lecture 2

• Penicillin is among the most widely effective antibiotics and are among the least toxic drug known
• The penicillin nucleus itself is the chief structural requirement for biological activity; Metabolic transformation or chemical alteration of this portion of the molecule causes loss of all significant antibacterial activity
• 1. lactam Antibiotics

  • Penicillins (Penicillin G, Penicillin V, Methicillin, Nafcillin, Oxacillin, Cloxacillin, Ampicillin, Amoxycillin, Carbenicillin, Ticarcillin, Pipercillin, Azlocillin)
  • Cephalosporins: Ist generation (cefazolin, cefadroxil, cephalexin), 2nd generation (cefaclor, cefoxitin, cefuroxime), 3rd generation (cefixime, ceftriaxone, cefotaxime), 4th generation (cefepime)
  • Carbapenems: Imipenem, Meropenem, Ertapenem
  • Monobactams: Aztreonam
• Core structures of four β-Lactam antibiotic families. The ring marked B in each structure is the β-lactam ring. The penicillins are susceptible to bacterial metabolism and inactivation by amidases and lactamases at the points shown. Note that the carbapenems have a different stereochemical configuration in the lactam ring that apparently imparts resistance to β-lactamases
• Mechanism of action of Penicillin

  • Interacts with penicillin binding protein (PBP) on the cytoplasmic membrane to inhibit transpeptidation reactions involved in cross-linking of peptidoglycan chains, the final step in cell wall synthesis
• Penicillin is bactericidal
• Production of beta-lactamase by the organism

  Results in the breakdown of penicillin to penicillonic acid, which has no antibacterial activity
• Activation of autolytic enzymes (autolysins)


  Group of enzymes stored inside bacteria that, once released, are activated and destroy the existing cell wall
• Penicillin is only effective against rapidly growing organisms that synthesize a peptidoglycan cell wall
• Mechanisms of Resistance to Penicillin
• Metabolic transformation or chemical alteration of a portion of the molecule causes loss of all significant antibacterial activity
• Penicillin is one of the most widely effective antibiotics and among the least toxic drugs known
• Reduction in the permeability of the outer membrane of bacteria to penicillins

  Can contribute to resistance
• Structural change in Penicillin Binding Proteins (PBPs)

  Can lead to methicillin-resistant S. aureus and penicillin-resistant pneumococci
• PHRS – 303 LECTURE 2: Beta lactam Antibiotics: Penicillin by Dr. Rawan Alnafisah


  3 Mar. 2024
• Subgroups and Antimicrobial Activity of Penicillin

  • Natural Penicillin: Narrow spectrum, β-lactamase sensitive: Penicillin G, Penicillin V
  • Antistaphylococcal: very Narrow spectrum, β-lactamase resistant: Nafcillin, Methicillin, Cloxacillin
  • Extended spectrum: ampicillin, amoxycillin, Ticarcillin, piperacillin, azlocillin
  • Beta lactamase inhibitors: Clavulanic acid, sulbactam, Tazobactam
• Penicillin G Indications: Pneumococcal, streptococcal (infective endocarditis), meningococcal meningitis, tetanus, gas gangrene, Tryponema used in syphilis, Gonococci used in gonorrhea
• Mechanisms of resistance to penicillin

  1. Enzymes (β-lactamase) break lactam ring structure. e.g., staphylococcal

  2. Structural change in PBPs: methicillin-resistant S. aureus, penicillin-resistant pneumococci

  3. Reduction in the permeability of the outer membrane of the bacteria to penicillins
• Penicillin G (Benzylpenicillin) Properties: Narrow spectrum, bactericidal in action with very high activity, destroyed by gastric HCL and beta-lactamase, short duration of action, highly water-soluble
• Penicillin Units: Penicillin G is calculated by units, each mg contains 1600 units per mg, 1 million units = 0.6 g. Solutions lose their activity rapidly and must be prepared fresh. Disadvantages of Penicillin G include short duration of action, beta-lactamase sensitivity, narrow spectrum, and being destroyed by gastric acid
• PHRS – 303 LECTURE 2: Beta-lactam Antibiotics: Penicillin Dr. Rawan Alnafisah


  3 Mar. 2024
• Natural Penicillin is a narrow-spectrum penicillin and β-lactamase sensitive
• Natural Penicillin: Penicillin G salts consist of Na+ & K+ salts of penicillin G, benzathine, procaine. Penicillin V is the oral form of this group (acid-stable). All are hydrolyzed by β-lactamases. Penicillin G benzathine and penicillin G procaine have low solubility and are slowly released from intramuscular injection
• Pharmacokinetics of penicillin

  1. Administration depends on the type: oral (amoxicillin), IV (methicillin, ticarcillin, carbenicillin, piperacillin), or IM route (procaine penicillin and benzathine penicillin)

  2. Absorption: most penicillins are incompletely absorbed after oral administration and reach the intestine in sufficient amount to affect the composition of the intestinal flora

  3. Distribution: good distribution throughout the body, does not cross the blood-brain barrier except in meningitis when the BBB becomes leaky, can cross the placenta but is not teratogenic as there is no target in the fetus

  4. Metabolism: usually insignificant, but some metabolism of penicillin G has been shown to occur in patients with impaired renal function

  5. Excretion: most are eliminated through active tubular secretion, nafcillin is eliminated largely in bile

  6. Plasma half-life: usually < 2 hours
• Penicillin G benzathine and penicillin G procaine

  1. Have low solubility and are slowly released from intramuscular injection sites

  2. Are hydrolyzed to penicillin G

  3. Combination of hydrolysis and slow absorption results in lower but more prolonged blood serum levels

  4. Addition of Benzathine extends half-life to 3-4 weeks, making it long-acting penicillin
• No antibiotic has as long a half-life as Benzathine Penicillin, so it is used for pregnant women infected with sexually transmitted diseases
• Indications for Penicillin V

  • Boil, abscess
  • Pneumonia
  • Prophylaxis before and after surgery
• Benzathine Penicillin is used as prophylactic against Rheumatic heart disease or infective endocarditis
• Penicillin + Probenecid

  Probenecid inhibits the tubular secretion of penicillin, raising the plasma concentration and prolonging the action of penicillin
• Antistaphylococcal Penicillins are narrow-spectrum, β-lactamase resistant
• Penicillin V

  Less potent activity than penicillin G, acid resistant (orally active), short duration of action, still destroyed by beta-lactamase
• Penicillin + Aspirin

  Aspirin inhibits the tubular secretion of penicillin, prolonging the action and increasing bio-availability
• Penicillin V is the oral form of this group (Acid stable)
• Salts consist of

  • Na+ & K+ salts of penicillin G
  • Benzathine
  • Procaine
• Antistaphylococcal Penicillins

  • Methicillin
  • Nafcillin
  • Oxacillin
  • Cloxacillin
  • Dicloxacillin
  • Flucloxacillin
• All of them are hydrolyzed by β-lactamases
• Beta-lactamase resistant penicillins are resistant to hydrolysis by beta-lactamase, have a very narrow spectrum of activity, are acid resistant (except methicillin), food interferes with drug absorption, and are indicated for infections caused by penicillinase-producing Staphylococci
• Properties of Extended-spectrum Penicillins

  • Semisynthetic penicillin
  • Acid resistant (not destroyed by HCL)
  • Destroyed by beta-lactamase, ineffective against bacteria secreting beta-lactamase
  • Less potent than benzylpenicillin
  • Short duration of action (4-6 hours) and plasma t1/2 1 hour
  • Usually given with beta-lactamase inhibitors
  • Adverse effects: Superinfection, hypersensitivity, GI upset
• Methicillin-resistant Staphylococcus aureus (MRSA) has developed resistance to Methicillin and other members by having an altered penicillin binding protein
• Carbenicillin is Anti-Pseudomonal