Cephalosporin, Carbapenem, and Monobactam

Question 1

What is the mechanism of action of cephalosporins?

Answer 1

Cephalosporins react with transpeptidases (penicillin-binding proteins) to inhibit peptidoglycan cross-linking. Many contain leaving groups ‘X’ that facilitate beta-lactam ring opening.

Question 2

How are cephalosporins acted on by beta-lactamase?

Answer 2

Cephalosporins are hydrolyzed by beta-lactamases.

Question 3

How do cephalosporins compare with penicillins in terms of allergenicity?

Answer 3

Cephalosporins have a lower incidence of allergenicity compared to penicillins. Reactions are less common and less severe, but caution is advised in penicillin-allergic patients.

Question 4

What is the main classification scheme for cephalosporins?

Answer 4

Cephalosporins are classified as 1st, 2nd, 3rd, 4th, or 5th generation, with a trend of enhanced gram-negative activity and reduced efficacy against gram-positive bacteria from 1st to 3rd generation.

Question 5

What are the characteristics of 1st generation cephalosporins?

Answer 5

1st generation cephalosporins are primarily active against gram (+) cocci.

Examples include cefazolin (parenteral) and cephalexin (oral).

Question 6

What are the 1st generation cephalosporins?

Answer 6

cefazolin: reactive side chain, good leaving group, sulfide dissociates
cephalexin: substituents at C-3 that aren’t chemically reactive (methyl group) and ampicillin-type side chain at C-7 makes it more stable

Question 7

What are the characteristics of 2nd generation cephalosporins?

Answer 7

2nd generation cephalosporins retain gram (+) activity and have better activity against gram (-) bacteria.

Example: cefuroxime.

Question 8

What are the second generation cephalosporins?

Answer 8

cefuroxime: has a carbamate side chain that is less reactive toward enzymatic hydrolysis because of the electron-donating NH2 on the carbamate. This neutralizes the partial (+) charge on the carbonyl carbon and makes it less susceptible to nucleophilic attack. Carbamate is also not a good leaving group, which enhances oral bioavailability.

Question 9

Oxime ether (methoximino) moeity

Answer 9

conveys resistance to hydrolysis by most beta-lactamases. Syn methoximino group is more resistant to enzymatic hydrolysis than the anti anti-isomer.

Question 10

What are the characteristics of 3rd generation cephalosporins?

Answer 10

3rd generation cephalosporins are less active against staphylococci but more active against gram (-) bacteria. Frequently used against nosocomial multi-drug resistant strains. Almost all have an aminothiazole substituent and contain an oxime ether at the 7-position.

Examples include ceftazidime and cefixime.

Question 11

What are the 3rd generation cephalosporins?

Answer 11

ceftazidime:large oxime ether moiety at C-7 conveys enhanced stability vs beta-lactamases. Charged pyridinium ring at C-3 is a very good leaving group and strongly activates the beta-lactam ring. Charged pyridinium ring imparts enhanced aqueous solubility and makes it parenterally active
cefixime: presence of an unreactive substituent at C-3 increases oral bioavailability. Cefixime doesn’t contain a leaving group at C-3. Has an oxime ether on the C-7 side chain that stabilizes the beta-lactam vs beta-lactamases

Question 12

What are the characteristics of 4th generation cephalosporins?

Answer 12

4th generation cephalosporins retain the antibacterial spectrum of 3rd generation and are more active against gram (+) organisms.

Example: Cefepime.

Question 13

What are the 4th generation cephalosporins?

Answer 13

cefepime: fixed positive charge, more susceptible to nucleophilic attack. The syn-methoximino group at C-7 stabilizes cefepime against beta-lactamase. N-methylpyrrolidine moiety is a good leaving group and therefore increases the reactivity of the beta-lactam and makes it parenterally active

Question 14

What are the characteristics of 5th generation cephalosporins?

Answer 14

5th generation cephalosporins are broad-spectrum antibiotics active against MRSA and resistant to beta-lactamases.

Example: ceftaroline fosamil.

Question 15

What are the 5th generation cephalosporins?

Answer 15

ceftaroline fosamil: prodrug that is hydrolyzed metabolically to ceftaroline (active species) by a plasma phosphatase; Unlike most beta-lactams, it is able to inhibit MRSA PBP2a!!
resistant to hydrolysis by beta-lactamases

Question 16

Cephalosporins with a positively charged nitrogen on the side chain…

Answer 16

are more likely to be active against gram-(-) bacteria because they are able to penetrate the porins in the outer membrane of gram-(-) bacteria

Question 17

What are cephamycins and their characteristics?

Answer 17

Cephamycins are often classified as 2nd generation cephalosporins with a 7-alpha methoxyl group that hinders attack by beta-lactamase and increases stability against beta-lactamases.

Example: cefotetan.

Question 18

Cephamycin example

Answer 18

cefotetan: It releases N-methylthiotetrazole, which can cause hypoprothrombinemia and can also cause a reaction to ethanol (don’t drink alcohol when taking!!)

Question 19

What distinguishes orally active cephalosporins from parenteral ones?

Answer 19

Orally active cephalosporins have an unreactive substituent at C-3, which increases oral bioavailability.

Examples of orally active: cephalexin, cefuroxime, cefixime. Parenteral: cefazolin, cefuroxime, ceftazidime, cefepime, ceftaroline.

Question 20

Orally active cephalosporins

Answer 20

cephalexin, cefuroxime, cefixime

Question 21

Parenteral cephalosporins

Answer 21

cefazolin, cefuroxime, ceftazidime, cefepime, ceftaroline

Question 22

How do cephalosporins with syn and anti-oxime ethers on the C-7 side chain differ in hydrolysis by beta-lactamases?

Answer 22

Syn methoximino is more resistant to enzymatic hydrolysis, while anti-methoximino is less resistant.

Question 23

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

Answer 23

Carbamate side chains are less reactive toward enzymatic hydrolysis due to the electron-donating NH2, making them more stable. Acetate side chains are highly susceptible to hydrolysis, leading to reduced stability and activity.

Question 24

What effect does the large oxime ether functionality of ceftazidime have on stability vs. beta-lactamases?

Answer 24

The large oxime ether moiety at C-7 conveys enhanced stability against beta-lactamases.

Question 25

What is the effect of the charged pyridinium ring of ceftazidime on beta-lactam reactivity and aqueous solubility?

Answer 25

The charged pyridinium ring at C-3 activates the beta-lactam ring, increasing susceptibility to nucleophilic attack and enhancing aqueous solubility, making it parenterally active.

Question 26

What effect does the charged N-methylpyrrolidine moiety of cefepime have on beta-lactam reactivity?

Answer 26

The N-methylpyrrolidine moiety is a good leaving group, increasing beta-lactam reactivity and making it parenterally active.

Question 27

How does the syn methoximino group on the C-7 side chain of cefepime affect stability vs. beta-lactamases?

Answer 27

The syn methoximino group at C-7 stabilizes cefepime against beta-lactamase. Ability to resist degradation is greater.

Question 28

Why can't thienamycin be used as a drug and how has this been overcome?

Answer 28

Thienamycin is too reactive due to the primary amino group attacking the beta-lactam. This is overcome by imipenem, the N-formiminoyl derivative, which prevents this reactivity.

Question 29

What is the effect of replacing the sulfur atom in penicillins with a methylene group in carbapenems?

Answer 29

The replacement increases reactivity due to greater ring strain, making the carbapenem's beta-lactam ring more chemically active.

Question 30

What unique feature does the antibiotic imipenem have vs. beta-lactamases?

Answer 30

Imipenem reacts with and inhibits beta-lactamases in addition to reacting with penicillin binding proteins.

Question 31

What effect does the renal enzyme dehydropeptidase-1 have on imipenem, and how is this limitation overcome?

Answer 31

Imipenem is hydrolyzed by renal dehydropeptidase-1, which can be overcome by coadministration of cilastatin.

Question 32

How do monobactams differ in origin from penicillins and cephalosporins?

Answer 32

The sulfamic acid group replaces the C-2 carboxyl group present in penicillins and cephalosporins.

Question 33

What structural feature of monobactams allows them to be biologically active despite lacking a carboxylic acid group?

Answer 33

The electronegativity of the sulfamic acid activates the beta-lactam ring toward hydrolysis and reaction with penicillin binding proteins. Stabilizes the binding with PBPs.

Question 34

What is the antibiotic spectrum of monobactams?

Answer 34

The spectrum focuses almost completely on gram-negative bacteria, mainly treating severe infections caused by penicillin-resistant organisms.

Question 35

How do monobactams react with penicillin-binding proteins?

Answer 35

Monobactams irreversibly bind to PBPs, specifically targeting the transpeptidase domain, inhibiting cell wall synthesis.

Question 36

What is the cross allergenicity of monobactams with penicillins and cephalosporins?

Answer 36

Cross allergenicity has not been reported except for ceftazidime. Monobactams can be used in patients with penicillin allergy.

Question 37

What effect does the sulfamic acid moiety of monobactams have on the reactivity of the beta-lactam ring?

Answer 37

The electronegativity of the sulfamic acid activates the beta-lactam ring, enhancing its reactivity and ability to bind and inhibit PBPs, by acting as an electron withdrawing group.