Lecture 18 Glycopeptides Flashcards
What type of drug is vancomycin and what is its MOA?
glycopeptide
MOA: bactericidal against rapidly multiplying organisms
inhibits peptidoglycan cell wall synthesis, binds to D-alanyl-D-alanine substituent of precursor of peptidoglycan
sterically hinders elongation and cross-linking of peptidoglycan by transglycolase and transpeptidase enzymes
also affects protoplasts by altering permeability of cytoplasmic membrane
may also impair RNA synthesis
What is the vanA gene?
most common type of resistance for VRE
encodes for this protein which is a cytoplasmic membrane protein produced which has D-Ala-D-Ala ligase activity - this protein binds to D-alanyl-D-alanine terminus and inhibits vancomycin binding
in addition the cell preferentially synthesizes modified precursors that can be incorporated into growing cell wall and not be recognized by vancomycin
protein results in high level resistance to vancomycin as well as other glycopeptides like teicoplanin
What is the vanB gene?
encodes for this protein that acts similarly to the gene before this
is inducible by vancomycin BUT NOT teicoplanin
these producing strains are vancomycin resistant and teicoplanin susceptible
What is the vanC gene?
acts similarly to the genes before this
strains demonstrate low-level vancomycin resistance but susceptible to teicoplanin
is constitutive and chromosomally encoded
How does VISA/GISA confer resistance to vancomycin?
thickened cell wall due to accumulation of peptidoglycan cell wall components
increased binding of vancomycin to cell wall material (trapped)
PBP are overproduced and compete with vancomycin for peptidoglycan precursors
leads to vancomycin MICs of 8-16 micrograms/mL
What are heteroresistant S. aureus (hVISA)?
intermediately resistant subpopulations existing within a population of organisms whose overall MIC considered to be susceptible
this population then may be selected out with vancomycin tx
organism may appear susceptible upon testing before tx, with admin these strains are selected
What are VRSA?
contain vanA gene (transferred from VRE),, leads to higher resistance to vancomycin (MIC >32 micrograms/mL)
found in coexistence with VRE
may be susceptible to linezolid, TMP/SMX, tetracycline
What is the spectrum of activity of vancomycin?
Gram +: S. aureus (MSSA, MRSA), S. epidermidis (MSSE, MRSE), Group B strep, S. pneumoniae, viridans Group strep, E. faecalis and faecium, L. monocytogenes, C. diphtheriae, C. diff, C. perfringens, Actinomyces, several oral anaerobes and anaerobes (not B. fragilis)
What is the absorption/distribution of vancomycin?
very poorly absorbed from GI, and IM is painful
variable penetration which may be affected by inflammation and disease state
What are AEs of vancomycin?
infusion rxn, nephrotoxicity, ototoxicity, anaphylaxis, rashes, neutropenia, leukopenia
What is a vancomycin infusion related AE, what does it look like, and how does it happen?
mainly related to infusion rate ⇒ > 15 mg/min
S&S: tingling and flushing of face, pruritis, rash on neck and upper torso
1 g dose should be given over 1 hour, 1.5-2 g over 1.5-2 hours
fever, chills, rigors, phlebitis if given too quickly, extravasation causes necrosis
What does vancomycin nephrotoxicity look like, when does it happen?
around 0-17%, risk increases to 7-35% in combo with aminoglycosides, increased risk of AKI with pip-tazo
defined as: increase of 38.3 mmol/L SCr OR >/=50% increase in SCr over baseline OR drop in CrCl of 50% from baseline on 2 consecutive days
occurs more common with ⇒ aminoglycosides, nephrotoxins, troughs >15mg/L, prolonged tx (>14-21 days), high doses (4g/day), hypotension, sepsis
hat does vancomycin ototoxicity look like, when does it happen?
around 1-9% usually with higher serum conc (>40 mg/L)
severe case is rare,, preceded by tinnitus and loss of high tones first then low-tones
may be followed by auditory nerve damage and total hearing loss,, is not reversible - should stop drug if possible if tinnitus and high tone hearing loss occurs
Risk Fx: rarely with monotherapy
other ototoxics: aminoglycosides, loop diuretics, cisplatin, ASA, NSAIDs
What is teicoplanin?
glycopolypeptide available in Europe,, complex of 6 analogues, similar spectrum to vancomycin
fewer AE than vanco ⇒ less ototoxicity and nephrotoxicity, and no infusion reactions
highly protein bound (90%), t1/2 40 hours
What is telavancin?
MOA: similar to glycopeptides - binds peptidoglycan precursors D-alanyl-D-alanine termini outside bacterial cell, transglycosylase inhibition
also rapid and conc dependent disruption of bacterial cell membrane
t1/2 6.1-9.1 hours, Vd similar to vanco, dose IV QD
similar spectrum to vanco,, Uses: may be useful for pt who failed tx with vanco, have recurrent MRSA infections after vanco, MRSA infections with vanco MIC >1 microgram/mL
dosage adjustment required for CrCl <50
READ BLACK BOX WARNINGS
What are the black box warnings for telavancin?
A: increased mortality in HABP/VABP pt with pre-existing moderate or severe renal impairment (versus vancomycin), nephrotoxicity
B: potential adverse developmental outcomes - avoid use during pregnancy unless potential benefit to pt outweighs risk (observed in 3 animal species at clinically relevant doses)
What is dalbavancin?
new lipoglycopeptide,, in-vitro activity against almost all significant Gram + bacteria except those intrinsically resistant to glycopeptides and those having Van A phenotype
usually dosed as 1500 mg IV (single dose)
What is oritavancin?
new lipoglycopeptide,, MOA: inhibition of transglycosylation, inhibiting transpeptidation, cell membrane disruption
good activity against most Gram +
usually admin as single 1200 mg IV dose
