Glycopeptides Flashcards
Glycopeptides - Vancomycin
Mechanism of Action
- bactericidal against rapidly multiplying organisms
-i nhibits peptidoglycan cell wall synthesis
- binds to D-alanyl-D-alanine substituent of the precursor of peptidoglycan
- stearically 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
late stages of cell wall synth
peptidoglycan monomer precursor is
basically brought to the outer layer
and then vancomycin binds to that
Resistance to Vancomycin
resistance started 1980s, late
q VRE (Vancomycin Resistant Enterococci)
(1986 Europe, 1987 USA)
q VISA (Vancomycin Intermediate-resistant S. aureus) (1997)
q Also referred to as GISA
(Glycopeptide Intermediate-resistant S. aureus)
q VRSA (Vancomycin Resistant S. aureus) (2002), not automatically beta lactam resistant
q Tolerance in S. pneumoniae reported
q No cross-resistance with penicillin
q Many patterns of resistance VanA, VanB….VanG …
9 types in enterococci..
vanA Gene Resistance in VRE
if it has small v in front, means we’re talking abt the gene
capital V is the protein
dont need to know teicoplanin
most common type of resistance
- vanA encodes for VanA, a cytoplasmic membrane protein produced which has D-Ala-D-Ala ligase activity
- VanA binds to the D-Alanyl-D-Alanine terminis of the peptidoglycan precursor, and inhibits vancomycin binding
- In addition, the cell preferentially synthesizes modified
precursors that can be incorporated into the growing cell wall and not be recognized by vancomycin (D-Ala-D-serine, or D-AlaD-Lactate instead of D-Ala-D-Ala)
- VanA results in high level resistance to vancomycin (MIC >256 mg/mL) as well as other glycopeptides like teicoplanin
- VanA protein is induced by either vancomycin or teicoplanin and may be plasmid encoded and encoded on a transposon
vanB Resistance in VRE
q vanB encodes for VanB protein that acts in a similar way to VanA (binding to the D-Alanyl-D-Alanine terminis and inhibiting vancomycin binding to the peptidoglycan
precursor)
q VanB synthesis is inducible by vancomycin, but not
teicoplanin
q VanB producing strains are vancomycin resistant and
teicoplanin susceptible
vanC Resistance in VRE
q Acts similarly to vanA and vanB
q Strains demonstrate *low-level vancomycin resistance,
but are susceptible to teicoplanin
q VanC is constitutive and chromosomally encoded
Vancomycin Tolerance
Tolerance may develop due to
q autolysin deficiency (deficiency in bacteria is destruction of cell walls)
enzymes breaking down peptidoglycan and enabling turnover of the cell wall
q Clinically, biofilms on foreign devices or tissues protecting bacteria
Tolerance in S. pneumoniae reported in Nature
(June 10,1999)
q however 100% S. pneumoniae at UAH susceptible to
vancomycin (2020)
Vancomycin Intermediate
S. aureus (VISA/GISA)
Different mechanism of resistance than VRSA
- 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 µg/mL
VISA Thickened Cell Wall- canco binds to outer layer, lower layer is unaffected and able to add peptid components and repair cell wall
Heteroresistant S. aureus (hVISA)
Have found intermediately resistant subpopulations
existing within a population of organisms whose overall
MIC considered to be susceptible
q Resistant subpopulation then may be selected out with vancomycin treatment
q Organism may appear susceptible to vancomycin upon testing before treatment
q With administration of vancomycin, susceptible strains destroyed and more resistant strains are selected
q May result in therapeutic failure
Vancomycin Resistant
S. aureus (VRSA)
q Contain vanA gene (transferred from VRE)
q Lead to high level resistance to vancomycin
(MIC >32 µg/mL)
q Found in coexistence with VRE
q assume conjugative transfer of vanA gene from
Enterococcus to S. aureus
q May be susceptible to linezolid, TMP/SMX, tetracycline
Vancomycin Spectrum
q S. aureus including MRSA (99% UAH 2014, 100% 2020) q S. epidermidis including MRSE (100% CoNS UAH 2014, 2020)
q Grp B Streptococci
q S. pneumoniae (100% UAH 2014, 2020) including strains highly penicillin-resistant
q Viridans Grp Streptococci (100% UAH 2014, 2020)
q E. faecalis (100% 2014, 100% 2020)
q E. faecium (97% 2014, 73% 2020)
q L. monocytogenes usually susceptible; C. diptheriae
q Anaerobes - many susceptible (but not B. fragilis) - G+ mainly
q C. difficile, C. perfringens, Actinomyces
q Several oral anaerobes
Vancomycin Absorption/Distribution
dosage form
q very poorly absorbed from GI tract, stays in GI –> used for C. difficile
q IM painful (not recommended)
q Penetration to many tissues variable and may be affected by inflammation and disease state
CSF (variable CSF levels in meningitis)
q Un-inflamed meninges CSF concentrations 0 - 4 mg/L
q Inflamed meninges CSF concentrations 6.4 - 11.1 mg/L
Lung
q Concentrations in lung tissue variable, 5 - 41% of serum concentrations
q Poor concentrations in lung epithelial lining fluid
q Blood/ ELF (epithelial lining fluid) ratio 6:1
Skin - penetration lower in patients with diabetes
Vancomycin Adverse Effects - 3 main ones
initial toxicities related to impurities (“Mississippi Mud”) q Early formulations ~70% pure q 1960s purity increased to 75% q 1985 purity increased to 92 - 95% q Concurrently, a decrease in reporting of adverse effects occurred
q* Infusion Related Reactions q Related to infusion rate q * Nephrotoxicity q * Ototoxicity q Other q Not dose related (anaphylaxis, rashes, neutropenia, leukopenia)
Vancomycin Adverse Effects
Infusion-Related
what to do if it occurs
q Most common infusion-related adverse effects not related to serum drug concentrations but to infusion rate
q Vancomycin Infusion Reaction if > 15 mg/min (fast rate)
q Tingling and flushing of face, pruritis, erythematous rash on neck and upper torso
q May be related to histamine release
q 1 g dose should be given over 1 hour
q 1.5 - 2 g over 1.5 - 2hr
(30min/500mg administered)
q fever, chills, rigors, phlebitis if given too quickly
q Extravasation causes tissue necrosis
if rash appears, slow infusion rate, increase dilution, or give in a larger saline minibag, give antihistamines before it
Vancomycin Adverse Effects
Nephrotoxicity
Definitions recommended by ASHP/IDSA consensus report:
q Increase of 0.5 mg/dL (38.3 mmol/L) serum creatinine
or
q ≥ 50% increase in serum creatinine over baseline in
consecutively obtained daily serum creatinine values
or
q A drop in calculated Clcr of 50% from baseline on 2
consecutive days
In the absence of an alternative explanation
q Nephrotoxicity estimated 0-17%
q as monotherapy (better after purification)
q 0-17% reports to 1986
q 5 – 7% up to 1993 (Cantu)(few clear-cut examples as
monotherapy)
q Risk of nephrotoxicity increases to 7 - 35% in
combination with aminoglycosides
q ↑ rate of acute kidney injury also associated with
combination with piperacillin-tazobactam
tend to accumulate in levels and go up, monitor at least weekly for prolonged courses
In humans, nephrotoxicity due to vancomycin monotherapy withtypical dosage regimens is uncommon and usually reversible
Occurs more commonly with:
q Aminoglycosides (concurrent aminoglycoside
administration 6.7 fold increase) (Rybak)
q Concurrent nephrotoxins
q Troughs > 15 mg/L
q Prolonged treatment (>14 - 21 days)
q With high doses (4 g/day)
q Concurrent hypotension, sepsis etc
