Cell wall synthesis inhibitors

Dr. Mohammed Al-Khawlani

Assist. Professor of pharmacology and Toxicology

1 Dr. M. Al-Khawlani
 Inhibitors of cell wall synthesis

❖ Inhibitors of cell wall synthesis:

Agents affecting
the cell wall

Non B-lactam
b-lactam antibiotics
Other antibiotics
Bacitracin
Vancomycin
Daptomycin

Penicillins Cephalosporins Carbapenems Monobactams

Amoxicillin Ertapenem
Imipenem/cilastatin* Aztreonam
Ampicillin Meropenem
Dicloxacillin
Indanyl carbenicillin
Methicillin 1st generation 2nd generation 3rd generation 4th generation
Nafcillin Cefadroxil
Oxacillin Cefaclor Cefdinir Cefepime
Cefazolin Cefprozil Cefixime
Penicillin G Cephalexin Cefuroxime
Penicillin V Cefotaxime
Cefoxitin Ceftazidime
Piperacillin Ceftibuten
Ticarcillin Ceftizoxime
Ceftriaxone
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(according to Lippincott´s Pharmacology, 2009)
 Inhibitors of cell wall synthesis

1 -B-Lactam Antibiotics:
AS: Penicillins, Cephalosporin, Carbapenem and Monobactam.
a) Contain B-Lactam ring (essential for anti-
bacterial activity)

b) Bactericidal and a time-dependent killing

c) They do not pass BBB except in cases of

inflammation, no hepatic metabolism

d) M.O.A: ↓ Cell Wall Synthesis by bind to specific Penicillin- Binding- Protein (PBP):

➢ ↓ Transpeptidase enzyme responsible for cross-linking of peptidoglycans, a

final step in cell wall synthesis → ↓ Cell Wall Synthesis.

➢ Activate Autolytic enzymes (Autolysins) → Lysis of cell wall

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 B-Lactam Antibiotics

▪ Have little or no effect on bacteria that are not growing and dividing

▪ No effect on organisms devoid of cell wall, e.g. Mycoplasma.

e) Selectivity: Human cells do not contain peptidoglycan cell wall.

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 B-Lactam Antibiotics

f) Resistance:

- Natural absence of peptidoglycan cell wall e.g. Mycoplasma, Mycobacteria, Fungi, and
Viruses.
- Production of B-lactamase (penicillinases) enzymes. e.g. S. aureus.
- Alteration in the PBP; e.g. MRSA, Pneumococci and enterococci.
- Decreased permeability to antibiotics (eg, Pseudomonas due to loss porin)

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 Penicillin

1. Penicillins:

▪ They possess a common nucleus: 6-Aminopenicillanic acid with a B-lactam ring.

▪ Most widely effective and safer.
▪ Increased resistance → limited their use.
.
❖ Preparations of Penicillin

1- Natural penicillins.as: penicillin G

➢ Advantage: Rapid onset, strongest effect.

➢ The disadvantage:
• Acid-sensitive: Not effect orally (given by IV injection).
• Inactivated by B-Lactamase (penicillinase): as Staph. aureus.
• Short acting due to rapid excretion in urine (4-6 h)
• Narrow spectrum

2- Anti- staphylococcal penicillin as: Methicillin

3- Extended—spectrum penicillin: Amoxicillin and Ampicillin

4- Antipseudomonal penicillin. Piperacillin & Carbenicillin

6 Dr. M. Al-Khawlani
 Penicillin

A. Natural Penicillin: from penicillium molds

1. Benzyl Penicillin (Penicillin G):

➢ Acid-sensitive, Inactivated by B-Lactamase (penicillinase), Short acting, Narrow

spectrum:
- Gm + ve cocci: streptococci, non-penicillinase producing staphylococci.
- Gm + ve bacilli: Cl. Perfringens (Gas gangrene), C. diphtheria and anthracis
- Gm- ve cocci: Gonococci and meningococci
- Some organisms: Treponema pallidum (syphilis) & actinomycosis .
- Not effect on all Gm-ve bacilli.

Uses:
- Serious infections: meningitis (especially in babies), gas
gangrene (DOC)

- Diphtheria, anthraxs, Acute & subacute bacterial endocarditis in rheumatic fever and
syphilis

Dose: 4-24 million u/day divided every 4-6 h

7 Dr. M. Al-Khawlani
 Penicillin

2. Phenoxy methyl Penicillin (Penicillin V): Weakest effect

1) Acid-Resistant Penicillin: effect orally
2) Inactivated by penicillinase, Short acting (6 h), Narrow spectrum: streptococcal

❑ Used: Dose: 250-500 mg /6-8 hours Orally.

- Treatment of minor infections as; streptococcal pharyngitis,
(Amoxicillin is used instead).
- Prophylaxis in rheumatic fever (Streptococcal infections)
250 mg PO bid . (2nd choice).

.3. Long acting penicillin ,e.g. benzathine penicillin- procaine penicillin

▪ Insoluble salts of Penicillin G → allow slow drug absorption with long Duration of action

➢ Acid-sensitive, B-Lactamase-sensitive, Narrow spectrum and Long acting penicillin

-Procaine penicillin: given every 12 hours.

-Benzathine penicillin: given once/month.
8 Dr. M. Al-Khawlani
 Penicillin

1) Procaine Penicillin.
- Combination of penicillin G + procaine that have longer duration (12-24 h) and less painful

- Used in: Dose: 600'000 U I.M /12-24 h.

➢ As Prophylaxis against subacute endocarditis in patients with valve disease or prosthetic
valves, 2-3 hours before dental procedures. Or Amoxicillin 2 g (1 hour before tooth
extraction).

➢ Treatment of moderate cases: syphilis , gonorrhea.

2) Benzathine Penicillin (Retarpin)® :

- Slowest onset but has longest duration of action among penicillin

- Used mainly in: Dose: 1.2 -2.4 million U I.M/ 1-4 Weeks.
- As Prophylaxis in rheumatic fever (β-hemolytic streptococcal infection), 1,200.000 units IM/
month for 5 years or until reaching 21 years age Or penicillin V 250 mg twice daily orally.
- Treatment of syphilis. (single dose)

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 Penicillin
B. Anti-staphylococci penicillin (B-Lactamase Resistant Penicillin)
Ex.
- Methicillin (given I.V only): It is not used now due to its nephrotoxicity
- cloxacillin, dicloxacillin, nafcillin and flucloxacillin (oral or parenteral)
➢ Narrow spectrum, B-Lactamase –resistant, Acid resistant (except methicillin),
Semisynthetic penicillin.

▪ They are active against staphylococci and streptococci (weaker than penicillin G). but
inactive against enterococci, anaerobic bacteria, and gram-negative cocci and rods.

▪ Used in the treatment of penicillinase producing staphylococci infections: as Abscess, skin

and soft tissues infection
▪ Nafcillin (I.V, I.M) and Oxacillin (orally) are considered the drugs of choice for serious
systemic staphylococcal infections
▪ MRSA (Methicillin-Resistant Staphylococcus Aureus) is a strain of Staphylococcus
aureus that are resistant to β-lactam antibiotics. (drug of choice is vancomycin)

▪ May combined with ampicillin to increase spectrum of activity.

Ampicillin + cloxacillin (Ampiclox)®
10 Ampicillin + dicloxacillin (Cloxapen)®
Dr. M. Al-Khawlani
 Penicillins

C. Extended-spectrum penicillin (Aminopenicillin): Semisynthetic penicillin

Ex: Ampicillin & Amoxicillin
a) Acid resistant (effective orally and parenterally).

b) wider spectrum (as natural penicillin + some Gram-ve bacilli).

- Gm -ve Bacilli e.g. H. influenza (R.T.I), E.coli (UT), salmonella typhi & H. pylori (GIT)
- Not effect on Pseudomonas, Proteus, and Klebsiella.

c) B-Lactamase sensitive: May combined with β– lactamase inhibitors (clavulanic acid or

sulbactam) to enhance activity.
Ex: [Amoxicillin/clavulanic acid (Augmentin)® - Ampicillin/sulbactam (Unasyn®)].

1) Ampicillin: 250-500 mg/6 h, more active on shigella, H. influenza, Listeria monocytopenia

▪ Incompletely absorbed orally especially in the presence of
food, causing diarrhea and superinfection.

▪ Useful in enteritis (bacillary dysentery)

▪ Ampicillin + gentamicin is used for Listeria monocytogenes
(bacterial meningitis) (DOC)
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 Penicillins
2) Amoxicillin (250-500 mg/TID): more active against Salmonella and Streptococcal fecalis.
▪ Absorption is much better than ampicillin (less affected
by food than ampicillin) & longer duration and Less GIT
disturbances & diarrhea
❖ Use:
➢ RTI: pharyngitis, tonsillitis, otitis, sinusitis, bronchitis, and pneumonia
➢ Typhoid fever and eradication of H. pylori in peptic ulcer.
➢ Prophylactically by dentists in subacute endocarditis before dental procedure (2 g/ 1 hour
before tooth extraction).
➢ U.T.I.
❖ B lactamase inhibitors: : Clavulonic acid , Sulbactam , Tazobactam
▪ They bind with the enzyme → Irreversible inhibition → Suicide substrate.
▪ They have very weak or no anti-bacterial activity
▪ They protect penicillin from inactivation by B-lactamases secreted by some bacteria
e.g. Proteus, E. coli, Pseudomonas, Staph aureus & H. influenza

❑ Clavulanic acid+ Amoxicillin (Augmentin)®. Oral, parenteral.

- Uses: - Acute otitis media, sinusitis, bronchitis, UTI.

❑ Sulbactam + Ampicillin Unasyn®. Oral, IM & IV.

12 Uses: Mixed intra-abdominal and Dr.
pelvic infection.
M. Al-Khawlani
 Penicillins

D. Anti-Pseudomonal Penicillin: Semisynthetic penicillin

Ex: Piperacillin (most potent) & Ticarcillin, Carbenicillin

a) Inactivated by B-lactamase: so they are combined with β– lactamase inhibitors
(clavulanic acid or Tazobactam).
b) carbenicillin is acid stable (oral); piperacillin is unstable (parenteral).
c) Broad spectrum: including Pseudomonas & many Gram-ve bacilli.
- Less active against gm+ve bacilli and cocci.

▪ They are given with aminoglycosides (synergistic effect) → treatment of serious infections
(pneumonias, UTI, burns) but should not be mixed in the same syringe or bottle.

▪ They are subdivided into:

- Carboxy penicillins: Carbenicillin (IV, IM) – Ticarcillin (IV)
- Ureido penicillins: Piperacillin - Azlocillin- Mezlocillin (IV, IM).

❑ Clavulanic acid + Ticarcillin (Timentin)®. IV, IM.

- Uses: Mixed nosocomial infection + aminoglycoside

❑ Tazobactam + Piperacillin (Zosyn)® IV.

Uses: Intra-abdominal, pelvic, urinary and respiratory infection.
13 Dr. M. Al-Khawlani
 Penicillins

❖ Pharmacokinetics:
A) Absorption:
- Most of the penicillin are incompletely absorbed after oral administration, → affect the
composition of the intestinal flora → Superinfection
- Most oral penicillin ( Except amoxicillin) is impaired by food, → should be administered at
least 1–2 hours before or after a meal.

B) Distribution:. low tissue distribution, not pass BBB except in cases of meningitis,
Pass placental (safe in pregnancy).

C) Excretion:
- Renal elimination (Except nafcillin & oxacillin, hepatic metabolism, biliary excreted).
- Probenecid → inhibits renal tubular secretion of penicillin by competing with it →
prolongs penicillin action.

NB: Benzyl penicillin is rapidly excreted and has shortest duration of action.

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 Penicillins

❖ Side effects: Penicillin are among the safest antibiotics

1) Hypersensitivity (allergic reactions):
- As rash, urticaria, angioedema, or anaphylactic shock
- There is cross allergy between penicillin and other B-lactam antibiotics

2) Diarrhea, pseudomembranous colitis and superinfection ; more with incompletely

absorbed & broad spectrum agents eg. ampicillin → caused by C.difficile (treated by
Metronidazole or Vancomycin).

3) Local pain due to IM injection (penicillin G), thrombophlebitis after IV injection

4) Neurotoxicity: Seizures and epileptic fits in case of large doses and patient with renal
failure.

5) Decreased coagulation: leading to bleeding ( carbenicillin, ticarcillin), due to defective

platelet aggregation

7) Nephritis: by methicillin (not used clinically).

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 Penicillins

❖ Drug interactions
➢ Penicillin (cidal) + Tetracyclines, Chloramphenicol, Erythromycin (static) → Antagonism.

➢ Penicillin + Aminoglycosides → Synergism (but should not be mixed in the same syringe
→ Inactive each other)

➢ Penicillin + Probenecid → Prolongs action of penicillin

❖ Contraindications:
➢ Allergy.
➢ Epilepsy

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