Mycobacterium tuberculosis

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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

Extra-Pulmonary Tuberculosis

Latent Tuberculosis

Other

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:

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

Immune Reconstitution Inflammatory Syndrome (IRIS)

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
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

Special Populations

Liver Disease

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

References

  1. ^  Daphne Yee, Chantal Valiquette, Marthe Pelletier, Isabelle Parisien, Isabelle Rocher, Dick Menzies. Incidence of Serious Side Effects from First-Line Antituberculosis Drugs among Patients Treated for Active Tuberculosis. American Journal of Respiratory and Critical Care Medicine. 2003;167(11):1472-1477. doi:10.1164/rccm.200206-626oc.
  2. ^  Jussi J. Saukkonen, David L. Cohn, Robert M. Jasmer, Steven Schenker, John A. Jereb, Charles M. Nolan, Charles A. Peloquin, Fred M. Gordin, David Nunes, Dorothy B. Strader, John Bernardo, Raman Venkataramanan, Timothy R. Sterling. An Official ATS Statement: Hepatotoxicity of Antituberculosis Therapy. American Journal of Respiratory and Critical Care Medicine. 2006;174(8):935-952. doi:10.1164/rccm.200510-1666st.

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