An Update on National Antibiotic Stewardship Activities

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 1 st 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 WA Lowest state: 501 per 1000 OR NV CA AK MT ID WY UT CO AZ NM HI ND SD NE KS OK TX MN WI IA IL MO AR MS LA NY MI PA OH IN WV VA KY NC TN SC AL GA FL ME VT NH MA RI CT NJ DE MD DC Highest state: 1,285 per 1000 prescriptions_per_k 501-648 692-744 768-852 853-925 927-1,000 1,021-1,285 Data: IMS Health Xponent http://www.cdc.gov/getsmart/community/programs-measurement/measuring-antibiotic-prescribing.html

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

Days of Therapy Most Common Reasons for Unnecessary Days of Therapy 576 (30%) of 1941 days of antimicrobial therapy deemed unnecessary 250 200 192 187 150 100 94 50 0 Duration of Therapy Longer than Necessary Noninfectious or Nonbacterial Syndrome Treatment of Colonization or Contamination Hecker MT et al. Arch Intern Med. 2003;163:972-978.

Antibiotic Stewardship and Decreased Risk of Resistant Infections Cipro Standard Antibiotic duration LOS ICU 3 days 10 days 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.

Defined daily doses in hospital inpatients Number of all (HA+CA) CDI cases in >65 yo Impact of Reductions in Antibiotic Prescribing on C. difficile in England 7,000,000 Cephalosporin doses C. difficile in > 65 y.o. Fluoroquinolone doses 60000 6,000,000 50000 5,000,000 4,000,000 3,000,000 2,000,000 1,000,000 70% reduction in C. 40000 30000 20000 10000 0 2004 2005 2006 2007 2008 2009 2010 2011 0 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

Percent Clinical outcomes better with antimicrobial stewardship program 100 80 60 40 20 0 AMP UP Appropriate Cure Failure RR 2.8 (2.1-3.8) RR 1.7 (1.3-2.1) RR 0.2 (0.1-0.4) Fishman N. Am J Med. 2006;119:S53. AMP = Antibiotic Management Program UP = Usual Practice

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

Number of facilities responding to NHSN Annual Hospital Surveys 2014-2016: Number and percentage meeting all 7 Core Elements 5,000 4,500 4,000 3,500 3,000 2,500 2,000 1,500 1,000 500 0 40.9% Meeting all 7 Not meeting all 7 48.1% 64.1% 2014 2015 2016 n=4,184 n=4,569 n=4,781

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 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) 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) No. of patients with potential for improvement in prescribing 17 (9.2) 40 (21.6) 9 (4.9) 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 Gandhi, 2009 Cope, 2009 Spivak, 2017 Catheter associated ASB n=29 Patients with UTI diagnosed n=49 Catheter associated ASB n=169 Patients with bacteruria n=2225 52% prescribed antibiotics 32.6% did not meet criteria for UTI 32% prescribed antibiotics 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 study 2 ) 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 administered 3 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. There are critical gaps in communication between nursing homes, emergency departments 1, 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 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

Percent Percent of U.S. Nursing Homes Reporting Implementation of All CDC Core Elements on 2016 Annual NHSN Survey* 45 40 35 30 25 20 15 10 5 0 42 24 15 9 5 3 0 1 0 1 2 3 4 5 6 7 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 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 47 million unnecessary antibiotic prescriptions per year 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 measurespharyngitis 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 Meeker, Linder, et al. JAMA 2016;315(6): 562-570. Slide courtesy of Jeff Linder

Be Antibiotics Aware A new educational effort to improve antibiotic prescribing and use. www.cdc.gov/antibiotic-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 Use and display in doctor s offices (e.g., lobby, waiting room), pharmacies and other health and public settings www.cdc.gov/antibiotic-use 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!