Please note: An erratum has been published for this issue To view the erratum, please click here Morbidity and Mortality Weekly Report Recommendations and Reports June 20, 2003 / Vol 52 / No RR-11 Treatment of Tuberculosis American Thoracic Society, CDC, and Infectious Diseases Society of America INSIDE: Continuing Education Examination department of health and human services Centers for Disease Control and Prevention MMWR CONTENTS The MMWR series of publications is published by the Epidemiology Program Office, Centers for Disease Control and Prevention (CDC), U.S Department of Health and Human Services, Atlanta, GA 30333 Purpose What’s New In This Document Summary 1 Introduction and Background 13 SUGGESTED CITATION Centers for Disease Control and Prevention Treatment of Tuberculosis, American Thoracic Society, CDC, and Infectious Diseases Society of America MMWR 2003;52(No RR-11):[inclusive page numbers] Organization and Supervision of Treatment 15 Drugs in Current Use 19 Principles of Antituberculosis Chemotherapy 32 Recommended Treatment Regimens 36 Practical Aspects of Treatment 42 Drug Interactions 45 Treatment in Special Situations 50 Centers for Disease Control and Prevention Julie L Gerberding, M.D., M.P.H Director David W Fleming, M.D Deputy Director for Public Health Science Dixie E Snider, Jr., M.D., M.P.H Associate Director for Science Management of Relapse, Treatment Failure, and Drug Resistance 66 10 Treatment Of Tuberculosis in Low-Income Countries: Recommendations and Guidelines of the WHO and the IUATLD 72 11 Research Agenda for Tuberculosis Treatment 74 Epidemiology Program Office Stephen B Thacker, M.D., M.Sc Director Office of Scientific and Health Communications John W Ward, M.D Director Editor, MMWR Series Suzanne M Hewitt, M.P.A Managing Editor, MMWR Series C Kay Smith-Akin, M.Ed Lead Technical Writer/Editor Lynne McIntyre, M.A.L.S Project Editor Beverly J Holland Lead Visual Information Specialist Malbea A Heilman Visual Information Specialist Quang M Doan Erica R Shaver Information Technology Specialists The following drugs, which are suggested for use in selected cases, are not approved by the Food and Drug Administration for treatment of tuberculosis: rifabutin, amikacin, kanamycin, moxifloxacin, gatifloxacin, and levofloxacin Michael Iseman, M.D., has indicated that he has a financial relationship with Ortho-McNeil, which manufactures Levaquin® The remaining preparers have signed a conflict of interest disclosure form that verifies no conflict of interest Vol 52 / RR-11 Recommendations and Reports Treatment of Tuberculosis American Thoracic Society, CDC, and Infectious Diseases Society of America Purpose The recommendations in this document are intended to guide the treatment of tuberculosis in settings where mycobacterial cultures, drug susceptibility testing, radiographic facilities, and second-line drugs are routinely available In areas where these resources are not available, the recommendations provided by the World Health Organization, the International Union against Tuberculosis, or national tuberculosis control programs should be followed What’s New In This Document • The responsibility for successful treatment is clearly assigned to the public health program or private provider, not to the patient • It is strongly recommended that the initial treatment strategy utilize patient-centered case management with an adherence plan that emphasizes direct observation of therapy • Recommended treatment regimens are rated according to the strength of the evidence supporting their use Where possible, other interventions are also rated • Emphasis is placed on the importance of obtaining sputum cultures at the time of completion of the initial phase of treatment in order to identify patients at increased risk of relapse • Extended treatment is recommended for patients with drug-susceptible pulmonary tuberculosis who have cavitation noted on the initial chest film and who have positive sputum cultures at the time months of treatment is completed • The roles of rifabutin, rifapentine, and the fluoroquinolones are discussed and a regimen with rifapentine in a once-a-week continuation phase for selected patients is described • Practical aspects of therapy, including drug administration, use of fixed-dose combination preparations, monitoring and management of adverse effects, and drug interactions are discussed This Official Joint Statement of the American Thoracic Society, CDC, and the Infectious Diseases Society of America was approved by the ATS Board of Directors, by CDC, and by the Council of the IDSA in October 2002 This report appeared in the American Journal of Respiratory and Critical Care Medicine (2003;167:603–62) and is being reprinted as a courtesy to the American Thoracic Society, the Infectious Diseases Society of America, and the MMWR readership • Treatment completion is defined by number of doses ingested, as well as the duration of treatment administration • Special treatment situations, including human immunodeficiency virus infection, tuberculosis in children, extrapulmonary tuberculosis, culture-negative tuberculosis, pregnancy and breastfeeding, hepatic disease and renal disease are discussed in detail • The management of tuberculosis caused by drug-resistant organisms is updated • These recommendations are compared with those of the WHO and the IUATLD and the DOTS strategy is described • The current status of research to improve treatment is reviewed Summary Responsibility for Successful Treatment The overall goals for treatment of tuberculosis are 1) to cure the individual patient, and 2) to minimize the transmission of Mycobacterium tuberculosis to other persons Thus, successful treatment of tuberculosis has benefits both for the individual patient and the community in which the patient resides For this reason the prescribing physician, be he/she in the public or private sector, is carrying out a public health function with responsibility not only for prescribing an appropriate regimen but also for successful completion of therapy Prescribing physician responsibility for treatment completion is a fundamental principle in tuberculosis control However, given a clear understanding of roles and responsibilities, oversight of treatment may be shared between a public health program and a private physician Organization and Supervision of Treatment Treatment of patients with tuberculosis is most successful within a comprehensive framework that addresses both clinical and social issues of relevance to the patient It is essential that treatment be tailored and supervision be based on each patient’s clinical and social circumstances (patient-centered care) Patients may be managed in the private sector, by public health departments, or jointly, but in all cases the health department is ultimately responsible for ensuring that adequate, appropriate diagnostic and treatment services are available, and for monitoring the results of therapy MMWR It is strongly recommended that patient-centered care be the initial management strategy, regardless of the source of supervision This strategy should always include an adherence plan that emphasizes directly observed therapy (DOT), in which patients are observed to ingest each dose of antituberculosis medications, to maximize the likelihood of completion of therapy Programs utilizing DOT as the central element in a comprehensive, patient-centered approach to case management (enhanced DOT) have higher rates of treatment completion than less intensive strategies Each patient’s management plan should be individualized to incorporate measures that facilitate adherence to the drug regimen Such measures may include, for example, social service support, treatment incentives and enablers, housing assistance, referral for treatment of substance abuse, and coordination of tuberculosis services with those of other providers Recommended Treatment Regimens The recommended treatment regimens are, in large part, based on evidence from clinical trials and are rated on the basis of a system developed by the United States Public Health Service (USPHS) and the Infectious Diseases Society of America (IDSA) The rating system includes a letter (A, B, C, D, or E) that indicates the strength of the recommendation and a roman numeral (I, II, or III) that indicates the quality of evidence supporting the recommendation (Table 1) There are four recommended regimens for treating patients with tuberculosis caused by drug-susceptible organisms Although these regimens are broadly applicable, there are modifications that should be made under specified circumstances, described subsequently Each regimen has an initial phase of months followed by a choice of several options for the continuation phase of either or months The recommended regimens together with the number of doses specified by the regimen are described in Table The initial phases are TABLE Infectious Diseases Society of America/United States Public Health Service rating system for the strength of treatment recommendations based on quality of evidence* Strength of the recommendation A Preferred; should generally be offered B Alternative; acceptable to offer C Offer when preferred or alternative regimens cannot be given D Should generally not be offered E Should never be offered Quality of evidence supporting the recommendation I At least one properly randomized trial with clinical end points II Clinical trials that either are not randomized or were conducted in other populations III Expert opinion * Reprinted by permission from Gross PA, Barrett TL, Dellinger EP, Krause PJ, Martone WJ, McGowan JE Jr, Sweet RL, Wenzel RP Clin Infect Dis 1994;18:421 June 20, 2003 denoted by a number (1, 2, 3, or 4) and the continuation phases that relate to the initial phase are denoted by the number plus a letter designation (a, b, or c) Drug doses are shown in Tables 3, 4, and The general approach to treatment is summarized in Figure Because of the relatively high proportion of adult patients with tuberculosis caused by organisms that are resistant to isoniazid, four drugs are necessary in the initial phase for the 6-month regimen to be maximally effective Thus, in most circumstances, the treatment regimen for all adults with previously untreated tuberculosis should consist of a 2-month initial phase of isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB) (Table 2, Regimens 1–3) If (when) drug susceptibility test results are known and the organisms are fully susceptible, EMB need not be included For children whose visual acuity cannot be monitored, EMB is usually not recommended except when there is an increased likelihood of the disease being caused by INH-resistant organisms (Table 6) or when the child has “adult-type” (upper lobe infiltration, cavity formation) tuberculosis If PZA cannot be included in the initial phase of treatment, or if the isolate is resistant to PZA alone (an unusual circumstance), the initial phase should consist of INH, RIF, and EMB given daily for months (Regimen 4) Examples of circumstances in which PZA may be withheld include severe liver disease, gout, and, perhaps, pregnancy EMB should be included in the initial phase of Regimen until drug susceptibility is determined The initial phase may be given daily throughout (Regimens and 4), daily for weeks and then twice weekly for weeks (Regimen 2), or three times weekly throughout (Regimen 3) For patients receiving daily therapy, EMB can be discontinued as soon as the results of drug susceptibility studies demonstrate that the isolate is susceptible to INH and RIF When the patient is receiving less than daily drug administration, expert opinion suggests that EMB can be discontinued safely in less than months (i.e., when susceptibility test results are known), but there is no evidence to support this approach Although clinical trials have shown that the efficacy of streptomycin (SM) is approximately equal to that of EMB in the initial phase of treatment, the increasing frequency of resistance to SM globally has made the drug less useful Thus, SM is not recommended as being interchangeable with EMB unless the organism is known to be susceptible to the drug or the patient is from a population in which SM resistance is unlikely The continuation phase (Table 2) of treatment is given for either or months The 4-month continuation phase should be used in the large majority of patients The 7-month Vol 52 / RR-11 Recommendations and Reports TABLE Drug regimens for culture-positive pulmonary tuberculosis caused by drug-susceptible organisms Initial phase Interval and doses‡ (minimal duration) Regimen Drugs INH RIF PZA EMB Seven days per week for 56 doses (8 wk) or d/wk for 40 doses (8 wk)¶ INH RIF PZA EMB Continuation phase Regimen Drugs 1a INH/RIF 1b 1c** Seven days per week for 14 doses (2 wk), then twice weekly for 12 doses (6 wk) or d/wk for 10 doses (2 wk),¶ then twice weekly for 12 doses (6 wk) INH RIF PZA EMB INH RIF EMB Interval and doses‡§ (minimal duration) Range of total doses (minimal duration) Rating* (evidence)† HIV– HIV+ 182–130 (26 wk) A (I) A (II) INH/RIF INH/RPT Seven days per week for 126 doses (18 wk) or d/wk for 90 doses (18 wk)¶ Twice weekly for 36 doses (18 wk) Once weekly for 18 doses (18 wk) 92–76 (26 wk) 74–58 (26 wk) A (I) B (I) A (II)# E (I) 2a 2b** INH/RIF INH/RPT Twice weekly for 36 doses (18 wk) Once weekly for 18 doses (18 wk) 62–58 (26 wk) 44–40 (26 wk) A (II) B (I) B (II)# E (I) Three times weekly for 24 doses (8 wk) 3a INH/RIF Three times weekly for 54 doses (18 wk) 78 (26 wk) B (I) B (II) Seven days per week for 56 doses (8 wk) or d/wk for 40 doses (8 wk)¶ 4a INH/RIF 273–195 (39 wk) C (I) C (II) 4b INH/RIF Seven days per week for 217 doses (31 wk) or d/wk for 155 doses (31 wk)¶ Twice weekly for 62 doses (31 wk) 118–102 (39 wk) C (I) C (II) Definition of abbreviations: EMB = Ethambutol; INH = isoniazid; PZA = pyrazinamide; RIF = rifampin; RPT = rifapentine * Definitions of evidence ratings: A = preferred; B = acceptable alternative; C = offer when A and B cannot be given; E = should never be given † Definition of evidence ratings: I = randomized clinical trial; II = data from clinical trials that were not randomized or were conducted in other populations; III = expert opinion ‡ When DOT is used, drugs may be given days/week and the necessary number of doses adjusted accordingly Although there are no studies that compare five with seven daily doses, extensive experience indicates this would be an effective practice § Patients with cavitation on initial chest radiograph and positive cultures at completion of months of therapy should receive a 7-month (31 week; either 217 doses [daily] or 62 doses [twice weekly]) continuation phase ¶ Five-day-a-week administration is always given by DOT Rating for day/week regimens is AIII # Not recommended for HIV-infected patients with CD4+ cell counts 100 18 After reading this report, I am confident I can describe how to treat TB in special situations A Strongly agree B Agree C Neither agree nor disagree D Disagree E Strongly disagree 15 How much time did you spend reading this report and completing the exam? A 2.0 hours but 3.0 hours but 4.0 hours 19 After reading this report, I am confident I can describe precautions regarding treatment regimens for TB A Strongly agree B Agree C Neither agree nor disagree D Disagree E Strongly disagree 16 After reading this report, I am confident I can describe the principles of antituberculosis chemotherapy A Strongly agree B Agree C Neither agree nor disagree D Disagree E Strongly disagree 20 After reading this report, I am confident I can describe how to manage disease relapse, treatment failure, and drug resistance A Strongly agree B Agree C Neither agree nor disagree D Disagree E Strongly disagree (Continued on pg CE-4) Date I Completed Exam ]E ]E ]E ]E ]E ]E ]E ]E ]E ]E ]E ]E [ ]F [ [ [ [ [ [ [ [ [ [ [ [ ]D ]D ]D ]D ]D ]D ]D ]D ]D ]D ]D ]D ]D [ [ [ [ [ [ [ [ [ [ [ [ [ ]C ]C ]C ]C ]C ]C ]C ]C ]C ]C ]C ]C ]C [ [ [ [ [ [ [ [ [ [ [ [ [ ]B ]B ]B ]B ]B ]B ]B ]B ]B ]B ]B ]B ]B [ [ [ [ [ [ [ [ [ [ [ [ [ ]A ]A ]A ]A ]A ]A ]A ]A ]A ]A ]A ]A ]A [ [ [ [ [ [ [ [ [ [ [ [ [ ]E ]E [ ]F ]E ]E ]E [ ]F [ [ [ [ [ [ ]E 15 16 17 18 19 20 21 22 23 24 25 26 27 [ ]E ]D ]D ]D ]D ]D ]D ]D ]D ]D ]D ]D ]D ]D ]D [ [ [ [ [ [ [ [ [ [ [ [ [ [ ]C ]C ]C ]C ]C ]C ]C ]C ]C ]C ]C ]C ]C ]C [ [ [ [ [ [ [ [ [ [ [ [ [ [ Signature ]B ]B ]B ]B ]B ]B ]B ]B ]B ]B ]B ]B ]B ]B [ [ [ [ [ [ [ [ [ [ [ [ [ [ ]A ]A ]A ]A ]A ]A ]A ]A ]A ]A ]A ]A ]A ]A [ [ [ [ [ [ [ [ [ [ [ [ [ [ 10 11 12 13 14 E-Mail Address Fill in the appropriate blocks to indicate your answers Remember, you must answer all of the questions to receive continuing education credit! Fax Number Phone Number ZIP Code State Apartment Street Address or P.O Box or City Suite Check One CME Credit CEU Credit CNE Credit CHES Credit First Name Last Name To receive continuing education credit, you must provide your contact information; indicate your choice of CME, CEU, CNE, or CHES credit; answer all of the test questions; sign and date this form or a photocopy; submit your answer form by June 20, 2006 Failure to complete these items can result in a delay or rejection of your application for continuing education credit Treatment of Tuberculosis American Thoracic Society, CDC, and Infectious Diseases Society of America MMWR Response Form for Continuing Education Credit June 20, 2006/Vol 52/No RR-11 Detach or photocopy CE-4 MMWR June 20, 2003 21 The objectives are relevant to the goal of this report A Strongly agree B Agree C Neither agree nor disagree D Disagree E Strongly disagree 25 The content of this activity was appropriate for my educational needs A Strongly agree B Agree C Neither agree nor disagree D Disagree E Strongly disagree 22 The teaching strategies used in this report (text, figures, boxes, and tables) were useful A Strongly agree B Agree C Neither agree nor disagree D Disagree E Strongly disagree 26 The availability of continuing education credit influenced my decision to read this report A Strongly agree B Agree C Neither agree nor disagree D Disagree E Strongly disagree 23 Overall, the presentation of the report enhanced my ability to understand the material A Strongly agree B Agree C Neither agree nor disagree D Disagree E Strongly disagree 27 How did you learn about this continuing education activity? 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Reports Treatment of Tuberculosis American Thoracic Society, CDC, and Infectious Diseases Society of America Purpose The recommendations in this document are intended to guide the treatment of tuberculosis. .. and management of adverse effects, and drug interactions are discussed This Official Joint Statement of the American Thoracic Society, CDC, and the Infectious Diseases Society of America was approved... the American Thoracic Society, the Infectious Diseases Society of America, and the MMWR readership • Treatment completion is defined by number of doses ingested, as well as the duration of treatment