Cushman 3 Flashcards
Gram (+)
- drugs can penetrate the outer layers of the ___ effectively, (membrane main barrier to drugs)
- b-lactamases are ____ through the cell wall to the ___ environment. (have to be produced in ___ quantities than gram neg)
- peptidoglycan is diaminopimelic acid residue ( ___ ), but residue replaced by ___ residue (COOH replaced with H)
- peptidoglycan is ___ by a bridge between the ___ strand and the terminal ___ of the 2nd molecule.
Gram (-)
- the outer ___ excludes drugs, but some drugs can still get in through the ___ in the outer membrane
- the b-lactamases are confined to the ___ space.
- more ___ cell wall that is more ___
- peptidoglycan contains a meso-diaminopimelic acid residue ( ___ )
- peptidoglycan is ___ by a bridge between the ___ residue of one strand and the terminal ___ of another.
Gram (+)
- cell wall
- excreted, external
- larger
- DAP, L-lysine
- crosslinked, L-Lys, D-Ala
Gram (-)
- membrane, porins
- periplasmic
- complex, lipoidal
- DAP
- crosslinked, DAP, D-Ala
cross-links are about 5 amino acids (varies in composition from spp. to spp.)
Gram (+) crosslinks
L-Lys - D-Ala
Gram (-) crosslinks
DAP - D-Ala
Transpeptidase
___ the peptidoglycan strands
- crosslinks
B-Lactam Antibiotic MOA
MOA: inhibition of ___ that “glue” the ___ strands together by cross-linking
1) B-lactams ___ the transpeptidase ___ residue in the enzyme active site. This inactivates the enzyme, inhibiting peptidoglycan ___ , which results in a defective bacterial cell wall. The resulting cell wall is subject to osmotic stress, resulting in cell lysis and cell death
2) The reactivity of the B-lactam system is due to a highly ___ four-membered ring
3) The structures of B-lactams resemble the ___ - ____ fragment that is acted on by transpeptidases (fools the transpeptidase)
- transpeptidases
- peptidoglycan
1) acylate, Ser, cross-linking
2) strained
3) D-Ala-D-Ala
Resistance to B-Lactam Antibiotics
Resistance may result from decreased cellular ___ of the drug, mutation of the ___ -binding proteins to ___ their affinity, or the presence of an ___ pump. A more common mechanism is induction or
elaboration of bacterial___ . These enzymes catalyze the ___ of the b-lactam moiety (happens super fast)
- uptake
- PCN
- decrease
- efflux
- B-lactamases
- hydrolysis
happens so fast, break down many drug molecules quickly
Allergenicity of B-Lactam Antibiotics
1) __ - __ % allergic (rash-anaphylactic shock)
2) B-lactam acts as a ___: acylates ___ cell proteins, which then raise ___ that result in an allergic reaction
3) cross-sensitivity is ___
4) allergen testing recommended if there is doubt
- 6-8%
- haptens, host, antibodies
- common
Penicillin Degradation
1) Penicillin hydrolysis products do not have ___ activity
2) Hydrolysis of the B-lactam is ___ . Once the ring is opened, it will not close.
3) ___ substituents on the side chain carbonyl reduce the ___ of the side chain amide carbonyl oxygen atom. This ___ the penicillin against hydrolysis under acidic conditions, since the first step in the hydrolysis reaction is decelerated.
Example: Penicillin __ is more stable to hydrolysis in the stomach than Penicillin __ because the electronegativity of the ether oxygen decreases the nucleophilicity of the amide carbonyl.
4) Solutions of penicillins for parenteral use should be used ___ . They are best stored in the refrigerator between pH 6.0 and 6.8
5) Heavy metal ions ___ penicillin degradation reactions and should therefore be kept away from penicillin solutions
- antibiotic
- irreversible
- electronegative, nucleophilicity, stabilizes
- V, G
- promptly
- catalyze
Serum Protein Binding
1) Penicillins with more ___ side chains are more highly protein bound
2) Protein binding ___ bioavailability by reducing the effective concentration of the free drug
rank the PCNs from least to most lipophilic
1) lipophilic
2) reduces
Ampicillin < Benzylpenicillin < Dicloxacillin
Excretion B-Lactams
1) Penicillins are rapidly excreted by the ___ or ___ routes. For those that are excreted by the kidneys, about 10% of renal excretion is by glomerular filtration and 90% is by ___ secretion
2) t1/2 ___ in those with renal failure
3) Two mechanisms exist for tubular secretion, one for anions and one for cations. Anionic penicillins compete with the anion ___ for the secretion mechanism (t1/2 ___ when administered together)
1) renal, biliary, tubular
2) increased
3) probenecid, increased
Nomenclature of B-Lactam Ring Systems
what are these called
B-Lactamase-Sensitive Penicillins
___ (Penicillin G)
1) Antimicrobial spectrum: Gram ( __ ) ___ . Since Pen G resistant microorganisms are common, therapy should be guided by susceptibility testing.
2) B-Lactamase sensitivity: ___
3) Administration: ___
4) Toxicity: acute ___ reactions
5) Precautions: caution in individuals with histories of significant
allergies and/or ___
Benzylpenicillin
1) + , cocci
2) yes
3) parenteral
4) allergic
5) asthma
B-Lactamase-Sensitive Penicillins
___ Penicillin (Penicillin V)
1) more stable in ___ .
The increase in stability in acid is attributed to the ___ ether oxygen, which decreases the ___ of the side chain amide carbonyl and therefore ___ its participation in the B-lactam hydrolysis reaction
2) Penicillin V is more stable in the ___ and produces higher and more sustained blood levels than penicillin G after ___ administration
Phenoxymethyl
1) acid, electronegative, nucleophilicity, decreases
2) stomach, oral
B-Lactamase-Resistant Parenteral Penicillins
Name: ___
B-Lactamase sensitivity: ___ . This is due to ___ hindrance of nucleophilic attack by the enzyme on the B-lactam carbonyl.
2) ___ to acid in the stomach so it must be administered by ___ (its half- life at pH 2 is 5 min). The instability is due to electron donation toward the amide carbonyl oxygen by the o-methoxy groups, making the amide carbonyl oxygen more ___
3) d/c’ed bc many bacteria are resistant
4) Methicillin-resistant ___ ___ (MRSA) occurs due to a mutation in a ___ protein (PBP) ( ___ ). The gene coding for this protein is called ___ , and it codes for PBP __ . It can cross-link peptidoglycans, but it does not react with methicilin and a
variety of other β-lactam antibiotics.
methicilin
1) no, steric
2) unstable, injection, nucleophilic
3) S. aureus, PCN binding, transpeptidase, mecA, PBP2A
B-Lactamase-Resistant Parenteral Penicillins
Name: ___
1) Lactamase sensitivity: ___
2) It is ___ more stable than methicillin in acid, but is clinically identical to methicillin
Nafcillin
1) no
2) slightly
B-Lactamase-Resistant Oral Penicillins
names: ___ , ___ , and ___
1) they are all ___
2) B-lactamase sensitivity: ___
3) ___ and ___ have been discontinued for oral use, but ___ is still
available for oral use. ___ for injection is still available.
oxacillin, cloxacillin, dicloxacillin
1) isoxazoles
2) no
3) oxacillin, cloxacillin, dicloxacillin, oxacillin
B-Lactamase-Sensitive, Broad-Spectrum, Oral Penicillins
Name: ___
1) Antimicrobial spectrum: many
Gram ( ___ ) microorganisms are sensitive, including ___ , ___ , ___ mirabilis, ___ coli , ___ influenzae, and Neisseria ___ . Porins on gram negative are hydrophillic ( ___ ) . The ___ amino group of ampicillin at physiological pH allows it to get in
2) The amino group is ___ in the stomach, so the positively charged nitrogen is more electron-attracting. This ___ the nucleophilicity of the amide carbonyl oxygen so that it does not participate in ring-opening of the lactam. It has a half-life of about __ - _ hours at
pH 2 and 35 ̊C
Ampicillin
1) negative, Salmonella, Shegella, Proteus, Escherichia, Haemophilis, gonorrhoeae, polar, charged
2) protonated, decreased, 15-20
B-Lactamase-Sensitive, Broad-Spectrum, Oral Penicillins
Name: ___
- analog of ___ in which a phenolic ___ group has been introduced into the aromatic ring. It has better ___ absorption
- ampicillin, hydroxyl, oral
B-Lactamase Inhibitors
used in combination with the B-lactamase- ___ penicillins. They ___ the ___ hydroxyl group in the active site of the B-lactamase
- enhance the activities of B-lactamase-sensitive B-lactams vs. b-
lactamase-producing resistant strains.
Examples:
- Potassium ___ + Amoxicillin = Augmentin
- ___ + Ampicillin = Unasyn
- Tazobactam + Pipericillin = ___
- ___ + Ceftazidime = Avycaz
- sensitive
- acylate, ser
- clavulanate
- sulbactam
- Zosyn
- avibactam
B-Lactamase-Sensitive, Broad-Spectrum, Parenteral Penicillin
Name: ___
1) It is known as an acylureidopenicillin because it incorporates a ___ moiety. It preserves activity against Gram (+) bacteria, but it is are also active vs. some strains of Gram-(–) bacteria, including Pseudomonas ___ , ___ pneumoniae, and Bacteroides ___ .
2) The enhanced potency may result because the added side chain fragment resembles a longer
section of the ___ chain than ampicillin does
pipericillin
1) urea, aeruginosa, Klebsiella, fragilis
2) peptidoglycan
Cephalosporins
MOA: The basic mechanism of action of the cephalosporins is the same as with the penicillins. Reaction with ___ (PBPs) results in inhibition of peptidoglycan
___
Note: many cephalosporins contain leaving groups “X” that facilitate B-lactam
ring ___
- transpeptidases
- opening
square opens
Cephalosporins: Resistance
Like the penicillins, the cephalosporins are hydrolyzed by ___
- Over 340 different B-lactamases are known. Some are mainly ___ and others are mainly ___ . They can also be specific for certain antibiotics (eg. for methicillin and isoxazoyl penicillins)
- B-lactamases
- penicillinases, cephalosporinases
Cephalosporins: Allergenicity
Allergic reactions to cephalosporins are generally ___ common and severe than with penicillins.
- However, since there is a small risk of cross allergenicity, cephalosporins should be used with caution in patients who are allergic to ___ .
- Fever and rashes (both idiopathic and delayed) are the most common manifestations and are exhibited in 1-3% of the population. The incidence of anaphylactic reactions to cephalosporins is estimated at 0.02%
less
- PCN
Cephalosporins: Classification
gens 1-5
- 1 to 3 trend: enhanced Gram ___ activity and loss of Gram ___ efficacy
- 1st gen: primarily active against gram ___ cocci ( S. ___ and S. ___ ), group ___ Streptococci (S. ___ ), and Streptococcus ___
- -, +
- +, S. aureus, S. pyogenes, B, agalactiae, pneumonia
Cephalosporins: Classification
In contrast to parenteral cephalosporins, the orally active cephalosporins have
substituents at ___ that are not chemically reactive.
___ is an example of an orally active first generation cephalosporin. Notice that it also has an ___ -type side chain at C-7 that makes it more stable and helps to confer oral activity, and it also confers activity against some Gram (–) bacteria
In general, the ___ active cephalosporins have unreactive side chains at C-3. The first generation, orally active cephalosporins have a ___ group at C-3.
- C-3
- cephalexin
- ampicillin
- orally, methyl
Second Generation Cephalosporins.
Example: ___
These retain the anti Gram ( ___ ) activity of the first group and ___ influenzae as well. In addition, the second generation cephalosporins have better activity against Gram ( __ ) bacteria including some strains of Acinetobacter,
Citrobacter, Enterobacter, Escherichia coli, Klebsiella, Neisseria, Proteus, Providencia and Serratia.
Cefuroxime
- positive
- Haemophilus
- negative
Second Generation Cephalosporins
1) The carbamate side chain is less reactive toward enzymatic hydrolysis because of the electron-donating ___ on the carbamate. This neutralizes the partial positive charge on the carbonyl carbon and makes it less susceptible to ___ attack. The carbamate is also not a good ___ ___ , which enhances ___ bioavailability in this case
1) NH2, nucleophilic, leaving group, oral
Second Generation Cephalosporins
2) The oxime ether (methoximino) moiety conveys resistance to hydrolysis by most ___ . The syn methoximino group is more resistant and can be photochemically isomerized to the anti isomer in solution to form a 1:1 mixture. Like other oxime ether antibiotics, it should be protected
from ___
- B-lactamases, light
Third Generation Cephalosporins
Example: ___
These are less active against ___ than the first generation agents, but they are much more active vs. Gram ( __ ).
They are frequently useful against nosocomial (hospital-acquired) multidrug-resistant strains. ___ , Bacteroides ___ and ___ aeruginosa and some ___ are often sensitive.
Almost all of the third generation ___ substituent and contain an ___ ether at the 7-position
Ceftazidime
- staphylococci, negative
- Morganella, fragilis, Pseudomonas, enterobacteria
- aminothiazole, oxime
Third Generation Cephalosporins
1) The large oxime ether moiety at ___ conveys ___ stability vs. B-lactamases.
2) The charged pyridinium ring at C-3 is a very good ___ ___ and strongly activates the B-lactam ring. Also, the charged pyridinium ring imparts enhanced aqueous solubility and makes it ___ active (too reactive for oral use).
3) The side chain carboxyl confers activity vs. Gram ___ organisms
- C-7, enhanced
- leaving group, parenterally
- negative
As with the other classes of cephalosporins, the presence of an ___ substituent at C-3 increases oral bioavailability. Example: ___
1) does not contain a ___ ___ at C-3. The vinyl group is chemically stable.
2) It also has an ___ ether on the C-7 side chain that ___ the B-lactam vs. B-lactamases.
3) The carboxylic acid in the side chain confers activity vs. Gram ___ microorganisms.
- unreactive
- Cefixime
1) leaving group
2) oxime, stabilizes
3) negative
Fourth Generation Cephalosporins
Name: ___
retain the antibacterial spectrum of the third generation cephalosporins and also add Pseudomonas ___ and some ___ that
are resistant to third generation cephalosporins. They are also more active against Gram ( ___ ) organisms
Cefepime
- P. aeruginosa, enterobacteria
- +
Fourth Generation Cephalosporins
1) The syn ___ group at C-7 stabilizes cefepime against ___ .
2) The N-methylpyrrolidine moiety is a good ___ ___ and therefore increases the
reactivity of the B-lactam and makes it ___ active (too reactive for ___ use).
1) methoximino, B-lactamase
2) leaving group, parenterally, oral
Fifth Generation Cephalosporins
1) Ceftaroline fosamil is a ___ that is hydrolyzed metabolically after ___to ceftaroline (active) by a plasma phosphatase.
2) Ceftaroline is a ___ spectrum, fifth-generation cephalosporin antibiotic that is active vs. ___ (used for this and community acquired bacterial ___ ). Unlike most B-lactams, it is able to inhibit the MRSA ___ .
3) 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 ___ in the
outer membrane
1) prodrug, IV infusion
2) broad, MRSA, pneumonia, PBP2A
3) N, negative, porin
