Penicillins

In 1928, Alexander Fleming, working at St.

Mary's Hospital in London, observed that a
culture plate on which staphylococci were
being grown had become contaminated with a
mould of the genus Penicillium, and that
bacterial growth in the vicinity of the mould
had been inhibited.
He isolated the mould in pure culture and
demonstrated that it produced an
antibacterial substance called penicillin.
This substance was subsequently extracted
and its antibacterial effects analyzed by Florey
and Chain and their colleagues at Oxford in
1940.
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Penicllins II
They showed that it had powerful chemotherapeutic
properties in infected mice and that it was non-toxic.
Its remarkable antibacterial effects in humans were
clearly demonstrated in 1941.
A small amount of penicillin, extracted from crude
cultures in the laboratories of the Dunn School of
Pathology in Oxford, was tested on a policeman
He had staphylococcal and streptococcal septicaemia
with multiple abscesses, and osteomyelitis with
discharging sinuses. He was in great pain and was
desperately ill.
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Mechanism of action
All -lactams interfere with the synthesis of the
bacterial cell wall peptidoglycan.
After attachment to binding sites on bacteria,
they inhibit the transpeptidation enzyme that
cross-links the peptide chains attached to the
backbone of the peptidoglycan.
The final bactericidal event is the inactivation of
an inhibitor of the autolytic enzymes in the cell
wall.
This leads to lysis of the bacterium.
Some organisms have defective autolytic
enzymes and are inhibited but not lysed-they
are referred to as 'tolerant'.
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Resistance to Penicillins
Production of -lactamases
About 50 different types of -lactamases
have been produced
Produced in staphylococci, Nesseria
gonorhoeae, Haemophillus spp.
This is overcomed by the use of
clavulanic acid, contains -lactam ring
and bind covalently to the enzyme or
near its active site.
Other -lactamase inhibitors include
sulbactam and tazobactam.
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Resistance to Penicillins II
Reduction in the permeability of the
other membrane
Thus decreased ability of the drug to
pnetrate to the target site.
This occurs with Gram-ve organisms with
an outer membrane that limits the
penetration of hydrophilic antibiotics.
Occurence of modified penicillinbinding sites
Particluar in methicillin-resistant
staphylococci (e.g. MRSA)
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Types of Penicillins
Earlier penicillins
Benzylpenicillin (Penicillin G)
Phenoxymethylpenicillin (Penicillin V)
-lactamase-resistant penicillins
Flucloxacillin, cloxacillin, dioxacillin, dicloxacillin,
methicillin, nafcillin
Broad-spectrum penicillins
Ampicillin, pivampicillin, amoxicillin,
becampicillin
Extended-spectrum penicillins
Carbenacillin, ticarcilin, aziocillin, mezlocillin,
piperacillin (with antipseudomonal activity)
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Clinical Uses
Bacterial meningitis (e.g. caused by Neisseria meningitidis,
Streptococcus pneumoniae): benzylpenicillin, high doses
intravenously
Bone and joint infections (e.g. with Staphylococcus aureus):
flucloxacillin
Skin and soft tissue infections (e.g. with Streptococcus pyogenes or S.
aureus): benzylpenicillin, flucloxacillin; animal bites: co-amoxiclav
Pharyngitis (from S. pyogenes): phenoxylmethylpenicillin
Otitis media (organisms include S. pyogenes, Haemophilus
influenzae): amoxicillin
Bronchitis (mixed infections common): amoxicillin
Pneumonia: amoxicillin
Urinary tract infections (e.g. with Escherichia coli): amoxicillin
Gonorrhea: amoxicillin (plus probenecid)
Syphilis: procaine benzylpenicillin
Endocarditis (e.g. with Streptococcus viridans or Enterococcus
faecalis)
Serious infections with Pseudomonas aeruginosa: piperacillin.
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Side effects
Hypersensitivity reactions, (main unwanted
effect) caused by the degradation products of
penicillin, which combine with host protein and
become antigenic
Skin rashes and fever
Delayed type of serum sickness
Acute anaphylactic shock
Penicillins, particularly the broad-spectrum type
given orally, alter the bacterial flora in the gut.
This can be associated with GIT disturbances
and suprainfection by microorganisms not
sensitive to penicillin
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CEPHALOSPORINS AND CEPHAMYCINS

Cephalosporins N and C, are chemically related to
penicillin
Cephalosporin P, a steroid antibiotic that resembles
fusidic acid
They were first isolated from Cephalosporium fungus.
The cephamycins are -lactam antibiotics produced
by Streptomyces spp and they are closely related to
the cephalosporins.
Semi-synthetic broad-spectrum cephalosporins have
been produced by addition, to the cephalosporin C
nucleus, of different side-chains.
These are water-soluble and relatively acid stable.
They vary in susceptibility to -lactamases.
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Types of Cephalosporins and Cephamycins

Important Properties

Other Similar Drugs

First-generation
compounds that have
reasonable activity against
Gram+ve and modest
activity against Gram-ve
organisms

Cefachlor is a secondgeneration compound with

greater potency against
Gram-ve organisms, but it
can cause unwanted
cutaneous lesions

Cefuroxime

Second-generation
compounds that show only
moderate activity against
most Gram+ve organisms
but reasonable potency
against Gram-ve organisms

Cephamandole, cefoxitin ,
good activity against Gramve organisms, resistant to lactamase from Gram-ve
rods, good potency against
Bacteroides fragilis, bowel
flora

Cefotaxime

Third-generation
compounds, which are less
active against Gram+ve
bacteria than those of the
second generation but more
active against Gram-ve
bacteria. Has some activity
against pseudomonads

Ceftizoxime ; ceftriaxone
excreted largely in the bile;
cefperazone, excreted mainly
in the bile, can cause
decrease of vitamin Kdependent clotting factors

Category
Oral drugs
Cefalexin

Parenteral drugs

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Mechanism of action
Same as that of the penicillins-interference with
bacterial peptidoglycan synthesis after binding to the
-lactam-binding proteins.
Resistance to this group of drugs has increased
because of plasmid-encoded or chromosomal lactamase.
Nearly all Gram-ve bacteria have a chromosomal gene
coding for a -lactamase that is more active in
hydrolysing cephalosporins than penicillins.
In several organisms a single-step mutation can result
in high-level constitutive production of this enzyme.
Resistance also occurs if there is decreased penetration
of the drug as a result of alterations to outer membrane
proteins or mutations of the binding-site proteins.
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Clinical Uses
Septicaemia (e.g. cefuroxime,
cefotaxime)
Pneumonia caused by susceptible
organisms
Meningitis (e.g. cefriaxone,
cefotaxime)
Biliary tract infection
Urinary tract infection (especially in
pregnancy, or in patients
unresponsive to other drugs)
Sinusitis (e.g. cefadroxil)
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Pharmacokinetics
Mostly available in injection and few oral dosage
forms
Injections administered IM (which may be painful
with some agents) or IV.
After absorption they are widely distributed in the
body
Some, such as cefoperazone, cefotaxime,
cefuroxime and ceftriaxone, also cross the
blood-brain barrier.
Excretion is mostly via the kidney, largely by
tubular secretion
40% of ceftriaxone and 75% of cefoperazone
are eliminated in the bile
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Side effects
Hypersensitivity reactions (similar to
penicillins)
Some cross-reactions occur (about
10% of penicillin-sensitive individuals
will have allergic reactions to
cephalosporins)
Nephrotoxicity (with cefradine)
Alcohol intolerance
Diarrhoea can occur with oral
cephalosporins and cefoperazone
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OTHER -LACTAM ANTIBIOTICS

Carbapenems and monobactams were developed
to deal with -lactamase-producing Gram-ve
organisms resistant to penicillins.
Imipenem, an e.g. of a carbapenem, acts in the
same way as the other -lactams
It has a very broad spectrum of antimicrobial activity,
being active against many aerobic and anaerobic
Gram+ve and Gram-ve organisms.
Many of the MRSA are less susceptible, and resistant
strains of P. aeruginosa have been reported.
Imipenem was originally resistant to all -lactamases
but some organisms now have chromosomal genes
that code for imipenem-hydrolyzing -lactamases.
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Side effects
Similar to other -lactams
Nausea and vomiting (most frequent)
Neurotoxicity (occur with high
plasma concentrations)
Other e.g.
Meropenem is similar to imipenem
but is not broken down by proximal
tubule dehdropeptidase.
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Monobactams
The main monobactam is Aztreonam
A simple monocyclic -lactam with a complex substituent,
which is resistant to most -lactamases.
This has an unusual spectrum-being active only against
Gram-ve aerobic rods, including pseudomonads, Neisseria
meningitidis and Haemophilus influenzae.
It has no action against Gram+ve organisms or anaerobes.
Given parenterally and has a plasma half-life of 2 hours
Side effects
Similar to those of other -lactam antibiotics
Do not cause allergic reactions in penicillin-sensitive
individuals.
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