Penicillin’s

Jagir R. Patel
Asst Professor
dept. Pharmacology
Cell wall synthesis inhibitors
 Some antimicrobial drugs selectively interfere with synthesis of the
bacterial “ cell wall”a structure that mammalian cells do not possess.
 The cell wall is composed of a polymer called peptidoglycan that consists
of glycan units joined to each other by peptide cross-links. To be
maximally effective, inhibitors of cell wall synthesis require actively
proliferating microorganisms; they have little or no effect on bacteria that
are not growing and dividing.
 All bacteria (except mycoplasma) lack sterols stabilizing their inner cell
membrane, thus rendering their inner cell membrane extremely vulnerable
to osmotic pressure however, these bacteria have a cell wall (again, except
mycoplasma) primarily consisting of peptidoglycan intimately surrounding
the outside of their inner cell membrane this peptidoglycan protects and
stabilizes the inner cell membrane, thus preventing the osmotic lysis of the
bacteria
 The peptidoglycan consists of 2 parts
 DISACCARIDE BACKBONE : - alternating molecules of N-
acetyl glucosamine (“NAG”) and N-acetyl muramic acid
(“NAM”)

 OLIGOPEPTIDE SIDE-CHAINS
 tetra- or pentapeptides of varying composition extending from
both sides of the disaccaride backbone covalently linked to
oligopeptide side-chains of adjacent disaccaride backbones

 Synthesis and remodeling of peptidoglycan is primarily done by

3 groups of enzymes residing within the peptidoglycan layer
(“penicillin-binding proteins”, “PBPs”)
 Penicillin binding proteins: they are bacterial enzymes involved
in synthesis of bacterial cell wall and maintenance of the
morphologic changes or lysis of susceptible bacteria.
 NAG-NAM POLYMERASE: covalently links alternating NAG and NAM
molecules to produce the disaccaride backbone

 TRANSPEPTIDASE: covalently links the oligopeptide side-chains of

adjacent disaccaride backbones

 AUTOLYSIN: many bacteria specially grm+ve produces “lysozyme”

,degrades parts of the disaccaride backbone during remodeling of
peptidoglycan is rapidly inactivated by autolysin inhibitors (“lysozyme
inhibitors”) upon completed remodeling

 PBPs are all involved in the final stages of the synthesis of peptidoglycan,
which is the major component of bacterial cell walls. Bacterial cell wall
synthesis is essential to growth, cell division (thus reproduction) and
maintaining the cellular structure in bacteria. Inhibition of PBPs leads to
irregularities in cell wall structure such as elongation, lesions, loss of
selective permeability, and eventual cell death and lysis
Cell wall synthesis inhibitors
Agents effecting cell wall

Beta lactams Others

Beta Lactam antibiotics
 Beta-lactam antibiotics are substances that contain a beta-lactam ring in
their chemical structure a beta-lactam ring is a 4-membered
hydrocarbon ring where 1 of the carbons has been exchanged with a
nitrogen, and the 2 hydrogen of the carbon adjacent to the nitrogen
have been exchanged with a double-bonded oxygen
 Classification of Penicillins
1. Natural penicillins : Penicillin G Penicillin V

2. Penicillinase resistant penicillins: Nafcillin, Oxacillin, Cloxacillin,

Dicloxacillin, Flucloxacilin,

3. Extended spectrum penicillins

 Aminopenicillins: 2nd generations: ampicillin, Bacampicillin, Amoxicillin,
Pivampicillins, Methampicillin, Talampicillin
 Carboxypenicilline: 3rd generations: Carbenicillin, Ticarcillin
 Uredopenicillins: 4th generations: Piperacillins, Mezlocilin, Azalocillin

 Beta lactamase inhibitors : clavulanic acid, Sulbactam, Tazobactam

 Others: Mecillinam, Sulbenicillin

Anti microbial spectrum
 It is narrow spectrum antibiotic limited to gram +ve bacteria

●
Streptococci, enterococci, pneumococci &

Cocci ●

●
Staph.aureus
Gram –ve cocci:
Neisseria gonorrhoeae and Neisseria meningitides

●
gram +ve:

Bacilli B.antharacis, Corynebacterium diphtheriae and

●

all Clostridia
●
( Clostridia tetani)
Mechanism of action
MOA
Mechanism of Resistance
 NATURAL RESISTANCE: due to the structure of the bacterial cell
envelope, 2 mechanisms
NO PEPTIDOGLYCAN in mycoplasma
does penicillin-binding proteins for
the betalactam antibiotics to attack

OUTER CELL MEMBRANE in gram-ve bacteria

- prohibits uptake of larger beta-lactam
antibiotics
- only smaller beta-lactam antibiotics
may pass through porins of the outer cell
membrane
 ACQUIRED RESISTANCE
 due to plasmid transfer and/or chromosomal mutations
 - 3 mechanisms
DECREASED UPTAKE • Due to decreased number of porins in the outer cell
membrane
• limits uptake of even the smaller beta-lactam antibiotics
• only in gram –ve bacteria (only gram – bacteria have
outer cell membrane)

DECREASED AFFINITY • Due to structural alterations of the penicillin binding

proteins

INCREASED • due to the presence of beta-lactamases

INACTIVATION (“penicillinases”)beta-lactamases cleave the beta-lactam
ring between the nitrogen and the oxygen-bound carbon,
thus inactivating the beta-lactam antibiotics
Most gram –ve bacteria (and many gram + bacteria) have
beta-lactamases
Penicillin G
 It is also called as “benzyl penicillin”
 PK: administered orally ( degradation by gastric juice)
 Intramuscularly( its pain full)
 IV ( its safe)

 Distribution :may cross the placental barrier, may cross the

blood-brain
 barrier (but only if the meninges are inflamed )

 Excretion: by active tubular secretion

Adverse effect
 Hypersensitivity reactions
 leading to fever, skin rashes, angioedema and/or anaphylactic shock,
urticaria, skin rashes, fever, dermatitis etc.
 Anaphylactic shock: hypotension, bronchospasm, laryngeal edema
 seizures (if high doses)

 Precautions for penicillins

 History of patient for any allergy, hay fever, asthma, allergic rhinitis
 In such cases penicillins should be avoided
 Penicillin sensitivity test can be done by intra dermal inj of penicillin
on the ventral aspect of forearm of patient, signs of itching erythema,
and wheal formation can b watched for.
 Adrenaline and hydrocortisone should be kept ready before
administration of penicillin. For anaphylactic shock
Drug-Drug interactions

 Penicillin + spironolactone : hyperkalemia

 Penicillin + colestipol = decreases absorption

 Penicillin + streptokinase = increases risk of bleeding

 Penicillin + contraceptives = decreased effect of

contraceptives
 uses
Pneumococcal infections: pneumonia, meningitis
Streptococcal infections: streptococcal pharyngitis, otitis media, rheumatic
fever
Meningococcal meningitis
Gonnococal infections : cephalosporin's are preferred or penicillin G
Syphilis: Penicillin is drug of choice for Syphilis
Diphtheria: acute infections like upper respiratory tract infections
Clostridial infections: tetanus and gas gangrene
Other infections: anthrax, rat bit fever, listeria infections

Draw backs of penicillin G

It is acid labile- orally no effective
Short duration of action
Narrow spectrum
Penicillin V
 Acid stable so can be given orally
 Susceptible to penicillinases
 It attains very low plasma concentration
 It is used only for mild streptococcal and Pneumococcal
infections
 Oxacillin
 Absorption: Incompletely absorbed from the GI tract, Due to presence of
food. Time to peak plasma concentration: 1 hr (oral); 30 min (IM).
Distribution: Distributed into synovial, bone, lungs, sputum and bile; cord
serum and amniotic fluid. Crosses the placenta and enters breast milk.
Plasma protein binding: Approx. 93%.
Metabolism: Partially metabolized to active and inactive metabolites in the
liver.
Excretion: Via urine (oral: approx. 20-30%; IM: >40%) as unchanged drug
and metabolites and bile. Plasma half-life: Approx. 30 min.
 Adverse effect: same as penicillin
 Indication: Staphylococcal infections resistant to benzyl penicillin
 Contraindication in hypersensitive to penicillin
 Interactions: Tetracycline + Oxacillin: antagonistic effect
 Probenecide + Oxacillin= increased plasma levels
 Ampicillin and Amoxicillin
Ampicillin
Spectrum It is active against all organism sensitive to Penicillin G it is
more active for pneumococci, meningococci, and gonococci
Gram –ve: H. influenza, E.coli, Proteus, Salmonella sp, Shigella

Route of admirations Oral, i.m. i.v.

Pharmacokinetics Not degraded by acid
Food interferes with absorption
Partially excreted in bile and reabsorbed
Excreted in urine

Uses Upper respiratory tract infections

Urinary tract infections
Meningitis
Bacillary dysentery
Typhoid fever

Amoxicillin It is close congener of Ampicillin,

Orally absorption is better as food don’t interfere in absorption
Incidence of diarrhoea is lower
It is less effective against Shigella and H. influenza
 Carbenicillin
 Special feature: this penicillin congener is active against Pseudomonas
aeruginosa which are no inhibited by Penicillin G and aminopenicillins
 It is less active for salmonella, E.coli, Enterobacter etc.
 This congener is neither Penicillinase resistant nor acid resistant
 It is inactive orally
 It is used in sodium salts and given I.m. or i.v.
 Enough sodium should be administered for fluid retention
 Half life is only 1hr so rapidly excreted in urine

Uses: serious infections by Pseudomonas or Proteus i.e. burs, UTI,

Septicaemia

 Side effect: same as penicillin but congestive cardiac failure may be

precipitated due to sodium content of Carbenicillin, it can also interfere
with platelet function and cause bleeding
Piperacillin
 Spectrum
 Antipseudomonal penicillin is about 8 times more active
then carbenicillin
 It have good activity against Klebsiella

 P.K. : administered i.m. or i.v. half life 1hr, rapidly

eliminated

 Uses: burns and UTI

 Azlocillins
 Azlocillin demonstrates antibacterial activity against a broad
spectrum of bacteria, including Pseudomonas aeruginosa, and in
contrast to most cephalosporins, exhibits activity against enterococci.

 Not significantly absorbed from the gastrointestinal tract.

 Eliminated predominantly by renal mechanisms, but also undergoes

biotransformation within body tissues and intraintestinal degradation
by bowel bacteria, with high concentrations found in bile.

 Used in infection caused by Pseudomonas aeruginosa, Escherichia

coli, and Haemophilus influenzae.

 Contraindicated in penicillin hypersensitivity.

 Mecillinam
 Mecillinam is an extended-spectrum penicillin and is only considered to be
active against Gram-negative bacteria. It is given i.m. or i.v.

 Use: urinary tract infections, and has also been used to

treat typhoid and paratyphoid fever.

 The adverse effect profile of mecillinam is similar to that of other

penicillins. Its most common side effects are rash and gastrointestinal upset,
including nausea and vomiting

 Contraindications : Hypersensitivity to penicillins; porphyria.

 Interactions: Antagonism with bacteriostatic drugs e.g. chloramphenicol,

tetracycline's.
 May prolong bleeding time when used with anticoagulants.