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Module 4: Treatment of Latent TB Infection and TB Disease

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Slide 1 (Title Slide): Module 4: Treatment of Latent Tuberculosis Infection and Tuberculosis Disease

Slide 2: Module 4: Objectives
At completion of this module, learners will be able to:

1. List groups of people who should receive high priority for latent TB infection (LTBI) treatment
2. Describe treatment regimens for LTBI
3. Describe treatment regimens for TB disease
4. Describe principles of preventing drug resistance
5. Describe patient monitoring during LTBI and TB disease treatment
6. Describe TB treatment adherence strategies
7. List common adverse reactions to drugs used to treat LTBI and TB disease

Slide 3: Module 4:  Overview

• Treatment of LTBI
• LTBI Treatment Regimens
• Special Considerations for LTBI Treatment
• Patient Medical Evaluation
• Treatment of TB Disease
• TB Disease Treatment Regimens and Dosage Recommendations

Slide 4: Module 4:  Overview (cont.)

• Treatment of TB Disease (cont.)
• Special Considerations and Alternative Treatment Regimens
• Treatment Monitoring Plan and Adverse Reactions
• Adherence and Evaluating Patients’ Response to Treatment
• Case Studies

Slide 5: (Title Slide) Treatment of LTBI

Slide 6: Treatment of LTBI (1)

• LTBI is treated to prevent the development of TB disease
• LTBI is treated with medication

Slide 7: Treatment of LTBI (2)

• Targeted testing should be used to identify and treat persons:
• At high risk for infection with M. tuberculosis
• At high risk for developing TB disease once infected with M. tuberculosis
• People in these groups should receive high priority for LTBI treatment if they have a positive tuberculin skin test (TST) or interferon-gamma release assay (IGRA)

Slide 8: High Priority for LTBI Treatment (1)

• High-priority groups for LTBI treatment if positive IGRA or TST result of > 5 mm
• Recent close contacts of people with infectious TB disease
• People living with HIV
• People with chest x-ray findings suggestive of previous TB disease
• Patients with organ transplants
• Other immunosuppressed patients

Slide 9: High Priority for LTBI Treatment (2)

• High-priority groups for LTBI treatment if positiveIGRA or TST result of  > 10 mm:
• People who have come to U.S. within last 5 years from countries where TB is common
• People who inject drugs
• People who live or work in high-risk facilities
• People who work in mycobacteriology laboratories

Slide 10: High Priority for LTBI Treatment (3)

• High-priority groups for LTBI treatment if positiveIGRA or TST result of  > 10 mm: (cont.):
• People with medical conditions that increase risk of TB disease
• Children younger than 4 years old
• Infants, children, and adolescents exposed to adults in high-risk groups

Slide 11: Low Priority for LTBI Treatment

• Individuals without any risk factors generally should not be tested for TB infection
• However, individuals with no risk factors who are tested and have a positive IGRA or TST result of >15 mm should be evaluated for LTBI treatment

Slide 12: Treatment of LTBI Study Question 4.1

• What is the purpose of LTBI treatment? (pg. 7)
• To prevent people with latent TB infection from developing TB disease.

Slide 13: Treatment of LTBI Study Question 4.2

• Which groups of people should receive high-priority for LTBI treatment if they have a positive IGRA or TST result of > 5 mm?  Name 5.  (pg. 7)
• People living with HIV infection
• Recent close contacts of people with infectious TB disease
• People with chest x-ray findings suggestive of previous TB disease
• Patients with organ transplants
• Other immunosuppressed patients

Slide 14: Treatment of LTBI Study Question 4.3

• Which groups of people should receive high priority for LTBI treatment if they have a positive IGRA or TST result of >10 mm?  Name 7. (pg. 7)
• People who come to U.S. within last 5 years from areas of the world where TB is common
• People who inject drugs
• People who live or work in high-risk facilities
• People who work in mycobacteriology laboratories
• People with medical conditions that increase risk of TB disease
• Children younger than 4 years old
• Infants, children, and adolescents exposed to adults in high-risk groups

Slide 15 (Title Slide) Treatment of Latent TB Infection (LTBI): LTBI Treatment Regimens

Slide 16: LTBI Treatment Regimens (1): Isoniazid

• Preferred regimen is isoniazid (INH) daily for 9 months
• INH may also be given for 6 months
• Cost effective and patients may find it easier to adhere, BUT:
• Not as effective if given for less than 6 months
• Not recommended for people living with HIV, individuals with previous TB disease, or children

Slide 17: LTBI Treatment Regimens (2): Rifampin

• Rifampin (RIF) is recommended for people who:
• Cannot tolerate INH
• Have been exposed to INH-resistant TB
• RIF should be given daily for 4 months
• RIF should not be used with certain combinations of anti-retroviral (ARV) therapy
• In some cases, rifabutin may be substituted when RIF cannot be used

Slide 18: LTBI Treatment Regimens (3): Rifampin and Pyrazinamide

• CDC advises against using a combination of RIF and pyrazinamide (PZA) for 2 months for people with or without HIV infection due to serious side effects:
• Severe liver injury
• Death

Slide 19 - 20: LTBI Treatment Regimens (4 - 5)

Table 4.2

Drug/Dose	Duration (months)	Interval	Minimum Doses	Comments
Isoniazid	9	Daily	270	The preferred regimen is daily treatment for 9 months Recommended regimen for people with HIV, children, and people with chest x-ray findings suggestive of previous TB disease DOT should be used with twice-weekly dosing
		Twice weekly	76
Isoniazid	6	Daily	180	Not recommended for people with HIV, children, and people with chest x-ray findings suggestive of previous TB disease DOT should be used with twice-weekly dosing
		Twice weekly	52
Rifampin	4	Daily	120	Recommended for patients who have isoniazid-resistant, rifampin-susceptible LTBI Alternative for people who cannot tolerate isoniazid Not recommended for HIV-infected patients on certain combinations of ARV therapy; rifabutin may be used instead
Rifampin/ Pyrazinamide	Generally should not be offered for treatment of LTBI

Slide 21: LTBI Treatment Regimens Study Question 4.4

• What is the preferred LTBI treatment regimen? (pg.10)
• INH given daily for 9 months.

Slide 22: LTBI Treatment Regimens Study Question 4.5

• What LTBI treatment regimen may be recommended for people with a positive IGRA or a TST result who have been exposed to INH-resistant TB? (pg. 10)
• Treatment with rifampin for 4 months may be recommended in this situation.

Slide 23: (Title Slide) Treatment of Latent TB Infection (LTBI): Special Considerations for LTBI

Slide 24: Special Considerations for LTBI (1): Directly Observed Therapy (DOT)

• DOT is when a health care worker (HCW) or another designated person watches a patient swallow each dose of medication
• Used to help patients adhere to treatment
• Should be considered for people who are at high risk for TB or suspected to be non-adherent
• Recommended for intermittent therapy

Slide 25: Special Considerations for LTBI (2): Close Contacts

• Close contacts are people who have had recent and prolonged exposure to a person with known or suspected infectious TB
• Close contacts should be evaluated for LTBI and TB disease
• If TST or IGRA result is positive, contacts should be given high priority for LTBI treatment
• If TST or IGRA result is negative, contacts should be retested in 8-10 weeks

Slide 26: Special Considerations for LTBI (3): Close Contacts at High Risk for TB Disease

• Some close contacts at high risk to progress to TB disease may start LTBI treatment even if test result is negative, but less than 8-10 weeks have passed since exposure to TB:
• Children younger than 5 years old
• People living with HIV
• Other immunocompromised persons

Slide 27: Special Considerations for LTBI (4): Close Contacts at High Risk for TB Disease

• Once active TB disease is ruled out, close contacts at high risk for TB disease should:
• Start LTBI treatment
• Be retested 8-10 weeks after last exposure
• If negative test result:  stop LTBI treatment
• If positive test result:  continue treatment
• Contacts with weakened immune systems may be given full course of LTBI treatment regardless of second TST or IGRA test result

Slide 28: Special Considerations for LTBI (5): Close Contacts

• In general, contacts with positive test result and a documented history of completion of LTBI treatment do not need to be retreated
• However, retreatment may be necessary for persons at high risk of:
• Becoming re-infected
• Progressing to TB disease

Slide 29: Special Considerations for LTBI (6): Contacts of INH-Resistant TB

• Contacts of patients with INH-resistant but RIF-susceptible TB should be treated with a 4-month daily regimen of RIF
• In some patients rifabutin may be substituted if RIF cannot be used

Slide 30: Special Considerations for LTBI (7): Contacts of Multidrug-Resistant TB (MDR TB)

• Contacts of patients with MDR TB
• May be treated for 6-12 months with an alternative regimen of drugs to which organism is susceptible
  OR
• Can be observed for signs and symptoms of TB disease for 2 years without treatment

Slide 31: Special Considerations for LTBI (8): Contacts of MDR TB

• Risk of developing TB disease should be considered before recommending LTBI treatment
• MDR TB treatment expert should be consulted

Slide 32: Special Considerations for LTBI (9): Infants and Children

• Infants and children are more likely to develop life-threatening forms of TB disease
• Children younger than 5 years old who have been exposed to TB should start taking LTBI treatment even if they have a negative TST result because they:
• Are at high risk for rapidly developing TB disease
• May have a false-negative TST reaction

Slide 33: Special Considerations for LTBI (10): Infants and Children

• Infants and children should be retested 8-10 weeks after last exposure
• LBTI treatment can be stopped if ALL of the following conditions are met:
• Second TST is negative
• Second TST was done 8-10 weeks after child was last exposed to TB
• Child is at least 6 months old

Slide 34: Special Considerations for LTBI (11): Pregnant Women

• For most pregnant women, LTBI treatment can be delayed until after delivery, unless they have certain medical conditions
• INH has not been shown to have harmful effects on the fetus
• Immediate treatment should be considered if woman is living with HIV, has another immunocompromising condition, or is a recent TB contact
• Preferred LTBI treatment regimen is 9 months of INH with a vitamin B6 supplement

Slide 35: Special Considerations for LTBI (12): Breastfeeding Women

• Women who are breastfeeding can take INH but should also be given a vitamin B6 supplement
• Amount of INH in breast milk is not enough to be considered treatment for infant

[IMAGE: Mother holding an infant.]

Slide 36: Special Considerations for LTBI (13): People Living with HIV

• Individuals living with HIV should be treated with 9-month regimen of INH
• RIF should not be used for people living with HIV who are being treated with certain combinations of ARV
• In some cases, rifabutin may be given

Slide 37: Special Considerations for LTBI Study Question 4.6

• In what circumstances may LTBI treatment be given to people who have a negative TST or IGRA result? (pg. 15)
• Some close contacts may start LTBI treatment if they have a negative test but less than 8-10 weeks have passed since last exposed to TB; these contacts include:
• Children who are younger than 5 years old
• People living with HIV
• Other immunocompromised persons

Slide 38: Special Considerations for LTBI Study Question 4.7

• What conditions must be met to stop LTBI treatment for children younger than 5 years old who are exposed to TB? (pg. 15)
• LTBI treatment can be stopped if ALL the following conditions are met:
• Second skin test is negative
• Second skin test was done 8-10 weeks after the child was last exposed to TB
• Child is at least 6 months old

Slide 39: Special Considerations for LTBI Study Question 4.8

• When should pregnant women be treated for LTBI and for how long? (pg. 15)
• For most pregnant women with TB infection, LTBI treatment can be delayed until after delivery.  If the pregnant woman is HIV-infected or a recent contact, immediate treatment should be considered.
• Preferred treatment regimen for pregnant women is 9 months of INH with a vitamin B6 supplement.

Slide 40: (Title Slide) Treatment of Latent TB Infection (LTBI): Patient Medical Evaluation

Slide 41: Patient Medical Evaluation (1)

• Medical evaluations should be done in order to:
• Exclude possibility of TB disease
• Determine whether patient has ever been treated for LTBI or TB disease
• Find out if patient has any medical conditions that may complicate therapy
• Establish and build rapport with patient

Slide 42: Patient Medical Evaluation (2)

• Exclude possibility of TB disease
• Treating TB disease with LTBI treatment regimen can lead to drug resistance
• Patients should be evaluated with chest x-ray
• Patients with symptoms or chest x-ray findings of TB disease should be given TB disease treatment, not LTBI treatment

Slide 43: Patient Medical Evaluation (3)

• Determine whether patient has ever been treated for LTBI or TB disease
• Patients who have been adequately treated should not be treated again
• TST or IGRA results cannot determine if patient has received treatment for LTBI or TB disease; or if they have been re-infected after treatment

Slide 44: Patient Medical Evaluation (4)

• Find out if patient has any medical conditions that may complicate therapy.  These patients include:
• People living with HIV
• People with history of liver disorder or disease
• People who use alcohol regularly
• Women who are pregnant or just had a baby (within 3 months of delivery)
• People who are taking other medications that may increase the risk of hepatitis

Slide 45: Patient Medical Evaluation (5)

• For patients with the medical conditions listed on the previous slide, baseline laboratory liver function tests (to detect injury to liver) are recommended before starting LTBI treatment

Slide 46:  Patient Medical Evaluation (6)

• It is important to find out if:
• Patient has ever had adverse reactions to LTBI drugs
• Patient is currently on medications that may interact with LTBI drugs

[IMAGE: Doctor and patient talking in examination room.]

Slide 47:  Patient Medical Evaluation (7)

• Establish and build rapport with patient
•  HCW should highlight important aspects of treatment:
• Benefits of treatment
• Importance of adherence to treatment
• Possible adverse reactions
• Establishment of a follow-up plan

Slide 48: Patient Medical Evaluation (8)

• Because of the interaction between TB and HIV, all patients should be recommended to undergo HIV screening and be offered an HIV test

Slide 49:  Adverse Reactions to INH (1)

• About 10%-20% of people treated with INH will have mild, abnormal liver test results during treatment
• In most cases test results return to normal

Slide 50:  Adverse Reactions to INH (2): Hepatitis

• A major risk of INH is hepatitis (inflammation of the liver)
• Hepatitis prevents the liver from functioning normally, causing symptoms such as:
• Nausea
• Vomiting
• Abdominal pain
• Fatigue
• Dark urine

Slide 51:  Adverse Reactions to INH (3): Hepatitis

• INH can cause hepatitis in anyone; however, hepatitis occurs in less than 1% of people taking INH
• Certain risk factors increase the risk of serious hepatitis, such as:
• Older age
• Alcoholism

Slide 52:  Adverse Reactions to INH (4): Peripheral Neuropathy

• INH can cause peripheral neuropathy
• Damage to sensory nerves of hands and feet
• Symptoms include a tingling sensation or weakened sense of touch
• Alcoholism, diabetes, and malnutrition increase risk for peripheral neuropathy
• People with these conditions should be given vitamin B6

Slide 53:  Adverse Reactions to RIF

• Hepatitis is more likely to occur when RIF is combined with INH
• Other side effects of RIF include:
• Rash
• Gastrointestinal symptoms
• Orange discoloration of urine, saliva, and tears
• Increased sensitivity to sun
• Interaction with other drugs, such as birth control pills and implants, warfarin, and methadone

Slide 54:  Patient Monitoring (1)

• Persons taking LTBI treatment should be educated about symptoms caused by adverse reactions
• Patients need to be evaluated at least monthly during therapy for:
• Adherence to prescribed regimen
• Signs and symptoms of active TB disease
• Adverse reactions

Slide 55:  Patient Monitoring (2)

• During evaluation, patients should be:
• Asked whether they have nausea, abdominal pain, or other symptoms of adverse reactions
• Examined by HCW for adverse reactions
• Instructed to stop medications and contact HCWs immediately if they have signs or symptoms of hepatitis

Slide 56:  Patient Monitoring (3)

• People at greatest risk for hepatitis should have liver function tests before starting INH LTBI treatment and every month during therapy:
• People living with HIV
• People with history of liver disorder or disease
• People who use alcohol regularly
• Women who are pregnant or just had a baby
• People taking medications that may increase risk of hepatitis

Slide 57:  Patient Monitoring (4)

• For all patients, INH should be stopped if liver function test results are:
• 3 times higher than upper limit of normal range and patient has symptoms
  OR
• 5 times higher than upper limit of the normal range and patient has no symptoms

Slide 58:  LTBI Treatment Follow-Up

• Patients should receive documentation of TST or IGRA results, regimens, and treatment completion dates
• Patients should present these documents any time they are required to be tested for TB
• Patients should be re-educated about signs and symptoms of TB disease

Slide 59: Medical Evaluation Study Question 4.9

• Name 4 reasons why patients should receive a medical evaluation before starting LTBI treatment. (pg. 21)
• Exclude possibility of TB disease
• Determine whether they have ever been treated for TB infection or disease
• Find out if patient has any medical conditions that may complicate therapy
• Establish and build rapport with patient

Slide 60:  LTBI Treatment Study Question 4.10

• Why is it important to exclude the possibility of TB disease before giving a patient LTBI treatment? (pg. 21)
• Treating TB disease with LTBI treatment regimen (usually a single drug) can lead to drug resistance.

Slide 61:  Adverse Reactions Study Question 4.11

• What are the symptoms of hepatitis? (pg. 21)
• Nausea
• Vomiting
• Abdominal pain
• Fatigue
• Dark urine

Slide 62:  Adverse Reactions Study Question 4.12

• Who is at greatest risk for hepatitis?  What special precautions should be taken for these patients? (pg. 21)
• People with greatest risk for hepatitis are:
• People living with HIV
• People with a history of liver disorder or disease
• People who use alcohol regularly
• Women who are pregnant or just had a baby
• People who are taking other medications that may increase the risk of hepatitis
• Should have liver function tests before starting INH LTBI treatment and during therapy  

Slide 63:  Adverse Reactions Study Question 4.13

• How often should patients be evaluated for signs and symptoms of adverse reactions during LTBI treatment? (pg. 21)
• All patients receiving LTBI treatment should be evaluated at least monthly during therapy.

Slide 64: (Title Slide) Treatment of TB Disease

Slide 65:  Treatment of TB Disease (1)

• Treating TB disease benefits both the person who has TB and the community
• For patient, prevents disability and death; restores health
• For community, prevents further transmission of TB
• TB disease must be treated for at least 6 months; in some cases, treatment lasts longer
• e.g., patients with cavities on chest x-ray and positive sputum cultures at 2 months should have treatment extended to 9 months

Slide 66:  Treatment of TB Disease (2)

• Initial Phase
• First 8 weeks of treatment
• Most bacilli killed during this phase
• 4 drugs used
• Continuation Phase
• After first 8 weeks of TB disease treatment
• Bacilli remaining after initial phase are treated with at least 2 drugs
• Relapse
• Occurs when treatment is not continued for long enough
•  Surviving bacilli may cause TB disease at a later time

Slide 67:  Treatment of TB Disease (3)

• Initial regimen should contain the following four drugs:
• Isoniazid (INH)
• Rifampin (RIF)
• Pyrazinamide (PZA)
• Ethambutol (EMB)

[IMAGE: INH, RIF, PZA, and EMB pills]

Slide 68:  Treatment of TB Disease (4)

• Treatment must contain multiple drugs to which organisms are susceptible
• Treatment with a single drug can lead to the development of drug-resistant TB

Slide 69:  Preventing Drug Resistance (1)

• Drug resistance can develop when patients are prescribed an inappropriate regimen
• TB disease must be treated with at least 2 drugs to which bacilli are susceptible
• Using only one drug can create a population of tubercle bacilli resistant to that drug
• Adding a single drug to failing regimen may have the same effect as only using one drug

Slide 70:  Preventing Drug Resistance (2)

• Resistance can develop when patients do not take drugs as prescribed
• Patients do not take all of their pills
• Patients do not take pills as often as prescribed
• When this happens, patients may expose the bacilli to a single drug

Slide 71:  Preventing Drug Resistance (3)

• Factors that increase chance of patient having or developing drug-resistant TB:
• Patient has spent time with someone with active drug-resistant TB disease
• Patient does not take their medicine regularly
• Patient does not take all of their medicine

Slide 72:  Preventing Drug Resistance (4)

• Factors that increase chance of patient having or developing drug-resistant TB (cont.):
• Patient develops active TB disease after having taken TB medicine in the past
• Patient comes from area of the world where drug-resistant TB is common

Slide 73:  (Title Slide) Treatment of TB Disease: Treatment Regimens and Dosage Recommendations

Slide 74 - 77:  TB Treatment Regimens^* (1 - 4)

Table 4.3 Drug Regimens for Pulmonary TB Caused by Drug Susceptible Organisms in Adults^*

Initial Phase			Continuation Phase
Regimen	Drugs	Interval and Doses ±	Regimen	Drugs	Interval and Doses± §	Range of Total Doses
1	INH RIF PZA EMB	7 days/week for 56 doses (8 weeks) or 5 days /week for 40 doses (8 weeks)¶	1a	INH RIF	7 days/week for 126 doses (18 weeks) or 5 days/week for 90 doses (18 weeks) ¶	182-130 (26 weeks)
			1b#	INH RIF	2 days/week for 36 doses (18 weeks) ¶	92-76 (26 weeks)
			1c**	INH RPT	1 day/week for 18 doses (18 weeks) ¶	74-58 (26 weeks)
2	INH RIF PZA EMB	7 days/week for 14 doses (2 weeks), then 2 days/week for 12 doses (6 weeks) or 5 days/week for 10 doses (2 weeks), ¶ then 2 days/week for 12 doses (6 weeks)	2a#	INH RIF	2 days/week for 36 doses (18 weeks) ¶	62-58 (26 weeks)
			2b**	INH RPT	1 day/week for 18 doses (18 weeks) ¶	44-40 (26 weeks)
3	INH RIF PZA EMB	3 times weekly for 24 doses (8 weeks)	3a	INH RIF	3 times weekly for 54 doses (18 weeks) ¶	78 (26 weeks)
4	INH RIF EMB	7 days/week for 56 doses (8 weeks) or 5 days/week for 40 doses (8 weeks) ¶	4a	INH RIF	7 days/week for 217 doses (31 weeks) or 5 days/week for 155 doses (31 weeks) ¶	273-195 (39 weeks)
			4b#	INH RIF	Twice weekly for 62 doses (31 weeks) ¶	(118-102) (39 weeks)

INH = isoniazid RIF = rifampin PZA = pyrazinamide EMB = ethambutol RPT = rifapentine

* For more information on strength of recommendation and quality of supporting evidence, refer to ATS, CDC, and IDSA MMWR Treatment of Tuberculosis Guidelines.

± When DOT is used, drugs may be given 5 days/week and the necessary doses adjusted accordingly.

§ Patients with cavitation on initial chest x-ray and positive cultures at completion of 2 months of therapy should receive a 7-month continuation phase.

¶ Patients on regimens given less than 7 days a week should receive DOT # Regimens give less than 3 times a week are not recommended for HIV-infected patients with CD4+ counts less than a 100 **Used only for HIV-negative patients with negative sputum smears at completion of 2 months of therapy and who do not have cavitation on initial chest x-ray. For patients started on this regimen and found to have positive culture from the 2-month specimen, treatment should be extended an extra 3 months.

Slide 78 - 80:  Drug Dosage Recommendations¹ (1 - 3)

Table 4.4 Dosage Recommendations for the Treatment of TB in Adults and Children¹

Dose in mg/kg (maximum dosage in parentheses)

Drug	Adults/Children2		Daily	1 time/week3	2 times/week3	3 times/week3
INH	Adults		5 mg/kg (300 mg)	15 mg/kg (900 mg)	15 mg/kg (900 mg)	15 mg/kg (900 mg)
	Children		10-15 mg/kg (300 mg)		20-30 mg/kg (900 mg)
RIF	Adults		10 mg/kg (600 mg)		10 mg/kg (600 mg)	10 mg/kg (600 mg)
	Children		10-20 mg/kg (600 mg)		10-20 mg/kg (600 mg)
RBT	Adults		5 mg/kg (300 mg)		5 mg/kg (300 mg)	5 mg/kg (300 mg)
	Children		Appropriate dosing for children unknown
RPT	Adults			10 mg/kg (600 mg) (continuation phase)
	Children		This drug is not approved for use in children
PZA	Adults	Weight
		40-55 kg	18.2-25 mg/kg (1000 mg)		36.4-50 mg/kg (2000 mg)	27.3-37.5 mg/kg(1500 mg)
		56-75 kg	20-26.8 mg/kg (1500 mg)		40-53.6 mg/kg (3000 mg)	33.3-44.6 (2500 mg)
		76-90 kg	22.2-26.3 mg/kg(2000 mg)		44.4-52.6 mg/kg (4000 mg)	33.3-39.5 mg/kg(3000 mg)
	Children		15-30 mg/kg (2000 mg)		50 mg/kg (2000 kg)
EMB4	Adults	40-55 kg	14.5-20 mg/kg (800 mg)		36.4-50 mg/kg (2000 mg)	21.8-30 mg/kg(1200 mg)
		56-75 kg	16-21.4 mg/kg (1200 mg)		37.3-50 mg/kg (2800 mg)	26.7-35.7 mg/kg(2000 mg)
		76-90 kg	17.8-21.1 mg/kg(1600 mg)		44.4-52.6 mg/kg (4000 mg)	26.7-31.6 mg/kg(2400 mg)
	Children		15-20 mg/kg (1000 mg)		50 mg/kg (2500 mg)

INH= isoniazid RIF= rifampin RBT= rifabutin RPT= rifapentine PZA= pyrazinamide EMB= ethambutol

¹Although these regimens are broadly applicable, modifications may be needed for certain circumstances (patients on ARVs). For more information, refer to the ATS, CDC, and IDSA MMWR Treatment of Tuberculosis Guidelines

² For purposes of this document adults dosing begins at age 15 years. Children weighing more than 40 kg should be dosed as adults. Adjust doses as the patient’s weight changes.

³All patients prescribed an intermittent regimen should be given DOT. ⁴Ethambutol should be used with caution in young children since it is difficult to monitor their vision. However, if they have TB that is resistant to INH or RIF, dose of 15 mg/kg per day can be used.

Slide 81:  Treatment of TB Disease Study Question 4.14

• Why must TB disease be treated for at least 6 months? (pg. 28)
• Even though most bacilli are killed in the first 8 weeks, some bacilli can survive.  Therefore, treatment must continue in order to kill all remaining bacilli.

Slide 82:  Treatment of TB Disease Study Question 4.15

• Which 4 drugs are recommended for the initial treatment of TB disease? (pg. 28)
• Initial regimen should include INH, RIF, PZA, and EMB.

Slide 83:  Treatment of TB Disease Study Question 4.16

• Why should at least 2 drugs be used to treat TB disease? (pg. 28)
• Using only one drug can create a population of tubercle bacilli that is resistant to that drug.  When 2 or more drugs are used together, each drug helps prevent the emergence of bacilli that are resistant to the other drugs.

Slide 84:  Drug Resistance Study Question 4.17

• Name 2 factors that can lead to drug resistance. (pg. 28)
• Drug resistance can develop when:
• Patients are prescribed an inappropriate regimen for treatment
• Patients do not follow treatment regimens as prescribed

Slide 85:  (Title Slide) Treatment of TB Disease: Special Considerations and Alternative Treatment Regimens

Slide 86: Special Considerations (1)

• TB medical experts should be consulted for complicated and challenging TB treatment issues
• Consultation can be provided by State TB Programs and/or the CDC-funded TB Regional Training and Medical Consultation Centers (RTMCCs)

Slide 87:  Special Considerations (2): People Living with HIV

• Treatment for HIV patients is generally the same as for those without HIV-infection with two exceptions:
• Once weekly INH and rifapentine in continuation phase should not be used
• Patients with advanced HIV should be treated daily or three times weekly in the initial and continuation phase

Slide 88:  Special Considerations (3): People Living With HIV

• Patients should receive a minimum of 6 months treatment and be closely monitored
• Continuation phase may need to be extended to 7 months (9 months total treatment time), if patient is responding slowly to treatment

Slide 89:  Special Considerations (4): People Living With HIV

• DOT should be provided for all TB patients living with HIV
• If TB patient is living with HIV and on ARV:
• It is important to be aware of the interaction of RIF with some ARV drugs
• Rifabutin has fewer drug interaction problems and may be used as a substitute for RIF for some patients

Slide 90:  Special Considerations (5): Pregnant Women

• Treatment should begin as soon as TB disease is diagnosed
• Preferred initial regimen is INH, RIF, and EMB for at least 9 months
• Drugs that should not be used
• Pyrazinamide (PZA)
• Streptomycin (SM)
• Vitamin B6 supplements are recommended for all pregnant women taking INH

Slide 91:  Special Considerations (6): Breastfeeding

• Women being treated with first-line TB drugs should not be discouraged from breastfeeding
• Only small concentration found in breast milk
• Not harmful to infant

Slide 92:  Special Considerations (7): Breastfeeding

• Drugs in breast milk should not be considered effective treatment for TB disease for infant
• Vitamin B6 supplements are recommended for breastfeeding women

Slide 93:  Special Considerations (8): Children

• Infants and children younger than 4 years should start TB treatment as soon as possible
• Recommended treatment:
• 6 months
• 3 drugs (INH, RIF, PZA) in initial phase

Slide 94:  Special Considerations (9): Children

• EMB is not recommended for children unless TB is resistant to INH, child is a contact of patient with INH-resistant TB, or TB manifestation is similar to TB in adults (e.g., cavities or extensive upper-lobe infiltrates)
• Pills may have to be crushed or given in liquid form
• It is not recommended to treat children 3 times a week

Slide 95:  Special Considerations (10): People with Extrapulmonary Disease

• Regimens used for treating pulmonary TB are also effective for treating extrapulmonary TB
• Infants and children with miliary TB (disseminated TB), bone and joint TB, or TB meningitis should receive at least 9-12 months of treatment

Slide 96:  Alternative Treatment Regimens (1): Drug-Resistant TB

• Alternative regimens should be used for treating drug-resistant TB
• Treatment of drug-resistant TB should always be done under the supervision of a medical expert

Slide 97:  Alternative Treatment Regimens (2): Drug-Resistant TB

• INH-resistant TB can be treated with the following regimens:
• RIF, EMB, and PZA for 6-9 months
• RIF and EMB for 12 months

Slide 98:  Alternative Treatment Regimens (3): MDR TB

• Resistant to INH and RIF
• More difficult to treat than drug-susceptible TB
• Drugs that can be used are less effective and are more likely to cause adverse reactions
• Treatment can last longer than 2 years or more
• Surgery is sometimes use to remove infected site

Slide 99:  Alternative Treatment Regimens (4): Extensively Drug-Resistant TB (XDR TB)

• XDR TB is resistant to INH, RIF, plus any fluoroquinolone, and at least one injectable second-line drug (e.g., amikacin, kanamycin, or capreomycin)
• XDR TB patients have less effective treatment options
• XDR TB is very difficult to treat

Slide 100:  Alternative Treatment Regimens (5): XDR TB

• Successful outcomes for patient depend greatly on:
• Extent of drug resistance
• Severity of disease
• Whether patient’s immune system is compromised

Slide 101:  Special Considerations Study Question 4.18

• What treatment regimens should be used for TB patients living with HIV? (pg. 32)
• Daily or three times weekly therapy
• 6 months of treatment; if not responding to treatment, patient should be reevaluated and continuation phase can be increased to 7 months (9 months total treatment)
• DOT should be used
• If HIV-infected TB patient is on ARVs, it is important to be aware of the interaction of rifampin with some ARV drugs

Slide 102:  Special Considerations Study Question 4.19

• In what special situations should treatment for TB disease last longer than the usual course of treatment? (pg. 32)
• Patients with cavities in chest x-ray and positive sputum culture at 2 months
• Patients living with HIV may need treatment for 9 months
• Pregnant women should receive at least 9 months treatment, if PZA is not used
• Infants and children with miliary TB, bone and joint TB, or TB meningitis should receive at least 9 - 12 months of treatment
• INH-resistant TB treatment can last 12 months; treatment for MDR TB can last 2 years or longer

Slide 103:  (Title Slide) Treatment of TB Disease: Treatment and Monitoring Plan and Adverse Reactions

Slide 104: Treatment and Monitoring Plan

• Every TB patient should have a specific treatment and monitoring plan developed in collaboration with local health department
• Plan should include:
• Description of treatment regimen
• Methods of:
• Monitoring for adverse reactions
• Assessing and ensuring adherence to treatment
• Evaluating treatment response

Slide 105:  Monitoring Adverse Reactions (1)

• Patients should have baseline blood and vision tests to detect problems that may complicate treatment
• Children only need vision tests, unless there are other medical conditions that may complicate treatment

Slide 106:  Monitoring Adverse Reactions (2)

• Follow-up tests should be done periodically if:
• Results of baseline tests indicate abnormalities
• Patient has symptoms that may be due to adverse reactions

Slide 107:  Monitoring Adverse Reactions (3)

• Patients should be educated about symptoms caused by adverse reactions to drugs
• Patients should be seen by clinician at least monthly during treatment and evaluated for possible adverse reactions
• Public health workers who have regular contact with patients should ask about adverse reactions to treatment

Slide 108:  Monitoring Adverse Reactions (4)

• If patient has symptoms of a serious adverse reaction, HCW should:
• Instruct patient to stop medication
• Report situation to clinician and arrange for medical evaluation
• Note symptoms in patient’s record

[IMAGE: Health care worker talking to a patient in the home.  The health care worker is wearing a respirator.]

Slide 109 to Slide 111:  Adverse Reactions to TB Drugs (1 - 3)

Table 4.5 Common Adverse Reactions to TB Drugs

Caused by	Adverse Reaction	Signs and Symptoms	Significance of Reaction*
Any drug	Allergic	Skin rash	Serious
Ethambutol	Eye damage	Blurred or changed vision Changed color vision	Serious
IsoniazidPyrazinamide Rifampin	Hepatitis	Abdominal pain Abnormal liver function test results Dark urine Fatigue Fever for 3 or more days Flulike symptoms Lack of appetite Nausea Vomiting Yellowish skin or eyes	Serious
Isoniazid	Nervous system damage	Dizziness Tingling or numbness around the mouth	Serious
	Peripheral neuropathy	Tingling sensation in hands and feet	Serious
Pyrazinamide	Stomach upset	Stomach upset, vomiting, lack of appetite	Serious
	Increased uric acid	Abnormal uric acid level Joint aches Gout (rare)	Serious
Rifampin	Bleeding problems	Easy bruising Slow blood clotting	Serious
	Discoloration of body fluids	Orange urine, sweat, or tears Permanently stained soft contact lenses	Minor
	Drug interactions	Interferes with certain medications, such as birth control pills, birth control implants, and methadone treatment	May be Serious or Minor
	Sensitivity to the sun	Frequent sunburn	Minor

*Patients should stop medication for serious adverse reactions and consult a clinician immediately. Patients can continue taking medication if they have minor adverse reactions.

 

Slide 112:  TB Treatment and Monitoring Plan Study Question 4.20

• What should be included in each patient’s treatment plan? (pg. 37)
• Description of treatment regimen 
• Methods of monitoring for adverse reactions
• Methods of assessing and ensuring adherence to the treatment
• Methods for evaluating treatment response

Slide 113:  Adverse Reactions to TB Drugs Study Question 4.21

• Name the drug or drugs that may cause each of the following symptoms or adverse reaction. (pg. 37)
• Peripheral neuropathy: INH
• Hepatitis: INH, PZA, RIF
• Eye damage: EMB
• Orange discoloration of the urine: RIF

Slide 114:  TB Treatment Monitoring Study Question 4.22

• How often should patients be monitored for adverse reactions to TB drugs? (pg. 37)
• All patients should be seen at least monthly during treatment and evaluated for possible adverse reactions.

Slide 115: (Title Slide) Treatment of TB Disease: Adherence and Evaluating Patients’ Response to Treatment

Slide 116: Adherence to TB Treatment (1)

• Most effective strategy to encourage adherence to treatment is DOT:
• Should be used for ALL patients, including children and adolescents
• Should be done at a time and place that is convenient for patients

[IMAGE: Health care worker administering DOT to a patient.]

Slide 117:  Adherence to TB Treatment (2)

• Incentives and enablers can be used to improve patient adherence
• Incentives are small rewards given to patient, e.g., gift cards
• Enablers help patient receive treatment, e.g., bus tokens

Slide 118:  Adherence to TB Treatment (3)

• Patients should be educated about TB disease and treatment
• Cause of TB, transmission, diagnosis, and treatment plan
• How to take medication

[IMAGE: Health care worker discussing a brochure on TB with a patient.]

Slide 119:  Monitoring Patients’ Adherence to Therapy

• Patients not receiving DOT should be monitored for adherence to treatment:
• Check if patient is reporting to clinic
• Ask about adherence
• Ask patient to bring medications to clinic and count number of pills taken
• Use urine tests to detect medication
• Assess patient’s clinical response to treatment

Slide 120:  Evaluating Patients’ Response to Treatment (1)

• Three methods to determine whether a patient is responding to treatment:
• Check to see if patient has TB symptoms (clinical evaluation)
• Conduct bacteriologic examination of sputum or other specimens
• Use chest x-rays to monitor patient’s response to treatment

Slide 121:  Evaluating Patients’ Response to Treatment (2)

• Check to see if patient has TB symptoms (clinical evaluation)
• TB symptoms should gradually improve and go away after starting treatment
• Patients whose symptoms do not improve during the first 2 months of treatment, or whose symptoms worsen after initial improvement, should be reevaluated

Slide 122:  Evaluating Patients’ Response to Treatment (3)

• Conduct bacteriologic examination of sputum or other specimens
• Specimens should be examined every month until culture results have converted from positive to negative
• Any patient whose culture results have not become negative after 2 months of treatment, or whose results become positive after being negative, should be reevaluated

Slide 123:  Evaluating Patients’ Response to Treatment (4)

• Use chest x-rays to monitor patient’s response to treatment

• Repeated x-rays are not as important as monthly bacteriologic and clinical evaluations
• Chest x-rays taken at end of treatment can be compared to follow-up x-rays

Slide 124:  Evaluating Patients’ Response to Treatment (5)

• TST or IGRA cannot be used to determine whether patient is responding to treatment
• Treatment completion is defined by number of doses patient takes within a specific time frame
• Length of treatment depends on drugs used, drug susceptibility test results, and patient’s response to therapy

Slide 125:  Reevaluating Patients Who Do Not Respond to Treatment (1)

• Reevaluating means repeating susceptibility tests and assessing whether patient has taken medication as prescribed
• TB treatment can be complicated, especially in patients who:
• Fail to respond to treatment
• Relapse
• Have drug-resistant TB
• Have serious adverse reactions to medications

Slide 126: Reevaluating Patients Who Do Not Respond to Treatment (2)

• Patients should be reevaluated if:
• Symptoms do not improve in 2 months of therapy
• Symptoms worsen after improving initially
• Culture results have not become negative after 2 months of treatment
• Culture results become positive after being negative

Slide 127:  Adherence to Therapy Study Question 4.23

• Name 4 ways clinicians can assess whether a patient is adhering to treatment. (pg. 43)
• Check whether patient is reporting to clinic as scheduled
• Ask patient to bring medications to each clinic visit and count the number of pills
• Use urine tests to detect medication
• Assess patient’s clinical response to therapy

Slide 128:  Adherence to Therapy Study Question 4.24

• What is the best way to ensure that a patient adheres to treatment? (pg. 43)
• Directly observed therapy (DOT)

Slide 129:  Response to Treatment Study Question 4.25

• How can clinicians determine whether a patient is responding to treatment? (pg. 43)
• Clinical evaluations
• Bacteriologic evaluations
• Chest x-rays

Slide 130:  Reevaluating the Patient Study Question 4.26

• Under what circumstances should patients be reevaluated? (pg. 43)
• Symptoms do not improve during first 2 months of therapy
• Symptoms worsen after improving initially
• Culture results have not become negative after 2 months of treatment
• Culture results become positive after being negative

Slide 131:  Reevaluating the Patient Study Question 4.27

• What does reevaluating the patient mean? (pg. 43)
• Reevaluating the patient means checking for drug resistance by repeating the drug susceptibility tests and assessing whether the patient has been taking medication as prescribed.

Slide 132: (Title Slide) Treatment of TB Disease: Role of Public Health Workers

Slide 133: Role of Public Health Workers (1)

• Successful TB treatment is the responsibility of medical providers and HCWs
• Case management can be used to ensure that patients complete TB treatment
• Elements of case management:
• Assign employee to manage patients
• Systematic routine review of patient’s treatment progress
• Plans to address barriers to adherence

Slide 134:  Role of Public Health Workers (2)

• Provide DOT
• Help monitor patients’ response to treatment
• Educate patients and families about TB
• Locate patients who have missed DOT visits or clinic appointments
• Act as interpreters, arrange and provide transportation for patients, and refer patients to other social services
• Work with private physicians to make sure TB patients complete an adequate regimen

Slide 135:  Role of Public Health Workers Study Question 4.28

• What are the three elements of case management? (pg. 47)
• Assignment of employee to manage specific patients
• Systematic review of each patient’s treatment progress
• Plans to address barriers to adherence

Slide 136:  Role of Public Health Workers Study Question 4.29

• What should a public health worker do if he or she notices that a patient has symptoms of an adverse reaction? (pg. 47)
• Instruct patient to stop taking medication if symptoms are serious
• Report situation to clinician and arrange medical evaluation
• Note symptoms in patient’s record

Slide 137:  (Title Slide) Case Studies

Slide 138:  Module 4: Case Study 4.1 (1)

• You are sent to visit the home a TB patient who was admitted to the hospital last week and diagnosed with infectious TB disease.  Living in the home are his wife and his 1-year-old daughter.  Neither one has symptoms of TB disease.  You give them both a TST and return 2 days later to read the results.  You find that the wife has 14 mm of induration, but the daughter has no induration. (pg. 16)

Slide 139:  Module 4: Case Study 4.1 (2)

•  Should either one start LTBI treatment?
• Yes, both should start LTBI treatment.

Slide 140:  Module 4: Case Study 4.1 (3)

• Why or why not?
• The wife is a close contact of someone with infectious TB disease and she has a positive skin test. She should complete an entire course of LTBI treatment, regardless of her age, after receiving a medical evaluation.

Slide 141:  Module 4: Case Study 4.1 (4)

• Why or why not? (cont.)
• The daughter is also a close contact.  She currently has a negative skin test, but only one week has passed since her last TB exposure.  It is possible the TST reaction may be false-negative.
• Since it is currently impossible to tell whether she has TB infection and because she may develop TB disease very quickly after infection, she should start LTBI treatment now and be retested 8-10 weeks after last exposure to TB. If negative, she may stop taking medicine. If positive, she should complete the entire course of LTBI treatment (9 months for children)

Slide 142:  Module 4: Case Study 4.2 (1)

• A 65-year-old man is prescribed INH LTBI treatment because he is a close contact of a person with infectious TB and he has an induration of 20 mm in reaction to the tuberculin skin test.  His baseline liver function tests are normal, but he drinks a six-pack of beer every day.  (pg. 22)

Slide 143:  Module 4: Case Study 4.2 (2)

• What kind of monitoring is necessary for this patient while he is taking INH?
• Although his liver function tests are normal, he is at high risk of INH-associated hepatitis because he is older than 35 and abuses alcohol.
• He should be educated about the symptoms of adverse reactions to INH and be instructed to seek medical attention immediately if these symptoms occur.
• He should be seen by a clinician monthly to ask about his symptoms, examine him for signs of adverse reactions, and consider performing liver function tests.

Slide 144:  Module 4: Case Study 4.3 (1)

• An 18-month-old girl is admitted to the hospital because of meningitis.  Doctors discover that her grandmother had pulmonary TB and was treated with a 6-month regimen.  The medical evaluation of the child confirms the diagnosis of TB meningitis.  (pg. 43)

Slide 145:  Module 4: Case Study 4.3 (2)

• How long should the child be treated?
• Infants and children with miliary TB, bone and joint TB, or TB meningitis should be treated for 12 months.

Slide 146:  Module 4: Case Study 4.4 (1)

• You are assigned to deliver medications to TB patients as part of the DOT program where you work.  When you visit Mr. Jackson’s house, you ask him how he is feeling.  He tells you that he was up all night vomiting.  (pg. 38)

Slide 147:  Module 4: Case Study 4.4 (2)

• What are the possible causes?
• His vomiting may be a symptom of hepatitis (caused by INH, RIF, and PZA) or of stomach upset due to PZA.  Mr. Jackson should be advised to stop his medication and the situation should be reported to the clinician immediately.  Mr. Jackson should be given a medical evaluation right away.

Slide 148:  Module 4: Case Study 4.5 (1)

• Ms. Young, a patient who started treatment for TB disease last week, calls the TB clinic to complain that her urine has changed to a funny color.  (pg. 38)

Slide 149:  Module 4: Case Study 4.5 (2)

• Name 2 possible causes, and explain how each would affect the color of the urine.
• One possible cause is the discoloration of body fluids, a common side effect of RIF.  This would cause Ms. Young’s urine to turn orange.  This is NOT a serious condition.
• Another possible cause is hepatitis, which can be caused by INH, RIF, or PZA.  Hepatitis, a serious condition, would cause Ms. Young’s urine to turn dark.  If Ms. Young’s urine is dark, the situation should be reported to the clinician and Ms. Young should receive a medical evaluation right away.

Slide 150:  Module 4: Case Study 4.6 (1)

• Mr. Vigo was diagnosed with smear-positive pulmonary TB in January.  He was treated with INH, RIF, and PZA by his private physician.  He visited his physician again in March.  His drug susceptibility test results were not available at the time of this appointment.  Nevertheless, the physician discontinued his prescription of PZA and gave him refills of INH and RIF.  Mr. Vigo visited his physician again in April.  He had a persistent cough, and his sputum smear was found to be positive.  (pg. 44)

Slide 151:  Module 4: Case Study 4.6 (2)

• What should be done next?
• Mr. Vigo’s persistent cough and positive sputum smear indicate that he is not responding to therapy.  The most likely explanations are:
• He is not taking his medication as prescribed
• He has drug-resistant TB and the regimen he has been prescribed is not adequate to treat his TB
• A combination of the two factors listed above
• The initial drug susceptibility test results should be located, and susceptibility tests should be repeated on a recent sputum specimen.  In addition, his adherence should be evaluated, and he should be given DOT if possible.

Slide 152: Module 4: Case Study 4.7 (1)

• Ms. DeVonne began treatment for pulmonary TB disease 2 months ago, at the beginning of September. You have been giving her DOT. During the first few weeks of therapy, you noticed that Ms. DeVonne’s symptoms were improving a little.  However, at a visit in October, you see that Ms. DeVonne is coughing up blood, and she tells you that she feels like she has a fever.  (pg. 48)

Slide 153:  Module 4: Case Study 4.7 (2)

• What should you do?
• Coughing up blood and feeling feverish are symptoms of TB disease.  You should report Ms. DeVonne’s symptoms to the clinician and arrange for her to receive a medical evaluation.  Note her symptoms in her record.
• Symptoms becoming worse after improving initially indicates that she is not responding to therapy. Because she is receiving DOT, Ms. DeVonne is probably taking her medications as prescribed.  Therefore, the most likely explanation is that she has drug-resistant TB.
• Ms. DeVonne’s initial drug susceptibility test results should be located, and drug susceptibility tests should be repeated.