Tuberculosis Treatment in Adults: FAQs

Who should be screened for TB, and how often?

Adults with increased risk of acquisition or activation of TB should be screened.^1,2,15 (But don’t test people that you don’t plan on treating if test is positive.¹⁵) At-risk groups include:

• those born or have resided in countries with high TB prevalence (e.g., most countries in Latin America, the Caribbean, Africa, Asia, Eastern Europe, and Russia).^1,2,15 See http://www.stoptb.org/countries/tbdata.asp.
  
• those who reside, work, or have resided in high-risk settings (e.g., jail, homeless shelter, nursing home)^1,2,15
  
• healthcare professionals who care for patients at increased risk for active TB (e.g., those with immunocompromising conditions, the very young, and the very old, IV drug users)^2,15
  
• populations considered at risk per your local or state health department (U.S.)¹
  
• IV drug abusers^1,15
  
• certain travelers.^15,16 (See [U.S.] https://www.cdc.gov/tb/topic/populations/travelers/default.htm or [Canada] https://www.canada.ca/en/public-health/services/infectious-diseases/canadian-tuberculosis-standards-7th-edition/edition-9.html#t_07-4.)
  
• close contacts of someone with TB^2,15
  
• Aboriginal communities (Canada)¹⁵
  
• those with immunocompromising conditions or treatments^2,15
  

For a risk assessment tool from the CDC, see https://www.cdc.gov/tb/publications/ltbi/appendixa.htm.

Frequency of testing depends on risk. A person at low risk may not need another test, but someone with continual potential exposure may need yearly testing.¹ Workers in healthcare facilities need to be tested at hire with the two-step TB skin test^8,15 or a TB blood test (U.S.), then periodic testing depending on local regulations and risk assessment.⁸ Details are available at (U.S.) http://www.cdc.gov/tb/topic/testing/healthcareworkers.htm or (Canada) https://www.canada.ca/en/public-health/services/infectious-diseases/canadian-tuberculosis-standards-7th-edition/edition-16.html#a5_0.

What tests are used to screen for TB infection?

Mantoux TB skin test read after 48 to 72 hours.^1,7,15

• Interpretation is based on the area induration and patient factors that affect the person’s risk of acquiring TB, or the risk of progression to active disease if infected. Specifics regarding interpretation are available at (U.S.) http://www.cdc.gov/tb/publications/ltbi/diagnosis.htm#TST and (Canada) https://www.canada.ca/en/public-health/services/infectious-diseases/canadian-tuberculosis-standards-7th-edition/edition-16.html#a5_1.
  
• The CDC has resources for healthcare workers who administer and interpret the test at http://www.cdc.gov/tb/education/mantoux/default.htm.
  
• An interactive website created by McGill University estimates positive predictive value, likelihood of developing active TB, and risk of INH-induced hepatotoxicity. It is available at http://www.tstin3d.com/en/calc.html.
  

OR

Interferon gamma release assay (T-Spot.TB, QuantiFERON TB Gold In-Tube)^1,7,15

• Consider for patients who may not return for skin test interpretation, for patients who have been vaccinated with BCG, or if staff lack training and expertise in skin test interpretation.^1,7
  
• A fact sheet on this assay is available from the CDC at http://www.cdc.gov/tb/publications/factsheets/testing/igra.htm.
  

Both tests are highly specific and moderately sensitive.¹ There are certain situations in which use of both tests may be helpful.¹ These are delineated at (U.S.) http://www.cdc.gov/tb/publications/ltbi/pdf/targetedltbi.pdf (See Appendix D)³ and (Canada) https://www.canada.ca/en/public-health/services/infectious-diseases/canadian-tuberculosis-standards-7th-edition/edition-16.html.

How is active TB identified?

Everyone with TB symptoms (e.g., unexplained weight loss, fever, night sweats, coughing for more than three weeks, hemoptysis, etc), or a positive TB test should be evaluated for active TB.^6,15

Workup includes history and physical, testing for infection (see above), posterior-anterior chest x-ray, three sputum samples (for AFB microscopy, NAAT, and culture [preferably both liquid and solid] of all samples regardless of AFB results).^6,7,15

• A negative NAAT in an AFB-positive specimen means TB disease is unlikely because in AFB-positive patients, NAAT produces a false negative only 4% of the time.⁷ In AFB-negative patients for whom there is intermediate or high suspicion of disease, disease can be presumed if NAAT is positive, but a negative NAAT does not rule out disease.⁷ NAAT is recommended for use on the first respiratory specimen on each patient.⁷ Guidelines for use, including a testing and interpretation algorithm is available at http://www.cdc.gov/mmwr/PDF/wk/mm5801.pdf (reference 13).¹³
  
• AFB and NAAT results can be available within hours.⁷
  
• A positive culture for Mycobacterium tuberculosis confirms the diagnosis.^6,7,15 Results take at least one to two weeks.⁷
  
• The isolate should be tested for drug resistance.^6,7,15 It can take over two weeks to grow an isolate for testing.⁷ However, rapid testing can be done as an adjunct (not a replacement) to culture-based testing in patients at risk for drug resistance.⁷ Rapid testing can detect rifampin resistance and sometimes isoniazid resistance.⁷
  

How do you treat latent TB in adults?

U.S. (CDC guidelines). (Information from 2014 Canadian guidelines is below.)

The regimens below are available for adults. Choose based on comorbidities, drug-drug interactions, and susceptibilities in the source case, if known.³ Special considerations regarding comorbidities are covered in the section below. Use the shortest regimen that is appropriate for the patient.⁴ The shorter courses are as effective as INH, with higher completion rates.^18,19

• 3 months (12-dose regimen) of INH plus rifapentine:⁴
  
• INH: 15 mg/kg rounded up to nearest 50 or 100 mg (max 900 mg) once weekly
  
• rifapentine: 32.1 to 49.9 kg, 750 mg; 50 kg and up, 900 mg once weekly
  
• Not for HIV patients on antiretrovirals with unacceptable interaction with rifapentine,¹⁴ or women who will be pregnant during the regimen.⁴
  
• Advise patients to stop rifapentine and seek medical help if they experience symptoms of a hypersensitivity reaction (e.g., flu-like symptoms, hypotension, facial swelling, bronchospasm, hives, eye redness). Patients with this reaction may also experience thrombocytopenia or neutropenia. The drug will be dispensed with a MedGuide.¹⁷
  
• 4 months of rifampin 10 mg/kg (600 mg max) once daily^3,4
  
• Consider rifabutin instead if HIV patient is taking an antiretroviral with an unacceptable rifampin interaction. Dosing will depend on interacting drug.¹² Not for women pregnant during the regimen.⁴
  
• 9 months or 6-months of INH: 5 mg/kg (300 mg max) daily, or 15 mg/kg (900 mg max) twice weekly via DOT.^3,4 The 9-month regimen is preferred for pregnant women. Preferred option (daily treatment for 9 months) for HIV patients taking antiretrovirals with unacceptable interactions with rifampin or rifapentine.⁴
  

Canada (2014 guidelines):¹⁵

• The decision to treat latent TB should be individualized, with consideration of the risks of therapy from adverse events, such as hepatotoxicity, balanced against the risk of development of active disease.
• The current standard for treatment of latent TB is self-administered INH (5 mg/kg; 300 mg max) taken daily for nine months.
• Acceptable alternatives include daily self-administered INH (5 mg/kg; 300 mg max) for six months, and daily self-administered INH (5 mg/kg; 300 mg max) plus rifampin (10 mg/kg; 600 mg max) for three to four months.
• Recent publications have reported good efficacy of a regimen of 12 doses of INH and rifapentine taken once weekly under direct observation (see U.S. info. above; DOT no longer required per CDC¹⁴). However, rifapentine is only available in Canada through the Special Access Program. If rifapentine is obtained through this program, clinicians should be aware that severe hypersensitivity reactions are a concern with this regimen.

Are there special considerations for treating latent TB in recent contacts?

Contacts are those with recent exposure to a person with known or suspected infectious TB (e.g., pulmonary or laryngeal TB with positive sputum smear). They should be evaluated immediately.^3,15 If they are found to be infected, the guidance below should be followed (U.S.). Those who have negative results should be retested in eight to ten weeks after exposure has ended.³ (Canada: eight weeks, or at eight weeks only in in the case of casual contact.¹⁵) However, treatment for latent TB should be started in immunocompromised contacts.^3,15 Treatment should be continued until the results of the second test and other medical evaluation are known.^3,15 For some high-risk contacts, a full course of latent TB treatment may be recommended even in the absence of a positive test (U.S.).³ Consult with your local TB control program about the management of such contacts.³

U.S.:

• If contact is exposed to known drug-susceptible TB or drug susceptibility is unknown: treat with INH or INH/rifapentine.³
  
• If contact is exposed to known INH-resistant TB, treat with rifampin (RIF) for 4 months.³
  
• If contact is exposed to known multidrug-resistant TB: consult an expert.³
  
• In general, contacts who test positive and can provide written documentation of prior adequate treatment for latent TB do not need to be retreated. Retreatment may be indicated for persons at high risk of becoming re-infected and progressing to TB disease (e.g., immunosuppressed persons).³
  

Should patients with active TB be put in isolation?

Note: This information applies to patients with suspected or confirmed TB disease, NOT latent TB.

• Outpatient: Your state health department (U.S.) might have specific recommendations, but in general, patients with pulmonary TB should stay at home until they are no longer infectious. That generally means that they have been taking TB medication for at least 14 days, are asymptomatic, and have negative AFB smears.^10,11 Home isolation may be discontinued when the patient has clinical evidence of improvement, three consecutive negative sputum smears for AFB and there is evidence of adherence to at least two weeks of effective therapy. Multi-drug resistant TB cases and those with mono-resistance to rifampin should have three consecutive negative sputum cultures after six weeks of incubation prior to discontinuing home isolation.¹⁵ Patients with a cough should be instructed to turn their heads away from persons and to cover their mouth and nose with their hands or preferably a cloth or tissue when coughing or sneezing.¹⁰ If the patient needs to go to an outpatient healthcare setting, they should wear a surgical or procedure mask, if possible, during transport, in waiting areas, or when other persons are present.¹⁰ If a patient comes to your office that your suspect has TB, they should be placed in a room with the door closed, away from other patients.¹⁰
  
• Inpatient: In general, expect these patients to be put in respiratory isolation. Make sure your infection control team is notified to coordinate care. Expect your institution to have specific policies and procedures. Information, including guidelines, is available from the CDC at http://www.cdc.gov/tb/publications/factsheets/prevention/rphcs.htm. For Canadian guidelines, see https://www.canada.ca/en/public-health/services/infectious-diseases/canadian-tuberculosis-standards-7th-edition/edition-11.html#f2.
  

What is preferred treatment regimen for active TB in adults?

For confirmed, newly diagnosed pulmonary TB caused by sensitive bacteria, the preferred adult regimen is:⁵

• INH 5 mg/kg (typically 300 mg) and rifampin 10 mg/kg (typically 600 mg) daily for eight weeks (56 doses) or five days per week via DOT for eight weeks (40 doses), then either daily for an additional 18 weeks (126 dose), or five days per week via DOT for an additional 18 weeks (90 doses).
  
• Patients with positive cultures at two months or cavitation on chest x-ray should receive a 31-week instead of an 18-week continuation phase.
  
• Daily dosing is preferred to 5-day per week dosing.
  

Plus

• Weight-based pyrazinamide and ethambutol daily for eight weeks (56 doses) or five days per week via DOT for eight weeks (40 doses). Ethambutol can be stopped if culture results show the isolate is sensitive to INH and rifampin.
  
• Suggested pyrazinamide dosing: 1,000 mg (40 to 55 kg), 1,500 mg (56 to 75 kg), or 2,000 mg (76 to 90 kg)
  
• Suggested ethambutol dosing: 800 mg (40 to 55 kg), 1,200 mg (56 to 75 kg), or 1,600 mg (76 to 90 kg)
  
• This dosing assumes normal renal function (renal dosing is discussed below), and is based on estimated lean body weight. Dosing in obese patients is not well-established.
  

Information on additional regimens, including treatment of extrapulmonary TB, are available at http://cid.oxfordjournals.org/content/early/2016/07/20/cid.ciw376.full.pdf. Consult experts when first-line drugs cannot be used due to adverse effects, resistance, extensive disease, or noncompliance concerns.

What are some adverse effects and drug interactions of concern with common TB medications?

(Also, see the How do you monitor TB medication? section below)

Isoniazid

• Hepatotoxicity. Elevated transaminases with symptomatic hepatitis occurs in about 0.1% of INH patients treated with monotherapy for latent TB, but is rare in patients younger than 20 years.³
  
• Risk factors for hepatotoxicity include exposure to other hepatotoxins or drugs metabolized by the liver, daily alcohol use, liver disease, risk factors for liver disease, pregnancy, and the first two to three postpartum months.³
  
• INH should be withheld if transaminases exceed three times the upper limit of normal with symptoms, or five times the upper limit of normal if asymptomatic.³
  
• Peripheral neuropathy. Pyridoxine 25 to 50 mg daily (100 mg daily if the patient already has neuropathy) is recommended for patients with risk factors (e.g., patients with HIV, diabetes, alcoholism, chronic renal disease, or malnutrition, and for elderly patients, or pregnant or nursing women) receiving INH.^3,5 (Canadian guidelines recommend no more than 25 mg due to potential to interfere with INH activity.¹⁵) It is also recommended for breastfed infants, even if they are not themselves taking INH, at a dose of 1 to 2 mg/kg/day.⁵
  
• Optic neuritis. Uncommon¹²
  
• Drug interactions. INH may increase levels of several medications to a potentially dangerous extent, including phenytoin, carbamazepine, diazepam, triazolam, theophylline, warfarin, valproate, antidepressants.⁵ If taken with rifamycins, which decreases levels of these and other medications, the net effect will generally be a decrease in drug levels.^5,12 However, both rifampin and INH can increase acetaminophen toxicity.^5,12
  

Rifampin and other rifamycins

• Hepatotoxicity.
  
• Occurs in 0.6% of rifampin patients and usually manifests as transient asymptomatic hyperbilirubinemia.³
  
• Bilirubin and alkaline phosphatase increase proportionately more than transaminases.⁵
  
• Use with INH increases risk.³
  
• Rifampin less likely to cause hepatotoxicity than INH or pyrazinamide.⁵
  
• Dermatologic reactions. Occur in 6% of patients taking rifampin.³ A petechial rash with a rifamycin suggests thrombocytopenia.⁵
  
• If thrombocytopenia occurs, the drug should be stopped, and platelet count monitored.⁵
  
• Drug interactions.
  
• Rifamycins are CYP enzyme inducers. Daily rifampin and rifapentine are the most potent inducers, and rifabutin the least.⁵ Weekly rifapentine has only a small effect on other drugs.⁵ Rifabutin can be substituted for rifampin to avoid a serious drug interaction.⁵
  
• Rifamycins may significantly reduce levels of HIV antiviral medications, most hormonal contraceptives, warfarin, phenytoin, lamotrigine, metoprolol, losartan, enalapril, digoxin, levothyroxine, itraconazole, sulfonylureas, statins, and methadone, among many others.^3,5,12 However, they may increase acetaminophen toxicity.¹²
  
• CYP3A4 inhibitors and inducers can affect levels of rifabutin.⁵
  
• HIV patients should be referred to a physician with expertise in treating these patients due to the complex interactions between of antiretroviral and antitubercular regimens.⁵ Expect therapy to be continued, but changes, such as dose adjustments or alternative medications, may need to be considered.
  
• It can take one to two weeks to see the maximum impact of a rifamycin on another drug, and two to four weeks for complete resolution after discontinuation of the rifamycin.^5,21
• Discoloration (orange) of urine, tears, and sweat is normal.^9,12 Soft contact lenses may be permanently stained.¹²
  

Pyrazinamide

• Hepatotoxicity⁵
  

Ethambutol

• Optic neuritis may occur in 2.25% of patients. Usually occurs after a month of treatment, but may occur within days. Discontinuation is required if visual abnormalities occur. If symptoms do not improve, stop INH as well.⁵
  

All TB drugs

• Hepatotoxicity: asymptomatic, transient liver enzyme elevation can occur in up to 20% of patients on a four-drug regimen.⁵ Treatment should be withheld if transaminases exceed three times the upper limit of normal with symptoms, or five times the upper limit of normal if asymptomatic.⁵ Experts may sequentially reintroduce each med once labs are near-normal.⁵
  
• Dermatologic reactions. Itchy rash with no mucous membrane involvement or systemic involvement, treatment may be continued with an antihistamine for symptoms. A generalized erythematous rash, rash with fever, or mucous membrane involvement necessitates discontinuation of all TB drugs. Some experts will sequentially rechallenge patients in an inpatient setting.⁵
  
• Drug fever. Look for other causes. Drug discontinuation usually results in defervescence within 24 hours. Once afebrile, the patient can be rechallenged with each drug, adding a new drug every two or three days.⁵
  

More guidance on management of TB drug-induced adverse effects is available at https://www.canada.ca/en/public-health/services/infectious-diseases/canadian-tuberculosis-standards-7th-edition/edition-17.html#a46.

What are some special considerations for specific comorbidities?

HIV, taking antiretrovirals:

• Daily 9-month INH regimen preferred for latent TB if the patient is taking an antiretroviral with an unacceptable interaction with rifampin or rifapentine (per CDC).⁴
  
• Supplement with pyridoxine 25 to 50 mg daily due to risk of INH-associated neuropathy.^3,5 Use pyridoxine 100 mg daily if the patient already has neuropathy.⁵
  
• HIV patients with active TB should be referred to a specialist due to complex drug interactions between antiretroviral regimens and TB drugs.⁵
  

Pregnancy:

• For latent TB, use the 9-month INH regimen (per CDC;⁴ Canadian guidelines do not state a preference¹⁵) with pyridoxine 25 to 50 mg daily.⁵ If breastfeeding, also supplement the infant with pyridoxine 1 to 2 mg/kg/day.⁵
  
• Unless the patient is HIV positive or a recent contact, wait two to three months after delivery to treat for latent TB.^3,15 This strategy prevents fetal medication exposure and reduces risk of hepatotoxicity.³
  
• For active TB, some experts suggest withholding pyrazinamide due to lack of information in pregnancy, except in cases of HIV, severe TB, or extrapulmonary TB. It should be noted that the World Health Organization recommends use of pyrazinamide in pregnancy, and there is much experience with it in pregnant women in countries with high TB prevalence. If pyrazinamide is withheld, a minimum nine-month course of INH/rifampin/ethambutol is used. Expert consultation is recommended.⁵
  

Renal disease:

• Pyrazinamide requires renal dose reduction. If CrCl is <30 mL/min., the suggested dose is 25 to 35 mg/kg three times per week, after hemodialysis if applicable.⁵ Experts may adjust dose based on levels.⁵
  
• Ethambutol requires renal dose reduction. If CrCl is <30 mL/min., the suggested dose is 20 to 25 mg/kg three times per week, after hemodialysis if applicable.⁵ Experts may adjust dose based on levels.⁵
  

Liver Disease: refer to specialist⁵

How do you monitor TB medications?

Latent TB

• CDC: For latent TB, baseline liver function tests are not routinely recommended, but are recommended for patients with a history of (risk factors for) liver disease; regular alcohol use; HIV; pregnancy or the first three postpartum months. Also consider testing other patients, such as those taking medications for chronic medical conditions.³ Periodic retesting is recommended for persons who had abnormal initial results and other persons at risk for hepatic disease.³
  
• Canada: Liver function tests. <35 years of age: baseline (if liver disease suspected), then as indicated; age 35 to 50 years: baseline, months one and end of treatment; and as indicated; >50 years of age or other risk factors: baseline and monthly.¹⁵
  
• At any time during treatment, laboratory testing is recommended for patients who have symptoms suggestive of hepatitis (e.g., fatigue, weakness, malaise, anorexia, nausea, vomiting, abdominal pain, pale stools, dark urine, chills) or who have jaundice.³
  
• Patients should be instructed, at the start of treatment and at each monthly visit, to stop taking treatment and to seek medical attention immediately if symptoms of hepatitis develop and not wait until the next clinic visit to stop treatment.³
  
• It is generally recommended that medication be withheld if a patient’s transaminase level exceeds 3 times the upper limit of normal if associated with symptoms or 5 times the upper limit of normal if the patient is asymptomatic.^3,15
  
• After treatment of latent TB, serial or repeat chest radiographs are not indicated unless the patient develops signs or symptoms suggestive of TB disease.^3,15
  

Active TB

• A checklist is available from the guidelines at http://cid.oxfordjournals.org/content/63/7/e147/F2.expansion.html.
• Patients do not typically require follow-up after completion of therapy, but should be instructed to seek care promptly if signs or symptoms recur.²⁰
  

How can I improve adherence?

Adherence is imperative to prevent the spread of the disease to others and the development of resistant organisms.

Collaborate with local health department to provide DOT treatment.³

Consult case management to coordinate care and services.³

Help the patient obtain free or low-cost medication.³

Provide patient education and instructions in patient’s primary language at every visit.³ The CDC’s Staying on Track with Tuberculosis Medicine is available at http://www.cdc.gov/tb/publications/pamphlets/tb_trtmnt.pdf. Many other patient education materials are available from the CDC at http://www.cdc.gov/tb/education/patient_edmaterials.htm, in English, Spanish, Tagalog, and Vietnamese. In Canada, patient education materials are available at https://www.canada.ca/en/public-health/services/infectious-diseases/canadian-tuberculosis-standards-7th-edition/appendix-c.html.

Suggest or provide patient reminders such as a pill box, calendar, or timer.³ See our chart of Medication Adherence Apps, to help your tech-savvy patients.

If the patient complains of nausea, rule out hepatotoxicity and suggest taking the meds at bedtime, with an antacid, or with a light, low-fat snack such as crackers. Food reduces absorption.⁵

In the event of interruption of treatment of active TB, consult an expert. One approach is presented in the guidelines at https://www.cdc.gov/tb/publications/guidelines/pdf/clin-infect-dis.-2016-nahid-cid_ciw376.pdf. For a suggested approach to management of missed doses for latent TB, see http://globaltb.njms.rutgers.edu/downloads/2012%20Handouts/Patrawalla%20Treatment%20of%20LTBI.pdf.

For more tips, see our toolbox, Medication Adherence Strategies.