Dr. Theoklis Zaoutis - Antimicrobial Use and Stewardship in the Pediatric Outpatient Setting
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Antimicrobial Use and Stewardship in the Pediatric Outpatient Setting - Dr. Theoklis Zaoutis, Chief, Division of Infectious Diseases, Professor of Pediatrics and Epidemiology of the University of Pennsylvania, from the 2014 NIAA Symposium on Antibiotics Use and Resistance: Moving Forward Through Shared Stewardship, November 12-14, 2014, Atlanta, Georgia, USA. More presentations at http://www.swinecast.com/2014-niaa-antibiotics-moving-forward-through-shared-stewardship
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Dr. Theoklis Zaoutis - Antimicrobial Use and Stewardship in the Pediatric Outpatient Setting
- 1. Antimicrobial Use and Stewardship in the Pediatric Outpatient Setting Theoklis Zaoutis, MD, MSCE Frederick McNair Scott Professor of Pediatrics University of Pennsylvania School of Medicine Chief, Division of Infectious Diseases The Children’s Hospital of Philadelphia NIAA Antibiotic Symposium 2014
- 2. Overview • Definitions and Scope of Problem • Antibiotic Use in Outpatient Pediatrics • Antibiotic Stewardship • Antibiotics and the Microbiome
- 3. Definition Commitment to always use antibiotics appropriately and safely-only when they are needed to treat disease, and to chose the right antibiotics and to administer them in the right way in every case = antibiotic stewardship
- 4. Framing the Issue • Although antibiotics have saved countless lives, their use is not benign • Antibiotic resistance is occurring in populations and individual patients • At least 5% of hospitalized patients experience an adverse reaction – Rash, nephrotoxicity, C. difficile infection • 50% are prescribed for people who do not need them or are not prescribed appropriately • Very few antibiotics are being developed
- 5. Antibiotic Resistance • CDC described antibiotic resistance as "one of the world's most pressing health problems” • WHO has identified antibiotic resistance as "one of the three greatest threats to human health.”
- 6. Impact of Antibiotic Resistance • Patients with resistant infections are at higher risk for disability and death • $20 billion in excess direct healthcare costs with additional costs to society of $35 billion • Loss of effective antibiotics • Increased number of immunosuppressed patients • Drug development is not sufficient to deal with this threat
- 9. Pediatric Antibiotic Use in the Community
- 10. Top 1 through 6 drug markets according to the total estimated number of outpatient prescriptions dispensed to the US pediatric population (ages 0–17 years) from US retail pharmacies, 2002 through 2010. *Statistically significant linear trend at P value = .05. Chai G et al. Pediatrics 2012;130:23-31 ©2012 by American Academy of Pediatrics
- 11. Antibiotic Prescribing in Ambulatory Pediatrics in US • Nationally representative sample • National ambulatory Medical Care Survey – 2006-2008 • Antibiotics prescribed during 21% pediatric ambulatory visits • 50% were broad-spectrum, mostly macrolides • Respiratory infections accounted for 70% of use Hersh AL, et al. Pediatrics 2011
- 12. Frequency of narrow- and broad-spectrum antibiotic use according to class for all pediatric ambulatory visits, 2006–2008. Hersh A L et al. Pediatrics 2011;128:1053-1061 ©2011 by American Academy of Pediatrics
- 13. Antibiotic-Prescribing Patterns Condition Estimated Annual No. of visits for Condition, Millions N. Of visits Antibiotics were prescribed, Millions (%) No. of Visits Broad Spectrum Antibiotics were prescribed, Millions (% of antibiotics that were broad-spectrum) Respiratory •ARTIs for which antibiotics are indicated •ARTIs for which antibiotics are not indicated •Other respiratory conditions for which antibiotics are not definitely indicated 65.6 29.9 19.5 16.2 31.7 (48.4) 21.5 (71.7) 2.8 (29.6) 4.5 (27.8) 16.9 (53.1) 10.3 (48.0) 3.6 (62.5) 2.9 (64.5) Other •Skin/cutaneous/mucosal •Urinary tract infections •Gastrointestinal infections •Miscellaneous infections •Other 158.6 28.2 1.4 2.3 8.7 117.9 12.2 (7.7) 5.2 (18.6) 0.9 (59.3) 0.1 (5.7) 0.8 (9.6) 5.1 (4.3) 5.1 (41.9) 2.1 (37.8) 0.3 (39.3) 0.1 (54.1) 0.2 (29.0) 2.5 (48.3) Total 224.2 5.2 (18.6) 22.0 (50.1) Hersh A L et al. Pediatrics 2011;128:1053-1061
- 14. Rates of antibiotic dispensing per person-year of enrollment for children aged as follows: A, 3 to 24 months; B, 2 to <4 years; C, 4 to <6 years; D, 6 to <12 years; and E, 12 to <18 years. Vaz L E et al. Pediatrics 2014;133:375-385 ©2014 by American Academy of Pediatrics
- 15. Distribution of antibiotic classes among health plans, 2000–2001 and 2009–2010, for children aged as follows: A, 3 to <24 months; B, 2 to <4 years; C, 4 to <6 years; D, 6 to <12 years; and E, 12 to <18 years. Vaz L E et al. Pediatrics 2014;133:375-385 ©2014 by American Academy of Pediatrics
- 16. Variability in Pediatric Antibiotic Use in the Community
- 17. Total outpatient antibacterial use in the United States and 27 European countries in 2004 (total use for Greece, Iceland, and Bulgaria, 2002 data for Poland, and 2003 data for Italy). Goossens H et al. Clin Infect Dis. 2007;44:1091-1095 © 2007 Infectious Diseases Society of America
- 18. Antibiotic Prescriptions per 1000 Persons of All Ages According to State, 2010. Hicks LA et al. N Engl J Med 2013;368:1461-1462.
- 19. Kronman M P et al. Pediatrics 2014;134:e956-e965 ©2014 by American Academy of Pediatrics
- 20. Antimicrobial prescription rates in outpatient ARTI visits using restrictive definitions, both individually and in aggregate, by year. Kronman M P et al. Pediatrics 2014;134:e956-e965 ©2014 by American Academy of Pediatrics
- 21. Antimicrobial Prescriptions for ARTI Condition Annual Visits in Thousands (% of all Outpatient Visits) Visits With Antimicrobial Prescription in Thousands (%) Visits With Expected Bacterial Pathogen in Thousands (%) Potentially Preventable Antimicrobial Prescriptions in Thousands All children AOM 12 141 (8.5) 10 428 (85.9) 7859 (64.7) 2569 Sinusitis 789 (0.6) 701 (88.8) 616 (78) 85 Pharyngitis 10 534 (7.3) 5991 (56.9) 2124 (20.2) 3867 Bronchitis 2512 (1.8) 1795 (71.5) 0 (0) 1795 URI 12 715 (8.9) 3108 (24.4) 0 (0) 3108 All ARTI 38 692 (27.0) 22 027 (56.9) 10 598 (27.4) 11 429 Children < 2 y AOM 5165 (11.5) 4314 (83.5) 3343 (64.7) 971 Sinusitis 59 (0.1) 51 (87.0) 46 (78) 5 Pharyngitis 1023 (2.3) 554 (54.1) 206 (20.2) 348 Bronchitis 608 (1.4) 331 (54.4) 0 (0) 331 URI 4656 (10.3) 871 (18.7) 0 (0) 871 All ARTI 11 511 (25.5) 6119 (53.2) 3153 (27.4) 2966 Children 2 - 17 y AOM 6960 (7.1) 6121 (88.0) 4505 (64.7) 1616 Sinusitis 728 (0.7) 641 (88.0) 568 (78) 73 Pharyngitis 9500 (9.7) 5409 (56.9) 1915 (20.2) 3494 Bronchitis 1910 (1.9) 1474 (77.2) 0 (0) 1474 URI 8072 (8.2) 2242 (27.8) 0 (0) 2242 All ARTI 27 161 (27.6) 15 894 (58.5) 7439 (27.4) 8455
- 22. Core Actions to Combat Resistance 1. Preventing Infections, Spread of Resistance – Immunization, infection control, handwashing, safe food preparation 1. Tracking 2. Improving Antibiotic Use/Stewardship – Perhaps most important action needed 1. Development of drugs and diagnostic tests
- 23. Improving Antibiotic Use/Stewardship • The use of antibiotics is the single most important factor leading to antibiotic resistance and the single most important action needed to greatly slow the development and spread of resistance
- 24. Leading Infectious Diseases Experts Call For Increased Focus On Protecting Antibiotics SHEA, IDSA, PIDS position paper outlines a national approach to antimicrobial stewardship Policy statement on antimicrobial stewardship by the Society for Healthcare Epidemiology of America (SHEA), the Infectious Diseases Society of America (IDSA), and the Pediatric Infectious Diseases Society (PIDS) Fishman N, et al. Infect Control Hosp Epidemiol. 2012 Apr;33(4):322-7.
- 25. Study Setting: CHOP Care Network •5 urban, academic •24 “private” practices urban, suburban, rural •common EHR
- 26. Antibiotic Prescribing for Sick Visits Excluding: preventive visits, CCC Standardized by: age, sex, age-sex, race, Medicaid
- 27. Broad Antibiotic Prescribing Excluding: preventive visits, CCC, antibiotic allergy, prior antibiotics Standardized by: age, sex, age-sex, race, Medicaid
- 28. Diagnosis Rate of AOM Excluding: preventive visits, CCC, prior antibiotics Standardized by: age, sex, age-sex, race, Medicaid
- 29. Broad Antibiotics for AOM Excluding: preventive visits, CCC, prior antibiotics Standardized by: age, sex, age-sex, race, Medicaid
- 30. Summary: Outpatient Variability • Antibiotic prescribing at sick visits varies significantly across practice sites • Broad-spectrum antibiotic prescribing at sick visits varies significantly across practice sites • The rate of diagnosis of ARTIs varies significantly across practice sites • Adherence to prescribing guidelines for AOM, sinusitis, GAS pharyngitis, and CAP varies significantly across practice sites
- 31. Effect of an Outpatient Antimicrobial Stewardship Intervention on Broad- Spectrum Antibiotic Prescribing by Primary Care Pediatricians: A Randomized Trial Gerber JS, Prasad PA, Fiks AG, Localio AR, Grundmeier RW, Bell LM, Wasserman RC, Keren R, Zaoutis TE: JAMA. 2013 Jun 12;309(22):2345-52
- 32. From: Effect of an Outpatient Antimicrobial Stewardship Intervention on Broad-Spectrum Antibiotic Prescribing by Primary Care Pediatricians: A Randomized Trial JAMA. 2013;309(22):2345-2352. doi:10.1001/jama.2013.6287 aThree clinicians in the intervention group and 5 in the control group did not attend acute-care encounters during the study period. Date of download: 10/11/2013 Copyright © 2012 American Medical Association. All rights reserved. Figure Legend:
- 33. Intervention 1. Guideline development 2. Education 3. Prescribing audit and feedback
- 34. Case Definitions • ICD9 codes for common infections (+/- GAS testing, antibiotic use) verified by chart review and provider feedback • Excluding: – antibiotic allergy – visit within prior 3 months with antibiotic – concurrent bacterial infection • AOM, SSTI, UTI, lyme, acne, chronic sinusitis, mycoplasma, scarlet fever, animal bite, proph, oral infections, pertussis, STD, bone/joint – children with complex chronic diseases
- 35. VIRAL common cold URI acute bronchitis tonsillitis pharyngitis (non-strep) Outcomes VIRAL common cold URI acute bronchitis tonsillitis pharyngitis (non-strep) no antibiotics BACTERIAL acute sinusitis Strep pharyngitis pneumonia BACTERIAL acute sinusitis Strep pharyngitis pneumonia penicillin/amoxicillin
- 36. Intervention: Timeline 12 months of audit/feedback 12 months after feedback ends Site presentation 12 months baseline data Feedback reports
- 37. ** * *
- 38. Figure Legend: The estimate of interest (and associated P value) is the treatment × time interaction term, representing the relative changes in trajectories before and during the intervention. Error bars indicate 95% CIs. Gerber JS, Prasad PA, Fiks AG, Localio AR, Grundmeier RW, Bell LM, Wasserman RC, Keren R, Zaoutis TE: Effect of an outpatient antimicrobial stewardship intervention on broad-spectrum antibiotic prescribing by primary care pediatricians: a randomized trial. JAMA. 2013 Jun 12;309(22):2345-52
- 39. From: Effect of an Outpatient Antimicrobial Stewardship Intervention on Broad-Spectrum Antibiotic Prescribing by Primary Care Pediatricians: A Randomized Trial JAMA. 2013;309(22):2345-2352. doi:10.1001/jama.2013.6287 The estimate of interest (and associated P value) is the treatment × time interaction term, representing the relative changes in trajectories before and during the intervention. Error bars indicate 95% CIs. Y-axis in blue indicates range 0% to 30%. Date of download: 10/11/2013 Copyright © 2012 American Medical Association. All rights reserved. Figure Legend:
- 40. From: Durability of Benefits of an Outpatient Antimicrobial Stewardship Intervention After Discontinuation of Audit and Feedback JAMA. Published online October 10, 2014. doi:10.1001/jama.2014.14042 Standardized Rates of Broad-Spectrum Antibiotic Prescribing Before, During, and After Audit and FeedbackThe estimate of interest is the treatment×time interaction term, representing the relative changes in trajectories before and during the intervention. Error bars indicate 95% CIs. Date of download: 11/4/2014 Copyright © 2014 American Medical Association. All rights reserved. Figure Legend:
- 41. Perceptions of the intervention • Qualitative study using semi-structured interview – 24 pediatricians from 6 primary care practices – All interviews were transcribed and analyzed using a modified grounded theory approach. • Results – Deep skepticism of the audit and feedback reports – Respondents ignored reports or expressed distrust about them. – One respondent admitted to gaming behavior. – Recognized it as a problem, but believed it was driven by the behaviors of non-pediatric physicians. – Parent pressure for antibiotics was identified by all respondents as a major barrier to the more judicious use of antibiotics – Respondents reported that they sometimes “caved” to parent pressure for social reasons Szymcak J et al. ICHE in press
- 44. Fig. 1. Representation of the impact of antibiotic administration on the bacterial community of the colon. Jernberg C et al. Microbiology 2010;156:3216-3223 SGM
- 45. A, Proportion of subjects developing IBD according to age and antianaerobic antibiotic exposure status. Kronman M P et al. Pediatrics 2012;130:e794-e803 ©2012 by American Academy of Pediatrics
- 46. Could Antibiotics Be A Factor In Childhood Obesity? -National Public Radio 2012 Antibiotics Could Be Driving Up Obesity -ABC News November 2012 Early use of antibiotics linked to obesity, research finds - Washington Post, August 22, 2012
- 47. Weight and body composition of control and STAT mice I Cho et al. Nature 000, 1-6 (2012) doi:10.1038/nature11400
- 48. Antibiotics in early life alter the murine colonic microbiome and adiposity • Mice fed subtherapeutic doses of antibiotics exhibited: - Increased adiposity - Increased hormone levels related to metabolism - Taxonomic changes of microbiome - Changes in copies of key genes involved in metabolism of carbohydrates to short-chain fatty acids - Alterations in hepatic metabolism of lipids and cholesterol - Increase in colonic levels of short chain fatty acids Cho I et al. Nature 2012
- 49. Summary 1. Antibiotic resistance is critical public health issue 2. Antimicrobial stewardship is key to reducing resistance 3. Antibiotic prescribing variable and often inappropriate in community 4. Develop community antimicrobial stewardship programs 5. Opening Pandora’s box by altering the microbiome
Notas del editor
- Some background that is relevant to ASP: Antibiotics are among the most commonly used drugs nationwide About half of hospitalized adults get antibiotics And, from data that we recently published, most kids in freestanding children’s hospitals get antibiotics HOWEVER, about half of all antibiotic use is inappropriate –the key driver of the need for an ASP
- Top 1 through 6 drug markets according to the total estimated number of outpatient prescriptions dispensed to the US pediatric population (ages 0–17 years) from US retail pharmacies, 2002 through 2010. *Statistically significant linear trend at P value = .05. Estimates were derived from the following source: VONA. Years 2002 through 2010; extracted December 2011. CIs for estimates are suppressed because the relative SEs of the estimates are &lt;1%.
- Frequency of narrow- and broad-spectrum antibiotic use according to class for all pediatric ambulatory visits, 2006–2008. Totals are slightly more than 100%, because multiple antibiotics were prescribed during a small number of visits.
- Rates of antibiotic dispensing per person-year of enrollment for children aged as follows: A, 3 to 24 months; B, 2 to &lt;4 years; C, 4 to &lt;6 years; D, 6 to &lt;12 years; and E, 12 to &lt;18 years. Values are for each health plan (A–C) between 2000 and 2010. Note: axes differ for the last 2 age groups. Enhanced marker reflects year of greatest change in decline of antibiotic rate. Although 95% CIs were calculated, the results were too small to be visible on graphs.
- Distribution of antibiotic classes among health plans, 2000–2001 and 2009–2010, for children aged as follows: A, 3 to &lt;24 months; B, 2 to &lt;4 years; C, 4 to &lt;6 years; D, 6 to &lt;12 years; and E, 12 to &lt;18 years. Changes in dispensing rate between 2000–2001 and 2009–2010 were statistically significant (P &lt; .05) for all antibiotic classes. Note: y-axis scaled differently in lower panels. AMOX-CLAV, amoxicillin/clavulanate; CEPH, cephalosporins; GEN, generation; PCN, 1st - line penicillins.
- Total outpatient antibacterial use in the United States and 27 European countries in 2004 (total use for Greece, Iceland, and Bulgaria, 2002 data for Poland, and 2003 data for Italy). DDD, defined daily dose; MLS, macrolides, lincosamides, and streptogramins; TMP, trimethoprim. *Includes amphenicols (J01B), aminoglycosides (J01G), combinations of antibacterial agents (J01R), and other antibacterial agents (J01X).
- Figure 1. Antibiotic Prescriptions per 1000 Persons of All Ages According to State, 2010.
- Antimicrobial prescription rates in outpatient ARTI visits using restrictive definitions, both individually and in aggregate, by year. Horizontal lines indicate overall means. Vertical bars represent 95% CI. Red triangles represent subjects of all ages; blue open circles represent subjects &lt;5 years of age; black closed circles represent subjects 5 to 17 years of age. No CI is available for the 2009 sinusitis estimate because there was no variation across subjects (100% of subjects received antimicrobial agents).
- The CHOP Care Network includes 29 primary care pediatric practice sites, including 5 urban, academic practices and 24 “private” practices – although owned and operated by CHOP, these sites are mostly former independent groups that are relatively isolated from academic influences, such as resident and medical student presence. These sites span urban, suburban, and rural locations across southeastern PA and southern NJ. Before designing an intervention to improve prescribing, we needed to find out if there was room to improve within this network.
- We performed a fixed effects analysis of the rate of antibiotic prescribing across the 25 practice groups in the CHOP care network, standardizing for various patient characteristics, including AGE, SEX, AGE-SEX interaction, RACE, and MEDICAID. The y-axis of this graph represents the rate at which antibiotics are prescribed per sick visit; each practice rate is depicted by a horizontal bar with a vertical confidence interval. As you can see, there is significant variability in antibiotic prescribing across the network, ranging from less than 20% to 35% of sick visits, after excluding or adjusting for variables that we felt could impact the indication for antibiotics.
- If a child is seen at a sick visit and receives an antibiotic, the proportion of broad-spectrum antibiotic use varies even more dramatically – 15% to over 50%. Again standardized using the same variables, with the added exclusion of children with antibiotic allergy or prior antibiotic use – each of which may be a rationale to use broad-spectrum agents.
- As suggested previously, the rate of dx of ARTI varies as well. This graph represents the rate of dx of AOM, irrespective of antibiotic use – a more than 2-fold difference across practices. Although the most prevalent, this is the least dramatic example; sinusitis, GAS, and PNA dx are more variable. Again, these analysis are performed are large numbers of visits - % of over 10,000 per practice over a full year (spanning all seasons) - designed to account for differences in chronic illness, age, race, sex, and insurance type and compare similar children.
- When dx with AOM, the rate of broad-spectrum use ranges significantly, despite exclusion of allergic pts and those who have received antibiotics recently, which should avoid comparing children with recurrent AOM or treatment failure. The same can be said for acute sinusitis, strep throat, and pneumonia; although current treatment guidelines recommend narrow spectrum antibiotics for these conditions, practice patterns vary.
- To summarize ...
- These guidelines pertain to only previously healthy children presenting without an identifiable condition warranting alternative antibiotic therapy; thus, we will exclude children with antibiotic allergy, chronic disease, a prior visit receiving an antibiotic, or a concurrent diagnosis consistent with a bacterial infection.
- With this, we have identified 5 conditions for which antibacterial agents are ineffective; thus, any antibiotic prescription during a non-preventive visit with one of the above diagnoses is considered at odds with this guideline.
- Representation of the impact of antibiotic administration on the bacterial community of the colon. After the onset of treatment, an increase in resistant bacteria (purple rods) can be seen. This increase is due to either a susceptible bacterium (green rods) becoming resistant or resistant bacteria, already present in low levels, increasing in number due to their ability to survive the selective pressure provided by the antibiotic. The acquired resistance is often due to horizontal gene transfer or mutation events (white arrow). As a consequence of treatment, a temporary decrease in diversity can also be seen. Some bacteria may be protected from antibiotic exposure in the mucin layer (yellow shading) or in grooves in between the villi formed by host epithelial cells that line the intestinal channel (not shown). The figure is not drawn to scale and the timescale is relative.
- A, Proportion of subjects developing IBD according to age and antianaerobic antibiotic exposure status. P &lt; .001 for the difference between groups by using the log-rank test. B, proportion of subjects developing IBD according to age and antianaerobic antibiotic exposure level. P &lt; .001 for the difference among groups by using the log-rank test.