Lecture 7: B-Lactamase Inhibitors & Cephalosporins

Cephalosporins with high polarity in their side chains tend to have poor absorption in the gastrointestinal tract (GIT). This makes them more difficult to isolate and purify.

Cephalosporins undergo lactonization, a chemical reaction that converts an active form to a less active or inactive form. This process involves an esterase enzyme and spontaneous ring formation.

The structural activity relationship (SAR) in cephalosporins explains how changes in their chemical structure affect their activity against bacteria.

First-generation cephalosporins are effective primarily against Gram-positive bacteria and a limited number of Gram-negative bacteria.

Cephalosporins are classified based on their route of administration (oral or parenteral) and their generation (based on their spectrum of activity).

Second-generation cephalosporins have expanded activity against Gram-negative bacteria, including Haemophilus influenzae.

Third-generation cephalosporins demonstrate broad-spectrum activity, including effectiveness against anaerobic bacteria.

Fourth-generation cephalosporins have expanded activity against Pseudomonas and can cross the blood-brain barrier, treating certain infections affecting the central nervous system (CNS).

The first cephalosporin antibiotic, derived from the fungus Acremonium chrysogenum. It was discovered in the mid-1940s from sewer waters in Sardinia.

An important building block for producing various cephalosporin antibiotics. It allows for diverse modifications to create different drugs with varying properties.

A key chemical feature in the cephalosporin structure. It contributes to the antibiotic's reactivity and ability to bind to bacterial enzymes.

The cephalosporin molecule's ability to resist breakdown by acids in the digestive system. This allows it to reach the desired target in the body.

This refers to the potential of a drug to trigger an allergic reaction in a patient. Certain cephalosporins have a lower risk of causing allergies compared to some penicillins.

Cephalosporins are effective against a wide range of bacterial infections, including both Gram-positive and Gram-negative bacteria.

The process by which certain types of bacteria develop resistance to antibiotics such as cephalosporins. This makes treating infections increasingly challenging.

A class of enzymes produced by many bacterial species that can break down and inactivate the beta-lactam ring structure in cephalosporins, making them less effective.

First-generation cephalosporins, like Cephalothin, are often administered intravenously or intramuscularly because they have poor absorption in the gut.

Cefalexin, a first-generation cephalosporin, is given orally. It's effective against Gram-positive bacteria and some Gram-negative bacilli.

Second-generation cephalosporins are similar to first-generation, but they have broader activity against Gram-negative bacteria and are more resistant to breakdown by beta-lactamases. They are particularly effective against Hemophilus influenza.

Cephamycins, like Cefoxitin, are a type of second-generation cephalosporin with a broader spectrum of activity, particularly against Gram-negative organisms. They are also more resistant to beta-lactamases.

Second-generation cephalosporins, including cephamycins, are not typically used in treating central nervous system infections because they cannot effectively cross the blood-brain barrier.

Second-generation cephalosporins are commonly used to treat infections of the upper and lower respiratory tract, including acute sinusitis and otitis media.

Second-generation cephalosporins are more resistant to beta-lactamases than first-generation cephalosporins. This makes them more effective against bacteria that produce beta-lactamases, an enzyme that can break down antibiotics.

Second-generation cephalosporins can cause diarrhea as a side effect.

Third generation cephalosporins are effective against a wide range of bacteria, including gram-negative bacteria. This makes them suitable for treating infections in various parts of the body.

Cefotaxime is a third-generation cephalosporin that is given intravenously (IV) because it is poorly absorbed by the body if taken by mouth. However, new formulations that complex with bile acid analogs are designed for oral absorption.

Ceftriaxone is a third-generation cephalosporin with a unique structure that makes it very effective and allows for once-daily administration. It's often used for treating serious infections, including meningitis.

Fourth generation cephalosporins are effective against a wide range of bacteria, including those that are resistant to other antibiotics. They are also particularly effective against infections of the central nervous system.

Fourth generation cephalosporins are more resistant to breakdown by beta-lactamases than third generation cephalosporins, providing a longer-lasting effect.

These are penicillanic acid sulphone derivatives that are semisynthetic beta-lactamase inhibitors. They act as 'suicide substrates', meaning they bind to and inactivate the enzyme that breaks down beta-lactam antibiotics.

A combination of sulbactam and ampicillin. They are a prodrug, meaning they are inactive until they are metabolized in the body. This is done to improve absorption of the antibiotic.

A combination of piperacillin and tazobactam that is used to treat serious hospital-acquired infections. The tazobactam helps the piperacillin fight off bacteria that have the potential to break down antibiotics.

These are compounds isolated from the bacteria Streptomyces olivaceus. They are very powerful beta-lactamase inhibitors and are much stronger than even clavulanic acid.

A vital component of various beta-lactam antibiotics. It contributes to the antibiotic's reactivity and ability to bind to bacterial enzymes, which disrupts bacterial cell wall synthesis.

Cefepime is a fourth generation cephalosporin. It is highly effective against various resistant organisms that were previously difficult to treat.

Ceftolozane is a fifth generation cephalosporin. It is used to treat complicated infections of the abdomen and urinary tract. Combined with tazobactam, it forms Zerbaxa.

The 7-aminothiadiazole group in the molecule enhances activity against gram-negative bacteria. The alkoximino group confers resistance to many beta-lactamases. The dimethylacetic acid group provides enhanced activity against Pseudomonas aeruginosa.

A bulky side chain, a pyrazole ring, positioned at the 3-position, provides steric hindrance, preventing the breakdown of the beta-lactam ring by hydrolysis.

Beta-lactamase inhibitors combine with penicillin antibiotics sensitive to beta-lactamases to treat infections caused by bacteria producing these enzymes. Examples include Clavulanic acid, Sulbactam, Tazobactam, and Olivanic acids.

Clavulanic acid is the first naturally occurring beta-lactam without sulfur. It is a potent inhibitor of beta-lactamases. It has weak antibacterial activity but acts as a suicide substrate for beta-lactamases.

Amoxicillin and clavulanic acid are combined to increase the spectrum of activity of amoxicillin and decrease the required dose of amoxicillin. This combination is known as Augmentin.