B-Lactam Intro Flashcards
Why can’t beta lactams be completely synthetic?
we can’t make the base structure chemically, it must come from natural sources
What are the four classes of beta lactams?
penicillins, cephalosporins, carbapenems, monobactams
Are beta lactams time dependent or concentration dependent, and what is the predictive PK/PD parameter?
time dependent, time above the MIC (PK/PD parameter)
Are beta lactams usually eliminated renally or hepatically?
renally
What is the mechanism of action of beta lactams?
it binds to penicillin-binding proteins which inhibits transpeptidase in the bacterial cell wall from cross-linking the peptidoglycan (affects cell wall synthesis)
What does it mean for a drug to be bactericidal?
it kills 99.9% of bacteria
What adverse reaction can be caused by all beta lactams and is not related to dosage strength?
hypersensitivity reactions
What are the two most serious hypersensitivity reactions?
acute interstitial nephritis (can lead to kidney failure), anaphylaxis
Beta-lactams can also cause seizures, which means they are called ________ drugs
epileptogenic
What is the most common reason why beta lactams cause seizures?
when the patient’s renal function changes (usually decreases) and the dose is not adjusted in time, the drug builds up in the blood and can cause the seizures
What is the approximate percent cross-reactivity between penicillins and cephalosporins?
5-10%
Which class of organisms are beta lactams NOT effective against?
atypical organisms (mycoplasma, chylamidia, etc)
Which beta lactam was approved for MRSA treatment in 2010?
ceftaroline
In what year did Alexander Fleming “discover” penicillin?
1929
How long after Fleming’s work did it take before someone actually worked out the structure and properties of PCN and considered its clinical properties? Who were they?
10 years (1939), Florey and Chain
When was resistance to PCN from S. aureus and E. coli observed and who observed it?
1942, Abraham and Chain
In what year did it become possible to make semisynthetic penicillins?
1959
Which part of 6-aminopenicillanic acid is the beta lactam part?
the square ring
Which penicillin binding protein (PBP) is the most important and effective drug target?
PBP 2
Are penicillin binding proteins enzymes?
yes
What are three bacterial mechanisms that account for resistance to beta lactams?
destruction of antibiotic by beta-lactamases, failure to penetrate to penicillin binding protein target, low affinity binding of antibiotic to PBP
How do beta-lactamases deactivate beta lactams?
break open the beta lactam ring
Why is drug penetration to the penicillin binding protein mostly a problem in gram negative organisms?
the beta lactam gets “hung up” in the lipopolysaccharide of the cell wall
What is the name of the penicilling binding protein that most commonly changes its shape to lower its affinity for beta lactam drugs?
PBP 2A
What is vertical resistance transfer?
when the parent cell passes its resistant genes on to its daughter cells
What is horizontal resistance transfer?
the passage of resistance from one species to another (usually through plasmids)
What is constitutive resistance?
bacteria produces low levels of beta lactamase at all times
What is inducible resistance?
bacteria produces a lot of beta lactamase only when needed
Why are staphylococcal beta lactamases called penicillinases?
because they are mostly active against penicillins
What are some characteristics of staphylococcal beta lactamases?
plasmid encoded, inducible, hydrolyzes (breaks open) penicillin before it reaches target PBPs
What are two examples of antistaphylococcal penicillins?
methicillin, isoxazolyl
Why can methicillin only by given IM or IV, not orally?
its beta lactam ring is broken open by stomach acid
Where are gram negative beta lactamases strategically located, and why is this effective?
in the periplasmic space; it doesn’t cost very much energy to create enough beta lactamase to make a really high concentration in the space because it is so small, so very little beta lactamase needed
gram negative beta lactamses can be coded on ____ or ______, and can be inducible or constitutive
plasmids, chromosomes
Where did TEM-1 come from and what drug did it break down?
came from E. coli, broke down ampicillin
What does ESBL stand for and what does it break down?
extended-spectrum beta lactamases, breaks down extended spectrum cephalosporins
What are three constraints that porin channels (in gram negative cells) use to control what enters the cell?
size, structure, charge of molecule
What are three mechanisms used to limit antibiotic concentrations in the periplasmic space?
exclusion of antibiotic by porins, destruction of antibiotic with beta lactamases, active transport of drug back across the membrane out of cell
What PBP does MRSA have that changes its affinity for beta lactam antibiotics?
PBP2a
What molecule is involved in crosslinking of peptidoglycan in the cell wall?
pentaglycine
