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Flashcards in MB7 Antimicrobials 2 Deck (36):
1

Lecture Outcomes (for general perusal)

 

Aim

Introduce antibacterial agents  

Outcomes

1.Outline the features of the bacterial cell that are relevant to antimicrobials

2.Identify the different classes of cell wall active antimicrobials, their site of action and common usage

3.Identify the different classes of antimicrobials acting at intracellular bacterial sites, their site of action and common usage

2

How is the topic relevant? (for general perusal)

Lots of physiological bacteria get killed by antibiotics

Antibiotic resistance:    drive to limit antibiotics

Sepsis:   drive to give antibiotics

No single definitive clinical or laboratory marker for infection

30-40% of all hospital inpatients are being prescribed one of the following drugs at any given time

3

What is covered in this lecture (for general perusal)

1.Beta lactams

2.Glycopeptides

3.Inhibitors of protein synthesis

i.Macrolides

ii.Aminoglycosides

iii.tetracyclines

4.Quinolones

5.Others

i.Metronidazole

ii.Nitrofurantoin

iii.Trimethoprim

4

Which drug groups act upon

  1. Cell wall
  2. Intracellular Bacterial Site

  1. Beta-lactams, glycopeptides
  2. Inhibitors of protein synthesis (Macrolides, Aminoglycosides, Tetracyclines), Quinolones, Others (i.Metronidazole, ii.Nitrofurantoin, iii.Trimethoprim )
     

5

Outline the antibacterial tree

  1. Beta-lactams
    1. PenicillinsBenzylpenicillin, Flucloxacillin, Amoxicillin
    2. Penicillin-Beta-lactamase inhibitor combinations - Co-amoxiclav, PiperacillinC-tazobactam
    3. CephalosporinsCefuroxime, Ceftriaxone
    4. Monobactam - Aztreonam
    5. Carbapanems - Meropenem, Ertapenem
  2. Glycopeptides - Vancomycin, Teicoplanin
  3. Macrolides Clarithromycin, Erythromicin
  4. Aminoglycosides Gentamicin
  5. Tetracyclines - Doxycycline
  6. Quinolones Ciprofloxacin, Levofloxacin
  7. Others - Metronidazole, Trimethoprim, Nitrofurantoin

3,4,5 are the protein synthesis inhibitors

6

What is the spectrum of activity of the antibacterial tree?

  • Gram-positive cocci
    • Staphylococcus aureus

      Staphylococcus epidermidis

      β-haemoyltic Streptococci:

      (Lancefield group A, B, G)

      Streptococcus oralis

      Streptococcus pneumoniae

      Enterococcus faecalis

  • Gram-positive rods
    • Clostridium tetani

      Clostridium difficile

      Clostridium perfringens

      Listeria monocytogenes

      Bacillus species

      Proprionibacterium acnes

      Lactobacillus acidophilus

  • Gram-negative cocci
    • Neisseria meningitidis

      Neisseria gonorrhoeae

      Haemophilus influenzae

  • Gram-negative rods
    • Escherichia coli

      Klebsiella pneumoniae

      Proteus mirabilis

      Salmonella enteritidis

      Bacteroides fragilis

      Pseudomonas aeruginosa

      Campylobacter jejuni

  • Others (cell wall deficient - don't gram stain)
    • Legionella  pneumophila

      Chlamydia trachomatis

      Mycoplasma pneumoniae

      Treponema pallidum

    • Mycobacterium tuberculosis

7

Beta-Lactams

  1. What is the base structure of all beta-lactam drugs?
  2. What is their site of action?

  1. Beta-lactam ring 
  2. Beta lactam ring binds to the transpeptidase enzyme (also known as the penicillin binding protein)

8

 

  1. What is the bacterial cell wall made from?
  2. Describe the structure of this wall

  1. Peptidoglycan
  2. Monomers of n-acetyl muramic acid (NAMA) and n-acetyl glucosamine (NAG)

    Formed in chains

    Chains ‘cross-linked’ by action of the  transpeptidase enzyme

9

Beta-Lactams - Penicillins

Benzylpenicillin (the original antibiotic)

  1. What is it's route of administration?
  2. What bacteria does it target?

  1. IV (oral equivalent = phenoxymethylpenicillin)
  2. b-haemolytic streptococci: Streptococcal pharyngitis/tonsillitis 
    1. Severe soft tissue infection
    2. Septic Arthritis

10

Beta-Lactams - Penicillins

Flucloxacillin

  1. ​Why is this important?
  2. What is it active against?
  3. How is it given?
  4. What conditions does it treat?

  1. Amended penicillin to be stable against the staphylococcal beta-lactamase

  2. Staphylococcus aureus

  3. Oral or IV

  4. Skin and soft tissue infection

    Bone and joint infection

    Device related infection

    Endocarditis

11

  1. What is Beta-lactamase?
  2. What antibiotic has been adapted to be stable against this?

  1. An enzyme which hydrolyses, breaks apart, the beta-lactam ring. Made by a bacteria to protect itself against a beta-lactam antibiotic

    One of the most important antibiotic resistance mechanisms

  2. Flucloxacillin

12

Beta-Lactams - Penicillins

Amoxicillin

  1. How has this antimicrobial been amended?
  2. What is it most active against?
  3. How is it given?
  4. What conditions does it therefore treat?

  1. to be better absorbed and broader spectrum

  2. Streptococcus pneumoniae

  3. PO/IV

  4. Pneumonia, Upper and lower respiratory tract infection

13

Beta-Lactams - Penicillin/Beta-lactamase inhibitor combinations

  1. How does the inhibitor help?

  1. Beta lactamase enzyme made by the bacteria to defend itself against the penicillin

    Beta lactamase inhibitor limits the action of beta lactamase enzymes

    Combination of penicillin with the inhibitor dramatically increases the spectrum of action

14

Beta-Lactams - Penicillin/Beta-lactamase inhibitor combinations

​Co-Amoxiclav

  1. What is this made up of?
  2. What is it used for?
  3. What is it active against?
  4. How is it given?

“the antibiotic of choice for people who don’t like to think about antibiotics”

 

  1. Amoxicillin & Clavulanic acid
  2. Intra-abdominal infection (both aerobic and anaerobic gram negative activity)

    Complicated ear/ nose/ throat/ paranasal sinus infections

  3. Staphylococcus aureus

    Streptococcus pneumoniae

    Enterococcus faecalis

    Escherichia coli

    Klebsiella pneumoniae

    Proteus mirabilis

    Salmonella enteritidis and Bacteroides fragilis

  4. PO/IV

15

Beta-Lactams - Penicillin/Beta-lactamase inhibitor combinations

Piperacillin-tazobactam

  1. What is it active against?
  2. How is it given?
  3. What is it used for clinically?

  1. Pseudomonas

  2. IV

  3. Severe sepsis when organ site source is unknown and Pyrexia in neutropenic cancer chemotherapy patients

16

Beta-Lactams - Cephalosporins

Cefuroxime

  1. What is it's common clinical usage?
  2. How is it given?
  3. What is it usually combined with?

  1. surgical prophylaxis

  2. IV

  3. Usually combined with Metronidazole ('others') (which covers anaerobic bacteria)

17

Beta-Lactams - Cephalosporins

Ceftriaxone

  1. What is it's clinical use?
  2. How is it given?
  3. When is it commonly used?

  1. First line treatment in bacterial meningitis
  2. IV
  3. Soft tissue infection, particularly as Outpatient Parenteral Antimicrobial Therapy (OPAT)

18

Beta-Lactams - Monobactam

Aztreonam

  1. What is a common clinical use?
  2. What is it active against?
  3. How is it given?
  4. What is it used in combination with when given to patients with a penicillin allergy

  1. It is a Beta-Lactem safe to give to patients with life threatening penicillin allergy
  2. Only against Gram-negative species
  3. IV
  4. Used in combination with gram positive active agents 

19

Beta-Lactams - Carbapanems

Ertapanems

  1. What is it used for?
  2. How often is it given? How?

 

 

  1. Urinary tract infection, particularly as Outpatient Parenteral Antimicrobial Therapy (OPAT)

  2. Once daily. IV

20

Beta-Lactams - Carbapanems

Meropanem

  1. What is it?
  2. How is it given?
  3. In what conditions is it used?

 

  1. The most broad spectrum agent; the antibiotic of last resort

  2. IV

  3. ICU, Cancer patients, severe structural lung diseases

21

Glycopeptides

  1. Describe the molecule
  2. Where does it act?

  1. large polar (hydrophilic) molecule.

  2. Bacterial Cell wall where it inhibits the addition of the NAMA monomor to the peptidoglycan chain

22

Glycopeptides

Vancomycin and Teicoplanin

  1. What do they act on?
  2. What are they used for?
  3. When is oral vancomycin only ever given?

  1. Gram-positive bacteria
  2. MRSA (and other resistant gram positives), Penicillin/ Beta-lactam allergy

  3.  for Clostridium difficile diarrhoea

23

Which groups carry out Protein Synthesis Inhibtion?

 

 

Where do these groups act?

  1. Macrolides
  2. Aminoglycosides
  3. Tetracyclines

 

bacterial ribosome; inhibiting the production of bacterial protein

24

Macrolides

Clarithromycin & Erythromicin

  1. What are they used for?
  2. How are they given?
  3. Which is better tolerated?

  1. Cover for ‘atypical’ causes of pneumonia. Oral alternative to penicillin in allergy

  2. PO/IV

  3. Clarithromycin

25

Aminoglycosides

Gentamicin

  1. What is it used for?
  2. What are the problems?
  3. How is it given?

 

  1. Gram negative sepsis
  2. but nephrotoxic and ototoxic 

Hydrophilic molecule that remains in the blood stream:  use in sepsis

Concentrates in the kidneys: UTI treatment but risk of nephrotoxicity

Narrow therapeutic window: Therapeutic Drug Monitoring (TDM)

3. IV

26

Tetracyclines

Doxycycline

  1. What is it used for?
  2. What is a drawback?
  3. How is it given?

  1. Oral treatment for MRSA

    Alternative in penicillin allergy

    Respiratory tract infection, including causes of ‘atypical’ pneumonia

  2. Stains bones and teeth: not for children
  3. PO

27

Quinolones

Broad spectrum, orally active, C difficile risk

  1. Give examples of this group
  2. What is their site of action?

  1. Ciprofloxacin, levofloxacin (and others)

  2. Inhibit enzymes that super-coil bacterial DNA (gyrase & topoisomerase) 

28

Quinolones

Ciprofloxacin

  1. What is it used for?
  2. How is it given?
  3. What does it cover well? And how is this useful clinically?
  4. What is a risk?

  1. Common clinical treatment for Pseudomonas
  2. PO/PI
  3. Excellent gram negative cover: UTI

  4. A ‘mutagen’. Drives resistance and associated with hospital outbreaks of Clostridium difficile

29

Quinolones

Levofloxacin

  1. What is it useful as?
  2. What can it be called?
  3. How is it given?

  1. Excellent activity against streptococcus pneumoniae and causes of ‘atypical’ pneumonia

  2. Respiratory quinolone

  3. PO/IV

30

'Others'

What are the following used for?

  1. Metronidazole
  2. Trimethoprim and Nitrofurantoin

  1. anaerobic infection
  2. UTI

31

Others

Metronidazole

  1. How does it act?
  2. What does it act on?
  3. How is it given?
  4. What is it used for?

  1. Nitroimidazole, Pro-drug: activated in low oxygen conditions. Once active is directly toxic through interaction with DNA

  2. Anaerobic ‘cover’

  3. PO/ IV

  4. Intra-abdominal infection

    Oral infections

    Clostridium difficile diarrhoea

32

Others

Trimethoprim

  1. How does it act?
  2. What is it used for?
  3. How is it given?
  4. What can it be combined with?
  5. What does the above treat?

  1. Diaminopyrimidine, ‘folate antagonist’, Dihydrofolate reductase inhibitor

  2. Uncomplicated UTI

  3. PO

  4. Can be combined with the sulphonamide Sulfamethoxazole as C0-trimoxazole

  5.   treat some multiresistant bacteria and Pneumonia caused by Pneumocystis jirovecii

33

Others

Nitrofurantoin

  1. How does it act?
  2. What is it used for?
  3. Who is it contra-indicated for?

  1. Multiple mechanisms of action, poorly understood. Inhibition of bacterial protein synthesis and toxic to DNA. Therapeutic levels are only attained in the urine

  2. Uncomplicated UTI

  3. Not given to patients with renal failure as not enough drug will be filtered into the urine

34

What is the mechanism of action for the following?

  1. Beta-Lactams
  2. Glycopeptides
  3. Macrolides, Aminoglycosides, Tetracyclines
  4. Quinolones
  5. Others
    1. Metronidazole
    2. Trimethoprim
    3. Nitrofurantoin

 

  1. Beta lactam ring binds to the transpeptidase enzyme (also known as the penicillin binding protein)

  2. Cell wall where it inhibits the addition of the NAMA monomor to the peptidoglycan chain

  3. bacterial ribosome; inhibiting the production of bacterial protein

  4. Inhibit enzymes that super-coil bacterial DNA (gyrase & topoisomerase) 

  5. Others

    1. Once active is directly toxic through interaction with DNA

    2. 'folate antagonist’. Dihydrofolate  reductase inhibitor

    3. Multiple mechanisms of action, poorly understood. Inhibition of bacterial protein synthesis and toxic to DNA

35

What are the following used to treat?

Beta-Lactams

  1. Penicillins
    1. Benzylpenicillin

    2. Flucloxacillin

    3. Amoxicillin

  2. Penicillin/ beta-lactamase inhibitor combinations

    1. Co-amoxiclav

    2. Piperacillin & tazobactam

  3. Cephalosporins

    1. Cefuroxime

    2. Ceftriaxone

  4. Monobactam

    1. Aztreonam

  5. Carbapenems

    1. Ertapenem

    2. Meropenem 

  1. Penicillins
    1. Targeting b-haemolytic streptococci: Streptococcal pharyngitis/ tonsillitis 

    2. Staphylococcus aureus: Skin and soft tissue infection, Bone and joint infection, Device related infection, Endocarditis

    3. Step. Pneumoniae: Pneumonia Upper and lower respiratory tract infection

  2. PBICs

    1. Intra-abdominal infection (both aerobic and anaerobic gram negative activity). Complicated ear/ nose/ throat/ paranasal sinus infections

    2. Pseudomonas: Severe sepsis when organ site source is unknown, Pyrexia in neutropenic cancer chemotherapy patients

  3. Cephalosporins

    1. surgical prophylaxis

    2. First line treatment for bacterial meningitis

  4. Monobactam

    1. safe to give to patients with life threatening penicillin allergy. Only active against gram negative species

  5. Carbapenems

    1. UTI

    2. Last resort. ICU, Cancer patients, severe structural lung diseases

36

What are the following used to treat?

  1. Glycopeptides
    1. Vancomycin and Teicoplanin 

  2. Macrolides

    1. Clarithromycin & Erythromicin

  3. Aminoglycosides

    1. Gentamicin

  4. Tetracyclines

    1. Doxycycline

  5. Quinolones

    1. Ciprofloxacin

    2. Levofloxacin

  6. Others

    1. Metronidazole

    2. Trimethoprim 

    3. Nitrofurantoin

  1. Glycopeptides
    1. Gram positive cover. MRSA. Penicillin/ Beta-lactam allergy
  2. Macrolides
    1. ‘atypical’ causes of pneumonia.  Oral alternative to penicillin in allergy

  3. Aminoglycosides

    1. Gram negative sepsis: but nephrotoxic and ototoxic 

  4. Tetracyclines

    1. MRSA. Respiratory tract infection, including causes of ‘atypical’ pneumonia

  5. Quinolones

    1. Pseudomonas. UTI (excellent gram neg cover)

    2. Excellent activity against streptococcus pneumoniae and causes of ‘atypical’ pneumonia

  6. Others

    1. anaerobic infection. Clostridium difficile diarrhoea

    2. UTI. treat some multiresistant bacteria and Pneumonia caused by Pneumocystis jirovecii

    3. UTI.