Antimycobacterials

Question 1

describe the image below

Answer 1

• Mycobacterium tuberculosis
• Small, aerobic, non-motile, bacillus
• Can lead to serious infections of the lungs, genitourinary tract, skeleton & meninges

Question 2

list 1st line TB drugs

Answer 2

“RIPE”

• Rifampin
  
  • Rifabutin (1st line in HIV pts)
• Isoniazid
• Pyrazinamide
• Ethambutol

Question 3

list 2nd line TB drugs

Answer 3

“SALE”

• Streptomycin
• Amikacin
• Levofloxacin
• Ethionamide

Question 4

describe people who are at high risk of TB/need prophylaxis

Answer 4

• Persons who have been recently infected with TB bacteria
• Persons with medical conditions that weaken the immune system

Question 5

describe isoniazid

Answer 5

• Synthetic analog of pyridoxine
• First-line agent
• Most potent antitubercular drug
• Part of COMBINATION THERAPY for active infection

Question 6

___ is the sole drug in treatment of latent infection

Answer 6

Isoniazid is the sole drug in treatment of latent infection

Question 7

Isoniazid is converted to its active form via ___ and targets enzymes required in _____ synthesis such as:

Answer 7

Isoniazid is converted to its active form via catalase- peroxidase - KatG and targets required in mycolic acid synthesis such as:

• enoyl acyl carrier protein reductase (InhA)
• b-ketoacyl-ACP synthase (KasA)

Question 8

what happens if INH is used alone?

Answer 8

resistant organisms rapidly emerge

Question 9

how does TB create resistance against INH?

Answer 9

• Chromosomal mutations resulting in:
  
  • mutation of deletion of KatG
  • mutations of acyl carrier proteins
  • overexpression of inhA
• Cross-resistance between other anti-tuberculosis drugs DOES NOT OCCUR

Question 10

describe adverse effects of INH

Answer 10

• Peripheral neuritis: corrected by pyridoxine supplementation
• Hepatotoxicity: clinical hepatitis & idiosyncratic
• CYP P450 inhibitor
• Lupus-like syndrome: rare

Question 11

is INH safe in pregnany?

Answer 11

yes, use pyridoxine supplementation

Question 12

describe Rifamycins

Answer 12

• Rifampin & rifabutin
• 1st drugs for treatment of all susceptible forms of TB
• Part of COMBINATION THERAPY for active infections
• Sole drug in treatment of latent infection (2nd line)

Question 13

Rifampin is usually given in ____

Answer 13

Rifampin is usually given in combination

Question 14

what is Rifampins MOA?

Answer 14

Blocks transcription: binds to B subunit of bacterial DNA-dependent RNA polymerase → inhibition of RNA synthesis

Question 15

describe resistance to Rifampin

Answer 15

• Point mutations in rpoB (gene for B subunit of RNA polymerase) → decreased affinity of bacterial DNA-dependent RNA polymerase for drug
• Decreased permeability

Question 16

what are the clinical applications of Rifampin?

Answer 16

• Active TB infections
• Latent TB in isoniazid intolerant patients
• Leprosy (delays resistance to dapsone)
• Prophylaxis for:
  
  • individuals exposed to meningitis
  • contacts of children with H.influenzae type B
• MRSA (with vancomycin)

Question 17

Rifampin is a strong ____ inducer

Answer 17

Rifampin is a strong CYP450 inducer

Question 18

list the AEs with Rifampin

Answer 18

• Light chain proteinuria
• GI distress
• Occasional effects: thrombocytopenia, rashes, nephritis, liver dysfunction
• Imparts harmless orange/red color to bodily fluids
• Strongly induces CYP P450
• SAFE IN PREGNANCY

Question 19

describe what caused this

Answer 19

Rifampin!

AE: yellow/orange bodily fluids

Question 20

___ is the referred drug for use in HIV patients (due to less induction of CYP enzymes)

Answer 20

Rifabutin is the referred drug for use in HIV patients (due to less induction of CYP enzymes)

Rifampin substitute to those that are intolerant

Question 21

describe Ethambutol

Answer 21

• 1st line for all susceptible forms of TB
• Specific for most strains of M.tuberculosis & M.kansasii
• Used in combination with pyrazinamide, izoniazid & rifampin
• Resistance occurs rapidly if used alone
  
  • mutations in emb gene

Question 22

Ethambutol inhibits ____ leading to decreased carbohydrate polymerization of cell wall

Answer 22

Ethambutol inhibits arabinosyltransferase leading to decreased carbohydrate polymerization of cell wall

Question 23

Ethambutol AEs

Answer 23

• Dose-dependent visual disturbances (eg, red/green color blindness) – cannot be used in children too young to receive sight tests
• Headache, confusion, hyperuricemia, peripheral neuritis (rare)
• Safe in pregnancy

Question 24

describe Pyrazinamide

Answer 24

• First-line agent
• Used in combination with isoniazid, rifampin & ethambutol
• Must be enzymatically hydrolysed to active pyrazinoic acid. Mechanism of action remains unclear
• Resistant strains lack pyrazinamidase or have increased efflux of drug

Question 25

Pyrazinamide AEs

Answer 25

* **Nongouty polyarthralgia (~ 40%)** * Acute gouty arthritis (rare unless predisposed) * Hyperuricemia * Hepatotoxicity, myalgia, GI irritation, porphyria, rash, photosensitivity * Recommended for use in pregnancy when benefits outweigh risks

Question 26

The aminoglycoside ____ is used for drug-resistant strains and is used in combinations for treatment of life-threatening tuberculous disease

Answer 26

The aminoglycoside **streptomycin** is used for drug-resistant strains * Life-threatening tuberculous disease: * meningitis * miliary dissemination * severe organ tuberculosis * Increasing frequency of resistance to streptomycin limits use of drug

Question 27

what is the duration of treatment with **INH** for latent TB?

Answer 27

6-9 months

Question 28

what is the duration of treatment with **Rifampin** with latent TB?

Answer 28

4 months

Question 29

describe the 2nd line TB drugs: Amikacin Levofloxacin Ethionamide What AE do they all have in common?

Answer 29

* Amikacin * Used for streptomycin- or multi-drug-resistant strains. Similar AE to streptomycin * Levofloxacin * Recommended for use against first-line drug- resistant strains. Always use in combination. * Ethionamide * Congener of INH (no cross-resistance). Severe GI irritation, adverse neurologic effects, hepatotoxicity & endocrine effects. * **Common AE: Teratogenic**

Question 30

describe standard regimens for **empiric treatment of pulmonary TB:**

Answer 30

Question 31

describe drug resistant strains

Answer 31

Question 32

describe drug resistant strains

Answer 32

Question 33

describe **Leprosy/Hansen's disase**

Answer 33

* Caused by **M. leprae & M. lepromatis** * Primarily granulomatous disease of peripheral nerves & mucosa of upper respiratory tract * ~ 70 % cases are in India

Question 34

what 3 drugs are used in combination for leprosy?

Answer 34

**Dapsone Clofazimine Rifampin**

Question 35

describe **Dapsone**

Answer 35

* Structurally related to sulfonamides * Bacteriostatic * **Inhibits folate synthesis (via dihydropteroate synthetase inhibition)** * Also used in treatment of pneumonia (P.jiroveci) in HIV +ve patients

Question 36

\_\_\_\_ is the repository form of dapsone

Answer 36

**Acedapsone** is the repository form of dapsone

Question 37

list the AEs for **Dapsone**

Answer 37

* **Hemolysis** (esp. G6PD deficiency) * **Erythema nodosum leprosum** (treated with corticosteroids or thalidomide) * **Other effects** – GI irritation, fever, hepatitis, methemoglobinemia * **CYP P450 inhibitor**

Question 38

what drug causes **erythema nodosum leprosum**

Answer 38

**Dapsone**

Question 39

describe Clofazimine

Answer 39

* Phenazine dye * Binds to DNA & inhibits replication * Redox properties may generate cytotoxic oxygen radicals * Bactericidal to M.leprae (some activity against M. avium- intracellulare complex)

Question 40

describe clofazimine AEs

Answer 40

* **Red-brown discoloration of skin** * GI irritation * Eosinophillic enteritis * **Erythema nodosum DOES NOT develop (drug has anti- inflammatory action)**

Question 41

describe WHO treatment recommendations for Leprosy

Answer 41

Question 42

describe atypical mycobacterium

Answer 42

* Present in environment * **not communicable from person to person** * Susceptible to different drugs to M.tuberculosis * Combination therapy required due to resistance

Question 43

describe treatment options for atypical mycobacterium

Answer 43

Question 44

describe treatment options for atypical mycobacterium

Answer 44