3_ Cell wall inhibitors

43. Drugs Affecting Bacterial Cell Wall & Membrane Rigidity Part 1

1. Overview of Antibiotics

  • Beta-lactams

    • Main classes: Penicillins, Cephalosporins, Monobactams, Carbapenems.

    • Glycopeptides & Lipoglycopeptides:

      • Examples: Vancomycin, Telavancin, Teicoplanin, Dalbavancin, Oritavancin.

    • Lipopeptides: Daptomycin.

    • Others: Fosfomycin, Bacitracin, Cycloserine, Polymyxins.

    • Beta-lactamase inhibitors: Avibactam, Tazobactam, Sulbactam, Clavulanic acid, Vaborbactam, Relebactam.

2. Penicillins

  • Classification:

    • Antistaphylococcal penicillins: effective against penicillinase-producing S. aureus spp.

    • Extended spectrum penicillins: Piperacillin is approved in the USA with a broad antibacterial profile.

  • Mechanism: Penicillins work by inhibiting transpeptidase, leading to compromised cell wall rigidity and cell death.

3. Mechanism of Action of Beta-lactams

  • Transpeptidation process: Bacterial enzyme transpeptidase catalyzes cross-linking of peptidoglycan layers.

  • Inhibition by penicillins:

    • Inhibits removal of D-Alanine from D-Ala-D-Ala, disrupting cross-link formation necessary for cell wall rigidity.

    • Results in leakage of cellular components and cell lysis.

4. Mechanisms of Resistance

  • Development of efflux pumps that expel drugs.

  • Decreased membrane permeability restricts drug entry.

  • Enzymatic inactivation through increased beta-lactamase production.

  • Altering bacterial targets reduces drug efficacy

  • Ribosomal protection proteins can lead to resistance against fluoroquinolones and tetracyclines.

5. Shared Properties of Penicillins

  • Distribution: Widely distributed with therapeutic concentrations in tissues and fluids but low in prostatic and brain tissues.

  • Absorption:

    • Penicillin G more potent than Penicillin V in treating certain infections.

    • Penicillin V has better GI absorption due to acid stability.

  • Common Side Effects: Hypersensitivity reactions and potential for seizures in renal failure patients.

6. Antistaphylococcal Penicillins & Extended Spectrum Penicillins

  • Cloxacillin and flucloxacillin available in South Africa.

  • Piperacillin is combined with tazobactam for extended activity against gram-negative bacteria.

  • Note on fluid retention and hypokalemia due to high sodium content in injectable forms.

  • Amoxicillin shows better bioavailability compared to ampicillin with fewer GI side effects.

7. Beta-lactamase Inhibitors

  • Traditional inhibitors: Glavulanic acid, sulbactam, and tazobactam prevent hydrolysis of beta-lactams.

  • Non-beta-lactam inhibitors: Avibactam offers reversible inhibition for prolonged effects.

  • Clinical Testing: Relebactam and vaborbactam under investigations for novel effects.

8. Cephalosporins

  • Generational classification from 1st to 5th:

    • 1st Generation: Cefalexin, Cefazolin, etc.

    • 2nd Generation: Cefuroxime, Cefoxitin, etc.

    • 3rd Generation: Ceftriaxone, Cefixime, etc.

    • 4th and 5th Generation agents have increasing efficacy against gram-negative and resistant organisms.