identiy and assess the diagnostic capabilities olaboratories used by physicians aliated with these visa pro-cessing posts.

14.1.3. Assure that evaluations and improvements in Blaboratory services used or medical evaluation o visa appli-cants are coordinated with overall eorts to improve nationaB programs.

14.1.4. Provide training on the basis o U.S. governmentpolicies or the medical examination o aliens (available a


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http://www.cdc.gov/ncidod/dq/health.htm)to B laboratoriesused by examining physicians to acilitate improvement olaboratory prociency or identication oM. tuberculosisanddiagnosis o drug-susceptible and drug-resistant B.

14.1.5. Provide oversight, prociency testing, and consulta-tion to ensure adequate B diagnostic and drug-susceptibility

testing capability are available or visa applicants in interna-tional screening laboratories.

Lead ederal agencies: U.S. Department o HomelandSecurity (DHS), and HHS (CDC).

Suggested collaborators: DOS and the InternationalOrganization or Migration.

Prblem 15

Limited capacity exists or the evaluation o new B diag-nostic tests (see Problem 54).

objective 15.1

Evaluate new methods to provide rapid and reliable labora-tory conrmation o B and identiy patterns o drug resistance(domestic).

Acti Steps

15.1.1. Contribute to the development and clinical evalua-tion o rapid and simple methods to identiy and characterizeMDR/XDR strains oM. tuberculosis.

15.1.2. Facilitate the development o improved diagnostictests or rapid diagnosis o B disease in persons with eithercompromised or intact immune systems.

15.1.3. Evaluate the specicity and sensitivity o candidate

tests to rapidly diagnose and identiy resistantM. tuberculosisstrains in eld settings.

15.1.4. Provide training in implementation research andeld evaluations, and build clinical trial capacity to evaluatenew laboratory tests.

Lead ederal agencies: HHS (CDC, FDA, and NIH), andUSAID.

Suggested collaborators: DoD, FIND, and academia.

Surveillace, Epidemilgy, adoutbreak Ivestigatis

Identiying outbreaks o XDR B to prevent urther trans-mission requires a rapid, accurate, and adaptable surveillancesystem and coordinated response strategies. In the UnitedStates, individual states require reporting o B cases byhealth-care providers and acilities to public health authorities.By mutual agreement, state health authorities report B casesto CDC. Substantial delays can occur in reporting to CDCbecause many states report on a quarterly basis or at the end othe year. Key domestic surveillance needs include immediate

case reporting, accurate and complete reporting o second-linedrug susceptibility and genotyping results, and active casending among contacts and other high risk groups. Centralnotication o MDR and XDR B is essential to identiy cross-jurisdictional issues and to outline specic areas that shouldbe targeted or rapid emergency (ederal) support. Improved

unambiguous technical guidance (including outcome stan-dards) is needed or collection, reporting, and data-qualityprocedures at the local, state, and ederal levels. Internationallyareas that require increased attention and improvement includecapacity or rapid DS surveys and more sustained, systematiccapture o DS inormation. Epidemiologic studies, includ-ing genetic analyses o host and pathogen, are recommendedto elucidate risk actors or acquiring XDR B, transmissiondynamics and determinants o host survival.

Prblem 16

No requirement exists or rapid reporting o B cases to the

National B Surveillance System (NSS), and many state andcity B programs report to NSS only quarterly or at the endo the year, thus substantially limiting the ability to identiyrapidly and respond promptly to outbreaks o MDR B andXDR B.

objective 16.1

Develop a plan or reporting known or suspect MDR B andXDR B cases to the NSS with notime lag (domestic).

Acti Steps

16.1.1. Convene a working group o stakeholders (CDC

NCA, local and state B control programs, laboratorians)to develop an integrated plan or immediate notication oMDR B and XDR B cases.

16.1.2. Establish clear requirements and methods or report-ing o MDR B and XDR B cases rom local clinics to labo-ratories, hospitals, and other partners who might diagnose Bin patients to the state B program and to NSS.

16.1.3. Develop standard reports o aggregated XDR Bcase data within the NSS to provide to local and state Bprograms.

16.1.4. Dene mechanisms to provide eedback to state andlocal programs and partners regarding missing data, incompletediagnostic inormation, and needed ollow-up inormation.

16.1.5. Develop procedures and data requirements that allowpublic health agencies to identiy and address large-scale andinterjurisdictional issues and to request rapid mobilization oa ederal response in case o emergencies.

16.1.6. Develop and maintain a national registry or MDRB and XDR B outside the NSS that is linked to thenational genotyping database or contains genotyping results
http://www.cdc.gov/ncidod/dq/health.htmhttp://www.cdc.gov/ncidod/dq/health.htm


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rom the state B programs. Te registry should include per-sons with reported cases and with nonreportable (noncounted)cases o MDR B and XDR B and persons with cases o Bidentied by clinical diagnosis alone who are known contactsto culture-conrmed MDR B or XDR B.

16.1.7. Develop required data elements or the national

registry that include relevant clinical data, inormation aboutprimary or secondary MDR B and XDR B cases, detailedhistory o prior and current drug treatment and susceptibilitytest results incorporating expanded second-line drug panels.

16.1.8. Develop web-based access to the national registry orstate and local health departments, diagnostic laboratories andrelevant public health ocials with appropriate saeguards toprotect sensitive inormation and personal identiers.

Lead ederal agencies: HHS (CDC and Health Resources andServices Administration [HRSA]), Bureau o Prisons (BOP),and DHS (Immigration and Customs Enorcement [ICE]).

Suggested collaborators: state B program directors, Bcontrollers, B program surveillance coordinators, state bor-der health oces, NCA, and private and state public healthlaboratories.

Prblem 17

Data reported to the NSS, including data or XDRB cases, oten are not ully validated or accuracy andcompleteness.

objective 17.1

Develop a plan to determine and assure completeness andaccuracy o all reported B data, including those or XDR B

cases (domestic).

Acti Steps

17.1.1. Review the data currently required or reports ocompleteness o inormation collection or each variablethat is requested o state B programs by NSS and expandthese reports to refect critical inormation pertinent to XDRB (e.g., initial and nal DS results and initial treatmentstrategy).

17.1.2. Conduct site visits or standardized surveys to reviewcurrent surveillance procedures or state and local healthdepartments and identiy opportunities or improvement.

17.1.3. Develop a standardized plan to validate Report oVeried Case o B (RVC) data among persons with caseso MDR B and XDR B, using medical and clinic recordreview at the local reporting area.

Lead ederal agencies: HHS (CDC).Suggested collaborators: state B program directors, B

controllers and surveillance coordinators, NCA, private com-mercial laboratories, and state public health laboratories.

Prblem 18

For 66% o MDR B cases reported to the NSS during20002006, DS results were incomplete and not sucient toestimate the proportion o XDR B among MDR cases, and20% o MDR B cases lacked inormation about susceptibilityto any o the second-line drugs.**

objective 18.1

Increase testing or and reporting o DS results to theNSS (domestic).

Acti Steps

18.1.1. Analyze annually the completeness o second-linedrug-susceptibility testing or all MDRM. tuberculosisisolateby state and contact each state with less than 100% completeness or second-line drug-susceptibility testing.

18.1.2. Determine whether incomplete DS data are theresult o incomplete testing or incomplete reporting.

18.1.3. Establish a notiication system through whichCDCs Division o uberculosis Elimination (DBE) programconsultants are alerted to visit state B programs to discussimprovements in drug-susceptibility testing and reportingincluding review o instructions or reporting DS results tothe current RVC and the newly-ormed MDR B and XDRB national registry.

18.1.4. Develop a process through which routine requestsor missing DS results or MDR B cases are requested romstate B programs.

18.1.5. Develop programs to ensure that personnel at the

local and state B programs are adequately trained in necessaryprocedures and reporting requirements or drug-susceptibilitytesting.


controllers and surveillance coordinators, NCA, private andstate public health laboratories, and APHL.

Prblem 19

Laboratory reporting o DS results to the state healthdepartment is not standardized across the United States.

objective 19.1

Standardize laboratory reporting to the state health depart-ments by state and private laboratories throughout the UnitedStates (domestic).

** Percentages are based on reported drug-susceptibility test results in the 2006NSS database. Adequate testing or XDR B uses the WHO denition: Bthat is resistant 1) to isoniazid and riampin and 2) to any fuoroquinoloneand at least one o three injectable second-line drugs (amikacin, kanamycinor capreomycin).


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Acti Steps

19.1.1. Convene a working group o B program and labo-ratory experts to develop a standardized ormat or laboratoryreporting. Disseminate the recommended reporting methodto B programs and public health and private laboratories viatheir proessional associations.


controllers and surveillance coordinators, NCA, private andstate public health laboratories, and APHL.

Prblem 20

Active case-nding procedures or XDR B and MDR Bat the state and local level are not standardized.

objective 20.1

Develop standard guidelines or state and local B programsto ensure prompt identication and reporting o newly diag-nosed cases o XDR B and MDR B (domestic).

Acti Steps

20.1.1. Review case-nding and reporting procedures amonglocal and state B programs and evaluate their eectivenessand promptness.

20.1.2. Convene a working group o state B programpersonnel to develop standardized guidelines or prompt casending and reporting at the state and local level.

20.1.3. Develop guidelines or contact tracing during inves-tigations o XDR B patients (see Problem 26) that acilitaterapid identication o close contacts at highest risk or activedisease.

Lead ederal agencies: HHS (CDC), BOP, and DHS(ICE).

Suggested collaborators: state B program directors, Bcontrollers and surveillance coordinators, NCA, and privateand state public health laboratories.

Prblem 21

Certain groups o oreign-born persons, persons living incorrectional acilities, and marginalized persons (i.e., personswho are isolated, excluded, or alienated rom mainstreamsociety) are at increased risk or B and XDR B.

objective 21.1

Enhance surveillance or MDR B and XDR B amongrisk groups o oreign-born persons, incarcerated persons, andother marginalized at-risk persons (domestic).

Acti Steps

21.1.1. Develop procedures or enhanced B disease surveil-lance among inmates who are either oreign-born or belong toother groups with high rates o tuberculosis who have residedoutside the United States or Canada or >6 months beoretheir incarceration.

21.1.2. Develop guidelines or medical ollow-up and reerrao persons with abnormal chest radiographs or microbiologicdiagnosis and treatment or B during incarceration and aterrelease.

21.1.3. Develop recommendations and guidelines or diag-nosis, treatment, and medical management o incoming andexisting inmates, transers, and those who are released romprison.

21.1.4. Contribute to the establishment o partner programsor evaluation o routine intake processes and surveillance usedby all types o correctional acilities and detention centers to

acilitate implementation o the recommended action plansor identication and management o XDR B.Lead ederal agencies: HHS (CDC), DHS (ICE and

Customs and Border Protection [CBP]), and U.S. Departmeno Justice (DOJ) (BOP and USMS).

Suggested collaborators: state B program directors, Bcontrollers and surveillance coordinators, NCA, correctionahealth systems administrators and providers, and private andstate public health laboratories.

Prblem 22

Reporting criteria or national surveillance o B currently

exclude patients who are expected to be in the United Statesor


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Prblem 23

In areas where XDR B has been identied, the actualprevalence o resistance to rst- and second-line drugs amongB cases is unknown.

objective 23.1

Estimate the prevalence o resistance to rst- and second-linedrugs among reported B cases (international).

Acti Steps

23.1.1. Conduct rapid drug-susceptibility surveys in areaswhere XDR B has been identied.

23.1.2. Contribute to the development o internationalguidelines or standardized drug-susceptibility testing.

23.1.3. In collaboration with international partners, identiybarriers to conducting drug-susceptibility testing and developsolutions to overcome these obstacles.

Lead ederal agencies: HHS (CDC) and USAID.Suggested collaborators: WHO, national health ministries,

supranational reerence laboratories, and IUALD.

objective 23.2

Increase capacity to perorm sustained drug-susceptibilitytesting on a routine basis and develop procedures and meth-ods or systematic recording and tracking o data trends(international).

Acti Steps

23.2.1. Develop national B registries/surveillance systemsthat include DS results or each case.

23.2.2. Identiy barriers to increasing capacity or drug-susceptibility testing in resource-limited settings.

23.2.3. Increase laboratory capacity (see Problems 2, 3, 6,and 10).

23.2.4. Support clinical evaluation o novel rapid diagnostictools and drug-susceptibility testing (see Problem 15).

Lead ederal agencies: HHS (CDC) and USAID.Suggested collaborators: WHO, national health ministries,

APHL, and IUALD.

Prblem 24

Te risk actors or and transmission dynamics o XDRB in domestic and international settings are not completelyunderstood.

objective 24.1

Determine global epidemiologic proles and transmissiondynamics o XDR B in dierent geographic areas (domesticand international).

Acti Steps

24.1.1. Conduct retrospective analyses o epidemiologic andgenotyping data and linkages rom existing XDR B contacinvestigations and national genotyping databases.

24.1.2. Develop an approach or regular and systematicanalysis o national genotyping data or XDRM. tuberculosisisolates.

24.1.3. Compare drug-resistance proles and treatmenthistories among previously treated and newly diagnosed caseso drug-resistant B and establish the proportion o XDR Band MDR B among these dierent patient groups.

24.1.4. Determine and report the relationship between viru-lence actors identied or XDRM. tuberculosisand clinicadisease maniestation o XDR B (see Problem 52).

Lead ederal agencies: HHS (CDC and NIH).Suggested collaborators: state and local health departments

WHO, and national health ministries.

objective 24.2

Determine the proportion o XDR B cases occurringamong newly diagnosed and previously treated B cases, andhow this distribution varies by geographic region and withinseparate patient groups (domestic).

Acti Steps

24.2.1. Conduct retrospective analyses o patterns o drugresistance and treatment histories or MDR B and XDR Bcases rom national surveillance system and cohort studies toidentiy risk actors or the development o secondary XDR

B.24.2.2. Design multisite prospective studies to evaluate theimpact o treatment strategies on the development and clinicaoutcomes or MDR B and XDR B patients on the basis othe results rom retrospective analyses o relevant cohorts.

Lead ederal agencies: HHS (CDC and NIH).Suggested collaborators: state and local health departments

public health laboratories, private physicians, and academia.

objective 24.3

Describe transmission dynamics o MDR B and XDR B(domestic).

Acti Steps

24.3.1. Analyze data rom existing XDR B contact investi-gations and national genotyping data to identiy actors drivingthe transmission o XDR B in high and low B incidencesettings.

Lead ederal agencies: HHS (CDC).Suggested collaborators: state and local health departments.


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objective 24.4

Identiy strains o XDRM. tuberculosisthat are associatedwith increased transmissibility and virulence (domestic).

Acti Steps

24.4.1. Conduct retrospective in-depth analyses o XDR

B cases or which linked clinical and M. tuberculosisstraingenotyping inormation is available rom national and othergenotyping databases.

24.4.2. Develop protocols to ollow these cases prospec-tively and to add new cases to the cohort as they receive adiagnosis.

Lead ederal agencies: HHS (CDC and NIH).Suggested collaborators: state and local health departments,

private and state public health laboratories, and APHL.

Prblem 25

Te survival rates among patients with B that is resistantto rst- and second-line therapeutics have not been adequatelyanalyzed, and host/pathogen determinants o survival, includ-ing the eect o co-morbidities, remain to be elucidated.

objective 25.1

Conduct studies to identiy determinants o survival amongMDR B and XDR B patients, and how survival varies byhost and pathogen actors (domestic and international).

Acti Steps

25.1.1. Conduct retrospective analyses o national surveil-lance data and other cohort studies to understand dierences

in and actors aecting survival among drug-susceptible andMDR B and XDR B patients.

25.1.2. Design multisite prospective studies o treatmentpractices and other actors that aect clinical outcomes orMDR B and XDR B patient on the basis o results romretrospective analyses in relevant cohorts.

Lead ederal agencies: HHS (CDC and NIH) and USAID.Suggested collaborators: DOS, state and local health depart-

ments, WHO, national health ministries, IUALD, andacademia.

Prblem 26

Methods or detecting and documenting outbreaks o XDRB both domestically and internationally are not currentlyoptimized to allow a rapid response.

objective 26.1

Improve speed and accuracy o detection and investigationo MDR B and XDR B outbreaks in the United Statesto include rapid identication o risk actors or transmis-

sion and recommendations to interrupt urther transmission(domestic).

Acti Steps

26.1.1. Develop systems to use surveillance data in combi-nation with strain genotyping or detection o MDR B and

XDR B transmission events immediately as they becomeknown to the local B clinic or local provider.

26.1.2. Establish rapid and enhanced procedures or reporting o MDR B and XDR B cases to CDC by B controllerand or identication and reporting o MDR B and XDRB clusters on the basis o monthly review o the genotypingdatabase combined with the RVC.

26.1.3. Expand processes available or triggering rapidinvestigation o B clusters to include MDR B and XDR Bthrough generation o MDR B and XDR B cluster reportsto be shared among DBE senior sta; establish proceduresto alert the respective State B Controllers and other relevant

interjurisdictional areas and rapidly review available data toprioritize on-site responses.

26.1.4. Establish plans to initiate case contact investigationsthrough state B programs and establish procedures or reporting o aggregate data (numbers o cases, contacts, numberstested, numbers treated or LBI and numbers completingtreatment) to DBE or each contact investigation o an MDRB and XDR B patient.

26.1.5. Develop policies to ensure complete evaluation andollow-up or all close and high-priority contacts o MDRB AND XDR B cases i state or local health departmentsare unable to complete contact investigations without outsideassistance.

26.1.6. Develop a ederal plan with clearly dened roleswithin and among ederal agencies to allow identication ointerjurisdictional issues in the tracing and management oMDR B and XDR B cases to ensure rapid and coordinatedmanagement o patients that travel to and rom, or within theUnited States.

Lead ederal agencies: HHS (CDC) and DHS.Suggested collaborators: state and local health departments

and state public health laboratories.

objective 26.2

Provide assistance to WHO and countries outside theUnited States or rapid investigation o MDR B and XDRB outbreaks, including the identication o risk actors ortransmission and the recommendation o responses to interrupttransmission and contain outbreaks (international).


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Acti Steps

26.2.1. Establish procedures or prioritization o invitedresponses to assist in the investigation o MDR B and XDR B cases by host countries on the basis o availableinormation.

26.2.2. Formulate goals and objectives or the outbreakresponse team that are consistent with the specic request orassistance by the host country.

26.2.3. Establish a rapid response team to investigate theoutbreak and dene procedures or communication betweenthe host countrys ministry o health, the CDC DirectorsEmergency Operation Center, DBE, and WHO that includeconsideration or potential large-scale interjurisdictional issuesthat will require rapid resolution.

Lead ederal agencies: HHS (CDC) and USAID.Suggested collaborators: DOS, WHO, and national health

ministries.

Ifecti CtrlBecause B is spread by the airborne route, anyone who

breathes air containing viable tubercle bacilli is at risk oracquiringM. tuberculosisinection. Tis includes persons caringor and exposed to inectious B patients, especially patientswithout an established diagnosis. o prevent the spread odisease and maintain the best possible care or patients, specialinection-control practices and procedures must be available.

Eective inection control depends on early detection anddiagnosis o B disease, prompt initiation o eective therapy,and airborne inection isolation to prevent urther diseasetransmission. Each institutional setting that might housepersons with undiagnosed B disease or in which B patientsare treated should have inection-control programs availablethat minimize the risk or B transmission, including MDRB and XDR B, to patients, workers, and others within theinstitutional setting.

Various inection-control strategies are available depend-ing on whether a setting will provide primary care or triageand reer patients with suspected or conrmed B disease.All inection-control strategies should be on the basis o athree-level hierarchy: administrative controls, environmental

controls, and personal respiratory protection. Combinations othese inection-control strategies have been demonstrated to beeective at preventing B transmission. However, these strat-egies are not implemented consistently, and their individualeectiveness and easibility are not well-characterized.

Prblem 27

Although administrative controls, environmental controls,and respiratory protection have been eective when used in

combination, ethical issues have prevented assessment o theirindividual eectiveness in settings in which B transmissionoccurs. Resulting knowledge gaps hamper eorts to prioritizeinterventions or optimal cost-benet in resource-limitedsettings.

objective 27.1Ensure dissemination and implementation o currently

recommended inection-control strategies across a range o high-risk institutional settings (e.g., health-care acilities, substanceabuse clinics, residential treatment centers, homeless sheltersand correctional and detention acilities) through education andregulatory programs (domestic and international).

Acti Steps

27.1.1. Conduct a public health inormation campaignto encourage dissemination o recommended B inection-control procedures to U.S. health-care settings (inpatient and

outpatient) that provide B care, institute measures to trackimplementation o these measures, and identiy barriers toimplementation.

27.1.2. In collaboration with high-burden country healthcare providers, identiy and prioritize B inection-controprocedures appropriate or health-care settings (inpatienand outpatient) in resource-limited areas where B care isprovided.

27.1.3. Provide regularly scheduled updates to CDCsinection-control guidelines or health-care settings and relateddocuments (e.g., guidelines or correctional and detentionacilities) (26,30) and provide clarication as needed.

27.1.4. Develop guidance statements on B prevention inHIV-inected and other immunocompromised health-careworkers.

27.1.5. Disseminate and implement recommendationsor use o airborne inection isolation rooms or known orsuspected B patients and use o local exhaust ventilation oraerosol generating procedures on these patients.

27.1.6. Disseminate and implement guidelines or selectionuse, and appropriate re-use o certied respiratory protectivedevices used to protect against inection with M. tuberculosiin domestic and international settings including those with

resource constraints.27.1.7. Disseminate, implement, and regularly update rec-ommendations or design, application, installation, monitoring, and maintenance o both upper air and in-duct ultraviolegermicidal irradiation (UVGI) xtures.

27.1.8. Develop guidelines or eective administrative andenvironmental measures to preventM. tuberculosistransmission in homeless shelters, community residences or specianeeds populations, correctional and detention acilities, and


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substance-abuse treatment centers. Guidelines are needed orcorrectional and detention acilities that can be applied inter-nationally; guidelines or domestic correctional and detentionacilities were published in 2006 (32) but might be relevantonly to other industrialized countries with similar correctionalsystems and similar B case rates.

27.1.9. Provide technical assistance to substance-abusecenters, shelters or the homeless, community residences orspecial needs populations, correctional and detention acilities,and health-care settings to determine the adequacy o localadministrative controls, environmental controls and respiratoryprotection to minimize transmission oM. tuberculosis.

27.1.10. Regularly interact and communicate with regulatoryagencies (e.g., Occupational Saety and Health Administration[OSHA]) and standard-setting organizations (e.g., the JointCommission [ormerly the Joint Commission on Accreditationo Healthcare Organizations (JCAHO)]; the American Societyo Heating, Rerigerating and Air-Conditioning Engineers[ASHRAE]; and the American Insti

mmwr plan to combat xdr

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