MG: Infectious diseases and Oncology
Lecture 1: Introduction
M. Balogh
Chemotherapy / anti-microbial therapy
- Selective toxicity needs to have as little effect on healthy cells/tissue as possible.
- Two types of effect:
Bactericide (in cancer cytotoxic) kill bacteria.
Needed in endocarditis, meningitis, immunocompromised patients.
Bacteriostatic (in cancer cytostatic) inhibit growth of bacteria and immune
mechanisms eliminate the bacteria.
Specific targets for the microorganisms
- Unique pathway only found in the pathogen.
Cell wall synthesis inhibition e.g. beta-lactams
Folic acid synthesis inhibition
Ergosterol synthesis inhibition e.g. azols
Binding to membrane ergosterol e.g. amphotericin
HIV protease inhibition
Neuraminidase inhibition influenza
- Similar pathway with some differences.
Dihydrofolate reductase inhibition e.g. trimethoprim, pyrimethamine
Topoisomerase inhibition e.g. fluoroquinolones
Protein synthesis inhibition e.g. macrolides, tetracyclines
DNA, RNA polymerase inhibition
- Same pathway but with different significance.
Dihydrofolate reductase inhibition e.g. methotrexate
Anti-metabolite nucleotides e.g. 5-fluorouracil
DNA polymerase e.g. cytarabine
Principles of antimicrobial therapy
Is antimicrobial therapy right for a given patient?
1. Is it indicated on the basis of clinical findings?
2. Have appropriate clinical specimens been obtained to establish a microbial diagnosis?
3. What are the likely etiologic agents for the patients illness?
4. What measures should be taken to protect individuals exposed to the index case (patient) to
prevent secondary cases, and what measures should be implemented to prevent further
exposure?
5. Is there clinical evidence (e.g. from well-executed clinical trials) that antimicrobial therapy
will confer clinical benefit for the patient most important question.
Once a cause is identifies following questions
1. Is there a narrower-spectrum agent available to substitute the initial empiric drug?
2. Is one agent or a combination of agents necessary?
3. What is the optimal dose, route of administration, and duration of therapy?
4. What specific tests should be undertaken to identify patient who will no response to
treatment?
5. What adjunctive measures can be undertaken to eradicate the infection?
Therapy might be
1
, - Targeted
- Empiric (based on experience)
- Prophylactic (to prevent something from happening) pre/post operative, during surgeries,
immune-deficient patients, recurrent infections, some infections.
Empiric AB therapy
- Based on experience with a particular clinical entity.
- Sometimes difficult to identify a specific pathogen clinical response to empiric therapy
may be an important clue.
- It is indicated when there is a significant risk of serious morbidity or mortality if therapy is
withheld or for public health reasons.
Importance of proper treatment regimens
1. Effectiveness of therapy
Time dependent Abs efficacy relates to the time that the concentration of a drug remains above
the MIC (minimal inhibitory concentration).
Concentration dependent Abs efficacy relates to the peak concentration/MIC ratio. (Cmax/MIC)
Both (fluoroquinolones) AUC/MIC.
Post-antibiotic effect (PAE) suppression of bacterial growth after short antimicrobial exposure to
microorganisms.
- E.g. carbapenems, aminoglycosides, tetracyclines, quinolones, rifampicin.
- PAE = T * c
T = time required for viable count in test culture to increase 10-fold above the count
before drug removal.
C = time required for the count in an untreated culture to increase 10-fold above
count after completion of same procedure as test culture.
- Possible mechanisms of PAE
Slow recovery after reversible nonlethal damage to cell structures.
Persistence of the drug at a binding site of within the periplasmic space.
The need to synthesize new enzymes before growth can resume.
- In vivo PAEs are usually much longer than in vitro PAEs.
- Aminoglycosides and quinolones possess concentration-dependent PAEs high doses once
daily.
PK considerations
- iv administrations are more costly, and more possible to complications.
- Various diseases and physiological states alter the PK of antimicrobial agents need
therapeutic drug monitoring (TDM)
- Most antimicrobial agents are well distributed to most body tissues and fluids, except
cerebrospinal fluid (BBB).
Therapeutic drug monitoring (TDM)
- General approach variability among individuals can be characterized with population PK
models.
Describing the typical behaviour, absorption/volume of distribution/clearance,
estimate of the influence of patient characteristics, development of such models.
- TDM
Integration of PK (generally from population PK model) and PD knowledge to
optimize and personalize drug therapy.
Important to consider the characteristics of the chosen population and the patient.
2
, Different parameters might be more important for different drugs.
Bayesian simulation application of population PK models in combination with individual patient
data (Cplasma) dose adjustment.
- Advantages flexible sampling (limited sampling strategy (LSS)) becomes applicable (1
sample enough to make predictions), population PK models counts for deviations and a
number of covariates.
Combination of drugs
- Most infections should be treated with a single antimicrobial agent.
- Antimicrobial combinations are often overused.
- Reasons for combinations
Provide broad-spectrum empiric therapy in serious ill patients.
Polymicrobial infections e.g. intra-abdominal abscesses.
To decrease the emergence of resistant strains tuberculosis.
To decrease dose-related toxicity.
Enhances inhibition of killing
- BUT bacteriostatic agents can antagonize the action of bactericidal cell wall-active agents.
General rule: do not combine cid + static.
2. Tolerance development
The misuse of AB therapy leads to the development of tolerance.
Do not use AB therapy for viral illnesses such as the common cold or sore throat. Patient compliance
if very important
Resistance
- Natural resistance
- Obtained resistance
Mutation, then selection
Mechanisms
Enzyme production.
Change in the target’s binding spot e.g. beta-lactamase.
Decreased accumulation (active efflux, decreased uptake).
Correction of damage, decrease in apoptosis (more in case of cancer).
Transfer between humans, between bacteria, via plasmids.
3
, The nosocomial ESKAPE pathogens extremely hard to treat or even impossible. Hard to ESKAPE.
“Superbugs” cause big trouble
Bacterial pathogens
- Gram negative two membranes with a small layer of
peptidoglycan in the middle.
- Gram positive thick peptidoglycan layer on top of their
membrane.
After gram staining they have a crystal violet stain.
Different shapes cocci (circles), bacilli (ovals), others
Bacterial pathogens examples
- Gram positive cocci
Staphylococcus aureus skin and wound infections, osteomyelitis, endocarditis.
Streptococcus pyogenes skin and wound infections, tonsillopharyngitis, scarlet
fever.
Streptococcus pneumonia (Pneumococcus) respiratory infections.
Streptococcus viridans group dental infections, caries (tooth decay), endocarditis.
Enterococcus urinary infections, endocarditis.
- Gram positive bacillus
Corynebacterium diphtheriae diphtheria (DTaP vaccine!).
Bacillus anthracis anthrax.
- Gram negative cocci
Neisseria meningitidis (Meningococcus) meningitis
Neisseria gonorrhoeae (Gonococcus) gonorrhea (urethritis)
Moraxella catarrhalis respiratory infections (opportunistic pulmonary invader)
- Gram negative (other forms)
Haemophilus influenzae respiratory infections
Helicobacter pylori gastric ulcer
Coliform bacteria (present in the environment and in the feces of all warm-blooded
animals and humans)
Escherichia coli, Klebsiella spp., Proteus spp. urinary infections
Salmonella ssp., Shigella ssp. diarrhea
Pseudomonas aeruginosa urinary infections, respiratory infections, wound
infections
Anaerobe bacteria
- Gram positive bacillus clostridium ssp.
- Gram negative bascillus
Bacteroides fragilis (and other B. ssp.) gastrointestinal, gynecological, dental
4
Lecture 1: Introduction
M. Balogh
Chemotherapy / anti-microbial therapy
- Selective toxicity needs to have as little effect on healthy cells/tissue as possible.
- Two types of effect:
Bactericide (in cancer cytotoxic) kill bacteria.
Needed in endocarditis, meningitis, immunocompromised patients.
Bacteriostatic (in cancer cytostatic) inhibit growth of bacteria and immune
mechanisms eliminate the bacteria.
Specific targets for the microorganisms
- Unique pathway only found in the pathogen.
Cell wall synthesis inhibition e.g. beta-lactams
Folic acid synthesis inhibition
Ergosterol synthesis inhibition e.g. azols
Binding to membrane ergosterol e.g. amphotericin
HIV protease inhibition
Neuraminidase inhibition influenza
- Similar pathway with some differences.
Dihydrofolate reductase inhibition e.g. trimethoprim, pyrimethamine
Topoisomerase inhibition e.g. fluoroquinolones
Protein synthesis inhibition e.g. macrolides, tetracyclines
DNA, RNA polymerase inhibition
- Same pathway but with different significance.
Dihydrofolate reductase inhibition e.g. methotrexate
Anti-metabolite nucleotides e.g. 5-fluorouracil
DNA polymerase e.g. cytarabine
Principles of antimicrobial therapy
Is antimicrobial therapy right for a given patient?
1. Is it indicated on the basis of clinical findings?
2. Have appropriate clinical specimens been obtained to establish a microbial diagnosis?
3. What are the likely etiologic agents for the patients illness?
4. What measures should be taken to protect individuals exposed to the index case (patient) to
prevent secondary cases, and what measures should be implemented to prevent further
exposure?
5. Is there clinical evidence (e.g. from well-executed clinical trials) that antimicrobial therapy
will confer clinical benefit for the patient most important question.
Once a cause is identifies following questions
1. Is there a narrower-spectrum agent available to substitute the initial empiric drug?
2. Is one agent or a combination of agents necessary?
3. What is the optimal dose, route of administration, and duration of therapy?
4. What specific tests should be undertaken to identify patient who will no response to
treatment?
5. What adjunctive measures can be undertaken to eradicate the infection?
Therapy might be
1
, - Targeted
- Empiric (based on experience)
- Prophylactic (to prevent something from happening) pre/post operative, during surgeries,
immune-deficient patients, recurrent infections, some infections.
Empiric AB therapy
- Based on experience with a particular clinical entity.
- Sometimes difficult to identify a specific pathogen clinical response to empiric therapy
may be an important clue.
- It is indicated when there is a significant risk of serious morbidity or mortality if therapy is
withheld or for public health reasons.
Importance of proper treatment regimens
1. Effectiveness of therapy
Time dependent Abs efficacy relates to the time that the concentration of a drug remains above
the MIC (minimal inhibitory concentration).
Concentration dependent Abs efficacy relates to the peak concentration/MIC ratio. (Cmax/MIC)
Both (fluoroquinolones) AUC/MIC.
Post-antibiotic effect (PAE) suppression of bacterial growth after short antimicrobial exposure to
microorganisms.
- E.g. carbapenems, aminoglycosides, tetracyclines, quinolones, rifampicin.
- PAE = T * c
T = time required for viable count in test culture to increase 10-fold above the count
before drug removal.
C = time required for the count in an untreated culture to increase 10-fold above
count after completion of same procedure as test culture.
- Possible mechanisms of PAE
Slow recovery after reversible nonlethal damage to cell structures.
Persistence of the drug at a binding site of within the periplasmic space.
The need to synthesize new enzymes before growth can resume.
- In vivo PAEs are usually much longer than in vitro PAEs.
- Aminoglycosides and quinolones possess concentration-dependent PAEs high doses once
daily.
PK considerations
- iv administrations are more costly, and more possible to complications.
- Various diseases and physiological states alter the PK of antimicrobial agents need
therapeutic drug monitoring (TDM)
- Most antimicrobial agents are well distributed to most body tissues and fluids, except
cerebrospinal fluid (BBB).
Therapeutic drug monitoring (TDM)
- General approach variability among individuals can be characterized with population PK
models.
Describing the typical behaviour, absorption/volume of distribution/clearance,
estimate of the influence of patient characteristics, development of such models.
- TDM
Integration of PK (generally from population PK model) and PD knowledge to
optimize and personalize drug therapy.
Important to consider the characteristics of the chosen population and the patient.
2
, Different parameters might be more important for different drugs.
Bayesian simulation application of population PK models in combination with individual patient
data (Cplasma) dose adjustment.
- Advantages flexible sampling (limited sampling strategy (LSS)) becomes applicable (1
sample enough to make predictions), population PK models counts for deviations and a
number of covariates.
Combination of drugs
- Most infections should be treated with a single antimicrobial agent.
- Antimicrobial combinations are often overused.
- Reasons for combinations
Provide broad-spectrum empiric therapy in serious ill patients.
Polymicrobial infections e.g. intra-abdominal abscesses.
To decrease the emergence of resistant strains tuberculosis.
To decrease dose-related toxicity.
Enhances inhibition of killing
- BUT bacteriostatic agents can antagonize the action of bactericidal cell wall-active agents.
General rule: do not combine cid + static.
2. Tolerance development
The misuse of AB therapy leads to the development of tolerance.
Do not use AB therapy for viral illnesses such as the common cold or sore throat. Patient compliance
if very important
Resistance
- Natural resistance
- Obtained resistance
Mutation, then selection
Mechanisms
Enzyme production.
Change in the target’s binding spot e.g. beta-lactamase.
Decreased accumulation (active efflux, decreased uptake).
Correction of damage, decrease in apoptosis (more in case of cancer).
Transfer between humans, between bacteria, via plasmids.
3
, The nosocomial ESKAPE pathogens extremely hard to treat or even impossible. Hard to ESKAPE.
“Superbugs” cause big trouble
Bacterial pathogens
- Gram negative two membranes with a small layer of
peptidoglycan in the middle.
- Gram positive thick peptidoglycan layer on top of their
membrane.
After gram staining they have a crystal violet stain.
Different shapes cocci (circles), bacilli (ovals), others
Bacterial pathogens examples
- Gram positive cocci
Staphylococcus aureus skin and wound infections, osteomyelitis, endocarditis.
Streptococcus pyogenes skin and wound infections, tonsillopharyngitis, scarlet
fever.
Streptococcus pneumonia (Pneumococcus) respiratory infections.
Streptococcus viridans group dental infections, caries (tooth decay), endocarditis.
Enterococcus urinary infections, endocarditis.
- Gram positive bacillus
Corynebacterium diphtheriae diphtheria (DTaP vaccine!).
Bacillus anthracis anthrax.
- Gram negative cocci
Neisseria meningitidis (Meningococcus) meningitis
Neisseria gonorrhoeae (Gonococcus) gonorrhea (urethritis)
Moraxella catarrhalis respiratory infections (opportunistic pulmonary invader)
- Gram negative (other forms)
Haemophilus influenzae respiratory infections
Helicobacter pylori gastric ulcer
Coliform bacteria (present in the environment and in the feces of all warm-blooded
animals and humans)
Escherichia coli, Klebsiella spp., Proteus spp. urinary infections
Salmonella ssp., Shigella ssp. diarrhea
Pseudomonas aeruginosa urinary infections, respiratory infections, wound
infections
Anaerobe bacteria
- Gram positive bacillus clostridium ssp.
- Gram negative bascillus
Bacteroides fragilis (and other B. ssp.) gastrointestinal, gynecological, dental
4
