Penicillin Antibiotics - Pharmacology

In this section, we describe Various types of Penicillin Antibiotics and most of the slides are cited from:
1- Lippincott's Illustrated Pharmacology
2- KD Triphati Pharmacology
3- Basic Katzung Pharmacology

1. Asst. Prof. Dr. Muhammad Haroon
MD, ECEA, MPH (JHSPH)

Head and Coordinator of MPH Programs
Former Biochemistry Guest lecturer at SMS
medical college, India.
Email:[email protected]

2. Overview

e These antibiotics are:

- Most widely effective
— Least toxic
— Increased resistance
e Members of this family differ from one another in:
- The R substituent
e The R affects:
— The antimicrobial spectrum

— Stability to stomach acid
— Susceptibility to bacterial degradative enzymes Penicillin

3. Penicillin Structure

e The general structure contains:
— Thiazolidine Ring
- Beta-Lactam Ring
- R- Side Chain

s

i H_H H NY BS
R-C-N- CC — e
—— CH,

Acyl Side] Beta-Lactam Thiazolidine
en Ring Ring
cé il
E N > COOH

General Structure of Penicillins

Penicillin

4. Mechanism of Action

e They are:
- Bactericidal
- Only effective against rapidly growing organisms
e They interfere with:
- The transpeptidation or cross-linkage

- Resulting in exposure of the osmotically less stable
membrane

e Cell lysis can occur through:
- Osmotic pressure

- Or through the activation of autolysins Penicillin

5. Mechanism of Action Cont.......

e Penicillin-binding proteins:
- Penicillin inactivate numerous proteins on the bacterial
cell membrane

e Inhibition of trans peptidase:

- Some PBPs catalyze formation of the cross-linkages
between peptidoglycan chains

e Production of autolysins

Penicillin

6. Cell Wall of Bacteria
COI

Cell wall of Gram Positive vs Gram Negative Bacteria

teichoic surface big ak:
acid protein

peptido-
glycan

TP con O
Sambre | | 900000000000 cas
AREA TES

www.majordifferences.com Penicillin

phospholipid

7. Cell Wall of Bacteria Cont.......

Bacterial Cell Wall

lipid A
murein
lipoprotein

peptidoglycan
cell wall

NN

membrane
periplasmic
space
inner
membrane

fatty acids

gram-negative bacteria

Penicillin

8. Mechanism of Action Cont.

B-lactam mechanism
of action

ABX-free
Cell Wall
Synthesis

Pen Ceph Mono Carbo Block of transpeptidase activity interrupts
cross-linking & cell wall synthesis

D-Ala-D-Alo structural mimi

DAL

Penicillin

9. CLASSIFICATION OF PENICILLINS ON THE BASIS OF
| SPECTRUM OF RESISTANCE TO RESISTANCE |
A ACTIVITY ENZYMES TO ACIDS

NATURAL NARROW | | RESISTANCE TO ACID
Penicillin-G Ampicillin SPECTRUM B-LACTAMASE STABLE
Penicillin-V Amoxycillin Methicillin Methicillin Penicillin-V
Penicillin-V Oxacillin Nafcillin Ampicillin
Oxacillin Nafcillin Oxacillin Amoxycillin
Cloxacillin Dicloxacillin Cloxacillin Oxacillin
Dicloxacillin BROAD Dicloxacillin Cloxacillin
PARENTERAL | SPECTRUM NON- Dicloxacillin
Penicillin-G Ampicillin RESISTANCE TO ACID
Methicillin Amoxycillin B-LACTAMASE UNSTABLE
Nafeillin INTERMEDIATE Penicillin-G
Carbencillin SPECTRUM Methicillin
|| Penicillin-G | Nafcillin
“|| Penicillin-V Carbencillin
EXTENDED | Piperacillin |
SPECTRUM Ticarcillin |
Carbencillin
Ticarcillin
Piperacillin
Mezlocillin sn
Penicillin

10. Anti-Bacterial Spectrum

11. Natural Penicillins

e They are obtained from:
- Fermentations of the mold Penicillium chrysogenum
e It includes:
- Penicillin G (Benzyl penicillin)
- Penicillin V (More acid stable/Used oral)
e They are effective against:
- Gr(+) and Gr(-) cocci
- Gr(+) bacilli
- Spirochetes

Penicillin

12. Natural Penicillin Cont.......
Cee

GONORRHEA

Streptococcus pneumoniae* © Silver nitrate drops in the eyes prevent
Streptococcus pyogenes gonococcal ophthalmia in newborns.
Viridans streptococci group

PNEUMOCOCCAL INFECTIONS © Penicillinase-producing strains are

¡Gram (+) bacilli treated using ceftriaxone, with

Bacillus anthracis azithromycin as a backup.
Corynebacterium diphtheriae

Gram (-) cocci
Neisseria gonorrhoeae

© Streptococcus pneumoniae
is a major cause of bacterial
pneumonia in all age groups and
of bacterial meningitis in infants
(excluding neonates) and adults.

Pneumococcal pneumonia occurs

Other chronic conditions suchas

diabetes, asthma, and chronic lung Clostridium perfringens SYPHILIS

sae © Acontagious venereal disease that
Resistance to penicillin G has progressively affects many tissues.

q cese pinte e ‘Treponema pertenue (yaws) atment with penicillin is curative

y and secondary syphilis. No
FL —— resistance has been reported.

Penicillin

13. Penicillin

14. Benzathine Penicillin Dosage in
Syphilis

Stage

Primary, secondary, or « Benzathine penicillin G 2.4 million units IM in a single dose
early latent syphilis If allergic to penicillin:
(<1 y) o Doxycycline 100 mg PO BID x 14d

o Tetracycline 500 mg PO four times daily x 14d
Late latent (>1 y), latent Benzathine penicillin G 2.4 million units IM x 3 doses at 1-wk

syphilis of unknown intervals
duration or tertiary If allergic to penicillin:
syphilis with normal Doxycycline 100 mg PO BID x 28d
cerebrospinal fluid tetracycline 500 mg po four times daily x 28 d
examination
Pregnant women Treat with appropriate penicillin regimen for stage of infection.

Additional doses may be indicted if evidence of fetal syphilis
on ultrasound

Syphilis patients with No additional doses of benzathine penicillin are indicated

HIV infection

Abbreviations: IM, intramuscularly; PO, orally.
Data from Refs.***'>*
Penicillin

15. Benzathine Penicillin in Secondary
Prevention of RHD
De,

Category of Patient Duration of Prophylaxis

RF without carditis

RF with carditis but no
residual valvular disease

RF with persistent valvular
disease, evident clinically
or on echocardiography

For 5 years after the last attack
or 21 years of age (whichever is
longer)

For 10 years after the last
attack, or 21 years of age
(whichever is longer)

For 10 years after the last
attack, or 40 years of age
(whichever is longer).
Sometimes lifelong prophylaxis.

Penicillin

16. Benzathine Penicillin in Secondary
Prevention of RHD Cont........

Antibiotic Dose
Benzathine penicillin G 600,000 units intramuscular (=27 kg) or

1,200,000 units intramuscular (>27 kg)
Every 4 weeks (3 weeks in high-risk

areas/populations)
Penicillin V 250 mg by mouth twice daily
Sulfadiazine 0.5 g by mouth daily (=27 kg) or
| g by mouth daily (>27 kg)
Macrolide* Drug-dependent

Notes: *In penicillin-allergic patients. Note, up to 5% of patients allergic to penicillin
may also be allergic to cephalosporins.
Source: American Heart Association, Inc.“

Penicillin

17. Penicillin G Preparations

Penicillin

18. Penicillin V Preparations
CE

Ey

WE
Penicillin VK

Tablets

Penicillin

19. Anti- staphylococcal Penicillins

e They include:
- Methicillin
— Naficillin
— Oxacillin
— Dicloxacillin
- Are penicillinase-resistant

e Use:

— Toxic

— Restricted to penicillinase-producing staphylococci

Penicillin

20. Anti- staphylococcal Penicillins

e MRSA is usually susceptible to:
— Vancomycin
- Rarely, to ciprofloxacin or rifampin
— TMP/SMX (Bacterium)
- Linezolid

Penicillin

21. Extended Spectrum Penicillin

e They include:
- Ampicillin and Amoxicillin

— Similar to Penicillin G spectrum

- More effective against Gr(-) bacilli
e Use:
- Respiratory infections

- Ampicillin is the drug of choice for the Gr(+) bacillus
Listeria Monocytogens

- Amoxicillin prophylactically for patients with abnormal
heart valves (Dentistry)

Penicillin

22. Extended Spectrum Penicillins
Cont.

of ampicillin
Gram (+) cocci
Enterococci

Gram (+) bacilli

| A. Antimicrobial spectrum |

Gram (-) rods
Escherichia coli

Haemoph influenzae
Proteus m lis
Salmonella typhi

Penicillin

23. Extended Spectrum Penicillin
Cont.......

e Resistance to these antibiotics is now:
- A major clinical problem (Enzymatic Hydrolysis)
e Formulation with a Beta-lactamase inhibitor:
- Protects amoxicillin or ampicillin from enzymatic
hydrolysis
e Beta-Lactamase Inhibitors include:
- Clavulanic acid
- Sulbactam
— Tazobactam

Penicillin

24. Extended Spectrum Penicillin
Cont.......

e Oral:
- Augmentin: Amoxicillin+ Clavulanic Acid

e Parenteral:
- Unasyn: Ampicillin + Sulbactam

Ticarcillin + clavulanic acid
Piperacillin + tazobactam

Penicillin

25. Anti- Pseudomonal Penicillin

e They include:

— Carbenicillin
— Ticarcillin

— Piperacillin (Most Potent)
e Use:
- P. aeruginosa (Also called Antipseudomonal Penicillins)

- Gram-negative bacilli, but not against Klebsiella

Penicillin

26. Anti- Pseudomonal Penicillin
Cont.....

B. Antimicrobial spectrum of
carbenicillin, ticarcillin,
and piperacillin

Gram (-) rods

Enterobacter species
Escherichia coli
Proteus mirabilis

Proteus (indole positive)
Haemophilus influenzae
Pseudomonas aeruginosa

Penicillin

27. Ampicillin Preparations

woc 0109-3718: Mi
Ampicillin m
for Injection, USP

ForlMorIVuse Si
5

Re Only 3

Penicillin

28. Amoxicillin Preparations

Amoxicillin
Capsules

E] alamy stock photo

29. unuswßny

Augmentin
(Co-amoxiclav)

= 625 mg
de 4
ST

6 Tablets

AH ciaxosmithktine

(QU9mentin

(Co-amoxiclav)

Penicillin

30. Penicillin and Aminoglycosides

e All the Beta-lactam antibiotics are:
- Synergistic with the aminoglycosides
e Mechanism of synergism:
- Penicillin alter the permeability of bacterial cells

- Facilitate the entry of Aminoglycosides to intracellular
target sites

- Results in enhanced antimicrobial activity
e Note:

- These drug types should never be placed in the same
infusion fluid Penicillin

31. Resistance to Penicillin

e Natural:
- Lack a peptidoglycan cell wall
— Or have cell walls that are impermeable to the drugs
- For example: Mycoplasma

e Acquired:
- Beta lactamase Activity (by organisms)
- Decreased permeability to the drug
- Altered PBPs

Penicillin

32. Pharmacokinetics

e Administration & Absorption:
- Slide No. 7

e Distribution:
- Distribute well throughout the body
- All cross the placental barrier (Not teratogenic)

- Penetration to bone or cerebrospinal fluid (CSF), is
insufficient unless these sites are inflamed

- Low levels in prostate (Not effective in prostatitis)

Penicillin

33. Pharmacokinetics

e Metabolism:
- Not metabolized (Except Penicillin G).

e Excretion:

- The primary route is organic acid (tubular) secretory
system of the kidney as well as by glomerular filtration

- Dose adjustment in renal failure

~ Probenecid inhibits the secretion of Penicillin

- Nafcillin biliary elimination

- The Penicillins are also excreted into breast milk

Penicillin

34. Adverse effects

e Common adverse reactions are:
- Hypersensitivity (Penicilloic acid)
— Diarrhea
— Nephritis (all but particularly Methicillin)
Neurotoxicity

- Hematologic toxicity
— Cation toxicity (administered as the sodium or potassium salt)

Penicillin

35. Adverse effects Cont..........

‘oxicities

Penicillin

36. References

Katzung, B. G., Masters, S. B., & Trevor, A. J. (2015). Basic & clinical
pharmacology. New York: McGraw-Hill Medical

e Whalen, K., Finkel, R., & Panavelil, T. A. (2017). Pharmacology
(Seventh Edition.). Philadelphia: Wolters Kluwer

e Tripathi, K. (2008). Essentials of medical pharmacology (6th ed.). New
Delhi: Jaypee Brothers

e The images are retrieved from: www.google.com/images

Penicillin

37. Thank You