Cell Wall Inhibitors Summary

Cell Wall Synthesis Inhibitors

Classification of Cell Wall Synthesis Inhibitors

• Beta-Lactam Antibiotics
  • Penicillins
  • Cephalosporins
  • Monobactams
  • Carbapenems
• Glycopeptides
  • Vancomycin
• Others
  • Bacitracin

Penicillins

Classification

1. Natural Penicillins: Penicillin G, Penicillin V
2. Antistaphylococcal Penicillins: Nafcillin
3. Extended-spectrum Penicillins
   • Aminopenicillins: Ampicillin, Amoxicillin
   • Antipseudomonal Penicillins: Ticarcillin, Azlocillin, Piperacillin
   • Combined with β-lactamase inhibitors (Clavulanic acid, Sulbactam, Tazobactam) to extend activity.

Pharmacokinetics

• Absorption: Affected by acid stability, protein binding, and food intake.
  • Nafcillin: erratic absorption (not for oral use).
  • Dicloxacillin, ampicillin, amoxicillin, and Penicillin V: acid-stable, well-absorbed.
  • Penicillin G: less acid-stable (parenteral).
  • Food impairs absorption (except amoxicillin).
  • Benzathine and procaine penicillins: delay absorption for prolonged action.
• Protein Binding: Varies among penicillins.
  • Highly protein-bound: Nafcillin.
  • Less protein-bound: Penicillin G, ampicillin.
• Distribution: Widely distributed; crosses the placenta (not teratogenic); crosses BBB when inflamed.
• Excretion: Primarily renal.
  • Tubular secretion (90%) and glomerular filtration.
  • Half-life of penicillin G: ~30 minutes (up to 10 hours in renal failure).
  • Nafcillin: biliary excretion.
  • Probenecid: prolongs penicillin action by inhibiting renal tubular secretion.
  • Excreted into sputum and breast milk.

Mechanism of Action

• Bactericidal: inhibits transpeptidation in cell wall synthesis by binding to penicillin-binding proteins (PBPs).
• Activates autolysins, leading to cell wall lysis.

Clinical Uses

• β-hemolytic streptococcal pharyngitis, syphilis: Benzathine penicillin (IM).
• Pneumococcal pneumonia, gonorrhea, meningococcal meningitis, bacterial endocarditis.
• Prophylaxis: rheumatic fever recurrence, bacterial endocarditis (with aminoglycoside).
• Aminopenicillins: broad spectrum infections.
• Antipseudomonal penicillins: Pseudomonas infections.
• Staphylococcal beta-lactamase resistant penicillins: methicillin-susceptible staphylococci infections.

Adverse Reactions

1. Hypersensitivity.
2. Seizures.
3. Neutropenia and interstitial nephritis (Nafcillin).
4. Hepatitis (Oxacillin).
5. Interstitial nephritis (Methicillin).
6. Gastrointestinal upset.
7. Pseudomembranous colitis (Ampicillin).
8. Secondary infections (vaginal candidiasis).

Contraindications

• Previous hypersensitivity to penicillin.

Cephalosporins

General

• Similar chemical structure to penicillin, contains beta-lactam ring.

Mechanism of Action

• Bactericidal: inhibits peptidoglycan synthesis by binding to PBPs (transpeptidases).

Antibacterial Spectrum

• Classified into generations (1st, 2nd, 3rd, 4th, and 5th) based on activity and resistance to β-lactamases.
• Traditional cephalosporins: inactive against MRSA (except 5th generation).

Traditional Classification

Coverage

• 1st Gen: Good Gram Positive, Poor Gram Negative
• 2nd Gen: OK Gram Positive, OK Gram Negative
• 3rd Gen: Poor Gram Positive, Good Gram Negative. Some cover Pseudomonas.
• 4th Gen: Pseudomonas +, Good Gram Pos/Neg
• 5th Gen: MRSA +, Good Gram Pos/Neg.

Pharmacokinetics

• Oral forms well absorbed (absorption affected by food).
• 1st & 2nd generations can't cross BBB; 3rd & 4th can.
• Excretion:
  • Active renal tubular excretion prevented by Probenecid.
  • Cefotaxime is partially de-acetylated and partially excreted unchanged in urine.
  • Ceftriaxone & Cefoperazone: biliary excretion.

Indications

1. Infections resistant to penicillins.
2. Pseudomonas infections: Cefoperazone & Ceftazidime.
3. Anaerobic infections: 3rd & 4th generations.
4. Gram -ve Meningitis: Cefotaxime, Ceftriaxone.
5. Respiratory tract infection.
6. Typhoid fever: Ceftriaxone & Cefoperazone.
7. Urinary tract infections.
8. Gonorrhea: Ceftriaxone.
9. Pre- & Post-operative prophylaxis: First or Second generation Cephalosporin.

Side Effects

1. Allergy & cross-allergy with Penicillins(10%).
2. GIT upsets and Superinfection.
3. Irritant: I.M. painful, I.V. Thrombophlebitis.
4. Nephrotoxicity (Cephaloridine).
5. Ceftriaxone + Calcium: Insoluble salts in Bile.
6. Disulfiram-like action.
7. Hypoprothrombinemia and bleeding disorders.

Contraindications

1. Allergic patient.
2. Ceftriaxone: contraindicated in neonates with hyperbilirubinemia and infants less than 28 days old if they are expected to receive any calcium-containing products.

Monobactams: Aztreonam

• Spectrum: aerobic Gram-negative organisms (including P. aeruginosa).
• No activity against Gram-positive bacteria or anaerobes.
• Highly resistant to beta-lactamase.
• No cross-hypersensitivity with penicillin.
• Penetrates well into the cerebrospinal fluid.
• Dosage: 1–2 g IV every 8 hours.
• Half-life: 1–2 hours; prolonged in renal failure.
• Caution with ceftazidime allergies due to structural similarity.
• Adverse effects: skin rashes and elevated serum aminotransferases.

Carbapenems: Imipenem, Meropenem

• Broad spectrum: Gram-positive, Gram-negative, & anaerobic.
• Highly resistant to β-lactamase.
• Indications:
  • Infections resistant to other drugs (e.g., P. aeruginosa).
  • Mixed aerobic and anaerobic infections.
  • Penicillin-resistant pneumococci.
  • Enterobacter infections.
  • Serious infections caused by extended-spectrum β-lactamase-producing Gram-negative bacteria.
• Adverse effects:
  • Blood disorders.
  • Seizures (high doses).
  • G.I.T: nausea, vomiting.

Resistance to β-lactam Antibiotics

1. Inactivation of antibiotic by β-lactamase.
2. Modification of target PBPs.
3. Impaired penetration of drug to target PBPs.
4. Antibiotic efflux.