Antimycobacterials

Question 1

Challenges to kill TB

Answer 1

• Difficult to kill
• vulnerable to cidal drugs only when metabolically active
• small populations are dormant
• Slow growth
• hampers identification/susceptibility test
• Lengthy therapy: compliance and toxicity
• intracellular forms
• chronic disease
• debilitating may go systemic
• becomes well established before symptoms occur

Question 2

spontaneous resistance to TB requires

Answer 2

multi-drug therapy

-requires cidal drugs to complete the cure

Question 3

describe the structure of mycobacterium tuberculosis

Answer 3

• cytoplasmic membrane
• cell wall
• outer membrane made up of mycolic acid

-it is able to survive on surfaces for months!!!

Question 4

List the first line drugs to TB

Answer 4

-Isoniazid
-Rifampin
-Ethambutol
Pyrazinamide
-Sreptomycin

Question 5

Isoniazid MOA

Answer 5

• cidal for actively growing bacilli
• inhibits synthesis of mycolic acid
• activated by catalse peroxidas (KatG protein)
• targets the enoyl-acyl carrier protein reductase (InhA protein)

Question 6

resistance to isoniazid

Answer 6

• mutations in KatG prevent drug activation

- mutations in InhA prevent activated drug from binding its target

Question 7

Isoniazid use

Answer 7

-all patients infected with INH-sensitive strains should receive INH if possible
for treatment of active TB always given in combination (but for latent can be given alone for 9 months)

Question 8

Explain acetylation polymorphism in INH

Answer 8

there are slow acetlyators and fast acetylators based on N-acetyltransferase genetic polymorphism that impact the half life of INh

Question 9

adverse effects of Isoniazid

Answer 9

• neurotoxicity esp peripheral neuritis
• significantly improved with pyridoxine (vitamin B6) administration
• hepatotoxicity

Question 10

Rifampin MOA

Answer 10

• inhibits bacterial RNA synthesis by binding RNA polymerase B
• cidal

Question 11

Rifampin adverse effects

Answer 11

• hepatotoxicity (short term it doesn’t matter but this is used for months so it is a concern)
• potent inducer of multiple CYPs causing increase metabolism of other drugs
• orange-red color

Question 12

Ethambutol MOA

Answer 12

• interferes with arabinosyl transferase, blocking cell wall synthesis
• tuberculostatsic (but it doesn’t interfere with the cidal effects of other drugs in fact it weakens the cell barrier enhancing drug entry )

Question 13

Ethambutol distribution

Answer 13

-Well absorbed and distributed including adequate levels in CSF

Question 14

Ethambutol adverse effects

Answer 14

• optic neuritis (5-15%)

- not hepatotoxic

Question 15

Pyrazinamide

Answer 15

• blocks mycolic acid synthesis by inhibiting fatty acid synthase I
• cidal
• used in combination therapy: important component of short-term therapy
• well absorbed, widely distributed: particularly useful for CNS involvement

Question 16

Pyrazinamide adverse effects

Answer 16

• Hepatic damage

* especially when combined with rifampin

Question 17

Streptomycin MOA

Answer 17

• aminoglycoside
• binds to several ribosomal sites at the 30S/50S interface. restricts polysome formation (ie stops initiation) and causes mRNA misreading

Question 18

Streptomycin use

Answer 18

-usually reserved for the most serious forms of TB

Question 19

Streptomycin adverse effects

Answer 19

• ototoxicity: affects balance and hearing

- nephrotoxicity

Question 20

explain the multi drug regimines

Answer 20

we use the more toxic drugs for shorter periods of time than the longer drugs

Question 21

why do we use four or more drugs for a TB infection

Answer 21

known exposure to drug resistant strains

Question 22

which TB drugs are bactericidal

Answer 22

isoniazid
rifampin
pyrazinamide

Question 23

List an Atypical mycobacterial infections

Answer 23

MAC=M.avium- intracellulare complex

Question 24

MAC

Answer 24

M. avium intracellulare complex
-MAC is less fatal than TB, so if you find acid fast bacillus institute an anti- TB regimen until the gaent is identified

Question 25

Rifabutin

Answer 25

• single agent prophylaxis of M avium intracellulare (MAC) in AIDS patients
• alternate to rifampin for multi drug resistant treatment of MAC or other mycobacteria

Question 26

RIfabutin adverse effects

Answer 26

• similar to rifampin but less frequent (esp at prohylactic doses)
• drug interactions similar to rifampin, but to a lesser extent

Question 27

Clarithromycin

Answer 27

• part of a multi-drug regimen for treatment of M. avium-intracellulare in AIDS patients
• also for MAC prophylaxis
• cidal

Question 28

Leprosy (Hansen’s Disease)

Answer 28

-only specialists should treat leprosy consult National Hansen’s Disease Program, Baton Rouge Lousiana

Question 29

Dapsone

Answer 29

• structural analog of para-aminobenzoic acid (PABA); inhibits folic acid synthesis
• bacteriostatic
• used in combination with other drugs
• alternative for prophylaxis (and treatment) of Pneumocystis jiroveci (carinii) in AIDSs patients
• metabolism similar to isoniazid, slow and fast acetylators

Question 30

Dapsone adverse effects

Answer 30

• hemolytic anemia

- methemoglobinemia

Question 31

Clofazimine

Answer 31

• phenazine dye that binds to DNA, interfering with reproduction and growth
• only used in combination therapy
• adverse: red brown pigmentation of the skin (sputum, urine sweat sclera)

Question 32

RIfampin

Answer 32

-widely used in combination therapy (eg with dapsone) for leprosy