Penicillins (VK)

1. CELL WALL SYNTHESIS CELL WALL SYNTHESIS
INHIBITORSINHIBITORS
A N.VIJAY KUMARA N.VIJAY KUMAR
November 26, 2013November 26, 2013

2. Site and Mechanism of action of AntibioticsSite and Mechanism of action of Antibiotics

3. PenicilliumPenicillium
The name Penicillium comes from Penicillus = brush, and this is based on
the  brush-like appearance of the fruiting structures

4. IntroductionIntroduction

The penicillins constitute one of the most important groups of The penicillins constitute one of the most important groups of
antibiotics. antibiotics.

Although numerous other antimicrobial agents have been produced Although numerous other antimicrobial agents have been produced
since the first penicillin became available, these still are widely used, since the first penicillin became available, these still are widely used,
major antibiotics, and new derivatives of the basic penicillin nucleus major antibiotics, and new derivatives of the basic penicillin nucleus
still are being produced.still are being produced.

Many of these have unique advantages, such that members of this Many of these have unique advantages, such that members of this
group of antibiotics are presently the drugs of choice for a large group of antibiotics are presently the drugs of choice for a large
number of infectious diseases.number of infectious diseases.

5. 
1928 - Alexander Fleming 1928 - Alexander Fleming

Bread mold (Bread mold (Penicillium notatumPenicillium notatum) growing on petri ) growing on petri
dishdish

1939 - Florey, Chain, and Associates1939 - Florey, Chain, and Associates

Began work on isolating and synthesizing large Began work on isolating and synthesizing large
amounts of Penicillin.amounts of Penicillin.

1941 – introduced in antibacterial therapy1941 – introduced in antibacterial therapy
HistoryHistory

6. the fused beta-lactam structure (shown in the blue and red the fused beta-lactam structure (shown in the blue and red
rings, rings,
a free carboxyl acid group (shown in red bottom right), a free carboxyl acid group (shown in red bottom right),
one or more substituted amino acid side chains (shown in one or more substituted amino acid side chains (shown in
black). black).
The lactam structure can also be viewed as the covalent The lactam structure can also be viewed as the covalent
bonding of pieces of two amino acids - cysteine (blue) and bonding of pieces of two amino acids - cysteine (blue) and
valine (red). valine (red).
StructureStructure

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 Clinically useful families of beta-lactam
compounds include the compounds include the

PenicillinsPenicillins

CephalosporinsCephalosporins

MonobactamsMonobactams

CarbapenemsCarbapenems

10. Mechanisms of ActionMechanisms of Action

All penicillin derivatives produce their All penicillin derivatives produce their
bactericidal effects by inhibition of bacterial cell bactericidal effects by inhibition of bacterial cell
wall synthesis. wall synthesis.

Specifically, the cross linking of peptides on the Specifically, the cross linking of peptides on the
polysaccharide chain is prevented. polysaccharide chain is prevented.

If cell walls are improperly made cell walls allow If cell walls are improperly made cell walls allow
water to flow into the cell causing it to burst. water to flow into the cell causing it to burst.

11. Penicillin Penicillin
Bind (PBP) on the cell wall of susceptible bacteriaBind (PBP) on the cell wall of susceptible bacteria
Inhibits transpeptidationInhibits transpeptidation

Prevents peptidoglycan synthesis Prevents peptidoglycan synthesis
Cell wall deficient forms spheroplasts & Cell wall deficient forms spheroplasts &
filamentous forms filamentous forms
Autolysis Autolysis
Cell death (bactericidal action) Cell death (bactericidal action)

12. MOA: Cell Wall productionMOA: Cell Wall production

The cell walls of bacteria are essential for their normal growth and The cell walls of bacteria are essential for their normal growth and
development. development.

Peptidoglycan is a heteropolymeric component of the cell wall that Peptidoglycan is a heteropolymeric component of the cell wall that
provides rigid mechanical stability by virtue of its highly cross-linked provides rigid mechanical stability by virtue of its highly cross-linked
latticework structure latticework structure

The peptidoglycan is composed of glycan chains, which are linear The peptidoglycan is composed of glycan chains, which are linear
strands of two alternating amino sugars (N-acetylglucosamine and strands of two alternating amino sugars (N-acetylglucosamine and
N-acetylmuramic acid) that are cross-linked by peptide chains. N-acetylmuramic acid) that are cross-linked by peptide chains.
(NAG-NAM). (NAG-NAM).

13. 
Binding to PBPs results in:Binding to PBPs results in:

Inhibition of transpeptidase: Inhibition of transpeptidase: transpeptidase catalyzes the transpeptidase catalyzes the
cross-linking of the pentaglycine bridge with the fourth residue cross-linking of the pentaglycine bridge with the fourth residue
(D-Ala) of the pentapeptide. The fifth residue (also D-Ala) is (D-Ala) of the pentapeptide. The fifth residue (also D-Ala) is
released during this reaction. Spheroblasts are formed.released during this reaction. Spheroblasts are formed.

Structural irregularities: Structural irregularities: binding to PBPs may result in binding to PBPs may result in
abnormal elongation, abnormal shape, cell wall defects.abnormal elongation, abnormal shape, cell wall defects.
Mechanisms of Action Mechanisms of Action Cont…Cont…

15. Comparison of the structure and composition of gram-positive and
gram-negative cell walls.

16. CLASSIFICATION CLASSIFICATION

NARROW SPECTRUM PENICILLINSNARROW SPECTRUM PENICILLINS
ββ-lactamase sensitive(NATURAL PENICILLINS)-lactamase sensitive(NATURAL PENICILLINS)

Acid resistantAcid resistant
- Penicillin V (oral)- Penicillin V (oral)
Acid labileAcid labile
- Penicillin-G (benzyl penicillin)- Penicillin-G (benzyl penicillin)
(I.M,IV)(I.M,IV)
- Procaine penicillin-G(I.M,depot - Procaine penicillin-G(I.M,depot
inj)inj)
- Benzathine penicillin-G(I.M, - Benzathine penicillin-G(I.M,
depot inj)depot inj)

17. ββ-lactamase resistant(ANTISTEPHYLOCOCCAL -lactamase resistant(ANTISTEPHYLOCOCCAL
PENICILLINS)PENICILLINS)
Acid resistantAcid resistant
- Cloxacillin - Cloxacillin
- Dicloxacillin - Dicloxacillin
- flucloxacillin- flucloxacillin
Acid labileAcid labile

- Methicillin (I.M,I.V)- Methicillin (I.M,I.V)
- Nafcillin (I.M,I.V) - Nafcillin (I.M,I.V)

18. 
EXTENDED SPECTRUM PENICILLINSEXTENDED SPECTRUM PENICILLINS
Acid resistantAcid resistant
•AminopenicillinsAminopenicillins: Ampicillin, Amoxicillin, Bacampicillin, : Ampicillin, Amoxicillin, Bacampicillin,
Talampicillin Talampicillin
Acid labileAcid labile ((ANTIPSEUDOMONAL PENICILLINS)ANTIPSEUDOMONAL PENICILLINS)
•CarboxypenicillinsCarboxypenicillins: Carbenicillin, Ticarcillin: Carbenicillin, Ticarcillin
•UreidopenicillinsUreidopenicillins: Piperacillin, Mezlocillin, Azlocillin: Piperacillin, Mezlocillin, Azlocillin

BETA LACTAMASE INHIBITORSBETA LACTAMASE INHIBITORS
•Sulbactam, Tazobactam, Clavulanic acidSulbactam, Tazobactam, Clavulanic acid

19. Natural penicillinsNatural penicillins

Listed as antistaphylococcalListed as antistaphylococcal

Obtained from fermentations of the mold Obtained from fermentations of the mold
Penicillium chrysogenumPenicillium chrysogenum

Penicillin G (benzylpenicillin) and Penicillin VPenicillin G (benzylpenicillin) and Penicillin V

20. Antimicrobial spectrum: Penicillin GAntimicrobial spectrum: Penicillin G

21. PharmacokineticsPharmacokinetics
Oral administration of Penicillin G:Oral administration of Penicillin G:

Acid labileAcid labile

About one-third of an orally administered dose of PenG is About one-third of an orally administered dose of PenG is
absorbed from the intestinal tract under favorable conditions. absorbed from the intestinal tract under favorable conditions.

Gastric juice at pH 2 rapidly destroys the antibiotic.Gastric juice at pH 2 rapidly destroys the antibiotic.
Parenteral Administration of Penicillin G:Parenteral Administration of Penicillin G:

From I.M site absorption is rapid and completeFrom I.M site absorption is rapid and complete

Peak plasma levels attained in 30minPeak plasma levels attained in 30min

22. 
PenG is distributed widely throughout the body, but the PenG is distributed widely throughout the body, but the
concentrations in various fluids and tissues differ widely. concentrations in various fluids and tissues differ widely.

Approx. 60% of the PenG in plasma is reversibly bound to albumin. Approx. 60% of the PenG in plasma is reversibly bound to albumin.

Significant amounts appear in liver, bile, kidney, semen, joint fluid, Significant amounts appear in liver, bile, kidney, semen, joint fluid,
lymph, and intestinelymph, and intestine

CSF:CSF: Penicillin does not readily enter the CSF when the meninges Penicillin does not readily enter the CSF when the meninges
are normal. However, when the meninges are acutely inflamed, are normal. However, when the meninges are acutely inflamed,
penicillin penetrates into the CSF more easily.penicillin penetrates into the CSF more easily.

Little metabolized because rapid excretionLittle metabolized because rapid excretion
Pharmacokinetics Pharmacokinetics Cont…Cont…

23. 
The half-time for elimination is about 30 minutes in The half-time for elimination is about 30 minutes in
normal adults (upto 10 hours in renal failure) . normal adults (upto 10 hours in renal failure) .

Approx. 10% of the drug is eliminated by glomerular Approx. 10% of the drug is eliminated by glomerular
filtration and filtration and 90% by tubular secretion90% by tubular secretion..

While While probenecidprobenecid markedly markedly ↓↓ss the tubular secretion of ss the tubular secretion of
the penicillins, this is not the only factor responsible for the penicillins, this is not the only factor responsible for
the elevated plasma concentrations of the antibiotic that the elevated plasma concentrations of the antibiotic that
follow its administration. follow its administration.
Pharmacokinetics Pharmacokinetics Cont…Cont…

24. Preparations and dosePreparations and dose

Benzylpenicillin (sodium and potassium Benzylpenicillin (sodium and potassium
salts)salts)

Repository preparations:Repository preparations:

Insoluble salts, only I.M injection never I.V injInsoluble salts, only I.M injection never I.V inj

Procaine penicillinProcaine penicillin

Benzathine penicillinBenzathine penicillin

25. Unitage of Penicillin

The IU of penicillin is the specific penicillin activity The IU of penicillin is the specific penicillin activity
contained in 0.6 mg of the crystalline sodium salt of contained in 0.6 mg of the crystalline sodium salt of
penicillin G.penicillin G.

1mg of pure penicillin G sodium thus equals 1667 units; 1mg of pure penicillin G sodium thus equals 1667 units;
1mg of pure penicillin G potassium represents 1595 units. 1mg of pure penicillin G potassium represents 1595 units.

The dosage and the antibacterial potency of the The dosage and the antibacterial potency of the
semisynthetic penicillins are expressed in terms of weight.semisynthetic penicillins are expressed in terms of weight.

26. Therapeutic Uses

Pneumococcal InfectionsPneumococcal Infections

Pneumococcal MeningitisPneumococcal Meningitis

Pneumococcal PneumoniaPneumococcal Pneumonia

Streptococcal InfectionsStreptococcal Infections

Streptococcal Pharyngitis (including Scarlet Fever)Streptococcal Pharyngitis (including Scarlet Fever)

Streptococcal Pneumonia, Arthritis, Meningitis, and EndocarditisStreptococcal Pneumonia, Arthritis, Meningitis, and Endocarditis

Staphylococcal InfectionsStaphylococcal Infections

Meningococcal InfectionsMeningococcal Infections

Gonococcal InfectionsGonococcal Infections

Syphilis, Actinomycosis, Diphtheria, AnthraxSyphilis, Actinomycosis, Diphtheria, Anthrax

Clostridial InfectionsClostridial Infections

Fusospirochetal InfectionsFusospirochetal Infections

Rat-Bite FeverRat-Bite Fever

Listeria InfectionsListeria Infections

Lyme DiseaseLyme Disease

ErysipeloidErysipeloid

Surgical Procedures in Patients with Valvular Heart DiseaseSurgical Procedures in Patients with Valvular Heart Disease

Tetanus and gas gangreneTetanus and gas gangrene

Prophylactic uses:Prophylactic uses:

Rheumatic fever, bacterial endocarditis and agranulocytosis ptsRheumatic fever, bacterial endocarditis and agranulocytosis pts

27. Mechanisms of Bacterial
Resistance to Penicillins

Resistance to penicillins and other beta Resistance to penicillins and other beta
lactams is due to one of four general lactams is due to one of four general
mechanisms:mechanisms:

Inactivation of the antibiotic by beta lactamaseInactivation of the antibiotic by beta lactamase

Modification of target PBPsModification of target PBPs

Impaired penetration of drug to target PBPsImpaired penetration of drug to target PBPs

The presence of an efflux pump.The presence of an efflux pump.

28. Other resistance mechanismsOther resistance mechanisms

A reductionA reduction in the permeability of the in the permeability of the
outer membrane.outer membrane.

Thus there is a decreased ability of the Thus there is a decreased ability of the
drug to penetrate to the target site.drug to penetrate to the target site.

The occurrence of modified penicillin The occurrence of modified penicillin
binding sites. This mechanism is binding sites. This mechanism is
responsible in methicillin resistance in responsible in methicillin resistance in
Pneumococci.Pneumococci.

29. Adverse effectsAdverse effects

Hypersensitivity ReactionsHypersensitivity Reactions

The basis of which is the fact that degradation products of The basis of which is the fact that degradation products of
penicillin combine with host protein and become antigenic.penicillin combine with host protein and become antigenic.

30. 
In approximate order of decreasing frequency, In approximate order of decreasing frequency,
manifestations of allergy to penicillins include manifestations of allergy to penicillins include
maculopapular rash, urticarial rash, fever, maculopapular rash, urticarial rash, fever,
bronchospasm, vasculitis, serum sickness, exfoliative bronchospasm, vasculitis, serum sickness, exfoliative
dermatitis, Stevens-Johnson syndrome, and anaphylaxis dermatitis, Stevens-Johnson syndrome, and anaphylaxis

The incidence of such reaction is 5-8% of the Pts The incidence of such reaction is 5-8% of the Pts
receiving Penicillins receiving Penicillins
Adverse effects Adverse effects Cont…Cont…

31. 
Very high doses of penicillin G can cause Very high doses of penicillin G can cause
seizures in kidney failure.seizures in kidney failure.

Pain at I.M injection sitePain at I.M injection site

Nausea on oral ingestionNausea on oral ingestion

Thromboplebitis of injected veinThromboplebitis of injected vein
Adverse effects Adverse effects Cont…Cont…

32. Penicillin VPenicillin V

Orally activeOrally active

Used for the treatment of bacteremia and oral Used for the treatment of bacteremia and oral
infectionsinfections

Higher minimum bactericidal concentrationHigher minimum bactericidal concentration

33. Semisynthetic penicillinsSemisynthetic penicillins

The major draw backs of benzylpenicillin are:The major draw backs of benzylpenicillin are:

Inactivation by gastric acidInactivation by gastric acid

Short duration of actionShort duration of action

Poor penetration into the CSFPoor penetration into the CSF

Narrow spectrum of activityNarrow spectrum of activity

Susceptibility to PenicillinaseSusceptibility to Penicillinase

Development of resistanceDevelopment of resistance

Possibility of anaphylaxisPossibility of anaphylaxis

34. Penicillinase-resistant penicillinsPenicillinase-resistant penicillins
(antistaphylococcal penicillins)(antistaphylococcal penicillins)

These congeners have side chains that protect the beta These congeners have side chains that protect the beta
lactam ring from attack by staphylococcal penicillinaselactam ring from attack by staphylococcal penicillinase

Indicated in infections caused by penicillinase producing Indicated in infections caused by penicillinase producing
staphylococci (drugs of choice, except in MRSA)staphylococci (drugs of choice, except in MRSA)

Methicillin, CloxacillinMethicillin, Cloxacillin

Oxacillin, Nafcillin, DicloxacillinOxacillin, Nafcillin, Dicloxacillin

35. Methicillin:Methicillin:

Acid labile Acid labile

Not used clinically, except to identify resistant Not used clinically, except to identify resistant
strainsstrains

MRSA is susceptible to Vancomycin/linezolid and MRSA is susceptible to Vancomycin/linezolid and
rarely Ciprofloxacinrarely Ciprofloxacin
Penicillinase-resistant penicillinsPenicillinase-resistant penicillins
(antistaphylococcal penicillins)(antistaphylococcal penicillins)Cont…Cont…

36. Cloxacillin:Cloxacillin:

Acid resistantAcid resistant

More active than methicillinMore active than methicillin

Less active against PnG sensitive organisms: should not be used as Less active against PnG sensitive organisms: should not be used as
its substituteits substitute

Incompletely but dependably absorbed (oral route)Incompletely but dependably absorbed (oral route)

>90% protein bound, eliminated primarily by kidney, also partly by >90% protein bound, eliminated primarily by kidney, also partly by
liverliver

Plasma half life is about 1hrPlasma half life is about 1hr
Penicillinase-resistant penicillinsPenicillinase-resistant penicillins
(antistaphylococcal penicillins)(antistaphylococcal penicillins)Cont…Cont…

37. Extended spectrum penicillinsExtended spectrum penicillins

Active against a variety of gram-negative bacilli as wellActive against a variety of gram-negative bacilli as well

Can be grouped according to their spectrum of activityCan be grouped according to their spectrum of activity
1. 1. Aminopenicillins:Aminopenicillins:
Ampicillins:Ampicillins:

Active against all organisms sensitive to PnG; in Active against all organisms sensitive to PnG; in
addition, many gram-negative bacilliaddition, many gram-negative bacilli

38. Extended spectrum penicillins Extended spectrum penicillins
Cont…Cont…

39. Pharmacokinetics:Pharmacokinetics:

Acid resistantAcid resistant

Oral absorption is incomplete but adequateOral absorption is incomplete but adequate

Primary excretion is kidney, partly enterohepatic circulation occursPrimary excretion is kidney, partly enterohepatic circulation occurs

Plasma half life is 1hrPlasma half life is 1hr
Uses:Uses:

UTI, RTI, Meningitis, GonorrhoeaUTI, RTI, Meningitis, Gonorrhoea, typhoid fever, bacillary dysentery, typhoid fever, bacillary dysentery, ,
Cholisystitis, Subacute bacterial endocarditis and SepticemiasCholisystitis, Subacute bacterial endocarditis and Septicemias
Extended spectrum penicillins Extended spectrum penicillins
Cont…Cont…

40. Adverse effects:Adverse effects:

DiarrhoeaDiarrhoea

RashesRashes

HypersensitivityHypersensitivity
Interactions:Interactions:

Hydrocortisone –inactivates ampicillin if mixed in the I.V solutionHydrocortisone –inactivates ampicillin if mixed in the I.V solution

OC –failure of oral contraceptionOC –failure of oral contraception

Probenecid –retards renal excretionProbenecid –retards renal excretion
Extended spectrum penicillins Extended spectrum penicillins
Cont…Cont…

41. 
Bacampicillin –ester prodrug of ampicillinBacampicillin –ester prodrug of ampicillin

Talampicillin, Pivampicillin and Hetacillin are other Prodrugs of Talampicillin, Pivampicillin and Hetacillin are other Prodrugs of
ampicillinampicillin
Amoxicillin:Amoxicillin:

Close congener of ampicillin but not a prodrugClose congener of ampicillin but not a prodrug

Similar to it in all aspects except:Similar to it in all aspects except:

Better oral absorptionBetter oral absorption

Higher and sustained blood levels are producedHigher and sustained blood levels are produced

Incidence of diarrhoea is lowerIncidence of diarrhoea is lower

Less effective against Less effective against ShigellaShigella and and H. influenzaeH. influenzae
Extended spectrum penicillins Extended spectrum penicillins
Cont…Cont…

42. 2. Carboxypenicillins (Carbenicillin, Ticarcillin)2. Carboxypenicillins (Carbenicillin, Ticarcillin)
andand
3. Ureidopenicillins (Piperacillin)3. Ureidopenicillins (Piperacillin)
Extended spectrum penicillins Extended spectrum penicillins
Cont…Cont…

43. 
These are called antipseudomonal penicillinsThese are called antipseudomonal penicillins

Piperacillin is more potent among thesePiperacillin is more potent among these

Carbenicillin is less effective against Carbenicillin is less effective against Salmonella, E. Coli Salmonella, E. Coli and and
enterobacter but not active against enterobacter but not active against KlebshiellaKlebshiella and gram-positive and gram-positive
coccicocci

Piperacillin has good activity against Piperacillin has good activity against KlebshiellaKlebshiella, and is used mainly , and is used mainly
in neutropenic/ immunocompromised patients having serious gram-in neutropenic/ immunocompromised patients having serious gram-
negative infections and in burnsnegative infections and in burns
Extended spectrum penicillins Extended spectrum penicillins
Cont…Cont…

44. Beta-lactamase inhibitorsBeta-lactamase inhibitors

Clavulanic acid, Sulbactam Clavulanic acid, Sulbactam
and Tazobactamand Tazobactam

They contain beta-lactam ring They contain beta-lactam ring
but themselves, do not have but themselves, do not have
significant antibacterial activitysignificant antibacterial activity

45. Clavulanic acidClavulanic acid::

Obtained from Streptomyces clavuligerusObtained from Streptomyces clavuligerus

Called a suicide inhibitorCalled a suicide inhibitor

Pharmacokinetics matches amoxicillin with which it is usedPharmacokinetics matches amoxicillin with which it is used
Sulbactam:Sulbactam:

Semisynthetic beta-lactamase inhibitorSemisynthetic beta-lactamase inhibitor

Related chemically as well as in activity to clavulanic acidRelated chemically as well as in activity to clavulanic acid

It is also a progressive inhibitorIt is also a progressive inhibitor

Combined with ampicillinCombined with ampicillin
Beta-lactamase inhibitors Beta-lactamase inhibitors Cont…Cont…

46. Tazobactam:Tazobactam:

Similar to SulbactamSimilar to Sulbactam

Pharmacokinetics matches with Piperacillin with which it is used for Pharmacokinetics matches with Piperacillin with which it is used for
used in severe infections like peritonitis, pelvic/urinary/respiratory used in severe infections like peritonitis, pelvic/urinary/respiratory
infectionsinfections

However, the combination is not effective against piperacillin-resistant However, the combination is not effective against piperacillin-resistant
PseudomonasPseudomonas
Beta-lactamase inhibitors Beta-lactamase inhibitors Cont…Cont…

47. They are available only in fixed combinations with They are available only in fixed combinations with
specific penicillins:specific penicillins:

Ampicillin + Sulbactam (1g+0.5g I.V/I.M inj)Ampicillin + Sulbactam (1g+0.5g I.V/I.M inj)

Amoxycillin + Clavulanic acid (250mg+125mg tab)Amoxycillin + Clavulanic acid (250mg+125mg tab)

Piperacillin + Tazobactam sodium (2g+0.25g I.V/I.M Piperacillin + Tazobactam sodium (2g+0.25g I.V/I.M
inj)inj)