Mycobacterium tuberculosis

• Mycobacterium tuberculosis causes tuberculosis
• Most commonly pulmonary TB but extrapulmonary tuberculosis is possible (including adenitis, gastrointestinal TB, pericarditis, meningitis)
• Standard treatment for susceptible TB is RIPE x2mo then RI x4mo

Background

Microbiology

• Fastidious, aerobic acid-fast bacillus
• Cell wall has high lipid content
• Generation time is very long (15 to 20 hours)
• M. tuberculosis is a complex that comprises seven species:
  • M. tuberculosis sensu stricto: most common causative organism worldwide
  • M. africanum: 50% of cases in West africa
  • M. canetti: rare cause in Eastern African
  • M. bovis: disease in cattle but can infect humans
  • M. caprae: disease in cattle
  • M. microti: disease in rodents
  • M. pinnipdeii: disease in seals, with rare human infection

Epidemiology

• Typically spread via airborne route
  • Droplets are expelled during coughing, sneezing, or talking, and are suspended in the air
  • They can remain for up to 30 minutes
  • Killed by ultraviolet light
  • Not transmitted via fomites
• About a third of the world is infected, mostly as latent tuberculosis
  • This progresses to active tuberculosis at about 3 or 4% in the first year and 5% over the rest of their life
• Reinfection accounts for ~40% of active tuberculosis in endemic countries
• Highest rates in sub-Saharan Africa and south/southeast Asia

Risk Factors

• Source factors, such as sputum smear positivity, cough, cavitations
• Exposure duration, closeness of contact
• Factors in the exposed person, such as immune compromise, HIV status

Clinical Manifestations

Classification

• Primary vs. reactivation vs. reinfection
• Latent vs. active

Primary Tuberculosis

• Primary tuberculosis is usually asymptomatic
• Possible presentations include mild URTI with cough and/or fever
• May be seen on CXR as infiltrate in mid-lung zones with hilar adenopathy
• Ghon complex, especially in children
• May progress in children and the immunocompromised patients
• Immunological phenomena
  • Erythema nodosum
  • Phlyctenular conjunctivitis
  • Erythema induratum

Pulmonary Tuberculosis

• Most common presentation of active tuberculosis
• Refer to separate article on pulmonary tuberculosis

Extra-Pulmonary Tuberculosis

• Pleural tuberculosis is most common extrapulmonary site
• Scrofula (cervical lymph node infection) next-most common
• Tuberculous meningitis
• Tuberculous pericarditis
• Renal tuberculosis
• Abdominal tuberculosis
• Gastrointestinal tuberculosis
• Cutaneous tuberculosis

Latent Tuberculosis

• Refers to chronic latent infection contained within granulomas that may reactivate in the future
• Refer to Latent tuberculosis infection

Other

• Neonatal tuberculosis

Investigations

• Radiography: chest x-ray with or without CT chest
  • Primary TB: consolidation, lymphadenopathy, pleural effusion, Ghon complex
  • Reactivation TB: patchy upper-lobe consolidation, cavitation, fibrosis, pleural disease
  • Miliary TB: uniform 1-3 mm diameter diffuse nodules

Diagnosis

• Latent tuberculosis testing
  • Tuberculin skin test (TST)
  • Interferon-gamma release assay (IGRA)
• Serology or immunologic testing
  • Urine lipoarabinomannan antigen
• Microbiology
  • Samples can include routine or induced sputum (x3) or bronchoscopy, or tissue sample
  • Spontaneous sputum should include at least one morning sputum, ideally, but can be done all in a row at least one hour apart if needed
  • Acid-fast bacillus culture of sputum x3 is about 70% sensitive, and PCR (ANTB) x1 is about 75% sensitive
• Molecular testing
  • PCR, including GeneXpert

Management

• Requires at least 2 effective drugs at all times, including at least 3 effective drugs during intensive phase
• Most patients are started on RIPE,
  • Typical duration is intensive therapy for 2 months (with at least 3 drugs), then narrowed to at least 2 drugs for the remainder of treatment
  • Rifampin is the most effective agent, and any regimen that excludes rifampin must be extended to 12-18 months
• See also:
  • Management of pulmonary tuberculosis
  • Management of tuberculous meningitis
  • Management of drug-resistant tuberculosis

Antibiotics

Drug	Dose	Side effects
First-Line Medications
Isoniazid	5 mg/kg daily, max 300 mg daily, with pyridoxine 25 mg po daily	Rash, hepatitis, neuropathy, CNS toxicity, anemia
Rifampin	10 mg/kg daily	Drug interactions, rash, hepatitis, flu-like illness, neutropenia, thrombocytopenia
Pyrazinamide	25 mg/kg daily, max 2 g daily	Hepatitis, rash, arthralgia, gout
Ethambutol	20 mg/kg daily, max 1.2 g daily	Optic/retrobulbar neuritis, rash
Second-Line Medications
Streptomycin	15 mg/kg daily, max 1 g	Auditory and vestibular toxicity, renal toxocity, avoid in pregnancy
Amikacin, kanamycin, or capreomycin	15 mg/kg daily, man 1 g
Ethionamide	250 mg BID to TID, max 1 g	GI disturbance, hepatotoxicity, endocrine effects, neurotoxicity, avoid in pregnancy
Para-amino salicylic acid	4 g BID or TID, max 10 g	GI disturbance, hepatic dysfunction, hypothyroidism, avoid in aspirin allergy
Cycloserine	250 mg BID to TID, max 1 g	Avoid in epilepsy, psychiatric illness, and alcoholism
Levofloxacin	500 to 1000 mg po daily	GI disturbance, headache, anxiety, tremor, long QT, avoid in pregnancy and children
Moxifloxacin	400 to 600 mg daily
Rifabutin	300 mg daily	Hepatotoxicity, uveitis, thrombocytopenia, neutropenia, drug interactions
Clofazimine	100 to 300 mg daily	Skin discolouration, conjunctiva, cornea, body fluid discolouration, GI intolerance, photosensitivity
Third-Line Medications
Linezolid	600 mg po daily
Bedaquiline	400 mg po daily for 2 weeks followed by 200 mg thrice weekly	Arthralgias, dizziness, headache, hyperuriemia, insomnia, myalgia, nausea, prolonged ECG QT interval, pruritus, and vomiting
Pretomanid
Delamanid
Adjunctive Therapies
Corticosteroids for patients with tuberculous meningitis or tuberculous pericarditis	Prednisone 40 to 80 mg po daily for 6 to 12 weeks

Duration

Syndrome	Total Duration	Notes
Pulmonary Tuberculosis
Standard	6 months
Cavitary disease, with diabetes	9 months
Elderly >75 years	9 months	without pyrazinamide
High risk of hepatitis	9 months	without pyrazinamide
High risk of recurrence	9 months	extensive disease, or baseline cavitary disease with smear or culture positive at 2 months
Pregnancy	6-9 months	with or without pyrazinamide
HIV (untreated)	9 months
Severe liver disease, avoiding RIF	12-18 months	without rifampin, isoniazid, and pyrazinamide
Solid-organ transplant	9 months
TNF-alpha inhibitors	9 months
Extra-Pulmonary Tuberculosis
Bone and joint	6-12 months	high risk of relapse; duration depends on severity of disease
CNS TB, meningitis	9-12 months	with steroids
CNS TB, tuberculoma or arachnoiditis	9-12 months	without steroids unless significant mass effect
Cutaneous	6 months
Disseminated disease	6 months
Disseminated disease, with diabetes	9 months
Genitourinary	6 months
Lymphadenitis	6 months	surgery not necessary
Ocular	6 months
Pericarditis	6 months	with steroids if HIV-negative, without steroids if untreated HIV, unclear use if treated HIV
Pleural	6 months	drainage not necessary

Drug-Induced Liver Injury (DILI)

• Most common complication leading to treatment interruption, with a mortality of 6-12% if drugs are not stopped
• Pyrazinamide, followed by isoniazid, then rifampin, are the most common causes of liver injury12
• Most patients can have the same TB drugs reintroduced without recurrence of DILI, though recurrence can be delayed
• Procedure
  • Hold if ALT >120 and symptoms, if ALT >200 even without symptoms, or bili >2x ULN
  • Switch to second-line meds
  • Reintroduce the original drugs once AST & ALT are <2x ULN
  • Only rechallenge with pyrazinamide if it was a mild case

Adherence to Treatment

• Refer to Let's Talk TB

Special Populations

Liver Disease

• Most of the first-line medications (except ethambutol) can cause drug-induced hepatotoxicity and should be avoided
  • Rifampin may be considered in more extensive disease
• In general, a combination of fluoroquinolone plus ethambutol plus an injectable such as amikacin for the first 2 months, followed by fluoroquinolone and ethambutol alone to complete 18 months total

Prevention

Vaccination

• BCG vaccine given at or shortly after birth in many countries

Infection Prevention and Control

• All cases of suspected tuberculosis should be placed in airborne isolation until three sputum smears are negative for tuberculosis, unless it is still suspected and no other diagnosis is made
  • Sputum samples minimum of 1 hour apart, and at least one early morning sample
  • Three induced sputa are preferable to one bronchoscopy
  • Can accept a single negative PCR test if patient is low probability
  • Can accept two negative PCR tests or 1 negative PCR and 2 negative smears if patient is high probability
• For patients with smear-negative, culture-positive, drug-susceptible respiratory TB:
  • Continue airborne precautions until clinical evidence of improvement and a minimum of 2 weeks of effective therapy
  • Can be discharged home provided there is clinical improvement, drug-resistant TB is not suspected, and there is no contraindication for home isolation
• For patient with smear-positive, culture-positive, drug-susceptible respiratory TB:
  • Continue airborne precautions as above, but additionally require three negative sputum smears to be negative before they are taken out of airborne isolation
  • Can be discharge home as above
• For patients with rifampin- or multidrug-resistant TB:
  • Continue airborne precautions as above, but additionally require three negative sputum cultures to be negative before they are taken out of airborne isolation

Further Reading

• Canadian Tuberculosis Standards, 8th Edition. Can J Respiratory Crit Care Sleep Med. 2022;6:sup1.
  • Chapter 1: Epidemiology of tuberculosis in Canada
  • Chapter 2: Transmission and pathogenesis of tuberculosis
  • Chapter 3: Diagnosis of tuberculosis disease and drug-resistant tuberculosis
  • Chapter 4: Diagnosis of tuberculosis infection
  • Chapter 5: Treatment of tuberculosis disease
  • Chapter 6: Tuberculosis preventive treatment in adults
  • Chapter 7: Extra-pulmonary tuberculosis
  • Chapter 8: Drug-resistant tuberculosis
  • Chapter 9: Pediatric tuberculosis
  • Chapter 10: Treatment of active tuberculosis in special populations
  • Chapter 11: Tuberculosis contact investigation and outbreak management
  • Chapter 12: An introductory guide to tuberculosis care to improve cultural competence for health care workers and public health professionals serving Indigenous Peoples of Canada
  • Chapter 13: Tuberculosis surveillance and tuberculosis infection testing and treatment in migrants
  • Chapter 14: Prevention and control of tuberculosis transmission in healthcare settings
  • Chapter 15: Monitoring tuberculosis program performance