Infection occurs when airborne bacteria settle in the lungs. There they multiply and are carried by the lymphatic system and blood to other parts of the body. After 2-10 weeks the infection is arrested, bacteria is dormant but may progress to active disease at some later stage in life. A person infected with M. tuberculosis is not infectious to others, in order to be infectious, active disease must be present. An immunocompetent person has a 10% lifetime risk of progression to tuberculosis. An immunocompromised person has an annual 10% risk of progression to active TB.

Infection with M. tuberculosis vs. Active disease

	Infection with M. tuberculosis	Active disease (tuberculosis)
Risk factors	Pre-diagnostic areas Prolonged close contact with infected individual in a room with inadequate ventilation Autopsy performing bronchoscopies and other cough inducing procedures Irrigating open infected wounds	infants and children <4 yrs old Elderly HIV- infected persons Diabetes mellitus Prolonged corticosteroid use immunosuppressive therapy Leukemia or Hodgkin's End stage renal disease malnutrition
Clinical presentation	Asymptomatic	Non specific: fatigue, weight loss, low-grade fever, chills, diaphoresis, myalgias, irregular menses. Pulmonary TB: cough with mucopurulent sputum, pleuritic chest pain

Principles of Treatment

Prophylactic treatment is thought to decrease or eliminate the bacterial population present thus preventing the progression of latent infection to active disease.

Treatment involves:

1. multiple drugs
2. used on a regular basis
3. for prolonged periods of time

The two major reasons for treatment failure and subsequent development of drug resistance are non-compliance and malprescribing.

There are three treatment options for drug sensitive TB.

Option 1: Isoniazid, Rifampin and Pyrazinamide daily for eight weeks followed by Isoniazid and Rifampin daily or two to three times weekly for 16 weeks. If Isoniazid resistance is greater than 4%, Ethambutol or Streptomycin should be included initially until susceptibility to Isoniazid and Rifampin is documented. Therapy should be continued for either six months or three months after culture conversion (whichever is greater). Expert advice should be sought if the smear or culture is positive or the patient is symptomatic after three months of therapy.

Option 2: Isoniazid, Rifampin, Pyrazinamide and Streptomycin or Ethambutol daily for two weeks, then twice weekly for 6 weeks, then Isoniazid and Rifampin twice weekly for 16 weeks. Expert advice should be sought if the smear or culture is positive or the patient is symptomatic after three months of therapy.

Option 3: Isoniazid, Rifampin, Pyrazinamide and Ethambutol or Streptomycin thrice weekly for six months. Expert advice should be sought if the smear or culture is positive or the patient is symptomatic after three months of therapy.

For HIV infected persons treatment optios 1,2 or 3 are suitable, however, treatment should be continued for nine months, or at least six months after culture conversion, (whichever is greater).

Antimycobacterial dosages for initial treatment of TB in adults

Drug	Daily dose	Twice-weekly dose	Thrice-weekly dose	Most common toxicities and precautions
Isoniazid	5 mg/kg max. 300 mg	15 mg/kg max 900 mg	15 mg/kg max 900 mg	Hepatitis (age related), peripheral neuropathy, skin rash. Monitor liver function tests if abnormal at baseline. Administer pyridoxine 10-50 mg/day to prevent neuropathy
Rifampin	10 mg/kg max 600 mg	10 mg/kg max 600 mg	10 mg/kg max 600 mg	Hepatitis, flu-like symptoms (intermittent dosing), red-orange discoloration of body fluids (contact lenses may be discolored), thrombocytopenia, skin rash. Monitor liver function tests if abnormal at baseline, complete blood count
Pyrazinamide	15-30 mg max 2 g	50-70 mg/kg max 4 g	50-70 mg/kg max 3 g	Hepatotoxicity, hyperurecemia, gout, arthralgias, skin rash. Monitor liver function tests if abnormal at baseline, caution with renal failure and history of gout
Ethambutol	15-25 mg/kg max 2.5 g	50 mg/kg max 2.5 g	25-30 mg/kg max 2.5 g	Optic neuritis (loss of red green color discrimination), hyperurecemia, dermatitis, pruritis. Perform monthly visual tests if dose > 15 mg/kg
Streptomycin	15 mg/kg max 1 g	25-30 mg/kg max 1.5 g	25-30 mg/kg max 1-1.5 g	Nephrotoxicity, ototoxicity : auditory (hearing loss) vestibular: ( nystagmus, ataxia), potentiates neuromuscular blockers Monitor creatinine and urea at least weekly, monthly serial audiograms if therapy > 2 weeks, caution in those >55 years and in uremics

Drug resistant TB is defined as resistance to one or more agents. Multiple drug resistant TB is defined as resistance to Isoniazid and Rifampin regardless of other susceptibility results.

In Ontario resistance to Isoniazid is 10% and MDRTB has increased from 0.1% in 1980 to 2.7% in 1992-3. The rate of increase of MDRTB is likely due to immigration from areas of high MDRTB (Asia, Africa, and Central America)

Second line antimycobacterial agents are reserved for cases where a first line agent is contraindicated, intolerable side-effects have developed or drug resistance is evident.

Second-line antimycobacterials

Agent	Daily dose	Toxicities
Para-aminosalicylic acid	150 mg/kg orally max 10-12 g	Gastrointestinal (nausea, vomiting, diarrhea), hypersensitivity reactions, hepatotoxicity
Ethaionamide	15-20 mg/kg orally max 1 g	Gastrointestinal (nausea, vomiting, anorexia, abdominal pain), hepatotoxicity, arthralgias, impotence, gynecomastia, photosensitivity, hypothyroidism, metallic taste
Cycloserine	15-20 mg/kg orally max 1 g	Psychosis, convulsions, rash, peripheral neuropathy,. Administer pyridoxine 150 mg/d
Capreomycin	15-30 mg/kg intramuscularly max 1g	Ototoxicity (auditory and vestibular), nephrotoxicity
Amikacin	15 mg/kg intravenously max 1 g	Ototoxicity (auditory and vestibular), nephrotoxicity
Kanamycin	15 mg/kg intramuscularly max 1 g	Ototoxicity (auditory and vestibular), nephrotoxicity
Ciprofloxacin	750 mg twice daily oral, 400 mg twice daily intravenous	Gastrointestinal, dizziness, hypersensitivity, elevated hepatic transaminases, and creatinine, arthropathies in animals
Ofloxacin	400 mg twice daily orally	see Ciprofloxacin
Rifabutin	300-450 mg orally	Hepatotoxicity, body fluid discoloration (orange-red), thrombocytopenia
Clofazimine	100-300 mg orally	Skin and eye discoloration, gastrointestinal upset, abdominal pain

References available by request