Penicillins

1. Antibacterials acting on the cell wall
biosynthesis
Dr Ravi Kant Agrawal, MVSc, PhD
Senior Scientist (Veterinary Microbiology)
Food Microbiology Laboratory
Division of Livestock Products Technology
ICAR-Indian Veterinary Research Institute
Izatnagar 243122 (UP) India

2. Cell Wall Inhibitors
• β-LACTAM ANTIBIOTICS
– Penicillins
– Cephalosporins
– Carbapenems
– Monobactams
• OTHER ANTIBIOTICS
– Vancomycin
– Bacitracin
β-LACTAMASE INHIBITORS
Clavulanic acid, Sulbactam, Tazobactam

3. The cell wall completely
surrounds the cytoplasmic
membrane, maintains cell shape
and integrity, and prevents cell
lysis from high osmotic pressure.
The cell wall is composed of a
complex cross-linked polymer of
polysaccharides and
polypeptides, peptidoglycan
(murein, mucopeptide).
The polysaccharide contains
alternating amino sugars, N-
acetylglucosamine (NAG), and N-
acetylmuramic acid (NAM).
A five-amino-acid peptide is
linked to the N-acetylmuramic
acid sugar.
This peptide terminates in D-
alanyl-D-alanine.
Transpeptidases removes the
terminal alanine in the process of
forming a cross-link with a nearby
peptide.
Cross-links give the cell wall its
structural rigidity.
The bacterial cell wallThe bacterial cell wall
Cell
Cell membrane
Thick porous cell wall
•Thick cell wall
•No outer membrane
•More susceptible to penicillins
L
CellCell
membrane
Thin cell wall
Lactamase
enzymes
Outer
membrane
Hydrophobic barrier
Periplasmic
space
Porin
L
L
L
•Thin cell wall
•Hydrophobic outer membrane
•More resistant to penicillins

4. Remember Peptidoglycan?Remember Peptidoglycan?

5. PeptidoglycanPeptidoglycan

6. Steps in Peptidoglycan synthesis
• For bacterial growth and multiplication, links in the
peptidoglycan must be broken.
• New peptidoglycan monomers must be inserted, and the
peptide cross links must be re-sealed.
• Autolysins of bacteria break the glycosidic bonds between the
peptidoglycan monomers at the point of growth.
• They also break the peptide cross-bridges that link the rows of
sugars together.
• Peptidoglycan monomers are synthesized in the cytosol of the
bacterium where they attach to a membrane carrier molecule
called bactoprenol.

7. Steps in Peptidoglycan synthesis
• First, N-acetylglucosamine (NAG) links up with uridine
diphosphate (UDP) to form UDP-NAG.
• Some of the NAG is enzymatically converted to N-
acetylmuramic acid (NAM) forming UDP-NAM.
• Sequential addition of Five amino acids to the UDP- NAM
forming a pentapeptide. The last two are D-alanine molecules
• For attachment of the NAM-pentapeptide to the bactoprenol
carrier, the energy being supplied by one of the high-energy
phosphate groups of the UDP.
• Attachment of the NAG to the NAM-pentapeptide on the
bactoprenol to complete the peptidoglycan monomer.

8. Steps in Peptidoglycan synthesis
• Bactoprenols then insert the peptidoglycan monomers into
the breaks in the peptidoglycan at the growing point of the cell
wall.
• Transglycosidase enzymes catalyze the formation of
glycosidic bonds between the NAM and NAG of the
peptidoglycan monomers and the NAG and NAM of the
existing peptidoglycan.
• Finally, Transpeptidase enzymes reform the peptide
cross-links between the rows and layers of peptidoglycan to
make the wall strong.
• http://pharmaxchange.info/press/2011/03/animation-of-synthesis-

9. Mechanism of action of β-lactams
• Penicillin mimic the structure of D-ala-D-ala, because of that the
transpeptidase mistakenly bind to penicillins, instead of D-ala-D-ala.
• The tranpeptidase is inactivated by ß-lactam antibiotics, they are the targetsThe tranpeptidase is inactivated by ß-lactam antibiotics, they are the targets
of β-lactam antibiotics and are namedof β-lactam antibiotics and are named penicillin-binding protein (PBPs).penicillin-binding protein (PBPs).
• This binding blocks the transpeptidase enzymes from cross-linking the sugar
chains and results in a weak cell wall.
• Interfere with the bacterial controls that keep autolysins in check, with
resulting degradation of the peptidoglycan and osmotic lysis of the
bacterium.
• Also this explains the lack of penicillin toxicity, since D-amino acids are not
present in human, only the L-amino acids present.
• Also targeting the cross linking in the peptidoglycan biosynthesis which is
only present in bacteria explains the selective toxicity on the bacteria.
• The PBPs vary in their affinities for different ß-lactam antibiotics and severalThe PBPs vary in their affinities for different ß-lactam antibiotics and several
kinds of PBPs have confirmed.kinds of PBPs have confirmed.
PenicillinPenicillin Acyl-D-Ala-D-AlaAcyl-D-Ala-D-Ala
HH
CO2H
H
N
O
Me
Me
N
S
C
R
O
Me
CO2H
H
N
O CH3
H
N
H
H
C
R
O

13.  1877 Pasteur and Joubert discovered that certain moulds could
produce toxic substances which killed bacteria.
 1928, Alexander Fleming noted that a bacterial culture which had
been left several weeks open to the air had become infected by a
fungal colony.
 1939 Ernst Chain, Howard Florey, Edward Abraham purified and
stabilized a form of penicillin.
 1941 Florey and Chain conducted first clinical trials using crude
extracts of penicillin and achieved spectacular success.
 1945 Dorothy Hodgkins established the structure of penicillin by X-
ray analysis.
 1957 Sheehan completed a full synthesis of penicillin, which was of
commercial use.
 1958-60 Beechams isolated a biosynthetic intermediate of penicillin
called 6-aminopenicillanic acid (6-APA) which provided a readily
accessible biosynthetic intermediate of penicillin, this revolutionized
the field of penicillins by providing the starting material for a huge
range of semi-synthetic penicllins.
 1960-70 Penicillins were used widely and carelessly, so the resistant
bacteria became a problem very soon.
 1976 Beechams discovered a natural product called clavulanic acid
which promoted fight against these penicillin-resistant bacteria.
Penicillins: History

14. β-lactam antibiotics
Penicillin, Cephalosporin, Carbapenem, Monobactum
Cephalosporin nucleusPenicillin nucleus
Monobactam nucleusCarbapenem nucleus
BA
DC
5-membered thiazolidine ring
Carbon atom
monocyclic
6-membered dihydrothiazine

15. Properties of β-lactam antibiotics
• Presence of β-lactam ring
• Inhibit bacterial cell wall synthesis
• Bactericidal
• Sensitive to β-lactamase

16. Penicillin
• Bicyclic system
consisting of a
four membered
β lactam ring
fused to a five-
membered
thiazolidine ring.
• The acyl side-
chain (R) varies
• Varying R,
properties of
Penicillin can be
altered.

18. Structure-activity relationships of penicillins
• The strained β-lactam
ring is essential.
• The bicyclic system is
essential.
• The acyl-amino side
chain is essential.
• The free carboxylic
acid is essential
• The stereochemistry of
the bicyclic ring with
respect to the
acylamino side chain is
important.
• Sulfur is usual but not
essential.
• Conclusion: Very little
variation is tolerated by the
penicillin nucleus and that
too is restricted to
acylamino side chain.

19. Structure of penicillin
• Partially folded book configuration.
• Obtained from Cysteine and valine.
H
NO
NH
C
O
R
H
S
CO2H
H
Me
Me
..S
N
Me
Me
O
H
N
CO2H
C
R
O
CYSCYS
S
N
Me
Me
O
H
N
CO2H
C
R
O
VALVALCYSCYS
S
N
Me
Me
O
H
N
CO2H
C
R
O

20. Biosynthetic (natural) penicillins
Properties of Benzyl penicillin (penicillin G)
• Narrow spectrum
• Ineffective orally since it breaks down in the acid conditions of the
stomach so parentral administration.
• Sensitive to all known β-lactamases
• Non-toxic! But may cause allergic reaction in susceptible patients.
• Short half life (can be enhanced by addition of procaine or
benzathine with penicillin)
• Used in Mastitis, pyelonephritis in cattle, Swine erysipelas, Lumpy
jaw, Tetanus, pulpy kidney, Lamb dysentry, Anthrax
NARROW SPECTRUM PENICILLINS

21.  Benzylpenicillin (Penicillin G®
) is used when high plasma
concentrations are required.
 The short t1/2 (0.5 h) means that reasonably spaced doses have to be
large to maintain a therapeutic concentration.
 The unusually large therapeutic ratio of penicillin allows the
resulting fluctuations to be tolerable.
 Benzylpenicillin is eliminated by the kidney, with about 80% being
actively secreted by the renal tubule and this can be blocked by
probenecid.
 Penicillin G® is a drug of choice for infections caused by
streptococci, meningococci, enterococci, penicillin-susceptible
pneumococci, non-β-lactamase-producing staphylococci, T. pallidum
and many other spirochetes, clostridium species, actinomyces, and
other Gram-positive rods and non-β-lactamase-producing Gram-
negative anaerobic organisms.
 Depending on the organism, the site, and the severity of infection,
effective doses range is between 4 and 24 million units per day
administered i.m. or i.v. in 4 to 6 divided doses.
 High-dose Penicillin G® Sodium can also be given as a continuous i.
v. infusion.

22.  Maintain low but prolonged drug levels.
 A single i.m. injection of benzathine penicillin, 1.2 million
units, is an effective treatment for β-hemolytic
streptococcal pharyngitis; given once every 3–4 weeks, it
prevents re-infection.
Benzathine penicillin G, 2.4 million units i.m. once a week
for 1–3 weeks, is effective in the treatment of syphilis.
Benzathine penicillin and Procaine Penicillin G®Benzathine penicillin and Procaine Penicillin G®

23. Acid sensitivity of penicillins
Reasons for the acid sensitivity of penicillin G
• Ring strain: The bicyclic system in penicillin consists of a
four-membered ring and a five membered ring. As a
result, penicillin suffers large angle and torsional strains.
Acid-catalysed ring opening relieves these strains by
breaking open the more highly strained four-membered
lactam ring
• A highly reactive β-lactam carbonyl group: The carbonyl
group in the β-lactam ring is highly susceptible to
nucleophiles.
• Influence of the acyl side chain (neighbouring group
participation): Penicillin-G has a self-destructive
mechanism built in to its structure in which the oxygen of
the carbonyl group will attack the carbonyl carbon of the
lactam ring causing the ring opening. This gives Penillic
acid and penicillenic acid as final products

25. Tackling the problem of acid sensitivity
• Nothing can be done for Ist two factors as β-lactam ring is
essential for antibacterial activity. Only the third factor, i.e.
reducing the amount of neighbouring group participation to
make it difficult for the acyl carbonyl group to attack the β-
lactam ring .
• This can be done by attaching a electron-withdrawing group to
the carbonyl group (of acyl side chain).
• Due to inductive pulling effect, electrons are drawn away from
the carbonyl oxygen and reduce its tendency to act as
nucleophile.

26. Penicillin V
 Phenoxymethyl Penicillin
 Penicillin V has an electron withdrawing group
 Better acid stability than penicillin G
 Stable enough to survive acid in stomach
 Available in oral form
 Low absorption
 Sensitive to penicillinases
 Antibacterial spectrum similar to Peniciilin G but less active than
penicillin G.
 Phenoxymethylpenicillin Potassium (Penicillin-VK®)Phenoxymethylpenicillin Potassium (Penicillin-VK®) the oral
form of penicillin, is indicated only in minor infections (e.g.
tonsillitis) because of its relatively poor bioavailability, the need
for dosing four times a day, and its narrow antibacterial
spectrum.
N
S
H
N
O
C
O
CH2PhO
H
Penicillin VPenicillin V
(orally active)(orally active)
electronegative
oxygen

27. Sensitivity to β-Lactamases
• β-Lactamases are enzymes produced by penicillin-resistant
bacteria which can catalyze the reaction - the same ring opening
and de-activation of penicillin.
• The problem of β-lactamases became critical in 1960 when the
widespread use of penicillin G led to an alarming increase of S.
aureus infections.
• These problem strains had gained the lactamase enzyme and had
thus gained resistance to the drug.
• At one point, 80% of all S. aureus infections in hospitals were due to
virulent, penicillin-resistant strains.
• Alarmingly, these strains were also resistant to all other available
antibiotics.
• Fortunately, a solution to the problem was just around the corner -
the design of penicillinase-resistant penicillins.
• How then does one tackle a problem of this sort?

28. Tackling the problem of β lactamase sensitivity
• The strategy is to block the penicillin from reaching the penicillinase
active site.
• One way of doing that is to place a bulky group on the side-chain.
This bulky group can then act as a 'shield' to ward off the
penicillinase and therefore prevent binding.
• Several analogues were made and the strategy was found to work.
However, If the side-chain was made too bulky, then the steric shield
also prevented the penicillin from attacking the enzyme responsible
for bacterial cell wall synthesis.
• Therefore, a great deal of work had to be done to find the “ideal
shield” which would be large enough to ward off the lactamase
enzyme, but would be small enough to allow the penicillin to do its
duty.
• The fact that it is the β-lactam ring which is interacting with both
enzymes highlights the difficulty in finding the ideal 'shield'.
• Fortunately, 'shields' were found which could make that
discrimination.

29.  Methicillin was the first semisynthetic penicillin unaffected by penicillinase
developed to treat the resistant S. aureus infections.
 The principle of the stearic shield can be seen by the presence of two ortho-
methoxy groups on the aromatic ring.
No electron withdrawing group on the side-chain and therefore acid sensitive,
and so has to be injected.
 But Methicillin is by not an ideal drug
 Less active than penicillin G (1/50th
) against penicillin G sensitive organisms
Poor activity against some streptococci, and it is inactive against Gram negative
bacteria
Methicillin- Ist β-lactamase resistant penicilin

30.  Modification in the structure was further made
 Incorporating into the side-chain a five-membered heterocycle which was
designed to act as a steric shield and also to be electron withdrawing.
 These compounds (oxacillin, cloxacillin, and flucloxacillin) are acid-resistant
and penicillinase-resistant, and are also useful against Staph. aureus
infections.
 The only difference between the above three compounds is the type of
halogen substitution on the aromatic ring.
 Stable in gastric acid so may be administered orally or parentrally
 Rapid and effective absorption
The influence of these groups was pharmacodynamic e.g. cloxacillin is better
absorbed through the gut than oxacillin whereas flucloxacillin is less bound to
plasma protein leading to higher levels of free drug in blood.
 Nafcillin its absorption is erratic.
 Nafcillin, Flucloxacillin used in mastitis as intramammary preparation.
Other β-lactamase resistant penicillins
Oxacilin, Cloxacillin, Dicloxacilin, Flucloxacillin, Nafcillin
Dicloxacillin R= cl, R’= cl

31. β lactamase resistant penicillins
• These three drugs were less active than original penicillins when
used against bacteria with out penicillinase enzymes.
• They were also inactive against Gram-negative bacteria.
• So, Acid-resistant penicillins should be the first choice against an
infection but if bacteria is penicillinase producer, therapy would be
changed to a penicillinase resistant penicillin.

32. Anti-staphylococcal penicillins
Isoxazolyl penicillins- Oxacillin,Cloxacillin, Dicloxacillin, Flucloxacillin
Others- Methicillin, Nafcillin
 These semisynthetic penicillins are indicated
for infection by beta-lactamase-producing
staphylococci, although penicillin-susceptible
strains of streptococci and pneumococci are also
susceptible.
 Listeria, enterococci and methicillin-resistant
strains (MRS) of staphylococci are resistant.
 An isoxazolyl penicillin (cloxacillin,
dicloxacillin, or oxacillin), 250–500 mg orally
every 4 to 6 h (25 mg/kg/d for children), is
suitable for the treatment of mild to moderate
localized staphylococcal infections.
 All are relatively acid-stable but food
interferes with their absorption, and the drugs
should be administered 1 h before or after
meals.

33. Reasons for Narrow spectrum
Penicillins show poor activity against Gram negative bacteria due to several
reasons
• Permeability barrier: Penicillins can not invade the Gram –ve bacterial cell wall
due to outer membrane. Outer membrane may have overall – or + charge
depending on the type of lipid present
Phosphatidyl glycerol – Overall anionic charge (-)
Lysylphosphatidyl glycerol – Overall cationic charge (+)
 Since Penicillin has a free carboxylic acid which if ionized would be repelled
from the gram negative cell membrane (by the first type).
 Alternatively, the fatty portion of the coating may act as a barrier to the polar
hydrophilic penicillin molecule.
 The only way in which penicillin can negotiate such a barrier is through protein
channels in the outer coating. Unfortunately, most of these are usually closed.
• High levels of transpeptidase produced: In some Gram – bacteria a lot of
transpeptidase is produced, and penicillin is uncapable of inactivating all the
enzyme.
• Modification of transpeptidse: A mutation may allow the bacterium to
produce a transpeptidase which is not antagonized by penicillin.
• Presence of β-lactamase: Present between cell wall and outer membrane and
inactivates penicillin.
• Transfer of β-lactamase enzyme: by conjugation
• Efflux mechanisms: Efflux mechanisms pumping penicillin out of periplasmic
space

34. Tackling the problem of narrow spectrum
The search for the broad spectrum antibiotic has been one of trial and error
making a huge variety of analogues by making changes in the side chain.
 Hydrophobic groups on the side chain (penicillin G) favour activity against
G + bacteria but result in poor activity against G -.
 If hydrophobic character in increased, no effect on G+ but G- activity further
drops.
 Hydrophilic groups on the side chain either have little effect on G+ activity
(penicillin T) or cause reduce activity (penicillin N) however, they favour
activity against G - bacteria.
 Enhancement of the G- activity is highest if hydrophilic group (NH2, OH,
COOH) is attached to carbon, alpha to the carbonyl group on the side chain.
 These penicillins having useful activity against both G+ and G- bacteria are
called “Broad Spectrum Antibiotics”.
 There are two classes of broad spectrum penicillins and both have alpha-
hydrophilic group, but in one class, the hydrophilic group is an amino
function (e.g. ampicillin or amoxycillin) while in other the hydrophilic group
is as an acid (e.g. carbenicillin).

35. Class I Broad-spectrum antibiotics- Aminopenicillins
Ampicillin and Amoxycillin
• Ampicillin is the second most used penicillin in medical practice.
• Amoxycillin differs merely in having a phenolic group.
• It has similar properties, but is better absorbed through the gut wall.
Properties:
• Active against Gram-positive bacteria and also against Gram-negative
bacteria which do not produce penicillinase.
• Acid-resistant due to the NH2 group, and is therefore orally active.
• Non-toxic.
• Oral and parentral preparations available.
• Sensitive to penicillinase (no 'shield').
• Antibacterial Spectrum: Streptococcus pneumoniae, H. influenzae,
Streptococcus pyogenes
• UTI: E. coli, Streptococcus, Proteus
• Salmonella, Shigella, Listeria
• Inactive against Pseudomonas aeruginosa (a particularly resistant species).
• Can cause diarrhoea due to poor absorption through the gut wall leading to
disruption of gut flora.

36. • The poor absorption from the gut is due to dipolar nature (one free
amino and one carboxyl group). The poor absorption problem can
be solved by using the prodrug where one of the polar moiety is
masked by a protecting group.
• This protecting group is removed metabolically ones the prodrug
has been absorbed from the gut wall.
Properties
Increased cell membrane permeability
Polar carboxylic acid group is masked by the ester
Ester is metabolised in the body by esterases to give the free drug

37.  The aminopenicillins have identical spectrum and activity,
but amoxicillin is better absorbed orally (70–90%).
 They are effective against streptococci, enterococci, and
some Gram-negative organisms (including H. pylori) but
have variable activity against staphylococci and are
ineffective against P. aeruginosa.
 Ampicillin (but not amoxicillin) is effective for shigellosis.
 Ampicillin, at dosages of 4–12 g/d i.v., is useful for treating
serious infections caused by penicillin-susceptible
organisms, including anaerobes, enterococci, L.
monocytogenes, and beta-lactamase-negative strains of
Gram-negative cocci and bacilli such as E. coli, and
salmonella species. Non-beta-lactamase-producing strains
of H. influenzae are generally susceptible.
 Many Gram-negative species produce beta-lactamases and
are resistant.
 Amoxicillin, 500 mg 3 times daily, is equivalent to the same
amount of ampicillin given four times daily.
 These drugs are given orally to treat urinary tract infections,
sinusitis, otitis, and lower respiratory tract infections.
 Aminopenicillins are the most active of the oral beta-
lactams against penicillin-resistant pneumococci and are
the preferred beta-lactams for treating infections
suspected to be caused by these resistant strains.
Aminopenicillins: Amoxicillin and Ampicillin

38. Class II Broad-spectrum antibiotics- Carboxypenicillins
Carbenicillin, Ticarcillin - Antipseudomonal drug
• Carbenicillin has an activity against a wider range of Gram-negative bacteria
than ampicillin.
• It is resistant to most penicillinases and is also active against the stubborn
Pseudomonas aeruginosa.
• Carbenicillin, the very first antipseudomonal carboxypenicillin, is obsolete.
There are more active, better tolerated alternatives.
• A carboxypenicillin with activity similar to that of carbenicillin is Ticarcillin. It
is less active than ampicillin against enterococci.
• It shows a marked reduction in activity against Gram-positive bacteria
• It is also acid sensitive and has to be injected.
• In general, carbenicillin is used against penicillin-resistant Gram-negative
bacteria.
• The broad activity against Gram-negative bacteria is due to the hydrophilic
acid group (ionized at pH 7) on the side-chain.
• Can be given in combination with β-lactamase inhibitors as clavulanic acid,
sulbactam, tazobactam.
• Carfecillin is a prodrug of carbenicillin with improved absorption from gut.

39. Class III Broad-spectrum antibiotics- Ureidopenicillins
Urea group at the α-position - Azlocillin, Mezlocillin, Piperacillin
• Administered by injection
• Generally more active than carboxypenicillins agaiinst streptococci and
Haemophilus species
• The ureidopenicillins, piperacillin, mezlocillin and azlocillin, are also active
against selected Gram-negative bacilli, such as K. pneumoniae.
• Generally have similar activity against Gram -ve aerobic rods
• Generally more active against other Gram -ve bacteria
• Azlocillin is effective against P. aeruginosa
• Piperacillin can be administered alongside tazobactam.
• Because of the propensity of P. aeruginosa to develop resistance, an
antipseudomonal penicillin is frequently used in combination with an
aminoglycoside or fluoroquinolone for pseudomonal infections outside the
urinary tract.
Azlocillin
Mezlocillin
Piperacillin
S
N
Me
Me
O
HH
CO2H
H
N
O
NH
O
R2N
HN
N
O
N
N
O
MeO2S
N N
OO
Et

40. BacterialBacterial Resistance to PenicillinsResistance to Penicillins
Various Factors are responsible.Various Factors are responsible.
• Permeability: Gram -ve bacteria have a lipopolysaccharide outer
membrane preventing access to the cell wall. Penicillins can only
cross via porins in the outer membrane. Porins usually allow small
hydrophilic molecules such as zwitterions to cross. ThereforeTherefore
concentration of antibiotics in target site is too low because ofconcentration of antibiotics in target site is too low because of porinporin
areare usually closed.usually closed.
• High levels of transpeptidase: Bacteria may produce igh levels of
transpeptidase enzyme.
• Alteration in the transpeptidase (PBPs): The transpeptidase
enzyme may have a low affinity for penicillins (e.g. PBP 2a for S.
aureus)
• Production of β-lactamases: Presence of β-lactamases degrades
the penicillins
• Concentration of β -lactamases in periplasmic space
•Mutations
• Acquiring β-lactamases production capability: Transfer of b-
lactamases between strains
• Efflux mechanisms: Efflux mechanisms pumping penicillin out of
periplasmic space

41.  The main hazard with the penicillins
is allergic reaction.
 These include itching, rashes
(eczematous or urticarial), fever and
angioedema.
 Rarely (about 1 in 10,000) there is
anaphylactic shock which can be fatal
(about 1 in 50 000 – 100 000 treatment
courses).
 Allergies are least likely when
penicillins are given orally and most
likely with local application.
 Metabolic opening of the β-lactam
ring creates a highly reactive
penicilloyl group which polymerizes
and binds with tissue proteins to form
the major antigenic determinant.
 The anaphylactic reaction involves
specific IgE antibodies which can be
detected in the plasma of susceptible
persons.
Adverse effects
Amoxicillin: rash 11 hours after administration

42. There is cross-allergy between all the various forms of penicillin, probably
due in part to their common structure, and in part to the degradation products
common to them all.
 Partial cross-allergy exists between penicillins and cephalosporins (10-15%)
which is of particular concern when the reaction to either group of
antimicrobials has been angioedema or anaphylactic shock.
 Carbapenems and the monobactams apparently have a much lower risk of
cross-reactivity.
 When the history of allergy is not clear and it is necessary to prescribe a
penicillin, the presence of of IgE antibodies in serum is a useful indicator of
reactions mediated by these antibodies, i.e. immediate (type 1) reactions.
 Additionally, an intradermal test for allergy may be performed; appearance
of a flare and wheal reaction indicates a positive response.
 Only about 10% of patients with a history of “penicillin allergy” respond
positively.

43.  Other (no-nallergic) adverse effects include diarrhoea due to alteration in
normal intestinal flora which may progress to Clostridium difficile associated
diarrhoea.
 Neutropenia is a risk if penicillins or other β-lactam antibiotics are used in
high dose and usually for a period of longer than 10 days.
 Rarely penicillins cause anaemia, sometimes haemolytic, and
thrombocytopenia or interstitial nephritis.
 Penicillins are presented as their sodium or potassium salts. Physicians should
be aware of this unexpected source of sodium or potassium, especially in
patients with renal or cardiac disease.
 Extremely high plasma penicillin concentrations cause convulsions.
 Co-amoxiclav, flucloxacillin or oxacillin given in high doses for prolonged
periods in the elderly may cause hepatic toxicity.

44. Adverse reactionsAdverse reactions
 The toxicity of penicillins is very low.The toxicity of penicillins is very low.
 Allergic reactions: drug rash, dermatitis, serum sickness,Allergic reactions: drug rash, dermatitis, serum sickness,
anaphylactic shockanaphylactic shock and hemolytic anemia.and hemolytic anemia.
 Before using this kind of drugs, the medical institution mustBefore using this kind of drugs, the medical institution must
prepare drugs for treatment of anaphylactic shock.prepare drugs for treatment of anaphylactic shock.
 Jarisch-Herxheimer reaction:Jarisch-Herxheimer reaction: after penicillin treatment ofafter penicillin treatment of
spirochetespirochete infection, some patients show symptoms of fever,infection, some patients show symptoms of fever,
chills, laryngeal pain, headache and tachycardia. It is sometimeschills, laryngeal pain, headache and tachycardia. It is sometimes
life threatening.life threatening. This reaction is due to the large number of killingThis reaction is due to the large number of killing
of spirochete, so the dose at the beginning should not be high.of spirochete, so the dose at the beginning should not be high.

45. HYPERSENSITIVITY REACTION TO β-LACTAMS
1. Antigenic properties reside in β-lactam ring structure.
--i.e. Cross-reactivity between penicillins and cephalosporins.
2. Skin-test materials are of two types: (a) MAJOR DETERMINANTS; (b) MINOR
DETERMINANTS.
(a) Major Determinants: Benzylpenicilloyl-polylysine (penicilloyl-
polylysine, PPL or pre-pen), available commercially. Patients showing
positive tests to major determinants are likely to react to therapeutic doses
of β-lactams and more likely to manifest slow onset type reactions.
(b) Minor Determinants: Penicillin G and some of its hydrolyzates.
Usually penicillin G is used for skin test. Positive tests indicate a high-
risk for an immediate, anaphylactic reaction.
**Even negative tests to either or both determinants do not exclude the
possibility of serious, immediate type reactions.
**The major and minor refer to the frequency of reaction and not the
seriousness of reaction (i.e. patients having positive reaction to minor
determinants are likely to have more serious reactions)

46. SOME PRECAUTIONS FOR POTENTIAL β-LACTAM ALLERGY
1. Always ask patients about previous allergic reactions
2. Patients should be kept in the office for at least 30 min after an
injection of β-lactam.
3. It is prudent to give a skin test with penicillin G 30 min before the
injection of procaine or benzathine penicillin.
4. Always have a syringe of epinephrine on hand.
5. Perform skin test with PPL and penicillin G for high-risk patient.
6. In the presence of positive test to skin test, preferably β-lactams not
be used. If used, be prepared for an emergency situation.

47. Summary - PenicillinsSummary - Penicillins

48. Summary…..Summary…..

49. Thanks
Acknowledgement: All the material/presentations available
online on the subject are duly acknowledged.
Disclaimer: The author bear no responsibility with regard to the
source and authenticity of the content.