ANTIMICROBIAL STEWARDSHIP: ADVANCING PATIENT CARE BY IMPROVING MEDICATION USE

ANTIMICROBIAL STEWARDSHIP: ADVANCING PATIENT CARE BY IMPROVING MEDICATION USE ANTHONY M. CASAPAO, PHARM.D. ASSISTANT PROFESSOR OF PHARMACY PRACTICE HUSSON UNIVERSITY SCHOOL OF PHARMACY CLINICAL INFECTIOUS DISEASE PHARMACOTHERAPY SPECIALIST EASTERN MAINE MEDICAL CENTER

DISCLOSURES Received Research Support (Grant Investigator) from Cerexa subsidiary of Activis Cubist Pharmaceuticals, wholly owned subsidiary of Merck Michigan Department of Community Health Forest Laboratories subsidiary of Activis Astellas Pharmaceuticals Inc. Served as Scientific Consultant with Cerexa subsidiary of Activis Served in Scientific Advisory Board with The Medicine s Company

THERE ARE DIFFERENT TYPES OF SHIPS There are different types of ships: There are good ships and wood ships, Ships that sail the sea but the best ships are stewardships Stewardship: careful and responsible management There are different types here in Maine: Maine Island Trail Association: Lake Stewardship Department of Agriculture, Conservation, and Forestry: Woodland Stewardship IMAGES ADAPTED FROM CLIPARTKID.COM

ANTIMICROBIAL STEWARDSHIP Strategies to improve the use of antimicrobial medications with the goals of: Enhancing patient health outcomes Decreasing unnecessary costs Reducing resistance to antimicrobials Executive order combating antibiotic resistant bacteria (2014) Other healthcare settings (other than inpatient) Office based practices, outpatient settings, emergency departments WORLD HEALTH ORGANIZATION. INTERVENTIONS AND STRATEGIES TO IMPROVE THE USE OF ANTIMICROBIALS IN DEVELOPING COUNTRIES. 2001. TP://WWW.WHO.INT/IRIS/HANDLE/10665/66839. WWW.FIGHTTHERESISTANCE.ORG

ANTIBIOTIC RESISTANCE IS EVERYWHERE Approximately 2,049,442 people are infected each year in the US with a resistant bacteria At least 23,000 people die each year from these infections Most infections occur in the community Deaths related to resistance occur in the healthcare setting Hospitals Nursing homes CENTERS FOR DISEASE CONTROL AND PREVENTION. ANTIBIOTIC RESISTANCE THREATS IN THE US 2013 REPORT. HTTP://WWW.CDC.GOV/DRUGRESISTANCE/THREAT-REPORT-2013/

ECONOMIC BURDEN OF ANTIMICROBIAL RESISTANCE Pediatric patients visiting the clinic for respiratory or ear infections $250 $216 $250 $200 $150 $100 $50 $0 $53 Provider Visit Costs $200 $150 $100 $50 $0 $75 $23 Drug costs n = 2,328 Treatment Failure Treatment Success Treatment failure = receiving another different antibiotic from the first episode HOWARD DH. PEDIATRICS. 2004;113:1352-6

BAD BUGS, NO DRUGS: NO ESCAPE! E = Enterococcus faecium S = Staphylococcus aureus C = Clostridium difficile A = Acinetobacter baumannii P = Pseudomonas aeruginosa E = Enterobacteriaceae Escherichia coli Klebsiella pneumoniae Enterobacter spp. SPELLBERG B, ET AL. CLIN INFECT DIS. 2004;38:1279-86. BOUCHER HW, ET AL. CLIN INFECT DIS. 2009;48:1-12. PETERSON LR. CLIN INFECT DIS. 2009;49(6):992-3

HOW ANTIBIOTIC RESISTANCE HAPPENS Lots of bacteria and a few of them are resistant to some of the conventional antibiotics Antibiotics kill the bacteria (both good and bad) Drug resistant ones are not eradicated and they overgrow Other ways is that bacteria can share their mechanism of resistance to other bacteria US DEPARTMENT AND HEALTH AND HUMAN SERVICES. ANTIBIOTIC RESISTANCE THREATS IN THE UNITED STATES 2013 REPORT. CENTERS FOR DISEASE CONTROL AND PREVENTION. HTTP://WWW.CDC.GOV/DRUGRESISTANCE/THREAT-REPORT-2013/. MAR 17, 2017.

MECHANISM OF RESISTANCE Reduced permeability or uptake Porin Pumps Efflux Pumps Alterations of target sites Altering Penicillin binding protein Topoisomerase mutation Enzymatic Degradation Aminoglycoside modifying enzyme Beta-lactamase production HANCOCK REW. CLIN INFECT DIS. 1998;27:S93-9.

HOW CAN ANTIBIOTICS RESISTANCE SPREAD? Antibiotics are given to animals and to humans Drug resistant bacteria can remain on the meat of our livestock When we do not handle food properly (washing hands) or cook properly Fertilizer or water containing animal feces used on food crops Drug resistant bacteria can remain in our gut Obtain drug resistant bacteria being in a healthcare facility Antibiotic use can lead to resistance should only use to treat infections

ANTIMICROBIAL STEWARDSHIP REQUIRES A TEAM EFFORT Core: Pharmacist Core: Physician Microbiologist Informatics Epidemiologist Infection Control Professional Clinical Pharmacist Patient Infectious Disease Physician Epidemiologist Microbiologist Informatics DELLIT TH. CLIN INFECT DIS 2007;44:159-177

MOST OF ANTIBIOTIC USE IS FROM THE OUTPATIENT SETTING Approximately 60% of US antibiotic expenditures for humans are related to care received in outpatient settings Other developed countries 80-90% Approximately 269 million antibiotic prescriptions were dispensed from an outpatient pharmacy 20% of pediatric visits receive an antibiotic 10% of adult visits receive an antibiotic

ANTIBIOTIC CONSUMPTION Outpatient Antibiotic Prescriptions Per 1,000 people by Region 30% were unnecessary prescriptions FLEMING-DUTRA KE. JAMA. 2016 MAY 3;315(17):1864-73

COMMUNITY ANTIBIOTICS PRESCRIPTIONS BY STATE - 2014 Outpatient setting ED Clinics Offices Acute respiratory conditions Ear infections Viral infections Maine dispenses 720 prescriptions per 1,000 FLEMING-DUTRA K, ET AL. JAMA 2016;315(17): 1864-1873. DATA ADAPTED FROM CDC.GOV

Prescriptions Dispensed MAINE ANTIBIOTICS DISPENSED IN COMMUNITY PHARMACIES Maine has been lower than national rate We continue to decline each year 1000 900 800 700 600 500 400 300 200 100 0 All Antibiotics Per 1,000 Population 877 867 849 835 769 765 726 720 2011 2012 2013 2014 Year ME state National DATA ADAPTED FROM CDC.GOV. OUTPATIENT ANTIBIOTIC PRESCRIPTIONS UNITED STATES, 2014. AVAILABLE VIA THE INTERNET: HTTP://WWW.CDC.GOV/GETSMART/COMMUNITY/PDFS/ANNUAL-REPORTSUMMARY_2014.PDF

Prescriptions Dispensed MAINE ANTIBIOTIC USE OF BETA-LACTAMS 200 180 160 140 120 100 80 60 40 20 0 Cephalosporins Per 1,000 Population 118 116 115 112 82 83 81 82 2011 2012 2013 2014 Year ME state National 200 180 160 140 120 100 80 60 40 20 0 174 Penicillins Per 1,000 Population 196 190 193 191 167 162 162 2011 2012 2013 2014 Year DATA ADAPTED FROM CDC.GOV. OUTPATIENT ANTIBIOTIC PRESCRIPTIONS UNITED STATES, 2014. AVAILABLE VIA THE INTERNET: HTTP://WWW.CDC.GOV/GETSMART/COMMUNITY/PDFS/ANNUAL-REPORTSUMMARY_2014.PDF

Prescriptions Dispensed MAINE ANTIBIOTICS OF DIFFERENT CLASSES 200 180 160 140 120 100 80 60 40 20 0 Fluoroquinolones Per 1,000 Population 102 105 105 103 85 86 82 81 2011 2012 2013 2014 Year ME state National 200 180 160 140 120 100 80 60 40 20 0 190 182 Macrolides Per 1,000 Population 182 171 143 162 134 154 2011 2012 2013 2014 Year DATA ADAPTED FROM CDC.GOV. OUTPATIENT ANTIBIOTIC PRESCRIPTIONS UNITED STATES, 2014. AVAILABLE VIA THE INTERNET: HTTP://WWW.CDC.GOV/GETSMART/COMMUNITY/PDFS/ANNUAL-REPORTSUMMARY_2014.PDF

ADVERSE DRUG EVENTS RELATED TO ANTIBIOTICS Each year, >140,000 ED visits are related to ADRs to antibiotics 79% of ED visits for antibiotic related ADR allergic reaction Mild rashes to serious itching/blistering Swelling of the face and throat and breathing problems In 2011, 453,000 cases of Clostridium difficile infections occurred 1/3 were caused by giving antibiotics for treating community associated infections Minimize unnecessary use to reduce the risk Gather information on patient s history SHEHAB N ET AL. CLIN INFECT DIS 2008;47:735 43; LESSA FC ET AL. N ENGL J MED 2015;372:825 34

ENTEROBACTERIACEAE IS A COMMON PATHOGEN IN THE COMMUNITY US DEPARTMENT AND HEALTH AND HUMAN SERVICES. ANTIBIOTIC RESISTANCE THREATS IN THE UNITED STATES 2013 REPORT. CENTERS FOR DISEASE CONTROL AND PREVENTION. HTTP://WWW.CDC.GOV/DRUGRESISTANCE/THREAT-REPORT-2013/. MAR 17, 2017.

CUMULATIVE ESCHERICHIA COLI RESISTANCE TO AMPICILLIN Sampled from 17 Hospitals Antibiogram Total of 18,345 Escherichia coli isolates 59% susceptible Piscataquis county 71% susceptible Androscoggin county 61% susceptible Percent Susceptibility ADAPTED FROM 2015 ANTIBIOGRAMS FROM 17 HOSPITALS (OUT OF 34 HOSPITALS) USING GOOGLE MAPS 50 60 65 70 75 80 100

CUMULATIVE ESCHERICHIA COLI RESISTANCE TO CIPROFLOXACIN Sampled from 17 Hospitals Antibiogram Total of 18,345 Escherichia coli isolates 74% susceptible Waldo county 90% susceptible Franklin county 78% susceptible Percent Susceptibility ADAPTED FROM 2015 ANTIBIOGRAMS FROM 17 HOSPITALS (OUT OF 34 HOSPITALS) USING GOOGLE MAPS 77 83 88.5 94 100

ESCHERICHIA COLI SUSCEPTIBILITY TO CIPROFLOXACIN AND LEVOFLOXACIN OVER TIME Data is only from 2005 to 2011 Cumulative data from 80% of the hospitals in MA From 2011 ECOL susceptibility was 80% ADAPTED FROM: COMMONWEALTH OF MASSACHUSETTS DEPARTMENT OF PUBLIC HEALTH 2013 PRESENTATION

PSEUDOMONAS AERUGINOSA ARE KNOWN TO BE MULTIDRUG RESISTANT PATHOGENS US DEPARTMENT AND HEALTH AND HUMAN SERVICES. ANTIBIOTIC RESISTANCE THREATS IN THE UNITED STATES 2013 REPORT. CENTERS FOR DISEASE CONTROL AND PREVENTION. HTTP://WWW.CDC.GOV/DRUGRESISTANCE/THREAT-REPORT-2013/. MAR 17, 2017.

PSEUDOMONAS AERUGINOSA RESISTANCE TO CIPROFLOXACIN Sampled 17 Hospitals Antibiogram Total of 1,580 Pseudomonas aeruginosa isolates 70% susceptible Washington county 100% susceptible Cumberland county 77% susceptible Percent Susceptibility ADAPTED FROM 2015 ANTIBIOGRAMS FROM 17 HOSPITALS (OUT OF 34 HOSPITALS) USING GOOGLE MAPS 77 83 88.5 94 100

Percent Susceptible to Ciprofloxacin RESISTANCE IN THE PAST 4 YEARS AT BANGOR, MAINE Pseudomonas aeruginosa (PSAR) and Escherichia coli (ECOL) Susceptibility to Ciprofloxacin 100 80 60 40 20 87 86 88 87 86 89 87 89 87 80 82 76 78 81 82 78 0 2012 2013 2014 2015 PSAR EMMC PSAR SJH ECOL EMMC ECOL SJH ADAPTED FROM 4 DIFFERENT CONSECUTIVE ANNUAL ANTIBIOGRAMS FROM 2 HOSPITALS IN BANGOR, MAINE

Percent Susceptible to Ciprofloxacin RESISTANCE IN THE PAST 15 YEARS AT EASTERN MAINE MEDICAL CENTER Pseudomonas aeruginosa (PSAR) and Escherichia coli (ECOL) Susceptibility to Ciprofloxacin 100 80 60 40 20 100 99 98 98 98 96 95 93 91 90 90 87 87 8887 89 89 82 80 82 79 80 82 76 76 76 72 73 73 69 69 71 0 1996 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 PSAR ECOL PSAR 5 Yr Median ECOL 5 Yr Median ADAPTED FROM 16 DIFFERENT YEARS OF ANTIBIOGRAMS COLLECTED IN EMMC

STRATIFICATION OF DATA TO SUPPORT CLINICAL DECISION Specific patient population pediatric and cystic fibrosis service Intensive care units Urinary tract infections outpatient vs inpatients Certain organisms of interest Methicillin-resistant Staphylococcus aureus Penicillin non-susceptible or macrolide-resistant Streptococcus pneumoniae Fluoroquinolone resistant Enterobacteriaceae

Percent Susceptible to Ciprofloxacin ANTIBIOGRAM IN SPECIAL POPULATION Escherichia coli (ECOL) Susceptibility to Ciprofloxacin: Urinary vs Non-Urinary 100 80 60 40 20 89 90 84 85 84 79 0 EMMC CMMC Overall ECOL Urine ECOL Non-Urine ECOL ADAPTED FROM TWO 2015 ANTIBIOGRAMS COLLECTED IN EMMC AND CMMC

EXECUTIVE ORDER TO COMBAT ANTIMICROBIAL RESISTANCE Infectious Diseases Society of America (IDSA) called an action for the medical community to raise awareness White house has now put a national security priority on antimicrobial misuse Preserve the efficacy of new and existing antimicrobials Accelerate research and facilitate development of new antimicrobials Make sure we have effective antimicrobials in the future SPELLBERG B, ET AL. CLIN INFECT DIS. 2004;38:1279-86. HTTPS://WWW.WHITEHOUSE.GOV/THE-PRESS- OFFICE/2014/09/18/EXECUTIVE-ORDER-COMBATING-ANTIBIOTIC-RESISTANT-BACTERIA

10 NEW ANTIMICROBIALS BY 2020 Development of new antibiotics Against these Gram negative bacteria BOUCHER HW, ET AL. CLIN INFECT DIS. 2013;56(12)1685-94

Number of Antimicrobial Agents NEW SYSTEMIC ANTIBACTERIAL AGENTS APPROVED BY THE US FDA 20 15 10 5 0 1983-1987 1988-1992 1993-1997 1998-2002 2003-2007 2008-2012 2013-2016 Year when US FDA granted Approval ADAPTED AND UPDATED FROM SPELLBERG B, ET AL. CLIN INFECT DIS. 2004;38:1279-86 BOUCHER HW, ET AL. CLIN INFECT DIS. 2013;56(12)1685-94

HEALTHY PEOPLE OF 2020 AND THE PLAN TO REDUCE INAPPROPRIATE USE 10 year national objective for improving the health of all Americans 2 are related to antibiotic use Reduce the number of courses of antibiotics for ear infections for young children Reduced the number of courses of antibiotics for the sole diagnosis of the common cold White House National Action plan: reduce inappropriate antibiotic outpatient use by 50% by the year 2020 ADAPTED FROM HEALTHYPEOPLE.GOV AND WHITEHOUSE.GOV

DECREASE OUR ANTIBIOTIC CONSUMPTION Provide some benchmarking purposes To determine the rate: proportion of antimicrobials utilized over patients eligible for antimicrobials within a system Defined daily dose (DDD) or days of therapy (DOT) DDD has been set by the WHO DDD population based parameters DOT number of days a patient is on antibiotics ATC/DDD INDEX 2011. WWW.WHOCC.NO/ATC_DDD_INDEX/

DURATION OF ANTIBIOTICS IS IMPORTANT Stopping antibiotics before a serious infection is cured will risk a relapse That s what happened to Albert Alexander, the London policeman who was one of the first people to be treated with penicillin by Howard Florey in 1941 Dutch study compared 3 vs 8 days of amoxicillin (n=63) vs placebo (n=56) and found no difference in duration for mild-moderate pneumonia 93% cure for both groups at 10 days after start of therapy French clinical trial compared 6 weeks (n=176) vs 12 weeks (n=175) of therapy for vertebral osteomyelitis and found no difference in cure (90.9%) WOODWARD, BILLY. "HOWARD FLOREY-OVER 6 MILLION LIVES SAVED." SCIENTISTS GREATER THAN EINSTEIN FRESNO: QUILL DRIVER BOOKS, 2009. EL MOUSSAOUI ET AL. BMJ. 2006 JUN 10; 332(7554): 1355. BERNARD L. LANCET. 2015 MAR 7;385(9971):875-82

DELAYING PRESCRIBING PRACTICES A patient is asked to wait 24-48hrs after a clinic visit To determine if an antibiotic is needed These are patients that may NOT appear to immediately warrant an antibiotic Several ways to delay a prescription Write a post dated prescription Re-contacting a patient after a clinical visit Providing a verbal order prescription to fill the prescription after a certain time if symptoms do not improve LITTLE P, ET AL. BMJ. 2014;348:G1606.

DELAYING ANTIBIOTICS REDUCES ANTIBIOTIC USE AND DECREASES COMPLICATIONS Prospective cohort study of 12,829 adult patients with pharyngitis Compared three strategies No antibiotic prescription (n=4,805) Immediate antibiotic prescription (n=6,088) Delayed antibiotic prescription (n=1,784) 1.4% of these patients developed complications 15% non-resolving symptoms Comparing to no antibiotic Complications RR; 95% CI NNT Immediate 0.62, 0.43-0.91 193 Delayed 0.58, 0.34-0.98 174 Non-resolving symptoms / Re-consultation Immediate 0.83, 0.73-0.94 40 Delayed 0.61, 0.50-0.74 18 LITTLE P, ET AL. LANCET INFECT DIS. 2014;14(3):213-9.

PHARMACISTS PLAY AN INTEGRAL ROLE IN PROMOTING APPROPRIATE ANTIBIOTIC USE IN THE COMMUNITY Educate patients and family members Properly taking the antibiotics Potential adverse events Antibiotic resistance Guidance for symptom relief for common infections Viral (do not require an antibiotic) Promote vaccination

SUMMARY: GIVE ANTIBIOTICS WHEN IT IS TRULY NECESSARY Antimicrobial resistance is a problem everywhere and is linked to antimicrobial use/abuse Antimicrobial stewardship can assist in decreasing the resistance by evaluating antimicrobial use Do you need antibiotics? Right Dose? Right Duration? Antimicrobial resistance is a problem in Maine and is growing Not as high as other places but we are seeing trends of increase of resistance