INFECTIONS CAUSED BY ANTIBIOTICresistant

ORIGINAL CONTRIBUTION Antibiotic Prescription Rates for Acute Respiratory Tract Infections in US Ambulatory Settings Carlos G. Grijalva, MD, MPH J. Pekka Nuorti, MD, DSc Marie R. Griffin, MD, MPH See also Patient Page. Context During the 199s, antibiotic prescriptions for acute respiratory tract infection (ARTI) decreased in the United States. The sustainability of those changes is unknown. Objective To assess trends in antibiotic prescriptions for ARTI. Design, Setting, and Participants The National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey data () were used to examine trends in antibiotic prescription rates by antibiotic indication and class. Annual survey data and census denominators were combined in 2-year intervals for rate calculations. Main Outcome Measures National annual visit rates and antibiotic prescription rates for ARTI, including otitis media (OM) and non-arti. Results Among children younger than 5 years, annual ARTI visit rates decreased by 17% (95% confidence interval [CI], 9%-24%), from 1883 per 1 population in to 156 per 1 population in, primarily due to a 33% (95% CI, 22%-43%) decrease in OM visit rates (95 to 634 per 1 population, respectively). This decrease was accompanied by a 36% (95% CI, 26%-45%) decrease in ARTI-associated antibiotic prescriptions (1216 to 779 per 1 population). Among persons aged 5 years or older, ARTI visit rates remained stable but associated antibiotic prescription rates decreased by 18% (95% CI, 6%-29%), from 178 to 146 per 1 population. Antibiotic prescription rates for non-om ARTI for which antibiotics are rarely indicated decreased by 41% (95% CI, 22%-55%) and 24% (95% CI, 1%- 37%) among persons younger than 5 years and 5 years or older, respectively. Overall, ARTI-associated prescription rates for penicillin, cephalosporin, and sulfonamide/ tetracycline decreased. Prescription rates for azithromycin increased and it became the most commonly prescribed macrolide for ARTI and OM (1% of OM visits). Among adults, quinolone prescriptions increased. Conclusions Overall antibiotic prescription rates for ARTI decreased, associated with fewer OM visits in children younger than 5 years and with fewer prescriptions for ARTI for which antibiotics are rarely indicated. However, prescription rates for broadspectrum antibiotics increased significantly. JAMA. 29;32(7):758-766 www.jama.com INFECTIONS CAUSED BY ANTIBIOTICresistant microorganisms are associated with increased morbidity, mortality, and substantial economic burden. 1 Antibiotic use creates selective pressure for the emergence of antibiotic-resistant bacteria. 2-4 During the past decade, a variety of US initiatives have promoted the judicious use of antibiotics, 5,6 particularly for acute respiratory tract infection (ARTI), which is a common cause of health care encounters and antibiotic prescriptions, especially in young children. In the late 199s, antibiotic prescription rates in both children and adults decreased, 7-1 but these decreases were initially accompanied by increased prescription of broad-spectrum antibiotics. 9-11 Interventions not directly targeting antibacterial use may also have reduced antibiotic prescriptions and limited the spread of antibiotic resistance. For example, routine US infant immunization with a 7-valent pneumococcal conjugate vaccine (PCV-7) resulted in decreases in rates of invasive disease due to antibiotic-resistant Streptococcus pneumoniae. 12 Data from the Centers for Disease Control and Prevention s (CDC s) laboratory and population-based surveillance indicate that decreases in pneumococcal isolates resistant to penicillin, sulfonamides, and selected cephalosporins has been sustained, but the proportion of erythromycin-resistant pneumococcus increased after the initial decreases. 13 In the late 199s, increasing rates of macrolide-resistant invasive pneumococcal disease were temporally associated Author Affiliations: Departments of Preventive Medicine (Drs Grijalva and Griffin) and Medicine (Dr Griffin), Vanderbilt University School of Medicine, Nashville, Tennessee; and The National Center for Immunization and RespiratoryDiseases,CentersforDiseaseControlandPrevention, Atlanta, Georgia (Dr Nuorti). Corresponding Author: Carlos G. Grijalva, MD, MPH, Department of Preventive Medicine, Vanderbilt University School of Medicine, 15 21st Ave, Ste 26, The Village at Vanderbilt, Nashville, TN 37232-2637 (carlos.grijalva@vanderbilt.edu). 758 JAMA, August 19, 29 Vol 32, No. 7 (Reprinted) 29 American Medical Association. All rights reserved.

with increasing use of macrolides, especially azithromycin. 14 Recent measurements of antibiotic prescription patterns in the United States are unavailable. This article assesses national trends in antibiotic prescriptions for ARTI in ambulatory settings. METHODS Sources of Information We analyzed annual data from the National Ambulatory Medical Care Survey (NAMCS) and the National Hospital Ambulatory Medical Care Survey (NHAMCS) between 1995 and. The NAMCS gathers data on a nationally representative sample of visits to office-based physicians engaged in direct patient care, whereas the NHAMCS collects data on a representative sample of visits to hospital-based emergency departments and outpatient clinics. These surveys record patient demographics, symptoms, procedures, diagnoses, and prescribed medications for a systematic sample of visits. During the study period, physician participation rates in NAMCS ranged from 59% to 73%, and the unweighted item nonresponse rates were typically 5% or less. 15 Rates of hospital participation in NHAMCS ranged from 9% to 98% and the unweighted item nonresponse rates were typically 5% or less. 16 Upto3diagnosespervisitarerecorded in the NAMCS and NHAMCS databases, using International Classification of Diseases, NinthRevision, ClinicalModification (ICD-9-CM) codes. The ARTI visits included those patients with any listed diagnosis of otitis media (OM), bronchitis, bronchiolitis, pneumonia, sinusitis, pharyngitis, tonsillitis, laryngitis, tracheitis, nasopharyngitis, andmastoiditis(icd-9-cm codes 381.x-383.x, 46.x-466.x, 48.x- 487.x, 49.x). Rates were also calculated forom, themostcommonreasonforphysician visits and antibiotic prescriptions in young children 8 (ICD-9-CM codes 381.x-382.x).Forspecificanalyses,wealso defined2mutuallyexclusivegroups:arti for which antibiotics are often indicated (OM, mastoiditis, sinusitis, pharyngitis, tonsillitis, and nonviral pneumonia) 17-19 ; and ARTI for which antibiotics are rarely indicated (acute nasopharyngitis, laryngitis, unspecified upper respiratory tract infection, bronchitis, bronchiolitis, viral pneumonia, and influenza). 17-19 We also exploredtheconcurrentpresenceofcommon non-arti diseases that could result in an antibiotic prescription, such as urinary tract infections (ICD-9-CM codes 599., 595., 595.9) and soft tissue infections (ICD-9-CM codes 68.x-682.x). 8,2 Antibiotic classes included in the study were penicillins, cephalosporins, sulfonamides, tetracyclines, macrolides (including azalides), lincosamides, and quinolones. Antibiotic prescriptions were identified using the National Drug Code directory, generic names, drug names, and the Multum classification of therapeutic classes. 15,16 Visits that resulted in the prescription of at least 2 antibiotic classes contributed 1 observation to each class and rates of specific antibiotic prescriptions during ARTI visits were estimated. Because use of some antibiotics was rare, estimates for sulfonamides and tetracyclines, and lincosamides and macrolides were analyzed together. Quinolone exposures were too rare to estimate rates for children. Separate estimates were obtained for azithromycin, amoxicillin, and amoxicillin/clavulanic acid. Azithromycin exposures were too rare to estimate prescription rates for OM for children younger than 5 years until 1997. Statistical Analysis For a comprehensive assessment of US ambulatory settings, the NAMCS and NHAMCS data were combined and to obtain robust estimates, annual survey data were combined in 2-year intervals. 8 All reported estimates were based on at least 3 unweighted observations and relative standard errors of less than 3%. 15,16 Because children younger than 5 years had the highest visit rates for ARTI and antibiotic prescriptions 8 and early activities promoting judicious use of antibiotics were primarily focused on them, 21 our analyses were stratified into 2 groups: children younger than 5 years and persons 5 years or older. To assess differential effects of age and the aging of the US population, 22 persons 5 years or older were further stratified (5-17 years, 18-49 years, 5-64 years, 65-79 years, and 8 years). Survey data were weighted to produce national estimates, with weights accounting for selection probabilities, adjustment for nonresponse, population ratio adjustments, and weight smoothing. 15,16 Weighted observations represented rate numerators and denominators were obtained from the US Census Bureau. For each 2-year period, the population was calculated by averaging the 2-year population estimates. To estimate average annual rates and rate ratios (RRs), we fitted Poisson regression models to the survey data. Census population estimates for each period and age groups provided an approximation to the person-time for each period and were distributed according to the aggregated weight factor of the national surveys, representing the offset term in the models. 22,23 Our models included terms for age, time, and an age time interaction term and accounted for the complex survey sampling design. Per our planned analyses, we compared the first ( ) with the most recent ( ) observation period, using RRs estimated by using linear predictors from the regression models. Rate differences and their 95% confidence intervals (CIs) were also calculated. We also assessed changes in prescribing practices by calculating the proportion of visits that resulted in antibiotic prescriptions. 8 Proportions were estimated accounting for the survey design and trends in proportions were tested by using weighted least square regressions. 8 All reported P values were 2-tailed and accounted for the complex survey design. P.5 indicated statistical significance. Data were analyzed by using SAS version 9.1 (SAS Institute, Cary, North Carolina) and Stata version 1. (StataCorp LP, College Station, Texas) survey packages. This study was considered exempt from review by the institutional review boards of Vanderbilt University and the CDC. 29 American Medical Association. All rights reserved. (Reprinted) JAMA, August 19, 29 Vol 32, No. 7 759

RESULTS Visit Characteristics During the 12-year period, the surveys estimated 6.2 billion ambulatory visits in the United States. Overall, 59% of patients were female and 84% were white. Approximately 82% of visits were to physician practices, 8% to hospitalbased outpatient clinics, and 1% to emergency departments. Overall, antibiotics were prescribed in 13% of all ambulatory visits. The ARTI visits accounted for 1% of all visits and for 44% of all antibiotic prescribing. Children younger than 5 years accounted for 9% of all visits and 34% of their visits were ARTI-associated. In this group, antibiotics were prescribed in 26% of all visits and in 56% of ARTI visits. Persons 5 years or older accounted for 91% of all visits and ARTI represented 8% of their visits. In this group, antibiotics were prescribed in 12% of all visits and in 58% of ARTI visits. Table 1. US Rate Differences and Rate Ratios of Ambulatory Visits and Antibiotic Prescriptions, a Visits by Age, y Rate Difference Rate Ratio All visits 5 4773 5174 42 ( 149 to 117) 1.8 (.97 to 1.21) 5-17 285 2436 351 (174 to 541) 1.17 (1.8 to 1.26) 18-49 2689 2977 287 (129 to 455) 1.11 (1.5 to 1.17) 5-64 3793 4627 834 (615 to 165) 1.22 (1.16 to 1.28) 65-79 5746 7166 142 (122 to 1841) 1.25 (1.18 to 1.32) 8 613 775 162 (186 to 2156) 1.26 (1.18 to 1.35) ARTI visits 5 1883 156 322 ( 461 to 171).83 (.76 to.91) 5-17 49 459 31 ( 84 to 29).94 (.83 to 1.6) 18-49 22 26 14 ( 4 to 14).93 (.82 to 1.7) 5-64 27 246 39 (2 to 83) 1.19 (1.1 to 1.4) 65-79 282 266 15 ( 66 to 46).95 (.77 to 1.16) 8 286 232 54 ( 111 to 22).81 (.61 to 1.8) Non-ARTI visits 5 289 3614 724 (547 to 91) 1.25 (1.19 to 1.31) 5-17 1595 1977 382 (317 to 449) 1.24 (1.2 to 1.28) 18-49 2469 2771 32 (273 to 331) 1.12 (1.11 to 1.13) 5-64 3586 4381 795 (755 to 836) 1.22 (1.21 to 1.23) 65-79 5464 6899 1435 (1373 to 1498) 1.26 (1.25 to 1.27) 8 5817 7473 1656 (157 to 1743) 1.28 (1.27 to 1.3) Antibiotics in all visits 5 1552 1128 424 ( 551 to 281).73 (.64 to.82) 5-17 552 495 57 ( 112 to 5).9 (.8 to 1.1) 18-49 385 396 1 ( 25 to 49) 1.3 (.93 to 1.13) 5-64 362 445 82 (3 to 141) 1.23 (1.8 to 1.39) 65-79 461 635 174 (87 to 274) 1.38 (1.19 to 1.59) 8 543 696 153 (27 to 37) 1.28 (1.5 to 1.57) Antibiotics in ARTI visits 5 1216 779 437 ( 542 to 315).64 (.55 to.74) 5-17 314 219 95 ( 127 to 58).7 (.6 to.82) 18-49 149 124 25 ( 45 to 1).83 (.7 to.99) 5-64 12 141 21 ( 6 to 54) 1.17 (.95 to 1.45) 65-79 145 134 11 ( 42 to 3).93 (.71 to 1.21) 8 154 11 44 ( 77 to 4).71 (.5 to 1.2) Antibiotics in non-arti visits 5 336 349 13 ( 47 to 84) 1.4 (.86 to 1.25) 5-17 238 276 38 (2 to 8) 1.16 (1.1 to 1.34) 18-49 236 271 35 (12 to 61) 1.15 (1.5 to 1.26) 5-64 243 34 62 (22 to 16) 1.25 (1.9 to 1.44) 65-79 316 51 185 (15 to 279) 1.58 (1.33 to 1.88) 8 389 586 197 (77 to 347) 1.51 (1.2 to 1.89) Abbreviations: ARTI, acute respiratory tract infection; CI, confidence interval. a Data are from the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey. Rates are average annual rates for each period (per 1 population). Children Younger Than 5 Years ARTI Visits. Overall annual visit rates were 4773 per 1 population in and remained stable during the study period. Although ARTI-associated visit rates decreased by 17% (RR,.83; 95% CI,.76-.91), non-arti visit rates increased by 25% (RR, 1.25; 95% CI, 1.19-1.31) (TABLE 1 and FIGURE 1). Concomitant conditions as a possible reason for antibiotic prescriptions associated with ARTI visits such as urinary tract infections (.26% of ARTI visits) or soft tissue infections (.6%) were uncommon. ARTI-Associated Antibiotic Prescriptions. Annual antibiotic prescription rates decreased by 27% or 424 per 1 children (95% CI, 281-551). This decrease was due to a 36% (RR,.64; 95% CI,.55-.74) reduction in ARTI-associated antibiotic prescriptions. Antibiotic prescription rates for non-arti visits remained stable (Table 1). The overall proportion of visits resulting in antibiotic prescriptions decreased from 33% in to 22% in (P =.8), due to reductions from 65% to 5% (P=.1) in the proportion of ARTI visits resulting in antibiotics. The proportion of non-arti visits resulting in antibiotic prescriptions remained stable (P=.16). In physician practices, the proportion of ARTI visits that resulted in antibiotics decreased from 65% to 48% (P=.9); no significant decreases were observed in emergency department visits (from 63% to 55%, P=.11) or in hospital-based outpatient clinics (from 6% to 54%, P=.12). Rates of ARTI visits resulting in penicillin prescriptions decreased by 31% (TABLE 2). Amoxicillin/clavulanic acid prescription rates remained stable, 76 JAMA, August 19, 29 Vol 32, No. 7 (Reprinted) 29 American Medical Association. All rights reserved.

whereas amoxicillin prescription rates decreased by 37%. Cephalosporin and sulfonamide/tetracycline prescription rates decreased by 47% and 91%, respectively. Azithromycin prescription rates for ARTI increased 9-fold from to, but overall prescription rates for macrolides/lincosamides remained stable (Table 2), mainly due to decreases in erythromycin use (data not shown because of unreliable estimates during last periods). Otitis Media. Annual OM rates decreased by 33% from 95 to 634 per 1 children from to, respectively (RR,.67; 95% CI,.57-.78). Similarly, rates of antibiotic prescriptions for OM decreased by 36% from 76 to 484 per 1 children (RR,.64; 95% CI,.54-.75). The proportion of OM visits that resulted in antibiotic prescriptions remained approximately 8% throughout the study years (P=.14) (FIGURE 2). Penicillin prescription rates for OM decreased from 39 to 37 per 1 children (RR,.79; 95% CI,.65-.96), amoxicillin rates decreased from 326 to 233 per 1 children (RR,.71; 95% CI,.58-.88), and amoxicillin/ clavulanic acid prescription rates remained stable. Cephalosporin prescription rates decreased from 211 to 13 per 1 children in (RR,.49; 95% CI,.35-.67). Sulfonamide/ tetracycline prescription rates decreased from 143 to 11 per 1 children (RR,.8; 95% CI,.4-.15), whereas macrolide/lincosamide prescription rates remained stable. Azithromycin prescription rates remained stable from to Figure 1. National US Rates of Ambulatory Visits and Antibiotic Prescriptions, Visit rates 6 5 All ambulatory visits ARTI visits Non-ARTI visits <5 Years 5 Years Visit Rate per 1 Population 4 3 1 21-22 23-24 21-22 23-24 21-22 23-24 Antibiotic prescription rates 18 All ambulatory visits ARTI visits Non-ARTI visits Antibiotic Visits per 1 Population 15 12 9 6 3 21-22 23-24 21-22 23-24 21-22 23-24 ARTI indicates acute respiratory tract infection. Error bars represent 95% confidence intervals. Data are from the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey. Rates are average annual rates for each period. 29 American Medical Association. All rights reserved. (Reprinted) JAMA, August 19, 29 Vol 32, No. 7 761

Table 2. US Rates, Rate Differences, and Rate Ratios of Antibiotic Prescriptions During ARTI Visits for Persons Younger Than 5 Years and 5 Years or Older a (RR, 1.1; 95% CI,.7-1.73); in, it was the most prescribed macrolide for OM with 65 (95% CI, 46-9) prescriptions per 1 children (approximately 1% of OM visits). Non-OM ARTI. Overall, rates of antibiotic prescriptions associated with non-om ARTI visits decreased by 35% (RR,.65; 95% CI,.52-.81). Rates of non-om ARTI for which antibiotics are often indicated, rates of antibiotic prescription associated with these visits, and the proportion of these visits resulting in an antibiotic prescription did not change significantly throughout the study years (Figure 2). Rates of ARTI visits for which antibiotics are rarely indicated remained stable, whereas associated antibiotic prescription rates decreased by 41% (RR,.59; 95% CI,.45-.78). The proportion of these non-om ARTI visits resulting in antibiotic prescriptions also decreased from 41% in to 23% in (P=.4) (Figure 2). Persons Aged 5 Years or Older ARTI Visits. Overall annual visit rates increased by 19% from 3154 to 3758 per 1 population (RR, 1.19; 95% CI, 1.15- Rate Difference Rate Ratio 5 Years Penicillins 653 448 24 ( 274 to 121).69 (.58 to.81) Amoxicillin 556 351 25 ( 26 to 139).63 (.53 to.75) Amoxicillin/clavulanic acid 81 92 11 ( 19 to 55) 1.13 (.76 to 1.68) Cephalosporins 315 167 148 ( 192 to 88).53 (.39 to.72) Macrolides/lincosamides 16 161 1 ( 41 to 57) 1. (.74 to 1.36) Azithromycin 16 14 124 (64 to 23) 8.78 (4.99 to 15.44) Sulfonamides/tetracyclines 24 18 186 ( 193 to 174).9 (.5 to.15) 5 Years Penicillins 82 47 34 ( 42 to 25).58 (.48 to.69) Amoxicillin 64 33 31 ( 37 to 24).51 (.42 to.63) Amoxicillin/clavulanic acid 8 11 3 (1 to 7) 1.44 (1.8 to 1.93) Cephalosporins 38 22 15 ( 2 to 1).59 (.47 to.74) Macrolides/lincosamides 47 58 1 ( to 23) 1.22 (1.1 to 1.48) Azithromycin 6 37 31 (22 to 44) 6.2 (4.63 to 8.3) Sulfonamides/tetracyclines 15 8 7 ( 9 to 3).53 (.35 to.81) Quinolones 4 21 17 (11 to 24) 5.39 (3.95 to 7.36) Abbreviations: ARTI, acute respiratory tract infection; CI, confidence interval. a Data are from the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey. Rates are average annual rates for each period (per 1 population). 1.23). This was primarily due to a 21% increase in non-arti visit rates (RR, 1.21; 95% CI, 1.2-1.23). ARTI rates remained stable and similar changes were observed in the age-stratified analyses (Table 1 and Figure 1). Although decreases in rates of OM and related antibiotic prescriptions in this age group were similar to those among children younger than 5 years, these rates were substantially lower (Figure 2). As with children, concomitant conditions during an ARTI visit that could result in antibiotic prescriptions such as urinary tract infections (.66%) or soft tissue infections (.15%) were uncommon. ARTI-Associated Antibiotic Prescriptions. Although overall antibiotic prescription rates remained stable among persons 5 years or older, the stratified analysis showed significant increases among persons 5 years or older. Overall antibiotic prescriptions associated with ARTI visits decreased by 18% (RR,.82; 95% CI,.71-.94) but significant decreases occurred only among persons younger than 5 years. Non-ARTI visit associated antibiotic prescriptions increased in all groups 5 years or older (Table 1). Overall, about 12% of all visits for persons 5 years or older consistently resulted in antibiotic prescriptions. The proportion of ARTI visits that resulted in antibiotic prescriptions was 63% in and 54% in (P=.7). The proportion of non-arti visits resulting in antibiotic prescriptions remained stable (P=.79). In physician practices, the proportion of ARTI visits that resulted in antibiotic prescriptions among persons 5 years or older decreased from 63% to 52% (P=.2), whereas no significant changes were observed in emergency department visits (from 63% to 64%, P=.51) or in hospital-based outpatient clinics (from 61% to 6%, P=.88). Overall rates of ARTI visits resulting in penicillin prescriptions decreased by 42% (Table 2). Amoxicillin prescription rates decreased by 49%, whereas amoxicillin/clavulanic acid rates increased by 44%. Cephalosporin prescription rates decreased by 41% and sulfonamide/tetracycline rates decreased by 47%. Macrolide/ lincosamide prescription rates increased by 22%, mainly due to a 6-fold increase in azithromycin prescription rates. Quinolone prescription rates increased 5-fold. Similar changes in prescriptions of antibiotic classes were observed across age groups (TABLE 3). Non-OM ARTI. Overall antibiotic prescription rates for non-om ARTI among persons 5 years or older decreased by 15% (RR,.85; 95% CI,.73-.98), due primarily to decreases in antibiotic prescriptions for ARTI for which antibiotics are rarely indicated. Rates of non-om ARTI visits for which antibiotics are often indicated showed a nonsignificant increase (RR, 1.12%; 95% CI,.97-1.3) and rates of antibiotic prescription associated with these visits remained stable. The proportion of these visits resulting in antibiotic prescriptions decreased by 13% (P=.4) and was 59% in (Figure 2). Rates of non-om ARTI visits for which antibiotics are rarely indicated had a nonsignificant decrease of 9% (RR,.91; 95% CI,.8-1.4), whereas antibiotic prescription rates associated with 762 JAMA, August 19, 29 Vol 32, No. 7 (Reprinted) 29 American Medical Association. All rights reserved.

these visits decreased by 24% (RR,.76; 95% CI,.63-.9). The proportion of these visits that resulted in an antibiotic prescription did not change significantly and was 48% in (Figure 2). COMMENT Our analysis of 12 years of national ambulatory survey data showed sustained decreases in ARTI-associated antibiotic prescription rates. These decreases were primarily observed in physician practices and were associated with a decrease in both OM visits (children 5 years) and antibiotic prescriptions associated with ARTI for which antibiotics are rarely indicated (all age groups). Although these observations are en- Figure 2. US Rates of Otitis Media and Non Otitis Media ARTI Visits, Antibiotic Prescriptions, and Proportion of Visits Resulting in Antibiotic Prescriptions, Visit rates Visit Rate per 1 Population 125 1 75 5 25 Otitis media 21-22 23-24 (antibiotics often indicated) 21-22 23-24 (antibiotics rarely indicated) 21-22 <5 Years 5 Years 23-24 Antibiotic prescription rates Antibiotic Visits per 1 Population 125 1 75 5 25 Otitis media 21-22 23-24 (antibiotics often indicated) 21-22 23-24 (antibiotics rarely indicated) 21-22 23-24 Antibiotic prescriptions during visits Proportion of Visits With Antibiotics, % 1 8 6 4 2 Otitis media 21-22 23-24 (antibiotics often indicated) 21-22 23-24 (antibiotics rarely indicated) 21-22 23-24 ARTI indicates acute respiratory tract infection. Error bars represent 95% confidence intervals. for which antibiotics are often indicated include mastoiditis, sinusitis, pharyngitis, tonsillitis, and nonviral pneumonia. for which antibiotics are rarely indicated include acute nasopharyngitis, laryngitis, unspecified upper respiratory tract infection, bronchitis, bronchiolitis, viral pneumonia, and influenza. Data are from the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Medical Care Survey. Rates are average annual rates for each period. 29 American Medical Association. All rights reserved. (Reprinted) JAMA, August 19, 29 Vol 32, No. 7 763

couraging, the prescription of broadspectrum antibiotics, namely azithromycin and quinolones, increased substantially during the study period. The decreases observed in antibiotic prescriptions in children younger than 5 years were largely related to decreases in OM visit rates. Moreover, our findings indicate that by the end of the study period, the Healthy People 21 target of 56 antibiotic courses prescribed for ear infections per 1 children younger than 5 years was already reached. 24 However, the proportion of OM visits that resulted in antibiotic prescriptions remained stable, suggesting that clinicians practices for antibiotic prescribing given a diagnosis of OM did not change. Although the American Academy of Pediatrics practice guidelines for the management of OM were updated in early 24 to encourage the initial observation of nonsevere OM cases in selected children (ie, watchful waiting ), 25,26 the largest observed decreases preceded these recommendations. Moreover, recent evidence suggests low adherence to the updated guidelines. 27 Although visit rates for non-om ARTI for which antibiotics are rarely indicated remained stable in children younger than 5 years, rates of antibiotic prescriptions Table 3. US Rates, Rate Differences, and Rate Ratios of Antibiotic Prescriptions During ARTI Visits for Each Period a Antibiotics by Age, y associated with these visits decreased. Furthermore, theproportionofvisitsthat resulted in antibiotic prescriptions decreased. Similarly, amongpersons5years or older, visit rates for ARTI for which antibiotics are rarely indicated remained stable and there was a significant reduction in antibiotic prescriptions associated with these visits. These findings suggest improvements in antibiotic prescribing practices and previous observed decreases in antibiotic prescriptions for these conditions were sustained through. 9,1,28,29 Starting in the mid-199s, the CDC, several state and local health departments, and other organizations launched interventions to promote appropriate antibiotic prescriptions. 6 In 1995, the CDC launched the Campaign for Appropriate Antibiotic Use in the Community and working with the American Academy of Pediatrics and the American Academy of Family Physicians, this initiative led to the publication of The Principles for appropriate use of antibiotics for pediatric upper respiratory tract infections. 6 Furthermore, a number of projects launched at local or state levels have shown significant improvements in antibiotic prescribing, including controlled interventions in Denver (), Boston/Seattle ( ), Tennessee (), Wisconsin (1997), and Alaska (-), among others. 6 The CDC also launched the media campaign Get Smart: Know When Antibiotics Work in 23. Although the specific reasons for decreasing ARTI visit rates cannot be established, several explanations could be hypothesized. First, the application of stricter diagnostic criteria for specific ARTI, a central component of the campaigns promoting the judicious use of antibiotics, could have increased the threshold to diagnose these conditions, 21 resulting in subsequent reductions in antibiotic prescriptions. 3 Second, parents might be less likely to bring their children to a clinician for mild ARTI. 31 Health care encounters can be prevented by educating parents to identify and relieve ear pain in their children. 26,32 Moreover, the CDC Get Smart campaign was asso- Rate Difference Rate Ratio Penicillins 5 653 448 24 ( 274 to 121).69 (.58 to.81) 5-17 19 122 68 ( 91 to 39).64 (.52 to.8) 18-49 62 33 29 ( 36 to 21).53 (.43 to.66) 5-64 38 26 12 ( 21 to 4).7 (.44 to 1.1) 65-79 44 22 21 ( 32 to 3).51 (.28 to.94) 8 33 18 16 ( 25 to 5).53 (.24 to 1.16) Cephalosporins 5 315 167 148 ( 192 to 88).53 (.39 to.72) 5-17 65 39 26 ( 36 to 12).6 (.44 to.82) 18-49 29 17 12 ( 17 to 5).59 (.43 to.82) 5-64 28 16 12 ( 18 to 2).59 (.37 to.94) 65-79 38 25 13 ( 22 to ).65 (.42 to 1.1) 8 48 24 24 ( 34 to 4).5 (.28 to.91) Macrolides/lincosamides 5 16 161 1 ( 41 to 57) 1. (.74 to 1.36) 5-17 53 54 1 ( 12 to 18) 1.2 (.78 to 1.33) 18-49 47 58 12 ( 1 to 28) 1.25 (.99 to 1.59) 5-64 42 63 21 (4 to 45) 1.51 (1.9 to 2.8) 65-79 46 54 8 ( 13 to 41) 1.17 (.73 to 1.88) 8 46 46 ( 23 to 44).99 (.5 to 1.95) Sulfonamides/tetracyclines 5 24 18 186 ( 193 to 174).9 (.5 to.15) 5-17 21 8 13 ( 17 to 1).37 (.15 to.93) 18-49 13 7 6 ( 9 to 1).53 (.3 to.93) 5-64 9 12 3 ( 2 to 12) 1.34 (.75 to 2.4) 65-79 15 5 1 ( 13 to 1).36 (.14 to.9) 8 23 5 18 ( 22 to 3).23 (.6 to.86) Quinolones 18-49 4 16 13 (7 to 23) 4.63 (2.88 to 7.43) 5-64 7 3 24 (1 to 49) 4.56 (2.49 to 8.36) 65-79 6 36 31 (13 to 65) 6.41 (3.28 to 12.52) 8 8 37 29 (1 to 7) 4.58 (2.18 to 9.65) Abbreviations: ARTI, acute respiratory tract infection; CI, confidence interval. a Data are from the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey. Rates are average annual rates for each period (per 1 population). 764 JAMA, August 19, 29 Vol 32, No. 7 (Reprinted) 29 American Medical Association. All rights reserved.

ciated with decreases in ARTI visits and related antibiotic prescriptions in Colorado. 33 Third, routine childhood immunization with PCV-7 since reduced the incidence of both OM and pneumonia during the study period. The decreases in OM visits we report herein are consistent with other estimates of the effect of this intervention. 34-38 Influenza vaccines, recommended for use among young children since 24 and among all children 6 months or older since 28, could further reduce the incidence of ARTI and associated antibiotic prescriptions. Although ARTI-associated prescriptionsformostantibioticclassesdecreased, prescription of selected macrolides and quinolonesincreasedsubstantially. Inthe early 199s, the recognition of the role of atypical microorganisms in ARTI and the emergence of penicillin-resistant bacteria led to the recommendation of macrolides as a first-line empirical treatment for community-acquired pneumonia. 3,39 Macrolides have since been used widely to treat ARTI 3,4 and, although decreases in invasive pneumococcal disease due to nonsusceptible pneumococci were documented after PCV-7 introduction, concerns remain about the increasing use of azithromycin in the United States. 7,9,12 Young children are commonly colonized with pneumococcus. Azithromycin is a bacteriostatic antibiotic and the least potentmacrolideagainstpneumococcus. Its longhalf-lifeofapproximately3daysmay result in prolonged exposure of bacteria to relatively inactive concentrations of the antibiotic and selection of resistant strains. 41,42 Although the ease of administration is an advantage, a recent meta-analysis of randomized and quasirandomized controlled trials showed that azithromycin efficacy against bronchitis or pneumonia was not better than amoxicillinoramoxicillin/clavulanicacid. 43 Recent guidelines for community-acquired pneumonia in ambulatory adults suggest that macrolide monotherapy should be restricted to selected patients (ie, previously healthy and without risk factors for drug-resistant S pneumoniae). 44 After introduction of PCV-7 in the United States, the incidence of pneumococcal disease due to nonvaccine serotypesincreased.theseincreaseshavebeen mostnotableforserotype19a,atypethat frequently is resistant to multiple antibiotics. 45 Increasing use of antibiotics, in particular selected macrolides, may contribute to the emergence of these antibiotic-resistantnonvaccineserotypes. Increases in disease due to antibioticresistant serotype 19A were reported among Alaskan Native, Bedouin, 46 and South Korean children, populations in which azithromycin is widely used, although the latter 2 groups were not routinely immunized with PCV-7. Interestingly, no increases in disease due to serotype 19A have been described among White Mountain Apache, 47 a population exposed to PCV-7 and in which azithromycin use is approved only for the treatment of sexually transmitted diseases and for children with documented penicillin allergy. 48 Our findings indicate that azithromycinprescriptionratesincreased substantially during recent years. The effects of these increases on the emergence of antibiotic-resistant pneumococcal serotypes not covered by PCV-7 remain to be determined. We also observed increasing prescription rates for quinolones for ARTI in persons 5 years or older. Increases in quinolone prescriptions and disease caused by quinolone-resistant bacteria have been reported in the United States and internationally. 49-51 Although the reported proportion of pneumococcal disease that is quinolone-resistant is small ( 1.8%), 5 the increasing trends are of concern and warrant monitoring. 49,5 Ourresultshadafewstudylimitations. First, we used ICD-9-CM codes to identifyartiandcouldnotconfirmdiagnoses or appropriateness of antibiotics prescribed.second,althoughourstudyevaluated antibiotic prescriptions, the adherence to these regimens is unknown. Additional antibiotic prescriptions or changes made by telephone were not captured by the surveys. Third, available information did not allow the distinction between initial and follow-up visits throughoutthestudyyears. Theinclusion of follow-up visits when no new antibioticwasprescribedwouldresultinanun- derestimation of the proportion of ARTI that resulted in an antibiotic prescription. Fourth, surveyparticipationrateshavedecreased and required adjustments in weighting strategies over time. Nevertheless, national survey data provided consistent information to assess changes in antibioticprescriptionpatterns. Fifth, federal institutions such as the Veterans Affairs ambulatory services are not included in the national surveys. Antibiotic use leads to the emergence of antibiotic-resistant bacteria. 2 Although prescriptions for most classes of antibiotics decreased, the prescription of quinolones and azithromycin increased. The potential role of these increases on the emergence of antibioticresistant microorganisms, in particular S pneumoniae, has been described. 2,3,14,52 Our results indicate that overall antibiotic prescription rates have decreased significantly. These changes coincided with efforts to reduce inappropriate antibiotic prescribing and the initiation of routine infant immunization with pneumococcal conjugate vaccine. Further efforts to improve antibiotic selection are needed. Author Contributions: Dr Grijalva had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Grijalva, Nuorti, Griffin. Acquisition of data: Grijalva. Analysis and interpretation of data: Grijalva, Nuorti, Griffin. Drafting of the manuscript: Grijalva. Critical revision of the manuscript for important intellectual content: Grijalva, Nuorti, Griffin. Statistical analysis: Grijalva. Obtained funding: Grijalva, Griffin. Administrative, technical, or material support: Nuorti, Griffin. Financial Disclosures: Drs Grijalva and Griffin reported receiving lecture fees and negotiating potential research support from Wyeth. Dr Griffin reported receiving grant support from MedImmune and Pfizer. Dr Nuorti reported no disclosures. Funding/Support: This study was funded by the Centers for Disease Control and Prevention (CDC) through Cooperative Agreements with the Association for Prevention Teaching and Research (TS-1392 and TS-1454). Dr Grijalva is supported by a CDC career development award (K1 CI163). Role of the Sponsor: An investigator from the CDC participated in the design and conduct of the study; in the analysis and interpretation of the data; and in the preparation, review, and approval of the manuscript. Disclaimer: The findings and conclusions in this article are those of the authors and do not necessarily represent the views of the CDC. Additional Contributions: We thank CDC investigators Cynthia G. Whitney, MD, MPH, and Lauri A. Hicks, DO, MPH, for critical, noncompensated review of the manuscript. 29 American Medical Association. All rights reserved. (Reprinted) JAMA, August 19, 29 Vol 32, No. 7 765

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