By medical student:

Dnia Nizar
Kurdistan region

19/7/2018
Table 1 cell wall synthesis inhibitors
Antibiotic Mnemonic Examples
β-lactams When 2C? Cephalosporin
At PM. Carbapenem
Penicillin
Monobactam
(aztreonam)
Non β-lactams Vomiting Beside Vancomycin
the Car. Bacitracin
Cycloserine

Bacterial cell wall

Figure 1 bacterial cell wall

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• One peptidoglycan is a macropolymer, consists of
sugars (glycan) that are cross linked by peptide bonds,
thus the name peptidoglycan.
• Penicillin binding proteins (PBP) are located on the
cytoplasmic cell membrane, therefore penicillin have to
pass through peptidoglycan, in G+ bacteria it has many
pores which makes it easy for large antibiotics to reach
PBP.
• In G- bacteria there is an additional outer cell
membrane, which prevents large penicillin from
reaching PBP, but this membrane has small pores called
porins, small antibiotics can pass through.
• Endotoxins (lipopolysaccharides) are part of outer cell
membrane, thus only present in G- bacteria.
• β-lactamases of G+ bacteria pass through
peptidoglycan and can reach β-lactams when still away
from bacteria.
• β-lactamases of G- bacteria can’t pass through the outer
cell membrane, therefore they become concentrated in
the periplasmatic space, which makes G- bacteria more
resistant to β-lactams.

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 Mechanism of action of β-lactams
1. They bind and inhibit PBP which is important enzyme
for transpeptidation.
2. They bind and inhibit autolysin inhibitors.
▪ Autolysins are enzymes normally present in
bacterial cell wall, they break down cell wall
backbones, this function is important allowing the
bacteria to grow.
▪ Autolysin activity is controlled by autolysin
inhibitors, for the cell wall not to be destroyed
completely.
❖ β-lactams are more active on actively dividing bacteria.

The exact structure of peptidoglycan

• NAM & NAG are two modified monosaccharides,
linked with each other by glycosylation to make one
basic unit (glycan).
• Each NAM has peptide chain attached to it.
• NAM are activated by UDP attaching to it, then amino
acids can attach to UDP, the activated NAM will be
transported towards the cell membrane.
• Peptide chains are crosslinked by transpeptidation.
• NAM & NAG are charged non-lipid soluble; they can’t
pass through cell membrane.

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• Therefore, a protein called BPP is present on the cell
membrane to transport NAM & NAG to the other side
of the cell membrane.

Figure 2 peptidoglycan structure.

The importance of peptidoglycan

The newly formed bacteria don’t have concentrated
intracellular environment, but as they become mature
intracellular environment becomes concentrated which
attracts water by osmosis, peptidoglycan presence
prevents water absorption and protects bacterial cell from
swelling and blowing.

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Table 2 penicillin types
Narrow spectrum Wide spectrum
Natural penicillin Smart penicillin
• Penicillin G • Amoxicillin
• Penicillin V • Ampicillin
Extremely narrow Super smart penicillin
spectrum • Carbenicillin
• Methicillin • Ticarcillin
• Nafcillin • Piperacillin
• Oxacillin • Azlocillin
• Cloxacillin • Mezlocillin
• Dicloxacillin
• Flucloxacillin

❖ Narrow spectrum are large in size and can act on few

types of bacteria.
❖ Wide (extended) spectrum are small in size and can act
on many types of bacteria.
Natural spectrum:
➢ Moderately large due to their R group.
➢ Effective against G+ cocci and bacilli, some G- cocci
but ineffective against G- bacilli.
➢ Are not effective against staphylococcus that
produces β-lactamases.
➢ Despite widespread use and increase in resistance to
many types of bacteria, penicillin remains the drug
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 of choice for the treatment of gas gangrene
(Clostridium perfringens) and syphilis (Treponema
pallidum).
o One shot of penicillin cures syphilis.
o Normally treponema pallidum is present in oral
cavity between gum and teeth but it’s not
pathogenic.

Differences between penicillin G & V

Penicillin G
• Administered parenterally (IV), because gastric acid
(HCl) can destroy its β-lactam ring.

Figure 3 typical therapeutic applications of penicillin G.

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Penicillin V
• Administered orally because its R group can protect β-
lactam ring from gastric acid.
• Given to children suffering from pharyngitis that is
caused by group A (β hemolytic) streptococci, 3% of
population are genetically prone to rheumatic fever
after such pharyngitis.
• Also given to mixed aerobic and non-aerobic oral
infections.
• not used for treatment of bacteremia because of its poor
oral absorption.
Extremely narrow spectrum:
➢ They are very large due to their large R group.
➢ They are only effective against staphylococci even if
are producing β-lactamases, therefore called
antistaphylococcal penicillin.
➢ Their large R group protects β-lactam ring from β-
lactamases.
Methicillin:
➢ Not used in USA anymore because it can cause severe
interstitial nephritis.
➢ Used in laboratories to check sensitivity of
staphylococcus to certain drugs.

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 ➢ Some staphylococci changed the shape of PBP,
therefore are methicillin resistant.
Nafcillin:
➢ Can cause neutropenia and nephritis but not like
methicillin.
Dicloxacillin, flucloxacillin and cloxacillin are available in
oral form.

Wide (extended) spectrum penicillin:

Smart penicillin:
Typical therapeutic applications of smart penicillin;
• HELPS to clear Enterococci
o H- Haemophilus influenzae.
o E- Escherichia coli.
o L- Listeria monocytogenes.
➢ Is the only G+ bacteria that have some
endotoxin.
o P- proteus.
o S- salmonella.
• Their R group is small; therefore, they can pass through
porins, but that makes them susceptible to β-
lactamases.

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 • They should be administered with other medication that
will protect them from β-lactamases, like:
o Clavulanic acid.
o Sulbactam.
o Tazobactam.
The combination of;
Amoxicillin + clavulanic acid = Augmentin
Ampicillin + sulbactam = unasyn
Super smart penicillin:
➢ Their R group is smaller than that of smart penicillin,
which makes them effective against pseudomonas,
called (antipseudomonal penicillin), but at the same
time susceptible to β-lactamases.
o Pseudomonas aeruginosa producing green pus,
have very small or even lacks porins.
Therefore, administered in combinations:
Piperacillin + tazobactam = zosyn
Ticarcillin + clavulanic acid = timentin

Table 3 beta lactamase types.

β-lactamase Action
Penicillinase Destroys penicillin
Cephalosporinase Destroys cephalosporine
Extended spectrum Destroys both penicillin &
cephalosporin.

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 ❖ Its important to know which β-lactamase bacteria are
producing to give effective treatment.

Mechanism of action of non β-lactams

I. Vancomycin (van):
o Inhibits the enzymes involved in glycosylation.
II. Bacitracin (bas):
o Prevents BPP from transporting NAM & NAG to
outside.
III. Cycloserine (bicycle):
o Prevents amino acids from linking together,
therefore NAM will have a short peptide chain that
can’t undergo transpeptidation with the peptide
chain of the opposite NAM.

The difference between bactericidal and

bacteriostatic antibiotics:
Bactericidal: these antibiotics are able to kill and remove
bacteria even in the absence of intact immunity.
Some bactericidal antibiotics;
❖ Penicillin & Cephalosporin Are (Aminoglycosides)
Very (Vancomycin) cidal For (Fluoroquinolones)
Microbes (Metronidazole).

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Bacteriostatic: theses antibiotics are able to stop the growth
of bacteria but the removal of bacteria to be done by the
intact immunity.
❖ these antibiotics are contraindicated in
immunocompromised patients, because whenever the
patient stops taking them the bacteria will start to grow.

Bacterial mechanisms of resistant

Table 4 cells having natural resistance
Natural resistance The exact mechanism
Human cells Don’t have peptidoglycan.
Fungi
Virus
Pseudomonas Have very small porins.
Mycoplasma Don’t have cell wall.
Mycobacteria Have a very thick and waxy outer
layer of mycotic acid in their cell
wall.
Chlamydia Multiplies intracellularly (within
human cells).

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Acquired resistance:
1. β-lactamase production.
• If the genes encoding for β-lactamases were on the
bacterial chromosome, then only that bacterial
progeny will have β-lactamases.
• But if the genes were on the plasmid, then it can
be transmitted through sex pilus to other bacteria
by a process called conjugation which makes it
more dangerous.
2. spontaneous mutations in genes encoding for porins.
• The new porins will be tighter.
3. Efflux pumps.
4. Mutations in the genes encoding for PBP.
• E.g. methicillin resistant staphylococcus aureus
and enterococci.
• Streptococcus pneumoniae is not producing β-
lactamases, but its new strains are penicillin
resistant because of alterations in PBP.
5. Alteration in the enzymes involved in glycosylation.
• Makes bacteria vancomycin resistant.

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 Pharmacokinetics of penicillin
Table 5 penicillin routes of administration:
Only orally Only Depot form
parenterally
Penicillin V Ticarcillin Procaine +
penicillin G
Amoxicillin Piperacillin Benzathine +
penicillin G
Augmentin Carbenicillin
Indanyl Unasyn
carbenicillin

❖ Depot form, is very long acting because the drug is

released gradually, up to 3-4 weeks.
❖ The remaining penicillin can be given by both routes.
Absorption of penicillin:
• Amoxicillin is completely absorbed from GIT which
makes it ineffective against GIT infections.
• Ampicillin is not absorbed efficiently from GIT which
makes it effective against GIT infections.
• The absorption of extremely narrow spectrum
penicillin is affected by food; therefore, patient must
take it 1 hour before or 2 hours after eating.
• Penicillin can’t cross the blood brain barrier (BBB), but
when there is infection there, as a response endothelial
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 cells shrink and penicillin can cross BBB and become
effective against CNS infections.
o Same is true for bone infections.
• Penicillin can cross the placenta but it’s not teratogenic.
• Ampicillin can pass to the infant by lactation (not
common) and eliminate many of the infants GIT
bacteria resulting in severe diarrhea.
Elimination of penicillin:
Penicillin is eliminated by liver and kidney, mostly kidney;
• 10% eliminated by glomerular filtration.
• 90% eliminated by organic acid pumps on the cells
of proximal convoluted tubule.
o If we want to prolong the action of penicillin,
probenecid is to be given because it will be
eliminated by this organic acid pumps more
than penicillin, as a result penicillin remains
longer in circulation.
The combination of penicillin & aminoglycosides gives
more bactericidal effect;

o Aminoglycosides actively enter bacterial cell by

transporters on cell membrane, therefore when
given with penicillin which will destroy the cell
wall, aminoglycosides will be able to reach their
transporters easily.
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 o Penicillin are (–) charged while aminoglycosides
are (+) charged, therefore they should not be put
in one container in order to prevent the formation
of an insoluble ineffective complex.
Adverse effects of penicillin
Penicillin are very safe medications; blood levels are not
monitored.
1. Hypersensitivity reactions: penicilloic acid can bind
with our proteins, its then that the size of penicillin will
become larger and can initiate an immune response
(hapten), 5-10% of population are allergic to penicillin.

o Type I hypersensitivity:
➢ IgE are produced and they will bind with
their receptors on mast cells and basophils.
➢ Mast cells will be degranulated and the
following substances are released
(prostaglandin, leukotrienes, histamine,
neutrophil & eosinophil chemotactic factors,
protease).
➢ With prolonged activation of mast cells,
their genes will be activated and IL-1 and
TNF can be released as well.
➢ The most dangerous type I reaction is
(anaphylactic shock) but it is very rare.
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 ➢ To avoid type I hypersensitivity;
penicillin is injected intradermally to see if an
immediate reaction will happen in few
minutes (redness, swelling).
➢ Type I hypersensitivity will result in
decreased blood pressure, abdominal pain
rashes, bronchoconstriction.
➢ If a patient had type I hypersensitivity
with penicillin don’t give cephalosporin
because there is 5-10% chance of cross
reactivity with cephalosporin.

o Type II hypersensitivity:
➢ Penicillin binds with proteins (Ags) on
erythrocytes and alter these proteins, so the
immune system recognizes these altered
proteins as foreign; complement system is
activated in order to remove these altered
proteins or they are to be removed by
opsonization.
➢ This will result in a condition called
penicillin induced hemolytic anemia.

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o Type III hyper sensitivity: happens 7-12 days
after taking penicillin.
➢ Antibodies against penicillin are
produced; when they bind with penicillin;
complexes are formed and then deposited in
different sites:
▪ Vasculitis: when the complex deposit in
blood vessels, complement is activated
and neutrophils are recruited.
▪ Multiple small rashes: if deposited
under the skin.
▪ Glomerulonephritis: if deposited in
glomerular structure; proteinuria or
hematuria are signs in this case.
▪ Polyarthritis: if deposited in synovial
membrane.
▪ Pericarditis: if in pericardium.
▪ Pleuritis: if in pleura.
▪ Generalized lymphadenopathy: if in
lymph nodes.
➢ Can also cause angioedema.
➢ If a patient had type II or III
hypersensitivity, cephalosporins can be
given.

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2. Diarrhea & pseudomembranous colitis:
o Happen when extended spectrum penicillin are
given in high concentrations and for a long time
e.g. ampicillin.
o Normal flora of intestine diminishes and
pathogenic bacteria like clostridium difficile can
overgrow.
3. Nephritis
4. Neurotoxicity:
o Penicillin can disrupt cation channels on neurons;
neurons become stimulated due to influx of Na &
Ca, seizures might happen especially if the patient
has epilepsy tendency or kidney disorders.
o Penicillin are not given intrathecally.
5. Bleeding tendency:
o Penicillin may bind with proteins (receptors) on
surface of platelets and alter their shape; reducing
platelet aggregation, e.g. ticarcillin, carbenicillin.
6. Neutropenia:
o If penicillin bond with proteins on surface of
neutrophils or granulocyte precursors and altered
their shape; as mentioned before Abs can bind
with these proteins.

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 7. Cation toxicity:
o Penicillin are given as Na or K salts, if so much Na
is loaded and as we know Na attracts water, this
will result in dilutional hypokalemia.
o High potent penicillin should be given to patients
with congestive heart failure.

Everyone infected with EBV will develop a maculopapular

rash if ampicillin is given;

o Ampicillin related maculopapular rashes are not

hypersensitivity reactions but simple direct toxic
damage in skin, that will disappear within few
days even if penicillin is still given.

Reference;

Dr Najeeb video lectures.

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