Penicillin

(Part 2)

By: Dr. Ahmad Abulshamat

 Pharmacokinetics
Oral absorption

 Acid-labile compounds (e.g. penicillin G, methicillin,

and anti-pseudomonal penicillins) are poorly
absorbed.

 Acid-stable compounds (e.g. Amoxicillin vs Ampicillin)

can have major differences in oral absorption. Where
ampicillin is only partially absorbed (30% to 60%), and
food decreases absorption, amoxicillin is almost totally
absorbed.
 Protein binding:

• Penicillins are bound to serum proteins in varying

degrees, ranging from 17% for the aminopenicillins
to 97% for dicloxacillin , and the major protein to
which they bind is albumin.

• Only unbound drug exerts antibacterial activity.

However, protein binding is a reversible process,
and it is possible for bound penicillin to be released
and then to kill bacteria in tissue or in the
bloodstream.
 Half-life —Penicillins are cleared by glomerular
filtration, and they also are rapidly secreted into
urine by renal tubular cells, and hence they have a
short half-life, ranging from less than 30 minutes
for penicillin to 70 minutes for carbenicillin.

  All of the parenteral agents are usually

administered on an every 4-6 hour basis when
treating serious systemic infections in patients with
normal renal function.
• Levels in different bodily fluids — All of the
penicillins achieve therapeutic levels in pleural,
pericardial, peritoneal and synovial fluids, as well as
urine. All achieve levels in bile higher than
corresponding serum levels (assuming the absence
of obstruction); nafcillin, ampicillin
and piperacillin achieve very high levels in bile.

• The penicillins penetrate the CSF poorly in the

absence of inflammation but achieve therapeutic
levels in patients with meningitis who are given
meningeal doses of parenteral therapy 
 Dosing & adjustments
• The major mechanism by which most of these drugs are
removed from the body is by excretion as intact
molecules via the kidney.

• Reduction in renal function must be taken into account in

the administration of certain penicillins

• Ampicillin and piperacillin, require dose modification

predominantly when the (GFR) is below 10 mL/min.
Ticarcillin requires dose modification when the GFR is
below 50 mL/min.
 Side effects
• The most important adverse effects of the penicillins are
hypersensitivity reactions, which range in severity from
rash to anaphylaxis.

• Penicillins can act as haptens to combine with proteins

contaminating the solution or with human proteins after
the penicillin has been administered to humans.

• Haptens are relatively small molecules that elicit an

immune response only when attached to a large carrier
such as a protein.
• Penicilloyl and penicillanic acid derivatives are
the major determinants of penicillin allergy.

• The penicilloyl determinant, which is produced

through opening of the β-lactam ring, thereby
allowing amide linkage to body proteins is the most
important antigenic component

• Penicillanic acid and its derivatives are produced

when reconstituted penicillins break down in
solution from acidity or temperature elevation
• Hoigne's syndrome is a pseudoanaphylactic or
pseudoallergic reaction that occurs after intramuscular
administration of penicillin G procaine or benzathine.
These are embolic toxic (psychiatric) reactions possibly due
to vascular occlusion by large crystals of the penicillin
salts.

• Patients develop mental confusion, visual and auditory

hallucinations, perceived changes of body shape, swelling
of the tongue and a fear of impending death.

• Hoigne's syndrome must be differentiated from authentic

anaphylactic shock due to penicillin. This distinction
allows treatment to be continued in Hoigne's syndrome,
whereas it is contraindicated in anaphylactic shock.
• Another allergic reaction is that of allergic vasculitis with
the development of cutaneous and visceral lesions similar
to that found with peri-arteritis nodosa. This reaction is
extremely rare

• Abnormalities in liver function test results such as

elevation of the alkaline phosphatase and aminotransferase
(transaminase) levels have been reported, most often after
the use of oxacillin and flucloxacillin.

• Human leukocyte antigen (HLA)-B*5701 genotype has

been identified as a major determinant of this reaction by
flucloxacillin. Major hepatic injury is uncommon.
 ß-lactamase inhibitors
• Beta-lactamases are a family of enzymes involved
in bacterial resistance to beta-lactam antibiotics.
They act by breaking the beta-lactam ring that
allows penicillin like antibiotics to work.

• Strategies for combating this form of resistance

have included the development of new beta-lactam
antibiotics that are more resistant to cleavage
through developing the class of enzyme inhibitors
called beta-lactamase inhibitors.
Beta-lactamase producing bacteria
• Staphylococcus
MRSA(Methicillin-resistant Staphylococcus aureus)
• Enterobacteriaceae:
Klebsiella pneumoniae
Citrobacter
Proteus vulgaris
Morganella
Salmonella
Shigella
Escherichia coli
• Haemophilus influenzae
• Neisseria gonorrhoeae
• Pseudomonas aeruginosa
• Mycobacterium tuberculosis
• β-lactamase inhibitors with a β-lactam core:

 Clavulanic acid or clavulanate: usually combined

with amoxicillin (Augmentin) or ticarcillin (Timentin)

Sulbactam: usually combined with ampicillin (Unasyn)

or cefoperazone (Sulperazon)

Tazobactam: usually combined with piperacillin (Zosyn

and Tazocin)

N.B: This group covers B-lactamase class A

• β-lactamase inhibitors without a β-lactam core:

Avibactam, approved in combination with ceftazidime

(Avycaz), currently undergoing clinical trials for
combination with ceftaroline

Relebactam, used in combination

with imipenem/cilastatin (Recarbrio)

Vaborbactam, used in combination

with meropenem (Vabomere)

N.B: this group covers class A, C and some of class D

 Research
• Boronic acid derivatives are currently under vast and
extensive research as novel active site inhibitors for beta-
lactamases because they contain a site that mimics the
transition state that beta-lactams go through when
undergoing hydrolysis via beta-lactamases.

• They have been found generally to fit well into the active
site of many beta-lactamases and have the convenient
property of being unable to be hydrolysed, and therefore
rendered useless.
• This is a favorable drug design over many clinically used
competing agents, because most of them, such as
clavulanic acid, become hydrolysed, and are therefore only
useful for a finite period of time. This generally causes the
need for a higher concentration of competitive inhibitor
than would be necessary in an unhydrolyzable inhibitor

• Different boronic acid derivatives have the potential to be

tailored to the many different isoforms of beta-lactamases,
and therefore have the potential to reestablish potency of
beta-lactam antibiotics
Thank
you