Inhoudsopgave
Antimicrobial resistance: a closer look at today’s critical threat ......................................................... 2
1. Antibiotic resistance ............................................................................................................. 2
1.1 Minimal inhibitory concentration .......................................................................................... 3
1.2 Antibiotic resistance: emergence ......................................................................................... 4
2. Bacterial targets of antibiotics .............................................................................................. 5
2.1 Beta-lactamases ................................................................................................................. 7
2.2 Adaptive resistance ............................................................................................................. 7
3. Antibiotic resistance: a “One Health” approach ..................................................................... 7
4. Examples of antibiotic resistance emergence and implications .............................................. 8
4.1 Resistance development Staphylococcus aureus ................................................................. 8
4.2 Klebsiella pneumoniae ........................................................................................................ 9
5. Beta-lactam resistance in Gram-negatives .......................................................................... 10
5.1 Enterobacterales: ESBL ..................................................................................................... 10
6. Carbapenem resistance in Gram-negatives ......................................................................... 10
Epidemiology of respiratory viruses ................................................................................................ 12
1. Origins of respiratory virus outbreaks .................................................................................. 12
2. Zoonotic infections ............................................................................................................. 12
2.1 Coronaviruses and animal reservoirs ................................................................................. 12
3. Transmission of respiratory viruses ..................................................................................... 12
3.1 Pathogen transport and global spread ................................................................................ 13
4. RNA viruses........................................................................................................................ 13
4.1 Orthomyxoviridae (Influenza A, B, C) .................................................................................. 13
4.2 Coronaviridae (SARS-CoV, MERS) ....................................................................................... 14
4.3 Arenaviridae (Lassa virus, LCMV) ....................................................................................... 15
4.4 Bunyaviridae (Hantaviruses: Seoul, Andes, Puumala) ......................................................... 16
4.5 Filoviridae (Ebola, Marburg) ............................................................................................... 16
4.6 Paramyxoviridae (RSV, Nipah virus) .................................................................................... 16
4.7 Rhabdoviridae (Rabies virus) .............................................................................................. 17
5. DNA virus with pandemic potential: Monkeypox (Mpox) ....................................................... 17
1
, Antimicrobial resistance: a closer look at today’s critical threat
Antimicrobial resistance (AMR) occurs when microorganisms such as
bacteria, viruses, fungi and parasites evolve and become resistant to the
drugs that are designed to kill them.
• You don’t die immediately from AMR → but if you get an infection
with a bacterium that is resistant → there are only two options:
(1) the body resolves the infection on its own; (2) the infection
cannot be treated.
How does AMR develop?
(1) Overprescribing antibiotics by doctors when they are not
needed.
(2) Incorrect use of antibiotics by patients (not finishing a full course
of treatment or using leftover drugs).
(3) Over-use of antibiotics in livestock and fish farming
(4) Poor infection control in hospitals and clinics
(5) Lack of hygiene and poor sanitation
→ Treatment with antibiotics: taking them for too long is worse than stopping too soon (if you stop too soon,
the immune system can still act) → more resistance occurs with a too long antibiotic treatment → some
patients do need to be treated longer with antibiotics because their immune system will not respond and
treat the infection.
WHO Global Action Plan (2015)
• Objective 1: improve awareness and understanding through communication, education and training.
• Objective 2: strengthen the knowledge and evidence base through surveillance and research.
• Objective 3: Reduce the incidence of infection through effective sanitation, hygiene and infection
prevention measures.
• Objective 4: optimize the use of antimicrobial medicines in human and animal health.
• Objective 5: develop the economic case for sustainable investment and increase investment in new
medicines, diagnostic tools, vaccines and other interventions.
→ Other ways to tackle antimicrobial resistance:
- Better water and sanitation reduce antibiotic consumption.
- Increasing coverage of vaccines can reduce antibiotic use
- Increasing the supply of antimicrobials to keep up with rising resistance
- Market entry rewards would have a powerful impact on antibiotic R&D
1. Antibiotic resistance
First clinically used antibiotic was sulfonamide: 1937
• Description of resistance since the late ‘30s
Penicillin was used clinically since the 1940’s
• Before the clinical use of penicillin, the existence of penicillinases was described.
• 1945: Nobel price Medicine for Fleming, Chain & Florey: “the use of antimicrobials can, and will, lead to
resistance.”
2
, Key concepts in antibiotic resistance:
• MIC = minimal inhibitory concentration
• Susceptible (= gevoeligheid voor een antibioticum); susceptible, increased exposure; resistant
• Selection pressure
• Intrinsic and acquired resistance
• Horizontal versus vertical resistance acquisition
1.1 Minimal inhibitory concentration
Important concept in microbiology and clinical pharmacology
Gold standard method to determine MIC = broth dilution or agar dilution
• MIC = lowest concentration of an antimicrobial agent that can inhibit the visible growth of a
microorganism.
• Broth dilution method
- The bacteria are placed in a series
of small tubes or wells containing
liquid nutrient broth.
- Each tube as a different
concentration of the antibiotic.
- After incubation, the tubes are
checked to see where bacterial growth has stopped.
- The lowest concentration with no visible growth is recorded as the MIC.
The lower the MIC, the more sensitive (susceptible) the micro-organism.
Pharmacokinetics and -dynamics: effectiveness antibiotic also depends on other factors
• Feasible concentration of the antibiotic in plasma and/or tissues
- Toxicity
- Metabolism
- Tissue distribution
• The type of antibiotic
- Time > MIC
- Peak concentration
- AUC > MIC
Aminoglycosides: their effectiveness depends on achieving a high peak
concentration compared to the MIC
• These antibiotics kill bacteria more efficiently when the peak
concentration is much higher than the MIC
- They are often given in high doses at longer intervals.
Beta-lactam antibiotics: the key factor is how long the drug concentration stays above the MIC during the dosing interval.
• These drugs are often given more frequently or via continuous infusion to keep the concentration above the MIC for as long as
possible.
Fluoroquinolones: efficacy depends on the total drug exposure over time (AUC)
• The drug must maintain sufficient levels over time to be effective.
3
Antimicrobial resistance: a closer look at today’s critical threat ......................................................... 2
1. Antibiotic resistance ............................................................................................................. 2
1.1 Minimal inhibitory concentration .......................................................................................... 3
1.2 Antibiotic resistance: emergence ......................................................................................... 4
2. Bacterial targets of antibiotics .............................................................................................. 5
2.1 Beta-lactamases ................................................................................................................. 7
2.2 Adaptive resistance ............................................................................................................. 7
3. Antibiotic resistance: a “One Health” approach ..................................................................... 7
4. Examples of antibiotic resistance emergence and implications .............................................. 8
4.1 Resistance development Staphylococcus aureus ................................................................. 8
4.2 Klebsiella pneumoniae ........................................................................................................ 9
5. Beta-lactam resistance in Gram-negatives .......................................................................... 10
5.1 Enterobacterales: ESBL ..................................................................................................... 10
6. Carbapenem resistance in Gram-negatives ......................................................................... 10
Epidemiology of respiratory viruses ................................................................................................ 12
1. Origins of respiratory virus outbreaks .................................................................................. 12
2. Zoonotic infections ............................................................................................................. 12
2.1 Coronaviruses and animal reservoirs ................................................................................. 12
3. Transmission of respiratory viruses ..................................................................................... 12
3.1 Pathogen transport and global spread ................................................................................ 13
4. RNA viruses........................................................................................................................ 13
4.1 Orthomyxoviridae (Influenza A, B, C) .................................................................................. 13
4.2 Coronaviridae (SARS-CoV, MERS) ....................................................................................... 14
4.3 Arenaviridae (Lassa virus, LCMV) ....................................................................................... 15
4.4 Bunyaviridae (Hantaviruses: Seoul, Andes, Puumala) ......................................................... 16
4.5 Filoviridae (Ebola, Marburg) ............................................................................................... 16
4.6 Paramyxoviridae (RSV, Nipah virus) .................................................................................... 16
4.7 Rhabdoviridae (Rabies virus) .............................................................................................. 17
5. DNA virus with pandemic potential: Monkeypox (Mpox) ....................................................... 17
1
, Antimicrobial resistance: a closer look at today’s critical threat
Antimicrobial resistance (AMR) occurs when microorganisms such as
bacteria, viruses, fungi and parasites evolve and become resistant to the
drugs that are designed to kill them.
• You don’t die immediately from AMR → but if you get an infection
with a bacterium that is resistant → there are only two options:
(1) the body resolves the infection on its own; (2) the infection
cannot be treated.
How does AMR develop?
(1) Overprescribing antibiotics by doctors when they are not
needed.
(2) Incorrect use of antibiotics by patients (not finishing a full course
of treatment or using leftover drugs).
(3) Over-use of antibiotics in livestock and fish farming
(4) Poor infection control in hospitals and clinics
(5) Lack of hygiene and poor sanitation
→ Treatment with antibiotics: taking them for too long is worse than stopping too soon (if you stop too soon,
the immune system can still act) → more resistance occurs with a too long antibiotic treatment → some
patients do need to be treated longer with antibiotics because their immune system will not respond and
treat the infection.
WHO Global Action Plan (2015)
• Objective 1: improve awareness and understanding through communication, education and training.
• Objective 2: strengthen the knowledge and evidence base through surveillance and research.
• Objective 3: Reduce the incidence of infection through effective sanitation, hygiene and infection
prevention measures.
• Objective 4: optimize the use of antimicrobial medicines in human and animal health.
• Objective 5: develop the economic case for sustainable investment and increase investment in new
medicines, diagnostic tools, vaccines and other interventions.
→ Other ways to tackle antimicrobial resistance:
- Better water and sanitation reduce antibiotic consumption.
- Increasing coverage of vaccines can reduce antibiotic use
- Increasing the supply of antimicrobials to keep up with rising resistance
- Market entry rewards would have a powerful impact on antibiotic R&D
1. Antibiotic resistance
First clinically used antibiotic was sulfonamide: 1937
• Description of resistance since the late ‘30s
Penicillin was used clinically since the 1940’s
• Before the clinical use of penicillin, the existence of penicillinases was described.
• 1945: Nobel price Medicine for Fleming, Chain & Florey: “the use of antimicrobials can, and will, lead to
resistance.”
2
, Key concepts in antibiotic resistance:
• MIC = minimal inhibitory concentration
• Susceptible (= gevoeligheid voor een antibioticum); susceptible, increased exposure; resistant
• Selection pressure
• Intrinsic and acquired resistance
• Horizontal versus vertical resistance acquisition
1.1 Minimal inhibitory concentration
Important concept in microbiology and clinical pharmacology
Gold standard method to determine MIC = broth dilution or agar dilution
• MIC = lowest concentration of an antimicrobial agent that can inhibit the visible growth of a
microorganism.
• Broth dilution method
- The bacteria are placed in a series
of small tubes or wells containing
liquid nutrient broth.
- Each tube as a different
concentration of the antibiotic.
- After incubation, the tubes are
checked to see where bacterial growth has stopped.
- The lowest concentration with no visible growth is recorded as the MIC.
The lower the MIC, the more sensitive (susceptible) the micro-organism.
Pharmacokinetics and -dynamics: effectiveness antibiotic also depends on other factors
• Feasible concentration of the antibiotic in plasma and/or tissues
- Toxicity
- Metabolism
- Tissue distribution
• The type of antibiotic
- Time > MIC
- Peak concentration
- AUC > MIC
Aminoglycosides: their effectiveness depends on achieving a high peak
concentration compared to the MIC
• These antibiotics kill bacteria more efficiently when the peak
concentration is much higher than the MIC
- They are often given in high doses at longer intervals.
Beta-lactam antibiotics: the key factor is how long the drug concentration stays above the MIC during the dosing interval.
• These drugs are often given more frequently or via continuous infusion to keep the concentration above the MIC for as long as
possible.
Fluoroquinolones: efficacy depends on the total drug exposure over time (AUC)
• The drug must maintain sufficient levels over time to be effective.
3
