Antimycobacterials

Question 1

Match the clinical manifestations with the specific mycobacterium:

1. Tuberculosis:
2. Leprosy (Hansen’s Disease):
3. Pulmonary; intestinal mucosa & lymph nodes:

Answer 1

1. M. tuberculosis
2. M. Leprae
3. M. avium-intracellulare (MAI or MAC)

Question 2

Why are mycobacteria challenging to treat?

Answer 2

1. Cells grow very slowly
   
   • Difficult to kill
   • Difficult to grow, identify, and do susceptibility testing
   • Requires very lengthy therapy
   • Chronic disease
   • Intracellular forms
2. Spontaneous resistance
   
   • Requires multi-drug therapy

Question 3

Drugs Used in TB Therapy (5):

Answer 3

1. Isoniazid
2. Rifampin
3. Ethambutol
4. Pyrazinamide
5. Streptomycin

Question 4

Isoniazid (INH™; Nydrazid®):

• Mechanism:
• Resistance:

Answer 4

Mechanism

• Bactericidal for actively growing bacilli
  
  • bacteriostatic for “resting cells”
• Inhibits synthesis of mycolic acids
  
  • prodrug which is activated by the catalase-peroxidase (KatG protein) of the tubercle bacillus
  • targets the enoyl-acyl carrier protein reductase (InhA protein)

Restistance​

• result from mutations in KatG or InhA

Question 5

Isoniazid:

• Use:
• Absorption/Excretion:
• Adverse Effects:

Answer 5

Use

• Most important primary TB drug
• all patients with INH-sensitive strains should receive INH if possible
• For treatment, always given in combination with other agents

Absoprtion/Excretion

• **N-acetylation: **under genetic control (polymorphisms)

Adverse Effects

• Neurotoxicity, esp. peripheral neuritis
  
  • significantly improved with B6 administration
• Hepatotoxicity (10-20%)

Question 6

Rifampin (Rifadin®, Rimactane®):

• Mechanism:
• Adverse Effects:

Answer 6

​Mechanism

• Inhibits bacterial DNA-dependent RNA polymerase, ⇒ suppressing RNA synthesis
• Bactericidal

Adverse Effects

• Hepatotoxicity
• Potent inducer of multiple CYPs ⇒ increasing metabolism of other drugs
• Orange-red color

Question 7

Ethambutol (Myambutol®):

• Mechanism:
• Adverse Effects:

Answer 7

Mechanism

• Interferes with arabinosyl transferase, blocking cell wall synthesis
• Tuberculostatic

Adverse Effects

• Not hepatotoxic
• Optic neuritis (5-15%)

Question 8

Pyrazinamide (PZA):

Answer 8

• Blocks mycolic acid synthesis
  
  • ​inhibits fatty acid synthase I
• bactericidal
• Well-absorbed
  
  • widely distributed, incl. CSF
• Hepatic damage
  
  • esp. when combined w/ Rifampin

Question 9

Streptomycin:

• Mechanism:
• Use:
• Adverse Effects:

Answer 9

• Mechanism
  
  • binds to several ribosomal sites
  • stops initiation
  • causes mRNA misreading
  • bactericidal
• Use
  
  • Usually reserved for the most serious forms of TB
• Adverse Effects
  
  • Ototoxicity (affecting both balance and hearing)
  • Nephrotoxicity

Question 10

Examples of Multi-Drug Regimens for Treating Active TB:

Answer 10

ALWAYS use at least two drugs

1. Short-Course Therapy for Uncomplicated Pulmonary TB
2. Disseminated TB
3. Use of 4 or More Drugs
   
   • known exposure to drug-resistant strains
   • severe or disseminated disease

Question 11

Eradication Vs. Stasis Of TB Infections:

Answer 11

1. Bacteriostatic
   
   • Intracellular and Extracellular
     
     1. ethambutol
     2. p-aminosalicylic acid
2. Bactericidal
   
   • ​​Intracellular and Extracellular
     
     1. ​​isoniazid
     2. rifampin
     3. pyarzinamide
   • Extracellular
     
     1. streptomycin

Question 12

“Atypical” Mycobacterial Infections:

Answer 12

• MAC = M. avium-intracellulare complex
• MAC is less fatal than TB, so if find AFB, institute anti-TB regimen until agent is identified

Question 13

Drugs Used to Treat “Atypical” Mycobacterial Infections:

Answer 13

1. Rifabutin
2. Clarithromycin
3. Azithromycin

Question 14

Rifabutin:

Answer 14

• Rifampin analog
• single-agent prophylaxis of M. avium-intracellulare (MAC) in AIDS patients
• multi-drug treatment of MAC
• Toxicities:
  
  • ​Similar to rifampin but less frequent
  • Drug interactions similar to rifampin
  • less potent CYP inducer

Question 15

Clarithromycin, azithromycin:

Answer 15

• Part of multi-drug regimen for treatment of M. avium-intracellulare in AIDS patients
• Also used for:
  
  • MAC prophylaxis
• ​Bactericidal

Question 16

What causes Leprosy (Hansen’s Disease)?

Answer 16

Mycobacterium leprae

Question 17

Drugs Used to Treat Leprosy (3):

Answer 17

1. Dapsone
2. Clofazimine
3. Rifampin

Question 18

Dapsone:

• Metabolism:
• Use:
• Absorption/Excretion:
• Adverse Effects:

Answer 18

• Metabolism:
  
  • ​structural analog of para-aminobenzoic acid (PABA)
  • inhibits synthesis of folic acid
  • bacteriostatic
• Use:
  
  • ​Used in combination with other drugs
  • prophylaxis (& treatment) of Pneumocystis jiroveci in AIDS patients
• Absorption/Excretion:
  
  • ​fast and slow acetylators
  • same enzyme which acetylates INH
• Adverse Effects:
  
  • ​Hemolytic anemia
  • methemoglobinemia

Question 19

Clofazimine (Lamprene®):

• Mechanism:
• Use:
• Adverse Effects:

Answer 19

• **Mechanism: **​Poorly understood
  
  • binds to mycobacterial DNA interfering with reproduction and growth
• Use:
  
  • ​combination chemotherapy
  • often for dapsone-resistant leprosy
• Adverse Effects:
  
  • ​red-brown pigmentation of the skin

Question 20

Describe the role of Rifampin in the treatment of leprosy:

Answer 20

• Widely used in combination therapy (e.g. with dapsone)
• Very active bactericidal antilepromatous drug