Mycobacterium tuberculosis

Background

• 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

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 q8h including 1 early AM) 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
  • Consider rapid rifampin resistance testing (PCR) in all patients
• Most patients are started on RIPE
  • In cases of increased risk for MDR-TB, still use RIPE while awaiting rapid rifampin testing
  • 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
Rifampin	10 mg/kg daily, no max	Drug interactions, rash, hepatitis, flu-like illness, neutropenia, thrombocytopenia
Isoniazid	5 mg/kg daily, max 300 mg daily, with pyridoxine 25 mg po daily	Rash, hepatitis, neuropathy, CNS toxicity, anemia
Pyrazinamide	25 mg/kg daily, max 2 g daily	Hepatitis, rash, arthralgia, gout
Ethambutol	15 mg/kg daily, max 1.6 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

Doses by Weight

Drug	Dose	Tabs	Weight (kg)
			30-35	36-45	46-55	56-70	>70
First-Line Medications
rifampin	10 mg/kg	150 & 300 mg	300 mg	450 mg		600 mg
isoniazid	5 mg/kg	100 & 300 mg	150 mg	200 mg	300 mg
pyrazinamide	25 mg/kg	500 mg	750 mg	1000 mg	1250 mg	1500 mg	1750-2000 mg
ethambutol	15 mg/kg	100 & 400 mg	600 mg	800 mg	1000 mg	1200 mg
Alternative Medications
rifabutin			300 mg
levofloxacin			750 mg		1000 mg
moxifloxacin			400 mg
ethionamide			500 mg		750 mg		1000 mg
prothionamide			500 mg		750 mg		1000 mg
cycloserine			500 mg			750 mg
p-aminosalicylic acid			4 g bid				4 g bid to tid
bedaquiline			400 mg daily for 2 weeks then 200 mg 3 times per week
clofazimine			200-300 mg for 2 months then 100 mg
linezolid			600 mg daily

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

Routine Monitoring

Clinical

• Start of treatment: physical examination, weight, visual acuity, colour vision testing
• Follow-up: weight, repeat vision testing monthly while on EMB
• Assess adherence, adverse events, and response to therapy

Radiology

• Chest x-ray at diagnosis (if not already done as part of diagnostic process), at 2 months, and at end of therapy

Laboratory

• Start of treatment: CBC, ALT, bilirubin, creatinine, HIV/HBV/HCV serologies, HbA1c
• Follow-up: monthly CBC, creatinine, ALT, and bilirubin

Microbiology

• Sputum culture twice monthly (~q2wk) until smear negative
  • Repeat susceptibility testing if sputum culture is positive at 3 months
  • Sputum induction not required if unable to produce sputum and smear negative
• Nearing end of therapy, sputum culture 2 months and one month before planned end
  • If sputum remains culture positive at 2 months, repeat sputum cultures should be performed monthly until culture conversion is confirmed

Adverse Drug Reactions

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 all medications if ALT >120 (3x ULN) and symptoms, if ALT >200 (5x ULN) even without symptoms, or bili >2x ULN
  • If severe disease and patient needs to continue treatment, immediately start two second-line agents (e.g. a fluoroquinolone and an injectable)
  • Once AST & ALT are less than twice the upper limit of normal, reintroduce the original drugs every 3 to 5 days, trending enzymes
  • Only rechallenge with pyrazinamide if it was a mild case

Dermatologic Reactions

Mild Reactions

• Post-dose flushing or itching with or without rash
  • Mostly face or scalp, and may involve redness or watering of the eyes
  • Usually 2 to 3 hours after drug ingestion
  • Caused by rifampin and pyrazinamide
  • Can use an antihistamine if it is bothersome
• Flushing and/or itching with or without a rash, plus hot flashes, palpitations, headaches, or increased blood pressure
  • Immediately after ingestion of certain foods
  • Usually resolves within 2 hours
  • Caused by isoniazid plus tyramine-containing foods (cheese, red wine) or certain fish (tuna, skipjack)
  • Avoid the causative foods

Moderate-to-Severe Reactions

• Hives with or without fever
• Caused by isoniazid < rifampin < pyrazinamide < ethionamide < cycloserine < ethambutol < PASA < streptomycin
• In children, viral infections may be confused for hives

Management

• Discontinue all drugs until the reaction resolves
• Can consider starting TB background regimen with levofloxacin 15-20 mg daily (max 1 g) plus linezolid 600 mg
  • Substitute amikacin 15 mg/kg daily if one of the above cannot be given
• Every 4 days, add a new drug back in the following order, with a lower challenge dose on the first day:
  • Isoniazid 50 mg challenge on day 1 followed by 300 mg on day 2
  • Rifampin 75 mg challenge on day 1 followed by 300 mg on day 2
  • Pyrazinamide 250 mg challenge on day 1 followed by 1 g on day 2
  • Ethionamide 125 mg challenge on day 1 followed by 375 mg on day 2
  • Cycloserine 125 mg challenge on day 1 followed by 250 mg on day 2
  • Ethambutol 100 mg on day 1 followed by 500 mg on day 2
  • PASA 1 g on day 1 followed by 5 g on day 2
  • Streptomycin 125 mg on day 1 followed by 500 mg on day 2
• If the reaction was severe, use 10% of the day 1 dose (e.g. isoniazid 5 mg)

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 until clinical evidence of improvement and a minimum of 2 weeks of effective therapy
  • Can be stopped at 4 weeks, or earlier if there are 3 negative smears
  • 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