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  December 2016 Newsletter
VSHP Day on the Hill
Tuesday, January 31, 2017

 Please join us for VSHP's annual Day on the Hill in Richmond on Tuesday, January 31. We will meet with our legislators in the afternoon and then end the day with light food and drinks at a reception. We had a great turnout last year and hope to have even more this year. Please submit this registration form to contact@vshp.org by Friday, January 20. This will allow us enough time to schedule appointments with your legislators.
 
 
 
Name:
Home Address:
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E-Mail:
Phone:
Pharmacy School (if applicable)

VSHP 2017 Spring Seminar

April 7-8
Portsmouth Renaissance
 
A wall calendar with tear-away pages and words that read Save the Date
 
New Drug Update:
Zinplava TM   (bezlotoxumab)
 
Isha Jariwala, PharmD Candidate 2017, Hampton University School of Pharmacy
and Emily Dyer, PharmD, BCPS, Sentara Martha Jefferson Hospital
 
 
Clostridium difficile infection (CDI) has become one of the most prominent causes of hospital-acquired infections.1 C. difficile, which is a Gram positive, spore forming, anaerobic bacillus, was first discovered in the year 1935 in the fecal flora of healthy neonates. Its pathogenicity, however, was not identified until 1978 and the incidence of CDI has been constantly rising since then. A significant increase in the severity and mortality related to the disease has been noted in the past decade.2 The rise in the incidence and severity of CDI is primarily associated with the emergence of a more virulent strain of C. difficile (PCR ribotype 027, also referred to as BI/NAP1/027 strain) that leads to increased production of the virulent factors: toxin A and B.According to the most recent surveillance data by the CDC, C. difficile caused about half a million infections amongst patients in the United States in a single year.3 It is estimated that CDI causes roughly 14,000 deaths in the United States annually, adding a burden to the overall healthcare cost as CDI associated cost approximates between one to three billion dollars every year. 1
 
C. difficile is more prevalent in the hospital setting due to its spores being resistant to alcohol-based cleaners. CDI due to toxigenic strains can clinically manifest with symptoms ranging from diarrhea and abdominal cramping in mild cases to the development of pseudomembranous colitis and ultimately death in severe cases. The major risk factor that leads to occurrence of CDI is due to the disruption of gut microbiota caused by exposure to antibiotics, especially clindamycin, penicillins, and cephalosporins. Some studies have shown that the use of proton pump inhibitors along with the antibiotics is associated with higher occurrence and recurrence of CDI.1, 4 In addition to the antibiotic exposure, other factors such as frequent hospitalizations, advanced age, underlying illness, gastrointestinal illness and immunocompromised state lead to increased risk of developing CDI.1
 
According to 2010 SHEA-IDSA treatment guidelines for Clostridium difficile infection, the current standard of care for the treatment of CDI includes: metronidazole 500 mg by mouth TID for 10-14 days for mild to moderate episode of CDI, vancomycin 125 mg every six hours by mouth for 10-14 days for severe episode, combination of vancomycin 500 mg by mouth every six hours and IV metronidazole every eight hours for severe episode with complications (hypotension, shock, ileus), and vancomycin in a tapered and/or pulsed regimen for recurrent infection.5 In 2011, fidaxomicin with the dosage regimen of 200 mg by mouth BID for 10 days was approved by the United States Food and Drug Administration for the treatment of C. difficile-associated diarrhea.6 Additionally, the use of fecal microbiota transplantation, an investigational new drug, as an alternative treatment for recurrent infection has increased in the recent years as several small-scale studies have demonstrated its effectiveness to reduce CDI recurrence rate.7
 
Despite the treatment options available, the recurrence of CDI post initial treatment still persists. According to the most recent CDC data, one out of five patients afflicted with healthcare related CDI experienced recurrent infection in 2011 and one out of nine patients with CDI, aged 65 years or older, died within 30 days of diagnosis. In 2013, the CDC declared C. difficile as one of the three urgent antibiotic resistance threats in the US.8 Recent data by Miller BA, et al. indicates that CDI had replaced MRSA as the most common infection in the community hospital setting.2 Until recently, there had been an unmet need for a drug to prevent recurrent C. difficile infection (rCDI). It became imperative to introduce a drug into the market to help curb rCDI with the increasing number of recurrent infections.
 
On October 21 2016, the United States Food and Drug Administration approved ZinplavaTM (bezlotoxumab) injection to decrease Clostridium difficile infection recurrence in patients 18 years and older, who are receiving antibiotic therapy for CDI and are at risk of developing recurrent infection.9 It is a novel approach to prevent recurrence of CDI and bezlotoxumab is the first drug approved for this indication.
 
The drug was granted a fast track designation in 2010 to fill an unmet medical need for rCDI. After the submission of Biologics License Application (BLA) for review in December 2015, the FDA granted a priority review in January 2016 due to no approved therapy to prevent rCDI. 10 In June 2016, the FDA antimicrobial drug advisory committee meeting was held and a decision to extend the Prescription Drug User Act Fee goal date was made to allow time to review additional analyses from the Phase 3 trials. Ultimately, in October 2016, bezlotoxumab attained its FDA approved indication for the prevention of rCDI in patients receiving CDI antibiotic therapy.
 
Bezlotoxumab is a fully humanized monoclonal antibody, an IgG1 immunoglobulin, that binds to toxin B produced by C. difficile and neutralizes its effects rather than targeting C. difficile itself. By binding to toxin B, it inhibits its binding and entry into the human cells, thereby preventing tissue damage and ultimately recurrence of the infection. Bezlotoxumab is not indicated for the treatment of CDI and must only be used in conjunction with CDI antibiotic therapy.9
 
Bezlotoxumab is available as a single-dose vial containing 1000 mg of the drug per 40 mL (25mg/mL) of the solution. The recommended dosage administration is to administer a one-time diluted dose (0.9% NaCl or D5W as the diluents) of 10 mg/kg (actual body weight) over an IV infusion of 60 minutes, while the patient is concomitantly receiving the antibiotic treatment for CDI. It can be administered via central or peripheral line, but it can neither be administered as an IV bolus or push, nor can it have other drugs co-administered through the same line.9
 
The FDA approval of bezlotoxumab was based upon two phase 3 clinical trials: MODIFY I and MODIFY II, which were multicenter, randomized, double blind, placebo-controlled trials. The safety and efficacy of bezlotoxumab for reducing rCDI were examined by comparing its use in combination with CDI standard of care treatment drugs: vancomycin, metronidazole, or fidaxomicin, versus placebo. Both the trials indicated that rate of recurrence of CDI through 12 weeks was significantly lower in bezlotoxumab arms versus placebo arms (17.4% vs 27.6%, p=0.0003 and 15.7% vs 25.7%, p=0.0003, respectively). 11 Bezlotoxumab led to a significant decrease in rCDI with a relative risk reduction of approximately 40%.The drug was studied in patients with various risk factors, including the hypervirulent strain, ribotype 027, and the results showed significant decrease in recurrence of the infection in comparison to the placebo.10 A computer-based model was developed by Prabhu VS, et al. to compare cost and effectiveness of bezlotoxumab+standard of care versus placebo+SoC. The model predicted that the treatment of patients with bezlotoxumab+SoC would be highly cost-effective and would reduce incidence as well as overall disease burden associated with rCDI.12
 
There are no known contraindications to receiving bezlotoxumab, however there is a warning for heart failure, especially in patients with underlying congestive heart failure (CHF). The use of this drug in two Phase 3 trials demonstrated the exacerbation of heart failure more commonly in the CHF patients of bezlotoxumab group (12.7%, 15/118) as compared to placebo group (4.8%, 5/104) during the 12-week study period. More deaths were reported during the study period in the treatment group, especially in the patients with underlying CHF (19.5%, 23/118) than placebo group (12.5%, 13/104). Hence, the use of this drug in patients with CHF should only be considered when the benefit outweighs the risk. Additionally, the most common adverse reactions associated with bezlotoxumab (within four weeks of infusion) include nausea, pyrexia, and headache. The use of bezlotoxumab in pregnant women and pediatric patients has not been studied.9
 
Based upon the population pharmacokinetic analysis of two Phase 3 trials, it was determined that bezlotoxumab has an elimination half-life of approximately 19 days. Its clearance increases with increase in body weight; thus, weight-based (patient's actual weight) dosing is indicated. Being a monoclonal antibody, bezlotoxumab is not expected to be metabolized by the liver, or be excreted by the kidneys. Furthermore, it is eliminated from the body mainly by catabolism, which is a process of degradation of proteins (monoclonal antibody) into small peptides and amino acids. Hence, no drug-drug interactions are predicted and renal and hepatic dose adjustments are not required.9, 13
 
In conclusion, with the use of antibiotics escalating day-by-day in the modern world, there is an increased risk of C. difficile infection as well as of recurrent CDI after appropriate treatment. Bezlotoxumab, in combination with standard of care antibiotic therapy for CDI, provides a novel approach to reduce recurrence of CDI, thereby decreasing the morbidity and mortality associated with C. difficile infection, and the overall burden of healthcare cost.
 
References:
 
1. Seekatz, AM, Young VB. Clostridium difficile and the microbiota. J Clin Invest. 2014; 124(10): 4182-4189. doi: 10.1172/JCI72336
 
2. Lessa FC, Gould, CV, McDonald LC. Current Status of Clostridium difficile Infection Epidemiology. Clin Infect Dis. 2012;55(2): S65-S70. doi: 10.1093/cid/cis319
 
3. Center for Disease Control and Prevention. Nearly half a million Americans suffered from Clostridium difficile infections in a single year. http://www.cdc.gov/media/releases/2015/p0225-clostridium-difficile.html Reviewed February 25, 2015. Accessed December 7, 2016.
 
4. McDonald EG, Milligan J, Fernette C, et al. Continuous Proton Pump Inhibitor Therapy and Associated Risk of Clostridium difficile Infection. JAMA Intern Med. 2015;175(5): 784-9.doi: 10.1001/jamainternmed.2015.42.
 
5. Cohen SH, Gerding DL, Johnson S, et al. Society for Healthcare Epidemiology of America. Infectious Diseases Society of America. Clinical Practice Guidelines for Clostridium difficile Infection in Adults: 2010 Update by the Society for Healthcare
Epidemiology of America (SHEA) and the Infectious Diseases
Society of America (IDSA). Infect Cont Hosp Epidemiol.2010;31(5) :431-55.
 
6. Dificid™ [package insert]. San Diego, CA: Optimer Pharmaceutical, Inc.; 2011
 
7. Karadsheh Z, Sule S. Fecal Transplantation for the Treatment of Recurrent Clostridium Difficile Infection. N Am J Med Sci. 2013;5(6): 339-343.doi:10.4103/1947-2714.114163
 
8. Centers for Disease Control and Prevention. Biggest Threats. http://www.cdc.gov/drugresistance/biggest_threats.html . Reviewed September 8, 2016. Accessed December 7, 2016.
 
9. ZinplavaTM [package insert]. Whitehouse station, NJ: Merck & Co, Inc.; 2016
 
10. Merck Research Laboratories (Merck). Bezlotoxumab (MK-6072) FDA Antimicrobial Drugs Advisory Committee Meeting. http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/anti-infectivedrugsadvisorycommittee/ucm507577.pdf Published June 2016. Accessed December 8, 2016.
 
Accessed December 7, 2016.
 
12. Prabhu VS, Elbasha EH, Dorr MB, et al. Cost effectiveness of bezlotoxumab+ standard of Care (SoC) versus placebo+SoC for the prevention of recurrenct Clostridium difficile infection in the United States. Society for Medical Decision Making. https://smdm.confex.com/smdm/16BEC/webprogram/Paper9898.html Published June 2016. Accessed December 8, 2016.
 
13. Food and Drug Administration. FDA Briefing Document. Bezlotoxumab injection. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Anti-InfectiveDrugsAdvisoryCommittee/UCM505290.pdf Published June 2016. Accessed December 7, 2016.

VSHP Leadership Profile:
  Cindy Wil liams, BS Pharm, FASHP 
What is your current leadership position in VSHP?
Board member at large
                                          
What benefits do you see in being active in a professional association such as VSHP?  
Networking with/learning from other health system pharmacists/pharmacy leadership at the state level
Quality educational activities offered close to home, minimizing the cost and travel to regional/national meetings
"Voice" of health system pharmacy at the state level (advocacy)
Development of pharmacists of tomorrow/support of schools of pharmacy through annual student clinical skills competition/Jennifer Stallings scholarship fund
 
What initially motivated you to get involved in VSHP?
Desire to give back to the profession at the state level
Networking with/learning from other health system pharmacy leaders
 
Where did you go to pharmacy school?
Medical College of Virginia/Virginia Commonwealth University
 
Where have you trained or worked?  
Worked: University of Virginia, Cardinal Health Innovative Solutions (pharmacy management), Riverside Health System
 
Describe your current area of practice and practice setting:
Pharmacy leadership as Vice President/Chief Pharmacy Officer. Responsible for overall leadership of pharmacy across care continuum that includes acute care, retail pharmacy, ambulatory care, long-term care, and PACE
 
What advice would you give to student pharmacists?
Embrace the learning opportunities provided through didactic and hands on experience. Leverage IPPE and APPE rotations to fullest extent possible. Rotational experiences allow student pharmacists to experience different aspects of pharmacy, as well as different leadership styles. Taking full advantage of the skill set of preceptors in order to apply the knowledge obtained in the classroom to patient care should be the goal for every rotation.
 
What pharmacy related issues keep you up at night?
Expanding regulatory oversight (340B, USP, DEA, CMS, Board of Pharmacy)
Declining reimbursements/increasing drug cost
Evolution of the role of the pharmacy in health systems, and the development needs of current staff to respond to change.
Shift from inpatient to outpatient
Pressure from payers
 
Do you have any special interests or hobbies outside of work?
Hiking, skiing, fly fishing
Travel
Food/Wine
 
What is your favorite place to vacation?
Anywhere in the mountains (Alps, Rockies)
 
What 3 adjectives would people use to best describe you?
Energetic
Determined
Friendly

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