Antibiotic Groupsβ-Lactams

Members

Amoxicillin Ampicillin Benzylpennicillin Cloxacillin Dicloxacillin Calvulanic acid Ceftazolin Cefoperazone Ceftaquin Ceftiofur Fefuroxime Cephalexin

History

In 1929, Fleming cultured Penicillium notatum which produced an antibacterial substance.

A decade later, the subsequent purification of penicillin and its use by Florey, Chain, and others lead to successfully treating infections in human patients.

In 1945, Fleming, Florey, and Chain were jointly awarded the Nobel Prize in Physiology or Medicine for this work.

Mechanism of Action

They act by disrupting peptidoglycan synthesis in actively multiplying bacteria.

1. β-Lactams bind to proteins in the cell membrane [penicillin-binding proteins (PBPs)]– These proteins are enzymes that catalyze cross-linkages between the

peptide chains on the N-acetylmuramic acid-N-acetylglucosamine backbone of the peptidoglycan molecule.

2. Lack of cross-linkages results in the formation of a weak cell wall and can lead to lysis of growing cells.

Spectrum

Bactericidal Gram positive The differences in susceptibility of Gram-positive and Gram

negative bacteria to β-lactams are due to:– The larger amount of peptidoglycan in the cell wall of gram positive.– The differences in PBPs (Penicillin Binding protein) between

organisms.– It is difficult for some β-lactams to penetrate the outer

lipopolysaccharide layer of the Gram-negative cell wall.

Resistance

Gram-positive bacterial resistance to β-lactams is due to:1. The action of β-lactamase enzymes that break the β-lactam ring. 2. Modification of PBPs.Resulting in reduced binding affinity of the β-lactam for the peptide chain.

Gram-negative bacteria are naturally resistant to some of the β-lactams because the β-lactam cannot penetrate the outer lipopolysaccharide membrane of the cell wall.

Pharmacokinetics

Antimicrobial activity is usually time dependent.– β-Lactams have a slower kill rate than do fluoroquinolones and

aminoglycosides, and killing activity starts after a lag phase. The β-lactams are wholly ionized in plasma. They have relatively small volumes of distribution. They have a short half-live. They do not cross biological membranes well but are widely

distributed in extracellular fluids. Elimination is generally through the kidneys.

β-Lactams Development

1. Penicillin development1. Benzylpenicillin (penicillin G)2. Phenoxymethylpenicillin (penicillin V)3. Anti-staphylococcal penicillins4. The extended or broad-spectrum penicillins5. Anti-pseudomonal penicillins 6. β-lactamase resistant penicillins (Gram-negative)

2. Cephalosporin development1. First generation cephalosporins2. Second generation cephalosporins3. Third generation cephalosporins4. Fourth generation cephalosporins

Cont. …

1. Penicillin development Penicillins are characterized by their 6-aminopenicillanic acid

(6-APA) core. – This is a thiazolidone ring linked to a β-lactam ring and a side chain at

position C6, which allows them to be distinguished from one another. – Penicillins can be separated into six groups on the basis of their

activity.

Cont. …

a) Benzylpenicillin (penicillin G) The first β-lactam purified for clinical use from Penicillium

cultures. Clinical limitations were soon recognized due to:

1. Instability in the presence of gastric acids2. susceptibility to β-lactamase enzymes3. Ineffectiveness against many Gram-negative organisms.4. It also has a short terminal half-life of around 30–60 min.

Benzylpenicillin is still the best antibiotic to use against most Gram-positive organisms (except resistant staphylococci and enterococci) and some Gram-negative bacteria.

Cont. …

It is administered by deep intramuscular injection as procaine penicillin, where procaine provides a depot effect as a result of slow absorption.

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b) Phenoxymethylpenicillin (penicillin V) The first modification to the 6-APA core was acylation to

produce phenoxymethylpenicillin (penicillin V), which is more acid-stable and active orally.

Cont. …

This development led to the ability to produce a wide range of semi-synthetic penicillins by adding side chains to the 6-APA core.

Cont. …

c) Anti-staphylococcal penicillins The first group to be developed Include methicillin They are resistant to staphylococcal β-lactamases From this group, cloxacillin is commonly used to treat mastitis

in dairy cows.

Cont. …

d) The extended or broad-spectrum penicillins It is the next class of penicillins Include ampicillin, which is active against Gram-negative

bacteria, including Escherichia coli. They are susceptible to the action of β-lactamases. Amoxicillin and amoxicillin + clavulanate are widely used in

livestock and companion animals to treat Gram-negative infections, particularly those caused by enteric Enterobacteriaceae.

Cont. …

e) Anti-pseudomonal penicillins It is the next development of penicillins include carbenicillin They are not commonly used in animals

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f) β-lactamase resistant penicillins (Gram-negative) It is the final class of penicillin development. Include temocillin.

Cont. …

Cephalosporins development Shortly after the development of benzypenicillin,

cephalosporin C was isolated from the fungus Cephalosporium acremonium.

Cephalosporins have a 7- aminocephalosporanic acid core that includes the β-lactam ring.

Cont. …

They were of early interest because:1. They have activity against Gram-negative bacteria. 2. They are less susceptible to the action of β-lactamases.

Over the years, the cephalosporin core molecule was also modified to provide a series of classes (generations) of semi-synthetic cephalosporins with differing activities.

Cont. …

a) The first-generation cephalosporins Cefadroxil (Duricef) – Cephradine (Velocef) – Cephalaxin

(Keflex) They were introduced to treat β-lactamase-resistant

staphylococcal infections. They also demonstrated activity against Gram negative

bacteria. They are no longer used commonly in companion animals but

are still used in dry-cow therapies in dairy cows.

Cont. …

b) Second-generation cephalosporins Cefuroxime (Zenacef) – Cefaclor (Ceclor) – Cefprozil (Cefzil) They are active against both Gram-positive and Gram-negative

organisms. Oral preparations are widely used to treat companion

animals. Products are registered for use in mastitis control in dairy

cows.

Cont. …

c) Third-generation cephalosporins Cefotaxime (Claforan) – Ceftriaxone (Rocephen) –

Cefoperazone (Cefobid) They demonstrate reduced activity against Gram-positive

bacteria but increased activity against Gram-negative organisms.

Because of their importance in human medicine, these products should be reserved for serious infections where other therapy has failed.

They are used to treat both livestock and companion animals.

Cont. …

d) Fourth-generation cephalosporins Cefipime (Maxipime) They have increased activity against both Gram-positive and

Gram-negative bacteria. These are reserve drugs in human medicine but in some

countries are registered for use in cattle and horses.

Cont. …

Other β-lactams with natural origins This include carbapenems and monobactams. These classes of β-lactams are not registered for use in food

producing animals but are used off-label in companion animals.

Cont. …

Carbapenems Meronem - Tienam They are resistant to most β-lactamases. They have a wide range of activity against Gram-positive and

Gram-negative bacteria

Monobactams Aztreonam They are resistant to most β-lactamases They have a narrow spectrum of activity with good activity

against many Gram-negative bacteria.

Safety

β-Lactam antibiotics are largely free of toxic effects, and the margin of safety is substantial.

The major adverse effect is acute anaphylaxis, which is uncommon and associated mostly with penicillins; – Symptoms include urticaria, angioneurotic edema, and

fever occur more commonly. Penicillin-induced immunity-mediated hemolytic anemia in

horses has also been reported.

Cont. …

The administration of procaine penicillin has led to:– Pyrexia, lethargy, vomiting, inappetance, and cyanosis in

pigs.– Signs of procaine toxicity, including death in horses.

In humans, sensitization and subsequent hypersensitivity reactions to penicillin are relatively common during treatment.

By comparison, adverse reactions attributed to occupational exposure to penicillin or the ingestion of food containing residues of penicillin are now seldom reported.