CHSPSC, LLC Antimicrobial Stewardship Education Series March 8, 2017 Pharmacokinetics/Pharmacodynamics of Antibiotics: Refresher Part 1 Featured Speaker: Larry Danziger, Pharm.D. Professor of Pharmacy and Medicine University of Illinois at Chicago Online Evaluation, Self-Assessment and CE Credit Submission of an online post test and evaluation is the only way to obtain CE credit for this webinar Go to www.proce.com/chsrx Webinar attendees will also receive an email with a direct link to the web page Print your CE statement of completion online Credit for live or enduring (not both) Deadline: April 7, 2017 CPE Monitor (applicable to pharmacists) CE credit automatically uploaded to NABP/CPE Monitor upon completion of post test and evaluation (user must complete the claim credit step) Attendance Code Code will be provided at the end of today s activity 2 www.proce.com 1
How to Ask a Question Locate menu bar on your computer desktop Click orange arrow button Menu box will open Type question into question box Click Send Do not close menu box This will disconnect you from the Webcast Please submit questions throughout presentation Enter question Click No! Click Accessing PDF Handout No! Click the hyperlink that is located directly above the question box Do not close menu box This will disconnect you from the Webcast Click hyperlink www.proce.com 2
March 8, 2017 Pharmacokinetics/Pharmacodynamics of Antibiotics: Refresher Part 1 2016 Pharmacy Education Series Featured Speaker: Larry Danziger, Pharm.D. Professor of Pharmacy and Medicine University of Illinois at Chicago It is the policy of to ensure balance, independence, objectivity and scientific rigor in all of its continuing education activities. Faculty must disclose to participants the existence of any significant financial interest or any other relationship with the manufacturer of any commercial product(s) discussed in an educational presentation. Dr. Danziger has disclosed the following financial/commercial relationships: Speaker for Allergan, MedCo, and Merck. Please note: The opinions expressed in this activity should not be construed as those of the CME/CE provider. The information and views are those of the faculty through clinical practice and knowledge of the professional literature. Portions of this activity may include unlabeled indications. Use of drugs and devices outside of labeling should be considered experimental and participants are advised to consult prescribing information and professional literature. 5 CE Activity Information & Accreditation (Pharmacist CE) 1.0 contact hour Funding: This activity is self funded through CHSPSC. 6 www.proce.com 3
Antimicrobial Pharmacokinetics / Pharmacodynamics: Optimizing Therapeutic Outcomes March 8, 2017 Larry H. Danziger, Pharm.D Professor of Pharmacy and Medicine University of Illinois at Chicago 7 Objectives Upon completion of this presentation, the participant should be able to: Describe the pharmacodynamic (PD) properties of antimicrobials Identify strategies to maximize the PD properties in selecting and dosing antimicrobials Describe the factors to consider to safely prescribe Gentamicin and Vancomycin, to be able to monitor levels logically and interpret them 8 www.proce.com 4
DeSear: Previous Discussion Selecting an antimicrobial agent and dosing scheme is based on a complex set of considerations What is the best pharmacodynamic (PD) predictor of efficacy for the drug chosen? AUC/MIC T>MIC C max : MIC How does the MIC impact PD? 9 Background The rational use of antibacterial drugs should be based upon two principles First, the specific identity of the infecting organism must be determined Second, a test must be devised which will provide an accurate estimate that the antibiotic will be effective in vivo Petersdorf and Plorde Annu. Rev. Med. 14:41-56; 1963 10 www.proce.com 5
Background Science has made tremendous progress over the last 30 years: Established critical values for outcome parameters that predict clinical & microbiologic success Identified PK parameters linked to a biologic measure of action, the MIC Devised tests to determine antibiotic performance characterized as concentration dependent or independent Established pharmacodynamic outcome parameters 11 Background Minimum inhibitory concentration (MIC) The lowest concentration of drug that prevents visible bacterial growth after 24 hours of incubation in a specified growth medium Organism and antimicrobial specific Interpretation Pharmacokinetics/Pharmacodynamics of the drug in humans Drug s activity versus the organism Site of infection Drug resistance mechanisms 12 www.proce.com 6
Factors Influencing Clinical Outcome HOST BUG DRUG 13 Factors Influencing Clinical Outcome Site of infection Infecting pathogen Resistance of infecting pathogen Host - Protein binding Host - Immune system Drug class Dosing regimen (dose & duration) Treatment endpoint 14 www.proce.com 7
Bug: How Do We Predict Antimicrobial Effect? Parameter Definition Limitations MIC (Minimum inhibitory concentration) MBC (Minimum bactericidal concentration) Concentration at which a standard inoculum of 10 5 organisms are inhibited after 24-48 hours Concentration at which a 99.9% reduction in the standard inoculum occurs In vitro conditions differ from those at infection site Only reflects a specific time point In vitro drug concentrations remain constant Measured against standard inoculum Lacks information on: - Rate of bactericidal activity - Persistent effects In vitro tests may not adequately predict outcome Levison ME. Infect Dis Clin North Am 2000;14:281-291. Craig WA. Clin Infect Dis 1998;26:1-12. 15 Host and Drug Factors Site of Infection Site defines the most likely organisms Especially helpful in empiric antimicrobial selection Site also determines the dose and route of administration of antimicrobial Efficacy determined by adequate concentrations of antimicrobial at site of infection Serum concentrations vs tissue concentrations and relationship to MIC 16 www.proce.com 8
Optimizing Antimicrobial Therapy DRUG Pharmacokinetics [C] @ Infection Site Pathogen MIC Host Bacteria Killed Pharmacodynamic Profile 17 Basic Pharmacokinetic Model Drug at Absorption Site Drug in Body Excreted Drug Metabolite in Body Eliminated Metabolite 18 www.proce.com 9
Basic Pharmacodynamics Model Dosage regimen Concentration vs. time in serum Absorption Distribution Elimination Concentration vs. time in tissue and other body fluids Concentration vs. time at site of infection Pharmacologic or toxic effect Antimicrobial effect versus time Pharmacokinetics Pharmacodynamics Craig WA. Clin Infect Dis 1998;26:1-12. 19 Pharmacokinetic Definitions C Max = Peak Concentration AUC C Min = Trough Time 20 www.proce.com 10
PK / PD Definitions AUC = area under the serum concentration curve, measurement of drug absorbed and persistence AUC 24 /MIC ratio = AUC over 24 hours divided by the MIC, predicts efficacy of concentration-dependent antibiotics C max = peak plasma level, highest concentration of drug in the blood C max /MIC ratio = Peak/MIC ratio, predicts efficacy of concentration-dependent antibiotics 21 PK / PD Definitions C min = trough level T>MIC = time above MIC, percentage of time over 24 hours that drug concentration exceeds the MIC PAE = Post Antibiotic Effect, delayed regrowth of bacteria following exposure to an antibiotic Varies according to drug-bug combination 22 www.proce.com 11
Efficacy and PK /PD Relationships Pharmacokinetics (PK) serum concentration profile penetration to site of infection Pharmacodynamics (PD) susceptibility MIC (potency) concentration- vs. time-dependent killing persistent (post-antibiotic) effects (PAE) Jacobs. Clin Microbiol Infect 2001;7:589 96 23 Antimicrobial Pharmacodynamics Correlates the drug concentration and the clinical effect (ie, bacteria killed) Often use surrogate marker such as minimum inhibitory concentration (MIC) Index serum concentration (pharmacokinetic profile) to MIC The pharmacodynamic relationship is different for different antimicrobial classes 24 www.proce.com 12
PK / PD Relationships Microbiology Susceptibility Testing MIC Bactericidal Rate Pharmacokinetics Peak/Trough concentration AUC Half-life Pharmacodynamics AUC / MIC Peak / MIC Time > MIC 25 Important PD Parameters Concentration dependent C max /MIC: Optimize dose to produce higher unbound drug concentrations AUC/MIC: Optimize the dose and exposure to unbound drug concentrations Concentration Dependent agents bacterial killing as the drug concentrations exceed the MIC Peak/MIC (AUC/MIC) ratio important Quinolones, aminoglycosides Craig WA. Clin Infect Dis 2001;33(Suppl 3):S233-37. 26 www.proce.com 13
Concentration Dependent Concentration C max = peak C max / MIC AUC/ MIC Aminoglycosides Fluoroquinolones Metronidazole Daptomycin Glycopeptides MIC C min = trough Adapted from: Roberts JA, et al. Crit Care Med.2009;37:840-851 Time 27 Log 10 CFU/ ml 9 8 7 6 5 4 3 2 Conc.-Dependent Tobramycin Bacterial Killing Time-Kill Curves of P. aeruginosa 0 2 4 6 0 2 4 6 8 Time (hours) Time-Dependent Control ¼ MIC 1 MIC 4 MIC 16 MIC 64 MIC Ticarcillin Craig WA, et al. Scand J Infect Dis, 1991;Suppl (74) 28 www.proce.com 14
AUC/MIC and Survival Relationship for Quinolones Relationship between AUC/MIC ratio for the nonprotein bound fraction of levofloxacin and ciprofloxacin Scaglione F, et al. Antimicrob Agents Chemother. 2003 Sep;47(9):2749-55. 29 Important PD Parameters Concentration independent T > MIC: Optimize duration of unbound drug concentration at or above the MIC Concentration Independent (Time-Dependent) agents kill bacteria when the drug concentrations exceed the MIC Time>MIC important Penicillins, cephalosporins, vancomycin Craig WA. Clin Infect Dis 2001;33(Suppl 3):S233-37. 30 www.proce.com 15
Concentration Independent Concentration C max = peak Beta-lactams Clindamycin Macrolides Linezolid Vancomycin T > MIC MIC C min = trough Adapted from: Roberts JA, et al. Crit Care Med.2009;37:840-851 Time 31 Relationship between Time above MIC and efficacy in animal infection models Cefotaxime in K. pneumoniae Log 10 CFU per lung at 24 h 10 10 9 9 8 8 7 7 6 6 5 5 01 1 10 100 1000 10000 3 10 30 100 300 1000 3000 Peak MIC ratio 24 h AUC/MIC ratio 10 9 8 7 6 5 R² = 94% 0 20 40 60 80 100 Time above MIC (%) Craig. Diagn Microbiol Infect Dis 1996; 25:213 217 32 www.proce.com 16
Relationship between Time above MIC and efficacy in animal infection models S. pneumoniae 100 80 Penicillins Cephalosporins 60 40 20 0 0 20 40 60 80 100 Time above MIC (%) Craig. Diagn Microbiol Infect Dis 1996; 25:213 217 33 PD of Specific Antimicrobials PD Parameter C max /MIC AUC/MIC T > MIC Aminoglycosides Fluoroquinolones Metronidazole Aminoglycosides Azithromycin Daptomycin Glycopeptides Ketolides Quinupristin/dalfopristin Beta-lactams Aztreonam Erythromycin Clarithromycin Linezolid Clindamycin Vancomycin Rodvold KA. Pharmacotherapy 2001;21:319S-330S. Nicolau DP. J Infect Chemother 2003;9:292-296. 34 www.proce.com 17
Pharmacodynamic Parameters for Prediction of Successful Outcomes Concentration (mg/l) 7 6 5 4 3 2 1 0 Peak/MIC 10x ( Gm - ) Aminoglycosides / Fluoroquinolones AUC/MIC >125 ( Gm - ) or >30 ( Gm + ) Fluoroquinolones AUC/MIC >100 Daptomycin or >50 Colistin Time > MIC >50% Cephalosporins / Macrolides 0 4 8 12 16 20 24 Time (h) MIC 35 Post Antibiotic Effect (PAE) C max = peak Concentration Persistent suppression of bacterial regrowth following brief exposure to an antimicrobial PAE MIC C min = trough Time Adapted from: Roberts JA, et al. Crit Care Med.2009;37:840-851 36 www.proce.com 18
Post Antibiotic Effect (PAE) Gram-positive organisms Most antibiotics (beta-lactams) exhibit PAE ~1-2 hours Aminoglycosides exhibit PAE < 1 hour Prolonged for Fluoroquinolones Gram-negative organisms Most beta-lactams (except imipenem) have a negligible PAE Aminoglycosides and quinolones have PAE > 2-3 hours Prolonged for Fluoroquinolones Clinical significance unknown Helps choose appropriate dosing interval Craig w, et al. The Post Antibiotic Effect. Ann Inter Med1987;106(6):900-902. 37 Clinical Applications Using PK and PD to predict patient outcome 38 www.proce.com 19
Clinical response (%) Relationship Between C max :MIC Ratio and Clinical Response Aminoglycosides 100 90 80 70 60 50 40 30 20 10 0 55 65 2 4 6 8 10 12+ Moore RD et al. J Infect Dis. 1987;155:93-99. C max :MIC 70 83 89 92 39 Relationship Between AUC / MIC and Clinical Response Ciprofloxacin in Seriously Ill Patients 100% - Clinical Microbiologic 16 7 22 % of Patients Cured 75% - 50% - 9 10 25% - 0-62.5 62.5-125 125-250 250-500 > 500 Forrest A., et al. Antimicrob Agents Chemother 1993;37:1073. 40 www.proce.com 20
No. of patients Relationship Between AUC / MIC and Clinical Response 100 90 80 70 60 50 40 30 20 10 0 4 3 AUC:MIC <25 Peak:MIC <3 Success Failure Levofloxacin Clinical Failure Rate 43% 11.5% 1% 23 3 AUC:MIC 25 100 Peak:MIC 3 12 100 1 AUC:MIC >100 Peak:MIC >12 134 hospitalized patients with respiratory tract, skin or complicated urinary tract infections treated with 500 mg qd for 5 14 days Jacobs. Clin Microbiol Infect 2001;7:589 96 ; [Adapted from Preston et al. JAMA 1998;279:125 9] 41 Limitation of Pharmacodynamics Bacterial sample should be in the fluid where the bacteria is obtained: difficult if not impossible to obtain Technology for measuring MIC s has 100% variability (1-2 fold dilutions) Antibiotic PD parameters, f-auc/mic & f-peak/mic incorporate MIC in the denominator One tube dilution can double or half the value of your PD outcome predictor or change the amount of time where f-antibiotic concentration > MIC 42 www.proce.com 21
Limitation of Pharmacodynamics All methods of determining MIC are not equal PD outcome parameter should specify MIC method Remember: Bacteria differ in their susceptibility to antibiotics, even among same species 43 Limitations of Pharmacokinetics Young healthy volunteers: worst case Most PK studies done in males Actual patients: clinically appropriate, usually not available May or may not account for protein-binding 44 www.proce.com 22
Other Considerations 45 Will the antibiotic get to the site of Infection? Blood and tissue concentrations Ampicillin/piperacillin concentrations in bile Fluoroquinolones concentrations in bone Quinolones, TMP/SMX, cephalosporins, amoxicillin concentrations in prostate 46 www.proce.com 23
Will the antibiotic get to the site of Infection? Ability to cross blood-brain barrier Dependent on inflammation, lipophilicity, low mw, low protein binding, low degree of ionization 3 rd or 4 th generation cephalosporins, chloramphenicol, ampicillin, PCN, oxacillin 47 Other Problems Local infection problems Aminoglycosides inactivated by low ph and low oxygen tension Beta-lactams inoculum effect More vulnerable to hydrolysis of betalactamases 48 www.proce.com 24
Timing of Antibiotics 49 Early treatment of infection Compliance with the 6-hour sepsis bundle and hospital mortality (n = 101). NNT, number needed to treat; RR, relative risk Gao F, et al. Critical Care. 2005; 9:R764 50 www.proce.com 25
Requirements For Short Course Antibiotic Therapy Fully susceptible pathogen; no risk of selection of resistance Bactericidal antibiotics (or combination) with optimum dose/dosing regimen Rapid onset of antibiotic action Good penetration of antibiotic into the infection site Antibiotic active against non-dividing bacteria Antibiotic action not affected by adverse infection conditions No foreign body present No abscess formation No signs of immunodeficiency 51 Short Course Antimicrobial Therapy Disease Longer Treatment (days) Equally Effective Shorter Treatment (days) Abdominal infection 10 4 Bronchitis in people with Chronic Obstructive Pulmonary Disease (COPD) 7 or more 5 or fewer Bacterial sinus infection 10 5 Cellulitis (skin infection) 10 5 to 6 Chronic bone infection 84 42 Kidney infection 10 to 14 5 to 7 Pneumonia acquired in the hospital Pneumonia acquired outside the hospital 10 to 15 8 or fewer 10 to 14 3 to 5 Adapted from: Spellberg B, The New Antibiotic Mantra: "Shorter is Better," JAMA Internal Medicine, July 25, 2016. 52 www.proce.com 26
What Factors Promote Antimicrobial Resistance? Exposure to sub-optimal levels of antimicrobial Exposure to microbes carrying resistance genes 53 Traditional hypothesis on emergence of AMR Plasma concentrations MIC Selective pressure for antibiotic concentration lower than the MIC Time 54 www.proce.com 27
The selection window hypothesis Plasma concentrations Mutant Selection window Mutant prevention concentration (MPC) (to inhibit growth of the least susceptible, single step mutant) MIC Selective concentration (SC) to block wild-type bacteria All bacteria inhibited Growth of only the most resistant subpopulation Growth of all bacteria Adapted from: Canton R, et al. Enferm Infecc Microbiol Clin 2013;31 Supl 4:3-11 55 Summary Antimicrobial PK/PD Through the integration of microbiologic data, pharmacodynamics data and pharmacokinetic parameters, determination of optimal antimicrobial therapy is possible DRUG BUG HOST 56 www.proce.com 28
57 www.proce.com 29