Cephalosporin, Carbapenem, and Monobactam Flashcards
What is the mechanism of action of cephalosporins?
Cephalosporins react with transpeptidases (penicillin-binding proteins) to inhibit peptidoglycan cross-linking. Many contain leaving groups ‘X’ that facilitate beta-lactam ring opening.
How are cephalosporins acted on by beta-lactamase?
Cephalosporins are hydrolyzed by beta-lactamases.
How do cephalosporins compare with penicillins in terms of allergenicity?
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.
What is the main classification scheme for cephalosporins?
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.
What are the characteristics of 1st generation cephalosporins?
1st generation cephalosporins are primarily active against gram (+) cocci.
Examples include cefazolin (parenteral) and cephalexin (oral).
What are the 1st generation cephalosporins?
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
What are the characteristics of 2nd generation cephalosporins?
2nd generation cephalosporins retain gram (+) activity and have better activity against gram (-) bacteria.
Example: cefuroxime.
What are the second generation cephalosporins?
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.
Oxime ether (methoximino) moeity
conveys resistance to hydrolysis by most beta-lactamases. Syn methoximino group is more resistant to enzymatic hydrolysis than the anti anti-isomer.
What are the characteristics of 3rd generation cephalosporins?
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.
What are the 3rd generation cephalosporins?
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
What are the characteristics of 4th generation cephalosporins?
4th generation cephalosporins retain the antibacterial spectrum of 3rd generation and are more active against gram (+) organisms.
Example: Cefepime.
What are the 4th generation cephalosporins?
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
What are the characteristics of 5th generation cephalosporins?
5th generation cephalosporins are broad-spectrum antibiotics active against MRSA and resistant to beta-lactamases.
Example: ceftaroline fosamil.
What are the 5th generation cephalosporins?
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
Cephalosporins with a positively charged nitrogen on the side chain…
are more likely to be active against gram-(-) bacteria because they are able to penetrate the porins in the outer membrane of gram-(-) bacteria
What are cephamycins and their characteristics?
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.
Cephamycin example
cefotetan: It releases N-methylthiotetrazole, which can cause hypoprothrombinemia and can also cause a reaction to ethanol (don’t drink alcohol when taking!!)
What distinguishes orally active cephalosporins from parenteral ones?
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.
Orally active cephalosporins
cephalexin, cefuroxime, cefixime
Parenteral cephalosporins
cefazolin, cefuroxime, ceftazidime, cefepime, ceftaroline
How do cephalosporins with syn and anti-oxime ethers on the C-7 side chain differ in hydrolysis by beta-lactamases?
Syn methoximino is more resistant to enzymatic hydrolysis, while anti-methoximino is less resistant.
How do cephalosporins with acetate vs. carbamate side chains at C-3 differ in enzymatic hydrolysis by esterases?
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.
What effect does the large oxime ether functionality of ceftazidime have on stability vs. beta-lactamases?
The large oxime ether moiety at C-7 conveys enhanced stability against beta-lactamases.
What is the effect of the charged pyridinium ring of ceftazidime on beta-lactam reactivity and aqueous solubility?
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.
What effect does the charged N-methylpyrrolidine moiety of cefepime have on beta-lactam reactivity?
The N-methylpyrrolidine moiety is a good leaving group, increasing beta-lactam reactivity and making it parenterally active.
How does the syn methoximino group on the C-7 side chain of cefepime affect stability vs. beta-lactamases?
The syn methoximino group at C-7 stabilizes cefepime against beta-lactamase. Ability to resist degradation is greater.
Why can’t thienamycin be used as a drug and how has this been overcome?
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.
What is the effect of replacing the sulfur atom in penicillins with a methylene group in carbapenems?
The replacement increases reactivity due to greater ring strain, making the carbapenem’s beta-lactam ring more chemically active.
What unique feature does the antibiotic imipenem have vs. beta-lactamases?
Imipenem reacts with and inhibits beta-lactamases in addition to reacting with penicillin binding proteins.
What effect does the renal enzyme dehydropeptidase-1 have on imipenem, and how is this limitation overcome?
Imipenem is hydrolyzed by renal dehydropeptidase-1, which can be overcome by coadministration of cilastatin.
How do monobactams differ in origin from penicillins and cephalosporins?
The sulfamic acid group replaces the C-2 carboxyl group present in penicillins and cephalosporins.
What structural feature of monobactams allows them to be biologically active despite lacking a carboxylic acid group?
The electronegativity of the sulfamic acid activates the beta-lactam ring toward hydrolysis and reaction with penicillin binding proteins. Stabilizes the binding with PBPs.
What is the antibiotic spectrum of monobactams?
The spectrum focuses almost completely on gram-negative bacteria, mainly treating severe infections caused by penicillin-resistant organisms.
How do monobactams react with penicillin-binding proteins?
Monobactams irreversibly bind to PBPs, specifically targeting the transpeptidase domain, inhibiting cell wall synthesis.
What is the cross allergenicity of monobactams with penicillins and cephalosporins?
Cross allergenicity has not been reported except for ceftazidime. Monobactams can be used in patients with penicillin allergy.
What effect does the sulfamic acid moiety of monobactams have on the reactivity of the beta-lactam ring?
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.
