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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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