October 24, 2018 Produced and Edited by: Gregory K. Perry, PharmD, BCPS-AQID Pharmacy Clinical Manager

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1 VOLUME FOUR; ISSUE 8 October 24, 2018 Produced and Edited by: Gregory K. Perry, PharmD, BCPS-AQID Pharmacy Clinical Manager

2 InPHARMation Pharmacy and Therapeutics Committee Update October 24 th, 2018 Meeting The Pharmacy and Therapeutics Committee at Hendrick Medical Center is a Medical Staff Committee that meets the fourth Wednesday of each month with five physicians and one pharmacist serving as voting members. P and T is Medical Staff Committee. The current Chair of P and T is Charles W. Fuller, M.D. Meaningful Use: eprescribing update: 44.64% Pediatric Post-Operative Pain Order Set Pedi Section and P and T Approved. The Pediatric Section and the P and T approved an order set specific to those less than 18 years of age who are post-operative. On January 1, 2018, The Joint Commission implemented new and revised pain assessment and management standards for accredited hospitals. One element of the standard was treatment and assuring non-opioid alternatives were available. HMC also has a multi-modal pain order set for adults across the continuum and orthopedic surgery patients. For more details or a copy of any of these order sets please contact Greg Perry at gperry@hendrickhealth.org or

3 Use of Codeine and Tramadol in Pediatric Patients Pedi Section and P and T approved. In response to multiple reports of serious side effects and death in children taking codeine-containing products, the FDA has issued several BLACK BOX WARNINGS against the use of codeine and tramadol in children and adolescents due to the potential for life-threatening events in children taking these medications. The purpose of this policy is to improve the safety of pediatric patients by restricting use of codeine and tramadol for children less than 18 years of age. Please see the post-operative pediatric pain order set for alternative options. This will now go to P.I. for review and approval then to MEC. Policy: A. Medications containing codeine or tramadol may not be prescribed for children < 18 years of age. These include (but are not limited to): a. Acetaminophen with codeine (Tylenol #3, Tylenol #4) b. Acetaminophen and tramadol (Ultracet) c. Butalbital, acetaminophen, caffeine, and codeine (Fioricet with Codeine) d. Codeine e. Guaifenisen and codeine (Cheratussin AC) f. Promethazine and codeine g. Promethazine, phenylephrine, and codeine (Promethazine VC/Codeine) h. Tramadol (Ultram) Daptomycin Restrictions P and T approved. Daptomycin injection is now restricted to Infectious Diseases only with the following exceptions. THIS APPLIES TO INPATIENT USE ONLY!!! NOT ED or INFUSION CENTER. 1. May be used for acute bacterial skin and skin structure infections (IE: cellulitis and erysipelas) if one of the following applies. a. Pt with acute kidney injury. b. Intolerance to vancomycin. 2. Any other use requires an Infectious Diseases consult (Dr. Canario or Kalla). a. Right sided IE. b. Left sided IE. c. Bacteremia. d. Osteomyelitis. e. Vancomycin failure (a vanco failure correlates with a daptomycin failure) daptomycin would not be recommended in cases of vanco failure. 2

4 Antimicrobial Stewardship Education by Gregory K. Perry, PharmD, BCPS-AQID Treatment of intraabdominal infections Duration of Therapy STOP-IT Trial The Study to Optimize Peritoneal Infection Therapy trial also known as the STOP-IT trial was a randomized study to compare two strategies guiding the duration of antimicrobial therapy for the management of complicated intraabdominal infection. Inclusion in the study required a complicated intraabdominal infection plus intervention to achieve adequate source control with one or more of the following: Temperature 38 C WBC 11,000/mm 3 Gastrointestinal dysfunction due to peritonitis, precluding intake of more than half their normal diet (as an indicator of an ileus) The intervention group received four days of antimicrobial therapy after source control (short course). The control group received antimicrobial therapy until two days after all of the following criteria were met: Temperature < 38 C for one entire calendar day WBC < 11,000/mm 3 Ability to consume more than half normal diet Antimicrobials were continued for a maximum of ten days The primary endpoint was a composite of surgical-site infection, recurrent intraabdominal infection requiring either surgical or percutaneous re-intervention and 30 day mortality. No difference was detected with 21.8% of the short course group meeting the endpoints vs. 22.3% in the normal course. There was no difference in the components of the composite outcomes between the groups. The median duration of therapy was 4 days in the short course group and 8 days in the control group. In conclusion please consider limiting therapy to 4 days post intervention in patients with intraabdominal infections who have undergone an adequate source control procedure as the outcome after fixed-duration antibiotic therapy (approximately 4 days) were similar to those after a longer course of antibiotics (approximately 8 days) that extended until after resolution of physiological abnormalities. Bottom line of this study: Complicated IAI can be treated with 4 days of antibiotics if adequate source control provided. Sanders JM et al. Surg Infect. (Larchmt) 2016;17: Rattan R et al. J Am Coll Surg. 2016;222: Hassinger TE et al. Surg Infect (Larchmt). 2017;18: Sawyer RG et al. N Engl J Med. 2015;372:

5 Antimicrobial Stewardship Committee (AMS) Update: Utilization Reports through July 2018 Overall utilization of antimicrobials as defined by the CDC/NHSN indicates Hendrick Medical Center is stable each month. We still are potentially using too many antibiotics. The SAAR for September 2018 was The recommendation would be if you do not need therapy directed towards Pseudomonas aeruginosa then please avoid all anti-pseudomonal antibiotics if at all possible. IF MRSA coverage is not needed please consider dc of anti-mrsa drugs sooner than later. The overall days of therapy per 1000 patient days represents a steady decline of antibiotics use over the past 5 months. If you would like to see a detailed report (Physician specific use, floor specific use, CDC specifics) please contact Greg Perry, PharmD, BCPS-AQID at gperry@hendrickhealth.org Always remember the premise of Antimicrobial Stewardship using the three R s. R = Right Drug. R = Right Dose. R = Right Duration of Therapy. 4

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9 Therapeutically Speaking: by Uyen Huynh, PharmD, PGY1 Pharmacy Practice Resident HMC According to the Centers of Disease Control and Prevention (CDC), the peak months of flu activity occur from December to March. 2 Since 2010, CDC has estimated about 9.2 to 35.6 million cases of the influenza virus infection each year in the United States. 1 The concern has increased as some influenza virus strains have developed resistance to current antiviral agents such as those inhibiting M2 protein and neuraminidase. Thus new targets to attack the virus have been identified and several novel drugs have been produced and are pending for FDA approval. Among them, baloxavir marboxil has just completed its Phase II and III trials for the treatment of uncomplicated influenza in adults and adolescents. Baloxavir marboxil acts as a prodrug which hydrolyzes into baloxavir acid and selectively inhibits the cap-dependent endonuclease. This enzyme is a polymerase acidic protein which plays an important role in the initiation of viral mrna synthesis. It is administered as a single dose and can suppress the activity of both type A and B influenza virus in vitro. 4 A phase I study has shown half-life of the drug can range anywhere from 49 to 91 hours. Maximum plasma concentration is reached within 3.5 hours. The available doses are 6mg, 20 mg, 40 mg, 60 mg, and max is 80mg. Food intake can decrease plasma exposure to about 40%. 3 Similar to other anti-influenza agents, the main adverse effects of baloxavir include headache, diarrhea, and increase liver transaminases. 4 A study has shown the positive synergistic effect of baloxavir with neuraminidase inhibitors in inhibiting the replication of influenza A virus in vitro. 6 The phase II trial found statically significant results in the median time to alleviation of flu symptoms between baloxavir and placebo. Baloxavir 10 mg was 54.2 hours, 20 mg was 51 hours, 40 mg was 49.5 hours, and placebo was 77.7 hours. On treatment days 2 and 3, there was a greater reduction in the influenza virus titers in the baloxavir groups compared to placebo group. The phase III trial enrolled 12 to 64 years of age participants and initiated either baloxavir and matching placebo to oseltamivir, oseltamivir and matching placebo to baloxavir, or placebos only. The alleviation of flu symptoms was noticeably greater in patients who started the novel antiviral agent within 24 hours. The antiviral activity was seen to be superior in the baloxavir treatment group compared to placebo and oseltamivir. The magnitude and rapidity effect of the novel antiviral agents were observed to be greater compared to previous trials of systemic neuraminidase inhibitors. However, the primary clinical outcome of median time to alleviation of flu symptoms was similar in both baloxavir and oseltamivir groups. The rate of adverse events was also similar in all three groups (20.7% in baloxavir, 24.6% in placebo, and 24.8% in oseltamivir). Both phase II and III trials also detected variant viruses with I38/T/M/F substitutions that reduced baloxavir susceptibility in about 2.2% and 9.7% of recipients, respectively. 5 8

10 With the great PK/PD profile and clinical outcome for reduction of viral load, baloxavir can be used optimistically for influenza infection if the strains are resistant to M2 protein and neuraminidase inhibitors. However, susceptibility patterns to baloxavir will need to be further analyzed. According to clinicaltrials.gov, studies for baloxavir safety and efficacy in the pediatric population are planned and pending for subjects recruitment Centers for Disease Control and Prevention. (2010). Disease Burden of Influenza. Retrieved from 2. Centers for Disease Control and Prevention. (2018). Flu Season. Retrieved from 3. Koshimichi H et al. Safety, Tolerability, and Pharmacokinetics of the Novel Anti-Influenza Agent Baloxavir Marboxil in Healthy Adults: Phase I Study Findings. Clin Drug Investig Pubchem. (2018). Baloxavir marboxil. Retrieved from 5. Hayden et al. Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents. NEJM. 2018;379(10), Kitano M, Yamamoto A, Noshi T, et al. Synergistic antiviral activity of S /S , a novel inhibitor of influenza virus capdependent endonuclease, in combination with neuraminidase inhibitors in vitro. Presented at ID- Week, San Diego, CA, October 4 8, abstract. 7. ClinicalTrials.gov. (2018). Baloxavir marboxil. Retrieved from Test Your Knowledge: AB is a 56-year-old female presenting to the emergency department with a chief complaint of severe acute abdominal pain in the lower right quadrant associated with nausea and vomiting. Past medical history: type 2 diabetes mellitus, end-stage renal disease (ESRD) and breast cancer on oral chemotherapy. No recent hospitalizations. No known drug allergies. Abdominal CT reading: free air suggestive of a perforated appendix. Hospital course: taken to the operating room and underwent an appendectomy with peritoneal washout due to gross contamination and diffuse peritonitis. Assuming AB is started on the appropriate antibiotics for High Risk, Community Acquired IAI and AB is improving on postoperative day 2 of antibiotic therapy. What total duration of antibiotic therapy do you recommend? A. 2 days (i.e., therapy can be discontinued immediately) B. 4 days C. 8 days 9 D 7-10 days Test Your Knowledge Answer: Answer: B 4 days. The STOP-IT Trial was a high-yield study that assessed appropriate duration of antimicrobial therapy with appropriate source control. This was discussed in the stewardship section of this newsletter. There was no difference in the group with established source control and discontinuation of antibiotics at 4 days

11 post-op/source control vs. the control group who received antibiotics for two days post resolution of all SIRS which was a median duration of 8 days (Answer C is not correct). In the case of AB she has received 2 days of appropriate therapy so based on the STOP-IT trial she would receive two more days of IV or PO antibiotic therapy. 10