Prevalence of Inappropriate Antibiotic Prescriptions Among US Ambulatory Care Visits,

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1 Research Original Investigation Prevalence of Inappropriate Antiiotic Prescriptions Among US Amulatory Care Visits, Katherine E. Fleming-Dutra, MD; Aam L. Hersh, MD, PhD; Daniel J. Shapiro; Monina Bartoces, PhD; Eva A. Enns, PhD; Thomas M. File Jr, MD; Jonathan A. Finkelstein, MD, MPH; Jeffrey S. Gerer, MD, PhD; Davi Y. Hyun, MD; Jeffrey A. Liner, MD, MPH; Ruth Lynfiel, MD; Davi J. Margolis, MD, PhD; Larissa S. May, MD, MSPH; Daniel Merenstein, MD; Joshua P. Metlay, MD, PhD; Jason G. Newlan, MD, ME; Jay F. Piccirillo, MD; Reecca M. Roerts, MS; Guillermo V. Sanchez, MPH, PA-C; Katie J. Sua, PharmD, MS; Ann Thomas, MD, MPH; Teri Moser Woo, PhD; Rachel M. Zetts; Lauri A. Hicks, DO IMPORTANCE The National Action Plan for Comating Antiiotic-Resistant Bacteria set a goal of reucing inappropriate outpatient antiiotic use y 50% y 2020, ut the extent of inappropriate outpatient antiiotic use is unknown. OBJECTIVE To estimate the rates of outpatient oral antiiotic prescriing y age an iagnosis, an the estimate portions of antiiotic use that may e inappropriate in aults an chilren in the Unite States. Eitorial page 1839 Supplemental content at jama.com CME Quiz at jamanetworkcme.com DESIGN, SETTING, AND PARTICIPANTS Using the National Amulatory Meical Care Survey an National Hospital Amulatory Meical Care Survey, annual numers an population-ajuste rates with 95% confience intervals of amulatory visits with oral antiiotic prescriptions y age, region, an iagnosis in the Unite States were estimate. EXPOSURES Amulatory care visits. MAIN OUTCOMES AND MEASURES Base on national guielines an regional variation in prescriing, iagnosis-specific prevalence an rates of total an appropriate antiiotic prescriptions were etermine. These rates were comine to calculate an estimate of the appropriate annual rate of antiiotic prescriptions per 1000 population. RESULTS Of the sample visits, 12.6% of visits (95% CI, 12.0%-13.3%) resulte in antiiotic prescriptions. Sinusitis was the single iagnosis associate with the most antiiotic prescriptions per 1000 population (56 antiiotic prescriptions [95% CI, 48-64]), followe y suppurative otitis meia (47 antiiotic prescriptions [95% CI, 41-54]), an pharyngitis (43 antiiotic prescriptions [95% CI, 38-49]). Collectively, acute respiratory conitions per 1000 population le to 221 antiiotic prescriptions (95% CI, ) annually, ut only 111 antiiotic prescriptions were estimate to e appropriate for these conitions. Per 1000 population, among all conitions an ages comine in , an estimate 506 antiiotic prescriptions (95% CI, ) were written annually, an, of these, 353 antiiotic prescriptions were estimate to e appropriate antiiotic prescriptions. CONCLUSIONS AND RELEVANCE In the Unite States in , there was an estimate annual antiiotic prescription rate per 1000 population of 506, ut only an estimate 353 antiiotic prescriptions were likely appropriate, supporting the nee for estalishing a goal for outpatient antiiotic stewarship. JAMA. 2016;315(17): oi: /jama Author Affiliations: Author affiliations are liste at the en of this article. Corresponing Author: Katherine E. Fleming-Dutra, MD, Centers for Disease Control an Prevention, 1600 Clifton R, MS A-31, Atlanta, GA (ftu2@cc.gov) (Reprinte) jama.com

2 Inappropriate Antiiotic Prescriptions Among Amulatory Care Visits, Original Investigation Research Antiiotic-resistant affect 2 million people an are associate with eaths annually in the Unite States, accoring to the Centers for Disease Control an Prevention (CDC). 1 Antiiotic use is the primary river of antiiotic resistance 1 an leas to averse events ranging from allergic reactions to Clostriium ifficile. 2 Data from other evelope nations suggest that 80% or more of antiiotic use (excluing agricultural use) occurs among outpatients. 3 In the Unite States in 2011, 262 million outpatient antiiotic prescriptions were ispense. 4 Declining trens in antiiotic prescriing in the Unite States occurre in the 1990s an early 2000s ut stailize y ,6 Reucing inappropriate use is essential to reuce oth antiiotic resistance an averse events. National guielines aressing when to prescrie antiiotics have een pulishe over the last 2 ecaes for many common iagnoses The CDC s Get Smart: Know When Work program focuses on promoting appropriate outpatient antiiotic use. 11 In March 2015, the White House release the National Action Plan for Comating Antiiotic-Resistant Bacteria, which set a target of reucing inappropriate antiiotic use in the outpatient setting y 50% y However, the fraction of antiiotic use that is inappropriate an amenale to reuction is unknown. 13 Previous goals an national measures of appropriate antiiotic use (eg, Healthy People 2020 targets an Healthcare Effectiveness Data an Information Set [HEDIS] measures) have targete specific age groups an conitions (eg, ear or acute ronchitis). 14,15 To our knowlege, there is no current overall estimate of appropriate outpatient antiiotic prescriing that consiers all ages an conitions that may receive antiiotics. The ojectives of this stuy were to estalish a aseline of the current rate of outpatient, oral antiiotic prescriptions y age an iagnosis an to estimate the overall rate of appropriate, outpatient antiiotic prescriptions in the Unite States to inform pulic health an antiiotic stewarship efforts. Methos Data Sources Baseline antiiotic prescriing rates were estimate using the National Amulatory Meical Care Survey (NAMCS) an National Hospital Amulatory Meical Care Survey (NHAMCS). These cross-sectional surveys are aministere annually y the CDC s National Center for Health Statistics. 16 NAMCS samples visits to nonfeerally-employe, officease physicians primarily engage in patient care an selects visits using a 3-stage proaility sampling esign. NAMCS samples geographic regions, physicians, an visits uring ranomly assigne 1-week reporting perios. NHAMCS is a survey of emergency epartments an outpatient epartments of nonfeeral general an short-stay hospitals. 16 NHAMCS uses a 4-stage proaility sampling esign. NHAMCS samples geographic regions, hospitals, outpatient epartment clinics, an emergency service areas, an visits uring 4-week reporting perios. Data collecte inclue patient emographics, up to 3 iagnoses that are coe y NAMCS/NHAMCS staff using the International Classification of Diseases, Ninth Revision, Clinical Moification (ICD-9-CM), an up to 8 meications mentione meaning prescrie, continue, or provie at the visit. visits in oth surveys are istriute ranomly throughout the year. Weights are assigne to visits so national estimates can e prouce. The most recent 2 years of ata availale in oth NAMCS an NHAMCS ( ) were use. response rates uring range from 54.1% to 58.3% for physicians in NAMCS, 66.7% to 73.6% for outpatient epartments, an 80.4% to 87.5% for emergency epartments in NHAMCS. Estimates from NAMCS are ajuste for physician an item nonresponse. Estimates from NHAMCS are ajuste for hospital nonresponse an for nonresponse at the level of the emergency epartments an outpatient epartments. The National Center for Health Statistics research ethics review oar approve NAMCS/NHAMCS, with waivers of informe consent an Health Insurance Portaility an Accountaility Act authorization for patients. These analyses were ase on pulically availale, eientifie ata, an therefore were not suject to institutional review oar requirements as etermine in consultation with the human sujects avisor for the National Center for Emerging an Zoonotic Infectious Disease. All visits uring were inclue unless resulting in hospital or oservation unit amission or if parenteral antiiotics were mentione without oral antiiotics (0.4% of visits). National estimates were prouce from unweighte visits in were coe in terms of their generic components an therapeutic classes using Lexicon Plus (Cerner Multum). 16 Data were not availale on route of aministration. supplie only in topical formulations were exclue. Oral antiiotics were efine as antiiotics with oral formulations, an parenteral antiiotics were efine as those antiiotics not availale in oral formulations (etale 1 in the Supplement). As outpatient, oral antiiotics are only availale via prescription, meication mentions of antiiotics were assume to e prescriptions, similar to previous stuies Estalishing the Baseline The mean annual rates per 1000 population of visits with antiiotic prescriptions y age group (0-2, 3-9, 10-19, 20-39, 40-64, 65 years) an US Census region (Northeast, South, Miwest, an West) for were calculate. The Northeast region inclue Maine, New Hampshire, Vermont, Massachusetts, Rhoe Islan, Connecticut, New York, New Jersey, an Pennsylvania. The Miwest region inclue Ohio, Michigan, Iniana, Illinois, Wisconsin, Missouri, Iowa, Minnesota, Kansas, Neraska, South Dakota, an North Dakota. The South region inclue Delaware, Marylan, District of Columia, Virginia, West Virginia, North Carolina, South Carolina, Floria, Georgia, Tennessee, Kentucky, Alaama, Mississippi, Louisiana, Arkansas, Oklahoma, an Texas. The West region inclue Montana, Wyoming, Colorao, New Mexico, Arizona, Utah, Iaho, Washington, Oregon, Nevaa, California, Alaska, an Hawaii. The mean annual rate per 1000 population, numer, jama.com (Reprinte) JAMA May 3, 2016 Volume 315, Numer

3 Research Original Investigation Inappropriate Antiiotic Prescriptions Among Amulatory Care Visits, an percentage of visits with antiiotics prescrie were also calculate y iagnosis an age group. For iagnosis-ase analyses, larger age groups (0-19, 20-64, 65 years) were use to prouce more reliale estimates. Diagnostic categories for common outpatient (etale 2 in the Supplement) were estalishe an visits were classifie into these categories. As NAMCS/NHAMCS o not contain links etween iagnoses an meication mentions, visit iagnoses were classifie ase on the most likely inication for an antiiotic prescription in a tiere fashion. Tier 1 iagnoses were iagnoses for which antiiotics are almost always inicate: pneumonia, urinary tract infection (UTI), or miscellaneous acterial (eg, pertussis an syphilis). Tier 2 iagnoses are iagnoses for which antiiotics may e inicate: sinusitis; suppurative otitis meia; skin, cutaneous, an mucosal ; pharyngitis; gastrointestinal ; an acne. Tier 3 iagnoses were all other iagnostic categories for which antiiotics are not inicate or the inication was unclear. In assigning each visit a single iagnosis, priority was given to tier 1 iagnoses, then tier 2 iagnoses, then tier 3 iagnoses. If a visit ha multiple iagnoses from a single tier, the first-liste iagnosis was assigne. Estimating Appropriate Antiiotic Prescriing To estimate appropriate oral antiiotic prescriing in amulatory care, the Pew Charitale Trusts convene a group of experts on outpatient antiiotic use to etermine methos for estimating the fraction of antiiotic use that is appropriate. Each author reviewe availale national guielines from professional societies for common conitions (etale 3 in the Supplement). Estimate levels of appropriate antiiotic prescriing y age group were ase on national guielines for iagnoses for which national guielines coul e use to recommen specific antiiotic prescriing rates: pharyngitis; asthma, allergy; ronchitis, ronchiolitis; influenza; nonsuppurative otitis meia; viral upper respiratory tract infection; viral an nonviral pneumonia; UTI; an miscellaneous acterial (eg, pertussis an syphilis). Regional variaility was use to prouce estimates of appropriate antiiotic prescriptions for iagnoses for which guielines coul not e use to recommen specific antiiotic prescriing rates: sinusitis, suppurative otitis meia, an the remaining other conitions. Regional analyses of antiiotic prescriing y age group were conucte to ientify regions with the lowest regional antiiotic prescription rates, recognizing there is evience of antiiotic overuse even in the lowest-prescriing regions. 20 Estimates were comine using national guielines an regional variaility to calculate an overall estimate of appropriate antiiotic prescriptions per 1000 population. Statistical Analysis Statistical analyses were performe using STATA 12 (STATA Corp) an accounte for the components of the complex survey esign incluing patient visit weights, strata, an primary sampling unit esign variales. Two years of survey ata were comine for analyses to increase sample size y age an iagnosis. Ninety-five percent confience intervals were calculate for all estimates. Antiiotic prescriing rates were compareusingχ 2 test for heterogeneity. Estimates were not calculate if ase on fewer than 30 sample visits or if the relative stanar error was less than 0.3, as such estimates o not meet stanars of reliaility or precision. 16 Significance was consiere at 2-sie P value less than.05. Population enominators were ase on the July 1, 2010, an July 1, 2011, set of estimates of the civilian, noninstitutional population of the Unite States, as evelope y the Population Division, US Census Bureau. 21 Aitionally, a post hoc sensitivity analysis was performe using the lowest-prescriing region as the enchmark for all estimates of appropriate antiiotic prescriing for iagnoses targete for reuction. Results In , of the sample amulatory care visits, 12.6% (95% CI, 12.0%-13.3%) were associate with antiiotic prescriptions (Tale 1), with an estimate 506 antiiotic prescriptions (95% CI, ) per 1000 US population annually (Tale 2). Per 1000 population, antiiotic prescriing rates range from 423 antiiotic prescriptions (95% CI, ) in the West to 553 antiiotic prescriptions (95% CI, ) in the South(Tale 3). The annual antiiotic prescription rate was highest among chilren age 0 through 2 years at 1287 antiiotic prescriptions (95% CI, ) per 1000 population. The top 3 iagnoses associate with antiiotic prescriptions per 1000 population were sinusitis (56 antiiotic prescriptions [95% CI, 48-64] ), suppurative otitis meia (47 antiiotic prescriptions [95% CI, 41-54]), an pharyngitis (43 antiiotic prescriptions [95% CI, 38-49]) (Tale 2). Collectively, acute respiratory conitions, efine as sinusitis, suppurative otitis meia, nonsuppurative otitis meia, pharyngitis, viral upper respiratory tract infection, ronchitis an ronchiolitis, asthma an allergy, influenza an viral an nonviral pneumonia, were associate with an estimate 221 antiiotic prescriptions (95% CI, ) per 1000 population annually. For pharyngitis, national guielines recommen antiiotic therapy only for streptococcal pharyngitis. 7 Base on recent literature, 37% of chilren presenting for meical visits with sore throat teste positive for group A Streptococcus. 22,23 However, 56.2% of visits (95% CI, 49.8%-62.4%) y chilren with pharyngitis were associate with antiiotic prescriing in (Tale 1). For aults presenting for meical visits with sore throat, aout 18% have streptococcal pharyngitis (ie, meet clinical criteria an have a positive test result for group A Streptococcus), 7,23 ut 72.4% (95% CI, 66.8%-77.4%) of visits y aults age 20 through 64 years with pharyngitis were associate with antiiotic prescriing. National guielines state that patients with ronchitis (excluing visits with iagnoses of chronic ronchitis, emphysema, or chronic ostructive pulmonary isease), 24,25 ronchiolitis, 26 viral upper respiratory tract, 25,27 asthma an allergy, 28 influenza, 29 viral pneumonia 30 an nonsuppurative otitis meia 31 shoul not receive antiiotics, an thus antiiotics for these conitions were consiere inappropriate JAMA May 3, 2016 Volume 315, Numer 17 (Reprinte) jama.com

4 Inappropriate Antiiotic Prescriptions Among Amulatory Care Visits, Original Investigation Research Tale 1. Visits an Amulatory Care Prescrie y Age Group an Diagnosis From the US NAMCS/NHAMCS, Diagnosis a Age Group, y No. Visits Visits With % (95% CI) Sinusitis ( ) Suppurative otitis meia ( ) Pharyngitis ( ) Skin, cutaneous, an mucosal Other skin, cutaneous, an mucosal conitions ( ) ( ) Urinary tract ( ) Viral upper respiratory tract infection ( ) Bronchitis or ronchiolitis c ( ) Other gastrointestinal conitions ( ) Other genitourinary conitions ( ) Miscellaneous acterial Other respiratory conitions (eg, chronic ronchitis) ( ) ( ) Gastrointestinal ( ) Pneumonia ( ) Acne ( ) Asthma or allergy ( ) Miscellaneous nonacterial Nonsuppurative otitis meia ( ) No. Visits % (95% CI) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) 299 c ( ) No. Visits % (95% CI) ( ) All Ages No. Visits % (95% CI) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) Influenza Viral pneumonia Remaining coes not liste elsewhere ( ) All conitions ( ) Areviation: NAMCS/NHAMCS, National Amulatory Meical Care Survey an National Hospital Amulatory Meical Care Survey. a Diagnostic categories were create ase on the most likely inication for an antiiotic prescription in a tiere fashion. Tier 1 iagnoses were those in which antiiotics are almost always inicate: pneumonia, urinary tract infection, or miscellaneous acterial (eg, pertussis an syphilis). Tier 2 iagnoses are those for which antiiotics may e inicate: sinusitis, suppurative otitis meia; skin, cutaneous, an mucosal, pharyngitis, gastrointestinal, an acne. Tier 3 iagnoses were all other iagnostic categories for which antiiotics are not inicate. In assigning each visit a single iagnosis, ( ) ( ) ( ) ( ) ( ) ( ) priority was given to tier 1 iagnoses, then tier 2 iagnoses, then tier 3 iagnoses. See etale 2 in the Supplement for full etails an inclue International Classification of Diseases, Ninth Revision, Clinical Moification coes for iagnostic categories. Value oes not meet stanar of reliaility or precision. c Bronchitis or ronchiolitis inclues visits with ronchitis, not specifie as acute or chronic, an acute ronchitis an ronchiolitis ut exclues visits in which the secon or thir iagnosis was chronic ronchitis, emphysema, or chronic ostructive pulmonary isease. Sinusitis an suppurative otitis meia sometimes warrant antiiotics; however, the appropriate rate of antiiotic prescriptions for these conitions is uncertain. Thus, the lowest regional rate of visits with antiiotic prescriptions was selecte as the estimate of the appropriate rate (etale 4 in the Supplement). For sinusitis, the estimate appropriate antiiotic prescription rates per 1000 participants y age group were as follows: 59 (95% CI, 32-86) for 0 through 19 years, 27 (95% CI, 17-36) for 20 through 64 years, an 37 (95% CI, 16-59) for 65 years an oler. For suppurative otitis meia, the estimate appropriate antiiotic prescription rates per 1000 participants y age group were as follows: 138 (95% CI, ) for 0 through 19 years an 6 (95% CI, 4-9) for 20 through 64 years. Estimates coul not e calculate for aults age 65 years jama.com (Reprinte) JAMA May 3, 2016 Volume 315, Numer

5 Research Original Investigation Inappropriate Antiiotic Prescriptions Among Amulatory Care Visits, Tale 2. Prescrie an Mean Annual Rate per 1000 Population of Amulatory Care Prescrie y Age Group an Diagnosis From the US NAMCS/NHAMCS, Diagnosis a Age Group, y No. of Prescrie Mean Annual Rate of % (95% CI),c No. of Prescrie Mean Annual Rate of % (95% CI),c No. of Prescrie Mean Annual Rate of % (95% CI),c All Ages No. Prescrie Mean Annual Rate of % (95% CI),c Sinusitis (51-79) (45-64) (32-57) (48-64) Suppurative otitis meia ( ) (7-11) (41-54) Pharyngitis (76-105) (23-35) (38-49) Skin, cutaneous, an (32-46) (33-44) (29-47) (34-43) mucosal Other skin, cutaneous, an (30-43) (25-39) (39-89) (30-45) mucosal conitions Urinary tract (17-28) (30-41) (51-77) (31-40) Viral upper respiratory tract (31-53) (15-23) (16-41) (21-31) Bronchitis or ronchiolitis e (18-39) (18-28) (20-40) (20-30) Other gastrointestinal (5-12) (17-25) (10-28) (14-21) conitions Other genitourinary (5-11) (14-23) (22-40) (14-21) conitions Miscellaneous acterial (13-26) (9-13) (11-17) Other respiratory conitions (6-14) (5-9) (21-45) (8-14) (eg, chronic ronchitis) Gastrointestinal (6-13) (9-14) (7-20) (9-13) Pneumonia (16-27) (4-7) (7-17) (9-13) Acne (17-27) (5-11) (8-13) Asthma or allergy (9-18) (6-11) (7-12) Miscellaneous nonacterial (1-4) (1-3) Nonsuppurative otitis meia 81 5 (3-7) (1-3) Influenza Viral pneumonia Remaining coes not liste elsewhere (39-57) All conitions ( ) (71-95) ( ) Areviation: NAMCS/NHAMCS, National Amulatory Meical Care Survey an National Hospital Amulatory Meical Care Survey. a Diagnostic categories were create ase on the most likely inication for an antiiotic prescription in a tiere fashion. Tier 1 iagnoses were those in which antiiotics are almost always inicate: pneumonia, urinary tract infection, or miscellaneous acterial (eg, pertussis an syphilis). Tier 2 iagnoses are those for which antiiotics may e inicate: sinusitis, suppurative otitis meia; skin, cutaneous, an mucosal, pharyngitis, gastrointestinal, an acne. Tier 3 iagnoses were all other iagnostic categories for which antiiotics are not inicate. In assigning each visit a single iagnosis, priority was given to tier 1 iagnoses, then tier 2 iagnoses, then tier 3 iagnoses. See etale 2 in the Supplement for full etails an inclue ( ) ( ) (77-100) ( ) International Classification of Diseases, Ninth Revision, Clinical Moification coes for iagnostic categories. Values are ase on 2-year averages. c Population enominators are ase on the July 1, 2010, an July 1, 2011, set of estimates of the civilian, noninstitutional population of the Unite States, as evelope y the Population Division of the US Census Bureau. 21 Figure oes not meet stanar of reliaility or precision. e Bronchitis or ronchiolitis inclues visits with ronchitis, not specifie as acute or chronic, an acute ronchitis an ronchiolitis ut exclues visits in which the secon or thir iagnosis was chronic ronchitis, emphysema, or chronic ostructive pulmonary isease. or oler with suppurative otitis meia ue to the small numer of sample visits. Antiiotic prescription rates were consiere appropriate for pneumonia ecause the iagnosis almost always warrants antiiotic therapy. 30 For other conitions, excluing acute respiratory conitions liste aove, antiiotic prescriptions were consiere appropriate for UTI an miscellaneous acterial (eg, pertussis an syphilis), as these conitions almost always warrant antiiotic therapy. 32 For the remaining other conitions (excluing acute respiratory conitions, UTIs, an miscellaneous acterial ), the lowest regional rate of visits with antiiotic prescriptions per 1000 participants y age group was selecte as the estimate appropriate rate (etale 4 in the Supplement): 137 (95% CI, ) for 0 through 19 years, 180 (95% CI, ) for 20 through 64 years, an 362 (95% CI, ) for 65 years or oler JAMA May 3, 2016 Volume 315, Numer 17 (Reprinte) jama.com

6 Inappropriate Antiiotic Prescriptions Among Amulatory Care Visits, Original Investigation Research Tale 3. Mean Annual Total Visit Rate an Rate of Prescrie per 1000 Population y US Census Region an Age Group From the US NAMCS/NHAMCS, a Amulatory Visits, Mean Annual Rate per 1000 Population (95% CI) P Value for Rate Total Among Antiiotic Prescriptions Regions f Among Regions g Northeast Miwest c South West e Total Prescrie Prescrie Total Prescrie Total Prescrie Total Prescrie Total Total Age Group, y 1287 ( ) 6851 ( ) 1071 ( ) 6717 ( ) 1492 ( ) 6837 ( ) 1240 ( ) 6021 ( ) 1196 ( ) ( ) ( ) 2953 ( ) 597 ( ) 2836 ( ) 738 ( ) 2862 ( ) 535 ( ) 2326 ( ) 864 ( ) ( ) ( ) 2563 ( ) 345 ( ) 2110 ( ) 491 ( ) 2654 ( ) 406 ( ) 2441 ( ) 510 ( ) ( ) ( ) 2962 ( ) 272 ( ) 2542 ( ) 469 ( ) 3024 ( ) 418 ( ) 2968 ( ) 393 ( ) ( ) ( ) 4083 ( ) 359 ( ) 3942 ( ) 463 ( ) 4031 ( ) 463 ( ) 3913 ( ) 440 ( ) ( ) ( ) 7317 ( ) 675 ( ) 8046 ( ) 594 ( ) 7056 ( ) 592 ( ) 6854 ( ) 623 ( ) ( ) ( ) 3999 ( ) 423 ( ) 3796 ( ) 553 ( ) 3970 ( ) 497 ( ) 3786 ( ) 525 ( ) All ages 4580 ( ) South region inclues Delaware, Marylan, District of Columia, Virginia, West Virginia, North Carolina, South Carolina, Floria, Georgia, Tennessee, Kentucky, Alaama, Mississippi, Louisiana, Arkansas, Oklahoma, an Texas. Areviation: NAMCS/NHAMCS, National Amulatory Meical Care Survey an National Hospital Amulatory Meical Care Survey. e West region inclues Montana, Wyoming, Colorao, New Mexico, Arizona, Utah, Iaho, Washington, Oregon, Nevaa, California, Alaska, an Hawaii. f P values are for χ 2 test for heterogeneity for ifferences among regions for rate of total visits per 1000 population. g P values are for χ 2 test for heterogeneity for ifferences among regions for rate of antiiotics prescriptions per 1000 population. a Population enominators are ase on the July 1, 2010, an July 1, 2011, set of estimates of the civilian, noninstitutional population of the Unite States, as evelope y the Population Division of the US Census Bureau. 21,22 Values are ase on 2-year averages. Northeast region inclues Maine, New Hampshire, Vermont, Massachusetts, Rhoe Islan, Connecticut, New York, New Jersey, an Pennsylvania. c Miwest region inclues Ohio, Michigan, Iniana, Illinois, Wisconsin, Missouri, Iowa, Minnesota, Kansas, Neraska, South Dakota, an North Dakota. The actual an estimate appropriate antiiotic prescription rates y age group for each conition an overall are shown in Tale 4. The estimate annual appropriate antiiotic prescription rate for acute respiratory conitions per 1000 population was 111 antiiotic prescriptions for all ages vs 221 antiiotic prescriptions (95% CI, ) annually for acute respiratory conitions in , a 50% reuction from the point estimate of the annual rate. The estimate annual appropriate rate per 1000 population for other conitions (excluing acute respiratory) was 242 antiiotic prescriptions vs 284 (95% CI, ) annually in , a 15% reuction from the point estimate of the annual rate. When all conitions were comine, the estimate appropriate annual antiiotic prescription rate for all conitions in all ages in the Unite States per 1000 population was 353 vs 506 (95% CI, ) annually in , a 30% reuction from the point estimate of the annual rate. The results of the sensitivity analysis using the lowest-prescriing region as the estimate of appropriate antiiotic prescriing for all iagnoses ientifie for reuction are shown in etale 5 in the Supplement. Discussion These analyses escrie antiiotic prescriing practices uring amulatory care visits in the Unite States y age group an iagnosis in , with an overall estimate annual rate of 506 antiiotic prescriptions per 1000 US population. In the Unite States, an estimate 154 million prescriptions for antiiotics were written in amulatory care settings annually uring Half of antiiotic prescriptions for acute respiratory conitions may have een unnecessary, representing 34 million antiiotic prescriptions annually. Collectively, across all conitions, an estimate 30% of outpatient, oral antiiotic prescriptions may have een inappropriate. Therefore, a 15% reuction in overall antiiotic use woul e necessary to meet the White House National Action Plan for Comating Antiiotic- Resistant Bacteria goal of reucing inappropriate antiiotic use in the outpatient setting y 50% y This estimate of inappropriate outpatient antiiotic prescriptions can e use to inform antiiotic stewarship programs in amulatory care y pulic health an health care elivery systems in the next 5 years. This estimate of inappropriate outpatient antiiotic prescriptions is ase on eriving an estimate for the rate of amulatory care visits uring which antiiotics are prescrie when not jama.com (Reprinte) JAMA May 3, 2016 Volume 315, Numer

7 Research Original Investigation Inappropriate Antiiotic Prescriptions Among Amulatory Care Visits, Tale 4. Mean Annual Antiiotic Prescriing Rates in US NAMCS/NHAMCS vs Estimate Appropriate Antiiotic Prescriing Annual Rates per 1000 Population y Age Group an Diagnosis Rates per 1000 Population Potential Mean Annual Rate of Antiiotic Prescriptions (95% CI) Estimate Appropriate Annual Rate of Antiiotic Prescriptions a Reuction in Annual Antiiotic Prescription Rates, % 0-19 y All acute respiratory conitions 421 (369 to 473) 278 c 34 Sinusitis 65 (51 to 79) 59 9 Suppurative otitis meia 154 (131 to 177) Pharyngitis 91 (76 to 105) Asthma or allergy; ronchitis or ronchiolitis; influenza; nonsuppurative otitis meia; viral URI; an viral pneumonia e 90 (71 to 108) Pneumonia 22 (16 to 27) 22 0 Other conitions 225 (197 to 252) 180 f 20 Urinary tract infection 23 (17 to 28) 23 0 Miscellaneous acterial 20 (13 to 26) 20 0 Remaining other conitions g 182 (160 to 205) Total h 646 (571 to 721) y All acute respiratory conitions 150 (129 to 170) 45 c 70 Sinusitis 55 (45 to 64) Suppurative otitis meia 9 (7 to 11) 6 33 Pharyngitis 29 (23 to 35) 7 75 Asthma or allergy; ronchitis or ronchiolitis; influenza; nonsuppurative otitis meia; viral URI; an viral pneumonia e 52 (43 to 60) Pneumonia 5 (4 to 7) 5 0 Other conitions 269 (239 to 298) 227 f 16 Urinary tract infection 35 (30 to 41) 35 0 Miscellaneous acterial 11 (9 to 13) 11 0 Remaining other conitions g 222 (197 to 248) Total h 418 (372 to 464) y All acute respiratory conitions 136 (111 to 162) 63 c 54 Sinusitis 44 (32 to 57) Asthma or allergy; ronchitis or ronchiolitis; influenza; nonsuppurative otitis meia; viral URI; an viral pneumonia e 66 (48 to 84) Pneumonia 12 (7 to 17) 12 0 Other conitions 480 (418 to 543) 441 f 8 Urinary tract infection 64 (51 to 77) 64 0 Remaining other conitions g 401 (346 to 456) Total h 617 (544 to 689) All Ages All acute respiratory conitions 221 (198 to 245) Other conitions 284 (256 to 313) Total h 506 (458 to 554) Areviations: NAMCS/NHAMCS, National Amulatory Meical Care Survey an National Hospital Amulatory Meical Care Survey; URI, upper respiratory tract infection. a Targets ase on lowest-prescriing regions for sinusitis, suppurative otitis meia,anremainingotherconitions; percent streptococcal pharyngitis for pharyngitis (37% for chilren, 18% aults); no antiiotics for asthma, allergy; ronchitis, ronchiolitis; influenza;nonsuppurativeotitismeia; URI;anviralpneumonia;nochangein antiiotic prescriing for pneumonia, urinary tract infection, an miscellaneousacterial.see Results section for further etails. All acute respiratory conitions inclue suppurative an nonsuppurative otitis meia; sinusitis; pharyngitis; pneumonia; ronchitis, ronchiolitis; URI; influenza, asthma, allergy, an viral pneumonia. c Difference etween the antiiotic rate for all acute respiratory conitions an sum of the ifferences etween the current an estimate appropriate antiiotic rate for each acute respiratory conition. Other conitions excluing acute respiratory conitions liste aove. e Bronchitis or ronchiolitis inclues visits with ronchitis, not specifie as acute or chronic, an acute ronchitis an ronchiolitis ut exclues visits in which the secon or thir iagnosis was chronic ronchitis, emphysema, or chronic ostructive pulmonary isease. f Difference etween the current antiiotic rate for other conitions an sum of the ifferences etween the an estimate appropriate antiiotic rate for urinary tract infection, miscellaneous acterial, an remaining other conitions. g Remaining other conitions exclue acute respiratory conitions, urinary tract infection, an miscellaneous acterial. h Sum of acute respiratory conitions an other conitions, slight ifferences may e present in sums ue to rouning. inicate an for iagnoses that are overuse (eg, sinusitis). To erive this estimate, a conservative, mixe approach was use incluing (1) no reuctions for conitions almost always warranting antiiotics, (2) application of clinical guielines for nonacterial respiratory conitions, (3) an estimate for group A streptococcal prevalence for pharyngitis, ase on eviencease guielines, an (4) use of geographic variaility y focusing on regions with the lowest antiiotic prescriing rates for suppurative otitis meia, sinusitis, an remaining conitions. Previous stuies estimating potential estimates of inappropriate outpatient antiiotic use have relie solely on estimates of acterial prevalence an have conclue that more than 50% of antiiotics for acute respiratory tract are unnecessary. 17,18 Although knowlege of acterial pathogen presence coul e informative, routine performance of sinus aspiration or tympanocentesis is impractical. Current treat JAMA May 3, 2016 Volume 315, Numer 17 (Reprinte) jama.com

8 Inappropriate Antiiotic Prescriptions Among Amulatory Care Visits, Original Investigation Research ment guielines for sinusitis an otitis meia avocate using stringent clinical criteria for iagnosis an to ientify caniates for watchful waiting an antiiotic therapy, 8-10,33 ut the fraction of iagnoses that meet these criteria is unknown. A sustantial amount of antiiotic overuse is likely riven y overiagnosis of certain conitions (eg, sinusitis iagnosis without meeting criteria). Evience supporting the prolem of overiagnosis, in particular for sinusitis an otitis meia, inclues variaility in iagnosis y race an y clinician. 34 Although the health of the populations in each region an thus the nee for antiiotic use may vary, the regional analyses from which the estimate appropriate rates are taken are ase on large regions with populations ranging from 55 million (Northeast) to 113 million (South). To our knowlege, no ata suggest worse outcomes for these conitions in low-prescriing regions ue to unertreatment; in fact, there is evience of antiiotic overuse even in low-prescriing regions. 20 For pneumonia, UTI an miscellaneous acterial, no specific goal was recommene at this time, even though overiagnosis of these conitions likely occurs, particularly with asymptomatic acteriuria iagnose as UTI. For this effort, the group focuse on conitions for which the iagnoses often or sometimes o not require antiiotics, rather than misiagnosis of conitions almost always requiring antiiotics. Misiagnosis will present important opportunities in the future, especially for like UTI an communityacquire pneumonia. The geographic variation nationally an gloally inicates that a 30% reuction in antiiotic prescriing is achievale. Per the sensitivity analysis, if national antiiotic prescriptions rates for targete iagnoses for each age group were at the rate of the lowest-prescriing region, prescriing woul e 19% lower than the rate. However, when lowprescriing regions are use to prouce estimates for appropriate prescriing, more antiiotic prescriptions are consiere appropriate than when estimates are ase on national guielines. Another stuy examining ispense antiiotics foun the lowest-prescriing 5 states ispense 36% fewer antiiotic prescriptions than the Unite States overall; this stuy foun a similar pattern to our stuy of higher prescriing in the South vs the West. 4 Sween ispense 328 antiiotic courses per 1000 population in compare with 877 antiiotic courses ispense per 1000 population in the Unite States in Sween has very low rates antiioticresistant. 36 By reucing antiiotic prescriing for common, 1 potential concern is increasing suppurative complications. However, in Sween, acute otitis meia iagnoses an antiiotic use ecrease uring y 50%, likely ue to stricter iagnostic criteria an eucational campaigns, with no increase in mastoiitis, 37 all prior to introuction of pneumococcal conjugate vaccine. 38 Effective interventions to reuce inappropriate prescriing, such as clinician an patient eucation, auit-an-feeack, acaemic etailing, communication training, rapi iagnostics, clinical ecision support, an elaye prescriptions, can e use in amulatory care settings to improve appropriate antiiotic use. 39 Strengths of NAMCS/NHAMCS inclue national representativeness an inclusion of oth iagnoses an therapy. However, the use of NAMCS/NHAMCS in this stuy also has the following limitations. First, the NAMCS an NHAMCS rely on clinician iagnoses an lack ata allowing for valiation of iagnoses an links etween meications an iagnoses. ICD- 9-CM coes, although assigne y NAMCS/NHAMCS staff, lack specificity to ifferentiate all iagnoses of interest an may not fully represent the clinician s iagnosis. NAMCS/NHAMCS allow for 3 iagnoses, an if the visit lacke antiioticappropriate iagnosis, it was assume that none existe. However, all 3 iagnoses fiels were use an antiiotic prescriing was consiere appropriate if there was any antiioticappropriate iagnosis. Secon, estimates in NAMCS an NHAMCS are ajuste for nonresponse for a limite numer of variales, an thus nonresponse ias may e present. 40 Thir, ata from NAMCS an NHAMCS represent visits, not illness episoes, such that multiple prescriptions for 1 person woul e capture separately, an therefore the overall estimate rates of antiiotic prescriing per population an inappropriate prescriing may e overestimate. For instance, in in NAMCS/NHAMCS, an estimate 1.2 illion amulatory care visits occurre annually from a population of 305 million people in the Unite States, suggesting that, on average, approximately 4 amulatory care visits occurre for each person in the Unite States. In reality, some iniviuals ha more than 4 amulatory care visits, an some ha fewer or no visits. Of these projecte 1.2 illion visits annually, an estimate 12.6% were associate with antiiotic prescriptions, which woul equate to a projecte 154 million antiiotic prescriptions written annually in these settings or an estimate population-ase rate of 506 antiiotic prescriptions per 1000 US population (ie, every person in the population woul have receive 0.5 antiiotic prescriptions per year from an office or emergency epartment ase visit). However, some patients receive no antiiotic prescriptions, an some likely receive more than 1 antiiotic prescription. In aition, ecause some iniviuals ha multiple visits an woul have een sample multiple times, it is almost certain that complex patients (who woul have many visits annually) are overrepresente in the stuy population compare with truly typical patients, an far more than healthy patients, who may not have ha any visits uring the sampling frame. It also is possile that for these complex patients, what may seem like inappropriate prescriptions coul have een appropriate. Moreover, the more times an iniviual sees a physician, the more likely that patient will get a prescription, inepenent of whether the prescription was appropriate or not. However, these multiple exposures for an iniviual are treate as on average a single exposure for multiple iniviuals an the ata were not ajuste for comoriities or for the numer of times an iniviual is inclue in the sampling frame, suggesting that the overall estimate rate of antiiotic prescriing per population may e iase upwar. Fourth, NAMCS/NHAMCS also have significant time elays, limiting the aility to use ata more recent than The jama.com (Reprinte) JAMA May 3, 2016 Volume 315, Numer

9 Research Original Investigation Inappropriate Antiiotic Prescriptions Among Amulatory Care Visits, same analysis of ata showe that antiiotic prescriing patterns were stale from an that 31% of outpatient antiiotic prescriptions were unnecessary. More recent ata inicate that overall outpatient antiiotic courses ispense have remaine stale from 2011 through 2013 with 877 an 849 antiiotic courses ispense per 1000 population, respectively. 35 The rate of antiiotic prescriptions in this stuy is just more than half the rate of antiiotics ispense in outpatient settings in the Unite States in ,35 It is not known how these rates in this stuy ase on ata from compare or reflect the rates of prescriing in Fifth, antiiotics prescrie at urgent care an retail clinic, feeral facilities, hospital ischarges, telemeicine encounters an for long-term care resients are not inclue in NAMCS/NHAMCS. In aition, visits to physician assistants an nurse practitioners are not systematically sample an may e unerrepresente. Sixth, these ata reflect meication mentions, not antiiotics ispense or consume, an elaye prescriptions cannot e ifferentiate from stanar prescriptions. Appropriate antiiotic selection was not aresse, ut a separate stuy is uner way to ientify opportunities to improve selection. Conclusions In the Unite States in , there was an estimate annual antiiotic prescription rate per 1000 population of 506, ut only an estimate 353 antiiotic prescriptions were likely appropriate, supporting the nee for an estalishing a goal for outpatient antiiotic stewarship. ARTICLE INFORMATION Author Affiliations: Centers for Disease Control an Prevention, Atlanta, Georgia (Fleming-Dutra, Bartoces, Roerts, Sanchez, Hicks); Peiatric Infectious Diseases, University of Utah, Salt Lake City (Hersh); School of Meicine, University of California, San Francisco, San Francisco (Shapiro); Division of Health Policy an Management, University of Minnesota, Minneapolis (Enns); Summa Health System an Northeast Ohio Meical University, Akron (File); Boston Chilren s Hospital an Harvar Meical School, Boston, Massachusetts (Finkelstein); Chilren s Hospital of Philaelphia, Philaelphia, Pennsylvania (Gerer); University of Pennsylvania Perelman School of Meicine, Philaelphia (Gerer, Margolis); Pew Charitale Trusts, Washington, DC (Hyun, Zetts); Brigham an Women s Hospital an Harvar Meical School, Boston, Massachusetts (Liner); Minnesota Department of Health, St Paul (Lynfiel); Department of Emergency Meicine, University of California-Davis, Sacramento (May); Department of Family Meicine, Georgetown University Meical Center, Washington, DC (Merenstein); Division of General Internal Meicine, Massachusetts General Hospital, Boston (Metlay); Division of Peiatric Infectious Diseases, Washington University School of Meicine, St Louis, Missouri (Newlan); Department of Otolaryngology-Hea an Neck Surgery, Washington University School of Meicine, St Louis, Missouri (Piccirillo); Department of Veterans Affairs, University of Illinois at Chicago, Chicago (Sua); Oregon Pulic Health Division, Portlan (Thomas); Pacific Lutheran University, Tacoma, Washington (Woo). Author Contriutions: Drs Fleming-Dutra an Hicks ha full access to all of the ata in the stuy an take responsiility for the integrity of the ata an the accuracy of the ata analysis. Stuy concept an esign: Fleming-Dutra, Hersh, Hicks. Acquisition, analysis, or interpretation of ata: All authors. Drafting of the manuscript: Fleming-Dutra. Critical revision of the manuscript: Hersh, Shapiro, Bartoces, Enns, File, Finkelstein, Gerer, Hyun, Liner, Lynfiel, Margolis, May, Merenstein, Metlay, Newlan, Piccirillo, Roerts, Sanchez, Sua, Thomas, Woo, Zetts, Hicks. Statistical analysis: Shapiro. Otaine funing: Hyun, Zetts. Aministrative, technical, or material support: Fleming-Dutra, Hyun, Zetts, Hicks. Stuy supervision: Fleming-Dutra, Hersh, Hicks. Conflict of Interest Disclosures: All authors have complete an sumitte the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr File reports receiving grant funing from Cempra an Pfizer an personal fees from Actavis, Melinta, Merck, MotifBio, Nariva, an Tetraphase. Dr Lynfiel reports eing co-eitor for a ook pulishe y Wiley-Blackwell on Infectious Disease Surveillance for which royalties are onate to the Minnesota Department of Health. Dr Merenstein reports giving expert avice to Proctor an Gamle, Bayer, an Nestle. Dr Newlan reports receiving grant funing from Pfizer an personal fees from RPS Diagnostics. No other isclosures are reporte. Funing/Support: This project was mae possile through a partnership with the Centers for Disease Control an Prevention (CDC) Founation. Support for this project was provie y Pew Charitale Trusts. Role of the Funer/Sponsor: The CDC participate in the esign an conuct of the stuy; collection, management, analysis, an interpretation of the ata; preparation, review, or approval of the manuscript; an ecision to sumit the manuscript for pulication. Pew Charitale Trusts participate in the interpretation of the ata; preparation, review, or approval of the manuscript; an ecision to sumit the manuscript for pulication. Pew Charitale Trusts sponsore in-person an telephone author meetings an supporte some author travel to in-person meetings. Disclaimer: The finings an conclusions in this report are those of the authors an o not necessarily represent the official position of the CDC or the Department of Veterans Affairs. Aitional Contriutions: We thank Tia Carter, MS, Allan Coukell, BSc Pharm, an Elizaeth Jungman, JD, MPH (all from Pew Charitale Trusts), for their assistance in convening author meetings. We also thank Allan Coukell, BSc Pharm (Pew Charitale Trusts), for his review of the manuscript. The aove name iniviuals i not receive any compensation for their role in the stuy. REFERENCES 1. Centers for Disease Control an Prevention. Antiiotic resistance threats in the Unite States, report-2013/. Accesse April 11, Liner JA. Eitorial commentary: antiiotics for treatment of acute respiratory tract : ecreasing enefit, increasing risk, an the irrelevance of antimicroial resistance. Clin Infect Dis. 2008;47(6): Sweres-Svarm Reports. Sweres-Svarm Accesse May 26, Hicks LA, Bartoces MG, Roerts RM, et al. US outpatient antiiotic prescriing variation accoring to geography, patient population, an provier specialty in Clin Infect Dis.2015;60 (9): Vaz LE, Kleinman KP, Raeel MA, et al. Recent trens in outpatient antiiotic use in chilren. Peiatrics. 2014;133(3): Sua KJ, Hicks LA, Roerts RM, Hunkler RJ, Taylor TH. Trens an seasonal variation in outpatient antiiotic prescription rates in the Unite States, 2006 to Antimicro Agents Chemother. 2014;58(5): Shulman ST, Bisno AL, Clegg HW, et al. Clinical practice guieline for the iagnosis an management of group A streptococcal pharyngitis: 2012 upate y the Infectious Diseases Society of America [pulishe correction appears in Clin Infect Dis. 2014;58(10):1496]. Clin Infect Dis. 2012;55 (10): Lieerthal AS, Carroll AE, Chonmaitree T, et al. The iagnosis an management of acute otitis meia [pulishe correction appears in Peiatrics. 2014;133(2):346]. Peiatrics. 2013;131(3):e964-e Chow AW, Benninger MS, Brook I, et al; Infectious Diseases Society of America. IDSA clinical practice guieline for acute acterial rhinosinusitis in chilren an aults. Clin Infect Dis. 2012;54(8): e72-e Rosenfel RM, Piccirillo JF, Chanrasekhar SS, et al. Clinical practice guieline (upate): ault sinusitis. Otolaryngol Hea Neck Surg. 2015;152(2) (suppl):s1-s JAMA May 3, 2016 Volume 315, Numer 17 (Reprinte) jama.com

10 Inappropriate Antiiotic Prescriptions Among Amulatory Care Visits, Original Investigation Research 11. Centers for Disease Control an Prevention. Get smart: know when antiiotics work. Accesse April 12, The White House. National action plan for comating antiiotic-resistant acteria. /ocs/national_action_plan_for_comating _antiotic-resistant_acteria.pf. Accesse April 12, Metlay JP. Eitorial commentary: setting national targets for antiiotic use. Clin Infect Dis. 2015;60(9): Healthy People Immunization an infectious iseases. -an-infectious-iseases/ojectives. Accesse Octoer 20, NCQA. HEDIS /HEDISQualityMeasurement/HEDISMeasures /HEDIS2016.aspx. Accesse Octoer 20, Centers for Disease Control an Prevention. Amulatory health care ata. /nchs/ahc.htm. Accesse Decemer 14, Gonzales R, Malone DC, Maselli JH, Sane MA. Excessive antiiotic use for acute respiratory in the Unite States. Clin Infect Dis.2001; 33(6): Kronman MP, Zhou C, Mangione-Smith R. Bacterial prevalence an antimicroial prescriing trens for acute respiratory tract. Peiatrics. 2014;134(4):e956-e Shapiro DJ, Hicks LA, Pavia AT, Hersh AL. Antiiotic prescriing for aults in amulatory care in the Unite States of America, J Antimicro Chemother. 2014;69(1): Levri K, Thomas A. Evaluation of Aministere for Acute Upper Respiratory Tract Infections Oregon, Paper presente at: EIS Conference; April 28, 2014; Atlanta, GA. 21. US Census Bureau, Population Division, Vintage 2010 Special Taulation an Vintage 2011 Special Taulation. 22. Shaikh N, Leonar E, Martin JM. Prevalence of streptococcal pharyngitis an streptococcal carriage in chilren: a meta-analysis. Peiatrics. 2010;126(3):e557-e Fine AM, Nizet V, Manl KD. Large-scale valiation of the Centor an McIsaac scores to preict group A streptococcal pharyngitis. Arch Intern Me. 2012;172(11): Irwin RS, Baumann MH, Bolser DC, et al; American College of Chest Physicians (ACCP). Diagnosis an management of cough executive summary: ACCP evience-ase clinical practice guielines. Chest. 2006;129(1)(suppl):1S-23S. 25. Hersh AL, Jackson MA, Hicks LA; American Acaemy of Peiatrics Committee on Infectious Diseases. Principles of juicious antiiotic prescriing for upper respiratory tract in peiatrics.peiatrics. 2013;132(6): Ralston SL, Lieerthal AS, Meissner HC, et al; American Acaemy of Peiatrics. Clinical practice guieline: the iagnosis, management, an prevention of ronchiolitis. Peiatrics. 2014;134(5): e1474-e Snow V, Mottur-Pilson C, Gonzales R; American College of Physicians-American Society of Internal Meicine; American Acaemy of Family Physicians; Centers for Disease Control; Infectious Diseases Society of America. Principles of appropriate antiiotic use for treatment of nonspecific upper respiratory tract in aults. Ann Intern Me. 2001;134(6): National Asthma Eucation an Prevention Program. Expert Panel Report 3: Guielines for the Diagnosis an Management of Asthma. Bethesa, MD: US Dept of Health an Human Services, National Institutes of Health, National Heart, Lung, an Bloo Institute; Fiore AE, Fry A, Shay D, Guareva L, Bresee JS, Uyeki TM; Centers for Disease Control an Prevention (CDC). Antiviral agents for the treatment an chemoprophylaxis of influenza recommenations of the Avisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2011;60(1): Braley JS, Byington CL, Shah SS, et al; Peiatric Infectious Diseases Society an the Infectious Diseases Society of America. The management of community-acquire pneumonia in infants an chilren oler than 3 months of age: clinical practice guielines y the Peiatric Infectious Diseases Society an the Infectious Diseases Society of America. Clin Infect Dis. 2011;53(7):e25-e American Acaemy of Family Physicians; American Acaemy of Otolaryngology-Hea an Neck Surgery; American Acaemy of Peiatrics Sucommittee on Otitis Meia With Effusion. Otitis meia with effusion.peiatrics. 2004;113(5): Gupta K, Hooton TM, Naer KG, et al; Infectious Diseases Society of America; European Society for Microiology an Infectious Diseases. International clinical practice guielines for the treatment of acute uncomplicate cystitis an pyelonephritis in women: a 2010 upate y the Infectious Diseases Society of America an the European Society for Microiology an Infectious Diseases.Clin Infect Dis. 2011;52(5):e103-e Wal ER, Applegate KE, Borley C, et al; American Acaemy of Peiatrics. Clinical practice guieline for the iagnosis an management of acute acterial sinusitis in chilren age 1 to 18 years. Peiatrics. 2013;132(1):e262-e Gerer JS, Prasa PA, Localio AR, et al. Racial ifferences in antiiotic prescriing y primary care peiatricians. Peiatrics. 2013;131(4): Centers for Disease Control an Prevention. Get smart know when antiiotics work: measuring outpatient antiiotic prescriing. Accesse Feruary 16, European Centre for Disease Prevention an Control. Annual epiemiological report 2014: antimicroial resistance an health care associate. /_layouts/forms/pulication_dispform.aspx?list =4f55a51-4ae af &ID =1292. Accesse April 12, Groth A, Enoksson F, Hermansson A, Hultcrantz M, Stalfors J, Stenfelt K. Acute mastoiitis in chilren in Sween no increase after new guielines. Int J Peiatr Otorhinolaryngol. 2011;75(12): Centers for Disease Control an Prevention (CDC). Progress in introuction of pneumococcal conjugate vaccine worlwie, MMWR Mor Mortal Wkly Rep. 2008;57(42): Drekonja DM, Filice GA, Greer N, et al. Antimicroial stewarship in outpatient settings: a systematic review. Infect Control Hosp Epiemiol. 2015;36(2): Hing E, Shimizu IM, Talwalkar A. Nonresponse ias in estimates from the 2012 National Amulatory Meical Care Survey. Accesse April 12, jama.com (Reprinte) JAMA May 3, 2016 Volume 315, Numer