Lincosamides and Amphenicols (MC) - Block 2 Flashcards
What are the lincosamides?
Lincomycin and clindamycin
What is the MOA of clindamycin?
Inhibits protein synthesis by inhibiting ribosomal translocation on the 50S -> interfering wih aminoacyl translocation
Describe the activity of lincosamides?
G+ cooci (CA-MRSA)
Clindamycin hascross resistance with what drug, due to its similar activity?
Macrolides
Erythromycin resistance methylase is encoded by?
Plasmid-borne gene erm
Describe the SAR of lincosamides?
- Tertiary amine
- Ester formation of 2-OH
Differntiate the esters formed on a lincosamide scaffold?
Phosphate -> water soluble
Palmitate -> lipophilic formulation to mask taste for pediatrics
ADRs of Lincosamides?
- Severe diarrhea with pseudomembranous colitis
- Overgrowth of C. diff.
Describe the metabolism of lincosamide?
- Tertiary amine undergoes N-Demethylation
- Sulfur oxidized (S-oxidation)
Describe the penetrability of clindamycin?
- Gets into the bone
- Cross resistance with macrolides
- Doesn’t get into the brain or CSF
What is the target level of clindamycin?
2-3 mcg/mL
What is the mechanism of chloramphenicol?
- Inhibits protein synthesis through reversible binding to the 50S of bac ribosome
- Inhibits the peptidyl transferase step of protein synthesis
Describe the scope of acitivity of chloramphenicol?
G+, G- aerobes and anaerobes
ADR of chloramphenicol?
- Toxicity: Fatal aplastic anemia (pancytopenia)
- GI distubances
- Gray baby syndrome (inadequate glucoronidation metabolism)
Resistance of chloramphenicol stems from what?
R-factor mediated acetylation of the 1-OH and to a less extent the 3-OH
Types of amphenicols?
Chloramphenicol
How are chloramphenicols metabolized?
Glucoronidation to become for soluble for elimination
What is the most common use of chloramphenicol?
- Rocky mountain spotted fever (Rickettsia)
- Menigococcal meningitis with severe b-lactam allergy or Penicillin resistant pneumococcus bacterial meningitis
What are the characteristics nitroaromatic?
- Prodrugs activated by bacteria
- Bacteriocidal
ADR of nitrroaromatics?
Genotoxicity: DNA damage and nicking of ribose
Source of nitroaromatic resistance?
Inactivation of prodrug activating enzymes
What is the active form of nitrofurans?
-N-OH
However, N=O and N-O. form radicals that are active as well
What is the backbone of a nitrofuran structure?
Schiff base
Urine color of nitrofurantoin?
Dark brown
ADRs of nitrofurantoin?
N/V
* Avoided by slowing absorption rate and Macrodantin (wax-coated, large particles)
Disulfuram reaction with alcohol
Describe the MOA of metronidazole?
- O free radicals cause oxidative stress and depletes thiol
- Reactive intermediate form adducts with protein and DNA -> nicking (DNA fragments)
Describe the formulation of methanamine?
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
What is the target of fosfomycin?
Inhibits the early stages of PG biosynthesis against E. coli and E. faecalis
What is the MOA of linezolid?
Inhibits protein synthesis by blocking complex between (initiation process): 70S, tRNA, mRNA
* binds to 23S rUnit and prevents the formation of 70S
Spectrum of linezolid activity?
MRSA, VRE
* May interfere with MAO (serotonin syndrome risk)
What causes linezolid resistance?
Mutation of 23S rRNA
Type of oxazolidinone?
- Linezolid
- Tedizolid
How is linezolid metabolize?
Synthetic due to morphalene -> hydroxylizes creating an anomeric carbon -> oxidizes to aldehyde breaking the ring open
How does tedizolid differ from linezolid?
More potent against MRSA and longer half-life due to tetrazole
* Reduce MAO interactions
