Pharmacy Practice News Special Edition by McMahon Group

The 2013 Annual Compendium of Clinical Educational Reviews Supplement to Pharmacy Practice News

pharmacypracticenewsse.com

Medication Errors: A Year in Review Institute for Safe Medication Practices

Immune Globulins: Therapeutic, Pharmaceutical, Cost, and Administration Considerations Jerry Siegel, PharmD, FASHP

Revisiting

Environmental Hygiene and Hospital-Acquired Infections Brian Currie, MD, MPH

Compatibility of

Commonly Used IV Drugs Lisa Cayo, PharmD

Safe Handling of Hazardous Drugs: Reviewing Standards for Worker Protection Luci A. Power, MS, RPh Martha Polovich, PhD, RN, AOCN

High-, Moderate-, and Low-Penetrance Genes Involved in the

Pathogenesis of a Hereditary Predisposition to Breast Cancer Larissa A. Korde, MD, MPH Stacey A. Shiovitz, MD

The Future of Antibiotics: Preserving a Precious Commodity Dorothy McCoy, PharmD, BCPS-ID

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EDITOR’S O S

DESK

Dear Readers,

elcome to the 2013 issue of Pharmacy Practice News Special Edition (PPNSE). We’d like to thank our authors for sharing their expertise in the following clinical reviews in this issue: • Medication Errors: A Year in Review (page 7). This review is a compilation of medication errors recently reported to the ISMP, with tips on how to prevent them. • Immune Globulins (page 21). Jerry Siegel, PharmD, offers an updated analysis of this important therapeutic class.

• The Future of Antibiotics: Preserving a Precious Commodity (page 71). In this review, Dorothy McCoy, PharmD, presents a reminder that antibiotics are a critical resource that should not be squandered. We welcome your feedback on these educational reviews as well as your ideas for future topics. Please stop by our booth at the ASHP Midyear Clinical Meeting (Booth 1416) or email us and let us know what clinical reviews you would like to see in upcoming issues.

• Revisiting Environmental Hygiene and Hospital-Acquired Infections (page 31). This new review details emerging environmental hygiene technologies that can help reduce the incidence of nosocomial infections. Sarah Tilyou Senior Editor Pharmacy Practice News Special Edition smtilyou@mcmahonmed.com

• Compatibility of Commonly Used IV Drugs (page 39). Lisa Cayo, PharmD, from Garden City Hospital in Michigan, offers an organized compilation of compatibility data for dozens of agents used regularly in health systems. • Safe Handling of Hazardous Drugs (page 49). Luci Power, MS, RPh, and Martha Polovich, PhD, RN, AOCN, review the latest guidelines for helping health care workers protect themselves from hazardous drugs. • High-, Moderate-, and Low-Penetrance Genes Involved in the Pathogenesis of a Hereditary Predisposition to Breast Cancer (page 63), offers insight into the expanding role of genetics in breast cancer management.

EDITORIAL BOARD

INFECTIOUS DISEASES

EDITORIAL STAFF

Steven J. Martin, PharmD, BCPS, FCCM, Toledo, OH

David Bronstein, Editorial Director davidb@mcmahonmed.com

Peggy McKinnon, PharmD, Lexington, M MA

Sarah Tilyou, Senior Editor smtilyou@mcmahonmed.com

David P. Nicolau, PharmD, Hartford, CT

ADMINISTRATION

Kevin Horty, Don Pizzi, Adam Marcus, Cynthia Gordon, Contributing Editors

Robert P. Rapp, PharmD, Lexington, KY

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INTERNAL MEDICINE

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ANESTHESIOLOGY/PAIN

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BIOTECHNOLOGY

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PEDIATRICS Gretchen Brummel, PharmD, BCPS, Hudson, OH

Larry Ereshefsky, PharmD, San Antonio, TX COMPLEMENTARY AND ALTERNATIVE MEDICINE Cathy Rosenbaum, PharmD, Cincinnati, OH CRITICAL CARE Judi Jacobi, PharmD, FCCM, Indianapolis, IN

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TABLE OF

CONTENTS

7 21 31 39 49 63

Medication Errors: A Year in Review Institute for Safe Medicaition Practices

Immune Globulins: Therapeutic, Pharmaceutical, Cost, and Administration Considerations Jerry Siegel, PharmD, FASHP

Revisiting

Environmental Hygiene and Hospital-Acquired Infections Brian Currie, MD, MPH

Compatibility of

Commonly Used IV Drugs Lisa Cayo, PharmD

Safe Handling of Hazardous Drugs: Reviewing Standards for Worker Protection Luci A. Power, MS, RPh Martha Polovich, PhD, RN, AOCN

High-, Moderate-, and Low-Penetrance Genes Involved in the

Pathogenesis of a Hereditary Predisposition to Breast Cancer Larissa A. Korde, MD, MPH Stacey A. Shiovitz, MD

The Future of Antibiotics: Preserving a Precious Commodity Dorothy McCoy, PharmD, BCPS-ID

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

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Medication Errors: A Year in Review

Horsham, Pennsylvania

he prevention of

medication errors

is an essential component of pharmaceutical care and

must be a core mission of every pharmacy. For medication error prevention efforts to be effective, they must become a priority.

The first step in setting up an error-reduction program is to establish a multidisciplinary team to improve medication use. The team must be given reasonable time and resources to assess medication safety and implement system-wide changes that make it difficult or impossible for practitioners to make mistakes that reach the patient. This multidisciplinary team should accept ownership of the medication-use process and enthusiastically embrace the opportunity

to improve medication safety. The goals of the team should include the following: • Promote a culture of safety to lower medication errors; • Increase detection and reporting of medication errors and potentially hazardous drug-use situations; • Explore and understand the root causes of medication errors; • Educate practitioners about the system-based Text continues on page 12

KEY TO TABLES

Computerized prescriber order entry (CPOE)—A fully integrated CPOE system includes the capability to build medication safety alerts (eg, look-alike names) and clinical decision rules. Additionally, the CPOE system should directly interface with the laboratory system and pharmacy, list drug– drug and drug–disease interactions, and offer clinical order-screening capability.

Bar code–enabled point-of-care (BPOC) systems—These systems are designed to prevent medication errors at the point of medication administration. BPOC systems verify and record all medications administered to the patient through the use of a barcode scanner that matches the medication to the patient by scanning a bar code on the medication and a bar code on the patient’s wristband.

“Smart” infusion pumps—These infusion systems allow users to enter various drug infusion protocols into a drug library with predefined dose limits. If a dose is programmed outside of established limits or clinical parameters, the pump halts or sounds an alarm, informing the clinician that the dose is outside the recommended range. Some pumps can integrate patient monitoring and other patient parameters, such as age or clinical condition.

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Automated dispensing cabinets (ADCs)—These are robust, point-of-use dispensing systems. ADCs should be integrated with the health care facility’s information system and directly interface with the pharmacy system. Additionally, ADCs must be able to use barcoding technology for the restocking process to prevent medication errors.

“Robust” pharmacy order entry system— This order entry system is fully interfaced with a CPOE system. The pharmacy system must be able to produce medication safety alerts as well as directly interface with a health care facility’s information systems, such as the laboratory system. Additionally, this system must be used to generate a computerized medication administration record (MAR) to be used by the nursing staff while administering medications.

P H A R M AC Y P R AC T I C E N E WS S P E C I A L E D I T I O N • 2 0 1 3

Table 1. S Safety f Issues A Associated i d Wi With hO Order d C Communication i i Title

Problem/Discussion Point

Recommendation

ARIXTRA (fondaparinux sodium, GlaxoSmithKline) and ARISTA AH (Medafor) mix-ups

• A pharmacy received a request for “Aristra” from the OR. • The pharmacy dispensed Arixtra, a factor Xa inhibitor, but the surgeon wanted Arista AH, a synthetic, absorbable hemostatic agent.

• Although Arixtra might be used postoperatively to prevent VTE in adults undergoing certain types of surgery, it isn’t started until 6 hours after the procedure, so OR requests for Arixtra should raise suspicion and require verification.

Chemotherapy mix-up between eribulin mesylate (HALAVEN, Eisai) and epirubicin

• An order for “eribulin” was misinterpreted by a pharmacist and entered into the computer as epirubicin. • Both drugs are associated with breast cancer treatment, but typical dosing is very different, and this should have prompted a call to the prescriber for verification.

• Add the salt “mesylate” to the eribulin listing in computer systems, and apply tall man lettering (eriBULin mesylate, EPIrubicin) to prevent name mix-ups. • A pharmacist should verify and independently recalculate the dose of any antineoplastic agent before dispensing it. • Any questions should result in a direct query to the prescriber.

1, 5

Insulin concentration rarely needed on orders

• On a medication reconciliation form, the U-100 strength for LANTUS (insulin glargine, Sanofi-Aventis) was listed instead of the dose under the “dosage” section. • This could be mistaken as an insulin dose of 100 units.

• Do not include the U-100 concentration with typical insulin orders. • The strength should only be listed parenthetically with doses of U-500 insulin. • Educate staff to be suspicious of an insulin dose that is exactly 100 units and to verify its accuracy.

Mismatched prescribing and pharmacy templates for PN lead to data entry errors

• A physician prescribed PN for a 16-year-old boy (72 kg) using a standard pediatric template that prompted orders for most nutrients in per kg units (eg, mEq/kg), but the pharmacy template for patients more than 40 kg required entry of nutrients in per day units (eg, mEq/day). • The pharmacist failed to change the prescribed per kg doses to per day doses and the patient received an exceedingly hypotonic solution (138 mOsm/L) because 2,600 mL of sterile water for injection was used erroneously.

• Be sure the templates for prescribing PN and entering orders into the automated compounding device software (or pharmacy computer) match, both in chronological order and measurement units. • Use a total daily dose when prescribing nutrients for adults and daily weight-based doses (mg/kg per day) when prescribing nutrients for pediatric patients. • Build and heed automated warnings regarding excessive nutrient doses.

1, 5

Mix-ups between RAPAFLO (silodosin, Watson) and RAPAMUNE (sirolimus, Pfizer)

• An order for Rapaflo 8 mg daily was transcribed incorrectly as Rapamune. • Due to a bug in a software upgrade (since corrected), some of the medications in the database would not appear on the screen if the full drug name was entered. • This reinforced an at-risk behavior of only typing in the first few characters of a drug name, which in this case (R-A-P) called up the wrong drug.

• Hospitals should add this drug name pair to their list of look-alike drug names. • Prescribers can help prevent mix-ups by including the drug’s purpose when ordering medications and regularly reviewing the patient’s medication list. • The full drug name should be used whenever feasible instead of the first few characters when entering orders into the pharmacy computer.

1, 5

Mix-ups between various formulations of amphotericin B

• Mix-ups have occurred between liposomal and conventional formulations of IV amphotericin B. • Harm, even death, may result if a mix-up between the 2 products occurs.

• Communicate orders using both the proprietary and complete generic name (eg, AMBISOME [amphotericin B liposomal]), and include the reason for use, the patient’s weight in kg, the mg/kg dose, and the final dosage calculation. • Restrict the preparation and dispensing of amphotericin B to the pharmacy. • Dose checking alerts should be used in computer systems for both liposomal and conventional formulations. • Consider adding warnings to “question all doses over 50 mg” in areas where the conventional form is stored.

1, 5

PRADAXA (dabigatran etexilate, Boehringer Ingelheim) and PLAVIX (clopidogrel, Bristol-Myers Squibb) mix-up

• Plavix was mistakenly dispensed in response to an order for Pradaxa. • Plavix is available in 75-mg and 300-mg tablets (usual dose is 75 mg/day), and Pradaxa is available in the US in 75-mg and 150-mg capsules.

• Use signs or reminders on shelves in storage areas to warn staff of this look-alike drug name risk to help prevent mix-ups.

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Technology

Table 1. S Safety f Issues A Associated i d Wi With hO Order d C Communication i i Title

Problem/Discussion Point

Recommendation

Technology

Searching by drug name gives information on wrong drug

• Tranexamic acid 500 mg, a drug for certain bleeding disorders was found on the discharge medication profile of a patient who takes RANEXA (ranolazine, Gilead) 500 mg for angina. • The hospital’s computer system, PowerChart by Cerner, listed tranexamic acid when searching for “Ranexa.” • Both options were listed when Ranexa was typed, and the wrong name was chosen for the list of discharge medications. • The name Ranexa is completely and correctly spelled within the word tranexamic acid.

• Hospitals should check their drug information and internal computer system to determine how it performs searches; it depends on the specific search functionality set up by the computer system vendor or the hospital. • There may be ways to modify how searches are performed; however, if you are using external databases, you may not have this option.

1, 5

Unnecessary drug release time (72 h) within fentaNYL order misunderstood as dose

• An order for “fentaNYL transdermal 72 h apply 1 patch 12 mcg/hour externally q3d” was misunderstood as 75 mcg/h because the number 72 was read as 75 and mistaken as the mcg/h dose.

• Advise prescribers to avoid listing the patch release rate (72 h) when ordering fentaNYL patches. • Ensure that patients who receive fentaNYL patches are opioid tolerant, not opioid naive.

1, 5

OR, operating room; PN, pa parenteral arenteral nutrition; VTE, venous thromboembolism

Table 2. Problems Involving Drug Information, Patient Information and Staff Education Title

Problem/Discussion Point

Recommendation

Technology

ADEs with dabigatran (PRADAXA, Boehringer Ingelheim) during 1st quarter of 2011

• QuarterWatch™ analysis of ADEs reported to FDA showed a large number (505) of hemorrhagic events with dabigatran, more than with any other drug including warfarin (176). • These events involved mostly elderly patients.

• Alert prescribers to reports of hemorrhagic events and dosing issues associated with elderly patients with renal impairment. • The drug’s manufacturer reported that it is working with the FDA to provide better guidance to physicians on treating elderly patients, especially those with either transiently impaired (eg, contrast media–related) or chronically impaired renal function.

Avoiding inadvertent IV injection of oral liquids

• Not all nurses know that oral syringes are available, their purpose, or how to use them. • One nurse expelled an oral syringe of LORazepam into a parenteral syringe and administered it IV after voicing frustration that the pharmacy-dispensed syringe could not be connected to the IV port. • Another nurse expelled oral morphine solution into a dosing cup, diluted it, drew it into a parenteral syringe, and injected it IV.

• Include education about accidental injection of oral liquids and the purpose for using oral syringes during nursing orientation and new graduate mentorship. • Ensure that oral syringes are available in all patient care units, and affix auxiliary labels that state “ORAL” to all medications dispensed in oral syringes.

Bortezomib (VELCADE, Millennium) deaths due to intrathecal misadministration

• At least 3 fatalities have been reported in Europe due to inadvertent administration of IV bortezomib into the intrathecal space. • These events involved intrathecal chemotherapy scheduled on the same day/time as IV bortezomib. • Intrathecal chemotherapy and IV bortezomib are both administered in small volumes via syringes, increasing the likelihood of a mix-up.

• Administer intrathecal chemotherapy at a different time than IV chemotherapy. • Verify that intrathecal medication has been administered before dispensing IV bortezomib (or vice versa) for patients receiving medications via both routes. • Label bortezomib syringes with warnings about IV use only. • Require a time-out procedure and an independent check before administering intrathecal medication or chemotherapy.

ADC, automated dispensing cabinet; ADE, adverse drug event; APhA, American Pharmacists Association; CPOE, computerized prescriber order entry; OTC, over-the-counte over the counter

Table continues on next page

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Table 2. Problems Involving Drug Information, Patient Information and Staff Education (continued) Title

Problem/Discussion Point

Recommendation

Do not infuse DACTINomycin in sterile water

• Studies show that DACTINomycin diluted at concentrations of 10 mcg/mL or higher in sterile water, normal saline, and 5% dextrose are stable for 10 hours (room temperature). • But dilution with sterile water could result in a hypotonic solution that would cause hemolysis if administered IV.

• Dilute DACTINomycin only in 5% dextrose or normal saline during preparation for IV administration.

ISMP survey reveals user issues with Carpuject™ prefilled syringes

• An ISMP survey of 540 nurses using Carpuject prefilled syringes found that 68% were unaware of significant cartridge overfill that could lead to overdoses. • Nurses also reported using the prefilled cartridges as multiple-dose vials, risking contamination and unlabeled syringe contents. • Factors that encourage this practice include unavailability of Carpuject syringe holders, the need to dilute the product, and preventing drug waste.

• Do not use the Carpuject cartridges as multiple-dose vials. • Drugs that require further dilution should be prepared by the pharmacy when possible. • If dilution is required on the unit and a 1:1 ratio is acceptable, drawing a small volume of a diluent from a single-dose vial directly into a cartridge (1 mL fill or less) may be considered. • Provide an adequate supply of Carpuject syringe holders.

Medications associated with ADEs that led to hospitalization

• According to a recent study (www.nejm.org/doi/ full/10.1056/NEJMsa1103053?query= featured_home), warfarin, insulin, oral antiplatelet agents, and oral hypoglycemics accounted for more than two-thirds of the drugs tied to hospitalization for ADEs in older adults. • Most ADEs were associated with unintentional overdoses.

• Provide specific medication error–prevention education to hospitalized patients who are discharged on warfarin, insulin, oral antiplatelet agents, and oral hypoglycemic agents. • Pay particular attention to the prevention of dosing errors.

Medication within IV tubing may be overlooked

• A nurse flushed a post-op patient’s IV line previously used by anesthesia. • The patient became unresponsive because several mg of rocuronium present in the tubing was inadvertently flushed into the patient. • Depending on the drug concentration, IV set volume, and point of injection, unintended doses of drugs are possible when lines are flushed or IV medications are administered.

• Flush IV lines as proximal to the patient access site as possible after clamping the line immediately above the point of injection. • For IV piggybacks, the insertion point should be at a Y-site closest to the patient’s access site. • Post-procedure, anesthesia should flush lines or change the tubing, and remove any source medication, before extubation.

NOVOLOG FLEXPEN (insulin aspart) dose misread by patient

• A patient administered 46 units instead of 6 units of insulin when she misread the dose she had dialed using a NovoLOG FlexPen by reading the numbers to the right of the dosing window, not within the dosing window. • Other pen issues experienced by patients include inserting the needle but not pressing the button to release the dose or turning the dial to release the dose.

• Patients who are prescribed an insulin pen should meet with a certified diabetes educator, pharmacist, or nurse to demonstrate proper dose selection and use.

Phosphate enemas may pose problems for renal patients

• A patient admitted with acute renal failure also had constipation and received 2 Fleet enemas, each containing 7 g of dibasic sodium phosphate and 19 g of monobasic sodium phosphate, or more than 160 mmol of phosphate. • The patient developed secondary hypocalcemia due to diminished phosphate clearance resulting from her renal failure. She required emergency hemodialysis, then daily hemodialysis followed by IV calcium.

• During order entry, computer systems should warn practitioners when these agents are about to be prescribed for patients with decreased renal function. • Fleet enemas should not be stored in patient care areas unless they are secured in an ADC with restricted access to limit removal before a pharmacist’s clinical review of the order.

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Technology

1, 5

Table 2. Problems Involving Drug Information, Patient Information and Staff Education Title

Problem/Discussion Point

Recommendation

Technology

Prescription drug time guarantees and their effects on patient safety in community pharmacies

• ISMP and APhA cooperatively conducted a survey between June 9 and July 7, 2012, that demonstrated how policies and procedures related to pharmacy guarantees to fill prescriptions within a specified time are implemented and how pharmacists link these pharmacy time guarantees to medication errors.

• Helping patients recognize what the pharmacist does behind the scenes and to accept, even demand, patient counseling is crucial to our collective efforts to improve patient safety. • We need to improve patients’ perceptions of the value of community pharmacies and to achieve this, every health care provider needs to be part of the effort to address the adverse effects of time guarantees on safety. • The adverse effects of time guarantees in community pharmacy practice spill over into the inpatient pharmacy practice. • It is crucial for hospital pharmacists, nurses, and physicians to promote the important role of both hospital and community pharmacists when teaching hospitalized patients about their medications.

Prevent counterfeit drugs from reaching patients

• The FDA discovered an unlicensed supplier selling fake injectable bevacizumab (using Genentech’s brand name AVASTIN) to oncology practices. • The fake product contained no active ingredient.

• All health care professionals, not just pharmacists, need to be aware of proper procedures for safely procuring medications for patients. • The Partnership for Safe Medicines provides the resources for pharmacists, nurses, and physicians to help prevent counterfeit medicines from reaching patients: http://safedr. ug/for_pharmacists, http://safedr.ug/for_ nurses, http://safedr.ug/for_physicians.

Protocol needed for drug concentration change

• A DOCEtaxel order was entered into the pharmacy computer system. • The pharmacy technician preparing the product saw that the DOCEtaxel concentration in stock had changed, but the computer system did not have the new concentration listed in its inventory, so the drug amount on the label in mL was incorrect.

• When purchasing alternative products or strengths that are different from those normally stocked, a verification process is needed to ensure that changes are made in computer systems, including IV compounders and robots, ADCs, CPOE systems, smart pumps, and other affected technology.

Reduce readmissions with pharmacy community liaison program and patient education

• Medicare is reducing payments to hospitals with high readmission rates for 3 conditions—heart failure, myocardial infarction, and pneumonia. • Studies have identified that ADEs are at the very core of readmissions.

• External programs offered by community pharmacies and hospital-run community liaison programs can help hospitals reach readmission goals and decrease preventable ADEs. • These programs provide in-home or telephone support of pharmaceutical care for recently discharged patients. • Before and after discharge, education should focus on patients prescribed high-alert medications, especially warfarin, insulin, antiplatelet agents, and hypoglycemic agents. • ISMP offers free patient handouts for several of these high-alert medications to help prevent errors and other ADEs with these drugs (www.ismp.org).

Remove glacial acetic acid from pharmacies

• Several patients sustained severe skin or mucosal burns after undiluted glacial acetic acid (99.5%) was dispensed and applied instead of a 5% acetic acid solution. • The strength of the solution was not readily visible on the bottle label, and the pharmacist believed glacial acetic acid was a 5% solution prediluted by the manufacturer.

• Remove glacial acetic acid from the pharmacy and replace it with vinegar (5% solution) or commercially available diluted acetic acid. • Educate staff about the differences between glacial acetic acid and lesser concentrations. • Take precautions if pharmacy dilution of acetic acid must occur, including development of a standard mixing procedure and double-checks.

ADC, automated dispensing cabinet; ADE, adverse drug event; APhA, American Pharmacists Association; CPOE, computerized prescriber order entry; OTC, over-the-counte over the counter

Table continues on next page

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Table 2. Problems Involving Drug Information, Patient Information and Staff Education (continued) Title

Problem/Discussion Point

Recommendation

Technology

Safe fentaNYL patch disposal

• A 2-year-old boy accidentally gained access to a used fentaNYL patch while visiting his greatgrandmother in a nursing home. • The boy died and the medical examiner found a fentaNYL patch in the boy’s throat. • Investigators later found improperly discarded used patches at the nursing home.

• The National Alert Network (NAN) issued a warning about proper disposal of fentaNYL patches (www.ismp.org/NAN/files/NAN-20120425.pdf). • Product labeling states used patches should be flushed down the toilet. • Follow-up with the FDA revealed that flushing is the recommended disposal method for used patches in the home; in health care organizations, patches should be disposed of in a secure sharps container, witnessed and documented according to policy.

Sterile compounding safety guidelines

• ISMP has finalized the Proceedings from the ISMP Sterile Preparation Compounding Safety Summit: Guidelines for SAFE Preparation of Sterile Compounds. • The proceedings and guidelines stem from the October 2011 National Sterile Preparation Compounding Safety Summit held by ISMP in response to frequent sterile compounding ADEs reported to the ISMP National Medication Errors Reporting Program and other reporting programs, and published in the scientific literature and lay press.

• The guideline can be found at www.ismp.org/ Tools/guidelines/IVSummit/IVCGuidelines.pdf.

Teach patients to remove older transdermal fentaNYL patches

• An unresponsive patient was brought to the hospital with multiple fentaNYL patches on his body. • The patient followed the directions to “apply one patch every 72 hours” but was not told to remove the older patch prior to applying a new patch.

• Ensure that patients who are prescribed transdermal patches understand proper use and disposal of patches. • ISMP has developed a safety checklist that can be used by those providing education and given to the patient afterward for reference (www.ismp.org/sc?id=90).

Topical analgesics and burns

• Certain OTC topical products used for muscle and joint pain have caused rare cases of firstto third-degree chemical burns. • These OTC products, including Icy Hot (Sanofi), Bengay (Johnson & Johnson), Capzasin (Sanofi), and Flexall (Sanofi), generally contain menthol, methyl salicylate, or capsaicin.

• Alert patients to the risk, and advise them to use these products exactly as stated on the label and to discontinue use if they feel actual pain (rather than a warming sensation) after applying them. • Additional strategies can be found at www.ismp.org/sc?id=103.

ADC, automated dispensing cabinet; ADE, adverse drug event; APhA, American Pharmacists Association; CPOE, computerized prescriber order entry; OTC, over-the-counte over the counter

Text continued from page 7

causes of errors and their prevention; • Recommend methods to facilitate the implementation of organization-wide, system-based changes to prevent medication errors; • Respond to potentially hazardous situations before errors occur; and • Learn from errors occurring in other organizations through the ISMP Medication Safety Alert! and other published accounts of medication errors, and proactively take measures to prevent similar errors. Effective results depend on understanding the entire medication-use process through varied perspectives and disciplines. ISMP is a nonprofit organization that works closely with health care practitioners and institutions, regulatory agencies, professional organizations, and the

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pharmaceutical industry to provide education about medication errors and their prevention. ISMP independently reviews medication errors that practitioners and patients have voluntarily submitted to the ISMP Medication Error Reporting Program. ISMP is an accessible resource for any pharmacist or organization interested in implementing the actions recommended herein. Among the many products and services that ISMP offers is the ISMP Medication Safety Alert!! Acute Care Edition, a biweekly newsletter that provides timely information related to error prevention. It identifies errors that have been reported by other organizations and offers recommendations to prevent those errors from occurring in the pharmacy. The information in the tables of this review summarizes many of the significant error-prevention Text continues on page 19

Table 3. Safety Issues Related to Labeling, Packaging, and Nomenclature Technology

Title

Problem/Discussion Point

Recommendation

Clear Care (CIBA Vision) contact lens cleaner still burning eyes

• People who wear contact lenses continue to be injured when using Clear Care as a multi-purpose solution for rinsing and soaking lenses. • Clear Care solution contains 3% hydrogen peroxide, which should never come in contact with the eyes. • People commonly miss the statement on the product label informing them to soak their lenses only in the special contact lens holder.

• ISMP has contacted the manufacturer and FDA for a labeling change to better distinguish Clear Care solution from other solutions. • Outpatient pharmacies that carry Clear Care or generic equivalents should separate the product from soaking solutions or put it behind the counter so instructions can be communicated orally.

Concentrated EPINEPHrine mistaken as lidocaine with EPINEPHrine

• Mix-ups between a local injection of EPINEPHrine 1:1,000 and lidocaine with EPINEPHrine (1:100,000) continue to happen even though this resulted in the death of a child more than 15 years ago.

• Supply EPINEPHrine for topical use in a pour-bottle with an auxiliary label that states “TOPICAL.” • Or use presoaked EPINEPHrine pledgets prepared in advance of procedures. • Do not place medication meant for injection (eg, local anesthetic) in an open container (eg, bowl).

Confusion between EPIPEN (EPINEPHrine injection) training device and active pen

• EpiPens are only available in a 2-Pak containing 2 EpiPens and a nonfunctioning training pen. • The training pen looks similar to the actual EpiPen. • An emergency department’s ADC was accidentally stocked with an EpiPen training device instead of the active pen.

• If hospitals store EpiPens on clinical units or in code carts, the pens should be removed from their carton and only the active pens should be stored in unit stock. • Be sure staff members know about the risk for confusion between the training pens and actual pens.

How much insulin is in a 3-mL vial?

• Eli Lilly introduced insulin 100 units/mL, 3-mL vials in 2009. • A nurse prepared an insulin drip (250 units/250 mL), reading the U-100 (100 units/mL designation) as 100 units per vial. She then used 2.5 vials of insulin (7.5 mL) instead of 2.5 mL, which resulted in the bag containing 750 units instead of 250 units. • Fortunately, the solution was never administered to the patient because the order was discontinued before the infusion was started.

• ISMP recently communicated with Lilly and the FDA about this issue so each could further investigate whether or not the per-container amount should be listed. • Whenever possible, pharmacy should prepare, label, and dispense all insulin infusions. • If this is not possible, an independent doublecheck of the preparation should occur before the infusion is administered.

Important change with heparin labels

• The FDA announced that, effective May 1, 2013, heparin vial labels must express the strength per the entire container followed by the strength per mL in parentheses. • Staff have mistaken the per mL strength as the total dose contained in a vial, which has led to heparin overdoses.

• There will be a transition period where both labeling styles will be on the market. • To minimize the potential for medication errors, purchasers and pharmacy managers should strongly consider separating the supplies of “current” and “revised” heparin, using all of the “current” heparin products before using products with the “revised” label.

Inadvertent IV injection of EXPAREL (bupivacaine liposome suspension injection, Pacira Pharmaceuticals)

• Exparel, a local anesthetic intended for infiltration into a surgical wound to produce postoperative analgesia, looks a lot like propofol, a drug used for sedation. • Both products are a milky white emulsion used in the operating room, so unlabeled syringes could result in misadministration, potentially resulting in a fatality.

• Separate the storage of these 2 drugs. • Require proper labeling of all syringes that contain propofol or Exparel, even if the medication will be immediately used. • Establish a routine double-check process to make sure that any unused medication in a syringe containing Exparel never leaves the sterile field without a label. • See additional recommendations at www.ismp. org/NAN/files/NAN-20120318.pdf.

ADC, automated dispensing cabinet; ISMP, Institute for Safe Medication Practices; NMBA, neuromuscular blocking agent; PBP, pharmacy bulk package; pack kage; USP, United States Pharmacopeia

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Table 3. Safety Issues Related to Labeling, Packaging, and Nomenclature

(continued)

Technology

Title

Problem/Discussion Point

Recommendation

Inappropriate use of PBPs of IV contrast media increases risk for infections

• Some staff members have been using PBPs of contrast media inappropriately as multidose containers for multiple patients in radiology, cardiac catheterization labs, and cardiac surgery locations. • Staff may believe the PBP is a multidose container because some manufacturers refer to it as a “multipack” and some power injector manufacturers suggest such use. • PBPs of contrast media do nott contain preservatives to help prevent contamination and the spread of infection.

• The pharmacy should oversee purchase, distribution, storage, and use of IV contrast media for inpatients and outpatients. • Staff should draw up doses of IV contrast media from single-dose vials or use prefilled single-use syringes from the pharmacy or manufacturers. • The contents of PBPs should be transferred only to single-dose containers or syringes in the pharmacy under a laminar flow hood or other USP <797>–suitable environment within 4 to 10 hours of initial entry into the bag.

Look-alike vials of calcium gluconate (100 mg/mL) from APP Pharmaceuticals and cupric sulfate (4 mg/10 mL) from American Regent

• Vials of calcium gluconate and cupric sulfate were mixed up when infusions were prepared. • Both vials are similar in size and have a similar pink color on the label, although one is from APP (calcium gluconate) and the other is from American Regent (cupric sulfate).

• Separate storage of these products in the pharmacy. • If possible, purchase one of the products from a different manufacturer.

Melphalan (Mylan) diluentt vial confused as actual drug vial

• Mylan’s lyophilized melphalan is packaged with a diluent that is not clearly labeled and has been confused with the actual drug. • The vials of drug and diluent are the same size, both have white caps and similar label colors, and the diluent label has the drug name listed prominently.

• Add an auxiliary label to the diluent to properly identify it, or, until Mylan improves the labeling, use a different manufacturer for this product.

Mix-ups between ENGERIX-B (hepatitis B vaccine, Novartis) and methylergonovine maleate (American Regent)

• Novartis sent a letter to hospitals that highlighted the accidental administration of methylergonovine instead of the ordered hepatitis B vaccine to newborns. • Two of the recent mix-ups involved Engerix-B and generic methylergonovine, which are packaged in vials that look very similar.

• Separate newborn medications from those used for mothers. • If newborn and perinatal medications must be stored together in ADCs, use locked, lidded medication bins for pediatric products, and highlight whether medications are for the mother or newborn on selection screens. • If possible, administer newborn medications in an area that is separate from where medications are administered to the mother.

2, 4, 5

Mix-ups between methadone and methylphenidate

• A community pharmacy dispensed methadone in a vial labeled with the prescribed drug, methylphenidate, to a child. • The mix-up also has happened in hospitals. • Both drugs have a 10-mg strength, and they may appear together on computer selection screens.

• Configure mnemonics in order-entry systems to prevent confusion between methadone and other drugs that start with “met” or “meth” and have similar strengths. • Separate methadone and methylphenidate in storage areas. • Implement bar-code scanning in the pharmacy to identify when the wrong product has been selected from the shelf.

1, 2, 5

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Table 3. Safety Issues Related to Labeling, Packaging, and Nomenclature Technology

Title

Problem/Discussion Point

Recommendation

Name mix-ups with cloBAZam (ONFI) and clonazePAM (KLONOPIN)

• Name similarity between cloBAZam and clonazePAM has led to several reports about the potential for confusion. • The drugs share some similar indications (eg, Lennox-Gastaut syndrome), but there is a 10-fold difference in the strength of available dosage forms.

• ISMP plans to add the pair of cloBAZam and clonazePAM to its List of Confused Drug Names and added cloBAZam to its List of Look-Alike Drug Names with Recommended Tall Man Letters. • Ensure that your institution has appropriate safeguards to allow health care providers to differentiate these 2 medications.

Potassium chloride (KCl) injection concentrate in a syringe

• Due to a shortage of KCl injection concentrate in vials and PBPs, a technician purchased KCl 20 mEq syringes from an outsourcing company. • An overwrap with a warning statement was removed and the syringes were left on a counter. • A pharmacist thought these were cefazolin syringes, because they had a similar red cap, and placed them in the refrigerator with other cefazolin syringes.

• The company no longer provides KCl syringes, but other companies may do so. • ISMP urges hospitals to only purchase KCl in vials, not syringes, and to never remove caps or overwraps with warning statements until just before use.

Potential mix-up of NOVOLOG (insulin aspart, Novo Nordisk) and NIMBEX (cisatracurium, Abbott Laboratories)

• In an emergency department, a pharmacist found a carton of NovoLOG insulin in a refrigerator bin where Nimbex cartons were stored. • Both have very similar-looking packaging. • A mix-up either way could be fatal.

• In pharmacy and clinical areas where NMBAs are needed, they should be stored separately in a sealed container, lidded bin, or intubation kit. • Affix a ‘warning label to NMBAs stating: Warning: Paralyzing Agent—Causes Respiratory Arrest.’ • When an NMBA is no longer needed, place any leftover vials, bags, and syringes of the drug in a sequestered bin for immediate pharmacy removal.

2, 4

Similarities between INTRALIPID (IV fat emulsion) and VIPERSLIDE

• A mix-up is possible between Intralipid (IV fat emulsion) and a non-drug product called ViperSlide, a lubricant to reduce friction with devices used during atherectomy procedures. • While conducting an inspection of an interventional vascular lab, a pharmacist found ViperSlide, which has a milky white appearance. • It is packaged in a 100-mL bag that looks almost identical to the 100-mL Intralipid 20% bag.

• Understanding the steps involved in various procedures where ViperSlide might be used at your hospital, and checking to see if these 2 look-alike products are available, can help you identify risks and implement strategies. • Store these products separately or in an ADC with separate lidded drawers to reduce the risk for a mix-up.

2, 4

USP Prescription Container Labeling standard

• USP has created a web page on outpatient prescription container labeling (General Chapter <17>) to guide organizations in the presentation of information in a patient-centered manner.

• Hospitals that provide outpatient prescription services to patients and/or staff should assess current labeling procedures to ensure they match the guidelines (www.ismp.org/sc?id=142).

1, 2, 4, 5

ADC, automated dispensing cabinet; ISMP, Institute for Safe Medication Practices; NMBA, neuromuscular blocking agent; PBP, pharmacy bulk package; pack kage; USP, United States Pharmacopeia

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Table 4. Addressing Concerns Involving Infection Control Title

Problem/Discussion Point

Recommendation

Avoid multidose vials in the OR

• The use of multidose vials in the OR has resulted in infection outbreaks and errors. • Cross-contamination is always a possibility when using multidose vials. • Also, when medications are supplied in quantities that exceed the amount typically given, practitioners may misinterpret the amount in the vial as a single dose, leading to overdoses.

• The Association of PeriOperative Registered Nurses recently released a set of recommended practices (http://alturl.com/xapaa) that include a recommendation to collaborate with pharmacists to procure and store only single-dose vials in ORs and postanesthesia units. • The document outlines other best practices to use in the OR when procuring, prescribing, dispensing, administering, and monitoring the effects of medications. • Multidose vials should be avoided.

CMS citing reuse of insulin pens

• In May 2012, CMS announced that hospitals will be cited if surveyors identify the sharing of insulin pens (www.ismp.org/sc?id=77). • Regurgitation of blood into the insulin cartridge after injection risks disease transmission if the pen is used for more than 1 patient, even if the needle is changed.

• Educate practitioners about the risks associated with sharing pens (CMS announcement suggested that some may not be aware of this risk). • Dispense pens for individual patients, with a pharmacy label that includes the patient’s name.

Do not use an insulin pen for multiple patients

• Repeated events suggest there is a widespread misunderstanding that sterility can be maintained between patients by affixing a fresh needle on a pen device. • Studies have shown that biological contamination occurs in up to half of all reused insulin pens. • This concern led the CDC to issue a clinical reminder regarding increasing reports of improper use of insulin pens (www.cdc.gov/injectionsafety/clinicalreminders/insulin-pens.html).

• To reduce the risk for cross-contamination, insulin pens should be assigned to individual patients and labeled using a “flag” attached to the body of the pen without covering the drug name. • If ongoing education and monitoring of proper use of pen devices cannot be accomplished, hazardous conditions may persist, and hospitals may need to consider whether patients would be safer with dispensing of vials or prefilled syringes of insulin.

Eye drop– related infections

• Sharing of eye drop containers between patients and between both eyes of 1 patient has led to serious eye infections from cross-contamination. • Although most products include preservatives to prevent the growth of bacteria and fungi, organisms can still thrive on the tip of the bottle. • Rates of contamination as high as 35% have been noted in some studies; although infections are rare, they can happen and even cause blindness in some cases.

• To reduce costs, ophthalmic specialty hospitals often have mandatory training, competency, and monitoring programs to teach and validate safe administration of eye drops. • Hospitals without this level of training and monitoring should dispense separate containers of eye drops for each patient and each eye. • Once they are discharged, patients can use a device (eg, Owen Mumford) that does not allow the bottle to touch the eye when they squeeze out the drops.

New tools on safe injection practices

• The CDC has had to investigate many outbreaks of life-threatening infections caused by injection errors. • Lack of initial and continued infection-control training, denial of the problem, drug shortages, and lack of appreciation for the consequences of unsafe injection practices all have been at the root of these outbreaks.

• The CDC and the Safe Injection Practices Coalition released a suite of new materials to help health care providers learn about and follow safe injection practices (http://blogs.cdc. gov/safehealthcare/?p=2802). • The tools include PowerPoint slides, videos, podcasts, posters, and a press release kit. • Health care facilities are encouraged to use the new tools.

Proper use of single-dose vials

• Use of single-dose or single-use vials for multiple patients can lead to contamination and spread of life-threatening infections and is not recommended. • The CDC has reiterated its position on improper use of single-dose vials in response to concerns that such a policy contributes to shortages (www.cdc.gov/injectionsafety/CDCpositionSingleUseVial.html).

• Drug shortages and drug waste concerns must be dealt with appropriately and single-dose or single-use vials must be used as intended. • However, the CDC notes that shortages of some essential medications may warrant pharmacy repackaging to subdivide contents of unopened single-dose/single-use vials via implementation of meticulously applied practice and quality standards following USP Chapter <797>.

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Technology

Table 4. Addressing Concerns Involving Infection Control Technology

Title

Problem/Discussion Point

Recommendation

Sterile compounding tragedy should spur assessment and action in hospitals

• The recent outbreak of fungal meningitis cases caused by contaminated steroid injections from a compounding pharmacy has led to scrutiny in these facilities. • The outbreak also should lead hospitals to assess their own internal sterile compounding practices. • Only 13% of pharmacy school deans feel their students have been adequately trained in sterile compounding before graduation.

• Use commercially available, ready-to-use, FDA-approved products from pharmaceutical manufacturers when possible. • For medically necessary products that are not commercially available, carefully select and use a compounding pharmacy (www.ismp.org/ sc?id=111) or internally compound the products. • Tools are available to help assess and train staff in sterile compounding (www.ashp.org, www.criticalpoint.info/home), including ISMP’s Guidelines for Safe Preparation of Sterile Compounds (www.ismp.org/Tools/guidelines/ IVSummit/IVCGuidelines.pdf). • Establish a surveillance team to regularly test compounded preparations and monitor for compliance with USP Chapter <797>.

C C, Ce CDC, Centers te s for o Disease sea ase Co Control to a and d Prevention; eve t o ; CMS, C S, Ce Centers te s for o Medicare ed ca e & Medicaid ed ca d S Services; e v ces; ISMP, S , Institute st tute for o Safe Sa e Medication ed cat o Practices; act ces; OR, O , ope operating att g room oo

Table 5. Medical Devices and Other Discussion Items Technology

Title

Problem/Discussion Point

Recommendation

Apothecary measurement system a factor in medication errors

• A nurse gave a patient 5 drams (18.45 mL, 1.845 g) of acetaminophen concentrate liquid (100 mg/mL) instead of 5 mL. • The dose was measured in a cup with scales labeled in drams, fluid ounces, cc, mL, tsp, and tbsp. • Confusion has been reported frequently between drams, ounces, mL, tsp, and tbsp.

• ISMP supports complete adoption of the metric system for prescribing and measuring liquid doses. • The hospital should use oral syringes or dose cups without apothecary gradations to measure and administer oral liquid medications.

Covidien ChemoPlus gown may not afford worker protection

• A technician accidentally sprayed iron dextran injection on her ChemoPlus Protective Gown sleeve and it seeped through onto her clothes. • Although the ChemoPlus product description states that the fabric is “splash resistant,” the gowns do not meet OSHA, ASHP, or ONS recommendations for chemotherapy protection. • Only the company’s ChemoPlus Poly-Coated and the ChemoBloc Poly-Coated Gowns meet the recommendations and are appropriate personal protective equipment for handling chemotherapy and other hazardous drugs.

• Don’t be misled into believing you are maximally protected during preparation and administration of chemotherapy and other hazardous drugs by the brand name “ChemoPlus.” • If you are using ChemoPlus gowns, be sure they are poly-coated and meet OSHA, ASHP, and ONS recommendations.

Distractions and interruptions contribute to medication errors

• Clinical staff are interrupted as often as once every 2 to 5 minutes. • Distractions and interruptions include anything that diverts attention away from the current task, forcing attention on a new task at least temporarily.

• Identify the sources of common interruptions and remedy any system issues, such as frequently missing medications; untimely dispensing of medications; or frequent invalid, insignificant, or overly sensitive computer alerts and device alarms. • Provide staff with a quiet area/no interruption zone with a dedicated medication room or a cordoned off area in which to select and prepare medications. • Avoid placement of ADCs in hallways or busy nurses’ stations. • Ask all staff to avoid interrupting other staff members during critical medication tasks.

ADC, automated dispensing cabinet; ASHP, American Society of Health-System Pharmacists; FMEA, failure mode and effects analysis; ISMP, Institute for Safe Medication Practices; MAR, MAR, medication administration record; ONS, Oncology Nursing S Society; ociety; OSHA, Occupational Safety and Health Administration

Table continues on next page

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Table 5. Medical Devices and Other Discussion Items Title

Problem/Discussion Point

Recommendation

Harm associated with drug shortages

• According to our recent survey, drug shortages— particularly with DOXOrubicin, fentaNYL, morphine, electrolytes, antibiotics, phentolamine, and phytonadione—have extracted a significant toll on patient safety during the past year. • The problems that have been cited most often involved suboptimal treatment from use of an alternative medication that was not the drug of choice, errors with alternative medications, and errors when a pharmacy attempted to compound a product or strength no longer available.

• When faced with a drug shortage, conduct a mini FMEA (sample format at http://www.ismp.org/ tools/FMEA.asp) to assess the potential hazard to patients and potential misuses of alternatives. Determine how to best manage the risk for serious errors and adverse reactions to alternative drugs, and make any necessary procedural and technological changes to support safe use. • When possible, have pharmacy prepare and dispense alternative drugs in the most ready-to-use form.

High-alert medications left behind by contracted services

• A 20,000 unit/mL heparin vial was found in a hospital’s OR, despite a decision to not stock this unsafe concentration. • It was determined that an organ harvesting team had left the unused vial behind. • In another case, a hospital-contracted renal transplant service left sodium chloride 23.4% (used to reduce cramping during hemodialysis) on several nursing units. • Staff unaccustomed to the atypical stock can mistake the products for less concentrated forms of the drugs.

• When outside groups contract to provide services, hospital leadership must work with the pharmacy to ensure that the medications and dosage forms that might be used are reviewed and agreed on by the pharmacy. • At that time, alternative products may be discussed and/or arrangements made to securely store products normally not available at the hospital. • Pharmacy staff should also conduct regular visits to patient care units to observe drug storage.

Is it insulin or heparin?

• Some health care practitioners are engaging in an at-risk behavior in which they intentionally draw heparin into an insulin syringe when they do not have a syringe with a 25-gauge needle to use for subcutaneous heparin injections. • Even if the insulin syringe is clearly labeled as containing heparin, health care practitioners may associate the orange-capped syringe with insulin, not heparin.

• Provide commercially available prefilled syringes of heparin with 25-gauge needles. • Be sure you have all the necessary medicationrelated supplies in all your patient care units, including parenteral and oral syringes (smallvolume oral syringes in neonatal/pediatric units), infusion pumps, infusion tubing, port caps, etc. • Do not employ policies that force staff to engage in workarounds to provide care to their patients.

ON-Q PainBuster Post-Op Pain Relief System (I-Flow Corporation) has a Luer connector

• The ON-Q pump, intended to infuse anesthetic solution around surgical wound sites, incorporates tubing that attaches to infusion equipment with a Luer connector, which is common to IV lines. • With bupivacaine and other local anesthetic solutions, patient harm is possible if the ON-Q pump is inadvertently attached to an IV line.

• Affix a label to the ON-Q solution container stating, Warning: Regional Block Only. • Always trace the solution to the patient access point or vice versa to prevent inadvertent attachment of the ON-Q tubing to an IV access port.

Red flags that represent credible threats to patient safety

• Intimidation in the workplace has repeatedly surfaced as a significant barrier to safety. • A natural deference to expertise can lead to unintended complacency and tolerance of risk that goes unchallenged.

• Raise the index of suspicion for errors, always anticipating and investigating the possibility when anyone, regardless of experience or position, voices a concern or when patients are not responding to treatment as anticipated. • Staff need to trust in their own experiences to augment the expertise of others, and to be receptive to staff who ask questions. • Visit www.ismp.org/sc?id=102 for a list of skills to encourage appropriate responses to concerns.

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Technology

Table 5. Medical Devices and Other Discussion Items Title

Problem/Discussion Point

Recommendation

Smart pump custom concentrations without hard “low concentration” alerts

• ISMP has received reports of overdoses due to misprogramming of infusions with custom concentrations that do not employ a hard minimum concentration alert. • Accidentally programming a lower concentration than the actual product concentration results in the delivery of a higher dose than prescribed because more volume will be infused. • The resulting “low concentration” alert from smart pumps has been misinterpreted as a “low-dose” alert. • Without a hard minimum concentration limit, errors due to the misprogramming of an infusion pump can lead to life-threatening events.

• Assess your facility’s vulnerability to this type of error. • Clarify with staff any confusion regarding the inverse relationship between dose and concentration, and the differences between “low-concentration” and “low-dose” alerts. • Limit the number of standard concentrations for drug infusions. • If a custom concentration is needed, set a hard minimum concentration limit. • Use distinctive labels to distinguish custom concentrations. • Express the drug concentration on the label and MARs the same way it needs to be entered into the pump (eg, mg/mL, total drug/total volume).

Teaspoonful– mL mix-ups with midazolam syrup

• A nurse preparing a 2-mg dose of midazolam syrup mixed up mL and teaspoonful and measured out 1 teaspoonful instead of 1 mL. • The BD oral syringe she used had both teaspoonful and mL scales. • Oral syringes with a mL-only scale are not available in 5 mL and larger sizes.

• ISMP has called for limiting the units of measure to the metric system for devices, computer screens, medication orders, and dosing instructions on labels. • Evaluate the oral liquid dosing devices used in your facility, and alert staff to the risk for measuring errors if both scales are on the syringe barrel. • ISMP has asked manufacturers of dosing cups and oral syringes to make mL-only devices available for hospital use.

Tubing misconnections self-assessment tool for health care facilities

• Tubing misconnections are frequent and preventable errors that pose a significant risk to patient safety and can result in devastating outcomes. • Because of human factors, the clinical environment, and the interconnectivity of Luer connectors, health care professionals have mistakenly connected the wrong devices and delivered substances via the wrong route.

• Hospitals are encouraged to complete a new self-assessment tool that guides users to evaluate current delivery systems and mating devices (www.baxter.com/healthcare_professionals/clinical_center_of_excellence/connections_portfolio/ programs/tubing_misconnection_index.html). • By completing the assessment, hospitals will identify potential tubing misconnection risks and develop an action plan to mitigate risks through processes, device selection, and education.

Technology 3

ADC, automated dispensing cabinet; ASHP, American Society of Health-System Pharmacists; FMEA, failure mode and effects analysis; ISMP, Institute for Safe Medication Practices; MAR, MAR, medication administration record; ONS, Oncology Nursing Society; Society; OSHA, Occupational Safety and Health Administration

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strategies that were recommended in the ISMP Medication Safety Alert! Acute Care Edition during 2012. The errors presented in the tables are actual or potential errors reported to ISMP. Each table consists of 4 columns. The first column lists the medications, devices, or other problematic issues involved. The second column describes the specific error or problem involved. The third column contains ISMP’s recommendations to proactively address and prevent errors from occurring. The fourth column lists technology that may help prevent these errors. Technology can be a powerful tool in the fight against medication errors but only when it

is used appropriately within a well-designed medication-use system. The key summarizes the technology addressed in the tables, along with specific criteria that ISMP feels should be included.

Suggested Reading Cohen MR, ed. Medication Errors. 2nd ed. Washington, DC: American Pharmacists Association; 2007. Institute for Safe Medication Practices. ISMP Medication Safety Alert! Acute Care Edition newsletters 2012. www.ismp.org/newsletters/ default.asp. Accessed March 19, 2013. Institute for Safe Medication Practices website: www.ismp.org.

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CO24-0413

PRINTER-FRIENDLY VERSION AVAILABLE AT PHARMACYPRACTICENEWS.COM

Immune Globulins: Therapeutic, Pharmaceutical, Cost, and Administration Considerations JERRY SIEGEL, PHARMD, FASHP Clinical Associate Professor The Ohio State University College of Pharmacy Columbus, Ohio

or the past several years, the availability of immune globulin (Ig) products has been very good, so product shortages have not played a major role in product choice. This allows clinicians to match the best product to the patient based on clinical condition and comorbidities.

New products have become available, providing more treatment options. For example, Bivigam (Biotest), a 10% liquid product for IV use, was released in early 2013. There now are 4 Ig products indicated for subcutaneous (SQ) use in patients with primary immunodeficiency: Gammagard Liquid (Baxter), Gammaked (Kedrion), and Gamunex-C (Grifols) come in 10% concentrations and can be administered intravenously or subcutaneously; Hizentra (CSL Behring) comes in a 20% concentration and can be administered subcutaneously. It should be noted that dosing adjustments are required for all SQ agents when converting from IV. Two products, Gammaked and Gamunex-C, are approved for use in patients with chronic inflammatory demyelinating polyneuropathy (IV only). Gammagard Liquid is approved to treat multifocal motor neuropathy. A common question regarding Ig products relates to whether they all are the same. Although clinicians have considered all Ig products to have comparable efficacy, they are not pharmaceutically equivalent. It is imperative that Ig products not be interchanged without full consideration of the pharmaceutical differences. The reasons for switching products may be clinical in nature and related to tolerability; they may be fiscal and based on contracting issues; or they may be due to product availability. It is best to consider product changes as if the patient is naive to Ig use, with increased monitoring and conservative infusion times. Whereas Tables 1 to 5 may help facilitate these

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

decisions, it is important to understand the clinical impact of changing products. Although all of the products contain primarily IgG, trace amounts of other Igs—IgA and IgM—as well as widely different stabilizing agents, may affect tolerability. The differences in salt, sugar, and overall osmolarity of these products are particularly important when patients have various comorbidities, such as renal dysfunction, diabetes mellitus, vascular disease, or heart failure. Differences between lyophilized and liquid products may result in changes in product concentration and infusion rate, as well as tolerability. The tables in this review may be helpful for providing optimal care for patients receiving Ig products. They should be used as a general guide to help determine the product that is best suited for a particular patient population. Because there is variation from batch to batch, the exact numbers represent averages of selected batches; any one batch of any Ig product may have ranges outside these average numbers. When comparing administration rates, clinicians need to keep in mind that each patient has a maximum tolerated rate. This rate is based on patient tolerability and may be different for each product. Ig must be administered slowly initially and titrated as tolerated. The rate should be adjusted based on comorbidities as well. The infusion should be slowed or stopped if adverse events (AEs) become evident during the infusion. (See the prescribing information for each agent for more information about AEs.)

P H A R M AC Y P R AC T I C E N E WS S P E C I A L E D I T I O N • 2 0 1 3

Table 1. Therapeutic Considerations FDAApproved Indications

IgA Content

pH (after reconstitution) Plasma Source

Halflife, db

Pathogen Inactivation/Removal

Producta

Manufacturer

Bivigam 10%

Biotest Pharmaceuticals Medical info: (800) 458-4244 www.biotestpharma.com www.bivigam.com

PID

≤200 mcg/mL

4.0-4.6

Plasmapheresis, 30 US donors

Precipitation and removal of fraction III from resuspended fraction II+III, SD, 35 nm filtration

Carimune NF

CSL Behring Customer service: (800) 683-1288 Medical info: (800) 504-5434 www.cslbehring.com

ITP, PID

1,000-2,000 6.4-6.8 mcg/mL (6%)

Plasmapheresis, 23 US donors (>16,000)

pH 4.0/pepsin, nanofiltration, TSE removal

Flebogamma 5% DIF Flebogamma 10% DIF

Instituto Grifols SA Barcelona, Spain Customer service: (888) GRIFOLS www.grifols.com

PID

<3.2 mcg/mLc,d

5.6±0.1 (5%)c,d 5.5±0 (10%)c,d

US source IQPP-certified plasma from FDA-registered sites

4-week dosing: 32±5 (5%) 37±13 (10%)

Pasteurization (60°C, 10 h), SD, 20 nm nanofiltration, fraction I precipitation, fraction II+III incubation, PEG precipitation, acid treatment, TSE removal

Gammagard Liquid 10%

Baxter Healthcare Corp Direct inquiries: (800) 423-2090 www.baxter.com

MMN, PID

37 mcg/mL

4.6-5.1

Plasma from FDA-registered sites

SD, low pH, nanofiltration

Gammagard S/D 5%

Baxter Healthcare Corp Direct inquiries: (800) 423-2090 www.baxter.com

CLL, ITP, KD, PID

<1 mcg/mLe

6.4-7.2

Plasmapheresis, 37.7±15 10,000 donors

Gammaked 10%

Manufactured by Grifols Therapeutics Inc for Kedrion Biopharma Customer service/medical info: (855) 353-7466; www.gammaked. com; www.kedrion.com

CIDP, ITP, PIDf

47±13 mcg/mLc,d

4.0-4.5c,d US source IQPP-certified plasma from FDA-registered sites

Caprylate precipitation/depth filtration, caprylate incubation, depth filtration, column chromatography, low pH incubation, TSE removal

Gammaplex 5%

Bio Products Laboratory (distributed by FFF Enterprises) Customer service: (800) 843-7477 www.fffenterprises.com

ITP, PID

<10 mcg/mL

4.8-5.1

Plasma from FDA-registered sites

4-week dosing: 41±14

SD, nanofiltration, terminal low pH incubation

Gamunex-C 10%

Grifols Therapeutics Inc Customer service: (800) 243-4153 Medical info: (800) 520-2807 www.gamunex-c.com

CIDP, ITP, PIDf

47±13 mcg/mLc,d

4.0-4.5c,d

US source IQPP-certified plasma from FDA-registered sites

Caprylate precipitation/depth filtration, caprylate incubation, depth filtration, column chromatography, low pH incubation, TSE removal

Hizentra 20%

CSL Behring Customer service: (800) 683-1288 Medical info: (800) 504-5434 www.cslbehring.com www.hizentra.com

PID

≤50 mcg/mL

4.6-5.2

Plasmapheresis, NA US donors

pH 4.0 incubation, nanofiltration, depth filtration, virus filtration, TSE reduction

Octagam 5%

Octapharma Pharmazeutika Octapharma USA Customer service: (866) 766-4860 www.octapharma.com

PID

<200 mcg/mLg

5.1-6.0

US source and recovered plasma from FDA-registered sites

Cold ethanol, pH 4.0 incubation, SD

Privigen 10%

CSL Behring Customer service: (800) 683-1288 Medical info: (800) 504-5434 www.cslbehring.com; www.privigen.com

ITP, PID

≤25 mcg/mL

4.6-5.0

Plasmapheresis, 36.6 US donors (≥60,000)

Footnotes on page 27; Key on page 28.

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pH 4.0 incubation, 20 nm virus filtration, depth filtration, TSE removal

IgG Subclass,c %

Streptococcus pneumoniaec Type 3

Haemophilus influenzae Type Bc

Streptolysin Oc

CMVc

HAVc

HBV Herpes (Surface Simplex Antibody)c Type 1c

IgG1

IgG2

IgG3

IgG4

Diphtheria Toxinc

62.5

30.1

1.4

18.2 IU/mL

17 IU/mL

Type 1: 0.99 x Ref (176)

60.5

30.2

6.6

2.8

3.6 IU/mL (NT)

313 (EIA)

180 (EIA)

1:60 (CF)

300 IU/mL (HAI)

1:512 (IFA); 1:2,560 (EIA)

1:348 (RIA)

1:64 (RIA)

1:128 (CF)

1:64 (NT)

66.6

28.5 (5%) 27.9 (10%)

2.7 (5%) 3.0 (10%)

2.2 (5%) 2.5 (10%)

7.0±1.0 NA IU/mL (5%); 13.7±1.4 IU/mL (10%)

15±1 mg/L (5%)

30±6 PEI U/mL (5%); 36±7 IU/mL (10%)

21±4 IU/mL (5%)

88.0± 41.8 IU/g Ig (5%); 80.7± 23.0 IU/g Ig (10%)

60.9

32.1

2.1

4.0 units/ mL (NT)

21.2 mcg/mL (EIA)

1:2,320 (EIA)

68 PEI U/mL (EIA)

16.4 IU/mL (RIA)

≥0.20 IU/mL (EIA)

VZV: 32 U/mL (NT)

Type 1: 1:190 mIU/mL (NT)

2-5 IU/ mL (NT); J5 lipid A 1:273

17.5 mcgAbN/ mL (EIA)

8.5 mcg/mL (EIA)

11 mcg/mL (EIA)

1,150 IU (HH)

37 PEI mcg/mL (EIA), 1:2,480 (NT)

1:267 (RIA)

820 mIU/mL (RIA)

1:1,000 (EIA)

1:305 (NT)

62.8

29.7

4.8

2.7

7±2 AU/mL

87.4±22.2 mcg/mL

26.1±7.7 mcg/mL

13.0±2.4 mcg/mL

16,846± 13,648 Todd units/mL

57 PEI U/mL

1:139

65±19 IU/g Ig

1:22±0.35

2.2 IU/mL

2.3 mcg/mL

791 mcg/mL

185 IU/mL

431 U/mL

20 IU/mL

4.7 IU/mL

5,129 AU/mL

62.8

29.7

4.8

2.7

7±2 AU/mL

87.4±22.2 mcg/mL

26.1±7.7 mcg/mL

13.0±2.4 mcg/mL

16,846± 13,648 Todd units/mL

57 PEI U/mL

1:139

65±19 IU/g Ig

1:22±0.35

68.7

26.6

2.7

≥2.5 IU/mL

≥1,000 IU/mL

≥0.4 IU/mL NA

5-30 IU/mL

600-800 IU/mL

33-40 IU/mL

21-25 IU/mL

51 IU/g

1:8,192

1:1601:320 (NT)

67.8

28.7

2.3

1.2

4.9 (3.8-7.3) IU/mL

36.1 (26.4-45.0) IU/mL

1,746 (1,3102,010) IU/mL

76.4 (51.2-116.8) IU/mL

5.3 (3.0-10.1) IU/mL

Type 1

Polio Type 2c

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Table 2. Pharmaceutical Considerations

Product

Method of Preparation h

Available Dosing Forms

Form

Gamma Globulin, %

Monomers, %

Bivigam 10%

Cohn-Oncley, cold ethanol fractionation, SD

Liquid

≥96

100 monomer + dimers

Carimune NF

Kistler-Nitschmann,h pH 4.0 + trace pepsin, nanofiltration

Lyophilized

≥96

Flebogamma 5% DIF Flebogamma 10% DIF

Cohn-Oncley,h ion-exchange chromatography, acid pH treatment, PEG precipitation, SD, pasteurization, dual nanofiltration (35+20 nm)

Liquid

≥99 (5%, 10%)c,d

>99.95 monomers + dimers (5%)c,d >99.89 monomers + dimers (10%)c,d

Gammagard Liquid 10%

Cohn-Oncley,h anion-exchange chromatography, SD, nanofiltration, ultrafiltration, low pH incubation

IV, SQ (PID only)

Liquid

≥98

≥95 monomers + dimers

Gammagard S/D 5%

Cohn-Oncley,h ultrafiltration, anion-exchange chromatography, SD

Lyophilized

≥90

96.4

Gammaked 10%

Cold ethanol fractionation, anion-exchange chromatography, caprylate chromatography purified, low pH incubation

IV, SQ (PID only)

Liquid

100

100 monomers + dimersc,d

Gammaplex 5%

Cold ethanol fractionation, ion-exchange chromatography, SD, nanofiltration (20 nm), ultrafiltration, terminal low pH incubation

Liquid

>99

≥99 monomers + dimers

Gamunex-C 10%

Cold ethanol fractionation, anion-exchange chromatography, caprylate chromatography purified, low pH incubation

IV, SQ (PID only)

Liquid

100

100 monomers + dimersc,d

Hizentra 20%

Cold ethanol fractionation, anion-exchange chromatography, octanoic acid fractionation, pH 4.0 incubation, depth filtration, nanofiltration (20 nm)

Liquid

≥98

≥90 monomers + dimers

Octagam 5%

Cold ethanol fractionation, ultrafiltration, anion-exchange chromatography, SD, pH 4.0 incubation

Liquid

≥96

≥90 monomers + dimers

Privigen 10%

Cold ethanol fractionation, octanoic acid fractionation, anion-exchange chromatography, pH 4.0 incubation, depth filtration, nanofiltration (20 nm)

Liquid

≥98

≥98 monomers + dimers

Footnotes on page 27; Key on page 28.

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IgM Content

Albumin

PEG

Sodium Content

Stabilizer

Osmolality/Osmolarity

2.3 mcg/mL

<0.5%

100-140 mEq/L

Glycine

≤510 mOsm/kg

Trace

0% water, 0.9% NS

5% sucrose

In sterile water: 3%, 192 mOsm/kg; 6%, 384 mOsm/kg; 12%, 768 mOsm/kg In NS: 3%, 498 mOsm/kg; 6%, 690 mOsm/kg; 12%, 1,074 mOsm/kg

Trace

<2-7 mcg/mL (5%) ≤2 mcg/mL (10%)

Not detectable

Trace (<3.2 mEq/L)c,d

5% sorbitol (polyol)

326±5.1 mOsm/kg (5%)c,d 343±6.1 mOsm/kg (10%)c,d

Trace

Not detectable

No sodium added

Glycine

240-300 mOsm/kg

Trace

<3 mg/mL

<2 mg/mL

0.85%

2% glucose, glycine

636 mOsm/L (5%), 1,250 mOsm/L (10%)i

Trace

<2 mcg/mL

Trace (<7 mEq/L)c,d

Glycine

264±4 mOsm/kgc,d

<0.02 mcg/mLj

30-50 mEq/L

Sorbitol, glycine, and polysorbate 80

420-500 mOsm/kg, but not less than 240 mOsm/kg

Trace

<2 mcg/mL

Trace (<7 mEq/L)c,d

Glycine

264±3 mOsm/kgc,d

Trace

≤2 mcg/mL

Trace

Proline

380 mOsm/kg

≤0.1 mg/mL

≤30 mEq/L

10% maltosek

310-380 mOsm/kg

3 mg/L

Trace

Proline

240-440 mOsm/kg

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Table 3. Cost Considerations Producta

Supply

Storagel

Distribution

Return Policy Warranty

Packaging or Labeling Enhancements

Bivigam 10%

5, 10 g

2°C-8°C, 24 mo; do not freeze

Wholesaler or direct

Shipping error; defective or damaged product; no out-of-date products

Tamper-evident seal, peel-off label with name, latex-free packaging, lot number, expiration date

Carimune NF

3, 6, 12 g

≤30°C, 24 mo

Wholesaler or direct

Shipping error; defective or damaged product; no out-of-date products

Tamper-evident seal, RSS bar code, peel-off label with lot number, expiration date

Flebogamma 5% DIF Flebogamma 10% DIF

2.5, 5, 10, 20 g (5%); 5, 10, 20 g (10%)

2°C-25°C, 24 mo; do not freeze

Wholesaler or direct

Shipping error; defective or damaged product; no out-of-date products

Tamper-evident seal with hologram, prior handling recognition, integral suspension band, laser-etched vials with UIN, bar code, peel-off label with product lot number

Gammagard Liquid 10%

1, 2.5, 5, 10, 20, 30 g

2°C-8°C, 36 mo; ≤25°C, 24 mo; do not freeze

Wholesaler or direct

Latex-free packaging, tamper-evident cap, RSS bar code, peel-off label with lot number, expiration date

Gammagard S/D 5%

2.5, 5, 10 g

≤25°C, 24 mo; do not freeze

Wholesaler or direct

Tamper-evident cap, peel-off label with lot number, expiration date

Gammaked 10%

1, 2.5, 5, 10, 20 g

2°C-8°C, 36 mo; ≤25°C, 6 mo; do not freeze

Wholesaler

Shipping error; defective or damaged product; no out-of-date products

Tamper-evident cap, laser-etched vials with UIN, NDC bar code, integral suspension band on larger vial sizes, peel-off label with product lot number, vial stopper not made with natural rubber latex

Gammaplex 5%

5, 10 g

2°C-25°C, 24 mo; do not freeze

Wholesaler

Shipping error; defective or damaged product; no out-of-date products

Latex-free, single-use vial, tamperevident cap, peel-off label with lot number, expiration date

Gamunex-C 10%

1, 2.5, 5, 10, 20 g

2°C-8°C, 36 mo; ≤25°C, 6 mo; do not freeze

Wholesaler or direct

Shipping error; defective or damaged product; no out-of-date products

Tamper-evident cap, laser-etched vials with UIN, NDC bar code, integral suspension band on larger vial sizes, peel-off label with product lot number, vial stopper not made with natural rubber latex

Hizentra 20%

1, 2, 4, 10 g

≤25°C, 30 mo

Wholesaler or direct

Shipping error; defective or damaged product; no out-of-date products

Latex-free packaging, single-use tamper-evident vials, peel-off label with lot number, expiration date

Octagam 5%

1, 2.5, 5, 10, 25 g

2°C-25°C, 24 mo; do not freeze

Wholesaler or direct

Shipping error; defective or damaged product; no out-of-date products

Tamper-evident, latex-free packaging, peel-off label with lot number, expiration date

Privigen 10%

5, 10, 20 g

≤25°C, 36 mo

Wholesaler or direct

Shipping error; defective or damaged product; no out-of-date products

Latex-free, single-use vial, tamperevident seal, RSS bar code, peel-off label with lot number, expiration date

Key on page 28.

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

Table 4. IVIG Administration Ratesm Initial Infusion Rate

Maintenance Infusion Rate

Maximum Infusion Raten

Bivigam 10%

0.3 mL/kg/h for 10 min

Increase by 0.48 mL/kg/h every 20 min if tolerated up to 3.6 mL/kg/h

3.6 mL/kg/h

No filter required; for patients at risk for renal dysfunction or failure, administer at the minimum dose recommended and the minimum infusion rate practicablep

Carimune NF 3%-12%

0.48 mL/kg/h

1-2 mL/kg/h

3 mL/kg/h

Reconstitution time is several minutes; no filter required; compatible with NaCl, D5W; increased risk for renal and thrombotic adverse effectsp

Flebogamma 5% DIF Flebogamma 10% DIF

0.6 mL/kg/h

Increase gradually as tolerated to: 6 mL/kg/h (5%); 4.8 mL/kg/h (10%)

6 mL/kg/h (5%) 4.8 mL/kg/h (10%)

No filter required; administer at the minimum infusion rate practical to patients >65 and those at risk for renal failure or thrombotic eventsp

Gammagard Liquid 10%

0.5 mL/kg/h for 30 min (PID)

Increase every 30 min if tolerated, up to 5 mL/kg/h (PID)

5 mL/kg/h (PID)

No filter required; patients at risk for renal dysfunction or thrombotic events should be gradually titrated up to a more conservative maximum rate <2 mL/kg/hp

Gammagard S/D 5%

0.5 mL/kg/h for 30 min

Increase gradually as tolerated to: 4 mL/kg/h

4 mL/kg/h (5%)

Reconstitution time is <5 min at RT & >20 min if cold; 15-micron filter required and supplied with administration set; compatible with sterile water

Gammaked 10%

0.6 mL/kg/h 1.2 mL/kg/h (CIDP)

Increase gradually as tolerated to: 4.8 mL/kg/h

4.8 mL/kg/h

No filter required; do not dilute with NaCl, but NaCl flush is fine; incompatible with heparin (refer to full PI for details); administer at minimum infusion rate practical to patients >65 or at risk for renal or thrombotic eventsp

Gammaplex 5%

0.6 mL/kg/h for 15 min

Increase gradually as tolerated every 15 min to: 4.8 mL/kg/h

4.8 mL/kg/h

15- to 20-micron in-line filter recommended; ensure that patients with pre-existing renal insufficiency are not volume depleted; discontinue Gammaplex if renal function deteriorates; administer at minimum infusion rate practical to patients at risk for renal dysfunction or thrombotic eventsp

Gamunex-C 10%

0.6 mL/kg/h 1.2 mL/kg/h (CIDP)

Increase gradually as tolerated to: 4.8 mL/kg/h

4.8 mL/kg/h

Octagam 5%

0.6 mL/kg/h for 30 min

1.2 mL/kg/h for 30 min, then 2.4 mL/kg/h for 30 min, then as tolerated, up to maximum rate

<4.2 mL/kg/h

No filter required or supplied; if an in-line filter is used, the pore size should be 0.2-200 microns; for patients at risk for renal dysfunction or thrombotic events, administer at the minimum infusion rate practical, not to exceed 0.07 mL/kg/minp

Privigen 10%

0.3 mL/kg/h

As tolerated, up to maximum recommended rate

2.4 mL/kg/h (ITP) 4.8 mL/kg/h (PID)

No filter required; administer at minimum infusion rate practical to patients at risk for renal dysfunction or thrombotic eventsp

IVIGa

Commentso

FOOTNOTES a

All agents are contraindicated for IgA deficiency with antibodies to IgA.

Varies with disease state, immune status, and age of the patient.

ethanol fractionation; Kistler-Nitschmann is the specific cold ethanol fractionation method used by the manufacturer (CSL Behring). i

Certain severe adverse drug reactions may be related to the rate of infusion. Slowing or stopping the infusion usually allows the symptoms to disappear promptly.

Unless specific compatibility information is available, do not mix with other drugs or solutions.

Patients at high risk for thromboembolic events include patients who are elderly, overweight, or immobilized; patients with a history of hypertension, cardiovascular disease, or thrombotic disorders; and those who are >65 or dehydrated.

Log reduction factor values obtained from those listed in the PI; most are available on respective websites.

Data on file at Octapharma.

Limit infusion rate to <3.3 mg IgG/kg per minute (2 mL/kg/h) for 10% solutions.

Average of sample lots.

Data on file at Grifols.

Data on file at Bio Products Laboratory.

As of Dec. 2012, Baxter has discontinued Gammagard S/D 5%; the low IgA product will remain available for patients with known reactions to IgA or IgA deficiency with antibodies; all Gammagard S/D will be manufactured with IgA <1; special request only.

Maltose does not significantly affect serum glucose or insulin levels and can be safely administered to diabetic patients. Certain BGMS falsely interpret maltose, icodextrin, galactose, and xylose as glucose and can provide falsely elevated glucose readings. If insulin is administered as a result of these readings, hypoglycemia can occur. The BGMS that use test strips containing GDH-PQQ and GDO can provide these false readings. See PI for full details.

DO NOT USE Gammaked or Gamunex-C subcutaneously for ITP or CIDP.

With additional purification steps added in 2010, current release lots contain <100 mcg/mL. Data on file at Octapharma.

Under appropriate storage conditions.

Cohn-Oncley is the original method of cold

Some infusion rates were converted from those

listed in the PI for consistency and reader convenience.

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Table 5. Log Reduction Factor Comparisonsq Enveloped Viruses

HIV Producta

Models for HCV

Model for Large DNA

SBV

BVDV

PRV

Nonenveloped Virus

TSE (Prion)

Bivigam 10%

>9.62

>7.11

>11.79

>8.65

5.29 (MEV), 6.18 (BPV), 4.0 (PPV), 7.02 (SV40)

Carimune NF

≥26

≥19

≥9

≥25

≥19 (BEV)

Flebogamma 5% DIF, 10% DIF

≥25.11

≥6.49

≥21.28

≥27.78

≥15.04 (PPV), ≥19.25 (EMCV)

≥11.64

Gammagard Liquid 10%

>14.8

>16.8

>16.9

>5.7 (HAV), >7.7 (EMCV), >5.1 (MMV)

Gammagard S/D 5%

>15 (HIV-1)

>7.5

>9.3

>5.2 (HAV), >5.0 (EMCV), >5.3 (MMV)

Gammaked 10%

≥14

≥16.3

≥12.2

≥5.0 (HAV), 8.2 (PPV)

≥6.6

Gammaplex 5%

>12.9

>20.2

>11.7

>5.9 (HAV), >7.5 (EMCV)

Gamunex-C 10%

≥14

≥16.3

≥12.2

≥5.0 (HAV)

≥6.6

Hizentra 20%

≥16.0

≥11.8

≥17.7

≥9.6 (EMCV), ≥7.8 (MMV)

≥14.8

Octagam 5%

≥14.6

≥16.7

≥16.1

≥9.5 (MEV), ≥7.7 (PPV)

≥6.7r

Privigen 10%

≥16.0

≥11.8

≥17.7

≥9.6 (EMCV), ≥7.8 (MMV)

≥14.8

Footnotes on page 27.

KEY BEV

HCV

hepatitis C virus

NDC

National Drug Code

BGMS blood glucose monitoring systems

bovine enterovirus (RNA model)

inhibition of hemolysis

normal saline

BPV

HIV

human immunodeficiency virus

neutralization test

PEG

polyethylene glycol

PEI

Paul Ehrlich Institute International Units

bovine papillomavirus

BVDV bovine viral diarrhea virus

IFA

immunofluorescence assay

complement fixation

IgA

immune globulin A

CIDP

chronic inflammatory demyelinating polyneuropathy

IgG

immune globulin G

prescribing information

CLL

chronic lymphocytic leukemia

IgM

immune globulin M

PID

primary immunodeﬁciency

CMV

cytomegalovirus

IQPP

International Quality Plasma Program

PPV

porcine parvovirus

D5W

dextrose 5% in water

ITP

idiopathic thrombocytopenic purpura

PRV

pseudorabies virus

EIA

enzyme immunoassay

international unit

RIA

radioimmunoassay

RSS

reduced space symbology

SBV

Sindbis virus

solvent detergent

subcutaneous

EMCV encephalomyocarditis virus (RNA model) FDA

Food and Drug Administration

GDH- glucose dehydrogenasePQQ pyrroloquinolone quinone

IU IVIG

intravenous immune globulin

Kawasaki disease

MEV

mouse encephalomyelitis virus

MMN

multifocal motor neuropathy

SV40 simian virus

MMV

mouse minute virus (model for non-lipid DNA virus)

TSE

transmissible spongiform encephalopathies

GDO

glucose-dye-oxidoreductase

HAI

heterologous anti-immunoglobulin

HAV

hepatitis A virus

information not available

UIN

unique identifier number

HBV

hepatitis p B virus

NaCl

sodium chloride

V V VZV

va ce a zoster varicella oste virus v us

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

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Revisiting Environmental Hygiene and

Hospital-Acquired Infections

BRIAN CURRIE, MD, MPH Professor of Clinical Medicine Division of Infectious Diseases Albert Einstein College of Medicine Assistant Dean for Clinical Research Montefiore Medical Center New York, New York

he role of environmental hygiene in preventing hospital-acquired infections (HAIs) has been a controversial topic.1,2 It was widely accepted that the bulk of HAIs were the result of transmission

from one patient to another via the contaminated hands of caregivers or contaminated equipment that was sequentially used on patients.

However, the role of noncritical environmental surfaces as a reservoir for nosocomial pathogens to contaminate the hands of health care providers and subsequently infect patients remained undefined. Of note, a literature survey published less than 10 years ago concluded that there was no evidence to support environmental hygiene practices as a method for reducing HAIs.3 The past 10 years have seen a progressive accumulation of evidence that clearly established environmental reservoirs of nosocomial pathogens as a cause of HAIs, and this information was used to shape what has become the foundation of currently recommended hospital-based environmental hygiene practices.

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It had long been appreciated that shortly after being placed into a patient room, individuals shed bacterial organisms that contaminated environmental surfaces, including those thought to be involved in horizontal transmission and HAIs such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), Acinetobacter and other gram-negative bacteria, and Clostridium difficile spores.2,3 Additional research also documented that these organisms can persist on environmental surfaces for weeks or even months.4 Culture sampling demonstrated that certain surfaces carried a much higher bacterial bioburden than others, a consequence of more frequent contact with

P H A R M AC Y P R AC T I C E N E WS S P E C I A L E D I T I O N 2 0 1 3

Table 1. Objective Methods To Evaluate Environmental Hygiene Practice Method

Difficulty Confirms Assesses Level Pathogens Cleaning

Direct observation

High

Yes

Swab culture

Low

Yes

Possibly

Agar slide culture

Medium

Limited

Possibly

Fluorescent markers

Low

Yes

Adenosine Low triphosphate bioluminescence

Possibly

Based on reference 14..

patients. A conceptual model of â&#x20AC;&#x153;high-touchâ&#x20AC;? surfaces evolved from these findings, which included the identification of key environmental surfaces in frequent contact with patients and health care workers such as bed rails, door knobs, etc.5-7 Subsequent studies have documented that routine cleaning and disinfection substantially reduces contamination and could be useful in controlling outbreaks.3,8-11 A landmark study published in 2013 reported that the risk for nosocomial infections could be substantially reduced by the use of environmental hygiene strategies that reduce the bacterial bioburden on high-touch room surfaces.12 A number of recent studies have documented that patients who were placed in rooms previously occupied by individuals infected or colonized with VRE, MRSA, C. difficile, or Acinetobacter were 73% more likely to acquire the same pathogens than patients who did not occupy such rooms.3,13 Bacterial strain typing often confirmed this chain of transmission. These findings strongly supported terminal cleaning, the practice of cleaning and disinfecting all room surfaces following patient transfer or discharge before use by a new patient. Current guidelines now encourage hospitals to develop programs for cleaning and disinfecting hightouch surfaces as part of terminal room cleaning using a properly applied, Environmental Protection Agency (EPA)-approved germicide.14,15

Monitoring Compliance Establishing a monitoring program for periodic or ongoing assessments of environmental hygiene practices has been shown to significantly improve compliance with hospital policies and protocols. An environmental cleaning toolkit released in 2010 by the Centers for Disease Control and Prevention encouraged hospitals to create such programs as an adjunct to terminal room cleaning to ensure high-touch surfaces are

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thoroughly cleaned.14 The toolkit further lists objective methods to assess hygiene practices, outlining a variety of approaches and technologies to accomplish this task (Table 1).14 Covert direct observation can provide an objective assessment of compliance with cleaning protocols and is the most frequently used monitoring tool in US hospitals. The process is labor intensive, should employ a checklist, and is quite difficult to accomplish in a truly covert fashion. As a result, data generated from this method are not likely to reflect or measure true hygiene practices. Serial swab cultures of environmental surfaces also can be used as a monitoring tool. Although samples are easy to acquire, processing costs and turnaround delays limit the practicality of this method. Furthermore, given the lack of established, concrete cutoffs to serve as a baseline for acceptable results, precleaning contamination levels must be determined for each surface to assess compliance with environmental cleaning policy. Agar slide cultures have been adapted for environmental surface monitoring in hospitals and are capable of quantifying aerobic colony counts (ACCs) per cm2. This technique is largely limited to culturing large flat surfaces and also requires measurements of precleaning contamination levels to assess the efficacy of environmental cleaning practices. Fluorescent markers also have been developed to assess hygiene practices.14,16 This commercially available method involves applying a fluorescent gel, which becomes transparent after it dries, to target surfaces. Following room cleaning, ultraviolet (UV) light will expose any areas that were not adequately cleaned. There is widespread hospital experience with the use of these markers, and a number of studies have demonstrated their accuracy for objectively evaluating environmental hygiene practices.16 A second commercially available solution is the adenosine triphosphate (ATP) bioluminescence assay, which measures ATP on surfaces using a luciferase assay and luminometer.14 A specialized swab is used to take a sample from a targeted surface area; the sample is then analyzed using a portable handheld luminometer. The total amount of ATP, both microbial and nonmicrobial, is expressed as relative light units. Low readings have shown a reasonable correlation with low ACCs, but very high readings may indicate bacterial contamination, organic debris containing dead bacteria, or both. Moreover, high concentrations of liquid bleach disinfectant can interfere with the assay and may result in reduced signal strength. Again, the lack of a threshold cutoff value necessitates an assessment of precleaning ATP levels to allow proper interpretation of the results. ATP systems have proven effective for documenting improvements in daily cleaning practices for high-touch surfaces.14

Assessing Current Practice Despite existing recommendations for hospitals to establish environmental hygiene programs and monitor their effectiveness, suboptimal practices

are common.13,17 Studies have established that terminal cleaning is about 49% effective; however, success rates for high-touch surfaces show significant variation, ranging from 30% to more than 75%.13 A recent survey of infection preventionists documented that many continue to rely on direct observation to monitor environmental cleaning practices (employed by 70% of respondents on a daily, weekly, or monthly basis) as well as poor uptake of fluorescent gel or ATP systems (used by 26% to 28% of respondents on a daily, weekly, or monthly basis).13 Other recent studies have documented that even when aggressive interventions are employed, including intensive staff education and the use of newer, objective-based evaluation techniques with performance feedback, efficacy rates for high-touch surface cleaning remain in the range of 77% to 82%.13 Although these studies have documented that cleaning and disinfection need to be improved in US health care settings as part of efforts to prevent nosocomial infections, they also have resulted in the development and introduction of a variety of new technologies.

Emerging Technologies The past 5 years have seen the rapid development of emerging technologies designed to enhance environmental hygiene practice. The proliferation of products is almost bewildering, and the pace at which new technologies are being introduced is accelerating rapidly. This section is not intended to provide an all-inclusive overview of every technology in development; instead, it will provide a broad overview of available technologies and the level of evidence supporting their use. Infection control practitioners should appreciate the need to revisit emerging technologies on an ongoing basis and should stay abreast of the burgeoning amount of literature that continues to surface regarding their performance and effectiveness. It also should be stressed that current recommendations and guidelines consider these products to be adjuncts, rather than replacements, to existing environmental hygiene programs and practices. Products and strategies have been divided into 4 categories for discussion: disinfectants and cleaning tools; soft-surface disinfection; hard-surface disinfection; and wholeroom disinfection.

DISINFECTANTS

AND

CLEANING TOOLS

Products in this category are summarized in Table 2. The development of new disinfectants is largely driven by a desire to decrease the long wet-contact time required with the use of iodine-based or quaternary disinfectants (ie, up to 10 minutes) and their apparent inability to optimally disinfect C. difficile spores. Current recommendations for C. difficile disinfection rely on the use of a 5% to 6% sodium hypochlorite solution (household bleach), which is corrosive to environmental fixtures, bleaches fabrics, and carries occupational exposure risks. The advantage of slow-release chlorine

Table 2. Disinfectants/Cleaning Tools Demand-release chlorine disinfectants 窶｢ Chlorine dioxide 窶｢ Sodium dichloroisocyanurate 窶｢ Chloramine-T7 Superoxidized water Microfiber mops Microfiber wipes

products is that, although they are fast acting, they exert a prolonged bactericidal effect.15 Unfortunately, they still retain the potential to damage equipment and facilities. Another option is superoxidized water, which is created when saline is electrolyzed to produce a solution of hypochlorous acid and chlorine, with free chlorine the active microbicide.15 Point-of-use production systems are commercially available, but they are expensive and complicated to operate.15 They appear to have a 48-hour shelf life.15 Although FDA-approved for high-level disinfection, such products need to be further studied to confirm their applicability as environmental disinfectants. Microfiber mops and microfiber wipe cloths have a long history of use in hospitals. Both types of products are made of a blend of microscopic polyester and polyamide fibers, which are split to create microscopic hooks that collect and retain dust, dirt, and bacteria. Microfiber mops have been demonstrated to have superior efficacy in reducing microbial levels on floors compared with conventional, cotton string mops, achieving 95% efficacy.18 Performance did not improve when they were used with a disinfectant. Microfiber mops are less work intensive than conventional mops, eliminate issues of cross contamination during environmental cleaning, and drastically reduce the use of water and chemicals due to more efficient cleaning and disinfection. Similarly, microfiber cleaning cloths have consistently outperformed conventional cloths in their ability to decontaminate across all surfaces, even when bacteria were coated on to the surfaces with phosphatebuffered saline (PBS) or PBS窶田ontaining horse serum.19 Designed to be used without detergents or biocides, they have been shown to effectively decontaminate hard surfaces seeded with S. aureus, Escherichia coli, and C. difficile spores under simulated conditions. An additional study compared the efficacy of 10 different microfiber cloths (9 reusable) under simulated conditions and found comparable performance among the products, even after 150 washes.20 Although the Joint Commission and the EPA have advocated for these products, continued research to evaluate their performance in real-world clinical settings is required, as well as to determine if their use can reduce HAI rates.

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Table 3. Soft-Surface Technologies

Table 4. Hard-Surface Technologies

Copper oxide impregnation

Copper and copper alloy cladding

Citric acid impregnation

Silver iodide and modified polyhexamethlyene biguanide coating

Organosilane-based quaternary ammonium impregnation

Silver nanoparticle incorporation

Silver-impregnated yarn

Triclosan incorporation Quaternary ammonium salt surfactant coating

SOFT-SURFACE DISINFECTION

Microtopography surface

Soft-surface disinfection strategies include fabric impregnation with copper or silver to take advantage of their intrinsic antimicrobial properties, citric acid impregnation of cotton cloth, and organosilane-based quaternary ammonium impregnation of fabric materials (Table 3).21 These materials have been used to produce scrubs, uniforms, linens, and privacy curtains. A double-blind, randomized controlled trial (RCT) evaluating the use of antimicrobial-impregnated privacy curtains in the ICU setting showed that they resulted in a significant delay in time to colonization and an 8-fold reduction in the risk for VRE contamination compared with standard fabric curtains.21 An ICU-based, blind, randomized crossover trial evaluating the efficacy of organosilane-based quaternary ammonium-impregnated scrub suits reported a significant reduction in MRSA contamination, with little effect on the burden of VRE or gram-negative rods.22 Further investigation is warranted to demonstrate the ability of these products to consistently perform under clinical conditions, followed by clinical trials to measure their effect on HAI rates.

Light-activated antimicrobial coatings • Cellulose acetate–containing toluidine blue O and rose Bengal • Silicon polymer–containing methylene blue and gold nanoparticles • Titanium dioxide coating

HARD-SURFACE DISINFECTION Hard-surface disinfection technologies are summarized in Table 4. Copper and copper alloy cladding of high-touch hard surfaces takes advantage of the natural antimicrobial properties of copper to significantly reduce high bacterial bioburden within 2 hours.23 Copper and copper alloy surfaces have demonstrated activity against a broad spectrum of bacteria, including nosocomial pathogens known to be transmissible from environmental reservoirs. Furthermore, copper technologies provide continuous bacterial disinfection on all surfaces where they are employed. More than 200 publications have documented its potent antimicrobial activity in both simulated and actual clinical conditions. A recent RCT conducted in 3 hospitals reported a significant reduction in HAIs when copper technologies were used in conjunction with an aggressive environmental hygiene program.12 A variety of copper-based products are commercially available, including countertops, IV poles, handles, support railings, bed rails, and sinks. The principal factor that limits the widespread adoption of this technology is its high cost. Similarly, silver iodide and silver nanoparticles also

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are being used to develop hard surfaces with intrinsic antimicrobial activity. Silver iodide–based coatings will need to demonstrate the ability to persist after repeated washings, and they also need to verify their disinfection efficacy in both simulated and actual clinical conditions. Silver nanotechnology products still are in the early stages of development. Disinfectant-based hard-surface technologies include the incorporation of triclosan into surfaces and the use of quaternary ammonium salt surfactants as a coating on hard surfaces. Triclosan-based products have been proven to have limited application in the health care environment.23 Triclosan has a limited spectrum of antimicrobial activity, and there is mounting evidence that bacteria can become triclosan-resistant with continued exposure. Triclosan-impregnated products are now primarily marketed for household use. Quaternary ammonium salt surfactants are in the early stages of development and, like all surface-coating technologies, they will need to demonstrate durability as well as efficacy. The final category of hard-surface disinfectants includes a group of light-activated antimicrobial compounds. Titanium dioxide is the most developed product, with considerable prior use in food, toothpaste, and tooth-whitening preparations, and as a disinfectant in Japanese health care environments. Titanium dioxide is produced by crystallizing titanic iron ore into a nanoliquid form. When exposed to UV light in the sub-400 nm range, it becomes a photocatalyst oxidizer that produces hydroxyl radicals and superoxide ions with potent antimicrobial activity. Patented technologies now allow for the nanoliquid to penetrate and form permanent bonds with the surface that last for years. Titanium dioxide requires exposure to sunlight or UV light for maximum antimicrobial activity, and it has shown a broad spectrum of antibacterial

Table 5. Whole-Room Technologies UV light Combination of ozone/UV light/hepafiltration Hydrogen peroxide vapor or aerosolization Titanium dioxide spray UV, ultraviolet

activity, although this effect is slower in decontaminating spores. The addition of zinc to the preparation provides effective antimicrobial action after exposure to indoor lighting of any type as well as continuous disinfection as long as room lighting is in use. A single application remains active on heavily used surfaces even after 1 year. Now marketed in the United States for disinfection in the health care setting, it will be interesting to see what efficacy information becomes available.

WHOLE-ROOM DISINFECTION Table 5 summarizes approaches to environmental disinfection using whole-room technology. As a group, they (with the exception of titanium dioxide) employ devices placed in patient rooms and all use toxic technologies that prohibit patient or staff occupancy during the disinfection process. As a result, they all are limited to use as adjunct disinfection technologies during terminal room cleaning between patients. Disinfection cycle duration times will effect room turnover times, and this should be considered in addition to disinfection efficacy rates. UV light room disinfection is probably the most studied of the whole-room technologies, and the products build on a long history of the use of UV light to disinfect well water, circulating dialysis fluid, and room air for tuberculosis control. Numerous products are commercially available and all employ the use of low-pressure mercury or xenon vapor lamps to generate UV light in the germicidally active wavelength range of 200 to 320 nm.24,25 Shortwave UV-C radiation, primarily at 254 nm, kills by damaging DNA. Photon absorption leads to formation of pyrimidine dimers between adjacent thymine bases in DNA, rendering the microbe incapable of replication. These technologies offer broad-spectrum microbicidal activity, including coverage against C. difficile spores.24 A typically sized hospital patient room can be disinfected within 10 minutes, minimally affecting room turnaround times during terminal cleaning. The principal issue with UV light disinfection is that it provides for â&#x20AC;&#x153;line-of-sightâ&#x20AC;? killing, meaning it does not work in shadowed areas and does not penetrate fabrics well; there is no evidence that lack of a proper room cleaning before UV light disinfection can markedly reduce its efficacy.24

Line-of-sight killing has been addressed through the use of careful device placement in the room, rotating the light source, and UV-reflective shields and wall paint.24,27 One manufacturer provides indicators that can be placed in potential problem areas in the room and are capable of monitoring for appropriate UV light exposure. UV light has proven effective as a hospital room disinfectant, reliably reducing the bacterial bioburden of a wide spectrum of pathogens under simulated and real-time clinical situations (provided the room is cleaned first). However, its ability to reduce HAI rates has yet to be studied. Several systems have been developed that produce hydrogen peroxide vapor, aerosolized dry-mist hydrogen peroxide, or vaporized hydrogen peroxide for whole-room disinfection. Hydrogen peroxide is converted by catalysis after bacterial contact to generate free oxygen radicals with rapid bactericidal activity. Under simulated and real-time clinical conditions, hydrogen peroxide has demonstrated broad-spectrum activity as a disinfectant, including the rapid decontamination of spores. Whole-room treatment leaves no residue.28 When used as a follow-up to bleach disinfection, whole-room disinfection is extremely effective. In a retrospective study conducted in 334 patient rooms previously occupied with individuals infected with C. difficile, use of hydrogen peroxide vapor within the terminal cleaning program reduced nosocomial infection rates from 0.88 to 0.55 cases per 1,000 patient-days. 29 Of note, the hydrogen peroxide intervention was used in only 54% of rooms. Additional evidence suggests that hydrogen peroxide room disinfection can reduce VRE infection rates, but 2 studies have now identified that the process may not be as effective in reducing MRSA infection rates.30,31 It has been suggested that this may be related to the fact that MRSA are catalase-producing organisms. Similar to UV room disinfection technologies, hydrogen peroxide room disinfection carries a significant capital expenditure cost and requires the removal of surface debris before use. Finally, titanium dioxide/zinc technologies have been developed and marketed as methods of wholeroom disinfection. The technologies and means of action already have been discussed above. Beyond hard surfaces, the products also can be sprayed onto soft surfaces and brushed into fabrics to provide a long-lasting, broad-spectrum biocidal coating. A single room application would cost less than $650 and last for 1 year. The room only needs to be vacant during the application process, and these products offer continuous room disinfection whenever room lights are on, providing a biocidal disinfectant action far beyond a terminal cleaning technology. Such products are in clinical testing and efficacy data should be available in the near future. A combined ozone/UV light/ hepafiltration technology product also is commercially available and requires further evaluation.

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Conclusion Accumulating evidence has established that bacterial contamination of the physical hospital environment can serve as a reservoir for transmission to patients and can contribute to the acquisition of HAIs. Study findings have been used to shape current recommendations for environmental hygiene interventions, but achieving a high degree of compliance with guidelines has proven difficult. Emerging environmental hygiene technologies may provide important adjunct interventions in helping to achieve these goals.

References 1.

Rutala WA, Weber DJ. Surface disinfection: should we do it? J Hosp Infect. 2001;48(suppl A):S64-S68.

2. Donskey C. Does improving surface cleaning and disinfection reduce health care-associated infections? Am J Infect Control. 2013;41(5 suppl):S12-S19. 3. Hota B. Contamination, disinfection and cross colonization: are hospital surfaces reservoirs for nosocomial infection? Clin Infect Dis. 2004;39:1182-1189. 4. Kramer A, Schwebke I, Kampf G. How long do nosocomial pathogens persist on inanimate surfaces? A systematic review. BMC Infect Dis. 2006;6:130. 5. Carling PC, Briggs JL, Perkins J, et al. Improved cleaning of patient rooms using a new targeting method. Clin Infect Dis. 2006;42(3): 385-388. 6. Huslage K, Rutala W, Sickbert-Bennett E, et al. A quantitative approach to disinfecting â&#x20AC;&#x153;high-touchâ&#x20AC;? surfaces in hospitals. Infect Control Hosp Epidemiol. 2010;31(1):850-853. 7. Moore G, Muzlay M, Wilson A. The type, level, and distribution of microorganisms within the ward environment: a zonal analysis of an intensive care unit and a gastrointestinal surgical ward. Infect Control Hosp Epidemiol. 2013;34(5):500-506. 8. Sitzlar B, Deshpande A, Fertelli D, et al. An environmental disinfection odyssey: evaluation of sequential interventions to improve disinfection of Clostridium difficile isolation rooms. Infect Control Hosp Epidemiol. 2013;34(5):459-465. 9. Weber DJ, Rutala WA. Understanding and preventing transmission of healthcare-associated pathogens due to the contaminated hospital environment. Infect Control Hosp Epidemiol. 2013;34(5): 449-452. 10. Weber DJ, Rutala WA, Miller MB, et al. Role of hospital surfaces in the transmission of emerging health care-associated pathogens: norovirus, Clostridium difficile, and Acinetobacterr species. Am J Infect Control. 2010;38(5 suppl):S25-S33. 11. Goodman E, Platt R, Bass R, et al. Impact of an environmental cleaning intervention on the presence of methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci on the surfaces in intensive care unit rooms. Infect Control Hosp Epidemiol. 2008;29(7):593-599. 12. Salgado CD, Sepkowitz KA, John JF, et al. Copper surfaces reduce the rate of healthcare-acquired infections in the intensive care unit. Infect Control Hosp Epidemiol. 2013;34(5):479-486. 13. Pyrek K. Environmental cleaning and monitoring for infection prevention. http://www.infectioncontroltoday.com/reports/2013/05/ importance-of-environmental-cleaning.aspx?endpointurl=/lib/ download.ashx?id=1190. Accessed August 14, 2013. 14. Centers for Disease Control and Prevention. Options for evaluating environmental cleaning. http://www.cdc.gov/HAI/pdfs/ toolkits/Environ-Cleaning-Eval-Toolkit12-2-2010.pdf. Accessed August 14, 2013.

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15. Centers for Disease Control and Prevention. Guideline for disinfection and sterilization in healthcare facilities, 2008. http://www.cdc. gov/hicpac/pdf/guidelines/Disinfection_Nov_2008.pdf. Accessed August 14, 2013. 16. Boyce JM, Havill NL, Havill HL, et al. Comparison of fluorescent marker systems with 2 quantitative methods of assessing terminal cleaning practices. Infect Control Hosp Epidemiol. 2011;32(12): 1187-1193. 17. Carling PC, Parry MF, Von Beheren SM; Healthcare Environmental Hygiene Study Group. Identifying opportunities to enhance environmental cleaning in 23 acute care hospitals. Infect Control Hosp Epidemiol. 2008;29(1):1-7. 18. Rutala WA, Gergen MF, Weber DJ. Microbiologic evaluation of microfiber mops for surface disinfection. Am J Infect Control. 2007;35(9):569-573. 19. Wren MV, Rollins MS, Jeanes A, et al. Removing bacteria from hospital surfaces: a laboratory comparison of ultramicrofibre and standard cloths. J Hosp Infect. 2008;70(3):265-271. 20. Smith D, Gillanders S, Holah J, et al. Assessing the efficacy of different microbibre cloths at removing surface micro-organisms associated with healthcare-associated infections. J Hosp Infect. 2011;78(3):182-186. 21. Schweizer M, Graham M, Ohl M, et al. Novel hospital curtains with antimicrobial properties: a randomized, controlled trial. Infect Control Hosp Epidemiol. 2012;33(11):1081-1085. 22. Bearman G, Rosato A, Elam K, et al. A crossover trial of antimicrobial scrubs to reduce methicillin-resistant Staphylococcus aureus burden on healthcare worker apparel. Infect Control Hosp Epidemiol. 2012;33(3):268-275. 23. Weber DJ, Rutala WA. Self-disinfecting surfaces. Infect Control Hosp Epidemiol. 2012;33(1):10-13. 24. Rutala WA, Gregen MF, Weber DJ. Room decontamination with UV radiation. Infect Control Hosp Epidemiol. 2010;31(10):1025-1029. 25. Levin J, Riley L, Parrish C, et al. The effect of portable pulsed xenon ultraviolet light after terminal cleaning on hospital-associated Clostridium difficile infection in a community hospital. Am J Infect Control. 2013;41(8):746-748. 26. Andersen DJ, Gergen MF, Smathers E, et al. Decontamination of targeted pathogens from patient rooms using an automated ultraviolet-C-emitting device. Infect Control Hosp Epidemiol. 2013;34(5):466-471. 27. Rutala WA, Gregen MF, Tande BM, Weber DJ. Rapid hospital room decontamination using ultraviolet (UV) light with a nanostructured UV-reflective wall coating. Infect Control Hosp Epidemiol. 2013;34(5): 527-529. 28. Rutala W, Weber D. Disinfectants used for environmental disinfection and new room decontamination technology. Am J Infect Control. 2013;41(5 suppl):S36-S41. 29. Manian F, Griesnauer S, Bryant A. Implementation of hospitalwide enhanced terminal cleaning of targeted patient rooms and its impact on endemic Clostridium difficile infection rates. Am J Infect Control. 2013;41(6):537-541. 30. Pottage T, Macken S, Walker J, et al. Methicillin-resistant Staphylococcus aureus is more resistant to vaporized hydrogen peroxide than commercial Geobacillus stearothermophilus biological indicators. J Hosp Infect. 2012;80(1):41-45. 31. Passaretti CL, Otter JA, Reich NG, et al. An evaluation of environmental decontamination with hydrogen peroxide vapor for reducing the risk of patient acquisition of multi-resistant organisms. Clin Infect Dis. 2013;56(1):27-35.

Dr. Currie reported that he serves on the advisory board for Clorox and has received grant support from the Agency for Healthcare Research and Quality.

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Compatibility of

Commonly Used IV Drugs LISA CAYO, PHARMD Clinical Pharma acy y Coordinator Garden City Ho osp pital Garden City, Mich higan

he number of available IV medications continues to expand. Many institutions have observed an increase in

patient acuity and a rise in the number of medications

administered to each patient. This increases the likelihood that multiple IV medications will need to be administered concurrently.

These factors contribute to the escalating complexity of IV drug administration and have resulted in an ever-increasing number of possible incompatibilities. The potential for serious and life-threatening adverse drug events exists when incompatible medications are infused together. Therefore, it is important to verify drug compatibility prior to coadministration. A clear and concise compatibility chart can be a useful tool in helping to deliver safe, high-quality IV therapy to patients. A chance of incompatibility exists whenever any

medication is combined or added to an IV fluid. It is important to recognize that compatibility is not just a function of the drugs themselves, but also can be dependent on a variety of factors including the concentration, temperature, storage vehicle, infusion solution, order of mixing, and administration technique. Compatibility differences even have been reported for different brands of the same drug. Three types of incompatibilities are commonly discussed: physical, chemical, and therapeutic. Physical Text continues on page 46

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P H A R M AC Y P R AC T I C E N E WS S P E C I A L E D I T I O N â&#x20AC;˘ 2 0 1 3

Amiodarone

N C

Ampicillin

C N N

Ampicillin-sulbactam

Anidulafungin

C C C C C

Argatroban

C C N C C C

Atracurium

C C C N N C C

Azithromycin

C N

Dextrose 5% in water

Dexmedetomidine

Dexamethasone

N C

Daptomycin

Cisatracurium

Clindamycin

Ciprofloxacin

Ceftriaxone

Ceftizoxime

Ceftazidime

C C C C C C

Ceftaroline

Cefoxitin

Cefotaxime

C C C N C

Cefazolin

Cefepime

Caspofungin

Calcium gluconate

Bumetanide

Bivalirudin

(Acyclovir through Dextrose 5% in water)

Aztreonam

Azithromycin

C C C C

Amikacin

Atracurium

Argatroban

Anidulafungin

Ampicillin

Amiodarone

C N C

Ampicillin-sulbactam

Acyclovir

Amikacin

Acyclovir

Table. Compatibility of Selected IV Drugs

C C C Acyclovir

C N N C C C N C C C C C C H C C C C C C N C C C C C C Amikacin

N I

C N C

C C C C C C N C N Amiodarone

N N N N N N N N N N S

C C N C N C N N

N C N N N N N N

C N C

Ampicillin

N N C N C A Ampicillin-sulbactam

C C C C C C C C C C C C N C C C C C C N C C C Anidulafungin C C C C C C C C

C C N C C C C C C C C C C Argatroban

C C C C C C C N C C N

C C C C C

C C C N C C C C C Atracurium

N C C C N C C N C C N C N N C N C C C C Azithromycin

Aztreonam

Bivalirudin

C C

C N N N C C C N

Bumetanide

C C C N N C C C C C C

C C C N N N N C

N C C N C N C N N

C C C C C C C C N C C C C C C C C C C Aztreonam

C C C C C C C

C C

C C C C N C C C C C C C C C C Bivalirudin

C C C C C C C C C C N C C C C C C Bumetanide

Calcium gluconate

C C C N N C C C C C C C

Caspofungin

N C C

Cefazolin

C C N N N C C C C C C C C

Cefepime

N C C C C C

Cefotaxime

C C N N N C C C N C C C C

Cefoxitin

C C N N N C C C C C C C C

C N C

Ceftaroline

C C C N N N N N C N N C C

N N N N

Ceftazidime

C C

C N

Ceftizoxime

C C C N N C C C C C C C C C C N

Ceftriaxone

C C C N N C C C N C C C

Ciprofloxacin

Cisatracurium

N C C N N C C N C C C C C C N N N N C N N C C

Clindamycin

C C C

Daptomycin

Dexamethasone

C C N N N C C C C C C C

Dexmedetomidine

C C C C C C C C C C C C C C C C C C N C C C C C C C C

D5W

C C N

Diltiazem

N C C N N C C C C C C C C C C

Diphenhydramine

N C N

N C C C C N C C C C

Dobutamine

C C

N C C C C C N N N C

Dopamine

C C

N C C C C C C C C C

Doripenem

C C C N N C N N C N N C C C N N N N C N N N C N N C C N C Doripenem

Doxycycline

C C C

Enalaprilat

C C N N N C C C C C C C C

Epinephrine

C C N N C C C C C C C C C C N C C N C C C N C C C C C C Epinephrine

Eptifibatide

C N C C C C C C C C C C N C C C C N C C C C C C C C N N Eptifibatide

Esmolol

C C N N C C C C C C C C C C N C C N C C C N C C C

Famotidine

C C C N N C C C N C C C C C N

C C C N C

H N N C C

N N C C

N C N

C C C C C C C C

C C

N C C C C I

A C C C

C C Calcium gluconate

C C

C N C C C N N C C C C C Cefazolin

N N N N N N N

C N

A C C C C C C C C

I I

C C C C C C C C C I

Caspofungin

N C C C C C Cefepime

C N N C C C C C Cefotaxime

N C

C N N C C C C C Cefoxitin

N N N C C C N C N C Ceftaroline C C C N C C C C C Ceftazidime

N C

C N N C C C C C Ceftizoxime N C

C C C C Ceftriaxone

N N C C N N

C C C C C C C

C C C C C C C C

C C Ciprofloxacin

C C C C C Cisatracurium C

C C C C Clindamycin

C C C C N C C C C C C C C C C C C N C C C C C C I

C N C C N C C

C C C N C C N A C N

S N C C C N C C C C

C C

C C C

C C C C C C C C C C C

Daptomycin

C C Dexamethasone C Dexmedetomidine

C C

D5W

C C C C C C C C C C C C C Diltiazem

C C C C

C C Diphenhydramine

N N C

C C C C

C C Dobutamine

N C C C C C C C C C C C C C Dopamine

N C

C N C C C

C C Doxycycline

C C C C C C N C C C C C C Enalaprilat

C C Esmolol

C N C C N N N C C C C C C Famotidine

KEY A = Physically compatible for at least 2 hours

H = Physically compatible for at least 1 hour

C = Physically compatible

I = Incompatible

D = Physically compatible in dextrose 5% in water

N = Information on compatibility is not available or not adequate

E = Physically compatible for at least 5 minutes

R = Physically compatible for 24 hours under refrigeration

G = Physically compatible in glass bottle only

S = Physically compatible in 0.9% sodium chloride

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

Dextrose 5% in water

Dexmedetomidine

Dexamethasone

Daptomycin

Clindamycin

Cisatracurium

Ciprofloxacin

Ceftriaxone

Ceftizoxime

Ceftazidime

Ceftaroline

Cefoxitin

Cefotaxime

Cefepime

(Acyclovir through Dextrose 5% in water)

Cefazolin

Caspofungin

Calcium gluconate

Bumetanide

Bivalirudin

Aztreonam

Azithromycin

Atracurium

Argatroban

Anidulafungin

Ampicillin-sulbactam

Ampicillin

Amiodarone

Amikacin

Acyclovir

Table. Compatibility of Selected IV Drugs

Fentanyl

C C N N N C C C N C C C C C C N C C C C C C N C C C C C C Fentanyl

Fluconazole

C C C

Furosemide

C C N S N C C

Gentamicin

N C C

Heparin

S N C C N C C C C C

Hydrocortisone

C C N N

Hydromorphone

C C N N C C C C C C C C C C N C C C C C C C C C C C C C C Hydromorphone

Imipenem-cilastatin

C C

Insulin, regular

C N C N N C C N N C C C C C C H C

Labetalol

C C N N C C C C C C C C C N N

Levofloxacin

C N

C C C C N C C C C C C Levofloxacin

Linezolid

C C C C C C C C C C C C C C C C C C N C C N C C C C C C C Linezolid

Lorazepam

C C C

Magnesium sulfate

C C N N N

C C C C C C N C N

C C N C C

Mannitol

C C N C N C C C C C C C C C C

C C C C C C N C C C C C N Mannitol

Meropenem

N N N N N C C N C N C N N C N N N N N N N N N N N C C C

Methylprednisolone

C C C N

Metoclopramide

N C N N N C C C C C C C C C C

Metronidazole

C C C C C C C C C

Micafungin

N N

C C

N C C C C C C C N C C C N C C N C N C C N C C C C Fluconazole I

N C C C C

C C C C C C C C

C C Gentamicin

N C C C C C Heparin

C C C C C C C N C C C C C C C C C

C C C C C C Hydrocortisone

C C C C I

N C C

C C

N N N C

C C Labetalol

C C I

C C C C

C C C

Meropenem

C C C C C C C C C C C C C Metoclopramide

C C N Metronidazole

N N N N C Micafungin

C C C

N C C N N C C C N C C C C C C N C C C C C C N C C C C C C Morphine sulfate I

C C Magnesium sulfate

N C C C C N Methylprednisolone

C C C N C C C C C C C C C C C

C C N C C C

Morphine sulfate

C C N Imipenem-cilastatin

Midazolam

C C

C C C

C C C N C C C C C C C C C C C C C C N Lorazepam

C C C C C C C I

C C C C N N C C C C C Insulin, regular

N N N N N N N N C C N N N N N N N N N N I

C C C C C N C C C C C

N C C C C C Furosemide

C C C C C C C C

N N C C C N N C C N C C C C C N C C

N C C C N C C C C C N N N C C N C N C C C C

C C C C N C

Nicardipine

Nitroglycerin

C C C N N C C C C C C C C C C N C C N C C C N C C

C C C C C C N C C N N C N C C N C I

I I

C C Midazolam C C Nicardipine

C C G Nitroglycerin

Nitroprussidea

Norepinephrine

N C N N N C C C N C C C C C C N C C C C C C C C C C C C C Norepinephrine

Octreotide

C C C C C C C C C C C C C C C C C C N C C C C C C C C C C Octreotide

Ondansetron

C N

Palonosetron

C C C C C C C C C C C C C C C C C N C C C C C C C C C C Palonosetron

Pantoprazoleb

N N N C C C C

Penicillin G

C C C C N N N C N C N C C N C N C C N C C C N N C N C N C Penicillin G

Phenylephrine

Phenytoin

Piperacillin-tazobactam

N N C C N N C C C C

N C N N N N N N

N C C C C C Piperacillin-tazobactam

Potassium chloride

C C C N N C C C N C C C C C C C C C C C C C C C C C C C C Potassium chloride

C N N N C C N C C C C C

C N C C N

C C C C C C C C C C I

N C N N N

I I

C C N N C C C C C Nitroprussidea

C C C N C N C C C C C C C Ondansetron I

N C N C C

C Pantoprazoleb

C C N N C C C C C C C C C C N C C N C C C N C C C C C C Phenylephrine I

Phenytoin

N N N

N N C N C C Potassium phosphate

N C N N N N N C N C C N C N C C C N C C

N C N C C C Propofol

Ringerâ&#x20AC;&#x2122;s, lactated

C C N N R N C

C C N C C C C N C C C C C

Sodium bicarbonate

C C

C C C C

Sodium chloride 0.9%

C C N C C C C C C C C C C C C C C C C C C C C C C C C C C Sodium chloride 0.9%

C C

C C N N C C C C C C C C C C

C C C C

N C C C C C Sodium bicarbonate

C C N C C Ringerâ&#x20AC;&#x2122;s, lactated

Tacrolimus

Tigecycline

C C

Tobramycin

C C C N N C C C N C C C C C N N C C C C C

C C N C

TMP-SMX

N N

Vancomycin

C C C N N C C C C N

Vasopressin

C C C N N C C C C C C C C C C C C C C C C C C C C C C C N Vasopressin

I N

N N N N

C N C N C N N

Propofol

Potassium phosphate

N N

C C N C C C C C C C C C N Tacrolimus

C C N C C C C C C C C C C C C N C C C C C C C C C C Tigecycline I

C C N C N C I

C C Tobramycin

C N TMP-SMX

C C C N N N N N N N N N C C

N C C Vancomycin

Vecuronium

C C C C C C N C C C C C C C

Voriconazole

C C C C C C C N C C C C C C C

C C C C C C C C C C C C C Voriconazole

C N C C C C N C C C C C Vecuronium

Protect from light. g b Testing g was p performed with ethylenediaminetetra-acetic y acid ((EDTA)-free ) formulation.

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

Metoclopramide

Methylprednisolone

Magnesium sulfate

C C C C N C N Acyclovir

Meropenem

Mannitol

Lorazepam

Linezolid

C C C C C C C C C C C C C C C

Levofloxacin

N N

Amikacin

Labetalol

Insulin, regular

Imipenem-cilastatin

Hydromorphone

Hydrocortisone sod. succ.

C C C C N C C C C C

Acyclovir

Heparin

Gentamicin

Furosemide

Famotidine

Fluconazole

Esmolol

Fentanyl

Eptifibatide

C C C

(Diltiazem through Metoclopramide)

Epinephrine

Doripenem

Enalaprilat

Dopamine

Doxycycline

Dobutamine

Diphenhydramine

Diltiazem

Table. Compatibility of Selected IV Drugs

C C C N C C C C C C N C C Amikacin N N

Amiodarone

C N C C C C N C N C C N C N C

Ampicillin

N N C N N N

S N N N N N C C

Ampicillin-sulbactam

N N N N N

N N C N N N N N N N

Anidulafungin

C C C C C C C C C C C C C C C C C C C C C C C C

Argatroban

C C C C N C C C C C C C C C C C C C C C C C C C C C C C C Argatroban

Atracurium

C C C C N C C C C C C C C

Azithromycin

C C C C C C C C C C N N C N N C C C N N C N C C C C C C C Azithromycin

Aztreonam

C N C C N C C C C C C C C C C C C C N C C C C

Bivalirudin

C C N C N C C C C C C C C C C C C C C C C C C C C C C C C Bivalirudin

Bumetanide

C C N C C C C C C C C C C C C C C C C C C C C C C C N C C Bumetanide

Calcium gluconate

C C N C C C C C C C C C N C C C N C N C C C C C N C N

C Calcium gluconate

Caspofungin

C C C C C C

C Caspofungin

Cefazolin

C C C C N C C C N C C N C C N

Cefepime

N N N N

Cefotaxime

C N C C C C C C C N C N C C C C C

Cefoxitin

C N

Ceftaroline

C C N C C N C N N N C C C C C C C C N C

Ceftazidime

N C N

C C C C C C N C N C C C C C C C C C C C N C C Ceftazidime

Ceftizoxime

C C C C N

C C C C N C C C C C C C C C C C C C C C N C C Ceftizoxime

Ceftriaxone

Ciprofloxacin

C C C C C N N N C N N N C

Cisatracurium

C C C C N C C C C C C C C N C N C C C N N C C C C C N N C Cisatracurium

Clindamycin

C C C C N C C C C C C C N C C C C C C C N C C C C C N C C Clindamycin

Daptomycin

C C C C C C C C C C C C C C C C C C

Dexamethasone

Dexmedetomidine

C C C C N C C C N C C C C C C C C C C C C C C C C C C C C Dexmedetomidine

D5W

C C C C C C C C N C C C C C C C C C N C C C C N C N

Diltiazem

I I

C N C C C C N C N

C C N N N C N Amiodarone I

N C N N N Ampicillin

N N N

C C C C

N Ampicillin-sulbactam

C C C C Anidulafungin

C C N C C Aztreonam

C C C C C C C N C C C I

C C N C N C C Cefazolin

N C C N C C C C H N C C C

C N C C C N C C C C C C N C C Atracurium

C C C C N C C C C C C C C

C C C

C C

C N N N C C

C N C C C C C N C N C N C C C

C C

N C

Cefepime

C Cefotaxime

C Cefoxitin

C N C N C N C C Ceftaroline

C C C C N

C N C

C N C C Ceftriaxone

C N N N N C C

N N

N C C C C N

C Ciprofloxacin

C C C C C C C C C C Daptomycin

C C C C C

C C C

C C C C Dexamethasone I

N C D5W

C C C C C C C C C C C C

C N N C C N C C C C C C C N C Diltiazem

C C C C C C C C C C C

C N N C C

Diphenhydramine

Dobutamine

C C

Dopamine

C C C

Doripenem

C C C C

Doxycycline

C C C C N

Enalaprilat

C C C C C C

Epinephrine

C C C C N C C

Eptifibatide

C C C C N C C C

Esmolol

C C C C C C C C C

Famotidine

C C C C C C C C C C

C C C C C C C C C C N C N

C C C C C C C

C Diphenhydramine

C N N C C C C N C C C C Dobutamine

C C C C C C C C C N C C C C C N C C C C C C C C C Dopamine N C N N C C C C C C C C C N C C C C C C C N C C Doripenem C C C C C C C

C C C C C C C C C N

C Doxycycline

C C C C C C C C C C C C C C C C C C C C C C Enalaprilat C C C C C C C C C C C N C C C C C C N C C Epinephrine C C C C

C C C C C N C C C C C C C C C Eptifibatide

C C C

C C N C C C C C C C C C N N C Esmolol

C C N C C C C C N C C C C C C N C C Famotidine

KEY A = Physically compatible for at least 2 hours

H = Physically compatible for at least 1 hour

C = Physically compatible

I = Incompatible

D = Physically compatible in dextrose 5% in water

N = Information on compatibility is not available or not adequate

E = Physically compatible for at least 5 minutes

R = Physically compatible for 24 hours under refrigeration

G = Physically compatible in glass bottle only

S = Physically compatible in 0.9% sodium chloride

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

Fentanyl

C C C C C C C C C C C

Fluconazole

C C C C C C C C C C C C

Furosemide

Gentamicin

C C C C C C C C C C C C C

Heparin

N N N C C

C C C C C C C C

Hydrocortisone

N N

C C C N C C C C N N

Hydromorphone

C C C C C C C C C C C C C C C C C

Imipenem-cilastatin

C C N C N C C C C C C C N C C C C C

Insulin, regular

Labetalol

C C C C C C C C C C C C C N C N

Levofloxacin

C C C C C C C C C C C C C

C C C N C

Linezolid

C C C C C C C C C C C C C C C C C C C C C C

Lorazepam

C C C C C C C C C C C C C C C C C C

Magnesium sulfate

C C N C C C C C C C C C C N C C N C C C C N C C

Mannitol

C C C C C C C C C C C C C C C C C C

N N C

C C

Metoclopramide

Methylprednisolone

Meropenem

Mannitol

Magnesium sulfate

Lorazepam

Linezolid

Levofloxacin

Labetalol

Insulin, regular

Imipenem-cilastatin

Hydromorphone

Hydrocortisone sod. succ.

Heparin

(Diltiazem through Metoclopramide)

Gentamicin

Furosemide

Fluconazole

Fentanyl

Famotidine

Esmolol

Eptifibatide

Epinephrine

Enalaprilat

Doxycycline

Doripenem

Dopamine

Dobutamine

Diphenhydramine

Diltiazem

Table. Compatibility of Selected IV Drugs

C C C C C C C C C C C C C C N C C Fentanyl N C C C C N C C C C C C C C C C Fluconazole

N C N

C C C C N N

I I

N C C C N C C C

C C N C C C N Furosemide

C C C C C N C Heparin

C C C N C N N C Hydrocortisone

C C C C C C C C C C C Hydromorphone C C C C

N N C C C N N C N C C N N C C C C I

N C C N C C C C C C C C C Gentamicin

C C

I I

N C C Imipenem-cilastatin

N C C C C C C C Insulin, regular C C C C C N C C Labetalol C N N C N C C Levofloxacin C C C C C C Linezolid

C C N C

C C C C C Lorazepam C C

C C C C C C

C Magnesium sulfate

C C Mannitol

Meropenem

C C C C N N C N C N N N C C C C N C N C N N C C C

Methylprednisolone

C N

Metoclopramide

C C C C C C C C C C C C C N C C C C C C C C C C C C C C

Metronidazole

C C C C C C C C C C C C C C C C C C C C C C C C C C C C C Metronidazole

C C C

C C C N C C C C C N N C C C C C C C

C C N N

C C N N N C N C N C N

Metoclopramide

Morphine sulfate

C C C C C C C C C C C C C N C N C C C N C C C C C C C C C Morphine sulfate

Nicardipine

C C C C N C C C C C C C C

Nitroglycerin

C C C C N C C C C C C C C N C C C C C C C

C C C C N C C Nitroglycerin

Nitroprussidea

C C C C N C C Nitroprussidea

Norepinephrine

C C C C C C C C N C C C C N C C C C C N C N C C C C C C C Norepinephrine

Octreotide

C C C C N C C C C C C C C C C C C C C C C C C C C C C C C Octreotide

Ondansetron

C C C C C C C C C C C C C

Palonosetron

C C C C N

N C C N N N N Micafungin

C C N C N N C C C C C C N N C Midazolam C N C C

N C C C N C C

N C N C C C C C C C C C C C C C N C C

C Methylprednisolone

C C N C C C C C C C C C C

N C Meropenem

Midazolam

Micafungin

C C C C C N C C C

C C C C C C C C C C C C

C C Nicardipine

C C N N C Ondansetron

C C C C C C C C N C Palonosetron

Pantoprazoleb

N C C N N N

Penicillin G

C C

C N

Phenylephrine

C C C C C C C C C C C C C N C C C C C

C C C C C C N C C Phenylephrine

Phenytoin

Piperacillin-tazobactam I

C N

C C C C

C C C N C C C N

C C C C N C C Piperacillin-tazobactam

Potassium chloride

N N N N N C N

N N

N Pantoprazoleb

C C N C C C C C C C C C C C N C N N C C N C C Penicillin G I

N N I

Phenytoin

C C C C C C C C C C C C C C C C C C N C C C C C C C N N C Potassium chloride

Potassium phosphate

C N

N C N C C C N N N N N N C N N C N C

Propofol

N C N N

C C N N C C C C C

Ringerâ&#x20AC;&#x2122;s, lactated

N C C C N N N C N C C C C C C N C C

N C N C N C N

N C Ringerâ&#x20AC;&#x2122;s, lactated

Sodium bicarbonate

C N C C C C C

C C Sodium bicarbonate

C C C C C C

C C C C C C C C C

N N N N C Potassium phosphate

N C N C N

Propofol

Sodium chloride 0.9% C C C C C C C C N C C C C C C C C C R N C C C N C N R C C Sodium chloride 0.9% Tacrolimus

C C C C C C C C N C C C C N C C C C C C C C C C C C C C C Tacrolimus

Tigecycline

C C C C C N C C C C C C C C C C C C C C C C C C C C C N C Tigecycline

Tobramycin

C C C C C C C C C C C C C C C

TMP-SMX

Vancomycin

C C C C C C C C C C C C C

N C N C C C C C C C C N C Vancomycin

Vasopressin

C C C C N C C C N C C C C N C C C C C N C C C C C C C C C Vasopressin

Vecuronium

C C C C N C C C C C C C C

Voriconazole

C C C C C C C C N C C C C C C C C N C C C C C C C C C C C Voriconazole

C N

N C C N C C C C C C N C C Tobramycin C

C C C C

N C N C N

C C C C C C C C

TMP-SMX

C Vecuronium

Protect from light. g b Testing g was p performed with ethylenediaminetetra-acetic y acid ((EDTA)-free ) formulation.

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

C C C N

N N N C N

C N C N

N N C C Ampicillin

Ampicillin-sulbactam

C N

N N N C

C C N N

N N N N R N C N C N

N N C C Ampicillin-sulbactam

Anidulafungin

C N C C C C C C C C C C N C

C C

Argatroban

C N C C C C C C C C C C N C

C C C N C C C C C C C C C C C Argatroban

Atracurium

C N C C C C N C C C C

C C

N C N N

Azithromycin

C N

C C N C C C C N C

N N C N C C C C C N C C C C C Azithromycin

C C C C C

N N I

I I

TMP-SMX

Pantoprazoleb

C C C C C C

C Acyclovir

C C C C Amikacin

C N C C C C Amiodarone

C C N C C C C C C Anidulafungin C C C C N C C N N Atracurium

Aztreonam

C C

C C N C C C C C C C N N C C C Aztreonam

Bivalirudin

C N C C C C C C C C C N N C

C C C N N C C C C C C

Bumetanide

C C N C C C C C C C C C C C

C C N C C C C C C C

C C C C Bumetanide

Calcium gluconate

C C C C C C C C C C C N C C

C C N C C

C C C C

C C C C Calcium gluconate

Caspofungin

N N C C C C

C C C C N N C

C C C C

C C C C Caspofungin

Cefazolin

C N C C C C C C C C C N C C

N C N C C C C C C N

N C C C Cefazolin

Cefepime

C N

N N

C C N N N C C

Cefotaxime

C N C C C C C C C C C

C C

N C N C C

C C C C

N C

Cefoxitin

C N C C C C C C C C C N C C

N C N C C

C C C C

N C C C Cefoxitin

Ceftaroline

C N C C N N N C N C N C N N N N C

Ceftazidime

C N

C C N C N C C

N C N N C C C C C C

N C C C Ceftazidime

Ceftizoxime

C N C C C C C C C C C C C C

N C N C C C C C C C

N C C C Ceftizoxime

Ceftriaxone

C N C C N C C C C N C C C C

N C N C

C C C C

N C C C Ceftriaxone

Ciprofloxacin

C N C N C N N C C C C

N N

Cisatracurium

N C N N C N N

N C C C C N C C N C Cisatracurium

Clindamycin

C N N C N C C C C C C N C C

C C N C C C C C C N

Daptomycin

Dexamethasone

C N

N N N N N C

C N C

C C C C N C C C C

N C C C

N C

C C C Bivalirudin

C N C N C

C Cefotaxime

Cefepime

C C C C N N C C N C N C Ceftaroline

C C C C N N C C C Ciprofloxacin I

C C C C Clindamycin

C C C C C

N C

C C C N C C C C C C C

C C C C C C

C C

C C N C N C C C C

N C C C Dexamethasone

Dexmedetomidine

C N C C C C C C C C C

N C

C C C C C C C C C C C C C C C Dexmedetomidine

D5W

N C C C C G C C C C C C C C

C C C C C C C N C C N C N C C D5W

Diltiazem

Diphenhydramine

C N C C C C

Dobutamine

Tigecycline

Palonosetron

N C C C C C C C C C

Tacrolimus

Ondansetron

Octreotide

N C

Voriconazole

N C

N N N C

Vecuronium

Vasopressin

N N

N C

Vancomycin

Tobramycin

Propofol

C C C C N N C N C N C C N

C N

Sodium chloride 0.9%

Potassium phosphate

Ampicillin

Sodium bicarbonate

Potassium chloride

Amiodarone

Ringerâ&#x20AC;&#x2122;s, lactated

Piperacillin-tazobactam

Penicillin G Potassium

C C C C

Norepinephrine

Nitroprussidea

C C N

Nitroglycerin

Nicardipine

Morphine sulfate

C N C C C C C C C C C N C C

Midazolam

C N

Amikacin

Micafungin

Acyclovir

Metronidazole

Phenytoin

(Metronidazole through Voriconazole)

Phenylephrine

Table. Compatibility of Selected IV Drugs

C C C Daptomycin

C C

C C C C

C C

C C N C C

C C C C

C C C C Diphenhydramine

N C C C N C C C C

N C

C C C C

C C C C Dobutamine

Dopamine

C C C C C C C C C C C N C C

C C N N C

C C C C

C C C C Dopamine

Doripenem

C C C C N N N C N C N C N C N N C

Doxycycline

C N C C C C C C C C

Enalaprilat

C N C C C C C C C C C N C C

C C C C N C C C C C N C C C C Enalaprilat

Epinephrine

C C C C C C C C C N C C

C C N N C

Eptifibatide

C C C C C C C N C C C N N C

C C C N N C N N C C C C N C N Eptifibatide

Esmolol

C C C C C C C C C C C

C C N C C C C C C C C C C N C C C C Esmolol

Famotidine

C N C C C C C C C C C

C C N

C C C C C C C C C

C C N N N C C C C C C C C C Diltiazem C

I I

N C C C C C N C N N C Doripenem

C N C N

I I

C C N C C C C C

C C C C C C C C C

I I

C C C C Doxycycline C C C C Epinephrine

C C C C Famotidine

KEY A = Physically compatible for at least 2 hours

H = Physically compatible for at least 1 hour

C = Physically compatible

I = Incompatible

D = Physically compatible in dextrose 5% in water

N = Information on compatibility is not available or not adequate

E = Physically compatible for at least 5 minutes

R = Physically compatible for 24 hours under refrigeration

G = Physically compatible in glass bottle only

S = Physically compatible in 0.9% sodium chloride

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

C C N C N C C C C

C C N C C C C C C N

N C C C Hydrocortisone

Hydromorphone

C C C C C C C C C C C N C C

C C C C C

C C C C C C C C N Hydromorphone

Imipenem-cilastatin

C N N C

N N N C

R C C C

N C

Insulin, regular

N N N C C N C N C N C

C N C N C N C C N

C N C C Insulin, regular

Labetalol

C C C C C C C C C

N C

C C C C N C C C C N C C C C Labetalol

Levofloxacin

C C C

N C C C

C C

C N

Linezolid

C N C C C C C C C C C

N C

C C C N C C C C C C N C C C C Linezolid

Lorazepam

C C C C N C C C C

N C

C C

Magnesium sulfate

C C C C C C C C C C C N C C

C C N N C C C C C C N C C C C Magnesium sulfate

Mannitol

C N C C C C C C C C C N C C

C C N C N C N C C C

Meropenem

C N N C

N N C C N C

N N N N N N N

Methylprednisolone

C N N C C C C C C N N

C C

C N N

N C C C N C

N C

Metoclopramide

C N C C C C C C C C C N C C

C C C

C C C C C C

C C C C Metoclopramide

N C N C C C C C C C C Metronidazole

Metronidazole

C N C C C

N C C C C C C C C C I

C C C

C N C N C C C C C C C C Lorazepam

C C C C Mannitol

R C C N N C C C C Meropenem

C C C C C C C N C C

C C N N C C C C C C N C C C C Morphine sulfate

Nicardipine

C C

Nitroglycerin

C C C C C

Nitroprussidea

C C C C C C

Norepinephrine

C C C C C C C

Octreotide

C C C C C C

Ondansetron

C C C C C C C

Palonosetron

C N C C C C C C C N

C C C

C C C C C C

C C C C N C C

C C C C C C C C C C

C C C

C C C N C C

C C N C C

C C C C Norepinephrine

C C N N C

C C C N N C C C C C C C C C C Octreotide C C C C C

N C

C C C C N C C C C C C C C C N Palonosetron

N C

N C N N C N C C N C

N C N N Penicillin G

C C N N C C C C C C I

C C C C C C C C C C C C C

Phenytoin

Piperacillin-tazobactam C N

C C C C C C N N C

Potassium chloride

C C C C C C C C C C C C C C

Potassium phosphate

C C N N N N C N C C C

C C C C Ondansetron

N C N C N C N N N C

C N C

C Piperacillin-tazobactam

N C C C C C C C N

N C N

G C C N C N C C C

C C

Sodium bicarbonate

C N

C C

C C N N C C

C C C C Potassium chloride

N N N N N Propofol

N N N C C N C N C N Ringer’s, lactated

C N N C

C C N C N

C C C N N C

Tacrolimus

C C C C C C C C C C C N C C

C C C N N C N

Tigecycline

C N C C

C C C C C C C N C

C C C C C C N C

Tobramycin

C N C C C C C C C C C N C C

C N

TMP-SMX

C N

Vancomycin

C N C C C C C C C C C N N C

N C N N C N C C C C

Vasopressin

C C C C C C C C C C C C C C

C C C N N C N C C C N C

Vecuronium

Voriconazole

C N C C C C

C N

C C C C C C C C C I

C C C N

Phenytoin

N C C C N N N C C C Potassium phosphate

Sodium chloride 0.9% N C C C C G C C C C C C C C

Pantoprazoleb

C C N C C C C C

N N

C C C C Phenylephrine

N C N C

Ringer’s, lactated

C C C C

N N N C N

N N N N C C C N C C N N N

Propofol

Nitroprussidea

Phenylephrine

C C C C

C C C C Nitroglycerin

C C

C N C C C C Nicardipine

N N C C C C C C N C N N I

N Micafungin

C C

C C C C Midazolam

C C N C G C G C C C

C C C C

C C C C C N C C

N N N N

C N N

Penicillin G

C N N N

C C

Pantoprazoleb

C Methylprednisolone

C C

Morphine sulfate

C C C

C C C C C C C C

N C C C C C C C C C C Levofloxacin

N C C N C N C C N N N N C

C Imipenem-cilastatin

Midazolam

C C C Heparin

N C

C Furosemide

N N N C

Micafungin

Voriconazole

C N N C C C C C C C C N C C

Vecuronium

Vancomycin

C C C N N C C C C C C N C C

Hydrocortisone

C C C C C C

Vasopressin

TMP-SMX

Heparin

Tobramycin

C C C C Gentamicin

Tigecycline

Tacrolimus

N C N

Sodium chloride 0.9%

Sodium bicarbonate

C N C C C C C C C C C N C C

Ringer’s, lactated

Gentamicin

Propofol

N C N C

Potassium phosphate

Piperacillin-tazobactam

C C N C C C C N C C

Potassium chloride

Phenytoin I

Phenylephrine

C N C N

Palonosetron

C C

Ondansetron

C C C C Fluconazole

Furosemide

Octreotide

C C C C Fentanyl

Norepinephrine

Nitroprussidea

C C N C C C C C C C

Nitroglycerin

C C N C C N C C C C C C C

Nicardipine

C C

Morphine sulfate

C N C C C C C C C C C

Midazolam

C N C C C C C C C C C

Fluconazole

Micafungin

Fentanyl

Metronidazole

Penicillin G Potassium

(Metronidazole through Voriconazole)

Pantoprazoleb

Table. Compatibility of Selected IV Drugs

C C C C

N C C N Sodium bicarbonate

C C N C C C C Tacrolimus C C C C C N Tigecycline

C C C C C

N N N

N N C N C N C C Sodium chloride 0.9%

N N C

I I

C C C C Tobramycin I

N C C TMP-SMX C C C Vancomycin C C Vasopressin

N C

C C N C C C C C C C C C

N C

C C C N N N C C N C C C C C

C Vecuronium Voriconazole

Protect from light. g b Testing g was p performed with ethylenediaminetetra-acetic y acid ((EDTA)-free ) formulation.

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

Text continued from page 39

incompatibilities are the most easily detected and are evidenced by visible changes, such as particulate formation, haze, precipitation, color change, and gas evolution. Chemical incompatibilities are those that result in decomposition of a drug. Loss of potency of greater than 10% over the defined testing period is considered chemical incompatibility. Most chemical incompatibilities can be detected only with a suitable analytic method. Therapeutic incompatibilities in which a drug combination results in undesirable antagonistic or synergistic pharmacologic activity are beyond the scope of most compatibility references. The purpose of this chart is to provide data in an organized, concise format from which compatibility information can be accessed quickly and conveniently. Although there are differing types of incompatibilities, the type of incompatibility or compatibility is not specified in this chart. A designation of “compatible” indicates that the combination evaluated appears to be compatible based on the tests performed, whether these tests measured physical, chemical, or both types of compatibility. All conditions that may affect compatibility cannot be included in such a format and it is not possible to predict all incompatibilities that may arise, but it is hoped that the information provided may help clinicians minimize their occurrence. Continuing

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

research adding to the existing body of knowledge on IV compatibilities is vital.

Suggested Reading Bertsche T, Mayer Y, Stahl R, Hoppe-Tichy T, Encke J, Haefeli WE. Prevention of intravenous drug incompatibilities in an intensive care unit. Am J Health Syst Pharm. 2008;65(19):1834-1840. Cohen MR, Smetzer JL. ISMP medication error report analysis-drug stability and compatibility; proper use of single-dose vials; what drugs are present on nursing units?; Arixtra—not a hemostat; Pradaxa–Plavix mix-up. Hosp Pharm. 2012;47(8):578-582. Kanji S, Lam J, Johanson C, et al. Systematic review of physical and chemical compatibility of commonly used medications administered by continuous infusion in intensive care units. Crit Care Med. 2010;38(9):1890-1898. DRUGDEX® System (Internet database). Greenwood Village, CO: Thomson Reuters (Healthcare) Inc. Nemec K, Kopelent-Frank H, Greif R. Standardization of infusion solutions to reduce the risk of incompatibility. Am J Health Syst Pharm. 2008;65(17):1648-1654. Newton DW. Crux of drug compatibility and incompatibility. Am J Health Syst Pharm. 2010;67(2):108-112. Singh BN, Dedhiya MG, DiNunzio J, et al. Compatibility of ceftaroline fosamil for injection with selected drugs during simulated Y-site administration. Am J Health Syst Pharm. 2011;68(22):2163-2169. Trissel LA, ed. Handbook on Injectable Drugs. 16th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2011.

Dr. Cayo reports no relevant conflicts of interest.

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EXPOSURE TO HAZARDOUS DRUGS THREATENS

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Safe Handling Of Hazardous Drugs: Reviewing Standards for Worker Protection

LUCI A. POWER, MS, RPH

MARTHA POLOVICH, PHD, RN, AOCN

Senior Pharmacy Consultant Power Enterprises San Francisco, California

Director Clinical Practice Duke Oncology Network Durham, North Carolina

n 2011, senior officials of the National Institute for Occupational Safety and Health (NIOSH), the Occupational Safety and Health Administration (OSHA), and the Joint Commission collaborated on a letter sent to

all hospital employers in the United States stating that hazardous drugs (HDs), such as antineoplastic drugs, can pose serious job-related health risks to workers if proper precautions are not used in handling the drugs.1

This unusual action was taken to remind hospital employers that protecting the health of their employees is vitally important, according to NIOSH Director John Howard, MD, as well as OSHA Assistant Secretary of Labor David Michaels PhD, MPH, and the Joint Commissionâ&#x20AC;&#x2122;s Senior Vice President of Healthcare Improvement Paul M. Schyve, MD.2,3

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

Health care worker exposure to HDs, including antineoplastic agents, antiviral agents, biological modifiers, hormones, and other agents, has been a concern since the late 1970s. Despite decades of research and guidance on safe handling, including a comprehensive NIOSH Alert issued in 2004,4 health care workers still experience HD exposure. A NIOSH-sponsored

P H A R M AC Y P R AC T I C E N E WS S P E C I A L E D I T I O N

â&#x20AC;˘ 2013

study published in 20105 reexamined risk points from a 1999 study6 and showed similar levels of HD surface contamination in both compounding and administration areas. A 2010 study describes evidence of drug uptake and chromosomal changes in oncology workers7 and a 2012 study documents adverse reproductive events in nurses exposed to HDs in the workplace.8 The reproductive results are similar to those reported in a 2005 metaanalysis of the increased occurrence of toxic events among HD handlers.9 These recently published studies demonstrate little improvement over earlier studies indicating that healthy workers exposed to HDs may experience adverse effects.10-12 Ongoing efforts are necessary to promote awareness of the health risks associated with this exposure to all health care workers involved in the handling of HDs and to assess whether the failure of existing programs is due to ineffective interventions or the lack of adherence to recommended precautions. This review focuses on existing guidance and some new activities of regulatory groups to improve adherence to safety precautions.

Routes of Occupational Exposure Many studies have documented both surface and worker contamination from HDs.13-19 Health care workers may breathe contaminated air or touch contaminated surfaces and take in HDs from the work environment through unprotected skin.13-17,20 Standard work practices for handling injectable drugs in vials and syringes can generate powder and liquid aerosols. These drug residues may contaminate the air and surfaces in the work area.13-19,21 A multisite 2005 study documented that many HD vials are delivered from the manufacturer with drug residue on the outside of the vials, creating yet another opportunity for contamination.22 A 2010 study looking at drug vials manufactured in Europe found similar results.23 Certain HDs have been shown to vaporize at room temperature, resulting in drug contamination of the air.24-26 Drug uptake also may occur through the ingestion of contaminated food or drink that is inappropriately located in or near drug-handling areas. The transfer of contaminated residues from hands to mouth may result in the ingestion of HDs. Needlesticks with HD-contaminated needles or cuts from glass fragments of vials or ampules may result in exposure by injection.

Guidelines and Standards for Safe Handling of Hazardous Drugs Since 1980, numerous organizations have issued guidelines for the safe handling of HDs. OSHA updated early guidelines in 1995,27 and made them available

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

online in 1999.28 In 2004, NIOSH issued an alert, “Preventing Occupational Exposure to Antineoplastic and Other Hazardous Drugs in Health Care Settings,” which reassessed the problem and existing guidance.4 The American Society of Health-System Pharmacists (ASHP) published updated and extensive guidelines on the safe handling of cytotoxic agents as a Technical Assistance Bulletin in 1990, and issued new guidelines on HDs in 2006.29,30 The 2006 guidelines were harmonized to the 2004 NIOSH Alert. To influence nursing practice and protect its members from exposure, the Oncology Nursing Society (ONS) published “Chemotherapy and Biotherapy Guidelines and Recommendations for Practice” and developed an extensive educational program.31-33 ONS’s latest recommendations harmonize with those of NIOSH and ASHP. In 2007, the United States Pharmacopeial Convention released USP Chapter <797>, “Pharmaceutical Compounding—Sterile Preparations,” which became effective in 2008.34 This revision of the 2004 standard includes a section specific to the compounding of HDs and is coordinated with much of the 2004 NIOSH Alert. More importantly, USP Chapter <797> is an enforceable standard and establishes many of the NIOSH recommendations as requirements. The standards set by USP Chapter <797> are applicable in all settings in which sterile doses of HDs are compounded, not just hospitals and clinics. Revisions to USP Chapter <797> for the 2012 edition currently are proposed in Pharmacopeial Forum (PF) but are not yet approved by an Expert Committee.35 USP also is proposing a separate chapter on compounding HDs that will provide guidelines and recommendations to reduce the potential harmful effects of HDs on health care workers. A Hazardous Drugs Expert Panel has been commissioned to work with the 2010-2015 USP Compounding Pharmacy Expert Committee to prepare this chapter.36 The Washington State Legislature required the State Department of Labor & Industries (L&I) to set requirements to protect workers who handle chemotherapy and other HDs. This landmark bill required L&I to adopt rules that are consistent with but do not exceed provisions in the 2004 NIOSH Alert on preventing occupational exposures to antineoplastic and other HDs in health care settings, as updated in 2010. L&I’s HDs rule was adopted on Jan. 3, 2012, and the rule will take effect in stages beginning Jan. 1, 2014.37

Continuing Exposure Studies of surface and worker contamination conducted in the late 1990s and through 2010 have

Table 1. Comparison of NIOSH 2004 and ASHP 1990 Definitions NIOSH

ASHP

Carcinogenicity

Carcinogenicity in animal models, in the patient population, or both, as reported by the International Agency for Research on Cancer

Teratogenicity or developmental toxicity

Teratogenicity in animal studies or in treated patients

Reproductive toxicity

Fertility impairment in animal studies or in treated patients

Organ toxicity at low doses

Evidence of serious organ or other toxicity at low doses in animal models or treated patients

Genotoxicity

Genotoxicity (ie, mutagenicity and clastogenicity in short-term test systems)

Structure and toxicity profile of new drugs that mimic existing drugs determined hazardous by the above criteria ASHP, American Society of Health-System Pharmacists; NIOSH, National Institute for Occupational Safety and Health Originally published in reference 30 © 2006, American Society of Health-System Pharmacists, Inc. All rights reserved. Reprinted with permission.

continued to document HD exposure.5-12,17-19,21 A NIOSHsponsored study from 2010 detected surface contamination with HDs in compounding and administration environments of all sites studied.5 The findings of the study included a correlation between the size and spatial design of the compounding area and the amount of surface contamination. Preliminary reports support the USP Chapter <797> design standard that requires an appropriate buffer area around the primary engineering control (PEC).34 One site studied in the 2010 NIOSH study had a smaller, less delineated compounding area and the investigators found a higher rate of surface contamination at that site. Surprisingly, the percentage of surfaces contaminated with HD residue in this study is almost identical to that found in a similar study published more than a decade earlier, in 1999.6 In both studies, 75% of surfaces sampled in the pharmacies were found to have residue of at least one of the marker HDs. This raises the question of whether the efforts of NIOSH and USP have made any difference with regard to HD contamination. Additional concern was generated by a substudy within the NIOSH research. In this companion study, also published in 2010, investigators at the University of Maryland evaluated the chromosomal effects of select

HDs in health care workers using fluorescence in situ hybridization.7 The DNA of exposed workers showed a statistically significant increased frequency of damage to chromosome 5 or 7 (P=0.01) and an increased frequency of damage to chromosome 5 alone (P=0.01). Myelodysplastic syndrome and acute myeloid leukemia are known to be associated with signature lesions in chromosomes 5, 7, and 11. These results provide additional evidence for harmful effects from occupational exposure to HDs. A 2011 retrospective study of occupational exposures and pregnancy outcomes in 8,461 participants in the Nurses’ Health Study II found an associated 2-fold increased risk for spontaneous abortion with HD exposure.8 The authors of this study noted that even though awareness of HD exposure has increased, protocols to reduce exposure of health care personnel to these chemicals have been insufficient to eliminate the exposure.8 However, other researchers have postulated other reasons for continuing HD exposure, including workers’ lack of awareness of the issue; poor facility design; a lack of vigilance in work practices; poor adherence to the use of personal protective equipment (PPE); less than supportive attitudes by supervisory personnel; and inadequate time to compound and administer and properly care for

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patients.5,38-42 In a 2006 review of the HD safe-handling literature, the authors reported the common finding that policies and procedures for handling HDs are in place but that employees who are directly involved in the preparation and administration of HD are not compliant.43 Possibly, the fact that HD precautions are referred to as guidelines instead of practice standards or rules promotes a lack of employer and individual worker concern. NIOSH actively continues to increase awareness of this issue by maintaining Safety and Health Topic pages online: “Hazardous Drug Exposures in Health Care”44 and “Occupational Exposure to Antineoplastic Agents.”45 These pages provide links to extensive background information, the latest studies, updates on related activities, and NIOSH publications.

Barriers Although many studies document continuing HD contamination and worker exposure, few have attempted to identify why the efforts to improve worker safety have not been successful. A recent study of nurses sought to explain this issue. The purpose of the study was to examine relationships among factors affecting nurses’ use of HD safe-handling precautions and to identify factors that promote or hinder the use of precautions. In a study with a cross-sectional, correlational design, 165 nurses from oncology centers throughout the United States who reported handling chemotherapy completed a mailed survey. Instruments measured the use of HD precautions and various factors thought to influence the use of precautions. Despite the fact that nurses were knowledgeable about chemotherapy exposure, overall use of precautions during administration and disposal of these drugs was low. The following factors were predictive of higher use of precautions: fewer patients per day per nurse, fewer barriers (eg, availability and convenience of PPE), and a better workplace safety climate (eg, training provided, supervisors’ encouragement of precaution use, and expectations that policies are followed). These findings have important implications because factors in the workplace environment seem to be the most important influences on safe-handling practices.38

Defining HDs A number of drug types that are potent and toxic in patients have the potential to cause adverse effects in persons who are occupationally exposed to them. Although the cytotoxic potential of the alkylating agents is of primary concern, there are multiple mechanisms by which drugs cause hazardous effects. In 1990, ASHP

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attempted to categorize these drugs in its “Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs,”29 for the first time using the term hazardous drug in reference to drugs that involve risks from occupational exposure. The terminology was selected to be inclusive of the types of drugs with safety concerns and to be compatible with the then newly developed OSHA Hazard Communication Standard (HCS).46 The HCS is intended to ensure that workers who are at risk for exposure to hazardous chemicals in the workplace are informed of the specific hazardous chemicals, their associated health and safety hazards, and the appropriate protective measures to be taken. The HCS (CFR 1910.1200) has been updated to align with the UN Globally Harmonized System of Classification and Labeling of Chemicals (GHS), Revision 3. This rule became effective on May 25, 2012.47 The revised HCS defines a hazardous chemicall as any chemical that is classified as a physical hazard or a health hazard, a simple asphyxiant, combustible dust, pyrophoric gas, or hazard not otherwise classified.47 It further defines a health hazard d as a chemical that is classified as posing one of the following hazardous effects: acute toxicity (any route of exposure); skin corrosion or irritation; serious eye damage or irritation; respiratory or skin sensitization; germ cell mutagenicity; carcinogenicity; reproductive toxicity; specific target organ toxicity (single or repeated exposure); or aspiration hazard. The criteria for determining whether a chemical is classified as a health hazard are detailed in Appendix A to §1910.1200—Health Hazard Criteria.48 ASHP has used similar criteria to define HDs.29,30 Data on the side effects of a drug are collected during both the drug’s premarket investigational phase and its clinical use. These data reasonably may be used to infer health hazards in workers occupationally exposed to the drug. As such, ASHP proposed the following criteria to define HDs29: • genotoxicity (ie, mutagenicity and clastogenicity in short-term test systems); • carcinogenicity in animal models, in the patient population, or in both, as reported by the International Agency for Research on Cancer; • teratogenicity or fertility impairment in animal studies or in treated patients; and • evidence of serious organ or other toxicity at low doses in animal models or treated patients. ASHP’s criteria for HDs were revised by NIOSH for the 2004 Hazardous Drug Alert.4 The NIOSH 2004 and ASHP 1990 definitions of HDs are compared in Table 1. USP Chapter <797> has adopted the following definition

Table 2. Comparison of the NIOSH, ASHP, and USP Chapter <797> Recommendations for the Hazardous Drug Compounding Environment NIOSH

ASHP

USP Chapter <797>

Storage environment

Store HDs separately from other drugs in an area with sufficient general exhaust ventilation to dilute and remove any airborne contaminants.

Segregate HD inventory and store in an area with sufficient general exhaust ventilation to dilute and remove any airborne contaminants.

HDs shall be stored separately from other inventory, preferably within a containment area such as a negative-pressure room.

Compounding

Prepare HDs in an area that is devoted to that purpose alone and is restricted to authorized personnel.

HDs should be compounded in a controlled area where access is limited to authorized personnel trained in handling requirements.

HDs shall be prepared in a PEC, which shall be placed in an ISO class 7 area that is physically separated from other preparation areas.

Ventilation

Where feasible, exhaust 100% of the filtered air to the outside.

Because of the hazardous nature of these preparations, a contained environment where air pressure is negative relative to that of the surrounding areas or that is protected by an air lock or anteroom is preferred.

Storage: area should have exhaust ventilation of at least 12 air changes per hour. Compounding: optimally at negative pressure relative to adjacent positive-pressure ISO class 7 or better ante-areas.

ASHP, American Society of Health-System Pharmacists; HDs, hazardous drugs; ISO, International Organization for Standardization; NIOSH, National Institute for Occupational Safety and Health; PEC, primary engineering control; USP, United States Pharmacopeia Based on references 4, 30, and 34.

of HDs, which supports both the HCS and the NIOSH Alert definitions: Drugs are classified as hazardous if studies in animals or humans indicate that exposures to them have a potential to cause cancer, developmental or reproductive toxicity, or harm to organs.34 NIOSH has adopted a mechanism both to review its HD criteria and to judge newly FDA-approved drugs against these criteria on a regular basis. The review process for the addition of the new listings is described in the Federal Register.49 The updated “NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings 2012” can be found on the NIOSH website.50

Recommendations Recommendations for the safe handling of HDs have been available since the early 1980s. As more research

has been conducted and more groups have been involved, the recommendations have been coordinated in an attempt to provide uniformity. Each group, however, has a somewhat different focus. The NIOSH Alert and OSHA Technical Manuals are broad guidelines; the ONS “Chemotherapy and Biotherapy Guidelines” focus on administration and patient safety information; ASHP addresses pharmacists’ concerns; and USP Chapter <797> deals exclusively with sterile compounding. All guidelines agree that to reduce exposure to HDs in the occupational setting, a comprehensive safety program must be developed that deals with all aspects of drug handling—from selection and receipt of the product to storage, compounding, administration, spill control, and waste management. Key components of such a program are administrative, environmental

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Table 3. Comparison of NIOSH, ASHP, and USP Chapter <797> Recommendations for Primary Engineering Controls NIOSH

ASHP

USP Chapter <797>

PECs

• Aseptic containment ventilation control class II BSC-type B2 is preferred. • Class III BSC or CACI.

• Class II BSC-type B2 with outside exhaust is preferred. • Total exhaust is required if the HD is known to be volatile. • Class III BSC or CACI.

• BSC or CACI that meets or exceeds the standards for CACI in USP Chapter <797>.

Ventilation

• Do not use a ventilated cabinet that recirculates air inside the cabinet or exhausts air back into the room environment if a drug is volatile.

• Without special design considerations, class II BSCs are not recommended in traditional, positive-pressure clean rooms.

• BSCs and CACIs optimally should be 100% vented to the outside air through HEPA filtration.

ASHP, American Society of Health-System Pharmacists; BSC, biological safety cabinet; CACI, compounding aseptic containment isolator; HD, hazardous drug; HEPA, high-efficiency particulate air; NIOSH, National Institute for Occupational Safety and Health; PEC, primary engineering control; USP, United States Pharmacopeia Based on references 4, 30, and 34.

engineering, and work practice controls, as well as PPE. These components are based on principles of industrial hygiene that have been successfully used to mitigate risks from other occupational exposures.51

ADMINISTRATIVE CONTROLS Administrative controls include policies, procedures, staff education and training, validation of competency, and medical surveillance. All aspects of HD handling must be identified, staff performance expectations clearly defined, methods for validating staff competency determined, and processes for the ongoing monitoring of adherence to policies judiciously established. USP Chapter <797> emphasizes administrative controls for the safe compounding of HDs by mandating conditions that protect health care workers and other personnel in preparation and storage areas. Additional requirements include extensive training of all personnel involved in the storage, handling, and disposal of these drugs. USP Chapter <797> reinforces the OSHA and NIOSH recommendations by requiring training before the preparation or handling of hazardous compounded sterile preparations, and by mandating that the effectiveness of training be verified by testing workers on specific HD preparation techniques. Ongoing training must be documented at least annually. The components

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of the training program are specified to include didactic overview of HDs and their mutagenic, teratogenic, and carcinogenic properties. The training program must address each new HD that enters the marketplace. Training in work practices also must include the following: aseptic manipulation; negative-pressure technique; correct use of safety equipment; containment, cleanup, and disposal procedures for breakages and spills; and treatment of personnel for contact and inhalation exposures. OSHA and NIOSH include medical surveillance in their safety program recommendations. Medical surveillance involves collecting and interpreting data to detect changes in the health status of working populations potentially exposed to hazardous substances. In 2007, NIOSH released “Workplace Solution: Medical Surveillance for Health Care Workers Exposed to Hazardous Drugs,” which provides directions for establishing such a program and the elements that should be included.52 USP Chapter <797> requires that all compounding personnel with reproductive capability confirm in writing that they understand the risks associated with handling HDs. Although USP Chapter <797> mandates this only for personnel responsible for compounding, prudent practice dictates that the requirement should extend to all personnel who handle HDs along the chain of custody.

Table 4. Comparison of NIOSH, OSHA, ASHP, And USP Chapter <797> Recommendations for PPE

General handling

NIOSH/OSHA

ASHP

USP Chapter <797>

• Use double gloving for all activities involving HDs.

• Wear double gloves for all activities involving HDs. • Guidelines for the safe handling of HDs recommend the use of gowns for compounding in the BSC, administration, spill control, and waste management to protect the worker from contamination by fugitive drug generated during the handling process.

• HDs shall be handled with caution at all times with the use of appropriate chemotherapy gloves during receiving, distributing, stocking, taking inventory, preparing for administration, and disposal.

OSHA: • Protective equipment, including PPE for eyes, face, head, and extremities, protective clothing, respiratory devices, and protective shields and barriers shall be provided, used, and maintained in a sanitary and reliable condition wherever it is necessary by reason of hazards of processes or environment, chemical hazards, radiological hazards, or mechanical irritants encountered in a manner capable of causing injury or impairment in the function of any part of the body through absorption, inhalation, or physical contact.

Receiving and storage

• Wear chemotherapy gloves, protective clothing, and eye protection when opening containers to unpack HDs.

• Gloves must be worn at all times when drug packaging, cartons, and vials are handled, including during the performance of inventory control procedures and the gathering of HDs.

Compounding

• Wear PPE (including double gloves and protective gowns) while reconstituting and admixing drugs. • Make sure that gloves are labeled as chemotherapy gloves. • Use disposable gowns made of polyethylene-coated polypropylene material (which is nonlinting and nonabsorbent).

• Select disposable gowns of material tested to be protective against the HDs to be used. • Coated gowns must not be worn for longer than 3 hours during compounding and must be changed immediately when damaged or contaminated. • Gowns worn as barrier protection in the compounding of HDs must never be worn outside the immediate preparation area.

• Wear PPE (including double gloves, goggles, and protective gowns) for all activities associated with drug administration.

• Gowns worn during administration should be changed when the patient care area is left and immediately if contaminated.

Administration

Sterile compounding: • Shoe covers, head and facial hair covers (eg, beard covers in addition to face masks), and face masks; a nonshedding gown that has sleeves that fit snugly around the wrists and is enclosed at the neck; sterile powder-free gloves. Hazardous drug compounding: • Appropriate PPE shall be worn during compounding in a BSC or CACI and during the use of CSTDs. PPE should include gowns, face masks, eye protection, hair covers, shoe covers or dedicated shoes, double gloving with sterile chemotherapy-type gloves, and compliance with manufacturers’ recommendations when a CACI is used.

ASHP, American Society of Health-System Pharmacists; BSC, biological safety cabinet; CACI, compounding aseptic containment isolator; CSTD, closed-system drug-transfer device; HD, hazardous drugs; NIOSH, National Institute for Occupational Safety and Health; OSHA, Occupational Safety and Health Administration; PEC, primary engineering control; PPE, personal protective equipment; USP, United States Pharmacopeia Based on references 4, 28, 30, and 34.

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ENVIRONMENTAL

AND

ENGINEERING CONTROLS

The 2008 revision to USP Chapter <797> contains extensive mandates to improve the environment in which sterile doses of HDs are compounded. These directives are designed to increase safety for patients by reducing the potential for the microbial contamination of sterile dosage forms, and to improve worker safety by addressing design concerns in traditional, positive-pressure compounding environments. Table 2 compares the NIOSH, ASHP, and USP Chapter <797> recommendations for the environment in which HDs are compounded.4,30,34 HDs must be stored separately from other inventory in a manner to prevent contamination and exposure of personnel. Because of the concerns of volatilization at room temperature, storage is preferably within a containment area such as a negative-pressure room with sufficient exhaust ventilation and at least 12 air changes per hour (ACPH) to dilute and remove airborne contaminants. An International Organization for Standardization (ISO) Class 5 PEC is required for HD compounding to prevent microbial contamination of sterile preparations and to protect workers and the environment by preventing the escape of HD aerosols or residue. Appropriate PECs for compounding sterile HD preparations include Class II biological safety cabinets (BSCs) and compounding aseptic containment isolators (CACIs) that meet or exceed the standards set forth in USP Chapter <797>. Isolators are recommended as a PEC in both the NIOSH Alert and the ASHP HD guidelines. The USP Chapter <797> revision sets performance standards for isolators used to compound sterile preparations, for compounding aseptic isolators (CAIs), and for isolators used to compound sterile HD preparations (CACIs). To meet the criteria of USP Chapter <797>, an isolator must provide isolation from the room and maintain ISO Class 5 air quality within the cabinet during dynamic operating conditions. CAI and CACI air quality must be documented by particle counts during compounding operations and during transfer of material in and out of the isolator. Recovery time to ISO Class 5 air in the main chamber must be documented after material is transferred into and out of the main chamber. Work practices must be developed to reduce disruption of the air quality in the isolator and to minimize recovery time. A CACI meeting all these conditions, as detailed in USP Chapter <797>, is exempt from the requirement that it be placed in an ISO Class 7 buffer area. For HD

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compounding, however, the compounding area must maintain negative pressure and have a minimum of 12 ACPH. A Class II BSC has an open front and depends on an air barrier to prevent HD contamination from escaping the cabinet.53 This air barrier can be compromised by worker technique, allowing escape of the contaminated air.54 The design of this type of cabinet is questionable for product protection because the air barrier is composed of air coming from the buffer area around the BSC. As air is pulled into the BSC, poor air quality in the buffer area may compromise the ISO Class 5 compounding environment within the Class II BSC. A Class II BSC or CACI that does not meet the conditions listed in USP Chapter <797> must be placed in an area that is physically separated from other compounding areas and have air quality of ISO Class 7. Optimally, this area should be at negative pressure relative to adjacent positive-pressure ISO Class 7 or better ante-areas, thus providing inward airflow to contain airborne drug. It also is optimal for a PEC used for compounding sterile HD preparations to be vented to the outside air through high-efficiency particulate air (HEPA) filtration. All environments in which sterile preparations are compounded must be provided with HEPA-filtered air from outside the environment. The PEC may not be the sole source of HEPA-filtered air and it may not provide more than 50% of the ACPH in that environment. The ISO Class 7 buffer area and the ante-area must be supplied with HEPA-filtered air providing at least 30 ACPH. The NIOSH, ASHP, and USP Chapter <797> recommendations for HD PECs are compared in Table 3.4,30,34

WORK PRACTICE CONTROLS Work practices must be designed to minimize the generation of HD contamination and maximize the containment of inadvertent contamination that occurs during routine handling or in the event of a spill. The compounding techniques described by Wilson and Solimando continue to be the standard for any procedure in which needles and syringes are used to manipulate sterile dosage forms of HDs.55 These techniques, when performed accurately, minimize the escape of drugs from vials and ampules. Many adjunct devices have been developed to reduce the generation of contamination during the compounding process. Vented needles with 0.2-micron hydrophobic filters were designed to reduce the powder and liquid drug residues that escape from vials through standard vented needles. Dispensing pins with small spikes and hydrophobic filters were introduced

to make the compounding process more efficient. One study documented the effectiveness of one of these devices, but the investigators used only visual inspection because no sensitive drug assays were available at the time of the study.56 Since then, sensitive, drug-specific assays have been developed that provide a means to validate work practice controls at different work sites. The persistent presence of contamination in hospitals and pharmacies generated interest in adjunct devices, generically named in the 2004 NIOSH Alert as “closed-system drug-transfer devices” (CSTDs). NIOSH defines a CSTD as a device that mechanically prevents the transfer of environmental contaminants into the system and the escape of hazardous concentrations of drug or vapor from the system.4 USP Chapter <797> similarly defines CSTDs as “vial transfer systems that allow no venting or exposure of hazardous substance to the environment.” USP Chapter <797> further states that CSTDs must be used within the ISO Class 5 environment of a BSC or a CACI. These devices provide some of the benefits of the earlier devices, but with the added protection that they can be locked into place on the drug vial. CSTD components also provide protection during the administration of IV push and IV infusion doses that previously had not been available. Numerous studies using markers for HDs have demonstrated the effectiveness of CSTDs in reducing HD contamination in the workplace.19-21 At clinical practice sites representing inpatient and outpatient compounding and administration, the implementation of a CSTD reduced surface contamination significantly compared with standard practice.19-21,57 In facilities that prepare a low volume of HDs, the use of 2 tiers of containment (eg, a CSTD within a BSC or a CACI that is located in a non–negative-pressure room) is acceptable. The NIOSH Alert specifies that CSTDs should be used only within a ventilated cabinet. Neither USP Chapter <797> nor NIOSH has developed performance standards for any device marketed as a CSTD. Because the configurations of available CSTDs vary from that of the tested device, it is unclear how effective these devices are in reducing environmental contamination resulting from the compounding and administration of HDs. Any device marketed as a CSTD should be clinically tested.

PERSONAL PROTECTIVE EQUIPMENT In addition to environmental and engineering controls, PPE is required to provide a barrier between the health care worker and HDs during episodes of potential contact. A recent Canadian study examined dermal

contamination of workers compounding and checking HDs and having contact with surfaces in HD work areas. Workers’ hands were wiped with a premoistened tissue and the tissues then were analyzed for marker drugs. Of 18 wipes tested, 28% had measurable levels of cyclophosphamide and methotrexate.58 Although the sample was small, this study supports the need for workers to wear gloves whenever they handle HDs or are in an area where HDs are handled. PPE is especially important during administration, spill control, handling of drug waste, and handling of patient waste because no PECs are in place for these activities. All PPE should be selected for effectiveness. Glove and gown materials should be capable of withstanding permeation by a variety of HDs.59-61 Several HDs require nonaqueous diluents for patient use and may permeate PPE more readily than others. ASHP and NIOSH recommend coated gowns for use with HDs.4,30 This recommendation was recently emphasized in an Institute for Safe Medication Practices (ISMP) Safety Brief that reported on a “chemo” gown being used for preparing a dose of iron dextran injection.62 The drug was sprayed onto the gown and penetrated it. A follow-up report noted that the FDA considers gowns to be medical devices.63 Companies that do not claim a gown has been tested for use with HDs and who do not describe it as a surgical gown are exempt from the requirement for 510(k) submission. It is important that, in the absence of a standard, PPE be selected according to the criteria developed by ASHP and NIOSH based on several peer-reviewed studies.60,61 The American Society for Testing and Materials (ASTM) has developed a standard for testing chemotherapy gloves (D 6978-05) that is specific to a battery of chemotherapy drugs and duration of exposure.64 There is no such standard for gowns or gowning materials to be tested for permeation by sample chemotherapy or other HDs. ASTM F739-07 is a test method for permeation by liquids and gases through protective clothing materials under conditions of continuous contact.65 This ASTM standard neither specifies drugs or concentrations to be tested nor has a performance standard for an acceptable resistance to permeation. Using provisions of both ASTM standards may be an appropriate testing method but that has not been determined. A comparison of PPE recommendations is presented in Table 4.4,28,30,34 During sterile compounding, barrier garments must be worn to prevent the shedding of human skin and hair cells and the deposition of mucus or respiratory residue into the compounding area. USP Chapter <797> specifies that compounding garb must include the following: dedicated shoes or shoe covers, face masks, head and

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facial hair covers (eg, beard covers in addition to face masks), a non-shedding gown that has sleeves that fit snugly around the wrists and is enclosed at the neck, and sterile powder-free gloves. Appropriate PPE still must be worn when the sterile compounding of HDs is performed in a BSC or a CACI and when CSTDs are used. PPE includes coated gowns, masks or respirators, eye protection, hair covers, shoe covers, and double gloving with sterile HDtested gloves.

New Technologies Technological advances include robotic devices that can compound sterile doses of HDs. Replacing the human compounder, robots reduce the occupational exposure of health care workers by using techniques to reduce the generation of HD residues during compounding. Robots also provide a degree of accuracy and patient safety not achievable with manual compounding. CytoCare from Health Robotics, Apoteca Chemo from Loccioni Humancare, and RIVA (Robotic IV Automation) from Intelligent Hospital Systems provide robotic solutions to the compounding of sterile preparations of HDs. Potential robot users must assess performance of each of the robots in their ability to produce sterile products, avoid cross-contamination from one drug dose to another, and reduce HD residue contamination during the compounding process and on final doses. A recent report on bacterial contamination in an IV compounding robot produced concern that robots had hidden problems.66 The robot involved is not designed for HD compounding, but the use of common tubing or needles that require cleaning has become an issue to monitor. A stringent quality assurance program to document ongoing performance must accompany the robots. The bacterial contamination that was reported was detected during routine media fills of tryptic soy broth and not in patient doses. Inadequate cleaning processes were discovered and remediated. There are limited published studies by robot users, but this should increase as the technology evolves.67 The robots require human staff to load and clean them. HD contamination may be generated in the compounding environment and transferred to the final product. Cleaning of the compounding environments requires both disinfection and decontamination of HD residues. No particular cleaner has been shown to effectively deactivate all known HDs,13 so routine cleaning and spill control continue to be challenges to the health care personnel working with robots. The robots help only with the compounding process, leaving the workers administering HDs without protection. Spill control and waste handling also remain issues for human workers to address.

working with OSHA and the Joint Commission to promote employer and employee awareness of safety. USP Chapter <797> has elevated many of the NIOSH recommendations to a standard, ensuring compliance with at least the compounding segment of safety program controls. USP also plans a separate chapter on HD compounding to further emphasize the issue. Washington State has promulgated an HD rule that will take effect in 2014, providing the first regulation of its kind in the United States. New generations of health care workers need to be educated about the risks of handling HDs and the importance of training in the proper techniques to reduce their exposure. Health care workers must promote continued vigilance about this important safety issue. In a discussion on the fragmented concept of safety, health care administration expert Gerald Goodman notes: Change requires a focus on safety, not occupational safety or patient safety, but just safety.68

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2. National Institute for Occupational Safety and Health. NIOSH Update. Work precautions for handling hazardous drugs highlighted by NIOSH, OSHA, Joint Commission. http://www.cdc.gov/niosh/ updates/upd-04-08-11.html. Accessed August 29, 2013. 3. Occupational Safety and Health Administration. Work precautions for handling hazardous drugs highlighted by NIOSH, OSHA, Joint Commission. http://www.osha.gov/pls/oshaweb/owadisp.show_ document?p_table=NEWS_RELEASES&p_id=19566. Accessed August 29, 2013. 4. National Institute for Occupational Safety and Health. Preventing occupational exposure to antineoplastic and other hazardous drugs in health care settings. DHHS (NIOSH) Publication No. 2004-165. http://www.cdc.gov/niosh/docs/2004-165/. Accessed August 29, 2013. 5. Connor TH, DeBord DG, Pretty JR, et al. Evaluation of antineoplastic drug exposure of health care workers at three university-based US cancer centers. J Occup Environ Med. 2010;52(10):1019-1027. 6. Connor TH, Anderson RW, Sessink PJ, Broadfield L, Power LA. Surface contamination with antineoplastic agents in six cancer treatment centers in Canada and the United States. Am J Health Syst Pharm. 1999;56(14):1427-1432. 7. McDiarmid MA, Oliver MS, Roth TS, Rogers B, Escalante C. Chromosome 5 and 7 abnormalities in oncology personnel handling anticancer drugs. J Occup Environ Med. 2010;52(10):1028-1034. 8. Lawson CC, Rocheleau CM, Whelan EA, et al. Occupational exposures among nurses and risk of spontaneous abortions. Am J Obstet Gynecol. 2012;206(4):327.e1-e8. 9. Dranitsaris G, Johnston M, Poirier S, et al. Are health care providers who work with cancer drugs at an increased risk for toxic events? A systematic review and meta-analysis of the literature. J Oncol Pharm Pract. 2005;11(2):69-78. 10. Baker ES, Connor TH. Monitoring occupational exposure to cancer chemotherapy drugs. Am J Health Syst Pharm. 1996;53(22):2713-2723.

Conclusion

11. Sessink PJ, Bos RP. Drugs hazardous to healthcare workers. Evaluation of methods for monitoring occupational exposure to cytostatic drugs. Drug Saf. f 1999;20(4):347-359.

Despite continuing reports of workplace and worker contamination, progress has been made. NIOSH is

12. Martin S. The adverse health effect of occupational exposure to hazardous drugs. Community Oncol. 2005;2(5):397-400.

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13. Sessink PJ, Boer KA, Scheefhals AP, Anzion RB, Bos RP. Occupational exposure to antineoplastic agents at several departments in a hospital. Environmental contamination and excretion of cyclophosphamide and ifosfamide in urine of exposed workers. Int Arch Occup Environ Health. 1992;64(2):105-112. 14. Sessink PJ, Van de Kerkhof MCA, Anzion RB, Noordhoek J, Bos RP. Environmental contamination and assessment of exposure to antineoplastic agents by determination of cyclophosphamide in urine of exposed pharmacy technicians: is skin absorption an important exposure route? Arch Environ Health. 1994;49(3):165-169. 15. Ensslin AS, Huber R, Pethran A, et al. Biological monitoring of hospital pharmacy personnel occupationally exposed to cytostatic drugs: urinary excretion and cytogenetics studies. Int Arch Occup Environ Health. 1997;70(3):205-208. 16. Nygren O, Lundgren C. Determination of platinum in workroom air and in blood and urine from nursing staff attending patients receiving cisplatin chemotherapy. Int Arch Occup Environ Health. 1997;70(3):209-214. 17. Pethran A, Schierl R, Hauff K, Grimm CH, Boos KS, Nowak D. Uptake of antineoplastic agents in pharmacy and hospital personnel. Part I: monitoring of urinary concentrations. Int Arch Occup Environ Health. 2003;76(1):5-10. 18. Vandenbroucke J, Robays H. How to protect environment and employees against cytotoxic agents, the UZ Ghent experience. J Oncol Pharm Pract. 2001;6(4):146-152. 19. Wick C, Slawson MH, Jorgenson JA, Tyler LS. Using a closedsystem protective device to reduce personnel exposure to antineoplastic agents. Am J Health Syst Pharm. 2003;60(22): 2314-2320.

30. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health Syst Pharm. 2006;63(12):1172-1191. 31. Brown KA, Esper P, Kelleher LO, O’Neil JEB, Polovich M, White JM, eds. Chemotherapy and Biotherapy Guidelines and Recommendations for Practice. Pittsburgh, PA: Oncology Nursing Society; 2001. 32. Polovich M, White JM, Kelleher LO, eds. Chemotherapy and Biotherapy Guidelines and Recommendations for Practice. 2nd ed. Pittsburgh, PA: Oncology Nursing Press; 2005. 33. Polovich M, Whitford JM, Olsen M, eds. Chemotherapy and Biotherapy Guidelines and Recommendations for Practice. 3rd ed. Pittsburgh, PA: Oncology Nursing Press; 2009. 34. US Pharmacopeial Convention. Chapter <797> Pharmaceutical compounding—sterile preparations. In: The United States Pharmacopeia, 35th rev, and The National Formulary, 30th ed. Rockville, MD: US Pharmacopeial Convention; 2011. 35. US Pharmacopeial Convention. Compendial Deferrals for USP36– NF31. http://www.usp.org/sites/default/files/usp_pdf/EN/USPNF/ compendial_deferrals_usp36-nf31.pdf. Accessed August 29, 2013. 36. Schnatz RG, Sun JH. USP practitioner related standards. http:// www.nabp.net/meetings/assets/USPNABPBreakfast.pdf. Accessed Accessed August 29, 2013. 37. Washington State Department of Labor & Industries. Hazardous drugs. http://www.lni.wa.gov/Safety/Topics/AtoZ/HazardousDrugs/. Accessed August 29, 2013. 38. Polovich M, Clark PC. Factors influencing oncology nurses’ use of hazardous drug safe handling precautions. Oncol Nurs Forum. 2012;39(3):E299-E309.

20. Dorr RT, Alberts DS. Topical absorption and inactivation of cytotoxic anticancer agents in vitro. Cancer. 1992;70(4 suppl):983-987.

39. Martin S, Larson E. Chemotherapy-handling practices of outpatient and office-based oncology nurses. Oncol Nurs Forum. 2003;30(4):575-581.

21. Harrison BR, Peters BG, Bing MR. Comparison of surface contamination with cyclophosphamide and fluorouracil using a closed-system drug transfer device versus standard preparation techniques. Am J Health Syst Pharm. 2006;63(18):1736-1744.

40. Nieweg R, de Boer M, Dubbleman R, et al. Safe handling of antineoplastic drugs. Results of a survey. Cancer Nurs. 1994;17(6):501-511.

22. Connor TH, Sessink PJ, Harrison BR, et al. Surface contamination of chemotherapy drug vials and evaluation of new vial-cleaning techniques: results of three studies. Am J Health Syst Pharm. 2005;62(5):475-484. 23. Schierl R, Herwig A, Pfaller A, Groebmair S, Fischer E. Surface contamination of antineoplastic drug vials: comparison of unprotected and protected vials. Am J Health-Syst Pharm. 2010;67(6):428-429. 24. Connor TH, Shults M, Fraser MP. Determination of the vaporization of solutions of mutagenic antineoplastic agents at 23 and 37 degrees C using a desiccator technique. Mutat Res. 2000;470(1):85-92. 25. Opiolka S, Schmidt KG, Kiffmeyer TK, Schoppe G. Determination of vapor pressure of cytotoxic drugs and its effects on occupational safety. J Oncol Pharm Pract. 2000;6:15. Abstract.

41. Valanis B, McNeil V, Driscoll K. Staff members’ compliance with their facility’s antineoplastic drug handling policy. Oncol Nurs Forum. 1991;18(3):571-576. 42. Valanis B, Vollmer WM, Labuhn K, Glass A, Corelle C. Antineoplastic drug handling protection after OSHA guidelines. Comparison by profession, handling activity, and work site. J Occup Med. 1992;34(2):149-155. 43. Gambrell J, Moore S. Assessing workplace compliance with handling of antineoplastic agents. Clin J Oncol Nurs. 2006; 10(4):473-477. 44. National Institute for Occupational Safety and Health. Hazardous drug exposures in health care. Workplace Safety and Health Topics. http://www.cdc.gov/niosh/topics/hazdrug. Accessed August 29, 2013.

26. Kiffmeyer TK, Kube C, Opiolka S, et al. Vapour pressures, evaporation behaviour and airborne concentrations of hazardous drugs: implications for occupational safety. Pharm J. 2002;268:331-337.

45. National Institute for Occupational Safety and Health. Occupational exposure to antineoplastic products. http://www.cdc.gov/niosh/ topics/antineoplastic/. Workplace Safety and Health Topics. Accessed August 29, 2013.

27. Occupational Safety and Health Administration. Controlling occupational exposure to hazardous drugs. OSHA Technical Manual (OSHA Instruction CPL 2-2.20B CH-4). Washington, DC: Directorate of Technical Support, Occupational Safety and Health Administration; 1995: Chap 21.

46. Occupational Safety and Health Administration. Hazard Communication. FR 59:6126-6184. http://www.osha.gov/pls/oshaweb/ owadisp.show_document?p_table=federal_register&p_id=13349. Accessed August 29, 2013.

28. Occupational Safety and Health Administration. Controlling occupational exposure to hazardous drugs. OSHA Technical Manual (TED 01-00-015 [TED 1-0.15A] Sec VI Chap 2); 1999. http://www. osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html. Accessed August 29, 2013. 29. American Society of Hospital Pharmacists. ASHP technical assistance bulletin on handling cytotoxic and hazardous drugs. Am J Hosp Pharm. 1990;47(5):1033-1049.

47. Occupational Safety and Health Administration. Hazard Communication Standard 1910.1200. http://www.osha.gov/pls/oshaweb/ owadisp.show_document?p_table=STANDARDS&p_id=10099. Accessed August 29, 2013. 48. Occupational Safety and Health Administration. Hazard Communication Standard 1910.1200. Appendix A to §1910.1200—health hazard criteria (mandatory). http://www.osha.gov/pls/oshaweb/ owadisp.show_document?p_table=STANDARDS&p_id=10100. Accessed August 29, 2013.

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49. National Institute for Occupational Safety and Health. NIOSH list of antineoplastic and other hazardous drugs in healthcare settings 2012: proposed additions and deletions to the NIOSH hazardous drug list. Fed Regist.2011;76(148). http://www.cdc.gov/niosh/docket/archive/pdfs/NIOSH-190/0190-080211-frn.pdf. Accessed August 29, 2013.

59. Connor TH. Permeability of nitrile rubber, latex, polyurethane, and neoprene gloves to 18 antineoplastic drugs. Am J Health Syst Pharm. 1999;56(23):2450-2453.

50. National Institute for Occupational Safety and Health. NIOSH list of antineoplastic and other hazardous drugs in healthcare settings 2012. DHHS (NIOSH) Publication Number 2012-150. http://www. cdc.gov/niosh/docs/2012-150/. Accessed August 29, 2013.

61. Connor TH. An evaluation of the permeability of disposable polypropylene-based protective gowns to a battery of cancer chemotherapy drugs. Appl Occup Environ Hyg. 1993;8:785-789.

51. US Department of Labor. 1998. Informational booklet on industrial hygiene. OSHA 3143 (revised). http://www.osha.gov/Publications/ OSHA3143/OSHA3143.htm. Accessed August 29, 2013. 52. National Institute for Occupational Safety and Health. Medical surveillance for healthcare workers exposed to hazardous drugs. NIOSH Publication No. 2007-117. http://www.cdc.gov/niosh/docs/ wp-solutions/2007-117/. Accessed August 29, 2013. 53. NSF International. NSF/ANSI 49-2007: NSF 49 Class II (Laminar Flow) Biosafety Cabinetry. Ann Arbor, MI: NSF International; 2007. 54. Clark RP, Goff MR. The potassium iodide method for determining protection factors in open-fronted microbiological safety cabinets. J Appl Bacteriol. 1981;51(3):439-460. 55. Wilson JP, Solimando DA Jr. Aseptic technique as a safety precaution in the preparation of antineoplastic agents. Hosp Pharm. 1981;16(11):575-576, 579-581.

60. Harrison BR, Kloos MD. Penetration and splash protection of six disposable gown materials against fifteen antineoplastic drugs. J Oncol Pharm Pract. 1999;5(2):61-66.

62. Institute for Safe Medication Practices (ISMP). Safety Brief: Caution! ChemoPlus gown may not afford worker protection. ISMP Medical Safety Alert!: June 14, 2012. http://www.ismp.org/newsletters/ acutecare/issue.asp?dt=20120614. Accessed August 29, 2013. 63. Thompson C. With protective gowns, look beyond brand name. Am J Health Syst Pharm. 2012;69(15):1270-1272. 64. American Society for Testing and Materials. D 6978-05 standard practice for assessment of resistance of medical gloves to permeation by chemotherapy drugs. West Conshohocken, PA: American Society for Testing and Materials; 2005. 65. American Society for Testing and Materials. ASTM F739 - 12 standard test method for permeation of liquids and gases through protective clothing materials under conditions of continuous contact. West Conshohocken, PA: American Society for Testing and Materials; 2007. http://www.astm.org/Standards/F739.htm. Accessed August 29, 2013.

56. Hoy RH, Stump LM. Effect of an air venting filter device on aerosol production from vials. Am J Health Syst Pharm. 1984;41(2):324-326.

66. Cluck D, Williamson JC, Glasgo M, Diekema D, Sherertz R. Bacterial contamination of an automated pharmacy robot used for intravenous medication preparation. Infect Control Hosp Epidemiol. 2012;33(5):517-520.

57. Sessink PJ, Connor TH, Jorgenson JA, Tyler TG. Reduction in surface contamination with antineoplastic drugs in 22 hospital pharmacies in the US following implementation of a closed-system drug transfer device. J Oncol Pharm Pract. 2011;17(1):39-48.

67. Cotugno MC. Automating chemotherapy preparation with robotic technology. Pharmacy Purchasing & Products. 2010. http://www. pppmag.com/article/793/November_2010/Automating_Chemotherapy_Preparation_with_Robotic_Technology/?Automating%20 Chemotherapy. Accessed August 29, 2013.

58. Hon CY, Astrakianakis G, Danyluk Q, Chu W. Pilot evaluation of dermal contamination by antineoplastic drugs among hospital pharmacy personnel. Can J Hosp Pharm. 2011;64(5):327-332.

68. Goodman GR. A fragmented patient safety concept: the structure and culture of safety management in health care. Nurs Econ. 2004;22(1):44-46.

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High-, Moderate-, and Low-Penetrance Genes Involved in the

Pathogenesis of a Hereditary Predisposition to Breast Cancer LARISSA A. KORDE, MD, MPH Director Prevention Center Shared Resource Assistant Professor Department of Medicine, Division of Oncology

STACEY A. SHIOVITZ, MD Hematology-Oncology Fellow Fred Hutchinson Cancer Research Center University of Wash hington Seattle, Washingto on

reast cancer is the most common malignancy in women in the United States

and the second leading cause of cancer-related death. The American Cancer

Society estimates that in 2013, there will be approximately 232,000 new

cases of breast cancer (of which 2,000 will be in males) and 40,000 related deaths.1

A family history of breast or ovarian cancer, bilateral breast cancer, and early age of onset suggest a hereditary predisposition. However, a predisposing gene is identified in less than 30% of cases with suggestive features.2 The vast majority of these cases are due to highly penetrant, but rare, genes. In recent years, additional rare, moderate-penetrance genes and

common, low-penetrance alleles also have been identified. Despite this, in many cases of suspected familial breast cancer, no predisposing gene is identified. This review will discuss the known genetic causes of breast cancer and the issues associated with characterizing and understanding hereditary predispositions to breast cancer.

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P H A R M AC Y P R AC T I C E N E WS S P E C I A L E D I T I O N â&#x20AC;˘ 2 0 1 3

Table 1. Breast Cancer High-Penetrance Genes and Their Associated Syndromes Breast Cancer Incidence

Gene

Syndrome

Other Associated Cancers

BRCA1 BRCA2

Hereditary breastovarian cancer syndromea

82% lifetime risk

Ovarian and fallopian tube cancer, prostate cancer, pancreas and biliary cancer, melanoma

PTEN

PTEN hamartoma tumor syndrome, Cowden syndrome

85% lifetime risk

Non-medullary thyroid cancer, endometrial cancer, GU tumors, especially renal cell carcinoma

TP53

Li-Fraumeni syndrome

25% by age 74

Sarcoma, brain tumor, adrenocortical carcinoma, leukemia, bronchoalveolar cancer; multiple other cancers are seen but more rarely

CDH1

Hereditary diffuse gastric cancer

39% lifetime risk for lobular breast cancer

Gastric cancer (diffuse subtype), colorectal cancer

STK11

Peutz-Jeghers syndrome

32% by age 60

GI cancers (esophagus, stomach, small bowel, colon), pancreatic cancer, sex-cord stromal tumors

Non-malignant Syndrome Features

Pathognomonic skin changes, macrocephaly, benign breast and thyroid disease, uterine fibroids, Lhermitte-Duclos disease, fibromas, lipomas, intestinal hamartomas, mental retardation

GI hamartomatous polyposis, hyperpigmented macules, hyperestrogenism

GI, gastrointestinal; GU, genitourinary a

There are additional patients with this clinical phenotype, but they do not have an identified mutation in either BRCA11 or BRCA2.

High-Penetrance Genes The first major gene associated with hereditary breast cancer was BRCA1, which was identified in 1990 via linkage analysis of families with suggestive pedigrees.3 In 1994, BRCA2 was mapped to chromosome 13.4 A mutation in either BRCA11 or BRCA2 confers an increased risk for breast and other cancers. Clinically, this is referred to as the hereditary breast-ovarian cancer (HBOC) syndrome, although there are patients with this same clinical picture who are found to be negative for mutations in both BRCA1 and BRCA2. Research into HBOC has focused on determining the associated risk for breast and other cancers, identifying specific clinical and histopathologic features, and developing therapeutic and prevention strategies. Tumors due to mutations in BRCA11 tend to be of the basal-like phenotype, with a higher histologic grade; they commonly are the so-called “triple-negative” tumor—negative for the estrogen receptor (ER), progesterone receptor (PR), and HER2/neu.5 BRCA2-related tumors more closely resemble sporadic tumors.6 BRCA1 and BRCA2 mutations are inherited in an autosomal dominant fashion but act recessively on the

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cellular level as tumor-suppressor genes involved in double-stranded DNA (dsDNA) break repair.2 Female carriers of mutations in BRCA1 or BRCA2 have a lifetime risk for breast cancer of 50% to 85%, which is greater than 10 times the average population risk.7 Male carriers of BRCA1 have an increased risk for breast cancer, although to a lesser degree than carriers of BRCA2, who have a 7% lifetime risk.8 Additional features of the syndromes are detailed in Table 1, most notably an increased risk for ovarian cancer, with an estimated lifetime risk of 54% for BRCA1 carriers and 23% for BRCA2 carriers.7,9,10 Bi-allelic BRCA2 greatly increases the risk for childhood cancers with the clinical picture of Fanconi anemia type D. There is no corresponding effect noted for BRCA1, and, thus, it is thought to be embryonically lethal.2 Mutations in BRCA1 and BRCA2 are estimated to explain only 15% of familial breast cancers.2,11 There are subpopulations with higher cancer frequencies due to founder mutations, most prominently the Ashkenazi Jewish population, in which 3 major mutations (BRCA1 185delAG, BRCA1 5382insC, and BRCA2 6174delT) alone account for approximately 10% of hereditary

cases.7 With sequencing and haplotype analysis, additional population subgroups also have demonstrated founder mutations.12 Additional rare but highly penetrant genes include PTEN,13,14 TP53,15-17 CDH1,18 and STK11,19,20 each connoting a distinct clinical syndrome, as described in Table 1. Collectively with BRCA1 and BRCA2, it is estimated that the known high-penetrance genes account for no more than 25% of cases based on prior studies and mathematical modeling.11,21 It is crucial to recognize individuals with a hereditary cancer syndrome because this greatly affects their clinical management. The National Comprehensive Cancer Network guidelines recommend that women with mutations in BRCA1, BRCA2, or one of the other high-penetrance genes should perform monthly breast self-examinations starting at age 18.22 From age 25 (or 10 years before the youngest case in the family, whichever is earlier), clinical breast exam, mammogram, and breast magnetic resonance imaging (MRI) should be performed annually. Prophylactic salpingo-oophorectomy is recommended for women with mutations in BRCA1/2 by age 35 to 40, or earlier if childbearing is complete or there is indication based on the family history.23 This reduces the risk for ovarian cancer (although there is a residual risk for primary peritoneal cancer), and reduces breast cancer risk if it is performed before menopause.23,24 Prophylactic mastectomy, with discussion of a nipple-sparing approach, also may be considered due to the high lifetime risk for both primary and contralateral breast cancers.25,26 Tamoxifen has been shown to reduce the risk for ER-positive breast cancer in women with increased risk based on the Gail model, but it has not been well studied in BRCA mutation carriers. Biologic characteristics and limited clinical data suggest that tamoxifen may reduce the risk for breast cancer in women with a BRCA2 mutation who have not undergone prophylactic oophorectomy before menopause.27-29 As for sporadic tumors, medical treatment of hereditary breast cancer historically has been dictated by histology, immunohistochemistry, and stage. Early clinical data suggest that BRCA-associated tumors are exquisitely sensitive to poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors, agents that inhibit the DNA damage-repair mechanism PARP, but these currently are only available in the setting of clinical trials.30

Moderate-Penetrance Genes Linkage studies have failed to demonstrate additional reproducible loci for highly penetrant genes that predispose individuals to breast cancer,11 prompting new directions for efforts to elucidate hereditary causes for this disease. Specifically, genes proposed to increase the risk for breast cancer based on their known cellular functions have been screened for mutations in families with pedigrees suggestive of a predisposition to breast cancer. Positive studies have found CHEK2,31 BRIP1 (BACH1),32 ATM,33 and PALB234 to be

associated with breast cancer; each confers about a 2-fold increase in risk for breast cancer. As described in Table 2, these genes play a role in DNA repair, interacting with either BRCA1 or BRCA2. CHEK2 *1100delC, the most common mutation, is seen in 1% of the population overall but in higher numbers in breast cancer patients.31 There is no additional increase in risk for cocarriers of a mutation in BRCA1 or BRCA2 with CHEK2, possibly due to an overlapping effect on DNA repair.31 Additional genes involved in DNA damage repair, C and genes in the MRN DNA repair including RAD51C pathway (MRE11, RAD50, NBN [NBS1]) also have been investigated. However, when high-risk families were screened, no mutations were clearly associated with cancer.35-37 It still is possible that somatic mutations within tumors, or founder effects in unique populations, are present and contribute to cancer development and progression.36,38,39 Studies performed in the United Kingdom in BRCA mutationâ&#x20AC;&#x201C;negative women with a personal or family history have estimated that these moderate-penetrance genes account for 2.3% of familial breast cancer cases. Some of these studies are underpowered to comment on an earlier age of onset or other associated syndrome features.2 Because these genes confer a lower lifetime risk for breast cancer than the highly penetrant genes described earlier, clinical management, including screening and preventive interventions, of women with mutations in moderate-penetrance genes is less clearly defined. Clinical management should incorporate risk assessment tools, such as the Gail and Tyrer-Cuzick models,40 which emphasize a womanâ&#x20AC;&#x2122;s personal and family history of cancer and precancerous lesions, along with established breast cancer risk factors, to determine risk. For women with a calculated lifetime risk for breast cancer of at least 20% by virtue of a family history, annual breast MRI is recommended in addition to standard mammography.41,42 Additionally, all women with a higher than average risk for breast cancer should have a clinical breast examination performed every 6 months.

Low-Penetrance Alleles As laboratory techniques and sequencing capabilities have advanced, genome-wide studies have been performed to identify single-nucleotide polymorphisms (SNPs) that may contribute to breast cancer risk in a polygenic fashion. These studies require thousands of cases and controls to have sufficient power to appreciate a change in risk because individual alleles may be relatively common and even found in a majority of the population.2 An extremely stringent P value (P<0.0001 or better) is required to minimize false-positives.11 A small number of polymorphisms associated with breast cancer risk have been noted in known breast cancerâ&#x20AC;&#x201C;associated genes. For example, a Pro919Ser polymorphism in BRIP1 is associated with an odds ratio of 1.39 (P=0.002) in premenopausal women but was not associated with an increased risk for breast

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Table 2. Breast Cancer Moderate-Penetrance Genes and Associated Breast Cancer Risks Gene

Gene Function

Breast Cancer Risk

Bi-allelic Phenotype

CHEK2

Protein kinase involved in cell cycle regulation at G2; rapidly phosphorylated in response to DNA damage; activated CHEK2 2 stabilizes p53 and interacts with BRCA1

Female: RR, 1.70; 95% CI, 1.3-2.2 Male: RR, 10.3; 95% CI, 3.5-30.0

None known –presumed to be embryonic lethal

BRIP1 (BACH1)

Interacts with the BRCA11 C-terminus (BRCT) domain of BRCA1

All women: RR, 2.0; 95% CI, 1.2-3.2 Women younger than 50 y: RR, 3.5; 95% CI, 1.9-5.7

Fanconi anemia, type J –no significant increase in childhood cancers

ATM

Protein kinase involved in monitoring RR, 2.37; 95% CI, 1.5-3.8 and repair of dsDNA and regulation of BRCA11 and CHEK2

Ataxia-telangiectasia –autosomal recessive inheritance

PALB2

Associates with BRCA2; involved in nuclear localization and stability

Fanconi anemia type N –higher incidence of childhood cancers

All women: RR, 2.3; 95% CI, 1.4-3.9 Women older than 50 y: RR, 3.0; 95% CI, 1.4-5.5

CI, confidence interval; RR, relative risk

cancer in the overall population.43 Often, low-penetrance SNPs are located in noncoding regions of the genome (eg, 2q35, 8q24), making it more difficult to identify an associated gene. The mutation mechanism may be activation of growth-promoting genes rather than inactivation of DNA repair. On average, each allele only mildly increases risk and is additive per allele rather than multiplicative, with a 1.07- to 1.26fold increase in risk for heterozygotes and a 1.65-fold increase for homozygotes.2 The majority of studies thus far have focused on one or a few variants at a time. However, a recent large meta-analysis assessed the examined variants to date, excluding those in highly penetrant genes.44 This analysis excluded the first report of a variant, as well as small studies (<500 samples) and studies involving groups not deemed to be in Harvey-Weinberg equilibrium. Strong associations were seen for 10 variants across 6 genes—ATM, CASP8 (cysteineaspartic acid protease family with a role in apoptosis), CHEK2, CTLA4 (encodes an inhibitory signal to T cells, affecting carcinogenesis via anti-tumor immunity), NBN, and TP53—and moderate associations were seen for 4 variants across 4 genes—ATM, CYP19A1, T and XRCC3. Odds ratios greater than 2 were TERT, seen for truncating mutations in ATM and NBN and for 3 rare variants in CHEK2. However, the remainder had a more minor calculated effect. Additional studies have not yet been published regarding the clinical application, frequency, or relative risk of these variants.44 Thus, evaluation for low-penetrance alleles is not part of standard clinical evaluation for breast cancer, and management of individuals found to carry

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these variants should be based on their estimated risk as calculated by validated risk assessment models, such as the Tyrer-Cuzick and Gail models.

Mutation Testing in Those With Suspected Hereditary Predisposition to Breast Cancer Individuals with a family and personal history suspicious for a familial syndrome should be referred to a genetic counselor for a comprehensive evaluation. Testing for mutations in cancer-associated genes is individually based, and requires a high index of suspicion for a particular gene based on the clinical situation. In general, when a family history is suggestive, it is best to test an individual with a cancer diagnosis because this increases the probability of a positive test result. Standard clinical BRCA1 and BRCA2 testing has been performed using polymerase chain reaction amplification and Sanger sequencing. For the Ashkenazi Jewish population, testing can be targeted to the 3 major founder mutations. In 2007, testing for large rearrangements was added for secondary analysis after research studies published the relatively frequent finding of missed large insertions and deletions.21,45 If a mutation is identified in one family member, targeted testing can be done for other members of the family to assess risk. With testing, possible outcomes are a true positive, a true negative (ie, an individual in a family with a known mutation tests negative for that mutation), uninformative (ie, a negative test in a family where a mutation has yet to be identified), or a variant of unknown significance (VUS). By definition, a VUS is a detected genetic change without a good description of any correlating clinical risk.

In patients who test negative for mutations in BRCA1 and BRCA2 but in whom the family history is suggestive of an inherited predisposition, there are emerging options for additional evaluation. For example, the BROCA assay, developed by researchers at the University of Washington, is a 21-gene assay that includes the 10 previously mentioned high- and moderate-penetrance genes, the panel of genes known to predispose to colon cancer, and promising low-penetrance genes. With next-generation sequencing, multiple genes can be tested for mutations at a fraction of the cost of sequencing genes individually,45 and this may be useful in detecting mutation changes not identified by conventional sequencing, such as large rearrangements.46 This is especially helpful in patients with a more rare cause for their hereditary predisposition to cancer or women with a less obvious history, including those with fewer female relatives, paternal inheritance of the gene, and few other relatives who have inherited the predisposing gene.45 However, with more detailed genetic analysis, an increased amount of indeterminate information often is obtained. Thus, next-generation sequencing testing will require careful analysis and interpretation of VUS. As costs for genomic assays have decreased, the number of commercially available assays billed as personal genomic testing (PGT) has increased substantially, but our ability to interpret the results of these assays remains limited. A major concern with this new avenue of medical risk assessment is that patients and physicians often feel underinformed regarding the interpretation of results. In a survey of more than 10,000 physicians, 98% felt that PGT results may influence drug therapy, but only 10% believed they were adequately informed about how to interpret the results.47 In a survey of individuals who elected PGT testing, 10% discussed their results with the company genetic counselor and only 27% chose to share results with their physician, increasing risk that the test would be associated with inadequate counseling and interpretation.48 Limited data suggest that in the appropriate clinical setting, PGT can be effective in modulating clinical behavior.47

Conclusion A hereditary predisposition to breast cancer significantly influences screening, treatment, and surveillance recommendations. However, despite decades of medical research, less than 30% of cases with a suggestive personal and/or family history of hereditary breast cancer have an identified causative gene mutation. The vast majority of these cases are due to a mutation in one of the highly penetrant breast cancer genes (BRCA1, BRCA2, PTEN, TP53, CDH1, and STK11), and current guidelines provide concrete direction for the management of these patients. A minority of cases are due to mutations in moderate-penetrance genes (CHEK2, ATM, BRIP1, and PALB2). A small number of low-penetrance alleles have been identified using advanced genetic

testing methods. Although these may contribute to risk in a polygenic fashion, this is likely to be relevant to a minority of cases, and identification of these low-penetrance alleles is not part of routine practice patterns. In such patients, standard models are used to predict an individualâ&#x20AC;&#x2122;s lifetime risk by clinical history rather than genomic information. At this point, mutation testing requires a high index of suspicion for a specific contributing etiology, but next-generation sequencing may improve the identification of such genes and the clinical management of breast cancer.

References 1.

National Cancer Institute. Breast cancer. http://www.cancer.gov/ cancertopics/types/breast. Accessed August 20, 2013.

2. Stratton MR, Rahman N. The emerging landscape of breast cancer susceptibility. Nat Genet. 2008;40(1):17-22. 3. Hall JM, Lee MK, Newman B, et al. Linkage of early-onset familial breast cancer to chromosome 17q21. Science. 1990;250(4988):1684-1689. 4. Wooster R, Neuhausen SL, Mangion J, et al. Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science. 1994;265(5181):2088-2090. 5. Rakha EA, Reis-Filho JS, Ellis IO. Basal-like breast cancer: a critical review. J Clin Oncol. 2008;26(15):2568-2581. 6. Lakhani SR, Van De Vijver MJ, Jacquemier J, et al. The pathology of familial breast cancer: predictive value of immunohistochemical markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and BRCA2. J Clin Oncol. 2002;20(9):2310-2318. 7.

King MC, Marks JH, Mandell JB, et al. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science. 2003;302(5645):643-646.

8. Liede A, Karlan BY, Narod SA. Cancer risks for male carriers of germline mutations in BRCA1 or BRCA2: a review of the literature. J Clin Oncol. 2004;22(4):735-742. 9. No authors listed. Cancer risks in BRCA2 mutation carriers. The Breast Cancer Linkage Consortium. J Natl Cancer Inst. 1999;91(15):1310-1316. 10. Thompson D, Easton DF. Breast cancer linkage C: cancer Incidence in BRCA1 mutation carriers. J Natl Cancer Inst. 2002;94(18):1358-1365. 11. Antoniou AC, Easton DF. Models of genetic susceptibility to breast cancer. Oncogene. 2006;25(43):5898-5905. 12. Kwong A, Ng EK, Law FB, et al. Novel BRCA1 and BRCA2 genomic rearrangements in Southern Chinese breast/ovarian cancer patients. Breast Cancer Res Treat. 2012;136(35):931-933. 13. FitzGerald MG, Marsh DJ, Wahrer D, et al. Germline mutations in PTEN are an infrequent cause of genetic predisposition to breast cancer. Oncogene. 1998;17(6):727-731. 14. Tan MH, Mester JL, Ngeow J, Rybicki LA, Orloff MS, Eng C. Lifetime cancer risks in individuals with germline PTEN mutations. Clin Cancer Res. 2012;18(2):400-407. 15. Garber JE, Goldstein AM, Kantor AF, Dreyfus MG, Fraumeni JR Jr, Li FP. Follow-up study of twenty-four families with Li-Fraumeni syndrome. Cancer Res. 1991;51(22):6094-6097. 16. Rapakko K, Allinen M, Syrjakoski K, et al. Germline TP53 alterations in Finnish breast cancer families are rare and occur at conserved mutation-prone sites. Br J Cancer. 2001;84(1):116-119. 17. Birch JM, Alston RD, McNally RJ, et al. Relative frequency and morphology of cancers in carriers of germline TP53 mutations. Oncogene. 2001;20(34):4621-4628.

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18. Pharoah PD, Guilford P, Caldas C, International Gastric Cancer Linkage Consortium. Incidence of gastric cancer and breast cancer in CDH1 (E-cadherin) mutation carriers from hereditary diffuse gastric cancer families. Gastroenterology. 2001;121(6): 1348-1353. 19. Boardman LA, Thibodeau SN, Schaid DJ, et al. Increased risk for cancer in patients with the Peutz-Jeghers syndrome. Ann Intern Med. 1998;128(11):896-899. 20. Lim W, Olschwang S, Keller JJ, et al. Relative frequency and morphology of cancers in STK11 mutation carriers. Gastroenterology. 2004;126(7):1788-1794. 21. Walsh T, Casadei S, Coats KH, et al. Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. JAMA. 2006;295(12):1379-1388. 22. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Genetic/Familial High-Risk Assessment: Breast and Ovarian V.1.2012. http://www. nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf. Accessed August 20, 2013. 23. Rebbeck TR, Lynch HT, Neuhausen SL, et al. Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med. 2002;346(21):1616-1622. 24. Kauff ND, Satagopan JM, Robson ME, et al. Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med. 2002;346(21):1609-1615. 25. Rebbeck TR, Friebel T, Lynch HT, et al. Bilateral prophylactic mastectomy reduces breast cancer risk in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group. J Clin Oncol. 2004;22(6):1055-1062. 26. Reynolds C, Davidson JA, Lindor NM, et al. Prophylactic and therapeutic mastectomy in BRCA mutation carriers: can the nipple be preserved? Ann Surg Oncol. 2011;18(11):3102-3109. 27. Gail MH, Costantino JP, Bryant J, et al. Weighing the risks and benefits of tamoxifen treatment for preventing breast cancer. J Natl Cancer Inst. 1999;91(21):1829-1846. 28. Gronwald J, Tung N, Foulkes WD, et al. Tamoxifen and contralateral breast cancer in BRCA1 and BRCA2 carriers: an update. Int J Cancer. 2006;118(9):2281-2284. 29. King MC, Wieand S, Hale K, et al. Tamoxifen and breast cancer incidence among women with inherited mutations in BRCA1 and BRCA2: National Surgical Adjuvant Breast and Bowel Project (NSABP-P1) Breast Cancer Prevention Trial. JAMA. 2001;286(18):2251-2256. 30. Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009;361(2):123-134. 31. Meijers-Heijboer H, van den Ouweland A, Klijn J, et al. Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat Genet. 2002;31(1):55-59. 32. Seal S, Thompson D, Renwick A, et al. Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles. Nat Genet. 2006;38(11):1239-1241.

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33. Renwick A, Thompson D, Seal S, et al. ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nat Genet. 2006;38(8):873-875. 34. Rahman N, Seal S, Thompson D, et al. PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat Genet. 2007;39(2):165-167. 35. De Leeneer K, Van Bockstal M, De Brouwer S, et al. Evaluation of RAD51C as cancer susceptibility gene in a large breast-ovarian cancer patient population referred for genetic testing. Breast Cancer Res Treat. 2012;133(1):393-398, PMID: 22370629. 36. Le Calvez-Kelm F, Oliver J, Damiola F, et al. RAD51 and breast cancer susceptibility: no evidence for rare variant association in the Breast Cancer Family Registry Study. PLoS One. 2012;7(12):e52374. 37. He M, Di GH, Cao AY, et al. RAD50 and NBS1 are not likely to be susceptibility genes in Chinese non-BRCA1/2 hereditary breast cancer. Breast Cancer Res Treat. 2012;133(1):111-116. 38. Shaag A, Walsh T, Renbaum P, et al. Functional and genomic approaches reveal an ancient CHEK2 allele associated with breast cancer in the Ashkenazi Jewish population. Hum Mol Genet. 2005;14(4):555-563. 39. Vaz F, Hanenberg H, Schuster B, et al. Mutation of the RAD51C gene in a Fanconi anemia-like disorder. Nat Genet. 2010;42(5): 406-409. 40. Gail MH, Brinton LA, Byar DP, et al. Projecting individualized probabilities of developing breast cancer for white females who are being examined annually. J Natl Cancer Inst. 1989;81(24):1879-1886. 41. Mainiero MB, Lourenco A, Mahoney MC, et al. ACR Appropriateness Criteria Breast Cancer Screening. J Am Coll Radiol. 2013;10:11-14, PMID: 23290667. 42. Saslow D, Boetes C, Burke W, et al. American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CA Cancer J Clin. 2007;57(2):75-89. 43. Pabalan N, Jarjanazi H, Ozcelik H. Association between BRIP1 (BACH1) polymorphisms and breast cancer risk: a meta-analysis. Breast Cancer Res Treat. 2013;137(2):553-558. 44. Zhang B, Beeghly-Fadiel A, Long J, et al. Genetic variants associated with breast-cancer risk: comprehensive research synopsis, meta-analysis, and epidemiological evidence. Lancet Oncol. 2011;12(5):477-488. 45. Walsh T, Lee MK, Casadei S, et al. Detection of inherited mutations for breast and ovarian cancer using genomic capture and massively parallel sequencing. Proc Natl Acad Sci U S A. 2010;107(28):12629-12633. 46. Rouleau E, Jesson B, Briaux A, et al. Rare germline large rearrangements in the BRCA1/2 genes and eight candidate genes in 472 patients with breast cancer predisposition. Breast Cancer Res Treat. 2012;133(3):1179-1190. 47. Riordan S, Rodriguez DF, Kieran S. Personal genomic testing as part of the complete breast cancer risk assessment: a case report. J Genet Couns. 2012;21(15):638-644. 48. Bloss CS, Schork NJ, Topol EJ. Effect of direct-to-consumer genomewide profiling to assess disease risk. N Engl J Med. 2011;364(6):524-534.

Convention Distribution Chemotherapy Foundation Symposium, November, New York, NY ASHP Midyear Clinical Meeting, December, Orlando, FL

Meeting Coverage NASP Strategic Business Exchange, San Antonio: • Updates on the Affordable Care Act and its impact on specialty pharmacy • Bioethics of cost control in specialty pharmacy

NASP Specialty Pharmacy Conference, San Diego: • Technologies that improve specialty patient outcomes— compliance and education aids, remote patient monitoring, etc. • Strategies for retailers to help them get in on limited-network distribution channels for specialty drugs

Educational Reviews • The Last Mile: Ensuring Temperature Integrity for Specialty Medications by William Bailey, RPh • The Future of Antibiotics: Preserving a Precious Commodity by Dorothy McCoy, PharmD

Editorial Features • How to manage aseptic meningitis due to IVIG therapy • Signs point to imminent approval of an impressive new treatment for chronic lymphyocytic leukemia and mantle cell lymphoma • Walgreens’ director of pharmacy discusses importance of crafting detailed protocols for high-risk medications in the home setting

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The Future of Antibiotics: Preserving a Precious Commodity DOROTHY MCCOY, PHARMD, BCPS-ID D Clinical Associate Professo o or Ernest Mario School of Pharmac cy Piscataway, New Jerse ey y Clinical Pharmacist, Infectious Disease e es Hackensack University Medical Cente e er Hackensack, New Jerse ey y

he perception of antibiotics has changed significantly since their

initial availability in the 1940s.

o Many of us have become desensitized tto their value as we either have forgotten or are unaware off th the morbidity bidit and d mortality that were associated with infections in the pre-antibiotic era.

The mortality rate for Staphylococcus aureus bacteremia, for example, was 82% in the 1940s1 compared with 1.3% to 23.4% for methicillin-susceptible and methicillin-resistant S. aureus, respectively, in the early 2000s2 (Figure). Another illustration of this is the dramatic 97% decrease in pediatric pneumonia-related mortality between 1939 and 1996,3 which was made possible by the availability of new antibiotics, expanded access to medical care, and immunizations. These examples demonstrate the lifesaving capacity of antibiotics. Very few other drugs are able to affect mortality in a similar fashion. Unfortunately, these lifesaving drugs have been taken for granted, and as a society we have become complacent about their overuse and abuse.

Antibiotics have become an ordinary part of life, with most people having taken an antibiotic at one point in time, whether it was truly necessary or not. Examples

of inappropriate antibiotic use abound in the literature. One prime example is the inappropriate use of antibiotics to treat viral infections.4-7 Patients may have the perception that their “cold” went away because they might have started taking an antibiotic a few days after the cold symptoms began. This false sense of “response” makes patients want to get an antibiotic the next time they have the same symptoms.8 Studies in the United States have found that antibiotics are used for viral infections between 15% and 72% of the time.4,7,9,10 Other practices, such as the continued use of broad-spectrum agents when narrower ones could be used, prolonged durations of therapy, unnecessary use of antibiotics to treat colonization, and inappropriate dosing, also have been reported.11-15 Additionally, misuse of antibiotics may lead to adverse effects, such as Clostridium difficile infection.16 The general public, patients, and prescribers have been focused on individual reasons for antibiotic use

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P H A R M AC Y P R AC I C E N E WS S P E C I A L E D I T I O N • 2 0 1 3

Misuse/Overuse of Antibiotics

100

Percent ?????????

80 60 40

23.4 20 0

1940s

2000s

Figure. Staphylococcus aureus bacteremia mortality rate. Based on references 1 and 2.

rather than the effect their decisions about antibiotics have on society as a whole,8,17 despite the well-established connection between abuse of antibiotics, resistance, and unnecessary adverse effects.18 As early as 1945, the medical literature included reports about antibiotic resistance and its implications,19 and as early as the 1960s, studies evaluating the appropriateness of antibiotic use began to surface.20 Guidelines published by the Infectious Diseases Society of America (IDSA) in the late 1980s described mechanisms to improve antibiotic use in hospitals.21 Approximately 20 years later, IDSA and the Society for Healthcare Epidemiology of America reiterated those recommendations in their guidelines for developing an antimicrobial stewardship program.22 Although these concerns about overuse and resistance are longstanding, the push to implement changes in practice only recently has gained momentum on societal, national, and global levels.23 Two critical factors impeding the acceptance and employment of judicious antibiotic use are the depreciation of the value of antibiotics and lack of education.

The Value of Antibiotics How much are we willing to pay for antibiotics? Most payors want these agents at a low price, but there is no consensus on an appropriate cost for these agents. There is a wide discrepancy in the range of prices for various antibiotics. For example, the cost of a course of therapy for a C. difficile infection may be $12.99 for a 10-day course of generic oral metronidazole (500 mg every 8 hours) versus $3,273.60 for a 10-day course of oral fidaxomicin (Dificid, Optimer) (200 mg every 12 hours).24 In comparison, the chemotherapeutic agent ipilimumab (Yervoy, Bristol-Myers Squibb), which is used

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for metastatic melanoma, costs approximately $120,000 for a course of therapy (4 infusions over 3 months).25 It is acceptable to pay more for a chemotherapeutic agent that may extend life by 3 to 4 months, but payors are not willing to pay for an antibiotic that can extend life indefinitely.26 This discrepancy may be due to the fact that the morbidity and mortality from infections differ from those due to an oncologic diagnosis that has the end result of death if left untreated. Not all infections are immediately “life-threatening,” and even within the same type of infection, the spectrum of disease severity varies (mild vs severe, complicated C. difficile infection). Moreover, when some of the “older” antibiotics are compared with the newer ones, paying more for the new agent may not be justified if it is not more efficacious or superior to the older drug. This variability in possible outcomes lends itself to inconsistency with respect to the price people are willing to pay for antibiotics. Further influencing the value of antibiotics are the recent programs by various pharmacies to give out free or very low-cost antibiotics to patients.26,27 These programs have been used as a mechanism to get patients into the store as well as to assist those who otherwise might not be able to afford the antibiotics.28 Many pharmacies are able to provide these programs because antibiotics only are given for a short period of time (5-14 days), and many generic antibiotics are inexpensive for the pharmacy to acquire.28 The effect (or lack of effect) this may have on patients’ perspective on the value of antibiotics and their misuse is very controversial. The providers of these programs argue that caregivers will prescribe as they see fit and these programs do not influence patients to ask for antibiotics just because they are free.29 However, others conjecture that these programs are not as altruistic as they seem because they promote inappropriate use of antibiotics. For example, many programs run concurrently with the cold and influenza season, which may give patients the misperception that antibiotics may be useful for those types of viral infections.27 Free antibiotic programs may be sending patients a message that underscores their value by promulgating the idea that antibiotics should be inexpensive, or that because they are inexpensive they are not valuable. Additionally, these programs may be counteracting campaigns that have been initiated to educate patients about appropriate antibiotic use. Instead of promoting free antibiotics, pharmacies should promote appropriate use of antibiotics and provide patients with free immunizations.30 Many additional factors have to be considered when evaluating the costs of antibiotics. Treating an antibiotic-resistant infection is more costly than treating an antibiotic-susceptible infection. For example, one study of 138 patients found a mean difference in attributable cost of $21,000 between antibiotic-resistant infections and non-resistant ones.31 Another study found that the average cost of hospitalization for patients with extended-spectrum β-lactamase (ESBL)–producing

Escherichia colii bloodstream infections (BSIs) was $19,758.77 compared with $12,514.80 for non-ESBL E. coli BSIs.32 This same study also reported an increased average hospital length of stay for patients with ESBL E. coli BSIs (20 vs 13 days).32 Furthermore, cost may have an effect on resistance rates. A study conducted in Denmark found that the use of ciprofloxacin increased when it became available as a generic at a lower cost, and this correlated with an increase in ciprofloxacin-resistant E. colii from urinary isolates.33 All of these issues must be considered when weighing in on how much antibiotics are worth.

Lack of Education Lack of education is another factor that contributes to the misuse of antibiotics. Many patients mistakenly believe that antibiotics should be prescribed for viral illnesses, that symptoms should be gone within 3 days, and that antibiotics should be discontinued once symptoms are resolved, and saved for future use.34 These patients do not realize that poor adherence to therapy (skipping doses, stopping therapy because they feel better) is linked to resistance.35,36 In a study of parents of children with respiratory tract infections, 63.8% expected an antibiotic prescription.9 Patients also have the misperception that taking an antibiotic will speed the process of recovery (from a viral illness) rather than waiting for the natural evolution of a viral infection to occur, and direct-to-consumer advertising also may give patients inappropriate expectations about antibiotics.37 For instance, in 1997, Zithromax (azithromycin; Pfizer) was ranked as one of the top 20 prescription drug products with the highest spending on direct-toconsumer advertising.38 Furthermore, in 2000, the branded products Augmentin (amoxicillin/clavulanate potassium), Cipro (ciprofloxacin; Bayer/Schering), Levaquin (levofloxacin; Janssen), and Zithromax were among the top 50 drugs by dollar sales to pharmacies and high direct-to-consumer advertising spending.38 This type of advertising may affect patient behavior. In one survey, 30% of consumers reported speaking with their physicians about a medication after seeing an ad.38 This might then put pressure on the prescriber to give antibiotics. Prescribers also need additional

Table. Initiatives To Help Preserve Antibiotics for the Future Antimicrobial Stewardship Programs Educating Patients/Patient Actions • Adherence to antibiotics • Role of antibiotics in common infections • Resistance • Untoward adverse effects, such as Clostridium difficile or other super-infections • Immunizations • Posters, pamphlets, one-on-one counseling, community health events

Educating Health Care Providers/Provider Actions • Adherence to antibiotics • Role of antibiotics in common infections • Resistance • Untoward adverse effects, such as Clostridium difficile or other super-infections • Journals, newsletters, continuing medical education, conferences, best practice alerts, guidelines, one-on-one discussions • Delayed antibiotic prescriptions • Free return visits • Follow-up phone calls • Providing information about symptom relief for viral infections • Using guidelines and clinical support tools • Involvement in infection control, immunization, and antimicrobial stewardship programs

Immunization Programs Professional Organizations (not a complete list) • Infectious Diseases Society of America • Society for Healthcare Epidemiology of America • Pediatric Infectious Diseases Society • Society of Infectious Diseases Pharmacists

Centers for Disease Control and Prevention Campaigns • Get Smart • Get Smart: Know When Antibiotics Work • Get Smart for Healthcare: Know When Antibiotics Work • Get Smart: Know When Antibiotics Work on the Farm • National MRSA Education Initiative • Hand Hygiene Saves Lives

National Institutes of Health • National Institute of Allergy and Infectious Diseases

Interagency Task Force on Antimicrobial Resistance Legislation • Food and Drug Administration Safety and Innovation Act (FDASIA) • Generating Antibiotic Incentives Now Act (GAIN Act) • Strategies to Address Antimicrobial Resistance Act (STAAR Act) • Preservation of Antibiotics for Medical Treatment Act (PAMTA) MRSA, methicillin-resistant Staphylococcus aureus Based on references 8, 22, 37, and 42 42-52. 52.

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education to encourage them toward more appropriate prescribing patterns. Unlike in specialties such as oncology or transplantation, where the prescribed drugs (chemotherapeutic agents, immunosuppressives) are predominantly limited to specialists in those areas, the prescribing of antibiotics is not solely limited to infectious diseases specialists. The availability of antibiotics to all clinicians may give the false perception that there are minimal risks to using them inappropriately or that the information learned about antibiotics during training still applies today. Prescribers may feel obligated to give antibiotics so that patients will return for future visits and to avoid medicolegal ramifications if a bacterial infection was missed and patients suffered consequences.37 International medical graduates, increased time in practice, and high practice volume were found to be associated with an increased likelihood of inappropriate antibiotic prescribing in one study.39 Studies have shown that trainees are less likely to abuse antibiotics.37 They perceive less of a medicolegal risk in the protected academic environment and/or are more familiar with recent guidelines in comparison with prescribers in practice for many years.37 For infectious diseases physicians who participate in antimicrobial stewardship programs, there also is the feared ramification of creating antagonistic relationships with fellow clinicians who are using antibiotics inappropriately, which could possibly result in decreased consultations. This belief was more frequent in nonteaching institutions.40 Clinicians in private practices may have limited access to current guidelines, unbiased medical information, real-time data about resistance patterns in the local area, and patient-specific information (diagnostic testing limitations, inability to follow up with patients).37 These issues may limit their ability to differentiate between bacterial and viral infections or to select among antibiotics.37 One study assessed the decision-making process for generalists in comparison with infectious diseases specialists. The prescribers had to choose between antibiotic A (an older drug available for many years, with reported resistance) and antibiotic B (a recently marketed drug, with no reported resistance) for community-acquired pneumonia due to Streptococcus pneumoniae. The study found that for outpatients, most prescribers would choose antibiotic B if the resistance to antibiotic A was above 5%. However, for hospitalized patients and patients in an ICU, the prescribers would choose antibiotic B even if there were low levels of resistance to antibiotic A.41 It is important for all clinicians to remain up to date and continue to receive education about antibiotics and the collateral damage of using them inappropriately (resistance, C. difficile infection, and other adverse drug reactions), so that they can make informed decisions in their clinical practices regarding antibiotics.

How To Make the Change There are multiple ways clinicians can be advocates for appropriate antibiotic use (Table). One role

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is in educating patients regarding adherence to antibiotics, the role of antibiotics in common infections, resistance, and untoward adverse effects such as C. difficile infection or other super-infections secondary to antibiotic exposure.22,37 Health professionals can use tools such as posters, pamphlets, one-on-one counseling, and participation in community health events. Prescribers can tell patients to fill an antibiotic prescription only if they don’t feel better within the next few days, allow free return visits if the patients need to come back, make follow-up phone calls to decrease patient hesitation about not taking antibiotics, and provide information about over-thecounter medications for symptom relief.8,37 Guidelines and clinical support tools are available in the United States and other countries that support holding or delaying antibiotics, as well as appropriate use of antibiotics for common infections such as acute otitis media, acute sore throat/acute pharyngitis/acute tonsillitis, common cold, acute rhinosinusitis, and acute cough/acute bronchitis.42-44 Clinicians also can get involved in infection control and immunization efforts and antimicrobial stewardship programs.22,45 Finally, improvements in diagnostic testing methods to assist clinicians in making treatment decisions are imperative. Ideally, in the future, testing methods will be able to assist in the rapid identification of specific pathogens and differentiation of viral and bacterial infections in the community and in hospitals.22 On a national level, government organizations have developed campaigns to promote appropriate antibiotic use. The Centers for Disease Control and Prevention (CDC) has resources available online for patients and health care providers, including the “National MRSA education initiative” and the “Hand Hygiene Saves Lives” campaign.46 The recognition of antibiotic resistance as a public health threat in the 1990s led to the creation of the Interagency Task Force on Antimicrobial Resistance (ITFAR). The ITFAR was created in 1999 and includes members from the CDC, FDA, National Institutes of Health, Agency for Healthcare Research and Quality, Centers for Medicare & Medicaid Services, Health Resources and Services Administration, Department of Agriculture, Department of Defense, Department of Veterans Affairs, and Environmental Protection Agency. This collaboration resulted in the development of a public health action plan to combat antibiotic resistance, which proposes measures for surveillance, prevention and control, research, and product development.45 The IDSA has published a position paper on combating antibiotic resistance that includes proposals for legislative action. The position paper includes recommendations for economic incentives and support for antibiotic development, new regulatory approaches to aid in antibiotic development and approval, coordination of federal agencies, improvement of resistance surveillance systems, strengthening of methods to prevent and control resistance, investment in antibiotic and diagnostics

research, and eradication of nonjudicious use of antibiotics in animal, plant, and marine habitats.47 Furthermore, state governments also have passed legislation to control or prevent resistance. One landmark example is California, which has a statewide initiative to require antimicrobial stewardship programs.48 Furthermore, 3 bills have been proposed to Congress to address antimicrobial use and resistance. One bill, titled Generating Antibiotic Incentives Now Act (GAIN), seeks to amend the Food, Drug, and Cosmetic Act to extend exclusivity for new qualified infectious diseases products by 5 years.49 The GAIN Act also proposes priority review for qualified infectious diseases products, a revision of the FDA guidelines for clinical trials for antibiotics, and a study to evaluate the need for incentives for qualified infectious disease biologic products. The GAIN Act was passed on July 9, 2012 as Title VIII to the Food and Drug Administration Safety and Innovation Act (FDASIA).50 It includes language regarding extension of the exclusivity period, priority review, fast tracking, and guidance on clinical trials for infectious disease drugs. The second bill is Strategies to Address Antimicrobial Resistance (STAAR) Act.51 This public health service act proposes the establishment of an Antimicrobial Resistance Office and a Public Health Antimicrobial Advisory Board. The goal for these 2 groups is to update the public health action plan created by the ITFAR and to meet, discuss, and review antimicrobial issues as necessary. This bill was referred to the House Subcommittee on Health on June 7, 2013. A third bill, Preservation of Antibiotics for Medical Treatment Act (PAMTA), will amend the Food, Drug, and Cosmetic Act to maintain effectiveness of medically important antibiotics in humans and animals.52 This bill was referred to the Subcommittee on Health on March 15, 2013. These examples demonstrate the various methods that are being proposed on a governmental level to tackle the future outlook of antibiotics.

Conclusion In summary, the attitudes regarding the value of antibiotics in society may slowly be starting to change, although there is still a long road ahead. It is concerning that this change in attitudes may almost be too late in the game as we are getting very close to the edge of losing this valuable resource. Luckily, the examples of actions that already have been taken are laying the groundwork for gaining the momentum necessary to accomplish the task of maintaining the effectiveness of antibiotics for the future.

References 1.

Skinner D, Keefer CS. Significance of bacteremia caused by Staphylococcus aureus. Arch Intern Med. 1941;68:851-875.

2. Blot SI, Vandewoude KH, Hoste ER, Colardyn FA. Outcome and attributable mortality in critically ill patients with bacteremia

involving methicillin-susceptible and methicillin-resistant Staphylococcus aureus. Arch Intern Med. 2002;162(19):2229-2235. 3. Dowell SF, Kupronis BA, Zell ER, Shay DK. Mortality for pneumonia in children in the United States, 1939 through 1996. N Engl J Med. 2000;342:1399-1407. 4. Gaur AH, Hare ME, Shorr RI. Provider and practice characteristics associated with antibiotic use in children with presumed vial respiratory tract infections. Pediatrics. 2005;115(3):635-641. 5. Misurski DA, Lipson DA, Changolkar AK. Inappropriate antibiotic prescribing in managed care subjects with influenza. Am J Manag Care. 2011;17(9):601-608. 6. Wang EE, Einarson TR, Kellner JD, Conly JM. Antibiotic prescribing for Canadian preschool children: evidence of overprescribing for viral respiratory infections. Clin Infect Dis. 1999;29(1):155-160. 7. Gonzales R, Malone DC, Maselli JH, Sande MA. Excessive antibiotic use for acute respiratory infections in the US. Clin Infect Dis. 2001;33(6):757-762. 8. McDonnell Norms Group. Antibiotic overuse: the influence of social norms. J Am Coll Surg. 2008;207(2):265-275. 9. Mangione-Smith R, Elliott MN, Stivers T, McDonald LL, Heritage J. Ruling out the need for antibiotics: are we sending the right message? Arch Pediatr Adolesc Med. 2006;160(9):945-952. 10. Gonzales R, Camargo CA, MacKenzie T, et al. Antibiotic treatment of acute respiratory infections in acute care settings. Acad Emerg Med. 2006;13(3):288-294. 11. Kollef MH, Morrow LE, Niederman MS, et al. Clinical characteristics and treatment patterns among patients with ventilator-associated pneumonia. Chest. 2006;129(5):1210-1218. 12. Chastre J, Wolff M, Fagon JY, et al. Comparison of 8 vs 15 days of antibiotic therapy for ventilator-associated pneumonia in adults: a randomized trial. JAMA. 2003;290(19):2588-2598. 13. Rotjanapan P, Dosa D, Thomas KS. Potentially inappropriate treatment of urinary tract infections in two Rhode Island nursing homes. Arch Intern Med. 2011;171(5):438-443. 14. Hall RG 2nd, Payne KD, Bain AM, et al. Multicenter evaluation of vancomycin dosing: emphasis on obesity. Am J Med. 2008; 121(6):515-518. 15. Leekha S, Terrell C, Edson RS. General principles of antimicrobial therapy. Mayo Clin Proc. 2011;86(2):156-167. 16. Cohen SH, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America and the Infectious Diseases Society of America. Infect Control Hosp Epidemiol. 2010;31(5):431-455. 17. Eggleston K, Zhang R, Zeckhauser RJ. The global challenge of antimicrobial resistance: insights from economic analysis. Int J Environ Res Public Health. 2010;7(8):3141-3149. 18. Shlaes DM, Gerding DN, John JF Jr, et al. Society for Healthcare Epidemiology of America and Infectious Diseases Society of America Joint Committee on the Prevention of Antimicrobial Resistance: guidelines for the prevention of antimicrobial resistance in hospitals. Clin Infect Dis. 1997;25(3):584-599. 19. Plough HH. Penicillin resistance of Staphylococcus aureus and its clinical implications. Am J Clin Pathol. 1945;15:446-451. 20. Reimann HA, Dâ&#x20AC;&#x2122;Ambola J. The use and cost of antimicrobics in hospitals. Arch Environ Health. 1966;13(5):631-636. 21. Marr JJ, Moffet HL, Kunin CM. Guidelines for improving the use of antimicrobial agents in hospitals: a statement by the Infectious Diseases Society of America. J Infect Dis. 1988;157(5):869-876. 22. Dellit TH, Owens RC, McGowan JE, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis. 2007;44(2):159-177.

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23. Chatterjee P, Fleck F. Mobilizing political will to contain antimicrobial resistance. Bull World Health Organ. 2011;89(3):168-169. 24. Fidaxomicin (Dificid) for Clostridium difficile infection. Med Lett Drugs Ther. 2011;53(1373):73-74. 25. Ipilimumab (Yervoy) for metastatic melanoma. Med Lett Drugs Ther. 2011;53(1367):51-52. 26. White AR; BSAC Working Party on The Urgent Need: Regenerating Antibacterial Drug Discovery and Development. Effective antibacterials: at what cost? The economics of antibacterial resistance and its control. J Antimicrob Chemother. 2011;66(9):1948-1953. 27. No authors listed. US supermarkets redefine antibiotic misuse. Lancet Infect Dis. 2009;9(5):265. 28. Santa J. The real cost of free antibiotics. Consumer News. January 9, 2009. http://news.consumerreports.org/health/2009/01/ free-antibiotic.html. Accessed July 15, 2013. 29. Ellis AN. Experts: no such thing as free antibiotics. The Star-Ledger. Jan. 10, 2009. Updated Jan. 11, 2009. http://www.nj.com/news/ index.ssf/2009/01/experts_no_such_thing_as_free.html. Accessed July 15, 2013. 30. Parker-Pope T. Free antibiotics may contribute to drug resistance, officials say. March 4, 2009. http://www. nytimes.com/2009/03/05/health/policy/05drugs. html?adxnnl=1&adxnnlx=1310676972-tvP9dkArVamKzx48IdOD8w. Accessed July 15, 2013. 31. Roberts RR, Hota B, Ahmad I, et al. Hospital and societal costs of antimicrobial-resistant infections in a Chicago teaching hospital: implications for antibiotic stewardship. Clin Infect Dis. 2009;49(8):1175-1184.

38. Frank R, Berndt ER, Donohue J, Epstein A, Rosenthal M. Trends in direct-to-consumer advertising of prescription drugs. Washington, DC: The Henry J. Kaiser Family Foundation; February 2002. 39. Cadieux G, Tamblyn R, Dauphinee D, Libman M. Predictors of inappropriate antibiotic prescribing among primary care physicians. CMAJ. 2007;177(8):877-883. 40. MacDougall C, Polk RE. Antimicrobial stewardship programs in health care systems. Clin Microbiol Rev. 2005;18(4):638-656. 41. Metlay JP, Shea JA, Asch DA. Antibiotic prescribing decisions of generalists and infectious diseases specialists: thresholds for adopting new drug therapies. Med Decis Making. 2002;22(6):498-505. 42. Wlodover CG, May C. Antibiotic stewardship: using clinical guidelines to control antibiotic overuse and deter microbial adaptation. Infect Dis Clin Pract. 2012;20:12-17. 43. Centers for Disease Control and Prevention. Get Smart: know when antibiotics work. treatment guidelines for upper respiratory tract infections. http://www.cdc.gov/getsmart/campaign-materials/ treatment-guidelines.html. Accessed July 15, 2013. 44. National Institute for Health and Care Excellence. CG69 respiratory tract infections: NICE guideline. Prescribing of antibiotics for selflimiting upper respiratory tract infections in adults and children in primary care. July 2008. http://guidance.nice.org.uk/CG69/NICEGuidance/pdf/English. Accessed July 15, 2013. 45. Interagency Task Force on Antimicrobial Resistance. A public health action plan to combat antimicrobial resistance. 2012 update. http://www.cdc.gov/drugresistance/pdf/action-plan-2012.pdf. Accessed July 15, 2013. 46. Centers for Disease Control and Prevention. Education campaigns. http://www.cdc.gov/drugresistance/campaigns.html. Accessed August 20, 2013.

32. Tumbarello M, Spanu T, Di Bidino R, et al. Costs of bloodstream infections caused by Escherichia colii and influence of extended-spectrum-β-lactamase production and inadequate initial antibiotic therapy. Antimicrob Agents Chemother. 2010;54(10):4085-4091.

47. Infectious Diseases Society of America. Combating antimicrobial resistance: policy recommendations to save lives. Clin Infect Dis. 2011;52(suppl 5):s397-s428.

33. Jensen US, Muller A, Brandt CT, et al. Effect of generics on price and consumption of ciprofloxacin in primary healthcare: the relationship to increasing resistance. J Antimicrob Chemother. 2010;65(6):1286-1291.

48. California Department of Public Health. The California antimicrobial stewardship program initiative. www.cdph.ca.gov/programs/ hai/Pages/Anti-microbialStewardshipProgramInitiative.aspx. Accessed August 20, 2013.

34. Branthwaite A, Pechere JC. Pan-European survey of patients’ attitudes to antibiotics and antibiotic use. J Int Med Res. 1996;24(3)229-238.

49. Generating Antibiotic Incentives Now Act of 2011, H.R. 2182/ 112th Congress. http://thomas.loc.gov/cgi-bin/bdquery/ z?d112:SN01734:@@@X. Accessed August 20, 2013.

35. Craig WA. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis. 1998;26(1):1-12.

50. Food and Drug Administration Safety and Innovation Act, S.3187/ 112th Congress. http://www.govtrack.us/congress/bills/112/s3187/ text. Accessed August 20, 2013.

36. McKinnon PS, Davis SL. Pharmacokinetic and pharmacodynamic issues in the treatment of bacterial infectious diseases. Eur J Clin Microbiol Infect Dis. 2004;23(4):271-288.

51. Strategies to Address Antimicrobial Resistance Act, H.R. 2285/ 113th Congress. http://thomas.loc.gov/cgi-bin/bdquery/ z?d113:HR02285:@@@X. Accessed August 20, 2013.

37. Gaur AH, English BK. The judicious use of antibiotics—an investment towards optimized health care. Indian J Pediatr. 2006;73(4):343-350.

52. Preservation of Antibiotics for Medical Treatment Act, H.R. 1150/ 113th Congress. http://thomas.loc.gov/cgi-bin/bdquery/ z?d113:HR01150:@@@X. Accessed August 20, 2013.

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

In just five short years, Amneal Pharmaceuticals has become the seventh largest generic pharmaceutical company in the U.S.* Our focus on quality, superb service levels and building strong relationships hasn’t changed. Now, we’re bringing that philosophy to the institutional market. With injectable and unit dose products populating our portfolio, we are fully-equipped to meet the critical need for dependable, high-quality product supply. Amneal’s collaborative, transparent and responsive way of doing business delivers unsurpassed customer service, consistent quality, convenience and a steady pipeline of essential products to your organization. At Amneal, we understand that you are committed to providing each and every patient with the best care, in the right form, accurately and in a timely manner. Amneal has proven itself as a vital partner in that equation. * In prescriptions of unbranded generics per IMS, +VOF 2013

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Volu ume 40 • Number 4 • April 2013

Printer-friendly versions available online

in this issue CLINICAL

3 12

Safety, quality pearls: collaboration a key to successs. E-alerts boost venous thromboembolism prevention.

TECHNOLOGY

16 23

Health IT pearls: telepharmacy, smarter IV pumps and more. When the carousel stops: a plan for drug dispensing.

POLICY

IOM urges trackand-trace system for protecting drug supply

OPERATIONS & MGMT

The case against overuse of proton pump inhibitors.

EDUCATIONAL REVIEW

Medication Errors: A Year in Review See insert after page 8.

REPORT Teﬂaro® (ceftaroline fosamil) for the Treatment of Acute Bacterial Skin and Skin Structure Infections Caused by Designated Susceptible Bacteria See insert after page 16.

OIG Says REMS Program Falling Short Of Goals

fter four years, the effectiveness of the FDA’s mandatory Risk Evaluation and Mitigation Strategies (REMS) program remains open to question because drug companies have failed to comply with key reporting requirements and the agency lacks adequate enforcement authority to take action against them, according to a report by the Department of Health and Human Services’ Office of Inspector General (OIG). Nearly one-fourth of the drug companies with medications in the REMS program were found to be in violation of legislatively approved timetables for data reporting, according to the OIG report. Furthermore, less than 15% of the companies had met all of the safety goals stipulated in their products’ REMS. As for the FDA, the agency has reviewed only one of 32 drugs whose REMS contain “elements to assure safe use” (ETASU)—usually reserved

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ospital pharmacists face several ral challenges in h helping l i manage antibiotic-resistant, gram-negative superbugs that produce carbapen nemases. One of the most worrisome is carba-penemase-producing Klebsiella pneumoniae (KPC). A report in the March issue off Infection Control and Hospital Epiidemiology (2013;34:259-268) foun nd that the proportion of K. pneumon niae cases resistant to carbapenems increa creaased d from 0.1% in 2001 to 4.5% in 2010 0. “That “ is huge,” said Robert Rapp, PhaarmD, a professor of pharmacy and sur-gery emeritus at the University of Kentucky Medical Center in Lexington, who is one of manyy pharmacists concerned about KPC C. Those concerns were compound ded by a Centers for Disease Control aand Prevention’s report on the rising prrevalence of carbapenem-resistant en nterobacteriaceae (CRE). According to the h report, in the last decade, hospitals have seen a fourfold increase in CRE, with most of the increase attrib-utable to Klebsiella species (MMWR ( 2013;62:1-6).

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see REMS, page 24

Addiction Cited As Powerful Diversion Driver

ontrolled substance diversion is a major challenge for hospitals across the country. The problem is being fueled, in part, by the power of addiction: It is estimated that 10% to 15% of health professionals will develop serious substance abuse/addiction problems during their career (Crit Care Med 2007;35:S106-S116). Experts warned during a recent webinar

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In Ranking of Superbugs, Klebsiella Takes the Lead

see CHALLENGE, page 20

see SUPERBUGS, pag ge 6

Shifting the Main Focus off Acid id Suppression to the Critically Ill Las Vegas—A San Antonio health care system markedly reduced unnecessary use of proton pump inhibitors (PPIs) for stress ulcer prophylaxis (SUP) in the ICU and ended up saving $80,000 annually. At a Boston-area hospital, researchers determined that reducing inappropriate PPI use among general medicine patients could lead to yearly cost avoidance in the neighborhood of $1 million. Both initiatives, presented at the Decem-

ber 2012 Midyear Clinical Meeting of the American Society of Health-System Pharmacists (ASHP), were undertaken to address persistent inappropriate use of PPIs, which has been linked to higher hospital costs and an increased risk for Clostridium difficile infections (sidebar, page 30). “Many of our general medicine patients were on PPIs or H2-receptor agonists constantly, and

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see STRESS ULCERS, page 30

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