Download CELL WALL SYNTHESIS INHIBITORS

LEARNING OBJECTIVES
• Describe the structural relationship of the penicillin
molecule with antimicrobial activity.
• Explain the mechanism of action of b-lactam
antibiotics.
• Describe the pharmacokinetic properties of penicillins.
• Discuss primary therapeutic indications for penicillin G.
• Explain the major side effects of penicillins.
• Describe the indications for broad-spectrum penicillins.
• List the penicillinase-resistant penicillins.
• List the combinations of inhibitors of b-lactamase with
Penicillins.
CELL WALL SYNTHESIS INHIBITORS
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INHIBITION OF CELL WALL SYNTHESIS:
In contrast to mammalian cell, bacterial cell possesses a rigid outer layer, the cell wall;
which completely surrounds the cell membrane.
The cell wall consists of cross linkage of peptidoglycans, which forms much thicker layer
in gram positive than gram negative bacteria.
Bacteria possess high internal osmotic pressure than the mammalian body fluids
The intact cell wall prevent movement of mammalian body fluids to inside the bacterium
and is responsible for maintaining the shape of bacterium.
If the cell wall has been damaged, movement of water into the cell will be followed by
swelling, extrusion of the cellular contents through weak areas of the cell wall and cell
lysis.
Penicillin and cephalosporins are inhibitors of cell wall synthesis.
The intact cell wall prevent movement of mammalian body fluids to inside the bacterium
and is responsible for maintaining the shape of bacterium.
If the cell wall has been damaged, movement of water into the cell will be followed by
swelling, extrusion of the cellular contents through weak areas of the cell wall and cell
lysis.
Penicillin and cephalosporins are inhibitors of cell wall synthesis.
CLASSIFICATION
β LACTAM ANTIBIOTICS:
• PENICILLINS
• CEPHALOSPORINS
• MONOBACTAMS
• AZTREONAM
• IMIPENEM
OTHER COMPOUNDS:
• VANCOMYCIN
• BACITRACIN
• FOSFOMYCIN
PENICILLINS
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Penicillins are highly effective antibiotics with high therapeutic index and wide margin of
safety.
• Penicillin is derived from mould penicillum crysogenum.
• 6-amino penicillanic acid (6APA) basic nucleus of all penicillins is composed of
thiazolidine ring fused to β lactam ring.
An intact nucleus with
side chain is essential for
the antimicrobial
action of penicillin.
NATURAL:
PENICILLIN- G PENICILLIN- V
SEMISYNTHETIC PENICILLINS:
ACID RESISTANT:
AMPICILLIN
AMOXICILLIN
OXACILLIN
CLOXACILLIN
DICLOXACILLIN
MECHANISM OF ACTION
• Bacterial cell wall consist of complex cross linked polymer,
peptidoglycan, consisting of polypeptides and polysaccharides.
• Cross linking of polymers is catalyzed by the enzyme
transpeptidase.
• Penicillin binds with penicillin binding proteins (PBPs), these
PBPs are the enzymes required for cross linking of polymers.
• Penicillins block transpeptidation (cross-linking) during the final
step of cell wall synthesis.
• Cell wall synthesis inhibitors are highly effective against rapidly
growing bacteria, they are less effective against mature bacteria.
• Fluid moves through weak cell wall and to cellular swelling,
extrusion of the cellular contents through weak areas of the cell
wall and cell lysis.
RESISTANCE
♦ Lack of peptidoglycan cell wall
♦ Impermeability of cell wall to penicillin
♦ Presence of enzyme  Lactamase
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♦ Increased  Lactamase activity
♦ Decreased permeability to drug
♦ Alteration in PBPs
ANTIMICROBIAL SPECTRUM
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Penicillin G & V are narrow spectrum penicillins, they are effective mainly against
Gram-positive organisms, anaerobes and spirochetes.
Penicillin G is also effective against meningococci & gonococci.
Extended spectrum penicillins are also effective against Gram-negative bacilli.
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PHARMACOKINETICS
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On oral administration penicillin G is inactivated in stomach by gastric acid,
penicillin V is effective when given orally.
Only 30% of Penicillin G is absorbed from gut therefore it is given I/M and I/V.
Ampicillin, Amoxicillin, Cloxacillin, Oxacillin are absorbed from gut and are
effective orally.
Food interferes with absorption of most of acid resistant penicillins except
amoxicillin, they should be given 30 minutes before or 2–3 hours after meals.
Amoxicillin is rapidly & completely absorbed from gut.
After absorption penicillins are widely distributed in the body, but penetration into
the eye, prostate and CNS is poor.
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• Normally penicillins do not cross BBB but in presence of
meningitis adequate concentrations are found in CSF.
• All penicillins crosses placenta, except Ticarcillin none of other
penicillins is harmful to fetus, Ticarcillin is C/I in pregnancy.
• Penicillins are the drugs of choice in susceptible infections
during pregnancy.
• 60% of plasma penicillin is bound to plasma proteins.
Only small amounts of penicillins are metabolized they are mostly excreted
unchanged in urine mainly by tubular secretion (80–85%).
• Probenecid decreases tubular secretion of penicillins & prolongs the halflife & duration of action of penicillins.
• Nafcillin is the penicillin that is excreted in bile, small amounts of ampicillin
are also found in bile.
• Procaine penicillin G and Benzathine penicillin G is given by deep I/M
injection, serve as depot (Repository) forms.
• Major purpose of repository forms is to maintain constant levels of
penicillins for prolonged periods.
• Repository forms are not suitable for acute infections; they are only used
for prophylaxis of infections e.g. rheumatic fever.
• Half-life of penicillin-G is 30 minutes, Ampicillin is about 1–1.5 hours,
Amoxicillin is about 1.5–2 hours.
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THERAPEUTIC USES
• Benzyl penicillin is highly effective antimicrobial agent, against susceptible
bacteria.
• It is the drug of choice for infections caused by streptococci,
meningococci, treponema pallidum, clostridia.
• Benzathine penicillin is used for prophylaxis of rheumatic fever.
• Methicillin, Oxacillin, Cloxacillin, Dicloxacillin are effective against βlactamase producing staphylococci.
• Amoxicillin & Ampicillin with β-lactamase inhibitors (Clavulanic acid,
tazobactum, sulbactum) are used for infections produced by β-lactamase
producing staphylococci.
• They are also effective against Gram Negative bacteria.
• Amoxicillins are used for the treatment of UTI, sinusitis, pharyngitis, otitis media,
pneumonia.
• Carbenicillin, Ticarcillin, Azlocillin Pipercillin are effective against pseudomonas.
• Penicillins are the drugs of choice for treatment of gonorrhea, syphilis, diphtheria,
tetanus.
Penicillin is used in prophylaxis of:
• Rheumatic fever.
• Subacute bacterial endocarditis.
• Gonorrhea and syphilis.
• Prior to surgery.
• Recurrent lymphangitis.
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Amoxicillins are used for the treatment of UTI, sinusitis, pharyngitis, otitis media,
pneumonia.
Carbenicillin, Ticarcillin, Azlocillin Pipercillin are effective against pseudomonas.
Penicillins are the drugs of choice for treatment of gonorrhea, syphilis, diphtheria,
tetanus.
Penicillin is used in prophylaxis of:
• Rheumatic fever.
• Subacute bacterial endocarditis.
• Gonorrhea and syphilis.
• Prior to surgery.
• Recurrent lymphangitis.
SIDE EFFECTS
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HYPERSENSITIVITY (ALLERGIC) REACTIONS
DIARRHEA
NEUROTOXICITY
CATION TOXICITY
ACUTE INTERSTITIAL NEPHRITIS
PLATELET DYSFUNCTION
HYPERSENSITIVITY (ALLERGIC) REACTIONS:
• It is the most important side effect of penicillins. reaction to some extent
can be avoided by doing subcutaneous sensitivity test.
• Penicilloic acid formed during metabolism reacts with proteins and
activates immune reaction.
• Hypersensitivity reactions range from urticaria to angioedema (marked
swelling of lips, tongue and periorbital region) and anaphylaxis and are
seen in nearly 5% of the patients receiving penicillins; severe
anaphylactic reactions are seen in 0.005% of the patients receiving
penicillins.
HYPERSENSITIVITY (ALLERGIC) REACTIONS:
• Frequency and severity of allergic reactions are governed by
route of administration & type of penicillin derivative used.
• Topical application is most likely to produce sensitization; most
severe forms of allergic reactions are caused by parenteral
administration of penicillins, but oral administration & even
intradermal injection of minute amounts have produced serious
allergic reactions.
HYPERSENSITIVITY (ALLERGIC) REACTIONS:
• Cross sensitivity among  lactam antibiotics occur.
• Ampicillin has highest incidence of skin rash and procaine
penicillin has highest incidence of allergic reactions among the
penicillins.
• Maculopopular rash is commonly seen with ampicillin, this is
extremely common in-patients with infectious mononucleosis.
ACUTE HYPERSENSITIVITY REACTIONS:
• Anaphylactic shock occur rapidly within 30 minutes of penicillin
administration. It is characterized by urticaria, angioedema,
bronchoconstriction & shock.
• Death can occur if it is not treated immediately.
• Epinephrine, corticosteroids and antihistamines are used to
treat anaphylactic shock.
DELAYED HYPERSENSITIVITY REACTIONS:
• Take more than 2 days to develop, approximately 80 –90% of all allergic
reactions occurring with penicillins are of this type.
• These reactions are manifested by skin rashes (bullous eruptions),
generally these are mild and reversible.
• These can also be seen in oral cavity as acute glossitis, brown or black
tongue, loss of buccal mucosa after topical use of penicillins in oral cavity
or following systemic use of penicillins.
• Allergic reactions to penicillins are relatively unpredictable.
DELAYED HYPERSENSITIVITY REACTIONS:
• Although patients who have experienced an allergic reaction to penicillin
is considered allergic unless proved otherwise; challenge tests have
shown that 75% of such individuals lose their sensitivity to penicillin with
time.
• On the other hand patients who have taken penicillins for prolonged
periods without any problem may suddenly develop an allergic reaction
ranging from mild to severe form.
• Patients with personal or familial history of allergy to food, dust, pollens
exhibit higher frequency of allergy than the normal individuals.
DIARRHEA:
• This occurs with agents that are incompletely absorbed from
gut. To some extent diarrhea can be reduced by administrating
drug ½ -1 hour before meals.
NEUROTOXICITY:
• This complication is commonly seen with procaine penicillin and
is mainly due to procaine. It is also common when penicillins are
given intrathecally, epileptic patients are at the risk.
CATION TOXICITY:
• Penicillins are usually administered as sodium and potassium
salts, which may produce cation toxicity.
• This can be avoided by using potent agents, which limit the
dose of drug.
• Sodium toxicity precipitates CCF, and potassium toxicity
aggravate the cardiac arrhythmias.
• Cation toxicity occur with Carbenicillin and Ticarcillin.
METHICILLIN:
• Large doses may produce acute interstitial nephritis.
CARBENICILLIN AND TICARCILLIN:
• They produce platelet dysfunction and may increase bleeding tendencies.
Prolonged use of extended spectrum penicillins particularly by oral route
can produce super-infections.
Accidental I/V injection of repository preparation may result in severe
neurovascular damage and pulmonary infarction.
OTHER  LACTAM DRUGS:
MONOBACTAMS (AZTREONAM):
• It is monocyclic  lactam ring containing compound that is
resistant to  lactamase.
• It is effective against gram negative bacilli including
Pseudomonas aeroginosa.
• It has no activity against gram positive and anaerobic bacteria.
• It is a narrow spectrum antibiotic.
MECHANISM OF ACTION:
• Aztreonam binds with penicillin binding proteins and disrupt
bacterial cell wall synthesis.
SIDE EFFECTS:
• It is relatively non-toxic. It shows little cross sensitivity with other
 l a c ta m a n ti b i o ti c s b e c a u s e o f i ts l o w i m m u n o g e n i c p o te n ti a l .
Patients sensitive to penicillins tolerate aztreonam very well.
• Some times it produces skin rashes and phlebitis.
IMIPENEM:
• It is active against wide variety of bacteria, including many gram
negative, gram positive and anaerobic organisms.
• It is resistant to  lactamase but is degraded by
dihydropeptidases present in renal tubules, resulting in low
urinary levels of the drugs.
• Drug is usually given with cilastatin, a drug that prevents
degradation of Imipenem in renal tubules.
MECHANISM OF ACTION:
• It binds with PBPs and disrupts bacterial cell wall synthesis.
SIDE EFFECTS:
• Nausea, vomiting, diarrhea, skin rashes occur frequently.
• In high doses drug may produces seizures. Patients allergic to
penicillin show hypersensitivity reactions to imipenem.
 LACTAMASE INHIBITORS:
• Antimicrobial activity of  lactam antibiotics depends upon the
intact  lactam ring. Destruction of the ring by acids or 
lactamase (penicillinase), destroys the antimicrobial activity.
• Clavulinic acid, sulbactam and tazobactam contain  Lactam
ring, have very weak antimicrobial activity. However, they are
potent inhibitors of  lactamase. They protect the  lactam
antibiotics from the destruction by  lactamase and are often
given with penicillins.
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