Lincosamides and Amphenicols (MC) - Block 2

Question 1

What are the lincosamides?

Answer 1

Lincomycin and clindamycin

Question 2

What is the MOA of clindamycin?

Answer 2

Inhibits protein synthesis by inhibiting ribosomal translocation on the 50S -> interfering wih aminoacyl translocation

Question 3

Describe the activity of lincosamides?

Answer 3

G+ cooci (CA-MRSA)

Question 4

Clindamycin hascross resistance with what drug, due to its similar activity?

Answer 4

Macrolides

Question 5

Erythromycin resistance methylase is encoded by?

Answer 5

Plasmid-borne gene erm

Question 6

Describe the SAR of lincosamides?

Answer 6

1. Tertiary amine
2. Ester formation of 2-OH

Question 7

Differntiate the esters formed on a lincosamide scaffold?

Answer 7

Phosphate -> water soluble
Palmitate -> lipophilic formulation to mask taste for pediatrics

Question 8

ADRs of Lincosamides?

Answer 8

1. Severe diarrhea with pseudomembranous colitis
2. Overgrowth of C. diff.

Question 9

Describe the metabolism of lincosamide?

Answer 9

1. Tertiary amine undergoes N-Demethylation
2. Sulfur oxidized (S-oxidation)

Question 10

Describe the penetrability of clindamycin?

Answer 10

1. Gets into the bone
2. Cross resistance with macrolides
3. Doesn’t get into the brain or CSF

Question 11

What is the target level of clindamycin?

Answer 11

2-3 mcg/mL

Question 12

What is the mechanism of chloramphenicol?

Answer 12

1. Inhibits protein synthesis through reversible binding to the 50S of bac ribosome
2. Inhibits the peptidyl transferase step of protein synthesis

Question 13

Describe the scope of acitivity of chloramphenicol?

Answer 13

G+, G- aerobes and anaerobes

Question 14

ADR of chloramphenicol?

Answer 14

1. Toxicity: Fatal aplastic anemia (pancytopenia)
2. GI distubances
3. Gray baby syndrome (inadequate glucoronidation metabolism)

Question 15

Resistance of chloramphenicol stems from what?

Answer 15

R-factor mediated acetylation of the 1-OH and to a less extent the 3-OH

Question 16

Types of amphenicols?

Answer 16

Chloramphenicol

Question 17

How are chloramphenicols metabolized?

Answer 17

Glucoronidation to become for soluble for elimination

Question 18

What is the most common use of chloramphenicol?

Answer 18

1. Rocky mountain spotted fever (Rickettsia)
2. Menigococcal meningitis with severe b-lactam allergy or Penicillin resistant pneumococcus bacterial meningitis

Question 19

What are the characteristics nitroaromatic?

Answer 19

1. Prodrugs activated by bacteria
2. Bacteriocidal

Question 20

ADR of nitrroaromatics?

Answer 20

Genotoxicity: DNA damage and nicking of ribose

Question 21

Source of nitroaromatic resistance?

Answer 21

Inactivation of prodrug activating enzymes

Question 22

What is the active form of nitrofurans?

Answer 22

-N-OH

However, N=O and N-O. form radicals that are active as well

Question 23

What is the backbone of a nitrofuran structure?

Answer 23

Schiff base

Question 24

Urine color of nitrofurantoin?

Answer 24

Dark brown

Question 25

ADRs of nitrofurantoin?

Answer 25

N/V * Avoided by slowing absorption rate and Macrodantin (wax-coated, large particles) Disulfuram reaction with alcohol

Question 26

Describe the MOA of metronidazole?

Answer 26

1. O free radicals cause oxidative stress and depletes thiol 2. Reactive intermediate form adducts with protein and DNA -> nicking (DNA fragments)

Question 27

Describe the formulation of methanamine?

Answer 27

Drug is active under acidic pH (urine) produces ammonia and formaldehyde * Ammonia increases pH * Drug must be given with hippurate and mandelate salts to maintain acidity and from pH getting too high

Question 28

What is the target of fosfomycin?

Answer 28

Inhibits the early stages of PG biosynthesis against E. coli and E. faecalis

Question 29

What is the MOA of linezolid?

Answer 29

Inhibits protein synthesis by blocking complex between (initiation process): 70S, tRNA, mRNA * binds to 23S rUnit and prevents the formation of 70S

Question 30

Spectrum of linezolid activity?

Answer 30

MRSA, VRE * May interfere with MAO (serotonin syndrome risk)

Question 31

What causes linezolid resistance?

Answer 31

Mutation of 23S rRNA

Question 32

Type of oxazolidinone?

Answer 32

1. Linezolid 2. Tedizolid

Question 33

How is linezolid metabolize?

Answer 33

Synthetic due to morphalene -> hydroxylizes creating an anomeric carbon -> oxidizes to aldehyde breaking the ring open

Question 34

How does tedizolid differ from linezolid?

Answer 34

More potent against MRSA and longer half-life due to tetrazole * Reduce MAO interactions