SPR L5 Antimicrobials 1

Question 1

Aim

Describe the mode of action of common antibacterial, antiviral and antifungal drugs and apply this knowledge to treat common infections in theoretical clinical scenarios.

Answer 1

Key reading: Rang and Dale’s Chapter 45 (p647-659), Chapter 46 (p661-678), Chapter 47 (p679-690), Chapter 48 (p692-697), or Integrated Pharmacology Chapter 6 (p87-138)

Learning Outcomes

• Describe the mode of action for commonly used antimicrobials (anti-biotics, anti-virals, anti-fungals and anti-protazoals)
• Compare the different methods of drug antibacterial action
• Discuss the development of antibiotic resistance
• List the common treatments for common bacterial and viral infections

Question 2

Anti-microbials 1-3

What will be covered (for general perusal)

Answer 2

1. Common classes of antibiotic
2. Other important antibiotic classes
3. Other anti-microbials

• Anti-virals
• Anti-fungals
• Anti-protazoals

Question 3

Antimicrobial agents and chemotherapy 1+2
(Microbiology)

​Describe the bacterial cell wall

Answer 3

Cell membrane and peptidoglycan cell wall

Question 4

Antibacterials

Name the cell wall active agents

Answer 4

• Β-lactams
  
  • Penicillins
  • Cephalosporins
  • Monobactam
  • Carbapenems
• Glycopeptides
  
  • Vancomycin
  • Teicoplanin

Question 5

Antibacterials

Name those with Action on nucleoside precursors

Answer 5

Trimethoprim

Sulphonamides

Question 6

Antibacterials

Name the Agents acting on nucleic acid synthesis

Answer 6

• Metronidazole
• Quinolones
• Rifampicin
• Nitrofurans

Question 7

Antibacterials

Name the Protein synthesis inhibitors

Answer 7

• Aminoglycosides
• Tetracyclines
• Macrolides
• Oxazolidinones
• Fusidic acid

Question 8

B-lactams

Penicillin

1. What do all b-lactam antibiotics interfere with?
2. What do the penicillins attach to?
3. What do they therefore inhibit

Answer 8

1. the synthesis of the bacterial cell wall peptidoglycan
2. Penicillin-binding proteins on bacteria
3. inhibit the transpeptidase enzyme activity that catalyses the NAMA/NAG peptide chain cross-linking, and they inactivate the inhibitor of the autolytic enzymes in the cell wall (switch off the off switch) leading to cell lysis (bacteriocidal)

Question 9

What is the structure of a penicillin?

Answer 9

see picture - be able to draw this

Question 10

Types of penicillin

1. Which shows poor GI absorption and is susceptible to b-lactamases?
2. Name a broader spectrum penicillin
   
   1. What is it?
3. Which is beta-lactamase resistant?
4. Which has an extended spectrum?

Answer 10

1. Benzylpenicillin
2. Amoxicillin
   
   1. combined with β-Lactamase inhibitor clavulinic acid- Co-Amoxiclav) – rope-a-dope
3. Flucloxacillin
4. Extended spectrum – Piperacillin /Ticarcillin (combined with β-Lactamase inhibitors to make Tazocin / Timentin)

Question 11

B-Lactams - Penicillin

Pharmacokinetics

1. Describe oral absorption
2. How is it distributed in body fluids?
3. How is it mainly excreted?
4. Describe the plasma half-life

Answer 11

1. Oral absorption variable
2. Widely distributed
3. Mainly renal excretion (tubular secretion)
4. Short plasma half-life

Question 12

Beta-Lactams - Penicillin

What are the uses of the following penicillins?

1. Benzylpenicillin
2. Amoxicillin
3. Flucloxacillin
4. Piperacillin

Answer 12

1. Bacterial meningitis
2. Resp Infections, UTI, Otitis media
3. Cellulitis
4. Severe infection / pseudomonas

Question 13

Beta-Lactams - Penicillins

What are the main adverse effects?

Answer 13

• Hypersensitivity
  
  • Skin rash / fever
• Anaphylaxis
• Oral – antibiotic associated diarrhoea

(generally very few adverse effects)

Question 14

Beta-Lactams - Cephalosporins

Give an example of the following

1. 2nd Generation
2. 3rd Generation

They are chemically related to penicillins, describe how this the case

Answer 14

1. Cefuroxime (Zinacef)
2. Cefotaxime

Ceftazidime

Ceftriaxone

3. Have an R₂

Question 15

B-lactams - Cephalosporins

1. Outline the mode of action of these
2. What is an issue?
   
   1. Why?

Answer 15

1. Mode of action similar to penicillins (interfere with the synthesis of the bacterial cell wall peptidoglycan, attach to Penicillin-binding proteins on bacteria and inhibit the transpeptidase enzyme activity that catalyses the NAMA/ NAG peptide chain cross-linking)
2. Resistance to these drugs has increased especially gram negative bacteria
   
   1. Chromosomal gene coding for β-Lactamase that is more active in hydrolysing cephalosporins

Question 16

B-lactams - Cephalosporins

Use had decreased in the last few years, but what are the following used for?

1. Cefotaxime/Ceftriaxone
2. Ceftazidime

Answer 16

1. Meningitis
2. Bronchiectasis infections (depending on organism)

Question 17

B-lactams - Cephalosporins

1. How do most need to be given?
2. What is excretion mostly by?
3. What is the cross-sensitivity with penicillins?
4. What can they sometimes give rise to?

Answer 17

1. parenterally
2. Excreted by the kidney (ceftriaxone 40% bile)
3. 10%
4. Occassional nephrotoxicity / alcohol intolerance

Question 18

Protein Syntesis Inhibitors - Macrolides

Give 3 examples of macrolides

Answer 18

• Erythromycin
• Clarithromycin
• Azithromycin

Question 19

Protein Syntesis Inhibitors - Macrolides

What is the mechanism of action of macrolides?

Answer 19

• Inhibit bacterial protein synthesis
• Bind to the 50S subunit of the bacterial ribosome and prevent translocation of the growing peptide chain
• Bacteriocidal or static depending on concentration and micro-organisim

Question 20

Protein Syntesis Inhibitors - Macrolides

1. Macrolides have an antimicrobial spectrum similar to penicillin, what benefit does this incur?
2. How is it usually administered?
3. What does it show some activity against?
4. Where does it have poor penetration?
5. Where does it concentrate?

Answer 20

1. alternative if allergic
2. orally (can be given IV but may cause phlebitis)
3. Atypical Pneumonia
4. in the synovial fluid
5. in phagocytes

Question 21

Protein Syntesis Inhibitors - Macrolides

​Adverse Effects

1. What is the most common AE seen?
2. What else can occur?

Answer 21

1. GI upset common
2. Hypersensitivity reactions (rash / fever) QT prolongation - proarrhythmic Interaction with other drugs due to their effects on cytochrome P450 system (liver) –Inhibit metabolism of ciclosporin / theophylline

Question 22

Agents Acting on Nucleic Acid Synthesis - Quinolones

Give 3 examples

Answer 22

• Ciprofloxacin
• Levofloxacin
• Moxifloxacin

Question 23

Agents Acting on Nucleic Acid Synthesis - Quinolones

What is their mechanism of action?

Answer 23

• They inhibit the bacterial DNA gyrase (Topoisomerase II)
• This prevents the DNA double-helix from becoming supercoiled preventing transcription and replication

Question 24

Agents Acting on Nucleic Acid Synthesis - Quinolones

1. Describe their absorption
2. Against what do they have good activity?
3. What do they have poor activity against?
4. What are they used for?

Answer 24

1. Well absorbed
2. Good activity against Gm–ve enteric coliforms as well as H influ and pseudomonas
3. Strep Pneum* and Staph
4. Used for UTI / *Pneumonia-Levofloxacin

Question 25

**Agents Acting on Nucleic Acid Synthesis - Quinolones** Outline the main adverse effects

Answer 25

* **GI upset** – **Caution re c. diff risk** * Hypersensitivity * Rarely convulsions – caution in epilepsy (or if on theophylline / NSAIDs) * Inhibits CYP450 _increasing theophylline toxicity_

Question 26

**Antibiotic Guidelines** 1. How do these vary? 2. What should ideally be done? 3. What is usually done?

Answer 26

1. Vary geographically and chronologically 2. Ideally match the anti-microbial to the micro-organism cultured along with the route of admin and pharmacokinetic properties 3. Usually best guess (usual causative organism) – Guided by infection location

Question 27

**Guidelines for management of community acquired pneumonia in adults** What do the guidelines state in terms of the following 1. Low severity (CURB65=0-1) 2. Moderate severity (CURB65=2) 3. High severity (CURB65 = 3-5)

Answer 27

1. Amoxicillin 500mg tds orally 2. benzylpenicillin 1.2g qds IV plus clarithromycin 500mg BD IV 3. Co-amoxiclav 1.2g tds IV plus clarithromycin 500mg BD IV If legionella is strongly suspected, use levofloxacin see picture!

Question 29

Outline the CREST Management of Cellulitis in Adults 1. Class I 2. Class II 3. Class III 4. Class IV

Answer 29

1. Flucloxacillin 500mg qds po 2. Ceftriaxone 1g od IV 3. Flucloxacillin 2g qds IV 4. Benzylpenicillin 2.4g 2-4 hourly IV see picture

Question 30

**Trust Guidelines - ICU** see picture of trust guidelines

Answer 30

Question 31

Bringing this together (summary)

Answer 31

Antibiotics have different: * Modes of action * Activity against micro-organisms * Susceptibility to bacterial defences e.g. β-Lactamases * Pharmacokinetic properties If you know the common causative micro-organisms then you can base you choice of antibiotic on that Consider the location of the infection and the drug delivery to that site As the causative organisms and their susceptibilities change then need to follow up-to-date local guidelines

Question 32

Next lecture covers the following

Answer 32