TB Treatment

Question 1

Drugs for M. tuberculosis

Answer 1

• Mycobacteria intrinsically resistant to many antibacterial agents – Impermeable lipid rich cell wall
• Drugs termed first line and second line

– Differences in efficacy and adverse effects

– Second line drugs utilized when resistance or adverse effects with first line agents

• Principles of treatment

– Long duration of therapy

– Combination therapy

Question 2

First Line Drugs

Answer 2

Question 3

Answer 3

Question 4

Isoniazid

Answer 4

•Most important TB drug

– Used in combination for active TB or 2nd line single drug for latent TB

• Prodrug

– Must be activated by bacterial catalase-peroxidase enzyme (katG gene)

Question 5

Isoniazid MOA

Answer 5

• Mechanism of action

– Activated drug binds acyl carrier protein reductase (InhA gene)—inhibits synthesis of mycolic acid (essential component of mycobacterial cell wall)

– Bactericidal

Question 6

Isoniazid Resistance

Answer 6

• Resistance

– High level resistance—deletion of katG gene

– Mutations in InhA gene

Question 7

Isoniazid Pharmacokinetics

Answer 7

• Pharmacokinetics

– Reaches intracellular organisms and CNS.

– Liver metabolism by acetylation—under genetic control

– Fast or slow inactivators (acetylators) of INH

• Asian origin (80-90%) fast acetylators
• European or African origin (~50%) fast acetylators

Question 8

Isoniazid Toxicity

Answer 8

Question 9

Rifampin MOA/Resistance

Answer 9

• Mechanism of action/Resistance

– Inhibits RNA synthesis by bacterial RNA polymerase; bactericidal

– Resistance—mutations in gene for RNA polymerase reduce rifampin binding

Question 10

Rifampin Pharmacokinetics

Answer 10

• Pharmacokinetics

– Reaches CNS

– Strongly induces cytochrome p450s increasing elimination of many drugs

• Oral contraceptives, corticosteroids, cyclosporine, statins, HIV drugs, others

Question 11

Rifampin Adverse Reactions

Answer 11

• Adverse reactions

– Liver dysfunction (cholestatic jaundice; rarely hepatitis)

– Causes harmless orange or red-orange discoloration of body fluids

– August, 2020: detection of nitrosamine impurities in rifampin

Question 12

Rifampin Clinical Uses

Answer 12

• Clinical use

– One of several rifamycin derivatives (rifabutin, rifapentine, rifaximin)

– Effective against a variety of bacteria

– First line drug in combination for active TB; first line (as of 2/2020) for latent TB

Question 13

Pyrazinamide - MOA/Resistance

Answer 13

• Mechanism of action/Resistance

– Prodrug—converted to pyrazinoic acid by mycobacterial pyrazinamidase

– Exact mechanism of action unknown

Question 14

Pyrazinamide Adverse Reactions

Answer 14

• Adverse reactions

– Hepatotoxicity 1-5% of patients

– Non-gouty polyarthralgia 40% of patients

– Asymptomatic hyperuricemia

Question 15

Pyrazinamide Clinical Uses

Answer 15

•Clinical use

– Important first line drug in combination with INH and rifampin

– Appears to accelerate sterilizing effect of INH and rifampin allowing reduction in duration of treatment

Question 16

Ethambutol - MOA/Resistance

Answer 16

• Mechanism of action/Resistance

– Inhibits arabinosyl transferase involved in synthesis of arabinogalactan (component of mycobacterial cell wall)

– Bacteriostatic

– Resistance—mutations causing overproduction of arabinosyl transferase enzyme

Question 17

Ethambutol Adverse Reactions

Answer 17

• Adverse reactions

– Optic neuritis causing loss of visual acuity and red-green color blindness—dose related

Question 18

Ethambutol Clinical Uses

Answer 18

• Clinical use

– Activity limited to mycobacteria

– Always used in combination with other drugs

– Most commonly in combination with INH, rifampin and pyrazinamide if possibility of INH resistance >4%

Question 19

Treatment Latent TB

Answer 19

Question 20

Treatment Pulmonary TB

Answer 20

Question 21

Treatment Pulmonary TB Standard Regimen

Answer 21

Question 22

Nontuberculous Mycobacteria—Syndromes

Answer 22

• 1. Pulmonary disease, especially in older persons with or without underlying lung disease
• 2. Superficial lymphadenitis, especially cervical lymphadenitis, in children
• 3. Disseminated disease in severely immunocompromised patients
• 4. Skin and soft tissue infection usually as a consequence of direct inoculation, caused primarily by Mycobacterium marinum and Mycobacterium ulcerans

Question 23

Mycobacterium Avium-Intracellulare Complex (MAC)

Answer 23

• Environmental source (e.g., water supply)
• No person to person transmission
• Colonization in patients with underlying lung disease
• Two basic syndromes in HIV-negative patients

– Middle-aged or elderly men with underlying lung disease (e.g., COPD). Disease resembles typical TB, with cough, weight loss, upper lobe infiltrates, and cavities

– Nonsmoking women over age 50 who have interstitial patterns (bronchiectasis and nodules) on CXR. Syndrome of right middle lobe or lingular disease (Lady Windermere syndrome) in elderly women without predisposing lung disease.

– (Rare- hypersensitivity pneumonitis [“hot-tub lung”]).

Question 24

NTM: treatment in HIV-negative patients

Answer 24

• Clarithromycin (or azithromycin)
• Rifampin
• Ethambutol

Question 25

MAC infections in HIV-infected patients

Answer 25

• Infection from environmental source
• Portals of entry the respiratory and gastrointestinal tract with bacteremia following dissemination via the lymphatics
• Risk increases CD4 count declines below 50 cells/mm3—Prophylaxis azithromycin or clarithromycin