Umweltsysteme 1 - Umwelt und Gesundheit
Teil Bonhöfer
Teil Bonhöfer
Where are antibiotics used?
Animals
- in chicken, pigs, cattle, aquaculture
- as growth promotion (banned in EU/US)
- Treatment
- Prophylaxis
Medicine
- community (primary care sector)
- hospitals (secondary care sector)
Difficulties in Discovery of new antibiotics
difficult to find new antibiotics
high cost (1-2 billion $)
small market (antibiotic will be used as last resort)
development of AMR (antimicrobiala resistance)
in 2050 expected to kill 10 million (more than cancer)
Recent attention on antibiotics
- UN general assembly meeting on antimicrobial resistance in 2016
Antibiotic resistance on agenda of recent G7 and G20 meetings
StAR (Strategy Antibiotic Resistance) in Switzerland
Abschnitte Antibiotikaforschung
1919-1949: Time of pioneers
1940-1960: Golden age
1960-1990: Deceleration
1990-jetzt: Discovery void
classification of antibiotics
Antibiotics can be grouped according to different criteria:
mechanism of action
effect on bacterial growth dynamics
breadth of activity (narrow/broad spectrum)
Mechanisms of action
- Cell wall synthesis
- Folate synthesis (folsäure)
- Protein synthesis
- Rna Polymerase
- Cell membrane disrupters
- Nucleid acis synthesis
- (LPS and/or TLR4 blockers)
Growth effect types:
Bacteriocidal antibiotics:
- • kill bacteria, i.e. increase death rate
- • e.g. Cell wall synthesis inhibitors; also nucleic acid synthesis inhibitors such as fluoroquinolon
Bacteriostatic antibiotics:
Prevent or reduce reproduction, i.e.reduce division rate
e.g. protein and folate synthesis inhibitors
Breadth of activity:
Broad spectrum:
- ‣ activity against different broad range of bacteria such as gram negative and gram positive bacteria
- • e.g. beta-lactams‣
Narrow spectrum:
effective against a narrow range of bacteria such as gram positives or gram negatives only
e.g. glycopeptides which act principally against gram-positives or aminoglycosides which act against gram-negatives
MIC
Minimum inhibatory concentration
concentration of antibiotics where growth rate is 0
Bacterial growth curve
Lag phase
- ‣ Bacteria adapt to growth conditionsExponential phase
Exponential phase
- ‣ Bacteria grow exponentially until resource is exhausted (net growth rate)
Stationary phase
- ‣ After depletion of a growth limiting factor bacterial population density stays constant
Death phase (not shown)
- After sufficiently long time bacteria begin to die
Drug effect
- ‣ Increasing drug decreases (for example) net growth rate (see dashed lines)
EC50
drug concentration at which net growth rate is half of max-min
MPC
Mutant prevention concentration
‣ The minimum drug concentration above with the resistant cannot grow (= MIC of resistant strain)
MSC
Mutant selection concentration
The minimum drug concentration above which the resistant has a growth advantage over sensitive
Fitness cost (in absence of drugs)
Cost equals 1 minus the relative growth rate of resistant to sensitive bacteria (in absence of drugs)
Resistance
‣ Most common measure for resistance is shift in MIC, but resistance can change of the four parameters of the Hill curve.
Quantification of drug resistance
Dose-response curve
fit hill function to data
\(f(c) = {min-max\over 1+{c\over EC50}^{slope}}\)
Denmark: Antibiotics as growth promoters
Decrease in antibiotic use in animal farming by banning AGP, stopping sales benefits to vets, and yellow card scheme
Antibiotics resistance mechanisms
‣ Enzymatic alteration of antibiotic
‣ Enzymatic degradation of antibiotic
‣ Efflux pumps that pump out antibiotics
‣ Alteration of the intracellular targets (not shown)
Development of Antibiotic resistance in CH
on the rise, but also cases where decreasing: ex. MRSA
Different types of mutations and reversion
‣ Fitness cost of resistance: Fitness gain in presence but loss in absence of anitbiotics
‣ Compensatory mutations: Increase in fitness in presence and absence of drugs (on the genetic background of resistance mutations)
‣ Lobster trap: Compensatory mutations may prevent the reversion back to drug sensitivity when antibiotics are withdrawn, because the path back to the sensitive wild- type goes through a fitness valley
Key Points
The challenge
- ‣ Rise of antibiotic resistance and decline of discovery rate of new antibioticsAntibiotic use
Antibiotic use
- ‣ Global and regional differences in use, human and animal use; antibiotics in the environment
Quantification of bacterial growth
- ‣ Lag/exponential/stationary phase; dose-response curve; minimal inhibitory concentration; mutant selection concentration
How antibiotics work
- ‣ antibiotic classes; mechanisms of action; bacteriostatic/bactericidal drugs; breadth of activity
Resistance
- ‣ Mechanisms of resistance; horizontal transfer of resistance (conjugation, transduction, transformation), population dynamics of resistance
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Lernkarten
Where are antibiotics used?
Animals
- in chicken, pigs, cattle, aquaculture
- as growth promotion (banned in EU/US)
- Treatment
- Prophylaxis
Medicine
- community (primary care sector)
- hospitals (secondary care sector)
Difficulties in Discovery of new antibiotics
difficult to find new antibiotics
high cost (1-2 billion $)
small market (antibiotic will be used as last resort)
development of AMR (antimicrobiala resistance)
in 2050 expected to kill 10 million (more than cancer)
Recent attention on antibiotics
- UN general assembly meeting on antimicrobial resistance in 2016
Antibiotic resistance on agenda of recent G7 and G20 meetings
StAR (Strategy Antibiotic Resistance) in Switzerland
Abschnitte Antibiotikaforschung
1919-1949: Time of pioneers
1940-1960: Golden age
1960-1990: Deceleration
1990-jetzt: Discovery void
classification of antibiotics
Antibiotics can be grouped according to different criteria:
mechanism of action
effect on bacterial growth dynamics
breadth of activity (narrow/broad spectrum)
Mechanisms of action
- Cell wall synthesis
- Folate synthesis (folsäure)
- Protein synthesis
- Rna Polymerase
- Cell membrane disrupters
- Nucleid acis synthesis
- (LPS and/or TLR4 blockers)
Growth effect types:
Bacteriocidal antibiotics:
- • kill bacteria, i.e. increase death rate
- • e.g. Cell wall synthesis inhibitors; also nucleic acid synthesis inhibitors such as fluoroquinolon
Bacteriostatic antibiotics:
Prevent or reduce reproduction, i.e.reduce division rate
e.g. protein and folate synthesis inhibitors
Breadth of activity:
Broad spectrum:
- ‣ activity against different broad range of bacteria such as gram negative and gram positive bacteria
- • e.g. beta-lactams‣
Narrow spectrum:
effective against a narrow range of bacteria such as gram positives or gram negatives only
e.g. glycopeptides which act principally against gram-positives or aminoglycosides which act against gram-negatives
MIC
Minimum inhibatory concentration
concentration of antibiotics where growth rate is 0
Bacterial growth curve
Lag phase
- ‣ Bacteria adapt to growth conditionsExponential phase
Exponential phase
- ‣ Bacteria grow exponentially until resource is exhausted (net growth rate)
Stationary phase
- ‣ After depletion of a growth limiting factor bacterial population density stays constant
Death phase (not shown)
- After sufficiently long time bacteria begin to die
Drug effect
- ‣ Increasing drug decreases (for example) net growth rate (see dashed lines)
EC50
drug concentration at which net growth rate is half of max-min
MPC
Mutant prevention concentration
‣ The minimum drug concentration above with the resistant cannot grow (= MIC of resistant strain)
MSC
Mutant selection concentration
The minimum drug concentration above which the resistant has a growth advantage over sensitive
Fitness cost (in absence of drugs)
Cost equals 1 minus the relative growth rate of resistant to sensitive bacteria (in absence of drugs)
Resistance
‣ Most common measure for resistance is shift in MIC, but resistance can change of the four parameters of the Hill curve.
Quantification of drug resistance
Dose-response curve
fit hill function to data
\(f(c) = {min-max\over 1+{c\over EC50}^{slope}}\)
Denmark: Antibiotics as growth promoters
Decrease in antibiotic use in animal farming by banning AGP, stopping sales benefits to vets, and yellow card scheme
Antibiotics resistance mechanisms
‣ Enzymatic alteration of antibiotic
‣ Enzymatic degradation of antibiotic
‣ Efflux pumps that pump out antibiotics
‣ Alteration of the intracellular targets (not shown)
Development of Antibiotic resistance in CH
on the rise, but also cases where decreasing: ex. MRSA
Different types of mutations and reversion
‣ Fitness cost of resistance: Fitness gain in presence but loss in absence of anitbiotics
‣ Compensatory mutations: Increase in fitness in presence and absence of drugs (on the genetic background of resistance mutations)
‣ Lobster trap: Compensatory mutations may prevent the reversion back to drug sensitivity when antibiotics are withdrawn, because the path back to the sensitive wild- type goes through a fitness valley
Key Points
The challenge
- ‣ Rise of antibiotic resistance and decline of discovery rate of new antibioticsAntibiotic use
Antibiotic use
- ‣ Global and regional differences in use, human and animal use; antibiotics in the environment
Quantification of bacterial growth
- ‣ Lag/exponential/stationary phase; dose-response curve; minimal inhibitory concentration; mutant selection concentration
How antibiotics work
- ‣ antibiotic classes; mechanisms of action; bacteriostatic/bactericidal drugs; breadth of activity
Resistance
- ‣ Mechanisms of resistance; horizontal transfer of resistance (conjugation, transduction, transformation), population dynamics of resistance
