October 2011 Digital Edition of Pharmacy Practice News by McMahon Group

The Pharmacist’s News Source

pharmacypracticenews.com

Volume 38 • Number 10 • October 2011

Printer-friendly versions available online

27.5% reduction documented

In Emergency Room, Pharmacists Slash Rate of Drug Errors

dd a study at the University of New Mexico, Albuquerque, to the growing body of evidence that demonstrates how on-site pharmacists improve safety in the emergency department (ED). When researchers compared medication error rates at the university’s level 1 trauma center with and without a pharmacist present, they found that 13 times more errors had been reported when there was no pharmacist reviewing drug therapy. Pharmacists are on-site at the 68-bed academic ED for 10 hours per day, where they attend all major trauma and resuscitations. Over the course of three months in 2009, 242 patients were admitted while pharmacists were present, and medication errors were recorded for six (2.5%) of them. By contrast, 452 patients presented when pharmacists were absent, and

•

see ED PHARMACY, page 30

Pharmacy-to-Bedside IV Management Team Scores at York Hospital

eading a small contingent through the halls of York Hospital, a 558-bed community teaching facility in central Pennsylvania, Hal Baker, MD, looked both convinced and relieved as he reported, “This is exactly how technology is supposed to work.” Dr. Baker, chief information officer of WellSpan Health, a network that includes York Hospital and more than 65 other patient-care sites, said he was struck by the ability of technology to bridge the gap that often exists between caregivers and automation.

•

see IV MANAGEMENT, page 22

in this issue Up Front

Up Front NSAIDs and heart disease a bad mix.

Clinical

Cardiology Weekly high-dose statin achieves lipid goals, may boost compliance.

Infectious Disease Preventing nosocomial infections saves lives, money.

Technology

Groups push for new guidelines on smart-pump drug libraries.

Antibiotic Stewardship Made Simple: Pointers for Small Sites Chicago—The prospect of launching an in-depth antimicrobial stewardship program (ASP) can be daunting—especially given the continuing financial pressures on health systems. Fortunately, smaller-scale strategies can help ensure proper antibiotic use, improve clinical outcomes and save health care dollars, according to research presented at the 51st annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC).

Community Hospital Targets Extended Regimens

Automation University of Chicago slashes labor costs, missed drug doses via tech rollout.

Limited resources not a barrier

24 26

Operations & Mgmt

Leadership in Action How to make the right choices—and repeat them.

When Kimberly Leuthner, PharmD, was hired directly from a fellowship in infectious disease to work on the overuse of antibiotics at Yuma Regional Medical Center in Yuma, Ariz., she knew that whatever she put into place could not require a lot of money or resources. “We’re a nonprofit community hospital and we get all the nonpayers, so we have to be frugal,” Dr. Leuthner said.

•

see STEWARDSHIP, page 11

NEW COLUMN

Wicked Change Sharon Murphy Enright on how to embrace practice change and advance the profession of pharmacy.

Educational Review

Clostridium difficile: Epidemiology, Transmission, and Treatment See page 14

Is That Lung Cancer Medication The Right One for Your Patient?

ung cancer patients are typically given drug regimens based largely on the outcomes of large, randomized clinical trials. But those trials may not be valid for a significant percentage of your hospital’s patient base—women, minorities and the elderly. In a study released at the recent 14th World Conference on Lung Cancer, researchers from the FDA reported that enrollment in major clinical trials of agents approved to treat non-small

cell lung cancer (NSCLC) significantly underrepresents these three groups. Between January 2000 and December 2010, the investigators reviewed 10 national and international trials for agents approved to treat NSCLC. They found the following: • Individuals over the age of 65 years made up just 36% of the drug trial population, but represent 73% of U.S. lung cancer patients.

•

see LUNG CANCER, page 8

New Product SPOTLIGHT ON

TECHNOLOGY Section begins on page

Sandoz launches albuterol sulfate inhalation solution, 0.083% and ipratropium bromide inhalation solution, 0.02%. See page 13.

Sandoz offers Enoxaparin Sodium Injection.

WARNING: SPINAL/EPIDURAL HEMATOMA

Epidural or spinal hematomas may occur in patients who are anticoagulated with low molecular weight heparins (LMWH) or heparinoids and are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: • Use of indwelling epidural catheters • Concomitant use of other drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants • A history of traumatic or repeated epidural or spinal punctures • A history of spinal deformity or spinal surgery Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary. Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis.

Please see brief summary of full prescribing information including boxed warning on following page. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088. www.us.sandoz.com a Novartis company

Available in 7 strengths in pre-filled syringes. ▲ 30 mg/0.3 mL pre-filled syringe; 40 mg/0.4 mL pre-filled syringe;

60 mg/0.6 mL pre-filled syringe; 80 mg/0.8 mL pre-filled syringe; 100 mg/1.0 mL pre-filled syringe; 120 mg/0.8 mL pre-filled syringe; 150 mg/1.0 mL pre-filled syringe

▲ Sandoz is a member of the Novartis family of companies — a name you can trust for quality and reliability

Choose the full potential of generics.

Enoxaparin Sodium Injection WARNING: SPINAL/EPIDURAL HEMATOMA Epidural or spinal hematomas may occur in patients who are anticoagulated with low molecular weight heparins (LMWH) or heparinoids and are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: • Use of indwelling epidural catheters • Concomitant use of other drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants • A history of traumatic or repeated epidural or spinal punctures • A history of spinal deformity or spinal surgery Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary. Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis.

- - - - - - RECENT MAJOR CHANGES - - - - - Administration (04/2011) - - - - - - INDICATIONS AND USAGE - - - - - Enoxaparin sodium injection, USP is a low molecular weight heparin [LMWH] indicated for: • Prophylaxis of deep vein thrombosis (DVT) in abdominal surgery, hip replacement surgery, knee replacement surgery, or medical patients with severely restricted mobility during acute illness • Inpatient treatment of acute DVT with or without pulmonary embolism • Outpatient treatment of acute DVT without pulmonary embolism • Prophylaxis of ischemic complications of unstable angina and non-Q-wave myocardial infarction [MI] • Treatment of acute ST-segment elevation myocardial infarction [STEMI] managed medically or with subsequent percutaneous coronary intervention [PCI] - - - - - - DOSAGE AND ADMINISTRATION - - - - - Indication

Dose

DVT prophylaxis in abdominal surgery

40 mg SC once daily

DVT prophylaxis in knee replacement surgery

30 mg SC every 12 hours

DVT prophylaxis in hip replacement surgery

30 mg SC every 12 hours or 40 mg SC once daily

DVT prophylaxis in medical patients

40 mg SC once daily

Inpatient treatment of acute DVT with or without pulmonary embolism

1 mg/kg SC every 12 hours or 1.5 mg/kg SC once daily*

Outpatient treatment of acute DVT without pulmonary embolism

1 mg/kg SC every 12 hours *

Unstable angina and non-Q-wave MI

1 mg/kg SC every 12 hours (with aspirin)

Acute STEMI in patients <75 years of age [For dosing in subsequent PCI, see Dosage and Administration]

30 mg single IV bolus plus a 1 mg/kg SC dose followed by 1 mg/kg SC every 12 hours (with aspirin)

Acute STEMI in patients ≥75 years of age

0.75 mg/kg SC every 12 hours (no bolus) (with aspirin)

• See recommended durations for enoxaparin sodium injection therapy • *See recommendations regarding transitioning to warfarin therapy • Adjust the dose for patients with severe renal impairment - - - - - - DOSAGE FORMS AND STRENGTHS - - - - - 100 mg/mL concentration: Prefilled syringes: 30 mg/0.3 mL, 40 mg/0.4 mL Graduated prefilled syringes: 60 mg/0.6 mL, 80 mg/0.8 mL, 100 mg/mL 150 mg/mL concentration: Graduated prefilled syringes: 120 mg/0.8 mL, 150 mg/mL - - - - - - CONTRAINDICATIONS - - - - - Active major bleeding Thrombocytopenia with a positive in vitro test for anti-platelet antibody in the presence of enoxaparin sodium Hypersensitivity to enoxaparin sodium Hypersensitivity to heparin or pork products - - - - - - WARNINGS AND PRECAUTIONS - - - - - Increased risk of hemorrhage: Use with caution in patients at risk Percutaneous coronary revascularization: Obtain hemostasis at the puncture site before sheath removal Concomitant medical conditions: Use with caution in patients with bleeding diathesis, uncontrolled arterial hypertension or history of recent gastrointestinal ulceration, diabetic retinopathy, renal dysfunction, or hemorrhage History of heparin-induced thrombocytopenia: Use with caution Thrombocytopenia: Monitor thrombocytopenia closely Interchangeability with other heparins: Do not exchange with heparin or other LMWHs Pregnant women with mechanical prosthetic heart valves and their fetuses, may be at increased risk and may need more frequent monitoring and dosage adjustment

- - - - - - ADVERSE REACTIONS - - - - - -

Most common adverse reactions (>1%) were bleeding, anemia, thrombocytopenia, elevation of serum aminotransferase, diarrhea and nausea To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. - - - - - - DRUG INTERACTIONS - - - - - Discontinue agents which may enhance hemorrhage risk prior to initiation of enoxaparin sodium injection or conduct close clinical and laboratory monitoring - - - - - - USE IN SPECIFIC POPULATIONS - - - - - Severe renal impairment: Adjust dose for patients with creatinine clearance <30 mL/min Geriatric patients: Monitor for increased risk of bleeding Patients with mechanical heart valves: Not adequately studied Hepatic Impairment: Use with caution Low-weight patients: Observe for signs of bleeding

Manufactured by Baxter Pharmaceutical Solutions LLC for Sandoz Inc., Princeton, NJ 08540 Rev. May 2011

4 Up Front

Pharmacy Practice News • October 2011

Capsules

surf

‘No Safe Window’ for NSAID Use In Heart Disease Patients

OCTOBER 2011

watch

The five most-viewed articles last month on pharmacypracticenews.com: 1. Pharmacists and Anesthesiologists Partner To Improve OR Outcomes 2. Compatibility of Commonly Used Intravenous Drugs 3. Pharmacists Phone Home for MTM Service 4. Pop-up e-Reminders At Point of Care May Boost HCAHPS Scores 5. Use of Atypical Antipsychotics After ICU Delirium Too Typical Register for free at pharmacypracticenews.com to read these and other articles on the latest developments in hospital pharmacy.

heard here first

‘I am … aghast that [the ASHP did not challenge] a legal precedent that leaves pharmacy as the only profession for which

committing a medication error is now a felony offense.’ —John Poikonen, PharmD

See article, page 28

he short-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) could pose serious danger to individuals with preexisting heart disease, according to a new study (Circulation 2011;123:22262235). Most NSAIDs were associated with a significantly increased risk for recurrent myocardial infarctions and death, said researchers. Despite contraindications in patients with existing cardiovascular disease, many are still given short-term courses of NSAIDs. Based on their results, the researchers did not recommend the use of NSAIDs, either short- or long-term, among patients who had previous heart attacks. “Our results indicate that there is no apparent safe therapeutic window for NSAIDs in patients with prior heart attack,” said Anne-Marie Schjerning Olsen, MB, lead author of the study and research fellow at Copenhagen University in Denmark. The study included a group of patients (N=83,677) older than age 30 years who had suffered heart attacks during a 10-year period. Researchers reported a 45% increase in risk for death and recurrent heart attacks within as little as one week of NSAID therapy. The number increased to 55% after three months of treatment. Although almost all NSAIDs were linked to an increased safety risk, the traditional NSAID diclofenac was associated with an almost three-times-higher risk than any of the other NSAIDs studied. Researchers also noted that the use of over-thecounter NSAIDs was unlikely to have a major impact on the study results. Researchers suggested that in the event that NSAID therapy is necessary, doctors should limit use to the “absolute minimum” in patients with prior heart disease. —PPN Staff

To Scan 2-D Bar Codes in PPN: 1.

Download the FREE Microsoft Tag Reader application through your smartphone browser.

Open the Tag Reader and let it focus on the bar-code image to instantly access related materials and/or Web sites.

The Book Page

McMahonmedicalbooks.com Pharmacology Flash Cards, Edition 2 George M. Brenner, PhD See page

EDITORIAL BOARD

ART/PRODUCTION STAFF

Administration

Michele McMahon Velle, MAX Graphics/Creative Director

Robert Adamson, PharmD, Livingston, NJ

Frank Tagarello, Senior Art Director/Managing Director, MAX Graphics

Ernest R. Anderson Jr., MS, RPh, Boston, MA

Volume 38 • Number 10 • October 2011 • pharmacypracticenews.com

Anesthesiology/Pain Julie A. Golembiewski, PharmD, Chicago, IL Melvin E. Liter, MS, PharmD, FASHP, Lexington, KY

Internal Medicine

EDITORIAL STAFF

David S. Craig, PharmD, BCPS, Tampa, FL

Geoffrey C. Wall, PharmD, FCCP, BCPS, CGP, Des Moines, IA

Biotechnology

NUCLEAR PHARMACY

David Bronstein, Editorial Director davidb@mcmahonmed.com

Indu Lew, PharmD, Livingston, NJ

Jeffrey Norenberg, PharmD, Albuquerque, NM

Cardiology

Charles F. Caley, PharmD, Storrs, CT Lawrence Cohen, PharmD, BCPP, FASHP, FCCP, Spokane, WA

Marty Barbieri, Production Manager Brandy Wilson, Circulation Coordinator

McMAHON PUBLISHING Raymond E. McMahon, Publisher and CEO, Managing Partner

James Prudden, Group Editorial Director

Robert Ignoffo, PharmD, San Francisco, CA

Matthew McMahon, General Manager, Partner

Robin B. Weisberg, Manager, Editorial Services

Philip E. Johnson, MS, RPh, FASHP, Tampa, FL

Elizabeth Zhong, Associate Copy Chief

Lauren Smith, Michael McMahon, Michele McMahon Velle, Rosanne C. McMahon, Partners

Robert T. Dorr, PhD, RPh, Tucson, AZ

CNS/Psychiatry

Dan Radebaugh, Director of Production and Technical Operations

Kevin Horty, Don Pizzi, Adam Marcus, Cynthia Gordon, Kate O’Rourke, Contributing Editors

Oncology

C. Michael White, PharmD, Storrs, CT

Sarah Tilyou, Senior Editor smtilyou@mcmahonmed.com

James O’Neill, Senior Systems Manager

Larry Ereshefsky, PharmD, San Antonio, TX

Cindy O’Bryant, PharmD, Aurora, CO

Complementary and Alternative Medicine

Ali McBride, PharmD, MS, BCPS, St. Louis, MO

Cathy Rosenbaum, PharmD, Cincinnati, OH

Sara S. Kim, PharmD, BCOP, New York, NY

Critical Care

Pediatrics

Judi Jacobi, PharmD, FCCM, Indianapolis, IN

Gretchen Brummel, PharmD, BCPS, Hudson, OH

SALES David Kaplan, Group Publication Director dkaplan@mcmahonmed.com Matt Spoto, Account Manager mspoto@mcmahonmed.com

Van Velle, President, Partner

McMahon Publishing mcmahonmed.com Sales, Production and Editorial Offices: 545 West 45th Street, 8th Floor, New York, NY 10036. Telephone: (212) 957-5300.

David P. Nicolau, PharmD, Hartford, CT

Technology

Robert P. Rapp, PharmD, Lexington, KY

Thomas Van Hassel, RPh, Yuma, AZ

Nick Roberts, Sales Associate nroberts@mcmahonmed.com

Copyright © 2011 McMahon Publishing, New York, NY 10036. All rights reserved. Pharmacy Practice News (ISSN 0886-988x) is published monthly by McMahon Publishing. Periodicals postage paid at New York, NY, and at additional mailing offices. POSTMASTER: Send address changes to Pharmacy Practice News, Circulation Dept., 545 W. 45th St., 8th Floor, New York, NY 10036.

Want to subscribe? Change your address? Here’s How All U.S. hospital pharmacists should receive Pharmacy Practice News free of charge. If you are a hospital pharmacist and do not receive the publication, you must add your professional address or make your address change directly

with Pharmacy Practice News, Circulation Dept., 545 W. 45th St., 8th Floor, New York, NY 10036. You can also fax your request to (212) 977-3645, or send it via email, circulation@mcmahonmed.com. If you are not a hospital pharmacist but would like to receive Pharmacy Practice News, please send a check for $70.00 (U.S.) or $90.00 (outside U.S.) for a year’s

subscription payable to Pharmacy Practice News to McMahon Publishing, 545 West 45th St., 8th Floor, New York, NY 10036. Please allow 8 to 12 weeks for delivery of the first issue. Individual issues are $7.00 (U.S.) or $10.00 (outside U.S.). McMahon Publishing is a 38-year-old, first-generation, family-owned publishing company dedicated to providing

medical professionals with essential, up-to-date news. As the second largest publisher of medical newspapers, McMahon produces Anesthesiology News, Clinical Oncology News, Gastroenterology & Endoscopy News, General Surgery News, Infectious Disease Special Edition, Pain Medicine News, Pharmacy Practice News and Rheumatology Practice News.

Infectious Diseases Steven J. Martin, PharmD, BCPS, FCCM, Toledo, OH Peggy McKinnon, PharmD, Detroit, MI

Reimbursement Bonnie E. Kirschenbaum, MS, FASHP, Breckenridge, CO

A family-owned medical publishing and medical education company. McMahon publishes seven clinical newspapers and several annual or semiannual Special Editions.

David Nathanson, Account Manager dnathanson@mcmahonmed.com Nancy Parker, Executive Manager, Classified Advertising nparker@mcmahonmed.com

http://video.webcasts.com/events/apce001/39551 There are no prerequisites

Current and Emerging Therapies in Chronic Pain This fall, join national experts in chronic pain management for a series of live, complimentary, interactive webinars

Supported by educational grants from Covidien, Millennium Laboratories, and Pfizer Presented by the Johns Hopkins School of Medicine, in collaboration with Applied Clinical Education

Course Director Michael R. Clark, MD, MPH, MBA Associate Professor and Director Chronic Pain Treatment Programs Department of Psychiatry and Behavioral Sciences The Johns Hopkins Medical Institutions Baltimore, Maryland

Statement of Need Four key areas in which clinicians have significant knowledge gaps are: • The knowledge of pain mechanisms and of the mechanisms of action of therapies • Recently approved therapies for chronic pain • Recently published or revised chronic pain treatment guidelines • Novel pain therapies in late-stage development that may be available soon

Schedule

All Sessions 2:00

Sponsorship Statement Presented by the Johns Hopkins University School of Medicine

Statement of Responsibility The Johns Hopkins University School of Medicine takes responsibility for the content, quality, and scientific integrity of this CME activity.

Intended Audiences Primary care physicians, physician pain specialists, neurologists, and other health care professionals with an interest in improving their professional skills relative to the treatment and management of chronic pain. The audience also may include nurses, nurse practitioners, physician assistants, and pharmacists.

Accreditation Statement The Johns Hopkins University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Credit Designation Statement The Johns Hopkins University School of Medicine designates this live activity for a maximum of 7 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Policy on Faculty and Provider Disclosure It is the policy of the Johns Hopkins University School of Medicine that the faculty and provider disclose real or apparent conflicts of interest relating to the topics of this educational activity, and also disclose discussions of unlabeled/ unapproved uses of drugs or devices during their presentations. The Johns Hopkins University School of Medicine Office of Continuing Medical Education has established policies in place that will identify and resolve all conflicts of interest prior to this educational activity. Detailed disclosure will be made in the course handout materials.

- 3:00

EST

October 5, 2011 • Multimodal therapy Faculty Presenter Charles E. Argoff, MD

Professor of Neurology Albany Medical College Director, Comprehensive Pain Center Albany Medical Center Albany, New York

Article

Multimodal Analgesia for Chronic Pain: Rationale and Future Directions Argoff CE, Albrecht P, Irving G, Rice F. Pain Med. 2009;10(suppl 2):S53-S66.

October 12, 2011 • Psychosocial comorbidities Faculty Presenter Dennis Turk, PhD

John and Emma Bonica Professor of Anesthesiology and Pain Research University of Washington School of Medicine Seattle, Washington

Article

Assessment and Treatment of Psychosocial Comorbidities in Patients With Neuropathic Pain Turk DC, Audette J, Levy RM, et al. Mayo Clin Proc. 2010;85(3 suppl):S42-S50.

October 19, 2011 • Pain management in older patients Faculty Presenter Perry G. Fine, MD

Professor of Anesthesiology University of Utah School of Medicine Salt Lake City, Utah

Learning Objectives After completing this activity, the participant will demonstrate the ability to: • Elucidate the pathophysiology of chronic pain and how treatment approaches can target chronic pain appropriately by mechanism of action. • Review currently available therapies, particularly recently approved treatments, for common chronic pain conditions (eg, rheumatologic disorders such as osteoarthritis and other musculoskeletal conditions; neuropathic pain and fibromyalgia; chronic low back pain; and chronic pain associated with other medical conditions). • Apply recommendations from recent evidence-based guidelines to inform the treatment of chronic pain. • Describe emerging therapies for chronic pain that are in late-stage development.

Article

Pharmacological Management of Persistent Pain in Older Persons: American Geriatrics Society Panel on the Pharmacological Management of Persistent Pain in Older Persons Ferrell B, Argoff CE, Epplin J, et al. Pain Med. 2009;10(6):1062-1083.

October 26, 2011 • Interventional therapies Faculty Presenter Richard Rosenquist, MD

Clinical Professor Director, Center for Pain Medicine and Regional Anesthesia University of Iowa Carver College of Medicine Iowa City, Iowa

Article

Interventional Therapies, Surgery, and Interdisciplinary Rehabilitation for Low Back Pain: An Evidence-Based Clinical Practice Guideline From the American Pain Society Chou R, Loeser JD, Owens DK, et al. Spine (Phila Pa 1976). 2009;34(10):1066-1077.

November 2, 2011 • Topical analgesics Faculty Presenter Roy D. Altman, MD

Professor of Medicine David Geffen School of Medicine University of California, Los Angeles Los Angeles, California

Article

Topical therapies for osteoarthritis. Altman RD, Barthel HR. Drugs. 2011;71(10): 1259-1279.

November 9, 2011 • Neuropathic pain Faculty Presenter Vera Bril, MD

Professor of Medicine Department of Neurology University Health Network Toronto General Hospital Toronto, Ontario, Canada

Article

Evidence-Based Guideline: Treatment of Painful Diabetic Neuropathy Bril V, England J, Franklin GM, et al. Neurology. 2011;76(20):1758-1765.

November 16, 2011 • Opioid therapy Faculty Presenter David A. Fishbain, MD

Professor, Department of Psychiatry & Behavioral Sciences Adjunct Professor, Neurological Surgery and Anesthesiology Miller School of Medicine Miami, Florida

Article Clinical Guidelines for the Use of Chronic Opioid Therapy in Chronic Noncancer Pain. Chou R, Fanciullo GJ, Fine RG, et al. J Pain. 2009; 10(2):113-130.

6 Clinical

Pharmacy Practice News • October 2011

Cardiology

Weekly High-dose Statin Comparable to Daily Dosing New Orleans—High-dose rosuvastatin given once per week led to improvements in serum lipids that were comparable to those achieved with daily doses of atorvastatin 10 mg, in a small study presented at the annual meeting of the American College of Cardiology. “Based on these findings, we think a high-dose weekly statin regimen may be an alternative for patients with major barriers to standard daily therapy,” said

‘We saw this as a means of addressing issues of [statin] adherence and cost, which can be barriers to successful treatment.’ —James M. Backes, PharmD principal investigator James M. Backes, PharmD, of the University of Kansas Atherosclerosis and LDL-Apheresis Center and the University of Kansas

School of Pharmacy, in Kansas City. Dr. Backes noted that testing the extended dosing regimen made sense, based on the types of patients he has

been seeing in his clinical practice. “Our clinic is referred many complex cases, including patients who cannot tolerate statins,” he explained. “A few years ago, we started using these statins every other day and then once a week in statin-intolerant patients, and the logical next step was to see what we could achieve by cranking up a weekly dose in statin-naive patients without a history of intolerance. We saw this as a means

Visit

Late-breaking News Links to Other Therapeutic Areas

Online Buyer’s Guides

Medical Education Archives

Most Popular Articles & Reader Comments Tabbed Navigation Podcast Library

Digital Editions

Free CME

Most-read Articles From Sister Publications

Opti

mize d for wide scr disp een lays

Change from Baseline (%)

Pharmacy Practice News • October 2011

Clinical 7

Cardiology

20 14

Rosuvastatin (extended dosing) Atorvastatin (daily dosing)

10 0

0 -6

-10 -20 -23

-19

-20

-30

-29

Total cholesterol

-29

LDL-C

HDL-C

hsCRP*

Figure. Impact of daily vs. extended statin dosing on lipid levels. HDL-C, high-density lipoprotein cholesterol; hsCRP, high-sensitivity C-reactive protein; LDL-C, low-density lipoprotein cholesterol. * Higher hsCRP in atorvastatin patients did not differ significantly from rosuvastatin; may have been due to noncardiovascular inflammation.

of addressing issues of adherence and cost, which can be barriers to successful treatment.” “Also, as pharmacists I think we are more conservative with medications, and I am concerned about what happens 30 years down the road,” Dr. Backes added. “Atorvastatin, for example, has been on the market since 1998, and we are now seeing blips of diabetes. Maybe less drug exposure might be better.”

Study Details In the eight-week, double-blind pilot

in Your Inbox ... to receive the monthly e-newsletter from

at www.pharmacypracticenews.com

Get the latest news delivered directly to your computer and PDA. The new interactive format has embedded Web site links that give you instant access to additional information as well as unique searching features and printing capabilities. Each installment contains brief summaries of the most important articles from the current month’s issue, and breaking news ahead of print.

study, 10 patients received rosuvastatin (Crestor, AstraZeneca) 80 mg per week and 10 received atorvastatin 10 mg per day. Baseline mean low-density lipoprotein cholesterol (LDL-C) levels were 148 mg/dL and 151 md/dL, respectively (P=0.847). Lipid profiles and high-sensitivity C-reactive protein (hsCRP) were assessed at baseline and one to four and five to eight days after the last dose. Both treatments produced significant reductions in total cholesterol (TC) and LDL-C from baseline at each assessment point, Dr. Backes reported. Final mean LDL-C levels were 105 mg/dL in the high-dose weekly rosuvastatin group and 109 mg/dL in the daily atorvastatin group (P=0.835). Percentage changes after treatment with rosuvastatin and atorvastatin, respectively, were –23% and –20% in TC; –29% and –29% for LDL-C; –6% and no change in high-density lipoprotein cholesterol (HDL-C); –20% and –20% in TC/HDL-C ratio; –3% and –5% in triglycerides; and –19% and +14% in hsCRP levels. The higher hsCRP levels seen with atorvastatin did not differ significantly from rosuvastatin, and may have been due to two patient outliers with “noncardiovascular inflammation,” Dr. Backes suggested. At a mean time of 2.3 days after the last statin dose, LDL-C levels were reduced by 34% with rosuvastatin and 35% with atorvastatin. At a mean time of six days after the last dose, the changes were 25% and 22%, respectively. These were highly significant changes from baseline (P<0.001) but the betweengroup differences were not statistically significant, he noted. Each regimen was well tolerated. One patient on rosuvastatin and three on atorvastatin developed moderate myalgias that resolved with treatment discontinuation. There were no changes in liver enzymes. “The high potency and prolonged halflife of rosuvastatin (19 hours) is a potential explanation for its prolonged efficacy as a weekly regimen,” Dr. Backes said.

More Study Needed C. Michael White, PharmD, professor and interim head of the Department of Pharmacy Practice at the University of Connecticut, in Storrs, said that “this is an interesting study but a small sample size. Future studies should determine if compliance with once-weekly cardiac medications is better than once-daily medications.” Additionally, Dr. White cautioned that clinicians should not interpret these findings as an acceptance of statin doses that are not yet FDA-approved, without further evidence of their safety. Drs. Backes and White reported no relevant conflicts of interest.

—Caroline Helwick

Hem/Onc Pharmacy

Pharmacy Practice News • October 2011

In Focus

LUNG CANCER continued from page 1

• Of trial enrollees, 68% were men and 32% were women. But according to the National Cancer Institute’s (NCI) Surveillance, Epidemiology and End Results (SEER) data, women represent 42% of all NSCLC patients. • Just 2% of trial participants were black, despite African Americans developing lung cancer at higher rates (72.7 per 100,000) than whites (68 per 100,000). Although troubling, these findings should not come as a surprise to anyone—and the issue isn’t confined to lung cancer research, said Joy Lewis, DO, PhD, assistant professor of family and community medicine and director of the Practice-Based Research Network at A.T. Still University School of Osteopathic Medicine in Mesa, Ariz., who has studied the issue of enrollment of the elderly in clinical trials. In 2003, while a researcher at RAND Health, she led a retrospective analysis of patient and trial characteristics for 59,300 patients enrolled into 495 NCIsponsored, cooperative group trials, active from 1997 through 2000. Published in the Journal of Clinical Oncology, her findings closely tracked the FDA researchers’ recent results: Overall, only 32% of participants in Phase II and III clinical trials were elderly, although elderly people account for 61% of U.S. cancer cases (J Clin Oncol 2003;21:1383-1389).

And a cross-sectional, populationbased analysis of all participants in therapeutic nonsurgical NCI Clinical Trial Cooperative Group breast, colorectal, lung, and prostate cancer clinical trials from 2000 through 2002, published in the Journal of the American Medical Association, found that not only were women, the elderly and minorities underrepresented in these trials, the situation seemed to actually be getting worse rather than better (JAMA 2004;291:2720-2726). “Although the total number of trial participants increased during our study period, the representation of racial and ethnic minorities decreased,” they noted. These disparities in representation can mean real problems in terms of incorporating the results of trials into clinical practice. Some drugs may have a different side-effect profile in women from that in men, for example, a fact that would be harder to tease out when men represent the lion’s share of enrollees. And elderly patients may be more vulnerable to a drug’s toxicities than younger patients. Before investigators can improve this picture, they must first understand what the actual barriers are that impede these patient groups from enrolling in trials, said Lynne Nguyen, MPH, director of the Minority & Women Clinical Trials Recruitment Resource in the Department of Health Disparities Research at the University of Texas MD Anderson Cancer Center, in Houston. “A common mistake made in academia

‘A fundamental step in applying the principles of evidence-based medicine is that when you look at a published study, you have to ask if the results apply to your patient. If the people in that study have fundamental differences from your patient, then the answer is no.’

—Joy Lewis, DO, PhD

‘Are we writing protocols so that people have to come into the medical center three times a week for blood draws that take an hour each time, so they have to take time off work and pay $15 to park?’

—Lynne Nguyen, MPH

is thinking too simply about the barriers facing our populations of interest,” Ms. Nguyen explained. “For example, for African Americans, we cite incidents such as the Tuskegee syphilis studies and say that there is a mistrust and fear of researchers among this community as a result. Of course, that’s true. But—are we looking at our own barriers, the ones we construct? Are we writing protocols so that people have to come into the medical center three times a week for blood draws that take an hour each time, so they have to take time off work and pay $15 to park?” Ms. Nguyen also cited health literacy as a key barrier for all populations, but particularly for the elderly. “We know from national health literacy surveys that people aged 65 and older have the lowest levels of health literacy. Are we writing consent forms in a way that’s understandable?” she asked. “And what about the legal piece of the consent form, written by lawyers? That’s the piece that causes mistrust. People read it and when they get the gist, they see that the institution is protecting its own interests, not theirs. That’s a significant issue.” Many trial protocols end up automatically excluding seniors in a way that may not be necessary, said Dr. Lewis. “Some exclusion criteria are used again and again [but] the criteria need to be evaluated in the context of each trial,” she noted. “For example, 41% of Phase II and 47% of Phase III trials have any history of congestive heart failure as an exclusion criterion. Is that always necessary? Are you using a cardiotoxic drug? Can you be more precise and say that you need an ejection fraction or cardiac output above a certain level?” Although exclusion criteria are there for a reason, Dr. Lewis said, due diligence should be taken in developing each screening instrument. “Make sure the investigators justify the use of each specific exclusion criteria for each specific study.” If that were to happen, and if this critical review resulted in fewer restrictions,

participation by the elderly in trials should increase markedly, Dr. Lewis said. “If you relax organ system and functional status exclusions, our model predicts 60% participation for the elderly, which is much more representative of the population of cancer patients generally.” Of course, researchers want to recruit the healthiest participants to their trials because they have the best chance of being successful with the drug. “But in reality, who is more likely to have cancer? Older people,” said Ms. Nguyen. “And they are the ones with all these other conditions. If you test drugs in people without these conditions, how generalizable are your results going to be?” Rather than focusing on changing how patients feel about clinical trials, Ms. Nguyen stressed, the emphasis must be on changing how trials are conducted in order to make recruitment more open to these groups. “We can’t change the patient’s economic situation. We can educate, but we can’t change core beliefs. But we can reduce inequities in our own internal system, and that’s what we’ve got to work on.” In the meantime, clinicians are well advised to read the literature closely, with an eye toward the “methods” section of each trial. “A fundamental step in applying the principles of evidencebased medicine is that when you look at a published study, you have to ask if the results apply to your patient. If the people in that study have fundamental differences from your patient, then the answer is no,” Dr. Lewis said. “That may make it difficult to generalize results related to efficacy and toxicity for your female patients, your minority patients, and in particular your elderly patients.” That doesn’t mean that they can’t receive the same drugs, of course. But it does mean that clinicians should be aware that the outcomes they expect based on the trial population may not, in fact, be the outcomes they get in the real world. —Gina Shaw

UNMET NEED. FILL IT.

FREE VVATER V2

CLEARANCE

Order SAMSCA® (tolvaptan)

15 mg

30 mg

NDC: 59148-020-50

NDC: 59148-021-50

Unique oral treatment for clinically significant hypervolemic and euvolemic hyponatremia

100 %

of physicians surveyed (N=57) would recommend SAMSCA to a colleague 1 In this same survey (patient cases; N=150), physicians were satisﬁed or very satisﬁed with SAMSCA 90% of the time1

Indication and important limitations • SAMSCA is indicated for the treatment of clinically significant hypervolemic and euvolemic hyponatremia (serum sodium <125 mEq/L or less marked hyponatremia that is symptomatic and has resisted correction with fluid restriction), including patients with heart failure, cirrhosis, and Syndrome of Inappropriate Antidiuretic Hormone (SIADH) • Patients requiring intervention to raise serum sodium urgently to prevent or to treat serious neurological symptoms should not be treated with SAMSCA. It has not been established that raising serum sodium with SAMSCA provides a symptomatic benefit to patients

Important safety information SAMSCA should be initiated and re-initiated in patients only in a hospital where serum sodium can be monitored closely. Too rapid correction of hyponatremia (e.g., >12 mEq/L/24 hours) can cause osmotic demyelination resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma and death. In susceptible patients, including those with severe malnutrition, alcoholism or advanced liver disease, slower rates of correction may be advisable. Contraindications: Urgent need to raise serum sodium acutely, inability of the patient to sense or appropriately respond to thirst, hypovolemic hyponatremia, concomitant use of strong CYP 3A inhibitors, anuric patients. • Subjects with SIADH or very low baseline serum sodium concentrations may be at greater risk for too-rapid correction of serum sodium. In patients receiving SAMSCA who develop too rapid a rise in serum sodium or develop neurologic sequelae, discontinue or interrupt treatment with SAMSCA and consider administration of hypotonic fluid. Fluid restriction should generally be avoided during the first 24 hours • Dehydration and hypovolemia can occur, especially in potentially volume-depleted patients receiving diuretics or those who are fluid restricted. In patients who develop medically significant signs or symptoms of hypovolemia, discontinuation is recommended • Gastrointestinal bleeding in patients with cirrhosis: Use in cirrhotic patients only when the need to treat outweighs this risk • Avoid use with: CYP 3A inhibitors and CYP 3A inducers. Reduced dose of SAMSCA may be needed if used with P-gp inhibitors • Co-administration with hypertonic saline is not recommended • Monitor serum potassium in patients with levels >5 mEq/L and in those receiving drugs known to increase serum potassium Commonly observed adverse reactions: (SAMSCA vs placebo) thirst (16% vs 5%), dry mouth (13% vs 4%), asthenia (9% vs 4%), constipation (7% vs 2%), pollakiuria or polyuria (11% vs 3%) and hyperglycemia (6% vs 1%). Reference: 1. Market Rx 2010.

For more information about SAMSCA, visit samsca.com or call 1-877-726-7220.

Please see Brief Summary of FULL PRESCRIBING INFORMATION, including Boxed WARNING, on the following page. Manufactured by Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan. Distributed and marketed by Otsuka America Pharmaceutical, Inc., Rockville, MD 20850. US Patent Nos: 5,258,510 and 5,753,677. Samsca is a registered trademark of Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan.

February 2011

0711A-2015B

6$06&$ WROYDSWDQ WDEOHWV IRU RUDO XVH %ULHI 6XPPDU\ RI 3UHVFULELQJ ,QIRUPDWLRQ )RU FRPSOHWH SUHVFULELQJ LQIRUPDWLRQ FRQVXOW RI¿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¿FDQW K\SHUYROHPLF DQG HXYROHPLF K\SRQDWUHPLD VHUXP VRGLXP P(T / RU OHVV PDUNHG K\SRQDWUHPLD WKDW LV V\PSWRPDWLF DQG KDV UHVLVWHG FRUUHFWLRQ ZLWK ÀXLG UHVWULFWLRQ LQFOXGLQJ SDWLHQWV ZLWK KHDUW IDLOXUH FLUUKRVLV DQG 6\QGURPH RI ,QDSSURSULDWH $QWLGLXUHWLF +RUPRQH 6,$'+ ,PSRUWDQW /LPLWDWLRQV 3DWLHQWV UHTXLULQJ LQWHUYHQWLRQ WR UDLVH VHUXP VRGLXP XUJHQWO\ WR SUHYHQW RU WR WUHDW VHULRXV QHXURORJLFDO V\PSWRPV VKRXOG QRW EH WUHDWHG ZLWK 6$06&$ ,W KDV QRW EHHQ HVWDEOLVKHG WKDW UDLVLQJ VHUXP VRGLXP ZLWK 6$06&$ SURYLGHV D V\PSWRPDWLF EHQH¿W WR SDWLHQWV &2175$,1',&$7,216 6$06&$ LV FRQWUDLQGLFDWHG LQ WKH IROORZLQJ FRQGLWLRQV 8UJHQW QHHG WR UDLVH VHUXP VRGLXP DFXWHO\ 6$06&$ KDV QRW EHHQ VWXGLHG LQ D VHWWLQJ RI XUJHQW QHHG WR UDLVH VHUXP VRGLXP DFXWHO\ ,QDELOLW\ RI WKH SDWLHQW WR VHQVH RU DSSURSULDWHO\ UHVSRQG WR WKLUVW 3DWLHQWV ZKR DUH XQDEOH WR DXWR UHJXODWH ÀXLG EDODQFH DUH DW VXEVWDQWLDOO\ LQFUHDVHG ULVN RI LQFXUULQJ DQ RYHUO\ UDSLG FRUUHFWLRQ RI VHUXP VRGLXP K\SHUQDWUHPLD DQG K\SRYROHPLD +\SRYROHPLF K\SRQDWUHPLD 5LVNV DVVRFLDWHG ZLWK ZRUVHQLQJ K\SRYROHPLD LQFOXGLQJ FRPSOLFDWLRQV VXFK DV K\SRWHQVLRQ DQG UHQDO IDLOXUH RXWZHLJK SRVVLEOH EHQH¿WV &RQFRPLWDQW XVH RI VWURQJ &<3 $ LQKLELWRUV .HWRFRQD]ROH PJ DGPLQLVWHUHG ZLWK WROYDSWDQ LQFUHDVHG WROYDSWDQ H[SRVXUH E\ IROG /DUJHU GRVHV ZRXOG EH H[SHFWHG WR SURGXFH ODUJHU LQFUHDVHV LQ WROYDSWDQ H[SRVXUH 7KHUH LV QRW DGHTXDWH H[SHULHQFH WR GH¿QH WKH GRVH DGMXVWPHQW WKDW ZRXOG EH QHHGHG WR DOORZ VDIH XVH RI WROYDSWDQ ZLWK VWURQJ &<3 $ LQKLELWRUV VXFK DV FODULWKURP\FLQ NHWRFRQD]ROH LWUDFRQD]ROH ULWRQDYLU LQGLQDYLU QHO¿QDYLU VDTXLQDYLU QHID]RGRQH DQG WHOLWKURP\FLQ $QXULF SDWLHQWV ,Q SDWLHQWV XQDEOH WR PDNH XULQH QR FOLQLFDO EHQH¿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ÀXLG )OXLG UHVWULFWLRQ GXULQJ WKH ¿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ÀXLG LQWDNH 'HK\GUDWLRQ DQG K\SRYROHPLD FDQ RFFXU HVSHFLDOO\ LQ SRWHQWLDOO\ YROXPH GHSOHWHG SDWLHQWV UHFHLYLQJ GLXUHWLFV RU WKRVH ZKR DUH ÀXLG UHVWULFWHG ,Q PXOWLSOH GRVH SODFHER FRQWUROOHG WULDOV LQ ZKLFK K\SRQDWUHPLF SDWLHQWV ZHUH WUHDWHG ZLWK WROYDSWDQ WKH LQFLGHQFH RI GHK\GUDWLRQ ZDV IRU WROYDSWDQ DQG IRU SODFHER WUHDWHG SDWLHQWV ,Q SDWLHQWV UHFHLYLQJ 6$06&$ ZKR GHYHORS PHGLFDOO\ VLJQL¿FDQW VLJQV RU V\PSWRPV RI K\SRYROHPLD LQWHUUXSW RU GLVFRQWLQXH 6$06&$ WKHUDS\ DQG SURYLGH VXSSRUWLYH FDUH ZLWK FDUHIXO PDQDJHPHQW RI YLWDO VLJQV ÀXLG EDODQFH DQG HOHFWURO\WHV )OXLG UHVWULFWLRQ GXULQJ WKHUDS\ ZLWK 6$06&$ PD\ LQFUHDVH WKH ULVN RI GHK\GUDWLRQ DQG K\SRYROHPLD 3DWLHQWV UHFHLYLQJ 6$06&$ VKRXOG FRQWLQXH LQJHVWLRQ RI À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¶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À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ÀHFW WKH UDWHV REVHUYHG LQ SUDFWLFH 7KH DGYHUVH HYHQW LQIRUPDWLRQ IURP FOLQLFDO WULDOV GRHV KRZHYHU SURYLGH D EDVLV IRU LGHQWLI\LQJ WKH DGYHUVH HYHQWV WKDW DSSHDU WR EH UHODWHG WR GUXJ XVH DQG IRU DSSUR[LPDWLQJ UDWHV ,Q PXOWLSOH GRVH SODFHER FRQWUROOHG WULDOV K\SRQDWUHPLF SDWLHQWV VHUXP VRGLXP P(T / ZHUH WUHDWHG ZLWK 6$06&$ 7KH PHDQ DJH RI WKHVH SDWLHQWV ZDV \HDUV RI SDWLHQWV ZHUH PDOH DQG ZHUH &DXFDVLDQ 2QH KXQGUHG HLJKW\ QLQH WROYDSWDQ WUHDWHG SDWLHQWV KDG D VHUXP VRGLXP P(T / DQG SDWLHQWV KDG D VHUXP VRGLXP P(T / +\SRQDWUHPLD ZDV DWWULEXWHG WR FLUUKRVLV LQ RI SDWLHQWV KHDUW IDLOXUH LQ DQG 6,$'+ RWKHU LQ 2I WKHVH SDWLHQWV ZHUH WUHDWHG ZLWK WKH UHFRPPHQGHG GRVH WLWUDWLRQ PJ WLWUDWHG WR PJ DV QHHGHG WR UDLVH VHUXP VRGLXP 2YHUDOO RYHU SDWLHQWV KDYH EHHQ WUHDWHG ZLWK RUDO GRVHV RI WROYDSWDQ LQ RSHQ ODEHO RU SODFHER FRQWUROOHG FOLQLFDO WULDOV $SSUR[LPDWHO\ RI WKHVH SDWLHQWV KDG K\SRQDWUHPLD DSSUR[LPDWHO\ RI WKHVH K\SRQDWUHPLF SDWLHQWV ZHUH WUHDWHG ZLWK WROYDSWDQ IRU PRQWKV RU PRUH 7KH PRVW FRPPRQ DGYHUVH UHDFWLRQV LQFLGHQFH PRUH WKDQ SODFHER VHHQ LQ WZR GD\ GRXEOH EOLQG SODFHER FRQWUROOHG K\SRQDWUHPLD WULDOV LQ ZKLFK WROYDSWDQ ZDV DGPLQLVWHUHG LQ WLWUDWHG GRVHV PJ WR PJ RQFH GDLO\ ZHUH WKLUVW GU\ PRXWK DVWKHQLD FRQVWLSDWLRQ SROODNLXULD RU SRO\XULD DQG K\SHUJO\FHPLD ,Q WKHVH WULDOV RI WROYDSWDQ WUHDWHG SDWLHQWV GLVFRQWLQXHG WUHDWPHQW EHFDXVH RI DQ DGYHUVH HYHQW FRPSDUHG WR RI SODFHER WUHDWHG SDWLHQWV QR DGYHUVH UHDFWLRQ UHVXOWLQJ LQ GLVFRQWLQXDWLRQ RI WULDO PHGLFDWLRQ RFFXUUHG DW DQ LQFLGHQFH RI ! LQ WROYDSWDQ WUHDWHG SDWLHQWV 7DEOH OLVWV WKH DGYHUVH UHDFWLRQV UHSRUWHG LQ WROYDSWDQ WUHDWHG SDWLHQWV ZLWK K\SRQDWUHPLD VHUXP VRGLXP P(T / DQG DW D UDWH DW OHDVW JUHDWHU WKDQ SODFHER WUHDWHG SDWLHQWV LQ WZR GD\ GRXEOH EOLQG SODFHER FRQWUROOHG WULDOV ,Q WKHVH VWXGLHV SDWLHQWV ZHUH H[SRVHG WR WROYDSWDQ VWDUWLQJ GRVH PJ WLWUDWHG WR DQG PJ DV QHHGHG WR UDLVH VHUXP VRGLXP $GYHUVH HYHQWV UHVXOWLQJ LQ GHDWK LQ WKHVH WULDOV ZHUH LQ WROYDSWDQ WUHDWHG SDWLHQWV DQG LQ SODFHER WUHDWHG SDWLHQWV 7DEOH $GYHUVH 5HDFWLRQV ! PRUH WKDQ SODFHER LQ 7ROYDSWDQ 7UHDWHG 3DWLHQWV LQ 'RXEOH %OLQG 3ODFHER &RQWUROOHG +\SRQDWUHPLD 7ULDOV 6\VWHP 2UJDQ &ODVV 0HG'5$ 3UHIHUUHG 7HUP

7ROYDSWDQ PJ GD\ PJ GD\ 1

3ODFHER 1

*DVWURLQWHVWLQDO 'LVRUGHUV 'U\ PRXWK

&RQVWLSDWLRQ

*HQHUDO 'LVRUGHUV DQG $GPLQLVWUDWLRQ 6LWH &RQGLWLRQV D 7KLUVW

$VWKHQLD

3\UH[LD

0HWDEROLVP DQG 1XWULWLRQ 'LVRUGHUV E +\SHUJO\FHPLD

$QRUH[LD F

5HQDO DQG 8ULQDU\ 'LVRUGHUV 3ROODNLXULD RU SRO\XULD G

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

6$06&$ WROYDSWDQ 7KH IROORZLQJ DGYHUVH UHDFWLRQV RFFXUUHG LQ RI K\SRQDWUHPLF SDWLHQWV WUHDWHG ZLWK 6$06&$ DQG DW D UDWH JUHDWHU WKDQ SODFHER LQ GRXEOH EOLQG SODFHER FRQWUROOHG WULDOV 1 WROYDSWDQ 1 SODFHER RU LQ RI SDWLHQWV LQ DQ XQFRQWUROOHG WULDO RI SDWLHQWV ZLWK K\SRQDWUHPLD 1 DQG DUH QRW PHQWLRQHG HOVHZKHUH LQ WKH ODEHO %ORRG DQG /\PSKDWLF 6\VWHP 'LVRUGHUV 'LVVHPLQDWHG LQWUDYDVFXODU FRDJXODWLRQ &DUGLDF 'LVRUGHUV ,QWUDFDUGLDF WKURPEXV YHQWULFXODU ¿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¿QDYLU ULWRQDYLU DQG QHID]RGRQH DW WKH KLJKHVW ODEHOHG GRVH ZRXOG EH H[SHFWHG WR FDXVH DQ HYHQ JUHDWHU LQFUHDVH LQ WROYDSWDQ H[SRVXUH 7KXV 6$06&$ DQG VWURQJ &<3 $ LQKLELWRUV VKRXOG QRW EH FR DGPLQLVWHUHG >VHH 'RVDJH DQG $GPLQLVWUDWLRQ DQG &RQWUDLQGLFDWLRQV @ 0RGHUDWH &<3 $ ,QKLELWRUV 7KH LPSDFW RI PRGHUDWH &<3 $ LQKLELWRUV H J HU\WKURP\FLQ À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¶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¿FDQW GHJUHH /RYDVWDWLQ 6$06&$ LV D ZHDN LQKLELWRU RI &<3 $ &R DGPLQLVWUDWLRQ RI ORYDVWDWLQ DQG 6$06&$ LQFUHDVHV WKH H[SRVXUH WR ORYDVWDWLQ DQG LWV DFWLYH PHWDEROLWH ORYDVWDWLQ ȕ K\GUR[\DFLG E\ IDFWRUV RI DQG UHVSHFWLYHO\ 7KLV LV QRW D FOLQLFDOO\ UHOHYDQW FKDQJH 3KDUPDFRG\QDPLF ,QWHUDFWLRQV 7ROYDSWDQ SURGXFHV D JUHDWHU KRXU XULQH YROXPH H[FUHWLRQ UDWH WKDQ GRHV IXURVHPLGH RU K\GURFKORURWKLD]LGH &RQFRPLWDQW DGPLQLVWUDWLRQ RI WROYDSWDQ ZLWK IXURVHPLGH RU K\GURFKORURWKLD]LGH UHVXOWV LQ D KRXU XULQH YROXPH H[FUHWLRQ UDWH WKDW LV VLPLODU WR WKH UDWH DIWHU WROYDSWDQ DGPLQLVWUDWLRQ DORQH $OWKRXJK VSHFL¿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¿FDWLRQ DQG HPEU\R IHWDO GHDWK RFFXUUHG 6$06&$ VKRXOG EH XVHG GXULQJ SUHJQDQF\ RQO\ LI WKH SRWHQWLDO EHQH¿W MXVWL¿HV WKH SRWHQWLDO ULVN WR WKH IHWXV ,Q HPEU\R IHWDO GHYHORSPHQW VWXGLHV SUHJQDQW UDWV DQG UDEELWV UHFHLYHG RUDO WROYDSWDQ GXULQJ RUJDQRJHQHVLV 5DWV UHFHLYHG WR WLPHV WKH PD[LPXP UHFRPPHQGHG KXPDQ GRVH 05+' RI WROYDSWDQ RQ D ERG\ VXUIDFH DUHD EDVLV 5HGXFHG IHWDO ZHLJKWV DQG GHOD\HG IHWDO RVVL¿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¿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¿W FDQ EH H[SHFWHG LQ SDWLHQWV ZKR DUH DQXULF >VHH &RQWUDLQGLFDWLRQV @ 8VH LQ 3DWLHQWV ZLWK &RQJHVWLYH +HDUW )DLOXUH 7KH H[SRVXUH WR WROYDSWDQ LQ SDWLHQWV ZLWK FRQJHVWLYH KHDUW IDLOXUH LV QRW FOLQLFDOO\ UHOHYDQWO\ LQFUHDVHG 1R GRVH DGMXVWPHQW LV QHFHVVDU\ 29(5'26$*( 6LQJOH RUDO GRVHV XS WR PJ DQG PXOWLSOH GRVHV XS WR PJ RQFH GDLO\ IRU GD\V KDYH EHHQ ZHOO WROHUDWHG LQ VWXGLHV LQ KHDOWK\ VXEMHFWV 7KHUH LV QR VSHFL¿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¿UVW VWHS $ WKRURXJK KLVWRU\ DQG GHWDLOV RI RYHUGRVH VKRXOG EH REWDLQHG DQG D SK\VLFDO H[DPLQDWLRQ VKRXOG EH SHUIRUPHG 7KH SRVVLELOLW\ RI PXOWLSOH GUXJ LQYROYHPHQW VKRXOG EH FRQVLGHUHG 7UHDWPHQW VKRXOG LQYROYH V\PSWRPDWLF DQG VXSSRUWLYH FDUH ZLWK UHVSLUDWRU\ (&* DQG EORRG SUHVVXUH PRQLWRULQJ DQG ZDWHU HOHFWURO\WH VXSSOHPHQWV DV QHHGHG $ SURIXVH DQG SURORQJHG DTXDUHVLV VKRXOG EH DQWLFLSDWHG ZKLFK LI QRW PDWFKHG E\ RUDO ÀXLG LQJHVWLRQ VKRXOG EH UHSODFHG ZLWK LQWUDYHQRXV K\SRWRQLF ÀXLGV ZKLOH FORVHO\ PRQLWRULQJ HOHFWURO\WHV DQG ÀXLG EDODQFH (&* PRQLWRULQJ VKRXOG EHJLQ LPPHGLDWHO\ DQG FRQWLQXH XQWLO (&* SDUDPHWHUV DUH ZLWKLQ QRUPDO UDQJHV 'LDO\VLV PD\ QRW EH HIIHFWLYH LQ UHPRYLQJ WROYDSWDQ EHFDXVH RI LWV KLJK ELQGLQJ DI¿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¿QDYLU VDTXLQDYLU LQGLQDYLU ULWRQDYLU RU PRGHUDWH &<3 $ LQKLELWRUV H J DSUHSLWDQW HU\WKURP\FLQ GLOWLD]HP YHUDSDPLO ÀXFRQD]RO RU 3 JS LQKLELWRUV H J F\FORVSRULQH >VHH 'RVDJH DQG $GPLQLVWUDWLRQ &RQWUDLQGLFDWLRQV :DUQLQJV DQG 3UHFDXWLRQV DQG 'UXJ ,QWHUDFWLRQV @ 1XUVLQJ $GYLVH SDWLHQWV QRW WR EUHDVWIHHG DQ LQIDQW LI WKH\ DUH WDNLQJ 6$06&$ >VHH 8VH ,Q 6SHFL¿F 3RSXODWLRQV @ )RU PRUH LQIRUPDWLRQ DERXW 6$06&$ FDOO RU JR WR ZZZ VDPVFD FRP 0DQXIDFWXUHG E\ 2WVXND 3KDUPDFHXWLFDO &R /WG 7RN\R -DSDQ 'LVWULEXWHG DQG PDUNHWHG E\ 2WVXND $PHULFD 3KDUPDFHXWLFDO ,QF 5RFNYLOOH 0' 86 3DWHQW 1RV DQG 6$06&$ LV D WUDGHPDUN RI 2WVXND 3KDUPDFHXWLFDO &R /WG 7RN\R -DSDQ

2WVXND 3KDUPDFHXWLFDO &R /WG

/ %

5HY

Pharmacy Practice News • October 2011

Clinical 11

Infectious Disease

STEWARDSHIP

‘We’re spending more money on antimicrobials, but we’re seeing improved outcomes and lower mortality.’

continued from page 1

Working closely with an infectious disease physician, Dr. Leuthner tried to identify interventions that could improve care and save money at the same time. “That’s where we found longduration antibiotics,” she explained. At the time, the hospital had no ASP, and patients at Yuma given IV antibiotics stayed on those medications for an average of 16 to 20 days. Dr. Leuthner instituted a multipronged intervention that included new dosing strategies and hand-hygiene awareness, as well as staff education on issues such as colonization versus active infection, empiric coverage versus deescalation of therapy, and durations of therapy and duplications of therapy. But the centerpiece of the plan, which she detailed during a session at the ICAAC annual meeting, was a “10-day hard stop” for all antibiotics. “In many cases, patients would be on IV antibiotics until the day they walked out of the hospital, which could be a very long time,” she told attendees. In September 2008, that all changed. Orderentry forms were modified so that once a patient had been on antibiotics for 10 days, the physician could not renew the order but instead had to create a new one. “The day before the stop, we insert a note on bright red paper into the patient’s chart,” Dr. Leuthner said. The “IV Antibiotic Stop Notice” reads: “An antibiotic order for this patient will be at its automatic 10-day expiration tomorrow. The recommended duration of antibiotic therapy is 10 days for most infections. Excessive antibiotic use may lead to selection of resistant organisms and increased antibiotic toxicity. In addition, failure to respond appropriately within the 10-day timeframe may indicate a need to reassess your diagnosis or change antibiotics. Please evaluate your patient to determine if there is clinical evidence to justify continued antibiotic therapy. If your clinical reassessment indicates that the benefits of continued antibiotic therapy outweigh the risks, a completely new order must be written. If you have any questions, a member of the anti-infective team is available for discussion.” Surprisingly, Dr. Leuthner said, the new system met with little resistance. “We educated the physicians ahead of time, and because most of the activity is being done behind the scenes by pharmacists and nurses, their world hasn’t changed too much except for this little speed bump.” Physicians also can bypass the automatic 10-day stop at the time of prescription, if need be. “If you know that the order needs to go for 42 days, you can write ‘for 42 days’ in the order,

—Debbie Goff, PharmD, FCCP

Table 1. Rate of Isolated Organisms 1st Quarter 4th Quarter 2008, % 2010, %

Difference

Acinetobacter

3.26

2.26

–1.00 (–30.7%)

Methicillinresistant Staphylococcus aureus

6.72

5.00

–1.71 (–25.5%)

Vancomycinresistant enterococci

0.89

0.74

–0.15 (–16.9%)

Pseudomonas aeruginosa

4.68

3.35

–1.15 (–24.6%)

‘Most institutions already have some policy in place that has a designated stop time for certain drugs; all you have to do is change it to a set duration and plug in antibiotics.’ —Kimberly Leuthner, PharmD

Table 2. Optimal Carbapenem Choice and Dose Antibiotic

Dosing

Percent Susceptible

CFR (%) 0.5-1 h Infusion

CFR (%) 3-4 h Infusion

Doripenem

0.5 g q8h

67 70

78 84

1 g q8h Imipenem

0.5 g q8h

0.5 g q6h 1 g q8h Meropenem

0.5 g q8h

1 g q8h CFR, cumulative fraction of response; q, every

which will bypass the automatic stop,” she explained. The results have been impressive. Overall duration of therapy has dropped by between three and five days. Previously, about 90% of antibiotic orders were renewed; now, the rate is less than 50%. The dispensing rate has dropped for every type of antimicrobial prescribed at Yuma. And as a result, the rate of organisms isolated has also been reduced (Table 1). “It’s very simple,” Dr. Leuthner said. “All we had to do is program the pharmacy computer system to do this. Most institutions already have some policy in place that has a designated stop time for certain drugs; all you have to do is change it to a set duration and plug in antibiotics.” The biggest expense associated with the program? The red paper that the 10-day stop notice is printed on. Elizabeth Dodds Ashley, PharmD, MHS, BCPS, associate director for clinical pharmacy services and infectious diseases pharmacist at the University of Rochester Medical Center in Rochester, N.Y., praised the initiative. “[Dr. Leuthner’s] data show that everything is moving in the right direction, and I anticipate that it will continue,” she said. “The littlest thing can make a big difference. It’s not just about big complicated programs with lots of full-time staff. You have to be creative when you have limited resources, and it’s great to have data from smaller programs.”

Using PD Data To Establish Optimal Carbapenem Choice Carbapenems, a class of broadspectrum antibiotics that are effective against gram-negative infections, are a mainstay of therapy for people with serious hospital-acquired infections. For about 28 years, The Ohio State University Medical Center’s formulary has contained imipenem as its carbapenem of choice. “It was about 71% susceptible to our Pseudomonas isolate,” said Debbie Goff, PharmD, FCCP, specialty practice pharmacist in infectious diseases at Ohio State, in Columbus, and a speaker at the ICAAC meeting. “When meropenem [Merrem, AstraZeneca] and doripenem [Doribax, Janssen] came onto the market, we evaluated those— they were a few percentage points

•

see STEWARDSHIP, page 12

12 Clinical

Pharmacy Practice News • October 2011

Infectious Disease

STEWARDSHIP

Dr. Goff asked David Nicolau, PharmD, FCCP, director of the Center for AntiInfective Research and Development at Hartford Hospital in Hartford, Conn., to conduct a Monte Carlo analysis of Ohio State’s isolates to definitively establish the optimal carbapenem choice and dose (Table 2, page 11). “Pharmacodynamic modeling showed us that doripenem was the best carbapenem given by extended infusion,” Dr. Goff said. “While all three had improved results with extended infusion, doripenem’s were the best. In addi-

continued from page 11

better, but not enough to make a formulary change from a 20-year-old drug that everyone was used to using.” But antibiotic resistance in Ohio State’s intensive care unit (ICU) continued to increase, as it is doing everywhere. Dr. Goff and her team decided that they wanted to switch to an extended-infusion carbapenem, which forced them to study the data: Would meropenem or doripenem be more effective?

WE’VE SPENT

18 YEARS

8 MONTHS AND12 DAYS

FIXATING ON ACCIDENTS THAT OCCUR

IN THE BLINK OF AN EYE BUT WHO’S COUNTING?

tion, meropenem and imipenem only have four-hour stability at room temperature, and given that we’re a 1,200bed hospital, that’s just logistically not feasible. We were able to go from our current imipenem 30-minute infusion regimen at about 67% CFR [cumulative fraction of response] to about 94% CFR with doripenem by extended infusion. It costs more, but it’s not about finding the least expensive drug, but about the best. We’re now in the process of doing an outcomes study to validate that this [strategy] results in better patient care.” Dr. Goff and her colleague, Karri A. Bauer, PharmD, BCPS, specialty practice pharmacist, infectious diseases, The Ohio State University Medical Center, presented the results of another study at ICAAC, “Extended Infusion

‘[This is] what we need to start thinking about: bootson-the ground stewardship that can be applied at hospitals of any size.’ —Elizabeth Dodds Ashley, PharmD, MHS, BCPS Cefepime for the Treatment of Invasive Pseudomonas aeruginosa Infections,” for which they already have outcomes data. “This study shows that the use of extended IV cefepime results in shorter time in the ICU, shorter infectionrelated length of stay, a lower mortality rate and decreased hospital costs overall,” Dr. Goff said. “We’re spending more money on antimicrobials, but we’re seeing improved outcomes and lower mortality.”

A First in the Literature?

Since we began in 1992, the safety of every patient in your hospital has been the focus of our attention. That’s why we’ve developed advanced automated solutions for medication and supply management. Our comprehensive systems are designed to track and verify accurate delivery to the point of care — reducing risks, minimizing mistakes, and closing the accountability loop. Learn how Omnicell can safely secure your greatest assets—the patients that depend on you. Visit us at omnicell.com. It will deﬁnitely be worth your time. O U R O B S E S S I O N I S YO U R S O LU T I O N

“Using pharmacodynamic data to dose your drugs has been more widely accepted in recent years, but what [Dr. Goff ] has done here is take the concept we usually apply to dosing and applied it to the formulary,” Dr. Dodds Ashley said. “I’ve heard of some centers doing this, but this is the first paper I’ve seen published on it suggesting formulary status. It’s the first time I’ve seen a true recommendation that you should be picking your formulary drugs based on PD targeting.” In the studies presented at ICAAC, she added, stewardship programs are using data derived from population analyses for one-stop interventions that can touch every patient in the hospital. “That’s what we need to start thinking about: boots-on-the ground stewardship that can be applied at hospitals of any size.” —Gina Shaw

Pharmacy Practice News • October 2011

Clinical 13

Infectious Disease

Preventing Nosocomial Infections Saves Lives, Money T

he use of an evidence-based prevention program for nosocomial infections leads to significant cost savings for the hospital, according to new data. Previous analyses of the Keystone ICU Project have shown its efficacy in preventing hospital-acquired infections (HAIs). But to implement a new intervention or program, hospitals require proof that the investment will yield a positive economic return within a certain period of time. “It seems strange to say, ‘well you’re saving lives, but how much does it cost us?’ but at some point in the health care system that’s an important consideration,” said Hugh Waters, PhD, adjunct associate professor, Johns Hopkins Bloomberg

School of Public Health in Baltimore, lead author of the economic analysis. Dr. Waters and colleagues sought to make a business case for the Keystone ICU Project by comparing its cost ($161,584 per year, which includes initial implementation costs) with the average cost of treating a catheterrelated bloodstream infection (CRBSI) or case of ventilator-associated pneumonia (VAP)—$36,500 and $10,000,

respectively. The intervention costs an estimated $3,375 per infection averted, leading to $1.1 million in annual savings for the typical hospital (Am J Med Qual 2011;26:333-339). The savings were derived from a 2010 observational study of the Keystone ICU Project in 106 ICUs across 67 hospitals (BMJ 2010;340:c309). The authors found that the intervention reduced the rate of CRBSIs from 7.7 to

•

see NOSOCOMIAL, page 42

Expanding APP’s Leading Oncology Portfolio: Gemcitabine 200 mg, 1 gram, and 2 gram.

New Products

The first generic Aztreonam for Injection, USP ® Available from APP

Advertisement Sandoz Launches Two Inhalational Agents

andoz announced the U.S. launches of albuterol sulfate inhalation solution, 0.083% and ipratropium bromide inhalation solution, 0.02% for the treatment of various respiratory diseases.

Albuterol sulfate inhalation solution is indicated for the relief of bronchospasm in patients 2 years of age and older with reversible obstructive airway disease and acute attacks of bronchospasm. Ipratropium bromide inhalation solution is indicated as a bronchodilator for maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease, including chronic bronchitis and emphysema. According to IMS Health, U.S. sales for all versions of albuterol sulfate inhalation solution, 0.083% and ipratropium bromide inhalation solution, 0.02% currently on the market were approximately USD 123 million and USD 56 million, respectively, for the 12 months ending in June 2011. Sandoz will market albuterol sulfate in unit-dose vials containing 2.5 mg albuterol per 3 mL, and ipratropium bromide in unit-dose vials containing 500 mcg ipratropium bromide, in 2.5 mL saline. For more information, visit www.us.sandoz.com

1.1 per 1,000 catheter-days, preventing 29.9 infections annually. A separate, unpublished analysis by Berenholtz and colleagues found the program prevented 18 cases of VAP per year. “In the bigger picture, I hope this helps open the door for more commonsense economic arguments for why good health practices should be adopted in the United States,” said Dr. Waters.

A Broad Spectrum of Multisource Oncology Therapeutics

See full prescribing information at www.APPpharma.com

Medical Affairs 800.551.7176 Customer Service 888.386.1300

14 Clinical

Pharmacy Practice News • October 2011

Educational Review

Clostridium difficile: Epidemiology, Transmission, and Treatment Lawrence J. Brandt, MD Emeritus Chief Division of Gastroenterology Montefiore Medical Center Bronx, New York

Paul Feuerstadt, MD

Division of Gastroenterology Danbury Hospital Danbury, Connecticut

lostridium difficile infection (CDI) is increasing in incidence, severity, and mortality; the annual financial

burden of CDI in the United States

is estimated to be more than $1 billion.1 This review discusses the changing epidemiology, transmission, risk factors, diagnostic tools, and treatment of both index and recurrent CDI.

Hypervirulent strains of C. difficile throughout North America and Europe have contributed to this epidemic—an increase in treatment failures for both index and recurrent infections is driving research to discover more effective treatment strategies. As a result, a variety of therapies, including antibiotic and probiotic regimens, immunotherapy, investigational vaccines, and fecal microbiota transplant (FMT), all have been used to treat CDI with varying success.2-5

Epidemiology Incidence The incidence of CDI in the United States is increasing at an alarming rate. Based on data from various medical centers throughout the United States, one study estimated that the incidence doubled between 1996 and 2003 from 31 to 61 per 100,000 population.6 During a similar time frame, a single center in St. Louis, MO, showed a parallel trend, with the incidence of CDI increasing from 8.5 to 15.9 per 1,000 hospital admissions.7 An estimated 500,000 cases of CDI occur in the United States each year, causing 15,000 to 20,000 deaths annually.1 This trend is not isolated to North America, however. A Belgian study reported a 3.75-fold increase in the incidence of CDI from 2000 to 2003 compared with 2004 to 2007.8 Virulence The current manifestations of CDI are quite different from those detailed in the hallmark publications by Hall and O’Toole in 19359 and those of Bartlett and colleagues in the late 1970s.10 Today,

hypervirulent strains that cause severe disease, as well as community-acquired (CA) infections not associated with antibiotic use, are routinely observed. Severe disease likely results from hypervirulent strains such as the North American pulsed-field type 1 (NAP1), restrictionendonuclease analysis type BI, and polymerase chain reaction (PCR) ribotype 027 (collectively referred to as NAP1/BI/027) strain, which is resistant to fluoroquinolones.1,11 This strain produces 10 times more toxin A and up to 23 times more toxin B than other strains and also produces a third toxin, referred to as binary toxin.12 Some authorities believe that it is to blame for the overall increase in the virulence of CDI. C. difficile was previously considered a hospital-acquired (HA) infection, but with the emergence of the NAP1/BI/027 strain, CDI increasingly is being observed in the community. Although there do not seem to be significant differences in the presentation and outcomes for patients with CA-CDI compared with HA-CDI,13 groups previously considered at low risk for CDI currently are becoming increasingly infected, such as young, healthy individuals without prior exposure to hospitals or antibiotics, peripartum women,1,11 patients with inflammatory bowel disease or cirrhosis,7,14 organ transplant patients, and immunocompromised individuals. As more studies look into the changing epidemiology, risk factors, and outcomes for CDI, clinical guidelines for the management of the infection are rapidly changing.15

Risk Factors Various risk factors for disease acquisition and severity are important to consider. Nasogastric tubes, prolonged hospital stays, and exposure to proton pump inhibitors, hydrogen pump blockers, corticosteroids, or other immunosuppressives all are associated with an increased risk for CDI in hospitalized patients.1,11 Risk factors associated with severe CDI and poor outcomes include being aged 65 years or older, fever, nasogastric tube placement, immunosuppression, cognitive impairment, and recent endoscopy.16,17 Peak white blood cell (WBC) counts, peak creatinine levels duringadmission, and WBC counts at the time of admission with CDI all have been associated with an increased risk for colectomy and short-term mortality in patients with CDI.18,19 Of note, patients exposed to corticosteroids within 15 days of CDI diagnosis were found to have a 30-day mortality rate twice that of patients not treated with these agents.20 Reducing patients’ exposure to these factors whenever possible might decrease the risk for both infection and severe disease.

Transmission Understanding the transmission of CDI is key to reducing the frequency of this epidemic and requires some insight into its pathogenesis. Kyne et al described the initial need for normal colonic microbiota to be altered, possibly by antibiotics. Once a person with intestinal flora disturbance ingests C. difficile, it colonizes in the large bowel, leading to the release of toxins A and B in the

Pharmacy Practice News • October 2011

Clinical 15

Educational Review colon and subsequent symptomatic colitis.21 There are 2 forms of the bacterium: vegetative and spore. The latter can survive on environmental surfaces such as countertops, door handles, faucets, and toilet seats for years. It is the survival ability of the spores that has contributed to the growth and persistence of this epidemic. Preventing the transmission of CDI involves reducing or eliminating the various factors listed above. Antibiotic therapy alters the normal colonic microbiota that serve as a protective barrier against CDI. Most antibiotics predispose patients to CDI, even those used to treat CDI (eg, metronidazole and vancomycin).22,23 The antibiotics most frequently implicated in causing CDI and diarrhea include ampicillin, amoxicillin, cephalosporins, clindamycin, and the fluoroquinolones.24,25 Minimizing the inappropriate use of antibiotics in all patients, especially CDI-susceptible patients (eg, hospitalized elderly patients), can help prevent infection. The incidence of CA-CDI has increased, but HA-CDI is still of major importance when discussing transmission26; patients may infect others in the community upon discharge from the hospital. Between 10% and 30% of hospitalized patients treated with antibiotics are estimated to be colonized with C. difficile.27-29 Throughout the hospital and infected patients’ homes, many hard external surfaces can be contaminated with C. difficile, including toilet seats, doorknobs, countertops, and bedpans. Caregivers must be aware that their stethoscopes, hands, and possibly clothing also may transmit the infection.27.28 Fekety et al wrote guidelines for the prevention of C. difficile transmission that include limiting the use of antimicrobial agents; washing hands before and after interacting with each patient; isolating patients with CDI from uninfected patients; wearing gloves when interacting with all patients with CDI; disinfecting all C. difficile–contaminated objects with sodium hypochlorite, alkaline glutaraldehyde, or ethylene oxide; educating hospital staff about the infection; and practicing good hand hygiene.30 It is important to note that alcohol-based sanitizing agents are not as effective at eradicating CDI as hand washing with soap and water; all caregivers of patients with CDI need to thoroughly wash their hands and even their stethoscopes for effective infection control.31

Diagnosis Testing for CDI should be performed on any patient who has acute diarrhea and who has received antibiotics within 3 months of presentation, or any patient who develops diarrhea within 72 hours of admission to the hospital. It is not recommended to test formed stool because treatment is indicated only for patients with symptomatic diarrhea.29,32 A stool sample should be obtained immediately after a bowel movement and submitted to the laboratory in a watertight container. There are several methods to analyze a stool for CDI, including culture, tissue culture cytotoxicity assay, enzymelinked immunoabsorbent assay (ELISA), PCR, and glutamate dehydrogenase (GDH) testing. ELISA is the most common method used to detect toxin antigens because it is inexpensive, fast (results are usually available in less than 6 hours), and highly specific. The main problem with this test is a relatively low sensitivity (~90%), leading to a slight

risk for false-negative results.33,34 The tissue culture cytotoxicity assay remains the gold standard for CDI diagnosis because of its high sensitivity and specificity35; however, it is not commonly used because it is expensive, requires technical expertise, and results take 1 to 3 days to develop. Because cultures for C. difficile need anaerobic conditions and several days are needed to obtain results, this method is rarely used for nonepidemiologic purposes. PCR assays also are less commonly performed than ELISA because of their price, but this methodology offers a highly sensitive and specific test that is likely to become widely used in the future. In certain institutions, a progression of diagnostic tests is performed. For example, a GDH assay might initially be performed. This test is highly specific for C. difficile. If the assay is negative, then no further testing is performed. If it is positive, an ELISA is performed; if the ELISA is positive, it confirms a toxin-producing form of C. difficile with no further testing required. However, if the ELISA is negative, a PCR is then performed. If the PCR is positive, the patient has toxin-producing C. difficile; negative results indicate that the patient has non–toxin-producing C. difficile. This type of sequenced testing optimizes the specificity of diagnosis and is cost-effective, although perhaps not as expedient as performing only a PCR test. With the observed epidemiologic changes of CDI, there is an increased urgency for more accurate, rapid testing also capable of detecting hypervirulent strains. The FDA recently approved the Cepheid Xpert C. difficile/Epi assay.36 This method offers a rapid test for toxin B and can detect the NAP1/BI/027 strain. Most practicing clinicians must rely on whatever diagnostic tools are available at their local laboratory or institution to test for CDI. Clinicians must understand the risk for false-positive or false-negative results with the methods available at their institution because this information might affect their decision making.

Treatment The first step in managing patients with CDI requires discontinuing any antibiotics that might be contributing to the infection whenever possible;

15% to 25% of cases will resolve without any further therapy.37,38 Because discontinuation of antibiotics is not always feasible—and this conservative measure alone is not appropriate in patients with persistent symptomatic disease—antibiotic therapy and other interventions must be considered. The Table (page 18) gives an overview of current treatment recommendations for CDI. Metronidazole is the first-line treatment for patients with mild to moderate CDI because of its efficacy and low cost. A 2007 Cochrane Review found that metronidazole (usually given as 500 mg orally 3 times daily for 10-14 days) had similar efficacy to vancomycin for non-severe CDI39; however, as the C. difficile epidemic continues to grow, the rate of treatment failure and the number of patients who experience relapses or recurrences are increasing as well. Data from the 1980s and 1990s showed that metronidazole had a low treatment failure rate (<5%),37,40 but recent studies have observed failure rates as high as 38%.41,42 Some blame hypervirulent strains for the reduced efficacy of metronidazole, but a study that compared a cohort from 1998 with one from 2004 to 2006 showed that metronidazole failure rates were similar and remarkably high in both groups (35%).43 Moreover, the incidence of NAP1/BI/027 was similar in patients who were treated successfully with metronidazole (21%) and those who experienced treatment failure (26%; P=0.67).43 Metronidazole is usually well tolerated, but about 1% of patients experience systemic side effects, including nausea and a metallic taste; peripheral sensory neuropathy may be seen with prolonged treatment.37 Because of the risks for birth defects associated with metronidazole, it should not be used in pregnant women. Metronidazole remains the first-line therapy for patients with mild to moderate disease and has the potential benefit of not causing vancomycin-resistant enterococci (VRE). Vancomycin is now considered first-line therapy for patients with moderate to severe CDI. Oral vancomycin has minimal systemic absorption, resulting in high concentrations in the colon, thus minimizing its systemic side effects and theoretically making it an ideal treatment. Zar and colleagues compared the efficacy of metronidazole with that of vancomycin in patients stratified by disease severity. In patients with mild disease, the efficacy of metronidazole was similar to that of vancomycin (90% vs 98%; P=0.36); patients with severe disease were significantly more likely to respond to treatment with vancomycin than with metronidazole (97% vs 76%; P=0.02).41 Vancomycin is indicated for the treatment of moderate to severe CDI in pregnant women, children aged 10 years or younger, and patients who either failed or are intolerant to metronidazole.30 Vancomycin 125 mg 4 times daily is as effective as 500 mg 4 times daily.44 It is recommended to use the lower dose with most patients; the higher dosing is reserved for critically ill patients. In the latter group, vancomycin may be given orally, by nasogastric tube, or via enema while IV metronidazole is administered.

Recurrent CDI Recurrent CDI has been observed in 15% to 30% of patients who successfully completed an initial treatment.45 There are no uniformly accepted criteria for disease recurrence, but most include patients who have repeat Text continues on page 16

16 Clinical

Pharmacy Practice News • October 2011

Educational Review predisposes patients to VRE and other organisms. In addition to maintaining an altered state of bowel flora,10 continued use of vancomycin may cause C. difficile resistance, although such resistance currently is rare.47

Text continued from page 15

symptomatic infection within 2 days to 2 months after completing an appropriate treatment. It is likely that initial treatment failure occurred in some of these patients and that they never fully cleared the infection. Wilcox et al ribotyped strains of C. difficile in index and recurrent disease and found that 56% of recurrences were caused by a different strain from the one that caused the initial infection.46 Most clinicians and authors do not distinguish relapse (ie, same strain) from recurrence (ie, different strain). Regardless of whether the strain that causes CDI recurrence is the same or different from the one that caused the original infection, patients who are unable to generate immunoglobulin G (IgG) against C. difficile toxin A are more likely to have repeat infections.45 Other risk factors for recurrent infection include those listed above for index infection and also being aged 65 years or older, increased WBC counts during initial infection, low serum albumin levels, and antibiotic use between the initial treatment and the recurrent infection.1,11 It seems that the greatest risk factor for recurrent infection is a recurrence itself—up to 65% of patients who have 1 recurrence may have future episodes.47 Treatment of Recurrent CDI When managing patients with recurrent CDI, it is important to eliminate the possibility of postCDI irritable bowel syndrome48 and other causes of diarrhea.45 Similar to the index presentation, once a diagnosis has been confirmed, clinicians should again attempt to limit or eliminate any potential offending antibiotics if possible. If a patient must remain on antibiotics, switching to one that is less commonly associated with CDI is advised, if possible.

Antibiotics In the past, the same 14-day treatment course with the antibiotic used to treat the initial infection was recommended. Recently, however, vancomycin has been recommended for patients with a moderate to severe recurrence, regardless of which initial antibiotic was used. Some authors recommend a 14-day course of vancomycin, but a tapered-pulse therapy regimen is generally being used, despite the absence of robust evidence to prove its value over a standard 14-day course of therapy for either the first or second recurrence of CDI. Tapered-pulse therapy allows the antibiotic-resistant spore form of the organism to convert into the antibiotic-sensitive, vegetative form as the antibiotic is withdrawn slowly and, in the final stages of tapering, is given on alternate days. Theoretically, spores convert to their vegetative form on days when vancomycin is not administered, and vegetative forms are killed on the days when the drug is taken.14 Although this tapered and pulse-dosing regimen is widely used and effective in many patients, the recurring and chronic use of antibiotics to treat recurrent CDI has its downsides, especially in terms of the intestinal microbiota. Vancomycin is a broad-spectrum antimicrobial agent with activity against almost all gram-positive aerobic and anaerobic organisms. As a result, it may increase host susceptibility to CDI by killing many of the normal intestinal microorganisms; its use also

Probiotics By restoring the “balance” of the normal colonic microbiota, probiotics are believed to help restore the “colonization resistance” or protective barrier of intestinal microflora. Saccharomyces boulardii has been the most extensively studied probiotic for recurrent CDI. Surawicz and colleagues conducted a double-blind, placebo-controlled trial that compared placebo or S. boulardii (added during day 7 of treatment) with high-dose vancomycin (2 g/d), low-dose vancomycin (500 mg/d), or metronidazole (1 g/d).3 The placebo or S. boulardii was then continued for 28 days. Patients who received high-dose vancomycin and S. boulardii showed a significantly lower recurrence rate than the placebo/high-dose vancomycin group (16.7% vs 50%; P=0.05), whereas there were no significant differences seen between patients on low-dose vancomycinand those on low-dose metronidazole.3 McFarland et al conducted a meta-analysis looking at all probiotics studied in the prevention of CDI and found that the only probiotic to show a significant risk reduction (41%) for recurrent disease was S. boulardii.49 It is believed that S. boulardii releases a protease that inactivates C. difficile toxin receptors, thereby preventing symptomatic disease.3 Despite this probiotic having no significant adverse side effects, there have been documented cases of immunocompromised patients suffering from fatal fungemia during its use.50 Clinicians should consider the most appropriate conditions for the use of probiotics to prevent recurrent CDI and avoid longterm use of S. boulardii.

Novel Therapies for CDI Along with the increasing virulence of CDI, treatment failure and disease recurrence have become more common. In response to this trend, several new treatments are being studied, including alternative antibiotics, C. difficile toxin–binding resins, monoclonal antibodies against toxins A and B, C. difficile vaccination,2 and FMT. Nitazoxanide Nitazoxanide is a nitrothiazolide that is commonly used to treat intestinal parasites such as cryptosporidia and giardia. A breakdown product of nitazoxanide, tizoxanide, actively inhibits the anaerobic metabolism of C. difficile; because approximately two-thirds of each dose is excreted in the feces, this medication potentially offers an alternative treatment. When the in vitro efficacy of nitazoxanide was investigated in 127 strains of C. difficile (including the most common and most virulentribotypes), it showed excellent bactericidal activity.51 A double-blind, placebo-controlled study that compared nitazoxanide 500 mg twice daily for 7 days with metronidazole 250 mg 4 times daily for 10 days found that 82.4% of patients receiving metronidazole and 89.5% of patients receiving nitazoxanide responded to treatment. The results proved that nitazoxanide is noninferior

to metronidazole for first-line therapy.52 A separate study that investigated patients who failed conventional treatment with metronidazole found that nitazoxanide 500 mg twice daily had a 74% response rate and a 54% cure rate.53 Nitazoxanide appears to have adequate efficacy in the treatment of CDI, but it is not superior to current treatments and thus likely will remain a third-line alternative used after other regimens fail. Rifaximin Rifaximin is a poorly absorbed rifamycin derivative that inhibits bacterial transcription and protein synthesis. Following its FDA approval for traveler’s diarrhea, many uses for this antibiotic have been studied, including small intestinal bacterial overgrowth, hepatic encephalopathy, and CDI. In vitro studies of rifaximin for the treatment of CDI have shown promising results,54 but some studies also have shown the development of rifaximin resistance.55 One small case series of 3 post–liver transplant patients who failed standard initial treatment found that vancomycin followed by a 28-day course of rifaximin (400 mg 3 times daily) resulted in resolution of diarrhea in all patients within 48 hours of treatment; all remained symptom-free at 6-month follow-up.56 Rifaximin 100 to 200 mg twice daily following treatment completion with vancomycin for recurrent CDI also showed efficacy in a separate case series.57 Although these results are encouraging, they must be confirmed with large-scale trials. Currently, the use of rifaximin following vancomycin for the treatment of recurrent CDI is considered to be useful. Fidaxomicin Fidaxomicin, a narrow-spectrum macrocyclic antibiotic, is a promising new antimicrobial treatment for CDI.58 A study that compared fidaxomicin with vancomycin in patients with recurrent CDI found a lower rate of recurrence with fidaxomicin than with vancomycin (20% vs 36%; P=0.045).59 A head-to-head comparison of fidaxomicin 200 mg 3 times daily with vancomycin 125 mg 4 times daily for 10 days found that fidaxomicin was noninferior to vancomycin, with clinical cure rates of 88.2% and 85.8%, respectively. The rates of recurrence were significantly lower in the fidaxomicin group than in the vancomycin group (15.4% vs 25.3%; P=0.005).60 For patients with the NAP1/ BI/027 strain, the rates of clinical cure and recurrence were similar for fidaxomicin (78.7% and 27.1%, respectively) and vancomycin (80.7% and 20.9%, respectively).60 Adverse events from fidaxomicin, although rare, include nausea, vomiting, headache, and abdominal pain. In May 2011, the FDA approved fidaxomicin for the treatment of C. difficile–associated diarrhea.61 Fidaxomicin is a good alternative to vancomycin and is less frequently associated with disease recurrence. Toxin Binders C. difficile toxins A and B are thought to be the main mediators of symptomatic CDI. Theoretically, binding resins should help to control CDI by binding the toxins without altering the colonic microbiota. Using 4 g of binding resin 3 or 4 times daily, previous studies have found varying efficacy, from 36% with colestipol to 68% with cholestyramine.4 Tolevamer was designed as a synthetic polysterol Text continues on page 18

18 Clinical

Pharmacy Practice News • October 2011

Educational Review Table. Treatments for C. difficile Infection Treatment

Indication

Administration

Comments

Metronidazole

Mild to moderate CDI

500 mg PO or IV tid for 10-14 d

First-line therapy for mild to moderate CDI, but increasing rates of refractory infection are being observed.

Vancomycin

Moderate to severe CDI

125-500 mg PO qid for 10-14 d

Lower dose should be given to most patients, reserving the higher dose for those who are critically ill. Oral, nasogastric, or rectal therapy may be combined with IV metronidazole in critically ill patients.

Recurrent CDI

Tapered-pulse PO therapy

It is unclear whether this should be used after the first or second recurrence, but this is a very effective treatment.

Saccharomyces boulardii

Prevention of recurrent CDI

500 mg PO bid for 28 d. Usually started after 7 d of antibiotic treatment

Avoid using in immunosuppressed patients; should not be given chronically.

Nitazoxanide

Index infection or recurrent CDI

500 mg PO bid for 7 d

This medication has been shown to be noninferior to metronidazole, but further studies are needed to clarify its role in CDI.

Rifaximin

Recurrent CDI

Variable dosing between studies and lack of well-controlled trials 200 mg PO bid to 400 mg PO tid for 28 d. May be given as a “chaser” limit the understanding of the usefulness of this treatment. after completion of vancomycin therapy for recurrent CDI

Fidaxomicin

Index infection or recurrent CDI

200 mg PO bid for 10 d

Recently approved by the FDA to treat CDI. This medication is noninferior to vancomycin and is associated with a significantly lower rate of recurrent infection.

Toxin binders

Symptomatic adjunct to antibiotic treatment

4 g PO tid or qid for the same duration as the antibiotic therapy

Toxin binders such as cholestyramine should be used to control symptomatic diarrhea but not as the only treatment.

Immunoglobulins Refractory CDI

IV infusion at a dose of 400 mg/kg (IVIG) of body weight given with antibiotic therapy

Appears to help treat refractory/recurrent infections by enhancing overall efficacy of treatment and minimizing further recurrences.

Fecal microbiota transplantation

300 cc of fecal suspension from a healthy donor that is colonoscopically placed throughout the colon

Excellent preliminary results in patients with severe and refractory disease. Best methodology is yet to be clarified.

Recurrent/refractory CDI Unclear role in severely ill CDI patients as first-line therapy

bid, twice daily; CDI, Clostridium difficile infection; IVIG, intravenous immunoglobulin; PO, by mouth; qid, 3 times daily; tid, 4 times daily

Text continued from page 16

that also is capable of binding C. difficile toxins, but it was shown to be significantly less effective than both vancomycin and metronidazole in clinical trials, resulting in the discontinuation of its production.62 The role of toxin binders in patients with symptomatic CDI likely is as an adjunct to primary antibiotic treatment; toxin binders act to control the symptoms of CDI while another agent treats the active infection. Immunotherapy Patients with elevated levels of serum IgG against toxin A are less likely to develop symptomatic infection,whereas patients with low levels following infection are more likely to have recurrent disease.45 Passive immunization with IV immunoglobulin (IVIG) is another therapeutic intervention that attempts to supplement a patient’s immune response to CDI. Several small studies using IVIG (usually 400 mg/kg of body weight) in patients with severe or recurrent disease have shown mixed results. One trial found up to a 100% response rate,63 whereas others found significantly lower efficacy.64 Antibodies more specific to CDI have been developed as well. Lowy et al conducted a doubleblind, placebo-controlled trial that compared

patients receiving metronidazole or vancomycin alone with those receiving metronidazole or vancomycin in combination with fully human monoclonal antibodies to C. difficile toxins A and B (10 mg/kg of body weight). Overall, patients receiving antibodies in combination with the antibiotic were less likely to have recurrent infections (7% vs 25%; P<0.001). Patients infected with the NAP1/BI/O27 strain showed a trend toward lower rates of recurrence as well (8% vs 32%; P=0.06).5 Targeted antibody treatments seem to be a very encouraging future option in the management of CDI. Fecal Transplantation Fecal transplantation, also known as fecal bacteriotherapy or, preferably, FMT (because we do not know which of the living organisms or metabolic products in stool are effective in the various diseases for which this therapy has been used), is another promising and interesting treatment option. The rationale behind FMT is simple: Antibiotics and other factors disrupt the normal balance of the colonic microbiome, and by reintroducing normal microbiota via donor feces, a balanced “colonization resistance” can be reestablished.21 Compared with stools from patients who had antibiotic-associated diarrhea not associated with C. difficile and

those with just a single episode of CDI,65 patients with recurrent CDI had a decreased species richness in their stool. There was a specific absence of Bacteroidetes and Firmicutes phyla, suggesting that this microbiome “fingerprint” is characteristic of recurrent CDI and that FMT might be a possible treatment modality.65 The clinical use of FMT dates back to 1958, although the bulk of published work, which is still very limited, has come in the last 2 decades.66,67 Initially, retention enemas were the most common technique for FMT, but fecal infusion via duodenal tube,68 rectal tube,69 and colonoscopy70-72 recently have been reported. One case series of 18 patients with CDI (17 had FMT via colonoscopy, 1 via gastrostomy) showed that 15 of 18 patients were cured with no relapses noted. The 3 patients who failed to respond had severe colitis.70 In a series of 12 patients with recurrent or refractory disease in whom donor feces were infused at colonoscopy, all 12 had prompt symptomatic cure within hours to days, with no adverse events.71 In another separate case series of 19 patients with recurrent CDI using a similar technique, 18 of 19 patients immediately responded to treatment. Three patients ultimately had recurrent infection following treatment, but all 3 recurrences occurred

Pharmacy Practice News • October 2011

Clinical 19

Educational Review immediately after antibiotic treatment, making a de novo infection rather than FMT treatmentfailure the likely cause.72 There is no consensus opinion on the exact technique to perform FMT at this time. The colonoscopic approach is now favored over the fecal enema because enemas only reach the splenic flexure,73 whereas with colonoscopy, the entire colon and ileum can be recolonized, and colonoscopy can elucidate the extent and severity of disease while the treatment is given.72 Regardless, FMT appears to be an effective treatment for refractory or recurrent CDI, with an 89% cure rate in 275 case reports from across the world.74 Further research on FMT is needed to clarify the optimal delivery methods, appropriate donors, and situations most appropriate to use this technique. A large randomized controlled trial, FECAL (Fecal therapy to Eliminate Clostridium difficile–Associated Longstanding diarrhea), is under way in Norway. It compares patients with refractory CDI receiving standard high-dose vancomycin with those receiving high-dose vancomycin and then FMT.60 When the results of the FECAL trial and other studies are published, the role of FMT in the management of CDI will be further clarified.

Conclusion CDI is an epidemic that is rapidly evolving. As we understand more about this infection, its risk factors, its modes of transmission, and potential treatments, we will be better equipped to both effectively prevent new cases and treat existing ones. Currently, many promising treatments beyond metronidazole and vancomycin are available. The most promising of these therapies include fidaxomicin and FMT for treatment of refractory infection and perhaps S. boulardii for the prevention of recurrence following treatment of primary infection.

References 1. Heinlen L, Ballard JD. Clostridium difficile infection. Am J Med Sci. 2010;340(3): 247-252.

7. Rodemann JF, Dubberke ER, Reske KA, et al. Incidence of Clostridium difficile infection in inflammatory bowel disease. Clin Gastroenterol Hepatol. 2007;5(3):339-344. 8. Bossuyt P, Verhaegen J, Van Assche G, et al. Increasing incidence of Clostridium difficileassociated diarrhea in inflammatory bowel disease.J Crohns Colitis. 2009;3(1):4-7. 9. Hall IC, O’Toole E. Intestinal flora in newborn infants with a description of a new pathogenic anaerobe, Bacillus difficilis. Am J Dis Child. 1935;49(2):390-402. 10. Bartlett JG, Chang TW, Gurwith M, et al. Antibiotic-associated pseudomembranous colitis due to toxin-producing clostridia.

11. Hookman P, Barkin JS. Clostridium difficile associated infection, diarrhea and colitis. World J Gastroenterol. 2009;15(13):1554-1580. 12. Feldman M, Friedman LS, Brandt LJ. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease. 9th ed. Philadelphia, PA: Elsevier Inc.; 2010. 13. Feuerstadt P, Nunez JC, Rahimi E, Das R, Brandt LJ. S1228 community-acquired Clostridium difficile-associated disease (CA-CDAD): characterization of an urban disease. Gastroenterology. 2010;138(5 suppl 1):S208-S209. 14. Bajaj JS, Ananthakrishnan AN, Hafeezullah M, et al. Clostridium difficile is associated with

THE

4. Leffler DA, Lamont JT. Treatment of Clostridium difficile-associated disease. Gastroenterology. 2009;136(6):1899-1912. 5. Lowy I, Molrine DC, Leav BA, et al. Treatment with monoclonalantibodiesagainst Clostridium difficile toxins. N Engl J Med. 2010; 362(3):197-205. 6. McDonald LC, Owings M, Jernigan DB. Clostridium difficile infectionin patients discharged from US short-stay

15. Ben-Horin S, Margalit M, Bossuyt P, et al. Combination immunomodulator and antibiotic treatment in patients with inflammatory bowel disease and Clostridium difficile infection. Clin Gastroenterol Hepatol. 2009;7(9):981-987. 16. Pepin J, Valiquette L, Gagnon S, et al. Outcomes of Clostridium difficile-associated disease treated with metronidazole or vancomycin before and after the emergence of NAP1/027. Am J Gastroenterol. 2007;102(12):2781-2788. Text continues on page 20

FIRST AND ONLY TETRASTARCH AVAILABLE IN THE U.S.

An established 12-year global track record of safety and efﬁcacy

•

Available in over 100 countries 1

•

Over

•

Studied in numerous surgical procedures and patients 2

•

Over 160 publications 1

30 million patients treated1

Voluven™ is the #1 iso-oncotic plasma volume expander in Europe1,3 • Used over 20 times more frequently than iso-oncotic albumin in Europe3

• Austria • Belgium • Denmark • France

• Germany • Greece • Ireland • Italy

• Poland • Spain • Sweden • Switzerland

2. Blossom DB, McDonald LC. The challenges posed by reemerging Clostridium difficile infection. Clin Infect Dis. 2007;15;45(2):222-227. 3. Surawicz CM, McFarland LV, Greenberg RN, et al. The search for a better treatment for recurrent Clostridium difficile disease: use of high-dose vancomycin combined with Saccharomyces boulardii. Clin Infect Dis. 2000;31(4):1012-1017.

poor outcomes in patients with cirrhosis: a national and tertiary center perspective. Am J Gastroenterol. 2010;105(1):106-113.

N Engl J Med. 1978;298(10):531-534.

hospitals, 1996-2003. Emerg Infect Dis. 2006;12(3):409-415.

Countries where Voluven is available

Indications and usage Voluven is a plasma volume substitute indicated for the treatment and prophylaxis of hypovolemia. Safety information Voluven is contraindicated in patients with a known hypersensitivity to starch, ﬂuid overload, renal failure with oliguria or anuria not related to hypovolemia, those receiving dialysis, severe hypernatremia, severe

hyperchloremia and intracranial bleeding. Avoid fluid overload; adjust dosage in patients with cardiac or renal dysfunction. Monitor kidney function, fluid balance, acid-base balance, coagulation parameters and serum electrolytes. In severe dehydration a crystalloid solution should be given first. Elevated serum amylase levels may occur and interfere with the

diagnosis of pancreatitis. Observe caution in patients with severe liver disease or bleeding disorders. High dosages may cause dilution of blood components. Anaphylactoid/hypersensitivity reactions can occur. Most common adverse reactions (incidence >1%) are pruritus, elevated serum amylase, and hemodilution (resulting in dilution of blood components, e.g., coagulation

References: 1. Data on ﬁle. Hospira, Inc. 2. Voluven [package insert]. Lake Forest, IL: Hospira, Inc; 2007. 3. IMS Sales Perspective 2009. Hospira Inc., 275 North Field Drive, Lake Forest, IL 60045

P11-3428-Sep., 11 Rx Only

factors and other plasma proteins and a decrease in hematocrit). Please see brief summary on following page.

20 Clinical

Pharmacy Practice News • October 2011

Educational Review Text continued from page 19

17. Kyne L, Merry C, O’Connell B, et al. Factors associated with prolonged symptoms and severe disease due to Clostridium difficile. Age Ageing. 1999;28(2):107-113. 18. Feuerstadt P, Aroniadis OC, Brandt LJ. S1273 standard admission lab values as predictors of outcome in patients with colon ischemia, Crohn’s disease, and Clostridium difficile associated disease. Gastroenterology. 2008;134(4 suppl 1):A215-A216. 19. Pepin J, Alary ME, Valiquette L, et al. Increasing risk of relapse after treatment of Clostridium difficile colitis in Quebec, Canada. Clin Infect Dis. 2005;40(11):1591-1597. 20. Das R, Feuerstadt P, Brandt LJ. Glucocorticoids are associated with

increased risk of short-term mortality in hospitalized patients with Clostridium difficile-associated disease. Am J Gastroenterol. 2010;105(9):2040-2049. 21. K yne L, Farrell RJ, Kelly CP. Clostridium difficile. Gastroenterol Clin North Am. 2001;30(3):753-777, ix-x. 22. Saginur R, Hawley CR, Bartlett JG. Colitis associated with metronidazole therapy. J Infect Dis. 1980;141(6):772-774.

during an epidemic in Quebec. Clin Infect Dis. 2005;41(9):1254-1260. 25. Gorbach SL. Antibiotics and Clostridium difficile. N Engl J Med. 1999;341(22): 1690-1691. 26. Surveillance for community-associated Clostridium difficile—Connecticut, 2006. MMWR Morb Mortal Wkly Rep. 2008; 57(13):340-343.

23. Hecht JR, Olinger EJ. Clostridium difficile colitis secondary to intravenous vancomycin. Dig Dis Sci. 1989;34(1):148-149.

27. McFarland LV. Epidemiology of infectious and iatrogenic nosocomial diarrhea in a cohort of general medicine patients. Am J Infect Control. 1995;23(5):295-305.

24. Pepin J, Saheb N, Coulombe MA, et al. Emergence of fluoroquinolones as the predominant risk factor for Clostridium difficile-associated diarrhea: a cohort study

28. Gerding DN, Johnson S, Peterson LR, et al. Clostridium difficile-associated diarrhea and colitis. Infect Control Hosp Epidemiol. 1995;16(8):459-477.

BRIEF SUMMARY CONSULT PACKAGE FOR FULL PRESCRIBING INFORMATION

VOLUVEN® (6% HYDROXYETHYL STARCH 130/0.4 IN 0.9% SODIUM CHLORIDE INJECTION) 1 INDICATIONS AND USAGE Voluven® (6% hydroxyethyl starch 130/0.4 in 0.9% sodium chloride injection) is indicated for the treatment and prophylaxis of hypovolemia. It is not a substitute for red blood cells or coagulation factors in plasma. 4 CONTRAINDICATIONS The use of Voluven® is contraindicated in the following conditions: • known hypersensitivity to hydroxyethyl starch [see General Warnings and Precautions (5.1)] • fluid overload (hyperhydration) and especially in cases of pulmonary edema and congestive heart failure • renal failure with oliguria or anuria not related to hypovolemia • patients receiving dialysis treatment • severe hypernatremia or severe hyperchloremia • intracranial bleeding. 5 WARNINGS AND PRECAUTIONS 5.1 General Warnings and Precautions Anaphylactoid reactions (mild influenza-like symptoms, bradycardia, tachycardia, bronchospasm, non-cardiac pulmonary edema) have been reported with solutions containing hydroxyethyl starch. If a hypersensitivity reaction occurs, administration of the drug should be discontinued immediately and the appropriate treatment and supportive measures should be undertaken until symptoms have resolved. [see Adverse Reactions (6)] Fluid status and rate of infusion should be assessed regularly during treatment, especially in patients with cardiac insufficiency or severe kidney dysfunction. In cases of severe dehydration, a crystalloid solution should be given first. Generally, sufficient fluid should be administered in order to avoid dehydration. Caution should be observed before administering Voluven® to patients with severe liver disease or severe bleeding disorders (e.g., severe cases of von Willebrand´s disease). 5.2 Monitoring: Laboratory Tests Clinical evaluation and periodic laboratory determinations are necessary to monitor fluid balance, electrolyte concentrations, kidney function, acid-base balance, and coagulation parameters during prolonged parenteral therapy or whenever the patient’s condition warrants such evaluation. 5.3 Interference with Laboratory Tests Elevated serum amylase levels may be observed temporarily following administration of the product and can interfere with the diagnosis of pancreatitis. At high dosages the dilutional effects may result in decreased levels of coagulation factors and other plasma proteins and a decrease in hematocrit. 6 ADVERSE REACTIONS 6.1 Overall Adverse Reaction Profile From the accumulated clinical development experience, expected adverse reactions after administration of Voluven® occurring in less than 10% of patients are as follows: Immune system disorders (Rare, >0.01% to <0.1%): Products containing hydroxyethyl starch may lead to anaphylactoid reactions (hypersensitivity, mild influenza-like symptoms, bradycardia, tachycardia, bronchospasm, non-cardiac pulmonary edema). In the event of an intolerance reaction, the infusion should be discontinued immediately and the appropriate emergency medical treatment initiated. [see General Warnings and Precautions (5.1)] Skin and subcutaneous tissue disorders (Common, >1 to <10%, dose dependent): Prolonged administration of high dosages of hydroxyethyl starch may cause pruritus (itching) which is an undesirable effect observed with all hydroxyethyl starches. Investigations (Common, >1% to <10%, dose dependent): The concentration of serum amylase can rise during administration of hydroxyethyl starch and can confound the diagnosis of pancreatitis. At high doses the dilutional effects may result in decreased levels of coagulation factors and other plasma proteins and in a decrease of hematocrit. [see Interference with Laboratory Tests (5.3)]

6.2 Adverse Reactions in Clinical Trials Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug may not reflect the rates observed in practice. During clinical development, 471 patients were exposed to Voluven®, and a total of 768 patients received the hydroxyethyl starch 130/0.4 drug substance contained in Voluven® at different concentrations (2%, 4%, 6%, or 10%) and at cumulative doses of several mL up to 66 L1). The mean duration of treatment with hydroxyethyl starch 130/0.4 was 3.9 ± 3.3 days, mean cumulative doses were 3338 ± 3695 mL, and the longest follow-up period was 90 days. In the US trial, 100 patients undergoing elective orthopedic surgery were treated either with Voluven® (N=49) or hetastarch (6% hydroxyethyl starch in 0.9% sodium chloride injection) (N=51) for intraoperative volume replacement. Mean infusion volumes were 1613 ± 778 mL for Voluven® and 1584 ± 958 mL for hetastarch. Adverse reactions observed in at least 1% of patients: In the US trial comparing Voluven® with hetastarch, a possible relationship to Voluven® was reported in five cases in a total of three patients (aPTT elevated, PT prolonged, wound hemorrhage, anemia, pruritus). A possible relationship to hetastarch was reported in five patients (three cases of coagulopathy; two cases of pruritus). The three coagulopathy cases in the hetastarch group were serious and occurred in patients receiving more than the labeled ceiling dose (20 mL/kg), whereas no serious coagulopathy occurred in the Voluven® group. 6.3 Postmarketing Experience The following adverse reactions have been identified during the post-approval use of Voluven® and other types of hydroxyethyl starch solutions. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The safety profile from postmarketing experience of Voluven® is not different from the profile obtained from clinical trials performed using the product. Based on spontaneous reporting of hypersensitivity reactions, urticaria, bronchospasm, or hypotension were the most frequently reported serious adverse drug reactions for patients treated with Voluven®. With the administration of hydroxyethyl starch solutions, disturbances of blood coagulation can occur depending on the dosage2). 10 OVERDOSAGE As with all plasma volume substitutes, overdosage can lead to overloading of the circulatory system (e.g. pulmonary edema). In this case, the infusion should be stopped immediately and if necessary, a diuretic should be administered. [see General Warnings and Precautions (5.1)] 16 HOW SUPPLIED/STORAGE AND HANDLING Voluven® (6% hydroxyethyl starch 130/0.4 in 0.9% sodium chloride injection) for intravenous infusion is supplied in the following primary container and carton sizes: Polyolefin bag (freeflex®) with overwrap: 500 mL Carton of 15 x 500 mL NDC 0409-1029-01 Store at 15° to 25°C (59° to 77°F). Do not freeze.

29. McFarland LV, Mulligan ME, Kwok RY, Stamm WE. Nosocomialacquisition of Clostridium difficile infection. N Engl J Med. 1989; 320(4):204-210. 30. Fekety R. Guidelines for the diagnosis and management of Clostridium difficileassociated diarrhea and colitis. American College of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol. 1997;92(5):739-750. 31. Wilcox MH, Fawley WN. Hospital disinfectants and spore formation by Clostridium difficile. Lancet. 2000;356(9238):1324. 32. Kyne L, Warny M, Qamar A, Kelly CP. Asymptomatic carriage of Clostridium difficile and serum levels of IgG antibody against toxin A. N Engl J Med. 2000;342(6):390-397. 33. Barbut F, Kajzer C, Planas N, Petit JC. Comparison of three enzyme immunoassays, a cytotoxicity assay, and toxigenic culture for diagnosis of Clostridium difficile-associated diarrhea. J Clin Microbiol. 1993;31(4):963-967. 34. Merz CS, Kramer C, Forman M, et al. Comparison of four commercially available rapid enzyme immunoassays with cytotoxin assay for detection of Clostridium difficile toxin(s) from stool specimens. J Clin Microbiol. 1994;32(5):1142-1147. 35. Walker RC, Ruane PJ, Rosenblatt JE, et al. Comparison of culture, cytotoxicity assays, and enzyme-linked immunosorbent assay for toxin A and toxin B in the diagnosis of Clostridium difficile-related enteric disease. Diagn Microbiol Infect Dis. 1986;5(1):61-69. 36. FDA clears test for bacteria that can cause serious intestinal disease [press release]. Silver Spring, MD: FDA; April 8, 2011. 37. Olson MM, Shanholtzer CJ, Lee JT Jr, Gerding DN. Ten years of prospective Clostridium difficile-associated disease surveillance and treatment at the Minneapolis VA Medical Center, 1982-1991. Infect Control Hosp Epidemiol. 1994;15(6):371-381. 38. Teasley DG, Gerding DN, Olson MM, et al. Prospective randomised trial of metronidazole versus vancomycin for Clostridium-difficile-associated diarrhoea and colitis. Lancet. 1983;2(8358):1043-1046. 39. Nelson R. Antibiotic treatment for Clostridium difficile associated diarrhea in adults. Cochrane Database Syst Rev. 2007(3):CD004610. 40. Zimmerman MJ, Bak A, Sutherland LR. Review article: treatmentof Clostridium difficile infection. Aliment Pharmacol Ther. 1997; 11(6):1003-1012. 41. Zar FA, Bakkanagari SR, Moorthi KM, Davis MB. A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity. Clin Infect Dis. 2007;45(3):302-307. 42. Kelly CP, LaMont JT. Clostridium difficile— more difficult than ever. N Engl J Med. 2008;59(18):1932-1940. 43. Hu MY, Maroo S, Kyne L, et al. A prospective study of risk factors and historical trends in metronidazole failure for Clostridium difficile infection. Clin Gastroenterol Hepatol. 2008;6(12):1354-1360. 44. Fekety R, Silva J, Kauffman C, Buggy B, Deery HG. Treatment of antibiotic-associated Clostridium difficile colitis with oral vancomycin: comparison of two dosage regimens. Am J Med. 1989;86(1):15-19. 45. Maroo S, Lamont JT. Recurrent Clostridium difficile. Gastroenterology.2006;130(4): 1311-1316. 46. Wilcox MH, Fawley WN, Settle CD, Davidson A. Recurrence of symptoms in Clostridium difficile infection—relapse or reinfection? J Hosp Infect. 1998;38(2):93-100.

Manufactured by: Fresenius Kabi Norge AS, P.O. Box 430, NO-1753 Halden, Norway Distributed by: Hospira, Inc. 275 North Field Drive Lake Forest, Illinois 60045 USA Made in Norway

47. Wong SS, Woo PC, Luk WK, Yuen KY. Susceptibility testing of Clostridium difficile against metronidazole and vancomycin by disk diffusion and Etest. Diagn Microbiol Infect Dis. 1999;34(1):1-6.

Pharmacy Practice News • October 2011

Clinical 21

Educational Review 48. Grinspan AM, Bernheim OE, Yousefzadeh E, et al. 637 Clostridium difficile as a causative agent of post-infection irritable bowel syndrome. Gastroenterology. 2008;134 (4 suppl 1):A91. 49. McFarland LV. Meta-analysis of probiotics for the prevention of antibiotic associated diarrhea and the treatment of Clostridium difficile disease. Am J Gastroenterol. 2006;101(4):812-822. 50. Lestin F, Pertschy A, Rimek D. Fungemia after oral treatment with Saccharomyces boulardii in a patient with multiple comorbidities. Dtsch Med Wochenschr. 2003;128(48): 2531-2533. 51. Freeman J, Baines SD, Todhunter SL, Huscroft GS, Wilcox MH. Nitazoxanide is active against Clostridium difficile strains with reduced susceptibility to metronidazole. J Antimicrob Chemother. 2011;66(6):1407-1408. 52. Musher DM, Logan N, Hamill RJ, et al. Nitazoxanide for the treatment of Clostridium difficile colitis. Clin Infect Dis. 2006; 43(4):421-427. 53. Musher DM, Logan N, Mehendiratta V, et al. Clostridium difficile colitis that fails conventional metronidazole therapy: response to nitazoxanide. J Antimicrob Chemother. 2007;59(4):705-710. 54. Hecht DW, Galang MA, Sambol SP, et al. In vitro activities of 15 antimicrobial agents against 110 toxigenic Clostridium difficile clinical isolates collected from 1983 to 2004. Antimicrob Agents Chemother. 2007;51(8):2716-2719. 55. O’Connor JR, Galang MA, Sambol SP, et al. Rifampin and rifaximinresistance in clinical isolates of Clostridium difficile. Antimicrob Agents Chemother. 2008;52(8):2813-2817. 56. Neff G, Zacharias V, Kaiser TE, Gaddis A, Kemmer N. Rifaximin for the treatment of recurrent Clostridium difficile infection after liver transplantation: a case series. Liver Transpl. 2010;16(8):960-963. 57. Garey KW, Jiang ZD, Bellard A, Dupont HL. Rifaximin in treatment of recurrent Clostridium difficile-associated diarrhea: an uncontrolled pilot study. J Clin Gastroenterol. 2009;43(1):91-93. 58. Finegold SM, Molitoris D, Vaisanen ML, et al. In vitro activities of OPT-80 and comparator drugs against intestinal bacteria. Antimicrob Agents Chemother. 2004;48(12):4898-4902. 59. Cornely OA, Miller M, Louie T, Crook D, Sears P, Gorbach SL. Randomized controlled trial of fidaxomicin versus vancomycin in treatment of recurrent Clostridium difficile infection. Presented at: 50th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 12-15, 2010; Boston, MA. 60. Louie TJ, Miller MA, Mullane KM, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med. 2011;364(5):422-431. 61. FDA approves treatment for Clostridium difficile infection [press release]. Silver Spring, MD: FDA; May 27, 2011. 62. Louie TJ. Results of a phase III trial comparing tolevamer, vancomycin, and metronidazole in Clostridium difficileassociated diarrhea. Presented at: 47th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 1720, 2007; Chicago, IL. Abstract K-425a. 63. Leung DY, Kelly CP, Boguniewicz M, et al. Treatment with intravenously administered gamma globulin of chronic relapsing colitis induced by Clostridium difficile toxin. J Pediatr. 1991;118(4 pt 1): 633-637. 64. Wilcox MH. Descriptive study of intravenous immunoglobulin for the treatment of recurrent Clostridium difficile diarrhea. J Antimicrob Chemother. 2004;53(5):882-884. 65. Chang JY, Antonopoulos DA, Kalra A, Tonelli A, Khalife WT, Schmidt TM, Young VB.

Decreased diversity of the fecal microbiome in recurrent Clostridium difficile-associated diarrhea. J Infect Dis. 2008;197(3):435-438. 66. Eiseman B, Silen W, Bascom GS, Kauvar AJ. Fecal enema as an adjunct in the treatment of pseudomembranous enterocolitis. Surgery. 1958;44(5):854-859. 67. Borody TJ, Warren EF, Leis SM, et al. Bacteriotherapy using fecal flora: toying with human motions. J Clin Gastroenterol. 2004;38(6):475-483. 68. Flotterod O, Hopen G. Refractory Clostridium difficile infection. Untraditional treatment of antibiotic-induced colitis. Tidsskr Nor Laegeforen. 1991;111(11):1364-1365. 69. Paterson DL, Iredell J, Whitby M. Putting

back the bugs: bacterialtreatment relieves chronic diarrhoea. Med J Aust. 1994;160(4):232-233. 70. Lund-Tonnesen S, Berstad A, Schreiner A, Midtvedt T. Clostridiumdifficile-associated diarrhea treated with homologous feces. Tidsskr Nor Laegeforen. 1998;118(7): 1027-1030. 71. Yoon SS, Brandt LJ. Treatment of refractory/ recurrent C. difficile associated disease by donated stool transplanted via colonoscopy: a case series of 12 patients. J Clin Gastroenterol. 2010;44(8):562-566. 72. Rohlke F, Surawicz CM, Stollman N. Fecal flora reconstitution for recurrent Clostridium difficile infection: results and methodology. J Clin Gastroenterol. 2010;44(8):567-570.

73. Persky SE, Brandt LJ. Treatment of recurrent Clostridium difficile-associated diarrhea by administration of donated stool directly through a colonoscope. Am J Gastroenterol. 2000;95(11):3283-3285. 74. Brandt LJ, Reddy S. Endoscopic fecal microbiota transplantation: “first-line” treatment for severe Clostridium difficile infection? J Clinical Gastroenterol. 2011 [Epub ahead of print].

Dr. Brandt disclosed that he is a consultant for Optimer Pharmaceuticals, Inc. Dr. Feuerstadt reported no relevant conflicts of interest.

22 Spotlight on Technology

Pharmacy Practice News • October 2011

Site Visit

IV MANAGEMENT continued from page 1

Jamie Kelly President Entropy Research San Diego, California

“People can’t always recognize things as quickly as computers can,” he explained. “But computers aren’t always able to see what a person can. Ideally, technology allows people and computers to work together.” We visited York Hospital on a cold and still-snowy April morning to verify reports of a medication safety breakthrough that, frankly, sounds a little too good to be true—a sort of infusion nirvana on earth. Dr. Baker guided us into the hospital’s state-of-the-art clinical simulation lab saying, “There is no point in building an electronic hospital unless you can accomplish things that you could not achieve with paper. Our infusion management system is a fine example of innovative thinking transcending current practice.” With that we turned our attention to WellSpan’s vice president of patient care services and clinical transformation officer Kris O’Shea, RN, MS, who greeted us warmly, standing before a computer on wheels parked beside an IV pole. She began a tale of two situations—life before and after infusion management.

towels and even their scrubs. After a code, the nurse must then rely on memory and the limited notes available in order to accurately document the infusions administered. This process can take as long as two hours to complete for a single code. Historically, infusion pumps have been unable to communicate infusion status information beyond what was displayed on the pump. As such, the standard practice for managing the supply of titratable infusions from pharmacy to the nursing unit relies on phone calls, faxes or—as was the case at York—electronic health record (EHR) communications initiated by the nurse to the pharmacy. Even with an elec-

the risk for the patient’s blood pressure quickly elevating creates an urgent need.” In the pharmacy, unplanned, urgent requests for infusion preparation and numerous phone calls checking on the status of the infusions’ preparation and delivery diminish operational efficiencies and create additional distractions for pharmacists and technicians. As these reorder requests come into the pharmacy electronically, a number of pharmacists charged with order verification process these requests, and labels are ultimately generated remotely in the IV lab. This process creates a challenge for the pharmacy’s technical staff charged with IV admixture

‘Although infusion medications have a direct impact on patient condition, [traditionally] there is no centralized visibility to realtime effects for nurses and physicians.’ —Hal Baker, MD

Problems With Unconnected Infusion Management “The infusion of IV medications is a complicated process with many steps highly reliant on the diligent performance of a single nurse. The opportunity for error is ever present,” Ms. O’Shea said. In fact, IV medication errors are twice as likely to cause harm to patients as medications delivered by other routes of administration. Wrongpatient errors, a double tap of a key that results in a 10-fold dose error, and the selection of dobutamine instead of dopamine from the smart infusion pump drug library are all inevitable consequences of human nature. With some high-acuity patients receiving up to eight different IV medications simultaneously, the potential for a mistake is high. Clinical risk aside, infusions also take an operational toll on caregivers. Documenting IV medication administrations is an especially time-consuming part of a nurse’s day as each new infusion and rate adjustment must be documented. The process is especially challenging in emergency situations when nurses document under the gun, jotting on paper

inefficiency surrounding the preparation of scheduled continuous and intermittent IVs that are generally pre- SPOTLIGHT ON pared in advance via a TECHNOLOGY set time frame (e.g., all IV medications scheduled to be administered within the next six hours). “The result is that medications are delivered to the unit well in advance of need. Subsequently, the orders for these medications may be discontinued after the infusion has already been delivered,” he said. Pharmacy staff must then collect the medication during a subsequent delivery and return it to the pharmacy for crediting and potential redistribution to another patient, when possible. In some cases, Mr. Gerhart added, returned infusions with limited stability “may be unusable upon return to pharmacy and must be destroyed, resulting in unnecessary waste.” Mr. Gerhart pointed out that this type of batch production in advance of need might present a risk to patient safety as well. When large supplies of infusions are available on the nursing unit in advance of their actual need, he noted, the risk for a wrong patient or wrong medication error increases significantly. Finally, Dr. Baker was quick to point out that infusion data traditionally reside solely within the pump and are not easily synchronized with laboratory results or other device data such as vital signs. “Although infusion medications have a direct impact on patient condition, there is no centralized visibility to real-time effects for nurses and physicians,” he said.

EHR Reaches Deep

The York Hospital implementation team received a Collaboration Way-Paver Award at the 2011 unSUMMIT in Louisville, Ky. Left to right: Mary Gannon, RN, BSN, senior strategist, nursing and care delivery, Cerner Corporation; Donald “Chip” Gerhart Jr., RPh, York Hospital’s medication safety officer; Kris O’Shea, RN, MS, WellSpan’s vice president of patient care services; and Scott Zielski, general manager, system technologies & services, Hospira Worldwide Inc.

tronic reorder system in place, nurses typically call the pharmacy when an infusion is running extremely low for “peace of mind” that the product that they requested electronically will be prepared and delivered prior to the completion of the current infusion. “With many patients receiving numerous medications, an infusion could run out before the nurse is able to notify the pharmacy,” Ms. O’Shea said. “In the case of a medication like nicardipine,

as they frequently do not have a sense of which label/medication has priority over another. “It is somewhat accepted that this sort of controlled chaos is a way of life in the pharmacy,” said Donald “Chip” Gerhart Jr., RPh, York Hospital’s medication safety officer and pharmacy quality assessment manager. “But it is a significant drain on our resources and ultimately on our productivity.” Mr. Gerhart shared another area of

With 14 years of information amassed in the Cerner Millennium EHR, WellSpan clinicians typically have ready access to a patient’s full medical history over the past decade. EHR use is pervasive throughout the organization from nurses and physicians to physical therapists and social workers, a fact that is evident when entering York Hospital’s patient care areas. Flat-panel monitors display Cerner iAware integrated data. Vital signs, laboratory results and hundreds of pieces of patient data are compiled in dashboard views that paint a picture of total situation awareness of a patient’s condition for the clinician. Building on a long history of partnership, Cerner approached WellSpan with the prospect of being the first hospital in the nation to implement Cerner Care Aware Smart Pump Auto Programming and Infusion Management, a technology that combines the safety features of an automatically programmed infusion pump with software that provides clinical visibility to real-time infusion

Spotlight on Technology 23

Pharmacy Practice News • October 2011

Site Visit data. Cerner shared its vision of an EHR able to display infusion data (medication, dose and rate), as well as hourly volume infused and a continuous volume countdown based on information received from the infusion device. Collected at a single location, pump data combined with patient data from other sources would enable WellSpan to realize unprecedented clinical productivity, effectiveness and patient safety improvements. “When Cerner asked if we wanted to alpha partner on Infusion Management, we knew it was the perfect project,” recalled Ms. O’ Shea. Technically, the project required substantial engineering resources. Cerner developed a data-exchange platform called CareAware iBus, to enable twoway communication between devices (pumps, monitors, etc) and the EHR. WellSpan’s infusion pumps would need to send dosage, rate and volume information into the EHR. WellSpan selected Hospira’s Symbiq Infusion System with Hospira MedNet safety software to do the job. “Hospira stood out as the company most ready to work with Cerner to make the pump and the electronic health record work together so that our staff could focus their time on caring for patients,” recounted Dr. Baker. Together, the solution suppliers created a system in which data flow from Cerner Millennium to CareAware iBus to the Hospira MedNet safety software to the Symbiq pump, and vice versa. Work began in December 2009 when CareAware Infusion Management was initiated in a 10-bed medical-surgical intensive care unit (ICU) at York Hospital. In January 2010, Symbiq pumps were launched. The following July, WellSpan expanded its infusion clinical integration with auto-documentation and smart pump auto-programming.

ciates the pump to the patient and the ordered drug within Cerner Millennium so the nurse is able to verify the “Sixth Right,” the right rate of infusion. An alert is displayed if one or more parameters do not match or if the dose or rate falls outside the established limits in the Hospira MedNet drug library. The nurse must correct the error and verify the infusion pump settings before the infusion is initiated. The benefit to nurses of CareAware Smart Pump Auto Programming and Infusion Management were immediately obvious. The number of steps required for programming the smart pump fell from more than 27 down to just seven with auto-programming. All infusion data are sent directly to the EHR, improving accuracy of documentation and allowing the nurse more time with the patient. “The system captures changes automatically so you don’t have to jump into the computer to constantly enter rates and titrations. It is all done for you to streamline the documentation process,” Ms. Muller said.

Pharmacy Impact Yet the benefits of Infusion Management are not limited to the nursing unit. For pharmacy, Infusion Management presents a never-before-possible path to operational efficiency, waste reduction and improved safety. Advanced data integration enables a real-time Phar-

Table. Auto-Programming: Scan, Scan, Scan Scan the patient to positively identify the patient.

Scan the medication to verify the medication to be given.

Point-of-Care Impact Sharon Muller, RN, MSN, York’s coordinator of nursing clinical informatics, summarized the point-of-care benefit of smart pump auto-programming. “Taking the human element out of programming the infusion pump greatly reduces the opportunity for error,” she explained. “The safeguards built into Infusion Management coupled with the safety limits built into the pump software allow us to avoid programming [mistakes such as] double-tap errors. The workflow begins with scan, scan, scan [Table].” Bar-code scanning provides a quick and easy user interface to the Infusion Management system. Via the hospital’s wireless network, bedside scanning confirms the “Five Rights” of medication administration—making sure that the right patient is receiving the right dose of the right medication at the right time and by the right route of administration. The scanning process also asso-

macy Infusion Management Dashboard View of all scheduled continuous and titratable medications currently infusing across the facility. Pharmacy technicians responsible for the ongoing preparation of these products monitor the dashboard and, based on the information provided, prioritize preparation based on the time remaining for the current infusion, the patient acuity based on location (i.e., ICU vs. general medical-surgical unit), or even the medication itself (i.e., admix all midazolam infusions due in next 60 minutes). As a result, pharmacy is no longer dependent on nurse requests to begin preparing infusions and scheduled meds are delivered in smaller batches to the units. “With the real-time view of all of the infusions’ status provided by Infusion Management, the pharmacy can dispense medications to the unit on a just-in-time basis prior to the current infusion bag’s completion so that the patient’s therapy is uninterrupted,” Mr. Gerhart explained. “We also avoid the stockpiling of medications on the unit that end up being returned to the pharmacy, thus reducing our crediting workload and waste as well as decreasing that opportunity for error resulting from the increased availability of medications.” To eliminate the need for nurses to continually call the pharmacy for status updates on requested IVs, the pharmacy took a page from the FedEx playbook.

Scan the pump to auto-program the device— information from the pharmacy-verified physician order is pulled directly into the pump.

Confirm/revise documentation—the nurse begins the pump and the administration, vital signs and IV fluid data are sent to the EHR.

EHR, electronic health record

Leveraging Cerner’s Workflow Monitor tool, pharmacy staff scan the infusion’s label throughout the preparation process to provide nurses with real-time updates on the preparation status via the Infusion Management Unit View Gadget. Progress on the infusions’ status can be viewed remotely by nurses as pharmacy staff scan the label through the tool from “Ready to Compound” to “Ready for Check” to “Checked” to “Ready for Delivery” to “En Route” and finally to “Delivered,” which will signal the nurse to look for the bag on the unit. In the future, bar codes added to the refrigerators will further add to the supply chain data trail. In the event a medication is dispensed to the wrong location, it will be quickly recognized upon investigation.

Measure of Success Across the board, clinicians consider the positive impact on patient safety to be the most important outcome of autoprogramming. “When patients see the technology we’ve helped develop, they know we are doing everything we can to keep them safe and deliver the best possible care,” said Ms. O’Shea. To date, WellSpan has documented more than 300 near-miss medication errors that have been prevented by the auto-programming system. Additionally, alerts prevent infusions that exceed the drug library limits set on the smart pumps. It is estimated that smart pump safety software prevents an average of 30 potential adverse drug events in each two-month period at an estimated cost savings of more than $260,000 and potential savings of more than $1.5 million per year. WellSpan also has documented significant improvements in caregiver efficiency. The reduction of infusion steps from more than 20 to just seven with auto-programming results in a 27% reduction in time to start and document each new infusion. Yet, the greatest time savings relates to the documentation of code blue cardiac arrest situations. Previously, retrospective charting took up to 120 minutes to recount from memory and handwritten notes the events and chronology of the code. Today, with one click, the CareAware system pulls information directly from the infusion pump during the code and back-associates all the information with physiologic and hemodynamic parameters from cardiac monitors. The nurse reviews the data and signs off on it. The synchronized data are recorded automatically in Infusion Management, reducing post-code documentation time to just five minutes. Although the frequency of IV documentation increased from once every eight hours to once hourly, there was an 87% reduction in time for a single

•

see IV MANAGEMENT, page 28

24 Spotlight on Technology

Automation

Medical Center Decentralizes With Omnicell Technology T

he University of Chicago Medical Center (UCMC) has embarked on an aggressive pharmacy technology rollout that, beginning in January 2012, promises to reduce inventory costs, nursing and pharmacy staff hours and speed medication delivery to patients, according to the team tasked with coordinating the program. The major goal of the technology rollout is to help the hospital decentralize pharmaceuticals distribution, coinciding with a multihospital expansion into a newly constructed third building on campus. The medication network will fully integrate with UCMC’s Epic electronic medical records (EMR) system by the end of a two-year rollout; the network will extend from new carousels in central pharmacies in two of the buildings to 94 automated dispensing cabinets (ADCs) at points of service for 594 beds, according to Dave Hicks, RPh, MBA, UCMC’s vice president and chief pharmacy officer. According to Mr. Hicks, the anticipated gains from implementing certain elements of the Omnicell G4 platform include: • Perpetual inventory management enabled by the carousels. These will improve inventory turns from 19 currently to 25 by fall 2012 in Comer Children’s Hospital and by spring 2013 in the new building for the Bernard A. Mitchell Hospital. “We will earn a one-time savings of $400,000 and ongoing annual savings of $60,000,” Mr. Hicks said. “It will also give us the capability to post online catalogues for our drug clinics that want to reorder supplies. It will list what they can obtain, and will bill it automatically to their cost centers.” • A 90% reduction in missing doses. “One of our overriding concerns was the large number of medication handoffs in our particular implementation of 24-hour cart fill, which created missing medications,” Mr. Hicks said. “The automated system will have fewer handoffs and higher integrity.” • Faster fills of routine first doses of new medication orders. Using Epic, pharmacists can verify a physician order in nine minutes on average. Because 90% of medications are available in an ADC on the patient unit, they are available for a nurse to administer as soon as a pharmacist completes verification in Epic. This is much quicker than the current 60-minute average cycle at UCMC. It takes that long, Mr. Hicks explained, because “in our current hybrid envi-

The Omnicell OmniDispenser (left) and Inventory Management Carousel (right) are part of a technology rollout that the University of Chicago Medical Center expects will streamline care and speed drug delivery to patients.

‘Our team developed a vision, then we went to the marketplace to see who could meet that [vision].’

—Dave Hicks, RPh, MBA

ronment, a label prints for manual filling or goes to the robot for automated filling. Manual picks are then checked and sent via pneumatic tubes or hand-delivered on hourly rounds. There are then one or two handoffs and potential waiting time for that medication on the nursing unit before the nurse knows it is there for her to administer.” • $10 million savings in nursing and pharmacy labor costs over 10 years. UCMC undertook an extensive business process-mapping project to document workflow savings. Primarily due to two Omnicell components—SinglePointe software to help track items not typically stored in cabinets (such as IV solutions usually kept on hooks or countertops) and the OmniDispenser module for controlled substances—the medical center projects a savings of 10% of its $100 million in nursing and pharmacy labor costs to distribute medications over the next decade. “This translates into about 22,000 hours

of nursing time per year that we can reallocate to other aspects of patient care,” Mr. Hicks said.

4.1 Million Doses Per Year UCMC has dispensed about 4.1 million doses per year for the past few years, and this level is expected to remain constant, noted Mr. Hicks, who believes the G4 platform will help the medical center avoid staff expansion, except for some new technicians. UCMC committed to five elements of the Omnicell G4 platform after two years of due diligence from a charter multidisciplinary team that included pharmacists, nurses, information technology, the facilities and engineering departments, the chief financial officer, the chief nursing officer and Mr. Hicks. “Our team developed a vision, then we went to the marketplace to see who could meet that [vision],” Mr. Hicks said. Physicians were updated on matters of medication safety and security and staff workflows. When asked about the technology’s potential

impact on patient safety and outcomes, Mr. Hicks said, “We can’t quantify we can reduce length of stay. But anytime we can improve the speed [at which] medications are administered, we improve opportunities for patients to get better faster.” UCMC’s technology users also were given the chance to sample systems from three vendors, including Omnicell, at a vendor fair held on the medical center campus. Most important to Mr. Hicks was the SinglePointe software, which he said provides a method for integrating “exception” products that are not typically stored in a particular nursing unit, such as IV solutions. “The software dedicates a bin for a specific solution for a specific patient, so the nurse on the next shift just goes to the bin and knows it is there,” he said. OmniDispenser, which dispenses controlled substances like a vending machine, was another differentiator for Mr. Hicks. “If a nurse needs one dose of morphine, she gets one dose only. So there’s no need to do a count to verify

Spotlight on Technology 25

Pharmacy Practice News • October 2011

Automation and there’s less potential for diversion,” he explained. “We’ll no longer need nurses to count controlled substances at the end of their shifts.” Moreover, the Omnicell Pharmacy Medication Management Carousels with WorkflowRx software will occupy central pharmacies in two buildings on campus, updating the current shelfstorage process; 94 OmniRx G4 Automated Medication Dispensing Cabinets will be dispersed throughout nursing floors (75 of them to be equipped with OmniDispenser because there is less need for them in ambulatory areas); and AnywhereRN allows nurses to review and select medication orders needed from the cabinet remotely. Another priority for UCMC is to have a single, integrated database—one goto place to maintain all its medication files more expediently and accurately, rather than have to separately update its formulary and drug files in distinct cabinets, narcotics and data systems— and the G4 platform provides this capability, said Mr. Hicks. The new era at UCMC begins to go live this coming January, when carousels start up in one central pharmacy. By July 2012, the same building will see replacement of all of its current cabinets with the OmniRx cabinets. By January 2013, carousels will go live in the new building, with the rest of the new cabinets to follow. According to Robert Adamson, PharmD, corporate vice president-clinical services, Saint Barnabas Health Care System, West Orange, N.J., a pri-

mary benefit of decentralized distribution is more time spent by pharmacists to use their cognitive abilities and less time on distributive functions. If pharmacists release medications from the ADC right on the floor, they are readily available to interact with patients and have face-to-face access with care providers, increasing collaboration, he noted. To measure how that workflow strategy improves customer satisfaction, Dr. Adamson uses metrics such as turnaround time, medication errors per High alert 7.625x9.375_F:Layout 1 10,000 doses and Hospital Consumer

Assessment of Healthcare Providers and Systems (HCAHPS) scores, which he says are often “medication-related and directly tie to the pharmacist– patient interaction.” Dr. Adamson cited what he looks for when selecting a vendor: reliability, durability, security (decreasing medication access to care providers until a pharmacist has verified an order) and the vendor’s interface with existing systems. “Many hospitals will charge for a medication when that medication 5/22/09 9:47 AM Page 1 is removed from the ADC. This needs

to interface with our billing system and drop the charge for the medication,” he said. As for hospitals seeking integration with EMR systems, “there are vendors that have medical records that can be for both outpatient and inpatient,” observed Dr. Adamson. “The challenge is [to find] resources to convert existing systems to EMR. They do exist, but [they require] huge commitments in time and money to implement.” —Al Heller

Innovative 3-part piggyback label design. Just peel & apply!

Epidural Heparin • Insulin • Chemo • Narcotic • IV Nutrition • Oxytocin • Paralytic • Magnesium Sulfate • Blank • •

in Your Inbox 2

... to receive the monthly e-newsletter from

at www.pharmacypracticenews.com

Choose our stock line tracing labels or easily customize your own for any medication with our exclusive MILT ® software.

EPS , INC. ®

Simplicity by Design...from EPS. A Member of The Medi-Dose® Group.

Milton Building, 70 Industrial Drive Ivyland, PA 18974 800-523-8966 Fax: 800-323-8966 215-396-8600 Fax: 215-396-6662 E-mail: info@medidose.com

www.medidose.com

1 3-part Line Tracing Label is placed on infusion container.

2 Line Tracing Label is easily removed and placed at the top of the line.

3 Second Tracing Label is placed at the bottom of the line.

26 Spotlight on Technology

Automation

Groups Call for Safer Smart-Pump Drug Libraries E

ach year, thousands of medication errors cause patient injury and death, and medications that are administered intravenously have the highest risk for errors. According to the FDA, more than 56,000 adverse incidents from programmable IV infusion devices, commonly called “smart pumps,” were reported from 2005 to 2009. Experts say the total number of incidents, reported and unreported, is likely closer to 400,000. In response to safety concerns, the Association for the Advancement of Medical Instrumentation (AAMI) announced in a press release last month that it is partnering with the American Society of Health-System Pharmacists (ASHP) and the FDA to reach out to the health care community for help developing guidelines and recommendations for the management of programmable pumps. “What we want to do is standardize the drug libraries to better protect our patients,” said Karl Gumpper, RPh, of ASHP and the group leader heading the collaborative effort. “We also want to encourage hospitals and health systems to use programmable devices that interface with their information systems and include the standardized libraries with dosing limits and clinical advisories.”

How Smart Pumps Work Smart pumps include software that allows a hospital to create a library of medications that provides dosing guidelines by establishing drug concentrations and hospital-defined upper and lower dosing limits. Various alerts and clinical advisories also can be built into the software to prevent errors. These notifications are designed to prevent users from programming in an overdose by signaling when the dose they’ve selected is out of the predetermined range for the medication. The user may easily override a “soft” stop, and the medication can be infused without changing the pump settings. But a “hard” stop won’t allow the user to administer the infusion unless the pump is reprogrammed within the acceptable range. The pumps can be tailored for patient weight and specific patient groups, such as those in cardiac, pediatric or intensive care units. The use of smart pumps is increasing. In 2010, 65% of nonfederal U.S. hospitals reported using smart pumps, up from 32% in 2005, according to the 2010 ASHP national survey of pharmacy practice in hospital settings.

What Can Go Wrong? “National standards for IV medication use are desperately needed because there are many possibilities for error

in infusion-device programming,” said Mark Sullivan, PharmD, director of pharmacy operations at Vanderbilt University Hospital in Nashville, Tenn. Vanderbilt was one of the first hospitals to implement smart pumps on a widespread basis. Dr. Sullivan said that the wrong medication with a similar sounding name may be administered, a medication may be accidentally programmed in micrograms per kilogram per minute instead of micrograms per minute, or an additional zero may result in a 10-fold overdose. “In many instances, pressing a single wrong key when programming delivery can harm a patient,” he stressed. To illustrate, here are several examples of errors involving smart infusion pump technology that occurred in Pennsylvania medical facilities. (PA-PSRS Patient Safety Advisory-Vol. 4, December 2007): Failure to use standardized concentrations of high-alert medications. Hospital policy dictates the standard Levophed solution is 4 mg/250 mL. The nurse programmed the smart pump incorrectly by entering the standard solution of 4 mg/500 mL. Wrong drug administered. Staff found Levophed running on a smart pump programmed for neosynephrine infusion

at 200 mcg/min. The Levophed solution was not scanned prior to administration and the wrong medication was administered. The patient had orders for both vasopressors. Wrong-rate medication error with no upper dosage alert. A nurse at a Pennsylvania hospital incorrectly programmed a smart pump to run a patient’s total parenteral nutrition at 625 mL/ hr, instead of 62.5 mL/hr for 24 hours. Unfortunately, there was no preprogrammed dose limit in the device’s drug library to alert the nurse to the error. The mistake was discovered 90 minutes later, when the patient became short of breath. Although he was treated appropriately for elevated potassium and glucose, the patient coded and died three hours later.

The Ideal: An Integrated System Creating the smart infusion pump system on a wireless network helps avert such errors. A wireless system allows the pumps to download drug library updates, and to be integrated with computerized prescriber order entry devices, bar codeassisted medication administration and electronic medication administration records. Another advantage of the system is that it provides a large amount of data

‘National standards for IV medication use are desperately needed because there are many possibilities for error in infusion-device programming.

—Mark Sullivan, PharmD

Tips: Analyze, Standardize and Do Your Homework

hat should be done to improve the technology? Matt Grissinger, RPh, who handles technology-related safety issues at the Institute for Safe Medication Practices (ISMP), offers these suggestions: • Do your homework before buying and implementing smart pumps. What drugs will you include in the library? Will you use different libraries for different patient groups? • Use the team approach. You have to get physicians, nurses, pharmacists and your IT people on board. Make sure everyone is properly trained. • Implement a wireless system. It will reduce errors and make it easier to update the pumps. • Make sure the pumps are automatically set to library mode when they’re turned on. It sounds like a small thing, but it decreases the chance that users will opt-out of using the library. • Standardize the concentrations. For example, you probably don’t need eight concentrations in your drug library; get it down to two or three. • Standardize your data terminology: dose, volume, unit of measure, bolus, loading dose, etc. • Analyze your data. Consider what drugs or alerts are most frequently overriden and make adjustments when needed. • Get user feedback. If nurses are employing “workarounds” to get out of using the library, find out why. Maybe it’s because it’s taking them too long to program the pump. If so, make it easier. —D.H.

that can be used to evaluate smart pump use. Data collection can include the number of infusions programmed into the drug library, soft stop overrides and how often an alert resulted in reprogramming of an infusion. Clearly, a completely integrated system is ideal. No facility is closer to reaching that goal than Lancaster General Hospital in Lancaster, Pa. “Ninety percent of the time it works really well,” said Tina M. Suess, BSN, RN, who has worked with Lancaster’s interoperable system for several years. “Sometimes it can be as simple as ‘plug and play,’ but there are a lot of factors involved, including the nurses, the pharmacy and the strength of the wireless infrastructure.” Ms. Suess said the biggest challenge initially was to convince nurses to use the system. Early on, they were using the drug library only 40% of the time; currently, that figure has risen to nearly 70%. Lancaster’s system may not be perfect, but it’s working. “You don’t realize how often manual pumps are programmed incorrectly because those errors oftentimes go under the radar,” said Amanda Prusch, PharmD, BCPS, Lancaster’s medication safety specialist who oversees the drug libraries. “But we’ve definitely seen a decrease in errors with integration.” For instance, interoperability expanded the role of the pharmacist to include checking infusion rates of IV medications, which resulted in a 32% reduction in monthly IV heparin errors reported from the telemetry and medical-surgical patient care areas (Am J Health Syst Pharm 2011;68:835-842). For now, Lancaster is one of a handful of hospitals in the country with an interoperable medication administration system. But that’s slowly changing. “We’ve made great strides over the past 10 years. But it will take another decade for one-fourth of the market to have achieved true interoperability,” Dr. Sullivan said. “We need to continue to beat the drum to ask vendors to make these systems talk and work better together.” He issued a call to action in an editorial that appeared in AJHP last year: “Health-system pharmacists must play a leadership role in helping achieve the full potential of infusion devices to improve patient safety.” —Dana Hawkins-Simons

Optimizing the Selection and Use of Topical Hemostats November 12, 2011 Omni Parker House 60 School Street • Boston, MA 7:30 AM - 8:30 AM 8:30 AM – 11:45 AM

Breakfast, Registration Lectures, Case Studies, Q&A

Online: www.mededpre-reg.com/topicalhemostats Email: topicalhemostats@appliedcme.com Phone: (212) 624-0571 Fax: (815) 377-2470 Mail: Applied Clinical Education 545 West 45th Street New York, NY 10036

Chair Cataldo Doria, MD, PhD, FACS Nicoletti Family Professor of Transplant Surgery Associate Professor of Surgery Director, Division of Transplantation Jefferson Medical College Thomas Jefferson University Hospital Philadelphia, Pennsylvania

Faculty Danial E. Baker, PharmD

Bradley A. Boucher, PharmD

Professor of Pharmacy Associate Dean for Clinical Programs Director, Drug Information Center College of Pharmacy Washington State University Spokane, Washington

Professor, Vice-Chair for Institutional Programs Department of Clinical Pharmacy Associate Professor Department of Neurosurgery University of Tennessee Health Science Center Nashville, Tennessee

Learning Objectives

Jointly sponsored by AKH Inc., Advancing Knowledge in Healthcare and Applied Clinical Education

At the completion of this activity, participants should be better able to: 1. Appraise the clinical and economic effects of excessive intraoperative or postoperative bleeding and common preoperative strategies for minimizing bleeding events. 2. Describe key clinical factors that influence the selection and use of topical hemostats as adjuncts for achieving surgical hemostasis. 3. Delineate clinical characteristics and pharmacoeconomic (direct and nonmedication costs) considerations by which topical hemostats should be evaluated, acquired, and used in hospitals. 4. Develop a plan for reconciling cautionary guidance and clinical best practices with regard to the selection and use of the full range of topical hemostats.

Target Audience Surgeons and pharmacists

Criteria for Success Brought to you by

To obtain credit for this activity, participants should listen to the presentation, complete the activity evaluation and submit the form to an ACE staff member upon departure. For questions regarding this CME/CE activity please email service@ akhealthcare.com.

Accreditation Statements

Supported by an educational grant from A Bristol-Myers Squibb Company

For complete activity information and to register, visit

www.mededpre-reg.com/topicalhemostats

Physicians: This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of AKH Inc. Advancing Knowledge in Healthcare and Applied Clinical Education. AKH Inc. is accredited by the ACCME to provide continuing medical education for physicians. AKH Inc. designates this live activity for a maximum of 3 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity. Pharmacists: AKH Inc. is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. AKH Inc. approves this application-based activity for 3 contact hours (0.3 CEUs). UAN 0077-9999-11-038-L04. Initial release date: November 12, 2011.

28 Spotlight on Technology

Pharmacy Practice News • October 2011

Q&A

Five Questions for … John Poikonen, PharmD Director, Clinical Informatics UMass Memorial Medical Center Worcester, Massachusetts

Dr. Poikonen, who has served as an executive committee member for the American Society of Health-System

Pharmacists’ Section of Pharmacy Informatics and Technology, has become a leading expert in pharmacy informatics. The winner of a Leadership Award from the American Medical Informatics Association (AMIA) in 2008, he has lectured and given continuing education seminars nationally on technologies that can benefit the pharmacy profession. He writes about informatics initiatives on his professional blog, rxdoc.org, contributes

to the informatics blog RxInformatics. com, and at press time had 805 followers to his Twitter account (@poikonen).

: Where do you think we will see the biggest growth in informatics technologies? A: I believe a much more robust clinical decision-support infrastructure will be critical to caring for patients. Currently, the rate of false-positives and noise

Anti-Infective Therapy You Can Take to The Bank

Nafcillin for Injection, USP ✓ Preservative Free

✓ AP Rated

✓ The container closure is not made from natural rubber latex

See full prescribing information at www.APPpharma.com ®

Medical Affairs 800.551.7176 Customer Service 888.386.1300

around clinical decision support is a sore spot SPOTLIGHT ON that has to get better, TECHNOLOGY and informatics can play a huge role in making that happen.

: You recently referenced the upcoming AMIA meeting on your blog. What’s the buzz from the meeting? A: AMIA is primarily focused on broad clinical informatics in relation to drug therapy but they do a lot more. A lot of the buzz is around transitions of care, and accountable care organizations and sharing of data across institutions—

Site Visit

IV MANAGEMENT continued from page 23

document intake session. Documenting hourly intake has provided greater clinical insight into a patient’s status across the care team without additional nursing time expenditure. Time was cut by 50% for titrations and the time necessary to document them. Although the difference is only 13 to 16 seconds per titration, the savings accumulates to more than 1,300 nursing-hours saved per year. The success of auto-programming at York Hospital is partly the result of nurses’ consistently high rate of compliance with system safeguards. After adjusting for select regimens that commonly require system overrides (sodium chloride, blood, plasma, and platelets), compliance was 78% in October and 79% in November. Likewise, average compliance with the Hospira MedNet safety software was 94%. Yet another success factor was the collaboration between WellSpan, Cerner and Hospira. In May 2011, the three organizations were given a Way-Paver Award at the unSUMMIT for Bedside Barcoding in acknowledgment of the years of joint development required to overcome technical limitations and satisfy workflow needs of WellSpan nurses, pharmacists and physicians. Together, the partners created an advanced infusion management system that accomplishes—true to Dr. Baker’s philosophy— what was not possible with paper. Ms. O’Shea beamed with all due pride, “I think we’ve forged new ground. It’s the wave of the future.” Ms. Kelly is an independent marketing consultant serving health care information technology vendors. Ms. Kelly and her partner, Mark Neuenschwander, organize the annual unSUMMIT for Bedside Barcoding educational forum. For more information on the 2011 summit, visit www.unsummit.com.

Spotlight on Technology 29

Pharmacy Practice News • October 2011

Q&A breaking down those silos. To do that there’s all kinds of data aggregation that needs to occur. One of the big buzzes there is how to aggregate and then disseminate all of that medical information in a meaningful way. It certainly will be one of the focuses of the AMIA meeting.

: How can pharmacists best use social media? A: I’m a very social guy and so I do a lot of social media and share my opinions and profession publicly, and I’m not afraid to do that. That’s typically not what pharmacists do, and that’s OK. The best practices for doing this are yet to emerge, but I think the sharing of scientific knowledge is necessary. Everybody does their own thing, and if everybody made that more public and more accessible, then I think we would all grow by having that out there in the clouds. For example, as I go through my daily routine and I come across clinical and scientific instances that are relevant in my practice, it takes just a moment out of my day—a few clicks or taps—to make that public. I think we need more of that. I can follow infectious disease experts and understand what they’re learning and doing when I need to, and other pharmacists can follow my informatics streams so they can learn. To me, that’s the true potential for social media, beyond the personal stuff. That’s why I use it. I follow some amazing people, who point me to just incredible stuff and I feel like I’ve grown tremendously with that.

What is your current take on whether pharmacy as a profession is doing enough to promote a “just culture” so that pharmacists feel safe coming forward if they make an error? A: I am disappointed that ASHP did not consider at least providing some support for Eric Cropp, but am aghast that they failed to perceive and deal with the larger issue of permitting a legal precedent that leaves pharmacy as the only profession for which committing a medication error is now a felony offense. Permitting Mr. Cropp to plead guilty to a felony charge

because he lacked the resources to fight the case has placed the entire profession at legal risk. While ASHP was missing in action on this issue, ISMP [the Institute for Safe Medication Practices] recently announced an upcoming webinar focusing on understanding the “second victims” of medication errors—the health care professionals who make the errors (www.ismp.org). This effort is very positive for promoting a just culture and is a step in the right direction.

Next Month Pro/Con: BCMA Bedside bar coding has been touted for years as a powerful tool for reducing medication errors. But more than 50% of U.S. hospitals have not yet embraced the technology. Two informatics specialists face off on whether bar coding is mature enough to warrant more widespread adoption.

—Reported by Karen Blum

: What does the future hold for clinical informatics in pharmacy? A: The current laws and regulations around pharmacists needing to verify every single medication order will need to be re-examined. In an era where technology can review orders and check them for appropriateness as well, does the pharmacist need to check every order or can that be offloaded in some technological way? That’s a game-changer: Can systems check and monitor drug therapy as good as or better than today’s pharmacists, the standard of care? I don’t know the answer to that but I think that’s where things are going. People will continually challenge me on that, and I think that’s great, but I also think that the volume of what pharmacists verify today is huge. There are people studying if clinical decision support can match the quality and safety of pharmacists’ verification; it’s a positive thing that will raise the [level] of all pharmacists to do more things at the patient bedside.

: You had criticized ASHP in a recent blog post for not stepping forward to defend pharmacist Eric Cropp, jailed for a medication error.

Help me cut costs, without cutting care. With so many variables to balance, pharmacists rely on Pyxis ® technologies to help improve workflow efficiency, reduce costs and protect all med types throughout the medication management process. From secure inventory management, to efficient tracking of meds, to proper disposal—we deliver solutions that help you keep meds moving, clinicians focused and patients satisfied. That’s the CareFusion difference. Visit carefusion.com/pyxisRXsolutions to learn more, or contact us at communications@carefusion.com.

Pyxis

30 Operations & Management

Pharmacy Practice News • October 2011

continued from page 1

medication errors were recorded for 137 (30.3%) of them. Pharmacists and pharmacy students gathered the data for the 10-hour shifts when pharmacists were present; resident physicians collected the data when pharmacists were absent. Antibiotics were most often subject to error, followed by pain medications, cardiac medications and gastrointestinal medications and antiemetics. Typical errors included wrong dose (either too little or too much), medications given or not given without regard to order status; wrong administration technique, and so on (Table 1). Pharmacist interventions consisted mainly of dosage corrections, which the pharmacists carried out themselves, and alternative suggestions, which were accepted by the physicians 91% of the time. Amy Ernst, MD, professor in the Department of Emergency Medicine and lead author of the study, noted that pharmacist intervention was simply a matter of communicating knowledge. “For example, we [physicians] use so many antibiotics, and the pharmacist will come up and say, ‘That’s not the best choice for that particular infection,’ and suggest something better.”

Go Where the Need Is The University of New Mexico study is the first to evaluate the impact of pharmacist intervention in the ED with respect to patient disposition. Pharmacist intervention had a particularly strong effect on patients in the intensive care unit (ICU), where there were 55 patients with medication errors. Of these, 51 had errors while no pharmacist was on-site (Table 2). “Overall, there will be more errors in the ICU,” said Dr. Ernst. “The cases are more complicated, the patients have more done to them, and there are more medications.” And there’s more potential for patient harm, Dr. Ernst stressed. Although most of the medication errors in the study did not cause harm or require intervention, “four patients experienced errors that required either intervention or prolonged hospitalization,” she noted. “All of these errors occurred when pharmacists were absent, and it is possible that the presence of an on-site pharmacist could have helped avoid these [mishaps].” In those four patients, the drug errors included a patient who was given albuterol/ipratropium nebulizers too frequently and developed supraventricular tachycardia; a patient given atropine with a known allergy who developed hallucinations; dopamine and norepinephrine started at the wrong rate of infusion; and epinephrine administered

Pharmacist present Pharmacist absent

40 31

20 0

13 7

0 Medications given, not ordered

Medications ordered, not given

Wrong dose (too little)

Wrong dose (too much)

Wrong administration technique

Wrong time (>30 min from order time)

Table 1. Incidence of medication errors based on error type and pharmacist status.

‘Of all the areas where clinical pharmacists can make an impact, the ED is one of the places we should go first.’ —Daniel P. Hays, PharmD, BCPS, FASHP

Pharmacist present Pharmacist absent

Total Medication Errors

ED PHARMACY

Total Medication Errors

Critical Care

40 18

20 6

0 ICU

Non-ICU admits

0 OR

Discharge home or mental health clinic

Table 2. Incidence of medication errors based on care site and pharmacist status. ICU, intensive care unit; OR, operating room

via an IV instead of intramuscularly. All of the errors resulted in ED patients being admitted to the hospital; two of the patients required ICU care. These results “tell us about risk,” said Kyle Weant, PharmD, BCPS, clinical pharmacy specialist in emergency medicine/critical care at University of Kentucky HealthCare in Lexington. “It answers the question of where you put your time and what populations you should focus on if you’re an ED pharmacist. If you have limited pharmacy resources, it tells you where you’re going to get the most bang for your buck.” Daniel P. Hays, PharmD, BCPS, FASHP, clinical pharmacist in the Departments of Pharmacy and Emergency Medicine at the University of Arizona Health Network, Phoenix, agreed. “Of all the areas where clinical pharmacists can make an impact, the ED is one of the places we should go first. Emergency rooms don’t have the

safety checks that are in place in other areas of the hospital, where doctors and nurses run checks,” he said. “We can provide that layer of safety and care in high-risk situations.” That the vast majority of physicians in the study accepted the pharmacists’ suggestions speaks to how far ED pharmacy has come, Dr. Hays said. “Once physicians know who you are and what you can do for them,” he noted, pharmacist recommendations are followed and have a direct impact on patient care. In a crisis such as resuscitation, Dr. Weant noted, that kind of trust can be a matter of life and death. “Things happen so quickly, you don’t have time to debate the literature,” he said. “You just have to trust that what the individual beside you says is right. “Even when you look at the authorship of the study [where a physician is the lead author], that helps you see that there is a wonderful collaboration,”

Dr. Weant added, noting that the study itself represents a significant shift in the literature. “If you look back on older studies, one of the challenges for pharmacists in the ED was whether they’d even be accepted.”

Study Limitations Dr. Ernst and her colleagues note the study’s limitations in their paper, namely that the study involved only one center and that it was part prospective, part retrospective. But, according to Dr. Weant, those limitations are a spinoff of the study’s strengths. “It is very challenging in a busy level 1trauma center to do a prospective study and identify and prevent all the errors that may be occurring simultaneously; it is far easier to sit in a quiet room in medical records and identify errors that may have occurred on a retrospective basis,” he explained. “The fact that the researchers were able to identify a difference given this inherent disadvantage is a tribute to both their program and the impact of their services. As most hospitals aren’t busy level 1 trauma centers, this bodes well for other institutions trying to replicate this data on a prospective basis and improve overall patient care and safety.”

Building a Case The University of New Mexico study bolsters the case for integrating pharmacists into the emergency care team. An earlier study at the University of Rochester Medical Center in New York, co-authored by Dr. Hays, found that a pharmacist’s presence can reduce the time it takes to get patients with ST-elevation myocardial infarction from the ED to the cardiac catheterization laboratory (J Emerg Med 2010 Aug 31 [Epub ahead of print]). In a 2010 study led by Dr. Weant at the University of Kentucky (Am J Health Syst Pharm 2010;67:1851-1855), researchers found that pharmacy personnel caught the lion’s share of medical errors compared with other health care workers (94.5% vs. 5.7%, P<0.001). Moreover, pharmacists’ interventions prevented 79.6% of drug errors from reaching patients. —Terri D’Arrigo

38 Operations & Management

Pharmacy Practice News • October 2011

FILE SLUG

ppn enews ad PROOF LAYOUT APPROVED Leadership in Action1ST INITIALS AND DATE

Current file:

Full Name of project

MAX sign-off

STATUS AND HISTORY FINAL OK INITIALS AND DATE

PROOF 1: 1/28 REV 1: 1/29 REV 2: 1/30 REV 3 1/30 REV 4 REV 5 REV 6 REV 7 REV 8 REV 9

PICKED UP FROM: APPLIED TO: AD LAYOUT EXPT’D: AD LAYOUT RECEIVED:

Make the Right Choices—and Repeat Them W Senior Editor

Style chges fr. prev.

Copy Editor

Revision #

Proof 1

Sales

Layout Date/Time

September 7, 2011 5:36 PM

Production

e continue this month with our choices. One great “lens” by which to Creative exploration of some of my favor- evaluate yourself might be to imagine Trim Size TABLOID 63p X 78p COMMENTS: ite leadership “nuggets” taken from the how you might respond in a crisis. For Color Specs 4C book Leadership Gold, by author John example, I heard an anecdote about a File Path Max: Server Data:Data:Magazines:PPN:Miscellaneous:Assorted:Ads:eNewsletter Ad:ppn enews ad.indd Maxwell (Nashville, Tenn. Thomas Nel- pilot who was about to land his private son Publishers; 2008). jet when an unexpected wind shear hit the plane—forcing it to dip straight down We Make Our Choices to the runway. The pilot immediately And Our Choices Make Us pulled up on the throttle and launched It has been said—and I firmly believe— the jet back up into the air. With widethat our character is the sum of our open mouths, passengers realized the

Editorial Date/Time

EDIT LAYOUT EXPT’D: EDIT LAYOUT RECEIVED: TO: David

FROM: Frank seriousness of the situation that the pilot had just narrowly averted. The jet circled and landed without incident. One of the thankful passengers asked the pilot at what point he decided that he would have to launch the plane back into the air to avoid calamity. The pilot responded, “Fifteen years ago. That is when I rehearsed how I would respond to each possible air problem.” The choice was made long before the crisis took place.›

in Your Inbox Pharmacy Practice News is now available as an E-newsletter.

“Leadership in Action” is authored by Ernest R. Anderson Jr., MS, RPh, System Vice President of Pharmacy, Steward Health Care System, Boston, Mass. Mr. Anderson welcomes your input on leadership issues, at ernest.anderson@ steward.org.

Ernest R. Anderson Jr., MS, RPh

As Maxwell states, “Successful people make right decisions early and manage those decisions daily.” What are those pivotal decisions that you have made or perhaps need to make now? If you decide these and rehearse them, if the time comes to use them, those decisions become the automatic response. And these decisions represent part of your character—as an individual, as a leader and as a member of your social network. The greatest power in life comes from your ability to choose. Your choices define who you are and make a statement to those around you. The key is to be true to yourself. Legendary basketball coach John Wooden said, “There is a choice you have to make in everything you do. So keep in mind that in the end, the choices you make, make you.” The way I “vet” my choices is by creating a framework composed of my morals and beliefs and use it as a decisionmaking matrix. The following are the beliefs and values I choose to measure my choices against: • Always support your people • Don’t compromise your values • Treat everyone with respect • Be a straight shooter • Be honest and fair • Be highly committed • Work hard • Do the right thing • Have others’ interests at heart • Operate with humility • Keep an even-keel disposition • Maintain a positive attitude • View challenges as a growing experience • See the big picture, but focus down to the most minute detail • Be trustworthy • Have strong convictions • Be caring toward others • Hold self and others accountable • Believe in others • Hold high expectations of self, others • Have a willingness to work with others • Maintain a willingness to admit mistakes, regroup and move forward • Have broad interests What’s on your list?

Choosing Our Choices

Get the latest news delivered directly to your computer and PDA. The new interactive format has embedded Web Site links that give you instant access to additional information, unique searching features and printing capabilities. Each installment contains brief summaries of the most important articles from the current month’s issue, as well as breaking news ahead of print.

In addition to the decision matrix, Maxwell identified three other principles related to making good choices: 1. Standards set for myself will be higher than those that others might set for me. Great leaders are never satisfied with their achievements.

•

see RIGHT CHOICES, page 42

Spotlight on Technology 39

Pharmacy Practice News • October 2011

Workflow

Leveraging 340B Savings To Re-engineer Pharmacy Optimized billing software gets Virginia Hospital on road to more patient-focused care

hen University of Virginia (UVA) Health System director of pharmacy Gary Johnson, PharmD, identified extra opportunities that enabled his hospital to save an additional $1 million in outpatient medication costs over the course of just six months through its participation in the federal 340B Drug Pricing Program—which limits the cost of covered outpatient drugs to certain entities, including qualified hospitals—he knew just what to do with the extra cash. Dr. Johnson and his team plowed the savings into a comprehensive re-engineering of the hospital’s inpatient pharmacy system—prescribing, dispensing, administration and monitoring. Working with pharmacy automation provider Talyst, which facilitated UVA’s ability to maximize its 340B savings through optimized billing software, the UVA pharmacy went from an outdated, patchwork-quilt set of silos with irregular monitoring to a virtually seamless, integrated, carefully overseen system. As a result, the hospital decreased inventory carrying costs by $500,000, reduced medication dispensing errors by 76% and administration errors by 40%,

improved order turnaround time by 92%, and decreased drug costs by $6 million (in addition to the 340B savings). How were these dramatic results achieved? Through fundamental changes to all of the core components of pharmacy operations (Table). The strategies aren’t just about switching from name brands to generics, Dr. Johnson stressed—that’s done automatically. “The real value of the pharmacist is to suggest an alternative drug, which may be less expensive but equally effective, or a drug that is more effective and gets the patient discharged and back home more quickly. A very rich environment for these sorts of interventions is found in the critical care units.” Pharmacists often help physicians with appropriate prescribing of antibiotics, Dr. Johnson said. “This is a very large and very expensive drug class, which is often prescribed inappropriately. Another opportunity to better manage medications was found with the drugs used to treat hemophilia patients and/or patients who require very expensive medications for blood disorders. These drugs are genetically engineered,

recombinant and can cost up to $75,000 per treatment regimen.” Overall, this more rational medication use model has led to a $7 million decrease in drug expenditures (including the 340B savings), putting that expense at 12% below budget for the fiscal year.

Key Outcomes  Medication errors: 76%  Inventory carrying costs: $500,000

 Order turnaround time: 92% The pharmacy received an Innovation Award from Virginia Gov. Bob McDonnell in August—an honor designed to recognize ideas that produce efficiencies or cost savings. “But this really goes beyond saving money,” Dr. Johnson said. “It’s about quality, reduction in errors and improvements in care.”

Praise From a Fellow Pharmacy Director Tom Van Hassel, RPh, MPA, director of pharmacy at Yuma Regional Medical Center in Yuma, Ariz., praised Dr. John-

son for “demonstrating exactly what pharmacy technology is supposed to be used for.” Mr. Van Hassel’s own hospital has long been leading the way in pharmacy automation. “This technology is designed to allow your staff to get involved in clinical care by allowing the mundane duties of the pharmacy to be done virtually error-free, and they’re [the University of Virginia Health System] really making the most of that.” Why aren’t more hospitals jumping on board? “Technology has a high startup cost,” Mr. Van Hassel said. “And pharmacy directors on the whole don’t have a lot of experience in dealing for capital dollars—not like radiology and labs. We’ve really only been involved in technology for about 10 years.” Dr. Johnson isn’t about to sit around polishing his Innovation Award. He’s got plans for the 340B savings that continue to come in. “Now, I want to go back and re-engineer the outpatient pharmacy environment,” he said. “I think we have a similar level of improvement and savings to achieve there.” —Gina Shaw

Table. Impact of Re-engineering on Pharmacy Operations Before

After

Prescribing

UVA had a physician order-entry system for medication prescription, but the system was dated and had limited functionality, giving prescribing physicians incomplete information.

Medications are prescribed within a new EMR that is fully integrated with patient-specific data systems, such as laboratory and radiology, as well as with ambulatory care.

Dispensing

Medications were dispensed through a centralized system that refilled medication carts in the pharmacy, and then exchanged those medication carts on the nursing units, every 24 hours. The process included an awkward combination of both robotic and manual systems for dispensing medications that was performed by both pharmacists and technicians.

Medication dispensing is now fully automated, driven by the bar codes found on every medication. The process begins by importing the daily delivery of medications from the distributor into perpetual inventory software—a function that decreased inventory levels from 11 to five days and generated a $500,000 inventory reduction. Medications are stored in four inventory management carousels that, in conjunction with the perpetual inventory software, ensure that each drug is scanned and then placed in a precise, software-determined storage location, as opposed to an alphabetized system. Automated dispensing devices, similar to ATM machines, now stand on each nursing unit and have replaced the old medication cart. Containing up to 250 different medications, the devices interface with the new EMR and the pharmacy’s perpetual inventory system, and allow nurses to retrieve all medications with active orders. Every 12 hours, the devices transmit replenishment data to the perpetual inventory software, which then causes the carousels to turn and dispense the required medications to replenish the devices. Bar-code functionality ensures that the correct medication is retrieved from the carousel to replenish each dispensing device—a step that’s largely responsible for the 76% decrease in dispensing errors.

Administration

Because patient-specific medications were only updated every 24 hours—with the exchange of the medication carts—the system was susceptible to errors, allowing discontinued medications to remain available for dispensing and newly prescribed medications to languish unavailable in the pharmacy.

Bar-code medication charting requires nurses to scan both the patient’s wristband, as the patient identifier, and the drug being given. The software then searches the EMR to ensure the patient has an active order for this medication. If not, the system will alert the nurse that an incorrect medication is about to be administered. Not only has it decreased medication administration errors by 40%, the new system also gives nurses immediate access to 90% of needed medications within five minutes of order entry—as opposed to the average processing time of 60 minutes required under the old system.

Monitoring

Saddled with dated information technology, UVA’s medication monitoring was rudimentary at best, with pharmacists monitoring remotely from the hospital’s basement—a location that hampered their integration into the patient care team.

Because automation has permitted so many more pharmacy tasks to be performed by technicians, a number of pharmacists have been reassigned to the nursing units. That doesn’t just make for happier pharmacists—turnover dropped from 23% to 8%—but it also leads to smarter prescribing. Pharmacists work closely with prescribing physicians, making recommendations for more effective and/or less expensive medications.

EMR, electronic medical record; UVA, University of Virginia

40 Operations & Management

Pharmacy Practice News • October 2011

Wicked Change

Wicked Problems and the Challenge of Constant Change At the center of your being, you have the answers. You know who you are, and you know what you want. —Lao Tzu, Taoist philosopher

ealth care organizations face enormous challenges. Costs are too high and there is too little associated value. Indeed, the United States spends 16% of its gross domestic product on health care—well over $6,000 per person, which is more than double the amount spent by most other free-market economies. Yet, outcomes in this country are in most cases no better and in many cases substantially worse.1 The transformational change in health care that is needed to meet this huge challenge has become one of our most critical macroeconomic issues. In fact, its complexities are so huge that they warrant characterization as “a wicked problem,” to borrow a phrase from the social sciences: that is, a problem whose solution is highly complex, requiring a great number of people to change their mindsets in order to foster a new way forward. After decades of discussion, it is seriously time to take action. Although the current economic crisis looms large and it is tempting to think we’ll eventually return to normal, the high-stakes urgency facing health care and the economy as a whole suggest that “normal” will never be the same again. This is not business as usual. In 2001, the Institute of Medicine (IOM) stated that “between the care we have, and the care we could have, this is not just a [quality] gap but a chasm.”2 In the intervening years, the gap has not changed substantially, in part because we tried to leap the chasm in short hops. The issues of safety, effectiveness, patientcenteredness, timeliness, efficiency and equity that IOM identified still serve as markers for what we need to change in transforming our practices—broadly for health care overall, and more specifically for our pharmacy. The recent American Society of Health-System Pharmacists–sponsored Pharmacy Practice Model Initiative (PPMI) highlights the need for pharmacy leaders to rethink, redesign and redeploy our professional resources to focus on the patient and to bring greater value to the patient care process. A host of recommendations resulted,3 but I continue to hear leaders struggling with just how to use the recommendations as tools to bring about change in their own practices. What will enable us—individually and collectively—to deliver care that is safe, effective, patient-centered, timely, efficient and equitable, designed to meet the

IOM challenge of more than a decade ago?2 Where do we focus efforts for the greatest impact? The Institute for Healthcare Improvement (IHI) offers a simple framework for achieving change that is based on three essential elements: will, ideas and execution.4 The will to improve is required at every leadership level. This is what John Kotter calls “a sense of urgency.”5 As leaders, we have to make the status quo sufficiently uncomfortable to create a tension for change that will pull others into the process. We need to cultivate creative thinking and ideas so that we can develop alternatives to the status quo. But we also need to act on those ideas to make the change real and embedded in our daily practice. Most critically, we need strategies for testing and rigorously evaluating our ideas for change. We also need to build small wins of innovation, learning and opportunity, without defaulting to the temptations of either incremental tinkering or the “big bang change” of untested ideas.

Embracing Change On a Daily Basis Transformation and improvement will mean change, and what we learn very quickly is that this shift cannot be realized unless “change making” becomes part of the fabric of every job, every day, in every part of the system. Indeed, that change-making process must function with an alignment of purpose that demands a whole

of care that taps the full expertise and value of every health professional in support of the patient’s health goals. Leaders need to recognize that in the course of developing new competencies, even our most talented professionals may feel insecure or even incompetent as they struggle in early stages of change. As a leader in such cases, you will need empathy and nurturing skills as surely as you will need your strategic and critical thinking skills, because you will need your people’s help and support as never before. And if you are going to prepare your team for that sharing of leadership and accountability for transforming care, you must equip them with the ability to perform in an environment of continuing uncertainty and uncontrollable change. This puts you in the environment of both improvisation and experimentation. The analytical problem solving, crisp decision making and articulation of clear direction that got you where you are can in fact get in the way of future success. Although they will still be an asset at times, the adaptive requirements of operating in a permanent crisis and dealing with wicked problems that have no apparent (i.e., traditionally acceptable) solution will require you to have new leadership practices.6,7 Today’s leaders need to continue to excel at those past best practices while developing the next practices for adaptation. Make no mistake that the patient must be the common barometer for the change value. Tolerance for ambiguity will be increasingly essential as a behavioral characteristic as we experiment to find the next best step forward.

‘As leaders, we have to make the status quo sufficiently uncomfortable to create a tension for change that will pull others into the process.’ new way of thinking and behaving. In a profession of highly skilled and trained individuals who are incredibly smart and very good at what they do in a narrow track, leaders will need to set new expectations for thinking outside the four walls of pharmacy, focusing first on the patient. New competencies and skills must be nurtured and developed to facilitate this shift in thinking. The shift needs to be toward health, not health care, and to a boundaryless, collaborative, team-based model

“Wicked Change” focuses on leadership development and change management. This month’s column is authored by Sharon Murphy Enright, BSPharm, MBA, President of EnvisionChange LLC, Richmond, Va. Ms. Enright is coordinating content over subsequent issues and welcomes your feedback at wickedchange@gmail.com.

Sharon Murphy Enright, BSPharm, MBA

As we move from the old paradigm for health care delivery to the emerging new paradigm, the disequilibrium that we experience every day is unsettling. Facing the new realities, the stress and distress of change, will demand that leaders orchestrate the conflict, chaos and confusion of the change to minimize disruption. A culture of discussion, dialogue and openness can create both the candor and risk-taking that allow you to establish antennae throughout the organization to identify risk and opportunity, leverage diverse perspectives and distribute leadership to generate solutions and build a culture of interdependence.

Setting a Course of Action For Change So what will get us there? How will your leadership set the course of action for change and how will we develop the skills, knowledge, behaviors and values that are essential to the change? The reality is that the challenges facing our organizations are beyond the capability of anyone’s current expertise. None of us have been here before. Our past experience got us to where we are and the organization that relies solely on senior leadership to resolve the challenges risks colossal failure. This column will focus on change: how to create it and how to cope with it. We will deal with the challenging change issues the

Pharmacy Practice News • October 2011

Operations & Management 41

Wicked Change pharmacy leaders—big and small L—face every day, and will provide resources and insights that you can use to strengthen your organization’s change, focus and effectiveness. Guest authors—from inside and outside pharmacy practice—will explore specific challenges and initiatives for change that have provided successful next steps in the right direction, and offer the potential for assessment and adaptation for use in your organization. Each topic (see box) will address issues of will, ideas and execution strategies that can serve to drive dialogue for change within your organization and teams. These human conversations allow people to discover mutual concerns and issues, hopefully creating networks of people who share common perspectives and meaning in the discovery of patterns and opportunities for improvement that

arise from the chaos. We look forward to engaging in the dialogue of change for transformation, and to your involvement with the evolution of the knowledge sharing we anticipate. Please contact me with issues that you struggle with as well as those where you have established a beachhead. Within all of our teams, we have the seeds of solutions, as suggested in the opening quote from philosopher Lao Tzu. Sharing our thinking, experience and results will stimulate the new directions that will reshape the value we

bring to the care team and the patient. We expect to travel well outside the traditional pharmacy comfort zone, and to visit previously unexplored ideas. Welcome to the conversation!

References 1. Shore DA, Lively CT. Forces of change: new strategies for the evolving healthcare marketplace. Harvard School of Public Health: Feb 2009 www.hsph.harvard.edu/ ccpe/Forces. Accessed September 12, 2011. 2. Committee On Quality Of Health Care In America. Institute of Medicine. Crossing the Quality Chasm: A New Health System for the

21st Century. Washington, DC: Institute of Medicine; 2001. 3. Pharmacy Practice Model Summit, Executive summary. Am J Health Syst Pharm. 2011;68:1079-1085; doi:10.2146/ajhp110110. 4. Nolan TW. Execution of strategic improvement initiatives to produce system level results. IHI Innovation Series white paper. Cambridge, MA: Institute for Healthcare Improvement; 2007. 5. Kotter J. A sense of urgency. Boston, MA: Harvard Business Press; 2008. 6. Camillus JC. Strategy as a wicked problem. HBR. 2008;86:98-101. 7. Denning PJ. Mastering the mess. Communications of the ACM. 2007;50(4):21-25.

Visit

More Wicked Change Coming

Late-breaking News Links to Other Therapeutic Areas

Online Buyer’s Guides

Medical Education Archives