12 Anti-microbial therapies

Question 1

What is Prontosil?

Answer 1

One of the very first examples of an anti-bacterial drug

Question 2

Prontosil details

Answer 2

• First sulphonamide
• Bacteriostatic
• Synthetic
• Some host toxicity

Question 3

What does bacteriostatic mean?

Answer 3

Does not kill bacteria but stops it from growing

Question 4

Gram positive bacteria

Answer 4

Thick peptidoglycan

Single mebrane

Question 5

Gram negative bacteria

Answer 5

Inner membrane- phospholipids

Outer membrane - mixture of phospholipids and lipopolysaccharides

Question 6

Why is it easier to develop drugs against gram +ve bacteria?

Answer 6

Gram negative –> To get something across outer layer - hydrophilic, to get something across inner layer- hydrophobic
Very difficult to find molecules with both of those properties

Question 7

How do Beta-lactams work?

Answer 7

Interfere with the synthesis of the peptidoglycan component of the bacterial cell wall
- Bind to penicillin binding proteins, binding to active sites and inactivating them

Question 8

Examples of Beta-lactams

Answer 8

Penicillin

Methicillin

Question 9

What is an antibiotic?

Answer 9

An antimicrobial agent produced by a microorganism that kills or inhibits other microirganisms

Question 10

What does antimicrobial mean?

Answer 10

Chemical that selectively kills or inhibits microbes

Question 11

What does bactericidal mean?

Answer 11

Kills bacteria

Question 12

What does antiseptic mean?

Answer 12

Chemical that kills or inhibits microbes that is usually used topically to prevent infection

Question 13

What is the minimal inhibitory concentration (MIC)?

Answer 13

The lowest concentration of antibiotics required to inhibit growth

Question 14

Three stages of resistance

Answer 14

• Sensitive (killed, inhibited by low concs)
• Intermediate
• Resistant

Question 15

What is a high concentration of antibiotics?

Answer 15

Any concentration that is above what can be achieved clinically (breakpoint)

Question 16

Antibiotic resistance comes about by

Answer 16

Natural selection (certain strains resistant before use due to mutations)

Question 17

What happens when a selection pressure such as an antibiotic is applied?

Answer 17

Susceptible bugs are killed off, resistant bugs are left - high prevalence of AB resistant strains

Question 18

Vancomycin

Answer 18

Resistance reported much later

Not used very much, very toxic

Question 19

Diagnostics and bacteriology can take

Answer 19

24-48 hrs to get susceptibility

Question 20

Examples of aminoglycosides

Answer 20

Gentamicin

Streptomycin

Question 21

How do aminoglycosides work?

Answer 21

Bactericidal

• Inhibit protein synthesis (30S ribosomal subunit) and RNA proofreading causing damage to the cell mebrane
• Very toxic

Question 22

How does rifampicin work?

Answer 22

Bacericidal

• Targets RpoB subunit of RNA polymerase
• Makes secretions go orange/red affecting compliance

Question 23

How does vancomycin work?

Answer 23

Bactericidal

• Targets Lipid II component of cell wall biosynthesis and cross linking
• Toxic (limited use)

Question 24

How does linezolid work?

Answer 24

Bacteriostatic

• Inhibits initiation of protein synthesis by binding to 50S rRNA subunit
• Gram +ve only

Question 25

How does daptomycin work?

Answer 25

Bactericidal

• Targets bacterial cell mebrane
• Gram +ve
• Toxic

Question 26

4 mechanisms of antibiotic resistance

Answer 26

• Altered target site
• Inactivation of antibiotic
• Altered metabolism
• Decreased drug accumulation

Question 27

How does an altered target site work?

Answer 27

• Gene encoding target modifying enzyme

- e.g. MRSA encodes alternative PBP with ow affinity for beta-lactams

Question 28

How does inactivation of antibiotic occur?

Answer 28

• Enzymatic degradation/alteration
• Beta-lactamase
• e.g. ESBL, NDM-1

Question 29

How does altered metabolism work?

Answer 29

• Increased production of enzyme substrate (competitive inhibition)
• Bacteria can switch to other metabolic pathways

Question 30

How does decreased drug accumulation work?

Answer 30

Reduced penetration of antiobiotic into bacterial cell or increased efflux of AB out of the cell (pumping out)

Question 31

How do macrolides work?

Answer 31

Target 50S ribosomal subunit preventing amino-acyl transfer (+ve + -ve)

Question 32

Examples of macrolides

Answer 32

Erythromycin

Azithromycin

Question 33

How do quinolones work?

Answer 33

Bactericidal

Target DNA gyrase in -ve and topoisomera IV in +ve

Question 34

How are plasmids sources of resistant genes?

Answer 34

Can be swapped between bacteria, carry multiple AB res genes

Question 35

How are transposons a source of resistance?

Answer 35

Integrate into chromosomal DNA, transfer genes from plasmid to chromosome

Question 36

How is naked DNA a source of resistance?

Answer 36

DNA from dead bacteria is released into the environment

Question 37

What is transformation?

Answer 37

Uptake of extracellular DNA

Question 38

What is transduction?

Answer 38

Phage-mediated DNA transfer

Question 39

What is conjugation?

Answer 39

Pilus-mediated DNA transfer

Question 40

Measurements made in vitro

Answer 40

May not fully reflect the situation in vivo

Question 41

Why is HAI a big problem?

Answer 41

Hospitals provide strong selective pressure for AB resistance
Large numbers of people re receiving high doses

Question 42

Examples of HAIs

Answer 42

• MRSA
• Clostridium difficile
• E. coli
• Acineterbacter baumannii
• VISA (vancomycin insensitive S aureus)

Question 43

Risk factors for HAI

Answer 43

• Immunosupression
• Crowded wards
• Presence of pathogens
• Broken skin (wounds)
• Staff –> vectors

Question 44

How to slow down resistance

Answer 44

• Reduce use of broad-spectrum
• Combination therapy
• Tighter controls, restrictions

Question 45

What may be used in the future?

Answer 45

• New antibiotics/vaccines
• Better screening
• Novel approaches (phae lysins, photo active compounds)