3. Penicillium
The name Penicillium comes from Penicillus = brush, and this is based on
the brush-like appearance of the fruiting structures
4. Introduction
The penicillins constitute one of the most important groups of
antibiotics.
Although numerous other antimicrobial agents have been produced
since the first penicillin became available, these still are widely used,
major antibiotics, and new derivatives of the basic penicillin nucleus
still are being produced.
Many of these have unique advantages, such that members of this
group of antibiotics are presently the drugs of choice for a large
number of infectious diseases.
5. History
1928 - Alexander Fleming
Bread mold (Penicillium notatum) growing on petri
dish
1939 - Florey, Chain, and Associates
Began work on isolating and synthesizing large
amounts of Penicillin.
1941 – introduced in antibacterial therapy
6. Structure
the fused beta-lactam structure (shown in the blue and red
rings,
a free carboxyl acid group (shown in red bottom right),
one or more substituted amino acid side chains (shown in
black).
The lactam structure can also be viewed as the covalent
bonding of pieces of two amino acids - cysteine (blue) and
valine (red).
7. thiazolidine ring (A) connected to a b-lactam ring (B), to which is attached a side
chain (R).
8.
The penicillin nucleus itself is the chief structural
requirement for biological activity
Metabolic transformation or chemical alteration of this
portion of the molecule causes loss of all significant
antibacterial activity
9.
Clinically useful families of beta-lactam
compounds include the
Penicillins
Cephalosporins
Monobactams
Carbapenems
10. Mechanisms of Action
All penicillin derivatives produce their
bactericidal effects by inhibition of bacterial cell
wall synthesis.
Specifically, the cross linking of peptides on the
polysaccharide chain is prevented.
If cell walls are improperly made cell walls allow
water to flow into the cell causing it to burst.
11. Penicillin
Bind (PBP) on the cell wall of susceptible bacteria
Inhibits transpeptidation
Prevents peptidoglycan synthesis
Cell wall deficient forms spheroplasts &
filamentous forms
Autolysis
Cell death (bactericidal action)
12. MOA: Cell Wall production
The cell walls of bacteria are essential for their normal growth and
development.
Peptidoglycan is a heteropolymeric component of the cell wall that
provides rigid mechanical stability by virtue of its highly cross-linked
latticework structure
The peptidoglycan is composed of glycan chains, which are linear
strands of two alternating amino sugars (N-acetylglucosamine and
N-acetylmuramic acid) that are cross-linked by peptide chains.
(NAG-NAM).
13. Mechanisms of Action
Cont…
Binding to PBPs results in:
Inhibition of transpeptidase: transpeptidase catalyzes the
cross-linking of the pentaglycine bridge with the fourth residue
(D-Ala) of the pentapeptide. The fifth residue (also D-Ala) is
released during this reaction. Spheroblasts are formed.
Structural irregularities: binding to PBPs may result in
abnormal elongation, abnormal shape, cell wall defects.
14.
15. Comparison of the structure and composition of gram-positive and
gram-negative cell walls.
19. Natural penicillins
Listed as antistaphylococcal
Obtained from fermentations of the mold
Penicillium chrysogenum
Penicillin G (benzylpenicillin) and Penicillin V
21. Pharmacokinetics
Oral administration of Penicillin G:
Acid
labile
About
one-third of an orally administered dose of PenG is
absorbed from the intestinal tract under favorable conditions.
Gastric
juice at pH 2 rapidly destroys the antibiotic.
Parenteral Administration of Penicillin G:
From
I.M site absorption is rapid and complete
Peak
plasma levels attained in 30min
22. Pharmacokinetics
Cont…
PenG is distributed widely throughout the body, but the
concentrations in various fluids and tissues differ widely.
Approx. 60% of the PenG in plasma is reversibly bound to albumin.
Significant amounts appear in liver, bile, kidney, semen, joint fluid,
lymph, and intestine
CSF: Penicillin does not readily enter the CSF when the meninges
are normal. However, when the meninges are acutely inflamed,
penicillin penetrates into the CSF more easily.
Little metabolized because rapid excretion
23. Pharmacokinetics
Cont…
The half-time for elimination is about 30 minutes in
normal adults (upto 10 hours in renal failure) .
Approx. 10% of the drug is eliminated by glomerular
filtration and 90% by tubular secretion .
While probenecid markedly ↓ss the tubular secretion of
the penicillins, this is not the only factor responsible for
the elevated plasma concentrations of the antibiotic that
follow its administration.
24. Preparations and dose
Benzylpenicillin (sodium and potassium
salts)
Repository preparations:
Insoluble salts, only I.M injection never I.V inj
Procaine penicillin
Benzathine penicillin
25. Unitage of Penicillin
The IU of penicillin is the specific penicillin activity
contained in 0.6 mg of the crystalline sodium salt of
penicillin G.
1mg of pure penicillin G sodium thus equals 1667 units;
1mg of pure penicillin G potassium represents 1595 units.
The dosage and the antibacterial potency of the
semisynthetic penicillins are expressed in terms of weight.
27. Mechanisms of Bacterial
Resistance to Penicillins
Resistance to penicillins and other beta
lactams is due to one of four general
mechanisms:
Inactivation of the antibiotic by beta lactamase
Modification of target PBPs
Impaired penetration of drug to target PBPs
The presence of an efflux pump.
28. Other resistance mechanisms
A reduction in the permeability of the
outer membrane.
Thus there is a decreased ability of the
drug to penetrate to the target site.
The occurrence of modified penicillin
binding sites. This mechanism is
responsible in methicillin resistance in
Pneumococci.
30. Adverse effects
Cont…
In approximate order of decreasing frequency,
manifestations of allergy to penicillins include
maculopapular rash, urticarial rash, fever,
bronchospasm, vasculitis, serum sickness, exfoliative
dermatitis, Stevens-Johnson syndrome, and anaphylaxis
The incidence of such reaction is 5-8% of the Pts
receiving Penicillins
31. Adverse effects
Cont…
Very high doses of penicillin G can cause
seizures in kidney failure.
Pain at I.M injection site
Nausea on oral ingestion
Thromboplebitis of injected vein
33. Semisynthetic penicillins
The major draw backs of benzylpenicillin are:
Inactivation by gastric acid
Short duration of action
Poor penetration into the CSF
Narrow spectrum of activity
Susceptibility to Penicillinase
Development of resistance
Possibility of anaphylaxis
34. Penicillinase-resistant penicillins
(antistaphylococcal penicillins)
These congeners have side chains that protect the beta
lactam ring from attack by staphylococcal penicillinase
Indicated in infections caused by penicillinase producing
staphylococci (drugs of choice, except in MRSA)
Methicillin, Cloxacillin
Oxacillin, Nafcillin, Dicloxacillin
37. Extended spectrum penicillins
Active against a variety of gram-negative bacilli as well
Can be grouped according to their spectrum of activity
1. Aminopenicillins:
Ampicillins:
Active against all organisms sensitive to PnG; in
addition, many gram-negative bacilli
39. Extended spectrum penicillins
Cont…
Pharmacokinetics:
Acid
resistant
Oral
absorption is incomplete but adequate
Primary
excretion is kidney, partly enterohepatic circulation occurs
Plasma
half life is 1hr
Uses:
UTI,
RTI, Meningitis, Gonorrhoea, typhoid fever, bacillary dysentery,
Cholisystitis, Subacute bacterial endocarditis and Septicemias
40. Extended spectrum penicillins
Cont…
Adverse effects:
Diarrhoea
Rashes
Hypersensitivity
Interactions:
Hydrocortisone
OC
–inactivates ampicillin if mixed in the I.V solution
–failure of oral contraception
Probenecid
–retards renal excretion
41. Extended spectrum penicillins
Cont…
Bacampicillin –ester prodrug of ampicillin
Talampicillin, Pivampicillin and Hetacillin are other Prodrugs of
ampicillin
Amoxicillin:
Close congener of ampicillin but not a prodrug
Similar to it in all aspects except:
Better oral absorption
Higher and sustained blood levels are produced
Incidence of diarrhoea is lower
Less effective against Shigella and H. influenzae
43. Extended spectrum penicillins
Cont…
These are called antipseudomonal penicillins
Piperacillin is more potent among these
Carbenicillin is less effective against Salmonella, E. Coli and
enterobacter but not active against Klebshiella and gram-positive
cocci
Piperacillin has good activity against Klebshiella, and is used mainly
in neutropenic/ immunocompromised patients having serious gramnegative infections and in burns
45. Beta-lactamase inhibitors
Clavulanic acid :
Obtained
Called
from Streptomyces clavuligerus
a suicide inhibitor
Pharmacokinetics
matches amoxicillin with which it is used
Sulbactam:
Semisynthetic
Related
It
beta-lactamase inhibitor
chemically as well as in activity to clavulanic acid
is also a progressive inhibitor
Combined
with ampicillin
Cont…
47. They are available only in fixed combinations with
specific penicillins:
Ampicillin
+ Sulbactam (1g+0.5g I.V/I.M inj)
Amoxycillin
+ Clavulanic acid (250mg+125mg tab)
Piperacillin
+ Tazobactam sodium (2g+0.25g I.V/I.M
inj)
Notas do Editor
Penicillins as well as cephalosporins are called beta-lactam antibiotics and are characterized by 3 fundamental structural requirements:
A bacterial cell from which da rigid cell wall has been incompletely removed . The bacterium loses its characteristic shape and becomes round
an inj of a substance in a vehicle that tends to keep it at the site of inj so that absorption occurs over a prolonged period