Beta-lactam Antibiotics: Mechanism of Action and Resistance

Beta-lactam Antibiotics: Mechanism of Action and Resistance

Beta-lactam antibiotics are a broad-spectrum class of antibiotics widely used in the treatment of bacterial infections. This group includes various subgroups:

1. By structure:

• Penam: Penicillin

• Penem: Imipenem, Meropenem, Ertapenem, Doripenem

• Cephem: Cephalosporin

• Monobactam: Aztreonam

2. By mechanism of action:

• Beta-lactams inhibit peptidoglycan synthesis, a crucial component of the bacterial cell wall.

• They bind to Penicillin Binding Proteins (PBPs), comprising two types of enzymes:

• Transpeptidase: Involved in cross-linking amino acid chains.

• Glycosyl-transferase: Connects glycopeptide polymer subunits.

• This leads to inhibition of peptidoglycan synthesis and subsequent bacterial cell lysis.

Mechanisms of bacterial resistance to beta-lactams:

• Production of ?-lactamases: Enzymes that hydrolyze (break down) antibiotics (penicillinase and cephalosporinase).

• Decreased permeability of the cell wall:

• Gram-negative bacteria alter the structure of porin channels.

• Modification of antibiotic binding sites:

• Reduced affinity of the target site for the antibiotic.

• Active efflux pumps:

• Export antibiotics across both the outer and inner membranes.

• Composed of at least 3 proteins.

• A significant cause of resistance: overexpression.

Classification and spectrum of activity of beta-lactam antibiotic groups:

1. Penam – Penicillin:

• Penicillin G & V:

• Benzylpenicillin (Peni G)

• Phenoxymethylpenicillin (Peni V)

• Penicillin A: Ampicillin, Amoxicillin, Bacampicillin

• Penicillin M: Methicillin, Oxacillin, Cloxacillin, Dicloxacillin, Nafcillin

• Carboxy-Penicillin: Carbenicillin, Ticarcillin

• Ureido-penicillin: Mezlocillin, Piperacillin

2. Penem:

• Imipenem (+cilastatin): Prevents breakdown of imipenem in the kidney.

• Ertapenem; Doripenem; Meropenem.

3. Monobactam:

• Aztreonam: Selective against aerobic Gram-negative bacteria.

Note:

• MRSA (Methicillin-Resistant Staphylococcus aureus): Resistant to methicillin and most beta-lactams, except imipenem and 4th generation cephalosporins.

• MSSA (Methicillin-Sensitive Staphylococcus aureus): Susceptible to methicillin.

• CA-MRSA (Community Acquired – MRSA): Methicillin-resistant Staphylococcus aureus acquired in the community.

• Clavulanic acid: Protects beta-lactam antibiotics by inhibiting ?-lactamases.

• Carbapenem: Resistant to most ?-lactamases.

Adverse effects of beta-lactams:

• Allergic reactions: Anaphylaxis, interstitial nephritis, hemolytic anemia, seizures.

• Gastrointestinal disturbances.

• High doses/renal impairment: Seizures, blood disorders.

Note:

• Peni G is only administered intramuscularly or intravenously due to breakdown in the acidic environment of the stomach.

• Peni V is stable in acidic environments and can be administered orally.

• Cephalosporins are alternative choices when Peni G or V are ineffective.

• Imipenem can cause seizures and epilepsy.

• Aztreonam is ineffective against Gram-positive and anaerobic bacteria.

• ?-Lactamase inhibitors: Clavulanic acid, Sulbactam, Tazobactam, Avibactam, Vaborbactam.

Combination therapy:

• Peni G + Probenecid: Prolongs the action of Peni G.

• Ampicillin/Amoxicillin + Clavulanic acid: Inhibits ?-lactamases.

• Piperacillin/Mezlocillin + Tazobactam: Inhibits ?-lactamases.

• Meropenem + Vaborbactam: Inhibits ?-lactamases.

• Cefazidim + Avibactam: For adults with intra-abdominal and urinary tract infections.

Antibiotic selection:

• Penicillinase-producing Staphylococcus aureus: Oxacillin.

• Treponema pallidum (syphilis): Penam.

• Aerobic Gram-negative infections: 3rd generation cephalosporins, Aztreonam.

• Pseudomonas resistant to imipenem: Meropenem.

• Community-acquired – hospital-acquired pneumonia – MRSA: Ceftobiprole.

In conclusion:

Beta-lactam antibiotics are a broad-spectrum class of antibiotics widely used in the treatment of bacterial infections. However, antibiotic resistance is a growing concern. Understanding the mechanism of action and resistance of beta-lactams facilitates appropriate and effective antibiotic selection for treatment.