Penicillins Classification and Mechanism Quiz

Penicillins

• Penicillins are a class of β-lactam antibiotics.
• Beta-lactam antibiotics are named because of their unique 4-membered β-lactam ring.
• Penicillins include: Penicillins, Cephalosporins, Monobactams & Carbapenems
• β-lactam antibiotics share chemistry, mechanism of action (MOA), pharmacology, and immunologic characteristics.

Classification of Penicillins

• Natural penicillins (Narrow-Spectrum, β-lactamase Susceptible): include Penicillin G (benzylpenicillin) and Pen V.
  • These have strong activity against gram +ve organisms, gram -ve cocci, & non-β-lactamase-producing anaerobes.
  • However, they have little activity against gram -ve rods and susceptible to hydrolysis by β-lactamases.
  • Penicillin G has greater antimicrobial activity than Pen V.
• Antistaphylococcal penicillins (Very-Narrow-Spectrum, β-lactamase-resistant): examples include methicillin, nafcillin, dicloxacillin, oxacillin, cloxacillin, and flucloxacillin.
  • These are semi-synthetic penicillins
  • Resistant to staphylococcal β-lactamases.
  • Active against staphylococci and streptococci.
  • Inactive against enterococci, anaerobic bacteria, and gram-ve bacteria.
• Extended-spectrum penicillins (Wider-Spectrum, β-lactamase-Susceptible): divided into two classes:
  • a. Enteric active penicillins (the aminopenicillins): include ampicillin and amoxicillin.
  • b. Enteric active and antipseudomonal penicillins: include carboxypenicillins (Carbenicillin, Ticarcillin), and ureidopenicillins (Piperacillin, Mezlocillin, Azlocillin).
    • Extended-spectrum penicillins retain the antibacterial spectrum of penicillin and have improved activity against gram-negative bacilli.

Mechanism of Action (MOA)

• Penicillin inhibits bacterial cell wall synthesis by interfering with the last step (transpeptidation reaction).
• The cell wall is composed of a complex cross-linked polymer called peptidoglycan, which consists of polypeptides and polysaccharides.
• The β-lactam antibiotic covalently binds to specific receptors on penicillin-binding proteins (PBPs) located in the bacterial cytoplasmic membrane.
• Inhibition of transpeptidase enzymes that cross-link linear peptidoglycan chains prevents the cell wall from maintaining its structural rigidity, leading to blockage of peptidoglycan synthesis and bacterial cell death.
• Activation of autolysins (=autolytic enzymes) causes lesions in the bacterial cell wall.

Resistance Mechanisms

• Resistance to penicillins and other β-lactam antibiotics is due to four mechanisms:
  • i. Inactivation by β-lactamases: β-lactamases are enzymes that hydrolyze the cyclic amide bond of the β-lactam ring.
  • ii. Impaired penetration of the drug to target PBPs: This is usually seen in gram-negative species due to their outer membrane.
  • iii. Alteration of target PBPs: resistant organisms produce PBPs with low affinity for β-lactam antibiotics .
  • iv. AB efflux: gram-negative organisms might produce an efflux pump that transports a portion of the β-lactam antibiotics out of the bacterial cell.

Pharmacokinetics (PK)

• Absorption of orally administered penicillins varies significantly based on acid stability and protein binding.
  • Methicillin is acid labile.
  • GIT absorption of nafcillin is erratic.
  • Pen V, dicloxacillin, ampicillin, and amoxicillin are acid-stable, well absorbed after oral administration.
  • Absorption of most oral penicillins (except amoxicillin) is impaired by food; take the drugs at least 1-2 hours before or after meals.
  • IV administration of penicillin G is preferred over IM to avoid pain.
• Highly protein-bound penicillins (e g, nafcillin) achieve lower free-drug concentrations in serum than pen G, ampicillin.
• Penicillins are widely distributed in bodily fluids and tissues, except in the eye, prostate, and central nervous system (CNS).
• With active inflammation in the meninges (e.g., bacterial meningitis), penicillin can reach high concentrations to kill susceptible strains of pneumococcus and meningococcus.
• Excreted into sputum and milk 3-15% of serum levels.
• Benzathine and procaine penicillins are formulated to delay absorption and serve as depot forms after IM administration.
• Metabolism of penicillins is usually insignificant; excretion mainly occurs via kidneys into urine (10%) by glomerular filtration and 90% by tubular secretion. Normal half-life of Pen G is about 30 minutes; potentially longer (up to 10 hours) in renal failure, while half-lives of ampicillin and extended spectrum penicillins are around 1 hour.
• Dosage should be adjusted in patients with impaired renal function, except for nafcillin, oxacillin, dicloxacillin, and cloxacillin.
• Nafcillin is primarily cleared via biliary excretion; oxacillin, dicloxacillin, and cloxacillin are cleared by both kidney and biliary excretion.
• Penicillin clearance is less efficient in newborns resulting in higher systemic concentrations for longer periods than in adults.

Clinical Uses

• Penicillin (Natural): Drug of Choice (DOC) for infections caused by streptococci, meningococci, some enterococci, penicillin susceptible pneumococci, non β-lactamase-producing staphylococci, Treponema pallidum, Clostridium, Actinomyces.
• Penicillin V: Often used in minor infections.
• Antistaphylococcal penicillins: Suitable for infections by β-lactamase-producing staphylococci, penicillinsusceptible strains of streptococci & pneumococci, Listeria monocytogenes, enterococci.
• Oxacillin, cloxacillin, dicloxacillin, Oral, every 4-6 hours, suitable for mild to moderate localized staphylococcal infections and IV for systemic staph infections.
• Extended-spectrum penicillins: Used for infections suspected to be caused by penicillin-resistant pneumococci, gram -ve bacteria.
  • Ampicillin and amoxicillin are given orally for UTIs, sinusitis, otitis media, and LRTIs. Ampicillin is effective in shigellosis and used for serious infections caused by penicillin-susceptible microorganisms. Ampicillin may prolong carrier state during uncomplicated Salmonella Gastroenteritis.
  • Ampicillin and amoxicillin have the same spectrum. Amoxicillin is better absorbed orally.
  • Benzathine penicillin G is used for syphilis and β-hemolytic streptococcal pharyngitis. Given IM once every 3-4 weeks.
  • Procaine penicillin G formerly used for pneumonia and gonorrhea.

Adverse Effects (AEs)

• Penicillins are generally well-tolerated.
• Adverse effects mainly due to hypersensitivity.
• All penicillins are cross-sensitizing.
  • Allergic reactions can include anaphylactic shock, serum sickness, urticaria, fever, joint swelling, angioedema, intense pruritus, respiratory compromise occurring 7-12 days after exposure/ and a variety of skin rashes.
  • Oral lesions, fever, interstitial nephritis (autoimmune rxn), eosinophilia, hemolytic anemia, and vasculitis may also occur.
  • Seizures may occur if high doses used in patients with renal failure.
• Nafcillin is associated with neutropenia.
• Oxacillin can cause hepatitis.
• Methicillin causes interstitial nephritis.
• GIT upset (nausea, vomiting, diarrhea) is possible with high oral doses.
• Ampicillin can be associated with pseudomembranous colitis and vaginal candidiasis.
• Skin rashes (not allergic) can occur when these drugs are inappropriately prescribed for viral illnesses.

Test your knowledge on penicillins, a class of β-lactam antibiotics. This quiz covers their classification, mechanisms of action, and pharmacological aspects, focusing on natural and antistaphylococcal penicillins. Challenge yourself to see how well you understand these important antibiotics!