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 Purpose ............................................................................... 1 Epidemiology Program Office, Centers for Disease What’s New In This Document ............................................. 1 Control and Prevention (CDC), U.S. Department of Health and Human Services, Atlanta, GA 30333. Summary ............................................................................. 1 1. Introduction and Background ......................................... 13 SUGGESTED CITATION 2. Organization and Supervision of Treatment ................... 15 Centers for Disease Control and Prevention. 3. Drugs in Current Use ..................................................... 19 Treatment of Tuberculosis, American Thoracic 4. Principles of Antituberculosis Chemotherapy .................. 32 Society, CDC, and Infectious Diseases Society of America. MMWR 2003;52(No. RR-11):[inclusive 5. Recommended Treatment Regimens .............................. 36 page numbers]. 6. Practical Aspects of Treatment........................................ 42 7. Drug Interactions ........................................................... 45 8. Treatment in Special Situations ...................................... 50 Centers for Disease Control and Prevention 9. Management of Relapse, Treatment Failure, Julie L. Gerberding, M.D., M.P.H. and Drug Resistance ....................................................... 66 Director 10. Treatment Of Tuberculosis in Low-Income Countries: David W. Fleming, M.D. Recommendations and Guidelines of the WHO Deputy Director for Public Health Science and the IUATLD ............................................................... 72 Dixie E. Snider, Jr., M.D., M.P.H. 11. Research Agenda for Tuberculosis Treatment ............... 74 Associate Director for Science 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 The following drugs, which are suggested for use in selected cases, are not approved by the Food and Drug Administration for treatment Erica R. Shaver of tuberculosis: rifabutin, amikacin, kanamycin, moxifloxacin, Information Technology Specialists 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 1 Treatment of Tuberculosis American Thoracic Society, CDC, and Infectious Diseases Society of America Purpose • Treatment completion is defined by number of doses ingested, as well as the duration of treatment administra- The recommendations in this document are intended to tion. guide the treatment of tuberculosis in settings where myco- • Special treatment situations, including human immuno- bacterial cultures, drug susceptibility testing, radiographic fa- deficiency virus infection, tuberculosis in children, cilities, and second-line drugs are routinely available. In areas extrapulmonary tuberculosis, culture-negative tuberculo- where these resources are not available, the recommendations sis, pregnancy and breastfeeding, hepatic disease and provided by the World Health Organization, the International renal disease are discussed in detail. Union against Tuberculosis, or national tuberculosis control • The management of tuberculosis caused by drug-resistant programs should be followed. organisms is updated. • These recommendations are compared with those of the What’s New In This Document WHO and the IUATLD and the DOTS strategy is • The responsibility for successful treatment is clearly described. assigned to the public health program or private provider, • The current status of research to improve treatment is not to the patient. reviewed. • It is strongly recommended that the initial treatment strat- egy utilize patient-centered case management with an Summary adherence plan that emphasizes direct observation of therapy. Responsibility for Successful Treatment • Recommended treatment regimens are rated according to The overall goals for treatment of tuberculosis are 1) to cure the strength of the evidence supporting their use. Where the individual patient, and 2) to minimize the transmission of possible, other interventions are also rated. Mycobacterium tuberculosis to other persons. Thus, successful • Emphasis is placed on the importance of obtaining treatment of tuberculosis has benefits both for the individual sputum cultures at the time of completion of the initial patient and the community in which the patient resides. For phase of treatment in order to identify patients at increased this reason the prescribing physician, be he/she in the public risk of relapse. or private sector, is carrying out a public health function with • Extended treatment is recommended for patients with responsibility not only for prescribing an appropriate regimen drug-susceptible pulmonary tuberculosis who have cavi- but also for successful completion of therapy. Prescribing phy- tation noted on the initial chest film and who have posi- sician responsibility for treatment completion is a fundamen- tive sputum cultures at the time 2 months of treatment is tal principle in tuberculosis control. However, given a clear completed. understanding of roles and responsibilities, oversight of treat- • The roles of rifabutin, rifapentine, and the fluoroquino- ment may be shared between a public health program and a lones are discussed and a regimen with rifapentine in a private physician. once-a-week continuation phase for selected patients is described. Organization and Supervision of Treatment • Practical aspects of therapy, including drug administra- Treatment of patients with tuberculosis is most successful tion, use of fixed-dose combination preparations, moni- within a comprehensive framework that addresses both clini- toring and management of adverse effects, and drug cal and social issues of relevance to the patient. It is essential interactions are discussed. that treatment be tailored and supervision be based on each patient’s clinical and social circumstances (patient-centered This Official Joint Statement of the American Thoracic Society, CDC, care). Patients may be managed in the private sector, by public and the Infectious Diseases Society of America was approved by the health departments, or jointly, but in all cases the health ATS Board of Directors, by CDC, and by the Council of the IDSA in October 2002. This report appeared in the American Journal of department is ultimately responsible for ensuring that adequate, Respiratory and Critical Care Medicine (2003;167:603–62) and is being appropriate diagnostic and treatment services are available, and reprinted as a courtesy to the American Thoracic Society, the Infectious for monitoring the results of therapy. Diseases Society of America, and the MMWR readership. 2 MMWR June 20, 2003 It is strongly recommended that patient-centered care be denoted by a number (1, 2, 3, or 4) and the continuation the initial management strategy, regardless of the source of phases that relate to the initial phase are denoted by the num- supervision. This strategy should always include an adherence ber plus a letter designation (a, b, or c). Drug doses are shown plan that emphasizes directly observed therapy (DOT), in in Tables 3, 4, and 5. which patients are observed to ingest each dose of antituber- The general approach to treatment is summarized in Figure 1. culosis medications, to maximize the likelihood of comple- Because of the relatively high proportion of adult patients with tion of therapy. Programs utilizing DOT as the central element tuberculosis caused by organisms that are resistant to isoniazid, in a comprehensive, patient-centered approach to case man- four drugs are necessary in the initial phase for the agement (enhanced DOT) have higher rates of treatment 6-month regimen to be maximally effective. Thus, in most completion than less intensive strategies. Each patient’s man- circumstances, the treatment regimen for all adults with pre- agement plan should be individualized to incorporate mea- viously untreated tuberculosis should consist of a 2-month sures that facilitate adherence to the drug regimen. Such initial phase of isoniazid (INH), rifampin (RIF), pyrazina- measures may include, for example, social service support, treat- mide (PZA), and ethambutol (EMB) (Table 2, Regimens ment incentives and enablers, housing assistance, referral for 1–3). If (when) drug susceptibility test results are known and treatment of substance abuse, and coordination of tuberculo- the organisms are fully susceptible, EMB need not be included. sis services with those of other providers. For children whose visual acuity cannot be monitored, EMB is usually not recommended except