The importance of pk pd newer concept in antibiotic therapy preserveincrease efficacy of existent antibiotics involves use of pharmacology, clinical outcomes and microbiology to optimize antimicrobial use improve outcomes minimize toxicity and resistance. In vivo pk pd work horses murine thigh and lung models mimics soft tissuesepsis and pneumonia, respectively neutropenic organism burden primary endpoint. The purpose was to explore the optimal dosage regimen of colistin using monte carlo simulations, for the treatment of carbapenemresistant klebsiella pneumoniae and carbapenemresistant escherichia coli based on pk pd targets in critically ill patients. For example, in vitro kill curves have the ability to display an antibiotic s pd without having to conduct an in vivo human study. Optimizing antimicrobials in the icu using pharmacodynamic. An understanding of the pharmacokinetic pk and pharmacodynamic pd principles that determine response to antimicrobial therapy can provide the clinician with betterinformed dosing regimens. Pkpd of antibiotics n a f r i a l d i department of pharmacology faculty of medicine, university of indonesia jakarta antimicrobial update april 12, 20 introduction successful antibiotic ab treatment depends on.
Use of old antibiotics now and in the future from a. In order to understand and use the software effectively, it is important to have a solid working knowledge of antibiotic classification. Use monte carlo simulations to compare the efficacy of four common antibiotic dosage regimes, and to determine the most effective dosing strategy. Fundamentals of antimicrobial pharmacokinetics and. How an antibiotic kills bacteria may fall into one of two very broad categories. This chapter describes the general concepts behind pk, pd, and pgx and their use as principles in clinical examples seen in the critical care setting. Ucl pk pd course april 2011 05 pk pd in action in the regulatory in europe inadequate dosing of antibiotics is probably an important reason for misuse and subsequent risk of resistance. One of the most popular guidelines used throughout the world is. Here, a specialist in the area provides a pharmacokinetics and pharmacodynamics 101 for antibiotics. The effectiveness of antibiotics abs is governed by achieving the adequate pharmacokinetic pkpharmacodynamics pd ratio. Pdf pkpd for prediction and contain of antimicrobial. Pharmacodyamics pd is concerned with the relationship between those concentrations and the antimicrobial effect. Pd refers to the relationship between the concentration of the drug at the site of action and the resulting effect. Pharmacokinetic considerations and dosing strategies of.
Pkpd approach, the case of antibiotic drug development the therapeutic efficacy of antibiotics is very dependent not only on the drug itself but also on. Pk pd principles for antibiotics were initially identified in the 1940s and 1950s by dr. Antibiotic dosing regimens have traditionally been determined by pk parameters. The only exception to this class has been the carbapenems, such as imipenem and meropenem, which produce prolonged paes, primarily with strains of p. Understanding antibiotic pkpd profiles to optimize patient outcomes. The term pharmacokinetics pk refers to the study of how fast and how completely the drug is absorbed into the body from the stomach and intestines if.
The magnitude of a pk pd index is calculated, when bacterial killing is observed, or clinical cure is obtained in clinical trials. In general, dosing regimens in table 1 provide pk pd optimized empiric therapy for highmic pathogens. Several reports have shown marked heterogeneity of antibiotic pharmacokinetics pk in patients admitted to icus, which might potentially affect outcomes. These simulations predicted the i efficacy of selected antibiotics at standard doses and ii minimum effective dose. Nevertheless, interest has grown in alternative antimicrobial dosing strategies that are better aligned with the antimicrobials pharmacokinetic pk and pharmacodynamic pd properties. Post antibiotic activity is generally associated with compounds that interfere with either protein synthesis or nucleotide function rna or dna synthesis.
Dec 29, 2016 pharmacokinetics and pharmacodynamics for antibiotics is a topic that can seem intimidating, but when broken down to basics may serve less challenging than anticipated. Individualized dosing regimens using known pkpd characteristics are important to optimize patient outcomes and minimize antimicrobial resistance. A pharmacokineticpharmacodynamic pkpd model that characterizes the full time course of in vitro timekill curve. Vikas manchanda, md, mba associate professor department of microbiology maulana azad medical college. A pharmacokineticpharmacodynamic pkpd model that characterizes the full time course of in vitro timekill curve experiments of antibacterial drugs was here evaluated in its capacity to predict the previously determined pk pd indices.
The relationship between drug potency, drug concentration and effect. Once the pd has been established, it can be combined with pk to determine what clinical outcome can. White paper derisking antibiotic drug development with pkpd. For timedependent antibiotics, microbiological and clinical outcomes are associated with the cumulative percentage of the dosing interval that the drug concentration exceeds the minimum inhibitory concentration mic for the organisms 2. Identify ways to optimize antimicrobial therapy in. In parallel, rapid emergence of antibioticresistant bacteria imposes. The broad principles laid out in this guideline are. In parallel, rapid emergence of antibiotic resistant bacteria imposes. Finally, we want to dose antibiotics in such a way that takes advantage of their pharmacokinetics and pharmacodynamics pk. For example, in vitro pd models and pk pd analyses have minimised or replaced clinical dosefinding studies and have grown in importance for identifying dose regimens for betalactamase inhibitors. The antibiotics were ciprofloxacin a fluorquinolone that acts by inhibiting bacterial dna gyrase enzyme, ampicillin a betalactam antibiotic acts by inhibiting bacterial cell wall. Pk pd analyses may also be used to explore the relationship between pk of the test antimicrobial agent and selected safety parameters. Factors influential on antibiotic disposition and clinical.
Pharmacokineticpharmacodynamic modeling of antibacterial. Pharmacokinetics and pharmacodynamics for antibiotics is a topic that can seem intimidating, but when broken down to basics may serve less challenging than anticipated. Pharmaco kinetic and dynamic pk pd approach to antibiotic therapy introduction 1. Pkpd models in antibacterial development sciencedirect. White paper derisking antibiotic drug development with. Exploring the collaboration between antibiotics and the. Pk pd measures are drug characteristics that may be used to identify the best therapeutic agent for a particular indication.
The peakmic ratio is simply the cpmax divided by the mic. The pk and pd of antibiotics are also used to try to predict the outcome of therapy via pharmacological indices determined from in vitro models, animal models or clinical trials. The aes decision process attempts to identify a phenotype for each drug class tested. However, pd plays an equal, if not more important, role.
Dosing optimisation requires a good knowledge of pkpd principles. Dosing strategies in patients with septic shock or extensive burns antibiotic pharmacokineticchange suggested dose adjustment. Establishing a new frontier in antimicrobial stewardship the pk pd compass, a step toward individualized patient therapy. The effectiveness of antibiotics abs is governed by achieving the adequate pharmacokinetic pk pharmacodynamics pd ratio. Develop a pk pd model to describe the antibacterial effect of doripenem against several pseudomonas aeruginosa strains. Concentrationdependent killing richard quintiliani, m. The pk pd compass is the manifestation of this goal. Pk pd target was net bacterial stasis in neutropenic mice for cap agents and 1 2 log.
Application of pharmacokineticspharmacodynamics pkpd in. The pk pd compass is a firstofits kind educational mobile antimicrobial stewardship program to help clinicians make better antibiotic decisions. Pkpd approach to antibiotic therapy canterbury scl. Finally, it is important to develop dosing guidelines based on pk pd modelling studies that can be used in clinical practice. The magnitude of a pk pd index is calculated, when bacterial killing is. Antibiotic dosing regimens have traditionally been determined by pk parameters only. Department of intensive care medicine, oxford university hospitals nhs foundation trust. Pharmacodynamics is sometimes abbreviated as pd and pharmacokinetics as pk, especially in combined reference for example, when speaking of pk pd models. Application of pharmacokinetics and pharmacodynamics to. Jul 01, 20 pharmacokineticpharmacodynamic pkpd modeling and simulation has evolved as an important tool for rational drug development and drug use, where developed models characterize both the typical trends in the data and quantify the variability in relationships between dose, concentration, and desired effects and side effects. Pk pd of antibiotic is aimed to develop a more effective dosage regimen to obtain successful treatment while avoiding the toxicity and the emergence of antibiotic resistance. Optimalization of pk pd can be obtained either by increasing the dose or extending the duration of infusion strategy for improving the pk pd is determined by.
Integrating the pk parameters with the mic gives us three pk pd parameters which quantify the activity of an antibiotic. Animal infection models play a critical role in the preclinical assessment of novel antibiotics. In this study, five antibiotics of five different classes were considered for pk pd analysis. Pharmacokineticpharmacodynamic pkpd indices of antibiotics. Understanding antibiotic pkpd profiles to optimize patient. In vitro pk pd models are less costly and resourceintensive and permit investigations of considerable duration which may not be feasible in animals mouse thigh infection model is the gold standard for antibacterial pk pd. Imagine if we could integrate patient demographic, pathogen susceptibility, and pk pd data, and stewardship documentation into one simpletouse interface. Pdf pkpd for prediction and contain of antimicrobial resistance.
Cefepime cep is approved by the food and drug adminstration fda for the treatment of febrile. Six drugs benzylpenicillin, cefuroxime, erythromycin, gentamicin, moxifloxacin, and vancomycin, representing a broad selection of mechanisms of action and pk. As you dive deeper into the field of biostatistics, youll need to develop a firm understanding of pharmacokinetics pk and pharmacodynamics pd and the differences between the two. Although there have been efforts to develop more com. In this age of increasing antimicrobial resistance, pd becomes even more important because these parameters may be used to design dosing regimens which counteract or prevent resistance. The main pkpd parameters using to predict drug efficacy. Extended infusions of betalactams in pediatric patients. Sophistication made simple make intricate pk pd principles work for you. The dosing of antibiotics for included patient populations should be based upon recommendations outlined in table 1. Chair of the working group on antimicrobial use, esicm.
Contribution of pharmacokinetic and pharmacodynamic parameters. Guideline on the use of pharmacokinetics and pharmacodynamics. Antibiotic pharmacokinetics and pharmacodynamics for. Special article pharmacokinetic considerations and dosing strategies of antibiotics in the critically ill patient snehal shah1, greg barton2 and andreas fischer1 abstract the treatment of sepsis remains a significant challenge and is the cause of high mortality and morbidity. Understanding antibiotic pkpd profiles to optimize. A recommendation on proper dosing regimens for different infections would be an important part of a comprehensive strategy.
In this study, fast lcmsms methods were developed and validated for the bioanalysis of cefaclor cfc, ciprofloxacin cfc, roxithomycin rxm and clindamycin cld. In the past pkpd was an afterthought, but today it is required by regulators and heres why. Pharmacokinetics pk is concerned with the time course of antimicrobial concentrations in the body 2. Pdf the pharmacokineticpharmacodynamic pkpd relationship. Factors influential on antibiotic disposition and clinical outcome are presented, with a focus on the primary site of infection. Pdf basic concepts of pharmacokineticpharmacodynamic pk. Pharmacokinetics, toxicity, resistance and multidrug.
The pk pd cutoff co pd originat e s from pk pd mode l ling, which utilize s knowledge of the antimicrobial pk pd parameters for th e identification of mics that accurately predict the. Keywords adult, antibiotics, antifungal agent, antituberculosis agent, antiviral agent, extracorporeal membrane oxygenation, pharmacokinetics. Antibiotic classification and modes of action in the aes knowledge base, phenotypes are organized by drug class. Pharmacokinetic pk and pharmacodynamic pd information from the scientific basis of modern pharmacotherapy. A pkpd approach to antibiotic therapy wsava2011 vin. Pharmacokinetic and pharmacodynamic principles of anti. Behind the scenes, the pkpd compass integrates population pharmacokinetics, exposureresponse relationships, and pathogen susceptibility data, using monte carlo simulation, to evaluate antibiotic regimens through the lens of pk pd. Pharmacokineticpharmacodynamic pkpd modeling and simulation has evolved as an important tool for rational drug development and drug use, where developed models characterize both the typical trends in the data and quantify the variability in relationships between dose, concentration, and desired effects and side effects. The importance of pkpd pharmacometrics, which includes the science of pharmacokineticspharmacodynamics pkpd, is one of the most commonly misunderstood, misused, and underappreciated resources available to drug developers. Pharmacokinetics deals with the movement of a drug from its administration site to the place of its pharmacologic activity and its elimination from the body. When the mic of the pathogen is known and is low, dose reductions should be completed to reoptimize antibiotic therapy.
In drug development, pk pd models are particularly important when the actual clinical situation cannot be achieved. Pk pd assays are one of the first steps in determining the potential. Antibiotic pd relates pk parameters to the ability of an antibiotic to kill or inhibit growth of bacterial pathogens. Once the appropriate pk pd index is identified, it can be used to predict efficacy or clinical outcome. Pharmacological indices in antibiotic therapy journal of. Pharmacokinetic and pharmacodynamic dose optimization of. Pharmaco kinetic and dynamic pkpd approach to antibiotic. Pharmacokinetic and pharmacodynamic principles of antiinfective. Pharmacokinetics, pharmacodynamics, and pharmacogenomics. In the case of antibacterial agents that can address an unmet need, pk pd. Effective antimicrobial therapy requires that concentrations of antimicrobial agents reach the environment of the organism i. Application of pharmacokineticspharmacodynamics pkpd.
Central to this rational as opposed to purely empirical approach to antibiotic treatment are pk pd indices. Therefore, the pharmacodynamic pd parameter of the efficacy of. Knowledge of pk and pd of commonly used antibiotics may help to select appropriate dosage regimens and schedule intervals that will contribute to therapeutic. Regarding the minimal information required for redevelopment, many of the old antibiotics lack significant aspects of this vital information. Guideline on pkpd in antibacterial medicinal products european. Table 1 provides a comprehensive list of old and revived antimicrobials and an indication of significant knowledge gaps in the areas of pk profiling in volunteers and patients, as well as pd targets derived from preclinical and clinical studies. Pharmacokinetics describes the drug concentrationtime courses in body fluids. Although clinical efficacy and safety remain the gold stan. Maintaining a t mic as high as 100% was associated with a significantly greater clinical cure and bacteriologic eradication than a shorter. Optimisation of antimicrobial dosing based on pharmacokinetic. Theres a lot that can go into doing this, so lets simplify and make it as painless as possible. Many host and drug factors influence the penetration of antibiotics into the site of concern. Table 1 summary data of the pk model data used in pk pd simulations antibiotic study. Pk profiles change over time in critically ill patients warranting periodic reconsideration of dosing regimens.
The post antibiotic drug effect pae is an antimicrobial effect beyond the time that a drug is measurable. Pharmacokineticpharmacodynamic pkpd simulation for dosage. Rising resistance and correlation with antibiotic use did we use antibiotics in a rational way. On the basis of pharmacokineticpharmacodynamic modeling concepts it has become possible to describe and predict the time course of antimicrobial effects under normal and pathophysiological conditions. Pkpd modeling and simulation to guide dosing strategy for. Over the past decade, significant progress has been made in the theory and applications of pharmacodynamics of antimicrobial agents.
Therapeutic drug monitoring of antibiotics in sgh p. This study evaluated pk pd of cep in 36 adult patients admitted between. Pharmacokinetics and pharmacodynamics for antibiotics. October 20, 2018 during lives 2018 in paris master class directors. Pharmacodynamics places particular emphasis on doseresponse relationships, that is, the relationships between drug concentration and effect.
Guideline on pkpd in antibacterial medicinal products. Discuss the pathophysiologic changes in critically ill patients that affect pk pd parameters in the context of antimicrobial therapy. The importance of pk pd pharmacometrics, which includes the science of pharmacokineticspharmacodynamics pk pd, is one of the most commonly misunderstood, misused, and underappreciated resources available to drug developers. The tmic time above mic is the percentage of a dosage interval in which the serum level exceeds the mic. Intrinsic sensitivity of bacteria to ab sufficient ab concentrationat the site of infection for a sufficient duration. In the past pk pd was an afterthought, but today it is required by regulators and heres why. A pharmacokineticpharmacodynamic assessment of oral. Basic concepts of pharmacokineticpharmacodynamic pkpd. Pharmacokinetics and pharmacodynamics pkpd studies dummies.