Cephalosporins Flashcards
What is the mechanism of action for cephalosporins?
- 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
How do B-lactamases act on cephalosporins?
- B-lactamases hydrolyze cephalosporins.
- This opens up the four-membered ring and sometimes creates a leaving group.
How does allergenicity compare between cephalosporins and penicillins?
- 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
What do the different classifications of cephalosporins indicate?
As you go down the generations (1st –> 3rd), there is enhanced gram-negative activity and a loss of efficacy toward gram-positive bacteria.
Which drugs are first generation cephalosporins?
- cefazolin
- cephalexin
What are the first generation cephalosporins active against?
Primarily active against gram-positive
- staphylococcus aureus
- staphylococcus pyogenes
- streptococcus agalactiae
- streptococcus pneumoniae
What drug is this?
- 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
What structural feature differentiates between orally active vs parenteral cephalosporins?
- orally active cephalosporins have unreactive side chains at C3
- 1st gen, orally active cephalosporins have a methyl group at C3
Which drug is a second generation cephalosporin?
cefuroxime
What drug is this?
- 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
Which conformation of cefuroxime is more resistant to enzymatic hydrolysis?
- syn is more resistant
Which drugs are third generation cephalosporins?
- ceftazidime
- cefixime
What are the characteristics of third generation cephalosporins?
- 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
Which drug is this?
- 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
What drug is this?
- 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
Which drug is a fourth generation cephalosporin?
- cefepime
- active against gram-negative and somewhat gram-positive
What drug is this?
- 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)
Which drug is a fifth generation cephalosporin?
ceftaroline
What drug is this?
- ceftaroline fosamil –> ceftaroline
- prodrug
- 5th gen cephalosporin
- parenterally active
- broad spectrum
- able to inhibit the MRSA PBP2A
Which cephalosporins are given orally?
- cephalexin (1st gen)
- cefuroxime (2nd gen) (and parenteral)
- cefixime (3rd gen)
Which cephalosporins are given parenterally?
- ceftazidime (3rd gen)
- cefuroxime (2nd gen) (and orally)
- cefipime (4th gen)
- ceftaroline (5th gen)
- cefotetan
What structural feature at C-3 will confer stability in acid?
- non-reactive
- poor leaving group
- methyl group
How does syn vs anti oxime ether at C7 change the resistance to against B-lactamase?
- 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.
How do cephalosporins with acetate vs carbamate side chains at C-3 differ with respect to enzymatic hydrolysis by esterases?
- 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
What is the impact of the N-methyl pyrrolidine moiety on cefepime?
- good leaving group
- increases the B-lactam activity
- too reactive for oral use
Why are cephalosporins that have a positively charged nitrogen on the side chain more likely to be active against gram-negative bacteria?
- They are better able to penetrate the porins in the outer membrane of gram-negative
What drug is this?
- cefotetan
- cephamycin / 2nd gen
- parenterally
- broad spectrum
Why can’t thienamycin be used as a drug?
- 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
What drug is this?
- imipenem
- parenteral
- reacts with and inhibits B-lactamases
What is the effect of replacing the sulfur in the thiazolidine ring of pcns with a methylene group?
- This increases reactivity because a methylene is smaller than a sulfur, so the ring strain is greater in the carbapenems.
What is the unique feature imipenem has against B-lactamases?
Imipenem inhibits B-lactamases
- What is the effect of dehydropeptidase-1 on imipenem?
- How has this been overcome?
- imipenem is hydrolyzed by renal dehydropeptidase-1
- this has been overcome by co-administration with cilastatin
Cilastatin is the dehydropeptidase-1 inhibitor
What is the antibiotic activity of imipenem + cilastatin?
- broad spectrum
- administered parenterally
How does the origin of monobactams differ from cephalosporins and penicillins?
- monobactams are derived from bacteria and are synthetic
What structural features of monobactams allow them to be active despite not having a carboxylic acid group?
- 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
What is the antibiotic spectrum of the monobactams?
- primarily gram-negative
- used for pcn resistant infections in hospitals
How do monobactams interact with PBPs?
- 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.
What is the allergenicity of the monobactams in relation to cephalosporins and pcns?
- 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
What drug is this?
- aztreonam disodium
- monobactam
- parentally active
