L4 Pharm: Antibiotics for Gram +: Vancomycin/Linezolid/Daptomycin Flashcards
Vancomycin, Linezolid, Daptomycin target what organisms?
GRAM POSITIVE
- Staphylococcus
- Strep
- Enterococcus
- Listeria
- Clostridium
- Bacillus
- Actinomyes
- Nocardia
What is the mechanism of action of Vancomycin?
What does it bind to and prevent?
- Inhibits bacterial cell wall synthesis at a site different than B-lactams
- inhibits synthesis & assembly of SECOND STAGE of cell wall synthesis! - Binds firmly to D - alanyl - D - alanine portion of cell wall precursors to prevent cross-linking & further elongation of peptidoglycan (weakening cell wall)
What is the mechanism of resistance of vancomycin?
Specifically what bacteria gain resistance?
VRE (Vancomycin resistance Enterococcus)
VRSA (Vancomycin resistant Staph Aureus)
- Modification of D-alanyl-Dalanine binding site of peptidoglycan
- -> replaces the terminal D alanine to D-lactate
D-ala D -ala to D-ala D-lac (Pay 2 D-alas for VANdalizing (vancomycin)
- changing to D-lactate results in a loss of critical hydrogen bond
- loss of antibacterial activity!
(3 phenotypes: van A, van B, van C)
What is VISA? How does it gain resistance to vancomycin?
Vancomycin Intermediate Staph Aureus
- THICKENED cell wall!
- Vancomycin: oral or IV for systemic infections?
- Exception?
- Because Vancomycin distributes widely (including adipose) what should be used for dosing?
- _____ dependent bactericidal activity (unlike aminoglycosides)
- Static against ______
- IV for systemic
- ORAL for patients with colitis
- TBW (total body weight)
- TIME - dependent bactericidal activity
- slowly kills bacteria
(ahminoglycosides are conc. dependent)
STATIC against Enterococcus
Spectrum of Activity for Vancomycin:
What gram positive bacteria? (12)
No activity against what?
- Methicillin susceptible AND
- methicillin Resistant S. Aureus
- Coagulase - Negative Staphylococci*** (Epedermidis)
- Strep. Pneumo (PSRSP*)
- Enterococcus
- Corynebacterium
- Bacillus
- Listeria
- Actinomyces
- Clostridium (C. difficile
- Peptococcus
- Peptostreptococcus
NO ACTIVITY AGAINST GRAM NEGATIVE!!
- In order to monitor the serum for renal insufficiency & concentration, when must vancomycin be drawn?
How is Vancomycin eliminated?
What does its elimination half life depend on? (test)
T/F: It is removed by hemodialysis
- Draw at least 60 minutes after end of infusion because it SLOWLY distributes from plasma into tissue compartment.
- RENAL elimination
- elimination half life depends on RENAL FUNCTION
- progressively increases with degree of renal dysfunction - FALSE: not removed by hemodialysis
Peak of vancomycin should be drawn when??
Although Vancomycin is widely distributed into body tissues & fluids (including adipose) what does it have VARIABLE penetration for?
ONE HOUR AFTER END OF INFUSION!!! (test)
- falsely elevated if drawn too early
2. Variable penetration into CSF! (even with inflamed meninges)
What are the 4 clinical uses for Vancomycin?
VANCOMYCIN!!
- Infections due to MRSA
(bactermia, empyema, endocarditis, peritonitis, pneumonia, skin & soft tissue infections, osteomyelitis, meningitis) - Serious gram positive infections in B-lactam allergic patients
- Infections due to multi drug resistant bacteria (PRSP) pen resistant staph pneumonia
- Oral treatment for C. Difficile colitis
What is the MAJOR adverse affect of vancomycin?
This is due to the release of what?
Does it resolve after vancomycin is discontinued?
How can it be avoided?
RED MAN SYNDROME!!!
- Flushing, pruritus, erythematous rash on
face, neck, and upper torso within 5 to 15
minutes of starting infusion
- Due to HISTAMINE release
- YES resolves spontaneously
- May lengthen infusion (over 2 to 3 hours) or - pre-treat with antihistamines in some cases
Red Man Syndrome is related to ____ of intravenous infusion and should deb infused over at least 60 minutes.
How can this be avoided?
RATE !!!!(test)
- red man usually occurs within 5-15 minutes of infusion
DUE TO RATE OF INFUSION
- Pretreat with anti-histamines and LENGTHEN infusion rate (over 2-3hours)
- not a hypersensitivity reaction!
(hypersensitivity occurs all over the body in a period of DAYS)
What are the 6 adverse effects of vancomycin
- Red Man syndrome
- Nephrotoxicity
- Ototoxicity
- Dermatologic - Rash
- Hematologic:
neutropenia, thrombocytopenia
- thrombophlebitis, interstitial nephritis
Does vancomycin need to be adjusted for renal dysfunction? (why or why not)
What gram positive anaerobes does Vancomycin have activity against?
- YES since it is renally eliminated
- Clostridium
Peptococcus
Peptostreptococcus
Dalbavancin is a semisynthetic _____.
What is it used against?
Does it have activity against van A?
- lipoglycopeptide
- Against resistant gram positive organisms
- MRSA
- VISA
- VRE w/ van B & vanC gene
- MRSE, Streptococcus
- vs. Bacillus
- Listeria
- Corynebacter - NO ACTIVITY for VanA
** no activity for GRAM NEGATIVE RODS!**
- What is the mechanism of action of Dalbavancin?
- Is it more or less potent & tidal than vancomycin? (why or why not)
- How is Dalbavancin administered?
- Binds to C terminal D-Ala-D ala interfering with cross linkage & polymerization
- can attach to the cell membrane from its lipophilic moiety - MORE POTENT because it can attach to the cell membrane!!!
- IV only
- once weekly dosing
(half life is 9-12 days)
A) What are the major side effects of Dalbavancin?(6)
B) Does dosing change with decreased CrCL?
C) Is there an adjustment with hemodialysis?
A)
- ANaphylaxis (hypersensitivity)
- Skin reactions
- Flushing w/ rapid RATE of infusion (Red Man infusion)
- Increased ALT!!
- Hemotologic
- Head aches
B) Decrease dose with decreased creatinine clearance!
C) No adjustment with hemodialysis !!! (not cleared by HD)
Telavancin:
- similar to Dalbavancin in that it is a _____
- Active against what organisms?
- What is its mechanism of action?
- lipoglycopeptide
- Gram positive organisms, MRSA
- Affects cell membrane permeability/depolarization
Which drug is used for:
a) complicated skin & skin structure infections
b) Staph. Healthcare associated pneumonia (HAP) & ventilator associated pneumonia (VAP)
Telavancin!!!
- nosocomial pneumonia
- What are the adverse affects of Telavancin?
- Compared to Vancomycin, it has a higher rate of _____
- Does Telavancin need to be adjusted with decreased CrCl?
- Nausea, Vomiting, Constipation, headache
- Higher rate renal toxicity than vancomycin
- Teratogenic in animals
- YES!!
State which drug does the following:
- A semisynthetic glycopeptide
- Disrupts cell membrane
- Affects transglycosilation/transpeptidation
- Has activity against
MSSA
MRSA
Oritavancin
- 1 dose over 3 hours
- IV only
BACTERIACIDAL!
Linezolid (oxazolidinone)
- How is it administered?
- Developed in response to need for antibiotics with activity against what?
- What specific bacteria? (3)
- IV & Oral
- Developed in response to need for
antibiotics with activity against resistant
gram-positives (VRE, MRSA, VISA) - Vancomycin Resistant Enterococcus, MRSA, Vancomysin Intermediate Staph. Aureus
What is the mechanism of action of linezolid?
What is the only drug that it is bactericidal against?
Binds to the 50s ribosomal subunit near the surface interface of 30s subunit
- causes inhibition of 70s initiation complex!!!
(unique binding site)
INHIBITS PROTEIN SYNTHESIS!!!
= bacteriostatic
- Cidal vs. Strep Pneumonia!!
What is the mechanism of resistance of Linezolid?
Alters ribosomal binding sites
Cross- resistance with other protein synthesis inhibitors is unlikely
What is the spectrum of activity of Linezolid? (11)
- Gram positive?
- Gram negative?
- Atypical Bacteria (1)
- MSSA
- MRSA
- VRSA
- Coagulase negative staph
- Strep Pneumoniae (including PRSP!!!)
- Enterococcus Faecum AND Faecalis (including VRE)
- Bacillus
- Listeria
- Clostridium (except C. Diff)
- Peptostreptococcus
- P. acnes
NO GRAM NEGATIVE!!
Atypical: Mycobacteria!!
Linezolid displays time or concentration dependent killing?
It shows ____ for Gram Positives
What is unique about its absorption?
How does its CSF penetration compare to Vancomycin?
How is it eliminated?
- TIME dependent bactericidal activity
- POST ANTIBIOTIC EFFECT for gram positives
- 100% Bioavailable
- CSF penetration = 30%
- Eliminated both really & non-renally
(primarily metabolized)
Linzeolid:
- Is there an adjustment for renal insufficiency?
- Is it affected by hemodialysis?
- NO ADJUSTMENT!! (unlike vancomycin & oritivancin & telavancin, & delvancin)
- YES REMOVED by HEMODIALYSIS! (different)
What is Linezolid reserved for?
What 3 types of infections?
- Serious/complicated infections caused by resistant gram-positive bacteria
a) VRE bacteremia (NOT UTI!!!)
b) complicated skin/soft tissue infections due to MSSA, MRSA, or Strep Pyogenes!
c) Nosocomial pneumonia due to MRSA
T/F: Linezolid is used for UTI
FALSE!!
What drug has the potential to interact with adrenergic or seratonergic agents?
What does it do?
- LINEZOLID!
2. Enhance pressor response to agents such as dopamine or epinephrine
What is the MAJOR adverse affect of Linezolid?
SERATONIN SYNDROME WITH SSRIs/MAOIs!!!
-hyperpyrexia, diarrhea, cognitive dysfunction,
restlessness, seizures, coma
- may need 2 week washout period
What drug causes:
- GI: nausea vomiting diarrhea
- Peripheral NEUROPATHY (test)
- Thrombocytopenia or ANEMIA
- Headache
- Seratonin Syndrome
LINEZOLID!!
- inhibits 50s subunit!
What drug is:
- more potent than linezolid
- Has no SSRI interaction like linezolid
- functions an oxazolidinone
- Acute bacterial SSSI
- staph, strep entero
- PO or IV
AE: Headache, dizziness, hematologic, neuropathy
TEDIZOLID
Daptomycin:
- Cyclic lipopeptide antibiotic with activity against what (3 specifically)
- Derived from ____
- VRE
- MRSA
- VISA
- disrupts cell membrane of gram positive COCCI
3. Streptomyces roseosporus (natural)
- What is the mechanism of action of daptomycin?
2. Concentration or Time dependent bactericidal activity?
- Binds to bacterial membranes
- rapid depolarization of membrane potential
- inhibits protein, DNA, and RNA synthesis - CONCENTRATION!
(similar to ahminoglycosides)
- vancomycin & linezolid both time dependent
What is the mechanism of resistance of daptomycin?
Rarely reported in VRE & MRSA due to altered cell membrane binding
What gram positive bacteria does daptomycin target?
- MSSA
- MSRA
- VRSA
- Coag - neg staph
- Strep pneumo (PRSP)
- ENTEROCOCCUS faecium AND faecalis (including VRE)
NO GRAM NEGATIVE ACTIVITY
Unlike linezolid or vancomycin, Daptomycin has a high level of what?
What is it excreted primarily by?
Does it require dosage adjustment with RI?
Is it removed by HD?
- PROTEIN BINDING
- 90% - Excreted primarily by the KIDNEYS
- YES dosage adjustments needed (only one that doesn’t is Linezolid!
- NOT REMOVED BY HD!
What is daptomycin reserved for?
- Serious/complicated infections caused by resistant bacteria
- Skin & soft tissue infection due to MSSA, MRSA, or Strep progenies
- Bacteremia due to Staph AUreus
** skin infections due to staph aureus, MRSA, bacteremia, endocarditis, VRE**
What drug is contraindicated in the treatment of pneumonia?
DAPTOMYCIN!!!
TEST, boards
What are the MAJOR adverse effects of Daptomycin?
- Myopathy
- CPK elevation (rhabdomyolysis)
GI - nausea, diarrhea
Headache
Rash
Injection site pain
Daptomycin is contraindicated with the use of what drugs? Why?
h HMG CoA - Reductase inhibitors like STATINS
- increased the incidence of myopathy
Quinupritin - Dalfopristin
- What is their function?
- What is the MAIN POINT of these drugs?
- Protein synthesis inhibitors
Synergistic: static + static –> CIDAL!!!
= SYNERGISM (both drugs become bactericidal)
How Does Dalfopristin affect quinupristin?
What does Quinipristin do as a result?
How are they both cleared?
Dalfopristin enhances binding of quinipristin –> inhibits PEPTIDYL TRANSFERASE
Quinipristin prevents elongation of pp chain & causes incomplete chain release
- LIVER CLEARANCE (only one from this section)
What is the adverse effect of Quinupristin-Dalfopristin
Severe GI intolerance!
