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2019 Pharmacy Education SeriesNovember 20, 2019

Pharmacy Pearls 2019

Today’s Presenters

Teresa Benites, PharmD

Teresa is a PGY1 pharmacy resident at Moses Taylor Hospital in Scranton, Pennsylvania. She recently earned her Doctorate of Pharmacy degree this year from Temple University in Philadelphia. Her professional interests include critical care and infectious diseases and is currently working on a research project to better improve antibiotic stewardship in the intensive care unit. Following the completion of her PGY1 residency she hopes to become a board certified specialist and work as a clinical pharmacist in an inpatient setting.

Joyce Jung, PharmD

Joyce Jung is a PGY‐1 Pharmacy Resident at Moses Taylor Hospital in Scranton, Pennsylvania. Joyce recently graduated from the University of the Sciences, Philadelphia College of Pharmacy. She enjoys effectively communicating with patients and aiding continuity of care. Her academic and research interest focuses on pain management and opioid stewardship.

Joel Martial Tchafack Kaze, PharmD, MS

Joel is currently a pharmacy postgraduate year one (PGY1) resident at Carlsbad Medical Center in New Mexico. Joel obtained his PharmD from the Appalachian College of Pharmacy. Joel also holds a M.S. in Molecular Biology from the University of Brussels, Belgium and a B.S. in Biochemistry from the University of Beau, Cameroon, which is his country of origin. He is the co‐founder of EradiCare, a nonprofit organization (NGO) whose goal is to improve the quality of the life of patients in developing countries by improving the educational standards, medication administration, patient outcomes, and preventing disease transmission. Joel selected to do a PGY‐1 in Carlsbad Medical Centers to improve his clinical knowledge in pharmacotherapy. Joel plans to further specialize in pharmacy informatics so that he can help optimize patient care.

Ola Khalil, B.S. Pharm, RPh

Ola earned a Bachelor Degree of Pharmaceutical Sciences from Alexandria University School of Pharmacy in Egypt. She became a licensed pharmacist in the USA in 2008 and worked as a retail pharmacist at Walgreens Pharmacy, Louisiana. After moving to Texas, she worked as a volunteer pharmacist at San Jose Charity Clinic in Houston. She started her clinical pharmacy practice and became the lead clinical pharmacy practice intern at San Jose Clinic. Currently, she is doing her PGY‐1 pharmacy residency at Carlsbad Medical Center at Carlsbad, New Mexico. She is completing her Antimicrobial Stewardship certification and plans on becoming a pharmacotherapy specialist.

Marie-Laur Killebrew, CPhT

Marie‐Laur has been a pharmacy technician for 37 years including serving in the armed forces for 7 years. Currently she is the pharmacy buyer at Tennova Healthcare‐Clarksville where she has served in this role for many years.

Jessica Liao, PharmD

Jessica Liao graduated from the University of Florida, College of Pharmacy. She is currently completing her postgraduate year one (PGY1) residency at Bayfront Health St. Petersburg.

Stephanie Longshaw, PharmD, MSc

Stephanie Longshaw is a PGY‐1 Resident at Carlsbad Medical Center, New Mexico. She earned her PharmD from Pacific University of Oregon in 2019, specializing in underserved populations and rural healthcare, with a prior MS in Biological research from the University of Alabama, Birmingham and BA in International Studies from the University of Washington, Seattle. Her professional interests include emergency medicine, drug information, and developing programs to optimize medication therapy at the time of patient discharge.

John Stanas, PharmD

John Stanas, PharmD is a 2019 graduate of the Medical University of South Carolina’s College of Pharmacy. He is currently training in the pharmacy postgraduate year one residency program (PGY1) at Bayfront Health ‐ St. Petersburg. He aspires to continue his training with a postgraduate year two residency training (PGY2) in Emergency Medicine.

Pharmacy Pearls 2019CHS Pharmacy Education Series

ProCE, Inc.www.ProCE.com 1

2019 Pharmacy Education SeriesNovember 20, 2019

Pharmacy Pearls 2019

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 Print your CE statement of completion online

– Credit for live or enduring (not both) Deadline: December 20, 2019 Pharmacists and Pharmacy Technicians: CE credit uploaded to CPE Monitor

– User must complete the “claim credit” step

Online Evaluation, Self-Assessmentand CE Credit

Attendance CodeCode will be provided at the end of today’s activity 2



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2019 Pharmacy Education Series

It is the policy of ProCE, Inc. 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. None of the presenters have any relevant commercial or financial relationships to disclose.

Disclosure: The information contained in the presentation is for Community Health System employees and hospital affiliates and is not for external distribution and/or use. The presentation may contain information that is proprietary, confidential, or legally privileged or protected. It is intended only for the use of Community Health System employees and hospital affiliates. Do not deliver, distribute or copy the presentation and do not disclose its contents or take any action in reliance on the information it contains outside of Community Health Systems and hospital affiliates.

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.

November 20, 2019Pharmacy Pearls 2019

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CE Activity Information & Accreditation

ProCE, Inc. (Pharmacist and Pharmacy Technician CE)This CE activity is jointly provided by ProCE, Inc. and CHSPSC, LLC. ProCE is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. ACPE Universal Activity Number 0221-9999-19-525-L04-P/T has been assigned to this knowledge-based live CE activity (initial release date 11-20-19). This CE activity is approved for 2.0 contact hours (0.2 CEU) in states that recognize ACPE providers. This CE activity is provided at no cost to participants. Successful completion of the online post-test and evaluation at www.ProCE.com/CHSRx is required to receive CE credit. CE credit will be uploaded to NABP/CPE Monitor. No partial credit will be given.

Funding:This activity is self-funded through CHSPSC.



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Successful purchasing practices for hospital pharmacies

Marie Laur Killebrew, CPhTTennova Healthcare - Clarksville

Objectives

By the end of this module, the learner should be able to:● Summarize the general responsibilities of a pharmacy buyer● Explain the process of purchasing medications● Formulate solutions to common issues of procurement

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Pharmacy Buyer

● Responsibilities include:○Inventory○Purchasing○Backorders○Recalls○Credits○Returns○Communication

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Inventory

● More than a physical count twice a year● Par Levels

○In Pharmacy■Walking the shelves to determine current inventory■Paying attention to medications that expire in large quantities

○In Automated Dispensing Cabinets■Running reports to optimize stock■Know how many patients have active orders

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Inventory

● High Cost Medications○ Only keep in areas of the hospital absolutely necessary○ Know par levels and only restock when replacement is needed

● Nonformulary Medications○ Should only be purchased when utilized by a patient

Goal: stock amount necessary to care for patients

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Purchasing● Know the Inventory

○ Total product in pharmacy and in automated dispensing cabinets● Cardinal Block List

○ Products will be ineligible when searched○ Exclusion list available from CHS Corporate Pharmacy

● Product Selection○ Choose products on contract○ Can see which items were previously purchased – assists in matching ID

number of product with medication orders

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Purchasing

● Contract Priority○Prioritized by primary and secondary

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Purchasing

● Alternate options○Place order for contracted item to show that the purchase was

attempted○Then search for alternate product to restock shelves for patient care

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Backorders

● Putting items on backorder● Tracking Items

○Order Express○Spreadsheet

● Communication about expected availability

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Recalls

● Inmar/RASMAS● Managing hospital stock

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Credits and Returns

● Restocking Fees● Expired Medications● Excess Product

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Communication

● Between Facilities● Backorders● Other Departments

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Practice Pearls

● Definitions:○Emergency Order○Drop Ship Item○Contract Compliance○Penalty○Fill Rate○Failure to Supply

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Practice Pearls

● Treat the pharmacy budget like your personal budget.● Backorders are going to happen. Period.● Bottom line of any job in pharmacy is patient care. ● Know what to communicate, at the right time, to the right person.

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The Clinical Utility of the MRSA Nares

Swab

John Stanas, PharmD

PGY1 Pharmacy Resident

Bayfront Health St Petersburg

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ObjectiveTo assess the utility of the MRSA Nares swab and where it fits in our diagnostic tool box for treatment



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Background

MRSA infections ~10% of community acquired

pneumonia Most common pathogen causing

ventilator-associated pneumonias Most common pathogen in surgical

site infections

Resistance Rates

Risk factors Intravenous antibiotic use in

previous 90 days

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Background

Most patients developing MRSA infections will have been colonized prior to infection ~20% persistently colonized ~60% intermittently colonized Remaining ~20% not susceptible to

MRSA colonization



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Nares

Fig 1: https://www.earthslab.com

Fig 2: https://www.123rf.com

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Specificity, Sensitivity, & Negative Predictive Value

Specificity

True Negative Rate

Probability that test will be negative when disease is not present

Sensitivity

True Positive Rate

Probability that test result will be positive when disease is present

Negative Predictive Value

Probability that disease is not present when test is negative



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The Literature

Clinical Infectious Diseases 2018;67(1):1–7

The Clinical Utility of Methicillin-Resistant Staphylococcus aureus (MRSA) Nasal Screening to Rule Out MRSA Pneumonia: A Diagnostic Meta-analysis With Antimicrobial Stewardship Implications (2018)

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Specificity: MRSA Nares

High Specificity If negative, strong chance MRSA not

associated with respiratory infection CAP/HAP: 92.1% VAP: 93.7%




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Sensitivity: MRSA Nares

If positive, may indicate MRSA infection but may simply indicate that patient is colonized CAP/HAP: 85% VAP: 40%

Moderate Sensitivity


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NPV:MRSA Nares

Negative Predictive Value If the test is negative, is it correct?

CAP/HAP: 98.1% VAP: 94.8%




MRSA Nares

Benefits Quick turnaround

time Allows for earlier

de-escalation Strong negative

predictive value

Limitations Non-pulmonary

sites of infection Structural lung

disease Nasal

decolonization

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New Data: SSTI

2018 publication in Emergency Medicine Journal 116 patients 52 with MRSA

Specificity Sensitivity NPVMRSA SSTI 92.2% 57.7% 72.8%

Emergency Medicine Journal 2018;35:357-360



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Where It Shouldn’t Be Used

Not to be used as a signifier that MRSA infection is present in respiratory tract Do not use to escalate therapy for

MRSA coverage

Cannot be interpreted accurately if patient has already been on anti-MRSA antibiotics for >72hrs

Summary & Current Recommendations

In Pneumonia: Positive test does not indicate MRSA

infection Negative test indicates MRSA highly

unlikely and de-escalation of MRSA coverage should be implemented

Per 2019 guidelines, recommended prior to respiratory culture isolation in CAP Not recommended for use in infections

outside of respiratory tract However, may be considered as adjunct to

clinical decision making in SSTI

Am J Respir Crit Med. 2019 Oct 1;200(7):e45-e6734



Vancomycin Dosing:From Trough to AUC/MIC

Teresa Benites, PharmDPGY1 Pharmacy Resident

Moses Taylor Hospital

November 20, 2019

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∗ Evaluate new anticipated guidelines regarding the utilization of 24-hour area under the curve to minimum inhibitory concentration (24-H AUC/MIC) for monitoring vancomycin efficacy and safety

Objectives



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∗ PK/PD modeling used to describe & predict time course of drug effects under physiological & pathological conditions

∗ Three main PK/PD parameters to describe antibiotic efficacy∗ Peak/MIC∗ AUC/MIC∗ T>MIC

PK/PD Modeling

RxKinetics. A PK/PD Approach to Antibiotic Therapy. 2018 February. http://www.rxkinetics.com/antibiotic_pk_pd.html

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PK/PD Parameters

(Vancomycin)

Image courtesy of Agency for Healthcare Research and Quality (AHRQ)



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24-h AUC/MIC

Ebert S. In vivo cidal activity and pharmacokinetic parameters for vancomycin against methicillin-susceptible and -resistant S. aureus. Abstract 439 presented at 27th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC; 1987.

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∗ Considered acute glomerular nephritis ∗ Typical onset 2-5 days and peaks 5-10 days

∗ VAN > 4g/d and troughs >15 mg/L associated with nephrotoxicity∗ Recent data suggest AUC levels of >600 mgxhr/L also

increases the risk

∗ Risk increases with concomitant nephrotoxic agents and pre-existing renal dysfunction

Toxicity of Vancomycin:Nephrotoxicity

Stevens RW, et al. Use AUC to Optimize Vancomycin Dosing. Pharmacy Times. 2019-04-04



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Toxicity of Vancomycin:Nephrotoxicity

R. Chavada, et al. Establishment of an AUC0–24 Threshold for Nephrotoxicity Is a Step towards Individualized Vancomycin Dosing for Methicillin-ResistantStaphylococcus aureus Bacteremia Antimicrobial Agents and Chemotherapy Apr 2017, 61 (5) e02535-16; DOI: 10.1128/AAC.02535-16

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∗ Historically, AUC/MIC > 400 has been a widely supported target to achieve clinical effectiveness

∗ Trough levels are instead utilized due to past impracticality of calculating AUC/MIC in the clinical setting ∗ Trough level serves as a surrogate marker for AUC

∗ Trough levels should be obtained prior to next dose at steady state∗ Therapeutic levels > 10 mg/L and 15-20 mg/L for complicated

infections

Current Published Guideline2009 Vancomycin Therapeutic Monitoring Guidelines:

A Consensus Review (ASHP/IDSA/SIDP)

Rybak M, Lomaestro B, Rotschafer JC, et al. Therapeutic monitoring of vancomycin in adult patients: a consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Am J Health Syst Pharm 2009; 66(1): 82-98.



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∗ As stated; acts as a surrogate marker for AUC

∗ Typical practice is to give weight-based dosing (15 mg/kg) then check trough typically after four doses targeting >10 mg/L

∗ Troughs cannot ensure safe dosing due to patient variability

Trough Monitoring

R. Chavada, et al. Establishment of an AUC0–24 Threshold for Nephrotoxicity Is a Step towards Individualized Vancomycin Dosing for Methicillin-Resistant Staphylococcus aureusBacteremia Antimicrobial Agents and Chemotherapy Apr 2017, 61 (5) e02535-16; DOI: 10.1128/AAC.02535-16

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Trough Monitoring



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∗ Using only troughs to monitor will no longer be recommended for serious MRSA infections

∗ Supports the use of AUC/MIC (assuming MIC of 1)

∗ Studies showed variability of AUC values with similar troughs∗ Bayesian software program most preferred approach to easily

calculate AUC/MIC∗ Practical and now readily available in clinical settings

∗ Looked into retrospective studies that showed AUC/MIC monitoring had favorable outcomes compared to troughs ∗ AUC/MIC showed significantly lower rates of AKI and higher rates of

bacterial eradication

Anticipated 2019 Guideline2019 Vancomycin Therapeutic Monitoring Guidelines:


Therapeutic monitoring of vancomycin: A revised consensus guideline and review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society and the Society of Infectious Diseases Pharmacists. Draft update, unpublished Accessed July 2019

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∗ Bayesian-derived AUC/MIC ratio of 400-600 (assuming MIC of 1 mg/L) should be advocated for serious MRSA infections

∗ Monitoring recommended for the following:∗ Aggressive dosing for MRSA infection∗ Patients at high risk of nephrotoxicity ∗ Patients with unstable renal function∗ Prolonged courses of therapy

∗ Once weekly monitoring for hemodynamically stable patients

Anticipated 2019 Guideline2019 Vancomycin Therapeutic Monitoring Guidelines:





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∗ Dosage based on MIC suboptimal∗ Variability in MIC due to different automated methodology

techniques used in laboratoriesFor example. . .

∗ If MIC is 2 mg/L, AUC targets of >800 would be required∗ This is likely above safety threshold

∗ If MIC < 1 mg/L, one could decrease dose (to AUC of 200 if MIC is 0.5 mg/L)∗ Not feasible due to lack of published data

Dose adjusting based on MIC

Heil EL, Claeys KC, Mynat RP et al. Making the change to area under the curve-based vancomycin dosing. Am J Health-Syst Pharm. 2018; 75: 1986-95

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Per 2019 anticipating guidelines:∗ Recommends under most circumstances that

MIC can be assumed to be 1 mg/dL∗ When MICBMD >1 mg/L probability of achieving

AUC/MIC >400 is unlikely ∗ Higher doses may risk unnecessary toxicity

∗ Important to know limitations, variability, and lack of precision with automated susceptibility testing methods

Dose adjusting based on MIC




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∗ Study: Prospective study∗ Population: 252 hospitalized patients∗ Primary Outcome: Proportion of therapeutic trough

versus proportion of therapeutic AUC∗ Method: Monitored trough 10-20 in year 1 versus Bayesian

AUC >400 year 2 and 3∗ Results: Nephrotoxicity occurred 8% of patients year 1 vs.

0-2% in years 2 and 3 (P=0.01)∗ AKI: Median Trough ~15.7 and AUC ~625

∗ Non AKI: Median trough ~8.7 and AUC ~423

AKI: AUC/MIC vs. Trough(Neely et al. 2017)

Neely MN, Kato L, Youn G, et al. A prospective trial on the use of trough concentration versus area under the curve (AUC) to determine therapeutic vancomycin dosing. Antimicrob Agents Chemother 2017.

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∗ Uses prior knowledge alongside current available data∗ Combines population information (Bayesian

prior) with patient-specific information (Bayesian posterior) to predict dose adjustments

∗ Advantageous in that it requires single serum level for desired AUC target ∗ Dynamic; as data grows so does optimization

Bayesian Approach




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Available Bayesian Software

o Turner and colleagues reviewed these software and concluded each produced similar estimates of AUC

o Difference in other characteristics (e.g. user-friendly, company support, difficulty)

Turner RB, et al. 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

Adult and Pediatric Kinetics BestDose DoseMeRx InsightRx PrecisePK

PROs

- Simple- Three post infusion levels can be input- Demographics can be saved

- Allows for modifications on population model- Saved patient data

- Simple- Visually rich- Saved patient data- Responsive customer support

- Simple- All data shown 1 screen- Displays 4 PK models - Visually rich- Saved patient data- Responsive customer support

- Input individual or fixed regimen- Saved patient data

CONs

- Single dosing regimen vs. individual doses- Dosing regimens/serum levels not saved

- Difficult navigation

- Multiple screens required for data input

- Cannot input fixed regimen

- Multiple screens required- Limited customer support- Moderate training

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∗ AUC can also be accurately estimated based on two timed steady-state vancomycin concentrations

∗ Advantage in that it is free and relies on fewer assumptions

∗ Disadvantageous in that it requires two steady states, time-consuming, prone to human error, and not adaptive vs. Bayesian approach

First-Order PK Analytic Equations




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∗ Meningitis/CNS infections∗ Troughs 15-20 recommended but low quality evidence in efficacy

∗ Renal replacement therapy∗ Inconsistency of timing/duration of dialysis can lead to

unpredictable elimination∗ Acute kidney injury

∗ Clearance is unpredictable/unstable and dramatically decreased

∗ Those where routine serum concentration unlikely to affect patient outcomes∗ E.g. Surgical prophylaxis

AUC/MIC Exclusion


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∗ Research predominantly retrospective∗ PK and MIC not available to clinicians in first 24-48

hours∗ Number of different commercial susceptibility

methods are used by laboratories to determine MIC∗ Many of these methods produce higher or lower MIC

values ∗ No data that assesses cost and benefits of AUC/MIC

on patient outcomes

Critiques of AUC/MIC

Wilson CG, Ulrich IP, Scott MA. Appropriateness of basing vancomycin dosing on area under the concentration-time curve. Am J Health-Syst Pharm. 2019; DOI 10.1093/ajhp/zxz187



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∗ AUC/MIC dosing strategy shows promise in decreasing risk of nephrotoxicity vs. trough-based dosing

∗ More research, especially prospective studies, needs to be conducted to determine efficacy of AUC/MIC dosing strategy in unique patient populations

∗ Overall, anticipating guidelines recommend target AUC/MICBMD ratio of 400-600 for serious infections caused by MRSA to maximize clinical efficacy and minimize AKI.∗ Preferably with the Bayesian approach.

Summary

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References:1.) RxKinetics. A PK/PD Approach to Antibiotic Therapy. 2018 February. http://www.rxkinetics.com/antibiotic_pk_pd.html

2.) Pharmacokinetic/Pharmacodynamic Measures for Guiding Antibiotic Treatment for Nosocomial Pneumonia. Agency for Healthcare Research and Quality (AHRQ). 2013 July.

3.) Ebert S. In vivo cidal activity and pharmacokinetic parameters for vancomycin against methicillin-susceptible and -resistant S. aureus. Abstract 439 presented at 27th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC; 1987

4.) Stevens RW, et al. Use AUC to Optimize Vancomycin Dosing. Pharmacy Times. 2019-04-04

5.) R. Chavada, et al. Establishment of an AUC0–24 Threshold for Nephrotoxicity Is a Step towards Individualized Vancomycin Dosing for Methicillin-Resistant Staphylococcus aureus Bacteremia Antimicrobial Agents and Chemotherapy Apr 2017, 61 (5) e02535-16; DOI: 10.1128/AAC.02535-16

5.) Rybak M, Lomaestro B, Rotschafer JC, et al. Therapeutic monitoring of vancomycin in adult patients: a consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Am J Health Syst Pharm 2009; 66(1): 82-98.

6.) Drennan PG, et al. The dosing and monitoring of vancomycin: what is the best way forward? Int J Antimicrob Agents 2019 PMID 30599240

7.) Therapeutic monitoring of vancomycin: A revised consensus guideline and review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society and the Society of Infectious Diseases Pharmacists. Draft update, unpublished Accessed July 2019

8.) Heil EL, Claeys KC, Mynat RP et al. Making the change to area under the curve-based vancomycin dosing. Am J Health-Syst Pharm. 2018; 75: 1986-95

9.) Neely MN, Kato L, Youn G, et al. A prospective trial on the use of trough concentration versus area under the curve (AUC) to determine therapeutic vancomycin dosing. Antimicrob Agents Chemother 2017.

10.) Turner RB, et al. 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

11.) Wilson CG, Ulrich IP, Scott MA. Appropriateness of basing vancomycin dosing on area under the concentration-time curve. Am J Health-Syst Pharm. 2019; DOI 10.1093/ajhp/zxz187



J ES S I CA L I AO, PH A R M D

PGY1 PHA RMACY PRAC T I CE R ES I D ENT

BAYFRONT HEA LT H ST. PET ERSBURG

C. the difference. .

An Overview of Updates on C. difficile Treatment

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DisclosuresThere are no financial interest/arrangement or affiliation concerning material discussed in this presentation



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Objective

• Identify the 2018 IDSA guideline updates in the management of C. difficile for adults

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What is Clostridium difficile?

• Spore-forming, anaerobic, gram positive bacillus

• Secretes toxin A and B• Toxin A makes the gut more permeable• Toxin B causes intense inflammation in the colon

Paddock C. Study reveals how C difficile disrupts the gut.



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Who should be tested for C. diff?

New onset diarrhea

3 or more unformed

stools in 24 hours

Unexplained diarrhea

In order to prevent likelihood of false positives and to

prevent unnecessary treatment, only test patients that exhibit

all of these characteristics.

McDonald LC. Clin Infect Dis. 2018, Pages e1–e48. https://doi.org/10.1093/cid/cix1085

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The 2-step, 3-step Process To test for C. difficile

Glutamate dehydrogenase (GDH)

+ Toxin

Toxin+

Nucleic acid amplification test (NAAT)

Glutamate dehydrogenase (GDH)

+ Toxin

+ Nucleic acid amplification

test (NAAT)




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Testing

Positive C difficile PCR and Negative Toxin May represent colonization, and not infections.Thus, take into account clinical presentation

Not recommended:C. diff toxin test aloneDo not repeat testing within 7 days during same

episode of diarrhea Do not test stool from asymptomatic patients


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Initial Treatment Changes

Old C. diff 1st line therapy: Metronidazole

New C. diff 1st line therapy: Vancomycin or Fidaxomicin

Reasoning: higher cure rates with Vancomycinand Fidaxomicin than Metronidazole




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Other reasons metronidazole no longer 1st line

Metronidazole has risk of: neurotoxicity drug interactions increased resistance

Overall, increased mortality was seen with metronidazole

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Comparative Effectiveness of Vancomycin and Metronidazole for the Prevention of Recurrence and Death in Patients With Clostridium difficile Infection

Stevens VW, et al. JAMA. doi:10.1001/jamainternmed.2016.9045

CONCLUSION:Recurrence rates were similar among patients treated with Vancomycin and Metronidazole. However, the risk of 30-day mortality was significantly reduced among patients who received Vancomycin.



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Regimen for Initial Episode

Same for non-severe and severe episodeNon-severe: diarrhea, WBC <15K, SCr <1.5 mg/dL Severe: diarrhea, WBC >15K, SCr >1.5 mg/dL

Treatment of choice: Vancomycin 125 mg by mouth every 6 hours

x 10 days


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Regimen for Fulminant C. diff. Fulminant infection may include hypotension, shock, ileusTransfer patient to ICU; may consult GI, infectious disease, or surgeryTreatment of choice: Vancomycin + Metronidazole

Vancomycin 500 mg by mouth every 6 hoursMetronidazole 500 mg intravenously every 8

hours

Napolitano FJ. Vancomycin Enema in the Treatment of Clostridium difficile Infection. doi: 10.1089/sur.2018.238.McDonald LC. Clin Infect Dis. 2018, Pages e1–e48. https://doi.org/10.1093/cid/cix1085



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If Ileus present/ NPO/ patient is unable to tolerate oral medications:

Consider adding Vancomycin rectally as a retention enema

Vancomycin 500 mg rectally in 500 mL every 6 hours for 60 minutes

Regimen for Fulminant C. diff. Cont.

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Treatment Failure/ RecurrenceRecurrence = symptoms + positive assay result following an episode of

positive assay in the previous 2-8 weeksFor 1st recurrence:

If Metronidazole used initially use VancomycinIf Vancomycin used initially use pulsed dose regimen of Vancomycin

OR Fidaxomicin (Dificid®) 200 mg PO every 12 hours x 10 days

For 2nd recurrence or more:

Alternative: Vancomycin 125 mg PO every 6 hours x 10 days followed by rifaximin 400 mg PO every 8 hours x 20 days after Vancomycin




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Fecal Microbiota Transplant

Recommended for patients with 2 or more recurrences of C. diff and for those whom failed appropriate antibiotic treatment


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New Agent: BezlotoxumabMonoclonal antibody directed against toxin B produced by C. difficile Approved as adjunctive therapy for patients who are receiving

antibiotic treatment for CDI and who are at high risk for recurrence

Category B agent at CHS Decreased recurrence rate (within 12 weeks of last episode)

MODIFY I : Rate of recurrent CDI 17% (Bezlotoxumab) vs 28% (placebo); 95% CI, -15.9 to -4.3; P<0.001

MODIFY II: Rate of recurrent CDI 16% (Bezlotoxumab) vs 26% (placebo); 95% CI, -15.5 to -4.3; P<0.001

Actoxumab, a monoclonal antibody that targets toxin A, did not significantly prevent recurrence

Wilcox MH, et al. MODIFY I and MODIFY II. N Engl J Med 2017; 376:305–17



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Take Home Points Only test patients with unexplained diarrhea,

that is new onset, >3 unformed stools within 24 hours

1st line therapy is now only either Vancomycinor Fidaxomicin for 10 days

Metronidazole has been removed from 1st line therapy due to increased mortality, and is reserved for use with Vancomycin in fulminant C. difficile

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ACUTE PAIN MANAGEMENT IN OPIOID NAÏVE VS. OPIOID TOLERANT

Joyce Jung, PharmDPGY-1 Pharmacy Resident Moses Taylor Hospital



Objectives Differentiate a patient who is opioid naïve vs. opioid tolerant

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Disclosure StatementI have no financial disclosure or affiliation with regard to the material discussed in this presentation

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Background• In 2017, there were more than

70,200 drug overdose deaths in the United States• From 2016 to 2017, drug

overdose deaths in Pennsylvania significantly increased by 16.9%

• Over 67% drug overdose deaths in the United States were related to opioids• More than half of the deaths

related to fentanyl and fentanyl analogs

• From 2016-2017, opioid-related death among people aged 65 or older increased by 10.5%

Drug overdose deaths, rate per 100,000 persons, in the U.S and Pennsylvania

Pennsylvania opioid summary. NIH.https://www.drugabuse.gov/opioid-summaries-by-state/pennsylvania-opioid-summary. Updated May 2019. Accessed October 1, 2019.

Definition• Acute Pain: Lasts few days to weeks

• Pain triggered by an illness or injury causing some form of tissue damage or inflammation

• Chronic Pain: Lasts more than 3 months • Persistent, on-going pain due to existing condition or disease

• Opioid Naïve: Patients who never received or are not receiving opioid therapy on daily basis.

• Opioid Tolerant: Patients who received opioid therapy for ≥ 1 week with any of the following:• Morphine 60mg PO /day • Or an equianalgesic dose of another opioid

Pino CA, Covinton M. Prescription of opioids for acute pain in opioid naïve patients. Uptodate. https://www.uptodate.com/contents/prescription-of-opioids-for-acute-pain-in-opioid-naive-patients. Updated May 14, 2019. Accessed October 6, 2019.Nafziger AN, Barkin RL. Opioid therapy in acute and chronic pain. J. Clin. Pharmacol. 2018. 00(0)1-12.78



Definition (cont.)• Opioid Tolerance: Reduced analgesic effect for the same

amount of drug. Patient may require higher dose of the drug to relive pain.

• Opioid Dependence: Physiological adjustment to opioids. Patient may experience withdrawal symptoms by abrupt discontinuation, rapid dose reduction or change .

• Opioid Addiction: A chronic, neurobiological disease characterized by one or more of the followings• Impaired control over drug use• Compulsive drug use• Continued drug use despite harm• Craving

Definitions Related to the Use of Opioids for the Treatment of Pain: Consensus Statement of the American Academy of Pain Medicine, the American Pain Society, and the American Society of Addiction Medicine. ASAM. 2001;e1-e4. https://www.asam.org/docs/default-source/public-policy-statements/1opioid-definitions-consensus-2-011.pdf. Accessed October 15, 2019.

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Equianalgesic Opioid Dosing

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Inpatient Acute Pain management

1. Pain Assessment

2. Setting a Treatment Goal

3. Treatment Options

4. Step-Down Therapy

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1. Pain Assessment

Pain Assessment ToolsFace Pain ScaleUsed in patients with mild-moderate cognitive impairment OR patients with cultural and language barrier

Numeric Pain Rating Scale Used in patients who can interpret pain into number scale OR patients with cultural and language barrier

PQRST-UComplete pain assessment

Palliative/Precipitate, Quality, Radiating, Severity, Time, YoU

Patient History• Past medical history • Family history • Social history• Home medications

• Current medications• Physical examination

• Neurologic assessment • Musculoskeletal assessment

Berry PH, Chapman CR, Covington EC, et al, eds. Pain: Current Understanding of Assessment, Management, and Treatments. Reston, VA: National Pharmaceutical Council, Inc. Joint Commission on Accreditation of Heathcare Organizations; 2001.

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Risk Assessment- RIOSORD• Risk Index for Overdose or Serious

Opioid-Induced Respiratory Depression (RIOSORD)• Higher the score, higher the risk for

opioid-induced respiratory emergencies

• Any patients on long-term opioids, on high-dose opioids (≥ 50mg morphine equivalents (MME)/day), or those with recent dose increase

• Any patient otherwise at risk of experiencing or witnessing an opioid overdose • Co-administering benzodiazepines,

sedatives, antidepressants

• History of chronic pulmonary disease

Zedler B, Xie L, Wang L et al. Development of a Risk Index for Serious Prescription Opioid-Induced Respiratory Depression or Overdose in Veterans’ Health Administration Patients. Pain Medicine. Jun 2015. 16;1566-1579.

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2. The Goal of Acute Pain Management

Relieve uncontrolled

pain

Relieve uncontrolled

painOptimize

opioid therapyOptimize

opioid therapy

Improve function

Prevent withdrawal symptoms

Facilitate recovery from

underlying condition

Reduce pain and associated

symptoms

Wilson PR. Clinical practice guideline: acute pain management. Clin J Pain. 1992;8:187-188.



3. Multimodal Pain Management • A combination of two or more analgesics that have different

mechanisms to provide analgesia• WHO 3-Step Analgesia Ladder

WHO's pain relief ladder. http://www.who.int/cancer/palliative/painladder/en/. Accessed September 25, 2019.

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Non-opioid Analgesia• Nociceptive Pain

• Acetaminophen • NSAIDS• Corticosteroid • NMDA receptor antagonist (i.e. ketamine)

• Neuropathic Pain• Anticonvulsants (i.e. gabapentin, pregabalin)• Antidepressants (i.e. duloxetine, venlafaxine)

• Muscle Pain• Muscle relaxants (i.e. baclofen,

methocarbamol, tizanidine) • Localized Pain

• Topical agents (i.e. lidocaine, capsaicin, menthol)

• Topical NSAIDS (i.e. diclofenac)

Nafziger AN, Barkin RL. Opioid therapy in acute and chronic pain. J. Clin. Pharmacol. 2018. 00(0)1-12.



Treatment Approach to Opioid Naïve Patients

• Start with scheduled non-opioid therapy and PRN short-acting opioid for breakthrough pain

Scheduled Non-opioids ±adjuvant

• Long-acting increases risk of respiratory depression

• Long-acting may not provide adequate pain relief

Initially Short-Acting Opioid

• CDC recommends ≤50 MME/day of opioids• 3- to 5-day supply for acute pain

Lowest effective dose for shortest

durationNafziger AN, Barkin RL. Opioid therapy in acute and chronic pain. J. Clin. Pharmacol. 2018. 00(0)1-12.Herzig SJ, Mosher HJ, Calcaterra SL, et. Al. Improving the safety of opioid use for acute noncancer pain in hospitalized adults: a consensus statement from the Society of Hospital Medicine. J Hosp Med. 2018;13(4):263–271

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Treatment Approach to Opioid Tolerant

Opioid tolerant

Continue the previous opioid therapy

Add PRN opioid for breakthrough pain(10-20% total daily

dose)

PRN pain medication scales should not

overlap

Add scheduled non-opioid medication

Opioid rotation

May start an equianalgesic dose of an alternative opioid

Cross-tolerance(25-50% reduction)

Add scheduled non-opioid medication

Nafziger AN, Barkin RL. Opioid therapy in acute and chronic pain. J. Clin. Pharmacol. 2018. 00(0)1-12.Huxtable CA, Roberts LJ, Somogyi AA, et. al. Acute pain management in opioid-tolerant patients: a growing challenge. Anaesth Intensive Care. 2011;39:804-823.

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Breakthrough pain• 10-20% of total daily dose given every 1-4 hours as needed OR

• Can be given as frequently as every 1 hour PO or every 15 minutes IV• 25-30% of the single-standing dose• Ex) NF is taking oxycodone 10mg every 6 hours.

• Oxycodone 10mg x 4 doses/day = oxycodone 40mg/day• 10-20% of 40mg = 4-8 mg• Breakthrough pain: oxycodone 5mg every 4 hours as needed for pain

McPherson ML. Demystifying opioid conversion calculations: a guide for effective dosing. Bethesda, MD: American Society of Health System Pharmacists; 2009 Nafziger AN, Barkin RL. Opioid therapy in acute and chronic pain. J. Clin. Pharmacol. 2018. 00(0)1-12.

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Cross Tolerance• Occurs when a patient develops tolerance to a current opioid

which does not confer direct tolerance to a different opioid. • When converting between different opiates, dose should be

lower due to incomplete cross-tolerance. • New opioid dose should be based on individual differences in

opioid pharmacokinetics, but generally reduce total daily dose by 25-50% to avoid unintentional overdose.

McPherson ML. Demystifying opioid conversion calculations: a guide for effective dosing. Bethesda, MD: American Society of Health System Pharmacists; 2009 Nafziger AN, Barkin RL. Opioid therapy in acute and chronic pain. J. Clin. Pharmacol. 2018. 00(0)1-12.

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4. Step-down Therapy• Currently, no standard guideline for specific tapering

schedule is available• Rule of thumb is change the dose first and the interval

second • Short-term

• Patient taking opioids for less than 2 weeks may be able to discontinue at once without going through withdrawal

• Long-term• Rapid Taper: decrease opioid doses by 25-50% every few days. More rapid

taper if patient is taking opioids on shorter period of time• Slow Taper: decrease opioid doses by 10-20% every 1-3 weeks

• Personalize tapering schedule for patient’s condition

Nafziger AN, Barkin RL. Opioid therapy in acute and chronic pain. J. Clin. Pharmacol. 2018. 00(0)1-12.Dave VH. A patient’s guide to opioid tapering. 2018. https://www.hss.edu/conditions_patient-guide-opioid-tapering.asp. Accessed October 8, 2019.

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Key Points• It is important to assess pain and appropriateness of pain

medications based on opioid naive vs. opioid tolerant• Combination of opioid and non-opioid therapy is

recommended to target different sites to relieve pain• Long-acting opioids are not recommended in opioid-naïve

patients • For patients with opioid tolerance, additional breakthrough

pain medication or opioid rotation may be required• Tapering schedule should be tailored to each patient’s

condition

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2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease

Focus: Statins therapy versus low dose Aspirin

Ola Khalil, B.S.Pharm, RPhPGY-1 Pharmacy ResidentCarlsbad Medical Center

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OBJECTIVE

Develop a CVD* prevention plan using statin therapy based on ASCVD risk score

*CVD includes: acute coronary syndromes, myocardial infarction, stable or unstable angina, arterial revascularization, stroke/transient ischemic attack, peripheral arterial disease, as well as heart failure and atrial fibrillation



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Assessment of ASCVD risks❏ The guideline suggests the use of race- and sex-specific Pooled Cohort

Equation (PCE) to estimate 10-year ASCVD risk for asymptomatic adults aged 40-79 years

❏ ACC/AHA recommend the use of “ASCVD Risk Estimator Plus” application as a tool to calculate PCE

❏ Adults should be categorized into low (<5%), borderline (5 to <7.5%), intermediate (≥7.5 to <20%), or high (≥20%) 10-year risk

❏ "Risk enhancers" are clinical factors that can be used to revise the 10-year ASCVD risk estimate for initiating or intensifying statin therapy which include: family history of premature ASCVD, (LDL-C) ≥160 mg/dl, and chronic kidney disease

❏ Coronary Artery Calcium (CAC) scanning for individuals in the borderline or intermediate-risk categories

If CAS score is zero: Withhold statin therapy and reassess in 5 to 10 years 1 to 99: Initiate statin therapy for patients ≥55 years of age≥ 100: Initiate statin therapy

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Statin Therapy Recommendation

First-line treatment for primary prevention of ASCVD

❏ Patients ages 20-75 years and LDL-C ≥190 mg/dl:High-intensity statin without risk assessment

❏ T2DM and age 40-75 yearsModerate-intensity statin and risk estimate to consider high-intensity statins

❏ Diabetics with multiple ASCVD risk factors, High-intensity statin with aim of lowering LDL-C by 50% or more.



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Statin Therapy-Cont’d❏ Age 40-75 years and LDL-C ≥70 mg/dl and <190 mg/dl,

Non Diabetics:

❏ Risk 5% to <7.5% (borderline risk)Patients with risk enhancing factors, discuss moderate-intensity statin and consider coronary CAC scanning in select cases

❏ Risk ≥7.5-20% (intermediate risk)Use moderate-intensity statins and increase to high-intensity with risk enhancers.

❏ Risk ≥20% (high risk)Initiate high-intensity statin to reduce LDL-C by ≥50%

❏ Age >75 years clinical assessment and risk discussion

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Statins Therapy Algorithm



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Recommendations for Aspirin use

Recommendations

1- Low-dose Aspirin (75-100 mg orally daily) might be considered for the primary prevention of ASCVD in select adults 40-70 years of age who are at higher ASCVD risk but not at increased bleeding risk

2- Low-dose Aspirin (75-100 mg orally daily) should not be administered on a routine basis for the primary prevention of ASCVD among adult > 70 years of age

3- Low-dose Aspirin (75-100 mg orally daily) should not be administered for the primary prevention of ASCVD among adults of any age who are at increased risk of bleeding

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Pearls on Aspirin RestrictionAccording to Journal of the American College of Cardiology, Aspirin is widely recommended for secondary prevention of ASCVD. However, in primary prevention, aspirin use is more controversial

❏ Recently conducted primary-prevention trials have shown less overall benefit of prophylactic aspirin if coadministered with current ASCVD preventive treatments such as evidence-based hypertension and cholesterol therapies

❏ For adults <40 years of age, there is insufficient evidence to judge the risk/benefit ratio of routine aspirin use for the primary prevention of ASCVD

❏ Prophylactic aspirin in primary-prevention for adults >70 years of age is potentially harmful and difficult to justify for routine use given the higher risk of bleeding in this age group

❏ Trial and observational data to date support avoiding prophylactic aspirin in patients with increased bleeding risk*

*Bleeding risk includes: a history of previous gastrointestinal bleeding or peptic ulcer disease or bleeding at other sites, age >70 years, thrombocytopenia, coagulopathy, CKD, and concurrent use of other medications that increase bleeding risk, such as nonsteroidal anti-inflammatory drugs, steroids, direct oral anticoagulants, and warfarin



Lifestyle Changes and Team Based Care are the core for CVD Prevention 101

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Healthy Lifestyle❏ Consume a healthy diet (vegetables, fruits, whole grains,

protein)Minimizes the intake of trans fats, processed meats, refined carbohydrates, and sugar-sweetened beverages

❏ Engage in 75-150 minutes per week of physical activity



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Team-Based Care The goal of the clinician is to match the preventive efforts with patient’s absolute risk of a future ASCVD event and with the their willingness and capacity to implement preventive strategies

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References

❏ American College of Cardiologyhttps://www.acc.org/latest-in-cardiology/ten-points-to-remember/2019/03/07/16/00/2019-acc-aha-guideline-on-primary-preventiogl-prevention (cited september 10-2019)

❏ American Association of Family Physicianshttps://www.aafp.org/news/health-of-the-public/20190320acc-ahacholguidln.htmlhttp://www.(cited september 18-2019)

❏ Journal of the American College of Cardiologyhttp://www.natap.org/2019/HIV/j.jacc.2019.03.010.full.pdf(Cited October 10-2019)



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DIRECT ORAL ANTICOAGULANTS

(DOACs) ReviewJoel Martial Tchafack Kaze

Pharm. D., MSc.

Objectives

• Identify factors that increase the risk of bleeding• Review the differences between Direct Oral Anticoagulants

(DOACs)

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IntroductionsDefinitions• Thrombosis: Blood clot formation • Antithrombotic therapy: Prevention of clot formation or further clot

development• Acute coronary syndrome• Cardioembolic stroke• Venous thromboembolism (VTE)

• Deep vein thrombosis (DVT)• Pulmonary embolism (PE

Anticoagulants• Institute of Safe Medication Practices (ISMP) classification as high alert

medications• Joint Commission requirements specific to anticoagulant therapy

• July 1, 2019, Added 8 Eight new Anticoagulant Therapy elements of performance (EPs)

Antithrombotic Therapies

Fibrinolytics Anticoagulants Antiplatelets

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Factors that increase bleeding risk• Injuries:

• Bodily injuries, dental procedures, liver injuries or failure, trauma, intercranial hemorrhage

• Genetic factors:• Deficiency of clothing factors: vitamin K, Factors II, V, VII,

X, XII, protein S and C, hemophilia, and Von Willebrand’s disease.

• High risk population: • Elderly patient• Pregnant women• Chronic Kidney disease (CKD)• Tobacco and alcohol use• Nonadherence to therapy



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Comparing DOACs to warfarin

• Approximately 32% of elderly patients seen in the emergency department are due to adverse drug reaction caused by warfarin and 50% of these patients are hospitalized. [1]

• About 6 million patients in the United States are treated with anticoagulants. [2]

1. Shehab, N., et al.,, US Emergency Department Visits for Outpatient Adverse Drug Events. JAMA, 2016;316:2115-2125, 2013-2014.2. Barnes, G.D., et al., National Trends in Ambulatory Oral Anticoagulant Use. The American Journal of Medicine, 2015. 128(12): p. 1300-1305.e2.

Characteristic Warfarin DOACOnset of action Slow RapidHalf-life Long ShortDosing Variable FixedFood effect Yes NoDrug interactions Many Few

Monitoring Recommended Yes No

Antidote Yes Yes

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Direct Oral Anticoagulants

Factor Xa Inhibitors• Apixaban (Eliquis®)• Betrixaban (Bevyxxa®)• Edoxaban (Savaysa®)• Rivaroxaban (Xarelto®)

Common pathway of

the coagulation

cascade

https://www.top10homeremedies.com/wp-content/uploads/2017/03/coumadin-or-warfarin.jpg

Direct Thrombin (Factor IIa) Inhibitor

• Dabigatran (Pradaxa®)

Antithromin



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Apixaban/Eliquis

Dosage by Indication

1. DVT/PE:Treatment: 10mg PO BID x 7 days then 5mg PO BID x 6moProphylaxis: 2.5 mg BID

2. Nonvalvular Afib:5mg BID

3. Surgical thromboprophylaxis:Hip: 2.5mg bid x 35 days, Knee: 2.5mg bid x 12 days

Antidote: Andexxa/Andexanet alfa, and Kcentra

Dosage Adjustment

Renal dosing for Afib:• 2.5 mg BID if patient meets at least 2 criteria:

Age ≥ 80 years, weight ≤ 60 kg, SrCr ≥ 1.5 mg/dl• Avoid in moderate to severe hepatic dysfunction.

Pharmacokinetics • Oral bioavailability = 50% • Onset of action = 3 – 4 hours

• Half-life = 12 hours• Renal elimination = 27%

Interaction

Substrate of CYP3A4 and P-gp• Strong dual CYP3A4 and P-glycoprotein inhibitors, and the dose > 2.5mg QDAY, decrease by 50%,

and avoid the use if the dose ≤ 2.5mg.• Avoid use with a strong inducer

Clinical Pearls

• Take missed dose immediately after remembering, do not double dose.• Transitioning from warfarin to apixaban, stop warfarin and start apixaban when the INR < 2• Transitioning from apixaban to warfarin, administer a parenteral anticoagulant and warfarin the

next time the apixaban dose is due and stop the parenteral anticoagulant when the INR is therapeutic.

• Transitioning from apixaban to another anticoagulant other than warfarin, discontinue the apixaban and start the new drug during the next schedule of apixaban.

• Stop 48 hours before surgery and continue after surgery when the patient is stable

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Rivaroxaban/Xarelto


DVT/PE• Treatment: 15mg PO BID x 21 days then 20mg PO QDAY, with supper. • Reduce recurrence of DVT/PE in high risk patients: 10 mg QDAY after at least 6 months of

standard therapy• VTE Prophylaxis in Medical Acutely Ill Patients at Risk for Thromboembolic Complications but

not at High Risk of Bleeding: 10 mg QDAY, in hospital and after hospital discharge for a total recommended duration of 31 to 39 days

• Reduction of Risk of Major Cardiovascular Events: 2.5 mg PO BID, plus aspirin (75-100 mg) QDAY.

Non valvular Afib : 20 mg QDAY with supper.Surgical thromboprophylaxis• Hip: 10 mg QDAY x 35 days, Knee: 10 mg QDAY x 12 days.Antidote: Kcentra and Andexxa/Andexanet alfa

Dosage AdjustmentRenal dosing for Afib:• CrCI 30-50 ml/min: 15 mg PO daily with evening mealAvoid use in ESRD and if CrCI < 30 ml/min

Pharmacokinetics • Oral bioavailability = 80% • Onset of action = 3 hours.

• Half-life = 7-11 hours.• Renal elimination = 27%

Interaction • Substrate of CYP3A4 and P-gp , avoid Dual inducers (3A4 + P-gp)

Clinical Pearls

• Avoid in moderate to severe hepatic dysfunction. • Transitioning from warfarin to Xarelto. Stop warfarin and start rivaroxaban when the INR < 3• Transitioning from rivaroxaban to warfarin, administer a parenteral anticoagulant and warfarin

the next time the rivaroxaban dose is due and stop the parenteral anticoagulant when the INR is therapeutic.

• Transitioning from rivaroxaban to another anticoagulant other than warfarin, discontinue the apixaban and start the new drug during the next schedule of Xarelto

• Stop 24 hours before surgery and give first dose 6 - 10 hours after surgery



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Betrixaban/BevyxxaDosage by Indication VTE prophylaxis in acute illness (in patients with moderate to severe restricted mobility):

160 mg x 1, then 80 mg PO QDAY with food; for 35 - 42 days

Dosage Adjustment

Renal dosing • CrCl: 15-30ml/min: 80mg x 1 dose, then 40mg PO QDAY x 35 - 42 days with food.In patients with CrCl > 30ml/min, no dose adjustment neededreduce the dose when used with P-gp inhibitors

Pharmacokinetics

Oral bioavailability = 34% Onset of action = 3 - 4 hoursHalf-life = 19 - 27 hoursRenal elimination = 11%

Interaction P-gp inhibitor: CrCl > 30 decrease dose by 50% Avoid use: If CrCl < 30ml/min or with a P-gp inducer

Clinical Pearls Avoid use in patient with moderate to severe hepatic impairment. Betrixaban is not approved for treating DVT/PE or nonvalvular AFib.

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Edoxaban/Savaysa


DVT/PE: 30mg PO QDAY if Pt weights ≤ 60 kg, CrCl 15 to 50 mL/minuteNonvalvular Afib: 60 mg PO QDAYCrCl 15 to 50 mL/minute: Oral: 30 mg once daily

Dosage Adjustment Avoid use if: Elderly patient > 65 years CrCl >95 mL/min or CrCl <15 mL/min

Pharmacokinetics• Oral bioavailability = 63.1 – 72.3 % • Onset of action = 1 - 2 hours• Half-life = 10 - 14 hours• Renal elimination = 35%

Interaction P-gp inhibitor: no dose adjustment is recommended.

Clinical Pearls

• Reduced efficacy in nonvalvular atrial fibrillation patients with CrCl > 95 mL/min• Fewer drug interaction• Notes Side effects: Rash and increase LFT.• Transitioning from warfarin to edoxaban, stop warfarin and start edoxaban when the INR ≤2.5• Transitioning from edoxaban to warfarin, decrease the initial dose of edoxaban by 50% and start

warfarin. Monitor the INR weekly and once the INR > 2, discontinue the edoxaban .• Transitioning from edoxaban to another anticoagulant other than warfarin, discontinue the

edoxaban and start the new drug during the next schedule of edoxaban • Stop 24 hours before surgery and restart edoxaban when the patient is stable.



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Dabigatran/Pradaxa, Pradax


DVT/PE: 150mg PO BID +/- food start after 5-10 days of parenteral administration. Take with FULL glass of H2O.Nonvalvular Afib: • 150 mg PO bid• CrCl 15 to 30 mL/minute: 75 mg PO BIDAfter completion of surgery = 110 mg given 1 to 4 hoursPost operative prophylaxis: 220mg PO QDAYAntidote: Idarucizumab/Praxbind/Praxbind

Dosage Adjustment CrCl >30 mL/minute: No dosage adjustment necessaryNot recommended if CrCl < 15 mL/minute

PharmacokineticsOral bioavailability = 3 -7 % Onset of action = 1-6 hoursHalf-life = 12-17 hoursRenal elimination = 80%

Interaction P-gp inhibitors should be avoided

Clinical Pearls

Potentially inappropriate in elderly patient Do NOT chew, crushPatients with underlying esophageal conditions may be more prone to dyspepsia.Must be kept in original container. Dabigatran is contraindicated in patients with a mechanical prosthetic heart valve. Transitioning from dabigatran to other parenteral: After the Last dose of dabigatran, wait 12 hours (CrCl ≥30 mL/minute) or 24 hours (CrCl <30 mL/minute) before starting a parenteral anticoagulant.Transitioning from dabigatran to warfarin: The overlap of both drugs is based on the CrClTransitioning from warfarin to dabigatran: stop warfarin and initiate dabigatran when the INR < 2

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Clinical Summary• Patients having VTE should be treated for at least 3 months.• DOACs preferred over warfarin for treatment of VTE in patients without cancer• DOACs should not be used in patients with a mechanical or prosthetic heart valves• Watch for specific drug allergy, drug reaction and other drugs that increase bleeding: e.g. NSAID, SNRI, SSNR.• Routine reversal of DOACs is not recommended• Premature discontinuation of DOACs may increase the risk of thrombotic events• Medication guide is required for all DOAC• Hemodialysis is NOT expected to remove apixaban (Eliquis®), rivaroxaban (Xarelto®), or edoxaban

(Savaysa®), since they are highly protein bound), but will remove 60% of dabigatran (Pradaxa®)• Watch for possible signs of abnormal bleeding;

• Gum bleeding, coughing up blood, coffee ground vomit• Head pain that does not go away• Red or dark brown urine - Urinary track bleeding• Dark and tarry black stool– Intestinal bleeding

• Black Box Warning• All DOACs have an increased risk of causing thrombotic event (Spinal/Epidural hematomas) in patients

undergoing a spinal procedure • Apixaban, edoxaban, rivaroxaban, and dabigatran carry an additional black box warning for the

increased risk of thrombotic events if the DOAC is discontinued prematurely



Conclusion• The traditional oral anticoagulant e.g. warfarin poses more managing problems to both the

patient and the prescriber as it requires more extensive monitoring for:• Genetic factors (S-warfarin - CYP 2C9, and R-warfarin - CYP 1A2 and 3A4) • Time to reach therapeutic dose, usually 5 days, decrease compliance• At least monthly visit to determine the INR, • Dietary control, having a consistent vegetable diet, vitamin K control

• DOACs are as effective as warfarin in preventing blood clots and require less monitoring• The onset of DOACs are quicker than warfarin. • They have fewer drug-drug interaction and food drug interaction. • The DOACs and their antidote are more costly • DOACs are not directly interchangeable

• Patient on anticoagulants should have an alert card with them in case of an emergency

https://www.top10homeremedies.com/wp-content/uploads/2017/03/coumadin-or-warfarin.jpg117

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References• Eliquis FDA packet insert• Xarelto FDA packet insert• CHS Anticoagulation Reversal Protocol• https://www.micromedexsolutions.com/micromedex2/librarian/PFDefaultActionId/e

videncexpert.DoIntegratedSearch?navitem=topHome&isToolPage=true#• https://ezproxy.pharm.uacp.org:2381/lco/action/doc/retrieve/docid/patch_f/120058

2?searchUrl=%2Flco%2Faction%2Fsearch%3Fq%3DDabigatran%2520Etexilate%26t%3Dname%26va%3Ddabigatra

• https://pdfs.semanticscholar.org/f297/5fee1371200de42ce61ef044df3d70cb996b.pdf

• Pharmacological and Non-Pharmacological Management Methods of DVT and Pulmonary Embolism Nabeel Kouka, MD, MBA; Len Nass, PhD; William Feist, PhD.

• Spahn, DR.; Bouillon, B.; Cerny, V.; Coats, TJ.; Duranteau, J.; Fernández-Mondéjar, E.; Filipescu, D.; Hunt, BJ.; et al. (Apr 2013). "Management of bleeding and coagulopathy following major trauma: an updated European guideline". Crit Care. 17 (2): R76. doi:10.1186/cc12685. PMC 4056078. PMID 23601765



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Sugammadex Usage:Clinical PearlsStephanie Longshaw PharmD, MSc

PGY-1 Pharmacy ResidentCarlsbad Medical Center

Learning Objectives• Evaluate comparative studies of sugammadex vs.

neostigmine.• Explore economic considerations of sugammadex and

short and long-term costs.

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Mechanism of Action • Sugammadex (Bridion®): gamma-cyclodextrin reversal agent

of neuromuscular blockade. • Forms a complex with vecuronium or rocuronium, thereby

decreasing binding to nicotinic cholinergic receptors.

Image: Merckconnect.com121

Neuromuscular Block • Residual effects of neuromuscular blockers rocuronium and

vecuronium associated with increased hospital stay and respiratory complications: hypoxemia, pneumonia, atelactasis

• Measured by TOF (train of four): responses to four electric stimulation of the ulnar nerve by a stimulator device

• Twitch number determines degree of NMB (neuromuscular block)

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Dosing for NMB Reversal • Rocuronium and Vecuronium Reversal

• 2 mg/kg ABW: If spontaneous recovery reaches T2 (re-appearance of second twitch)

• 4 mg/kg ABW: If spontaneous recovery reaches 1 to 2 post-tetanic counts and no twitch to TOF (Train of Four) stimulation

• Single Dosing rocuronium Reversal (within 3 minutes) • 16 mg/kg ABW if 1.2 mg/kg rocuronium given

• Administration: Single bolus over 10 seconds. Monitor ventilation and airway

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Pharmacokinetics• Linear first-order kinetics• Onset: 3 min • Vd: 11-14 L• Half-life: 2h plasma, 8d teeth, 172d bone • Half-life renal impairment: mild 4h, moderate 6h, severe 9h• Metabolism: none• Excretion: renally unchanged

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Adverse Effects• Moderate: Vomiting, pain, nausea, hypotension, headache,

dizziness, QT prolongation • Severe: dyspnea, wheezing, pulmonary embolism,

respiratory arrest, bradycardia requiring atropine

Image: Merckconnect.com125

Administration:• 0.9% Saline • 5% Dextrose • 0.45% Saline and 2.5% Dextrose • 5% Dextrose in 0.9% Saline• Lactated Ringer’s Solution • Isolyte P with Dextrose• Flush lines with saline between administration of other

medications • Incompatible with verapamil, ondansetron, ranitidine, and

interacts with estrogen, progesterone, and toremifene• Light sensitive (5 day limit if exposed), stored at room

temperature, clear to amber solution

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Resources: • CHS Inc. has provided resources at intranet

http:/mycommunity.chs.net• Monograph• Formulary review• Sugammadex Procedure• FAQ (frequently asked questions)• MUE (Medication Use evaluation)

• Education for criteria and costs, pharmacy central management, stocking in ADC (automated dispensing cabinets) and assisting with MUE (medication use evaluation)

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Approved Sugammadex UseStewardship initiatives at CHS to reserve sugammadex

• Emergency use where neostigmine is not feasible • Inability to extubate due to excess neuromuscular blockade• High risk populations:

• Frail elderly, morbidly obese • Severe neuromuscular, neurologic, respiratory impairment • Severe liver, cardiac or kidney impairment

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Medication Use Evaluation.

Sugammadex (Bridion®) MUE Form• Please use this form for gathering information for medication use evaluation • Demographics:

• Patient ID: _________________ Age: ____ years Gender: M or F • Location: ICU OR/PACU Other • For ICU reversal of neuromuscular blockade:• Admit date: __/__/___ DC/Death/Tsfr date: __/__/____ Ordering Physician: ______________

• Administration time: _________• For immediately post-surgical reversal of neuromuscular blockade:

• Procedure date: __/__/___ Surgery: ________________ Ordering Physician: ______________• Administration time: _________

• Reason for use:• Emergency use only in settings where reversal with neostigmine is not possible• Inability to extubate due to excessive neuromuscular blockade• Lost airway situation requiring reintubation• Avoidance of ICU admission• High risk population including frail elderly, morbidly obese, or those with severe neurologic, neuromuscular,

respiratory, cardiac, kidney, or liver impairment• Other (unapproved)

• Weight used for dosing: _____ kg• Dose of sugammadex given:• 2 mg/kg x _____ dose(s)• 4 mg/kg x _____ dose(s)• 16 mg/kg• Other medications given for reversal of neuromuscular blockade:________

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Cost ExamplePatient: 120 kg male in OR indicated for reversal of NMB with

sugammadex or glycopyrrolate/neostigmine

• Pharmacy stocks:• Sugammadex (Bridion)

• 500 mg / 5 mL Box of 10 = $1700

• Reversal: 16mg/kg = 1920mg• Vials used = 4

• Total Cost= $680

• Pharmacy stocks: • Neostigmine

• 1mg/mL 10 mL vial = $71• Reversal: 0.06 to 0.08

mcg/kg = 9.6 mg • Vials used = 1

• Glycopyrrolate• 1mg / 5 mL vial = $14 • Reversal: 0.2 mg / 1 mg of

neostigmine = 1.92 mg • Vials used = 2

• Total cost = $99



Unrestricted Sugammadex • Two recent studies illustrate the pitfalls of unrestricted

sugammadex access.• Shah et al., 2017 International survey of 5500 anesthesiologists.

• < 10% of respondents with unrestricted access were concerned with adverse events.

• Ledowski and Ong 2015 2 year single-center study. • Medication errors: 200 mg one-size fits-all dosage.• Overdosing errors: desire to use entire sugammadex vial. • Less neuromuscular monitoring and TOF count.

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Neostigmine vs. No Reversal • Studies of neostigmine versus no reversal agent illustrate the

benefits of neostigmine. • In a VA study in 2017, Bronsert and Henderson show

significant decrease in re-intubation, pneumonia and extended ventilation.

• Vanderbilt Study by Bulka and Terekhov in 2016 indicate significant decrease in post-operative pneumonia.

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Sugammadex vs. Neostigmine• The results of recent meta analyses report benefits of

sugammadex over neostigmine• Hristovka and Allingstrup, 2017

• Faster time to recovery and fewer adverse events• Carron and Zarontello, 2016

• Significantly faster NMB reversal • Significantly lower adverse cardiac and respiratory effects

• Cammu, 2018 • No difference in critical respiratory events

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Faster Recovery time?• De Souza and Tardelli 2015 state that sugammadex gains in recovery

time are decreased by severe renal impairment. • Cocchio in 2016 Pharmacy Times article states an average of 9

minutes elapses from clinical decision to actual administration. • Paton and Paulsen 2010 stated that faster recovery time of

sugammadex drive gains in value per minute of staff productivity time.

• A retrospective analysis by Oh and Oh in 2019 indicated significantly shorter hospital stay and decreased costs with sugammadex, yet no reduction in 30-day readmissions.

• A review by Cammu 2018 discussed benefits in long-term cost savings are more likely in large hospitals than in rural clinics.

• Caveat: can minutes gained in productivity time be easily incorporated into routine practice? Faster recovery time, faster discharges, or likelihood to re-admit?

• Suggests usage of sugammadex or neostigmine on a patient-by patient basis.

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Participate in the MUE • Medication Use Evaluation: Sugammadex vs Neostigmine • Benefit: Patients of CHS Inc. and our communities • Submit de-identified 2019 data to:

• [email protected]

• [email protected]

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Post-Discussion Points• Educate clinicians regarding sugammadex usage with

resources provided. • Empower pharmacy technicians to centrally manage

sugammadex ordering and stocking. • Collaborate with P&T committee and OR departments to

reserve sugammadex for approved usage.• Participate in sugammadex MUE to enable patient safety,

fiscal responsibility and responsible usage of sugammadex.

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References• Sugammadex Resources. CHS Inc. Available from: https://www.mycommunity.chs.net [cited October 15th 2019]

• How to Monitor a Train of Four https://www.anesthesiologyhub.com/nimbex/ICU/train-of-four.html [cited October 15th 2019]

• Oh, A, Oh, Retrospective analysis of 30-day unplanned readmission after major abdominal surgery with reversal by sugammadex or neostigmine British Journal of Anesthesia. 2019. Available from: https://doi.org/10.1016/j.bja.2018.11.028 [cited October 15th 2019]

• Carron, M. Zarantello F. Efficacy of Sugammadex compared to neuromuscular blockade: a meta-analysis of RCTs. Journal of Clinical Anesthesia, 2016-12-01, Volume 35, Pages 1-12. Available with subscription from http://www.clinicalkey.com [cited October 15th 2019]

• Cocchio, C. Key Considerations for Sugammadex Administration: Pharmacy Times March 2016 Available from: https://www.pharmacytimes.com/contributor/craig-cocchio-pharmd/2016/03/3-key-considerations-for-sugammadex-administration [cited October 15th 2019]

• Sugammadex 2019. Available from www.micromedex.com [cited October 15th 2019] •

Sugammadex: Package Insert FDA. Available from https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/022225lbl.pdf [cited October 15th 2019]

• Sugammadex: Prescriber Information: Available from: https://www.merckconnect.com [cited October 15th 2019]

• Paton, F. Paulden, M. Sugammadex compared with neostigmine/glycopyrrolate for routine reversal of neuromuscular block: a systematic review and evaluation. British Journal of Anaesthesia Volume 105 Issue 5 2010. Available from: https://www.sciencedirect.com/science/article/pii/S0007091217334323?via%3Dihub] [cited October 15th 2019]

• Cammu 2018 Suggamadex: Appropriate Use in Context of Budgetary Constraints. Current Anesthesiology Reports. 2018 8:178-185 Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5988778/ [cited October 15th 2019]

• De Souza, C., and Tardelli, M. Efficacy and Safety of sugammadex in the reversal of deep neuromuscular block induced by rocuronium in patients with end stage renal disease: a comparative prospective clinical trial. Eur J Anaesthesiol. 2015 Oct;32(10):681-6. Available from: https://www.ncbi.nlm.nih.gov/pubmed/26225497 [cited October 15th 2019]

• Bulka, C., Terekhov M. October 2016 Nondepolarizing neuromuscular blocking agent, reversal and risk of postoperative pneumonia. Anesthesiology. 125(4):647–655 October 2016 available from OVID. [cited October 15th 2019]

• Ledowski, T. Ong, J. Neuromuscular monitoring, muscle relaxant use, rversal at a tertoary teaching hospital 2.5 years after introduction of sugammadex: changes in opinions and clinical practice. Hindawi Publishing Corporation Anesthesiology Research and Practice Volume 2015, Article ID 367937. Available from: https://www.hindawi.com/journals/arp/2015/367937/ [cited October 15th 2019]

• Bronsert, M. Henderson , w. Intermediate-acting Nondepolarizing neuromuscular blocking Agents and Risk of Post-operative 30-day morbidity and mortality and long-termsurvival .W. Anesthesia and Analgesia 124(5):1476–1483, MAY 2017 Available from: https://insights.ovid.com/anesthesia-analgesia/asag/2017/05/000/intermediate-acting-nondepolarizing-neuromuscular/22/00000539 [cited October 15th 2019]

Hristovska, A.-M. Allingstrup M. Anaesthesia 2018. Comparative efficacy and safety of sugammadex and neostigmine in reversing neuromuscular block in adults. A Cochrane systematic Available from: https://onlinelibrary.wiley.com/doi/pdf/10.1111/anae.14160 [cited October 15th 2019]

•Shah V., Wolf F., Using a worldwide in-app survey to explore sugammadex usage patterns: a prospective observational study. British Journal of Anesthesia. 2017. available from: https://bjanaesthesia.org/article/S0007-0912(17)33303-2/pdf [cited October 15th 2019]

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Disclosure: The information contained in the presentation is for Community Health System employees and hospital affiliates and is not for external distribution and/or use. The presentation may contain information that is proprietary, confidential, or legally privileged or protected. It is intended only for the use of Community Health System employees and hospital affiliates. Do not deliver, distribute or copy the presentation and do not disclose its contents or take any action in reliance on the information it contains outside of Community Health Systems and hospital affiliates.



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Heather Weese, Pharm.D., MSHI, BCPS, BCPPSSenior Director, Pharmacy Services

Community Health Systems

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