Glycoprotein/ membrane and cell wall agent Flashcards
ABX Target of CELL WALL SYNTHESIS (other than Beta Lactams)
- Vancomycin (Glycopeptide) and its derivatives lipoglycopeptide
- Bacitracin (topical)
- Polymyxins
MOA of Vancomycin (Glycopeptide)
Inhibits cell wall synthesis by binding to the D-Ala-D-Ala side chain of the precursor pentapeptide. Prevents transglycosylation and peptidoglycan polymerization
Vancomycin targets the cell wall building blocks!!!
Timmin- Vancomycin binds to the D-alanyl—D-alanine
residues (yellow spheres in illustrations) of the
peptidoglycan monomers. The monomer no
longer presents a suitable substrate for PBP. Cross
links are not created, so the peptidoglycan chains
only form a weak cell wall. Intense osmotic
pressure ruptures the cell.
Vancomycin (a Glycopeptide), prevents cell wall synthesis via a mechanism different than β-lactams! (5 diff/ vanco characteristics)
- Vancomycin acts by binding the D-Ala-D-Ala terminus of the pentapeptide (prevents access) (stops crosslinking activity of transpeptidases) HOWEVER, B LACTAM BINDS TO PBP.
- Active against gram + (particularly staphylococci as well as many
streptococcus strains), but no Gram negative coverage (doesn’t pass through the outer membrane of Gram negative species). - Important because of its effectiveness against multiple drug-resistant organisms (MRSA, MRSE and some Enterococci). Used for sepsis
or endocarditis caused by resistant strains. - SLOW acting.
- Synergistic action in combination with aminoglycosides, used to treat enterococcal endocarditis.
PK OF VANCOMYCIN
a. Poorly absorbed orally usually given IV. (PO for C. diff BECAUSE it is poorly absorbed) .
b. Time-dependent efficacy, TIME>MIC (same as PNC)
c. Renally excreted unchanged. Dosage adjustments required in cases of renal insufficiency
Adverse effects of VANCOMYCIN
a. Fever, chills and phlebitis at the injection site.
b. Flushing (Red Man syndrome) and shock due to histamine release
caused by rapid infusion. JUST SLOW THE INFUSION! NOT AN
ALLERGIC REACTION!
c. Neutropenia, thrombocytopenia
d. Dose related ototoxicity and nephrotoxicity when combined with an
aminoglycoside (Vanco plus gentamicin for Enterococcus spp.)
Vancomycin resistance (2 mechanisms)
- VISA (sensitive) Thickened cell wall so no penetration –> 5 hydrogen bonds - no cell wall syn!
Unaffected level at bottom where cross link is stronger! - VRSA (resistance) D-ala-D-lactate and decrease binding strength! cuz decrease HB –> 4 hydrogen bonds – cell wall form but no more Dala-Dala!!
What is Lipoglycopeptide?? Drug names?
Lipoglycopeptides are a class of antibiotic that have lipophilic side-chains linked to glycopeptides. Vanco derivatives
Drugs: Telavancin (Vibativ®), Dalbavancin (Dalvance®), Oritavancin (Orbactiv®)
Telavancin (Vibativ®) - Lipoglycopeptide
1.) MOA: Inhibits cell wall crosslinking & disrupts bacterial membrane.
Depolarization inhibits other cell functions
- Active against VISA
- Excreted by kidneys (dose adjust w/ renal insufficiency)
- Inhibits CYP3A4 and CYP3A5
- AE: Red-man syndrome, Nephrotoxicity, QT interval prolongation
- Concentration-dependent efficacy (AUC/MIC)
- Daily dosing
Dalbavancin (Dalvance®) - Lipoglycopeptide
- MOA: Binds D-Ala-D-Ala of pentapeptide prevents cell wall crosslinking. Dimerizes and anchors in cell membrane
- Treatment of cSSSIs AND Active against VISA
- ½ life 147-248 hours. IV, once per week
- Concentration dependent efficacy (AUC/MIC)
Oritavancin (Orbactiv®) - Lipoglycopeptide
- MOA: Inhibits transglycosylation & transpeptidation & disrupts bacterial membrane.
- Treatment of cSSSIs, Active against both VISA/VRSA
- ½ life 393 hours, 1 dose (IV infusion over 3 hours) ~$4000
- Concentration-dependent efficacy (AUC/MIC)
Daptomycin . . . (cyclic lipopeptide)
- MOA: Calcium-dependent membrane depolarization leads to arrest of
DNA/RNA/protein synthesis and cell death (without lysis). - Spectrum of activity is similar to that of vancomycin (Gram +) except that it is more rapidly bactericidal in vitro and it is active against vancomycin-resistant strains of Enterococci and S aureus.
- Concentration dependent activity (AUC/MIC)
- AE: Myalgias – CPK monitoring
Why should Daptomycin not be used to treat pneumonia????
Pulmonary surfactant antagonizes daptomycin, and it should not be used to treat pneumonia.
Hydrophobic tail. Somehow involved in insertion into lung surfactant: lowers
free levels in lung, so ineffective in treating pneumonia.
Disruption of cell membrane–> Polymyxins
drugs, MOA
- Polymyxin B and 2. Colistin (polymyxin E) -Available IV, inhaled, topical. Very much last line in many cases.
MOA: Selective for Gram negative organisms (bind LPS in membrane)
AE - Neuro and nephrotox…
Bacitracin is a cyclic peptide . . .
MOA: inhibits dephosphorylation of the lipid carrier and inhibits transport.
Activity: Active against Gram + organisms. Very nephrotoxic, so limited to topical use. Often combined with neomycin (aminoglycoside mostly targets Gram ‐) or polymyxin (disrupts outer membrane of Gram –) or both
Translocation of M and G across the cytoplasmic membrane
Translocation requires a lipid carrier molecule (C55 isoprenyl pyrophosphate or
bactoprenol phosphate - BP).
C-55 isoprenyl pyrophosphate is formed by phosphorylation of C-55 isoprenyl alcohol phosphate
