This module is on the principles of antibacterial Pharmacokinetics and

Pharmacodynamics part one. The goal of antimicrobial therapy is the effective and
safe treatment of patients suffering from infections. This involves careful
consideration of three elements: the bug, the drug, and the host. Also of
importance is the consideration of the fact that the effect of antibiotic
administration extends beyond the individual patient and the target pathogen, and
that antibiotics affect the general bacterial ecology of the patient and the
patient's environment. It must be recognized that there are 10 times as many
bacterial cells as there are human cells in and on the patient. Now this entire
varied and massive bacterial burden is exposed to the administer and antibiotic,
not just the target pathogen. An important consideration is that different
antimicrobial classes affect organisms differently. Which is why those optimization
of antimicrobials is an essential component of antimicrobial stewardship. The
clinician must take into account host and pathogen factors in choosing an
appropriate antibiotic, its dose, and it's route and duration of administration.
Critical to this decision making process is a firm understanding of antibiotic
pharmacokinetics and pharmacodynamics, also known as PKPD. The pharmacokinetics of
an antibiotic describes this disposition within the body, including its absorption,
distribution, metabolism, and elimination. Whereas antibiotic pharmacodynamics
examines the relationship between measured drug concentrations in serum, tissues,
and body fluid and it's antimicrobial effect on the target organism. Simply put,
pharmacokinetics is what the body does to the drug and pharmacodynamics is what the
drug does to the body. Or in our case, what the antibiotic does to the target
organism. Knowledge of these two characteristics is important for the selection of
breakpoints for interpretation of in Vitro susceptibility testing results as well
as optimal antibiotic selection together with the most effective dosing regimen.
When an antibiotic is administered to a patient, the pharmacokinetics describes the
relationship between an antibiotic dosage regimen and concentration in serum at the
infection site. Pharmacokinetics however does not correlate the concentration of
antibiotic at the site with the antibiotics affects. Pharmacodynamics on the other
hand, describes the relationship between antibiotic concentration at the site of
infection and its biologic effect on the organism. This effect could be bacterial
killing or inhibition of growth. Most drugs are irreversibly bound to serum
proteins such as albumin and alpha-acid glycoproteins. The extensive protein
binding varies considerably between different drugs. For example, only 10 to 30
percent of total serum concentration of gentamycin is bound to serum protein
compared with 90 to 95 percent of ertapenem. Serum protein binding is important
consideration because: one, only unbound drug is thought to exert an antibacterial
effect, two, only unbound drug diffuses into the extravascular sites, and three,
protein binding may slow the rate of drug elimination increasing the half-life and
thus allowing a longer dosing interval. The most commonly used pharmacodynamic
measure of in vitro antimicrobial activity against pathogens is the minimum
inhibitory concentration, also known as MIC and minimum bactericidal concentration
also known as MBC. The MIC describes the lowest concentration of an antibiotic
capable of inhibiting the visible growth of an organism in in vitro, while MBC is
the lowest concentration of an antibiotic to achieve 99.9 percent bacterial kill.
Although MIC and MBC are excellent predictors of the potency of antimicrobial agent
against infecting organism, it suffers from the static nature of the methods used
for its determination. MICs and NBCs do not take into account the time course of
antimicrobial activity nor does it mimic physiologic conditions such as the
intermittent administration of an antibiotic to a patient. Which results in a
target pathogen being subjected to a constantly changing concentration of the drug.
The MIC also does not provide information on the effects of antibiotic
concentrations below the MIC, also known as the sub-MIC effect. As well as the
post-antibiotic effect which is the persistent inhibition of bacterial replication
after removal of the antibiotic from the system. Individual pharmacodynamic
modeling systems allow continuous adjustment of antibiotic concentration over time
in order to mimic human pharmacokinetics. This approach allows the determination of
antibiotic exposure thresholds associated with optimal bacterial inhibition or
killing. These may also be determined using animal models of infections such as the
rodent bimodal with endpoints that include measurements of colony-forming units at
the site of infection. The most direct and clinically relevant determination of
optimal pharmacodynamics is derived from the study of infected patients, linking
antibiotic exposure to microbiologic and clinical outcomes. Such data is
unfortunately seldom available. The knowledge of pathogen's MIC against a certain
antibiotic, the antibiotics pharmacokinetics, the clinical status of the patient as
well as data on inter-subject variability is necessary to prevent treatment
failures. The consideration of all of these factors and the probability of
attaining successful therapeutic outcomes based on the drug pharmacokinetics and
pharmacodynamics, can be estimated using Monte Carlo simulations. Monte Carlo
simulations use advance mathematical modeling to apply the principles of
antimicrobial PKPD to clinical practice. If a group of patients are given an
antibiotic, it is expected that there will be a variability in drug concentration
time profiles between patients, the Pietra concentration and the time for drug
clearance will vary among individuals. Monte Carlo simulations incorporates the
variability in pharmacokinetics among a sample population when predicting
antibiotic exposure, then calculates the probability for obtaining a target
exposure for a range of MICs that an organism can have to a particular antibiotic
regimen. An example would be determining the probability of achieving free drug
concentration over 50 percent of the dosing interval for [inaudible] against
pseudomonas aeruginosa with an MIC of eight. A commonly used measurement is Cmax,
which is the maximum drug peak concentration and Cmin, the trough, that is the
lowest antibiotic concentration. By using MIC as a measure of potency of drug
organism interactions, the pharmacokinetic parameter determining efficacy can be
converted to PKPD indices. Since only the fraction of antibiotic not bound to serum
protein is considered active, these ratios are expressed as the free fraction over
the MIC. The three most common PKPD indices used to predict drug response are: one,
ratio of maximum free drug concentration to the MIC, two, the duration of time or
Friedrich concentration remains above the MIC, and three, MIC ratio of free area
under the concentration time curve to the MIC. Understanding these three PKPD
parameters which quantify the activity of antibiotic, allows us to optimize
antimicrobial treatment regimens. The next module we will review PKPD of different
classes of antibiotics and dosing strategies developed to optimize efficacy as well
as minimizing toxicity.