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Fall 2013 Vol. 5, No. 4

Arizona Journal of Pharmacy

THE OFFICIAL PUBLICATION OF THE ARIZONA PHARMACY ASSOCIATION Brought to you by Pharmacy Network of Arizona

Ray N. Clark, Jr., Pharm.D. AzPA President 2013-2014

“i’M AlWAyS WAtChing Out fOr My PAtientS, but whO’s watChiNg Out fOr Me?”

we are. We are the Alliance for Patient Medication Safety (APMS), a federally listed Patient Safety Organization. Our Pharmacy Quality Commitment (PQC) program helps you implement and maintain a continuous quality improvement program that offers strong federal protection for your patient safety data and your quality improvement work. PQC also helps you comply with quality assurance requirements found in network contracts, Medicare Part D, and state regulations. We offer flexible and powerful tools, ongoing training and support to keep your pharmacy running efficiently, and most importantly, to keep your patients safe.

LearN MOre: Call toll free (866) 365-7472 or visit www.pqc.net

Arizona Journal of Pharmacy

THE OFFICIAL PUBLICATION OF THE ARIZONA PHARMACY ASSOCIATION Brought to you by Pharmacy Network of Arizona

Vol. 5, No. 4

Fall 2013

In This Issue Columns

President’s Message CEO’s Message Academy News • Community Pharmacy Academy • Geriatric Care Academy • Health-System Academy • Managed Care Academy • Technician Academy • Student Pharmacist Academy

Featured Article

A Look Back - Tobacco Enema by Robert E. Kravetz, MD, FACP, MACG American College of Gastroenterology

The enema or clyster has played a major role in promoting health throughout the history of civilization. It has been recommended for its restorative as well as its healing qualities. The many forms that is has taken have depended upon the prevailing social attitudes and customs that were present at various times in history. One of the most unusual devices in the “anals of enematology” has been the tobacco enema similar to the one illustrated here. This bellows-operated tobacco enema is the type recommended by the Royal Humane Society of London in 1774. It is made of wood, leather, brass, and ivory. It is fitted in a mahogany case lined with green baize, circa 1790. The four bottles contained a cordial mixture, spirits of hartshorn, camphorated spirits, and emetic tartar. These medications were prescribed orally in conjunction with the administration of the enema. (Courtesy of C. B. Fleet) Tobacco fumes were proposed as a laxative in 1643. “It is not only the admission of kindly warmth in the internal parts of the body, which proves advantageous, but it is a stimulus to excite the irritability and to restore the languid peristaltic motion of the intestines.”

Pharmacy Time Capsules Fourth Quarter 2013 1988—Twenty-five Years ago:

1938—Seventy-five Years Ago:

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Average price of prescription in the U.S. is 89 cents.

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70% of the drugstores in the U.S. had total annual sales of under $30,000 (approximately $500,000 in 2013 dollars).

C. Douglas Hepler defined pharmaceutical care “as a relationship between a patient and a pharmacist in which the pharmacist accepts responsibility for drug-use-control functions.’

1963—Fifty Years Ago:

1913—One hundred Years Ago:

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The average independent pharmacy dispensed 17,320 prescriptions per year, less than 50% were new.

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Aldomet ( methyldopa) launched by Merck Sharp & Dohme.

Phenobarbital (Luminol and Luminol sodium) marketed in the U.S. by Bayer as the first effective epileptic treatment.

By: Dennis B. Worthen, PhD, Cincinnati, OH One of a series contributed by the American Institute of the History of Pharmacy, a unique non-profit society dedicated to assuring that the contributions of your profession endure as a part of America’s history. Membership offers the satisfaction of helping continue this work on behalf of pharmacy, and brings five or more historical publications to your door each year. To learn more, check out www.aihp.org.

Fall 2013 • Arizona Journal of Pharmacy • 15

Featured Article Responsible Means of Utilizing Social Media for Pharmacy Education

by M. Scott Hardy, Pharm.D., R.Ph., BCACP, Mayo Clinic Scottsdale; Meera Grimsley, Pharm.D. Candidate, Midwestern University College of Pharmacy - Glendale, Class of 2015; Nathaniel A. Poole, D.O., Pharm.D. Candidate Midwestern University College of Pharmacy - Glendale, Class of 2015; and S. Dalila Mendoza, Pharm.D. Candidate Midwestern University College of Pharmacy - Glendale, Class of 2015

Introduction Social media, ubiquitous in the private lives of contemporary Americans, has invaded territory that was once off-limits – the educational and professional setting. Social media has evolved into a powerful, online form of communication amongst professionals in nearly all business arenas, including the field of pharmacy, particularly with respect to communication amongst students and preceptors. It can be used to enhance relationships with other health care professionals and/or students and maximize the learning experience, effectively creating an “always on” learning environment, not only while in pharmacy school, but well beyond. Social networking services such as Twitter, Yammer, and wikis are increasingly being used by health care professionals in this capacity.1 Twitter is an online service that allows users to post 140-character messages called “tweets” to share ideas or conversations in real-time. Yammer is an enterprise social network used for private communication within businesses and schools. A wiki (e.g., SharePoint) is a web application that allows a collaboration of information by multiple users. The integration of these social networking services is currently underway and should benefit the pharmacy profession by increasing the ease of their use, as well as overall productivity in the pharmacy setting. Wikis and other social media are currently being used for educational purposes, but the use of integrated social networks in the context of pharmacy education has not been thoroughly explored, nor well documented. Literature searches result in limited published data on the impact of social media on pharmacy education. One study reported 16 • Arizona Journal of Pharmacy • Fall 2013

positive survey results from pharmacy students who took a hybrid elective course that was a combination of vis-à-vis and online wiki interaction. The researchers concluded that wikis were a valuable tool that enhanced the student experience.2 Another study surveyed students who used wikis during their advanced pharmacy practice experiences (APPE) in which wikis were available to only the APPE students that were currently or previously enrolled, as well as the faculty members that edited the site. This limited access helped control the content of the wikis and relieve liability and copyright concerns. The study found that wikis can provide a method of sharing student notes and collaborating on group projects in addition to improving critical thinking and writing skills.3 Research pertaining specifically to the use of Twitter and Yammer in pharmacy education is currently lacking. There is also a shortage of publications demonstrating how multiple social media sites can be used synergistically for the purpose of educating pharmacy students. The prime objectives of this project were to utilize social media to advance and augment the Mayo Clinic Introductory Pharmacy Practice Experience (IPPE) and to demonstrate the benefits of integrated, responsible social media use on pharmacy education. Experimental Design By using social media during the IPPE at Mayo Clinic, two students enrolled in an ambulatory rotation and one student enrolled in an oncology rotation were able to collaborate on assignments and learn from each other during the course of their respective four-week rotations. During the day, students used instant messaging through Mayo Clinic’s Yammer site to keep each other and their preceptors updated on their progress or to get feedback and clarification on assignments; this was performed at two spatiallyseparated facilities – the Mayo Clinic Hospital and the Mayo Clinic Outpatient Facility. Students also used a private group on Yammer specifically for their rotation to share ideas and collaborate on upcoming projects related to pharmacy. A wiki page was created via SharePoint under the Mayo Clinic oncology website, giving students a place to post daily learning material. The oncology pharmacy student posted disease state summaries of common malignancies, as well as daily

outlines of didactic material that had been reviewed. The ambulatory students were then encouraged to review this material on SharePoint. Of considerable benefit, the SharePoint wiki page allowed students to discuss or ask questions in real time even though all three students were physically in different locations. The acquisition of knowledge was assessed using a pre-test/ post-test format. The ambulatory students were given a pre-test in the morning to assess base level knowledge of a particular oncology topic; then, after perusing the oncology information that was posted on the wiki page and utilizing Yammer and SharePoint to discuss the information, the ambulatory students participated in a post-test. In this manner, the efficacy regarding the integration of social media into the IPPE learning environment was scientifically assessed. Lastly, students used Twitter to post summaries of what they had learned about oncology after the rotation had concluded for the day and the students had left the facility. This not only further disseminated the information that had been learned, but also solidified its place in the memories of the ambulatory students – encouraging the retention of the material. Evaluation and Assessment As a result of the integrated social media, it was possible to expand the boundaries of the rotation curricula for both the ambulatory and oncology rotations. The oncology student could focus on their rotation while gleaning useful information from their cohorts in the ambulatory rotation, and vice versa. Despite being two different rotations in two different locations, all of the students were able to learn from one another and save their learning experiences in the SharePoint wiki, thus allowing future students to also learn from their experiences. Discussion An important caveat in implementing the use of a social media model within student pharmacy practice experiences is that students must exercise professional judgment. It is imperative that patient information is protected and privacy requirements are complied with (i.e., HIPAA) when discussing specific patient cases. For example, discussion of patient cases on a social site such as Twitter requires respecting the ethical and legal

Featured Article Social Media (continued from page 16) standards of the pharmacy profession. Pharmacy students are held to the same professional standards as pharmacists and have a responsibility to use social media appropriately.1 Successfully implementing social media into a pharmacy clinical rotation will require the development of clear policies and guidelines that address training, privacy, and productivity issues.4 Conclusion The perpetual learning environment created by this social media experiment proves to be promising for the future of pharmacy practice rotations and education as a whole. The responsible use of social programs like Twitter, Yammer, and SharePoint can have a profound impact on student learning – the educational environment can truly exist without the restricting boundaries of time and space. However, far more research, data, and responsible use guidelines are needed regarding the application of social media for IPPEs and APPEs in the realm of pharmacy education. References 1. Barrett P, Bruecki J, Cain J, et al. ASHP statement on use of social media by pharmacy professionals. Am J Health-Syst Pharm 2012; 69: 2095–97. 2. Cain J. Social media in health care: The case for organizational policy and employee education. Am J Health-Syst Pharm 2011; 68: 1036-40. 3. Miller AD, Norris LB, Bookstaver PB. Use of wikis in pharmacy hybrid elective courses. Curr Pharm Teach Learn 2012; 4: 256–61. 4. Miller AD, Bookstaver PB, Norris LB. Use of Wikis in advanced pharmacy practice experiences. Am J Pharm Educ 2009; 73: 139.

TWEET IT OUT!

On October 3, 2013 join us in celebrating pharmacists and their contributions to health care and our communities. Take a moment to tweet about the real things you are doing or have done to help patients, other health professionals, and your community that day. Tweet about an action you took that day to help a patient, a health care professional, your industry, or your community and use the hashtag #Pharmacist. Don’t forget to follow AzPA at @azpharmacy and like the Arizona Pharmacy Association on Facebook.

Evaluation of the Risks and Benefits of Using Codeine and Codeine-containing Products in Pediatric Patients by Carrie Hammer, Pharm.D., PGY1 Pharmacy Practice Resident, Maricopa Integrated Health System and Erica Domer, Pharm.D., Pediatric Clinical Pharmacist Specialist, Maricopa Integrated Health System

Codeine is an opioid analgesic that decreases the perception of pain by binding to opioid receptors in the central nervous system and inhibiting the transmission of ascending pain signals.1 It is commonly used to provide relief of moderate to severe pain in pediatric patients and is listed by the World Health Organization as the second step on the analgesic ladder for management of cancer pain in children.2 Codeine also acts as a cough suppressant via direct central action in the medulla.1 Codeine is a prodrug that is converted to its active metabolite, morphine, by the cytochrome P450 (CYP) isoenzyme 2D6.3 Polymorphisms in the gene encoding this enzyme result in variable conversion of codeine to morphine. Among the Caucasian population, about 50% of patients are classified as extensive metabolizers.4 These patients carry two functional copies of the CYP2D6 allele and metabolize approximately 10% of the parent drug to morphine. In poor metabolizers, CYP2D6 activity is dramatically reduced and morphine production is negligible, often resulting in subtherapeutic pain control. In contrast, conversion to morphine is elevated in ultra-rapid metabolizers. Ultra-rapid metabolism results from functional gene duplication and overexpression of CYP2D6, with morphine production dependent on the number of gene copies. Ultra-rapid metabolizers can produce 50% to 75% more morphine than extensive metabolizers, resulting in a much higher risk of dose-dependent opioid-related side effects, including sedation and respiratory depression. The ultra-rapid metabolizer genotype occurs in an estimated 1% to 10% of European descendants, but may be present in up to 30% of individuals descended from North Africa.5 Thus, the unpredictable pharmacokinetics of codeine

could result in variable pain control or unexpected central nervous system depression. Life-threatening central nervous system depression following the receipt of codeine has been described in adults with the ultra-rapid metabolizer genotype.6 However, recent reports of codeineinduced opioid toxicity in pediatric patients have prompted the Food and Drug Administration (FDA) to address the safety of codeine use. To further evaluation codeine-induced toxicity in this special population, the OVID (Medline) database was queried from 1966 to November 2, 2012 with the key search word “codeine” and further limited to all child (0 to 18 years), English language, and human. A total of 431 articles were retrieved. Each abstract was screened for relevance to the purpose of the drug information question. Reference lists were also reviewed to identify additional articles. In 2009, Ciszkowski et al. reported the opioid-induced respiratory depression and death of a 2-year-old male (13 kg) who received codeine following the uncomplicated surgical removal of the tonsils and adenoids for obstructive sleep apnea syndrome (OSAS).7 The boy was discharged home with instructions to administer 10 mg to 12.5 mg of codeine (approximately 0.8-1 mg/kg/dose) and 120 mg of acetaminophen syrup every 4 to 6 hours as needed. The child developed fever and wheezing on the second evening after surgery, and he was found without vital signs the next morning. Post-mortem genotyping revealed functional duplication of the CYP2D6 allele, resulting in the ultra-rapid metabolizer phenotype. Similarly, Kelly et al. reported two additional postoperative deaths in a 4-year-old male and a 5-year-old male following adenotonsillectomy for OSAS and recurrent tonsillitis in 2012.8 The 4-year-old boy (28 kg) was prescribed codeine 8 mg (approximately 0.3 mg/ kg/dose) up to five times per day as needed. He was reported to be sedated and lethargic the day after discharge, and the next afternoon he was brought to the hospital without vital signs after receiving a total of 4 doses of codeine. The ultra-rapid metabolizer genotype was confirmed after death. The 5-year-old male (29 kg) was given acetaminophen and 12 mg of codeine (approximately 0.4 mg/kg/dose) every 4 hours and was Fall 2013 • Arizona Journal of Pharmacy • 17

Featured Article Evaluation of the Risks and Benefits of Codeine (continued from page 17) found without vital signs 24 hours after surgery. Despite receiving appropriate weight-based doses of codeine, both of these patients were found to have normal levels of codeine and supratherapeutic morphine levels after death, confirming the presence of the ultra-rapid metabolizer phenotype. Kelly et al. also described a life-threatening case of respiratory depression in a 3-year-old female (14 kg) after the receipt of codeine following adenotonsillectomy for OSAS.8 The girl was given codeine 15 mg (approximately 1 mg/kg/dose) and acetaminophen 150 mg every 4 to 6 hours as needed. After receiving a total of 60 mg of codeine, she was found unresponsive and was taken to the hospital, where she recovered after successful resuscitation, mechanical ventilation, and the administration of naloxone. Genotyping revealed that the patient was an extensive metabolizer, though supratherapeutic morphine levels suggested an overlap with the ultra-rapid metabolizer phenotype. These reports prompted the Food and Drug Administration (FDA) to release a Drug Safety Communication on August 15, 2012, urging physicians to be aware of the risks of using codeine in pediatric patients, especially those who have undergone tonsillectomy or adenoidectomy for OSAS.9 The FDA cautioned prescribers to use the lowest effective dose for the shortest period of time and on an as-needed basis only, rather than scheduled. The advisory statement also instructed parents and caregivers to monitor pediatric patients who have received codeine for signs of overdose, including lethargy, confusion, or difficult or noisy breathing. Health care providers are also reevaluating the safety and efficacy of codeine for other indications. Traditionally, acetaminophen with codeine has been used to treat moderate pain due to musculoskeletal injury in children.10 However, due to the unpredictable metabolism of codeine and its potential for suboptimal pain control or toxicity, other oral opioids are gaining popularity and may be suitable alternatives to codeine. Charney et al. investigated the efficacy and tolerability of codeine and oxycodone in 107 children aged 4 to 17 years with suspected forearm fractures.11 During triage, each child was randomized to 18 • Arizona Journal of Pharmacy • Fall 2013

receive a one-time dose of codeine 2 mg/ kg up to 120 mg (N = 56) or oxycodone 0.2 mg/kg up to 15 mg (N = 51). Pain was assessed every 30 minutes using a 5-point facial scale (0 = no pain, 4 = severe pain). Patients who received oxycodone reported a significantly greater reduction in pain scores compared to patients who received codeine (difference of 0.4 faces, P = 0.01). Differences in minor adverse events were not significant, though itching occurred more frequently in children receiving codeine (23% versus 16%, P = 0.049). The relative effectiveness and safety of codeine when compared to hydrocodone has not been evaluated in pediatric patients. However, Turturro et al. found no significant difference between pain scores in adult patients who presented to the emergency department with musculoskeletal pain and received acetaminophen 500 mg in combination with either codeine 30 mg or hydrocodone 5 mg.12 Each intervention was administered every 4 hours as needed for up to 48 hours. The incidence of adverse effects was higher in patients receiving acetaminophen with codeine (72% versus 32%, P = 0.005). These studies indicate that oxycodone or hydrocodone may be suitable, and possibly superior, alternatives to codeine for the management of musculoskeletal pain in children and adults. Multiple studies have also evaluated the role of non-opioid analgesics in the management of musculoskeletal pain. Clark et al. investigated the efficacy of a single dose of acetaminophen 15 mg/kg, ibuprofen 10 mg/kg, or codeine 1 mg/kg for the treatment of pain due to injuries to the neck, back, or extremities in 300 children aged 6 to 17 years.13 Pain was measured at baseline and 60 minutes after administration of the analgesic using a 100-mm visual analog scale (VAS). Patients who received ibuprofen had a significantly greater improvement in VAS scores compared to those who received acetaminophen or codeine (mean decrease of 24 mm versus 12 mm and 11 mm, respectively), while there was no significant difference in analgesia between children receiving acetaminophen versus codeine. There is also evidence demonstrating the superiority of ibuprofen over a combination of acetaminophen and codeine. In a study by Friday et al., 66 pediatric patients aged 5 to 17 years with traumatic extremity pain were

randomized to receive a one-time dose of ibuprofen (10 mg/kg up to 400 mg) or acetaminophen with codeine (1 mg/ kg as codeine up to 60 mg).14 Pain was assessed using a color analog scale, and the difference in the changes in pain score was calculated by subtracting the change in acetaminophen-codeine pain score from the change in ibuprofen pain score, with negative values favoring the ibuprofen group. A clinically significant difference was defined as greater than 2 cm. The intergroup differences in pain score at 20 minutes (-0.6 cm), 40 minutes (-0.4 cm), and 60 minutes (0.2 cm) were all less than 2 cm, indicating similar analgesic efficacy. Both treatments were generally welltolerated. Both of these studies provide evidence supporting the use of ibuprofen as an alternative to codeine alone or in combination with acetaminophen for the management of musculoskeletal pain in children. In addition to its indication for analgesia, codeine has traditionally been prescribed for the management of cough due to its antitussive properties. However, several studies have demonstrated that codeine may have no benefit over placebo for the treatment of cough in either adult or pediatric patients.15-18 For example, Schroeder et al. investigated the efficacy of codeine for the treatment of acute cough in 57 pediatric patients aged 18 months to 12 years.18 No significant difference in cough frequency or symptom-rating score was observed between codeine and placebo. Due to the lack of evidence supporting the efficacy of codeine for this indication, the American Academy of Pediatrics Committee on Drugs cautioned against the use of codeine for cough suppression in pulmonary and inflammatory diseases.19 However, the most appropriate alternative medication for the treatment of cough in children remains unknown, as comparative studies of cough suppressants in pediatric patients are scarce and have yielded inconclusive results. Taylor et al. conducted a randomized, controlled trial in children aged 18 months to 12 years affected by a significant night cough with a duration of less than 14 days.20 A total of 49 patients were randomized to receive codeine 5 mg (age ≤5 years) or 10 mg (age >5 years), dextromethorphan 7.5 mg (age ≤5 years) or 15 mg (age >5 years), or placebo at bedtime for 3 consecutive nights. Patients in the active treatment groups also

Featured Article Evaluation of the Risks and Benefits of Codeine (continued from page 18) received guaifenesin 50 mg (age ≤5 years) or 100 mg (age >5 years), while patients in the placebo group did not. Mean cough and symptom scores decreased in all 3 treatment groups on each day of the study. Neither codeine-guaifenesin nor dextromethorphan-guaifenesin was significantly more effective than placebo for the reduction of cough score (P = 0.41 and 0.70, respectively). Thus, the authors could not support the use of codeine, dextromethorphan, or guaifenesin for cough suppression in pediatric patients. Furthermore, a recent meta-analysis by the Cochrane Collaboration reviewed a total of 8 studies evaluating the safety and efficacy of over-the-counter medications for the treatment of acute cough in children in ambulatory settings (N = 616).21 The regimens investigated included dextromethorphan (3 studies), antihistamines alone or in combination with decongestants (4 studies), and mucolytics (1 study). The authors found no conclusive evidence for or against the effectiveness of these regimens. Reported adverse drug reactions were mild and infrequent, though the authors cautioned that larger numbers of patients would be required to observe less common though serious side effects such as central nervous system depression or serotonin syndrome. Therefore, dextromethorphan, antihistamines, and other over-thecounter medications may be considered as an alternative to codeine for cough suppression in pediatric patients, though they should be used with caution, as further studies are needed to evaluate their safety and efficacy for this indication. In conclusion, codeine is an opioid analgesic that is converted to its active metabolite morphine by CYP2D6.3 Polymorphisms in the gene encoding this enzyme result in unpredictable conversion to morphine and the potential for suboptimal pain control or toxicity. Due to recent reports of life-threatening respiratory depression and death in pediatric patients who received age- and weight-appropriate postoperative doses of codeine, the FDA has cautioned prescribers to be aware of the risks of using codeine in pediatric patients, especially those who have undergone tonsillectomy or adenoidectomy for OSAS.6-8 It may be reasonable to consider alternative therapies for treatment of

musculoskeletal pain, such as oxycodone, hydrocodone, or ibuprofen.10-13 The American Academy of Pediatrics Committee on Drugs has also cautioned against the use of codeine for cough suppression, though it is unclear whether or not alternative medications such as dextromethorphan and antihistamines are effective and safe for this indication in children.18-20 If codeine is administered to pediatric patients, it should be used at the lowest effective dose for the shortest period of time and on an as-needed basis only.8 Additionally, patients should be monitored for both inadequate pain control and signs of overdose, including lethargy, confusion, and difficult or noisy breathing. References: 1. Codeine. In: Lexi-Drugs Online [Internet Database]. Hudson, OH: Lexi-Comp, Inc. Updated 2012. 2. World Health Organization. Cancer pain relief and palliative care in children. Geneva: World Health Organization, 1998. 3. Gaedigk A, Simon SD, Pearce RE, et al. The CYP2D6 Activity Score: translating genotype information into a qualitative measure of phenotype. Clin Pharmacol Ther. 2008;83:234-42. 4. Kirchheiner J, Schmidt H, Tzvetkov M, et al. Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication. Pharmacogenomics J. 2007;7:257-65. 5. Williams DG, Patel A, Howard RF. Pharmacogenetics of codeine metabolism in an urban population of children and its implications for analgesic reliability. Br J Anaesth. 2002;89:839-45. 6. Gasche Y, Daali Y, Fathi M, et al. Codeine intoxication associated with ultrarapid CYP2D6 metabolism. N Engl J Med. 2004;351:2827-31. 7. Ciszkowski C, Madadi P, Phillips MS, et al. Codeine, ultrarapid-metabolism genotype, and postoperative death. N Engl J Med. 2009;361:827-8. 8. Kelly LE, Rieder M, van den Anker J, et al. More codeine fatalities after tonsillectomy in North American children. Pediatrics. 2012;129:e1343.

9. FDA Drug Safety Communication: Codeine use in certain children after tonsillectomy and/or adenoidectomy may lead to rare, but life-threatening adverse events or death. Available at : http:// www.fda.gov/Drugs/DrugSafety/ucm313631.htm. Accessed on: 4 November 2012. 10. Ali S, Drendel AL, Kircher J, et al. Pain management of musculoskeletal injuries in children: current state and future directions. Pediatr Emer Care. 2010;26:518-28. 11. Charney RL, Yan Y, Schootman M, et al. Oxycodone versus codeine for triage pain in children with suspected forearm fracture. Pediatr Emerg Care. 2008;24:595-600. 12. Turturo MA, Paris PM, Yealy DM, et al. Hydrocodone versus codeine in acute musculoskeletal pain. Ann Emerg Med. 1991;20:1100-3. 13. Clark E, Plint AC, Correll R, et al. A randomized, controlled trial of acetaminophen, ibuprofen, and codeine for acute pain relief in children with musculoskeletal trauma. Pediatrics. 2007;119:460-7. 14. Friday JH, Kanegaye JT, McCaslin I, et al. Ibuprofen provides analgesia equivalent to acetaminophen-codeine for acute pain relief in children with extremity injuries: a randomized clinical trial. Acad Emerg Med. 2009;16:711-6. 15. Eccles R, Morris S, Jawad M. Lack of effect of codeine in the treatment of cough associated with acute upper respiratory tract infection. J Clin Pharm Ther. 1992;17:175-80. 16. Freestone C, Eccles R. Assessment of the antitussive efficacy of codeine in cough associated with common cold. J Pharm Pharmacol. 1997;49:1045-9. 17. Smith MB, Feldman W. Over-the-counter cold medications. A critical review of clinical trials between 1950 and 1991. JAMA. 1993;269:2258-63. 18. Schroeder K, Fahey T. Should we advise parents to administer over the counter cough medicines for acute cough? Systematic review of randomized controlled trials. Arch Dis Child. 2002;86:170-5. 19. American Academy of Pediatrics, Committee on Drugs. Use of codeine- and dextromethorphancontaining cough remedies in children. Pediatrics. 1997;99:918-20. 20. Taylor JA, Novack AH, Almquist JR. Efficacy of cough suppressants in children. J Pediatr. 1993;122:799-802. 21. Smith SM, Schroeder K, Fahey T. Over-thecounter (OTC) medications for acute cough in children and adults in ambulatory settings. Cochrane Database Syst Rev. 2012;8:CD001831.

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Arizona Journal of Pharmacy • Fall 2013 • 19

Featured Article Arizona Delegates Report on 65th Session of the ASHP House of Delegates

Prepared by: Mindy Throm Burnworth, Pharm.D., BCPS Approved by: Carol Rollins, MS, RD, Pharm.D., BCNSP; Christi Jen, Pharm.D., BCPS The Arizona Delegates (Mindy Throm Burnworth, Carol Rollins, and Christi Jen) advocated for Pharmacist Recognition as a Health Care Provider during this year’s American Society of Health-System Pharmacists (ASHP) House of Delegates (HOD) session. The HOD is the authority over ASHP professional policies, which express the Society's stance on important issues related to health-system pharmacy practice and medication use in society. The House meets annually at the ASHP Summer Meeting where it reviews policy proposals that have been approved by the Board of Directors. Most professional policies are initially proposed by ASHP members and then drafted by ASHP Councils or the Executive Committees of Sections and Forums. The development of good policy takes time and benefits from active, constructive discussion. In early May 2013, the Arizona Delegates and Alternate Delegate (Mitchell Buckley) attended the Regional Delegate Conference in Phoenix, AZ. During this conference, proposed changes to policies are discussed and then posted to ASHP Connect (ASHP’s online member communication tool). ASHP Connect allows individuals to connect with peers, discuss topics of interest, and share ideas and expertise (http://connect.ashp.org/ASHP/Home). Finally, the policies are voted on during the HOD session. During the House meetings (June 2 and 4, 2013), the Arizona Delegates along with approximately 200 other Delegates collectively approved 19 policy items. The Arizona Delegates wish to communicate the outcome of the policy process to you, our Arizona constituents. The approved policies (including policies on Pharmacist Recognition as a Health Care Provider, Compounding by Health Professionals, ASHP Statement on the Pharmacist’s Role in Substance Abuse Prevention, Education, and Assistance, and others) are available online at: www.ashp.org/DocLibrary/Policy/HOD/ OfficialLang2013Policies.aspx (abbreviated version) • www.ashp.org/DocLibrary/Policy/HOD/ OfficialLang2013PoliciesRationale.aspx (includes rationale). Alternatively, these are published in the American Journal of Health-System Pharmacists (Am J Health Syst Pharm. 2013;70:e16-e19). Other documents including the Report of the President and Inaugural Address of the Incoming President are available at ASHP’s official HOD website: www.ashp.org/menu/ PracticePolicy/HOD.aspx. Check here often for important policy updates. In addition, approximately 20 recommendations were made by members of the HOD and will serve as agenda items for the 2013-2014 policy year. Two of these recommendations were brought forth by the Arizona delegation. All recommendations will be referred to an appropriate Council. Recommendations brought forth by the Arizona Delegates can make a difference. For example, in 2012, the Arizona Delegates

(Burnworth and Rollins), proposed a new recommendation on Pharmacists as Health care Providers. In 2013, the Arizona delegation took the lead on collating comments and finalizing the language on Pharmacists as Health care Providers that was unanimously approved by the ASHP HOD this year and then approved by the ASHP Board of Directors. This is now official ASHP policy 1307. Approved language is as follows: Pharmacist Recognition as a Health Care Provider Source: Council on Public Policy • To advocate for changes in federal (e.g. Social Security Act), state, and third-party payment programs to define pharmacists as health care providers; further, • To affirm that pharmacists, as medication-use experts, provide safe, accessible, high-quality care that is cost effective, resulting in improved patient outcomes; further, • To recognize that pharmacists as health care providers improve access to patient care and bridge existing gaps in health care; further, • To collaborate with key stakeholders to describe the covered direct patient-care services provided by pharmacists; further, • To pursue a standard mechanism for compensating pharmacists who provide these services. Thank you for electing us to represent Arizona during the 65th Session of the ASHP HOD. Your voice is important to the profession especially to advance pharmacists as health care providers! Your feedback is encouraged. Please contact Mindy Burnworth mburnw@midwestern.edu, Carol Rollins carol. rollins@uahealth.com, or Christi Jen christi.jen@bannerhealth. com.

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20 • Arizona Journal of Pharmacy • Fall 2013

Arizona Delegates discuss policies with ASHP leadership at the Regional Delegate Conference May 2013 in Phoenix, Arizona: (left to right) Stan Kent, ASHP Immediate Past President; Carol Rollins, Christi Jen, Mindy Burnworth, Arizona Delegates; John Murphy, ASHP Past President; Brian Meyer, Director of ASHP Government Affairs Division Not pictured: Mitchell Buckley, Arizona Alternate Delegate

Featured Article The Mentor Connection Program: Perspectives from Both Sides

by Hillary Aphaisuwan, Pharm.D. Candidate, Midwestern University College of Pharmacy Glendale, Class of 2014; Stacy Lee, Pharm.D. Candidate, Midwestern University College of Pharmacy Glendale, Class of 2014 and Laura Tsu, Pharm.D., Midwestern University College of Pharmacy Glendale. The Arizona Pharmacy Association (AzPA) Mentor Connection Program matches practicing pharmacists with student pharmacists seeking professional mentorship beyond the scope of the Doctor of Pharmacy academic curriculum. A central goal of the program is to promote professional development of both members of the mentor-mentee relationship. Unlike more traditional mentorship programs, in which the benefits are mostly one-sided, this relationship has numerous benefits for both sides. The mentor’s role is to be an advisor that helps the mentee to develop their personal and professional goals. In return, the mentees provide insight into the changing world of pharmacy education and help their mentors maintain passion for the pharmacy profession. The AzPA Mentor Connection Program is anticipated to occur annually each October – July. To become involved, mentors and mentees must be AzPA members and submit an application and a current Curriculum Vitae (CV) to the AzPA Mentor Connection Program Standing Committee. Students and pharmacists are paired based on their geographical location, mentee area of practice interest/mentor primary AzPA academy affiliation, common professional affiliations and preference for individual or group mentorship. Mentors and mentees are encouraged to set goals for the nine month mentoring cycle which may include career planning, CV review, interview coaching, project collaborations, co-attendance at a professional meeting and/or discussions relating to professional growth and practice. Included in this article are perspectives from both sides of the mentor-mentee relationship for two mentees paired to a single mentor during the October 2012 – July 2013 mentoring cycle. Mentees: The AzPA mentorship program has been an extremely valuable experience and has exceeded my initial expectations. I thought that I would be seeing my mentor sporadically and exchanging emails only when I needed more insight regarding my professional and educational career. It has been comforting to know that I can go to my mentor for any advice or help that I may need. She has been a wonderful resource for helping me think about my future career path and the kind of pharmacist that I want to become. I did not expect to develop such a relationship with my mentor where I felt comfortable discussing any sort of problem, be it professional or personal. The most beneficial part of the mentor connection was the accessibility of my mentor. At first, I was concerned that since my mentor was a faculty member at my own school, I would not be able to ask for advice or discuss certain experiences that involved those at the school. However, my mentor assured me that confidentiality would be respected and that the AzPA Mentor Connection program is a separate entity from our faculty-student relationship. I also discovered that having a faculty member as my mentor gave me better insight into some of the issues I wanted to know more about. Because my mentor was so

accessible, I also felt I could stop by her office any time I needed guidance. My mentor has become my greatest resource during my educational career and has helped me greatly in all aspects of my time here at Midwestern. I have received much insight into becoming a great residency candidate, maximizing my rotations, and succeeding at difficult classes. Mentor: When I initially signed up for the Arizona Pharmacy Association’s Mentor-Connection program as a mentor, my goal was to develop a close working relationship with a few pharmacy students in order to provide guidance and support for their professional pharmacy goals. I assumed that I would be teaching the mentees and giving them advice. However, my mentormentee experience has shown me that I benefit just as much from my mentees as they have from me. Being a mentor allows me to give back to the pharmacy profession. It has been personally satisfying to watch the growth and development of my mentees as they face and overcome the challenges in their pharmacy curriculum, extracurricular activities, and personal life. My discussions with the mentees allow me to expand my viewpoints about pharmacy and help me to better understand the issues that student pharmacists face. Advising my mentees has helped me to reinforce important lessons and has made me a better faculty member for other students. Ultimately, being involved in the Mentor Connection program helps me stay motivated and continue to be a life-long learner. To learn more about AzPA’s Mentor Connection Program or to apply to be a mentor or mentee in an upcoming mentoring cycle (October – July), please visit the AzPA website or contact the current Mentor Connection Program Standing Committee Chair Jonathan Merchen jonathan.merchen@va.gov.

Arizona Pharmacy Association Mentor Connection Program

go ment t ors?

The AzPA Mentor Connection Program (AzPA MCP) provides the opportunity to build relationships, further professional networks, and strengthen continuous professional development on behalf of both mentors and mentees. The scope of this program supports AzPA’s vision of empowering pharmacy professionals to provide optimal patient care. AzPA MCP Program Goals • Promote personal and professional development of pharmacy students beyond curricular goals • Provide direction, foster confidence, and instill values needed to develop professionally • Create an engaging environment that instills renewed enthusiasm within the profession • Cultivate long-term relationships that evolve with time and are mutually beneficial Participation as a mentor or a mentee is open to all Arizona Pharmacy Association pharmacist (mentor) and student pharmacist (mentee) members. For more information about how to be a part of the AzPA MCP, contact Kelly Ridgway, AzPA CEO at kelly@azpharmacy.org Arizona Journal of Pharmacy • Fall 2013 • 21

Student Perspective AzPA Annual Convention: Exceeding Expectations

by Ryan Gries, Pharm. D. Candidate, Midwestern University College of Pharmacy - Glendale, Class of 2014. To say that this year’s AzPA’s annual convention, in particular the Student Tracks, exceeded my expectations would be a bold understatement. After going to the conference last year at the Wigwam, I was thoroughly impressed with the presence of Arizona’s world of Pharmacy. This inspired me to find ways to become more involved at this summer’s meeting. I can tell you firsthand that the Student Track Planning Committee, with the help of Dr. Lindsay Davis and Kathy Harty, AzPA Director of Professional Development, put a lot of time and effort into our programming. As I am certain a lot of those who attended the convention experienced, those efforts paid remarkable dividends in quality educational programming like the Lightning Rounds of Student Pearls as well as tremendous excitement at the Casino Royale Night. Altogether, some 150 students attended the convention. The weekend was filled with amazing presentations, a plethora of networking opportunities, luxurious accommodations, and smiles all around. The La Paloma was an excellent choice to house this year’s convention. Nestled up to Tucson’s mountain landscape, the views were incredible and the pool was refreshing for those who had time to sneak away from the Phoenix heat. Seriously, who decided to bring in the sweltering warm front for the weekend? Between the stops at the pool, dessert receptions, and social hours there was a great deal of business attended to. First off for the Student Track were five incredible presentations brought to us by our peers. I want to give a big shout out to Lara Petrossian, Ben Thompson, Karen Liu from Midwestern University and Steven Boyles and Marti Larriva from University of Arizona for their captivating works. Well done indeed! Next up was the Mock Interview Session. Over 50 students from both universities took advantage of the opportunity to hone their interviewing skills and receive some feedback on their CV’s. From the friendly sounds of chatter both during and after the event I’d say both the students and the preceptors took a lot away from this experience. The Finding Your Pharma-Niche Round Table discussions during the afternoon session were a pleasant change of pace. Here students were able to talk with Drs. Sandra Leal, Rick Herring, Mary Brubaker and several other prominent pharmacy practitioners in a nice, conversational setting. Many students later remarked on how fortunate they were to be able to directly ask questions to these leaders about their respective pharmacy roles.

Karen Paredes, Pharm.D. Candidate, U of A Class of 2015 carefully removes a Giant Jenga piece.

Easily the most entertaining, exciting, and amazing experience this year was the Casino Royale Night. Shout out to Quan Pham and his sharply dressed crew who helped make this party quite the success! I kid you not, this event rivaled the rest of the convention for highest attendance throughout the night, and I am certain, more fun was had nowhere else. From Black Jack tables, to a rowdy crowd playing Casino War, to the tumbling Jenga tower (sorry if the falling tower startled you!), the room was in a steady uproar!

The night reached its pinnacle with the crowd anxiously watching over the final round of Giant Jenga that reached close to 7 feet tall! This was a perfect integration of the new and youngat-heart members of AzPA. The games were going so strong we decided to delay closing so everyone could get a piece of the action. Our last event occurred Sunday morning, so those of you who stayed up too late might have missed out. Five collegiate teams competed in the first PharmOlympics. Here they had to accomplish such tasks as Rx deciphering, perfect pours, speed counting and tossing prescriptions. What better way to cap a solid weekend of activities than with a little friendly competition? As a student, this event continued to provide value to my peers and me. There are no better examples of leadership, opportunities for growth, and mentors with whom to connect in Arizona. Last year’s meeting may have been impactful, but this year’s was even more influential. We, as students, felt welcomed, embraced, and charged to lead the next chapter of Arizona’s pharmacy legacy.

MISSION STATEMENT The Arizona Pharmacy Association is committed to serving and representing all practice settings. AzPA will foster safe and effective medication therapy, promote innovative practice, and empower its members to serve the health care needs of the public. VISION

Gina Buiocchi, Pharm.D., and Ryan Gries, Pharm.D. Candidate, MWU, Class of 2014 enjoyed the annual convention.

Empowering pharmacy professionals to provide optimal patient care.

The Voice of Pharmacy in Arizona 22 • Arizona Journal of Pharmacy • Fall 2013

Student Perspective A Change of Perspective

by Marben Mopera, Pharm.D. Candidate, University of Arizona College of Pharmacy, Class of 2014 My time on rotation with AzPA was a great change of perspective. I wanted to see other sides of pharmacy, to know how pharmacy at large works, and to see how we interact with other organizations. There were many valuable experiences I gained, working with everyone to move our profession forward. Oddly enough, what I came here for was the same thing we need to move forward. A 2012 Gallup poll shows that the public sees pharmacy as being the most honest profession with the highest ethical standards1, second only to nurses, but we are still struggling to find places where we can make the most of our skills and knowledge in the community. In many places we are still in the basement. In many places we are still behind the counter. The people in our community trust us, as do so many of our colleagues in the health care team, but there is only so much we can do from our current positions. Things are changing, but they can still change more. On one task force where we were dealing with prescription narcotic abuse, we had to address issues with push back from some physician offices when pharmacists tried confirming new or odd narcotic prescriptions. In our eyes, we see ourselves as protecting patient and physician from abuse, but some doctors felt that pharmacists were over stepping boundaries, that this was a therapeutic decision that pharmacists should not judge. In another meeting, we were addressing challenges to the Appointment Based Model. This model involves pharmacists making regular monthly appointments with their patients, allowing them to synchronize all their medications for one pickup, as well as set aside time to privately counsel the patient and answer any questions and concerns they might have. Where this model was piloted it was very popular with patients and successful in increasing adherence, but one of the biggest barriers recognized was resistance from payers. Insurance would not be flexible with co-pays to allow partial fills in order to synchronize medications to the appointment date. They would also resist paying pharmacists for the counseling service that would be provided during the appointment. In these cases, we are mostly seen as dispensers, only in charge of making sure the medication was correct and giving it to the patient with correct instructions. They don’t look at us as the experts we are, with clinical skills and judgment, as well a wealth of experience and history with the patients we see much more often than any other health care provider. They don’t see us fitting in anywhere outside the role

Marben Mopera, Pharm.D. Candidate, U of A COP, Class of 2014

they are used to seeing us, and are missing out on all the other services we can provide. Things have changed, and are continuing to change for us. As organizations like AzPA continue to advocate for us, bit by little bit, the world is seeing us differently. We can now immunize without a prescription or collaborative practice agreement. Whereas before, it was a thing left for the doctor’s office, vaccines are now much more accessible by just visiting your local pharmacy. I attended a meeting with the Arizona Department of Health where they were seeking support for a five-year grant to help with their chronic disease management initiative. Department of Health staff at the meeting had stories about being able to rely on a pharmacist for advice and information, and wanted to know if they could get pharmacists involved in their plans for improving chronic disease management in the state. We are working towards a place where we can be fully utilized, find the best use of our abilities, and give to our communities the most we have to offer. As time goes on, we are moving in front of the counter, and being accepted in a place where our interaction is welcome and our expertise relied on. That work becomes easier the more we are seen differently. The greatest thing I’ve learned from being at AzPA was that the biggest catalyst for that change was the same thing I came here to find; a great change in perspective of the practice of pharmacy. 1. Gallup. (2012). Honesty/Ethics in Professions. Retrieved Sep. 12, 2013, from http://www.gallup.com/poll/1654/honesty-ethics-professions.aspx#1

The Arizona Pharmacy Association presents PTCB EXAM REVIEW COURSE COMPLETELY REVISED CONDUCTED IN 7 ONLINE PRE-RECORDED WEBINARS*. Only $395 Go to www.azpharmacy.org to register. *Class requirements: Internet connectivity, Windows Media Player and Adobe Acrobat Reader are required for participation in this class. System Requirements PC-based attendees • Required: Windows® 7, Vista, XP or 2003 Server Macintosh®-based attendees • Required: Mac OS® X 10.6 or newer Mobile attendees • Required: iPhone®, iPad®, Android™ phone or Android tablet **This course does not provide training to become a pharmacy technician. It is intended for those preparing to take the PTCB technician certification exam. Prior work experience is strongly recommended. This review course does not include nor does it register you for the PTCB National Certification Exam. Fall 2013 • Arizona Journal of Pharmacy • 23

Academy News Community Pharmacy Academy I am looking forward to serving as Chair of the Community Pharmacy Academy (CPA) and representing you on the AzPA Board of Directors. Thank you to Kristin Calabro, the immediate past Chair, for her leadership and contributions during the last year and welcome to Grace Akoh-Arrey as Chair-Elect. The CPA was well represented at the AzPA Membership Event on August 24, 2013. “Team Betty” recruited 14 new members for the Association and had a great time competing against the other three teams. Everyone was a winner as we increased the current number of AzPA members and then celebrated by watching the Arizona Cardinals game. Thank you to all who participated. Be sure to attend the 2013 AzPA Fall Pharmacy Conference on Saturday, October 26, 2013 (details on page 7.) This day-long event will offer 6.0 contact hours (0.60 CEUs) of continuing pharmacy for pharmacists and pharmacy technicians. Topics include a law session on e-prescribing controlled substances, an update on immunizations for the geriatric population, and a program on over-thecounter drugs. Breakout sessions are planned based on practice specialty, including community pharmacy. The CPA is in need of committee members to represent the Academy on the Membership and Communications Committees. This is a small time commitment but our Academy’s participation and contributions to these AzPA Standing Committees is vital to our organization. If you enjoy writing or have a knack for proof-reading, give the Communications Committee a try. Are you a natural networker? We need you to help recruit and retain active AzPA members. If you are interested in representing CPA, please contact me at cpa@azpharmacy.org. Let’s have great year!

Betty Louton, Pharm.D. Community Pharmacy Academy Chair cpa@azpharmacy.org

Geriatric Care Academy It is my pleasure to take over as chair of the Geriatric Care Academy. Thank you to Dr. Tara Storjohann for her guidance and mentorship over the past year when I served under her as the GCA Chair-Elect, and welcome to Dr. Nicole Kitts to the Board of Directors as the current GCA Chair-Elect. I invite everyone that is interested in geriatrics to get more involved in the GCA. The 2012-13 goals for the GCA are to increase AzPA member involvement in our academy, provide education about geriatric medicine to other health care professionals and to serve the geriatric population. The GCA is currently planning several events and I invite all members to be part and attend our monthly conference calls on the second Wednesday of the month at 12 noon. We are in the process of planning the AzPA Fall Pharmacy Conference which will be held at Desert Willow Conference Center in Phoenix on October 26, 2013. This conference is a joint effort between the Community Pharmacy Academy, the Geriatric Care Academy, and the Technician Academy. I encourage everyone to attend this jam-packed day of CE and networking. The GCA is looking for volunteers to participate in the Arizona Mission of Mercy, a dental mission held at the Arizona Fairgrounds on December 13th and 14th that serves those who are less fortunate in the community. We are looking for pharmacists and pharmacy technicians who want to give a few hours of their time to provide medication dispensing and counseling services at the event. If you are interested in getting more involved, please e-mail me at gca@azpharmacy.org. Finally, I would like to remind everyone of the 2013 ASCP Annual Meeting & Exhibition that is schedule for November 20-22nd in Seattle Washington. I am looking forward to an exciting and fun year for the GCA. As always, if anyone has any questions or wants to get more involved in the GCA, feel free to contact me at any time.

Elizabeth Pogge, Pharm.D., MPH, BCPS, FASCP Geriatric Care Academy Chair gca@azpharmacy.org 24 • Arizona Journal of Pharmacy • Fall 2013

Academy News Health-System Academy News Fall is in the air and just like football, Health-System Academy (HSA) kicks off another year! I would like to thank Lindsay Davis for all her hard work this past year. With her leadership, our academy has developed strong goals with great representation in pharmacy. Thank you is not enough for all the effort and dedication you put into our academy! I want to welcome and introduce the members of this year’s HSA Executive Committee, who are volunteering their time and effort to achieve goals we set forth during the Annual Meeting: • Mitch Buckley Chair Elect and Annual Spring Conference Planning Chair (2014) • Lindsay Davis Immediate Past Chair • Jon Merchen Mentorship Connection Chair (and HSA Past Chair) • Carol Rollins Communication Director and ASHP House of Delegate Representative • Christi Jen Education Director and ASHP House of Delegate Representative • Mindy Burnworth ASHP House of Delegate Representative (and HSA Past Chair) • Whitney Shields Membership Director • Patty Ritz Annual Spring Conference Poster Session Coordinator • Nisa Cooper Technician Representative • Abbey Siegler Tucson New Practitioner Representative • Scott Hall Phoenix Metro New Practitioner Representative • Pritesh Patel UA COP SSHP President • Pearce Engelder UA COP SSHP President-Elect • Heather Kober MWU CPG President Planning is just starting for the Spring Clinical Conference. If you have a topic you would like to see discussed, have a dynamic speaker in mind or are interested in being on the planning committee, please contact Mitch Buckley (via hsa@azpharmacy.org). This year’s conference will be held in Tucson and will be a joint effort between Health-System, Geriatric and Managed Care Academies. It should be a record year for attendance and will provide our members with some great CE and poster presentations! The Mentor Connection Program is in its third year. Led by Jon Merchen, mentees (students and technicians) and mentors (practicing pharmacists) were recently trained and matched for the 10-month mentoring cycle. Our ASHP House of Delegate (HOD) Representatives are actively representing Arizona at the national level by bringing policy recommendations forward. These recommendations come from you, our members. They are always looking for new ideas, so please speak up! You will be receiving quarterly emails soliciting recommendations, but they are always welcome. We will be holding ASHP HOD Elections in the months to come, so if you want more information, please do not hesitate to ask. Just a reminder that the articles in this journal come from you; if you have a topic you are interested in presenting or a student or resident has written a great piece that should be shared, please submit it to AJP. If you have any questions, please reach out to Christi Jen (via hsa@azpharmacy.org). We are always looking for new members who want to get involved. Many of the responsibilities may only take a couple hours a month. If you are interested in getting involved at any level, contact us at hsa@azpharmacy.org. We are only as good as our members and want to hear from you! When you are reluctant to change, think of the beauty of autumn. - V. B. Brown

Kristen Allison, Pharm.D., BCPS, BCPP Health-System Academy Chair hsa@azpharmacy.org The Health-System Academy of the Arizona Pharmacy Association is the Arizona affiliate of the American Society of Health-System Pharmacists (ASHP).

Fall 2013 • Arizona Journal of Pharmacy • 25

Academy News Managed Care Academy News The Managed Care Academy has set its goals for the coming year. Mentoring students and developing opportunities for community engagement are top priorities. We were fortunate to have Ann Sears at the helm of our Academy last year. We congratulate her on her election as AzPA President Elect and look forward to more great things from her. Congratulations to Paul Lynne our new Chair-Elect. I look forward to working with him and all our members as we represent managed care on the AzPA Board of Directors. Thank you to all the members of the MCA who participated in the AzPA Membership Event on August 24, 2013. “Team Eric” was the top-recruiting team with 53 new members for the Association. It was a fun and friendly-competitive day at the University of Phoenix Stadium with our AzPA peers. The MCA will be actively involved in planning the 2014 AzPA Spring Clinical Conference scheduled for April. If you have a topic or speaker of particular interest that would like to recommend for this Conference, please contact me at mca@azpharmacy.org. MCA Executive Committee: Chair: Eric Luecht Chair-Elect: Paul Lynne Past Chair: Ann Sears CE Committee: Jackie Griffith Communications Committee: OPEN Conference Planning Committee: OPEN Legislative Affairs Committee: Ken Bykowski Membership Committee: Nicole Henry We still have a few openings to fill on our MCA Executive Committee. This is a great way to get involved in our Association and give back to the profession of pharmacy. I hope you will consider volunteering your time to represent MCA on one of these committees. Contact me at mca@azpharmacy.org or contact the AzPA office with your questions.

Eric Luecht, R.Ph. Managed Care Academy Chair mca@azpharmacy.org

Technician Academy News The Pharmacy Technician Certification Board (PTCB) will introduce its updated Pharmacy Technician Certification Exam (PTCE) on November 1, 2013. The updated exam measures the knowledge pharmacy technicians need to effectively support pharmacists and advance patient safety in today’s pharmacies. Candidates who apply for PTCB certification before November 1, 2013 will be given the current PTCE, and those who apply on or after November 1, 2013 will take the updated exam. The Arizona Pharmacy Association offers a PTCB Exam Review Course designed to prepare pharmacy technicians to successfully pass PTCB’s technician certification exam. Completely revised and available online and on demand, the course consists of seven online sessions to help you study and prepare for the PTCB Exam. The course is ideal for those technicians-in-training needing to become certified, as well as those technicians who wish to become recertified through PTCB. For complete information about the PTCB Exam Review Course, visit the AzPA website at www.azpharmacy.org Plan to attend the AzPA Fall Pharmacy Conference on Saturday, October 26, 2013, offering 6.0 contact hours (0.60 CEUs) of continuing pharmacy education including two programs accredited specifically for technicians. The theme of the conference is Expanding the Partnership of Pharmacy Care. Details are on page 7. During the 2013 AzPA Membership Drive, 55 new member technicians were recruited, raising our total to 165, an all-time high. Congratulations to Reg Roy, C.Ph.T, Technician Academy Chair-Elect for his award for recruiting the most number of new members and compiling the highest number of points. We want to hear from all our Arizona pharmacy technicians with ideas for future programming and involvement in our profession. Please email me at tech@azpharmacy.org.

Judi Day, C.Ph.T Technician Academy Chair tech@azpharmacy.org 26 • Arizona Journal of Pharmacy • Fall 2013

Academy News Student Pharmacist Academy News Thank you the 2012-2013 SPA Co-Chairs, Sophia Galloway from Midwestern University and Eric Wong from the University of Arizona. Under their leadership the Student Pharmacy Academy is considered a student organization within each of the respective universities. We now count nearly 500 AzPA student pharmacist members! Student members are going to significantly benefit by being able to become more involved within our profession. Congratulations to the AzPA Student Pharmacist Academy Co-Chairs Elect: Nicole Runge, Midwestern University, and Pearce Engelder, University of Arizona. They were elected by the AzPA members at their respective schools to serve on the AzPA Board of Directors, along with current Co-chairs Sabrina Pennock, Midwestern University, and Pritesh Patel, University of Arizona. The 2013 AzPA annual meeting was incredibly beneficial for the student pharmacists of the University of Arizona and Midwestern University. There was a new record with a total of over 150 students in attendance and large participation in the “Student Track” portion of the convention. Students were able to participate in a mock interview and CV review session, present ‘clinical pearls,’ participate during a roundtable discussion, test their pharmacy skills in the PharmOlympics, and network during Casino Night. The student track planning committee did a fantastic job and the Student Pharmacist Academy looks forward to this track next year. Thank you to the students how organized and coordinated these sessions and activities: Sophia Galloway, Sikeat Yip, Eric Wong, Pritesh Patel, Kevin Yee, Ryan Gries, Sabrina Pennock, Quan Pham, Stacy Padilla, Laura Johnson, Mary Salem, Melissa Thomas, Connor Scheidt, Ross Rosenburg, and Thu Nguyen. Kelly Ridgway, R.Ph., Arizona Pharmacy Association CEO will be visiting both colleges of pharmacy during the month of October to meet the student body and provide an update on current issues and initiatives for the pharmacy profession. Be sure to wear your AzPA tee or polo shirt to the event and get in the photo for AzPA on Campus Day! Bring your friends and encourage them to join the only statewide organization in Arizona that represents all pharmacy professionals - including students. It’s not too early to mark your calendar for 2014 PD@C - Pharmacy Day at the State Capitol - on Tuesday, February 12, 2014. Plan to take this opportunity to meet our state legislators and provide information about the value of our profession to our communities. We are looking forward to another exciting year brought on by these new opportunities. Email us with your suggestions, questions, and ideas for this year. Sabrina Pennock, SPA Co-Chair, Midwestern University College of Pharmacy Glendale spennock67@midwestern.edu Pritesh Patel, SPA Co-Chair, University of Arizona College of Pharmacy pritesh.patel@pharmacy.arizona.edu

Do you know someone who is not a member of the Arizona Pharmacy Association . . . and should be?! Invite them to join the only statewide organization that represents the pharmacy profession in Arizona. Annual dues for a pharmacist are just $20 per month! This equates to: • Approximately 2/10 of 1% of the annual wage for a new practitioner pharmacist • Less than 5 hours of work per year, after taxes • Less than 62 cents per day

Arizona Pharmacy Association

Visit the AzPA website at www.azpharmacy.org to join online or to download a printable Membership Investment Statement. AzPA values its members and recognizes that your time is valuable. Monthly payment plans are available for pharmacist membership categories, as well as an automatic annual renewal option, when you provide your credit card information.

Fall 2013 • Arizona Journal of Pharmacy • 27

Drug Information Question

Question: What evidence is available on aldosterone antagonists for use in heart failure with preserved ejection fraction? by Vivian Loo, Pharm.D. Candidate, Class of 2014, and Laura Tsu, Pharm.D., BCPS, Midwestern University College of Pharmacy – Glendale

Answer: Introduction

Heart failure (HF) is primarily caused by abnormalities in cardiac systolic or diastolic function, which dictate the prevalence, prognosis, and pharmacotherapy used to treat the patient. Diastolic heart failure can be referred to using several interchangeable terms such as HF with normal ejection fraction, diastolic dysfunction, or the newest terminology being HF with preserved ejection fraction (HFpEF). HFpEF is accountable for over half of HF patients and its prevalence depends on various factors, with age being the most important determinant. Several large, randomized, multi-center, doubleblinded trials have been conducted to create guidelines for systolic HF treatment, which is also known as HF with reduced ejection fraction (HFrEF). In contrast, few trials have been published on the treatment of HFpEF.1,2 Currently, the Heart Failure Society of America (HFSA) 2010 guidelines recommend the use of diuretics, angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), beta-blockers, and calcium channel blockers as possible treatments for HFpEF.3 While there are options for the treatment of HFpEF, most of the currently suggested medications for treatment have grade C recommendations, which are based on “expert opinion, epidemiologic findings from observational studies, and safety findings from large-scale use” unless specifically indicated for a compelling indication.1,3 The lack of concrete evidence and treatment recommendations for HFpEF signals a further need for other therapy options, leading to the investigation of aldosterone antagonists as a potential treatment option. Studies have demonstrated that the mineralocorticoid aldosterone is stimulated by angiotensin II and activates mineralocorticoid receptors to cause sodium retention, potassium excretion, endothelial dysfunction, vascular inflammation, hypertrophy, and fibrosis—all mechanisms that contribute to the pathophysiology of HF.4,5 Despite the use of ACEIs in HF treatment, aldosterone levels may still potentially increase, indicating that ACEIs may not fully suppress angiotensin formation. Increased levels of aldosterone have been associated with impaired functional capacity, decreased ventilator response during exercise, and an increase in cardiovascular mortality, making aldosterone a potential target for HF treatment.5 The 2 most commonly used aldosterone antagonists are spironolactone and eplerenone. Spironolactone (Aldactone®) is generically available and is a nonselective aldosterone receptor antagonist. Its nonselectivity is associated with the adverse effect of gynecomastia. Eplerenone (Inspra®) is a spironolactone derivative, is not yet available as a generic, and has higher 28 • Arizona Journal of Pharmacy • Fall 2013

selectivity for the mineralocorticoid receptor with less binding to androgen and progesterone receptors compared to spironolactone.1,5 Aldosterone antagonists have been proven to be effective in the treatment of HFrEF in the Randomized Aldactone Evaluation Study (RALES) trial, demonstrating a 31% decrease in cardiovascular mortality and a 30% risk reduction in all-cause mortality in the spironolactone treatment group compared to placebo. Similarly, the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF) trial evaluated death from cardiovascular causes and hospitalization for HF as the primary outcome in which the eplerenone treatment group experienced a significantly decreased incidence (18.3% eplerenone group vs. 25.9% control group). The treatment group also had a statistically significant 38% reduction in hospitalizations for HF and demonstrated a decrease in all-cause mortality in comparison to the control group.5 The HFSA 2010 guidelines strongly recommend (grade A) the use of an aldosterone antagonist for New York Heart Association (NYHA) class IV HF with left ventricular ejection fraction (LVEF) < 35% in addition to standard therapy classified as ACEI/ARB and beta-blocker therapy.3 While the RALES and EMPHASIS-HF trials have demonstrated a place for aldosterone antagonists in HFrEF treatment, aldosterone antagonists have not been included in HFpEF treatment guidelines yet. Spironolactone and eplerenone have been further investigated as options for HFpEF treatment in 3 clinical trials over the past 2 years. Clinical Trials The RAAM-PEF (Randomized Aldosterone Antagonism in Heart Failure with Preserved Ejection Fraction) trial was a randomized, double-blinded, placebo-controlled, single-center study conducted by Deswal et al. comparing eplerenone 25-50 mg to placebo over 24 weeks in 44 patients. Investigators determined that a sample size of 21 patients in each group was necessary to provide 85% power with a 2-tailed α level of 0.05 in order to detect differences in endpoints. The primary endpoint was defined as a change in 6-minute walk distance (6MWD) from baseline after the 24 weeks of randomization and treatment.6 The 6MWD measures the distance that a patient can walk on a flat, hard surface in a period of 6 minutes to determine functional capacity and is predictive of hospitalization rates and mortality in HF patients.4,7 Secondary endpoints included echocardiographic measurements of diastolic dysfunction, biomarkers such as collagen turnover and B-type natriuretic peptide, HFrelated quality of life using the Kansas City Cardiomyopathy Questionnaire, and NYHA class.6

Drug Information Question (continued from page 28) The results of this study showed an improvement in the primary endpoint of 6MWD in both placebo and treatment groups, although the difference was not significant (p = 0.91). Similarly, all secondary endpoints were not found to be statistically significant with the exception of the E/E’ ratio and amino-terminal peptide of procollagen type I (PINP) and carboxyl-terminal telopeptide of collagen type I (CITP) biomarkers. The E/E’ ratio, which measures left ventricular filling pressure and is regarded as the best index for detecting diastolic dysfunction in HFpEF, was significantly decreased in the eplerenone group (p = 0.01) compared to the placebo group, which demonstrated an increase in the E/E’ ratio. The PINP and CITP biomarkers evaluate collagen turnover and are used as noninvasive markers to monitor the regression of myocardial fibrosis. At baseline versus 24 weeks in the eplerenone group, both PINP and CITP levels were significantly decreased (p = 0.009 and p = 0.026, respectively). The trial concluded that although eplerenone treatment in patients with HFpEF did not improve exercise capacity as measured through the 6MWD test, it did result in beneficial changes to collagen turnover and diastolic function.6 The Aldo-DHF (The Aldosterone Receptor Blockade in Diastolic Heart Failure) trial was a randomized, doubleblinded, placebo-controlled, prospective, multi-center trial conducted by Edelmann et al. comparing spironolactone to placebo. Four hundred thirty-three patients were randomized to receive spironolactone 25 mg or placebo and were followed for approximately 12 months. Type I and II error rates were set at 0.05 (α) and 0.1 (β), respectively, with a power of 90% and an estimated sample size of 420 patients. The co-primary endpoints compared spironolactone therapy to placebo on diastolic function (E/E’ ratio) and maximal exercise capacity (peak VO2) during cardiopulmonary exercise testing in patients with HFpEF. Peak VO2 was defined by the study as the maximum value of the last three 10-second averages during exercise. Secondary endpoints included echocardiographic measures of cardiac function and remodeling, submaximal and maximal exercise capacity, serum biomarkers, quality of life, morbidity, and mortality.4 The results of the Aldo-DHF trial showed an improvement in the primary endpoint of diastolic dysfunction as measured by the E/E’ ratio. Echocardiographic results of the treatment group showed a decrease in the E/E’ ratio after 12 months compared to placebo (95% CI, -2.0 to -0.9, p < 0.001). The primary endpoint of maximal exercise capacity did not differ significantly between the treatment and placebo group after 12 months (p = 0.81). Other secondary endpoints of note in the spironolactone group versus placebo group included an increase in LVEF (95% CI, 0.1 to 3.1, p = 0.04), increase in 6MWD (95% CI, -27 to -2, p = 0.02), decrease in left ventricular mass index (95% CI, -10 to -1, p = 0.009), and decrease in left ventricular end diastolic diameter (95% CI, -2.5 to -0.3, p = 0.01). The study also acknowledged that it was not adequately powered to assess the secondary endpoints of morbidity and mortality. The trial concluded that spironolactone treatment in HFpEF patients improved diastolic function and left ventricular function but had no

effect on maximal exercise capacity.4 The clinical study TOPCAT (Treatment Of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) is a multi-center, international, randomized, double-blinded, placebo-controlled trial using 15-45 mg of spironolactone. The study was conducted with 3,445 subjects aged 50 years or older, recruited from over 200 clinical centers, with HF and LVEF ≥ 45%, HFpEF, controlled systolic blood pressure, and a serum potassium < 5.0 mEq/L. The primary endpoint was a composite of cardiovascular mortality, aborted cardiac arrest, or hospitalization for the management of HF. Secondary endpoints included all-cause mortality, new onset of diabetes mellitus or atrial fibrillation, and quality of life. The study ended in January of 2012 and the results are expected to be published in the near future.8 Discussion The RAAM-PEF and Aldo-DHF trials found that aldosterone antagonist use in patients with HFpEF improved diastolic dysfunction as measured by the E/E’ ratio. However, according to the Aldo-DHF trial, there is currently no accepted minimal clinically important difference in E/E’ that should be achieved to alter the prognosis of HFpEF.4 Both trials also studied exercise capacity as measured by the 6MWD. The RAAM-PEF trial, which evaluated patients after 6 months of therapy, did not find a statistically significant difference between the eplerenone and placebo group while the AldoDHF trial, which evaluated patients after 12 months, found a marked improvement in the spironolactone group. The difference in these results may be attributed to the length of the 2 trials in which the RAAM-PEF trial may not have had adequate time for eplerenone to exert a clinical effect on 6MWD. It is also important to note that the RALES and EMPHASIS-HF trials evaluated aldosterone antagonists in HFrEF patients through the primary outcomes of differences in morbidity and mortality. In contrast, the RAAM-PEF and Aldo-DHF trials were only able to evaluate surrogate markers of morbidity and mortality in HFpEF such as diastolic function and exercise capacity. In addition, the populations in both trials consisted mainly of NYHA class II patients. Therefore, the results of these studies may not be generalizable to sicker populations in the NYHA class III and IV categories. Also, RAAM-PEF was studied at the Veterans Affairs Medical Center in Houston, Texas, and all but 3 patients were male, indicating that the results are most applicable to men. There is also concern with the risk of hyperkalemia because a major adverse effect of aldosterone antagonists is an elevation in potassium levels. Most, if not all, HF patients’ medication lists include an ACEI/ARB to prevent cardiac remodeling. The combination of an ACEI/ARB with an aldosterone antagonist may potentially increase the risk of an elevated potassium level leading to hyperkalemia and subsequent arrhythmias. In both trials, a nonstatistically significant difference was found between groups in the development of hyperkalemia, defined as a serum potassium ≥ 5.5 mEq/L.3,5 Thus, it can be concluded that with appropriate Fall 2013 • Arizona Journal of Pharmacy • 29

Drug Information Question (continued from page 29) and routine laboratory monitoring of serum potassium levels, aldosterone antagonists can be safely used in HFpEF patients who are on concurrent ACEI/ARB therapy. Based on the evidence provided by RAAM-PEF and AldoDHF, an aldosterone antagonist may be a potential additive therapy for HFpEF if the patient’s blood pressure and heart rate are controlled and serum potassium levels are carefully monitored. While these trials have shown improvement in diastolic function and potential increases in exercise capacity, the effects of aldosterone antagonists on the long-term morbidity and mortality of HFpEF patients still remains to be seen as investigated through the TOPCAT trial. The results of the TOPCAT trial will provide more evidence about aldosterone antagonist use in HFpEF due to its clinical endpoints. References 1. Nappi JM, Page II RL. Diastolic heart failure and the cardiomyopathies. In: DiPiro JT, Talbert RL, Yee GC et al., eds. Pharmacotherapy: a pathophysiologic approach. 8th ed. New York: McGraw-Hill; 2011. 2. Parker RB, Cavallari LH. Systolic heart failure. In: DiPiro JT, Talbert RL, Yee GC et al., eds. Pharmacotherapy: a pathophysiologic approach. 8th ed. New York: McGraw-Hill; 2011. 3. Heart Failure Society of America, Lindenfeld J, Albert NM et al. Management of heart failure in special populations: HFSA 2010 comprehensive heart failure practice guideline. J Card Fail. 2010; 16:e169-75. 4. Edelmann F, Wachter R, Schmidt AG et al. Effect of spironolactone on diastolic function and exercise capacity in patients with heart failure with preserved ejection fraction: the Aldo-DHF randomized controlled trial. JAMA. 2013; 309:781-91. 5. Talatinian A, Chow SL, Heywood JT. Expanding role of mineralocorticoid receptor antagonists in the treatment of heart failure. Pharmacotherapy. 2012; 32:827-37. 6. Deswal A, Richardson P, Bozkurt B et al. Results of the Randomized Aldosterone Antagonism in Heart Failure with Preserved Ejection Fraction trial (RAAM-PEF). J Card Fail. 2011; 17:634-42. 7. ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med. 2002; 166:111-7. 8. Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist, TOPCAT. www.topcatstudy.com/index.asp (accessed 2013 Jul 13).

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www.azpharmacy.org/jobs AzPA Calendar of Events October American Pharmacists Month Friday, October 18, 2013 Residency Training Symposium & Workshop Wednesday, October 23, 2013 AzPA @ Work Day Friday, October 25, 2013 AzPA Anticoagulation Certificate Program Saturday, October 26, 2013 AzPA Fall Pharmacy Conference Thursday, February 20, 2014 Llyn Lloyd Scholarship Golf Tournament Friday, February 21, 2014 AzPA Psychiatric Certificate Program and Pharmacist and Patient-Centered Diabetes Care Certificate Training Program Saturday, February 22, 2014 APF Southwest Pharmacy Symposium Visit www.azpharmacy.org for all upcoming events. Arizona Pharmacy Association

The Voice of Pharmacy in Arizona 30 • Arizona Journal of Pharmacy • Fall 2013

Continuing Education

Antimicrobial resistance: A review of antimicrobial mechanisms, bacterial resistance, and pharmacotherapy options for the treatment of resistant bacterial infections in adults

by Jon G. Merchen, Pharm.D., BCPS, Davena M. Norris, Pharm.D., PGY1, Alicia Ortega, Pharm.D. PGY1, Southern Arizona VA Health Care System, Tucson, AZ Department of Internal Medicine Goal: This program has been developed to update pharmacists and/or pharmacy technicians on the treatment of resistant bacterial infections in adults Objectives: At the conclusion of this lesson, successful participants should be able to: 1. Identify mechanisms of antimicrobials and bacterial resistance. 2. Describe treatment options of antibiotic resistant gram (-) bacterial infections, specifically ESBL and KPC. 3. Describe treatment options of antibiotic resistant gram (+) bacterial infections, specifically VRE and MRSA. Introduction Antimicrobial resistance is becoming a growing concern throughout the world, and drug resistant infections have become one of the world’s greatest health threats according to the World Health Organization (WHO). It is evident that as more knowledge is gained regarding the mechanisms of bacterial resistance, new solutions to combat these issues are desperately needed. While many bacteria have shown some form of antimicrobial resistance, extended spectrum betalactamase (ESBL) producers, Klebsiella pneumoniae carbapenemase (KPC) producers, and resistant Enterococci and Staphylococcus aureus are among the most concerning. As reported by the IDSA, methicillin-resistant Staphylococcus aureus (MRSA) kills more Americans annually than emphysema, HIV/AIDS, Parkinson’s disease, and homicide combined.1 This program will discuss the mechanisms of drug resistance and the management of antimicrobial resistant bacterial infections. Antimicrobial Mechanisms of Action Antimicrobial agents can be classified based on the mechanism of action. The four main modes of antimicrobial action are: 1) interference with cell wall synthesis, 2) inhibition of protein

Table 1. Mechanisms of action of antibacterial agents2

Mechanism of action Interference with cell wall synthesis Inhibition of protein synthesis

Interference with nucleic acid synthesis Inhibition of metabolic pathway Disruption of bacterial membrane structure

synthesis, 3) interference with nucleic acid synthesis, and 4) inhibition of a specific metabolic pathway (table 1). Within each category of action, a particular antimicrobial agent may affect each process in a different way.2 Mechanisms of Resistance of Microorganisms to Antimicrobials Clinical resistance of organisms to antimicrobial agents occurs when the minimum inhibitory concentration (MIC) of a drug to a particular strain of bacteria exceeds the concentration capable of being achieved in vivo. Resistance can develop in a single step or from accumulation of multiple mutations. Cross resistance implies that a single mechanism confers resistance to multiple agents, while multiple resistance implies more than one mechanism is involved. The former is seen with agents within the same class, while the latter is seen with agents from different classes. Some bacterial species may have innate resistance to one or more antibacterial agents.2 The main mechanisms in which resistance to antimicrobials occurs include: 1) altered permeability of the antimicrobial agent, such as efflux pumps, 2) inactivation of the antimicrobial agent through genes that code for enzymes, such as beta lactamases that destroy the antibiotic, 3) an altered target site for the antibiotic agent, and 4) replacement of a sensitive pathway, such as acquisition of a new enzyme. Multidrug resistance occurs through several genetic exchange mechanisms, including transformation, conjugation, and transduction. Multidrug resistant organisms (MDRO) are those that are non-susceptible to ≥ 3 antibacterial categories to which the organism is

Antibacterial agents Beta lactams: penicillins, cephalosporins, carbapenems, monobactams (aztreonam) glycopeptides: vancomycin, televancin Binds 50S ribosome: macrolides, chloramphenicol, clindamycin, quinupristin-dalfopristin, linezolid Binds 30S ribosome: aminoglycosides, tetracyclines DNA synthesis: fluoroquinolones, metronidazole RNA synthesis: rifampin tRNA synthetase: mupirocin Sulfonamides, folic acid analogues Polymixins, daptomycin

usually susceptible and are a growing cause for concern.2 Gram Negative Resistance Extended Spectrum Beta-lactamase (ESBL) producers ESBL was first discovered in Germany in K. pneumoniae in 1983, but has now spread across the world.3 The first case in the U.S. occurred in 1988. The primary organisms expressing ESBL are K. pneumoniae, K. oxytoca, and E. coli.4 Other potential species are Acinetobacter, Burkholderia, Citrobacter, Enterobacter, Morganella, Proteus, Pseudomonas, Salmonella, Serratia, and Shigella. Resistance of an isolate to thirdgeneration cephalosporins or aztreonam is suspicious for ESBL, but requires phenotypic confirmation testing.5 ESBL confers resistance to penicillins, older generation cephalosporins, and oxyiminocephalosporins (cefotaxime, ceftazidime, ceftriaxone).4 Some laboratory evidence exists regarding the susceptibility of ESBL to carbapenems, cephamycins (cefoxitin, cefotetan), and beta-lactam/beta-lactamase inhibitor combinations. Epidemiology and Risk Factors for Resistance The National Nosocomial Infection Surveillance System Report recorded ESBL resistance rates in the U.S. from January 1998 to June 2002.5 This report determined ESBL K. pneumonia occurs in 6.1% of ICU isolates and 1.8% of nonICU isolates. The incidence of ESBL infections is not well established and may be underreported. ESBL mainly occur in nosocomial infections, but community-acquired infections have also occurred.4 Risk Fall 2013 • Arizona Journal of Pharmacy • 31

Continuing Education (continued from page 31) factors for ESBL include longer hospital stays (especially in the ICU), presence of catheters and feeding tubes, emergency abdominal surgery, low birth weight, prior antibiotic use, mechanical ventilation, and hemodialysis. Mechanism of Resistance ESBL targets the beta-lactam ring for hydrolysis, causing opening of the ring and inactivation of the beta-lactam antibiotic.4 Over 100 varieties have been characterized, all of which reside on plasmids.3 The most common variety is CTX-M, followed by SHV and TEM.4 Varieties may have slightly different resistance patterns, but the clinical importance of these differences has not been elucidated. Treatment of ESBL Infections The best clinical outcomes for ESBL treatment have been found using carbapenems. An Italian study compared response to ciprofloxacin versus imipenem in susceptible ESBL K. pneumoniae bacteremia.6 Eighty percent of patients in the imipenem group attained a complete response compared to the ciprofloxacin group that had only 29% with a partial response and the rest failing therapy. A study investigated the 14-day mortality rates of different antibiotics in ESBL K. pneumoniae.7 Patients treated with carbapenems had a significantly lower mortality rate compared to those who received other antibiotics (4.8% vs. 27.5%, p=0.012). Other antibiotics used included ciprofloxacin, cephalosporins, beta-lactam/beta-lactamase inhibitor combinations (BLBLI), and amikacin. Another study compared mortality rates in ESBL E. coli bacteremia for patients treated with BLBLIs or a carbapenem.8 The IV BLBLIs used were either piperacillin-tazobactam or amoxicillinclavulanate. Of note, amoxicillinclavulanate IV is not available in the US. All organisms were susceptible. No difference in mortality between the two groups was found. The results of this study indicate IV BLBLIs may be used for ESBL bacteremia, but the susceptibilities must be known before initiating treatment. However, IV BLBLIs should be used cautiously as case reports indicate resistance may develop during therapy despite initial susceptibility.9 A final study investigated the potential of using cefepime in ESBL E.coli, K. pneumoniae, 32 â€˘ Arizona Journal of Pharmacy â€˘ Fall 2013

and E. cloacae bacteremias.10 Clinical failure, microbiological failure, and 30day mortality were significantly worse in those treated with cefepime compared to those receiving carbapenems. Overall, carbapenems attain the best clinical outcomes in treating ESBL infections of the antibiotics studied thus far. While any of the carbapenems should work, clinicians should note new data indicating worse outcomes in ventilator-associated pneumonia (VAP) with doripenem.11 BLBLIs can potentially be used once susceptibilities are known. Treatment failures with carbapenems occur and there is some interest in using colistin in these cases. However, no clinical studies have been completed. Klebsiella pneumoniae carbapenemase (KPC) producers North Carolina was the first known case of KPC in 1996.12 Endemic areas include the northeastern U.S., Greece, Israel, Puerto Rico, and Columbia.13 The primary organism expressing KPC is its namesake, K. pneumoniae.13,14 This resistance gene has also been detected in E. coli, Pseudomonas aeruginosa, Proteus mirabilis, Acinetobacter baumannii, Citrobacter, Salmonella, Serratia, and Enterobacter. KPC causes resistance to all beta-lactams including carbapenems and aztreonam.14 Epidemiology and Risk Factors for Resistance In the U.S., carbapenemases in K. pneumoniae has increased from <1% of isolates in 2000 to 8% in 2007.13 Average reported susceptibilities to colistin, tigecycline, and gentamicin are 88%, 95%, and 97%, respectively. KPC can cause many types of infections with the most common being systemic infections in patients with multiple lines and catheters, especially if they are immunocompromised.12 Other risk factors include prolonged hospitalizations, prior antibiotic use (especially with cephalosporins or carbapenems), trauma, diabetes, malignancy, and mechanical ventilation.14 Mechanism of Resistance KPC are plasmid-mediated enzymes that hydrolyze beta-lactam rings and inactivate the antibiotic.12 The ease of transmission of the KPC gene is evidenced by the large number of microbial species

with KPC. Seven varieties are known that differ by their amino acid substitutions and hydrolysis efficiency. The clinical impact of the different varieties is unknown. Treatment of patients with KPC becomes difficult as these isolates tend to also contain genes for other resistance types.14 Fluoroquinolone resistance occurs in 98% and aminoglycoside resistance occurs in 50% of KPC-containing K. pneumoniae. Additionally, the clinical evidence thus far for treating KPC is limited. Treatment of KPC Infections A study looked at 28-day mortality of NYC and Pittsburgh KPC K. pneumoniae bacteremia patients.15 The only factor associated with survival was combination antimicrobial treatment. Those on combination therapy had a mortality of 13.3% compared to 57.8% in those receiving monotherapy (p=0.01). The most common antibiotic combination was a carbepenem plus colistin or tigecycline. Seven of the eight patients who received this regimen survived. All the isolates in this group were resistant to carbapenems, but susceptible to colistin and tigecycline. Adding further credence to the need for combination therapy is the fact that all colistin or tigecycline monotherapy patients had susceptible isolates, but still fared worse than the combination group. The mechanism of why carbapenems remain effective in combination for treating infections with carbapenemresistance is unknown, but has been shown in both in vitro and in vivo data.16 Two other studies confirm combination therapy improves survival in KPC K. pneumoniae bacteremia.16,17 Again, combinations including colistin or tigecycline were frequently used. However, the most common regimens differed between all three studies. This regimen difference in clinical studies makes determining the ideal treatment of KPC infections difficult. Currently, no standard recommendation for treating KPC infections exists. Using a combination of antimicrobials seems to attain the best clinical outcomes. Gram Positive Resistance Vancomycin-Resistant Enterococci (VRE) Enterococci are gram-positive, facultative, anaerobic cocci normally found in intestinal flora. They have low virulence in otherwise healthy individuals, but can cause urinary tract infections (UTIs),

Continuing Education (continued from page 32) bacteremia, and endocarditis in those who are vulnerable and immunocompromised.18 Less frequently enterococci are associated with osteomyelitis, intra-abdominal, and surgical wound infections, usually as a co-pathogen. Pneumonia and meningitis due to enterococci are rare in adult patients. While there are several different enterococcal species, Enterococcus faecalis is the most common isolate associated with infections in humans, followed by Enterococcus faecium. Epidemiology and Risk Factors for Resistance Enterococci are intrinsically resistant to cephalosporins and can acquire genetic modifications conferring resistance to penicillins, aminoglycosides, and glycopeptides (vancomycin).18 Vancomycin-resistant enterococci (VRE) are an increasingly common and difficult to treat cause of nosocomial infections. Recent data shows that over 30% of enterococci isolates in North America are resistant to vancomycin, with rates of VRE seen in over 70% of E. faecium isolates.19,20 This has become a significant infection-control issue because VRE infections are associated with increased health care costs, morbidity, and mortality.21 Risk factors for VRE infection include previous treatment with antimicrobials (particularly vancomycin and cephalosporins), prolonged hospitalization, significant medical conditions (cancer, end-stage renal disease, transplant recipient, diabetes), and proximity to a colonized or infected person.18 Treatment of Clostridium difficile infections with oral metronidazole and vancomycin has shown to promote overgrowth of VRE.22 Mechanism of Resistance Vancomycin inhibits enterococci by binding to the D-Ala-D-Ala terminus of cell wall precursors, interfering with cell wall synthesis.23 Enterococcal resistance to vancomycin occurs when gene clusters, most commonly vanA and vanB, encode changes to the peptidoglycan precursor terminus. The D-alanine is replaced with D-lactate, resulting in significantly lower binding affinity of vancomycin to the terminus of cell wall precursors. Treatment of VRE Infections If susceptible, ampicillin is the treatment

of choice of enterococcal infections.18 According to the Clinical and Laboratory Standards Institute (CLSI) breakpoints for VRE, Vancomycin susceptibility is defined as an MIC ≤4 mcg/ml while resistance is defined as an MIC ≥ 32 mcg/ ml.24 Other aminopenicillins (amoxicillin, pipercillin) and imipenem-cilastin also have activity against enterococci. Betalactam agents with limited or no activity against enterococci include nafcillin, oxacillin, ertapenem, most cephalosporins, and aztreonam. Beta-lactams are bacteriostatic against enterococci, but may achieve bacteriocidal activity when combined with aminoglycosides.25 In the case of life-threatening infections, such as endocarditis, an aminoglycoside should be added if the organism is susceptible to synergism with gentamicin or streptomycin. Tobramycin and amikacin should not be used because they fail to show susceptibility to synergism. Most vancomycin-resistant E. faecium (VREfm) isolates also have high-level resistance to beta-lactams and aminoglycosides. However, vancomycin-resistant E. faecalis (VREfc) are usually susceptible to beta-lactams. Options for oral administration for the treatment of VRE include nitrofurantoin and fosfomycin, which are used exclusively for UTIs, and linezolid. Agents that are available for intravenous (IV) administration include linezolid, daptomycin, quinupristin/ dalfopristin (Q/D), and tigecycline. In the case of lower tract UTIs that are resistant to ampicillin, nitrofurantoin can be an alternative. Nitrofurantoin achieves excellent therapeutic levels in the urine; however, due to inadequate systemic drug levels, it should not be used for upper UTIs (i.e. pyelonephritis). Nitrofurantoin should be avoided in patients with a creatinine clearance (CrCl) of < 60 ml/min because of inadequate urine concentrations and concern for neuropathy from accumulation of toxic metabolites. Fosfomycin is also approved for uncomplicated UTIs. Urinary concentrations of fosfomycin are maintained allowing it to be administered as a single dose.25 Use of fosfomycin may be limited by difficulty in drug acquisition and drug cost relative to alternative agents. Unnecessary use of antibiotics in patients who are colonized and not infected with VRE in the urine has become a problem in hospitals and long-term care facilities.25

Thus, it is important for clinicians to appropriately distinguish between urinary colonization, asymptomatic bacteriuria, and UTIs in order to determine the need for treatment and optimal therapeutic options. Linezolid is FDA approved for the treatment of community acquired pneumonia (CAP), nosocomial pneumonia, and complicated and uncomplicated skin and soft tissue infections (SSTIs), including those caused by VREfm. The IDSA recommends linezolid as a first line agent for VRE infections in neutropenic patients.26 Linezolid is a bacteriostatic, oxazolidinone antibiotic that inhibits the protein synthesis of gram (+) bacteria. It is available oral and IV, has 100% oral bioavailability, and does not require dosage adjustment in renal insufficiency. Safety concerns may limit the use of linezolid, particularly if prolonged treatment is required. Hematologic toxicities, including thrombocytopenia and pancytopenia, has been reported during clinical trials and postmarketing use.18 The incidence of thrombocytopenia is 0.7-3% in adults, appears to occur more frequently in patients with end-stage renal disease, and typically resolves after discontinuation of the drug.27 Complete blood counts should be monitored every week, especially in patients receiving linezolid for longer than 2 weeks, those who have preexisting myelosuppresion, or those receiving concomitant drugs can cause myelosuppression. Peripheral neuropathy and lactic acidosis are uncommon but serious adverse reactions that can occur with prolonged use. Linezolid is also a weak, reversible, nonselective monoamine oxidase inhibitor that can lead to serotonin syndrome if co-administered with other serotonergic agents. A recent review reported the incidence of serotonin syndrome with concomitant linezolid and serotonergic agents ranges from 0.24% to 4%.28 If treatment with linezolid is required, coadministration with other medications should be avoided if possible. Daptomycin, a lipopeptide antibiotic with concentration-dependent, bactericidal activity against gram (+) microorganisms, has also been recommended as one of the first-line agents for VRE.26 It is only available IV and is usually dosed once daily based on actual body weight. Since it is renally cleared, the dose should be adjusted for renal dysfunction and Fall 2013 • Arizona Journal of Pharmacy • 33

Continuing Education (continued from page 33) the dosing interval should be extended to every 48 hours for patients with a CrCl < 30 ml/min. The most clinically significant adverse reactions observed with 4 mg/kg complicated skin and soft tissue infections (cSSTI trials) and 6 mg/ kg (S. aureus bacteremia/endocarditis trials) were abnormal liver function tests, elevated CPK, and dyspnea. Other common adverse reactions include GI disruption, peripheral edema, and anemia. Daptomycin is useful for SSTIs, VRE bacteremia and osteomyelitis, and complicated UTIs where one of the previously discussed agents cannot be used. Daptomycin is inactivated by pulmonary surfactant and should not be used for pneumonia. Patients receiving daptomycin should be evaluated for clinical evidence of myopathy. Serum creatine phosphokinase (CPK) should be monitored at least weekly, and the drug should be discontinued in patients with symptomatic myopathy and CPK > 5 times upper limit of normal (ULN) or asymptomatic patients with CPK > 10 times ULN.29 Coadministration with statins is not recommended due to the increased risk of myopathy and rhabdomyolysis. There are no other drug interactions with daptomycin.30 Q/D is a streptogramin antibiotic with bacteriostatic activity against E. faecium, but poor activity against E. faecalis.18 Q/D is available for IV administration and does not require dosage adjustment in renal insufficiency. This drug has several limitations including the need for central venous administration due to infusion site reactions, metabolism via CYP3A4 resulting in multiple drug interactions, and adverse effects including severe arthralgias (11%), myalgias (9%), nausea (9%), and hyperbilirubinemia.47 These toxicities, in addition to infusion-related reactions, have limited its use in general. Tigecycline is a bacteriostatic glycylcycline antibiotic derived from minocycline that inhibits protein translation. Unlike previously discussed antibiotics, tigecycline has broadspectrum against many gram positive, gram negative, anaerobic, and atypical pathogens.29 Although not FDA approved for VRE, tigecycline appears to have activity against VRE and may be useful for patients intolerant to other agents, or when VRE is present with other pathogens susceptible to tigecycline. Due to concerns for achieving adequate serum 34 â€˘ Arizona Journal of Pharmacy â€˘ Fall 2013

drug concentrations, tigecycline should be used with caution in bacteremia.31 Tigecycline is only available IV and widely distributes to tissues and has a long half-life allowing dosing of every 12 hours. Tigecycline is not extensively metabolized and is eliminated unchanged primarily through the biliary and fecal route; therefore, tigecycline has a minimal risk for drug or disease interactions. Adverse effects include GI intolerability and hepatic toxicity, and it is recommended to be used in caution in patients with severe hepatic dysfunction (Child Pugh class C).32 The American Heart Association (AHA) guidelines for the treatment of infective endocarditis (IE) recommend double beta-lactam combinations of ampicillin and ceftriaxone or imipenem/cilastin for the treatment of E. faecalis endocarditis resistant to vancomycin, penicillin, and aminoglycosides .33 Synergistic bactericidal activity in vitro and in vivo has been demonstrated with double beta-lactam combinations, probably as a result of saturation of different penicillinbinding protein targets. An open-label, observational study conducted in 43 patients with high-level aminoglycoside resistant (HLAR) and non-HLAR E. faecalis found a clinical cure rate of 67.4% when ampicillin was combined with ceftriaxone.34 This combination has not been compared to ampicillin alone. Despite limited evidence, double betalactam combination is recommended for enterococcal endocarditis caused by multidrug resistant E. faecalis since there are few therapeutic options available. Although there is no clinical data regarding its use for enterococcal infections, telavancin is a lipoglycopeptide that is four-fold more potent than vancomycin against enterococci.35 The addition of telavancin to another agent, such as gentamicin, may be a reasonable consideration for multi-drug resistant E. faecium. Chloramphenicol is an older broad-spectrum antibiotic that has in vitro bacteriostatic activity against enterococci. However, significant toxicities including blood dyscrasias and GI intolerance limit its use. Microbiology labs often do not report susceptibilities of each of the agents discussed above to enterococcus. Clinicians may need to contact the lab regarding susceptibilities for VRE isolates.

Methicillin-resistant Staphylococcus aureus (MRSA) Staphylococcus aureus resistance is a gram (+), coagulase positive bacteria that grows in clusters. In both health careassociated and community-associated infections, resistance is becoming a growing concern. The IDSA published clinical practice guidelines in 2011 for the treatment of methicillin-resistant S. aureus (MRSA) infections in adults and children. The objective of the guidelines was to provide recommendations for providers on the management of patients with MRSA infections including management of issues relating to vancomycin therapy, susceptibility testing, and use of alternative therapies in patients that experience treatment failure or have infections with reduced vancomycin susceptibility.36 Epidemiology and Risk Factors for MRSA It has been reported that MRSA is responsible for 50-60% of all S. aureus infections throughout the world and represents more than half of the hospitalizations related to S. aureus infections in the U.S. Common risk factors for CA-MRSA include IV drug abuse, crowded facilities, men having sex with men, HIV infection, incarceration, military service, and being from a minority population. The spread of the infection can occur through multiple methods such as direct contact between infected or colonized individuals or indirectly from contact with contaminated fomites or air. Risk factors for HA-MRSA include prior hospital admission, long duration of hospital stay, previous surgery, residence at a long-term care facility, head trauma, kidney failure, and hemodialysis. Additionally, recent antibiotic therapy and comorbid conditions can increase risk, which include diabetes mellitus and head trauma.37 Mechanism of Resistance Methicillin resistance is mediated by the mecA gene, which encodes PBP 2a. The mecA gene is located on a mobile genetic element called staphylococcal chromosome cassette (SCCmec) and is absent from susceptible strains and present in all resistant strains. Communityacquired MRSA (CA-MRSA) strains contain chromosome mec (SCCmec) type IV and V genes, whereas most hospitalacquired (HA-MRSA) strains contain

Continuing Education (continued from page 34) SCCmec type I, II, and III genes. Pulsefield gel electrophoresis, another technique used to determine the colonal lineage of isolates, has linked pulsefield types USA 300 and USA 400 to CA-MRSA strains and USA 100 and USA 200 to HA-MRSA strains. Genetic encoding for virulence factors is also distinctly different between CA-MRSA and HA-MRSA. CA-MRSA strains will usually carry the Panton-Valentine leukocidin (PVL) gene, which codes for the production of a potent cytotoxin that can lead to a severe, necrotizing pneumonia or skin lesions. Recent reports are now describing this gene in up to 25% of HA-MRSA, which further supports the idea that these strains are evolving and it is becoming more and more difficult to distinguish between CAfrom HA-MRSA just based on clinical presentation and risk factors.37 Identification of MRSA Traditionally, in the clinical setting, MRSA has been identified through obtaining a culture from the patient and waiting several days for speciation and susceptibility data to become available, thereby, contributing to delays in appropriate antibiotic therapy. Automation has streamlined this process; however, clinicians may still be waiting up to 3 days. Rapid detection tests for identifying MRSA have been developed and are available on the market, which may assist with appropriate antibiotic selection thus reducing duration of empiric therapy and possibly improving patient outcomes. In February of this year, a review of the rapid testing products was conducted and published in the American Journal of Health-System Pharmacy.38 One review of the literature conducted by Brown et al demonstrated that these rapid tests may provide cost savings and improved patient outcomes.39 Currently available FDA approved rapid MRSA detection methods involve the use of PCR techniques to amplify particular staphylococcal DNA sequences from a patient sample. Several products are available but are not all considered equal in terms of specificity and sensitivity. The genetic targets for these products can differ slightly, and those tests that are able to differentiate coagulase-negative staph from S. aureus are particularly useful in a clinical setting. Additionally, those tests that have been studied and FDA approved for multiple specimen site testing,

especially wound and blood cultures, are of high value with regards to clinical usefulness and antimicrobial stewardship. The available tests can provide results in as little 60 minutes. With further research to identify how these tests can contribute to the efforts of an antimicrobial stewardship, they may become more routinely used.38 Treatment of MRSA infections The management of MRSA infections may include pharmacologic and nonpharmacologic options. Incision and drainage (I&D) is important in the treatment of MRSA SSTIs. In the cases of cellulitis or abscess, this surgical procedure is the mainstay of therapy and has been shown to be effective without need for adjunctive antibiotics in patients who do not have signs or symptoms of systemic infections. The IDSA guidelines recommend I&D alone as the treatment for simple abscess or boils. There are several first-line pharmacologic options for treatment of MRSA bacterial infections. Infection site and severity, adverse effect profiles, and patient allergies often dictate which agent(s) are most appropriate. Usual Agents for the Treatment of MRSA Vancomycin is the most widely used and accepted treatment option for MRSA infection both CA and HA. Although still considered first line, over time the use of vancomycin has been called into question due to concerns of increasing resistance and a phenomenon known as “MIC creep”, slow bactericidal effect, and variable tissue penetration. MIC creep refers to the phenomenon in which the MIC of S. aureus to vancomycin has increased to a point where isolates previously considered susceptible are now considered intermediate resistant or resistant. Vancomcyin failures have been found to significantly increase when the MIC is >0.5 mcg/ml and isolates with an MIC in the range of 1-2 mcg/ml have been associated with higher mortality rates. In these cases, alternative therapy should be considered. Additionally, there is no standardized dosing for vanomycin, and data for vancomycin trough monitoring in terms of treatment effectiveness are lacking. The IDSA has published a separate section specifically addressing vancomycin dosing, monitoring, and susceptibility testing.36 Generally, dosages of 15-20 mg/kg/dose every 8-12

hours (max 2 gram/dose) based on actual body weight and adjusted for CrCl are recommended. Based mainly on expert opinion and clinical experience, a loading dose of 25-30mg/kg should be considered for patients that are critically ill suspected to have MRSA. Clindamycin is FDA approved for treatment serious infections due to S. aureus, but not specifically MRSA infections. Clinically, it has been used widely with success to treat SSTIs and susceptible CA-MRSA, including osteomyelitis, septic arthritis, pneumonia, and lymphadenitis. It has a very good tissue penetration, but is not recommended for treatment of CNS infections due to limited penetration or endovascular infections due to its bacteriostatic versus bactericidal nature. A wide range of inducible clindamycin resistance has been reported in the literature, 5%-80%, and varies geographically. Strains of MRSA that are initially clindamycin susceptible but erythromycin resistant can have inducible clindamycin resistance. In these cases, further testing with a disk diffusion test (D-test) is recommended to detect inducible resistance. The clinical application of this in vitro testing remains unclear because in some cases, patients have still responded to therapy despite having inducible clindamycin resistant strains of MRSA. In general, it should be recommended that positive D-test results should preclude the use of clindamycin for serious infections.36 One of the more concerning adverse effects of clindamycin compared to other agents is the occurrence of Clostridium difficile-associated diarrhea (CDAD), which is a result of a disruption of GI flora and overgrowth of the opportunistic bacteria. It can occur in up to 20% of patients and lead to hospitalization and even death. Due to the high rates and seriousness of Clostridium difficile infections, the IDSA has recently published management guidelines.36 Tetracyclines, such as doxycycline and minocycline, have been used widely with reasonable clinical success for the treatment of S. aureus infections and MRSA, mainly community-acquired SSTIs, but data are lacking for their use in treating more invasive infections, such as pneumonia and bacteremia. Doxycycline is FDA approved for the treatment of S. aureus SSTIs. Due to the potential for doxycycline induced resistance, minocycline can be considered as an Fall 2013 • Arizona Journal of Pharmacy • 35

Continuing Education (continued from page 35) alternative in these cases.36 Tigecycline, a newer tetracycline derivative, is another option for the treatment of MRSA infections and will be discussed in the “Alternative Agents for the Treatment of MRSA” section. Rifampin has been used for treatment of MRSA. It is highly bactericidal and has the ability to penetrate tissue and most importantly biofilms, making it a preferred drug in cases of infected prosthetic joints and mechanical valves. However, due to high levels of resistance, rifampin should not be used as monotherapy in the treatment of MRSA infections. Several combination therapies with rifampin have been evaluated, but there is a lack of adequate controlled trials to clearly delineate its usefulness in therapy. Additionally, dosing has been variable in the published literature ranging from 600mg daily, single or divided, up to 900mg daily in 2 to 3 divided doses. The use of rifampin adjunctively with vancomycin for treating MRSA infection can be considered, and the IDSA endorses the AHA recommendations for this combination plus gentamicin in treatment of MRSA prosthetic valve endocarditis.40 Other combinations with rifampin have been evaluated, but clinical data are limited. In general, this agent is reserved for combination therapy for treatment of MRSA infections of prosthetic joints, prosthetic valve endocarditis, and osteomyelitis, which are based on limited clinical studies and expert opinion. Trimethoprim-sulfamethoxazole (TMPSMX) has not been FDA approved for treatment of staphylococcus infections; however, in vitro and clinical data confirm the susceptibility of MRSA to this agent and shows greater bactericidal activity than other agents. It has been reported that 95-100% of CA-MRSA strains are susceptible in vitro and the drug has been widely used clinically in the treatment of S. aureus SSTIs. A prospective cohort study of 1100 isolates from patients with both CA (75%) and HA (25%) MRSA infections found that CA isolates were more likely to be susceptible than HA isolates to clindamycin, ciprofloxacin, gentamicin, and TMP-SMX. Susceptibilities were high for TMP-SMX for both CA and HA isolates at 95% and 90% respectively.41 According to the IDSA recommendations, TMP-SMX has a role in the treatment of MRSA infections for outpatient treatment of SSTIs and 36 • Arizona Journal of Pharmacy • Fall 2013

joint and bone infections in adults and children, but not for invasive CA-MRSA in children. Due to high potential to cause harm in elderly, it should be used cautiously, especially in those on other drugs that inhibit the renin-angiotensin system or those with chronic kidney disease due to risk of renal failure and hyperkalemia.36 Alternative Agents for the Treatment of MRSA Linezolid has been shown to have in vitro activity against vancomycinintermediate and vancomycin-resistant S. aureus (VISA and VRSA). Regarding superiority to vancomycin, several prospective trials and meta-analyses have been conducted comparing these agents in treating health care-acquired MRSA and health care-associated MRSA pneumonia, revealing conflicting results. A prospective, double-blind, controlled trial compared linezolid to vancomycin, 224 cases in each, in patients with culture proven MRSA pneumonia.42 Vancomycin troughs were monitored by a pharmacist and adjusted with average levels reaching 12 mcg/ml by day 3 and 15 mcg/ml by day 6. Linezolid showed a statistically higher rate of clinical and microbiological cure by the end of study; however, the 60-day mortality was similar. Of note, more patients in the vancomycin group had higher rates of DM, kidney disease, were mechanically ventilated with more ventilator-associated pneumonia, and bacteremia compared to the linezolid group. A meta-analysis published in 2010, reviewed 9 prospective randomized trials that compared linezolid to vancomycin or teicoplanin for treatment of nosocomial pneumonia.43 The authors concluded that these trials did demonstrate superiority of linezolid and no differences were found in rates of renal failure or all-cause mortality between the groups; however, linezolid was found to have higher rates of thrombocytopenia and GI side effects. Although linezolid is bacteriostatic and not cidal, it does have the benefit of a fixed dosing of 600mg BID, being 100% orally bioavailable, and achieves very good serum concentrations in patients expected to have normal GI absorption. These reasons give linezolid the advantage of being an option for outpatient-based therapy for MRSA. Although very rare, linezolid-resistant MRSA infection in patients with prolonged use has been

described in the literature. Tigecycline was first FDA-approved in 2005 for the treatment of cSSTIs and complicated CA-intraabdominal infections (IAIs), including infections caused by MRSA and VREfc, and later for community-acquired pneumonia (CAP) mainly caused by Streptococcus pneumoniae. Clinical cure rates have been very comparable to the standard first line therapies for the approved indications based on published data with clinical cure rates for cSSTIs of 77-88%, cIAIs of 65-86%, and bacterial CAP of 89%.32 As stated earlier in this review, due to a lack of adequate blood concentrations and bacteriostatic nature, it is not recommended for bacteremia based on published data showing an increase in mortality in tigecycline treated serious infections. As a result, the FDA issued a safety alert in September of 2010 warning about increased mortality in these cases. The Tigecycline Evaluation and Surveillance Trial (T.E.S.T.) which is a global surveillance program initiated in 2004 to study in vitro susceptibilities of tigecycline to several gram (+) and gram (-) species, has shown that susceptibilities to isolates collected in the United States remain very good: S. aureus: 100.0% (n=8299), MRSA: 100.0% (n=4533), K. pneumoniae: 95.28% (n=6913), ESBL K. pneumoniae: 92.77% (n=692), and E. coli: 100.0% (n=8649), and ESBL E. coli: 100.0% (n=284).32 Daptomycin is approved to treat S. aureus bacteremia, right-sided IE, and cSSTIs in adults. Daptomycin has not been studied in the treatment of leftsided IE or in patients with prosthetic valve IE. The efficacy of daptomycin for the treatment of cSSTIs in a small, randomized study of 45 patients was found to be similar to that of vancomycin (84%).44 Additionally, daptomycin was found to be non-inferior to vancomycin plus low-dose gentamicin (N= 246) with S. aureus bacteremia with or without right-sided endocarditis, of which MRSA was isolated in about 38% of patients in both groups.45 Nonsusceptible isolates have been reported in association with treatment failures, and previous exposure to vancomycin therapy has been associated with increased MICs for daptomycin, suggesting possible cross-resistance. The mechanism for this resistance is thought to be due to a single-point mutation, mprF, although it is not clear.36 Doses of 8mg/

Continuing Education (continued from page 36) kg to 12mg/kg have been used to counter these potential resistance issues. Trough monitoring is not recommended as steadystate concentrations are not predictive of efficacy or toxicity.46 Q/D has an FDA-approved indication for the treatment of cSSTIs caused by MSSA or S. pyogenes in adults and children > 16 years of age. It also has been found to have in vitro activity against a wide variety of gram (+) bacteria, including VISA and MRSA. Currently, the drug is reserved as a salvage therapy for MRSA due to its poor tolerability, as described previously, and the treatment of MRSA bacteremia in vancomycin failures is an off-label use. Due to limited data demonstrating poor response in patients with nosocomial pneumonia, the use of Q/D for pneumonia is not recommended.36 Ceftaroline fosamil is a new IV fifth generation cephalosporin recently approved by the FDA for the treatment of acute bacterial skin and soft tissue infections (ABSSTIs). It also has an FDA-approved indication for the treatment of CAP, excluding those caused by MRSA. Ceftaroline covers gram (+) bacteria (including vancomycinintermediate S. aureus, CA-MRSA, HA-MRSA, and macrolide-resistant S. pyogenes) and gram (-) bacteria (but not pseudomonas or ESBL organisms). Ceftaroline has a much higher affinity for the penicillin-binding protein, which gives it a better efficacy in treating MRSA compared to other beta-lactam antibiotics. This antibiotic exhibits bactericidal activity. There have been two Phase 2 cSSSI studies and four Phase 3 studies, including two each involving ABSSSIs. No difference was found between ceftaroline and vancomycin with or without aztreonam in clinically or microbiologically curing ABSSTIs caused by MRSA in the Canvas 1 and 2 trials. The safety profile for ceftaroline was similar to comparator drugs.47 The usual dose is 600mg every 12 hours for CAP and cSSTIs. Renal adjustments are necessary when CrCl drops below 50ml/ min. Common adverse reactions include hematologic, headache, insomnia, GI upset, hypokalemia, and risk for CDAD.30 IDSA guidelines do not include a review or make specific recommendations regarding the use of ceftaroline. Telavancin is another new drug in the lipoglycopeptide class with FDAapproved labeling for treatment of cSSTIs,

however, its role in the treatment of pneumonia, bacteremia, and endocarditis is yet to be determined. It has a dual mechanism exhibiting concentrationdependent bactericidal effects against gram (+) organisms through inhibiting cell wall synthesis and depolarizing bacterial membranes. Additionally, it has been shown to have activity against VISA and VRSA, and in vitro pharmacodynamics data shows it to have about 16 times higher potency than vancomycin.37 A study of 1867 patients with cSSTIs, predominantly major abscesses and deep and/or extensive cellulitis, compared intravenous telavancin (10 mg/kg every 24 h) to vancomycin (1 g every 12 h) with individualized vancomycin dosing adjustments permitted.48 Overall success rates between the two drugs were comparable, 88% for telavancin and 87% for vancomcyin. Of the 579 clinically evaluable patients infected with MRSA at baseline, 90.6% of patients in the telavancin group and 84.4% of patients in the vancomycin group were cured. The incidence of serious adverse events was higher in the telavancin treatment group (79%) than in the vancomycin treatment group (72%), mainly due to taste disturbance, nausea and vomiting, and foamy urine. Slightly more patients discontinued telavancin therapy because of an adverse event. Renal dysfunction occurred in 3% and 1% of patients treated with telavancin and vancomycin, respectively, with the serum creatinine levels returning to baseline or trending down after completion of treatment. Benefits for telavancin include once daily dosing with a post-antibiotic effect of 4-6 hours and there is no need to monitor serum drug concentrations as with vancomycin. Some disadvantages include potential increased risk of nephrotoxicity and the need for renal adjustments and monitoring. Telavancin has been given a pregnancy category C, but according to package labeling a black box warning has been placed. Health care providers are encouraged to enroll women exposed to telavancin during pregnancy in the Vibativ Pregnancy Registry.36,37 Investigational compounds under review by the FDA Dalbavancin, a lipoglycopeptide in the same class as telavancin and oritavancin, is under review by the FDA for the treatment of cSSTIs including MRSA.

It also has shown good results in killing VISA, and VRSA in vitro and was shown to be as effective dosed once weekly compared to vancomycin twice daily in a phase 2 trial of 75 patients with gram (+) catheter-related, bacteremia including MRSA.49 Dalbavancin was statistically superior compared to vancomycin with overall success rates at 18-24 days after end of therapy of 87% and 50%, respectively. Adverse events were similar between groups. Explanations for the differences in efficacy could be in part due to the reduce ability of vancomycin to penetrate biofilms, such as those associated with catheter infections, and vancomycin trough monitoring was not mentioned in the study. In another phase 3 trial of 854 patients, with MRSA identified in 51%, once-weekly dalbavancin was compared to twice-daily linezolid in the treatment of cSSTIs.50 Clinical success was comparable between agents, 91% and 89%, respectively, in patients with MRSA. Adverse events were commonly GI in both groups with a higher proportion in the linezolid group. Dalbavancin has a very long half-life of 6-12 days and significant distribution into tissues permits the once-weekly dosing. Trial data has used dosing of 1000mg day 1 loading followed by 500mg once weekly thereafter, which is an attractive option for outpatientbased therapy. Side effects to consider include GI intolerances, increased LFTs, hypokalemia, and hypotention.51 Oritavancin, another new glycopeptide, has a unique mechanism of inhibiting peptidoglycan carbohydrate chain formation, which is different from the other glycopeptide agents. A New Drug Application (NDA) was submitted in December of 2008 to the FDA seeking approval for the treatment of cSSTIs; however, it has been on hold while the FDA awaits further trial data to be submitted on the treatment of MRSA. Oritavancin shows activity against staphylococci in addition to enterococci, including VRE. It has high potency in vitro against all gram (+) organisms; however, activity against VRSA has not been established.37 Several phase 2 and phase 3 trials in human subjects have been conducted; primarily noninferiority trials comparing oritavancin to vancomycin 15-20 mg/kg. In one intention-to-treat trial of 517 patients comparing oritavancin to vancomycin followed by oral cephalexin for cSSTIs, Fall 2013 â€˘ Arizona Journal of Pharmacy â€˘ 37

Continuing Education (continued from page 37) 33 of which were infected with MRSA, showed clinical and microbial cure rates of 74-80% for all patients with no difference between groups.52 In a second similar non-inferiority study of 1267 patients showed no significant difference between the groups with cure rates of 76% in the oritavancin group and 78% in the vancomycin/cephalexin group, overall, and 61% and 66% with regards to MRSA eradication, respectively.52 The long halflife of 100-200 hours allows for daily or every other day dosing, which is weight based ranging from 0.2mg-10mg/kg. It has displayed post-antibiotic effects in vitro of 2.4-7.7 hours for MRSA. Adverse effects were similar to dalbavancin, but it differs with regards to metabolism. Oritavancin is hepatically metabolized with renal clearance being < 5%. Two Phase 3 trials evaluating oritavancin for the treatment of acute bacterial SSSIs and safety and efficacy are ongoing. Ceftobiprole, another fifth generation cephalosporin, had a NDA originally submitted to the FDA in 2007 for the treatment of cSSTIs. It is capable of binding to PBP 2a, which confers resistance of S. aureus to betalactam antibiotics and PBP 2x, which confers resistance of S. pneumonia to penicillins. It may have activity against Enterobacteriaceae and enterococci as well. Ceftobiprole was found to be as effective as vancomcyin plus ceftazidime in treating cSSTIs in a trial of 828 patients. Clinical cure rates in ceftobiprole-treated patients ranged from 86.2% among those with diabetes who had foot infections to 93% among those with cellulitis.53 These results were confirmed in another trial comparing ceftobiprole to vancomycin alone.54 The dosing regimen of 500mg every 12 hours was used in the phase 3 trials for cSSTIs, however, data suggests that for treatment of polymicrobial diabetic foot infections and gram-positive or gram-negative HAP or VAP may require a frequency of every 8 hours. As with other cephalosporin agents, renal adjustments are necessary in patient with renal insufficiency (CrCl < 50ml/min) but information regarding dosing in hemodialysis is not available. It does not undergo hepatic metabolism, therefore no adjustments are needed in hepatic dysfunction.55 Ceftobiprole has been approved for use in other countries for the treatment of gram (+) and gram (-) organisms, however, the FDA has 38 • Arizona Journal of Pharmacy • Fall 2013

requested additional information and recommended additional clinical studies be conducted in order to consider approval in the US. Decolonization of MRSA While 25% to 30% of people are colonized in the nose with staphylococcus, less than 2% are colonized with MRSA. As reported by the Center for Disease Control (CDC), studies demonstrating initial clearance of MRSA following decolonization therapy have reported a high frequency of subsequent colonization. They also note that several factors limit the utility of decolonization on a widespread basis: 1) identification of candidates for decolonization requires surveillance cultures; 2) candidates receiving decolonization treatment must receive follow-up cultures to ensure eradication; 3) recolonization with the same strain, initial colonization with a mupirocin-resistant strain, or emergence of resistance to mupirocin during treatment can occur. There may be a few indications for the use of decolonization therapy, which include implementation in areas of MRSA outbreaks, in patients colonized that may be undergoing surgery, or health care workers who have been implicated in the transmission of MRSA in the hospital setting. Therefore, most health care facilities have limited the use of decolonization to MRSA outbreaks or other high prevalence situations, especially those affecting special-care units. Regimens that have been used alone or in combination for decolonization include topical mupirocin, rifampin, TMP-SMX, and ciprofloxacin. The CDC recommends prevention efforts be focused on better hand hygiene, use of contact precautions until patients are culturenegative for a target MDRO, active surveillance cultures (ASC), education, enhanced environmental cleaning, and improvements in communication about patients with MDROs within and between health care facilities.56 Conclusion According to the Infectious Disease Society of America (IDSA), up to 50% of antibiotic use is unnecessary or inappropriate. Treating resistant microbial infections costs the U.S. health care system between $23 billion and $34 billion annually.57 It has also been reported in 2006, two common nosocomial infections,

pneumonia and sepsis, killed 50,000 Americans and cost the U.S. health care system $8 billion. In an attempt to combat the problem, the IDSA and the Society for Health care Epidemiology of America (SHEA) published guidelines for implementing antimicrobial stewardships in 2007 and has introduced its 10x’20 Initiative this past year. The program calls for the development of 10 new systemic antibacterial drugs by 2020.1,57 Pharmacists can play a major role in the multidisciplinary efforts through participation in antimicrobial stewardship programs and increasing awareness of important issues, such as local resistance patterns and appropriate dosing and monitoring of antimicrobial agents. References 1. Infectious Disease Society America. Facts about antibiotic resistance. www.idsociety.org/IDSA/Site_Map/Topics_of_Interest/ Antimicrobial_Resistance/Public_Policy/Facts_about_ Antibiotic_Resistance.aspx (accessed 2013 March 7) 2. Tenover FC. Mechanisms of Antimicrobial Resistance in Bacteria. Am. J of Medicine. 2006; 119:S3-10. 3. Gniadkowski M. Evolution and epidemiology of extended-spectrum β-lactamases (ESBLs) and ESBLproducing microorganisms. Clin Microbiol Infect. 1991; 7: 597-608. 4. Munoz-Price LS and Jacoby GA. Extended-spectrum beta-lactamases. In: Hooper DC, ed., UpToDate. Waltham (MA): UpToDate; 2012. 5. Paterson DL and Bonomo RA. Extended-spectrum beta-lactamases. Clin Microbiol Review. 2005; 18: 657-86. 6. Endimiani A, Luzzaro F, Perilli M et al. Bacteremia due to Klebsiella pneumoniae isolated producing the TEM-52 extended-spectrum β-lactamase: treatment outcome of patient receiving imipenem or ciprofloxacin. Clin Infect Dis. 2004; 38: 243-51. 7. Paterson DL, KoWC, Gottberg AV et al. Antibiotic therapy for Klebsiella pneumoniae bacteremia: implications of production of extended-spectrum β-lactamases. Clin Infect Dis. 2003; 39: 31-7. 8. Rodriguez-Bano J, Navarro MD, Retamar P et al. β-lactam/β-lactam inhibitor combinations for the treatment of bacteremia due to extended spectrum β-lactamase-producing Escherichia coli: a post hoc analysis of prospective cohorts. Clin Infect Dis. 2012; 54:167-74. 9. Zimhony O, Chmelnitsky I, Bardenstein R et al. Endocarditis caused by extended-spectrum-betalactamase-producing Klebsiella pneumoniae: emergence of resistance to ciprofloxacin and piperacillin-tazobactam during treatment despite initial susceptibility. Antimicrob Agents Chemother. 2006; 50: 3179-82. 10. Lee NY, Lee CC, Huang WH et al. Cefepime therapy for monomicrobial bacteremia caused by cefepime-susceptible extended-spectrum beta-lactamaseproducing Enterobacteriaceae: MIC matters. Clin Infect Dis. 2013; 56: 488-495. 11. Kollef MH, Chastre J, Clavel M et al. A randomized trial of 7-day doripenem versus 10-day imipenemcilastatin for ventilator-associated pneumonia. Crit Care. 2012; 16: R218. 12. Nordmann P, Cuzon G, and Naas T. The real threat of Klebsiella pneumoniae carbapenemase-producing bacteria. Lancet Infect Dis. 2009; 9: 228-36. 13. Hirsch EB and Tam VH. Detection and treatment options for Klebsiella pneumoniae carbapenemases (KPCs): an emerging cause of multidrug-resistant

Continuing Education (continued from page 38) infection. J Antimicrob Chemother. 2010; 65: 1119-25. 14. Quale J and Spelman D. Carbapenemases. In: Hooper DC, ed., UpToDate. Waltham (MA): UpToDate; 2012. 15. Qureshi ZA, Paterson DL, Potoski BA et al. Treatment outcome of bacteremia due to KPC-producing Klebsiella pneumoniae: superiority of combination antimicrobial regimens. Antimicrob Agents Chemother. 2012; 56: 2108-13. 16. Tumbarello M, Viale P, Viscoli C et al. Predictors of mortality in bloodstream infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae: importance of combination therapy. Clin Infect Dis. 2012; 55: 943-50. 17. Zarkotou O, Pournaras S, Tselioti V et al. Predicators of mortality in patients with bloodstream infections caused by KPC-producing Klebsiella pneumoniae and impact of appropriate antimicrobial treatment. Clin Microbiol Infect. 2011; 17: 1798-1803. 18. Menichetti F, Tagliaferri E. Antimicrobial resistance in internal medicine wards. Intern Emerg Med. 2012 Oct;7 Suppl 3:S271-81. 19. Sader HS, Moet GJ, Farrell DJ, Jones RN. Antimicrobial susceptibility of daptomycin and comparator agents tested against methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci: trend analysis of a 6-year period in US medical centers (2005-2010). Diagn Microbiol Infect Dis. 2011 Jul;70(3):412-6. 20. Deshpande LM, Fritsche TR, Moet GJ, Biedenbach DJ, Jones RN. Antimicrobial resistance and molecular epidemiology of vancomycin-resistant enterococci from North America and Europe: a report from the SENTRY antimicrobial surveillance program. Diagn Microbiol Infect Dis. 2007 Jun;58(2):163-70. 21. Butler AM, Olsen MA, Merz LR, Guth RM, Woeltje KF, Camins BC, et al. Attributable costs of enterococcal bloodstream infections in a nonsurgical hospital cohort. Infect Control Hosp Epidemiol. 2010 Jan;31(1):28-35. 22. Al-Nassir WN, Sethi AK, Li Y, Pultz MJ, Riggs MM, Donskey CJ. Both oral metronidazole and oral vancomycin promote persistent overgrowth of vancomycin-resistant enterococci during treatment of Clostridium difficile-associated disease. Antimicrob Agents Chemother. 2008 Jul;52(7):2403-6. 23. Zirakzadeh A, Patel R. Vancomycin-resistant enterococci: colonization, infection, detection, and treatment. Mayo Clin Proc. 2006 Apr;81(4):529-36. 24. Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing: Sixteenth Informational Supplement. M100-S16 Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically: Approved Standard. Vol 26. No 3. CLSI, Wayne, Pennsylvania, USA, 2006. 25. Heintz BH, Halilovic J, Christensen CL. Vancomycin-resistant enterococcal urinary tract infections. Pharmacotherapy. 2010 Nov;30(11):1136-49. 26. Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of america. Clin Infect Dis. 2011 Feb 15;52(4):e56-93. 27. Product Information: ZYVOX(R) IV injection, oral tablets, oral suspension, linezolid IV injection, oral tablets, oral suspension. Pharmacia and Upjohn Company, New York, NY, 2008. 28. Ramsey TD, Lau TT, Ensom MH. Serotonergic and adrenergic drug interactions associated with linezolid: a critical review and practical management approach. Ann Pharmacother. 2013 Apr;47(4):543-60. 29. Murray BE. Treatment of enterococcal infections. UpToDate. Last updated 12 Oct 2011. Cited 27 April 2013. Available from www.uptodate.com. 30. Lexicomp drug information Handbook 21st edition 2012-2013 31. Rodvold KA, Gotfried MH, Cwik M, Korth-Bradley JM, Dukart G, et al. Serum, tissue and body fluid concentrations of tigecycline after a single 100 mg dose. J Antimicrob Chemother. 2006;58(6):1221. 32. Tygacil® (tigecycline) Prescribing Information.

Philadelphia, PA: Wyeth Pharmaceuticals Inc. 2011 Nov 33. Baddour LM, Wilson WR, Bayer AS, Fowler VG Jr, Bolger AF, Levison ME, et al. Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications: a statement for health care professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: endorsed by the Infectious Diseases Society of America. Circulation. 2005 Jun 14;111(23):e394-434. 34. Gavaldà J, Len O, Miró JM, Muñoz P, Montejo M, Alarcón A, et al. Brief communication: treatment of Enterococcus faecalis endocarditis with ampicillin plus ceftriaxone.Ann Intern Med. 2007 Apr 17;146(8):574-9. 35. Bérenger R, Bourdon N, Auzou M, Leclercq R, Cattoir V. In vitro activity of new antimicrobial agents against glycopeptide-resistant Enterococcus faecium clinical isolates from France between 2006 and 2008. Med Mal Infect. 2011;41(8):405. 36. Liu C, Bayer A, Cosgrove SE et al. Clinical practice guidelines by the Infectious Disease Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011;52:1-38. 37. Huang V, Owen P. Resistant S. aureus Infections In: Richardson M, Chant C, Chessman KH, Finks SW, Hemstreet BA, Hume AL, et al, eds. Pharmacotherapy Self-Assessment Program, 7th ed. Infectious Disease. Lenexa, KS: American College of Clinical Pharmacy, 2012:139-47. 38. ASHP Rapid testing for methicillin-resistant Staphylococcus aureus: Implications for antimicrobial stewardship K Geiger J. Brown Am J Health-Syst Pharm. 2013; 70(4):335-42. 39. Brown & Paladino. Rapid testing MRSA Cost effectiveness. Pharmacoeconomics. 2010; 28(7): 567-75. 40. Baddour LM, Wilson WR, Bayer AS et al. Infective endocarditis: Diagnosis, antimicrobial therapy, and management of complications: a statement for health care professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: endorsed by the Infectious Disease Society of America. Circ. 2005; 111: e394-e434. 41. Naimi TS, LeDell KH, Como-Sabetti K et al. Comparison of community-and health care-associated methicillin-resistant Staphylococcus aureus infection. JAMA 2003; 290(22):2976-84. 42. Wunderlink RG, Niederman MS, Kollef MH et al. Linezolid in methicillin-resistant Staphylococcus aureus nosocomial pneumonia: a randomized, controlled study. Clin Infect Dis. 2012; 54 (5): 621-29. 43. Kalil AC, Murthy MH, Hermsen ED, et al. Linezolid versus vancomycin or teicoplanin for nosocomial pneumonia: a systematic review and meta-analysis. Crit

Care Med. 2010; 38:1802. 44. The safety and efficacy of daptomycin for the treatment of complicated skin and skin-structure infections. AU Arbeit RD, Maki D, Tally FP, Campanaro E, Eisenstein BI, Daptomycin 98-01 and 99-01 Investigators SO Clin Infect Dis. 2004;38(12):1673. 45. Fowler VG Jr, Boucher HW, Corey GR, et al. Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. N Engl J Med 2006; 355:653. 46. Cubicin® (daptomycin) Prescribing Information. Lexington, MA: Cubist Pharmaceuticals, Inc. Last updated January 2013. 47. Saravolatz LD, Stein GE, Johnson LB. Ceftaroline: a novel cephalosporin with activity against methicillinresistant Staphylococcus aureus. Clin Infect Dis. 2011; 52:1156-63. 48. Stryjewski ME, Graham DR, Wilson SE, et al. Telavancin versus vancomycin for the treatment of complicated skin and skin-structure infections caused by gram-positive organisms. Clin Infect Dis 2008; 46:1683-93. 49. Raad I, Darouiche R, Vazquez J, et al. Efficacy and safety of weekly dalbavancin therapy for catheterrelated bloodstream infection caused by gram-positive pathogens. Clin Infect Dis. 2005; 40:374. 50. Jauregui LE, Babazadeh S, Seltzer E, et al. Randomized, double-blind comparison of once-weekly dalbavancin versus twice-daily linezolid therapy for the treatment of complicated skin and skin structure infections. Clin Infect Dis. 2005; 41:1407. 51. Pope SD, Roecker AM. Dalbavancin: a novel lipoglycopeptide antibacterial. Pharmacotherapy 2006; 26:908. 52. Karaoui LR, El-Lababidi R, and Chahine EB. Oritavancin: An investigational lipoglycopeptide antibiotic. Am J Health-Syst Pharm. 2013; 70:23-33. 53. Noel GJ, Bush K, Bagchi P, et al. A randomized, double-blind trial comparing ceftobiprole medocaril with vancomycin plus ceftazidime for the treatment of patients with complicated skin and skin-structure infections. Clin Infect Dis. 2008; 46:647. 54. Noel GJ, Strauss RS, Amsler K, et al. Results of a double-blind, randomized trial of ceftobiprole treatment of complicated skin and skin structure infections caused by gram-positive bacteria. Antimicrob Agents Chemother. 2008; 52:37. 55. Bazan JA, Martin SI, Kaye KM. Newer beta-lactam antibiotics: doripenem, ceftobiprole, ceftaroline, and cefepime. Infect Dis Clin North Am. 2009; 23(4): 98396. 56. www.cdc.gov/hicpac/pdf/MDRO/ Pages11_28MDROGuideline2006.pdf 57. Boucher HW, Talbot GH, Benjamin DK Jr. 10 × ‘20 Progress—Development of New Drugs Active Against Gram-Negative Bacilli: An Update From the Infectious Diseases Society of America. Clin Infect Dis. 2013; April 17, 2013

Fall 2013 • Arizona Journal of Pharmacy • 39

Continuing Education

Acute Coronary Syndromes: Current Treatment Guidelines and Updates

by Bernard Lau, Pharm.D. Candidate 2014, Michael Lee, Pharm.D. Candidate 2014, Thien Tran, Pharm.D. Candidate 2014, Laura Tsu, Pharm.D, Midwestern University College of Pharmacy-Glendale Goal: This home-study CPE activity has been developed to educate pharmacists on acute coronary syndrome (ACS) and its medical management. Objectives: At the conclusion of this CPE activity, successful participants should be able to: 1. Identify the type of ACS (STEMI, NSTEMI, or UA) based on imaging and laboratory values. 2. List the recommendations for emergency department management for ACS. 3. Assess the eligibility of patients (STEMI or NSTEMI/UA) for PCI or fibrinolytic therapy. 4. Develop an appropriate pharmacotherapy treatment plan in patients admitted into hospital with ACS (STEMI or NSTEMI/UA). 5. Discuss the medication management for discharge in the patient with ACS. Introduction Cardiovascular disease (CVD) is a major leading cause of death worldwide. Acute coronary syndromes (ACS) make up the majority of CVD related mortalities, with more than 1.2 million Americans suffering from some sort of ACS every year.1 ACS, a result of having coronary heart disease, is very costly to health care and the economy, with direct and indirect costs totaling more than $177 billion in 2010. Etiology ACS is a result of occlusion and rupturing of atherosclerotic plaques in the vasculature of the heart.1 Atherosclerosis is a narrowing of the arteries that involves excess cholesterol and inflammation. The initial stage of this disease begins with an atherosclerotic plaque, or atheroma. These plaques normally occur in humans starting in the adolescent years. They are composed of macrophages that have taken up oxidized low density lipoproteins (LDL). Over time, these macrophages become foam cells, which subsequently become calcified as they become older and less metabolically active. The calcified plaque causes the artery to become stiff, which induces more stress on the arteries 40 â€˘ Arizona Journal of Pharmacy â€˘ Fall 2013

when blood flows through them as they are less compliant. As a result, gene regulation is altered and the endothelial cells lining the blood vessels decrease their production of nitric oxide, a potent endogenous vasodilator. The alteration in gene regulation also causes an increase in the rate of oxidation of LDL and enables them to enter the arterial wall. Monocytes also become more adhesive to the arterial wall, which causes smooth cell proliferation and the release of local vasoconstrictors and prothrombotic substances into the blood, resulting in an inflammatory response. Pathophysiology The leading cause of ACS in most patients is rupture of an unstable atherosclerotic plaque with subsequent thrombus development resulting in the limitation or interruption of coronary blood flow.1 In contrast to a stable plaque, an unstable plaque has an irregular shape, a thin fibrous cap, minimal amount of smooth muscle cells and a large lipid core that is highly populated with inflammatory cells such as macrophages and lymphocytes. These inflammatory cells release proteolytic enzymes and cause the thinning of the fibrous cap resulting in a plaque that is more susceptible to tear under constant shear stress. It is also noted that plaques that occlude less than 50% of the diameter of the coronary artery are more likely to rupture than those with a higher degree of occlusion. Following plaque rupture, tissue factor and subendothelial collagen are exposed to the blood components at the site of rupture, leading to platelet adhesion and activation. Activated platelets release thromboxane A2, adenosine diphosphate (ADP), and other vasoactive and prothrombotic substances that further intensify platelet recruitment and aggregation. Additionally, during platelet activation, ADP binds to the P2Y12 receptors and induces a conformational change in the glycoprotein (GP) IIb/IIIa receptors located on the surface of platelets, thereby facilitating the binding of fibrinogens responsible for cross-linking other platelets to form a preliminary clot. At the same time, the extrinsic coagulation cascade pathway is also activated by the

exposed tissue elements at the site of injury. Thrombin (factor IIa), the final product of this cascade and a potent platelet aggregation agonist, stabilizes the cross-linked platelets by converting the fibrinogen bridges to fibrin, thus trapping the red blood cells to form a stable clot. Other clotting factors also contribute to clot extension by gathering on the anionic surface of activated platelets and promoting more thrombin production. When a thrombus causes complete occlusion of the coronary artery and interruption of coronary blood flow, myocardial ischemia occurs and may lead to necrosis of myocardial tissues (i.e. myocardial infarction or MI). Most ACS cases involve only one ruptured atherosclerotic plaque in a major coronary artery; however, multiple ruptured plaques can occur and may affect more than one coronary artery. ACS patients with multiple coronary artery involvement usually have a worse prognosis. Types of ACS The spectrum of ACS encompasses all clinical syndromes related to acute myocardial ischemia as a result of an imbalance between the oxygen supply and demand in the myocardium.1 As mentioned before, the disruption of oxygen balance is primarily due to diminished myocardial blood flow secondary to one or more occlusive or partially occlusive coronary artery thrombi. The types of ACS are ST segment elevation myocardial infarction (STEMI), non-ST segment elevation myocardial infarction (NSTEMI), and unstable angina (UA). They are classified according to the electrocardiogram (ECG) and cardiac chemical biomarkers. In STEMI, the coronary artery thrombus is completely occlusive and the ST segment on the ECG is elevated. In both NSTEMI and UA, the coronary artery thrombus is partially occlusive and the ST segment on the ECG is depressed or the T wave is inverted. In order to differentiate between NSTEMI from UA, the level of cardiac biomarkers of myocardial necrosis such as troponin I or T, or creatine kinase myocardial band (CK-MB) are obtained from a blood test. NSTEMI differs from UA in that the extent of ischemia is

Continuing Education (continued from page 40) usually severe enough to cause myocardial necrosis, resulting in the subsequent release of biomarkers from the damaged tissues into the bloodstream. Therefore, elevated level of cardiac biomarkers is often seen in NSTEMI but not in UA. Diagnosis & Clinical Presentations Patients typically present to the emergency department with chest pain greater than 20 minutes that radiates to shoulder, left arm, back, or jaw.1 Atypical symptoms that can also be seen in patients include nausea and vomiting, diaphoresis, and shortness of breath. These atypical symptoms are more common in women, diabetics, and the elderly. A 12-lead ECG should be obtained and interpreted within 10 minutes of presentation to the emergency department with ischemic symptoms. Upon reviewing the findings on the ECG, patients are either classified as having STEMI or NSTEMI/UA, or their complaint may be due to a noncardiac issue. Since myocardial ischemia in some parts of the heart may not be detected on the surface by the ECG, it is important to review the ECG along with the cardiac biomarkers. Following the onset of myocardial ischemia, an increase in troponin and CK-MB level in the blood can be detected. One set of cardiac biomarkers obtained in the emergency department is often not long enough to detect any changes in the level of the cardiac biomarkers. Therefore, three sets of cardiac biomarkers are usually obtained 6 to 8 hours apart to avoid a false negative result. Further workup and individual patient risk assessment should be included in the definitive diagnosis of ACS. ACS Treatment Because time is crucial in stopping the expansion of infarction and tissue death in ACS patients, early treatment goals involves timely restoration of blood supply to the occluded artery in both STEMI and NSTEMI patients, and in the case of UA, prevention of complete occlusion and MI.1 Other short-term goals include symptom relief and prevention of other MI complications, recurrent MI, and death. General treatment approaches for all STEMI and intermediate to high risk NSTEMI or UA patients include hospital admission, continuous ECG and vital signs monitoring, glycemic control, pain relief, and bed rest.1 Upon

emergency department arrival, MONA therapy (see below), and beta-blocker therapy if not contraindicated, should be initiated immediately for all ACS patients. Patients should be triaged by ACS type as determined from ECG and laboratory findings, after which subsequent treatment plan is chosen based on individual patient’s signs and symptoms and past medical history. Initial treatment (MONA therapy plus Beta-blocker) Initial treatment of ACS patients involves the MONA therapy, which stands for Morphine, Oxygen, Nitroglycerin, and Aspirin. Beta-blockers should also be given to patients if not contraindicated with one or more of the following: 1) signs of heart failure, 2) evidence of low cardiac output, 3) increased risk of cardiogenic shock, 4) second or third degree heart block, or 5) active asthma or reactive airway disease.2,3 Intravenous morphine is administered as an analgesic to patients who continue to have pain refractory to nitroglycerin and also acts as a vasodilator to reduce preload. Oxygen is administered by nasal cannula to patients with oxygen saturation less than 90% for no more than 6 hours. For patients who do not appear at risk of hypoxemia or respiratory distress, excessive use beyond 6 hours can lead to systemic vasoconstriction, and high flow rates can be harmful to patients with chronic obstructive airway disease.2,3 Nitroglycerin is administered as continuous IV infusion if patients have continued chest pain, and should be titrated to pain relief. However, there are contraindications to the use of nitrates in patients presenting to emergency department with hypotension, marked bradycardia or tachycardia, MI in the right side of the heart, documented use of a phosphodiesterase type 5 inhibitor such as sildenafil or vardenafil within 24 hours or tadalafil within 48 hours. Enteric-coated aspirin must be chewed and swallowed immediately to break the enteric coating to achieve rapid platelet inhibition. Non-enteric coated formulations may be used for more rapid buccal absorption.2,3 Beta-blockers should be administered orally early in hospitalization and continue indefinitely to help reduce heart rate, blood pressure, and myocardial contractility. The use of beta-blocker can reduce the risk of recurrent ischemia, infarct size, and ventricular arrhythmias following

MI. Cardioselective beta-blockers, such as metoprolol and atenolol, are commonly used, but are not required. IV betablockers are no longer recommended routinely due to a high risk of cardiogenic shock.2,3 Pharmacologic agents for in-hospital management of ACS Once the patients have been stabilized with MONA therapy, proper treatment for their specific ACS condition needs to be initiated. Drugs used in this process include anticoagulants, antiplatelets, and fibrinolytics. We will outline the mechanism of action and monitoring parameters of these agents prior to discussing each agent’s place in therapy. Anticoagulant Agents Anticoagulants essentially inactivate clotting factors to prevent thrombus formation and extension.2,3 The anticoagulant agents that are commonly used in the treatment of ACS include unfractionated heparin (UFH), enoxaparin, fondaparinux, bivalirudin, and warfarin. UFH inhibits both factor IIa (thrombin) and factor Xa with equal selectivity.2,3 The dose is adjusted according to activated clotting time (ACT) or activated partial thromboplastin time (aPTT), but initial dose adjustment for renal or hepatic dysfunction is not required. Some contraindications to therapy include active bleeding, a history of heparin-induced thrombocytopenia (HIT), risk of severe bleeding, and recent stroke. The major side effect is bleeding. When the patient is on UFH, the monitoring parameters are bedside monitoring of ACT or aPTT, platelet count, and signs and symptoms of active bleeding.2,3 Enoxaparin (Lovenox) is a low molecular weight heparin (LMWH) that inhibits factor Xa more strongly than factor IIa.3 Dose reduction is required ifcreatinine clearance (CrCl) < 30 mL/min, and it is to be avoided completely if CrCl < 15 mL/min. Some contraindications include active bleeding, history of HIT, risk of severe bleeding, and recent stroke. The major side effects are bleeding and bruising. Monitoring parameters for enoxaparin include serum creatinine, platelet count, and signs and symptoms of bleeding. An advantage of using enoxaparin over UFH is that it can be administered subcutaneously. Fondaparinux (Arixtra) is a synthetic Fall 2013 • Arizona Journal of Pharmacy • 41

Continuing Education (continued from page 41) pentasaccharide that selectively inhibits factor Xa.3 Dose adjustment is not required for renal or hepatic impairment, but the use of fondaparinux is contraindicated if CrCl < 30 mL/min. Other contraindications are active bleeding and risk of severe bleeding. Furthermore, it has an increased risk of catheter thrombosis if used as monotherapy. When the patient is on fondaparinux, the monitoring parameters include serum creatinine and bleeding. Bivalirudin (Angiomax) is a direct thrombin inhibitor that specifically targets thrombin.3 Dose reduction is required for severe renal impairment, and contraindications are active bleeding and risk of severe bleeding. Also, it has an increased risk of stent thrombosis. Monitoring parameters include serum creatinine and signs and symptoms of bleeding. Bivalirudin monotherapy has a lower risk of bleeding than the combination therapy of UFH or enoxaparin with GP IIb/IIIa inhibitors. However, the combination of bivalirudin with GP IIb/IIIa inhibitors has a higher risk of bleeding without a corresponding increase in efficacy, and therefore is not recommended to use the combination of bivalirudin and GP IIb/IIIa inhibitors. Warfarin, a vitamin K antagonist, reduces thrombus formation by inhibiting the activation of vitamin K-dependent clotting factors.1 The dose is adjusted to maintain a target international normalized ratio (INR) of 2 to 3. Some contraindications include active bleeding, risk of severe bleeding, pregnancy (except in pregnant women with mechanical heart valves)and uncontrolled hypertension. The major side effect is bleeding. When the patient is on warfarin, the monitoring parameters are INR and signs and symptoms of bleeding. Warfarin is not commonly used as monotherapy in ACS and should be prescribed for patients with certain indications for warfarin, such as atrial fibrillation, left ventricular thrombus, and mechanical prosthetic heart valves. Antiplatelet Agents Aspirin (ASA) ASA irreversibly inhibits cyclooxygenase-1 (COX-1) and COX-2 enzymes which prevents the formation of prostaglandin derivative, thromboxane-A, thereby inhibiting platelet aggregation.1 Dose adjustment is not required for renal or hepatic impairment, but avoid 42 â€˘ Arizona Journal of Pharmacy â€˘ Fall 2013

using ASA if CrCl < 10 mL/min or in patient with severe liver disease. Some contraindications are active bleeding, hemophilia, severe untreated hypertension, an active peptic ulcer, or another serious source of gastrointestinal or genitourinary bleeding. The major side effect is gastrointestinal bleeding. It is the preferred antiplatelet agent in all ACS scenarios. It should be administered to patients within 24 hours of hospital admission. The patients will be on ASA therapy indefinitely regardless of the type of ACS. Glycoprotein IIb/IIIa Inhibitors GP IIb/IIIa inhibitors bind to the GP IIb/ IIIa receptors on the platelet preventing platelet aggregation and thrombus formation.3 The GP IIb/IIIa inhibitors that are used in the treatment of ACS include abciximab, eptifibitide, and tirofiban.2,3 Abciximab (ReoPro) does not require dose adjustment for renal or hepatic impairment.2,3 Some contraindications include active bleeding, thrombocytopenia, prior stroke and severe uncontrolled hypertension. Abciximab, being a monoclonal antibody, has a risk of immune-mediated thrombocytopenia, which can be treated with platelet transfusions as needed for control of bleeding. The major side effect of abciximab is bleeding, so the main monitoring parameters include signs and symptoms of bleeding and platelet counts. Eptifibitide (Integrillin) requires dose reduction by 50% in patients with CrCl < 50mL/min.2,3 Some contraindications include active bleeding, thrombocytopenia, prior stroke, renal dialysis and severe uncontrolled hypertension. Patients can be treated with platelet transfusions as needed to control bleeding due to a risk of thrombocytopenia. The major side effect with eptifibatide is bleeding. Monitoring parameters for this drug include signs and symptoms of bleeding, serum creatinine, and platelet counts. Tirofiban (Aggrastat) requires dose to be reduced by 50% in patients with CrCl < 30mL/min.2,3 Some contraindications are active bleeding, thrombocytopenia, prior stroke and severe uncontrolled hypertension. Patients can be treated with platelet transfusions as needed to control bleeding due to risk of thrombocytopenia. The major side effect is bleeding. Monitoring parameters for this drug

include signs and symptoms of bleeding, serum creatinine, and platelet counts. P2Y12 receptor antagonists P2Y12 receptor antagonists block the P2Y12 receptors on platelets which prevents activation of the GP IIb/IIIa receptor complex, thereby reducing platelet aggregation.3 The P2Y12 receptor antagonists that are used in the treatment of ACS include clopidogrel, prasugrel, and ticagrelor.2,4 Clopidogrel (Plavix) is the most frequently prescribed P2Y12 receptor antagonist. An advantage of clopidogrel is that it does not require dose adjustment for renal or hepatic impairment.2,3 It has a Black Box Warning against its use in patients who are poor CYP2C19 metabolizers. This is because clopidogrel is a prodrug that requires a two-step conversion to an active metabolite, and the effectiveness of the drug is dependent on its activation to an active metabolite by CYP2C19. Poor CYP2C19 metabolism results in a smaller antiplatelet effect and an increased risk of cardiovascular events. Some contraindications are hypersensitivity to clopidogrel, active bleeding, and risk of severe bleeding. The major side effect is bleeding. Prasugrel (Effient) also does not require dose adjustment for renal or hepatic impairment.2,4 It is also a prodrug, but it requires only a one-step conversion to active metabolite. Some contraindications with prasugrel include history of transient ischemic attack (TIA), stroke, and active bleeding. It has a FDA-labeled warning against its use in patients greater than 75 years old or with a weight less than 60kg due to concerns of an increased risk of fatal and intracranial bleeding. Prasugrel is most beneficial when used in STEMI and diabetic patients. Ticagrelor (Brilinta) is the most recently approved P2Y12 receptor antagonist. It must be administered with a low ASA maintenance dose (less than 100mg daily). Some contraindications include hypersensitivity to ticagrelor, active bleeding, and history of intracranial hemorrhage. Caution should be taken in patients when taking ticagrelor with CYP3A4 inducers or inhibitors. The major side effects of this drug include bleeding and dyspnea. Fibrinolytic Agents Fibrinolytics work by degrading existing

Continuing Education (continued from page 42) fibrin clots to open up the blockage in the arteries in order to increase blood flow.1 In NSTEMI/UA patients, fibrinolytic therapy is not recommended as clinical trials showed no significant benefit and an increased risk of MI and death.3 Fibrinolytic therapy is recommended in STEMI patients who do not have timely access to a cardiac catheterization laboratory.2 Available fibrinolytics differ based on their fibrin-specificity; streptokinase is non-specific, whereas tenectaplase, reteplase and alteplase have a higher fibrin-specificity.1 Streptokinase non-selectively binds to either free-flowing or fibrin-bound plasminogen and converts it to plasmin.5 Plasmin is a proteolytic enzyme that dissolves the fibrin in the blood clot. Dose adjustment is not required for renal or hepatic impairment.2 Absolute contraindications to fibrinolysis include history of hemorrhagic stroke, ischemic stroke within 3 months, known malignant intracranial neoplasm or arteriovenous malformation, active internal bleeding, suspected aortic dissection, or significant facial or closed head trauma in the last 3 months. Relative contraindications to fibrinolysis include history of prior ischemic stroke more than 3 months ago, significant hypertension with blood pressure over 180/110 mmHg, recent trauma, major surgery within 3 weeks, internal bleeding within 2 to 4 weeks, oral anticoagulant therapy, active peptic ulcer or pregnancy. The major side effect is bleeding. When the patient is on streptokinase, the monitoring parameters include performing a complete blood count (CBC), aPTT, and watching for signs and symptoms of bleeding. Streptokinase has a higher risk of systemic bleeding than the fibrin-specific fibrinolytics. Tenecteplase, reteplase, and alteplase all selectively bind to plasminogens that are bound to fibrin and convert them to plasmin.5 Dose adjustment is not required for renal or hepatic impairment. The major side effect for these drugs as with all fibrinolytics is bleeding.2 Contraindications and monitoring parameters are the same as non-fibrinspecific fibrinolytics. These fibrin-specific fibrinolytics have higher risk of ICH than streptokinase. STEMI Treatment STEMI patients are at the highest risk

of death according to the Global Registry of Acute Coronary Events (GRACE) report, so initial therapy should be started immediately for these patients, regardless of cardiac biomarkers levels.1 All STEMI patients should be evaluated for reperfusion therapy immediately upon arrival at the emergency department. Fibrinolytic therapy or primary percutaneous coronary intervention (PCI) is considered first line treatment for restoring coronary artery blood flow in STEMI patients. Primary PCI is generally deemed superior to fibrinolytics due to lower stroke and bleeding risk, lower mortality rate, and higher success rate in opening up an occluded coronary artery than the latter. Timing of treatment is also crucial to patient survival and reducing the extent of damages to the infarcted myocardium. For STEMI patients presenting to a hospital with a cardiac catheterization laboratory, PCI should be performed within 90 minutes of initial presentation.2 If the hospital is not equipped to perform primary PCI, the next treatment choice should be selected based on individual patient risks such as the time from onset of symptoms, risk of STEMI complications, risk of bleeding with fibrinolysis, presence of shock or severe heart failure, and the time required for transfer to a PCI-capable hospital. Ideally, all patients should be transferred to a PCI-capable hospital immediately if the procedure can be performed within 120 minutes of first medical contact. If the anticipated time for inter-hospital transfer exceeds the target goal, fibrinolytic therapy should be chosen as the primary reperfusion therapy in the absence of contraindications. If appropriate, fibrinolytic agents should be administered within 30 minutes of hospital arrival. Primary PCI PCI is a minimally invasive revascularization procedure that is performed by skilled interventional cardiologists in hospitals equipped with a cardiac catheterization laboratory.6 The procedure can be for diagnostic or interventional purposes, depending on whether revascularization is performed. The initial procedure involves cardiac catheterization whereby access to coronary arteries is commonly obtained through the femoral or radial artery up the aorta to the suspected occlusion site. After inserting the diagnostic catheter, coronary

angiography is performed by injecting contrast dye into the blood to visualize the coronary arteries and determine narrowing and blockages of vessels. If, upon examination, an occlusion site is identified and revascularization is indicated, balloon angioplasty can be performed with the help of a guidewire. Balloon angioplasty works by dilating the occluded artery with an inflatable balloon, thereby compressing the atherosclerotic plaque into the vessel wall in order to restore coronary perfusion. Most often, a coronary stent is deployed and left in place to prevent acute closure of the artery. Common types of stents include bare metal stents (BMS) or drug-eluting stents (DES), which are coated with an antiproliferative agent such as sirolimus or paclitaxel. The most common complication of angioplasty is restenosis (i.e. a renarrowing of a previously dilated coronary stenosis). It occurs most frequently in patients with angioplasty without stent placement, less frequently with BMS, and least frequently with DES. DES implantation decreases restenosis rates and the need for subsequent target vessel revascularization owning to the anti-proliferative effect of the coated drugs that helps to retard and minimize cell growth. Despite the advantage of DES over BMS, it is also associated with a higher risk of stent thrombosis, so patients must be adherent to dual antiplatelet therapy for one year following the procedure. If patients are unable to commit to the dual antiplatelet regimen due to factors such as a high risk of bleeding, patient incompliance, or anticipated invasive or surgical procedures in the next year, BMS should be considered as an alternative.2 Because PCI is an invasive procedure, all patients should receive antithrombotic therapy to prevent thrombotic complications. The regimen should include antiplatelet agents such as ASA, a P2Y12 receptor antagonist, and a GP IIb/IIIa inhibitor. In addition, adequate anticoagulation should be achieved throughout the duration of the procedure to prevent thrombosis of the catheter, guidewire, and other thrombotic complications. ASA should be administered early to all patients without contraindications, most often included in the MONA therapy upon emergency room arrival and within 24 hours of hospital admission, and continued indefinitely after the procedure.2 High-dose ASA is preferred for patients Fall 2013 â€˘ Arizona Journal of Pharmacy â€˘ 43

Continuing Education (continued from page 43) undergoing primary PCI in order to achieve a rapid antiplatelet inhibition. If a stent is implanted, patients should continue high-dose ASA for a definite period of time based on the type of stent selected and switch to low-dose ASA thereafter. Low-dose ASA is generally recommended for maintenance due to the lack of clinical efficacy and risk of major bleeding, particularly gastrointestinal bleeding, that is associated with high dose ASA. Since ASA only inhibits platelet aggregation through one pathway, it does not provide sufficient antiplatelet effect when used alone. Therefore, concomitant administration of a P2Y12 receptor antagonist, such as clopidogrel, prasugrel, or ticagrelor, is recommended.2 In order to achieve faster platelet inhibition effects, a loading dose should be provided to STEMI patients as early as possible or at the time of primary PCI. Following PCI, P2Y12 receptor inhibitor therapy should be continued on a maintenance dose for at least 14 days for patients without a stent and up to 1 year for patients with either a BMS or DES implanted in the absence of bleeding complications. In general, selection of a P2Y12 receptor antagonist should be based on patientâ€™s bleeding risk, genetic predisposition, comorbidities, and additional contraindications for individual agent. Among the P2Y12 inhibitors, clopidogrel has the longest history of use for treatment of ACS. Nonetheless, due to the pharmacokinetics of clopidogrel, patients who carry a certain allele of the CYP450 enzyme may have reduced capabilities to metabolize the drug, leading to significant lower levels of active metabolites and diminished platelet inhibition. Consequently, clopidogrel may be undesirable for these patients. Newer agents such as prasugrel and ticagrelor had demonstrated greater efficacy in platelet inhibition and improved patient outcome comparing to clopidogrel in their corresponding landmark trials, namely TRITON-TIMI 38 and PLATO respectively.7,8 GP IIb/IIIa inhibitors work on the final common pathway of platelet aggregation and provide additional platelet inhibition when used in combination with other antiplatelet agents. The adjunctive use of GP IIb/IIIa inhibitors in STEMI patients at the time of PCI should be considered on an individual basis and should depend on factors such as choice of anticoagulant, 44 â€˘ Arizona Journal of Pharmacy â€˘ Fall 2013

presence of large thrombus, or inadequate P2Y12 receptor inhibitor loading.2 While GP IIb/IIIa inhibitors may be used together with either UFH or enoxaparin, co-administration with bivalirudin should be avoided if possible due to increased risk of major bleeding. If abciximab or tirofiban is chosen, a bolus dose should be administered prior to continuous IV infusion. For eptifibatide, two boluses should be given 10 minutes apart prior to continuous IV infusion. Dosing adjustment is required for eptifibatide and tirofiban in patients with renal dysfunction. For patients presenting with severe renal or hepatic impairment, abciximab may be a better alternative since no dose adjustment is necessary. Following PCI, abciximab can be continued for up to 12 hours, eptifibatide for 12 to 18 hours, and tirofiban for up to 18 hours at the discretion of the physician.9 Anticoagulants that are recommended for STEMI patients undergoing primary PCI include UFH and bivalirudin.2 UFH has a long standing history of use in STEMI and is the most common anticoagulant used in cardiac catheterization laboratory.1 One advantage of UFH over other anticoagulants is the availability of an antidote (i.e. protamine), which is very useful if a reversal of anticoagulation is necessary. Intensity of anticoagulation, which can be easily monitored at the bedside with ACT, is often dependent on whether a GP IIb/ IIIa inhibitor has been administered. Additional boluses may be given as needed to maintain therapeutic ACT levels. Due to bleeding concerns, frequent monitoring is required and is often deemed a limitation for its use. For patients with a contraindication for UFH or are at high risk of bleeding, bivalirudin may be a reasonable alternative to UFH. Bivalirudin has been shown to have a lower bleeding risk than combination of UFH and a GP IIb/IIIa inhibitor, making it the preferred agent for STEMI patients at high risk of bleeding.2 However, bivalirudin has also been associated with increased risk of acute stent thrombosis.10 Since the majority of patients receiving PCI have stent placement, bivalirudin should be reserved for those with HIT, higher risk of bleeding, or when the use of GP IIb/IIIa inhibitors is undesirable.2 Other anticoagulants such as enoxaparin and fondaparinux may be used in primary

PCI in certain ACS settings although they are not specifically recommended as first line anticoagulants in primary PCI. Enoxaparin may be continued uninterrupted during rescue PCI in patients who received enoxaparin with prior fibrinolytic therapy.2 A supplemental IV dose of enoxaparin should be administered if the last dose was administered between 8 and 12 hours earlier. After 12 hours, patients should either receive a full dose of enoxaparin or switch to UFH or bivalirudin for anticoagulation. Fondaparinux should not be used alone because it does not provide adequate anticoagulation for PCI and is associated with higher risk of catheter thrombosis.2 Therefore, a second anticoagulant like UFH or bivalirudin should be administered together if fondaparinux is to be selected for specific reasons. Regardless of choice of anticoagulant, anticoagulant therapy should be discontinued immediately after PCI to avoid bleeding complications. Fibrinolysis Fibrinolytic therapy is recommended for STEMI patients who are ineligible for PCI and present to hospital within 12 hours of the onset of chest discomfort.2 This time frame has been shown to be most beneficial in decreasing the incidence of mortality. For STEMI patients presenting to the hospital within 12 to 24 hours of symptom onset, fibrinolytic agent may be administered if they experience ongoing ischemia. Because fibrinolytic agents work by dissolving existing clots, patients at high risk of bleeding should be assessed for absolute and relative contraindications (as described previously) prior to administration.1 While patients presenting with any absolute contraindication are precluded from receiving fibrinolytic therapy, patients presenting with a relative contraindication may still receive treatment if the risk of death from MI outweighs the risk of major bleeding. Special consideration should be taken in patients over 75 years of age. Although the use of fibrinolytics in this age group is not recognized as a contraindication, this patient population has a higher MI mortality rate associated with fibrinolytic use compared to a younger patient population. Therefore, careful dosing efforts should be made to prevent bleeding when administering fibrinolytic and anticoagulation therapies to these patients. In terms of selection of

Continuing Education (continued from page 44) a fibrinolytic agent, fibrin-specific agents such as tenecteplase, reteplase, or alteplase are preferred over non-fibrin-specific agent like streptokinase. All fibrinolytic agents may potentially cause major bleeding including intracranial hemorrhage (ICH). Regardless of the choice of a fibrinolytic agent, adjunctive antithrombotic therapy, such as anticoagulant and/or antiplatelet therapies, should be initiated for STEMI patients receiving fibrinolytic therapy.2 Antiplatelet therapy with fibrinolysis includes both ASA and clopidogrel, which should be administered before or with the fibrinolytic agent. ASA should be continued indefinitely following fibrinolytic therapy. Clopidogrel should be continued for at least 14 days and up to 1 year based on individual patient’s risk of reinfarction. Currently, prasugrel and ticagrelor are not recommended to be administered with fibrinolytics because these agents have not been studied with fibrinolytic therapy. GP IIb/IIIa inhibitors are also not recommended for use with fibrinolytics. Furthermore, patients should receive an anticoagulant in addition to their fibrinolytic regimen in order to minimize vessel obstruction and prevent re-occlusion. Enoxaparin is the preferred agent for anticoagulation with fibrinolytic therapy. However, other anticoagulants such as UFH and fondaparinux are also good alternatives. The selected anticoagulant should be continued for a minimum of 48 hours, up to 8 days or until revascularization is performed. In the event of re-occlusion or failed reperfusion after fibrinolytic therapy, patients may show ongoing ischemic symptoms, or worst, develop cardiogenic shock or acute severe heart failure.2 These patients are at high risk of mortality, and are good candidates for a rescue PCI and should be transferred to a PCI-capable hospital immediately. If these patients have not received a previous loading dose of clopidogrel with fibrinolytic therapy, a supplemental loading dose should be given before or at the time of PCI. Coronary Artery Bypass Graft Surgery (CABG) CABG is a surgical alternative to PCI or medical management for severe coronary artery disease.2 The indications for CABG are based on severity of ischemia, coronary anatomy, and left ventricular function. In the setting of STEMI, major indications for CABG include patients

with multi-vessel (> 3) disease, significant left anterior descending artery stenosis, cardiogenic shock, or failed primary PCI.11 A number of clinical trials have found CABG to be superior to aggressive medical management or PCI in the long term survival of high risk patients.12,13 The surgery is performed by cardiothoracic surgeons rather than cardiologists. During the surgical procedure, an artery (internal mammary or radial) or vein (usually the saphenous) harvested from another part of the body is used to form a connection between the aorta and the section of the coronary artery distal to the occlusion site, and consequently, bypassing the occluded area and restoring coronary blood flow.14 Although this type of surgery most often requires a cardiopulmonary bypass machine, it may be performed “off-pump” by skilled cardiac surgeons and can significantly reduce serious bleeding and thrombotic complications (stroke, MI) after the procedure.11 Since CABG is an invasive procedure and puts the patients at high risk of bleeding, all antiplatelet agents, except for ASA, should be withheld before the procedure.11 Preoperative ASA use has been shown to reduce operative morbidity and mortality rates in CABG patients. In contrast, use of P2Y12 receptor antagonists is associated with increased rates of major bleeding which necessitates blood transfusions in post-CABG patients. Therefore, patients undergoing urgent CABG should discontinue clopidogrel and ticagrelor for at least 24 hours prior to surgery. Often, CABG may be an elective surgery for certain patients with high risk of severe MI. In these patients referred for elective CABG, clopidogrel and ticagrelor should be discontinued for at least 5 days and prasugrel for at least 7 days to decrease major bleeding complications. Other IV antiplatelet agents such as eptifibatide and tirofiban should be withheld for at least 2 to 4 hours and abciximab for at least 12 hours before surgery to limit blood loss and transfusions. During the surgery, adequate anticoagulation should be maintained with UFH per institutional practice.3 In the absence of contraindications, betablockers should be given 24 hours before CABG to decrease the incidence of postoperative atrial fibrillation. Because the CABG procedure puts the patient at increased risk of developing wound or systemic infections, prophylactic

antibiotics (a first or second generation cephalosporin with or without MRSA coverage) should be given to all patients. In addition, tight postoperative glycemic control and lipid management are necessary to ensure the best possible outcome for all patients. NSTEMI/UA Treatment Invasive vs. Conservative Strategy Initial treatment of NSTEMI/UA involves the use of the Thrombolysis In Myocardial Infarction (TIMI) scoring system.1 This system calculates the risk of composite endpoint of death, MI, or urgent need for revascularization within 14 days. One point (1) is assigned if the patient has each of the following: age greater than 65, three or more cardiac risk factors (HTN, DM, hyperlipidemia, smoking, family history), known history of CAD (greater than 50% stenosis seen on angiogram), two or more episodes of chest discomfort in the last 24 hours, ASA use within the last 7 days, elevated cardiac biomarkers, and ST-segment deviation on an ECG. These criteria are serious risk factors for developing either an MI, death, or urgent revascularization within the next 14 days. Patients presenting with multiple criteria should be treated urgently with an invasive strategy. ASA should be initially given to NSTEMI/UA patients, with a loading dose of clopidogrel, prasugrel, or ticagrelor being as a substitute if ASA is intolerant to the patient.4 Initial Invasive Strategy An initial invasive strategy involves cardiac catheterization, usually within 4 to 24 hours following hospital admission, followed by either revascularization with PCI or CABG.3 This strategy is recommended for patients with a moderate to high risk of an event according to their TIMI score and other high risk features such as patients who have refractory angina, hemodynamic or electrical instability, or initially stabilized NSTEMI/ UA with an elevated risk for clinical events.4 Patients with definite NSTEMI/ UA who are at moderate to high risk should be given dual antiplatelet therapy upon presentation, with ASA being one of the agents.3 The choice for the second antiplatelet agent can be either clopidogrel, prasugrel, ticagrelor, and a GP IIb/IIIa inhibitor (tirofiban and eptifibatide being the preferred agents).4 These agents are to be given either before PCI or at Fall 2013 • Arizona Journal of Pharmacy • 45

Continuing Education (continued from page 45) the time of PCI. This is to reduce the risk of ischemic events that may occur during PCI, as trauma frequently occurs during these types of procedures. This results in platelet activation, aggregation, and subsequently a coronary thrombosis. Anticoagulants are needed in invasive strategies because they limit thrombotic complications of ischemic events, especially during angioplasty. They also help prevent thrombosis of catheters and guidewires used during these procedures. Depending on the results of the diagnostic angiography, there are three possible postangiography management strategies one can initiate, depending on the findings of the angiography: CABG, PCI, or medical therapy.3 CABG CABG surgery is strongly recommended in NSTEMI/UA patients with significant left main coronary artery disease (CAD), 3-vessel disease, 2-vessel disease, or when PCI is not optimal or possible.11 If CABG is selected, continue ASA therapy; discontinue clopidogrel for least 5 days, prasugrel for at least 7 days, and ticagrelor for at least 5 days prior to CABG procedure.4 ASA is used to provide antiplatelet therapy during the procedure, while the other antiplatelets are discontinued as they incur a serious risk of bleeding.3 Prasugrel has an earlier discontinuation time than clopidogrel and ticagrelor because it has a much higher risk of bleeding than those two agents. Intravenous GP IIb/IIIa inhibitors (eptifibatide and tirofiban) must also be discontinued 2 – 4 hours prior to CABG procedure. UFH is to be continued, while enoxaparin must be discontinued 12 to 14 hours, fondaparinux 24 hours, and bivalirudin 3 hours prior to CABG. PCI PCI is recommended for NSTEMI/UA patients with 1- or 2- vessel CAD and multi-vessel coronary disease with suitable coronary anatomy.3 If PCI is selected, ASA is to be continued. A loading dose of clopidogrel, prasugrel, or ticagrelor, and/or GP IIb/IIIa should be given if not given prior to angiography.4 GP IIb/ IIIa inhibitors are highly recommended in addition to ASA and P2Y12 inhibitors in PCI patients to reduce morbidity and mortality based on several randomized control trials. A study involving abxicimab or placebo given to patients 46 • Arizona Journal of Pharmacy • Fall 2013

showed that the patient group receiving abxicimab in addition to clopidogrel showed a significant reduction in the primary end points of death, nonfatal reinfarction, or urgent target-vessel vascularization within 30 days.15 Once PCI is completed, anticoagulant therapy can be discontinued.3 Medical Therapy Medical therapy is recommended for post-angiographic NSTEMI/UA patients with no signs of significant obstructive CAD on angiography.4 Antiplatelet and anticoagulant therapy is used in these patients at a physician’s discretion. If CAD is detected on angiography, ASA should be continued.3 A loading dose of clopidogrel or ticagrelor should be given to provide a rapid antiplatelet effect if not given prior to angiogram, as maintenance doses require a few days to achieve full effect. Prasugrel is not recommended because it has only proven benefit in patients undergoing PCI. IV GP IIb/ IIIa inhibitors should be discontinued after at least 12 hours if it was started before the angiogram. IV UFH should be continued for at least 48 hours or enoxaparin or fondaparinux for the duration of hospitalization, up to 8 days. Bivalirudin can be continued at a dose of 0.25 mg/kg/hr for up to 72 hours at a physician’s discretion if it was given prior to diagnostic angiography. Initial Conservative Strategy An initial conservative treatment strategy is recommended for NSTEMI/ UA patients with a low stratified TIMI risk score.4 This treatment strategy involves initial medical management, followed by catheterization and revascularization if an ischemic event occurs despite active drug treatment. Patients presenting with a low risk of death, MI (either initial or recurrent), or refractory angina are usually evaluated in the emergency department. Serum biomarkers are obtained from the patient, and if they are negative for these biomarkers, the patient may be directed to a general medical area to undergo ECG monitoring for any ischemic events or arrhythmias. In addition, a stress test, such as an exercise stress test, can be performed. If there are positive findings in the stress test, diagnostic angiography should be performed. For these low risk patients, ASA should be initially given, along with either

clopidogrel or ticagrelor (loading dose followed by daily maintenance doses) as soon as possible after admission.4 ASA is to be continued indefinitely while clopidogrel or ticagrelor should be continued for one month and up to 12 months. If the patient is stable and their symptoms are controlled, they can be discharged with recommended antiplatelet therapy such as clopidogrel or ticagrelor for a duration ranging from one month to one year. If an ischemic event does occur while the patient is on drug therapy, an angiography should be performed, and invasive strategies (CABG, PCI, or medical therapy for CAD) are initiated.4 Prior to angiography, either an IV GP IIa/ IIIb inhibitor (tirofiban or eptifibatide) or a P2Y12 inhibitor (clopidogrel or ticagrelor, loading dose followed by daily maintenance doses) should be added to ASA and anticoagulant therapy. Discharge Medications and Secondary Prevention Once a patient has received appropriate treatment for ACS and is recovering, it is imperative that they be put on appropriate medications for secondary prevention of ischemic events prior to discharge.1 ACS patients should be on ASA indefinitely, in addition to a beta-blocker and statin therapy. ASA has been shown in a large number of clinical trials to decrease the risk of death, recurrent MI, and stroke following an MI.3 If the patient is unable to take ASA due to contraindications, clopidogrel is recommended. All patients should be given sublingual nitroglycerin (SL NTG) tablets or a lingual nitroglycerin spray in the event if they experience recurrent chest pain and discomfort. Betablockers are recommended indefinitely because they have been shown to decrease the incidence of recurrent MI. However, they are contraindicated in HF patients with acute decompensation. ACE inhibitors are indicated in patients who are not at blood pressure goals on betablocker therapy, as well as patients with a reduced ejection fraction or diabetic patients. Angiotensin II receptor blockers can be given if the patient suffers from ACE inhibitor induced angioedema. According to ACC/AHA guidelines, the goal blood pressure for HTN patients with ACS is 130/80 mmHg. In addition, it is imperative that ACS patients receive lipidlowering agents such as statins, as they are

Continuing Education (continued from page 46) used to prevent total mortality and stroke. Furthermore, all ACS patients should be provided appropriate pharmacological and non-pharmacological therapy to achieve a goal LDL level of less than 100 mg/dL. Other modifiable risk factors such as diabetes mellitus and smoking are also important in secondary prevention of ACS. According to ADA guidelines, the goal HgB A1c level for ACS patients with diabetes is < 7%. Smoking cessation is correlated with a significant reduction in all-cause mortality in all ACS patients, and can be achieved by various products such as varenicline or nicotine patches/gums. Proper diet and exercise is also important, as maintaining an ideal weight is essential in preventing the reoccurrence of ACS events. In certain patients with atrial fibrillation with a CHADS2 score of greater than or equal to 2, mechanical heart valves, venous thromboembolism, or a hypercoagulable disorder, warfarin may be indicated.2 Co-administration of warfarin and dual antiplatelet therapy may put patients at high risk of severe bleeding. Therefore, the duration of use should be limited to the extent of anticoagulation deemed necessary. A lower INR goal (2.0 – 2.5) should also be considered. Conclusions Acute coronary syndromes contribute to a significant number of cardiovascular related deaths in the US.1 Pharmacists have an important role in managing the disease state for the patient from the beginning in the emergency room to discharging the patients from the hospital. Pharmacists need to be vigilant in selecting the most appropriate therapy for their patients based on the type of ACS and patient specific factors in order to help reduce the risk of developing side effects and complications, re-infarction, and most importantly, death. Pharmacists are an integral part of the health care team that can provide dosing and monitoring recommendations for medications, as well as provide education to patients to prevent recurrent cardiac events.

2013 ACCF/AHA guidelines for the management of versus clopidogrel in patients with acute coronary ST-elevation myocardial infarction: a report of the syndromes. N Engl J Med. 2009;361(11):1045-57. American College of Cardiology Foundation/American 9. Kushner FG, Hand M, Smith SS et al. 2009 focused Heart Association Task Force on practice guidelines. J updates: ACC/AHA guidelines for the management Am Coll Cardiol. 2013;61(4):e78-e140. of patients with ST-elevation myocardial infarction 3. Anderson JL, Adams CD, Antman EM et al. ACC/ (updating the 2004 guideline and 2007 focused update) AHA 2007 guidelines for the management of patients and ACC/AHA/SCAI guidelines on percutaneous with unstable angina/non-ST-Elevation myocardial coronary intervention (updating the 2005 guideline and infarction: a report of the American College of 2007 focused update): a report of the American College Cardiology/American Heart Association Task Force of Cardiology Foundation/American Heart Association on Practice Guidelines (Writing Committee to Revise Task Force on practice gudielines. the 2002 Guidelines for the Management of Patients 10. Stone GW, Witzenbichler B, Guagliumi G, et al. With Unstable Angina/Non-ST-Elevation Myocardial Bivalirudin during primary PCI in acute myocardial Infarction) developed in collaboration with the American infarction. N Engl J Med. 2008;358:2218-30. College of Emergency Physicians, the Society for 11. Hillis LD, Smith PK, Anderson JL, et al. 2011 Cardiovascular Angiography and Interventions, and ACCF/AHA guideline for coronary artery bypass graft the Society of Thoracic Surgeons endorsed by the surgery: a report of the American College of Cardiology American Association of Cardiovascular and Pulmonary Foundation/American Heart Association Task Force on Rehabilitation and the Society for Academic Emergency Practice Guidelines. Circulation. 2011;124:e652–735. Medicine. J Am Coll Cardiol. 2007;50(7):e1-e157. 12. Serruys PW, Morice MC, Kappetein AP et al. 4. Jneid H, Anderson JL, Wright RS et al. 2012 ACCF/ SYNTAX Investigators. Percutaneous coronary AHA focused update of the guideline for the management intervention versus coronary-artery bypass grafting for of patients with unstable angina/non ST-elevation severe coronary artery disease. N Engl J Med. 2009; myocardial infarction (updating the 2007 guideline 360:961-972. and replacing the 2011 focused update): a report of the 13. Farkouh ME, Domanski M, Sleeper LA, et American College of Cardiology Foundation/American al; FREEDOM Trial Investigators. Strategies for Heart Association Task Force on practice guidelines. J multivessel revascularization in patients with diabetes. N Am Coll Cardiol. 2012;60(7):645-81. Engl J Med. 2012 Dec;367:2375-84 5. Grossc PL, Murray RK, Rand ML. Chapter 51. 14. Antman EM, Selwyn AP, Loscalzo J. Chapter 243. Hemostasis & Thrombosis. In: Murray RK, Kennelly Ischemic Heart Disease. In: Fauci AS, Kasper DL, PJ, Rodwell VW, Botham KM, Bender DA, Weil PA, eds. Jameson JL, Longo DL, Hauser SL, eds. Harrison’s Harper’s Illustrated Biochemistry. 29th ed. New York: Principles of Internal Medicine. 18th ed. New York: McGraw-Hill; 2011. http://0-www.accesspharmacy. McGraw-Hill; 2012. http://0-www.accesspharmacy.com. com.millennium.midwestern.edu/content. millennium.midwestern.edu/content.aspx?aID=9104321. aspx?aID=55886653. Accessed April 8, 2013. Accessed April 10, 2013. 6. Faxon DP, Bhatt DL. Chapter 246. Percutaneous 15. Kastrati A, Mehilli J, Neumann Fj et al. Abciximab Coronary Interventions and Other Interventional in patients with acute coronary syndromes undergoing Procedures. In: Fauci AS, Kasper DL, Jameson JL, percutaneous coronary intervention after clopidogrel Longo DL, Hauser SL, eds. Harrison’s Principles of pretreatment: the ISAR-REACT 2 randomized trial. Internal Medicine. 18th ed. New York: McGraw-Hill; JAMA. 2006 Apr 5;295(13):1531-8. 2012. http://0-www.accesspharmacy.com.millennium. 16. Levine GN, Bates ER, Blankenship JC et al. 2011 midwestern.edu/content.aspx?aID=9104769. Accessed ACCF/AHA/SCAI guideline for percutaneous coronary April 8, 2013. intervention: executive summary: a report of the 7. Wiviott SD, Braunwald E, Mccabe CH, et al. American College of Cardiology Foundation/American Prasugrel versus clopidogrel in patients with acute Heart Association Task Force on practice guidelines coronary syndromes. N Engl Composite J Med. 2007;357(20):2001therevascularization Society for Cardiovascular Angiography Risk Score endpoint of MI, death, orand urgent 15. and Interventions. Catheter Cardiovasc Interv. - 1Becker RC, Budaj A, et al. Ticagrelor 4.7% 2012;79(3):453-95. 8. Wallentin0L, 2 Score 3

Composite endpoint of MI, death, or urgent revascularization 13.2%

04- 1

4.7% 19.9%

8.3% 26.2%

6 -37

13.2% 40.9%

4 Source: Adapted from information found in reference 1 5 6-7

Risk Moderate Low High Moderate

19.9% 26.2%

High

40.9%

Source: Adapted from information found in reference 1 Agents Blood Pressure

Goals of Therapy

Beta-blocker (BB)

< 130/80 mmHg

Non-DHP CCB (if intolerant to BB)

ACEi and AA if LVEF < 40%

ACE inhibitors (ACEi) Agents Blood Pressure

References 1. Spinler SA, De Denus S. Chapter 24. Acute Coronary Syndromes. In: Talbert RL, DiPiro JT, Matzke GR, Posey LM, Wells BG, Yee GC, eds. Pharmacotherapy: A Pathophysiologic Approach. 8th ed. New York: McGraw-Hill; 2011. http://0-www.accesspharmacy.com. millennium.midwestern.edu/content.aspx?aID=7972196. Accessed February 17, 2013. 2. O’Gara PT, Kushner FG, Ascheim DD et al.

Low

8.3%

Aldosterone (AA) Beta-blockerAntagonists (BB) Non-DHP CCB (if intolerant to BB)

Goals of Therapy < 130/80 mmHg ACEi and AA if LVEF < 40%

Lipid Management

ACE inhibitors (ACEi) Statins

LDL < 100 mg/dL

Diabetes

Aldosterone Antagonists (AA) Various

HgB A1c < 7% (ADA Guidelines)

Smoking Cessation

Various

No smoking

Lipid Management BMI

Statins 5-7 times/week Exercise

2 LDL–<24.9 100 kg/m mg/dL 18.5

Diabetes Various Source: Adapted from information found in reference 1,3 Smoking Cessation Various BMI

Fall Exercise 5-7 times/week

HgB A1c < 7% (ADA Guidelines) No smoking

2013 • Arizona Journal of Pharmacy • 47 2 18.5 – 24.9 kg/m

ST-elevation myocardial infarction (STEMI)

Table for Continuing Education Article - Acute Coronary Syndromes: Current Treatment Guidelines and Updates Fibrinolytics

Alteplase (tPA) {Activase®}

Procedure[ACC/AHA Guideline Recommendations] Fibrinolytic therapy ≤ 30 min of hospital arrival [IB]

Reteplase (rPA) {Retavase®}

Fibrinolytic therapy ≤ 30 min of hospital arrival [IB]

Tenecteplase (TNK-tPA) {Tnkase®}

Fibrinolytic therapy ≤ 30 min of hospital arrival [IB]

Streptokinase {Streptase®}

Fibrinolytic therapy ≤ 30 min of hospital arrival [IB]

Unfractionated Heparin (UFH)

Fibrinolytic therapy [IC]

Dose Adjustment

Warnings / DDI/ Contraindications*

Monitoring

Dose and Duration of Therapy

 Prior ICH*  Known structural cerebrovascular lesions, such as arterial venous malformation*  Known intracranial malignant neoplasm*  Ischemic stroke ≤ 3 months*  Active bleeding* (excluding menses)  Significant closed head or facial trauma ≤ 3 months*  Active bleeding*  History of HIT*  Risk of severe bleeding  Recent stroke

 CBC  aPTT  Bleeding

 15 mg IV bolus, followed by 0.75 mg/kg IV (max 50 mg) over 30 min, then 0.5 mg/kg (max 35 mg) over 60 min (max dose = 100 mg)  10 unit IV x 2, 30 min apart

PCI [IC]

Enoxaparin (LMWH) {Lovenox®}

Anticoagulants

Source: Adapted from information found in references 1,2,11,16. DDI indicates drug-drug interaction; ICH, intracranial hemorrhage; CBC, complete blood count; aPTT, activated partial thromboplastin time; HIT, heparin-induced thrombocytopenia; ACT, activated clotting time; GPI, glycoprotein IIb/IIIa inhibitor; IV, intravenous; PCI, percutaneous coronary intervention; LMWH, low molecular weight heparin; SCr, serum creatinine; CrCl, creatinine clearance; SC, subcutaneous; CABG, coronary artery bypass graft; BBW, black box warning; PO, per os (by mouth); BMS, bare metal stent; DES, drug eluting stent.

Drug

Fondaparinux {Arixtra®}

Bivalirudin {Angiomax®} Drug

Full article, including charts, is available for download on the AzPA website in the Journal archives.

Aspirin (ASA)

Abciximab {Reopro®}

Eptifibatide {Integrilin®}

Antiplatelets

Tirofiban {Aggrastat®}

Clopidogrel {Plavix®}

Prasugrel {Effient®}

Ticagrelor {Brilinta®}

48 • Arizona Journal of Pharmacy • Fall 2013

Fibrinolytic therapy [IA]

Reduce if CrCl < 30 mL/min

 < 60 kg: 30 mg IV bolus 60 – 69 kg: 35 mg IV bolus 70 – 79 kg: 40 mg IV bolus 80 – 89 kg: 45 mg IV bolus > 90 kg: 50 mg IV bolus  1.5 MU (million units) IV over 60 min

 aPTT: 50 – 70 sec  ACT: 200-300 sec (with GPI); 250-350 sec (no GPI)  HIT  Bleeding  SCr  HIT  Bleeding

 60 units/kg IV bolus, then 12 units/kg/hr IV infusion  Continue for 48 hours  With GPI: 50-70 units/kg IV bolus No GPI: 70-100 units/kg IV bolus  Discontinue at the end of PCI

 Active bleeding*  < 75 y.o.: 30 mg IV bolus, then 1mg/kg  History of HIT SC every 12 hr  Risk of severe > 75 y.o.: 0.75 mg/kg SC every 12 hr bleeding  Continue for the duration of  Recent stroke hospitalization (up to 8 days)  Avoid if CrCl < 15 PCI after fibrinolytic  1 mg/kg SC every 12 hours (if last dose > mL/min therapy [IB] 8 hours prior to PCI, administer 0.3  Avoid if CABG mg/kg IV bolus) surgery  Discontinue at the end of PCI Fibrinolytic therapy No  Active bleeding*  SCr  2.5 mg IV, then 2.5 mg SC daily [IB]  Risk of severe  Bleeding  Continue for the duration of bleeding hospitalization (up to 8 days)  Avoid if CrCl < 30 PCI [III, B]  2.5 mg IV, then 2.5 mg SC daily (MUST mL/min *not as administer UFH 50-60 units/kg IV bolus  Increase risk of monotherapy* prior) catheter  Discontinue at the end of PCI thrombosis if used as monotherapy  0.75 mg /kg IV bolus, then 1.75 PCI [IB] Severe renal myocardial Active bleeding* infarction  SCr ST-elevation (STEMI) *can be used in place function  Risk of severe  Bleeding mg/kg/hr IV of UFH + GPI if high bleeding Dose Discontinue at theofend of PCI Procedure[ACC/AHA Dose Warnings / DDI/ Monitoring and Duration Therapy risk of bleeding Contraindications* Increase risk of Guideline Adjustment [IIa, B]* stent thrombosis Recommendations] Initial treatment after No  Hypersensitivity  162-325 mg before PCI, then 81 mg  Bleeding hospital admission  Active bleeding maintenance dose daily indefinitely [IB]  Risk of severe  If a stent is placed after PCI, continue bleeding 162-325 mg daily - for a minimum of 30 days (bare metal stent) - for 3 months (sirolimus-eluting stent) - for 6 months (paclitaxel-eluting stent) - then continue 75-162 mg daily indefinitely PCI [IIa, A] No  Active bleeding*  SCr  0.25 mg/kg IV bolus, then 0.125  Thombocytopenia*  Platelet count mcg/kg/min IV infusion  Prior stroke ≤ 2  Bleeding  Continue for up to 12 hr years* PCI [IIa, B] CrCl <50  Active bleeding*  SCr  180 mcg/kg IV bolus x 2, then 2 mL/min:  Prior stroke ≤ 30  Platelet count mcg/kg/min IV infusion reduce days*  Bleeding  Continue for 12 – 18 hr after PCI infusion 50%  Renal dialysis*  Thombocytopenia  25 mcg/kg IV bolus, then 0.15 PCI [IIa, B] CrCl <30  Active bleeding*  SCr mL/min:  Thombocytopenia*  Platelet count mcg/kg/min IV infusion reduce  Prior hemorrhagic  Bleeding  Continue for 18 hr after PCI infusion 50% stroke* Fibrinolytic [IA] No  Hypersensitivity  SCr  < 75 y.o.: 300 mg PO loading dose, then  Active bleeding*  Bleeding 75 mg  Risk of severe daily maintenance dose bleeding > 75 y.o.: 75 mg daily  Reduced 2C19  Continue for 14 days to 1 year in absence of bleeding function (BBW)  Caution with 2C19 PCI [IB]  300 mg (PCI ≤ 24 hr) or 600 mg (PCI > 24 inhibitors hr) PO loading dose, then 75 mg PO  Hold 5 days prior daily maintenance dose to CABG surgery  Continue for 14 days if no stent is placed or 1 year if either a BMS or DES is placed PCI [IB] No  Active bleeding*  SCr  60 mg PO loading dose, then 10 mg PO  History of TIA or  Bleeding daily maintenance dose stroke (BBW)  Continue for 14 days if no stent is  Age > 75 y.o.(BBW) placed or 1 year if either a BMS or DES  Weight < 60 kg is placed (BBW)  Hold 7 days prior to CABG surgery PCI [IB] No  Hypersensitivity  SCr  180 mg PO loading dose, then 90 mg PO  Active bleeding*  Bleeding twice a day maintenance dose  History of ICH  Continue for 14 days if no stent is placed or 1 year if either a BMS or DES (BBW) is placed  Must use with low dose aspirin (BBW)  Caution with 3A4 inducers/ inhibitors  Hold 5 days prior to CABG surgery

Non-ST elevation myocardial infarction (NSTEMI) / Unstable angina (UA) Drug

Procedure[ACC/AHA Guideline Recommendations]

Dose Adjustment

Warnings / DDI/ Contraindications*

Unfractionated Heparin (UFH)

Invasive strategy:  Before PCI [IA]  PCI [IA]

   

Active bleeding* History of HIT* Risk of severe bleeding Recent stroke

Conservative strategy [IA]

Enoxaparin (LMWH) {Lovenox®}

Invasive strategy:  Before PCI [IA]  PCI [IA]

Reduce if CrCl < 30 mL/min

Anticoagulants

Conservative strategy [IA]

Fondaparinux {Arixtra®}

Bivalirudin {Angiomax®}

     

Invasive strategy:  Before PCI [IB]  PCI [III,C] *not as monotherapy* Conservative strategy [IB]

Invasive strategy:  Before PCI [IB]  PCI [IB] *can be used if high risk of bleeding*

Severe renal function

   



   

Active bleeding* History of HIT Risk of severe bleeding Recent stroke Avoid if CrCl < 15 mL/min Avoid if CABG surgery (discontinue 12-24 hrs prior) Active bleeding* Risk of severe bleeding Avoid if CrCl < 30 mL/min Avoid if CABG surgery (discontinue 24 hrs prior) Increase risk of catheter thrombosis if used as monotherapy Active bleeding* Risk of severe bleeding Avoid if CABG surgery (discontinue 3 hrs prior) Increase risk of stent thrombosis

Conservative strategy:  Angiography [IB]

Non-ST elevation myocardial infarction (NSTEMI)

Monitoring

Dose and Duration of Therapy

 aPTT: 50 – 70 sec  ACT: 200300 sec (with GPI); 250-350 sec (no GPI)  HIT  Bleeding  SCr  HIT  Bleeding

 60 units/kg IV bolus, then 12 units/kg/hr IV infusion  Continue for 48 hr or discontinue at the end of PCI

 SCr  Bleeding

 Before PCI, 0.1 mg/kg IV bolus, then 0.25 mg/kg/hr IV infusion  If given before PCI, 0.5 mg/kg IV bolus, then 1.75 mg/kg/hr IV infusion  If not given before PCI, 0.75 mg/kg IV bolus, then 1.75 mg/kg/hr IV infusion  Discontinue at the end of PCI  Before angiography, 0.1 mg/kg IV bolus, then 0.25 mg/kg/hr IV infusion  Discontinue at the end of / Unstable angina (UA) angiography or continue at 0.25 Monitoring Dose and Duration of Therapy mg/kg/hr for up to 72 hr if prolonged anticoagulation necessary

Dose Adjustment

Warnings / DDI/ Contraindications*

Aspirin (ASA)

Initial treatment after hospital admission [IA]

 Hypersensitivity  Active bleeding  Risk of severe bleeding

 Bleeding

Abciximab {Reopro®}

Invasive strategy:  PCI [IA]

 Active bleeding*  Thombocytopenia*  Prior stroke ≤ 2 years*

Eptifibatide {Integrilin®}

Invasive strategy:  Before PCI [1B]  PCI [IA]

CrCl <50 mL/min: reduce infusion 50%

   

 SCr  Platelet count  Bleeding  SCr  Platelet count  Bleeding

Antiplatelets

Conservative strategy:  Before angiography [IIb, B]  Angiography [IA] Invasive strategy:  Before PCI [1B]  PCI [IA] Conservative strategy:  Before angiography [IIb, B]  Angiography [IA]

CrCl <30 mL/min: reduce infusion 50%

 Active bleeding*  Thombocytopenia*  Prior stroke ≤ 2 years*

Clopidogrel {Plavix®}

Invasive strategy:  Before PCI [1B]  PCI [IA]

   

Conservative strategy:  Before angiography [IB]  Angiography [IB] Prasugrel {Effient®}

Invasive strategy:  PCI [IB]

  No

    

Ticagrelor {Brilinta®}

Invasive:  Before PCI [1B]  PCI [IB] Conservative strategy:  No angiography [IB]  Angiography [IB]

     

Hypersensitivity Active bleeding* Risk of severe bleeding Reduced 2C19 function (BBW) Caution with 2C19 inhibitors Hold 5 days prior to CABG surgery Active bleeding* History of TIA or stroke (BBW) Age > 75 y.o.(BBW) Weight < 60 kg (BBW) Hold 7 days prior to CABG surgery Hypersensitivity Active bleeding* History of ICH (BBW) Must use with low dose aspirin (BBW) Caution: 3A4 inducers/ inhibitors Hold 5 days prior to CABG surgery

 2.5 mg SC daily (MUST administer UFH 50-60 units/kg IV bolus prior)  Discontinue at the end of PCI  2.5 mg SC daily  Continue for the duration of hospitalization (up to 8 days)

Procedure[ACC/AHA Guideline Recommendations]

Tirofiban {Aggrastat®}

 1 mg/kg SC every 12 hours (if last dose > 8 hours prior to PCI, administer 0.3 mg/kg IV bolus)  Discontinue at the end of PCI  1 mg/kg SC every 12 hours  Continue for the duration of hospitalization (up to 8 days)

Drug

Active bleeding* Prior stroke ≤ 30 days* Renal dialysis* Thombocytopenia

 60 units/kg IV bolus, then 12 units/kg/hr IV infusion  Continue for 48 hr or until discharge

 SCr  Platelet count  Bleeding

 SCr  Bleeding

Table for Continuing Education Article - Acute Coronary Syndromes: Current Treatment Guidelines and Updates Source: Adapted from information found in references 1,3,4,11. DDI indicates drug-drug interaction; ICH, intracranial hemorrhage; aPTT, activated partial thromboplastin time; HIT, heparin-induced thrombocytopenia; ACT, activated clotting time; GPI, glycoprotein IIb/IIIa inhibitor; IV, intravenous; PCI, percutaneous coronary intervention; LMWH, low molecular weight heparin; SCr, serum creatinine; CrCl, creatinine clearance; SC, subcutaneous; CABG, coronary artery bypass graft; BBW, black box warning; PO, per os (by mouth).

 162-325 mg before procedure, then 81 mg maintenance dose daily indefinitely  If a stent is placed after PCI, continue 162-325 mg daily - for at least 30 days (bare metal stent) - for 3 months (sirolimus-eluting stent) - for 6 months (paclitaxel-eluting stent) - then continue 75-162 mg daily indefinitely  0.25 mg/kg IV bolus, then 0.125 mcg/kg/min IV infusion  Continue for up to 12 hr after PCI  180 mcg/kg IV bolus x 2 (10 min apart), then 2 mcg/kg/min IV infusion  Continue for 12 – 18 hr after PCI  180 mcg/kg IV bolus, then 2 mcg/kg/min IV infusion  If no angiography, discontinue  If angiography, continue for up to 72 hr  25 mcg/kg IV bolus, then 0.15 mcg/kg/min IV infusion  Continue for up to 18 hr after PCI  50 mcg/mL administered at a rate of 0.4 mcg/kg/min over 30 min, then 0.1 mcg/kg/min IV infusion  If no angiography, discontinue  If angiography, continue for up to 72 hr  300 – 600 mg PO loading dose, then 75 mg PO daily maintenance dose  If PCI, continue for at least 12 months.  If no PCI, continue for up to 12 months

 SCr  Bleeding

 60 mg PO loading dose, then 10 mg PO daily maintenance dose  Continue for up to 12 months

 SCr  Bleeding

 180 mg PO loading dose, then 90 mg PO daily maintenance dose  If PCI, continue for at least 12 months  If no PCI, continue for up to 12 months

Fall 2013 • Arizona Journal of Pharmacy • 49

Continuing Education Quiz Answer Sheet

Antimicrobial resistance: A review of antimicrobial mechanisms, bacterial resistance, and pharmacotherapy options for the treatment of resistant bacterial infections in adults ACPE UAN#0100-0000-13-057-H01-P Activity accredited date: 10-15-2013 Expiration date: 10-15-2016. This activity is accredited for 1.5 hours of CPE credit (CEUs 0.15) In order to qualify for ACPE credit, participants must achieve a grade of 70% or above on the quiz and submit a completed activity evaluation.

CE Assessment Answers - Please circle your answers (one answer per question.) Questions on page 51. 1. a. b. c. d. 6. a. b. c. d. e. b. 11. a. b. 2. a. b. c. d. e. 7. a. b. c. d. e. 12. a. b. 3. a. b. c. d. e. f. g. 8. a. b. c. d. e. 4. a. b. c. d. 9. a. b. c. d. 5.

10. a.

c. c.

ACTIVITY EVALUATION – Must be completed to receive credit. 1. The activity met the stated learning objectives. (Full list of learning objectives in article.)

AGREE

DISAGREE

2. Please rate the activity based on the following (please circle one): • Overall evaluation of the article content: • Relevance to pharmacy practice • Value of the content

Poor Poor Poor

2 2 2

3. The information presented (check all that apply): Reinforce my current practice/treatment habits Provided new ideas or information I expect to use

d. d.

1 1 1

3 3 3

4 4 4

5 5 5

Excellent Excellent Excellent

Will improve my practice/patient outcomes Adds to my knowledge

4. Will the information presented cause you to make any changes to your style or method?

Yes

5. Will the information presented cause you to make any changes in your practice?

Yes

6. How committed are you to making these changes?

Not committed

7. Do you feel future activities on this subject matter are necessary and/or important?

Yes

5 Very committed

Acute Coronary Syndromes: Current Treatment Guidelines and Updates ACPE UAN#0100-0000-13-056-H01-P Activity accredited date: 10-15-2013 Expiration date:10-15-2016. This activity is accredited for 1.5 hours of CPE credit (CEUs 0.15) In order to qualify for ACPE credit, participants must achieve a grade of 70% or above on the quiz and submit a completed activity evaluation.

II.

CE Assessment Answers - Please circle your answers (one answer per question.) Questions on page 52. 1. a. b. c. d. e 6. a. b. c. d. 11. a. b. 2. a. b. c. d. e 7. a. b. c. d. 12. a. b. 3. a. b. c. d. 8. a. b. c. d. 13. a. b. 4. a. b. c. d. 9. a. b. c. d. 5.

10.

d. d. d.

e e e

ACTIVITY EVALUATION – Must be completed to receive credit. 1. The activity met the stated learning objectives. (Full list of learning objectives in article.)

AGREE

DISAGREE

2. Please rate the activity based on the following (please circle one): • Overall evaluation of the article content: • Relevance to pharmacy practice • Value of the content

Poor Poor Poor

2 2 2

3. The information presented (check all that apply): Reinforce my current practice/treatment habits Provided new ideas or information I expect to use

c. c. c.

1 1 1

3 3 3

4 4 4

5 5 5

Excellent Excellent Excellent

Will improve my practice/patient outcomes Adds to my knowledge

4. Will the information presented cause you to make any changes to your style or method?

Yes

5. Will the information presented cause you to make any changes in your practice?

Yes

6. How committed are you to making these changes?

Not committed

7. Do you feel future activities on this subject matter are necessary and/or important?

Yes

No No 1

5 Very committed

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City, State, Zip ___________________________________________________ Birthdate (MM/DD only) ______________ NABP e-Profile ID# ________________ Continuing education home-study activities are a benefit to AzPA members. Non-members of AzPA must enclose $25.00 per activity. Make check payable to AzPA. As part of our ongoing quality-improvement effort, may we contact you to participate in a survey to assess the impact of our continuing pharmacy educational activities? Yes No

This activity was developed by the Arizona Pharmacy Association for pharmacists as a knowledge-based learning activity. The Arizona Pharmacy Association is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

Continuing Education Quiz Questions

Antimicrobial resistance: A review of antimicrobial mechanisms, bacterial resistance, and pharmacotherapy options for the treatment of resistant bacterial infections in adults ACPE UAN#0100-0000-13-057-H01-P 1. Multidrug resistant organisms (MDROs) are those: a. Non-susceptible to ≥2 different antibiotics b. Non-susceptible to ≥3 different antibiotics c. Non-susceptible to ≥2 different antibiotic classes d. Non-susceptible to ≥3 different antibiotics classes 2. Klebsiella pneumonia carbapenemases (KPC) have been found in which of the following: a. Klebsiella pneumonia b. Citrobacter c. Pseudomonas d. All of the above e. a & b 3. Which of the following drug(s) usually retain activity against extended-spectrum-lactamase (ESBL) producing organisms? a. Aztreonam b. Meropenem c. Vancomycin d. Ceftazidime e. a and b f. a, b and c g. b and c 4. A 71 y.o. male is admitted with AMS, right flank pain, pyuria, and fever of 101° F. He is diagnosed with pyelonephritis and started empirically on cefazolin. Two days later, the urine culture is growing KPC-producing K. pneumoniae. How would you treat this patient? a. Continue cefazolin b. Switch to imipenem c. Switch to colistin d. Switch to colistin + imipenem 5. A 68 y.o. female develops VAP and empiric treatment with vancomycin and aztreonam is started. Two days later, BAL culture grows ESBL-producing K. pneumonia but susceptibilities are not available yet. How would you treat this patient? a. Discontinue vancomycin and continue aztreonam b. Switch to imipenem c. Switch to doripenem d. Switch to piperacillin-tazobactam 6. Which of the following are true statements regarding enterococci? I. Enterococci are gram positive cocci that are commonly found in normal GI flora I. Enterococci have both an intrinsic and acquired resistance to antibiotics, making them important nosocomial pathogens II. Enterococcus faecalis and Enterococcus gallinarum are the most prevalent species causing infections in humans a. I only c. I and II e. I, II, and III

b. III only d. II and III

7. 84 year-old man is admitted for worsening confusion, burning on urination, and increased frequency of urination. Patient is afebrile, vital signs are stable, and labs show an elevated WBC and creatinine clearance of 42 ml/min. Urinalysis reveals large leukocyte esterase, positive nitrites, and many bacteria. He is started on ceftriaxone 1 gram every 24 hours. Urine culture comes back with Enterococcus faecalis; sensitivities are pending. What recommendation would you make to the medicine team? a. Continue ceftriaxone b. Continue ceftriaxone and add vancomycin c. Change ceftriaxone to nitrofurantoin d. Change ceftriaxone to ampicillin e. Change ceftriaxone to gentamicin plus ampicillin 8. Which of the following medication pairs represent clinically relevant drug-drug interactions? I. Linezolid and citalopram II. Tigecycline and lovastatin III. Daptomycin and simvastatin a. I only c. I and III only e. I, II, and III

b. I and II only d. II and III only

9. All of the following agents for the treatment of MRSA are bactericidal except a. Clindamycin b. TMP-SMX c. Daptomycin d. Vancomycin 10. The following agents are acceptable for the treatment of MRSA bacteremia except: a. Daptomycin b. Linezolid c. Tigecycline d. Vancomycin 11. Which of the following agents pending FDA approval for use has shown good killing in vitro against VISA and VRSA? a. Oritavancin b. Ceftobiprole c. Dalbavancin d. All of the above 12. Which of the following is NOT a reasonable indication for decolonization of MRSA? a. Use in areas of MRSA outbreaks b. Health-care workers in high prevalence areas c. Patients undergoing surgery d. Family members of patients sick in the hospital with MRSA

ANSWER SHEET AND EVALUATION FOR THIS HOME-STUDY ACTIVITY ARE ON PAGE 50.

Fall 2013 • Arizona Journal of Pharmacy • 51

Continuing Education Quiz Questions Acute Coronary Syndromes: Current Treatment Guidelines and Updates ACPE UAN#0100-0000-13-056-H01-P 1. A 72-year old female presents to the hospital for chest pain that started about 11 hours ago, but has been getting worse in the last 30 minutes. Her EKG reveals STsegment depression and T- wave inversions. Her first two set of cardiac biomarkers reveals elevated CK-MB and troponins. Which of the following is the most likely diagnosis? a. NSTEMI b. STEMI c. Unstable angina d. Non-cardiac cause of chest pain e. Cannot determine based on the information given 2. A 68-year old female patient presents to the hospital with crushing chest pain that started 30 minutes ago. She has received 3 doses of sublingual nitroglycerin, but has been getting worse in the last 15 minutes. According to her past medical history, she has asthma and heart failure (left ventricular ejection fraction 10-15%). Her vital: BP 156/92, HR 72, O2 saturation on room air 79%. Which of the following is the BEST recommendation for this patient? a. Chew aspirin 325 mg, titrate oxygen to 100% O2 saturation, nitroglycerin 0.4 mg SL, metoprolol 25 mg IV b. Chew aspirin 325 mg, titrate oxygen to 100% O2 saturation, nitroglycerin 0.4 mg SL, metoprolol 25 mg PO c. Chew aspirin 325 mg, morphine 2 mg IV, and titrate oxygen to 100% O2 saturation d. Chew aspirin 325 mg. morphine 2 mg IV, titrate oxygen to 100% O2 saturation, metoprolol 25 mg IV e. Chew aspirin 325 mg. morphine 2 mg IV, titrate oxygen to 100% O2 saturation, metoprolol 25 mg PO 3. TG is a 60 year old female that was presented to the emergency room with complaints of throbbing chest pain. She was initially given 3 SL tablets of NTG in the last 15 minutes, however she is still having chest pain. Her O2 sats are at 86%. Her LVEF is at 30% according to TTE. What medications and or therapy should this patient being receiving next? a. Initial invasive strategy with preference for PCI b. IV morphine + ASA c. IV morphine + oxygen administered via nasal cannula + ASA d. Patient does not need anything, as this not an ACS case

4. BN is an 80 year old male who develops crushing chest pain that started 30 minutes ago. The EKG in the ambulance reveals that the patient is having a STEMI. The nearest hospital with a cardiac catheterization laboratory is three hours away. What is the most appropriate initial treatment strategy for this patient? a. Transfer directly to hospital with catheterization laboratory for PCI b. Admit to nearest hospital for fibrinolytic therapy c. Admit to nearest hospital for diagnostic stress test d. Admit to nearest hospital for CABG 5. JT is a 75 year old male who presents to the emergency department with complaints of chest pain. He states that he has 3 episodes of chest pain in the past 24 hours. In addition, he has a history of coronary artery disease, as well at hypertension and diabetes. A preliminary ECG shows sinus tachycardia. What is his risk assessment based on his TIMI score? a. Low risk b. Moderate risk c. High risk d. No risk 6. YU has been diagnosed with having NSTEMI because on his ECG readings and cardiac biomarkers. Based on his TIMI score and risk assessment, he is stratified as being moderate risk. What initial strategy should YU undergo for treatment of his NSTEMI? a. Invasive strategy b. Conservative strategy c. No further therapy is needed d. More information is needed 7. Which of the following laboratory values should be monitored for a patient treated with abciximab? a. Serum creatinine b. Liver function tests c. Platelets d. Troponin 8. Which of the following describes an advantage of UFH over other anticoagulants used in ACS patients? a. Lower incidence of heparin-induced thrombocytopenia b. Can be monitored in catheterization lab with ACT c. Administration routes include subcutaneously or intravenously d. Lower incidence of bleeding compared to bivalirudin

ANSWER SHEET AND EVALUATION FOR THIS HOME-STUDY ACTIVITY ARE ON PAGE 50. 52 â€˘ Arizona Journal of Pharmacy â€˘ Fall 2013

9. Which of the following is an absolute contraindication to fibrinolytic therapy? a. Ischemic stroke within the last 3 months b. Blood pressure greater than 180/110 mmHg c. Chronic warfarin therapy d. Pregnancy 10. A 45 year old male patient weighing 120 kg was admitted to the hospital and diagnosed with having STEMI. He has a history of recent gastrointestinal bleeding and is currently taking omeprazole for it. Which antiplatelet medication would be best given to initially treat this patient for his STEMI? a. ASA b. ASA + clopidogrel c. ASA + prasugrel d. ASA + ticagrelor e. None of the above 11. LK is an 80 year old male with a history of COPD. He is afraid taking medications that may exacerbate his COPD. He was admitted to the hospital and was diagnosed with having STEMI. A PCI was performed and a sirolimus stent was implanted in his coronary artery. What medication regimen is appropriate for this patient upon discharge for maintenance of his ACS? a. ASA 325mg daily for 1 months + clopidogrel 75mg daily for 2 months b. ASA 325 mg daily for 3 months + ticagrelor 90mg BID for 12 months c. ASA 325 mg daily for 3 months + prasugrel 10 mg daily for 12 months d. ASA 325 mg daily for 3 months + clopidogrel 300mg daily for 12 months e. ASA 325 mg daily for 3 months + prasugrel 10 mg daily for 3 months 12. A 57 year old male patient who is currently on eptifibatide, prasugrel, and unfractionated heparin is about to undergo elective CABG for his NSTEMI. Which of the following changes in his drug are appropriate to make prior to his upcoming procedure? a. Hold the UFH for at least 2 days b. Hold the prasugrel for at least 5 days c. Hold the prasugrel for at least 7 days d. Hold the eptifibatide for at least 2 hours e. c and d 13. HT is a 50 year old male patient that was recently treated at the hospital for his STEMI and is ready to be discharged. His past medical history includes hypertension and type 2 diabetes. What medications should HT be placed on prior to him being discharged for secondary prevention of ACS? a. Atorvastatin b. Aspirin c. Metoprolol d. b and c e. All of the above

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