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PHRM 865 > Cephalosporins > Flashcards

Cephalosporins Flashcards

1
Q

What is the mechanism of action for cephalosporins?

A
  • cephalosporins interact with transpeptidases (PBPs) which results in the inhibition of peptidoglycan cross-linking
  • prevents strengthening of cell wall

  • many cephalosporins contain leaving groups that facilitate B-lactam ring opening
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2
Q

How do B-lactamases act on cephalosporins?

A
  • B-lactamases hydrolyze cephalosporins.
  • This opens up the four-membered ring and sometimes creates a leaving group.
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3
Q

How does allergenicity compare between cephalosporins and penicillins?

A
  • allergic reactions to cephalosporins are less common and less severe
  • there is a small risk of cross allergenicity

Cephalosporins should be used with caution in patients who are allergic to penicillins

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4
Q

What do the different classifications of cephalosporins indicate?

A

As you go down the generations (1st –> 3rd), there is enhanced gram-negative activity and a loss of efficacy toward gram-positive bacteria.

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5
Q

Which drugs are first generation cephalosporins?

A
  • cefazolin
  • cephalexin
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6
Q

What are the first generation cephalosporins active against?

A

Primarily active against gram-positive

  • staphylococcus aureus
  • staphylococcus pyogenes
  • streptococcus agalactiae
  • streptococcus pneumoniae
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7
Q

What drug is this?

A
  • cephalexin
  • first gen cephalosporin
  • orally active

  • substituent at C3 that is not chemically reactive allows for oral absorption
  • ampicillin-type side chain at C7 that makes it more stable, helps confer oral activity, and helps confer activity against some gram-negative bacteria
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8
Q

What structural feature differentiates between orally active vs parenteral cephalosporins?

A
  • orally active cephalosporins have unreactive side chains at C3

  • 1st gen, orally active cephalosporins have a methyl group at C3
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9
Q

Which drug is a second generation cephalosporin?

A

cefuroxime

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10
Q

What drug is this?

A
  • cefuroxime
  • 2nd gen cephalosporin
  • parenteral and oral
  • activity against gram-negative and gram-positive

  • carbamate side chain is less reactive towards hydrolysis because of the electron-donating NH2.
  • carbamate is not a good leaving group which enhances oral bioavailability in this case
  • oxime ether conveys resistance to hydrolysis by most B-lactamases
  • should be protected from light
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11
Q

Which conformation of cefuroxime is more resistant to enzymatic hydrolysis?

A
  • syn is more resistant
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12
Q

Which drugs are third generation cephalosporins?

A
  • ceftazidime
  • cefixime
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13
Q

What are the characteristics of third generation cephalosporins?

A
  • less active against staphylococci
  • much more active vs gram-negative
  • almost all 3rd gens have an aminothiazole substituent and contain an oxime ether at the 7-position
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14
Q

Which drug is this?

A
  • ceftazidime
  • parenterally active
  • 3rd gen cephalosporin

  • large oxime ether at C7 conveys enhances stability vs B-lactamase
  • charged pyridinium ring at C3 is very good leaving group –> enhanced aqueous solubility –> too reactive for oral use
  • side chain carboxyl confers activity to gram-negative organisms
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15
Q

What drug is this?

A
  • cefixime
  • 3rd gen cephalosporin
  • orally active

  • unreactive substituent at C3 –> increases oral bioavailability
  • oxime ether at C7 stabilizes it against B-lactamases
  • carboxylic acid in the side chain confers reactivity against gram-negative
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16
Q

Which drug is a fourth generation cephalosporin?

A
  • cefepime

  • active against gram-negative and somewhat gram-positive
17
Q

What drug is this?

A
  • cefepime
  • 4th gen cephalosporin
  • parenterally active

  • syn oxime ether at C7 stabilizes against B-lactamase
  • N-methyl pyrrolidine 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)
18
Q

Which drug is a fifth generation cephalosporin?

A

ceftaroline

19
Q

What drug is this?

A
  • ceftaroline fosamil –> ceftaroline
  • prodrug
  • 5th gen cephalosporin
  • parenterally active

  • broad spectrum
  • able to inhibit the MRSA PBP2A
20
Q

Which cephalosporins are given orally?

A
  • cephalexin (1st gen)
  • cefuroxime (2nd gen) (and parenteral)
  • cefixime (3rd gen)
21
Q

Which cephalosporins are given parenterally?

A
  • ceftazidime (3rd gen)
  • cefuroxime (2nd gen) (and orally)
  • cefipime (4th gen)
  • ceftaroline (5th gen)
  • cefotetan
22
Q

What structural feature at C-3 will confer stability in acid?

A
  • non-reactive
  • poor leaving group

  • methyl group
23
Q

How does syn vs anti oxime ether at C7 change the resistance to against B-lactamase?

A
  • If the oxime ether is syn, there will be more steric hindrance, so there will be increased stability against the B-lactamase.
  • If the oxime ether is anti, there is less steric hindrance, and it will be easier for B-lactamase to hydrolyze it.
24
Q

How do cephalosporins with acetate vs carbamate side chains at C-3 differ with respect to enzymatic hydrolysis by esterases?

A
  • cephalosporins with carbamate at C3 (such as cefuroxime) are more stable and less prone to hydrolysis by esterases

  • the NH2 is electron donating
  • this neutralizes the partial positive charge on the carbonyl carbon and makes it less susceptible to nucleophilic attack
25
Q

What is the impact of the N-methyl pyrrolidine moiety on cefepime?

A
  • good leaving group
  • increases the B-lactam activity
  • too reactive for oral use
26
Q

Why are cephalosporins that have a positively charged nitrogen on the side chain more likely to be active against gram-negative bacteria?

A
  • They are better able to penetrate the porins in the outer membrane of gram-negative
27
Q

What drug is this?

A
  • cefotetan
  • cephamycin / 2nd gen
  • parenterally
  • broad spectrum
28
Q

Why can’t thienamycin be used as a drug?

A
  • too reactive because the primary amino group attacks the B-lactam intermolecularly
  • the N-formiminoyl group on imipenem prevents this from happening

  • N-formiminoyl is how it has been overcome
29
Q

What drug is this?

A
  • imipenem
  • parenteral
  • reacts with and inhibits B-lactamases
30
Q

What is the effect of replacing the sulfur in the thiazolidine ring of pcns with a methylene group?

A
  • This increases reactivity because a methylene is smaller than a sulfur, so the ring strain is greater in the carbapenems.
31
Q

What is the unique feature imipenem has against B-lactamases?

A

Imipenem inhibits B-lactamases

32
Q
  • What is the effect of dehydropeptidase-1 on imipenem?
  • How has this been overcome?
A
  • imipenem is hydrolyzed by renal dehydropeptidase-1
  • this has been overcome by co-administration with cilastatin

Cilastatin is the dehydropeptidase-1 inhibitor

33
Q

What is the antibiotic activity of imipenem + cilastatin?

A
  • broad spectrum
  • administered parenterally
34
Q

How does the origin of monobactams differ from cephalosporins and penicillins?

A
  • monobactams are derived from bacteria and are synthetic
35
Q

What structural features of monobactams allow them to be active despite not having a carboxylic acid group?

A
  • the sulfamic acid group takes the place of the carboxyl group
  • the electronegativity of the sulfamic acid activates the B-lactam ring toward chemical hydrolysis and to reaction with PBPs
36
Q

What is the antibiotic spectrum of the monobactams?

A
  • primarily gram-negative

  • used for pcn resistant infections in hospitals
37
Q

How do monobactams interact with PBPs?

A
  • The electronegativity of the sulfamic acid activates the B-lactam ring toward chemical hydrolysis and to reaction with penicillin-binding proteins
  • This nucleophilic attack opens the β-lactam ring and forms a stable acyl-enzyme intermediate between the monobactam and the PBP.
  • Once acylated, the PBP is inactivated and cannot catalyze the cross-linking of peptidoglycan strands.
38
Q

What is the allergenicity of the monobactams in relation to cephalosporins and pcns?

A
  • no cross allergenicity has been reported aside from with ceftazidime
  • this is a main advantage for monobactams because they can be used in patients with pcn allergy

Ceftazidime has an identical oxime ether side chain

39
Q

What drug is this?

A
  • aztreonam disodium
  • monobactam
  • parentally active

PHRM 865 (12 decks)

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