T7

Question 1

DNA disruptors

Answer 1

sulfonamides
fluoroquinolones

Question 2

microbial folate synthesis

Answer 2

bacterial cell must synthesize their own folate to be used for DNA synthesis

two enzymes play a major role in folic acid synthesis
-dihydropteroate synthase
-dihydrofolate reductase

Question 3

sulfonamides MOA

Answer 3

sulfonamides competitively inhibit dihydroperoate synthase

dihydrofolate reductase inhibitors cause sequential blockage of folate synthesis

combination provides synergistic activity and is more effective than either agent alone

Question 4

sulfonamides resistance mechanisms

Answer 4

reduced concentration at target
-reduced permeability
-increased efflux
-bacterial utilization of alternative pathway
-increased production of drug antagonist (PABA)

alteration to bacterial target
-reduced affinity of dihydropteroate/DHFR for antimicrobials
-drug resistance dihydropteroate synthase/DHFR

Question 5

sulfonamides spectrum of activity

Answer 5

gram + (MRSA)
gram -

Question 6

sulfonamides adverse effects

Answer 6

N/V/D
crystalluria
-adequate hydration of 2L per day is recommended

Question 7

sulfonamides toxicity

Answer 7

sulfa allergy -> dermatologic hypersensitivity reactions

Sulfonamide moiety is responsible for reactivity

Antimicrobial sulfonamide is uncommonly cross-reactive with non-antimicrobial sulfa drugs

Question 8

fluoroquinolones MOA

Answer 8

Fluoroquinolones inhibits two key bacterial enzymes
-DNA gyrase
-Topoisomerase IV
Inhibition of these enzymes results in DNA breakage and disruption of DNA
replication
The bacterial cell is then unable to replicate, and the cell ultimately dies
Fluoroquinolones only inhibit eukaryotic topoisomerases at exceedingly high
concentrations

Question 9

Topoisomerase IV

Answer 9

Separates interlinked daughter DNA molecules that are produced during DNA replication

Question 10

DNA Gyrase

Answer 10

Introduces negative super coils into DNA to combat excessive positive supercoiling

Question 11

fluoroquinolones resistance

Answer 11

Reduced drug concentration at target
-Reduction in porin channels limiting microbial permeability
-Increased efflux pumps

Inactivation of antimicrobial agent
-Enzymatic inactivation of fluoroquinolones

Alterations to bacterial target
-Mutations in the quinolone binding region of DNA Gyrase or topoisomerase
IV
-Develop specialized proteins that protect DNA Gyras

Question 12

fluoroquinolones spectrum of activity

Answer 12

some gram +
gram - including pseudomonas
atpicals (levofloxacin, moxifloxacin, and gemifloxacin only)

Question 13

fluoroquinolones adverse effects

Answer 13

N/V/D (impaired w dairy and antacids)
QT prolongation and Torsades de pointes

Question 14

fluoroquinolones toxicity

Answer 14

box warnings for serious ADRs
tendinitis/tendon rupture
peripheral neuropathy
CNS effects

Question 15

aminoglycosides MOA

Answer 15

block initiation of protein synthesis
blocks further translation and elicits premature termination
Incorporation of incorrect amino acid

Question 16

aminoglycosides resistance

Answer 16

Reduced antimicrobial concentration at target
-Mutation or deletion of porin proteins
-Lack of oxidative metabolism for transport (anaerobes)

Inactivation of drug by microbial enzymes
-Aminoglycoside-modifying enzymes

Alterations to bacterial target
-Receptor protein on ribosomal subunit may be deleted or altere

Question 17

aminoglycosides spectrum

Answer 17

some gram +
gram - including pseudomonas
mycobacterium (Amikacin only)

Question 18

aminoglycosides adverse effects

Answer 18

Acute neuromuscular blockade and apnea
-Most frequently occurs in association with anesthesia or neuromuscular blocking agents

Question 19

aminoglycosides toxicity

Answer 19

ototoxicity
nephrotoxicity

Question 20

aminoglycosides ototoxicity

Answer 20

Irreversible degeneration of hair cells and neurons in the cochlea
-Auditory damage resulting in bilateral, high-frequency hearing loss
-Vestibular damage with ataxia, vertigo, and balance changes

Initial symptoms (tinnitus/headache) may be reversible, and discontinuation of aminoglycoside therapy should be considered

Question 21

aminoglycosides nephrotoxicity

Answer 21

Commonly causes reversible, mild rise in serum creatinine
Can also cause acute tubular necrosis and irreversible damage if prolonged toxicity

Question 22

aminoglycosides monitoring

Answer 22

Demonstrate concentration dependent effects
Peak concentrations used to determine efficacy and trough concentrations are used to determine toxicity
High-dose, extended-interval (once daily) administration is preferred due to lower incidence of toxicity

Question 23

common mycobacterial infections

Answer 23

mycobacterium tuberculosis
mycobacterium lepare
mycobacterium avium complex

Question 24

mycobacterium unique characteristics

Answer 24

Grow more slowly than most bacteria
Mycobacteria can be dormant
Unique cell wall that is impermeable to many antimicrobial drugs
Made up of waxy lipid material (mycolic acid)
Intracellular pathogens
Exceptional capability to develop drug resistance
-Abundance of efflux pump

Question 25

antimycobacterial drugs

Answer 25

rifamycins isoniazid pyrazinamide ethambutol

Question 26

rifamycins MOA

Answer 26

Binds to the bacterial RNA polymerase to form a stable drug-enzyme complex that inhibits RNA synthesis

Question 27

rifamycins resistance

Answer 27

Alterations to drug target, RNA polymerase, resulting in reduced drug binding Efflux pump induction Mutations in efflux pumps

Question 28

rifamycins side effects

Answer 28

Turns all bodily fluids orange (sweat, saliva, tears, urine, feces) Rash N/V Fever

Question 29

rifamycins special considerations

Answer 29

Strong inducer of most CYP enzymes -Increases metabolism of numerous drugs (including autoinduction) When taken with food absorption can be reduced by up to 1/3

Question 30

rifamycins toxicity

Answer 30

hepatotoxicity -Cholestasis (most common) -Drug induced liver injury (rare) -Increased risk if preexisting chronic liver disease, alcoholism, and increased age

Question 31

isoniazid MOA

Answer 31

Activated by the bacterial enzyme, KatG Once active, inhibits synthesis of mycolic acid, an essential component of the mycobacterial cell wall

Question 32

isoniazid resistance

Answer 32

KatG mutations leading to reduced ability to convert isoniazid to its active form

Question 33

isoniazid side effects

Answer 33

Fever Skin rash Increased liver function tests (LFTs)

Question 34

isoniazid special considerations

Answer 34

When taken with food absorption can be reduced by up to 50% Metabolized in the liver by N-acetyltransferase type 2 (NAT2) -Reduced NAT2 enzyme function = increased toxicity risk -Increased NAT2 enzyme function = reduced cure rates and infection relapse

Question 35

isoniazid toxicity

Answer 35

peripheral neuropathy -Paresthesia of hands and feet -Caused by vitamin B6 deficiency -Reversible with supplementation of vitamin B6 (pyridoxine) overdose -coma -seizures refractory to treatment -anion gap metabolic acidosis

Question 36

pyrazinamide MOA

Answer 36

Converted to its active form by mycobacterial pyrazinamidase Once activated, inhibits cell membrane metabolism and transport functions leading to accumulation of toxins in the mycobacterial cell leading to death

Question 37

pyrazinamide resistance

Answer 37

Mutations in pyrazinamidase, reducing conversion to the active form of the drug Mutations to efflux pumps

Question 38

pyrazinamide side effects

Answer 38

N/V drug fever photosensitivity

Question 39

pyrazinamide special considerations

Answer 39

Readily removed by hemodialysis and should be re-dosed following hemodialysis sessions

Question 40

pyrazinamide toxicity

Answer 40

hyperuricemia -high uric acid levels leading to gout -may present as arthralgias, N/V, and fever hepatotoxicity -jaundice most common -hepatic necrosis and death may occur in rare instances -baseline LFTs and periodically through treatment recommended

Question 41

ethambutol MOA

Answer 41

Inhibits mycobacterial arabinosyl transferase III which disrupts assembly of the mycobacterial cell wall

Question 42

ethambutol resistance

Answer 42

Mutations to arabinosyl transferase Enhanced efflux pump activity

Question 43

ethambutol side effects

Answer 43

very rare rash, fever, pruritis

Question 44

ethambutol special considerations

Answer 44

dose reduced in renal dysfunction

Question 45

ethambutol toxicity

Answer 45

optic neuritis -Results in loss of visual acuity and loss of red/green color discrimination -Greatest risk beyond the first month of treatment and in patients with renal dysfunction -Baseline and monthly vision tests are recommended -Full recovery is typical with discontinuation although visual changes can be permanent

Question 46

TB first line drugs

Answer 46

rifamycin isoniazid pyrazinamide ethambutol moxifloxacin

Question 47

leprosy first line drugs

Answer 47

rifampin clofazimine dapsone

Question 48

mycobacterium avium complex first line drugs

Answer 48

rifamycins ethambutol clarithromycin/azithromycin