Abx CE HO [Repaired]

4/29/16

ANTIBIOTIC UPDATE CONTINUING EDUCATION FOR PHARMACISTS

Jeffrey A. Kyle, Pharm.D., BCPS Associate Professor of Pharmacy Practice McWhorter School of Pharmacy

DISCLOSURE Jeffrey Kyle reports no relevant financial relationships.

1 4/29/16

OBJECTIVES Following this session participants should be able to: 1. Describe the prescribing habits of antibiotics in the United States. 2. List the most common reasons for inappropriate prescribing of antibiotics by health care providers. 3. Characterize the current trends and problems of antibiotic resistance in the United States. 4. Explain core elements and Centers for Medicare & Medicaid Services (CMS) requirements of antimicrobial stewardship programs and how they are involved in addressing antibiotic resistance. 3

OBJECTIVES Following this session participants should be able to: 5. Discuss the recent FDA approved antibiotic entities over the last five years as well as emerging therapies. 6. Discuss new and emerging clinical data or guidelines affecting antibiotic pharmacotherapy in infectious diseases.

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ANTIBIOTIC FACTS • Annually, ~263 million courses of antibiotics are prescribed in the outpatient setting • About 50% all hospital patients receive an antibiotic during the course of their stay • Up to 70% of long-term care facilities’ residents receive an antibiotic every year • In 2009 = $10.7 billion spent on antibiotics – Outpatient = $6.5 billion – Inpatient = $3.5 billion

– Long-term care = $38 - $137 million per year. 5 MMW R. 2014;63:1-7. http://www.cdc.g ov/ get sm ar t/h eal thc ar e/l ea rn -fr o m- oth er s/f acts he ets /n ursi ng -homes.html

PRESCRIBING HABITS

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Estimated Annual Antibiotic Use in the U.S. Data based on approximate numbers of kilograms of antibiotic use per year 150,000 70,000 150,000

Livestock 3,290,000 Humans

Aquaculture

Crops 13,540,000 Pets

N Engl J Med. 2013;369:247 4- 24 76.

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ANTIBIOTICS ARE POPULAR • Ambulatory Care and Physician offices – Approximately ~928.6 million MD visits • Most frequent principal-illness related reason for visit… • Hospital ED visits – Approximately ~131 million ED visits • Most frequent reason for admission (<18 yo)… • Most frequent reason for admission (>18 yo)… • Most common reasons for discharge –<18 yo… –>18 yo… 9 http://www.cdc.g ov/ nch s/f ast ats/ ph ysici an -visit s.h tm http://www.hcup -us .a hr q.g ov/ re po rts /st atb rie fs/sb174-Emergency-Department-Visi ts- Ov ervi ew. pd f

MOST COMMON NURSING HOME INFECTIONS

Unknown 13% Other UTIs 10% 32%

SSTI 12% RTIs 33%

10 J Am Geriatr Soc. 2008;56:203- 9- 44 . J Antimicrob Chemother. 2011;66:2856 -63.

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ANTIBIOTIC PRESCRIBING HABITS • Estimated inappropriate or unnecessary antibiotic use1 – Outpatient setting - 50% – Inpatient - 30-50% – Nursing homes - 40-75%

1. Defined as overuse, inappropriate selection, inappropriate dose, inappropriate duration, or use of antimicrobials as growth promoters

11 MMWR Morb Mortal Wkly Rep. 2011;60:115 3- 6. JAMA. 2002;287:313 3- 5. J Antimicrob Chemother. 2014;69:234- 40 .

ANTIBIOTIC PRESCRIBING HABITS: OUTPATIENT

• While a 24% decrease in prescribing of antibiotics in those < 15 yo has been reported…

MMWR Morb Mortal Wkly Rep. 2011;60(34 ):1 15 3- 6.

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A!Retrospec+ve!Review!Analyzing!Appropriate!Diagnosis!and!!

An+bio+c!Selec+on!for!the!Treatment!of!Urinary!Tract!Infec+ons!! Adrienne!Darby,!PharmD!Candidate1;!Jeffrey!A.!Kyle,!PharmD,!BCPS1;!Amy!B.!Clark,!PharmD,!BCPS2! 1MCWHORTER!SCHOOL!OF!PHARMACY!●!SAMFORD!UNIVERSITY!●!BIRMINGHAM,!ALABAMA! 2SHELBY!BAPTIST!MEDICAL!CENTER!●!DEPARTMENT!OF!PHARMACY!●!ALABASTER,!ALABAMA! Introduc+on! Results! Results! • A$total$of$86$pa/ent$charts$were$reviewed.$ • Urinary$tract$infec/ons$(UTIs)$are$among$the$most$prevalent$ Culture!Results!(%)! Empiric!An+bio+c!(%)! bacterial$infec/ons$in$the$United$States$with$an$es/mated$annual$ ! 81$(94.1%)$pa/ents$met$the$inclusion$criteria.$ E.!coli!(40.9)! Levofloxacin!(24.1)! direct$and$indirect$cost$of$$2.3$billion.$$ Contaminated!(13.6)! Ciprofloxacin!(21.7)! • Those$who$were$misdiagnosed$as$having$a$UTI:$8$(9.9%)$ • In$a$seKng$such$as$an$emergency$department$(ED),$physicians$ Other!GNR!(11.4)! Ce[riaxone!(14.5)! • Number$of$pa/ents$who$received$guidelineNbased$empiric$ No!Growth!(11.4)! Cephalexin!(13.3)! rely$on$rapid$urinalyses$to$determine$if$treatment$is$warranted.$ P.!mirabilis!(7.9)! Nitrofurantoin!(8.4)! an/bio/c$therapy:$53$(65%)$$ • Rapid$urinalysis$results$oUen$vary$significantly$in$sensi/vity$and$ Gram!Posi+ve!Organisms!(7.9)! SMZ/TMP!(7.2)! • Intermediate$or$resistant$sensi/vity$to$fluoroquinolone$therapy$ ESBL!E.!coli!(3.4)! Vancomycin!+!betablactam!(4.8)! specificity,$which$may$lead$to$overdiagnosis$and$overtreatment.$ P.!aeruginosa!(2.3)! Nothing!Prescribed!(4.8)! was$displayed$with$20$bacteria$species.$ • An/bio/c$overuse$is$associated$with$the$development$of$ Other!(1.1)! Amoxicillin/clavulanate!(1.2)! resistant$organisms$and$poten/al$adverse$events$including$ Discussion! allergic$reac/ons$and$the$development$of$Clostridium+difficile+ Posi+ve! Nega+ve! Pathogen!Sensi+vity!to!! • The$2013$an/biogram$results$for$the$community$hospital$ Signs!or!Symptoms! UA! UA! Empiric!An+bio+c!Therapy! revealed$E.+coli$isolates$to$have$a$69%$and$70%$suscep/bility$ infec/ons.$ ! of!UTI! Posi+ve! Posi+ve! • In$a$2010$update,$the$Infec/ous$Diseases$Society$of$America$ Culture! Culture! Sensi+vity!Results! #!of!Pathogens! rate$to$ciprofloxacin$and$levofloxacin,$respec/vely.$ Specific!(dysuria,! • (IDSA)$reported$increasing$resistance$rates$of$uropathogens$ 39$ 13$ Suscep+ble! 40$ Fluoroquinolones$are$to$be$reserved$for$invasive$infec/ons$ urgency,!frequency,! causing$acute$uncomplicated$cys//s.$$ flank,!pain,!hematuria,! such$as$pyelonephri/s$and$acute$complicated$cys//s,$ 26$ 2$ Resistant! 14$ • The$IDSA$stresses$the$importance$of$adhering$to$the$ etc.)!n=52! especially$when$local$resistance$rates$exceed$10%.$ Nonspecific!(altered! 17$ 2$ Intermediate! 1$ • an/microbial$algorithm$which$was$determined$based$on$ mental!status,!syncope,! In$the$seKng$of$increased$fluoroquinolone$resistance,$limi/ng$ unexplained!myalgias,! Cannot!be!determined! resistance$rates,$efficacy,$and$propensity$of$collateral$damage.$$ 11$ 0$ the$use$of$these$an/bio/cs$may$be$an$op/on$to$improve$ or!seizures)!n=19! based!on!reported! 4$ culture!results! guidelineNbased$treatment$of$UTIs.$ None! 5$ 5$ n=10! • Based$on$UTI$symptoms$alone,$no$treatment$is$warranted$for$ Objec+ves! 3$ 2$ No!sensi+vi+es!reported! 31$ any$of$the$pa/ents$with$asymptoma/c$bacteriuria.$However,$ • To$determine$the$number$of$pa/ents$appropriately$diagnosed$ An+bio+c!Selec+on!Based!on!Infec+on!Classifica+on! 6! all$of$the$pa/ents$presented$with$a$concomitant$illness$that$ and$prescribed$guidelineNbased$empiric$therapy$for$urinary$tract$ required$the$use$of$an$an/bio/c.$$ 5! infec/ons.$ • Approximately$63%$of$pa/ents$included$in$the$chart$review$ • To$$iden/fy$strategies$to$improve$guidelineNbased$treatment$of$ 4! were$classified$as$having$a$complicated$infec/on.$$ urinary$tract$infec/ons.$ Nitrofurantoin! 3! ! Treatment$guidelines$for$these$infec/ons$are$lacking.$ Fluoroquinolone! ! Expert$opinion$on$the$treatment$of$complicated$cys//s$ Methods! 2! Betablactam! SMZ/TMP! recommends$the$prudent$use$of$fluoroquinolones$or$thirdN • Retrospec/ve$chart$review$(July$1,$2014$–$July$14,$2014)$ 1! genera/on$cephalosporins.$

• Inclusion$criteria:$Pa/ents$over$18$years$old$who$presented$to$ 0! the$ED$with$an$admiKng$diagnosis$of$UTI,$iden/fied$by$ICDN9$ Acute! Pyelonephri+s! Asymptoma+c! CAUTI! Applica+on! Uncomplicated! Bacteriuria! codes.$ • Poten/al$strategies$for$increasing$guideline$adherence$rates$ 30! 3.5! • Data$collected:$date$of$admission,$age,$gender,$urinalysis$results,$ and$preven/ng$an/bio/c$overuse:$ 3! urine$culture$results,$an/bio/cs$ordered,$UTI$symptoms$present$ 25! ! Development$of$an$ins/tu/onNspecific$protocol$for$ 2.5! on$admission,$presence$of$indwelling$catheter$or$renal$ 20! treatment$of$UTIs$$ Nitrofurantoin! 2! Nitrofurantoin! dysfunc/on,$residence$in$a$nursing$home,$previous$history$of$ Fluoroquinolone! ! Implementa/on$of$an$inNservice$on$proper$urine$collec/on$ 15! Fluoroquinolone! UTIs,$concomitant$diabetes$mellitus,$and$presence$of$structural$ Betablactam! 1.5! SMZ/TMP! Betablactam! methods$and$interpreta/on$of$urinalyses$ 10! abnormali/es.$$ None!Given! 1! SMZ/TMP! 14 • Descrip/ve$sta/s/cs$were$calculated.$ 5! 0.5! Disclosure! • Ins/tu/onal$Review$Board$(IRB)$approval$was$obtained$from$ 0! 0! The$authors$of$this$presenta/on$have$nothing$to$disclose$concerning$ Complicated!UTI! Symptoma+c! Misclassified! Samford$University$and$Bap/st$Health$System.$ Abacteriuria! as!UTI! possible$financial$or$personal$rela/onships$with$commercial$en//es.!

7 4/29/16

!The!Diﬃculty!with!Clostridium+diﬃcile:!A!Retrospec5ve!Review!Analyzing!Appropriate!!

Guideline=Based!Diagnosis!and!Risk!Factors!for!Non=Response+ ! Adrienne+Darby,+PharmD+Candidate+2015;+Tim+Lewis,+PharmD+Candidate+2015;++ Jeffrey+A.+Kyle,+PharmD,+BCPS;+Kim+Benner,+PharmD,+BCPS,+FASHP+ MCWHORTER!SCHOOL!OF!PHARMACY!●!SAMFORD!UNIVERSITY!●!BIRMINGHAM,!ALABAMA! Introduc5on! Results! Results! • Clostridium+difficile+infec)on+(CDI)+stands+as+the+leading+cause+of+ Rate!of!Guideline=Based!Ini5al!Treatment!! • A+total+of+107+charts+were+reviewed.++ !! Inappropriate!Ini5al!Treatment! hospitalPassociated+gastrointes)nal+illness+and+carries+a+health+ Appropriate!Ini5al! ! 96+pa)ents+met+the+inclusion+criteria+with+110+separate+ ̶!!no.!(%)! care+burden+of+approximately+3.2+billion+dollars+annually.++ Treatment! documented+CDI+occurrences.+ Inadequate! Excessive! ̶!!no.!(%)!! • In+a+2013+report,+the+CDC+iden)fied+CDI+as+an+immediate+threat+ Treatment! Treatment! • Ini)al+guidelinePbased+treatment+for+CDI+was+received+in+26.3%+ that+requires+urgent+and+aggressive+ac)on.++ Mild=to=moderate!disease! of+pa)ents.+ 18+(27.3)+ 4+(6.1)+ 44+(66.7)+ • CDI+is+responsible+for+250,000+infec)ons+and+14,000+deaths+each+ (n=66)! • Iden)fied+poten)al+risk+factors+for+nonPresponders+included:+ year.+ Severe!disease!(n=16)! 3+(18.8)+ 5+(31.2)+ 8+(50.0)+ ! BMI,+concurrent+infec)on,+presence+of+a+NG+tube,+albumin++ Severe!and!complicated! • The+American+College+of+Gastroenterology+Guidelines+for+ 0+(0.0)+ 4+(57.1)+ 3+(42.9)+ <3+g/dL,+diabetes,+use+of+medica)ons+associated+with+CDI+ Diagnosis,+Treatment,+and+Preven)on+of+Clostridium+difficile+ disease!(n=7)! • Fluoroquinolones+were+the+most+common+an)bio)cs+previously+ Reinfec5on!with!CD! infec)ons+stress+the+importance+of+appropriate+ini)al+treatment+ 8+(38.1)+ 2(9.5)+ 11+(52.4)+ (n=21)! used+in+both+responders+(26.4%)+and+nonPresponders+(19.4%).+ as+a+significant+factor+in+limi)ng+health+care+costs+as+well+as+ 15+ 66+ • An)diarrheal+medica)ons+(e.g.+loperamide)+were+ordered+in+ Total! 29+ reducing+an)microbial+resistance. 81+ 28.2%+of+pa)ents+on+CDI+therapy.+ Previous!An5bio5c!Use! Previous!An5bio5c!Use!! Objec5ves! !in!Responders!(%)! in!Non=Responders!(%)! Discussion! • Most+pa)ents+did+not+receive+ini)al+guidelinePbased+treatment.+ • To+determine+the+number+of+pa)ents+who+received+ini)al+ Fluoroquinolone+(26.4)+ Fluoroquinolone+(19.4)+ • Of+those+who+did+not+receive+ini)al+guidelinePbased+treatment,+ guidelinePbased+treatment+for+Clostridium+difficile+infec)on+ IV+Vancomycin+(12.4)+ IV+Vancomycin+(16.1)+ Penicillin+(9.9)+ Penicillin+(16.1)+ most+received+excessive+ini)al+treatment.+ • To+iden)fy+poten)al+risk+factors+for+nonPresponse+to+ini)al+ Cephalosporin+(19.8)+ Cephalosporin+(12.9)+ ! Excessive+treatment+defined+as:+increased+strength+or+dosing+ therapy+for+Clostridium+difficile+infec)ons+ Carbapenem+(8.3)+ Carbapenem+(6.5)+ Clindamycin+(3.3)+ Clindamycin+(3.2)+ frequency,+combina)on+therapy+instead+of+monotherapy,+a+ Other+(1.7)+ Other+(12.9)+ Methods! Bactrim+(2.5)+ Bactrim+(0)+ later+line+agent+was+used+ini)ally,+or+any+combina)on+thereof+ Macrolide+(4.1)+ Macrolide+(0)+ None+Reported+(11.6)+ None+Reported+(12.9)+ • Ini)al+guidelinePbased+treatment+rates+were+similar+to+those+of+ • Retrospec)ve+chart+review+(April+2012+–+March+2014)+ previously+published+studies.+ • Inclusion+criteria:+Pa)ents+over+18+years+old+with+a+posi)ve+assay+ • Study+limita)ons:+ for+Clostridium+difficile+infec)on+treated+inpa)ent++ Poten5al!Risk!Factors!for!Non=Response!to!Ini5al!Treatment!! ! Retrospec)ve+design+with+a+rela)vely+small+number+of+ • Data+collected:+age,+body+mass+index+(BMI),+drug+allergies,+ (Pa5ent!Characteris5cs)! pa)ents+who+did+not+respond+to+ini)al+therapy.+ history+of+CDI,+albumin+levels,+WBC,+abdominal+tenderness,+ !! Median! Median! Concurrent! Presence!of! Albumin!! Diabetes! ! Inconsistent+char)ng+may+have+led+to+the+misclassifica)on+of+ Age! BMI!! Infec5on! NG!Tube!

ANTIBIOTIC PRESCRIBING HABITS: LONG-TERM CARE • Areas of potential misuses – Prescribing for… • Upper RTIs or acute bronchitis • UTIs –Prophylactic abx use for UTIs –Treating asymptomatic bacteriuria – Empiric prescribing without microbiological investigation – Prolonged duration of antibiotic treatment 16

Clin Interv Aging. 2014;9:165–177.

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FACTORS CONTRIBUTING TO INAPPROPRIATE ANTIBIOTIC PRESCRIBING

• Underuse of C&S testing methods • Neglect of local resistance patterns

• Insufficient knowledge and time

• Prescriber beliefs and attitudes

• Patient expectations and demands

DO MD’S USE HOSPITAL ANTIBIOGRAMS? Always Frequently 1% 3%

Rarely 32%

Never 64%

Clin Infect Dis.2008:46;1 78 -89.

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PRESCRIBER KNOWLEDGE, BELIEFS, AND ATTITUDES • Infect Control Hosp Epidemiol. 2015;36:1065-72. – Inpatient physician survey (n=30) – Results • All recognized overuse of abx – Many prescribed even when clinical evidence was uncertain – Admit their anxiety about missing an infection played a role • Abx ADRS did not influence decision making • Physicians in training strongly influenced by supervisors • Avoidance of conflict with another prescriber 19

ARE YOU TIRED?

JAMA Intern Med. 2014;174(1 2): 20 29 -2031. 20

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Br J Gen Pract. 2007 Dec;57(545):942-7.

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23 http://www.fda.g ov/ do wnl oa ds/ Fo rI nd ust ry/U se rFee s/Ani m alDr ug Use r Fe eActAD UFA /UC M4 76 25 8. pdf

RISKS

• Cost • Adverse drug events • Drug interactions • Resistance

Emerg Infect Dis. 2015;21:1578 -81.

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COST OF INAPPROPRIATE ANTIBIOTIC USE • IMS Health Study identifies $34 billion in avoidable health-care costs • Infect Control Hosp Epidemiol. 2014;35:1229-35. – Retrospective analysis of non-federal facilities (n=505) – Included only redundant therapies – Results • Redundant therapies - 78% –Metronidazole and piperacillin/tazobactam (53%)

• Potential avoidable cost - $12 million 25

Avoidable Costs in U.S. Healthcare: The $200 Billion Opportunity from Using Medicines More Responsibly. Report by the IMS Institute for Healthcare Informatics.

ADES AND INAPPROPRIATE ANTIBIOTIC USE • Antibiotics cause 1 out of 5 ED visits for ADE – Antibiotics are the most common cause of ED visits for ADEs in children < 18 yo • Seven of the top 15 drugs involved in ADEs are antibiotics • 78.7% for allergic events • 19.2% for other events (e.g. diarrhea, vomiting) – Approximately 50% due to β-lactams • 6.1% required hospital admission

Clin Infect Dis. 2008;47:735

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!The!Diﬃculty!with!Clostridium+diﬃcile:!A!Retrospec5ve!Review!Analyzing!Appropriate!!

• two million people are sickened every • year with antibiotic-resistant infections, with at least 23,000 dying as a result

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FACTORS CONTRIBUTING TO ANTIMICROBIAL RESISTANCE • Misuse of antimicrobials – Overuse – Inappropriate selection – Inappropriate dose and duration – Use of antimicrobials as growth promoters • Evolution of pathogens • Inadequate infection control • Greater severity of illness

CURRENT RESISTANCE TRENDS/THREATS • Urgent Threats – Clostridium difficile – Carbapenem-resistant Enterobacteriaceae (CRE) – Drug-resistant Neisseria gonorrhea • Serious Threats – MDR Acinetobacter, Pseudomonas aeruginosa – Drug-resistant Campylobacter, Salmonella, Shigella, S. pneumoniae, tuberculosis – MRSA – ESBL Enterobacteriaceae • Concerning Threats – Vancomycin-resistant Staphylococcus aureus – Erythromycin-resistant Group A Streptococcus – Clindamycin-resistant Group B Streptococcus 34 http://resistancemap.cddep.org/resmap/resistance

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COMBATING ANTIBIOTIC RESISTANCE

• Preventing infections • Tracking • Improving antimicrobial prescribing and stewardship • Developing new drugs and diagnostic tests

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IMPROVING ANTIBIOTIC PRESCRIBING • Does behavioral interventions affect rates of inappropriate antibiotic prescribing? – R, CCT (n=47 primary care practices, 248 MDs) • 0, 1, 2, or 3 interventions x 18 months • Interventions EHR based – Suggested alternatives – Accountable justification – Peer comparison – Results • Evaluated 31,712 patient visits – Suggested alternatives: 22.1%è6.1% (p=0.66) – Accountable justification: 23.2%è5.2% (p<0.001) – Peer comparison: 19.9%è3.7% (P<0.001) 33 JAMA. 2016;315(6): 56 2- 57 0.

JAMA Intern Med. 2013;173(4):267-273.

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ANTIMICROBIAL STEWARDSHIP • Antimicrobial stewardship is an activity that promotes the appropriate antimicrobial: – Selection – Dosing – Route – Duration

ANTIMICROBIAL STEWARDSHIP • IDSA/SHEA 2007 Antimicrobial Guidelines for developing a program • Primary goal – Optimize clinical outcomes while minimizing unintended consequences of antimicrobial use –Toxicity –Selection –Resistance • Secondary goal – Reduce health care cost 36

Clin Infect Dis. 2007;44(2): 15 9- 17 7.

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ANTIMICROBIAL STEWARDSHIP CORE PROGRAM STRATEGIES • Core Strategies – Prospective Audit – Formulary Restriction/Preauthorization • Supplemental Strategies – Education – Guideline and clinical pathways – Antimicrobial order forms – De-escalation of therapy – Dose optimization

– IV to PO conversion 37 Clin Infect Dis. 2007;44(2): 15 9- 17 7.

ANTIMICROBIAL STEWARDSHIP GUIDELINE UPDATE • Clin Infect Dis. 2016;62:1-27. – Primary focus • Implementing and measuring antibiotic stewardship programs (ASPs) in inpatients settings, including long-term care • Not on cost, but on improving patient outcomes and reducing antibiotic resistance – Interventions should based on local issues and resources – ASPs should be led by MDs and PharmDs

http://cid.oxfor djo ur nal s.o rg /co nt ent /e arly /2 01 6/0 4/ 11/ cid. ciw1 18 .full .p df+ ht ml

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ANTIMICROBIAL STEWARDSHIP GUIDELINE UPDATE • A total of 28 measures are recommended – Preauthorization or prospective audit and feedback for antibiotic use – Syndrome-specific stewardship – Pharmacokinetic monitoring and adjustment programs for aminoglycosides and vancomycin – Increase appropriate use of oral over IV antibiotics – Rapid viral testing of respiratory specimens – Use of days of therapy to monitor antibiotic use 39

http://cid.oxfor djo ur nal s.o rg /co nt ent /e arly /2 01 6/0 4/ 11/ cid. ciw1 18 .full .p df+ ht ml

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COMMUNITY PHARMACY STEWARDSHIP • Encourage parents/adults take responsibility of care – Decrease pressure for antibiotic prescribing • Encourage adherence to therapy • Printed and phone-call reminders • Other infection control procedures

41 http://www.cdc.g ov/ get sm ar t/c om m unit y/ mat eri als -r efe re nc es/i nd ex. ht ml

ANTIBIOTIC STEWARDSHIP CLINICAL OUTCOMES 100 AMP UP 80

40 Percent 20

0 Appropriate Cure Failure RR 2.8 (2.1-3.8) RR 1.7 (1.3-2.1) RR 0.2 (0.1-0.4)

AMP = Antibiotic Management Program 42 UP = Usual Practice Fishman N. Am J Med 2006;119:S 53.

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Leadership Commitment

Education Accountability

Antimicrobial Stewardship Core Drug Reporting Elements Expertise

Tracking Action 43

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ANTIMICROBIAL STEWARDSHIP AND CMS • By the end of 2016 è inpatient facilities must “implement robust antibiotic stewardship programs that adhere to best practices.” • By the end of 2017 è President’s Council of Advisors on Science and Technology (PCAST) recommended that ASPs be mandated as a Condition of Participation (CoP) for the Centers for Medicare & Medicaid Services (CMS) for inpatient and long-term care facilities 1. The White House, Office of the Press Secretary. Executive order—combating antibiotic-resistant bacteria. Exec. Order No. 13676, 3 CFR. www.whitehouse.gov/the-press- office/2014/09/18/executive-ord er-co mbatin g-antibiotic- resistant -bact eria. Effective September 18, 2014. 2. National action plan for combating antibiotic-resistant bacteria. The White House website. www.whitehouse.gov/sites/default/files/docs/natio nal_actio n_pla n_for _com bating _antib otic- 45 resistant_bacteria.pdf. Published March 2015. 3. President’s Council of Advisors on Science and Technology. Report to the President on combating antibiotic resistance. The White House website. http://1.usa.gov/1qhDgF6. Published September 2014.

ANTIMICROBIAL STEWARDSHIP AND CMS • Potential regulations for all hospitals and LTCF – Written policies and procedures whose purpose is to improve antibiotic use (antibiotic stewardship) – Requires practitioners to document indication, dose, and duration for all antibiotics, – Designated leader(s) responsible for program outcomes – A formal procedure for all practitioners to review the appropriateness of any antibiotics prescribed after 48 hours from the initial orders – Monitoring of antibiotic use at the unit and/or hospital

level 46

Centers for Medicare & Medicaid Services. Hospital Infection Control Worksheet. Nov. 26, 2014:http://g o.c ms. go v/1B 6NCSV

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ANTIMICROBIAL STEWARDSHIP AND CMS • California is the only state with mandated ASPs in acute- care hospitals • As of July 1, 2015, further California legislation states ASPs: – follow professional and society guidelines – establish a physician-led multidisciplinary committee or work group for antimicrobial stewardship – have 1 MD or PharmD on the committee who is knowledgeable about antimicrobial stewardship – report program activities to the hospital committee undertaking quality improvement activities 47

Cal SB 1311 (2014) (codified at Cal Health and Safety Code 1288.85).

ANTIMICROBIAL STEWARDSHIP AND CMS • By 2020… – Establishment of ASPs in all acute care hospitals and improved antimicrobial stewardship across all healthcare settings – Reduction of inappropriate antibiotic use by 50% in outpatient settings and by 20% in inpatient settings – Establishment of State Antibiotic Resistance Prevention Programs in all 50 states to monitor regionally important MDR organisms and provide feedback and technical assistance to health care facilities 48

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ANTIBIOTIC DRUG DEVELOPMENT

20 19 1980 - PRESENT 18 16 14 12 11 11 11 10 8 6 6 4 4 3 2 1 0

DRUG DEVELOPMENT NEEDS “ESKAPE” • Enterococci faecium • Staphylococcus aureus

• Klebsiella pneumoniae

• Acinetobacter baumannii

• Pseudomonas aeruginosa

• Enterobacter spp.

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DRUG DEVELOPMENT PROMOTION • Generating Antibiotics Incentives Now (GAIN) – July 9, 2012 • Extends exclusivity by 5 additional years • Priority review • Fast track approval – Designates candidate antibiotics as “qualifying infectious disease products” (QIDPs) • As of September 2015 –~39 new antibiotics under development »~23 are considered QIDPs »12 in Phase 3 trials »11 target ESKAPE pathogens »17 target CDC urgent threats 51 http://www.fda.g ov/ New sEve nts /Ne wsr oo m/P re ssAn no un ce me nts /uc m 32 06 43. ht m

NEW ANTIBIOTICS 2011 - PRESENT

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FIDAXOMICIN (DIFICID®) • FDA approved May 2011 • Efficacy: Clostridium difficile-associated diarrhea • Dosing and administration – 200 mg PO BID for 10 days – No renal/hepatic dose adjustments necessary • Safety – GI upset (11%), Abd. pain (6%), GI bleed (4%), • Clinical Considerations – Cost – Place in therapy 53

Dificid(R) [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; 2015.

DALBAVANCIN (DALVANCE®) • FDA approved May 2014 • Efficacy: ABSSSI – S. aureus, Streptococcus spp., Enterococcus spp. • Dosing and administration – 1000 mg IV on day 1, 500 mg IV on day 8 – 1500 mg IV on day 1 – Renal dose adjustments necessary • Safety – HA (5%), GI upset (> 3%), “Red man syndrome” (3%) • Clinical Considerations – Cost – Place in therapy 54

Dalvance(R) [package insert]. Parsippany, NJ: Duranta Therapeutics U.S. Limited; 2016.

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TEDIZOLID PHOSPHATE (SIVEXTRO®) • FDA approved June 2014 • Efficacy: ABSSSI – S. aureus, Streptococcus spp., Enterococcus spp. • Dosing and administration – 200 mg PO/IV daily for 6 days – No renal/hepatic adjustments • Safety – HA (8%), GI upset (> 2%) • Clinical Considerations – Drug interactions – Cost

– Place in therapy 55

Sivextro(R) [package insert]. Whitehouse Station, NJ: Merck & Co.; 2015.

ORITAVANCIN (ORBACTIV®) • FDA approved August 2014 • Efficacy: ABSSSI – S. aureus, Streptococcus spp., Enterococcus spp. • Dosing and administration – 1200 mg IV x 1 dose over 3 hrs – No renal dose adjustments necessary • Safety – HA (7%), GI upset (> 3%), abscesses (3%) – ”Red man syndrome” • Clinical Considerations – Use with anticoagulants – Osteomyelitis – Cost 56

Orbactiv(R) [package insert]. Parsippany, NJ: The Medicines Company; 2016.

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CEFTOLOZANE/TAZOBACTAM (ZERBAXA®) • FDA approved December 2014 • Efficacy: Complicated IAI, Complicated UTIs – GNRs, some Streptococcus spp., B. fragilis • Dosing and administration – cIAIs: 1.5 gm IV q8hrs x 4-14 days + metronidazole – cUTIs: 1.5 gm IV q8hrs x 7 days – Renal dose adjustments necessary • Safety – Fever (6%), GI upset (6%), • Clinical Considerations – Older population cure rates – HAP and VAP PNAs? 57

Zerbaxa(R) [package insert]. Whitehouse Station, NJ: Merck & Co.; 2015.

CEFTAZIDIME/AVIBACTAM (AVYCAZ®) • FDA approved February 2015 • Efficacy: Complicated IAI, Complicated UTIs – GNRs, some Streptococcus spp., B. fragilis • Dosing and administration – cIAIs: 2.5 gm IV q8hrs x 5-14 days + metronidazole – cUTIs: 2.5 gm IV q8hrs x 7-14 days – Renal dose adjustments necessary • Safety – Anxiety (10%), dizziness (6%), GI upset (10%), • Clinical Considerations – Older population cure rates

– HAP and VAP PNAs? 58

Avycaz(R) [package insert]. Cincinnati, OH: Forrest Pharmaceutical s, Inc.; 2015.

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SO WHERE DO WE STAND? 1. Ceftaroline fosamil (11/10) 2. Dalbavancin (5/14) 3. Tedizolid phosphate (6/14) 4. Oritavancin (8/14) 5. Ceftolozane/tazobactam (12/14) 6. Ceftazidime/avibactam (2/15) 5 7. ….. 8. ….. 9. …..

10.….. 59

Active Active against Novel against CDC “Urgent Antibiotic Compound “ESKAPE” Threat” pathogens? pathogens? Ceftaroline No Yes No fosamil Dalbavancin No Yes No Tedizolid No Yes No phosphate Oritavancin No Yes No Ceftolozane/ No Yes No tazobactam Ceftazidime/ No Yes Yes 60 avibactam

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EMERGING THERAPIES

EMERGING THERAPIES • Solithromycin – Phase 3 – CAP, STDs – Expected activity against • CDC urgent threat pathogens - Yes • ESKAPE pathogens - No • Carbavance (RPX7009+meropenem) – Phase 3 – cUTIs, cIAIs, HAP/VAP – Expected activity against • CDC urgent threat pathogens - Yes

• ESKAPE pathogens - Yes 62 J Antimicrob Chemother. 2013;68:1825 -31. http://www.pewtr ust s.o rg /e n/ multi m edi a/d at a-vi su aliza tio ns/ 20 14/ an tibi otics -currently-in -clini cal -d evel op m ent

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EMERGING THERAPIES • Imipenem/cilastatin + relebactam – Phase 3 – cUTIs, cIAIs, HAP/VAP – Expected activity against • CDC urgent threat pathogens - Yes • ESKAPE pathogens - Yes • Plazomicin – Phase 3 – cUTIs, cIAIs, bacteremia, HAP/VAP – Expected activity against • CDC urgent threat pathogens - Yes

• ESKAPE pathogens - Yes Antimicrob Agents Chemother. 2015;59:5029 -31. 63 Antimicrob Agents Chemother. 2011;55:5874 -80. http://www.pewtr ust s.o rg /e n/ multi m edi a/d at a-vi su aliza tio ns/ 20 14/ an tibi otics -currently-in -clini cal -d evel op m ent

EMERGING THERAPIES • Omadacycline, eravacycline – Phase 3 – cUTIs, CAP, ABSSSI – Expected activity against • CDC urgent threat pathogen - Oma - in vitro/Era - Yes • ESKAPE pathogens - Yes • Delafloxacin, finafloxacin – Phase 3, Phase 2 respectively – cUTIs, CAP, ABSSSI – Expected activity against • CDC urgent threat pathogen - In vitro • ESKAPE pathogens - Yes Antimicrob Agents Chemother. 2014;58(4):1 84 7- 54. 64 Antimicrob Agents Chemother. 2012;56:5650 -4. Int J Infect Dis. 2015 Jan;30:67-73. Antimicrob Agents Chemother. 2011;55:4386 -93.

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OTHER EMERGING THERAPIES • Surotomycin – Phase 3, C. difficile • Cadazolid – Phase 3, C. difficile • Fusidic acid – Phase 3, ABSSSI • Iclaprim – Phase 3, ABSSSI, HAP • Radazolid

– Phase 2, ABSSI, CAP 65 http://www.pewtr ust s.o rg /e n/ multi m edi a/d at a-vi su aliza tio ns/ 20 14/ an tibi otics -currently-in -clini cal -d evel op m ent

EMERGING CLINICAL DATA & GUIDELINES

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Clin Infect Dis.2011;52:31-40.

Antimicrob Agents Chemother. 2012;56:2231-6.

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CMAJ. 2015 Mar 3;187(4):E138-43.

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JAMA. 2015;313(7):677-686. 71

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BMJ. 2016; 352 :i843.

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ENDOCARDITIS GUIDELINES EUR HEART J. 2015;36:3075-128. CIRCULATION. 2015;132:1-53. • Updates the 2005 AHA and 2009 ESC guidelines • Emphasizes ‘early’ timing along with an “Endocarditis Team” • Therapies – Native-valve (Streptococcus) • No changes – Native-valve (Staphylococcus) • Nafcillin or cefazolin x 6 wks, no synergistic AG – ORSA or PCN allergy: vancomycin or daptomycin – Prosthetic-valve (Streptococcus spp. or Staphylococcus) • No changes – Native or Prosthetic-valve (Enterococcus) • Traditional gentamicin dosing preferred (Pk: ~3;Tr: <1) • Ampicillin plus ceftriaxone + AG 79 • Resistant Enterococcus: Linezolid or daptomycin

ENDOCARDITIS GUIDELINES EUR HEART J. 2015;36:3075-128. CIRCULATION. 2015;132:1-53. • Key points – PCN susceptible Staphylococcus, Streptococcus, Enterococcus • Penicillin G, ceftriaxone, nafcillin and ampicillin – More judicious use of AG are recommended – Resistant strains • Vancomycin, with an increasing role of daptomycin – Dental prophylaxis • A prosthetic heart valve • PMH of endocarditis • Heart transplant with abnormal heart valve function • Certain congenital heart defects 80 J Am Coll Cardiol. 2014;63(22 ):e 57 .

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SSTI GUIDELINE CLIN INFECT DIS. 2014;59:E10-E52. • Updates the 2005 IDSA SSTI guidelines • Management for SSTIs depends on… – Purulent • Furuncle, carbuncle, or abscess – Non-purulent • Cellulitis, erysipelas, or necrotizing infection – Stratified based on severity • Empiric and defined antibiotic recommendations • Duration of therapies varies widely • Newly approved abx not included 81

Purulent Furuncle, Carbuncle, Abscess Severe Mild I&D + C&S Moderate I&D I&D + C&S Empiric Tx Vancomycin Empiric Tx No Abx Daptomycin TMP/SMX warranted Linezolid Doxycycline Te le v a nc in Ceftaroline Defined Tx TMP/SMX (MRSA) Defined Tx Dicloxacillin (MSSA) See Empiric (MRSA) Cephalexin (MSSA) Doxycycline (MRSA) Nafcillin (MSSA) Cefazolin (MSSA) 82 Clindamycin (MSSA) Clin Infect Dis. 2014;59:e10 -e52.

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N Engl J Med. 2016;374:823-32.

Non-Purulent Cellulitis, Erysipelas, Necrotizing

Severe Moderate Mild Debridement + C&S Empiric Tx Empiric Tx PCN Pen VK Empiric Tx Ceftriaxone Cephalosporin Vancomycin + Dicloxacillin Pip/Tazo Cefazolin Clindamycin Clindamycin

Defined Tx Polymicrobial è Vancomycin + Pip/Tazo Monomicrobial S. pyogenes è PCN + Clinda Clostridium spp. è PCN + Clinda Vibrio vulnifcusè Doxy + Ceftazidime

84 Aeromonas hydrophila è Doxy + Cipro Clin Infect Dis. 2014;59:e10 -e52.

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RHINOSINUSITIS CLIN INFECT DIS. 2012;54:E72-E112. • New guideline • Scope: children and adults with acute bacterial sinusitis • Emphasizes identifying bacterial vs. viral infections – Persistent s/sx ≥ 10 days without improvement – Severe s/sx ≥ 3 days – Worsening s/sx or “double-sickening” lasting 5-6 days • Initially watchful waiting may be appropriate • Symptomatic relief – Analgesics and antipyretics – Intranasal corticosteroids – Hypertonic saline nasal irrigation 85 – Decongestants or antihistamines…not recommended!

RHINOSINUSITIS CLIN INFECT DIS. 2012;54:E72-E112. • Recommended Therapies – Amoxicillin/clavulanate preferred over amoxicillin • Weak, low = adults; strong moderate = children – PCN allergic? • Doxycycline • Levofloxacin or moxifloxacin – Not recommended • Macrolides • TMP/SMX • Duration of therapy – Adults: 5-7 days

– Pediatrics: 10-14 days 86

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RHINOSINUSITIS • Zinc inhibits rhinovirus in vitro – Cochrane Database Syst Rev. 2013;6:CD001364. • 18 R, DB, PCT (n=1387) • Zinc daily for at least 5 consecutive days to treat or at least 5 months to prevent – Results • Reduction in severity (p=0.11) • Reduction in duration (days) (p=0.003) • Reduction in antibiotic consumption (p<0.00001) • May lead to temporary side effects –Bad taste and nausea 87

GROUP A STREPTOCOCCAL PHARYNGITIS CLIN INFECT DIS. 2012;55:E86-E102. • Updates the 2002 IDSA guidelines • Emphasizes identifying bacterial vs. viral infections – Rapid antigen detection test and/or culture • Symptomatic relief – Analgesics and antipyretics, avoid aspirin • Recommended Therapies – Penicillin V, Amoxicillin, Penicillin G – PCN allergy? • Cephalexin, cefadroxil • Clindamycin • Azithromycin – Chronic Carrier? • Penicillin G, Penicillin V + rifampin • Clindamycin

• Duration of therapy ~10 days 88 – Azithromycin 5 days

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UTI Guidelines Clin Infect Dis. 2011;52:e103-e120.

• Updates the 1999 IDSA UTI guidelines • Scope: healthy, premenopausal, non-pregnant women with acute uncomplicated acute cystitis (AUC) or pyelonephritis (AUP) • Increased appreciation of “collateral damage” • Conventional vs. short course therapies • Newly approved UTI abx not included – Ceftolozane/tazobactam and ceftazidime/avibactam 89

UTI Guidelines Clin Infect Dis. 2011;52:e103-e120. • Recommended empiric therapies for AUC – Nitrofurantoin 100 mg BID x 5 days (AI) – TMP/SMX – DS one tablet BID x 3 days (AI) – Fosfomycin 3 gm x 1 dose (AI) – Alternative therapies • Levofloxacin, ciprofloxacin, or ofloxacin (AIII) x 1 or 3 days • Amoxicillin/clavulanate, cefdinir, cefaclor, or cefpodoxime (BI) x 3-7 days • Recommended empiric therapies for AUP – Ciprofloxacin or levofloxacin daily x ~7 days (AI) – TMP/SMX – DS one tablet BID x 14 days (AI)

– β-lactams (BIII) 90 – An initial 1-time IV dose with ceftriaxone, AG, or FQ (BIII)

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PEDIATRIC CA-PNEUMONIA GUIDELINES CLIN INFECT DIS. 2011;53:E25-76. • New guideline • Despite similar pathogens found in adult CAP, abx therapy is not routinely required • Site of treatment recommendations • Outpatient – High-dose amoxicillin – High-dose amoxicillin-clavulanate • Allergy? –PO 2nd or 3rd generation cephalosporin PO • Inpatient – Ampicillin – Penicillin G – Ceftriaxone – Cefotaxime 91

PEDIATRIC CA-PNEUMONIA GUIDELINES CLIN INFECT DIS. 2011;53:E25-76. • Suspect CA-MRSA? – Add one of the following to regimen: 1.Vancomycin 2.Clindamycin • Suspect influenzae pneumonia? • Suspect an atypical organism? • Duration of therapy ~10-14 days

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MRSA GUIDELINES CLIN INFECT DIS. 2011;52:1-38. • New guideline • Scope – MRSA in SSTI, bacteremia and endocarditis, pneumonia, osteomyelitis, CNS in adults and children – Vancomycin dosing monitoring, and susceptibility testing • Newly approved abx not included • More current guidelines may supersede

Adult MRSA Infection Recommendations Bacteremia and See 2015 IE IDSA Guidelines endocarditis See 2014 SSTI IDSA SSTI Guidelines Pneumonia Vancomycin (AII), linezolid (AII) (CA-MRSA or HA-MRSA) clindamycin (BIII) x ~7-21 days Vancomycin (BII), daptomycin (BII), TMP/SMX (BII), linezolid Osteomyelitis (BII), clindamycin (BIII) ± rifampin (BIII) x ~8 weeks Vancomycin (BII), linezolid Meningitis (BII), or TMP/SMX (CIII) x ~2 weeks 94

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MRSA GUIDELINES CLIN INFECT DIS. 2011;52:1-38. • Vancomycin – Refer to Am J Health-Syst Pharm. 2009;66:82-98. – Adult dosing • Continuous infusions not recommended (AII) • Normal renal function –25-30 mg/kg (ABW) IV x 1 dose (CIII) –15-20 mg/kg (ABW) IV q8-12hrs (not to exceed 2 gm) (BIII) – Monitoring • Trough concentrations –Serious 15-20 mcg/mL (BII) • Troughs for some may not be obtained (BII) 95

OTHER RECENT GUIDELINES • Diabetic Foot Infections – Clin Infect Dis. 2012;54:132-73. • Vertebral Osteomyelitis – Clin Infect Dis. 2015;61:1-21. • Prosthetic Joint Infections – Clin Infect Dis. 2013;56:1-25.

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EMERGING GUIDELINES

• Bacterial Meningitis – Fall 2016

• LRTIs – Fall 2016

• Pediatric Bone and Joint Infections – Summer 2016

• Asymptomatic Bacteriuria – Spring 2017

http://www.idsocie ty. or g/IDSA _Pr acti ce _G uid elin es/

TAKE HOME POINTS • Antibiotics save lives • Resistance is real and is occurring now • Appropriate antimicrobial stewardship and infection control are vital and will be soon mandated • “Bad Bugs, Need Drugs” • Antibiotics are unlike any other drug • Pharmacist should be active participants in judicious use of antibiotics and stay up to date with new antibiotics and emerging clinical data 98