Antimycobacteria

Question 1

List of drugs for Mycobacteria

Answer 1

1st line agents for Tuberculosis

• Isoniazid
• Rifampin
• Ethambutol
• Pyrazinamide

2nd line agents;

• Streptomycin
• kanamycin, Amikacin
• Linezolid
• Ciprofloxacin
• Ofloxacin
• Cycloserine

Leprosy
- Dapsone + Rifampin +/- Clofazamine

M. Avium

• Clarithromycin / Azithromycin
• Ethambutol
• Rifabutin

Question 2

MOA for 1st line agents of Tuberculosis

Answer 2

Isoniazid

• requires activation by catalase enzyme to Iproniazid.
• inhibits enzymes involved in Mycolic acid synthesis = inhibit cell was synthesis
• also inhibits mycobacterial peroxidase and cause accumulation of Hydrogen peroxide = damage

Rifampin
- inhibits mycobacterial DNA dependent RNA polymerase

Ethambutol
- inhibits Arabinogalactan synthesis by Arabinosyltransferase = inhibit cell wall synthesis

Pyrazinamide
- inhibits fatty acid oxidase involved in mycolic acid synthesis = inhibit cell wall synthesis

Question 3

MOA for 2nd line Tuberculosis agents

Answer 3

Streptomycin, Kanamycin, Amikacin *PAE
- bind to 30S ribosomal subunit and interfere with protein synthesis.

Linezolid

• bind to 50S ribosomal subunit and inhibits the formation of the initiation complex.
• Inhibitor of MAO-A and MAO-B

Cycloserine
- cyclic analogue of D-Ala = inhibits peptidoglycan synthesis *no further clinical use b/c side effects

Fluoroquinones *PAE
- interfere with bacterial DNA synthesis by inhibition of Topoisomerase II (DNA gyrase) in gram negatives and Topoisomerase IV in gram positive bacteria.

Question 4

MOA for Leprosy and M. Avium drugs

Answer 4

Dapsone
- inhibits folic acid synthesis (similar to sulfonamides) *Enterohepatic cycling

Rifampin

Clofazamine
- unknown mechanism - Bacteriostatic

Clarithromycin/ Azithromycin

• bind to 50S ribosomal subunit
• inhibit translocation of peptidyl tRNA from acceptor to donor site.

Ethambutol

Rifabutin
- similar to Rifampin with less inducer effect on CYP450

Question 5

1st line agents side effects

Answer 5

Isoniazid

• Hepatotoxic
• vitamin B6 deficiency = Ataxia, peripheral neuropathy, insomnia
• Drug induced Lupus
• G6PD - acute hemolysis
• AG Metabolic acidosis

Rifampin

• Hepatotoxic
• Orange coloured secretions
• Nephrotoxic
• Thrombocytopenia

Ethambutol

• Optic neuritis, red-green colour blindness, decreased visual acuity, retinal damage.
• Headache, confusion
• Hyperuricemia

Pyrazinamide

• Hepatotoxic
• Hyperuricemia
• Arthralgia
• avoid in Pregnancy

Question 6

2nd line agents side effects

Answer 6

Streptomycin, Kanamycin, Amikacin
- Ototoxicity 
(irreversible-auditory, reversible-vestibular)
- Nephrotoxic 
- Neuromuscular blockade 
- Allergic skin reaction
- Teratogenic 

Linezolid

• Thrombocytopenia
• Neutropenia
• Optic neuropathy
• Serotonin syndrome

Cycloserine no further clinical use
- CNS dysfunction, Peripheral neuropathy

Ciprofloxacin, Ofloxacin

• long QT syndrome, Torture de pointe
• Teratogenic
• Cartilage and Tendon damage
• Hepatotoxic
• insomnia, dizziness, headache
• phototoxicity
• GI distress

Question 7

Leprosy and m.avium drug side effects

Answer 7

Dapsone Enterohepatic cycling

• GI symptoms
• rash, fever
• Methemoglobinemia
• G6PD- acute hemolysis

Clofazamine

• GI symptoms
• Discolouration of skin and conjunctiva

Clarithromycin/Azithromycin

• Acute Cholestatic hepatitis *erythromycin
• QT prolongation
• Ototoxicity at high doses
• Eosinophilia
• GI distress (increases motility)
• skin rash