INFECTIOUS DISEASES AND ONCOLOGY
Antimicrobial therapy (“chemotherapy”) is designed with the principle of selective
toxicity. This means the treatment targets harmful microorganisms with minimal
impact on healthy cells and tissues.
Based on their mechanism of action, antimicrobial agents are classified as
either bactericidal or bacteriostatic. Bactericidal agents kill bacteria at
plasma concentrations that are safe for the patient. These drugs are
particularly useful in severe infections or in cases where the immune
system is compromised. Bacteriostatic agents inhibit bacterial growth
without directly killing the organisms. This allows the immune system to
take over and eliminate the bacteria.
In conditions such as endocarditis, meningitis, or
immunocompromised patients, bactericidal agents are necessary to directly
eliminate the pathogens and prevent life-threatening complications.
Antimicrobial agents are designed to target specific pathways that are crucial for the
survival and replication of microorganisms. These targets are chosen to maximize the
effectiveness of the drug against the pathogen while minimizing harm to the host.
The specificity of these targets can be categorized into three main types: unique
pathways found only in the microorganism, pathways that are similar but not
identical to those in humans, and pathways that exist in both humans and
microorganisms but have different levels of importance.
Unique pathways:
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 viruses)
Bacteria synthesize folic acid, a precursor required for DNA and RNA production.
Ergosterol is a component of fungal cell membranes. Azole antifungals inhibit fungal
enzymes involved in ergosterol synthesis. Without ergosterol, the fungal cell
membrane becomes dysfunctional, leading to cell death. Amphotericin binds directly
to ergosterol in fungal cell membranes, creating pores that disrupt the membrane's
integrity. This causes essential ions and molecules to leak out of the fungal cell,
leading to its death.
HIV protease is an enzyme essential for the maturation of HIV viral particles. It
cleaves large polyproteins into functional proteins needed for the virus to infect new
cells. Protease inhibitors block this process, preventing the formation of infectious
viral particles.
1
,Neuraminidase is an enzyme on the surface of influenza viruses that helps them
release newly formed viral particles from infected cells. Neuraminidase inhibitors
block this enzyme, trapping the virus in the host cell and preventing its spread.
Similar pathways / targets:
Dihydrofolate reductase inhibition (e.g. trimethoprim, pyrimethamine)
Topoisomerase inhibition (e.g. fluoroquinolones)
Protein synthesis inhibition (e.g. macrolides, tetracyclines)
DNA, RNA polymerase inhibition
Dihydrofolate reductase (DHFR) converts dihydrofolate to tetrahydrofolate, which is
crucial for DNA and RNA synthesis. Drugs like trimethoprim bind to bacterial DHFR,
inhibiting bacterial growth.
Topoisomerases are enzymes that regulate DNA supercoiling during replication and
transcription. Bacteria rely on DNA gyrase (a type of topoisomerase) for these
processes. Fluoroquinolones selectively inhibit bacterial DNA gyrase, disrupting
bacterial DNA replication.
DNA and RNA polymerases are enzymes responsible for synthesizing DNA and
RNA, respectively.
Same (co-existent) pathways / targets:
Dihydrofolate reductase inhibition (e.g. methotrexate)
Anti-metabolite nucleotides (e.g. 5-fluorouracil)
DNA polymerase inhibition (e.g. cytarabine)
5-fluorouracil mimics normal nucleotides used in DNA and RNA synthesis. Once
incorporated into nucleic acids, it disrupts their function, preventing cell replication.
Therapy might be:
Targeted
Empiric
Prophylactic
- Pre/post operative
- During surgeries
- Immune-deficient patients
- Recurrent infections
- Some infections (e.g. HIV)
Empiric antibiotic therapy refers to the administration of antibiotics based on clinical
experience and knowledge of pathogens, rather than definitive microbiological
confirmation. This approach is used when it is difficult to identify the specific
pathogen. The patient’s clinical response to the empiric treatment serves as an
important clue about the appropriateness of the therapy.
2
,Indications for empiric antibiotic therapy:
High risk of serious morbidity or mortality if therapy is withheld
Public health considerations
- For instance, urethritis in a sexually active young man is commonly treated
for both Neisseria gonorrhoeae and Chlamydia trachomatis. This is done
not only to treat the patient effectively but also to prevent further
transmission, especially given the likelihood of noncompliance with follow-
up visits in this population.
For time-dependent antibiotics, the efficacy is related to the duration of
time that the drug's concentration remains above the minimum inhibitory
concentration (MIC) of the target pathogen (T > MIC, time above MIC).
Time-dependent antibiotics are beta-lactams, glycopeptides, linezolid,
and macrolides.
For concentration-dependent antibiotics, the efficacy depends on the
maximal concentration peak of the drug (Cmax) in relation to the MIC. This
means that the higher the peak concentration relative to the MIC, the more
effective the antibiotic will be (Cmax / MIC ratio). Concentration-dependent
antibiotics are aminoglycosides.
For fluoroquinolones, both the concentration and time are crucial. The
parameter of interest is the AUC / MIC ratio, where AUC reflects the
overall exposure of the organism to the antibiotic.
The post-antibiotic effect (PAE) refers to the persistent suppression of
bacterial growth after a brief exposure to an antibiotic, even when the drug
concentration has fallen below the MIC.
The PAE is determined by an experimental setting. Bacteria are initially exposed to
an antibiotic, and after a period, the drug is diluted to remove it, reducing its
concentration by 1:1000. The time required for bacterial regrowth is then compared
between treated and untreated cultures. In the treated sample, bacterial growth is
delayed even after the antibiotic has been removed, whereas the control sample
without antibiotic exposure grows uninhibited.
PAE = T – C
T is the time it takes for the bacterial count in the treated culture to increase tenfold
above the count immediately after drug removal, and C is the time required for the
untreated culture to achieve the same level of growth (tenfold increase).
Possible mechanisms of PAE:
Slow recovery after reversible non-lethal damage to bacterial cell structures
Persistence of the drug at a binding site or within the periplasmic space
The need to synthesize new enzymes before growth can resume
3
, In vivo PAEs are generally much longer than in vitro PAEs due to additional
factors present in the complex biological environment of a living organism that
enhance the effect of antibiotics. One of these factors is post-antibiotic leukocyte
enhancement (PALE). It refers to the enhancement of the immune system's activity,
specifically the function of leukocytes, during and after exposure to antibiotics. This
increased activity leads to an increased duration of killing bacteria and a longer PAE.
Most antimicrobial agents are well distributed to most body tissues and fluids, except
cerebrospinal fluid (CNS).
Therapeutic drug monitoring (TDM) involves measuring drug concentrations in a
patient's blood at designated intervals to ensure that drug levels remain within the
therapeutic range—neither too low to be ineffective nor too high to cause toxicity.
The goal of TDM is to optimize and individualize drug therapy to meet the needs
of each patient. Variability in drug absorption, distribution and elimination can differ
among individuals due to factors such as age, organ function and disease states.
These differences mean that standardized dosages may not always be appropriate.
By monitoring drug levels, healthcare providers can adjust doses to achieve and
maintain optimal concentrations.
Bayesian simulations represent a sophisticated approach to dose optimization in
TDM, leveraging population pharmacokinetic (PK) models and individual patient
data, such as plasma drug concentrations (cplasma). Population PK models are pre-
established mathematical models derived from large datasets of patients. Population
models account for variability among individuals and include factors like age, weight,
organ function, and genetic differences. By using the individual patient data, the
model creates individualized predictions about drug behavior. This allows for
precise dose adjustments tailored to the patient's unique characteristics and needs.
Bayesian simulation advantages:
Flexible sampling and limited sampling strategy (LSS)
Incorporation of population variability (covariates)
Traditional TDM often requires multiple blood samples at specific time points to
estimate pharmacokinetic parameters accurately (e.g. peaks and troughs). Bayesian
simulations simplify this process by enabling predictions from one blood sample.
For example, in patients with renal insufficiency, the elimination of many antimicrobial
agents is impaired due to reduced kidney function. This can lead to drug
accumulation and an increased risk of adverse effects if doses are not adjusted
appropriately. Dose reduction is often necessary to maintain drug levels within the
therapeutic range and prevent toxicity.
Another example involves genetic variations in drug metabolism, such as differences
between fast and slow acetylators. Slow acetylators metabolize the drug more slowly,
leading to higher plasma concentrations and prolonged drug exposure, while fast
acetylators metabolize the drug more rapidly, potentially reducing its efficacy. TDM
helps to identify these individual differences and guides dose adjustments to ensure
optimal treatment outcomes.
4
Antimicrobial therapy (“chemotherapy”) is designed with the principle of selective
toxicity. This means the treatment targets harmful microorganisms with minimal
impact on healthy cells and tissues.
Based on their mechanism of action, antimicrobial agents are classified as
either bactericidal or bacteriostatic. Bactericidal agents kill bacteria at
plasma concentrations that are safe for the patient. These drugs are
particularly useful in severe infections or in cases where the immune
system is compromised. Bacteriostatic agents inhibit bacterial growth
without directly killing the organisms. This allows the immune system to
take over and eliminate the bacteria.
In conditions such as endocarditis, meningitis, or
immunocompromised patients, bactericidal agents are necessary to directly
eliminate the pathogens and prevent life-threatening complications.
Antimicrobial agents are designed to target specific pathways that are crucial for the
survival and replication of microorganisms. These targets are chosen to maximize the
effectiveness of the drug against the pathogen while minimizing harm to the host.
The specificity of these targets can be categorized into three main types: unique
pathways found only in the microorganism, pathways that are similar but not
identical to those in humans, and pathways that exist in both humans and
microorganisms but have different levels of importance.
Unique pathways:
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 viruses)
Bacteria synthesize folic acid, a precursor required for DNA and RNA production.
Ergosterol is a component of fungal cell membranes. Azole antifungals inhibit fungal
enzymes involved in ergosterol synthesis. Without ergosterol, the fungal cell
membrane becomes dysfunctional, leading to cell death. Amphotericin binds directly
to ergosterol in fungal cell membranes, creating pores that disrupt the membrane's
integrity. This causes essential ions and molecules to leak out of the fungal cell,
leading to its death.
HIV protease is an enzyme essential for the maturation of HIV viral particles. It
cleaves large polyproteins into functional proteins needed for the virus to infect new
cells. Protease inhibitors block this process, preventing the formation of infectious
viral particles.
1
,Neuraminidase is an enzyme on the surface of influenza viruses that helps them
release newly formed viral particles from infected cells. Neuraminidase inhibitors
block this enzyme, trapping the virus in the host cell and preventing its spread.
Similar pathways / targets:
Dihydrofolate reductase inhibition (e.g. trimethoprim, pyrimethamine)
Topoisomerase inhibition (e.g. fluoroquinolones)
Protein synthesis inhibition (e.g. macrolides, tetracyclines)
DNA, RNA polymerase inhibition
Dihydrofolate reductase (DHFR) converts dihydrofolate to tetrahydrofolate, which is
crucial for DNA and RNA synthesis. Drugs like trimethoprim bind to bacterial DHFR,
inhibiting bacterial growth.
Topoisomerases are enzymes that regulate DNA supercoiling during replication and
transcription. Bacteria rely on DNA gyrase (a type of topoisomerase) for these
processes. Fluoroquinolones selectively inhibit bacterial DNA gyrase, disrupting
bacterial DNA replication.
DNA and RNA polymerases are enzymes responsible for synthesizing DNA and
RNA, respectively.
Same (co-existent) pathways / targets:
Dihydrofolate reductase inhibition (e.g. methotrexate)
Anti-metabolite nucleotides (e.g. 5-fluorouracil)
DNA polymerase inhibition (e.g. cytarabine)
5-fluorouracil mimics normal nucleotides used in DNA and RNA synthesis. Once
incorporated into nucleic acids, it disrupts their function, preventing cell replication.
Therapy might be:
Targeted
Empiric
Prophylactic
- Pre/post operative
- During surgeries
- Immune-deficient patients
- Recurrent infections
- Some infections (e.g. HIV)
Empiric antibiotic therapy refers to the administration of antibiotics based on clinical
experience and knowledge of pathogens, rather than definitive microbiological
confirmation. This approach is used when it is difficult to identify the specific
pathogen. The patient’s clinical response to the empiric treatment serves as an
important clue about the appropriateness of the therapy.
2
,Indications for empiric antibiotic therapy:
High risk of serious morbidity or mortality if therapy is withheld
Public health considerations
- For instance, urethritis in a sexually active young man is commonly treated
for both Neisseria gonorrhoeae and Chlamydia trachomatis. This is done
not only to treat the patient effectively but also to prevent further
transmission, especially given the likelihood of noncompliance with follow-
up visits in this population.
For time-dependent antibiotics, the efficacy is related to the duration of
time that the drug's concentration remains above the minimum inhibitory
concentration (MIC) of the target pathogen (T > MIC, time above MIC).
Time-dependent antibiotics are beta-lactams, glycopeptides, linezolid,
and macrolides.
For concentration-dependent antibiotics, the efficacy depends on the
maximal concentration peak of the drug (Cmax) in relation to the MIC. This
means that the higher the peak concentration relative to the MIC, the more
effective the antibiotic will be (Cmax / MIC ratio). Concentration-dependent
antibiotics are aminoglycosides.
For fluoroquinolones, both the concentration and time are crucial. The
parameter of interest is the AUC / MIC ratio, where AUC reflects the
overall exposure of the organism to the antibiotic.
The post-antibiotic effect (PAE) refers to the persistent suppression of
bacterial growth after a brief exposure to an antibiotic, even when the drug
concentration has fallen below the MIC.
The PAE is determined by an experimental setting. Bacteria are initially exposed to
an antibiotic, and after a period, the drug is diluted to remove it, reducing its
concentration by 1:1000. The time required for bacterial regrowth is then compared
between treated and untreated cultures. In the treated sample, bacterial growth is
delayed even after the antibiotic has been removed, whereas the control sample
without antibiotic exposure grows uninhibited.
PAE = T – C
T is the time it takes for the bacterial count in the treated culture to increase tenfold
above the count immediately after drug removal, and C is the time required for the
untreated culture to achieve the same level of growth (tenfold increase).
Possible mechanisms of PAE:
Slow recovery after reversible non-lethal damage to bacterial cell structures
Persistence of the drug at a binding site or within the periplasmic space
The need to synthesize new enzymes before growth can resume
3
, In vivo PAEs are generally much longer than in vitro PAEs due to additional
factors present in the complex biological environment of a living organism that
enhance the effect of antibiotics. One of these factors is post-antibiotic leukocyte
enhancement (PALE). It refers to the enhancement of the immune system's activity,
specifically the function of leukocytes, during and after exposure to antibiotics. This
increased activity leads to an increased duration of killing bacteria and a longer PAE.
Most antimicrobial agents are well distributed to most body tissues and fluids, except
cerebrospinal fluid (CNS).
Therapeutic drug monitoring (TDM) involves measuring drug concentrations in a
patient's blood at designated intervals to ensure that drug levels remain within the
therapeutic range—neither too low to be ineffective nor too high to cause toxicity.
The goal of TDM is to optimize and individualize drug therapy to meet the needs
of each patient. Variability in drug absorption, distribution and elimination can differ
among individuals due to factors such as age, organ function and disease states.
These differences mean that standardized dosages may not always be appropriate.
By monitoring drug levels, healthcare providers can adjust doses to achieve and
maintain optimal concentrations.
Bayesian simulations represent a sophisticated approach to dose optimization in
TDM, leveraging population pharmacokinetic (PK) models and individual patient
data, such as plasma drug concentrations (cplasma). Population PK models are pre-
established mathematical models derived from large datasets of patients. Population
models account for variability among individuals and include factors like age, weight,
organ function, and genetic differences. By using the individual patient data, the
model creates individualized predictions about drug behavior. This allows for
precise dose adjustments tailored to the patient's unique characteristics and needs.
Bayesian simulation advantages:
Flexible sampling and limited sampling strategy (LSS)
Incorporation of population variability (covariates)
Traditional TDM often requires multiple blood samples at specific time points to
estimate pharmacokinetic parameters accurately (e.g. peaks and troughs). Bayesian
simulations simplify this process by enabling predictions from one blood sample.
For example, in patients with renal insufficiency, the elimination of many antimicrobial
agents is impaired due to reduced kidney function. This can lead to drug
accumulation and an increased risk of adverse effects if doses are not adjusted
appropriately. Dose reduction is often necessary to maintain drug levels within the
therapeutic range and prevent toxicity.
Another example involves genetic variations in drug metabolism, such as differences
between fast and slow acetylators. Slow acetylators metabolize the drug more slowly,
leading to higher plasma concentrations and prolonged drug exposure, while fast
acetylators metabolize the drug more rapidly, potentially reducing its efficacy. TDM
helps to identify these individual differences and guides dose adjustments to ensure
optimal treatment outcomes.
4
