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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
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.
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
– It is difficult for some β-lactams to penetrate the outer
lipopolysaccharide layer of the Gram-negative cell wall.
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
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.
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.
1. Penicillin development
1. Benzylpenicillin (penicillin G)
2. Phenoxymethylpenicillin (penicillin V)
3. Anti-staphylococcal penicillins
4. The extended or broad-spectrum penicillins
5. Anti-pseudomonal penicillins
6. β-lactamase resistant penicillins (Gram-negative)
2. Cephalosporin development
1. First generation cephalosporins
2. Second generation cephalosporins
3. Third generation cephalosporins
4. Fourth generation cephalosporins
1. Penicillin development
Penicillins are characterized by their 6-aminopenicillanic acid
– 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
a) Benzylpenicillin (penicillin G)
The first β-lactam purified for clinical use from Penicillium
Clinical limitations were soon recognized due to:
1. Instability in the presence of gastric acids
2. susceptibility to β-lactamase enzymes
3. 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.
It is administered by deep intramuscular injection as procaine
penicillin, where procaine provides a depot effect as a result
of slow absorption.
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.
This development led to the ability to produce a wide range of
semi-synthetic penicillins by adding side chains to the 6-APA
c) Anti-staphylococcal penicillins
The first group to be developed
They are resistant to staphylococcal β-lactamases
From this group, cloxacillin is commonly used to treat mastitis
in dairy cows.
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
e) Anti-pseudomonal penicillins
It is the next development of penicillins
They are not commonly used in animals
f) β-lactamase resistant penicillins (Gram-negative)
It is the final class of penicillin development.
Shortly after the development of benzypenicillin,
cephalosporin C was isolated from the fungus
Cephalosporins have a 7- aminocephalosporanic acid core
that includes the β-lactam ring.
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.
a) The first-generation cephalosporins
Cefadroxil (Duricef) – Cephradine (Velocef) – Cephalaxin
They were introduced to treat β-lactamase-resistant
They also demonstrated activity against Gram negative
They are no longer used commonly in companion animals but
are still used in dry-cow therapies in dairy cows.
b) Second-generation cephalosporins
Cefuroxime (Zenacef) – Cefaclor (Ceclor) – Cefprozil (Cefzil)
They are active against both Gram-positive and Gram-
Oral preparations are widely used to treat companion
Products are registered for use in mastitis control in dairy
c) Third-generation cephalosporins
Cefotaxime (Claforan) – Ceftriaxone (Rocephen) –
They demonstrate reduced activity against Gram-positive
bacteria but increased activity against Gram-negative
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.
d) Fourth-generation cephalosporins
They have increased activity against both Gram-positive and
These are reserve drugs in human medicine but in some
countries are registered for use in cattle and horses.
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
Meronem - Tienam
They are resistant to most β-lactamases.
They have a wide range of activity against Gram-positive and
They are resistant to most β-lactamases
They have a narrow spectrum of activity with good activity
against many Gram-negative bacteria.
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.
The administration of procaine penicillin has led to:
– Pyrexia, lethargy, vomiting, inappetance, and cyanosis in
– Signs of procaine toxicity, including death in horses.
In humans, sensitization and subsequent hypersensitivity
reactions to penicillin are relatively common during
By comparison, adverse reactions attributed to occupational
exposure to penicillin or the ingestion of food containing
residues of penicillin are now seldom reported.