A presentation about natural and semisynthetic penicillins

1. By: Dr. Shruthi Rammohan
PG in Pharmacology
RRMCH

2. Penicillin Learning Objectives:
 History
 Classification (Natural Penicillins)
 Structure and Properties
 Mechanism of Action
 Antibacterial Spectrum
 Uses
 Adverse Effects

3. History
 Who discovered Penicillin?
Alexander Fleming
(1881-1955)

4. History
 Scottish biologist and pharmacologist
 After World War I  elected Professor of
Bacteriology at the University of London in
1928
 Accidentally discovered Penicillin while studying
properties of Staphylococci
 Described the mould as being from the genus
Penicillium
 Named the substance released as Penicillin
 PENICILLIN WAS BORN 7TH MARCH, 1929

5. History
 Mass production of
the new drug for use
in World War II
 Penicillin saved
many lives during
the war that may have been lost due to infected
wounds
 Penicillin was also said to treat diphtheria,
gangrene, pneumonia, syphilis and
tuberculosis
 Penicillin- first antibiotic to be used clinically
 Fleming received the Nobel Prize in 1945

6. Classification

7. Semisynthetic
Penicillins
Acid
Labile
• Penicillin- G
(Benzyl
Penicillin)
•Procaine
penicillin- G
•Benzathine
penicillin- G
• Penicillin- V
(Phenoxymethyl
penicillin)
Acid
Resistant
Penicillinase
Resistant
β-Lactamase
inhibitors
Natural
Extended
Spectrum
• Originally obtained from fungus Penicillium nonatum
• Present source from Penicillium chrysogenum

8. Preparations
 Sodium Penicillin G (crystalline penicillin)
◦ 0.5 – 5 MU i.m./i.v. 6-12 hourly
◦ Dry powder to be dissolved in sterile water
 Repository Penicillin G Injections
- Insoluble salts given deep i.m ONLY
1. Procaine Penicillin G
◦ 0.5 – 1 MU i.m. 12-24 hourly
2. Fortified Procaine Penicillin G
◦ 3 lac U Procaine Pen + 1 lac U Sod. Pen G
3. Benzathine Penicillin G
◦ 0.6 – 2.4 MU i.m. every 2-4 weeks

9. Structure
 Penicillin Nucleus
◦ β- Lactam Ring
◦ Thiazolidine Ring
◦ Side Chain

10.  Side chain can be split off by amidase
 Other side chains can be attached
 Beta-lactamases breakdown β– lactam ring

11.  Water soluble
 Acid Labile
 Thermolabile
 A- Rapid and complete absorption (i.m.)
 D- Distributed extracellularly
 E- Rapid renal excretion
◦ Tubular secretion
* What happens if PROBENECID is
given along with Penicillin?
 Tubular secretion is blocked by
probenecid, therefore higher and longer
lasting plasma concentrations of penicillin

12. Mechanism of Action
 Interferes with bacterial cell wall synthesis
PEPTIDOGLYCAN LAYER
N- ACETYL MURAMIC ACID
(NAM)
N- ACETYL GLUCOSAMINE
(NAG)
AMINO ACID CHAINS

13. β- Lactam Antibiotic
(Penicillin)
TRANSPEPTIDASE
CROSS-LINKING
PENICILLIN BINDING PROTEINS
(PBPs)
(ANIMATION)

14. β- Lactam Antibiotic
(Penicillin)
PENICILLIN BINDING PROTEINS
(PBPs)
X - Inhibition of cross-linking
(ANIMATION)

15. Mechanism of Action
 Cross-linking is blocked by:
◦ X- cleavage of terminal D-alanine
◦ X- transpeptidation of 5- glycine chain residues
 Inhibiting cell wall synthesis DAMAGES cell
 High osmotic pressure inside cell and low
osmotic pressure outside causes cell to BURST
due to a weak and unstable cell wall
 Bactericidal
 Autolysins released from penicillin-PBP
complex to digest remaining cell wall remnants

16. Antibacterial Spectrum
 Narrow spectrum
◦ Gram positive bacteria
 Cocci- Streptococci, Pneumococci
 Bacilli- B. anthracis, C. diphtheriae,
Clostridia and Listeria species
◦ Limited gram negative bacteria
 Cocci- Gonocci, Meningococci
◦ Actinomyces
◦ Spirochetes
 Treponema
 Leptospira

17. Uses
 Streptococcal Infections:
◦ Pharyngitis, Otitis Media, Scarlet Fever
◦ Rheumatic Fever
◦ Subacute Bacterial Endocarditis
 Pneumococcal Infections:
◦ Lobar Pneumonia
 Meningococcal Infections:
◦ Meningitis
 Gonococcal Infections:
◦ Ophthalmia Neonatorum
 Syphilis
 Leptospirosis

18.  Diphtheria
 Tetanus
 Anthrax
 Actinomycosis
 Rat bite fever
 Prophylaxis
◦ Rheumatic Fever
◦ Bacterial Endocarditis
◦ Agranulocytosis

19. Uses
Penicillin G- DRUG OF CHOICE IN:
 Subacute Bacterial Endocarditis
◦ Sodium PnG 10-20 MU i.v daily + Gentamicin
for 2-6 weeks
 Ophthalmia Neonatorum
◦ Saline irrigation
◦ Sodium PnG 10,000-20,000 U/mL
 1 drop in each eye every 1-3hours

20.  Syphilis
◦ Early/Latent Syphilis
 Procaine Pn 1.2 MU i.m. daily for 10 days OR
 Benzathine Pn 2.4 MU i.m. weekly for 4 weeks
◦ Late Syphilis
 Benzathine Pn 2.4 MU weekly for 4 weeks
◦ Cardiovascular/Neurosyphilis
 Sodium PnG 5 MU i.m. 6 hourly for 2 weeks
 Leptospirosis
◦ Sodium PnG 1.5 MU i.v. 6 hourly for 7 days

21.  Diphtheria
 Tetanus and Gas gangrene
 Anthrax
 Actinomycosis
 Rat bite fever
Prophylaxis
 Rheumatic Fever
◦ Benzathine Pn 1.2 MU every 4 weeks until 18
years of age or 5 years after attack
(whichever is more)

22. Adverse Effects
 Hypersensitivity-
◦ rash, itching, urticaria, fever
◦ wheezing, angioneurotic edema, serum sickness,
exfoliative dermatitis (less common)
◦ Anaphylaxis
(rare, but fatal)

23. Adverse Effects
 Hypersensitivity-
*Commonly seen after PARENTERAL
administration
*Incidence highest with PROCAINE pn
*History of penicillin allergy should be
elicited
*Scratch test or Intradermal Test dose
- negative test does not rule out
delayed hypersensitivity reactions!

24. Adverse Effects
 Superinfections
◦ Rare with PnG
◦ Bowel, respiratory and cutaneous microflora can
undergo changes
 Jarisch- Herxheimer Reaction
◦ Shivering, fever, myalgia, exacerbation of lesions,
vascular collapse
◦ Seen in syphilitic patients injected with Penicillin
◦ Due to sudden release of spirochetal lytic products
◦ Symptomatic treatment with aspirin and sedation

25. Adverse Effects
 Local irritation
◦ Pain at injection site
◦ Thrombophlebitis
 Neurotoxicity
◦ Mental confusion, muscular twitching,
convulsions, coma
 Bleeding
◦ Due to interference of platelet function
 Intrathecal PnG injections (not recommended)
◦ Arachnoiditis, degenerative changes in spinal cord
 Accidental IV procaine penicillin injection
◦ CNS stimulation, hallucinations, convulsions

26. Phenoxymethyl Penicillin
 Penicillin V
 Acid stable
 Given orally
 Plasma t½ = 30-60 min
 Antibacterial spectrum- same as PnG
 Not used for serious infections (preferred
only when oral drug is to be selected)
 Dose- 250-500mg 6 hourly

27. Semisynthetic Penicillins

28. Learning Objectives:
 Classification (Semisynthetic Penicillins)
 Structure and Properties
 Penicillinase- resistant penicillins
 Extended spectrum penicillins
 β-Lactamase inhibitors
 Bacterial Resistance

29. Why Semisynthetics?
Penicillin G has…
1. Poor oral efficacy
2. Susceptibility to penicillinase
3. Not stable in gastric acid; rapidly broken
down in stomach
4. Narrow spectrum of activity
5. Hypersensitivity reactions

30. Semisynthetic
Penicillins
Acid
Labile
• Penicillin- G
(Benzyl
Penicillin)
•Procaine
penicillin- G
•Benzathine
penicillin- G
• Penicillin- V
(Phenoxymethyl
penicillin)
Acid
Resistant
Penicillinase
Resistant
β-Lactamase
inhibitors
Natural
Extended
Spectrum

31. Semisynthetic Penicillins
Penicillinase
Resistant
β-Lactamase
inhibitors
Extended
Spectrum
• Methicillin
• Cloxacillin
• Dicloxacillin
• Ampicillin
• Bacampicillin
• Amoxicillin
• Carbenicillin • Piperacillin
• Mezlocillin
• Clavulanic acid
• Sulbactam
• Tazobactam
Aminopenicillins Carboxypenicillins Ureidopenicillins

32. Structural Difference
 Semisynthetic Pns - produced by chemically combining
specific side chains to 6-aminopenicillanic acid
6- aminopenicillanic
acid

34. Penicillinase Resistant:
 Methicillin
 Cloxacillin
 Dicloxacillin
• Side chains protect β– Lactam ring from penicillinase
(staphylococcal)
• Partially protects bacteria from β– Lactam ring.
 Oxacillin
 Flucloxacillin
 Nafcillin

35. Methicillin:
 Highly penicillinase resistant
 Acid Labile… should be administered parenterally
 Narrow spectrum- was used to treat certain Gram
positive bacteria
 Induces penicillinase production
 Adverse effects- interstitial nephritis, hematuria,
albuminuria
 Not in use due to resistance
 Replaced by other drugs in same group

36. MRSA:
 Methicillin Resistant
Staphylococcus Aureus
 Insensitive to penicillinase-
resistant penicillins, other
β–lactams as well as other antibiotics
 Evolved from horizontal gene transfer
 altered PBPs  do not bind to penicillins
 Drugs to be used in MRSA:
◦ Vancomycin
◦ Linezolid
◦ Ciprofloxacin

37. Cloxacillin/Dicloxacillin
 Highly penicillinase resistant
 Acid stable… can be given orally
 Used against staphylococcal infection EXCEPT MRSA
 Mostly binds to plasma proteins
 Dose: 0.25 – 0.5g every 6 hours
Oxacillin/Floxacillin
 Similar to cloxacillin
Nafcillin
 Given parenterally
 Other side effects- oral thrush, agranulocytosis,
neutropenia

38. Extended Spectrum:
AMINO-
 Ampicillin
 Bacampacillin
 Amoxacillin
CARBOXY-
 Carbenicillin
UREIDO-
 Piperacillin
 Mezlocillin
Amino substitution in side chain
Carboxylic acid group in side chain
Cyclic ureas in side chain

39. AMPICILLIN AMOXICILLIN BACAMPACILLIN
• Acid Stable
• Incomplete oral
absorption
-Food interference
• t½ = 1 hour
• Spectrum similar to PnG
+ S. viridans, enterococci
and Listeria
• Partially excreted in bile
and reabsorbed
-Enterohepatic circulation
-Primary excretion via
kidney
• Acid Stable
• Not a prodrug
• Better oral absorption
-No food interference
• t½ = 1 hour
• Spectrum similar to
ampicillin + more active
against penicillin
resistant S. pneumoniae
• Similar to ampicillin
• Acid Stable
• Ester prodrug of ampicillin
• Complete GIT absorption
• t½ ≈ 1 hour
• Spectrum similar to
ampicillin
• Similar to ampicillin

40. AMPICILLIN AMOXICILLIN BACAMPACILLIN
Uses:
• UTI
• Respiratory tract
-Bronchitis
-Otitis media
-Sinusitis
• Meningitis
• Gonorrhea
(Single dose 3.5g + 1g of
probenecid)
• Cholecystitis
• SABE
(2g i.v. 6th hourly with
gentamicin)
• H. pylori
• Septicemia
• ANUG
Uses same as ampicillin
• Preferred over
ampicillin in many cases
- Bronchitis
- UTI
- SABE
- Gonorrhea
Uses same as ampicillin

41. AMPICILLIN AMOXICILLIN BACAMPACILLIN
Ampicillin + Cloxacillin
• Post operative infections
• Not synergistic
• Irrational and harmful
Adverse Effects:
• Diarrhea
• Rashes
- HIV
- EB virus infection
- Lymphatic leukemia
Dose
• 0.5 - 2g 6th hourly
(oral/i.m/i.v)
Coamoxiclav
• Lower incidence of
diarrhea
• 0.25 – 1g TID
(oral/i.m/slow i.v)
•Less incidence of diarrhea
• 400 – 800mg BD
(oral)

42.  Other prodrugs of ampicillin
◦ Talampicillin
◦ Pivampicillin
◦ Hetacillin

43. Carbenicillin:
 Has activity against Pseudomonas and
Proteus
 Acid Labile… should be administered parenterally
 t½= 1 hour
 Excreted rapidly in urine
 Uses- serious Pseudomonas or Proteus infections
 Can be combined with Gentamicin BUT SHOULD NOT
BE MIXED IN THE SAME SYRINGE
 Dose- 1-2g i.m or 1-5g i.v every 4-6 hours
 Adverse effects- fluid retention & CHF in patients with
borderline renal and cardiac function, bleeding

44.  Other carboxypenicillins
◦ Ticarcillin
◦ Temocillin

45. Piperacillin:
 Has more activity against Pseudomonas and
Klebsiella, Enterobacteriaceae and
Bacteroides
 Acid Labile… should be administered parenterally
 t½= 1 hour
 Excreted rapidly in urine
 Uses- serious Pseudomonas or Klebsiella infections like
UTI
 Concurrent use of Gentamicin or tobramycin is advised
 Dose- 100-150mg/kg/day i.m/i.v in 3 divided doses
 Adverse effects- diarrhea, nausea, headache

46.  Other ureidopenicillins
◦ Mezlocillin
◦ Azlocillin

47. β- Lactamase Inhibitors:
 Clavulanic Acid
 Sulbactam
 Tazobactam

48. CLAVULANIC
ACID
SULBACTAM TAZOBACTAM
• Streptomyces
clavuligerus
• β-Lactam ring present
but no antibacterial
activity
• Inhibits a wide variety
of β-Lactamases
• Inhibition increases
with time “progressive”
• “Suicide” inhibitor
Pharmacokinetics
• Rapid oral absorption
• t½= 1 hour
• Eiminated by
glomerular filtration
• Combined with Amox
• Related chemically to
clavulanic acid
• Some antibacterial activity
present; too weak
• Irreversible β-Lactamase
inhibitor
• Less potent than clavulanic
acid; same inhibition with
higher dose
• Inconsistent oral
absorption
• Combined with Ampicillin
• Similar to sulbactam
• Antipseudomonal
• Broadens spectrum of
Piperacillin
•Combined with Piperacillin

49. CLAVULANIC ACID SULBACTAM TAZOBACTAM
COAMOXICLAV
• Combined with Amox
•Does not potentiate
action of amox
Uses:
• Skin, intra-abdominal,
gynecological, urinary
tract, biliary tract and resp
tract infections
Dose:
250mg + 125mg tab
500mg + 125mg tab
1g + 0.2g vial deep i.m/i.v
Adverse Effects:
• Poor GI tolerance
• Candida infections
• Combined with Ampicillin
Uses:
• PPNG gonorrhea
• Intra-abdominal
infections
•Gynecological
•Skin/soft tissue infections
Dose:
1g + 0.5g vial (1-2 vials
Deep i.m/i.v 6-8th hourly
Adverse Effects:
• Pain at site of injection
• Thrombophlebitis
• Diarrhea
• Combined with
Piperacillin
• Combined with
ceftriaxone also
Dose:
4g + 0.5g iv over 30min,
8th hourly

50. Bacterial Resistance:
 Primarily due to production of penicillinase
 Mechanisms of resistance:
◦ Transformation
◦ Plasmid donor via Conjugation
 Bacteria resistant to penicillins
◦ Staphylococci
◦ S. pneumoniae
◦ Strains of Gonococci- PnG
◦ Strains of E. coli
 Penicillinase used to destroy PnG in blood samples

51. Bacterial Resistance:
https://www.youtube.com/watch?v=qBdYnRhdWcQ

52. THANK YOU!