Tuberculosis

Tuberculosis (TB) is an infectious disease caused by the Mycobacterium tuberculosis complex (Mtb), spread person-to-person through inhalation of airborne droplet nuclei — most often from someone with untreated, infectious pulmonary or laryngeal disease.^[1] Most people who acquire Mtb mount an immune response that contains, but does not eliminate, the organism: this dormant state is now called TB infection (previously "latent TB") — asymptomatic and non-infectious, but capable of progressing to active disease at any point in life.^[2] When containment fails, the organism proliferates and causes TB disease (previously "active TB"), most often in the lungs but potentially in any organ; pulmonary or laryngeal disease is the form capable of person-to-person transmission. TB remains a leading global cause of infectious disease morbidity and mortality, and Canada's approach — set out in the Canadian Tuberculosis Standards — centres on early diagnosis, multidrug therapy with adherence support, and interrupting transmission through both treatment of active disease and preventive therapy for TB infection.^[1]

Pulmonary TB disease

Cough persisting more than 2-3 weeks (productive or dry), hemoptysis, dyspnea, and pleuritic chest pain are the classic respiratory symptoms. Systemic symptoms — fever, night sweats, anorexia, and unintentional weight loss — are common and may precede respiratory symptoms.^[3] Onset is typically gradual over weeks and can be subtle, particularly in older adults.

Extrapulmonary TB disease

Any organ can be involved. Common extrapulmonary sites include lymph nodes (peripheral lymphadenopathy), pleura, bone and joint, the genitourinary tract, and the central nervous system (TB meningitis). Neck stiffness, meningeal signs, choroid tubercles on fundoscopy, and erythema nodosum or induratum can be presenting findings.^[3] Concomitant pulmonary involvement should always be assessed for, since it is common in extrapulmonary disease and determines infectiousness and isolation requirements.

Atypical presentation

The radiographic appearance of TB is variable and may even be normal in some patients, including those with HIV. A high index of suspicion is needed in patients with HIV, young children, and older adults, all of whom can present atypically or with minimal symptoms.^[3]

Risk factors for Mtb exposure and/or infection

• Known contact with a person with infectious TB.
• Country of birth/origin or travel to a high-TB-incidence region.
• Occupation with TB exposure risk, e.g., health-care worker.
• Incarceration, current or past.
• Substandard housing — underhoused, high household density, poor air quality, inadequate ventilation.
• High-risk social environment, including substance use.

Risk factors for progression to TB disease once infected

• Recent Mtb exposure or infection (within 2 years).
• Documented TST or IGRA conversion within 2 years.
• Predisposing medical conditions — HIV, organ transplantation, advanced kidney disease, diabetes, certain hematologic and solid malignancies, malnutrition.
• Use of immunosuppressive medications — systemic corticosteroids, tumour necrosis factor inhibitors.
• Abnormal chest x-ray compatible with prior TB (e.g., fibronodular pattern).
• Current tobacco smoking or heavy alcohol use.

Risk factors for drug-resistant TB

• Previous TB treatment or previous drug-resistant disease, especially if directly observed therapy (DOT) was not used.
• Previous non-adherence or prior interruptions during TB treatment.
• HIV infection.
• Residence in, or frequent travel to, a country with a high prevalence of drug-resistant TB.
• Contact with a person with drug-resistant TB.
• Younger age.

History and physical examination

Take a thorough history focused on symptoms compatible with TB disease (cough, hemoptysis, dyspnea, chest pain, fever, night sweats, anorexia, weight loss, neck stiffness); risk factors for Mtb exposure/infection, progression to disease, and drug resistance; previous TST/IGRA results; details of any previous TB infection or disease treatment; BCG vaccination history, including age at last vaccination; comorbidities affecting treatment (HIV, diabetes, liver disease, chronic kidney disease, malnutrition, mental health conditions, substance use); and medications that may affect treatment (antiretrovirals, anticoagulants, anticonvulsants, methadone, hormone therapy).^[3]

Physical examination findings can include low body mass index/cachexia, fever, peripheral lymphadenopathy, meningeal signs, choroid tubercles, and erythema nodosum or induratum. Record baseline weight, visual acuity, and colour vision before starting treatment.^[3]

Investigations for TB disease

Microbiologic confirmation is central to diagnosis — growth of Mtb on mycobacterial culture and/or detection of Mtb on nucleic acid amplification testing (NAAT). NAAT expedites diagnosis but does not replace the need for culture and drug susceptibility testing (DST); sensitivity is markedly lower in smear-negative sputum than in smear-positive sputum, and lower still in extrapulmonary specimens — a negative NAAT alone does not exclude TB.^[3]

For pulmonary TB: chest radiograph (compared to any prior films), with CT considered especially if hemoptysis is present; at least 3 sputum specimens (spontaneous or induced, collected at least 1 hour apart) for AFB smear and culture — a negative smear does not exclude active pulmonary TB, since a substantial proportion of patients with TB disease have negative sputum smears; fiberoptic bronchoscopy when spontaneous/induced sputum cannot be obtained, an alternative diagnosis is suspected, or miliary TB is a concern.^[3]

For extrapulmonary TB: make every effort to obtain microbiologic confirmation from the involved site — tissue biopsy generally has a higher diagnostic yield than fluid aspiration and should be sent for both culture and histopathology. Always assess for concomitant pulmonary involvement, since it is common in extrapulmonary cases and determines infectiousness and isolation needs. Suspected pleural TB warrants thoracentesis (AFB smear usually negative; culture sensitivity variable and often low) plus consideration of pleural biopsy, since combining the two significantly increases diagnostic yield. Suspected TB meningitis warrants lumbar puncture with AFB smear, culture, and NAAT of cerebrospinal fluid, plus glucose, protein, and cell count/differential.^[3]

Not routinely indicated in Canada — adenosine deaminase testing of pleural, peritoneal, pericardial, or cerebrospinal fluid; despite reasonable sensitivity/specificity in high-burden settings, it does not replace microbiologic confirmation and is not routinely available in Canada.^[3]

Baseline investigations before starting treatment: CBC and differential, ALT or AST, bilirubin, and creatinine; glycated hemoglobin (HbA1c); hepatitis B and C serology; HIV testing in all patients with newly diagnosed TB disease unless the patient declines (an "opt-out" approach); visual acuity and colour vision testing if ethambutol is planned; and weight.^[3]

Investigations for TB infection

TB infection is a clinical diagnosis made by combining a patient's TB exposure risk assessment and risk of progression to disease with chest radiograph and TST or IGRA results. Neither TST nor IGRA should be used to diagnose TB disease in adults — both assess for previous Mtb exposure but cannot distinguish TB infection from active disease, and a negative result does not exclude TB disease.^[2]

The TST (Mantoux test) uses an intradermal injection of tuberculin, read at 48-72 hours by measuring the widest transverse diameter of induration (not erythema). It should not be repeated in a person with a documented previous positive result, and should not be performed in those with extensive burns/eczema, a current major viral infection, or recent live-virus vaccination (within 4 weeks).^[2]

The IGRA (QuantiFERON-TB Gold Plus or T-SPOT.TB) has similar sensitivity to TST but is more specific in populations with prior BCG vaccination. IGRA is preferred over TST when the patient is 2-9 years old with prior BCG vaccination, received multiple BCG vaccinations or was vaccinated after age 1 or at an unknown time, is unlikely to return for TST reading, or when TST is unavailable/contraindicated. IGRA is not appropriate when serial testing is needed to detect new infection, e.g., health-care worker screening or contact investigations.^[2]

Interpreting TST induration

Interpretation should also weigh pre-test probability and clinical context.^[2]

Causes of false TST results

• Prevent person-to-person transmission through early diagnosis, appropriate infection control, and prompt initiation of effective treatment.
• Eradicate Mtb from the affected organ(s) in TB disease.
• Achieve cure without relapse.
• Prevent the development of drug resistance.
• Prevent TB-related morbidity and mortality.
• Prevent TB infection from progressing to TB disease through TB preventive therapy (TPT), breaking the cycle of transmission.

Person-centred and culturally sensitive care

Provide culturally sensitive, person-centred care — understand the social and historical forces that put a person at risk for TB and how these may affect health-care engagement, remain aware of potential bias or discrimination within the health-care system, and use professional interpreters in the patient's preferred language rather than family or friends. Use empowering, non-stigmatizing language when discussing TB.^[1]

Adherence support and directly observed therapy (DOT)

Educate patients on the nature of the disease and the importance of completing the full course of treatment, and optimize adherence with incentives and enablers — financial and social assistance, reminders, and blister packaging.^[1]

Directly observed therapy (DOT) — a health-care professional or trained personnel routinely witnessing the patient swallow their TB medications — is a core adherence-support strategy given the intensive, prolonged nature of TB treatment and the public health consequences of non-adherence, including the emergence of drug resistance. DOT is mandatory for any intermittent (non-daily) regimen, and is especially important for patients at high risk of non-adherence, treatment failure, or transmission, including drug-resistant disease, HIV infection, and significant social or mental health barriers to care. DOT can be delivered at home, in the community, or in a health-care facility; video-observed therapy (VDOT) is an emerging, more convenient alternative. The decision to implement DOT should be made together with the patient, respecting patient autonomy.^[1]

Infection prevention and control

Notify the local public health department or equivalent authority for contact tracing whenever TB disease is confirmed or strongly suspected — a mandatory reporting obligation. The scope of contact tracing varies with the site(s) of involvement, symptoms, level of infectivity, length of illness, and drug resistance.^[3]

All patients with known or suspected pulmonary TB should be hospitalized in a single-occupancy negative-pressure room with airborne precautions, or isolated at home if high-risk contacts (e.g., young children, immunocompromised individuals) and unexposed contacts can be avoided. Health-care providers should wear a properly fitted N95 respirator when caring for a patient with known or suspected infectious TB; the patient should wear a surgical mask to reduce expulsion of infectious droplets.^[3]

Sputum smear conversion is no longer an absolute requirement for de-isolation — smear status becomes a less reliable marker of infectiousness once a patient is established on effective therapy, and prolonging isolation unnecessarily while waiting for conversion can cause real patient harm.^[3]

Adjunctive measures

• Adequate nutrition may enhance healing and reduce relapse risk.
• Counsel against alcohol and other hepatotoxins during treatment, since they can aggravate drug-induced hepatitis.
• Encourage smoking cessation.
• Encourage active diabetes management — glycemic control affects the risk of treatment failure, relapse, and mortality.
• Refer for management of comorbid conditions such as HIV, hepatitis C, and substance use disorder.
• Mandatory close follow-up throughout treatment — monthly clinic visits with bloodwork, regular chest radiographs, and a final radiograph at treatment completion.
• Continue follow-up after treatment completion to monitor for recurrence, which occurs mostly in the first 12-24 months post-treatment, and ensure continuity of care given ongoing morbidity/mortality risk and the possibility of post-TB lung disease.

Pediatric TB

When TB is diagnosed in a young child, undertake reverse-contact tracing without delay to identify the infectious source case, typically an adolescent or adult household contact. With rare exceptions (e.g., cavitary or laryngeal TB), children under 5 are not considered infectious themselves, but untreated TB in this age group carries a substantially higher risk of severe disease (miliary or meningeal TB) — investigate and treat promptly on clinical suspicion, often without waiting for microbiologic confirmation.^[7]

Dosing of TB medications in children is weight-based (mg/kg), and the recommended mg/kg range differs from adult dosing for some drugs (see Drug Tables) — do not simply scale an adult dose. Ethambutol requires caution in young children who cannot be reliably assessed for visual toxicity.^[7]

Children under 5 who are exposed to an infectious case and are initially TST-negative may be eligible for primary preventive therapy ("window period prophylaxis") with rifampin or isoniazid until a repeat TST is performed 8-12 weeks after the last exposure. Consult a TB specialist for exposures involving children under 6 months of age, since TST results can be difficult to interpret at that age.^[7]

HIV co-infection

Maintain a high index of suspicion — patients with HIV can present atypically and asymptomatically, sputum smears are often negative, and miliary/disseminated disease is more common at lower CD4 counts.^[8]

Manage HIV-TB co-infection in consultation with a TB or HIV specialist, given extensive antiretroviral drug interactions (particularly with rifamycins) and the risk of immune reconstitution inflammatory syndrome (IRIS). Rifabutin is generally preferred over rifampin in patients on protease inhibitors or certain non-nucleoside reverse transcriptase inhibitors, since it has more manageable interactions, though dose adjustment is still required. Intermittent TB treatment regimens are not recommended in people living with HIV.^[8]

Extrapulmonary and disseminated disease

Management principles mirror pulmonary TB, but prolonged treatment (minimum 9-12 months) is recommended for CNS TB (including TB meningitis) and may be required for disseminated or bone/joint TB with high-risk features. Adjunctive corticosteroids are routinely recommended for meningeal TB, since they reduce short-term mortality; for pericardial TB, corticosteroids are recommended in HIV-negative patients but not in HIV-positive patients who are not on antiretroviral therapy. Always consult a TB specialist for CNS or pericardial TB.^[8]

Pregnancy

TB in pregnancy can be harder to recognize, since fatigue and malaise may be attributed to pregnancy itself and pregnancy-related immune suppression can make presentation atypical or even asymptomatic. Untreated TB disease in pregnancy is associated with adverse maternal outcomes and a higher risk of prematurity/low birth weight, and can be transmitted to the baby in utero (congenital TB) or postpartum — treatment should never be withheld during pregnancy or postpartum, since the risk of untreated disease outweighs the risk of treatment.^[8]

Preferred initial regimen in pregnancy: isoniazid + rifampin + ethambutol — these cross the placenta but have not shown teratogenic effects. Add pyridoxine for any pregnant patient on isoniazid.^[8]

Pyrazinamide's use in pregnancy is controversial in North America due to limited teratogenicity data, though it is recommended by the WHO and used widely elsewhere; consider including it for pregnant patients with advanced HIV, extensive/disseminated disease, or smear-positive pulmonary TB. If pyrazinamide is excluded, extend treatment duration to a minimum of 9 months.^[8]

TB disease is not an indication for pregnancy termination. Drug-resistant disease in pregnancy needs specialist counselling given the teratogenic potential of some second-line agents. A patient in labour with infectious TB should wear a mask, with airborne precautions maintained until no longer considered infectious; separation from the newborn is a last resort, generally unnecessary once both are receiving appropriate therapy.^[8]

TB infection screening is not routinely indicated in pregnancy but may be considered in patients at very high risk of progression (e.g., HIV). In lower-risk patients, TPT can be deferred to 3 months postpartum to reduce hepatotoxicity risk; if treatment is needed during pregnancy, rifampin for 4 months is preferred. If isoniazid therapy is unavoidable in pregnancy or postpartum, monitor closely for hepatotoxicity and give pyridoxine.^[4]

Breastfeeding

Breastfeeding is not contraindicated with first-line TB therapy (isoniazid, rifampin, pyrazinamide, ethambutol) — drug concentrations in breast milk are small and have not been shown to cause infant toxicity, and are not sufficient to treat an infant's own TB. Give pyridoxine to all breastfeeding patients taking isoniazid; the breastfed infant does not need supplemental pyridoxine unless the infant is separately taking isoniazid. Consult a TB specialist before breastfeeding on second-line therapy.^[8]

Renal and hepatic impairment

Consult a TB specialist for patients with severe liver disease before starting isoniazid or rifampin. Dosage adjustment of some first-line drugs may be required in significant renal impairment (see Drug Tables) — pyrazinamide and ethambutol are renally cleared and often require adjusted dosing or frequency, while isoniazid and rifampin are primarily hepatically metabolized.^[1]

Reassess patients at least monthly throughout treatment, combining clinical, radiologic, and microbiologic parameters. Obtain follow-up chest imaging at 2 months and at the end of therapy. If initially smear-positive, collect sputum cultures every 2 weeks until smear conversion is documented, then again at 2 months and 1 month before the anticipated end of therapy; if culture remains positive at 2 months, obtain monthly sputum samples until culture conversion. Repeat drug susceptibility testing if cultures remain persistently positive after 3 months of treatment.^[1]

Hepatotoxicity monitoring: drug-induced liver injury is defined as AST or ALT at least 3 times the upper limit of normal in a symptomatic patient (nausea, vomiting, abdominal pain, jaundice), or at least 5 times the upper limit of normal in an asymptomatic patient. Asymptomatic transaminase elevation is common; any decision to stop or withhold hepatotoxic drugs should include an explicit plan to reassess and safely rechallenge. Pyrazinamide is the most hepatotoxic of the 4 first-line drugs.^[1]

Ethambutol/visual monitoring: assess visual acuity and colour vision at baseline and monthly in any patient on ethambutol for longer than 2 months — Ishihara-type colour vision diagrams can be used.^[1]

Therapeutic drug monitoring (TDM) is not routinely indicated but can help guide dosing in patients with liver or kidney dysfunction, drug-resistant disease, or malabsorption risk (e.g., low body mass index, HIV co-infection); samples currently need to be sent to the United States for analysis, since routine TDM is not available in Canada.^[1]

After treatment completion, continue follow-up to monitor for recurrence — which occurs mostly within the first 12-24 months — and ensure continuity of care, given the risk of post-TB sequelae such as post-TB lung disease.^[1]

For TB infection treatment: obtain baseline CBC and liver enzymes, with monthly testing suggested during TPT, particularly in patients with pre-existing liver disease or older age, given the higher hepatotoxicity risk in these groups.^[4]

1. Suspected drug-induced hepatitis (symptomatic, or asymptomatic transaminases meeting the threshold above): withhold all hepatotoxic drugs (isoniazid, rifampin, pyrazinamide) immediately and consult a local TB specialist to re-establish therapy — with a substitute regimen if needed — as quickly as possible.
2. GI intolerance: evaluate for drug-induced hepatitis first and review concomitant/new medications; if hepatotoxicity is excluded, try administering first-line drugs with a small amount of food, changing the time of administration, or adding an antiemetic/antacid before switching to a second-line agent.
3. Treatment interruption of at least 14 days during the intensive phase, or at least 2 months during the continuation phase with less than 80% of planned doses taken: restart the full 4-drug intensive phase from the beginning.
4. Cultures remain persistently positive after 3 months of treatment: repeat drug susceptibility testing and consult a TB specialist to reassess the regimen.
5. Any suspected or confirmed drug resistance, treatment failure, or relapse: refer immediately to a TB specialist — never add a single drug to a regimen suspected of failing, since this risks amplifying resistance.

• Using single-drug therapy for TB disease, or adding a single new drug to a failing or suspected drug-resistant regimen.
• Using twice-weekly dosing — no longer recommended in Canada under any circumstance.
• Using intermittent (thrice-weekly) dosing during the intensive phase — associated with worse outcomes; intermittent dosing is only appropriate, with DOT, in the continuation phase in select circumstances.
• Relying on a negative sputum smear or NAAT alone to exclude active pulmonary TB — roughly half of patients with TB disease have negative smears.
• Using TST or IGRA to diagnose, or exclude, TB disease in an adult — neither test distinguishes infection from disease.
• Starting TB preventive therapy without first ruling out TB disease.
• Forgetting pyridoxine in a patient on isoniazid who has risk factors for peripheral neuropathy — poor nutrition, HIV, alcohol or substance use, diabetes, chronic kidney disease, or a seizure disorder — or in a pregnant/breastfeeding patient on isoniazid.
• Missing rifampin's extensive CYP-mediated drug interactions — hormonal contraceptives, anticoagulants, antihyperglycemic agents, immunosuppressants, and methadone all need review whenever a rifamycin is started or stopped.
• Not warning patients that rifampin (and, to a lesser extent, rifabutin) causes harmless orange discoloration of urine, sweat, tears, and other body fluids, and can permanently stain soft contact lenses.
• Discontinuing ethambutol without first confirming full first-line drug susceptibility.
• Not extending treatment to a minimum of 9 months when pyrazinamide is omitted, or when disease is extensive/cavitary with a persistently positive smear or culture at 2 months.
• Missing the mandatory public health notification obligation for confirmed or strongly suspected TB disease.
• Combining isoniazid with acetaminophen, ethanol, or rifampin without counselling on additive hepatotoxicity risk.

The drugs below are the first-line agents for drug-susceptible TB infection and TB disease. Drug-resistant TB requires individualized, specialist-directed second-line regimens and is beyond the scope of this reference table — refer any patient with suspected or confirmed drug-resistant TB to a TB specialist.

Drug-resistant TB — brief overview

Monoresistance to isoniazid is the most common resistance pattern in Canada. Isolated rifampin resistance is less common and should prompt immediate susceptibility testing of other first- and second-line drugs. Multidrug-resistant TB (MDR-TB) refers to strains resistant to both isoniazid and rifampin. Extensively drug-resistant TB (XDR-TB) refers to MDR-TB or rifampin-resistant TB (RR-TB) with additional resistance to fluoroquinolones and at least one other Group A drug; Group A drugs — the most potent second-line agents — currently include levofloxacin, moxifloxacin, bedaquiline, and linezolid. Pre-XDR-TB is MDR-TB or RR-TB with fluoroquinolone resistance but no resistance to other Group A drugs. MDR-TB and XDR-TB carry high morbidity and mortality — refer all patients with MDR-TB to a TB specialist with expertise in MDR-TB therapy.^[5] The 2025 ATS/CDC/ERS/IDSA international guideline now recommends a 6-month all-oral regimen (bedaquiline + pretomanid + linezolid + moxifloxacin) over regimens lasting 15 months or longer for most rifampin-resistant, fluoroquinolone-susceptible TB — this reflects a broader international shift toward shorter drug-resistant regimens; specific regimen selection remains fully specialist-directed and is not addressed further here.

Non-rifamycin antimycobacterials

Rifamycin antimycobacterials

Every rifamycin carries extensive drug interactions, mainly through hepatic enzyme induction — review the complete medication list whenever one is started or stopped.

Adjunct therapy