Handout PDF - St. Charles Health System

Antibiotic Stewardship: What are Opportunities? Thomas Ward, MD OHSU Infectious Diseases Portland VA Medical Center

Which drug with Pseudomonas aeruginosa activity is most likely to result in resistance on therapy? 1) 2)

3) 4) 5)

Imipenem Ertapenem Zosyn Cipro Cefepine or ceftazidine

Which Rx’s are most likely to be active for a CA-MRSA soft tissue infection? 1) 2) 3) 4) 5)

Cipro, Bactrim, linezolid Augmentin, Bactrim, linezolid Doxycycline, Bactrim, linezolid Clindamycin, Bactrim, linezolid Cefuroxime, Bactrim, linezolid

Which two drugs below are likely to have the least activity against S. pneumoniae? 1) 2) 3) 4) 5)

Amoxicillin Moxifloxacin Clindamycin Bactrim Azithromycin

Which is the oral drug of choice for a proven MSSA soft tissue infection? 1)

2) 3) 4)

5)

Amoxicillin Cephalexin Dicloxacillin Doxycycline Ciprofloxacin

California Antimicrobial Stewardship Program Initiative California Senate Bill 739 Mandated that, by January 1, 2008, CDPH require general acute care hospitals to develop a process for the judicious use of antibiotics and monitor antibiotic use by a quality improvement committee http://www.cdph.ca.gov/programs/hai/Pages/AntimicrobialStewardshipProgramInitiative.aspx

California: Current Program Activities • Assessment of ASP in CA healthcare facilities – Collected via website tool – Developing implementation guidelines based on resources

• Consultative advice and practical evidence on how to gain administrative and pharmacy buy-in

California: Current Program Activities • Regional collaborations among hospitals with similar difficulties and/or healthcare systems • A committee of experts across CA charged with recommending internal and external outcome antimicrobial metrics

• Educating long-term care facilities on the benefits of ASPs

Oregon Antibiotic Stewardship Initiative & System Funded by CDC

Antimicrobial Stewardship: Definition Processes designed to measure and optimize the appropriate use of antimicrobials. Achieved by selecting the appropriate agent, dose, duration of therapy and route of administration.

Antimicrobial Stewardship: Objectives • Achieve optimal clinical outcomes • Minimize toxicity and other adverse events • Minimize development of antimicrobial resistance May also reduce excessive costs attributable to: – Inappropriate/unnecessary therapy – Suboptimal outcomes – Toxicity and other adverse events – Antimicrobial resistance

Why Antimicrobial Stewardship?  Antibiotics are misused in hospitals, LTCFs, and outpatient

care settings  Antibiotic misuse adversely impacts patients and society  Improving antibiotic use is a public health imperative

 Improving antibiotic use improves patient outcomes and can

save money

Case Expanded Beta Lactamase Producing E. coli

JOURNAL OF CLINICAL MICROBIOLOGY, Nov. 2009, p. 3780–3782 Vol. 47

Transmission of an Extended-Spectrum-Beta-LactamaseProducing Escherichia coli (Sequence Type ST131) Strain between a Father and Daughter Resulting in Septic Shock and Emphysematous Pyelonephritis Peter T. Ender,1* Deepakraj Gajanana,2 Brian Johnston,3 Connie Clabots,3 Frank J. Tamarkin,4 and James R. Johnson3

Father

Daughter

Cx –E coli • • • • • • • •

Ampicillin/sulbactam – R Ciprofloxacin– R Cefuroxime - R Ceftriaxone – R Aztreonam – R Amikacin and Gentamicin – R Pip/tazobactam – S Imipenem – S

E coli Expanded Spectrum BetaLactamase (ST 131)  Origin uncertain. First apparent 2007 in traveler’s to Asia.  Now single most common strain E coli worldwide  Contains CTX-M-(15) beta-L’ase + FQ R + AMG RST 131 E coli have

acquired often unique virulence factors along with antibiotic R genes  Sensitive only carbapenems, colistin, and fosfomycin (+ amikacin) High degree of transmissibility  Family studies, hospital and LTCF outbreaks, domestic pets to human

spread, and widespread presence on retail poultry and meats

 Carriage of ST 131 increases with age  FQ use may drive acquisition and spread

 E. coli causes 35,000 deaths per year in USA  Of E coli that are cipro R, 2/3 are ST 131 and of E coli that have ESBL

pattern ½ are ST 131

Geographical Distribution of KPC-Producers

Widespread

Sporadic isolate(s)

November 2006 Centers for Disease Control and Prevention.

Geographical Distribution of KPC-Producers

Sporadic and Widespread isolate(s)

2010 Centers for Disease Control and Prevention.

ABC’s of Antimicrobial resistance • • • • • •

E S K A P E

nterococci – VRE taphylococcus aureus – MRSA, VRSA lebsiella – KPC – carbapenem resistant cinetobacter – MDR seudomonas - MDR SBL Clin Infect Dis, 1/09

MDR=Multi-drug resistant= altered pharmacokinetics > toxicity. • Costs and clinical studies rarely differentiate new from old therapies

Current Antibiotic shortages • IV Bactrim – None until? • IV foscarnet • FDA approval to import from UK • IV Amikacin • Short supply • Tetracycline • Oral no longer made • Meropenem • Short supply • Erythromycin IV

• Imported – IV Acyclovir – IV Aztreonam – Leucovorin

HISTORY OF ANTIMICROBIAL USE IN INFECTIOUS DISEASES 2000 B.C. • “Here, eat this root.” 1000 A.D. • “That root is heathen. Here, say this prayer.” 1850 A.D. • “That prayer is superstition. Here, drink this potion.” 1940 A.D. • “That potion is snake oil. Here, take this penicillin; it’s a miracle drug.” 1985 A.D. • “Penicillin is worthless. Here, take this new antibiotic; it’s bigger and better.” 2008 A.D. • “Those antibiotics don’t work any more. Here eat this root.”

Why Does This Matter? • 200-300 million antibiotics are prescribed annually – 45% for outpatient use • 25-40% of hospitalized patients receive antibiotics – At least 30% are unnecessary or sub-optimal – 5% of hospitalized patients experience an adverse reaction • >$1.1 billion spent annually on unnecessary adult antibiotic prescriptions for URI – 50-80% of outpatient antibiotic use is inappropriate • Antibiotics are unlike any other drug: use of the agent in one patient can compromise efficacy in another

Impact of Antibiotic Resistance Organism

Increased risk of death (OR)

Attributable LOS (days)

Attributable cost

MRSA bacteremia

1.9

2.2

$6,916

MRSA surgical infection 3.4

2.6

$13,901

VRE infection

2.1

6.2

$12,766

Resistant Pseudomonas infection

3.0

5.7

$11,981

Resistant Enterobacter infection

5.0

9

$29,379

• Total cost of antimicrobial resistance is estimated to be $30 billion annually. Cosgrove SE. Clin Infect Dis. 2006; 42:S82-9.

Most Common Reasons for Unnecessary Days of Therapy in Inpatients 576 (30%) of 1941 days of antimicrobial therapy deemed unnecessary

Days of Therapy

250

200

192

187

150

94

100 50 0

Duration of Therapy Longer than Necessary

Noninfectious or Treatment of Colonization Nonbacterial Syndrome or Contamination

Hecker MT et al. Arch Intern Med. 2003;163:972-978.

Duration: Too Short  Higher rates of clinical failure  Higher rates of relapse  Development of bacterial resistance  Limited studies on ultra-short durations

Circulation 2005; 111:e394-e433 Am J Respir Crit Care Med 2005; 171: 388-416

Duration: Too Long  Increased duration of IV line

 Increased length of stay  More likelihood of antimicrobial toxicity  Increased risk of colonization with resistant organisms (P.

aeruginosa and Enterobacteriaceae)  Increased risk of C. difficile infection  No evidence of improved outcomes

Am J Respir Crit Care Med 2005; 171: 388-416 Infect Control and Hosp Epidemio 2010; 31:431-455

Duration  ? Too Short

 ? Too Long

 Use guidance documents that attempt to summarize the

evidence

Evidence Rating Strength Grade A Good evidence Grade B Moderate evidence Grade C Poor evidence

Evidence Level I Level II

At least 1 randomized controlled trial At least 1 non-randomized controlled trial; cohort/case control; multiple time series; dramatic results without controls Level III Expert opinion; clinical experience; descriptive studies

CID 2007; 44:S27-72

CAP Guidelines

Recommendation

Level of Evidence

Treat minimum 5 days

I

Afebrile for 48-72 h and should have no more than 1 CAP-associated sign of clinical instability before discontinuation

II

Longer duration of therapy may be needed if initial therapy was not active against the identified pathogen or if it was complicated by extrapulmonary infection

III

CID 2007; 44:S27-72

Criteria for clinical stability Temperature ≤ 37.8°C Heart rate ≤ 100 beats/min Respiratory rate ≤ 24 breaths/min

Systolic blood pressure ≥ 90 mm Hg Arterial oxygen saturation ≥ 90% or pO2 ≥ 60 mm Hg on room air Ability to maintain oral intake Normal mental status

CID 2007; 44:S27-72

Duration for CAP Randomized trial comparing levo 750mg qd x 5 days vs. levo 500mg qd x 10 days

Percent

All p-values NS

CID 2003; 37:752-760

Duration for CAP Randomized trial comparing azithro 500mg qd x 3 days vs. clarithro 250mg bid x 10 days

Percent

p-value NS

Eur Respir J 1995; 8:398-402

Am J Respir Crit Care Med 2005; 171:388-416

VAP/HCAP Guidelines

Recommendation With initially appropriate regimen provided patient does not have P. aeruginosa and has good clinical response

Antibiotic Duration

Level of Evidence

7+ days

I

Am J Respir Crit Care Med 2005; 171:388-416

Duration for VAP Determination of time for resolution of symptoms after antibiotic start

Am J Respir Crit Care Med 2001; 163:1371-1375

Duration for VAP Determination of time for eradication of organisms after antibiotic start

Am J Respir Crit Care Med 2001; 163:1371-1375

CID 2010; 50:133-164

CID 2005; 40:643-654

CID 2011; 52(5):e103-e120

CID 2010; 50:625-663

Remember the Goals? Optimize Patient Safety

Reduce Resistance

Decrease or Control Costs

Stewardship Decreases Costs Strategy

Type of Institution

Annual Cost Savings

Pre-prescription approval

County teaching hospital

$803,910

Tertiary care hospital

$302,400

Tertiary care hospital

VA hospital

Decrease abx charge per patient ($1287 vs. $1873, p95% CDI-related deaths are in > 65 yr of age population

Figure. Yearly Clostridium difficile–related mortality rates per million population, United States, 1999•2004.

Strain of C difficile

States with the Epidemic Strain of C. difficile Confirmed by CDC and Hines VA labs (N=27), Updated 3/30/2007

30%

2030%

HYPERVIRULENT STRAIN DC • fluoroquinolone resistant •4-10 x toxin production • hypersporulation HI AK

2030%

PR

The Original Model

Dellit TH et al. “Guidelines for Developing an Institutional Program to Enhance Antimicrobial Stewardship” Clin Infect Dis 2007;44: 159-77.

The New Model: A Spectrum of Activities Individual interventions based on goals of institution led by individual (s) with interest

Comprehensive program led by ID trained physician and pharmacist

Many approaches in between

Who Can Be A Steward? • Not realistic to expect that all institutions have ID trained physicians and pharmacists • Basic requirements: 1. Interest in stewardship/patient safety/performance improvement 2. Basic knowledge of antibiotics 3. Dedicated time • Alternatives to ID physician: hospitalist, microbiology director, surgeon, intensivist • Alternatives to ID pharmacist: pharmacist with advanced training (e.g. critical care, medicine), pharmacist with training in stewardship • Activities scalable to comfort level

Pitch to Providers  You are trying to make their lives better, not telling them to

eat their peas  Help with bug/drug mismatches  Help with dosing  Help with IV to PO switch for earlier discharge

 Prevent adverse events, like C. difficile, nephrotoxicity

 Education is a carrot  Let me remind you of most recent endocarditis prophylaxis

guidelines  Best if lead by thought leaders from different specialities

Goals of Prescribers  Optimize patient safety

 Reduce resistance  We all have a role in public health issues

 Regulatory compliance  Decrease and control costs of care

Make Your ASP Essential  Improve availability and use of guidelines: surgical

prophylaxis, CAP, etc.  Order sets for ease and consistency of use  Provide expertise in dosing, treating resistant pathogens, antibiotic choice, interpretation of microbiology reports  Manage antibiotic shortages

The Society for Healthcare Epidemiology of America

“Get Smart for Healthcare” Campaign by CDC

Examples of Initiatives by Health Dept for Outpatient Use California: Partnership with health plans to identify and target education for high prescribers Michigan: Webcast to improve provider/patient communication about antibiotic use NYC: Computer-based clinical decision support tools to improve antibiotic prescribing Indiana: Movie theater advertisements

M I

H I

N M CH A NT J

Oregon Antibiotic Stewardship Initiative & System Funded by CDC

DROP-CRE Network: Goals for 2013  Needs assessment surveys for infection control,

laboratories, and long term care facilities (already sent out).  CRE education via invited speakers, educational handouts, and web-based references.  Real-time assistance to facilities on CRE prevention, detection, and control.  Tracking CRE between facilities.

DROP-CRE Network  Currently recruiting an Advisory Committee  Committee to help guide Oregon’s strategy for CRE and

promote the Network  Ideally include representatives from:  Major hospital systems in Oregon  Infectious disease physicians  Infection Preventionists  Laboratorians

 Long Term Care Facility Representatives

DROP-CRE Network  Would like to have representatives from Bend and other

non-metro sites for DROP-CRE Advisory Committee  If interested please contact Zints Beldavs or Chris Pfeiffer at:  [email protected] (971-673-0166)  [email protected]

Which drug with Pseudomonas aeruginosa activity is most likely to result in resistance on therapy? 1) 2)

3) 4) 5)

Imipenem Ertapenem Zosyn Cipro Cefepine or ceftazidine

Which drug with Pseudomonas aeruginosa activity is most likely to result in resistance on therapy? 1) 2)

3) 4) 5)

Imipenem Ertapenem (no pseudomonal activity) Zosyn Cipro Cefepine or ceftazidine

Which Rx’s are most likely to be active for a CA-MRSA soft tissue infection? 1) 2) 3) 4) 5)

Cipro, Bactrim, linezolid Augmentin, Bactrim, linezolid Doxycycline, Bactrim, linezolid Clindamycin, Bactrim, linezolid Cefuroxime, Bactrim, linezolid

Which Rx’s are most likely to be active for a CA-MRSA soft tissue infection? 1) 2) 3) 4) 5)

Cipro, Bactrim, linezolid Augmentin, Bactrim, linezolid Doxycycline, Bactrim, linezolid Clindamycin, Bactrim, linezolid Cefuroxime, Bactrim, linezolid

Which is the oral drug of choice for a proven MSSA soft tissue infection? 1)

2) 3) 4)

5)

Amoxicillin Cephalexin Dicloxacillin Doxycycline Ciprofloxacin

Which is the oral drug of choice for a proven MSSA soft tissue infection? 1)

2) 3) 4)

5)

Amoxicillin Cephalexin Dicloxacillin Doxycycline Ciprofloxacin

BAD ANSWER

Cephalexin is Usually the Wrong Choice if S aureus is Possible Pathogen  Cmax = 10-15 microgm/ml  MIC90 = 16-64 m microgm/ml for S aurues

Never exceeds MIC, Let alone T> MIC of 40-50%

99

Which two drugs below are likely to have the least activity against S. pneumoniae? 1) 2) 3) 4) 5)

Amoxicillin Moxifloxacin Clindamycin Bactrim Azithromycin

Rank order the activity of the following drugs against S. pneumoniae? Moxifloxacin = amoxicillin > clindamycin > Bactrim>azithromycin

Erythromycin-resistant S. pneumoniae: U.S. 1992-2000 % S. pneumoniae strains

40

34.6

30

25.1

20

10

14.0 8.2

6.4

26.8

16.9

7.4

1.6

0 1992 1993 1994 1995 1996 1997 1998 1999 2000 N=125 N=185 N=147 N=81

N=79

N=124 N=1100 N=801 N=1037

Resistance defined as erythromycin MIC >1 µg/mL Data on file. Alexander Project 1992-2000. AXR0203-0206. GlaxoSmithKline.

Correlation Between Short-acting and Long-acting Macrolide Use and Rates of Resistance in Canadian Provinces Relative Percent of Macrolide Consumption 1995-2001 100

Clari+Ery

% Increase in Macrolide

Azithromycin

80

< 5% 60

10-12% 40

> 20% 20

0

BC

AB

SK

MB

ON

QC

Canadian Provinces

NB

NS

NF Davidson et al. ECCMID, 2003

Overuse of Azithromycin  Acute bronchitis

 Acute exacerbation of chronic bronchitis, as 1st choice  GABHS when not penicillin allergic  Skin/soft tissue infection when other options available

 Sinusitis as 1st or 2nd option  AOM as 1st or 2nd option

Take a handful of our complimentary antibiotics on your way out! New Yorker 1998

Stewardship Pitch for Hospital Administration  This is an intervention that, if done right, will:  Save money  Reduction in antibiotic costs  Reduction in LOS  Improve outcomes

 Increase provider satisfaction  Fulfill other missions  Patient safety  Regulatory compliance

Cost Data From Your Institution  Review the formulary  Are there redundant agents?  Could better deals be negotiated?

 Pick an expensive drug that is not a workhorse antibiotic  Linezolid, daptomycin, echinocandins, carbapenems,

aztreonam, tigecycline  Review use and estimate how much you could decrease use

Cost Data From Your Institution  Pick a clinical syndrome with evidence-based management

guidelines  Asymptomatic bacteriuria, surgical prophylaxis, CAP  Review current treatment and estimate how much you could

improve treatment by stopping therapy earlier  Estimate LOS decrease with earlier discharge  IV to PO switch  A popular cost-savings approach  Lots of IV quinolone use could be PO

Ways to Discuss Patient Safety with Hospital Administration  Evidence from other programs  Reduction C difficile infection  Improved antibiotic use  Improved dosing  Improved patient level outcomes Decreased ICU stay and decreased ICU emergence of resistance

 Focus on an active recent event  Antibiotic-warfarin drug-drug interaction, etc.

Pharmacy Benefits Management Services

IMPLEMENTATION OF AN AVOIDANCE OF DOUBLE ANAEROBIC COVERAGE INTERVENTION PBM-NIDS National Antimicrobial Stewardship Taskforce (ASTF) Webinar June 2012

Optimize Patient Safety: Decreased C. difficile • The Netherlands: restricted use of cephalosporins and a complete ban on fluoroquinolones plus infection control ended NAP1 outbreak • Canada: education about limiting use of targeted antibiotics (cephalosporins, ciprofloxacin, clindamycin, and macrolides) but not infection control ended NAP1 outbreak Debast SB et al. Clin Microbiol Infect. 2009;15:427 Valiquette et al. Clin Infect Dis 2007;45:S112-21.

Stewardship Programs: Core Elements

Primary Approaches Approach Definition Eliminate Formulary management unnecessary

duplication of agents

Pros

Cons

•Control over how and why antibiotics are used •Better pricing

Impact on good use of antibiotics likely minimal

Phone call placed •Reduces starting •Impacts use of Prerestricted agents only prescription or form filled out unnecessary before pharmacy antibiotics •Addresses empiric use approval dispenses antibiotic

•Useful way to deal with high cost antibiotics

>> downstream use •Resource intensive in real time

Primary Approaches Approach

Definition

Pros

Cons

Postprescriptio n review

Downstream review of appropriateness of antibiotic therapy, usually at 24-72 hours

•More clinical data available to enhance uptake of recommendations •Greater flexibility in timing of interventions

Recommended action is optional and may not be followed by prescribers

Examples • Formulary management – Pick one antibiotic in class

• Pre-prescription review – Restrict expensive agents such as daptomycin, linezolid, carbapenems, echinocandins

• Post-prescription review – Focus on use of an expensive drug (see above) or commonly used agent like vancomycin – Focus on a disease state such as bacteremia, asymptomatic bacteriuria, CAP – Focus on IV to PO conversion

Other Examples for ASP 1. Developed evidence based guidelines and implemented them – Automatic IV-PO – CAP, VAP guidelines – C. diff guidelines – Surgical prophylaxis – Vancomycin targeting – Narrowing and windowing redundant coverage – Emphasize safety – Extended interval antibiotics

REMEMBER  ANTIBIOTIC STEWARDSHIP IS EVERYONE’S

RESPONSIBILITY!  Should not just be a fad  Should build on standard guidelines  Should not have to require enforcement or

regulation!

Conclusions Antimicrobial Stewardship: 1. Has been shown to be feasible in several healthcare settings 2. Is highly justifiable economically 3. Must become a critical component of healthcare in all settings in the 21st century

DROP-CRE Network (Drug Resistant Organism Prevention and Coordinated Regional Epidemiology Network)

 Primary Objective: establish the statewide coordination of

prevention and control of multidrug-resistant organisms (MDROs) with an initial focus on carbapenem-resistant Enterobacteriaciae (CRE).  Statewide effort including OHA/PVAMC/OHSU/OSU/CDC

DROP-CRE Network: Advisory Committee Expectations  Consultation meeting in Jan 2013 to review draft

guidelines for coordinated management of CRE (in person or teleconference)  Availability by phone/email to provide additional comments on final draft  Depending on availability of continued funding, future meetings to revise guidelines or add more MDROs

Oregon Survey of ASP in Hospitals

Duration for VAP Randomized trial comparing 8 days vs. 15 days (antibiotic selection per treating physician)

Percent

All p-values NS

Patients with non-fermenting GNR had a higher rate of recurrence with 8 days (40.6% vs. 25.4%; 90%CI 3.9%-26.6%)

Patients with recurrence developed MDRO less with 8 days (42.1% vs. 62.0%, p=0.04)

JAMA 2003; 290:2588-2598

Acute Cystitis Guidelines

Antibiotic Duration

Level of Evidence

Nitrofurantoin bid

5 days

A-I

TMP-sulfa DS bid (if resistance rates < 20%)

3 days

A-I

Fosfomycin

1 dose

A-I

Flouroquinolones -- reserved for more important uses

3 days

A-I A-III

3-7 days

B-I

Recommendation

β-lactams

CID 2011; 52(5):e103-e120

Asymptomatic Bacteriuria Guidelines Recommendation

Level of Evidence

Screening/Treatment not recommended

A-I

Pyuria without symptoms not an indication for treatment

A-II

Do not screen/treat Premenopausal/non-pregnant women

A-I

Diabetic women

A-I

Elderly, institutionalized

A-I

Elderly, community

A-II

Persons with SCI

A-II

Catheterized patient with retained catheter

A-I

Renal transplant patients

CID 2005; 40:643-654

Asymptomatic Bacteriuria Guidelines Who to screen/treat? Recommendation

Antibiotic Duration

Pregnant woman

Level of Evidence A-I

Treat

3-7 days

Prior to transurethral prostate resection

A-II A-I

Initiate treatment shortly before

A-II

Discontinue after unless catheter remains

B-II

Other urologic procedure with potential mucosal bleeding

A-III

Bacteriuric men develop bacteremia: 25% post-cystoscopy 80% post-open prostatectomy 10-16% post-procedure bacteremia develop sepsis CID 2005; 40:643-654 Can J Infect Dis Med Microbiol 2005; 16:349-360

Duration in women with UTI

Percent

Randomized trial compared 3 days vs. 7 days of cipro 250mg po bid

Symptomatic Improvement

CMAJ 2004; 170:469-473

Acute Pyelonephritis Guidelines

Antibiotic Duration

Level of Evidence

Oral cipro 500mg bid

7 days

A-I

Oral cipro 1gm qd

7 days

B-II

Oral levo 750 mg qd

5 days

B-II

14 days

A-I

Recommendation Non-hospitalized and FQ resistance