National Center for Emerging and Zoonotic Infectious Diseases

An Update on National Antibiotic Stewardship Activities CAPT Arjun Srinivasan, MD beu8@cdc.gov

Antibiotics Are Different From All Other Drugs

Antibiotics lose their effectiveness over time- even if we use them perfectly.

Every specialty (almost) uses them on a regular basis.

They are a shared resource- the use of antibiotics for in one patient can

compromise how they work for someone else through the spread of

resistance or lead to complications for someone else through spread of C.

difficile.

Consequences of Any Antibiotic Exposure

Selective pressure for antibiotic resistance.Increased risk of candidemia.

Increased risk for C. difficile infection

– 7-10 fold increased risk for up to 3 months

Adverse drug reactions

Disruption of normal gut bacteria.

– Which could increase the risk of sepsis.

Increased Risk of Sepsis After Antibiotic Exposure

Disruption of the gut microbiome increases the risk of sepsis in animal models.

Retrospective study of ~9 million patients discharged without sepsis in 473 US hospitals.

0.6% were readmitted with sepsis in 90 days.

Exposure to broad spectrum antibiotics during hospitalization was independently associated with risk of sepsis:

– OR=1.50 95% CI:1.47-1.53

Baggs, J. et al. Clin Infect Dis 2017

It’s a Matter of Patient Safety—it is more than just about antibiotic resistance

What if something bad happens without an antibiotic? What is the number needed to treat?

– Complications to common respiratory infections are very rare

– Over 4400 patients with colds need to be treated to prevent 1 case of pneumonia

What if something bad happens with an antibiotic? What is the number needed to harm?

– Antibiotic adverse events can be severe

• Life-threatening allergic reactions (e.g., anaphylaxis)

• Antibiotic-associated diarrhea (e.g., C. difficile infection)

• 1 in 1000 antibiotic prescriptions leads to an ER visit for an adverse event (~200,000 estimated ER visits/year in U.S.)

– Antibiotic adverse events have long-term consequences for chronic disease: disruption of microbiota and microbiome linked to chronic disease

Petersen et al. British Medical Journal. 2007;335(7627): 982. Shehab, et al. Clin Infect Dis. 2008 Sep 15;47(6):735-43. 3. Shehab et al. JAMA 2016:316:2115-25. 4. Bourgeois, et al. Pediatrics. 2009;124(4):e744-50. 5. Vangay, et al. Cell host & microbe 2015; 17(5): 553-564.

Adverse Events from Hospital Antibiotics • In a review of 1488 hospitalized patients given antibiotics.

• 20% of patients experienced at least 1 antibiotic-associated adverse event.

– 4% of all patients got C. difficile, 6% got an MDRO infection

• 20% of non-indicated antibiotic regiments were associated with an adverse

event, including 7 cases of C. difficile.

• Every 10 days of antibiotics was associated with a 3% increased risk of an

adverse event.

• Most common in 1st 30 days:

– GI (diarrhea, nausea, vomiting): 42%

– Renal (>1.5 times rise in creatinine): 24%

– Hematologic (anemia, leukopenia, thrombocytopenia): 15%

Tamma et al. JAMA Intern Med, 2017

Adverse Events from Hospital Antibiotics

97% of antibiotic adverse events resulted in additional testing and/or additional medical care (prolonged or new hospitalization or clinic and/or ED visit).

Community Antibiotic Prescribing Rates per 1000 Population — United States, 2014

prescriptions_per_k 501 - 648 692 - 744 768 - 852853 - 925 927 - 1,000 1,021 - 1,285

AL

AK

AZAR

CA CO

CT

DE

DC

FL

GA

HI

ID

IL IN

IA

KSKY

LA

ME

MD

MA

MI

MN

MS

MO

MT

NENV

NH

NJ

NM

NY

NC

ND

OH

OK

OR

PA

RI

SC

SD

TN

TX

UT

VT

VA

WA

WV

WI

WY

Data: IMS Health Xponent http://www.cdc.gov/getsmart/community/programs-measurement/measuring-antibiotic-prescribing.html

Lowest state: 501 per 1000

Highest state: 1,285 per 1000

55.1% of patients got at least 1 dose.

Overall use was 755 DOT/1000 patient days

Use did not vary by bed size.

Non-teaching hospitals had higher use than teaching.

Use of many classes went up:

Vancomycin (32%), beta-lactam/inhibitor (26%), 3rd/4th generation cephalosporins (12%)

Biggest increase in carbapenem use: 37%.

47 million unnecessary antibiotic prescriptions per year

Most Common Reasons for Unnecessary Days of Therapy

192 187

94

0

50

100

150

200

250

Duration of Therapy

Longer than Necessary

Noninfectious or

Nonbacterial Syndrome

Treatment of Colonization

or Contamination

Da

ys

of

Th

era

py

576 (30%) of 1941 days of antimicrobial therapy deemed unnecessary

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

Antibiotic Stewardship and Decreased Risk of Resistant Infections

Cipro Standard

Antibiotic

duration

3 days 10 days

LOS ICU 9 days 15 days

Antibiotic

resistance/

superinfection

14% 38%

Study terminated early because attending physicians began to treat standard care group with 3 days of therapy

Singh N et al. Am J Respir Crit Care Med. 2000;162:505-11.

Impact of Reductions in Antibiotic Prescribing on C. difficile in England

0

10000

20000

30000

40000

50000

60000

0

1,000,000

2,000,000

3,000,000

4,000,000

5,000,000

6,000,000

7,000,000

2004 2005 2006 2007 2008 2009 2010 2011

Cephalosporin doses Fluoroquinolone dosesC. difficile in > 65 y.o.

70% reduction in C.

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Ashiru-Oredope et al. J Antimicrob Chemother 2012; 67 Suppl 1: i51–i63

Wilcox MH et al. Clinical Infectious Diseases 2012;55(8):1056–63

http://www.hpa.org.uk/web/HPAweb&Page&HPAwebAutoListName/Page/1179745282388

Clinical outcomes better with antimicrobial stewardship program

0

20

40

60

80

100

Appropriate Cure Failure

AMP

UP

RR 2.8 (2.1-3.8) RR 1.7 (1.3-2.1) RR 0.2 (0.1-0.4)

Pe

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AMP = Antibiotic Management Program UP = Usual Practice Fishman N. Am J Med. 2006;119:S53.

The Goal

Every patient gets:

An antibiotic only when one is needed

The right agent

At the right dose

For the right duration

Major Policy Developments for Antibiotic Stewardship: No Longer “Whether” but “How”

The US has set a national goal for all hospitals to have stewardship programs by 2020.

CMS issued a final rule requiring nursing homes to have antibiotic stewardship programs.

CMS issued a proposed rule requiring hospitals to have antibiotic stewardship programs.

The Joint Commission issued a standard requiring all accredited hospitals to have stewardship programs

– Enforcement began in January of 2017.

CDC’s Core Elements of Antibiotic Stewardship for Hospitals, Nursing Homes, and Outpatient Settings

0

500

1,000

1,500

2,000

2,500

3,000

3,500

4,000

4,500

5,000

2014 2015 2016

n=4,184 n=4,569 n=4,781

Meeting all 7 Not meeting all 7

Number of facilities responding to NHSN Annual Hospital Surveys 2014-2016: Number and percentage meeting all 7 Core Elements

48.1% 64.1%

40.9%

Measuring For Improvement- Antibiotic Use

Broad (ideally national) assessments of aggregate use.

Facility, practice and provider specific assessments of antibiotic administration data

Assessments of appropriate antibiotic use.

National Healthcare Safety Network Antibiotic Use Option

Captures electronic data on antibiotics administered, along with admission/discharge/transfer data.

Calculates rates of administration for use: – By facilities to monitor interventions on single units or facility wide

– To collect aggregate information on antibiotic use at a regional and national level

– Eventually, to create antibiotic use benchmarks.

Standardized Antibiotic Administration Ratio (SAAR)

CDC’s 1st attempt at developing a risk-adjusted benchmarking measure for hospital antibiotic use.

SAAR expresses observed antibiotic use compared to predicted use. – Expected use is modeled based on hospital characteristics.

CDC working with many partners to develop the SAAR measure to try and make it most useful for stewardship.

There are challenges with a quality measure that is not all or nothing.

Measuring Appropriate Use

We all agree that the ultimate goal of stewardship is to improve appropriate use of antibiotics.

It will be hard to measure progress towards that goal if we don’t have measures of appropriate use.

National data from outpatient clinics with diagnoses and medications prescribed.

12.6% of all outpatient visits resulted in an antibiotic prescription.

About 30% of all visits that resulted in an antibiotic prescription had no diagnosis that would justify an antibiotic.

– “Viral upper respiratory tract infections” prescribed antibiotics in 26% of cases.

JAMA. 2016;315(17):1864-1873

Assessing Appropriate Use in Hospitals

Is trickier.

Simply looking at discharge diagnosis does not usually help assess if antibiotic use was appropriate.

Most inappropriate use in hospitals occurs in patients who are either mis-diagnosed with an infection or who have an infection, but are treated incorrectly.

That is labor intensive to assess and has not been done nationally.

Assessment of Vancomycin Use in 36 Hospitals

Patients treated with intravenous vancomycin 185 —

No diagnostic culture obtained around antibiotic initiation, although standard practice with most infections

17 (9.2)

Diagnostic culture showed no Gram-positive bacterial growth, but patient still treated for long duration (>3 days) (excludes presumed SSTI, which often can be culture negative)

40 (21.6)

Diagnostic culture grew only oxacillin-susceptible Staphylococcus aureus, but patient still treated for long duration (>3 days) (likely missed opportunity to switch antibiotic based on culture result)

9 (4.9)

No. of patients with potential for improvement in prescribing

66 (35.7)

MMWR March 7, 2014 / 63(09);194-200

Advancing Assessments of Appropriate Use in Hospitals

Exploring ways to use electronic health information to assess appropriate antibiotic use. – Vancomycin assessment could probably be automated pretty easily.

Could we do this for others agents or infections? – Unnecessary duplicate antibiotic therapy

– Overly long durations of therapy

– Bug-drug mismatch

But Programs and Core Elements Won’t Solve the Problem

Ultimately, improving antibiotic use comes down to implementing interventions that will improve prescribing.

The goal of a stewardship program is to create an environment where improvement interventions will be most successful.

Key Moments for Antibiotic Stewardship- Hospitals

Patients with C. difficile

Patients with positive blood cultures

Patients being given IV antibiotics at discharge

Patients on unnecessarily duplicative therapy.

Patients being treated for: – Community acquired pneumonia (CAP)

– Urinary tract infection (UTI)

– Skin and soft tissue infections

Patients who have gotten 3 days of therapy.

Stewardship After Day Three

Audit and Feedback to Reduce Broad Spectrum Antibiotic Use in an ICU.

Gave providers feedback on antibiotics on days 3 and 10 of antibiotics.

Mean monthly antibiotic use decreased from 644 DOT/1000 pt days to 503 (P<0.001).

C. difficile decreased (11 cases to 4)

Meropenem susceptibility increased.

ICHE 2012;33:354

Targeting Specific Infections

In a 2011 survey in ~180 hospitals, CDC and state collaborators reviewed charts of patients who got antibiotics to determine the reason for use: – Lower respiratory tract infections: 34.6%

– Urinary tract infections: 22.3%

– Skin and soft tissue infections: 16.1%

Total for these three: 73%!

JAMA. 2014;312(14):1438-1446

Therapy for Skin and Soft Tissue Infections (SSTI)

Facility implemented a SSTI diagnosis and treatment guideline.

Intervention resulted in:

–3 day reduction in antibiotic treatment (13 v 10d)

– Less use of agents with gram negative and anaerobic activity

–Better use of diagnostic studies and consults

Jenkins TC Arch Intern Med 2011;171(12):1072-1079.

Many Patients Diagnosed with Community Acquired Pneumonia Don’t Have It

106 patients met criteria for CAP per

ED CAP pathway

103 patients had CAP diagnosis by

ED physician

76 patients had CAP diagnosis by

treating team

68 patients had CAP diagnosis by

external adjudication

Sara Cosgrove, Johns Hopkins Hospital

Duration of Therapy for CAP

Guidelines recommend that most patients should get 5-7 days of antibiotics for CAP.

Average duration of treatment is 10 days – No difference between immune competent and suppressed patients.

Simple, prospective intervention for patients being treated for CAP.

Treatment duration reduced from 10 d to 7 d (p<0.001) with 148 fewer antibiotic days.

CID 2012;54:1581-7

Asymptomatic Bacteriuria (ASB) Too Often Treated Like Infection

Study Patient Population Lack of Adherence to

Guidelines

Dalen,

2005

Catheter associated ASB

n=29

52% prescribed

antibiotics

Gandhi,

2009

Patients with UTI diagnosed

n=49

32.6% did not meet

criteria for UTI

Cope,

2009

Catheter associated ASB

n=169

32% prescribed

antibiotics

Spivak,

2017

Patients with bacteruria

n=2225

72% of patients with ASB

got antibiotics

Dalen DM et al. Can J Infect Dis Med Microbiol. 2005;16:166. Gandhi T et al. Infect Control Hosp Epidemiol. 2009;30:193.

Cope M et al. Clin Infect Dis. 2009;48:1182. Spivak ES et al. Clin Infect Dis, 2017;65:910

“Kicking CAUTI”

Developed a simple algorithm to guide sending of urine cultures.

Overtreatment of ASB during intervention fell:

From 1.6 to 0.6 per 1000 bed-days; (IRR, 0.35; 95% CI, 0.22-0.55)

Reductions persisted during the maintenance period: 0.4 per 1000 bed-days; (IRR, 0.24; 95% CI, 0.13-0.42)

P < .001 for both

JAMA Intern Med. 2015 Jul;175(7):1120-7.

Clinicians Face Unique Challenges Related to Antibiotic Prescribing in Nursing Homes.1

Older adults may not express the classic signs and symptoms of infection

Availability of diagnostic tests

The decision to initiate antibiotics is frequently made offsite and influenced by family preferences and nursing staff communication

– Many antibiotic prescriptions (66% in one study2) are started by telephone orders without a physician examination

Documentation of the assessment and the decision making process is sometimes limited

– Key prescribing information was not documented for 38% of antibiotic

courses administered3

1. Crnich et al. Drugs Aging. 2015 Sep;32(9):699-716. 2. Richards et al, J Am Med Dir Assoc. 2005 Mar-Apr;6(2):109-12. 3. Thompson et al. J Am Med Dir Assoc. 2016 Dec 1;17(12):1151-1153.

Opportunity for Improvement: Testing and Treatment for Suspected Urinary Tract Infections in Nursing Homes.

Asymptomatic bacteriuria is common in NH residents.1,2

– Urine cultures are positive for bacteria in 25-50% of women and 15-35% of men in NHs.3

Up to 1/2 of antibiotics prescribed to treat UTI in older adults are unnecessary or inappropriate.4-7

– Foul-smelling or cloudy urine frequently leads to unnecessary urine testing and treatment.6

Overtesting leads to overdiagnosis of UTI, treatment of asymptomatic bacteriuria, risk for adverse drug events (ADE)and delays in diagnosis.8

1. Nicolle et al. Int J Antimicrob Agents. 2006 Aug;28 Suppl 1:S42-8.

2. Nicolle et al. Infect Control Hosp Epidemiol. 2001 Mar;22(3):167-75.

3. Nicolle et al, Clin Infect Dis. 2005;40(5):643-654.

4. Crnich et al, J Am Geriatr Soc. 2017 Aug;65(8):1661-1663.

5. Trautner. Nat Rev Urol. 2012;9(2):85-93.

6. Nicolle et al, Infect Dis Clin North Am. 1997; 11(3):647-662.

7. Eure et al, Infect Control Hosp Epidemiol 2017 Aug;38(8):998-1001.

8. Wald. JAMA Intern Med. 2016 May 1;176(5):587-8.

Drug Expertise: Support for Antibiotic Stewardship Implementation.

Establishing access to individuals with antibiotic expertise:

– Engage consultant pharmacists

• Incorporate monitoring of antibiotic use during monthly medication regimen review

• Provide antibiotic use reports

– Partner with antibiotic stewardship leads in referring hospitals in the same network

• Mutually beneficial given transfers of patients with MDROs and C. difficile and desire to reduce readmissions.

– Develop partnerships with infectious disease consultants in the community who are interested in supporting antibiotic stewardship efforts in NHs

Action: Implementing Practices that Improve Testing and Treatment for Suspected Urinary Tract Infections.

Implementing protocols for appropriate urine testing can help avoid diagnosing and treating asymptomatic bacteriuria

– 17 MA LTC facilities implemented tools promoting urine testing based on specific evaluation and indications • Urine cultures decreased by 1/4, UTI diagnosis decreased by 1/3 and CDI decreased by ~1/2

Treating residents with clear signs and symptoms of a UTI

– Multifaceted intervention focused on a diagnostic and treatment algorithm for UTI implemented in 12 NH in Canada led to fewer courses of antibiotics for UTI without increase in mortality or hospital admission • 1.17 v 1.59 courses; weighted mean difference -0.49, 95% confidence intervals -0.93 to -0.06

1. Doron et al, Abstract presented at ID week 2014 https://idsa.confex.com/idsa/2014/webprogram/Paper46381.html. 2. Loeb et al, BMJ 2005;331(7518):669

Action: Implementing Practices that Improve Communication: Communicating with Offsite Providers.

Assess residents for any infection using standardized tools and criteria

– Standardized assessment and communication tools will ensure that important clinical information is: • Collected when there is a change in the resident’s clinical condition or when an infection is

suspected

• Documented in the medical chart

• Communicated with the offsite provider

– One example is the SBAR (Situation, Background, Assessment input and Request)1

• A quasi-experimental trial assessing a quality improvement program that

included tools to improve nurse-provider communication was conducted.

– The number of antibiotic prescriptions decreased significantly (adjusted incidence rate ratio = 0.86, 95% confidence interval = 0.79-0.95).2

1. https://www.ahrq.gov/sites/default/files/wysiwyg/nhguide/4_TK1_T1-SBAR_UTI_Final.pdf 2. Shrestha et al. Infect Control Hosp Epidemiol. 2012 Apr;33(4):401-4

Action: Implementing Practices that Improve Communication: Communicating with Emergency Departments and Acute Care Hospitals.

1. Griffiths et al, Int J Nurs Stud. 2014 Nov;51(11):1517-23. 2. Dalawari et al, Geriatr Nurs. 2011 Jul-Aug;32(4):270-5. 3. Terrell et al, Acad Emerg Med. 2005 Feb;12(2):114-8. 4. https://www.cdc.gov/hai/pdfs/toolkits/InfectionControlTransferFormExample1.pdf

There are critical gaps in communication between nursing homes, emergency departments1, and acute care hospitals

– Antibiotic stewardship at hospital discharge is important

Standardized transfer forms can improve the communication of important information related to resident care when residents are transferred to other healthcare settings.2-4

Percent of U.S. Nursing Homes Reporting Implementation of All CDC Core Elements on 2016 Annual NHSN Survey*

0 1 3

5

9

15

24

42

0

5

10

15

20

25

30

35

40

45

0 1 2 3 4 5 6 7

Pe

rce

nt

Number of Core Elements Fulfilled

*Preliminary results courtesy of Danielle Palms, adapted from presentation at SHEA Spring Conference 2017; St. Louis, MO. Abstract 9026 Please do not reproduce without permission

Outpatient Prescribing Quality in the United States

47 million unnecessary antibiotic prescriptions

per year

“Prescribing of first-line antibiotics ranged from a low of 37% (95% CI, 32%-43%) for adult patients with sinusitis and pharyngitis to a high of 67% (95% CI, 63%-71%) for pediatric patients with otitis media. For all 3 conditions overall, use of first-line agents was 52% (95% CI, 49%-55%).” JAMA Intern Med. 2016;176(12):1870-1872

For adults with sinusitis: “The median duration of therapy was 10.0 days (interquartile range, 7.0-10.0 days), and 69.6% (95% CI, 63.7%-75.4%) of therapies were prescribed for 10 days or longer.” JAMA Intern Med. Published online March 26, 2018

Have We Made Progress in Reducing Inappropriate Antibiotic Use?

Outpatient antibiotic prescribing rates to children decreased by 13%

Outpatient antibiotic prescribing rates to adults have been stable

IQVIA pharmacy dispensing data

gis.cdc.gov/grasp/PSA/indexAU.html

Outpatient Stewardship Implementation

CMS Quality Innovation Network and Quality Improvement Organizations (QIN-QIOs) helping outpatient facilities to implement CDC’s Core Elements.

– ~7000 outpatient practices are participating

– CDC hosting educational webinars to support effective implementation.

CDC funding University of Utah to implement and evaluate CDC’s Core Elements of Outpatient Antibiotic Stewardship

Outpatient Stewardship Implementation

CMS Merit-Based Incentive Payment System–

– Several antibiotic use measures are included as options for clinical performance improvement activities (e.g. three current HEDIS measures- pharyngitis testing, avoiding antibiotics for bronchitis and URI).

– CDC developed an online antibiotic stewardship training course which CMS will provide to clinicians meet improvement activity requirement.

– Now available on CDC training website.

CDC working with National Committee for Quality Assurance to expand antibiotic use HEDIS (Healthcare Effectiveness Data and Information Set) quality measures

Public commitment posters: inappropriate prescribing for acute respiratory infections

Adjusted absolute reduction: -20% compared to controls, p=0.02

Meeker. JAMA Intern Med. 2014;174(3):425-31.

Peer Comparison to Top Performers “You are a Top Performer:

You are in the top 10% of clinicians. You wrote 0 prescriptions out of 21 acute respiratory infection cases that did not warrant antibiotics. ”

“You are not a Top Performer: Your inappropriate antibiotic prescribing rate is 15%. Top performers' rate is 0%. You wrote 3 prescriptions out of 20 acute respiratory infection cases that did not warrant antibiotics.”

Mean antibiotic prescribing for antibiotic-inappropriate diagnoses decreased from 19.9% to 3.7% (-16.3%)

– Statistically significant versus controls

Slide courtesy of Jeff Linder Meeker, Linder, et al. JAMA 2016;315(6): 562-570.

Be Antibiotics Aware www.cdc.gov/antibiotic-use

A new educational effort to improve antibiotic prescribing and use.

CDC launched Be Antibiotics Aware during U.S. Antibiotic Awareness Week in November 2017.

This initiative emphasizes the following key points:

• Antibiotics are critical tools for treating a number of infections and for life-threatening conditions, such as sepsis.

• Antibiotics only treat bacterial infections – not viral illnesses like colds and flu.

• Prescribe or take antibiotics only when necessary – prescribe or take the right drug, dose and duration.

• When antibiotics are not needed, they won’t help you – and the side effects could still hurt you.

Materials & Resources www.cdc.gov/antibiotic-use

Use and display in doctor’s offices (e.g., lobby, waiting room), pharmacies and other health and public settings

We’ve designed a variety of Be Antibiotics Aware resources that appeal to patients, parents and the public:

• Web buttons and badges; animated videos and GIF images

• “The Right Tool” public service announcements in print, video and radio

• Brochures, fact sheets, infographics and posters

• Content for social media, newsletters and press releases

• To view the online toolkit and download materials, visit https://spark.adobe.com/page/pd0u80TFAsq6G.

Be Antibiotics Aware is an ongoing educational effort – so stay tuned for new and exciting additions throughout 2018!

There is a misperception that efforts to improve sepsis care and stewardship are in conflict.

They should be complimentary.

Getting patients with suspected sepsis on the right antibiotic quickly is good stewardship.

Working with the stewardship team to determine how to optimize early identification of potentially septic patients and what the best antibiotics are is good sepsis care.

Stewardship Education Resources- FREE CME!

– CDC Training on Antibiotic Stewardship, up to 8 hours of free CE, 4 section throughout 2018. Open to all clinicians, pharmacists, physician assistants, nurses, certified health educators, and public health practitioners with an MPH.

• https://www.train.org/cdctrain/course/1075730

Here in New Hampshire

There is a lot going on to:

– Improve the collection and dissemination of antibiotic use and resistance data for action.

– Assess and improve stewardship practices and programs across the spectrum of healthcare.

– You are about to hear a lot more about all of it!

– I’m impressed by the collaboration and cooperation to get this done- NH is better together!

Conclusion

There has never been a more important, or better, time to improve antibiotic use.

There is some momentum here- how can we build on in it?

We need to focus on finding practices, measures and interventions that will have the most impact.

Please share your ideas and let us know how we can help!