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.
