Antimicrobial Action and Beta-Lactamases Quiz

Mechanism of Action of β-Lactam Antibiotics

• Inhibit the transpeptidase enzyme required for the synthesis of peptidoglycan, which is responsible for the integrity of bacterial cell walls
• Water enters the deficient cell wall of bacteria, leading to spheroblast formation and finally lysis of bacteria
• Activate autolytic enzymes that cause lesions in the cell wall

Antimicrobial Spectrum and Uses of Penicillins

• Penicillin G (Pen G):
  • Active against Gram-positive cocci (Streptococci, Non-β-lactamase-producing staphylococci, Penicillin-susceptible pneumococci)
  • Active against Gram-positive bacilli (Clostridium species, Bacillus anthracis, Corynebacterium diphtheriae, Actinomyces, and other Gram-positive rods)
  • Active against Treponema pallidum (Syphilis) and other spirochetes
• Penicillin V (Pen V):
  • Active against Gram-positive cocci (except penicillinase-producing staphylococci)
  • Used for minor infections (streptococcal pharyngitis) due to relatively poor bioavailability and narrow antibacterial spectrum

Terminology

• Selective toxicity: Interfering with metabolic processes that exist only in infectious organisms, but not in host cells, at concentrations tolerated by the host
• Bacteriostatic: Inhibiting the growth or multiplication of bacteria, requiring host defense mechanisms to eradicate the infection
• Bactericidal: Lethal effect on mature bacteria, capable of eradicating an infection in the absence of host defense mechanisms
• β-Lactam antibiotics: Drugs with structures containing a β-lactam ring, including penicillins, cephalosporins, and carbapenems
• β-Lactamases: Bacterial enzymes that hydrolyze the β-lactam ring of certain penicillins and cephalosporins, conferring resistance
• β-Lactamase inhibitors: Potent inhibitors of some bacterial β-lactamases, used in combinations to protect hydrolysable penicillins from inactivation
• Minimal inhibitory concentration (MIC): Lowest concentration of antimicrobial drug capable of inhibiting growth of an organism in a defined growth medium
• Penicillin-binding proteins (PBPs): Bacterial cytoplasmic membrane proteins that act as the initial receptors for penicillins and other β-lactam antibiotics
• Antibacterial spectrum: List of bacteria which are normally susceptible to antibacterial action of a particular agent
• Resistance: Resistance of microorganisms to anti-infective agents

Combination Chemotherapy and Superinfection

• Combination chemotherapy: Use of two or more anti-infective agents simultaneously to:
  • Obtain potentiation
  • Delay development of drug resistance
  • Broaden the spectrum of antibacterial activity
• Superinfection (Opportunistic infection): Appearance of bacteriological and clinical evidence of a new infection during chemotherapy of a primary one, due to suppression of normal bacteria flora

Spectrum and Clinical Uses of Antipseudomonal Penicillins

• Carbenicillin indanyl and Ticarcillin (carboxypenicillins): Active against Pseudomonas, Enterobacter, and Proteus
• Mezlocillin, Azocillin, and Piperacillin (uridopenicillins): Excellent activity against Pseudomonas, Klebsiella, and certain other Gram-negative microorganisms
• Piperacillin retains activity against Gram-positive cocci and Listeria monocytogenes

Pharmacokinetics of Penicillins

• Penicillin G:
  • Destroyed by acid, should be given parenterally
  • Widely distributed in body fluids, but does not cross the blood-brain barrier (BBB) unless the meninges are inflamed
• Orally active penicillins (Dicloxacillin, Amoxicillin, and Ampicillin):
  • Acid-stable
  • Absorption impaired by food
• Mainly excreted by the kidney as unchanged forms, with 10% by glomerular filtration and 90% by tubular secretion
• Probenecid inhibits renal tubular secretion of penicillin and prolongs its action

Untoward Effects of Penicillins

• Hypersensitivity reactions:
  • Anaphylactic shock
  • Urticaria
  • Fever
  • Joint swelling
  • Angioneurotic oedema
  • Skin rash
  • Oral lesions
• Nausea, vomiting, diarrhoea due to superinfection (common with oral penicillins)

β-Lactamase Inhibitors

• Clavulanic acid, Sulbactam, and Tazobactam:
  • Poor intrinsic antimicrobial activity
  • 'Suicide' inhibitors that irreversibly bind to β-lactamases produced by a wide range of Gram-positive and Gram-negative microorganisms
  • Well-absorbed orally and parenterally
  • Widen antibacterial spectrum of penicillins when used in combination
• Combinations:
  • AUGMENTIN (Coamoxiclav): Amoxicillin + Clavulanic acid
  • TIMENTIN: Ticarcillin + Clavulanic acid
  • UNASYN: Ampicillin + Sulbactam
  • Piperacillin + Tazobactam
• Uses: Infections caused by β-lactamase-producing strains of bacteria
• Untoward effects: Same as penicillins