Antimicrobial Pharmacology I Study Quiz

Antimicrobial Pharmacology I - Study Notes

• Course taught by Altaf Darvesh, M. Pharm., Ph.D. on 11-12-2024
• Recommended Reading:
  • Katzung's Basic and Clinical Pharmacology (16th edition) by Vanderah, McGraw Hill
  • Goodman and Gilman's The Pharmacological Basis of Therapeutics (14th edition) by Brunton, Knollman, McGraw Hill (Available online on Access Medicine & Access Pharmacy)
• Objectives:
  • Identify targets of antimicrobial pharmacotherapy
  • Distinguish between bacteriostatic and bactericidal agents
  • Describe general mechanisms of antimicrobial resistance
  • Describe the structure of the bacterial cell wall
  • Distinguish between Gram-positive and Gram-negative bacteria
  • Classify beta-lactam antibiotics
  • Describe the mechanism of action of beta-lactams
  • Describe the mechanism of resistance of beta-lactams
  • Describe the adverse effects of beta-lactams
  • Discuss beta-lactamase inhibitors

Targets of Antimicrobial Pharmacotherapy

• Antibiotics target microbial proteins essential for biochemical reactions.
• Antibiotics disrupt biochemical pathways and inhibit microbial replication or directly kill microorganisms.
• Common inhibited processes include cell wall synthesis, cell membrane synthesis/function, ribosomal translation, and nucleic acid metabolism.

Bacteriostatic and Bactericidal Agents

• Bacteriostatic agents reversibly inhibit bacterial growth.
• Minimum Inhibitory Concentration (MIC) is the lowest drug concentration that inhibits bacterial growth.
• Bactericidal agents irreversibly kill bacteria.
• Minimum Bactericidal Concentration (MBC) is the lowest drug concentration that kills bacteria

Bacteriostatic and Bactericidal Classification

• Primarily bacteriostatic agents have lower concentrations than bactericidal agents.
• Cell wall-active agents are generally bactericidal; drugs inhibiting protein synthesis are bacteriostatic.
• Bacteriostatic antibiotics prevent bacterial growth through interference with protein production, DNA replication, or other metabolic processes.
• Bactericidal antibiotics disrupt bacterial cell parts like walls or DNA.

Bactericidal Agents

• Agents exhibiting concentration-dependent killing (e.g., aminoglycosides, quinolones) are more effective with increased concentration.
• Agents exhibiting time-dependent killing (e.g., beta-lactams) maintain bactericidal activity as long as serum concentrations exceed the Minimum Bactericidal Concentration (MBC).

Structure of Bacterial Cell Wall

• The cell wall is a rigid structure surrounding the cytoplasmic membrane.
• The cell wall maintains integrity and prevents osmotic pressure damage
• The cell wall is composed of peptidoglycan, a complex polymer of polysaccharides and peptides.
• Alternating N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM) compose the polysaccharide.
• A five-amino-acid peptide is attached to NAM terminating in D-alanyl-D-alanine
• Transpeptidase (PBP) enzyme forms cross-links in the peptidoglycan to maintain cell wall rigidity.

Gram Positive and Negative Bacteria

• Gram-positive bacteria have a thick peptidoglycan layer, retaining crystal violet.
• Gram-negative bacteria have a thin peptidoglycan layer, retaining safranin/carbol fuchsin.

Beta-lactam Antibiotics

• Penicillins, cephalosporins, carbapenems, and monobactams are beta-lactams
• Share a common 4-membered beta-lactam ring.
• They have a common mechanism of action, inhibiting bacterial cell wall synthesis by binding to and inactivating PBP.

Mechanism of Action of Beta-Lactams

• Beta-lactam antibiotics block the transpeptidase reaction.
• This prevents cross-linking of peptides in the peptidoglycan, resulting in a weakened cell wall and eventual bacterial death.

Beta-lactamase Inhibitors

• Beta-lactamase inhibitors bind to beta-lactamases, preventing these enzymes from hydrolyzing beta-lactam antibiotics.

Mechanisms of Resistance

• Reduced antibiotic concentration at the target site (efflux pumps)
• Inactivation/alteration of antibiotic targets through enzyme production
• Alteration of the bacterial target site

Vancomycin

• A Glycopeptide antibiotic.
• Large molecular weight (1,449.3).
• Targets Gram-positive bacteria.
• Poorly absorbed orally; usually administered intravenously.
• Inhibits bacterial cell wall synthesis by binding to the D-alanyl-D-alanine terminus.
• Vancomycin mechanisms of resistance involve altering the D-alanyl-D-alanine target.

Lipoglycopeptides

• Telavancin, Dalbavancin, and Oritavancin are lipoglycopeptides.
• Mechanism of action and resistance are similar to vancomycin.
• Indicated for complicated skin and skin structure infections (CSSI)

Cephalosporins

• Newer generations have greater activity against Gram-negative bacteria than previous ones.
• Simpler mechanisms of action that mimic beta-lactams.

Cephamycins

• A subclass of cephalosporins.
• Possess a methoxy group and activity against anaerobic bacteria.

Ceftaroline fosamil

• Fifth-generation cephalosporin.
• Active against methicillin-resistant Staphylococcus aureus (MRSA).

Cefiderocol

• Unique cephalosporin that uses a siderophore moiety.
• Resistant to many beta-lactamases.
• Shows activity against multi-drug-resistant Gram-negative bacteria via iron-binding capability.

Pharmacodynamics of Penicillins

• Diverse pharmacokinetic properties (Oral absorption)
• Penicillins exhibit differences in oral absorbability and resistance to beta-lactamases.

Adverse Effects of Penicillins/Cephalosporins

• Hypersensitivity reactions (allergies) are common.
• Nephrotoxicity and ototoxicity are potential adverse effects.
• Infusion reactions, including flushing, itching, or hypotension.

Oral/Intravenous Administration; Indications

• Specific indications for oral vs. intravenous administration exist based on drug and infection characteristics.
• Usage varies with drug type, infection severity or drug sensitivity from patient/bacteria.

Practice Questions

• Provided in pages 44 and 45. Refer to those sections for detailed questions and answer choices.