Olsen part 3

β-Lactam Antibiotics: Overview

  • This discussion focuses on cephalosporins and carbapenems, key classes of β-lactam antibiotics.

β-Lactam Ring Structures

  • Highlighted core structures:

    • Penam: 4-Thia-1-azabicyclo-[3.2.0]heptane-7-one

    • Penem: 4-Thia-1-azabicyclo-[3.2.0]hept-2-ene-7-one

    • Carbapenem: 1-Azabicyclo[3.2.0]-hept-2-ene-7-one

    • Cefem: 5-Thia-1-azabicyclo-[4.2.0]oct-2-ene-8-one

    • Monobactam: 1-Azacyclobutan-4-one

Peptidoglycan in Gram(+) and Gram(-) Organisms

  • The structural differences and antibiotic effects on gram-positive and gram-negative bacteria are illustrated.

    • Gram(+) Structure: Thick peptidoglycan layers, sensitive to certain antibiotics.

    • Gram(-) Structure: Thinner peptidoglycan layers, outer membrane present (lipopolysaccharides, porins).

    • Role of ß-lactamase in antibiotic resistance discussed.

Learning Objectives

  1. Identify first generation cephalosporins and their therapeutic applications.

  2. Recognize second generation cephalosporins and understand significance of side-chain chemistry.

  3. Identify third and fourth generation cephalosporins and their spectrum of activity.

  4. Understand the β-lactamase classification system: Penicillinases, Cephalosporinases, Carbapenemases.

  5. Classify β-lactams based on sensitivity to β-lactamases.

Cephalosporins versus Penicillins

  • Structural Differences:

    • Penicillins have one side chain at the 6-position; cephalosporins have two side chains at the 7- and 3-positions.

    • Differences in side chains influence activity and metabolic parameters.

  • Impact of Substitution:

    • Modifications at the 6-position in penicillins generally enhance potency.

    • Alterations at the 7-position in cephalosporins affect microbiologic activity.

    • Changes at the 3-position primarily influence pharmacokinetics and drug metabolism.

  • Properties of Cephalosporins:

    • Structurally akin to penicillins but less allergenic.

    • Broader spectrum than comparable penicillin generations.

    • Have increased resistance to hydrolysis by β-lactamases (3rd > 2nd > 1st generation).

    • Generally less potent than penicillins.

    • More costly but less toxic.

Key Structural Positions of Cephalosporins

  • Identified important functional groups and parameters affecting activity.

Synthetic Strategies for Cephalosporins

  • Explained the synthetic pathway for Cephalosporin C and derivatives.

  • Example structures:

    • 7-Aminocephalosporanic Acid (7-ACA)

    • 7-Amino-3-deacetoxy-cephalosporanic Acid (7-ADCA)

Cephalosporin Inactivation by Metabolism

  • Discussed metabolic pathways leading to inactivation of cephalosporins.

General Spectrum of Activity

  • First Generation: Effective against S. aureus, S. pneumoniae, S. pyogenes, P. mirabilis.

  • Second Generation: Similar to 1st + H. influenzae, M. catarrhalis, N. meningitidis, N. gonorrhoeae. Less potent against Gram+.

  • Third Generation: More potent, especially against H. influenzae, E. coli, Klebsiella but inactive against Bacteroides.

  • Fourth Generation: Highly potent, effective against Pseudomonas, less against Bacteroides.

Cephalosporins by Generation

  • First Generation: Oral options (Cephalexin, Cefadroxil) and parenteral (Cefazolin).

  • Second Generation: Oral (Cefaclor, Cefuroxime Axetil) and parenteral (Cefamandole, Cefoxitin).

  • Third Generation: Oral (Cefixime, Cefpodoxime Proxetil) and parenteral agents (Cefotaxime, Ceftriaxone).

  • Fourth Generation: Primarily parenteral (Cefepime).

Specific Cephalosporin Characteristics

First Generation Cephalosporins

  • All agents are highly bioavailable.

  • Cefazolin: Known for being less stable to β-lactamases.

Second Generation Cephalosporins

  • Cefaclor: Noted for its 95% absorption orally and potential serum-sickness-like reactions.

  • Cefuroxime Axetil: More resistant to β-lactamases, serves as a prodrug.

  • Cefamandole: MTT side chain may cause disulfiram-like reactions.

  • Cephamycins: Unique activity against Bacteroides fragilis.

Third Generation Cephalosporins

  • Comprised of aminothiazole syn-oxime ether side chains.

  • Active against a range of Gram(-) organisms, especially H. influenzae.

Fourth Generation Cephalosporins

  • Noted for high stability against β-lactamases and broad-spectrum activity.

  • Cefepime: Effective against Pseudomonas but lacks MRSA activity.

Fifth Generation Cephalosporins

  • Ceftaroline: Broad-spectrum with activity against MDR Staphylococcus aureus and respiratory pathogens.

  • Ceftobiprole: Extended-spectrum for both Gram (+) and (-) bacteria, including MRSA.

Carbapenems

  • Imipenem: A synthetic analog of thienamycin, notable for high stability to β-lactamases

    • Formulated with cilastatin to prevent nephrotoxicity.

  • Meropenem: Comparable spectrum with better potency against Gram (-).

    • Does not require cilastatin.

  • Ertepenem: Less potent against Pseudomonas, suitable for empiric therapy.

  • Doripenem: Seizure risk debated; effective against a broad range but lacks efficacy against MRSA.

Aztreonam

  • Synthetic and preferentially targets Gram(-) aerobes.

  • Very stable to β-lactamases with no cross-allergies with penicillins.