Lec 3 Beta Lactams/Cephalosporins Cushman Flashcards
in Gram-(+) bacteria, b-lactamases are excreted through the _____ _____ to the external environment. In Gram-(–) bacteria, the b-lactamases are confined to the _______ _______. The b-lactamases in Gram-(+) bacteria therefore have to be produced in _______ quantities
cell wall
periplasmic space
larger
how many membranes are in gram positive bacteria?
1
how many membranes are in gram negative bacteria?
2
in gram negative bacteria, the peptidoglycan contains a ____ residue, but in gram positive that residue is replaced by ______
DAP
L-lysine
DAP of gram neg and L-lysine of gram pos is crosslinked with what amino acid?
D-Ala
the cross-link bridge varies from species to species, but typically consists of about ___ amino acids
5 (ex. staph aureus has bridge of 5 glycine residues)
which AA residue do transpeptidases use to catalyze cross-linking?
serine
beta-lactam antibiotic MOA:
1. they acylate the transpeptidase ____ residue in active site, inactivates enzyme and cell wall is subject osmotic stress
2. highly strained ___-membered ring made
3. the structures of the beta-lactams resemble the _________ fragment that is acted on by transpeptidases
serine
four
D-Ala-D-Ala
resistance to beta-lactam antibiotics: induction or elaboration of bacterial beta-lactamases leads to _______ of the acylated beta-lactamase intermed, so the enzyme can hydrolyze many drug molecules rapidly
hydrolysis
~___-___ % of US population is allergic to beta-lactam antibiotics
~6-8%
the allergenicity of beta-lactam antibiotics results from the drug acting as a _____, acylating host cell proteins which raises antibodies
hapten
two tests for beta-lactam allergy
topical flare and wheal tests
which of the following is TRUE about penicillin degradation?
a. penicillin hydrolysis products have antibiotic activity
b. hydrolysis of beta-lactam is reversible
c. electroneg substituents reduce nucleophilicity, which stabilizes the penicillin against hydrolysis under acidic conditions
d. parenteral pencillins should be stored in fridge between pH 5 and 6
c. electroneg substituents reduce nucleophilicity, which stabilizes the penicillin against hydrolysis under acidic conditions
(a is no activity; b is irreversible; d is between pH 6 and 6.8)
why is penicillin V more stable to hydrolysis in the stomach than penicillin G?
bc electroneg of the ether oxygen dec nucleophilicity of amide carbonyl
T or F: penicillins with more lipophilic side chains are more highly protein bound
T (this reduces bioavailability)
T or F: heavy metal ions catalyze penicillin degradation rxns and should therefore be kept away from penicillin solutions
T
T or F: penicillins are only renally excreted
F (renally or biliary)
for penicillins that are excreted by kidneys, ~10% is by _______ ______ and 90% is by _______ _______
glomerular filtration; tubular secretion
penicillins are anionic, so adminstering with which drug will cause an increase in half-life?
probenecid
T or F: penicillin G should be used with caution in those with asthma
T
are penicillin G and V beta-lactamase sensitive or resistant?
sensitive
penicillin G and V target gram _______ cocci
positive
main diff between penicillins G and V
V is more stable in acid due to ether oxygen (meaning it is more stable in the stomach so blood levels are higher when given orally)
why is methicillin not beta-lactamase sensitive?
steric hindrance of nucleophilic attack
MRSA:
-due to mutation in __________ (PBP)
-the gene encoding for this protein is _____
-the PBP that it codes for is called _____
transpeptidase
mecA
PBP2A
is nafcillin sensitive to beta lactamase?
no
which of the following beta-lactamase resistant oral penicillins is still available for oral use?
a. oxacillin
b. cloxacillin
c. dicloxacillin
c. dicloxacillin
T or F: oxacillin for injection is no longer available
F
two beta-lactamase sensitive broad-spectrum oral penicillins
ampicillin
amoxicillin
which has better oral absorption, amoxicillin or ampicillin?
amoxicillin
antimicrobial spectrum for ampicillin
many gram neg organisms, including salmonella, shegella, proteus mirabilis, E. coli, many strains of haemophilis influenzae and neisseria gonorroeae
beta lactamase inhibitors MOA
They acylate the serine hydroxyl group in the active site of the b-lactamase
amoxicillin + potassium clavulanate
a. augmentin
b. unasyn
c. zosyn
d. avycaz
a. augmentin
ampicillin + sulbactam
a. augmentin
b. unasyn
c. zosyn
d. avycaz
b. unasyn
piperacillin + tazobactam
a. augmentin
b. unasyn
c. zosyn
d. avycaz
c. zosyn
ceftazidime + avibactam
a. augmentin
b. unasyn
c. zosyn
d. avycaz
d. avycaz
piperacillin is known as an acylureidopenicillin because it incorporates a _____ moiety
urea
why does piperacillin have enhanced potency compared to ampicillin?
added side chain fragment resembles a longer section of the peptidoglycan chain than ampicillin does
cephalosporins have a ___ membered ring instead of a ___ membered ring in penicillins
6; 5
In contrast to parenteral cephalosporins, the orally active cephalosporins have substituents at ___ that are not chemically reactive.
a. C-2
b. C-3
c. C-4
d. C-8
b. C-3
cephalexin is an orally active _____ gen cephalosporin
a. first
b. second
c. third
d. fourth
e. fifth
a. first
first gen cephalosporins are primarily active against what bacteria? (4 ones listed)
-gram positive cocci (staph aureus and pyogenes)
-group B streptococci (streptococcus agalactiae)
-streptococcus pneumoniae
cefuroxime is a _____ gen cephalosporin
a. first
b. second
c. third
d. fourth
e. fifth
b. second
The _______ side chain of cefuroxime is less reactive toward enzymatic hydrolysis. This makes it less susceptible to nucleophilic attack. The carbamate is also not a good leaving group, which enhances oral bioavailability in this case
carbamate
second gen cephalosporins such as cefuroxime should be protected from light due to what moiety?
oxime ether (syn isomer methoximino can be photochemically isomerized)
Third gen cephalosporins are less active against ________ than the first gen agents, but they are much more active vs. Gram _______ bacteria than either the first or second gen agents
staphylcocci; negative
T or F: third gen cephalosporins are frequently useful against nosocomial (hospital-acquired) multidrug-resistant strains
T
ceftazidime is a _____ gen cephalosporin
a. first
b. second
c. third
d. fourth
e. fifth
c. third
ceftazidime leaving group
charged pyridinium ring at C-3
ceftazidime:
1. large _____ _____ moiety at C-7
2. charged _______ _______ ring at C-3 is very good leaving group, makes it parenterally active
3. the side chain ______ confers activity vs gram neg
oxime ether
pyridinium ring
carboxyl
why is cefixime orally active and ceftazidime is not?
cefixime does not have a LG at C-3, the presence of an unreactive substituent at C-3 inc oral bioavailability
Fourth gen cephalosporins: They retain the antibacterial spectrum of the third gen cephalosporins and also add ________ ________ and some enterobacteria that are resistant to third gen cephalosporins
pseudomonas aeruginosa
cefepime is a ____ gen cephalosporin
a. first
b. second
c. third
d. fourth
e. fifth
d. fourth
cefepime:
1) The syn ________ group at C-7 stabilizes cefepime against b-lactamase.
2) The __________ moiety is a good leaving group and therefore increases the reactivity of the b-lactam and makes it parenterally active (too reactive for oral use).
methoximino
N-methylpyrrolidine
is cefepime orally or parenterally active?
parenterally
ceftaroline is a ____ gen cephalosporin
a. first
b. second
c. third
d. fourth
e. fifth
e. fifth
T or F: ceftaroline fosamil is a prodrug
T
T or F: unlike most beta-lactams, ceftaroline is able to inhibit the MRSA PBP2a
T
Cephalosporins that have a positively charged _____ on the side chain are more likely to be active against Gram ____ bacteria because they are better able to penetrate the porins in the outer mem
nitrogen; negative
T or F: ceftaroline is hydrolyzed by beta lactamases
F (resistant)
