Tuberculosis
Clinical Snapshot
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]
Recognize the Condition
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]
The two states of Mtb infection
TB infection (previously "latent TB")
Dormant Mtb contained by host immune defenses. Asymptomatic and non-infectious, but carries a real lifetime risk of progressing to TB disease, substantially higher in specific risk groups (see Risk Factors).[4] Diagnosed by TST or IGRA plus a normal chest radiograph and absence of symptoms; treated with TB preventive therapy (TPT) to reduce future progression risk.
TB disease (previously "active TB")
Active proliferation of Mtb causing symptomatic illness, most often pulmonary but potentially involving any organ. Diagnosed by microbiologic confirmation (culture and/or NAAT) wherever possible. Pulmonary or laryngeal TB disease is potentially infectious to others and requires airborne isolation, multidrug treatment, and public health notification.
Risk Factors
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.
Red Flags & Refer
Any confirmed or strongly suspected TB disease requires urgent escalation to a TB specialist and mandatory public health notification — this is not a condition to manage independently in primary care or community pharmacy.
- Hemoptysis — assess urgently; can indicate cavitary disease or, rarely, erosion into a major vessel.
- Signs of disseminated or miliary TB — high fever, marked constitutional symptoms, or a miliary pattern on chest imaging — refer immediately, especially in children under 5 and immunocompromised patients, given the high risk of severe disease.
- Suspected CNS TB — neck stiffness, meningeal signs, altered mental status, or new neurologic deficits — refer emergently; managed only in consultation with a TB specialist.
- Signs of severe hepatotoxicity on TB treatment — jaundice, dark urine, marked nausea/vomiting, abdominal pain, or unusual fatigue — hold all hepatotoxic TB drugs immediately and refer for urgent assessment.
- New or worsening visual symptoms in a patient on ethambutol — decreased visual acuity, altered colour vision, or visual field changes — hold ethambutol immediately and refer for urgent ophthalmologic assessment.
- Any confirmed or suspected active TB disease must be reported to the local public health authority for contact tracing and case management — a mandatory legal reporting obligation, not a discretionary referral.
- Suspected drug-resistant TB — prior TB treatment, a known drug-resistant contact, or persistently positive cultures — refer to a TB specialist with drug-resistant TB expertise; never add a single drug to a failing or suspected drug-resistant regimen.
- Signs of a severe cutaneous drug reaction (e.g., blistering rash, mucosal involvement, fever) in a patient on TB medications — hold all agents and refer urgently.
Assessment & Diagnosis
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
| Induration | Interpretation |
|---|---|
| Less than 5 mm | Generally considered negative. |
| 5 mm or more | Positive in: recent (under 2 years) contact with infectious TB; HIV infection; stage 4-5 chronic kidney disease (with or without dialysis); before organ transplantation or immunosuppressive therapy; before biologic or disease-modifying antirheumatic drug therapy; before corticosteroid therapy (prednisone-equivalent 15 mg/day or more for at least 1 month); fibronodular disease on chest radiograph. |
| 10 mm or more | Positive in all other individuals being tested. |
Interpretation should also weigh pre-test probability and clinical context.[2]
Causes of false TST results
| False-positive | False-negative |
|---|---|
| Prior BCG vaccination | Impaired cell-mediated immunity |
| Exposure to nontuberculous mycobacteria | TB disease or other serious infection/illness |
| Inappropriate technique or reading (e.g., recording erythema instead of induration) | Extremes of age; inappropriate technique or reading (e.g., tuberculin drawn up more than 20 minutes before administration); storage/stability issues (sunlight exposure, cold-chain excursions, expired vials) |
Treatment Targets
- 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.
Choose Initial Treatment
Before treating TB infection: rule out TB disease
Confirm the absence of TB disease through clinical assessment and chest radiograph before starting TB preventive therapy (TPT) — treating TB disease with a TPT regimen risks selecting for drug resistance.[4]
TB infection: regimen selection
1st line rifampin 10 mg/kg (up to 600 mg) PO once daily for 4 months, OR isoniazid + rifapentine once weekly by DOT for 3 months (12 doses) — the isoniazid + rifapentine option is only for patients 2 years of age or older, and rifapentine availability in Canada is limited to Health Canada's Urgent Public Health Need program.[4]
2nd line — use when a rifamycin-containing regimen is contraindicated or not tolerated: isoniazid alone, daily, for 9 months.[4]
Consult a TB specialist for alternative regimens, or whenever the source case has known or suspected drug-resistant TB.[4]
TB disease: intensive phase
All patients, 1st line: start empiric 4-drug therapy — isoniazid + rifampin + pyrazinamide + ethambutol, daily — for 2 months, pending drug susceptibility results. Never start TB disease treatment with fewer than 3-4 drugs, and never use single-drug therapy or add a single drug to a failing regimen.[1]
Once the isolate is confirmed fully susceptible to first-line drugs, and the patient is tolerating, adhering to, and responding to treatment, ethambutol may be discontinued.[1]
Consider omitting pyrazinamide — use when hepatotoxicity risk is elevated (e.g., age over 65): treat with isoniazid + rifampin + ethambutol instead, and extend total treatment duration to a minimum of 9 months.[1]
TB disease: continuation phase and total duration
Fully susceptible disease, standard risk: continue isoniazid + rifampin daily (or thrice weekly under DOT) for 4-7 additional months, for a minimum total treatment duration of 6 months.[1]
Extend total duration to a minimum of 9 months — use for extensive or cavitary pulmonary TB with a persistently positive sputum smear or culture at 2 months, or whenever pyrazinamide is omitted from the regimen.[1]
Do not use intermittent (thrice-weekly) dosing during the intensive phase — associated with worse outcomes. Twice-weekly regimens are no longer recommended in Canada under any circumstance. Any intermittent dosing requires DOT throughout.[1]
Emerging option — not yet adopted in Canada
A 4-month regimen (isoniazid + rifapentine + moxifloxacin + pyrazinamide) is conditionally recommended in the 2025 ATS/CDC/ERS/IDSA international guideline for drug-susceptible pulmonary TB in patients aged 12 years and older. This regimen is not currently recommended by the Canadian Tuberculosis Standards, given a higher observed rate of treatment failure and relapse relative to the standard 6-month regimen in the trial supporting it — do not substitute it for the standard regimen above outside a specialist-directed context.[6]
Non-Pharmacologic Treatment
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]
| Clinical scenario | Criteria for de-isolation |
|---|---|
| Smear-negative, rifampin-susceptible | Clinical improvement, plus a minimum of 2 weeks of effective therapy completed. |
| Smear-positive, rifampin-susceptible | Clinical improvement, a minimum of 2 weeks of effective therapy completed, and 3 consecutive negative AFB sputum smears — or, if smears remain persistently positive, a minimum of 4 weeks of effective therapy with clinical improvement. |
| Rifampin- or multidrug-resistant | Consult local TB and public health experts — de-isolation criteria are individualized. |
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.
Special Populations
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]
Monitoring & Follow-Up
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]
Common Errors to Avoid
- 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.
Clinical Decision Algorithm
Drug Tables
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
| Drug | Dosage | Adverse effects | Drug interactions | Comments |
|---|---|---|---|---|
| Ethambutol | TB disease — adults, daily: 15-20 mg/kg/day (up to 1600 mg/day) PO TB disease — adults, DOT thrice weekly: 25-40 mg/kg (up to 2400 mg/dose) PO TB disease — children, daily: 15-25 mg/kg/day (up to 1600 mg/day) PO TB disease — children, DOT thrice weekly: 30-50 mg/kg (up to 2400 mg/dose) PO | Dose-related ocular toxicity (decreased visual acuity, central scotomata, red-green colour blindness, rare retrobulbar neuritis), skin rash including rare Stevens-Johnson syndrome/toxic epidermal necrolysis, hematologic effects, GI upset, neurologic effects (headache, dizziness, confusion, hallucinations) | Decreased ethambutol levels with concomitant aluminum hydroxide — separate doses by at least 4 hours | 1st-line agent. Assess colour vision and visual acuity at baseline and monitor monthly if used beyond 2 months (Ishihara-type diagrams available online). Can be used in pregnancy. |
| Isoniazid | TB infection — adults, daily: 5 mg/kg/day (up to 300 mg) PO TB infection — adults, with rifapentine (DOT, weekly): 15 mg/kg (up to 900 mg) PO TB infection — children, daily: 10-15 mg/kg/day (up to 300 mg) PO TB disease — adults, daily (preferred over intermittent): 5 mg/kg/day (up to 300 mg/dose) PO TB disease — adults, DOT thrice weekly: 10-15 mg/kg (up to 900 mg/dose) PO TB disease — children, daily: 10-15 mg/kg/day (up to 300 mg/day) PO TB disease — children, DOT thrice weekly: 20-30 mg/kg (up to 900 mg/dose) PO | Asymptomatic transaminase/bilirubin increase (common), clinical hepatitis (symptoms typically within 2 weeks to 6 months), dose-related peripheral neuropathy, hematologic effects, GI upset, gynecomastia, seizure, drowsiness, drug-induced lupus, toxic encephalopathy, pancreatitis, fever, skin rash, mood changes, lymphadenopathy | Increases serum levels of carbamazepine, phenytoin, and theophylline; increased hepatotoxicity with rifampin, ethanol, or acetaminophen; cross-hepatotoxicity can occur between chemically related drugs (isoniazid and pyrazinamide) — avoid both if a reaction to one occurs | 1st-line agent. Educate on hepatitis symptoms. Can be used in pregnancy. Give pyridoxine to reduce peripheral neuropathy risk. Best absorbed on an empty stomach; may take with a small amount of food if GI intolerance occurs. Consult a specialist in severe liver disease. |
| Pyrazinamide | Adults, daily: 20-25 mg/kg/day (up to 2000 mg/day) PO Adults, DOT thrice weekly: 30-40 mg/kg (up to 3000 mg/dose) PO Children, daily: 30-40 mg/kg/day (up to 2000 mg/day) PO Children, DOT thrice weekly: 60-80 mg/kg (up to 3000 mg/dose) PO | Hepatotoxicity (the most hepatotoxic first-line drug, though rare within the first 2 months of therapy), rash, arthralgia, increased uric acid (acute gout rarely seen), drug fever, GI upset, hematologic effects | Increased pyrazinamide levels with concomitant allopurinol (xanthine oxidase inhibition) | 1st-line agent. Consider omitting in patients over 65 or others at high hepatotoxicity risk, extending total treatment duration to at least 9 months if omitted. |
Rifamycin antimycobacterials
Every rifamycin carries extensive drug interactions, mainly through hepatic enzyme induction — review the complete medication list whenever one is started or stopped.
| Drug | Dosage | Adverse effects | Drug interactions | Comments |
|---|---|---|---|---|
| Rifampin | TB infection — adults: 10 mg/kg/day (up to 600 mg/day) PO TB infection — children: 10-20 mg/kg/day (up to 600 mg/day) PO TB disease — adults, daily: 10 mg/kg/day (no maximum) PO TB disease — adults, DOT thrice weekly: 10 mg/kg (no maximum) PO TB disease — children, daily: 10-20 mg/kg/day (up to 600 mg/day) PO TB disease — children, DOT thrice weekly: 10-20 mg/kg (up to 600 mg/dose) PO | GI upset, diarrhea, flulike illness, orange discoloration of body fluids (can permanently stain contact lenses) and teeth, urticaria/rash (a petechial rash may suggest thrombocytopenia), subclinical disseminated intravascular coagulation, ataxia, confusion, visual disturbances, hepatotoxicity, acute interstitial nephritis, hematologic effects | Many interactions with HIV medications — consult a TB/HIV specialist. Decreases serum concentration of drugs via hepatic enzyme induction, including estrogen-containing contraceptives, anticoagulants, antihyperglycemic agents, immunosuppressants, and methadone — reassess the affected drug's dose whenever a rifamycin is started or stopped. Avoid combining with doravirine, etravirine, elvitegravir, nevirapine, protease inhibitors, rilpivirine, or tenofovir alafenamide. Integrase inhibitor or maraviroc doses may need to be increased if used concomitantly. | 1st-line agent. Can be used in pregnancy. Frequently implicated in drug interactions — the single most important interaction check for any new TB disease patient. Best absorbed on an empty stomach; may take with a small amount of food if GI intolerance occurs. Consult a specialist in severe liver disease. |
| Rifabutin | Adults: 5 mg/kg/day (up to 300 mg/day) PO | GI upset, flulike illness, rash, orange discoloration of body fluids (can stain contact lenses), hepatotoxicity, neutropenia, leukopenia, thrombocytopenia, myalgia, taste perversion, uveitis | Adjust the rifabutin dose when combined with efavirenz or protease inhibitors — protease inhibitors decrease rifabutin clearance while efavirenz increases it. Do not use with elvitegravir, bictegravir, or tenofovir alafenamide. Consult a TB/HIV specialist. Decreases serum concentration of other drugs via hepatic enzyme induction, similar to rifampin. | Preferred rifamycin in HIV-infected patients treated with protease inhibitors or non-nucleoside reverse transcriptase inhibitors. Should not be used first-line in HIV-negative patients unless medication interactions preclude rifampin use. |
| Rifapentine | 10 to 14 kg: 300 mg PO once weekly More than 14 to 25 kg: 450 mg PO once weekly More than 25 to 32 kg: 600 mg PO once weekly More than 32 to 50 kg: 750 mg PO once weekly More than 50 kg: 900 mg PO once weekly | GI upset, flulike illness, orange discoloration of body fluids (can stain contact lenses), hepatotoxicity, anemia, leukopenia | Many interactions with HIV medications — consult a TB/HIV specialist. Decreases serum concentration of drugs via hepatic enzyme induction, including estrogen-containing contraceptives, anticoagulants, antihyperglycemic agents, immunosuppressants, and methadone. May be safe with dolutegravir; more data are needed for boosted protease inhibitors and tenofovir. | Use in Canada is limited — available only through Health Canada's Urgent Public Health Need program. Only for TB infection, combined with isoniazid, in patients 2 years of age or older. Give pyridoxine 50 mg with each weekly dose. |
Adjunct therapy
| Drug | Dosage | Adverse effects | Drug interactions | Comments |
|---|---|---|---|---|
| Pyridoxine (vitamin B6) | Isoniazid neuropathy prevention — adults: 25 mg PO daily, up to 100 mg PO daily if neuropathy develops Isoniazid + rifapentine (3HP) regimen: 50 mg PO with each weekly dose | Well tolerated at neuropathy-prevention doses; chronic use of very high doses (well above these doses) has been associated with sensory neuropathy | None significant at the doses used for isoniazid neuropathy prevention | Routinely offered to patients on isoniazid, especially with poor nutrition, HIV infection, alcohol or substance use disorder, diabetes, chronic kidney disease, or a seizure disorder, and to pregnant/breastfeeding patients on isoniazid. At much higher intravenous doses, pyridoxine is also the specific antidote for isoniazid overdose, given gram-for-gram with the amount of isoniazid ingested. |
References
- Chapter 5: Treatment of Tuberculosis Disease — Canadian Tuberculosis Standards, 8th Edition — Canadian Journal of Respiratory, Critical Care, and Sleep Medicine, Canadian Thoracic Society / Public Health Agency of Canada (Johnston JC, Cooper R, Menzies D). Can J Respir Crit Care Sleep Med 2022;6(sup1):66-76
- Chapter 4: Diagnosis of Tuberculosis Infection — Canadian Tuberculosis Standards, 8th Edition — Canadian Journal of Respiratory, Critical Care, and Sleep Medicine, Canadian Thoracic Society / Public Health Agency of Canada (Campbell JR, Pease C, Daley P, et al.). Can J Respir Crit Care Sleep Med 2022;6(sup1):49-65
- Chapter 3: Diagnosis of Tuberculosis Disease and Drug-Resistant Tuberculosis — Canadian Tuberculosis Standards, 8th Edition — Canadian Journal of Respiratory, Critical Care, and Sleep Medicine, Canadian Thoracic Society / Public Health Agency of Canada (Behr MA, Grandjean Lapierre S, Kunimoto DY, et al.). Can J Respir Crit Care Sleep Med 2022;6(sup1):33-48
- Chapter 6: Tuberculosis Preventive Treatment in Adults — Canadian Tuberculosis Standards, 8th Edition — Canadian Journal of Respiratory, Critical Care, and Sleep Medicine, Canadian Thoracic Society / Public Health Agency of Canada (Alvarez GG, Pease C, Menzies D). Can J Respir Crit Care Sleep Med 2022;6(sup1)
- Chapter 8: Drug-Resistant Tuberculosis — Canadian Tuberculosis Standards, 8th Edition — Canadian Journal of Respiratory, Critical Care, and Sleep Medicine, Canadian Thoracic Society / Public Health Agency of Canada (Brode SK, Dwilow R, Kunimoto D, et al.). Can J Respir Crit Care Sleep Med 2022;6(sup1):109-128
- Updates on the Treatment of Drug-Susceptible and Drug-Resistant Tuberculosis: An Official ATS/CDC/ERS/IDSA Clinical Practice Guideline — American Journal of Respiratory and Critical Care Medicine, American Thoracic Society / CDC / European Respiratory Society / Infectious Diseases Society of America (Saukkonen JJ, Duarte R, Munsiff SS, et al.). Am J Respir Crit Care Med 2025;211(1):15-33
- Chapter 9: Pediatric Tuberculosis — Canadian Tuberculosis Standards, 8th Edition — Canadian Journal of Respiratory, Critical Care, and Sleep Medicine, Canadian Thoracic Society / Public Health Agency of Canada (Dwilow R, Hui C, Kakkar F, et al.). Can J Respir Crit Care Sleep Med 2022;6(sup1)
- Chapter 10: Treatment of Active Tuberculosis in Special Populations — Canadian Tuberculosis Standards, 8th Edition — Canadian Journal of Respiratory, Critical Care, and Sleep Medicine, Canadian Thoracic Society / Public Health Agency of Canada (Cooper R, Houston S, Hughes C, Johnston JC). Can J Respir Crit Care Sleep Med 2022;6(sup1):149-166
Professional reference only. Apply clinical judgment and verify patient-specific decisions against current authoritative guidance and product information.