Antibiotic Resistance

Question 1

Explain how antibiotic resistance is a global concern

Answer 1

• 25,000 people die every year across Europe because of infections related to Antimicrobial Resistance (AMR)
• In USA, MDR infections cost the health-care system – 20 billion US dollars annually and generate more than 8 million additional hospital days

Question 2

What can antibiotic resistance do?

Answer 2

• Increases mortality
• Challenges control of infectious diseases
• Threatens a return to the pre-antibiotic era
• Increases the costs of health care
• Jeopardizes health-care gains to society

Question 3

What is the common misconception about superbugs (drug-resistant bacteria)?

Answer 3

Drug resistant bacteria are NOT MORE pathogenic

We just have fewer antibiotic options for treatment, so therefore they are more difficult to treat

Question 4

What are some mechanisms of intrinisc antibiotic bacterial resistance?

Answer 4

1. Drug inactivation
   
   • Bacteria will acquire enzymes which will destroy the active component of antibiotics rendering them useless
     
     • e.g Bacteria can acquire beta lactamases which destroy beta lactams, we can develop drugs which are resistant to this however bacteria can overcome this which are then called extended spectrum beta lactamases
2. Altered or Mutated new target
   
   • E.g mutated RNA polymerase = Rifampicin resistance
   • Acquisition of a new penicillin binding protein (PBP2A) and can no longer be inhibited by beta lactams = MRSA
   • Mutation of DNA gyrase = Quinolones will no longer work
   • Porins = bacteria can exchange genes and acquire a new gene for a completely different mutation, or a mutation can undergo in current porins
3. Efflux pumps
   
   • Bacteria can upregulate proteins which produce efflux pumps or acquire new efflux pumps.
     
     • They pump out anything that the bacteria doesnt want intracellularly There is more efflux of the drug than influx through porin and amount of drug will never be sufficient to reach MIC
4. Intrinsic Permeabillity
   
   • The membranes are impermeable so that the antibiotic cannot access them
   • Intrinsic permeabillity is a problem for many gram negative bacteria
5. Overproduction of target
   
   • Drugs like sulphonamide and trimethoprim will act as enzymes involved in Folic acid metabolism
   • Bacteria can overcome the effective of these comp. inhibitors by overproducing targets through upregulation of genes coding for those enzymes
6. Metabolic By-Pass
   
   1. Vancomycin resistance bacteria will acquire genes to encode a new biosynthetic pathway so instead of generating terminal D-ala D-ala they will generate D-ala D-lac. Vancomycin will no longer be able to bind to this

Question 5

What are the three types of mechanisms of resistance?

Answer 5

1. Natural
2. Genetic Mechanisms (Acquired)
3. Non-Genetic Mechanisms (Growth Phases)

Question 6

Describe some natural mechanisms of resistance

Answer 6

Natural (opposed to acquired)

• The drug must be able to reach the target (overcoming natural barriers, porins, export pumps)
• Gram posotive peptidoglycan is highly porous = no barrier to diffusion
• Gram negative bacteria the outer membrane is a barrier to antibiotics so confers a natural resistance advantage

Question 7

Describe the genetic mechanisms of resistance

Answer 7

CHROMOSOME MEDIATED

• Bacteria can generate many spontaneous mutations in
  
  • Target molecule
  • Drug uptake system
• In the presence of an antibiotic pressure these spontaneous mutants will be selected (not induced)

PLASMID MEDIATED

• Common in gram negative rods
• Transferred via conjugation
• Multidrug resistance

Question 8

What are the three mechanisms by which bacteria exchange genetic information?

Answer 8

• Transformation → uptake of naked DNA from one bacterium that is lysed and taken up by another bacteria
• Transduction → Infected by a bacteriophage, it normally takes a bit of DNA from the previously infected host and takes it over to the next bacterial host
• Conjugation → Two bacteria will form pilli through which DNA is exchanged either chromosomal or plasmid

Question 9

What do penicillinase (beta-lactamase enzymes) do?

Answer 9

Penicillinase (beta-lactamase) enzymes will destroy the 3D structure and break the bond and therefore no longer a competitive structural mimic of the enzyme

Question 10

What is Augumentin/co-amoxiclav?

Answer 10

• Drug composed of clavulanic acid (no anti-bacterial activity of its own) and amoxicillin.
• On its own amoxicillin is a broad spectrum beta lactam antibiotic
• Clavulanic acid will inhibit beta lactamases and allow amoxicillin to work
• These combinations can be very potent when dealing with antibiotic resistant organisms
  
  • Some bacteria have acquired extended spectrum beta lactamases = not inhibited by clavulanic acid

Question 11

Describe the mechanisms through which bacteria become resistant to penicillin

Answer 11

• Produce penicillinases which will cleave the beta-lactam ring = penicillin inactivation
• Acquire alternative forms of/ or mutations in penicillin binding protein (gram posotive bacteria)
• Acquire alternative forms of mutations in porins = penicillin cannot get into the cell (gram negative bacteria)
• Acquire alternative forms of mutations in efflux pumps = penicillins are pumped out faster

Question 12

Describe how bacteria can become vancomycin resistant?

Answer 12

• Acquisition of van operon by transposition
  
  • Set of genes which regulate the biosynthesis of D-ala D-lac instead of D-ala D-ala
  • D-ala D-lac will only bind vancomycin weakly which the bacteria is able to overcome

Question 13

Describe some non-genetic mechanisms of resistance

Answer 13

• INACCESSIBILITY TO DRUGS
  
  • Some drugs it is difficult to pharmacologically get the drug to the MIC that you need
    
    • E.g abscess, TB lesion
• STATIONARY PHASE/ VEGETATIONS AND BIOFILMS
  
  • Bacteria can sit and create biofilms which are very difficult to treat as antibiotics are not able to get through the mucopolysaccharide structure

Question 14

What are some ways in which we can prevent antibiotic resistance?

Answer 14

• Control use
  
  • Not in animal feeds
  • Complete course [DOTS for TB]
  • Appropriate prescribing
• New or modified drugs
  
  • There have only been few in past 25 years
• Combination theory
  
  • Medications will go for different targets
  • They will be able to overcome mutation rates
• Infection control
  
  • Can be of the individual, ward or society

Question 15

Briefy explain the war of resistance of Neisseria gonorrhoeae

Answer 15

• In the 1950s-60s Gonorrhoea could be cleared with a single dose of penicillin however after a few years resistance increased by 15%
• The treatment was switched to ciprofloxacin (DNA gyrase inhibitor), this could be used at a high dose to clear the infection however resistance rates also increased
• A new cephalosporin (cefixime) was developed where a single oral dose was able to cause the infection to be cleared in three days
• New treatment therapy is Ceftriaxone (3rd generation cephalosporin) and azithromycin
  
  • This has been used for the last 2-3 years to treat gonorrhoea, hwoever there is a gradual increase in resistance