Antimicrobials and β-lactam Antibiotics Quiz

Antibiotics 1 - Beta Lactams and other cell wall agents

• Antibiotics are drugs used to fight microorganisms, including bacteria, viruses, and fungi.
• Beta-lactams are a group of antibiotics that work by interfering with the synthesis of bacterial cell walls.
• The presenter Dr. Jo Chua is a Clinical Microbiologist & Senior Clinical Lecturer.

On Noongar land

• Acknowledges the traditional owners of the land (Noongar people).
• Pays respects to their cultural custodians, values, languages, beliefs, and knowledge.

The battle against infectious agents

• Antimicrobials are essential tools in fighting infections.
• Strategies include precision, minimizing collateral damage (to the body's microbiome) and preserving effectiveness for future use.

Learning outcomes (for antibiotics 1)

• List key beta-lactam and glycopeptide antibiotics.
• Discuss the modes of action, spectrum of activity, and mechanisms of resistance of beta-lactam and glycopeptide antibiotics.
• Outline their pharmacology, toxicology, and potential side effects.
• Explain susceptibility testing methods (phenotypic and genotypic).

Framework of learning antibiotics

• The presentation provides a framework encompassing various topics related to antibiotics, including mechanisms of action, spectrum of activity, resistance, clinical use, pharmacology and toxicity effects.

Definitions

• Antimicrobials/anti-infectives are drugs acting against microorganisms (bacteria, viruses, fungi).
• Antibiotics are natural or synthetic compounds inhibiting bacterial biochemical functions (e.g., cell wall synthesis, protein synthesis, DNA replication).
• Antiseptics/disinfectants are antimicrobial substances too toxic for internal use—they are used externally.
• Broad-spectrum antibiotics target a wide range of bacterial species.
• Narrow-spectrum antibiotics are effective against specific bacterial species.

Cidal vs Static

• Cidal antibiotics kill microorganisms.
• Static antibiotics inhibit microbial growth but don't kill them, allowing body defenses to eliminate the microorganism.

Antibiotic Mechanisms of Action

• Antibiotics work in various ways.
  • Some target cell wall synthesis (beta-lactams and glycopeptides).
  • Other antibiotics target bacterial cell membrane synthesis, DNA replication, RNA polymerase, or protein synthesis. (including examples of antibiotics targeting synthesis processes)

Cell Wall

• Gram-negative bacteria have an outer membrane, plus peptidoglycan.
• Gram-positive bacteria have a thick peptidoglycan layer.
• The cell wall is comprised of repeating N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM) subunits.
  • NAM subunits have short peptide chains (D-Ala to L-Ala).
  • Penicillin-binding proteins (PBPs) catalyse the crosslinking of peptide chains in the peptidoglycan assembly process.
  • Teichoic acid is found in Gram-positive bacteria and contributes to cell wall stability and attachment.

Beta-Lactam Antibiotics

• Key beta-lactam antibiotics include penicillin, cephalosporin, monobactam and carbapenem.

• These antibiotics work by interfering with bacterial cell wall synthesis.

• The common beta-lactam ring structure is a key feature.

• Beta-lactams bind to bacterial transpeptidases (penicillin-binding proteins-PBPs) and block peptide crosslinking.

Quiz on Penicillin

• The first beta-lactam antibiotic discovered was penicillin.

Penicillin Classification and Example

• Different types of penicillins have different spectra of activity.
• Various types of penicillin include penicillin G, penicillin V, methicillin, oxacillin, amoxicillin, pipreacillin and methicillin.

Which penicillins are active against Pseudomonas aeruginosa?

• Piperacillin is one such penicillin exhibiting activity against Pseudomonas aeruginosa.

Cephalosporins

• Cephalosporins are a group of beta-lactam antibiotics widely used for infections.
• They are classified into generations based on their spectrum of activity, resistance to breakdown by enzymes, resistance to breakdown in the body, and effectiveness in CNS infections.

Cephalosporins: Pharmacokinetics

• Cephalosporins are commonly administered orally and intravenously .
• Some cephalosporins exhibit broad distribution throughout the body.
• Specific generations show varying effectiveness in the central nervous system (e.g., poor penetration for the first and second generations, while some third-generation cephalosporins have good penetration).

Patient Case Study

• Treatment for intra-abdominal infections comprising multiple anaerobic organisms should be evaluated on a patient-by-patient basis
• Whether ceftriaxone is an adequate treatment needs to be assessed based on the patient's condition, specific pathogens, and individual needs.

Monobactam and Carbapenem

• Monobactams (e.g., aztreonam) are primarily effective against Gram-negative bacteria.
  • They are stable and resistant to beta-lactamases.
• Carbapenems (e.g., ertapenem, imipenem, meropenem) offer a broader spectrum of activity, targeting both Gram-negative and Gram-positive bacteria, as well as some anaerobes.
  • These are also beta-lactam resistant.

Mechanism of Beta-Lactam Resistance:

• Mechanisms of beta-lactams resistance exist (e.g., low affinity binding, breakdown by beta-lactamase, failure to penetrate outer membrane).

Altered Target Mechanism

• Some bacteria develop resistance by modifying their penicillin-binding proteins (PBPs), lowering their affinity for beta-lactam antibiotics like methicillin.
• This is seen commonly with Staphylococcus aureus.
• Stepwise mutations in penicillin-binding proteins (PBPs) of Streptococcus pneumoniae and viridans streptococci lead to resistance.

Beta-Lactamase

• Different types of beta-lactamases are produced by both Gram-positive and Gram-negative bacteria (there are more than 1,000).
• Beta-Lactamase inhibitors are used with beta-lactams to protect them from enzymatic breakdown by beta-lactamases.

Genotypic Detection

• Real-time PCR is a powerful tool for identifying specific resistance genes (e.g., mecA in MRSA) in bacteria.

Vancomycin Resistance in Enterococci

• The vanA and vanB genes are commonly associated with vancomycin resistance.

Other cell wall and cell membrane agents (agents usually restricted for specific indications)

• Fosfomycin is primarily used for urinary tract infections, polymyxins treat multi-drug resistant gram-negative rods whereas Isoniazid and Ethambutol are first-line drugs used against tuberculosis.

Susceptibility Testing

• Disk diffusion (Kirby-Bauer), gradient (E-test), and automated systems are used to determine antibiotic susceptibility.
• The minimum inhibitory concentration (MIC) is the lowest antibiotic concentration needed to prevent bacterial growth.

Glycopeptides

• Glycopeptides (e.g., vancomycin, teicoplanin) interfere with peptidoglycan synthesis.
• Glycopeptides are mainly active against Gram-positive bacteria, including MRSA.

Glycopeptide Resistance Mechanism

• Resistance is frequently seen as a result of substitution of D-alanyl-D-alanine (D-Ala-D-Ala) with D-alanyl-D-lactate (D-Ala-D-Lac) in peptidoglycan precursors, altering binding affinity for vancomycin.