Antibiotic Prescription Rates for Acute Respiratory Tract Infections in US Ambulatory Settings FREE

Infections caused by antibiotic-resistant 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 1990s, antibiotic prescription rates in both children and adults decreased,^7- 10 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 1990s, increasing rates of macrolide-resistant invasive pneumococcal disease were temporally associated 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.

We analyzed annual data from the National Ambulatory Medical Care Survey (NAMCS) and the National Hospital Ambulatory Medical Care Survey (NHAMCS) between 1995 and 2006. 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 90% to 98% and the unweighted item nonresponse rates were typically 5% or less.¹⁶

Up to 3 diagnoses per visit are recorded in the NAMCS and NHAMCS databases, using International Classification of Diseases, Ninth Revision, Clinical Modification (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, and mastoiditis (ICD-9-CM codes 381.x-383.x, 460.x-466.x, 480.x-487.x, 490.x). Rates were also calculated for OM, the most common reason for physician visits and antibiotic prescriptions in young children⁸ (ICD-9-CM codes 381.x-382.x). For specific analyses, we also defined 2 mutually exclusive groups: 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 explored the concurrent presence of common non-ARTI diseases that could result in an antibiotic prescription, such as urinary tract infections (ICD-9-CM codes 599.0, 595.0, 595.9) and soft tissue infections (ICD-9-CM codes 680.x-682.x).^8,20

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.

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 30 unweighted observations and relative standard errors of less than 30%.^15- 16

Because children younger than 5 years had the highest visit rates for ARTI and antibiotic prescriptions⁸ 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, 50-64 years, 65-79 years, and ≥ 80 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 (1995-1996) with the most recent (2005-2006) 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<.05 indicated statistical significance. Data were analyzed by using SAS version 9.1 (SAS Institute, Cary, North Carolina) and Stata version 10.0 (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.

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 hospital-based outpatient clinics, and 10% to emergency departments. Overall, antibiotics were prescribed in 13% of all ambulatory visits. The ARTI visits accounted for 10% 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.

ARTI Visits. Overall annual visit rates were 4773 per 1000 population in 1995-1996 and remained stable during the study period. Although ARTI-associated visit rates decreased by 17% (RR, 0.83; 95% CI, 0.76-0.91), 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 (0.26% of ARTI visits) or soft tissue infections (0.06%) were uncommon.

ARTI-Associated Antibiotic Prescriptions . Annual antibiotic prescription rates decreased by 27% or 424 per 1000 children (95% CI, 281-551). This decrease was due to a 36% (RR, 0.64; 95% CI, 0.55-0.74) 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 1995-1996 to 22% in 2005-2006 (P = .008), due to reductions from 65% to 50% (P = .01) 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 = .009); no significant decreases were observed in emergency department visits (from 63% to 55%, P = .11) or in hospital-based outpatient clinics (from 60% to 54%, P = .12).

Rates of ARTI visits resulting in penicillin prescriptions decreased by 31% (Table 2). Amoxicillin/clavulanic acid prescription rates remained stable, 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 1995-1996 to 2005-2006, 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 950 to 634 per 1000 children from 1995-1996 to 2005-2006, respectively (RR, 0.67; 95% CI, 0.57-0.78). Similarly, rates of antibiotic prescriptions for OM decreased by 36% from 760 to 484 per 1000 children (RR, 0.64; 95% CI, 0.54-0.75). The proportion of OM visits that resulted in antibiotic prescriptions remained approximately 80% throughout the study years (P = .14) (Figure 2).

Penicillin prescription rates for OM decreased from 390 to 307 per 1000 children (RR, 0.79; 95% CI, 0.65-0.96), amoxicillin rates decreased from 326 to 233 per 1000 children (RR, 0.71; 95% CI, 0.58-0.88), and amoxicillin/clavulanic acid prescription rates remained stable. Cephalosporin prescription rates decreased from 211 to 103 per 1000 children in 2005-2006 (RR, 0.49; 95% CI, 0.35-0.67). Sulfonamide/tetracycline prescription rates decreased from 143 to 11 per 1000 children (RR, 0.08; 95% CI, 0.04-0.15), whereas macrolide/lincosamide prescription rates remained stable. Azithromycin prescription rates remained stable from 1997-1998 to 2005-2006 (RR, 1.10; 95% CI, 0.70-1.73); in 2005-2006, it was the most prescribed macrolide for OM with 65 (95% CI, 46-90) prescriptions per 1000 children (approximately 10% of OM visits).

Non-OM ARTI. Overall, rates of antibiotic prescriptions associated with non-OM ARTI visits decreased by 35% (RR, 0.65; 95% CI, 0.52-0.81). 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, 0.59; 95% CI, 0.45-0.78). The proportion of these non-OM ARTI visits resulting in antibiotic prescriptions also decreased from 41% in 1995-1996 to 23% in 2005-2006 (P = .04) (Figure 2).

ARTI Visits. Overall annual visit rates increased by 19% from 3154 to 3758 per 1000 population (RR, 1.19; 95% CI, 1.15-1.23). This was primarily due to a 21% increase in non-ARTI visit rates (RR, 1.21; 95% CI, 1.20-1.23). 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 (0.66%) or soft tissue infections (0.15%) 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 50 years or older. Overall antibiotic prescriptions associated with ARTI visits decreased by 18% (RR, 0.82; 95% CI, 0.71-0.94) but significant decreases occurred only among persons younger than 50 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 1995-1996 and 54% in 2005-2006 (P = .07). 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 = .02), 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 60%, 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, 0.85; 95% CI, 0.73-0.98), 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, 0.97-1.30) and rates of antibiotic prescription associated with these visits remained stable. The proportion of these visits resulting in antibiotic prescriptions decreased by 13% (P = .004) and was 59% in 2005-2006 (Figure 2). Rates of non-OM ARTI visits for which antibiotics are rarely indicated had a nonsignificant decrease of 9% (RR, 0.91; 95% CI, 0.80-1.04), whereas antibiotic prescription rates associated with these visits decreased by 24% (RR, 0.76; 95% CI, 0.63-0.90). The proportion of these visits that resulted in an antibiotic prescription did not change significantly and was 48% in 2005-2006 (Figure 2).

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 encouraging, the prescription of broad-spectrum 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 2010 target of 56 antibiotic courses prescribed for ear infections per 100 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 2004 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 associated with these visits decreased. Furthermore, the proportion of visits that resulted in antibiotic prescriptions decreased. Similarly, among persons 5 years 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 2006.^{9- 10,28- 29}

Starting in the mid-1990s, 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 (1997-1998), Boston/Seattle (1997-1998), Tennessee (1997-1998), Wisconsin (1997), and Alaska (1998-2000), among others.⁶ The CDC also launched the media campaign “Get Smart: Know When Antibiotics Work” in 2003.

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.³⁰ 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 associated with decreases in ARTI visits and related antibiotic prescriptions in Colorado.³³ Third, routine childhood immunization with PCV-7 since 2000 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 2004 and among all children 6 months or older since 2008, could further reduce the incidence of ARTI and associated antibiotic prescriptions.

Although ARTI-associated prescriptions for most antibiotic classes decreased, prescription of selected macrolides and quinolones increased substantially. In the early 1990s, 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^3,40 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 potent macrolide against pneumococcus. Its long half-life of approximately 3 days may 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 quasi-randomized controlled trials showed that azithromycin efficacy against bronchitis or pneumonia was not better than amoxicillin or amoxicillin/clavulanic acid.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 serotypes increased. These increases have been most notable for serotype 19A, a type that frequently is resistant to multiple antibiotics.⁴⁵ Increasing use of antibiotics, in particular selected macrolides, may contribute to the emergence of these antibiotic-resistant nonvaccine serotypes. Increases in disease due to antibiotic-resistant 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 azithromycin prescription rates increased 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%),⁵⁰ the increasing trends are of concern and warrant monitoring.^49- 50

Our results had a few study limitations. First, we used ICD-9-CM codes to identify ARTI and could not confirm diagnoses or appropriateness of antibiotics prescribed. Second, although our study evaluated 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 throughout the study years. The inclusion of follow-up visits when no new antibiotic was prescribed would result in an underestimation of the proportion of ARTI that resulted in an antibiotic prescription. Fourth, survey participation rates have decreased and required adjustments in weighting strategies over time. Nevertheless, national survey data provided consistent information to assess changes in antibiotic prescription patterns. 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 antibiotic-resistant 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.