Lecture 1: Introduction
Paul Ehrlich used systematic screening programs which became a cornerstone in drug
research.
Alexander Fleming used inhibition zones for screening and he found out about the
potential resistance to penicillin.
1950s and 1970s was golden era of discovery of novel antibiotic classes, with no new
classes since then
Chemotherapy should have as little effect on healthy cells/tissue as
possible
Bactericide (cytotoxic) = killing bacteria at safe plasma conc. Levels
➔ Needed for endocarditis, meningitis, immunocompromised
patients (bacteriostatic is not sufficient for these diseases)
Bacteriostatic (cytostatic) = inhibit bacterial growth. Immune
mechanisms eliminate the bacteria
In some cases we have specific targets for the microorganism:
- Unique pathways (not present otherwise in humans):
o
- Similar pathways:
o
- Same (co-existent) pathways:
o
1
, ➔ After the course, use this figure to check whether you know it
General principles of antimicrobial therapy:
1. Indicated?
2. Clinical specimens been obtained?
3. Etiologic agents?
4. Prevent further exposure?
5. Clinical evidence?
Following further principles:
1. Narrower-spectrum agent?
2. Combination?
3. Optimal therapy? (dose, route, duration, etc)
4. Specific tests?
5. Adjunctive measures? (e.g. surgery)
What types of therapy do we have:
- Targeted
- Empiric
- Prophylactic -> means inhibit development of infections
It is always very important to have a proper dose for a proper time
Empiric therapy is based on experience with a particular clinical entity. Whether a
patient reacts to treatment or not gives a clue about the type of pathogen.
2
,Indicated when there is a risk of serious morbidity or mortality or for public health
reasons.
What is mainly influenced by a proper treatment regimen:
PAE = post-antibiotic effect = suppression of bacterial growth after antimicrobial
exposure to microorganisms. The PAE is shorter for time dependent ABs compared to
conc. Dependent ABs.
It is not really clear what the possible mechanisms are. It could be slow recovery after
reversible nonlethal damage, persistence of the drug at a binding site or within the
periplasmic space, or the need to synthesize new enzymes before growth can resume.
3
, TDM: variability among individuals can be characterized with population PK models ->
the typical behaviour is described and estimate the influence of patient characteristics
- Integration of PK and PD
- Different parameters might be more important for different drugs
- Sampling is not feasible in the clinic, but for this Bayesian simulations are used
which predict changes with mathematic calculations based on a couple of
samples. So, they apply the population PK model in combination with individual
patient data. -> Limited sample strategy (LSS)
It is also possible to use a combination of drugs. However, only when it is particularly
needed:
- Seriously ill patients
- Polymicrobial infections
- Decrease emergence of resistant strains
- Decrease dose-related toxicity
- Enhanced inhibition or killing
o
o But NEVER combine bacteriostatic agents with bactericide agents since
they can antagonize each other’s action
4
Paul Ehrlich used systematic screening programs which became a cornerstone in drug
research.
Alexander Fleming used inhibition zones for screening and he found out about the
potential resistance to penicillin.
1950s and 1970s was golden era of discovery of novel antibiotic classes, with no new
classes since then
Chemotherapy should have as little effect on healthy cells/tissue as
possible
Bactericide (cytotoxic) = killing bacteria at safe plasma conc. Levels
➔ Needed for endocarditis, meningitis, immunocompromised
patients (bacteriostatic is not sufficient for these diseases)
Bacteriostatic (cytostatic) = inhibit bacterial growth. Immune
mechanisms eliminate the bacteria
In some cases we have specific targets for the microorganism:
- Unique pathways (not present otherwise in humans):
o
- Similar pathways:
o
- Same (co-existent) pathways:
o
1
, ➔ After the course, use this figure to check whether you know it
General principles of antimicrobial therapy:
1. Indicated?
2. Clinical specimens been obtained?
3. Etiologic agents?
4. Prevent further exposure?
5. Clinical evidence?
Following further principles:
1. Narrower-spectrum agent?
2. Combination?
3. Optimal therapy? (dose, route, duration, etc)
4. Specific tests?
5. Adjunctive measures? (e.g. surgery)
What types of therapy do we have:
- Targeted
- Empiric
- Prophylactic -> means inhibit development of infections
It is always very important to have a proper dose for a proper time
Empiric therapy is based on experience with a particular clinical entity. Whether a
patient reacts to treatment or not gives a clue about the type of pathogen.
2
,Indicated when there is a risk of serious morbidity or mortality or for public health
reasons.
What is mainly influenced by a proper treatment regimen:
PAE = post-antibiotic effect = suppression of bacterial growth after antimicrobial
exposure to microorganisms. The PAE is shorter for time dependent ABs compared to
conc. Dependent ABs.
It is not really clear what the possible mechanisms are. It could be slow recovery after
reversible nonlethal damage, persistence of the drug at a binding site or within the
periplasmic space, or the need to synthesize new enzymes before growth can resume.
3
, TDM: variability among individuals can be characterized with population PK models ->
the typical behaviour is described and estimate the influence of patient characteristics
- Integration of PK and PD
- Different parameters might be more important for different drugs
- Sampling is not feasible in the clinic, but for this Bayesian simulations are used
which predict changes with mathematic calculations based on a couple of
samples. So, they apply the population PK model in combination with individual
patient data. -> Limited sample strategy (LSS)
It is also possible to use a combination of drugs. However, only when it is particularly
needed:
- Seriously ill patients
- Polymicrobial infections
- Decrease emergence of resistant strains
- Decrease dose-related toxicity
- Enhanced inhibition or killing
o
o But NEVER combine bacteriostatic agents with bactericide agents since
they can antagonize each other’s action
4
