1. TREATMENT OF TUBERCULOSIS, 2003
American Thoracic Society Centers for Disease Control and Prevention Infectious Diseases Society of America
Division of Tuberculosis Elimination
Centers for Disease Control and Prevention

2. Why a New TB Treatment Statement?
Last TB treatment statement published in 1994
Several new drugs available e.g., rifapentine, newer fluoroquinolones
New research information on treatment regimens

3. What’s New? (1)
Provider/program responsibility for successful treatment, not the patient
Patient-centered case management with emphasis on directly observed therapy (DOT)
Evidence-based ratings of treatment options
Role of two-month sputum cultures to identify patients at increased relapse risk

4. What’s New? (2)
Extend treatment for patients with drug-susceptible pulmonary TB at increased risk for relapse
Role of new drugs (rifabutin, rifapentine, and fluoroquinolones)
Practical aspects of therapy: drug administration, fixed-dose combinations, adverse effects monitoring and management, and drug interactions

5. What’s New? (3)
Treatment completion defined primarily by number of doses ingested within specified time
Description of special treatment situations:
HIV/AIDS
Children
Extrapulmonary TB
Culture-negative TB
Pregnancy and breast feeding
Hepatic and renal disease

6. What’s New? (4) Updated guidelines for management of drug-resistant TB
Recommendations compared with those of the World Health Organization (WHO) and the International Union Against TB and Lung Disease (IUATLD); WHO DOTS strategy described
Current research status to improve treatment

7. Fundamental Responsibility and Approach in TB Treatment
Provider (or program) responsible for prescribing appropriate regimen AND ensuring successful completion of therapy
Directly observed therapy (DOT) with patient-centered case management is preferred approach

8. Antituberculosis Drugs
First-Line Drugs
Second-Line Drugs
Isoniazid
Rifampin
Pyrazinamide
Ethambutol
Rifabutin*
Rifapentine
Streptomycin
Cycloserine
p-Aminosalicylic acid
Ethionamide
Amikacin or kanamycin*
Capreomycin
Levofloxacin*
Moxifloxacin*
Gatifloxacin*
* Not approved by the U.S. Food and Drug Administration for use in the treatment of TB

9. Drug Abbreviations Ethambutol EMB Isoniazid INH Pyrazinamide PZA
Rifampin RIF
Rifapentine RPT
Streptomycin SM

10. Role of New Drugs (1)
Rifabutin: For patients receiving medications having unacceptable interactions with rifampin (e.g., persons with HIV/AIDS)
Rifapentine: Used in once-weekly continuation phase for HIV-negative adults with drug-susceptible noncavitary TB and negative AFB smears at completion of initial phase of treatment

11. Role of New Drugs (2)
Fluoroquinolones (Levofloxacin, Moxifloxacin, Gatifloxacin): Used when
-first-line drugs not tolerated;
-strains resistant to RIF, INH, or EMB; or
-evidence of other resistance patterns with fluoroquinolone susceptibility

12. Factors Guiding Treatment Initiation
Epidemiologic information
Clinical, pathological, chest x-ray findings
Microscopic examination of acid-fast bacilli (AFB) in sputum smears
Nucleic acid amplification test (when performed)

13. When to Consider Treatment Initiation
Positive AFB smear
Treatment should not be delayed because of negative AFB smears if high clinical suspicion:
History of cough and weight loss
Characteristic findings on chest x-ray
Emmigration from a high-incidence country

14. Baseline Diagnostic Examinations for TB
Chest x-ray
Sputum specimens (= 3 obtained 8-24 hours apart) for AFB microscopy and mycobacterial cultures
Routine drug-susceptibility testing for INH, RIF, and EMB on initial positive culture

15. Other Examinations to Conduct When TB Treatment Is Initiated (1)
Counseling and testing for HIV infection
CD4+ T-lymphocyte count for HIV-positive persons
Hepatitis B and C serologic tests, if risks present

16. Other Examinations to Conduct When TB Treatment Is Initiated (2)
Measurements of aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin, alkaline phosphatase, serum creatinine, and platelet count
Visual acuity and color vision tests (when EMB used)

17. IDSA/USPHS* Rating System for Treatment Recommendations
Strength of the Recommendation
Quality of Supporting Evidence
A. Preferred; should generally be offered
B. Alternative; acceptable to offer
C. Offer when preferred/ alternative regimens cannot be given
D. Should generally not be offered
E. Should never be offered
I. At least one properly randomized trial with clinical endpoints
II. Clinical trials that either are not randomized or were conducted in other populations
III. Expert opinion
*IDSA-Infectious Diseases Society of America; USPHS-U.S. Public Health Service

18. Treatment Regimens
Four regimens recommended for treatment of culture-positive TB, with different options for dosing intervals in continuation phase
Initial phase: standard four drug regimens (INH, RIF, PZA, EMB), for 2 months, (except one regimen that excludes PZA)
Continuation phase: additional 4 months or (7 months for some patients)

19. Why Extend Continuation-Phase Treatment for 3 Months?
Cavitary disease and positive sputum culture at 2 months associated with increased relapse in clinical trials
Extended continuation phase decreased relapses in silicotuberculosis (from 20% to 3%)

20. When to Extend Continuation-Phase Treatment for 3 Months?
Cavitary pulmonary disease and positive sputum cultures at completion of initial phase
Initial phase excluded PZA
Once-weekly INH and rifapentine started in continuation phase and sputum specimen collected at the end of initial phase is culture positive
HIV-infected with positive 2-month sputum culture

21. Algorithm to Guide Duration of Continuation-Phase Treatment for Culture-Positive TB Patients
High clinical suspicion for active TB
Place patient on initial-phase regimen:
INH, RIF, EMB, PZA for 2 months
Is specimen collected at end of initial phase (2 months) culture positive? NO
YES
Give continuation-phase treatment of INH/RIF daily or twice weekly for 4 months

22. Algorithm to Guide Duration of Continuation-Phase Treatment for Culture-Positive TB Patients (Continued)
Was there cavitation on initial CXR? NO
YES
Is the patient HIV positive?
Give continuation-phase treatment of INH/RIF daily or twice weekly for 7 months NO
YES
Give continuation- phase treatment of INH/RIF daily or twice weekly for 4 months
Give continuation- phase treatment of INH/RIF daily for 7 months

23. Treatment of Culture-Positive TB (1)
(Rated: AI in HIV-negative, AII in HIV-positive patients)
Initial Phase
2 months - INH, RIF, PZA, EMB daily (56 doses, within 8 weeks)
Continuation Phase
Options:
4 months - INH, RIF daily (126 doses, within 18 weeks)
4 months - INH, RIF twice / week (36 doses, within 18 weeks)
7 months - INH, RIF daily (217 doses, within 31 weeks)*
7 months - INH, RIF twice / week (62 doses, within 31 weeks)*
* Continuation phase increased to 7 months if initial chest x-ray shows cavitation and specimen collected at end of initial phase (2 months) is culture positive

24. Treatment of Culture-Positive TB (2)
Twice-Weekly Options (Rated: AII for HIV-negative, BII for HIV-positive patients*)
Initial Phase
0.5 months - INH, RIF, PZA, EMB daily (10-14 doses, within 2 weeks)
THEN
1.5 months - INH, RIF, PZA, EMB twice / week (12 doses, within 6 weeks)
Continuation Phase
Options:
4 months - INH, RIF twice / week (36 doses, within 18 weeks)
7 months - INH, RIF twice / week (62 doses, within 31 weeks)
* Regimen rated BII for HIV-positive patients with CD4+ T-lymphocytes cell count >100/µl. Not recommended for those with CD4+ T-lymphocytes cell count < 100/µl

25. Treatment of Culture-Positive TB (3)
Thrice-Weekly Options (Rated: BI for HIV-negative, BII for HIV-positive patients)
Initial Phase
2 months - INH, RIF, PZA, EMB 3 times / week (24 doses, within 8 weeks)
Continuation Phase
Options:
4 months - INH, RIF 3 times / week (54 doses, within 18 weeks)
2) 7 months - INH, RIF 3 times / week (93 doses, within 31 weeks)

26. Treatment of Culture-Positive TB (4)
Regimens without Pyrazinamide (Rated: CI for HIV-negative, CII for HIV-positive patients)
Initial Phase
2 months - INH, RIF, EMB daily (56 doses, within 8 weeks)
Continuation Phase
Options:
7 months - INH, RIF daily (217 doses, within 31 weeks)
2) 7 months - INH, RIF twice / week (62 doses, within 31 weeks)*
* Twice weekly dosing is not recommended for persons with CD4+ T-lymphocytes cell count < 100/µl

27. Algorithm to Guide Rifapentine (RPT) Use in Continuation Phase
Is the patient HIV positive? NO
YES
Not eligible for RPT
Was there cavitation on initial CXR? NO
YES
Not eligible for RPT
Was the sputum AFB smear positive at 2 months? NO
YES
Not eligible for RPT

28. Algorithm to Guide Rifapentine (RPT) Use in Continuation Phase (Continued)
Is RPT considered for treatment? NO
YES
Begin treatment with once-weekly INH/RPT
Give treatment of INH/RIF daily or twice weekly for 4 months
Is specimen collected at end of initial phase (2 months) culture positive? NO
YES
Continue treatment until 4 months of INH/RPT completed
Extend treatment with INH/RPT for total of 7 months

29. Treatment of Culture-Positive TB
Rifapentine in Continuation Phase (Rated: BI for HIV-negative*, EI for HIV-positive patients)
Initial Phase
Options:
2 months - INH, RIF, PZA, EMB daily (56 doses, within 8 weeks)
0.5 months - INH, RIF, PZA, EMB daily (10-14 doses, within 2 weeks)
THEN 1.5 months - INH, RIF, PZA, EMB twice / week (12 doses, within 6 weeks)
Continuation Phase
Options:
1) 4 months - INH, RPT once weekly (18 doses, within 18 weeks)
2) 7 months - INH, RPT once weekly (31 doses, within 31 weeks)
* Regimen is limited to noncavitary disease in HIV-negative patients. Sputum must be smear negative at completion of 2 months of treatment

30. Algorithm to Guide Treatment of Culture-Negative TB
High clinical suspicion for active TB despite negative smears based on:
Abnormal chest x-ray
Clinical symptoms
No other diagnosis
Positive tuberculin skin test
Patient placed on initial phase regimen:
INH, RIF, EMB, PZA for 2 months

31. Algorithm to Guide Treatment of Culture-Negative TB (Continued)
Is initial culture positive? NO
YES
Was there symptomatic or chest x-ray improvement after
2 months of treatment?
Continue treatment for culture-positive TB NO
YES
Discontinue treatment
Patient presumed to have LTBI
Treatment completed
Give continuation- phase treatment of INH/RIF daily or twice weekly for 2 months

32. Treatment of Culture-Negative TB*
Initial Phase
2 months - INH, RIF, EMB, PZA daily (56 doses, within 8 weeks)
Continuation Phase
Options:
2 months - INH, RIF daily (56 doses, within 8 weeks)
2) 2 months - INH, RIF twice / week (16 doses, within 8 weeks)
* All cultures are negative, but evaluation at 2 months reveals clinical and chest x-ray response to antituberculosis drug therapy

33. Treatment Monitoring (1)
Monthly sputum for AFB smear and culture (until 2 consecutive cultures negative)
Serial sputum smears every 2 weeks to assess early response
Additional drug-susceptibility tests if culture-positive after 3 months of treatment

34. Treatment Monitoring (2)
Periodic (minimum monthly) evaluation to assess adherence and identify adverse reactions
Repeat chest x-ray:
-At completion of initial treatment phase for patients with initial negative cultures
-At end of treatment for patients with culture-negative TB
-Generally not necessary for patients with culture positive TB

35. Treatment Monitoring (3)
Renal function, AST, ALT, bilirubin, and platelet count if abnormalities at baseline
Visual acuity and color vision monthly if EMB used > 2 months or doses > mg/kg

36. Determining Drug Completion (1)
Completion primarily defined by number of ingested doses within specified time frame
Examples
1) 6-month daily regimen (7 days/wk) = at least 182 doses of INH and RIF, and doses of PZA
2) 6-month daily regimen (5 days/wk) = at least 130 doses

37. Determining Drug Completion (2)
Specified doses must be administered
1) Within 3 months for initial phase
2) Within 6 months for 4-month continuation phase
$ Consider therapy interrupted if target doses not met within specified time period

38. Management of Initial Phase Treatment Interruptions
If lapse > 14 days, start from beginning
If lapse < 14 days, continue treatment to complete total doses warranted (if can be completed within 3 months)

39. Algorithm for Management of Treatment Interruptions in the Initial Phase
How long is the interruption? NO
Is it < 14 days?
YES
Start over from the beginning
Is the treatment completed within 3 months? NO
YES
Start over from the beginning
Continue treatment to complete total doses warranted

40. Management of Continuation Phase Treatment Interruptions
If received > 80% continuation-phase doses and:
1) sputum AFB smear negative on initial presentation, further therapy not necessary
2) sputum AFB smear positive on initial presentation, continue to complete full course

41. Management of Continuation Phase Treatment Interruptions
If received < 80% continuation-phase doses and:
1) lapse < 3 months duration, continue to complete full course (as long as all doses can be completed within 6 months)
2) lapse was 3 months or greater, then start initial phase 4-drug regimen from the beginning

42. Algorithm for Management of Continuation Phase Treatment Interruptions
What is the total percentage of doses completed? NO
Is it <80%?
YES
-Additional treatment may not be necessary if sputum was AFB smear negative at baseline
-If sputum smear was positive, continue treatment to complete planned total number of doses warranted
Is the duration of interruption <3 months? NO
YES
Continue treatment; if not completed in 6 months, start initial phase 4-drug regimen from beginning
Start initial phase 4-drug regimen from beginning

43. Common Adverse Reactions to Drug Treatment (1)
Caused by
Adverse Reaction
Signs and Symptoms
Any drug
Allergy
Skin rash
Ethambutol
Eye damage
Blurred or changed vision
Changed color vision
Isoniazid,
Pyrazinamide, or
Rifampin
Hepatitis
Abdominal pain
Abnormal liver function test
results
Fatigue
Lack of appetite
Nausea
Vomiting
Yellowish skin or eyes
Dark urine

44. Common Adverse Reactions to Drug Treatment (2)
Caused by
Adverse Reaction
Signs and Symptoms
Isoniazid
Peripheral neuropathy
Tingling sensation in hands and feet
Pyrazinamide
Gastrointestinal intolerance
Arthralgia
Arthritis
Upset stomach, vomiting, lack of appetite
Joint aches
Gout (rare)
Streptomycin
Ear damage
Kidney damage
Balance problems
Hearing loss
Ringing in the ears
Abnormal kidney function test results

45. Common Adverse Reactions to Drug Treatment (3)
Caused by
Adverse Reaction
Signs and Symptoms
Rifamycins
Rifabutin
Rifapentine
Rifampin
Thrombocytopenia
Gastrointestinal intolerance
Drug interactions
Easy bruising
Slow blood clotting
Upset stomach
Interferes with certain medications, such as birth control pills, birth control implants, and methadone treatment

46. Drug Interactions
Relatively few drug interactions substantially change concentrations of antituberculosis drugs
Antituberculosis drugs sometimes change concentrations of other drugs
-Rifamycins can decrease serum concentrations of many drugs, (e.g., most of the HIV-1 protease inhibitors), to subtherapeutic levels
-Isoniazid increases concentrations of some drugs (e.g., phenytoin) to toxic levels

47. Relapse (1)
A patient’s cultures become and remain negative while receiving antituberculosis drugs, but at some point after completion of therapy:
patient develops culture-positive TB disease again, or
2) patient experiences clinical or radiographic deterioration consistent with active TB disease
Most relapses occur within the first 12 months after completion of therapy

48. Relapse (2)
Patients with cavitation on initial chest radiograph and a positive culture at completion of 2 months of therapy are at increased risk of relapse with standard 6-month regimens
Patients with relapse are at increased risk for acquired drug resistance, especially if the therapy was not directly observed

49. Treatment Failure
Defined as positive cultures after 4 months of treatment in patients for whom medication ingestion was ensured
Single new drug should never be added to a failing regimen; it may lead to acquired resistance to the added drug
Add at least three new drugs (e.g., fluoroquinolone, ethionamide, and an injectable drug: SM, amikacin, kanamycin, or capreomycin) to the existing regimen being cognizant of the possibility of drug resistance

50. Drug Resistance (1) Established only by drug-susceptibility testing
Treatment of TB caused by drug-resistant organisms should be done in close consultation with an expert
Patients not on DOT in the past or who had irregular treatment are at risk of drug resistance

51. Drug Resistance (2)
Consider the following expanded regimen for drug resistance:
INH, RIF, PZA, EMB plus three additional agents based on probability of in vitro susceptibility (e.g., fluoroquinolone, ethionamide, or an injectable drug: SM, amikacin, kanamycin, or capreomycin)

52. Special Treatment Situations HIV/AIDS
Treatment for HIV-positive patients same as for HIV-negative patients, except
Once-weekly INH-rifapentine in continuation phase is contraindicated in HIV-positive patients
Twice-weekly INH-RIF or INH-rifabutin should not be used in patients with CD4+ T-lymphocyte counts less than 100/l
Every effort should be made to use a rifamycin-based regimen for the entire course of therapy

53. Special Treatment Situations (Children and Adolescents)* (1)
Use DOT
Treat young children (<5 years old) with three (rather than four) drugs in initial phase (i.e., INH, RIF, and PZA)
EMB not recommended unless increased likelihood of INH resistance or diagnosis of adult-like TB**
* Defined as persons <15 years old
** Defined as upper-lobe infiltration and cavitation associated with sputum production

54. Special Treatment Situations Children and Adolescents (2)
Thrice-weekly therapy not recommended
Recommended duration of treatment is 6 months (absence of factors associated with increased risk of relapse)

55. Special Treatment Situations Extrapulmonary TB
Similar treatment regimen for pulmonary TB*
6- to 9-month regimens that include INH and RIF are effective
Corticosteroids used as adjunctive therapy for patients with TB meningitis and pericarditis
If PZA cannot be used in the initial phase, continuation phase must be increased to 7 months
* Except for central nervous system (CNS) TB, including meningitis; length of therapy is 9-12 months

56. Special Treatment Situations Pregnancy and Breastfeeding (1)
Untreated TB represents greater hazard to a woman and her child than treatment of disease
Treatment of pregnant woman with suspected TB should be started if probability of TB is moderate to high
Initial phase treatment regimen should consist of INH, RIF, and EMB

57. Special Treatment Situations Pregnancy and Breastfeeding (2)
SM should not be substituted for EMB because of possible teratogenic effects
PZA not generally recommended for pregnant women in the United States

58. Special Treatment Situations Renal Insufficiency and End-Stage Renal Disease (1)
Renal insufficiency complicates management of TB because some antituberculosis medications are cleared by the kidneys
Dosage should not be decreased because peak serum concentrations may be too low; smaller doses may decrease drug efficacy

59. Special Treatment Situations Renal Insufficiency and End-Stage Renal Disease (2)
Dosing interval of antituberculosis drugs should be increased
Most drugs can be given 3 times weekly after hemodialysis; for some drugs, dose must be adjusted

60. Special Treatment Situations Hepatic Disease (1)
Must consider regimens with fewer hepatotoxic agents for patients with liver disease
Recommended regimens:
Treatment without PZA Initial phase (2 months): INH, RIF, and EMB Continuation phase (7 months): INH and RIF
Treatment without INH Initial phase (2 months): RIF, PZA, and EMB Continuation phase (4 months): RIF, EMB, and PZA

61. Special Treatment Situations Hepatic Disease (2)
Recommended regimens: (continued)
Regimens with only one potentially hepatotoxic drug
RIF should be retained
Duration of treatment is months
Regimens with no potentially hepatotoxic drugs
Duration of treatment is months

62. Continuing Education Credits (1)
Participants will be able to receive one of the following:
Continuing Medical Education (CME) credit = 3.75
Continuing Nursing Education (CNE) credit = 4.3
Continuing Education Unit (CEU) = 0.43
Certified Health Education Specialist (CHES) credit = 3.5
Participants are required to read and study the treatment guidelines, take a test, and complete an evaluation

63. Continuing Education Credits (2)
Continuing education credit will be awarded through:
CDC’s Public Health Training Network (PHTN) or
MMWR at

64. Treatment Guidelines Online Availability
CDC’s Morbidity and Mortality Weekly Report:
American Thoracic Society:

65. Additional TB Resources
For additional information on tuberculosis, visit the Division of Tuberculosis Elimination Web site at: