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1
Q

Learning Outcomes (for general perusal)

A

Aim

Introduce core concepts of selective toxicity, ecologic damage, antimicrobial allergy and antiviral agents

Outcomes

  1. Apply the terms selective toxicity, antimicrobial prophylaxis and broad spectrum antimicrobials appropriately
  2. Identify from a list drugs that would be contra-indicated in a patient with type 1 hypersensitivity reaction to a beta-lactam antimicrobial
  3. Identify a core list of antiviral agents, their site of action and common usage

a tension here between the drive to conserve antibiotics which often requires restricting prescription and tackling sepsis which requires more antibiotics

2
Q

What will be covered? (for general perusal)

A
  1. Some language associated with antimicrobial use
  2. 7 categories of antibacterials
  3. A basic approach to using antimicrobials: ‘Start smart then focus’
  4. Penicillin allergy
  5. Antiviral therapy
3
Q

1. Some language associated with antimicrobial use

  1. What is selective toxicity?
  2. What can the toxicity of antibiotics be dependant upon?
  3. How can antimicrobials be selectively toxic?
A
  1. Antimicrobials are intended to be drugs that kill microorganisms but do not harm the host cells
  2. Antibiotics are generally toxic to eukaryotic cells, this can be dependent on dose and duration
  3. By targeting Cell wall, Protein synthesis, Process of DNA supercoiling, Folate metabolism

Human Ecosystem:

100 trillion non human cells

90 trillion bacteria

10 trillion fungi

500 trillion viruses

8 000 000 genes

4
Q

2. 7 Categories of Antibacterials

Name the 7 Categories

A

Cell Wall Active

  1. Beta-Lactams
  2. Glycopeptides

Protein Synthesis Inhibitors

​3. Macrolides

  1. Aminoglycosides
  2. Tetracyclines
  3. Quinolones
  4. Others
5
Q

Antibacterial Tree

What are the sub groups within the group

Beta lactams

Give examples of drugs

A
  • Penicillins
    • Benzylpenicillin, Flucloxacillin, Amoxicillin
  • Penicillin/beta-lactamase inhibitor combinations
    • Co-amoxiclav, Piperacillin-tazobactam
  • Cephalosporins
    • Cefuroxime, Ceftriaxone
  • Monobactam
    • Aztreonam
  • Carbapanems
    • Meropenem, Ertapenem
6
Q

Give examples of drugs from the following groups (all except beta lactams)

  1. Glycopeptides
  2. Macrolides
  3. Aminoglycosides
  4. Tetracyclines
  5. Quinolones
  6. Other
A
  1. Vancomycin, Teicoplanin
  2. Clarithromycin, Erythromicin
  3. Gentamicin
  4. Doxycycline
  5. Ciprofloxacin, Levofloxacin
  6. Metronidazole, Trimethoprim, Nitrofurantoin
7
Q

What does Broad Spectrum mean?

A

Denoting antibiotics used in human medicine, that are effective against a large variety of medically important organisms

8
Q

Recap: How can bacteria be classified?

A
  • Gram Positive
    • ​Cocci
      • ​Clusters -

Staphylococcus aureus

Staphylococcus epidermidis

    * **Chains**

β-haemoyltic Streptococci:

(Lancefield group A, B, G)

Streptococcus oralis

Streptococcus pneumoniae

Enterococcus faecalis

* **Rods****​**

Clostridium tetani

Clostridium difficile

Clostridium perfringens

Listeria monocytogenes

Bacillus species

Proprionibacterium acnes

Lactobacillus lacti

  • Gram Negative
    • ​Cocci

Neisseria meningitidis

Neisseria gonorrhoeae

Haemophilus influenzae

* **Rods**
    * **​Enterobactericeae**

Escherichia coli

Klebsiella pneumoniae

Proteus mirabilis

Salmonella enteritidis

    * **Non-enterobactericeae**

Bacteroides fragilis

Pseudomonas aeruginosa

Campylobacter jejuni

  • Others
    • ​Mycobacterium tuberculosis
    • Legionella pneumophila
    • Chlamydia trachomatis
    • Mycoplasma pneumoniae
    • Treponema pallidum
9
Q

Name the

  1. Gram positive bacteria
  2. Gram-negative bacteria
  3. Other bacteria
A
  1. Staphylococcus aureus

Staphylococcus epidermidis

β-haemoyltic Streptococci:

(Lancefield group A, B, G)

Streptococcus oralis

Streptococcus pneumoniae

Enterococcus faecalis

Clostridium tetani

Clostridium difficile

Clostridium perfringens

Listeria monocytogenes

Bacillus species

Proprionibacterium acnes

Lactobacillus lacti

  1. Neisseria meningitidis

Neisseria gonorrhoeae

Haemophilus influenzae

Escherichia coli

Klebsiella pneumoniae

Proteus mirabilis

Salmonella enteritidis

Bacteroides fragilis

Pseudomonas aeruginosa

Campylobacter jejuni

  1. Legionella pneumophila

Chlamydia trachomatis

Mycoplasma pneumoniae

Treponema pallidum

1. Mycobacterium tuberculosis
10
Q

Narrow vs. Wide Spectrum

For general persual

In GREEN: usually effective or >60% susceptible

In AMBER: clinical trails lacking or 30-60% susceptible

In RED: not clinically effective or <30% susceptible

A
11
Q

Narrow vs. Wide Spectrum

  1. Name a narrow spectrum antibacterial drug
  2. From what group is it from?
  3. What is it usually effective in (or 60% susceptible)
  4. What are clinical trails lacking for use in?
  5. What is it NOT clinically effective in?
A
  1. Flucloxacillin
  2. Beta-lactams, Penicillins
  3. Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, Clostridium tetani, Clostridium perfringens
  4. Streptococcus oralis
  5. All others
12
Q

Narrow Vs. Wide Spectrum

  1. Name a wide spectrum antibacterial drug
  2. From what group is it from?
  3. For which bacteria is it NOT effective?
  4. For which are clinical trials ongoing?
  5. For which bacteria is it effective?
A
  1. Meropenem
  2. Beta-lactem, Carbapanem
  3. Legionella pneumophila

Chlamydia trachomatis

Mycoplasma pneumoniae

  1. Enterococcus faecalis, Mycobacterium tuberculosis
  2. All others
13
Q

3. A basic approach to using antimicrobials

‘Start smart then focus’

  1. What is a huge cause of mortilty?
  2. What is the issue with infection and diagnosis?
  3. What are the principles of antimicrobial use?
A
  1. Sepsis
  2. There is not a single definitive clinical or laboratory marker of infection. Temperature and laboratory tests cause more harm than good if the diagnostic process is not followed. Focus on patient and the symptoms and signs at the inflamed organ site
  3. Do not start antibiotics in the absence of clinical evidence of infection. Thorough drug allergy history required.
14
Q

Penicillin Allergy

  1. Why is it so prevalent?
  2. What is the prevalence?
  3. What is the pathological process and symptoms involved?
A
  1. 10% of patients report allergy to penicillin: nausea, diarrhoea, thrush, rash, headache, fever, collapse, wheeze, swelling of face, mouth or tongue
  2. Probably <1% have had a type one hypersensitivity reaction
  3. •IgE mediated with mast cell degranulation of histamine
  • Immediate onset
  • collapse, wheeze, swelling of face, mouth or tongue, rash of urticarial (nettle-sting) appearance
15
Q

Penicillin Allergy

What is the effect of so many people reporting penicillin allergies?

A

Fewer choices

Less efficacious choices

More toxic choices

Specific patient group problems: pregnancy, renal failure

16
Q

What does a thorough drug history entail?

A
  • What drug
  • When did you take it (i.e. What age were you)
  • How long after taking the drug did the adverse reaction start (type 1, IgE reactions tend to be immediate)
  • Describe the reaction (paying attention to the appearance of rash)
17
Q

Penicillin Reactions

  1. What is a life-threatening reaction?
  2. What CANNOT be given?
  3. What can be given in a reaction that wasn’t life-threatening?
A
  1. IgE Mediated type one hypersensitivity reaction
  2. NO Beta-lactams, except Aztreonam (from Monobactam group)
  3. Avoid penicillins, all other beta lactams are fine
    1. Penicillin / beta-lactamase inhibitor combinations, Cephalosporins, Monobactam, Carbapanems
18
Q

Outline the ‘Start Smart then Focus’ approach to antimicrobial use?

A
  • Do not start antibiotics in the absence of clinical evidence of infection
  • Thorough drug allergy history
  • Rapid assessment for Sepsis
  • Comply with local guidelines
  • Document diagnosis and treatment
  • Document review and stop date
  • Obtain cultures prior to starting treatment
19
Q

‘Start Smart then Focus’ approach to antimicrobial use

  1. When should a clinical review take place?
  2. What decisions can be made?
A
  1. with microbiological results at 48-72 hours
    1. Stop
  2. IV to oral switch
  3. change antibiotic
  4. Continue
  5. OPAT (Outpatient Parenteral Antimicrobial Therapy)

Document all decisions

20
Q

Antimicrobial prophylaxis

  1. What is prophylaxis?
  2. Why is this uncertain?
  3. When is this common practice?
A
  1. the prevention of disease
  2. Breaks (or bends) the cardinal rule of infection: no antibiotic unless there is clinical evidence of infection
  3. Surgery: excellent evidence of reduced post operative infection rates when prophylaxis is given

A single dose at start of anaesthesia is generally enough

21
Q

5. Antiviral Therapy

  1. What does viral infection involve?
  2. Describe the pathological process.
A
  1. Obligate intracellular parasites.
  2. Receptors on host cells at the site of entry to the body (eg respiratory epithelium)

Viruses uncoat (remove their protein coat) then start utilising host cell metabolism

Replicate viral nucleic acid, make new protein coat, release from the host cell

Spread and infect new cells

22
Q

5. Antiviral Therapies

Recap: How are viruses classified?

A
  • DNA Viruses
    • Herpesviruses:
  • Herpes simplex v. (HSV)*
  • Varicella zoster v.(VZV)*
  • Epstein-Barr v.(EBV)*
  • Cytomegalovirus v. (CMV)*
    • Papillomavirus
    • Parovirus B19
    • Smallpox Virus
  • RNA Viruses
    • ​Rotavirus
    • Picornavirus
      • Enterovirus
      • Rhinovirus
      • Poliovirus
      • Hepatovirus
    • ​​​Norovirus
    • Rubella virus
    • Hepatitis C virus
    • Influenza viruses
    • Paromyxoviruses
      • Respiratory Syncytial virus
      • Measles virus
      • Mumps virus
    • Rabies virus; Ebola virus
  • Reverse Transcribing Viruses
    • ​DNA: Hepatitis B virus
    • RNA: Retroviruses including HIV
23
Q

Which Viruses can be treated with Antiviral agents?

A
  • Herpesviruses: HSV, HZV, EBV, CMV
  • HCV
  • Influenza Viruses: RSV
  • Ebola Virus
  • HBV
  • Retroviruses including HIV
24
Q

What is the core list of antiviral agents?

A

Herpesvirus infections - Aciclovir, Ganciclovir

Influenza - Oseltamivir

Viral Hepatitis - Tenovovir, Peginterferonalfa, Ribavarin

Respiratory Syncytial Virus - Palivizumab, Ribavarin

HIV Infection

  • Reverse transcriptase inhibitors
    • Nucleoside RTI - Zidovudine, Tenovovir
    • Non-nucleoside RTI - Efavirenz
  • Protease inhibitors - Lopinavir, Ritonavir
  • Integrase inhibitors - Raltegravir
  • Fusion Inhibitors - Enfuviritide
25
Q

Antiviral Agents

  1. Name the agents used for Herpesvirus infections
  2. What do nucleoside analogues target?
  3. What does aciclovir target?
  4. What does Ganciclovir target?
A
  1. Aciclovir, Ganciclovir
  2. faulty DNA
  3. HSV and VZV
  4. CMV
26
Q

Antiviral Agents

  1. Name the agent used for influenza
  2. How does it act?
A
  1. Oseltamivir
  2. Inhibitor of Neuraminadase enzyme: Neuraminadase promotes viral release and spread from respiratory cells
27
Q

Antiviral Agents

  1. What agents are used for Hepatitis B
    1. How do they act?
  2. What agents are used for Hepatits C
    1. How do they act?
A
  1. Tenovovir - analogue of adenosine: a nucleoside reverse transcriptase inhibitor
    * Peginterferon alfa -* naturally occurring cytokine with wide variety of antiviral properties
  2. Peginterferon alfa - as above
    * Ribavarin -* analogue of Guanosine: broad antiviral activity, including RNA viruses. Toxic. Multiple modes of action
28
Q

Antiviral Agents

  1. What is used to treat Respiratory Syncytial Virus?
    1. How do they act?
A
  1. Palivizumab - Monoclonal antibody Given as prophylaxis to children at risk of serious RSV infection
    * Ribavarin -* Analogue of Guanosine: broad antiviral activity, including RNA viruses. Toxic. Multiple modes of action
29
Q

Antiviral Agents

Outline the antiviral agents that are used to treat HIV infection

A

HIV Infection

Reverse transcriptase inhibitors

  • Nucleoside RTI - Zidovudine, Tenovovir
  • Non-nucleoside RTI - Efavirenz

Protease inhibitors - Lopinavir, Ritonavir

Integrase inhibitors - Raltegravir

Fusion Inhibitors - Enfuviritide

30
Q

Antiviral Agents (HIV Therapies)

  1. How does fusion inhibition act?
  2. What is reverse transcriptase?
  3. What is integrase enzyme?
  4. How does HIV protease act?
A
  1. Inhibits HIV virus fusion to host cell
  2. Viral enzyme, transcribes viral RNA to DNA
  3. integrates ‘Viral’ DNA into host genome
  4. New virus needs to be tidied up by HIV Protease
31
Q

What is Highly Active Anti Retroviral Therapy (HAART)?

What drugs does it involve?

A

Multiple agents limit development of resistance

  • Backbone of 2 Nucleoside RTIs
  • Plus one other agent (PI, Non Nucleoside RTI, integrase inhibitor)
32
Q

Next antimicrobial lecture (for general perusal)

A