Podcast
Questions and Answers
What is the role of the acetyloxy group in the mechanism of inhibition?
What is the role of the acetyloxy group in the mechanism of inhibition?
Which cephalosporin is known for being poorly absorbed through the gut wall?
Which cephalosporin is known for being poorly absorbed through the gut wall?
How does the protonated –NH2 group contribute to cephalosporin stability?
How does the protonated –NH2 group contribute to cephalosporin stability?
Which generation of cephalosporins shows increased activity against Gram-negative bacteria?
Which generation of cephalosporins shows increased activity against Gram-negative bacteria?
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What effect does replacing the furan ring with an aminothiazole ring have?
What effect does replacing the furan ring with an aminothiazole ring have?
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What is a major disadvantage of Cefuroxime regarding Pseudomonas aeruginosa?
What is a major disadvantage of Cefuroxime regarding Pseudomonas aeruginosa?
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Which feature of Cefotaxime contributes to its reduced activity?
Which feature of Cefotaxime contributes to its reduced activity?
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Why are cephalosporins with a 3-substitution pattern favored for oral activity?
Why are cephalosporins with a 3-substitution pattern favored for oral activity?
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What is the structure of cephalosporins characterized by?
What is the structure of cephalosporins characterized by?
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Which characteristic is true of first generation cephalosporins?
Which characteristic is true of first generation cephalosporins?
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What modification is NOT commonly associated with cephalosporin synthesis?
What modification is NOT commonly associated with cephalosporin synthesis?
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How do third generation cephalosporins compare to first generation ones?
How do third generation cephalosporins compare to first generation ones?
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Which cephalosporin generation adds activity against Pseudomonas aeruginosa?
Which cephalosporin generation adds activity against Pseudomonas aeruginosa?
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What is a drawback of cephalothin (Cefalotin)?
What is a drawback of cephalothin (Cefalotin)?
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What type of activity do second generation cephalosporins have?
What type of activity do second generation cephalosporins have?
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What method is commonly used for achieving semisynthetic modifications of cephalosporins?
What method is commonly used for achieving semisynthetic modifications of cephalosporins?
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Which agent is co-administered with imipenem to protect it from hydrolytic metabolism?
Which agent is co-administered with imipenem to protect it from hydrolytic metabolism?
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What modifies the antibacterial activity spectrum of imipenem?
What modifies the antibacterial activity spectrum of imipenem?
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What unique feature of doripenem enhances its potency against Pseudomonas species?
What unique feature of doripenem enhances its potency against Pseudomonas species?
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Which of the following drugs is NOT classified as a carbapenem?
Which of the following drugs is NOT classified as a carbapenem?
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What is the primary consequence of imipenem being metabolized by renal dehydropeptidase-I?
What is the primary consequence of imipenem being metabolized by renal dehydropeptidase-I?
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What is the FDA-approved indication for the combination of meropenem and vaborbactam?
What is the FDA-approved indication for the combination of meropenem and vaborbactam?
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How does the α-oriented methyl group at C-2 affect aztreonam?
How does the α-oriented methyl group at C-2 affect aztreonam?
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Which carbapenem has a lower incidence of nephrotoxicity due to intrinsic stability in hydrolysis?
Which carbapenem has a lower incidence of nephrotoxicity due to intrinsic stability in hydrolysis?
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What characteristic makes the discussed pharmacological agent suitable for once daily administration?
What characteristic makes the discussed pharmacological agent suitable for once daily administration?
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Which feature contributes to the agent's ability to penetrate the outer membrane of Gram-negative bacteria?
Which feature contributes to the agent's ability to penetrate the outer membrane of Gram-negative bacteria?
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What type of activity does Ceftaroline fosamil exhibit?
What type of activity does Ceftaroline fosamil exhibit?
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What is a primary advantage of the discussed cephalosporin regarding β-lactamase?
What is a primary advantage of the discussed cephalosporin regarding β-lactamase?
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Which cephalosporin is classified as a second generation?
Which cephalosporin is classified as a second generation?
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Which of the following cephalosporins is an oximinocephalosporin derivative?
Which of the following cephalosporins is an oximinocephalosporin derivative?
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Which statement is true regarding the characteristics of carbapenems?
Which statement is true regarding the characteristics of carbapenems?
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What is a notable limitation of carbapenems?
What is a notable limitation of carbapenems?
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Study Notes
Cephalosporins
- Second major group of β-lactam antibiotics
- First cephalosporin (cephalosporin C) derived from a fungus in the mid-1940s
- Bicyclic system containing a four-membered β-lactam ring fused to a six-membered dihydrothiazine ring
- Act similarly to penicillins
- Modifications can be made at different positions on the molecule
- Semisynthetic modifications of the 7-ACA nucleus include acylation of the 7-amino group, nucleophilic substitution or reduction of the acetoxy group, and extra substitution at carbon 7
Generations of Cephalosporins
- First generation: Primarily active against Gram (+) bacteria, not significantly active against Gram (-) bacteria, lack activity against Pseudomonas aeruginosa, ineffective against methicillin-resistant Staph.aureus
- Second generation: Retain anti-Gram (+) activity and add better anti-Gram (-) activity
- Third generation: Less active against staphylococci than first generation, more active against Gram(-) bacteria than first or second generation drugs
- Fourth generation: Antibacterial spectrum like third generation drugs, but also includes activity against Pseudomonas aeruginosa and some enterobacteria resistant to third generation cephalosporins, also more active against some Gram (+) organisms
Cephalothin (Cefalotin)
- Short duration of action due to rapid hydrolysis of the acetyloxy group at C-3 by esterase enzyme
- Acetyloxy group is important for the mechanism of inhibition and acts as a good leaving group
Cephaloridine
- Replacing the acetoxy group with a metabolically stable pyridinium group
- Pyridine can still act as a good leaving group for the inhibition mechanism, but is not cleaved by esterases
- Exists as a zwitterion and is poorly absorbed through the gut wall, requires injection
Cephalexin
- Contains a 3-CH3 group which helps oral absorption but is bad for activity as it is not a good leaving group
- Electron-withdrawing character of the protonated –NH2 group improves the stability of the β-lactam leading to orally active drugs
- Good oral activity, broad spectrum activity (G +ve) & some Gram-negative bacilli, poor β-lactamase stability, poor ability to penetrate cerebrospinal fluids, lacks activity against Pseudomonas aeruginosa
Cephradine
- Dihydro-analog of cephalexin and undergoes aromatization in the body producing cephalexin
Cefaclor
- 3-substitution pattern and electron-withdrawing character of the protonated –NH2 improves the stability of the β-lactam ring, making it orally active
- Less active against Gram-negative bacteria than other second-generation cephalosporins
Cefuroxime
- Contains a syn (Z) methoxyimino substituent which provides β-lactamases stability due to its steric effect
- Z-oxime is much more stable than the E-oxime
- Wide spectrum of activity, useful against organisms resistant to penicillin, poor activity against Pseudomomnas aeruginosa due to lack of drug penetration
Third Generation Cephalosporins
- Replacing the furan ring of Cefuroxime with an aminothiazole ring enhances penetration through the outer membrane of Gram-negative bacteria and increases affinity for the transpeptidase enzyme (PBPs)
- Increase in activity against Gram-negative bacteria
- Variety of structures with different substituents at position 3 to vary pharmacokinetic properties
Cefotaxime
- Metabolically vulnerable acetoxy group attached to C-3, losing about 90% of its activity when hydrolyzed
- Greater anti–Pseudomonas aeruginosa activity
Ceftriaxone
- Metabolically stable, activating and highly acidic 3-thio-2-methyl-1,2-dihydro-1,2,4-triazine-5,6-dione at C-3 that forms an enolic sodium salt at normal pH, making the commercial product a disodium salt
- 95% serum bound and exhibits an extended serum profile, suitable for once daily administration
- Greater anti–Pseudomonas aeruginosa activity
- First-line drug for meningitis due to its best CSF penetration and coverage for bacteria causing meningitis
Fourth Generation Cephalosporins
- Contain Z-methoxyimine moiety at C-7 in addition to quaternary ammonium group at C-3, enhancing water solubility, ability to penetrate the outer membrane, and broader anti-Gram-negative activity, active vs.Gram +ve cocci, good affinity for the transpeptidase enzyme, greater β-lactamase stability, excellent anti–Pseudomonas aeruginosa activity
- Contain “Ceft” + “ol” in their name
- Contain 5-amino-1,2,4-thiadiazole moiety in the acyl side chain
Ceftazidime
- Contains a 3-thio-2-methyl-1,2-dihydro-1,2,4-triazine-5,6-dione at C-3, metabolically stable, activates and is highly acidic, leading to the formation of an enolic sodium salt at normal pH and making commercial product a disodium salt
Ceftaroline fosamil
- Activity against strains of methicillin-resistant Staphylococcus aureus (MRSA) and multi-resistant Streptococcus pneumonia (MDRSP)
- Acts as a prodrug for ceftaroline
Carbapenems
- Potent with an extraordinarily broad range of activity against Gram-positive and Gram negative bacteria, including P.aeruginosa
- High resistance to β-lactamases
- Combine the functional features of the best β-lactam antibiotics and β-lactamase inhibitors
- Poor metabolic and chemical stability, not absorbed from the gut
- Subjected to hydrolytic inactivation by renal dehydropeptidase-I (DHP-I), leading to an unacceptably short t1/2 in vivo and higher incidence of nephrotoxicity
Thienamycin
- N-formimidoyl derivative
- Administration by IM injection or by IV infusion
- Metabolized by renal dehydropeptidase-l (DHP-1) which deactivates thienamycin through hydrolysis of the β-lactam, producing kidney toxic metabolites
Imipenem
- Substituents at the 3-position affect the spectrum of antibacterial activity by influencing penetration into bacteria
- Administered by IM injection or by IV infusion
Meropenem
- More active against Gram-negative and anaerobic bacteria than imipenem, but less active against Gram-positive species
- Contains an extra methyl group at C-4 which conveys intrinsic resistance and stability to hydrolysis by renal DHP-1, leading to a lower incidence of nephrotoxicity and allowing for single agent administration
- Administered by IV injection or infusion
Doripenem
- Newest of the approved carbapenems
- Also contains the 4-β-methyl group, which confers stability toward renal DHP-1, so it is given as a single agent
- Similar spectrum to imipenem and meropenem, considered more potent against Pseudomonas species
Monobactams
- Sulfamic acid moiety attached to the β-lactam ring resembles COOH in penicillins
- Strong electron-withdrawing character of the sulfamic acid group makes the β-lactam bond more subjected to hydrolysis
- α-oriented methyl group at C-2 is associated with stability of aztreonam toward β-lactamases
Aztreonam
- Shows good activity against Gram-negative bacteria and is resistant to β-lactamases
- Often used for patients with penicillin allergies
Key Points to Remember
- Second generation cephalosporins offer improved Gram (-) activity over first generation
- Third generation cephalosporins offer even greater Gram (-) activity, but reduced Staphylococcal activity
- Fourth generation cephalosporins add activity against Pseudomonas aeruginosa and some resistant enterobacteria
- Carbapenems are potent against Gram (+) and Gram (-) bacteria, including P.aeruginosa, and are resistant to β-lactamases
- Imipenem is the most commonly used carbapenem, but is metabolized by renal DHP-1, leading to kidney toxicity, requiring co-administration of cilastatin to protect it from degradation
- Meropenem is more stable than imipenem due to a methyl group at C-4, allowing for single agent administration and reducing nephrotoxicity
- Doripenem is the newest carbapenem with a similar spectrum to imipenem and meropenem, but is considered more potent against Pseudomonas species
- Monobactams have a distinct structure with a β-lactam ring and a sulfamic acid moiety
- Aztreonam is the only approved monobactam, effective against Gram (-) bacteria, and resistant to β-lactamases
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Description
This quiz explores the structure, history, and classifications of cephalosporins, a major group of β-lactam antibiotics. It covers their generational differences, including their effectiveness against various types of bacteria. Test your understanding of cephalosporin modifications and their clinical significance.
