Antibacterials: Cell Wall Synthesis Inhibitors

Antibacterial Drug Targets and Classes

• Differences Between Human and Bacterial Cells:

  • Human cells do not possess a cell wall.
  • Human cells utilize $60S$ and $40S$ ribosomal units, whereas bacterial ribosomes differ.
  • Human cells possess different forms of metabolic enzymes compared to bacteria.

• Primary Antibacterial Drug Classes:

  • Cell wall synthesis inhibitors.
  • Protein synthesis inhibitors.
  • Nucleic acid synthesis or function inhibitors.

Beta-Lactam Antibiotics

• Core Structure and Types:
  • All beta-lactam antibiotics contain a characteristic beta-lactam ring.
  • Penicillins: Feature a five-membered ring attached to the beta-lactam ring.
  • Cephalosporins: Feature a six-membered ring attached to the beta-lactam ring.
  • Carbapenems: Contain a fused ring structure.
  • Monobactams: Consist of a standalone beta-lactam ring (e.g., Aztreonam).
  • Structural Precursor: These antibiotics are structural analogues of the acyl-$D-Ala-D-Ala$ cell wall precursor.

Penicillins: Mechanism and General Classification

• Mechanism of Action (MOA):

  • Binding: The initial step involves the drug binding to specific cell receptors known as penicillin-binding proteins (PBPs).
  • Inhibition: Penicillins inhibit transpeptidase activity, which prevents the cross-linking of peptidoglycans during the formation of the cell wall in growing bacterial cells.
  • Lysis: The weakened cell wall leads to the osmotic lysis and death of the bacterial cell.

• Spectrum of Activity:

  • Primarily active against $Gram+$ bacteria, particularly streptococci.
  • Exceptions include cloxacillin and flucloxacillin, which are specifically tailored for staphylococcal infections.

• Sub-Classifications:

  • Beta-lactamase sensitive penicillins (Narrow spectrum, $Gram+$): Benzylpenicillin, Benzathine benzylpenicillin, Phenoxymethylpenicillin, Procaine benzylpenicillin.
  • Beta-lactamase sensitive penicillins with extended spectrum ($Gram+$, some $Gram-$): Amoxicillin, Ampicillin, Piperacillin.
  • Combinations of penicillins and beta-lactamase inhibitors (Broad spectrum, $Gram+$ and $Gram-$): Co-amoxiclav (Amoxicillin + Clavulanic acid), Piperacillin + Tazobactam.
  • Beta-lactamase resistant penicillins (Narrow spectrum, Staphylococcal/skin infections): Cloxacillin, Flucloxacillin.

Detailed Beta-Lactamase Sensitive Penicillins

• Benzylpenicillin (Pen G):

  • Pharmacokinetics: It is acid labile and inactivated by gastric acid; therefore, it must be administered parenterally (preferably IV). Intramuscular (IM) administration is painful. It has a short half-life requiring frequent dosing and is eliminated mainly via the kidneys.
  • Drug Interactions:
    • Probenecid: Decreases renal tubular secretion, delaying renal elimination and extending the half-life of all penicillins.
    • Aminoglycosides: High doses of Pen G can inactivate aminoglycosides if mixed.
  • Side Effects: Common hypersensitivity reactions and Gastrointestinal (GI) issues like nausea, vomiting, and diarrhea.

• Procaine Benzylpenicillin & Benzathine Benzylpenicillin:

  • Pharmacokinetics: These are depot preparations intended for IM administration only. Accidental intravenous administration can cause a life-threatening syndrome.
  • Elimination: Primarily renal.

Extended Spectrum and Combination Penicillins

• Amoxicillin:

  • Pharmacokinetics: Oral absorption is approximately $85\%$ and is not reduced by food. It penetrates well into most body fluids and is eliminated renally.
  • Contraindications: Infectious mononucleosis (high risk of rash) and true penicillin hypersensitivity.
  • Side Effects: GI intolerance (diarrhea) and skin rashes. Rash and diarrhea are generally less frequent than with ampicillin.
  • Prescribing Points: Avoid in acute purulent pharyngitis/tonsillitis if the causative organism is Epstein-Barr virus due to the high risk of rash.

• Beta-Lactamase Inhibitors:

  • Include Clavulanic acid, Sulbactam, and Tazobactam.
  • Co-amoxiclav: A combination of amoxicillin and clavulanic acid. Clavulanic acid is a beta-lactamase inhibitor with minimal intrinsic antibacterial action. It improves $Gram-$ coverage and effectiveness against resistant community-acquired organisms. It causes more GI irritation than amoxicillin alone.
  • Piptaz: A combination of Piperacillin and Tazobactam, highly active against Pseudomonas aeruginosa.

Beta-Lactamase Resistant Penicillins

• Agents: Cloxacillin and Flucloxacillin.
• Clinical Use: Restricted to infections caused by methicillin-sensitive Staphylococci, specifically skin infections (cellulitis, boils/abscesses, impetigo) and bone infections.
• Absorption: Flucloxacillin has better oral absorption than cloxacillin. Absorption is optimal when taken on an empty stomach ($1\,hour$ before or $3\,hours$ after meals).

Penicillin Hypersensitivity

• Acute Reaction: Occurs immediately or within $1-2\,hours$. Symptoms include sudden anaphylaxis, hypotension, bronchospasm, angioedema, and urticaria.
• Sub-acute Reaction: Occurs $7$ to $10\,days$ after treatment starts, or $1-2\,days$ after repeat therapy. Symptoms include urticaria, fever, and arthralgia/arthritis.
• Risk Factors: More common with parenteral administration and specific agents like Procaine or Benzylpenicillin. Less common with oral administration.
• Cross-reactivity: Cross-reactivity between penicillin and second/third-generation cephalosporins is low, potentially lower than cross-reactivity with unrelated antibiotics.

Cephalosporins

• General Information: Beta-lactam structure and mechanism identical to penicillins. Side effects include hypersensitivity, renal impairment, neurotoxicity (especially in the elderly), and GI disturbances.

• Generations and Spectrum:

  • First-Generation ($J01DB$): Effective against $Gram+$ bacteria. Includes Cefadroxil, Cefalexin (oral for skin/soft tissue infections), and Cazolin (IV for surgical prophylaxis).
    • Cefazolin: Does not penetrate the Central Nervous System (CNS); eliminated via glomerular filtration and tubular secretion; requires dose adjustment in renal failure.
  • Second-Generation ($J01DC$): Active against $Gram+$ and some $Gram-$ bacteria. Includes Cefuroxime, Cefoxitin, Cefprozil, and Cefamandole.
  • Third-Generation ($J01DD$): High efficacy against $Gram-$ (including H. influenzae) and some $Gram+$. Includes Ceftriaxone, Cefixime, Cefotaxime, Cefpodoxime, and Ceftazidime.
    • Pharmacokinetics: Penetrate tissues and CSF well. Mostly renally excreted except for Ceftriaxone.
    • Ceftriaxone Warning: Excreted via the biliary tract (no renal adjustment needed). Avoid co-administration with calcium-containing IV fluids (e.g., Ringer Lactate) due to precipitation risk. If used in patients over $28\,days$ old, flush lines with $0.9\%$ sodium chloride between sequential administrations.
  • Fourth-Generation ($J01DE$): Very broad spectrum ($Gram+$ and $Gram-$), including Pseudomonas. Includes Cefepime and Cefpirome.

Carbapenems, Monobactams, and Glycopeptides

• Carbapenems ($J01DH$):

  • Agents: Imipenem, Doripenem, Ertapenem, Meropenem.
  • Imipenem: Inactivated by renal dehydropeptidases; must be co-formulated with Cilastatin (a dehydropeptidase inhibitor).
  • Spectrum: Drug of choice for Extended-Spectrum Beta-Lactamase (ESBL)-producing $Gram-$ infections, including Pseudomonas (except Ertapenem) and Enterobacter.
  • Resistance: Carbapenem-resistant Enterobacteriaceae (CRE) include Klebsiella, Salmonella, and E. coli. Alternatives include Colistin, Tigecycline, or Fosfomycin.

• Monobactams ($J01DF$): Aztreonam.

• Vancomycin (Glycopeptide - $J01XA$):

  • Spectrum: $Gram+$ only, specifically Methicillin-resistant Staphylococcus aureus (MRSA).
  • Pharmacokinetics: Parenteral administration required for systemic infections; oral use is restricted to C. diff infections.
  • Safety: Narrow therapeutic index requiring Therapeutic Drug Monitoring (TDM). Trough levels are monitored immediately prior to the next dose.
  • Side Effects: "Red man syndrome" (caused by fast IV infusion), nephrotoxicity (increased when used with aminoglycosides).

Polymyxins and Fosfomycin

• Polymyxins ($J01XB$):

  • Agents: Colistin (Colistimethate sodium) and Polymyxin B.
  • Mechanism: Disruption of outer membrane integrity by binding to lipopolysaccharides (LPS) and phospholipids, leading to membrane destabilization.
  • Use: Last-line salvage therapy for Multidrug-resistant (MDR) and Extensively drug-resistant (XDR) $Gram-$ infections, such as Acinetobacter baumanni.
  • Toxicity: Highly nephrotoxic, often causing Acute Kidney Injury (AKI).

• Fosfomycin ($J01XX$):

  • Mechanism: Inhibits very early stage of cell wall synthesis by blocking peptidoglycan precursors.
  • Indications: Urinary Tract Infections (UTI) as a single dose; prophylaxis in urethral procedures.
  • Administration: Absorption is reduced by food; take $2\,hours$ before a meal.

Mechanisms of Antibacterial Action Summary

• (A) Inhibition of cell wall synthesis.
• (B) Inhibition of DNA synthesis.
• (C) Inhibition of protein synthesis.
• (D) Destabilizing the cell membrane.
• (E) Inhibiting metabolic pathways.