Skip to content

2 4 Principles of Antibacterial Pharmacokinetics & Pharmacodynamics 18 19

  • by

This module is on the principles of antibacterial pharmacokinetics and pharmacodynamics the goal of antimicrobial therapy is the effective efficient 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 a consideration that the fact that the effective antibiotics

Administration extend 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 ten times as many bacterial cells as there are human cells in and on the patient and that this entire dreary and massive bacterial burden is exposed

To the administered antibiotic not just the target pathogen an important consideration is that different antimicrobial classes affect organisms differently which is why dosed 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 it’s

Dose it’s route in the duration of administration critical to this decision-making process is a firm understanding of antibiotic pharmacokinetics and pharmacodynamics also known as pk/pd the pharmacokinetics of an antibiotic describes its disposition within the body including its absorption distribution metabolism and elimination whereas antibiotic pharmacodynamics

Examines the relationship between the measured drug concentration in the serum tissue and body fluid and its antimicrobial effect on the target organism simply put pharmacokinetics is what the body does to the drug and pharmacodynamics is what the drug does the body or in our case with the antibody does to the target organism knowledge of these two characteristics

Is important for the selection of breakpoints for interpretation of an in vitro susceptibility testing results as well as optimal antibiotic selection together with the most effective dosing regimen the pharmacokinetics describes the relationship between an antibiotic dosage regimen and concentration in serum and at the site of infection pharmacokinetics however

Does not correlate the concentration of antibiotic at the site with antibiotics effect pharmacodynamics on the other hand describes the relationship between antibiotic concentration at the site of infection and its biological fact on the organism the effect could be bacterial killing or inhibition of growth most drugs are reversibly bound to serum proteins such as

Albumin and alpha acid glycoproteins the extent of protein binding varies considerably between different drugs for example only 10 to 30 percent of total serum concentration of gentamicin is bound to sam protein compared to 90 to 95 percent of repente serum protein binding is an important consideration because one only unbound drug is thought to exert an antimicrobial

Effect to only unbound drug diffuses into 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 delineation of pharmacodynamic properties of any antibiotic requires knowledge of multiple factors the most commonly used pharmacodynamic measure of in vitro antimicrobial

Activity against pathogens is the minimum inhibitory concentration also known as mi c and also the minimum bacterial seidel concentration also known as mbc the mi c describes the lowest concentration of antibody capable of inhibiting the visible growth of an organism in vitro while nbc is the lowest concentration of an antibiotic to achieve 99.9 percent bacterial kill

Although mi see an mvc are excellent predictors of potency of an antibiotic against an infecting organism it suffers from the static nature of the method used for its determination mi c’s and nbc’s did not take into account the time course of antimicrobial activity nor doesn’t mimic physiologic conditions such as the interment and administration of an antibiotic a

Patient which results in the target pathogen being subjected to a constantly changing concentration of the drug also of importance are effects of antibiotic concentration below the mse this is also known as the sub m ic effect as well as the post-antibiotic effect which is the persistent inhibition of bacterial replication after removal of antibiotic from the system

This potential deficit can be overcome by the use of in vitro or in vivo pharmacodynamic models 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 rodent by models and 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 a pathogens m.i.c against a certain antibiotic the antibiotics pharmacokinetics and the clinical status of the patient as well as data on interest subject variability was necessary to prevent umaine failures the consideration of all of these factors and the probability of attaining

A successful therapeutic outcome based on drug pharmacokinetics and pharmacodynamics can be estimated using monte carlo simulations monte carlo simulations use advanced mathematical modeling to apply the principles of antimicrobial pk/pd to clinical practice if a group of patients are given an antibiotic it is expected that there will be a variability and drug

Concentration time profiles between patients the peak drug concentrations and the time for drug clearance will vary among individuals monte carlo simulations incorporates the variability in pharmaco among a sample population when protecting antibiotic exposure and then calculates the probability of a for obtaining a target exposure for a range of mi sees that an

Organism can have to a particular antibiotic regimen an example would be determining the probability of achieving free drug concentration over the 50% of the dosing interval for pepra cilenti so backed him against pseudomonas aeruginosa with an mi c of 8 by using mi c as a measure of potency of drug organism interactions the pharmacokinetic parameters determining

Efficacy can be converted into pk/pd indexes the three most common pk/pd indices is redic drug response are one ratio of maximum free drug concentration to mi c2 ratio a free area under the concentration time curve to mse and three the duration of time where free drug concentration remains above the mse in general antimicrobials are categorized into two major patterns

Of antimicrobial activity concentration dependent and time dependent bacterial seidel activity for concentration dependent antibiotics the goal with this pattern of activity is to maximize the concentration and obtain the highest possible antimicrobial concentration at the site of infection because higher drug concentrations result in a greater rate and extent of

Microbial killing the major pharmacodynamic perimeter that correlates with clinical and bacterial logic efficacy of these drugs is the peak drug concentration to m.i.c ratio into microbial classes that exhibit this pattern of antimicrobial activity includes amino glycosides fluoroquinolones daptomycin and metronidazole amino glycosides are a class of antibiotics

That display concentration-dependent killing high peak aminoglycoside concentration to m.i.c ratios are correlated with clinical response parental aminoglycoside particularly gentamicin tauber mason and amikacin have long been used empirically for the treatment of febrile neutropenia are patients with life threatening most kamiel infections aminoglycosides are

Commonly utilized with cell active agents for synergistic activity for gram-positive infections for the treatment of gram-negative infections there are two methods of aminoglycoside dosing the older the true approach is to administer multiple doses using 1.7 to two mig’s per cake every eight hours for gentamicin and tropomyosin the second method of dosing is

Referred to as once daily extent interval dosing it has also been recognized that ototoxicity and nephrotoxicity are potential complications of aminoglycoside therapy application of pharmacodynamic principles may be another method to reduce our toxicity of amino glycosides recent data has suggested that toxicity is related to drug simulation within the air and not

Peak concentrations when considering the pharmacodynamic profile of amino glycosides there are distinct advantages to using high dose extender interval first giving amino acids as a single daily dose as opposed to conventional strategies provides the opportunity to maximize peak concentration to m.i.c ratios resulting in bacterial seidel activity second high dose

Extended interval dosing minimizes drug accumulation within the inner ear and kinney and therefore minimizes the potential for toxicity also of consideration is the post-antibiotic effect which allows for a longer period of bacterial suppression during the dosing interval and finally dosing amino glycosides with high dose extended interval may prevent a development

Of bacterial resistance the hartford nomogram was one of the first methods of high dose extended interval proposed and implemented by hartford hospital in connecticut this method aims at optimizing peaked m.i.c ratio by administering a dose of seven weeks per cake of either gentamicin october meissen based on renal function the juice requires modification in order

To minimize scrub accumulation due to the high peak concentrations obtained and the drug-free period at the end of each dosing interval this nomogram eliminated the need to draw standard peaks and troughs samples rather a random single blood sample is obtained between 6 to 14 hours after the administration of an aminoglycoside the serum concentration obtained is

Then plotted on the nomogram to determine the appropriate dosing interval fluoroquinolones are another class of antibiotics that display concentration-dependent activity the pk/pd measure for fluoroquinolone is the 24-hour area under the curve to m.i.c ratio an auc to m.i.c ratio of greater than 125 correlates with optimal clinical and microbiologic outcomes and

Seriously ill patients infected with gram-negative enteric pathogens as well as pseudomonas the fluoroquinolone goal auc to m.i.c ratio varies depending on the target organism for respiratory tract infections evolving strep pneumonia the free drug 24 hour auc to m.i.c ratio associated with high probability of bacterial eradication is around 30 which is significantly

Lower than the goal auc to m.i.c involving gram-negative microorganisms the second pattern of killing is characterized by time-dependent killing which refers to the time it takes for a pathogen to be killed by an exposure to an antimicrobial agent the goal of time-dependent killing is to optimize the duration of exposure this pattern is observed with beta-lactam

Antibiotics macrolides clindamycin glycol peptides the target pharmacokinetics pharmacodynamics index which estimates clinical success this is time during which concentration remains above the m.i.c within each class of beta-lactam antibiotics the optimal time over m ic varies for different bug drug combinations bacteriostatic effects are typically observed when

The free drug concentration exceeds m ic for 35 to 40 percent of the dosing interval for cephalosporins 30% for penicillins and 20% for carbapenems to achieve maximal bactericidal effect the drug concentration has to be above the m ic 60 to 70 percent of the dosing interval for cephalosporins 50% for penicillins and 40% for carbapenems we can apply these principles

To pip ursuline tazo back team proposal intesa backed him is a commonly used first-line agent especially for nosocomial infections due to its wide spectrum of activity and safety profile at the initiation of impera therapy the mi c’s of an organism are often not available and clinicians must rely on the patient’s clinical history as well as the institutions local

Antibiogram to select an agent that will be active against the likely pathogen in the setting of healthcare associated infections it is critical to select an agent and regimen that has a high probability of achieving the pharmacodynamic target for efficacy per brazil intesa backed him as part of the beta-lactam antibiotics loss and like other beta-lactam antibiotics

The major pharmacodynamic parameter most predictive of efficacy is time over m ic for prepara sil entire back time specifically its activity is optimized when free drug concentration exceeds m ic for 50% of the dosing interval in order to maximize time over m.i.c want to either administer a higher dose increase the dosing frequency or increase the duration of the

Infusion it is also important to note that the cls ibrid points for pseudomonas aeruginosa is less than sixty four and four milligrams per liter if the mit of the pathogen is 32 the pepper is silent azo back to myrrh german of three point three seven five grams iv every six hours has approximately 30% chance of attaining the target goal which is free drug above

The mse for 50% of the dosing interval in order to meet the pharmacodynamic target for maximizing time above m.i.c one may consider increasing the dose to four point five iv every six hours which is the typical dose for treatment of pseudomonas aeruginosa infections however the probability of target attainment is still only about 50% when you prolong the infusion

Of four point five grams iv every six hours to be administered over four hours the probability of target attainment is increased significantly upwards of 90% this method of prolonging or continuous infusion of time-dependent antibiotics allows for a higher probability of achieving the goal pharmacodynamic target compared to intermittent dosing and can be especially

Beneficial in critically ill populations and those infected with organisms that have a higher mse the third pattern of antimicrobial activity splays mix properties and is characterized by time-dependent killing and a moderate persistent effect the ideal dosing regimen for these antimicrobials include maximizing the amount of drug received therefore the 24 hour auc

To m.i.c ratio is the parameter that correlates with advocacy antimicrobials that displayed this pattern of activity includes macro lights clindamycin tetracycline linezolid and vancomycin to summarize the three major patterns of anti microbial activity the first pattern of antimicrobial activity is characterized by concentration-dependent killing and includes

Antibiotic classes such as amino glycosides and fluoroquinolones these antibiotics demonstrate concentration-dependent killing over a great range of concentrations and have a prolonged post antibiotic effect with such antibiotics the appropriate strategy is the administration of large improvement doses thus the high peak drug concentration maximizes killing while

At the same time the persistent post antibiotic effects helped to maintain two antimicrobial activity between doses in contrast to the second pattern of antimicrobial activity such as beta-lactam antibiotics that exhibit time-dependent activity as a result of saturable microbial killing with minimal persistence affect one’s exposure to the antibiotic has ended in

This circumstance the goal is to optimize the duration of exposure of the pathogen to concentrations of antibiotic in excess of the m ic and finally the third pattern is also characterized by time-dependent killing but the duration of persistent affect is moderately prolonged because anti-infective very significantly in their time course of antimicrobial activity

Understanding the exposure response relationship between bug drug combinations is critical when designing an antibiotic dosing regimen the role of antimicrobial stewardship is to consider as a pharmacokinetic and pharmacodynamic of each antimicrobial agent and promote the use of optimal dosing regimens in order to obtain maximal bacterial eradication as well as

Preventing the development of resistance on therapy you

Transcribed from video
2 4 Principles of Antibacterial Pharmacokinetics & Pharmacodynamics 18 19 By Abity