Vancomycin and beyooond Flashcards
What is the MOA of Vancomycin?
- Vancomycin inhibits cell wall synthesis by binding firmly to the D-Ala-D-Ala terminus of nascent peptidoglycan pentapeptide
- This inhibits the transglycosylase, preventing further elongation of peptidoglycan and cross-linking.
- The peptidoglycan is thus weakened and the cell becomes susceptible to lysis.
- The cell membrane is also damaged, which contributes to the antibacterial effect.
What are common toxicities of vancomycin?
* Rapid infusion associated with “red man” syndrome: flushing of face, neck and upper thorax, pruritis and hypotension o due to sudden release of histamine; not an allergic reaction o minimized by infusing vancomycin over 1 hr o Phlebitis can occur commonly when infused peripherally
* Ototoxicity leading to deafness uncommon; may be preceded by tinnitus o associated with very high serum levels (> 80 ug/mL)
*** Nephrotoxicity **is uncommon, though it may potentiate AG-induced nephrotoxicity o associated with high serum levels (> 30 ug/mL)
o reversible when d/c
What are the PK of vancomycin?
- oral absorption is very poor; only administered orally for treatment of C. difficile diarrhea or Staphylococcal enterocolitis
- IV preparation has variable CSF penetration
- IM administration not recommended due to pain on injection
- elimination is primarily renal and must be dose-adjusted in renal dysfunction; not removed by dialysis
Describe therapeutic drug monitoring for vancomycin?
- routine monitoring of vancomycin serum levels is recommended due to its fairly predictable levels at standard doses
o For MRSA, you need an AUC/MIC ratio of 400 to produce an effective kill.
o This means that for less severe infections (skin and soft tissue) a trough of 10-15 is required and more severe infections (meningitis, endocarditis MRSA pneumonia/sepsis/ osteomyelitis) you need a minimum trough of 15-20.
o Most standard adult doses start at 1g IV q8h to attain this AUC/MIC ratio
What is the spectrum activity of vancomycin?
- Because it is a big fat molecule it will not penetrate into gram-ve bacteria.
Only active against gram positive aerobic bacteria: - Strep species o methicillin-sensitive, methicillin-resistant and coagulase negative Staphylococcus species o Enterococcus species (usually in combination with an AG)
o Clostridium difficile - Vancomycin-resistant strains of Staph aureus and Enterococci have been reported; usually preserve use of vancomycin unless necessary
Describe the MOA of Daptomycin?
MOA: * The precise mechanism of action is not fully understood, but it is known to bind to the cell membrane via calcium-dependent insertion of its lipid tail. This results in depolarization of the cell membrane with potassium efflux. The synthesis of protein, DNA and RNA is inhibited by this disruption, leading to bacterial cell death. (Gilbert et al.)
Describe the Toxicities of Daptomycin?
- Mostly MSK and may see an increase in CPK at doses greater than 4mg/kg o May consider monitoring CPK weekly while on daptomycin.
What is the PK of daptomycin
PK/PD: * Exerts its effect in a bactericidal concentration dependent manner. * Has a PAE of up to 7 hours * Is excreted via the kidneys and needs to be dose adjusted in renal dysfunction * Highly protein bound and mainly found in extracellular fluid with penetration to vascular tissues * It does not cross the BBB * It is inactivated by pulmonary surfactant and cannot be used in pneumonias
Describe the spectrum of activity of Daptomycin?
- Covers all species of Staph (MSSA, MRSA and Epidermidis) strep species, enterococcus (both species including VRE)
- No gram -ve coverage
- Primarily used in skin and soft tissues infections and bacteremia/right sided endocarditis
Which is the instructors least favourite AB and why?
CLindamycin!
It stinks
Lots of toxicities - Diarrhea due to C.Difficile - may lead to toxic megacolon and death
- Allergic reactions, hepatotoxicity, neutropenia, and thrombocytopenia
- Can cause cross resistance to other macrolides due to - mutation of the ribosomal receptor site; Modification of the receptor by a constitutively expressed methylase, enzymatic inactivation of clindamycin
- Covers Strep species, and MSSA and B. Fragilis.
- BUT covers MRSA unreliably
- Does not cover enterococcus, no gram -ve coverage,
What is the MOA of Clindamycin?
- Binds to 50S robosomal subunit, inhibiting protein synthesis.
What is the MOA of Linezolid?
- It inhibits protein synthesis by binding to the 23S ribosomal RNA of the 50S subunit. It exhibits no-cross resistance with any other drug classes
What is the mechanism of resistance of Linezolid?
When it occurs is usually due to a mutation of the binding site on 23S
Describe the toxicities of linezolid?
- Mostly hematologic, usually reversible
o Thrombocytopenia if have been on drug for longer than 2 weeks o Anemia and neutropenia can occur if the patient is already susceptible to bone marrow suppression.
- Optic, peripheral neuropathy can occur and lactic acidosis can occur with prolonged therapy.
- Is a weak MAO inhibitor so you have to be careful with patients on SSRIs, SNRIs or any serotonergic drug (ie. one of them has to go).
Describe the PK/PD of linezolid?
- Is bacteriostatic against most pathogens but bactericidal against streptococci. * It is 100% bioavailable and is both PO and IV * It does not affect CP450 enzymes
