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7/10/2019
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#FSHP2019
Can We Do Better: Antibiotic Dose Optimization in the Hospitalized PatientCan We Do Better: Antibiotic Dose Optimization in the Hospitalized Patient
Jamie Kisgen, PharmD, BCPS-AQ IDPharmacy Manager, Infectious Diseases Services
Sarasota Memorial Hospital
#FSHP2019DisclosureDisclosureI have (or an immediate family member has) a vested interest in or affiliation with any corporate organization offering financial support or grant monies for this continuing education activity or with any organization that has a specific interest in the therapeutic areas under discussion as follows:Consultant: Tetraphase Pharmaceuticals, Spero TherapeuticsSpeaker with honorarium: Merck & Co, Inc
#FSHP2019Pharmacist Objectives: Identify patient-specific scenarios in which antibiotic
regimen personalization may be beneficial Discuss the benefits of therapeutic drug monitoring in
beta-lactam antibiotics Compare and contrast vancomycin AUC-based dosing
with traditional trough-based dosing strategies Discuss challenges to implementation of vancomycin
AUC-based dosing, and apply practical implementation solutions for health-systems
#FSHP2019Technician objectives• List which antibiotics may require dose optimization
strategies in the hospitalized patient• Recognize specific patient scenarios which may benefit
from dose optimization• Identify barriers to timely delivery and administration of
antibiotics
#FSHP2019Vancomycin Overview5
• Discovered in soil samples from Borneo by Eli Lilly in 1952• FDA approved in 1958 • Bactericidal(ish) against most gram-positive organisms• Adverse Effects: • Nephrotoxicity (more likely when used with other nephrotoxic
agents), neutropenia, thrombocytopenia• "Red-Man syndrome" (rash on face, neck, upper torso related
to infusion rate)• Ototoxicity: rarely reported these days
#FSHP2019Vancomycin Pharmacodynamics:Time>MIC vs. AUC/MIC
• This PD parameter best predicts vancomycin efficacy against S. aureus
• Initially described in 2004
• Goal AUC/MIC >400
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Moise-Broder PA, et al. Clin Pharmacokinet. 2004;43(13):925-42.Hilal-Dandan R, et al. Goodman and Gilman's Manual of Pharmacology and Therapeutics, 2e; 2016
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#FSHP2019
AUC-Guided or Trough-Guided Dosing?
#FSHP2019
• Trough-guided dosing was considered “the most accurate and practical method for monitoring efficacy”• A goal trough of 15-20 mg/L for serious infections was thought to be a
good surrogate marker for reaching the target AUC/MIC > 400
Rybak, M. et al, Am J Health‐Syst Pharm. 2009: 66(1), 82–98.
#FSHP2019Let’s Look at the Level of Evidence
Rybak, M. et al, Am J Health‐Syst Pharm. 2009: 66(1), 82–98.
#FSHP2019Do Troughs Correlate with AUC?
• Retrospective study of 100 patients with culture-confirmed MRSA infection
• No difference in AUC target attainment in patients with troughs of 10-14.9 vs 15-20 mg/L
• Average vancomycin trough was higher in patients developing nephrotoxicity• 19.5 vs 14.5 mg/L, p < .001 0%
10%
20%
30%
40%
50%
60%
70%
80%
< 10 mg/L(n=28)
10-14.9 mg/L(n=31)
15-20 mg/L(n=35)
> 20 mg/L(n=6)
Serum Vancomycin Trough Concentration
Hale CM, et al. J Pharm Pract. 2017;30(3):329-335
AUC
/MIC
≥ 4
00 (%
)
#FSHP2019
Do Higher Troughs Improve Outcomes?• Meta-analysis of 14 observational cohort studies in patients
with MRSA bacteremia
Prybylski JP. Pharmacotherapy 2015;35(10):889-898.
#FSHP2019What about AUC and Outcomes?
Prybylski JP. Pharmacotherapy 2015;35(10):889-898.
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#FSHP2019Elevated Troughs and Nephrotoxicity• Systematic review and meta-analysis of 15 studies that
assessed nephrotoxicity and stratified patients based on levels
van Hal SJ, Antimicrob Agents Chemother. 2013;57(2):734-744.
#FSHP2019
• Single-center, retrospective study• 1,280 adult patients
• AUC-guided dosing independently associated with ↓ nephrotoxicity relative to trough-guided dosing
• aOR 0.52; 95% CI, 0.34-0.80; P=0.003
14AUC/MIC‐Guided Dosing has been Associated with ↓ Nephrotoxicity
(HR, 0.53; 95% CI, 0.35‐0.78; P=0.002)
Finch, N. et al. Antimicrob Agents Chemother. 2017 doi: 10.1128/AAC.01293-17. e01293-17.
#FSHP2019New Vancomycin Guidelines - DRAFT• New guidelines only address Staphylococcus aureus infections
• AUC-guided dosing preferred over trough-guided• Two different methods AUC estimation
1. Bayesian Approach• Using 2 post-distribution levels or a single trough• Preferred, but more expensive/less readily available
2. Two post-distribution levels • Target AUC/MIC: 400-600
• Preferred approach for serious infections• Assume MIC of 1 mg/L• Timing of levels should be within 24-48 hours
https://www.ashp.org/Pharmacy-Practice/Policy-Positions-and-Guidelines/Draft-Guidance-Documents
#FSHP2019
How to Implement AUC-Guided Dosing
#FSHP2019Barriers to Implementation
• Deciding the best approach for AUC at your institution• Pharmacist workload and expectation• Physician acceptance • Nursing and phlebotomy • Communication of results to the team• Documentation
#FSHP2019Methods for Estimating AUC
1. Two Level Pharmacokinetics2. PK modeling using Bayesian software
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#FSHP2019
Method 1: Two Level Pharmacokinetics• Relies on the collection of 2 post-distribution levels
• Ideally at or near steady state and during the same interval• Cmax 1-2 hours post infusion and a trough level
• First-order PK equations are used to estimate the AUC• Multiple options to assist with calculations
• Spreadsheet-based methods• Electronic medical record-based calculators• Commercially available dosing calculators
Heil EL, et al. Am J Health Syst Pharm. 2018 Dec 15;75(24):1986-1995
#FSHP2019Method 2: PK modeling using Bayesian software
• Bayesian dosing incorporates population PK data, MIC of the pathogen, and individual patient data to estimate drug exposure• Some models can be done using a single level or two
level approach• Two level approach is typically more accurate
• This approach requires the use of one of several commercially available software programs • Preferred approach mentioned in the draft guideline
#FSHP2019Comparison of the Most Commonly Used AUC Software Programs
AUC Program Availability EHR
IntegrationTraining
RequiredEstimated
Cost More Information
APK
Downloadedand installed No
Minimal $ http://www.rxkinetics.com/apk.html
BestDose Extensive Free http://www.lapk.org/bestdose.php
Precise PK Moderate $$ https://precisepk.com
DoseMeWeb based Yes Minimal $$$
https://doseme-rx.com
InsightRx https://insight-rx.com
Adapted from Turner RB et al, Pharmacotherapy 2018;38(12):1174-1183
#FSHP2019Impact on Pharmacist Workflow• How many patients are on vancomycin/day?• Who is currently managing vancomycin dosing?• Will the consult load increase after the transition to AUC?• Number of clinical pharmacists involved in dosing?• What is the hospital EMR and will additional IT resources be
available?
#FSHP2019Our Experience…• 839 bed community-teaching hospital • 45 - 60 patients/day on therapeutic vancomycin• At the time, pharmacy managed 80-90% of vanco patients• Over 60 clinical pharmacists involved in vancomycin dosing
• Practice in a variety of patient care areas (e.g., ER, ICU, unit-based, etc)• EMR and IT resources
• Allscripts EMR; lack of resources at the time to purchase and implement an EMR-based or commercial AUC software program
#FSHP2019
Step 1: Create and Validate AUC Calculator
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#FSHP2019
Step 2: Create a Dosing Guideline#FSHP2019
Step 2: Best Practices for Developing a Dosing Guideline• Provide clear guidance on when it’s appropriate to use
AUC vs trough-guided dosing• Hint…AUC is not needed for everyone!
• Outline expectations for ordering initial and follow levels• Add the equations as a second check• How should follow-up levels be managed? • How should a change in clinical status be addressed?
#FSHP2019
Step 3: Medical and Pharmacy Staff Approval• Experienced clinicians may remember the practice of
checking peaks and troughs• This may be a new concept for younger practitioners!
• Understand the clinical data behind AUC and value of getting extra levels• Gain support from infectious diseases physicians and the
Pharmacy & Therapeutics Committee is vital
#FSHP2019
Step 4: Pharmacist Education/ Competency• Developed a comprehensive training and validation process to
ensure competency for both initial dosing and AUC monitoring• Included:
• Pre-recorded, on-demand, voiceover slideshow presentation• Practice cases utilizing the new guideline and spreadsheet calculator• Small group discussions to address questions or concerns• Random audit and feedback of individual cases after the new dosing
method was rolled out
#FSHP2019Pharmacist Competency• Create 2 different competencies for pharmacist• Centralized pharmacists (initial dosing only) • Decentralized pharmacists (order and evaluate levels)
#FSHP2019Step 5: Engage Nursing and Lab
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#FSHP2019Step 6: Documentation #FSHP2019Final Step: Audit and Feedback
• Expect questions and phone calls from pharmacists, nurses, and physicians• Evaluate successes and areas for
improvement• Dosing guideline and calculator will
need to be updated frequently• Track FAQ and post as reference
#FSHP2019Conclusion• Growing evidence shows that trough-guided dosing does
not improve the likelihood of target attainment for vancomycin and has been associated with toxicity• New guidelines are coming soon and will likely advocate
AUC-guided dosing for most patients• Hospitals can either continue trough-guided dosing until the
guidelines are published or embrace the change!• Determine the best approach, hospitals need to factor in
volume, complexity, cost, and resources
#FSHP2019Key Articles• Deryke CA, Alexander DP. Optimizing Vancomycin Dosing through
Pharmacodynamic Assessment Targeting Area under the Concentration-Time Curve/Minimum Inhibitory Concentration. Hospital Pharmacy 2009;44(9):751–765.
• Finch NA, Zasowski EJ, Murray KP, et al. A Quasi-Experiment To Study the Impact of Vancomycin Area under the Concentration-Time Curve-Guided Dosing on Vancomycin-Associated Nephrotoxicity. Antimicrob Agents Chemother. 2017 Nov 22;61(12). pii: e01293-17. doi: 10.1128/AAC.01293-17.
• Heil EL, Claeys KC, Mynatt RP, et al. Making the change to area under the curve-based vancomycin dosing. Am J Health Syst Pharm. 2018 Dec 15;75(24):1986-1995
• Turner RB, Kojiro K, Shephard EA. Review and Validation of Bayesian Dose-Optimizing Software and Equations for Calculation of the Vancomycin Area Under the Curve in Critically Ill Patients. Pharmacotherapy. 2018 Dec;38(12):1174-1183.
#FSHP2019Additional References
• Moise-Broder PA, Forrest A, Birmingham MC, et al. Pharmacodynamics of vancomycin and other antimicrobials in patients with Staphylococcus aureus lower respiratory tract infections. ClinPharmacokinet. 2004;43(13):925-42.
• Hale CM, Seabury RW, Steele JM, Darko W, Miller CD. Are vancomycin trough concentrations of 15 to 20 mg/L associated with increased attainment of an AUC/MIC ≥ 400 in patients with presumed MRSA infection? J Pharm Pract. 2017;30(3):329-335. doi: 10.1177/0897190016642692.
• Prybylski JP. Vancomycin trough concentration as a predictor of clinical outcomes in patients with Staphylococcus aureus bacteremia: a meta-analysis of observational studies. Pharmacotherapy 2015;35(10):889-898. doi: 10.1002/phar.1638.
• van Hal SJ, Paterson DL, Lodise TP. Systematic review and meta-analysis of vancomycin-induced nephrotoxicity associated with dosing schedules that maintain troughs between 15 and 20 milligrams per liter. Antimicrob Agents Chemother. 2013;57(2):734-744. doi: 10.1128/AAC.01568-12.
• Neely MN, Youn G, Jones B, et al. Are vancomycin trough concentrations adequate for optimal dosing? Antimicrob Agents Chemother.2014;58(1):309-316. doi: 10.1128/AAC.01653-13.
#FSHP2019
Therapeutic Drug Monitoring of Beta-Lactams: No Longer a Shot in the Dark
FSHP 2019 Annual Meeting
Therapeutic Drug Monitoring of Beta-Lactams: No Longer a Shot in the Dark
FSHP 2019 Annual Meeting
Veena Venugopalan, PharmD, BCIDPAssistant ProfessorDepartment of Pharmacotherapy and Translational ResearchCollege of Pharmacy, University of Florida
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#FSHP2019DisclosureDisclosure
I do not have (nor does any immediate family member have):– a vested interest in or affiliation with any corporate
organization offering financial support or grant monies for this continuing education activity
– any affiliation with an organization whose philosophy could potentially bias my presentation
#FSHP2019
Optimized Dose
Positive clinical
outcomes
Reduced resistance selection
Reduced toxicity
What am I going to tell you?
#FSHP2019
Pharmacokinetics
Concentration‐Time
Pharmacodynamics
Concentration‐Effect
Pharmacokinetics/Pharmacodynamics(PK/PD)
Dose‐Effect Relationship
#FSHP2019PK/PD of Beta-Lactams
Drug Class % of Dosing Interval for Bactericidal Activity
Carbapenems 40Penicillins 50Cephalosporins 60-70
Drusano GL. Clin Infect Dis. 2003;36(Suppl 1):42-50.
#FSHP2019Optimal PK/PD Targets for Beta-Lactams
ƒCmin>5 X MIC predictor of clinical success
Bactericidal activity of beta-lactams optimized at ~4x MIC
Bactericidal activity of ceftazidime optimized when CI targeted 4 X> MIC
#FSHP2019
Pharmacokinetic Variability of Beta-Lactams: Critical Illness
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#FSHP2019Augmented Renal Clearance (ARC)
Cook AM et al. Pharmacotherapy. 2019;39(3):346-354.
#FSHP2019Piperacillin Concentrations in Critical Illness
Carlier M et al. Int J Antimicrob Agents.2014;43(5):470-3.
MIC
#FSHP2019Variability in Piperacillin Concentration in Relation to Tazobactam
Piperacillin target ≥ 70 mg/L to prevent tazobactam falling below 5.7 mg/L
Zander J et al. IJAA. 2016;48(4):435-9.
#FSHP2019Beta-lactam TDM in Critically Ill
Ampicillin Cefazolin Ceftriaxone Meropenem PiperacillinStandard dose
2000 mg q6h 1000 mg q8h 1000 mg q12h 1000 mg q8h 4500 mg q8h
Dosage range 1000 mg q12h-2000 mg q4h
1000 mg q4h-2400 mg q4h
1000 mg q12h-2000 mg q8h
500 mg q12h-2000 mg q6h
4500 mg q12h-4500 mg q4h
50%ƒT>MIC 60.0% 100.0% 96.2% 92.1% 90.4%50%ƒT>4xMIC 53.3% 28.6% 96.2% 68.5% 53.2%100%ƒT>MIC 53.3% 57.1% 96.4% 72.2% 61.0%100%ƒT>4xMIC 33.3% 0.0% 71.4% 29.9% 33.5%
Wong G et al. J Antimicrob Chemother. 2018;73(11):3087-3094.
#FSHP2019DALI: Defining Antibiotic Levels in Intensive Care Unit Patients
Roberts JA et al. CID. 2014;58(8):1072-83.
Methods • Prospective, multinational PK study including 8 beta-lactams• Primary PK targets were free drug concentration > MIC of the
pathogen at both 50% ƒ T>MIC and 100% ƒ T>MIC
Results 248 patients treated for infection• 16% (n=40) did not achieve 50% ƒ T>MIC and these patients
were 32% less likely to have a positive clinical outcome (OR 0.68; 95% CI: 0.52- 0.91)
• 50% f T>MIC and 100% f T>MIC (higher PK/PD ratio) was associated with higher likelihood of a positive clinical outcome (OR, 1.02 [95% CI, 1.01–1.04] and OR, 1.56 [95% CI, 1.15–2.13]
#FSHP2019Association between ARC and Clinical Outcomes between II or CI
54%
73%85%
56%67% 64%
Low ARC (n=134) Moderate ARC (n=33) High ARC (n=27)
Clincal Cure at 14 Days Post-AntibioticsCI
II
Udy AA et Int J Antimicrob Agents. 2017;49(5):624-630.ARC- Augmented renal clearance; CI- Continuous Infusion; II- Intermittent infusion
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#FSHP2019
Pharmacokinetic Variability of Beta-Lactams: Obesity
#FSHP2019Effects of Obesity on Immune Function
Schetz M et al. Intensive Care Med; 2019:1-13.
#FSHP2019Impact of Vd on Antibiotic Concentrations
Sime FB et al. Clin Microbiol Infect. 2015;21(10):886-93.
#FSHP2019Beta-lactam Dosing in Obesity
79% 76% 80%
28%21%
31%
All patients Obese Non-obese
Piperacillin PK/PD Targets
fT>MIC fT>4xMIC
* *
Alobaid A et al. JAC. 2016;71:696-702.
#FSHP2019
Beta-Lactam TDM: A look at our experience at UF Health
#FSHP2019Beta-Lactams Testing at UF Health Antimicrobial
AmpicillinAmoxicillinAztreonamCefazolinCefepimeCeftriaxoneOxacillinImipenemMeropenemPiperacillin/tazobactamAztreonam
https://idpl.pharmacy.ufl.edu
Cost/test- $80
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#FSHP2019 #FSHP2019Beta-Lactam TDM
Bowden J et al. Data presented at ID Week. San Diego, 2017.
n=44
n=14
n=6
n=32
n=6 n=5
Cefepime Piperacillin/tazobactam Meropenem
T>MIC 100% Cmin:MIC≥496%
69%
50% 42%
38%
16%
#FSHP2019Incidence of Cefepime Neurotoxicity
Nys C et al. Abstract submitted for ID Week. 2019.
Methods Retrospective review of adult patients with cefepimeconcentrations ≥ 25 mcg/ml between March 2016-May 2018
Results 142 patients were included in the analysis• Neurotoxicity related to cefepime occurred in 18/142 (13%)
• 67% (12/18) were considered “High Likelihood of Toxicity”• Median age 68 (IQR, 57-74)• Median CrCl at the time of neurotoxicity 35.8 ml/min (IQR, 19.2-
50.9 ml/min)• Median cefepime trough concentration was 62 mcg/ml (IQR,
50-73 mcg/ml)
#FSHP2019Meropenem Continuous Infusion
Meropenem 1 % in 0.9% Sodium Chloride at 25°CTime (hr) Concentration
(mg/ml)% Concentration Compared to Time Zero
0 98.7 -4 96.6 99.88 95.1 96.412 95.3 97.4
Venugopalan V et al. Microbiol Insights. 2018.14;11.
#FSHP2019Target Attainment of Meropenem
95%
5%
Yes No
100%FT>MIC
74%
26%
100%FT>4xMIC
Venugopalan V et al. Microbiol Insights. 2018.14;11.
Meropenem 3g IV every 12 hours as a continuous infusion
#FSHP2019Unbound Concentrations
Al-Shaer et al. [manuscript under review]
Cefepime 20%Meropenem 2%
Piperacillin/tazobactam 30%
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#FSHP2019Bacterial Resistance Selection
Drusano GL et al. Antimicrob Agents Chemother. 2015;60(3):1183-93.
#FSHP2019Analysis of Resistant Organisms by PK/PD Target
Burch G et al. Data Presented at American Burn Association 51st Annual Meeting. Las Vegas, 2019.
#FSHP2019Acknowledgements
• Infectious Disease Pharmacokinetics Lab, University of Florida
• Director: Charles Peloquin, PharmD• Chemists/Staff: Theodore Zagurski; Kyung Mee Kim, PhD; Emily
Graham; Stacy Stoneberger• Trainees: Gena Burch, PharmD, MS; Mohammad Alshaer,
PharmD
#FSHP2019
Summary:
• Beta-lactam levels are highly variable, particularly in critically ill patients
• Optimize dosing to improve patient outcomes
• Use of beta-lactam TDM can individualize dosing
#FSHP2019
Therapeutic Drug Monitoring of Beta-Lactams: No Longer a Shot in the Dark
FSHP 2019 Annual Meeting
Therapeutic Drug Monitoring of Beta-Lactams: No Longer a Shot in the Dark
FSHP 2019 Annual Meeting
Veena Venugopalan, PharmD, BCIDPAssistant ProfessorUniversity of Florida, College of Pharmacy
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